WO2016175223A1 - Tricyclic compounds and uses thereof - Google Patents

Tricyclic compounds and uses thereof Download PDF

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Publication number
WO2016175223A1
WO2016175223A1 PCT/JP2016/063138 JP2016063138W WO2016175223A1 WO 2016175223 A1 WO2016175223 A1 WO 2016175223A1 JP 2016063138 W JP2016063138 W JP 2016063138W WO 2016175223 A1 WO2016175223 A1 WO 2016175223A1
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substituted
unsubstituted
hydrogen atom
group
compound
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PCT/JP2016/063138
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French (fr)
Japanese (ja)
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健二 山脇
博喜 草野
俊明 青木
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塩野義製薬株式会社
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Priority to JP2017515564A priority Critical patent/JPWO2016175223A1/en
Publication of WO2016175223A1 publication Critical patent/WO2016175223A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/897—Compounds with substituents other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D507/00—Heterocyclic compounds containing a condensed beta-lactam ring system, not provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D505/00; Such ring systems being further condensed
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel tricyclic compound having an antibacterial action, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and an antibacterial agent containing them. Further, a tricyclic compound having an antibacterial action, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a compound having a ⁇ -lactamase inhibitory action, a pharmaceutically acceptable salt thereof, Or it is related with the pharmaceutical characterized by combining those solvates.
  • ⁇ -lactamases are broadly classified into four classes. Class A (TEM type, SHV type, CTX-M type, KPC type, etc.), Class B (NDM type, IMP type, VIM type, L-1 type, etc.), Class C (AmpC type, ADC type, CMY type) Type, DHA type, etc.) and class D (OXA type, etc.).
  • Class A TEM type, SHV type, CTX-M type, KPC type, etc.
  • Class B NDM type, IMP type, VIM type, L-1 type, etc.
  • Class C AmpC type, ADC type, CMY type
  • Type DHA type, etc.
  • OXA type OXA type, etc.
  • Class A, C, and D types are broadly classified into serine- ⁇ -lactamases, while Class B types are broadly divided into metallo- ⁇ -lactamases, which are known to hydrolyze ⁇ -lactam drugs by different mechanisms.
  • Class B types are broadly divided into metallo- ⁇ -lactamases, which are known to hydrolyze ⁇ -lactam drugs by different mechanisms.
  • KPC Klebsiella pneumoniae Carbapeenase
  • class B metallo- ⁇ -lactamases The existence of Gram-negative bacteria highly resistant to many ⁇ -lactam drugs including carbapenem and carbapenem has become a clinical problem.
  • Enterobacteriaceae bacteria that produce KPC and metallo- ⁇ -lactamase are known to exhibit high resistance to carbapenem antibacterial agents, which are important for the treatment of Gram-negative bacterial infections.
  • Cephem compounds that exhibit moderate activity against gram-negative bacteria, including metallo- ⁇ -lactamase-producing gram-negative bacteria are known (eg, Patent Document 1), but stronger antibacterial activity, especially various ⁇ -lactamase-producing gram Development of ⁇ -lactams effective against negative bacteria is eagerly desired.
  • Patent Documents 2 to 4 report ⁇ -lactam compounds having a novel skeleton, but do not describe antibacterial activity against the above-mentioned carbapenem-resistant bacteria and the like that have been problematic in recent years. Moreover, from the described antibacterial activity, it cannot be imagined at all that the compound group having this skeleton has an antibacterial activity in carbapenem-resistant bacteria. Furthermore, these patent documents do not describe or suggest a combination of a ⁇ -lactam compound having a novel skeleton with other drugs or the combined use effect.
  • the present invention relates to a 5-oxotetrahydrofuran ring, a 6-oxotetrahydropyran ring or a 2-oxo-1,3-dioxolane exhibiting a strong antibacterial spectrum against various bacteria including Gram negative bacteria and / or Gram positive bacteria.
  • a tricyclic compound comprising a ring is provided.
  • carbapenem-resistant bacteria including tricyclic compounds containing a 5-oxotetrahydrofuran ring or a 6-oxotetrahydropyran ring, esters thereof or pharmaceutically acceptable salts thereof, or hydrates thereof.
  • a pharmaceutical composition having antibacterial activity is provided.
  • a compound showing strong antibacterial activity against ⁇ -lactamase-producing gram-negative bacteria, or a pharmaceutical composition containing the compound is provided. More preferably, a compound exhibiting strong antibacterial activity against a carbapenem-resistant bacterium, a multidrug-resistant bacterium, particularly a class B metallo- ⁇ -lactamase (MBL) -producing gram-negative bacterium, or a pharmaceutical composition containing the compound is provided. . More preferably, a compound showing effective antibacterial activity also against a substrate-specific extended ⁇ -lactamase (ESBL) -producing bacterium or a compound containing the compound is provided.
  • ESBL substrate-specific extended ⁇ -lactamase
  • the present invention provides a compound or a pharmaceutical composition having an antibacterial action against a carbapenem-resistant bacterium, which has at least the following structural characteristics to solve the above problems. 1) It has a tricyclic mother nucleus containing a 5-oxotetrahydrofuran ring, a 6-oxotetrahydropyran ring or a 2-oxo-1,3-dioxolane ring. 2) It has an amide substituent (a carbonylamino group having a substituent) on the lactam ring or cyclic carbonyl hydrazide ring in the tricyclic mother nucleus.
  • R 11 is amino or amino substituted with acyl
  • R 12 is a hydrogen atom, —OCH 3 or —NH—CH ( ⁇ O)
  • R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl
  • U is —S—, —S—CH 2 — or —CH 2 —S—).
  • (Item 3) —Z— is a single bond
  • R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted
  • the compound according to Item 2 which is carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino, or hydroxy, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof .
  • Item 4 Item 1 wherein —Z— is —CR 7A R 7B —, Y is N, —W— is —CH 2 —, and —T— is —CR 4A R 4B —. Or its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, an ester thereof, or the like Or a hydrate thereof.
  • R 1 is the following formula: (Wherein X is CH, CCl, CF, CBr or N) 6.
  • X is CH, CCl, CF, CBr or N.
  • R 1 is the following formula: (Wherein X is CCl, CF or CBr) 6.
  • X is CCl, CF or CBr 6.
  • R 2A and R 2B taken together have a methylidene having a substituent shown below: Or substituted or unsubstituted hydroxyimino:
  • R 10 is a hydrogen atom or substituted or unsubstituted alkyl, and in the formula, R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted Or an unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R 8 and R 9 taken together to form a substituted or unsubstituted methylidene, or R 8 and R 9 May be taken together with adjacent atoms to form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle;
  • Q is a single bond, substituted or unsubstituted carbocyclic diyl Or substituted or unsubstituted
  • R 2A and R 2B together form the following formula: (In the formula, each symbol is as defined above.) 8.
  • R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) Is; R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (In the formula, each definition has the same meaning as item 8) Is; R 3 is a hydrogen atom or —OCH 3 , R 16 is carboxy, and R 17 is a hydrogen atom, a compound thereof, an ester thereof, a pharmaceutically acceptable salt
  • R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) A group represented by: For R 2A and R 2B a) R 2A is a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or carbonyloxy having a substituent And R 2B is
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • a disease associated with bacterial infection which comprises administering the compound according to any one of items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Treatment or prevention.
  • R 11 is the following formula: Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
  • R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
  • R 13 is a hydrogen atom;
  • R 14 and R 15 are each independently a hydrogen atom or methyl, and a carbapenem-resistant bacterium containing the compound according to item 22, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof
  • R 1 ′ is the following formula: (Where X ′ is CH or N) A group represented by R 2′A and R 2′B each independently represent a hydrogen atom, or the following formula: Or R 2′A and R 2′B together are represented by the following formula: Wherein R 10 ′ is a hydrogen atom or alkyl, and R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl. 24.
  • a carbapenem-resistant compound comprising the compound of item 22 or 23, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 12 is a hydrogen atom or methoxy: A pharmaceutical composition having an antibacterial action against bacteria.
  • R 11 is amino or amino substituted with acyl
  • R 12 is a hydrogen atom, —OCH 3 or —NH—CH ( ⁇ O)
  • R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl
  • U is —S—, —S—CH 2 — or —CH 2 —S—
  • a pharmaceutically acceptable salt thereof or a hydrate thereof, and a compound having an inhibitory action on (B-1) ⁇ -lactamase, an ester thereof or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical comprising a combination of a salt or a solvate thereof.
  • R 11 in (A-2) is the following formula: Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
  • R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
  • R 13 is a hydrogen atom; 26.
  • the medicament according to item 25, wherein R 14 and R 15 are each independently a hydrogen atom or methyl, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 ′ in (A-2) is the following formula: (Where X ′ is CH or N)
  • R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, substituted or unsubstituted alkyl, or hydroxy Or its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, the compound according to any one of items 1A to 4A, an ester thereof, or a pharmaceutically acceptable salt thereof Salts, or hydrates thereof.
  • R 1 is the following formula: (Wherein X is CH, CCl, CF, CBr or N) The compound according to any one of items 1A to 5A, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a group represented by the formula:
  • R 2A and R 2B taken together have a methylidene having the substituents shown below: Or substituted or unsubstituted hydroxyimino: (Wherein R 10 is a hydrogen atom or substituted or unsubstituted alkyl)
  • R 10 is a hydrogen atom or substituted or unsubstituted alkyl
  • R 2A and R 2B together form the following formula: Wherein R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic A group, R 8 and R 9 together form a substituted or unsubstituted methylidene, or R 8 and R 9 together with an adjacent atom are substituted or unsubstituted non-aromatic carbocycle Or may form a substituted or unsubstituted non-aromatic heterocyclic ring; Q is a single bond, substituted or unsubstituted carbocyclic diyl or substituted or unsubstituted heterocyclic diyl; m is 0-3 Is an integer)
  • (Item 10A) -Z- is a single bond; Y is CH; -W- is -S-CH 2- ; -T- is -CR 4A R 4B - or -CR 5A R 5B -CR 6A R 6B - a and; R 4A and R 4B are each independently a hydrogen atom or hydroxy; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) Is; R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (In the formula, each definition has the same meaning as item 8) Is; The compound according to Item 1A, wherein R 3 is a hydrogen atom or OCH 3 , an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 is the following formula: (In the formula, each definition has the same meaning as item 6) A group represented by: R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (In the formula, each definition has the same meaning as item 8) A group represented by: The compound according to item 1A, wherein R 3 is a hydrogen atom, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • (Item 12A) A pharmaceutical composition comprising the compound according to any one of items 1A to 11A, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 11 is the following formula: Wherein R 1 is a substituted or unsubstituted heterocyclic group;
  • R 2A and R 2B are each independently a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Carbamoyl, hydroxy, or substituted carbonyloxy, or b)
  • R 2A and R 2B may be taken together to form a substituted or unsubstituted hydroxyimino)
  • R 13 is a hydrogen atom;
  • R 14 and R 15 are each independently a hydrogen atom or methyl, and the compound according to item 14A, its ester or pharmaceutically acceptable salt thereof, or a carbapenem-resistant bacterium, including hydrates thereof, A pharmaceutical composition having an antibacterial action.
  • R 1 is the following formula: (Wherein X is CH, CCl or N)
  • a group represented by R 2A and R 2B are each independently a hydrogen atom, or the following formula: Or R 2A and R 2B together are represented by the following formula: (Wherein R 10 is a hydrogen atom or alkyl, and R 8 and R 9 are each independently a hydrogen atom or alkyl) Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, including the compound of item 14A or 15A, wherein R 12 is a hydrogen atom or methoxy;
  • a pharmaceutical composition having an antibacterial action against bacteria wherein X is CH, CCl or N
  • the compound according to the present invention is useful as a pharmaceutical in that it has at least one of the following characteristics.
  • a strong antibacterial spectrum is shown against various bacteria including Gram negative bacteria and / or Gram positive bacteria.
  • CRE carbapenem-resistant Enterobacteriaceae
  • KPC Klebsiella pneumoniae Carbapenemase
  • NDM New Delhi metallo-beta-lactamase
  • H Does not show cross resistance with existing cephem and / or carbapenem drugs.
  • I Does not show side effects such as fever after in vivo administration.
  • J) The stability of the compound (for example, solution stability and light stability in various liquid properties) and / or solubility in water is high.
  • CYP enzymes for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, they are a fluorine atom or a chlorine atom.
  • Alkyl includes a straight or branched carbon hydrogen group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, Examples include isooctyl, n-nonyl, n-denyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group.
  • vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
  • Alkynylene refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position.
  • a linear or branched divalent hydrocarbon group is included.
  • “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, still more preferably 3 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • aromatic carbocycle means a ring derived from the above “aromatic carbocyclic group”.
  • non-aromatic carbocycle means a ring derived from the above “non-aromatic carbocyclic group”.
  • Cycloalkyl means a cyclic saturated hydrocarbon group, preferably having 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 3 to 8 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like can be mentioned.
  • Preferable embodiments of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • “Cycloalkane” means a ring derived from the above “cycloalkyl”.
  • the “carbocyclic group” includes the above “aromatic carbocyclic group” and “non-aromatic carbocyclic group”.
  • Carbocycle means a ring derived from the above “carbocyclic group”.
  • Carbocyclic diyl means a divalent group derived from the above “carbocyclic group”.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • the 5-membered monocyclic aromatic heterocyclic group includes pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like, and includes a 6-membered monocyclic aromatic group.
  • group heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • non-aromatic heterocyclic group having two or more rings examples include, for example, indolinyl, isoindolinyl, chromanyl, isochromanyl, octahydro-7H-pyrano [2,3-c] pyridin-7-yl, hexahydro-2H-pyrano [3, 2-c] pyridin-6 (5H) -yl, 7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -yl and the like.
  • Aromatic heterocycle means a ring derived from the above “aromatic heterocyclic group”.
  • the “non-aromatic heterocyclic ring” means a ring derived from the above “non-aromatic heterocyclic group”.
  • heterocyclic group includes the above “aromatic heterocyclic group” and “non-aromatic heterocyclic group”.
  • Heterocycle means a ring derived from the above “heterocyclic group”.
  • Heterocyclic diyl means a divalent group derived from the above “heterocyclic group”.
  • “Acyl” means formyl and substituted carbonyl. “Substituted carbonyl” means substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic Examples thereof include carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl and the like.
  • “Acyl-substituted amino” means a group in which one or two hydrogen atoms bonded to the nitrogen atom of “amino” are replaced with the above “acyl”, that is, monoacylamino or diacylamino. . Preferably, it is monoacylamino. Two “acyl” of “diacylamino” may be the same or different. Preferred examples of the “acyl” include substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, etc., more preferably substituted or unsubstituted. Of alkylcarbonyl.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, hexyloxy and the like.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Preferable embodiments of “haloalkyloxy” include trifluoromethoxy, trichloromethoxy and the like.
  • “Acyloxy” means formyloxy and carbonyloxy having a substituent.
  • “Carbonyloxy having a substituent” means a group in which the above “carbonyl having a substituent” is bonded to an oxygen atom.
  • substituted or unsubstituted alkylcarbonyloxy substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted nonaromatic carbon Ring carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy and the like.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom.
  • methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
  • Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxyalkyl means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” replaces the hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and the like. . Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfanyl” include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, hexylsulfanyl and the like.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Haloalkylsulfanyl means a group in which the above “haloalkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like can be mentioned.
  • Preferable embodiments of “haloalkylsulfanyl” include trifluoromethylsulfanyl, trichloromethylsulfanyl and the like.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • Trialkylsilyl means a group in which three of the above “alkyl” are bonded to a silicon atom.
  • the three alkyl groups may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • Carbocyclic alkyl “Aromatic carbocyclic alkyl”, “Non-aromatic carbocyclic alkyl”, “Heterocyclic alkyl”, “Aromatic heterocyclic alkyl”, “Non-aromatic heterocyclic alkyl”, “Carbocyclic alkyl” “Oxy”, “aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “heterocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, “non-aromatic heterocyclic alkyloxy", “carbon” Ring alkyloxycarbonyl ",” aromatic carbocyclic alkyloxycarbonyl ",” non-aromatic carbocyclic alkyloxycarbonyl ",” heterocyclic alkyloxycarbonyl “,” aromatic heterocyclic oxycarbonyl ",” non-aromatic heterocyclic " "Oxycarbonyl”, “carbocyclic alkyloxyalkyl”, "ar
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below: Etc.
  • aromatic carbocyclic alkyl Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl, benzhydryl and the like.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below: Etc.
  • Carbocyclic alkyl includes “aromatic carbocyclic alkyl” and “non-aromatic carbocyclic alkyl”.
  • Preferable embodiments of “carbocycle alkyl” include benzyl, phenethyl, benzhydryl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and groups shown below: Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • Non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • Heterocyclic alkyl includes “aromatic heterocyclic alkyl” and “non-aromatic heterocyclic alkyl”. Preferred embodiments of “heterocyclic alkyl” include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, iso Pyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below: Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below: Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below: Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below: Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below: Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below: Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic oxy” means a group in which the above “aromatic carbocycle” is bonded to an oxygen atom.
  • aromatic carbocycle for example, phenyloxy, naphthyloxy and the like can be mentioned.
  • Aromatic carbocyclic carbonyl means a group in which the above “aromatic carbocycle” is bonded to a carbonyl group. Examples include benzoyl and naphthylcarbonyl.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfinyl” means a group in which an “aromatic carbocyclic ring” is bonded to a sulfinyl group. Examples thereof include phenylsulfinyl and naphthylsulfinyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic sulfinyl”, and “non-aromatic
  • the “non-aromatic carbocyclic” portion of the “aromatic carbocyclic sulfonyl” is the same as the above “non-aromatic carbocyclic group”.
  • Non-aromatic carbocyclic oxy means a group in which the “non-aromatic carbocycle” is bonded to an oxygen atom.
  • Non-aromatic carbocyclic carbonyl means a group in which the above “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclopropenylcarbonyl, indanylcarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxycarbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. Examples thereof include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
  • non-aromatic carbocyclic oxycarbonyl means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • non-aromatic carbocyclic sulfanyl means a group in which the “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • non-aromatic carbocyclic sulfinyl means a group in which the “non-aromatic carbocyclic ring” is bonded to a sulfinyl group.
  • examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, cyclohexenylsulfinyl, tetrahydronaphthylsulfinyl, adamantylsulfinyl and the like.
  • non-aromatic carbocycle sulfonyl means a group in which the above “non-aromatic carbocycle” is bonded to a sulfonyl group.
  • cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • “Aromatic heterocycle oxy” means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom.
  • aromatic heterocycle oxy means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • “Aromatic heterocycle carbonyl” means a group in which the above “aromatic heterocycle” is bonded to a carbonyl group.
  • pyrrolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, oxazolylcarbonyl, indolylcarbonyl and the like can be mentioned.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • aromatic heterocyclic oxy means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • “Aromatic heterocycle sulfanyl” means a group in which the above “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • aromatic heterocycle means a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • “Aromatic heterocycle sulfinyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group.
  • aromatic heterocycle a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group.
  • pyridylsulfinyl, oxazolylsulfinyl and the like can be mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group.
  • aromatic heterocycle a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group.
  • pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy “Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic oxycarbonyl”, “Non-aromatic heterocyclic sulfanyl”, “Non-aromatic heterocyclic sulfinyl”, and “Non-aromatic”
  • the “non-aromatic heterocyclic” part of the “aromatic heterocyclic sulfonyl” is the same as the above “non-aromatic heterocyclic group”.
  • Non-aromatic heterocyclic oxy means a group in which the above “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • dioxanyloxy, thiranyloxy, oxiranyloxy, oxetanyloxy, oxathiolanyloxy, azetidinyloxy, thianyloxy, thiazolidinyloxy, pyrrolidinyloxy, pyrrolinyloxy, imidazolidinyloxy, imidazo Examples include linyloxy, pyrazolidinyloxy, pyrazolinyloxy, piperidyloxy, piperazinyloxy, morpholinyloxy, indolinyloxy, chromanyloxy and the like.
  • non-aromatic heterocyclic carbonyl means a group in which the above “non-aromatic heterocyclic” is bonded to a carbonyl group. Examples include dioxanylcarbonyl, oxetanylcarbonyl, pyrazolinylcarbonyl, morpholinocarbonyl, morpholinylcarbonyl, indolinylcarbonyl and the like.
  • non-aromatic heterocyclic oxycarbonyl means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • non-aromatic heterocyclic oxycarbonyl for example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which the “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • non-aromatic heterocyclic sulfinyl means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfinyl group.
  • piperidinylsulfinyl, tetrahydrofurylsulfinyl and the like can be mentioned.
  • non-aromatic heterocyclic sulfonyl means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • Carbamoyloxy means a group in which an oxygen atom is bonded to carbamoyl.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituent group A.
  • Substituent group A halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl,
  • the atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B.
  • Substituent group B oxo, halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano , Cyanoalkyl, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, hydroxyalkyloxy, alky
  • Substituent group B can also be mentioned as substituents on the “carbocycle” and “heterocycle” rings of “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl”.
  • the atom at any position on the ring may be bonded to one or more groups selected from the substituent group B. When two or more substituents are present, they may be the same or different.
  • the substituent group A can be exemplified as the substituent of the “alkyl” part of “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl”.
  • the hydrogen atom at any position may be substituted with one or more groups selected from the substituent group A. When two or more substituents are present, they may be the same or different.
  • substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted sulfamoyl” and “substituted or unsubstituted carbamoyloxy” include the following substituent group C: It is done. When two substituents are present, they may be the same or different.
  • Substituent group C hydroxy, amino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic Aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aro
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”.
  • oxo means a group in which two hydrogen atoms on a carbon atom are substituted with oxo as follows.
  • substituents of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino” include a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or An unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, etc. are mentioned. When substituted with a plurality of substituents, the substituents may be the same or different.
  • Examples of the “leaving group” include halogen, C 1-6 alkylsulfonyloxy, halo C 1-6 alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy and the like.
  • a preferred embodiment of the ring of the “substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group” of R 1 and R 1 ′ is a 5- to 6-membered ring, and a more preferred embodiment is substituted Or an unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group.
  • the carbocyclic group include phenyl, hydroxyphenyl, dihydroxyphenyl, phenyl having halogen as a substituent, and phenyl having halogen and hydroxy as a substituent.
  • heterocyclic group examples include aminothiazole, aminothiazole having halogen as a substituent, aminothiadiazole, thiophene, furan, benzothiazole, pyridine, pyrimidine, pyridazine, aminopyridine and the like.
  • carbocyclic group examples include phenyl, hydroxyphenyl, dihydroxyphenyl, chlorodihydroxyphenyl and the like.
  • heterocyclic group include aminothiazole, aminothiazole having a halogen as a substituent, and aminothiadiazole.
  • heterocyclic group are aminothiazole, aminochlorothiazole, aminofluorothiazole, aminobromothiazole or aminothiadiazole.
  • carbocyclic group include the groups shown below.
  • heterocyclic group include the groups shown below.
  • Other preferred examples of the heterocyclic group include the groups shown below. More preferable examples of the heterocyclic group include the groups shown below.
  • R 2A and R 2B and R 2′A and R 2′B are each independently a hydrogen atom, substituted or unsubstituted When it is amino, sulfo, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, for example: Preferred examples of are: The substituted amino shown below: Substituted sulfamoyl, shown below: (Wherein ring C represents a substituted or unsubstituted heterocyclic group); Substituted carbamoyl shown below: (Wherein ring B represents a substituted or unsubstituted heterocyclic group); or substituted carbonyloxy as shown below: (Wherein, ring C represents a substituted or unsubstituted
  • R 2A and R 2B , or R 2′A and R 2′B together form a substituted or unsubstituted methylidene preferably the formula: (R 21 is substituted or unsubstituted alkyl.) It is group shown by these.
  • the wavy line between the carbon atom forming a double bond and R 21 means a cis bond, a trans bond, or a mixture thereof.
  • a wavy line between a carbon atom forming a double bond and a carboxy group or an alkyl group means a cis bond, a trans bond or a mixture thereof
  • R 2A and R 2B may be taken together to form a substituted or unsubstituted hydroxyimino, preferably having the formula: (Wherein R 10 is a hydrogen atom or an alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carbamoylalkyl optionally substituted with one or more groups selected from substituent group D.
  • substituent group D is A group consisting of halogen, hydroxy, amino, carbamoyl, alkyloxycarbonylamino and phenyl), or a group represented by the formula:
  • R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic
  • Q is a single bond, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group
  • m is 0-3 Is an integer). More preferably, Wherein each definition is as defined above.
  • R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group.
  • Examples of the case include a hydrogen atom, a fluorine atom, a chlorine atom, hydroxy, carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, hydroxyethyl, carbamoylmethyl, Carbamoylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, allyloxycarbonylaminomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybe Zyl, 4-carboxybenzyl, 3,4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazoly
  • R 8 and R 9 is (hydrogen atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, hydrogen atom), (hydrogen atom, methyl), (Methyl, hydrogen atom),), (hydrogen atom, ethyl), (ethyl, hydrogen atom) (hydrogen atom, isopropyl), (isopropyl, hydrogen atom), (hydrogen atom, phenyl), (phenyl, hydrogen atom), (Hydrogen atom, carboxymethyl), (carboxymethyl, hydrogen atom), (hydrogen atom, hydroxymethyl), (hydroxymethyl, hydrogen atom), (hydrogen atom, aminomethyl), (aminomethyl, hydrogen atom), (methyl , Methyl) and the like.
  • R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino, preferably having the formula: (Wherein R 10 ′ is a hydrogen atom or alkyl), or a group represented by the formula: Wherein R 8 ′ and R 9 ′ are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted A cyclic group, R 8 ′ and R 9 ′ together form a substituted or unsubstituted methylidene, or R 8 ′ and R 9 ′ together with adjacent atoms are substituted or unsubstituted Or a substituted or unsubstituted heterocyclic group; Q ′ is a single bond, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group M
  • R 8 ′ and R 9 ′ are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group.
  • ⁇ is a hydrogen atom, fluorine atom, chlorine atom, hydroxy, carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, hydroxyethyl, carbamoyl '' Methyl, carbamoylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-carboxybenzyl, 3, 4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
  • R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl
  • examples of the case where “R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl” include a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, tert-butyl and the like.
  • R 8 ′ and R 9 ′ , (R 8 ′ , R 9 ′ ) is (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (methyl, hydrogen atom), or (methyl, methyl) ).
  • R 8 and R 9 , or R 8 ′ and R 9 ′ together form a substituted or unsubstituted methylidene include: (Wherein R 22 and R 23 are each independently a hydrogen atom or substituted or unsubstituted alkyl). Preferable examples of R 22 and R 23 are each independently a hydrogen atom, methyl, fluoromethyl, trifluoromethyl, ethyl or the like, more preferably a hydrogen atom at the same time.
  • R 8 and R 9 , or R 8 ′ and R 9 ′ together with adjacent atoms form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle”
  • a 3- to 6-membered monocycle is preferable, and a 3- or 4-membered ring is more preferable.
  • Preferred examples include cyclopropane, cyclobutane, cycloheptane, cyclohexane, aziridine, oxirane, thiirane, azirine, thylene, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran and the like.
  • a more preferred example is cyclopropane.
  • R 3 is a hydrogen atom, OCH 3 or NH—CH ( ⁇ O), preferably a hydrogen atom.
  • R 16 is carboxy, tetrazolyl or substituted or unsubstituted carbamoyl, preferably carboxy, carbamoyl or the following formula: It is. More preferably, it is carboxy. Another preferred embodiment of R 16 is tetrazolyl.
  • R 17 is a hydrogen atom or substituted or unsubstituted alkyl, preferably a hydrogen atom or alkyl. More preferably, it is a hydrogen atom.
  • R 7A and R 7B are each independently a hydrogen atom, hydroxy, carboxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkyl, haloalkyl, alkyl Examples include oxy and haloalkyloxy. More preferably, R7A is a hydrogen atom or methyl, and R7B is a hydrogen atom, methyl, trifluoromethyl, hydroxy or methoxy.
  • a preferred embodiment of —Z— is a single bond, —CH 2 —, —C (CH 3 ) H— or — (CH 3 ) 2 —, and a more preferred embodiment is a single bond or —CH 2 —. is there.
  • -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -.
  • Preferred is —S—CH 2 —, —CH 2 —S— or —S—. More preferred is —S—CH 2 —.
  • R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, halogen, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, carboxy, sulfamoyl, mono Examples include alkylsulfamoyl, dialkylsulfamoyl, alkyl, haloalkyl, haloalkyloxy, alkyloxy, acyl, acyloxy, cyano, amidino, guanidino, carbamoyloxy, alkylcarbonyloxy and the like.
  • R 4A and R 4B are each independently a hydrogen atom, hydroxy, amino, carboxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, carbamoyloxy, acetyloxy, and the like, and more preferably R 4A is a hydrogen atom or methyl, and R 4B is a hydrogen atom, methyl, hydroxy, carbamoyloxy or acetyloxy. More preferably, R 4A is a hydrogen atom or methyl, and R 4B is a hydrogen atom or methyl.
  • R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, hydroxy, amino, carboxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyano.
  • R 5A and R 6A are hydrogen atoms
  • R 5B and R 6B are each independently a hydrogen atom and hydroxy. More preferably, R 5A , R 5B , R 6A and R 6B are hydrogen atoms.
  • -T- is -CR 4A R 4B -, more preferably an, -CH 2 -, - C ( CH 3) H -, - C (CH 3) 2 - or -C (OH) H- It is.
  • -Z- when is a single bond, Y is CH, -W- is -S-CH 2 - and is, and -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B — or —O—.
  • -Z- -CR 7A R 7B is - when, Y is N, -W- is -CH 2 - and is, and -T- is -CR 4A R 4B - is.
  • —U— is —S—, —S—CH 2 — or —CH 2 —S—.
  • Preferred is —S—CH 2 —.
  • R 11 is amino or amino substituted with acyl. Preferred is substituted or unsubstituted alkylcarbonylamino. In a preferred embodiment of R 11 , the following formula: Wherein R 1 ′ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; For R 2′A and R 2′B , a) R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino) It is group shown by these.
  • R 1 ′ is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group
  • R 10 ′ is a hydrogen atom or alkyl
  • R 8 ′ and R Each 9 ′ is independently a hydrogen atom or alkyl
  • R 12 is a hydrogen atom, OCH 3 or NH—CH ( ⁇ O), preferably a hydrogen atom.
  • R 13 is preferably a hydrogen atom.
  • R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl. Preferably, they are each independently a hydrogen atom or methyl. More preferably, they are simultaneously hydrogen atoms or simultaneously methyl.
  • R 1 is the following formula: (Wherein each definition has the same meaning as above) A group represented by: For R 2A and R 2B a) R 2A each independently has a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituent.
  • R 2B is a hydrogen atom, b-1)
  • R 2A and R 2B taken together have a methylidene having the following substituents: Or b-2)
  • Embodiment 2-1 Formula (I) is: (Wherein, -Z- is -CR 7A R 7B - is; Y is N; -W- is -CH 2- ; -T- is -CR 4A R 4B - a and; R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino; R 1 is the following formula: (Wherein each definition has the same meaning as above) A group represented by: For R 2A and R 2B a) R 2A and R 2B each independently have a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituent
  • R 2A and R 2B taken together have a methylidene having the following substituents: Or b-2)
  • Formula (I) is: Wherein -Z- is a single bond; Y is CH; -W- is -S-, -S-CH 2 -or -CH 2 -S-; -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is; R 4A and R 4B are each independently a hydrogen atom, hydroxy, acetyloxy, carbamoyloxy, methyl, or amino; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: (Wherein each definition has the same meaning as above) Is; R 2A and R 2B taken together have a methylidene having the substituents shown below: Or the following formula: (Wherein each definition has the same meaning as above) Is; R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy; and R 17
  • -Z- is a single bond; Y is CH; -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -; -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is; R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: Where X is CCl, CF or CBr; For R 2A and R 2B a) each R 2A is independently substituted or unsubstitute
  • -Z- is a single bond; Y is CH; -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 - is the be; -T- is -CR 5A R 5B -CR 6A R 6B -or -O-; R 5A , R 5B , CR 6A and R 6B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted Of amino; R 1 is the following formula: (Wherein each definition has the same meaning as above) Is; For R 2A and R 2B a) each R 2A is independently substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alky
  • -Z- is a single bond; Y is CH; -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -; -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is; R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino; R 5A , R 5B , CR 6A and R 6B are hydrogen atoms; R 1 is the following formula: Where each definition is as defined above; For R 2A and R 2B a) each R 2A is independently substituted or unsubstituted amino, sulf
  • the compounds (I) and (IA) of the present invention are not limited to specific isomers, but all possible isomers (for example, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical Isomers, rotamers, geometric isomers, etc.), racemates or mixtures thereof.
  • Formula (II) has all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, except where stereo designations are specified) , Geometric isomers, etc.), racemates or mixtures thereof.
  • Is Etc Preferably, It is. More preferably, It is.
  • substitution positions on the skeletons of formula (I) and formula (II) are as follows.
  • the ⁇ -position side chain and the ⁇ -position side chain represent groups bonded to the ⁇ -position and ⁇ -position of the following mother nucleus.
  • the ester form of the formula (I), (IA) or (II) preferably includes an ester form of carboxy on the ⁇ -position and / or carboxy on the ⁇ -position side chain.
  • Esters in carboxy on the ⁇ -position side chain have the formula: (In the formula, each symbol is as defined above.) Substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted lower alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituent at the end of R 1 or R 2A or R 2B represented by In which carboxy in carbonyloxy or the like having an ester structure has an ester structure (for example, in the case of carboxy (—COOH), a structure of —COOR P1 shown together with R P1 indicating an ester residue such as a carboxy protecting group) And esters that are easily metabolized in the body to form a carboxy
  • Protecting groups such as carboxy described above include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected, such as lower alkyl (eg, methyl, ethyl, t-butyl), lower alkylcarbonyloxymethyl (eg, pivaloyl), An optionally substituted arylalkyl (eg, benzyl, benzhydryl, phenethyl, p-methoxybenzyl, p-nitrobenzyl), a silyl group (eg, t-butyldimethylsilyl, diphenyl t-butylsilyl) and the like can be mentioned.
  • lower alkyl eg, methyl, ethyl, t-butyl
  • lower alkylcarbonyloxymethyl eg, pivaloyl
  • Protecting groups for amino groups include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected, such as lower alkyloxycarbonyl (eg, t-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), substituted Aralkylanoyl (eg: benzoyl, p-nitrobenzoyl), acyl (eg: formyl, chloroacetyl) and the like which may be used may be mentioned.
  • the amino-protecting group also includes a group that is easily metabolized in the body to become amino.
  • One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), (IA) or (II) may be replaced by hydrogen, carbon and / or isotopes of other atoms, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compounds of formula (I), (IA) or (II) also include compounds substituted with such isotopes.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I), (IA) or (II).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • Radiolabeled compounds of the compounds represented by formula (I), (IA) or (II) can be prepared by methods well known in the art.
  • a tritium-labeled compound represented by the formula (I), (IA) or (II) is represented by the formula (I), (IA) or (II) by, for example, catalytic dehalogenation reaction using tritium. It can be prepared by introducing tritium into a specific compound.
  • This method is a precursor in which a compound of formula (I), (IA) or (II) is appropriately halogen-substituted in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. It includes reacting the body with tritium gas.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • the salt of the compound represented by the formula (I), (IA) or (II) means that the ⁇ -position carboxy group and / or the ⁇ -position carboxy group and / or the ⁇ -position side chain amino group is an inorganic acid or an organic acid. Includes those forming a salt.
  • a compound represented by the formula (I), (IA) or (II) and an alkali metal for example, Lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanol) Amine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, iodine) Hydrofluoric acid etc.) and organic acids (eg formic acid, acetic acid) Propionic acid, tri
  • the compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystalline polymorph.
  • the present invention also encompasses such various solvates and polymorphs.
  • the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I), (IA) or (II).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing a compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is hydrolyzed by a compound, gastric acid, etc., which is enzymatically oxidized, reduced, hydrolyzed and converted to a compound represented by the formula (I), (IA) or (II) under physiological conditions in vivo. The compound etc.
  • the compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof has a hydroxy group, for example, a compound having a hydroxy group and an appropriate acyl halide, an appropriate acid anhydride
  • examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride and a mixed anhydride, or reacting with a condensing agent.
  • CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p— CH 3 —O—PhSO 3 —, PhSO 3 —, and p—CH 3 PhSO 3 — can be mentioned.
  • the present invention relates to (A) a compound represented by formula (I), (IA) or (II), an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (B) ⁇ - There is provided a medicament characterized by combining a compound having a lactamase inhibitory action, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound having a ⁇ -lactamase inhibitory action include a compound having a metallo ⁇ -lactamase inhibitory action and a compound having a serine ⁇ -lactamase inhibitory action, and a compound having a serine ⁇ -lactamase inhibitory action is preferable.
  • Specific examples of the compound having ⁇ -lactamase inhibitory action include clavulanic acid, sulbactam, tazobactam, dipicolinic acid (DPA), 3-aminophenylboronic acid (APB), ethylenediaminetetraacetic acid (EDTA), abibactam (AVI) and the like.
  • compounds having ⁇ -lactamase inhibitory activity described in Expert Opinion Therapeutic Patents (2013), 23 (11), 1469-1481 can be mentioned.
  • the compounds of the present invention represented by the formulas (I) and (IA) have side chain sites bonded to the ⁇ -position and ⁇ -position of the skeleton of the intermediate shown below Can be obtained.
  • the protecting group P include protecting groups described in the following general synthesis. Preferred examples include a benzhydryl group, a paramethoxybenzyl group, a trityl group, a 2,6-dimethoxybenzyl group, a methoxymethyl group, Examples thereof include a benzyloxymethyl group and a 2- (trimethylsilyl) ethoxymethyl group.
  • the leaving group include halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • Process 2 It subjected the compound protecting group P 3 of (V) under acidic conditions deprotection reaction to obtain subsequently a compound by subjecting the intramolecular cyclization reaction under condensing agent present in the (VI).
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • dichloromethane examples include organic acids and inorganic acids.
  • Trifluoroacetic acid examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 0 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 3 Compound (VII) is obtained by subjecting the carboxy protecting group P 1 containing an acyl group of compound (VI) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 4 Compound (IX) is obtained by subjecting Compound (VII) to a condensation reaction with Compound (VIII) in the presence of a base.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • dichloromethane examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, phosphorus oxychloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, carbonyldiimidazole, phenyl phosphate dichloride, and the like.
  • the base used include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferable.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • reaction solvent examples include, for example, ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-acetate).
  • ethers eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether
  • esters eg, ethyl formate, ethyl acetate, n-acetate.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, carbon tetrachloride
  • hydrocarbons eg, n-hexane, benzene, toluene
  • amides eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
  • ketones eg acetone, methyl ethyl ketone
  • nitriles eg acetonitrile, propionitrile
  • nitros eg nitromethane, nitroethane, nitrobenzene
  • dimethyl sulfoxide Water It is shown.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • R 16a and R 16b are each independently a hydrogen atom or substituted or unsubstituted alkyl, R 16A is cyano or tetrazolyl optionally having a protecting group, and other symbols are as defined above.
  • Process 1 P 2 of compound (VI) can be deprotected by catalytic reduction or acidic conditions with a protecting group.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (Eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides ( Examples: formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile),
  • ethers eg, anisole, dioxane, tetrahydrofuran,
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • an organic acid or an inorganic acid can be used as the acid. Examples thereof include trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • the carboxylic acid of compound (VII) can be converted to an amide.
  • the activating agent for carboxylic acid include thionyl chloride, oxalyl chloride, ethyl chlorocarbonate, di-tert-butyl dicarbonate, carbonyldiimidazole, dicyclohexylcarbodiimide and the like. Preferred is di-tert-butyl dicarbonate.
  • amidating agent examples include ammonia, ammonium chloride, ammonium formate, and ammonium carbonate. Ammonium carbonate is preferred.
  • base examples include pyridine, dimethylaminopyridine, picoline, triethylamine, diisopropylethylamine and the like. Pyridine is preferred.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 3 The amide group of compound (VII) can be converted to a tetrazolyl optionally having a protecting group via a cyano group or a cyano group. Conversion to a cyano group can be performed using a dehydrating reagent.
  • Examples of the dehydrating reagent include thionyl chloride, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, phosphorus pentachloride, diphosphorus pentoxide, and the like. Preferred is trifluoroacetic anhydride.
  • a base may coexist in the reaction. Examples of the base include pyridine, picoline, triethylamine, lutidine, diisopropylethylamine and the like. Pyridine is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Subsequent conversion to tetrazolyl can be done using trimethylsilyl azide, sodium azide, hydrazoic acid, diphenylphosphoric acid azide. Trimethylsilyl azide is preferred.
  • Dibutyltin oxide can coexist as a catalyst.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 50 to 150 ° C., preferably about 20 to 120 ° C., more preferably about 60 to 100 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • the tetrazolyl group can be protected as necessary.
  • a protecting group similar to the protecting group for carboxy group can be used. Preferred protecting groups include benzhydryl, p-methoxybenzyl and the like.
  • Process 4 Compound (VII) is obtained by subjecting carboxy protecting group P 1 containing an acyl group of compound (IX) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 1 Compound (XI) can be led to compound (XII) by oxidation.
  • the oxidizing agent include selenium dioxide and oxon.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 50 to 150 ° C., preferably about 20 to 120 ° C., more preferably about 60 to 100 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 2 Compound (XIV) can be led to compound (XIV) by alkylation reaction of compound (XII) and compound (XIII) and subsequent cyclization reaction.
  • the base include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 10 to 30 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 3 By reacting compound (XIV) with ⁇ -haloacetic acid halide, compound (XV) can be derived.
  • the base used include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 0 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 4 The halide of compound (XV) can be converted to a phosphonium salt and subsequently led to compound (XV) by intramolecular cyclization that occurs in the presence of a base.
  • Examples of the phosphonium salt formation include triphenylphosphine, triethylphosphine, tributylphosphine, and the like, and triphenylphosphine is preferable.
  • Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
  • Sodium bicarbonate is preferable.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about 10 to 30 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 5 Reduction of the double bond of compound (XVI) can lead to compound (XVII).
  • the reduction is performed using catalytic hydrogenation or a reducing agent, and examples of the reducing agent include sodium borohydride, lithium borohydride, and borohydride.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • Step 6 Compound (VII) is obtained by subjecting amino protecting group P 1 containing a carbonyl group of compound (IX) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • Step 1-1 The compound (XIX) or compound (XXII) can be derived by acylating the cyclic amide nitrogen atom of the compound (XIX) or compound (XX) in the presence of a base.
  • the acylating agent include tert-butyl 2-chloro-2-oxoacetate.
  • the base include triethylamine, diisopropylethylamine, pyridine, lutidine and the like.
  • Diisopropylethylamine is preferable.
  • the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg,
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Step 1-2 Ozonolysis of the double bond of compound (XXII) can lead to compound (XXIII).
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • the reaction temperature is usually about ⁇ 100 to 0 ° C., preferably about ⁇ 70 to ⁇ 40 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 2 The compound (XXIV) typified by the compound (XXI) or the compound (XXIII) can be cyclized with a reducing agent to lead to the compound (XXV).
  • the reducing agent include samarium iodide.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • the reaction temperature is usually about ⁇ 100 to 0 ° C., preferably about ⁇ 70 to ⁇ 40 ° C.
  • the reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
  • Process 3 The dihydroxy group of compound (XXV) can be led to a cyclic carbonate structure by an acylating agent.
  • the acylating agent include carbonyldiimidazole and triphosgene.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • Process 4 Compound (VII) is obtained by subjecting amino protecting group P 1 containing a carbonyl group of compound (XXVI) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions.
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzen
  • the alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride.
  • the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred.
  • alcohol As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable.
  • Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 70 to 20 ° C., more preferably about ⁇ 70 to ⁇ 30 ° C. for the alcoholysis reaction.
  • the deprotection reaction under acidic conditions is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 20 to 40 ° C., more preferably about ⁇ 20 to 20 ° C.
  • Process 1 Compound (XXVIII) is obtained by subjecting the amine body to a condensation reaction with compound (VII) in the presence of a base.
  • the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone,
  • ethers eg, anisole, dioxane
  • solvents may be used alone or in combination of two or more.
  • the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, phosphorus oxychloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, carbonyldiimidazole, and phenyl phosphate dichloride.
  • the base include triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 2 Compound (XXIX) is obtained by oxidizing compound (XXVIII).
  • reaction solvent examples include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulf
  • solvents may be used alone or in combination of two or more.
  • the oxidizing agent include peracetic acid, m-chloroperbenzoic acid, hydrogen peroxide, sodium tungstate, and the like.
  • the reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • the reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • Process 3 All protecting groups of compound (XXIX) are subjected to a deprotection reaction under acidic conditions to give compound (I).
  • the acid an organic acid or an inorganic acid can be used.
  • reaction temperature is usually about ⁇ 100 to 100 ° C., preferably about ⁇ 80 to 20 ° C., more preferably about ⁇ 20 to 20 ° C.
  • reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
  • the obtained compound (I) or (IA) can be further chemically modified to synthesize ester forms, or pharmaceutically acceptable salts or solvates thereof.
  • the compound of the present invention has a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, gallbladder It can be used for the prevention or treatment of inflammation, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.
  • the compound of the present invention is a gram-negative bacterium, preferably a gram-negative bacterium of the family Enterobacteriaceae (E. coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.) (Hemophilus, Moraxella, etc.) and glucose non-fermenting Gram-negative bacteria (Pseudomonas other than Pseudomonas aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.).
  • the compounds of the present invention are stable against ⁇ -lactamases belonging to classes A, B, C and D produced by these gram-negative bacteria.
  • the compound of the present invention also has antibacterial activity against gram-positive bacteria including methicillin-sensitive Staphylococcus aureus (MRSA), penicillin-resistant pneumococcus (PRSP) and the like.
  • MRSA methicillin-sensitive Staphylococcus aureus
  • PRSP penicillin-resistant pneumococcus
  • Further preferable compounds have characteristics such as high blood concentration, long duration of effect, and / or remarkable tissue transferability as pharmacokinetics.
  • Preferred compounds are safe in terms of side effects such as no fever and no nephrotoxicity.
  • preferred compounds have high water solubility and good pharmacokinetics, and are suitable as injections and oral drugs.
  • the compound of the present invention can be administered orally or parenterally.
  • the compound of the present invention is any of ordinary preparations, for example, solid preparations such as tablets, powders, granules and capsules, liquid preparations, oil suspensions, or liquid preparations such as syrups and elixirs. It can also be used as a dosage form.
  • the compound of the present invention can be used as an aqueous or oily suspension injection or nasal solution.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used.
  • the formulations of the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent.
  • the compound of the present invention can be administered parenterally or orally as an injection, capsule, tablet or granule, but is preferably administered as an injection.
  • the dose is usually about 0.1 to 100 mg / day, preferably about 0.5 to 50 mg / day per kg of the body weight of the patient or animal, if desired divided into 2 to 4 times a day.
  • the carrier is, for example, distilled water, physiological saline or the like, and a base for adjusting pH may be used.
  • Carriers when used as capsules, granules, tablets are known excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose) , Hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.).
  • excipients eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.
  • binders eg, starch, gum arabic, carboxymethyl cellulose) , Hydroxypropyl cellulose, crystalline cellulose, etc.
  • lubricants eg, magnesium stearate, talc, etc.
  • Boc tert-butoxycarbonyl
  • DMF N, N-dimethylformamide
  • DMA N, N-dimethylacetamide
  • DMAP N, N-dimethyl-4-amino Pyridine
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • HMPA hexamethylphosphoric triamide
  • HOBt 1-hydroxybenzotriazole
  • mCPBA m-chloroperbenzoic acid
  • Me methyl
  • TBS tert-butyldi
  • the LCMS analysis obtained in the examples was measured under the following conditions. Measurement condition 1: Column: ACQUITY UPLC® BEH C18 (1.7 ⁇ m id 2.1 ⁇ 50 mm) (Waters) Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, [B] was 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 5% -100% solvent [B] was performed in 3.5 minutes Thereafter, 100% solvent [B] was maintained for 0.5 minutes.
  • Measurement condition 2 Column: Shim-pack XR-ODS (2.2 ⁇ m, id 50 ⁇ 3.0 mm) Flow rate: 1.6 mL / min PDA detection wavelength: 254 nm
  • Step 2 Synthesis of Compound 3c
  • a solution of Compound 3b (4.79 g, 12.7 mmol) in tetrahydrofuran (24 mL) was added dropwise a solution of diphenyldiazomethane (2.60 g, 13.4 mmol) in tetrahydrofuran (24 mL) over 20 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 3c (3.37 g, yield 49%) as a white solid. .
  • Step 3 Synthesis of Compound 3f After cooling a suspension of phosphorus pentachloride (1.04 g, 5.0 mmol) in dichloromethane (6.8 mL) to ⁇ 78 ° C., pyridine (0.444 mL, 5.5 mmol) was added, Then, a solution of compound 3c (1.36 g, 2.5 mmol) in dichloromethane (6.8 mL) was added dropwise. After stirring at ⁇ 10 ° C. for 1 hour, the reaction mixture was cooled to ⁇ 78 ° C. and methanol (6.8 mL) was added. After stirring at ⁇ 30 ° C.
  • Step 4 Synthetic compound 3f (367 mg, 0.39 mmol) in dichloromethane (3.7 mL) was cooled to ⁇ 40 ° C., then anisole (0.344 mL, 3.15 mmol) and 2 mol / L aluminum chloride were used. / Nitromethane solution (1.58 mL, 3.15 mmol) was sequentially added, and the mixture was stirred for 30 minutes under ice cooling. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated.
  • Step 2 Synthesis of Compound I-004
  • Compound 4a (295 mg, 0.35 mmol) in dichloromethane (3.0 mL) was cooled to ⁇ 20 ° C., then anisole (0.385 mL, 3.5 mmol) and 2 mol / L titanium chloride.
  • Dichloromethane solution (1.23 mL, 2.47 mmol) was sequentially added, and the mixture was stirred for 40 minutes under ice cooling. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated.
  • Step 2 Compound 4 of Compound 4 (18.0 g, 27.2 mmol) was dissolved in dichloromethane (180 mL), cooled to 50 ° C. below freezing, and anisole (11.9 mL, 109 mmol) and 2 mol / L aluminum chloride-nitromethane solution (47.7 mL, 95.0 mmol) was added dropwise and stirred at the same temperature for 20 minutes. Purified water was added to the reaction solution, and the target product was extracted with dichloromethane. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to obtain Compound 4. The entire amount obtained was used in the next reaction without purification.
  • Step 3 Synthesis of Compound 5
  • the residue obtained in the entire reaction was dissolved in dichloromethane (130 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.21 g, 27.2 mmol) was added thereto at room temperature. For 1 hour 30 minutes. To this solution was again added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.61 g, 13.6 mmol), and the mixture was stirred at room temperature for 1 hour. Purified water was added to the reaction solution, and the target product was extracted with dichloromethane.
  • Step 4 Synthesis of Compound 6
  • Compound 6 (2.80 g, 5.88 mmol) was suspended in dichloromethane (30.0 mL), 4 mol / L hydrochloric acid-ethyl acetate (22.0 mL, 88.0 mmol) was added, and the mixture was stirred at room temperature. Stir for minutes. The resulting solid was collected by filtration and washed with ethyl acetate to obtain Compound 8 as an inseparable mixture.
  • Step 5 Synthesis of Compound 8
  • Compound 8 (202 mg) was suspended in dichloromethane, cooled to 0 ° C., compound 9 (189 mg, 0.538 mmol) and N-methylmorpholine (0.118 mL, 1.08 mmol) were added overnight.
  • Stir with. 5% multistory water and tetrahydrofuran were added to the reaction solution, and the target product was extracted from the aqueous layer with dichloromethane.
  • the collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography to give a compound.
  • Step 2 Synthesis of Compound 1c
  • Compound 1b (13.87 g, 35.2 mmol) was treated in the same manner as in Step 2 of Synthesis Example of Compound I-031 to give Compound 1c (9.64 g, yield 67.4%). Obtained as a clear colorless oil.
  • Step 3 Synthesis of Compound 1e
  • acetone 50.2 mL
  • Compound 1d 5.02 g, 21.26 mmol
  • hexamethylphosphoric triamide (12.95 mL)
  • Water was added and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • Step 5 Synthesis of Compound 1h
  • Compound 1f-isomer B and Compound 1f-isomer C mixture 500 mg, 1.09 mmol
  • compound 1g 525 mg, 1.31 mmol
  • To give compound 1h-isomer C 96.7 mg, 12.3% yield) as a single isomer.
  • Step 6 Synthesis of Compound I-009
  • Compound 1h—isomer C 90.2 mg, 0.125 mmol
  • Step 7 of the synthesis of Compound I-031 was treated in the same manner as in Step 7 of the synthesis of Compound I-031 to give compound I-009 (14.2 mg, yield). 21.0%) was obtained as a brown solid.
  • Process 3 Compound 4 (590 mg) was dissolved in dichloromethane (6.0 mL), cooled to 20 degrees below freezing, and anisole (1.03 mL, 9.45 mmol) and a 2 mol / L aluminum chloride-nitromethane solution (4.72 mL, 9.45 mmol). ) And stirred at -20 degrees for 30 minutes. Purified water and diisopropyl ether were added to the reaction solution. Acetonitrile was added to the reaction solution, and the aqueous layer was separated. The organic layer was extracted with a water / acetonitrile / dilute hydrochloric acid mixture, and the pH was adjusted to 1.3 using 2 mol / L hydrochloric acid.
  • HP20SS was added to the aqueous layer and concentrated.
  • the concentrated suspension was subjected to column chromatography connecting HP20SS and ODS and eluted with water-acetonitrile, and fractions containing the desired product were collected.
  • the aqueous solution was adjusted to pH 9.0 using a 2 mol / L aqueous sodium hydroxide solution, and a piece of dry ice was added to adjust the pH to 5.2. This aqueous solution was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound I-018 as a powder.
  • Step 4 Synthesis of Compound 29f
  • the system was replaced with nitrogen gas, dimethyl sulfide (7.77 mL, 105 mmol) was added, and the mixture was stirred at ⁇ 78 ° C. for 5 minutes.
  • prenyl alcohol (5.33 mL, 53 mmol) was added, and the mixture was stirred at ⁇ 78 ° C. for 1.5 hours.
  • reaction mixture was raised to about 0 ° C., 5% aqueous sodium carbonate solution was added, and the mixture was stirred at room temperature for 5 minutes.
  • Dichloromethane was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure.
  • the resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 29f (6.67 g, yield 41%) as a colorless oil.
  • Step 5 Compound 29g Synthesis compound 29f (6.67 g, 14.4 mmol) in dichloromethane (33 mL) was added with N, N, N′N′-tetramethylmethanediamine (7.82 mL, 57.4 mmol) under ice cooling. ) was added, and acetic anhydride (6.78 mL, 71.8 mmol) and acetic acid (5.75 mL, 100 mmol) were slowly added in this order. After stirring at room temperature for 3 hours, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 7 Synthesis of Compound 29k
  • Compound 29i 700 mg, 0.98 mmol
  • dichloromethane 3.5 mL
  • trifluoroacetic acid 3.5 mL
  • dichloromethane 3.5 mL
  • dichloromethane 3.5 mL
  • ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane.
  • the organic layer was washed 4 times with water, then with saturated brine, and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure to obtain Compound 29j as a white foam.
  • the obtained 29j was used in the next reaction without purification.
  • Step 8 Synthesis of Compound 29n
  • Compound 29n (255 mg, 82% yield) was converted into white foam from Compound 29k (212 mg, 0.37 mmol) and Compound 29m (178 mg, 0.44 mmol) in the same manner as in Step 3 of Example 1. Obtained.
  • Step 3 Synthesis of Compound 1e
  • Compound 1c (10.0 g, 25.5 mmol) in acetone (100 mL)
  • Compound 1d (6.02 g, 25.5 mmol) and hexamethylphosphoric triamide (15.5 mL, 89 mmol) were added.
  • the mixture was further stirred at room temperature for 1 hour.
  • Water was added and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain Compound 1e (2.1 g, yield: 13.1%).
  • Step 4 Synthesis of Compound 1f Under a nitrogen atmosphere, a solution of compound 1e (6.80 g, 10.8 mmol) in dichloromethane (34 mL) was cooled to ⁇ 10 ° C. A solution of TFA (34 mL, 441 mmol) in dichloromethane (34 mL) was added dropwise thereto, and the mixture was stirred at ⁇ 10 ° C. for 30 minutes. Water was added and extracted with dichloromethane. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and a solution of the obtained residue in dichloromethane (50 mL) was cooled to 0 ° C.
  • Step 5 Synthesis of Compound 1i
  • triphenylphosphine 8.80 g, 33.5 mmol
  • DIAD 6.52 mL, 33.5 mmol
  • hydroxyacetic acid benzhydryl were added thereto, and the mixture was stirred at 0 ° C. for 1 hour.
  • the reaction mixture was poured into a hexane-ethyl acetate mixture, and the resulting insoluble material was filtered.
  • Step 7 Synthesis of Compound I-031
  • a suspension of phosphorus pentachloride (0.754 g, 3.62 mmol) in dichloromethane (10 mL) was cooled to ⁇ 40 ° C., and pyridine (0.584 mL, 7.24 mmol) was added.
  • Compound 1f (0.805 g, 1.81 mmol) was then added.
  • the reaction mixture was cooled to ⁇ 78 ° C., and methanol (8.1 mL) was added.
  • an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane.
  • Step 2 Synthesis of Compound 34c
  • tetrahydrofuran 2.0 mL
  • chlorosulfonyl isocyanate 43 ⁇ L, 0.50 mmol
  • sodium hydrogen carbonate 116 mg, 1.38 mmol
  • water 200 ⁇ L
  • the mixture was further stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 2 Synthesis of Compound I-35
  • Compound I-35 (37 mg, 33% yield) was obtained as a white powder from Compound 35a (161 mg, 0.21 mmol) in the same manner as in Step 3 of Example 2.
  • reaction solution was dissolved in water, 2 mol / L hydrochloric acid and acetonitrile, and then washed with diisopropyl ether.
  • HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure.
  • the resulting mixture was subjected to ODS column chromatography and eluted with water / acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure and lyophilized to give compounds I-36 and I-37 as white powders.
  • Step 2 Synthesis of Compound 39c
  • Compound 39b (135 mg, 0.207 mmol) was dissolved in dichloromethane (1.50 mL) and cooled to 30 degrees below freezing. Pyridine (0.050 mL, 0.621 mmol) was added to this solution, and then trifluoroacetic anhydride (0.044 mL. 0.311 mmol) was added, followed by stirring at 30 ° C. for 45 minutes. To this reaction solution were added pyridine (0.033 mL, 0.414 mmol) and trifluoroacetic anhydride (0.029 mL. 0.207 mmol), and the mixture was stirred at 0 ° C. for 2 hours and 30 minutes.
  • Step 3 Synthesis of Compound 39d
  • Compound 39c 120 mg, 0.189 mmol was dissolved in 1,4-dioxane (1.20 mL), trimethylsilyl azide (0.050 mL, 0.379 mmol) and dibutyltin oxide (4.71 mg, 0.0189 mmol) was added and stirred at 70 degrees.
  • purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with ethyl acetate.
  • the collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to give compound 39d.
  • Process 4 Compound 39d (128 mg, 0.189 mmol) was dissolved in dichloromethane (1.0 mL), cooled to 30 ° C. below freezing, and anisole (0.124 mL, 1.13 mmol) and 2 mol / L aluminum chloride-nitromethane solution (0.567 mL) were cooled. 1.13 mmol) and stirred at 0 degrees for 45 minutes. Purified water and diisopropyl ether were added to the reaction solution. Acetonitrile, 2 mol / L hydrochloric acid was added to the reaction solution to dissolve the precipitate, and then the aqueous layer was separated.
  • the organic layer was extracted with a water / acetonitrile / dilute hydrochloric acid mixture, and HP20SS was added to the combined aqueous layer and concentrated.
  • the concentrated suspension was subjected to column chromatography in which HP20SS and ODS were connected, and eluted with water-acetonitrile. Fractions containing the target product were collected, and the pH was adjusted to 6.5 using 0.2 mol / L aqueous sodium hydroxide solution. A piece of dry ice was added. This solution was concentrated under reduced pressure, and the concentrate was lyophilized to obtain Compound I-39 as a powder.
  • Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was extracted with an aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted again with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Step 3 Synthesis of Compound I-40 Dimedone (616 mg, 4.39 mmol) and tetrakis (triphenylphosphine) palladium (0) (169 mg, 0.146 mmol) were added to a DMF solution of the composition of compound 40c (500 mg) at room temperature. The mixture was stirred for 30 minutes. To this, compound 40d (770 mg, 2.20 mmol) was added and stirred at room temperature for 1 hour. Insoluble matters in the reaction solution were removed by Celite filtration. Diisopropyl ether, acetonitrile and dilute hydrochloric acid were sequentially added to the filtrate and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated.
  • Step 4 Synthesis of Compound I-41 Dimedone (689 mg, 4.91 mmol) and tetrakis (triphenylphosphine) palladium (0) (379 mg, 0.328 mmol) were added to a DMF solution of 41 g of the composition compound (600 mg), at room temperature. Stir for 1 hour. To this, compound 1d (861 mg, 2.46 mmol) was added and stirred at room temperature for 1 hour. Insoluble matters in the reaction solution were removed by Celite filtration. Diisopropyl ether, acetonitrile and dilute hydrochloric acid were sequentially added to the filtrate and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated.
  • Step 2 Synthesis of Compound I-42
  • Compound I-42 was synthesized by the method described in EP253337A using Compound 42b (100 mg, 0.18 mmol) and Compound 42d (184 mg, 0.52 mmol) and purified by ODS column chromatography. This gave compound I-42 (15 mg, 19%).
  • Step 2 Compound 43c
  • Compound 43b (6.85 g, 33.7 mmol) and t-butyldimethylsilyl chloride (7.62 g, 50.6 mmol) were added to a solution of imidazole (3.44 g, 50.6 mmol) in dichloromethane (192 mL) at 0 ° C. And left at room temperature overnight.
  • Water was added and extracted with ethyl acetate.
  • the organic layer was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure.
  • Step 3 Compound 43e To a solution of compound 43c (11.32 g, 35.7 mmol) in tetrahydrofuran (192 mL) was added 8N aqueous sodium hydroxide solution (8.91 mL, 71.3 mmol) at 0 ° C., and the mixture was allowed to stand overnight at room temperature. A 1N aqueous hydrochloric acid solution (78 mL, 78 mmol) was added at 0 ° C., the mixture was concentrated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate.
  • Step 4 Compound 43f A solution of compound 43e (5.0 g, 10.65 mmol) in tetrahydrofuran (50 mL) was added acetic acid (0.913 mL, 15.97 mmol) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 15.97 mL, 15.97 mmol) at 0 ° C. ) And stirred at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic layer was washed sequentially with an 8.4% aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
  • Step 5 Compound 43g To a solution of compound 43f (3.2 g, 9.0 mmol) in tetrahydrofuran (32 mL) at room temperature was added 2-hydroxyindoline-1,3-dione (1.763 g, 10.81 mmol) and triphenylphosphine (2.83 g, 10 .81 mmol) was added, and diisopropyl azodicarboxylate (2.10 mL, 10.81 mmol) was added dropwise, followed by stirring at room temperature for 1.5 hours.
  • Step 6 Compound 43k To a solution of compound 43g (2.96 g, 5.91 mmol) in dichloromethane (20.7 mL), methylhydrazine (0.351 mL, 6.50 mmol) was added at once at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. The obtained solution was filtered and washed with dichloromethane (8.9 mL), methanol (14.8 mL) was added to the obtained dichloromethane solution, and compound 43h (1.545 g, 5.67 mmol) was added at 0 ° C. And stirred at 0 ° C. for 1 hour.
  • Step 7 Compound I-43
  • Compound I-43 In the same manner as in Step 4 of Example 1, using Compound 43k, Compound I-43 (252.5 mg, 29.6%) was obtained as a white solid.
  • Step 2 Synthesis of Compound 45c
  • a solution of Compound 45b (8.07 g, 33 mmol) in tetrahydrofuran (32 mL) was added dropwise a solution of diphenyldiazomethane (7.12 g, 37 mmol) in tetrahydrofuran (24 mL).
  • the mixture was stirred at room temperature for 5 days and concentrated under reduced pressure.
  • the resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 45c (4.80 g, yield 35%) as a white solid.
  • Step 4 To a solution of compound 45f and 45 g of compound 45d (4.83 g, 10.7 mmol) in acetone (48 mL), compound 45e (2.79 g, 11.8 mmol), hexamethylphosphoric triamide (6.54 mL, 37 .6 mmol) was added. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure.
  • Step 5 Synthesis of compound 45i
  • dichloromethane 4.7 mL
  • trifluoroacetic acid 2.4 mL, 30.9 mmol
  • the reaction mixture was added to an ice-cooled mixture of aqueous sodium bicarbonate and dichloromethane.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration, and the compound 45h was obtained by concentrating under reduced pressure.
  • the obtained 45 h was used in the next reaction without purification.
  • the total amount of the obtained 45 h was dissolved in a dichloromethane (6.8 mL) solution, and then EDC hydrochloride (217 mg, 1.13 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure.
  • Step 6 Synthesis of Compound 45l After cooling a solution of Compound 45k (361 mg, 0.90 mmol) in dimethylacetamide (1.8 mL) to ⁇ 20 ° C., triethylamine (0.156 mL, 1.12 mmol) methanesulfonyl chloride (0.082 mL) 1.05 mmol). Solution A was obtained by stirring at ⁇ 20 ° C. for 30 minutes. After cooling a suspension of phosphorus pentachloride (312 mg, 1.5 mmol) in dichloromethane (1.8 mL) to ⁇ 78 ° C., pyridine (0.133 mL, 1.65 mmol) was added, followed by compound 45i (354 mg, 0.
  • Step 7 Synthesis of Compound I-45 After cooling a solution of Compound 45l (407 mg, 0.55 mmol) in dichloromethane (4 mL) to ⁇ 40 ° C., anisole (0.48 mL, 4.4 mmol), 2 mol / L aluminum chloride / nitromethane The solution (2.2 mL, 4.4 mmol) was added in order and stirred at ⁇ 30 ° C. for 30 minutes. Diisopropyl ether, ice water, and acetonitrile were added to the reaction solution and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated.
  • Step 3 Synthesis of Compound 47e
  • a solution of Compound 47d (20.8 g, 33.5 mmol) in tetrahydrofuran (208 mL) was degassed under reduced pressure, and then morpholine (6.42 mL, 73.7 mmol), Pd (PPh 3 ) 4 (1. 94 g, 1.68 mmol) was added in order.
  • Boc 2 O (21.8 mL, 94 mmol) was added.
  • the mixture was further stirred at room temperature for 1.5 hours and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 47e (20.12 g, 94% yield) as a white foam.
  • Step 3 Synthesis of Compound 48g After cooling a suspension of phosphorus pentachloride (611mg, 2.94mmol) in dichloromethane (3.3mL) to -78 ° C, pyridine (0.261mL, 3.2mmol) was added, and then compound A solution of 48d (658.2 mg, 1.47 mmol) in dichloromethane (3.3 mL) was added dropwise. After stirring at ⁇ 10 ° C. for 2 hours, the reaction mixture was cooled to ⁇ 78 ° C. and ethanol (3.3 mL) was added. After stirring at ⁇ 30 ° C.
  • the organic layer was washed successively with an 8.4% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the inorganic substance was removed by filtration and concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 48 g (453.7 mg, yield 43.4%) of a compound as a yellow oil.
  • Step 4 Synthesis of Compound I-48 48 g (453.7 mg, 0.64 mmol) in dichloromethane (6.8 mL) was cooled to ⁇ 30 ° C., then anisole (0.833 mL, 7.63 mmol) and 2 mol / L. An aluminum chloride / nitromethane solution (3.81 mL, 7.63 mmol) was sequentially added, and the mixture was stirred at ⁇ 30 ° C. for 20 minutes. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated.
  • Step 2 A solution of compound 50m and 50n in 50 ml of synthetic compound 50j (21.0 g, 51.9 mmol) in dichloromethane (420 mL) is stirred for 40 minutes while blowing ozone gas at ⁇ 78 ° C. Nitrogen was blown into the obtained blue solution for 5 minutes, dimethyl sulfide (11.5 mL, 156 mmol) was added, and the mixture was stirred at ⁇ 78 ° C. for 15 minutes, stirred at 0 ° C. for 1 hour, added with ice water, and extracted with ethyl acetate. . The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 3 Synthesis of Compound I-50
  • Compound I-50 (169.9 mg, 27.3% yield (2 steps)) was obtained as a yellow solid.
  • Step 2 Synthesis of Compound 52c Selenium oxide (IV) (40.4 g, 364 mmol) was added to a solution of compound 52b (41.5 g, 165 mmol) in dioxane (215 mL), and the mixture was stirred at 80 ° C. for 15 hours. The reaction solution was cooled to room temperature, and the insoluble material was filtered through celite and washed with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52c (21.3 g, 46%).
  • Step 4 Compound 52g Synthetic compound 52e (5.54 g, 13.2 mmol) in dichloromethane (55 mL) was ice-cooled, bromoacetyl bromide (2.06 mL, 23.7 mmol) was added, and then triethylamine (3.29 mL). 23.7 mmol). After stirring for 2 hours under ice cooling, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure.
  • Step 5 Synthesis of Compound 52h Triphenylphosphine (2.45 g, 9.33 mmol) was added to a DMF (42 mL) solution of compound 52 g (4.21 g, 7.78 mmol). After stirring at room temperature for 1 to 5 hours, 8.4% aqueous sodium hydrogen carbonate solution (20.0 mL, 20.0 mmol) was added. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure.
  • reaction mixture A Pyridine (0.051 mL, 0.629 mmol) was added to the dichloromethane solution of 52j obtained in step 7 under ice-cooling, and then reaction mixture A was added dropwise. After stirring at 0 ° C. for 40 minutes, water was added and dichloromethane was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound 53d
  • a mixture of Compound 53d and 53d-ii (25.88 g, Yield 58%) was mixed with white from a mixture of Compound 53c and 53c-ii (21 g, 83 mmol) in the same manner as in Step 2 of Example 6. Obtained as a foam.
  • Step 3 Synthesis of Compound 53e
  • a mixture of Compound 53e and 53e-ii (6.11 g, yield 36%) was prepared in the same manner as in Step 4 of Example 6 from a mixture of Compound 53d and 53d-ii (25.9 g, 48 mmol).
  • Step 4 Synthesis of Compound 53g
  • a solution of a mixture of compound 53e and 53e-ii (6.11 g, 17.5 mmol) in dichloromethane (30 mL) was added N, N, N′N′-tetramethylmethanediamine (7 .17 mL, 52.6 mmol) was added, and acetic anhydride (6.30 mL, 66.6 mmol) and acetic acid (5.32 mL, 93 mmol) were added dropwise in this order.
  • ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 5 Synthesis of Compound I-53 Synthesis was performed from 53 g of Compound I in the same manner as in Steps 5 to 7 of Example 19 to obtain Compound I-53.
  • Step 2 Synthesis of Compound 54d
  • Compound 54c (corresponding to 28.7 mmol) obtained was dissolved in tetrahydrofuran (30 ml), and acetic acid (4.92 ml, 86 mmol) and 1 mol / L TBAF tetrahydrofuran solution (86 ml, 86 mmol) were added. . After stirring for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 5 Synthesis of Compound 54h Compound 54h (1.60 g, 92 g) was obtained in the same manner as in Step 3 of Example 12 using Compound 54f (1.04 g, 2.25 mmol) and Compound 54 g (1.00 g, 2.25 mmol). %) Crude product as a mixture of about 1.2: 1.
  • Step 2 Synthesis of Compound 55c
  • Compound 55b (19.1 g, 89.0 mmol) was suspended in tetrahydrofuran (38 mL), 4-methoxyphenylmethanol (36.8 g, 267 mmol) was added, and the mixture was stirred at 50 ° C. for 10 hours.
  • purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with dichloromethane.
  • the collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure.
  • the obtained residue was subjected to silica gel chromatography to obtain compound 55c.
  • Step 4 Synthesis of Compound 55e
  • Compound 55e was synthesized in the same manner as in Step 3 of Example 6 using Compound 55d (20.2 g, 31.7 mmol). (Yield 5.01 g, Yield 35%)
  • Step 5 Synthesis of Compound I-55
  • Compound I-55 was synthesized in the same manner as in Step 5 of Example 6 using Compound 55e.
  • MS (m + 1) 500.95, retention time: 0.32 minutes, measurement condition 1
  • Test Example 1 In vitro antibacterial activity of the compound of the present invention was confirmed.
  • the minimum inhibitory concentration (MIC) is measured according to the method recommended by CLSI (Clinical and Laboratory Standards Institute), the inoculum is 1 ⁇ 10 5 CFU / mL, the test medium is cation-adjusted Mueller Hinton broth, It was carried out by a micro liquid dilution method. The strains used are shown in the table below. (result) The test results are shown in Tables 20 and 21. In the table, the unit of the numerical value of the inhibitory activity is ⁇ g / mL.
  • the compound represented by the formula (I), (IA) or (II) has a broad antibacterial spectrum, particularly a strong antibacterial spectrum against gram-negative bacteria, and / or multidrug resistance. It exhibits strong antibacterial activity against bacteria, particularly crumb B type metallo- ⁇ -lactamase producing Gram negative bacteria, and / or strong antibacterial activity against substrate-specific extended ⁇ -lactamase (ESBL) producing bacteria. It is also effective against multi-drug resistant bacteria including carbapenemase resistance, and has high stability against ⁇ -lactamase producing gram-negative bacteria.
  • Test Example 1-2 In vitro antibacterial activity was confirmed in order to confirm the combined effect of the compound of the present invention and a compound having ⁇ -lactamase inhibitory action.
  • Test method Minimum growth inhibitory concentration (MIC: ug / mL) is measured according to the CLSI (Clinical and Laboratory Standards Institute) method. Implemented by law.
  • the amount of the compound having ⁇ -lactamase inhibitory action was 3-aminophenylboronic acid: 400 ug / ml and abibactam: 4 ug / ml.
  • the strains used are shown in the table below.
  • the test results are shown in Table 24. In the table, the unit of the numerical value of the inhibitory activity is ug / ml, APB means 3-aminophenylboronic acid, and AVI means abibactam.
  • the compound of the present invention represented by the formula (I), (IA) or (II) in combination with a compound having ⁇ -lactamase inhibitory activity, it has a broader antibacterial spectrum, It exhibits strong antibacterial activity against strains producing all types of ⁇ -lactamases of class A, B, C and D. That is, it exhibits strong antibacterial activity against crumb B-type metallo- ⁇ -lactamase-producing gram-negative bacteria and / or strong antibacterial activity against substrate-specific extended ⁇ -lactamase (ESBL) -producing bacteria. It is also effective against multidrug-resistant bacteria including carbapenemase resistance, and shows high stability against various ⁇ -lactamase-producing gram-negative bacteria.
  • ESBL substrate-specific extended ⁇ -lactamase
  • Test Example 2 O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the residual activity (%) at each concentration of the compound of the present invention added to the solvent was calculated by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the concentration and inhibition rate were calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • Test Example 4 Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
  • the compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%.
  • the hydrolysis reaction can be carried out in the absence of NADPH, the glucuronic acid conjugation reaction can be carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation can be carried out thereafter.
  • Test Example 5 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in the K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition.
  • a part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer.
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ mol / L or more was designated as (+), and the case where it was 3 ⁇ mol / L or less was designated as ( ⁇ ).
  • Test Example 6 Fluctuation Ames Test The mutagenicity of the compounds of the present invention was evaluated. Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.
  • MicroF containing 110 mL Exposure medium Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • Test Example 7 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role, was investigated. Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of ⁇ 80 mV by whole cell patch clamp, a +40 mV depolarization stimulus was applied for 2 seconds, followed by a ⁇ 50 mV repolarization.
  • I Kr delayed rectifier K + current
  • the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
  • Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Test Example 10 About 5 mg of visual solubility test compound is weighed into three microscopic test tubes, and each medium (water for injection, saline feed, 0.5% glucose solution) is added to a compound concentration of 20%. After stirring by vortex, visually check for dissolution. If so, the solubility in the medium is> 20%. Each medium (water for injection, raw food injection, glucose solution) is further added to these test solutions to prepare a test solution with a compound concentration of 10%. After stirring by vortexing, the presence or absence of dissolution is visually confirmed. If dissolved, the solubility in the medium should be 20% to 10%. Similarly, test to 5% concentration, 2.5% concentration, 1% concentration, and if not soluble at 1% concentration, the solubility in the medium should be ⁇ 1%. Measure and record the pH with 1% test solution.
  • Test Example 11 pKa measurement (capillary electrophoresis method (capillary electrophoresis method, CE method) measurement method) This is a separation method using capillary zone electrophoresis technology and free migration of each sample component in a buffer solution containing an electrolyte. After injecting a compound solution into a fused silica capillary filled with a buffer solution adjusted to pH 2.5 to 11.5 and then applying a high voltage (Inlet side +, Outlet side-) to the capillary, the compound is at the buffer pH. It moves at a speed that reflects the ionization state (+ charged compounds are fast, -charged compounds are slow).
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
  • Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
  • Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
  • the compound according to the present invention has a broad antibacterial spectrum particularly against gram-negative bacteria and is effective as an antibacterial drug having high stability against ⁇ -lactamase-producing gram-negative bacteria. In addition, since it has good pharmacokinetics and high water solubility, it is particularly effective as an injection or oral drug.

Abstract

Provided are the following: compounds having a powerful anti-bacterial spectrum against a variety of bacteria, including gram-negative bacteria and gram-positive bacteria; and pharmaceutical compositions having antibacterial activity against carbapenem-resistant bacteria. Provided are the following: a compound represented by formula (I): (in the formula, -Z- is a single bond or -CR7AR7B-, R7A and R7B are each independently a hydrogen atom or the like, Y is N or CH, -W- is -S-, -S-CH2-, -CH2-S- or -CH2-, -T- is -CR4AR4B- or -CR5AR5B-CR6AR6B-, R4A, R4B, R5A, R5B, R6A and R6B are each independently a hydrogen atom or the like, R16 is a carboxyl group, a tetrazolyl group, or the like, R17 is a hydrogen atom or the like, R1 is a substituted or unsubstituted heterocyclic group or the like, R2A and R2B are each independently a hydrogen atom or the like or R2A and R2B bond together to form a substituted or unsubstituted methylidene group or the like, and R3 is a hydrogen atom or the like); esters of this compound; and pharmaceutically acceptable salts and hydrates thereof.

Description

三環性化合物、およびそれらの使用Tricyclic compounds and their use
　本発明は抗菌作用を有する新規な三環性化合物、そのエステル体、もしくはそれらの製薬上許容される塩、またはそれらの水和物、およびそれらを含有する抗菌剤に関する。さらに、抗菌作用を有する三環性化合物、そのエステル体、もしくはそれらの製薬上許容される塩、またはそれらの水和物と、β－ラクタマーゼ阻害作用を有する化合物、その製薬上許容される塩、またはそれらの溶媒和物を組み合わせることを特徴とする医薬に関する。 The present invention relates to a novel tricyclic compound having an antibacterial action, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and an antibacterial agent containing them. Further, a tricyclic compound having an antibacterial action, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a compound having a β-lactamase inhibitory action, a pharmaceutically acceptable salt thereof, Or it is related with the pharmaceutical characterized by combining those solvates.
　これまで、さまざまなβ－ラクタム薬の開発がなされており、β―ラクタム薬は臨床上非常に重要な抗菌薬となっている。しかし、β‐ラクタム薬を分解するβ－ラクタマーゼを産生することによりβ－ラクタム薬に対して耐性を獲得した菌種が増加している。
　アムブラー（Ａｍｂｌｅｒ）の分子分類法によると、β－ラクタマーゼは大きく４つのクラスに分類される。すなわち、クラスＡ（ＴＥＭ型、ＳＨＶ型、ＣＴＸ－Ｍ型、ＫＰＣ型など）、クラスＢ（ＮＤＭ型、ＩＭＰ型、ＶＩＭ型、Ｌ－１型など）、クラスＣ（ＡｍｐＣ型、ＡＤＣ型、ＣＭＹ型、ＤＨＡ型など）、クラスＤ（ＯＸＡ型など）である。これらのうち、クラスＡ，Ｃ，Ｄ型はセリンーβ－ラクタマーゼ、一方、クラスＢ型はメタロ－β－ラクタマーゼに大別され、それぞれ異なるメカニズムによってβ－ラクタム薬を加水分解することが知られている。
　近年、基質域を拡張したクラスＡ型（ＥＳＢＬ）やクラスＤ型に加えＫｌｅｂｓｉｅｌｌａ ｐｎｅｕｍｏｎｉａｅ Ｃａｒｂａｐｅｎｅｍａｓｅ（ＫＰＣ）を含むセリン‐β－ラクタマーゼや、さらにはクラスＢ型のメタロ‐β－ラクタマーゼの産生により、セフェムやカルバペネムを含む多くのβ－ラクタム薬に高度耐性化したグラム陰性菌の存在が臨床上問題となっている。特に、ＫＰＣやメタロ‐β－ラクタマーゼを産生する腸内細菌科細菌は、グラム陰性菌感染症治療に対し重要な位置付けであるカルバペネム系抗菌薬に高度の耐性を示すことが知られている。
メタロ‐β－ラクタマーゼ産生グラム陰性菌を含むグラム陰性菌に対して中程度の活性を示すセフェム化合物が公知である（例：特許文献１）が、さらに強い抗菌活性、特に各種β－ラクタマーゼ産生グラム陰性菌に対して有効なβ－ラクタム系薬の開発が切望されている。また、クラスＡ型、Ｂ型、Ｃ型およびＤ型のβ－ラクタマーゼ産生グラム陰性菌に対して幅広く有効なβ－ラクタム系薬は少なく、開発が切望されている。
　特許文献２～４には、新規な骨格を有するβ－ラクタム系化合物が報告されているが、近年問題となっている上記カルバペネム耐性菌などに対する抗菌活性は記載されていない。また、記載された抗菌活性から、本骨格を持つ化合物群がカルバペネム耐性菌に抗菌活性を有することは到底想像できることではない。さらに、これらの特許文献には、新規な骨格を有するβ－ラクタム系化合物とその他の薬剤との組み合わせや併用効果については記載も示唆もされていない。 Various β-lactam drugs have been developed so far, and β-lactam drugs have become clinically very important antibacterial drugs. However, an increasing number of bacterial strains have acquired resistance to β-lactam drugs by producing β-lactamase that degrades β-lactam drugs.
According to Ambler's molecular taxonomy, β-lactamases are broadly classified into four classes. Class A (TEM type, SHV type, CTX-M type, KPC type, etc.), Class B (NDM type, IMP type, VIM type, L-1 type, etc.), Class C (AmpC type, ADC type, CMY type) Type, DHA type, etc.) and class D (OXA type, etc.). Of these, Class A, C, and D types are broadly classified into serine-β-lactamases, while Class B types are broadly divided into metallo-β-lactamases, which are known to hydrolyze β-lactam drugs by different mechanisms. Yes.
In recent years, by the production of serine-β-lactamases including Klebsiella pneumoniae Carbapeenase (KPC) in addition to class A (ESBL) and class D with an extended substrate range, and further, class B metallo-β-lactamases, The existence of Gram-negative bacteria highly resistant to many β-lactam drugs including carbapenem and carbapenem has become a clinical problem. In particular, Enterobacteriaceae bacteria that produce KPC and metallo-β-lactamase are known to exhibit high resistance to carbapenem antibacterial agents, which are important for the treatment of Gram-negative bacterial infections.
Cephem compounds that exhibit moderate activity against gram-negative bacteria, including metallo-β-lactamase-producing gram-negative bacteria are known (eg, Patent Document 1), but stronger antibacterial activity, especially various β-lactamase-producing gram Development of β-lactams effective against negative bacteria is eagerly desired. In addition, there are few β-lactams that are widely effective against class A, B, C, and D-type β-lactamase-producing gram-negative bacteria, and development is eagerly desired.
Patent Documents 2 to 4 report β-lactam compounds having a novel skeleton, but do not describe antibacterial activity against the above-mentioned carbapenem-resistant bacteria and the like that have been problematic in recent years. Moreover, from the described antibacterial activity, it cannot be imagined at all that the compound group having this skeleton has an antibacterial activity in carbapenem-resistant bacteria. Furthermore, these patent documents do not describe or suggest a combination of a β-lactam compound having a novel skeleton with other drugs or the combined use effect.
国際公開第２００７／１１９５１１号International Publication No. 2007/119511 欧州特許出願公開０２５３３３７号European Patent Application Publication No. 0253337 欧州特許出願公開０２４９９０９号European Patent Application Publication No. 0249909 特開平０１－２２６８８７号公報Japanese Patent Laid-Open No. 01-226887
　本発明は、グラム陰性菌および／またはグラム陽性菌を含む種々の細菌に対して、強力な抗菌スペクトルを示す５－オキソテトラヒドロフラン環、６－オキソテトラヒドロピラン環または２－オキソ－１，３－ジオキソラン環を含む三環性化合物を提供する。さらに、５－オキソテトラヒドロフラン環または６－オキソテトラヒドロピラン環を含む三環性化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を包含する、カルバペネム耐性菌に対して抗菌活性を有する医薬組成物を提供する。好ましくは、β－ラクタマーゼ産生グラム陰性菌に対し強い抗菌活性を示す化合物、またはその化合物を含有する医薬組成物を提供する。より好ましくは、カルバペネム耐性菌、多剤耐性菌、特にクラスＢ型メタロ－β－ラクタマーゼ（ＭＢＬ）産生グラム陰性菌に対し強い抗菌活性を示す化合物、またはその化合物を含有する医薬組成物を提供する。さらに好ましくは、基質特異性拡張型β－ラクタマーゼ（ＥＳＢＬ）産生菌に対しても効果的な抗菌活性を示す化合物、またはその化合物を含有する化合物を提供する。 The present invention relates to a 5-oxotetrahydrofuran ring, a 6-oxotetrahydropyran ring or a 2-oxo-1,3-dioxolane exhibiting a strong antibacterial spectrum against various bacteria including Gram negative bacteria and / or Gram positive bacteria. A tricyclic compound comprising a ring is provided. Furthermore, against carbapenem-resistant bacteria including tricyclic compounds containing a 5-oxotetrahydrofuran ring or a 6-oxotetrahydropyran ring, esters thereof or pharmaceutically acceptable salts thereof, or hydrates thereof. A pharmaceutical composition having antibacterial activity is provided. Preferably, a compound showing strong antibacterial activity against β-lactamase-producing gram-negative bacteria, or a pharmaceutical composition containing the compound is provided. More preferably, a compound exhibiting strong antibacterial activity against a carbapenem-resistant bacterium, a multidrug-resistant bacterium, particularly a class B metallo-β-lactamase (MBL) -producing gram-negative bacterium, or a pharmaceutical composition containing the compound is provided. . More preferably, a compound showing effective antibacterial activity also against a substrate-specific extended β-lactamase (ESBL) -producing bacterium or a compound containing the compound is provided.
　本発明は、少なくとも以下の構造的特徴を有することにより上記課題を解決した化合物またはカルバペネム耐性菌に対して抗菌作用を有する医薬組成物を提供する。
１）５－オキソテトラヒドロフラン環、６－オキソテトラヒドロピラン環または２－オキソ－１，３－ジオキソラン環を含む三環性母核を有する。
２）三環性母核内のラクタム環または環状カルボニルヒドラジドの環上にアミド置換基（置換基を有するカルボニルアミノ基）を有する。 The present invention provides a compound or a pharmaceutical composition having an antibacterial action against a carbapenem-resistant bacterium, which has at least the following structural characteristics to solve the above problems.
1) It has a tricyclic mother nucleus containing a 5-oxotetrahydrofuran ring, a 6-oxotetrahydropyran ring or a 2-oxo-1,3-dioxolane ring.
2) It has an amide substituent (a carbonylamino group having a substituent) on the lactam ring or cyclic carbonyl hydrazide ring in the tricyclic mother nucleus.
（項目１）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000028
（式中、
－Ｚ－は単結合または－ＣＲ７ＡＲ７Ｂ－であり；
Ｒ７ＡおよびＲ７Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、または置換もしくは非置換の芳香族複素環スルホニルであり；
ＹはＮまたはＣＨであり；
－Ｗ－は－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－であり；
－Ｔ－は－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－であり；
Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、または置換もしくは非置換の芳香族複素環スルホニルであり；
Ｒ１６はカルボキシ、シアノ、テトラゾリルまたは置換もしくは非置換のカルバモイルであり；
Ｒ１７は水素原子または置換もしくは非置換のアルキルであり；
Ｒ１は置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２ＡおよびＲ２Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、スルホ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
ｂ）Ｒ２ＡおよびＲ２Ｂが一緒になって、置換もしくは非置換のメチリデン、または置換もしくは非置換のヒドロキシイミノを形成し；
Ｒ３は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）である。
ただし、以下の化合物を除く。
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000033
で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 1) Formula (I):
Figure JPOXMLDOC01-appb-C000028
(Where
-Z- is a single bond or -CR 7A R 7B- ;
R 7A and R 7B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, Substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or non-substituted Substituted aromatic heterocyclic oxy, substituted if Or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted non-substituted Aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted Or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic An aromatic carbocyclic sulfonyl, or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
Y is N or CH;
-W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -;
-T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is;
R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynyl Rusulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or Unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted Substituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic Elementary ring oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy Substituted, unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted Aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic Heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or An unsubstituted aromatic carbocyclic sulfonyl, or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
R 16 is carboxy, cyano, tetrazolyl or substituted or unsubstituted carbamoyl;
R 17 is a hydrogen atom or substituted or unsubstituted alkyl;
R 1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
For R 2A and R 2B
a) R 2A and R 2B are each independently a hydrogen atom, substituted or unsubstituted amino, sulfo, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl , Hydroxy, or substituted carbonyloxy, or
b) R 2A and R 2B together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
R 3 is a hydrogen atom, —OCH 3 or —NH—CH (═O).
However, the following compounds are excluded.
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000033
Or an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１－１）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000034
（式中、
－Ｚ－は単結合または－ＣＲ７ＡＲ７Ｂ－であり；
Ｒ７ＡおよびＲ７Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、または置換もしくは非置換の芳香族複素環スルホニルであり；
ＹはＮまたはＣＨであり；
－Ｗ－は－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－であり；
－Ｔ－は－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－であり；
Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、または置換もしくは非置換の芳香族複素環スルホニルであり；
Ｒ１６はカルボキシ、シアノ、テトラゾリルまたは置換もしくは非置換のカルバモイルであり；
Ｒ１７は水素原子または置換もしくは非置換のアルキルであり；
Ｒ１は置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２ＡおよびＲ２Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、スルホ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
ｂ）Ｒ２ＡおよびＲ２Ｂが一緒になって、置換もしくは非置換のメチリデン、または置換もしくは非置換のヒドロキシイミノを形成し；
Ｒ３は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）である。
ただし、以下の化合物を除く。
Figure JPOXMLDOC01-appb-C000035
（式中、
Ｒ１１はアミノ、またはアシルで置換されたアミノであり；
Ｒ１２は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）であり；
Ｒ１３、Ｒ１４およびＲ１５はそれぞれ独立して水素原子または置換もしくは非置換のアルキルであり；
Ｕは－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である）。 (Item 1-1) Formula (I):
Figure JPOXMLDOC01-appb-C000034
(Where
-Z- is a single bond or -CR 7A R 7B- ;
R 7A and R 7B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, Substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or non-substituted Substituted aromatic heterocyclic oxy, substituted if Or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted non-substituted Aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted Or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic An aromatic carbocyclic sulfonyl, or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
Y is N or CH;
-W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -;
-T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is;
R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynyl Rusulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or Unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted Substituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic Elementary ring oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy Substituted, unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted Aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic Heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or An unsubstituted aromatic carbocyclic sulfonyl, or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
R 16 is carboxy, cyano, tetrazolyl or substituted or unsubstituted carbamoyl;
R 17 is a hydrogen atom or substituted or unsubstituted alkyl;
R 1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
For R 2A and R 2B
a) R 2A and R 2B are each independently a hydrogen atom, substituted or unsubstituted amino, sulfo, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl , Hydroxy, or substituted carbonyloxy, or
b) R 2A and R 2B together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
R 3 is a hydrogen atom, —OCH 3 or —NH—CH (═O).
However, the following compounds are excluded.
Figure JPOXMLDOC01-appb-C000035
(Where
R 11 is amino or amino substituted with acyl;
R 12 is a hydrogen atom, —OCH 3 or —NH—CH (═O);
R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl;
U is —S—, —S—CH 2 — or —CH 2 —S—).
（項目２）－Ｚ－が単結合であり、ＹがＣＨであり、－Ｗ－が－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である、項目１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 2) The compound according to item 1, its ester or those thereof, wherein —Z— is a single bond, Y is CH, and —W— is —S—CH 2 — or —CH 2 —S—. Or a hydrate thereof.
（項目３）－Ｚ－が単結合であり、Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアミノ、またはヒドロキシである、項目２記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 3) —Z— is a single bond, and R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted The compound according to Item 2, which is carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino, or hydroxy, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof .
（項目４）－Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり、ＹがＮであり、－Ｗ－が－ＣＨ２－であり、－Ｔ－が－ＣＲ４ＡＲ４Ｂ－である、項目１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 4) Item 1 wherein —Z— is —CR 7A R 7B —, Y is N, —W— is —CH 2 —, and —T— is —CR 4A R 4B —. Or its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目５）Ｒ１が置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基である、項目１～４のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 5) The compound according to any one of Items 1 to 4, R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, an ester thereof, or the like Or a hydrate thereof.
（項目６）Ｒ１が下式：
Figure JPOXMLDOC01-appb-C000036
（式中、ＸはＣＨ、ＣＣｌ、ＣＦ、ＣＢｒまたはＮである）
で示される基である、項目１～５のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 6) R 1 is the following formula:
Figure JPOXMLDOC01-appb-C000036
(Wherein X is CH, CCl, CF, CBr or N)
6. The compound according to any one of items 1 to 5, which is a group represented by the following formula, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目７）Ｒ１が下式：
Figure JPOXMLDOC01-appb-C000037
（式中、ＸはＣＣｌ、ＣＦまたはＣＢｒである）
で示される基である、項目１～５のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 7) R 1 is the following formula:
Figure JPOXMLDOC01-appb-C000037
(Wherein X is CCl, CF or CBr)
6. The compound according to any one of items 1 to 5, which is a group represented by the following formula, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目８）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000038
または以下に示す置換もしくは非置換のヒドロキシイミノ：
Figure JPOXMLDOC01-appb-C000039
（式中、Ｒ１０は水素原子または置換もしくは非置換のアルキルであり、式中、Ｒ８およびＲ９はそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換の炭素環式基、もしくは置換もしくは非置換の複素環式基であるか、Ｒ８およびＲ９が一緒になって置換もしくは非置換のメチリデンを形成するか、またはＲ８およびＲ９は隣接原子と一緒になって置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成していてもよく；Ｑは単結合、置換もしくは非置換の炭素環ジイルまたは置換もしくは非置換の複素環ジイルであり；ｍは０～３の整数である）
である、項目１～７のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 8) R 2A and R 2B taken together have a methylidene having a substituent shown below:
Figure JPOXMLDOC01-appb-C000038
Or substituted or unsubstituted hydroxyimino:
Figure JPOXMLDOC01-appb-C000039
(Wherein R 10 is a hydrogen atom or substituted or unsubstituted alkyl, and in the formula, R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted Or an unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R 8 and R 9 taken together to form a substituted or unsubstituted methylidene, or R 8 and R 9 May be taken together with adjacent atoms to form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle; Q is a single bond, substituted or unsubstituted carbocyclic diyl Or substituted or unsubstituted heterocyclic diyl; m is an integer from 0 to 3)
The compound according to any one of items 1 to 7, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目９）Ｒ２ＡおよびＲ２Ｂが一緒になって下式：
Figure JPOXMLDOC01-appb-C000040
（式中、各記号は上記と同意義である。）
で示される基である、項目１～７のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 9) R 2A and R 2B together form the following formula:
Figure JPOXMLDOC01-appb-C000040
(In the formula, each symbol is as defined above.)
8. The compound according to any one of items 1 to 7, which is a group represented by the following: an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１０）Ｒ３が水素原子または－ＯＣＨ３である、項目１～９のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 10) The compound according to any of items 1 to 9, wherein R 3 is a hydrogen atom or —OCH 3 , an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１１）Ｒ１６がカルボキシである、項目１～１０のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 11) The compound according to any one of Items 1 to 10, wherein R 16 is carboxy, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１２）Ｒ１７が水素原子であり、項目１～１１のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 12) The compound according to any one of Items 1 to 11, wherein R 17 is a hydrogen atom, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１３）Ｔが－ＣＲ４ＡＲ４Ｂ－である、項目１～１２のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 13) The compound according to any one of Items 1 to 12, wherein T is —CR 4A R 4B —, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１４）－Ｚ－が単結合であり；
ＹがＣＨであり；
－Ｗ－が－Ｓ－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－または－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、アセチルオキシ、カルバモイルオキシ、メチル、またはアミノであり；
Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂが水素原子であり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-C000041
（式中、各定義は項目６と同意義である）
であり；
Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000042
または下式：
Figure JPOXMLDOC01-appb-C000043
（式中、各定義は項目８と同意義である）
であり；
Ｒ３が水素原子または－ＯＣＨ３であり、Ｒ１６がカルボキシであり、Ｒ１７が水素原子である、項目１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 14) -Z- is a single bond;
Y is CH;
-W- is -S-CH 2- ;
-T- is -CR 4A R 4B - or -CR 5A R 5B -CR 6A R 6B - a and;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, acetyloxy, carbamoyloxy, methyl, or amino;
R 5A , R 5B , CR 6A and R 6B are hydrogen atoms;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-C000041
(In the formula, each definition has the same meaning as item 6)
Is;
R 2A and R 2B taken together have a methylidene having the substituents shown below:
Figure JPOXMLDOC01-appb-C000042
Or the following formula:
Figure JPOXMLDOC01-appb-C000043
(In the formula, each definition has the same meaning as item 8)
Is;
R 3 is a hydrogen atom or —OCH 3 , R 16 is carboxy, and R 17 is a hydrogen atom, a compound thereof, an ester thereof, a pharmaceutically acceptable salt thereof, or a water thereof Japanese products.
（項目１５）－Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり；
ＹがＮであり；
－Ｗ－が－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルキル、または置換もしくは非置換のアミノであり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-C000044
（式中、各定義は項目６と同意義である）
で示される基であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２Ａが、水素原子、置換もしくは非置換のアミノ、スルホ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであり、およびＲ２Ｂが水素原子であり、
ｂ－１）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000045
または、
ｂ－２）下式：
Figure JPOXMLDOC01-appb-C000046
（式中、各定義は上記と同意義である）
であり；
Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６はカルボキシ、テトラゾリルまたはカルバモイルであり；かつ、Ｒ１７が水素原子またはアルキルである、項目１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 15) -Z- is -CR 7A R 7B - a and;
Y is N;
-W- is -CH 2- ;
-T- is -CR 4A R 4B - a and;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-C000044
(In the formula, each definition has the same meaning as item 6)
A group represented by:
For R 2A and R 2B
a) R 2A is a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or carbonyloxy having a substituent And R 2B is a hydrogen atom,
b-1) R 2A and R 2B taken together have a methylidene having the following substituents:
Figure JPOXMLDOC01-appb-C000045
Or
b-2) The following formula:
Figure JPOXMLDOC01-appb-C000046
(Wherein each definition has the same meaning as above)
Is;
R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy, tetrazolyl or carbamoyl; and R 17 is a hydrogen atom or alkyl, a compound thereof, an ester thereof, or a pharmaceutically acceptable salt thereof Salts or hydrates thereof.
（項目１６）化合物Ｉ－００２，　Ｉ－００３，　Ｉ－０１１，　Ｉ－０１７，　Ｉ－０１８，　Ｉ－０１９，　Ｉ－０２９，　Ｉ－０３１，　Ｉ－０３９，　Ｉ－０５３，　Ｉ－０５５，　Ｉ－０６３，　Ｉ－０７０，　Ｉ－０７２，　Ｉ－０７５,　Ｉ－０７６,　Ｉ－０７７,　およびＩ－０８６の項目１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 16) Compound I-002, I-003, I-011, I-017, I-018, I-019, I-029, I-031, I-039, I-053, I-055, I -063, I-070, I-072, I-075, I-076, I-077, I-086, I-086, the compound according to item 1, its ester or pharmaceutically acceptable salt thereof, or their Hydrate.
（項目１７）項目１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する医薬組成物。 (Item 17) A pharmaceutical composition comprising the compound according to any one of items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１８）抗菌作用を有する、項目１７記載の医薬組成物。 (Item 18) The pharmaceutical composition according to item 17, which has an antibacterial action.
（項目１９）項目１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を投与することを特徴とする、菌感染に関連する疾患の治療またはその予防法。 (Item 19) A disease associated with bacterial infection, which comprises administering the compound according to any one of items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Treatment or prevention.
（項目２０）菌感染に関連する疾患を治療または予防するための、項目１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 20) The compound according to any one of items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof for treating or preventing a disease associated with bacterial infection.
（項目２１）（Ａ－１）項目１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物と、（Ｂ－１）β－ラクタマーゼ阻害作用を有する化合物、その製薬上許容される塩、またはそれらの溶媒和物を組み合わせることを特徴とする医薬。 (Item 21) (A-1) The compound according to any one of Items 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (B-1) β-lactamase A pharmaceutical comprising a compound having an inhibitory action, a pharmaceutically acceptable salt thereof, or a solvate thereof.
（項目２２）式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000047
（式中、
Ｒ１１はアミノ、またはアシルで置換されたアミノであり；
Ｒ１２は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）であり；
Ｒ１３、Ｒ１４およびＲ１５はそれぞれ独立して水素原子または置換もしくは非置換のアルキルであり；
Ｕは－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である）
で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。 (Item 22) Formula (II):
Figure JPOXMLDOC01-appb-C000047
(Where
R 11 is amino or amino substituted with acyl;
R 12 is a hydrogen atom, —OCH 3 or —NH—CH (═O);
R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl;
U is —S—, —S—CH 2 — or —CH 2 —S—)
A pharmaceutical composition having an antibacterial action against carbapenem-resistant bacteria, comprising a compound represented by the formula:
（項目２３）Ｒ１１が下式：
Figure JPOXMLDOC01-appb-C000048
（式中、Ｒ１’は置換もしくは非置換の複素環式基であり；
Ｒ２’ＡおよびＲ２’Ｂについては、
ａ）Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、ＳＯ３Ｈ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
ｂ）Ｒ２’ＡおよびＲ２’Ｂが一緒になって、置換もしくは非置換のヒドロキシイミノを形成してもよい）
で示される基であり；
Ｒ１３は水素原子であり；
Ｒ１４およびＲ１５はそれぞれ独立して水素原子またはメチルである、項目２２記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。 (Item 23) R 11 is the following formula:
Figure JPOXMLDOC01-appb-C000048
Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
For R 2′A and R 2′B ,
a) R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or
b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
A group represented by:
R 13 is a hydrogen atom;
R 14 and R 15 are each independently a hydrogen atom or methyl, and a carbapenem-resistant bacterium containing the compound according to item 22, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof A pharmaceutical composition having an antibacterial action.
（項目２４）Ｒ１’が下式：
Figure JPOXMLDOC01-appb-C000049
（式中、Ｘ’はＣＨまたはＮである）
で示される基であり、
Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して水素原子、または下式：
Figure JPOXMLDOC01-appb-C000050
で示される基であるか、またはＲ２‘ＡおよびＲ２’Ｂが一緒になって下式：
Figure JPOXMLDOC01-appb-C000051
（式中、Ｒ１０’は水素原子またはアルキルであり、Ｒ８’およびＲ９’はそれぞれ独立して水素原子またはアルキルである）
で示される基であり、Ｒ１２が水素原子またはメトキシである、項目２２または２３記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。 (Item 24) R 1 ′ is the following formula:
Figure JPOXMLDOC01-appb-C000049
(Where X ′ is CH or N)
A group represented by
R 2′A and R 2′B each independently represent a hydrogen atom, or the following formula:
Figure JPOXMLDOC01-appb-C000050
Or R 2′A and R 2′B together are represented by the following formula:
Figure JPOXMLDOC01-appb-C000051
Wherein R 10 ′ is a hydrogen atom or alkyl, and R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl.
24. A carbapenem-resistant compound comprising the compound of item 22 or 23, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 12 is a hydrogen atom or methoxy: A pharmaceutical composition having an antibacterial action against bacteria.
（項目２５）（Ａ－２）式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000052
（式中、
Ｒ１１はアミノ、またはアシルで置換されたアミノであり；
Ｒ１２は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）であり；
Ｒ１３、Ｒ１４およびＲ１５はそれぞれ独立して水素原子または置換もしくは非置換のアルキルであり；
Ｕは－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である）
で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物と（Ｂ－１）β－ラクタマーゼ阻害作用を有する化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの溶媒和物を組み合わせることを特徴とする医薬。 (Item 25) (A-2) Formula (II):
Figure JPOXMLDOC01-appb-C000052
(Where
R 11 is amino or amino substituted with acyl;
R 12 is a hydrogen atom, —OCH 3 or —NH—CH (═O);
R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl;
U is —S—, —S—CH 2 — or —CH 2 —S—)
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a compound having an inhibitory action on (B-1) β-lactamase, an ester thereof or a pharmaceutically acceptable salt thereof. A pharmaceutical comprising a combination of a salt or a solvate thereof.
（項目２６）（Ａ－２）のＲ１１が下式：
Figure JPOXMLDOC01-appb-C000053

（式中、Ｒ１’は置換もしくは非置換の複素環式基であり；
Ｒ２’ＡおよびＲ２’Ｂについては、
ａ）Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、ＳＯ３Ｈ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
ｂ）Ｒ２’ＡおよびＲ２’Ｂが一緒になって、置換もしくは非置換のヒドロキシイミノを形成してもよい）
で示される基であり；
Ｒ１３は水素原子であり；
Ｒ１４およびＲ１５はそれぞれ独立して水素原子またはメチルである化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物である、項目２５記載の医薬。 (Item 26) R 11 in (A-2) is the following formula:
Figure JPOXMLDOC01-appb-C000053

Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
For R 2′A and R 2′B ,
a) R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or
b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
A group represented by:
R 13 is a hydrogen atom;
26. The medicament according to item 25, wherein R 14 and R 15 are each independently a hydrogen atom or methyl, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目２７）（Ａ－２）のＲ１’が下式：
Figure JPOXMLDOC01-appb-C000054

（式中、Ｘ’はＣＨまたはＮである）
で示される基であり、
Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して水素原子、または下式：
Figure JPOXMLDOC01-appb-C000055
で示される基であるか、またはＲ２’ＡおよびＲ２’Ｂが一緒になって下式：
Figure JPOXMLDOC01-appb-C000056

（式中、Ｒ１０’は水素原子またはアルキルであり、Ｒ８’およびＲ９’はそれぞれ独立して水素原子またはアルキルである）
で示される基であり、Ｒ１２が水素原子またはメトキシである化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物である、項目２６記載の医薬。 (Item 27) R 1 ′ in (A-2) is the following formula:
Figure JPOXMLDOC01-appb-C000054

(Where X ′ is CH or N)
A group represented by
R 2′A and R 2′B each independently represent a hydrogen atom, or the following formula:
Figure JPOXMLDOC01-appb-C000055
Or R 2′A and R 2′B together are represented by the following formula:
Figure JPOXMLDOC01-appb-C000056

Wherein R 10 ′ is a hydrogen atom or alkyl, and R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl.
27. The medicament according to item 26, which is a compound represented by the formula: wherein R 12 is a hydrogen atom or methoxy, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１Ａ）
式（ＩＡ）：
Figure JPOXMLDOC01-appb-C000057
（式中、
－Ｚ－は単結合または－ＣＲ７ＡＲ７Ｂ－であり；
Ｒ７ＡおよびＲ７Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のアルキルスルファニル、置換若しくは非置換のアルケニルスルファニル、置換若しくは非置換のアルキニルスルファニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換若しくは非置換の非芳香族炭素環スルファニル、置換若しくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換の非芳香族炭素環スルホニル、置換若しくは非置換の非芳香族複素環スルホニル、置換若しくは非置換の芳香族炭素環スルファニル、置換若しくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換若しくは非置換の芳香族炭素環スルホニル、または置換若しくは非置換の芳香族複素環スルホニルであり；
ＹはＮまたはＣＨであり；
－Ｗ－は－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－であり；
－Ｔ－は－ＣＲ４ＡＲ４Ｂ－または－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－であり；
Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のアルキルスルファニル、置換若しくは非置換のアルケニルスルファニル、置換若しくは非置換のアルキニルスルファニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換若しくは非置換の非芳香族炭素環スルファニル、置換若しくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換の非芳香族炭素環スルホニル、置換若しくは非置換の非芳香族複素環スルホニル、置換若しくは非置換の芳香族炭素環スルファニル、置換若しくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換若しくは非置換の芳香族炭素環スルホニル、または置換若しくは非置換の芳香族複素環スルホニルであり；
Ｒ１は置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２ＡおよびＲ２Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、スルホ、置換もしくは非置換のスルファモイル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
ｂ）Ｒ２ＡおよびＲ２Ｂが一緒になって、置換もしくは非置換のメチリデン、または置換もしくは非置換のヒドロキシイミノを形成し；
Ｒ３は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）である。
ただし、以下の化合物（Ａ－１）～（Ａ－２８）を除く。
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000059
 で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 1A)
Formula (IA):
Figure JPOXMLDOC01-appb-C000057
(Where
-Z- is a single bond or -CR 7A R 7B- ;
R 7A and R 7B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, Substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or non-substituted Substituted aromatic heterocyclic oxy, substituted if Or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted non-substituted Aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted Or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic An aromatic carbocyclic sulfonyl, or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
Y is N or CH;
-W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -;
-T- is -CR 4A R 4B - or -CR 5A R 5B -CR 6A R 6B - a and;
R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkynyl Ruoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted Alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted fragrance Aromatic carbocyclic oxy, substituted or young Unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic Aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic Heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic hetero Ring sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted Substituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic Ring sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, or substituted or unsubstituted aromatic heterocyclic sulfonyl;
R 1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
For R 2A and R 2B
a) R 2A and R 2B are each independently a hydrogen atom, substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, Hydroxy, or substituted carbonyloxy, or
b) R 2A and R 2B together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
R 3 is a hydrogen atom, —OCH 3 or —NH—CH (═O).
However, the following compounds (A-1) to (A-28) are excluded.
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000059
 Or an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目２Ａ）
ＹがＣＨであり、－Ｗ－が－Ｓ－ＣＨ２－である、項目１Ａ記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 2A)
The compound according to item 1A, its ester or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein Y is CH and —W— is —S—CH 2 —.
（項目３Ａ）
－Ｚ－は単結合であり、Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂはそれぞれ独立して、水素原子、置換もしくは非置換のアルキル、またはヒドロキシである、項目２Ａ記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 3A)
-Z- is a single bond, and R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, substituted or unsubstituted alkyl, or hydroxy Or its ester form or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目４Ａ）
－Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり、ＹがＮであり、－Ｗ－が－ＣＨ２－であり、－Ｔ－が－ＣＲ４ＡＲ４Ｂ－である、項目１Ａ記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 4A)
The compound according to item 1A, wherein —Z— is —CR 7A R 7B —, Y is N, —W— is —CH 2 —, and —T— is —CR 4A R 4B —, An ester or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目５Ａ）
Ｒ１が置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基である、項目１Ａ～４Ａのいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 5A)
R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, the compound according to any one of items 1A to 4A, an ester thereof, or a pharmaceutically acceptable salt thereof Salts, or hydrates thereof.
（項目６Ａ）
Ｒ１が下式：
Figure JPOXMLDOC01-appb-C000060
（式中、ＸはＣＨ、ＣＣｌ、ＣＦ、ＣＢｒまたはＮである）
で示される基である、項目１Ａ～５Ａのいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 6A)
R 1 is the following formula:
Figure JPOXMLDOC01-appb-C000060
(Wherein X is CH, CCl, CF, CBr or N)
The compound according to any one of items 1A to 5A, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a group represented by the formula:
（項目７Ａ）
Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000061
または以下に示す置換もしくは非置換のヒドロキシイミノ：
Figure JPOXMLDOC01-appb-C000062
（式中、Ｒ１０は水素原子または置換もしくは非置換のアルキルである）
である、項目１Ａ～６Ａのいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 7A)
R 2A and R 2B taken together have a methylidene having the substituents shown below:
Figure JPOXMLDOC01-appb-C000061
Or substituted or unsubstituted hydroxyimino:
Figure JPOXMLDOC01-appb-C000062
(Wherein R 10 is a hydrogen atom or substituted or unsubstituted alkyl)
The compound according to any one of items 1A to 6A, an ester form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目８Ａ）
Ｒ２ＡおよびＲ２Ｂが一緒になって下式：
Figure JPOXMLDOC01-appb-C000063
（式中、Ｒ８およびＲ９はそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換の炭素環式基、もしくは置換もしくは非置換の複素環式基であるか、Ｒ８およびＲ９が一緒になって置換もしくは非置換のメチリデンを形成するか、またはＲ８およびＲ９は隣接原子と一緒になって置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成していてもよく；Ｑは単結合、置換もしくは非置換の炭素環ジイルまたは置換もしくは非置換の複素環ジイルであり；ｍは０～３の整数である）
で示される基である、項目１Ａ～６Ａのいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 8A)
R 2A and R 2B together form the following formula:
Figure JPOXMLDOC01-appb-C000063
Wherein R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic A group, R 8 and R 9 together form a substituted or unsubstituted methylidene, or R 8 and R 9 together with an adjacent atom are substituted or unsubstituted non-aromatic carbocycle Or may form a substituted or unsubstituted non-aromatic heterocyclic ring; Q is a single bond, substituted or unsubstituted carbocyclic diyl or substituted or unsubstituted heterocyclic diyl; m is 0-3 Is an integer)
The compound according to any one of items 1A to 6A, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a group represented by the formula:
（項目９Ａ）
Ｒ３が水素原子または－ＯＣＨ３である、項目１Ａ～８Ａのいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 9A)
The compound according to any one of Items 1A to 8A, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 3 is a hydrogen atom or —OCH 3 .
（項目１０Ａ）
－Ｚ－が単結合であり；
ＹがＣＨであり；
－Ｗ－が－Ｓ－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－または－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子またはヒドロキシであり；
Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂが水素原子であり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000064

（式中、各定義は項目６と同意義である）
であり；
Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000065
または下式：
Figure JPOXMLDOC01-appb-C000066
（式中、各定義は項目８と同意義である）
であり；
Ｒ３が水素原子またはＯＣＨ３である、項目１Ａ記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 10A)
-Z- is a single bond;
Y is CH;
-W- is -S-CH 2- ;
-T- is -CR 4A R 4B - or -CR 5A R 5B -CR 6A R 6B - a and;
R 4A and R 4B are each independently a hydrogen atom or hydroxy;
R 5A , R 5B , CR 6A and R 6B are hydrogen atoms;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000064

(In the formula, each definition has the same meaning as item 6)
Is;
R 2A and R 2B taken together have a methylidene having the substituents shown below:
Figure JPOXMLDOC01-appb-C000065
Or the following formula:
Figure JPOXMLDOC01-appb-C000066
(In the formula, each definition has the same meaning as item 8)
Is;
The compound according to Item 1A, wherein R 3 is a hydrogen atom or OCH 3 , an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１１Ａ）
－Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり；
ＹがＮであり；
－Ｗ－が－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子またはヒドロキシであり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000067

（式中、各定義は項目６と同意義である）
で示される基であり；
Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000068
または下式：
Figure JPOXMLDOC01-appb-C000069
（式中、各定義は項目８と同意義である）
で示される基であり；
Ｒ３が水素原子である、項目１Ａ記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。 (Item 11A)
-Z- is -CR 7A R 7B - a and;
Y is N;
-W- is -CH 2- ;
-T- is -CR 4A R 4B - a and;
R 4A and R 4B are each independently a hydrogen atom or hydroxy;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000067

(In the formula, each definition has the same meaning as item 6)
A group represented by:
R 2A and R 2B taken together have a methylidene having the substituents shown below:
Figure JPOXMLDOC01-appb-C000068
Or the following formula:
Figure JPOXMLDOC01-appb-C000069
(In the formula, each definition has the same meaning as item 8)
A group represented by:
The compound according to item 1A, wherein R 3 is a hydrogen atom, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１２Ａ）
項目１Ａ～１１Ａのいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する医薬組成物。 (Item 12A)
A pharmaceutical composition comprising the compound according to any one of items 1A to 11A, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
（項目１３Ａ）
抗菌作用を有する、項目１２Ａ記載の医薬組成物。 (Item 13A)
The pharmaceutical composition according to item 12A, which has an antibacterial action.
（項目１４Ａ）
式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000070
（式中、
Ｒ１１はアミノ、またはアシルで置換されたアミノであり；
Ｒ１２は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）であり；
Ｒ１３、Ｒ１４およびＲ１５はそれぞれ独立して水素原子または置換もしくは非置換のアルキルであり；
Ｕは－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である）
で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を包含する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。 (Item 14A)
Formula (II):
Figure JPOXMLDOC01-appb-C000070
(Where
R 11 is amino or amino substituted with acyl;
R 12 is a hydrogen atom, —OCH 3 or —NH—CH (═O);
R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl;
U is —S—, —S—CH 2 — or —CH 2 —S—)
A pharmaceutical composition having an antibacterial action against carbapenem-resistant bacteria, including a compound represented by the formula:
（項目１５Ａ）
Ｒ１１が下式：
Figure JPOXMLDOC01-appb-C000071
（式中、Ｒ１は置換もしくは非置換の複素環式基であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２ＡおよびＲ２Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、ＳＯ３Ｈ、置換もしくは非置換のスルファモイル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
ｂ）Ｒ２ＡおよびＲ２Ｂが一緒になって、置換もしくは非置換のヒドロキシイミノを形成してもよい）
で示される基であり；
Ｒ１３は水素原子であり；
Ｒ１４およびＲ１５はそれぞれ独立して水素原子またはメチルである、項目１４Ａ記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を包含する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。 (Item 15A)
R 11 is the following formula:
Figure JPOXMLDOC01-appb-C000071
Wherein R 1 is a substituted or unsubstituted heterocyclic group;
For R 2A and R 2B
a) R 2A and R 2B are each independently a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Carbamoyl, hydroxy, or substituted carbonyloxy, or
b) R 2A and R 2B may be taken together to form a substituted or unsubstituted hydroxyimino)
A group represented by:
R 13 is a hydrogen atom;
R 14 and R 15 are each independently a hydrogen atom or methyl, and the compound according to item 14A, its ester or pharmaceutically acceptable salt thereof, or a carbapenem-resistant bacterium, including hydrates thereof, A pharmaceutical composition having an antibacterial action.
（項目１６Ａ）
Ｒ１が下式：
Figure JPOXMLDOC01-appb-C000072
（式中、ＸはＣＨ、ＣＣｌまたはＮである）
で示される基であり、
Ｒ２ＡおよびＲ２Ｂがそれぞれ独立して水素原子、または下式：
Figure JPOXMLDOC01-appb-C000073
で示される基であるか、またはＲ２ＡおよびＲ２Ｂが一緒になって下式：
Figure JPOXMLDOC01-appb-C000074
（式中、Ｒ１０は水素原子またはアルキルであり、Ｒ８およびＲ９はそれぞれ独立して水素原子またはアルキルである）
で示される基であり、Ｒ１２が水素原子またはメトキシである、項目１４Ａまたは１５Ａ記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を包含する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。 (Item 16A)
R 1 is the following formula:
Figure JPOXMLDOC01-appb-C000072
(Wherein X is CH, CCl or N)
A group represented by
R 2A and R 2B are each independently a hydrogen atom, or the following formula:
Figure JPOXMLDOC01-appb-C000073
Or R 2A and R 2B together are represented by the following formula:
Figure JPOXMLDOC01-appb-C000074
(Wherein R 10 is a hydrogen atom or alkyl, and R 8 and R 9 are each independently a hydrogen atom or alkyl)
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, including the compound of item 14A or 15A, wherein R 12 is a hydrogen atom or methoxy; A pharmaceutical composition having an antibacterial action against bacteria.
　本発明に係る化合物は、少なくとも以下のいずれかの特徴を有する点で医薬品として有用である。
Ａ）グラム陰性菌および／またはグラム陽性菌を含む種々の細菌に対して、強力な抗菌スペクトルを示す。
Ｂ）β－ラクタマーゼ産生グラム陰性菌に対し強い抗菌活性を示す。
Ｃ）多剤耐性菌、特にクラムＢ型のメタロ－β－ラクタマーゼ産生グラム陰性菌に対し強い抗菌活性を示す。
Ｄ）基質特異性拡張型β－ラクタマーゼ（ＥＳＢＬ）産生菌に対し強い抗菌活性を示す。
Ｅ）カルバペネム耐性菌に対し強い抗菌活性を示す。
Ｆ）市販薬に耐性のある腸内細菌科細菌に対し強い抗菌活性を示す。
Ｇ）Ｋｌｅｂｓｉｅｌｌａ ｐｎｅｕｍｏｎｉａｅ Ｃａｒｂａｐｅｎｅｍａｓｅ（ＫＰＣ）やＮｅｗ　Ｄｅｌｈｉ　ｍｅｔａｌｌｏ－ｂｅｔａ－ｌａｃｔａｍａｓｅ（ＮＤＭ）などのカルバペネマーゼを産生するカルバペネム耐性腸内細菌科細菌（ＣＲＥ）に対し強い抗菌活性を示す。
Ｈ）既存のセフェム薬および／またはカルバペネム薬と交叉耐性を示さない。
Ｉ）生体内への投与後に、発熱などの副作用を示さない。
Ｊ）化合物の安定性（例えば、各種液性における溶液安定性、光安定性等）および／または水に対する溶解性が高い。
Ｋ）血中濃度が高い、経口吸収性が高い、膜透過性が高い、効果持続時間が長い、または組織移行性が高い等の薬物動態面での優れた特徴を有する。
Ｌ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４等）に対する阻害作用が弱い。
Ｍ）代謝安定性が高い。
Ｎ）消化管障害（例えば、下痢、出血性腸炎、消化管潰瘍、消化管出血等）を起こさない。
Ｏ）腎毒性、肝毒性、心毒性（例えば、ＱＴｃ延長等）、痙攣等を起こさない。 The compound according to the present invention is useful as a pharmaceutical in that it has at least one of the following characteristics.
A) A strong antibacterial spectrum is shown against various bacteria including Gram negative bacteria and / or Gram positive bacteria.
B) Strong antibacterial activity against β-lactamase producing gram-negative bacteria.
C) Strong antibacterial activity against multidrug-resistant bacteria, especially crumb B-type metallo-β-lactamase-producing gram-negative bacteria.
D) Strong antibacterial activity against a substrate-specific extended β-lactamase (ESBL) -producing bacterium.
E) Strong antibacterial activity against carbapenem resistant bacteria.
F) Strong antibacterial activity against Enterobacteriaceae bacteria resistant to over-the-counter drugs.
G) Strong antibacterial activity against carbapenem-resistant Enterobacteriaceae (CRE) that produces carbapenemases such as Klebsiella pneumoniae Carbapenemase (KPC) and New Delhi metallo-beta-lactamase (NDM).
H) Does not show cross resistance with existing cephem and / or carbapenem drugs.
I) Does not show side effects such as fever after in vivo administration.
J) The stability of the compound (for example, solution stability and light stability in various liquid properties) and / or solubility in water is high.
K) It has excellent pharmacokinetic characteristics such as high blood concentration, high oral absorption, high membrane permeability, long duration of effect, and high tissue migration.
L) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
M) High metabolic stability.
N) Does not cause gastrointestinal disorders (eg, diarrhea, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
O) Does not cause nephrotoxicity, hepatotoxicity, cardiotoxicity (for example, QTc prolongation, etc.), convulsions or the like.
　以下、本発明に関して、発明の実施の形態を説明する。本明細書の全体にわたり、単数形の表現（例えば、英語の場合は「ａ」、「ａｎ」、「ｔｈｅ」など、他の言語における対応する冠詞、形容詞など）は特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。また、明細書において使用される用語は、特に言及しない限り、当該分野で通常用いられる意味で用いられることが理解されるべきである。したがって、他に定義されない限りは、本明細書中で使用されるすべての専門用語および化学技術用語は、本発明の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する場合、本明細書（定義を含めて）が優先する。以下に、本明細書において具体的に使用される用語について具体的な定義を記載する。
「からなる」という用語は、構成要件のみを有することを意味する。
「含む」という用語は、構成要件に限定されず、記載されていない要素を排除しないことを意味する。 Hereinafter, embodiments of the present invention will be described with respect to the present invention. Throughout this specification, expressions in the singular (eg, “a”, “an”, “the” in the case of English, corresponding articles, adjectives, etc. in other languages, etc.) It should be understood to include the concept of shape. In addition, it is to be understood that terms used in the specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and chemical technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. Hereinafter, specific definitions of terms specifically used in the present specification will be described.
The term “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.
　本明細書における各用語は、特に断りのない限り、単独または他の用語と組み合わされて以下の通り定義される。 Each term in this specification is defined as follows, alone or in combination with other terms, unless otherwise specified.
「ハロゲン」とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。好ましくは、フッ素原子または塩素原子である。 “Halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, they are a fluorine atom or a chlorine atom.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の炭素水素基を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－ヘプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デニル等が挙げられる。
　「アルキル」の好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチルが挙げられる。さらに好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 “Alkyl” includes a straight or branched carbon hydrogen group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, Examples include isooctyl, n-nonyl, n-denyl and the like.
Preferred embodiments of “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
「アルケニル」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖または分枝状の炭化水素基を包含する。例えば、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
「アルケニル」の好ましい態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。 “Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl and butenyl.
「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。さらに任意の位置に二重結合を有していてもよい。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等を包含する。
「アルキニル」の好ましい態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。 “Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
　「アルキレン」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の２価の炭化水素基を包含する。例えば、メチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、ペンタメチレン、ヘキサメチレン等が挙げられる。 “Alkylene” is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
　「アルケニレン」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の２価の炭化水素基を包含する。例えば、ビニレン、プロペニレン、ブテニレン、ペンテニレン等が挙げられる。 The term “alkenylene” refers to a carbon number of 2 to 15, preferably 2 to 10, more preferably 2 to 6 and even more preferably 2 to 4 having one or more double bonds at an arbitrary position. And a linear or branched divalent hydrocarbon group. For example, vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.
　「アルキニレン」とは、任意の位置に１以上の三重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の２価の炭化水素基を包含する。さらに任意の位置に二重結合を有していてもよい。例えば、エチニレン、プロピニレン、ブチニレン、ペンチニレン、ヘキシニレン等が挙げられる。 “Alkynylene” refers to carbon atoms of 2 to 15, preferably 2 to 10, more preferably 2 to 6, more preferably 2 to 4 carbon atoms having one or more triple bonds at any position. A linear or branched divalent hydrocarbon group is included. Furthermore, you may have a double bond in arbitrary positions. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.
「芳香族炭素環式基」とは、単環または２環以上の環状芳香族炭化水素基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。
「芳香族炭素環式基」の好ましい態様として、フェニルが挙げられる。 “Aromatic carbocyclic group” means a monocyclic or bicyclic or more cyclic aromatic hydrocarbon group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
「非芳香族炭素環式基」とは、単環または２環以上の、環状飽和炭化水素基または環状非芳香族不飽和炭化水素基を意味する。２環以上の「非芳香族炭素環式基」は、単環または２環以上の非芳香族炭素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
さらに、「非芳香族炭素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000075
単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは、炭素数３～１２、さらに好ましくは炭素数３～８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
２環以上の非芳香族炭素環式基としては、例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000075
The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, still more preferably 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
「芳香族炭素環」とは、上記「芳香族炭素環式基」から導かれる環を意味する。「非芳香族炭素環」とは、上記「非芳香族炭素環式基」から導かれる環を意味する。 The “aromatic carbocycle” means a ring derived from the above “aromatic carbocyclic group”. The “non-aromatic carbocycle” means a ring derived from the above “non-aromatic carbocyclic group”.
「シクロアルキル」とは、環状飽和炭化水素基を意味し、炭素数３～１６が好ましく、より好ましくは、炭素数３～１２、さらにこの好ましくは炭素数３～８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル等が挙げられる。
「シクロアルキル」の好ましい態様としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルが挙げられる。 “Cycloalkyl” means a cyclic saturated hydrocarbon group, preferably having 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 3 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like can be mentioned.
Preferable embodiments of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
「シクロアルカン」とは、上記「シクロアルキル」から導かれる環を意味する。 “Cycloalkane” means a ring derived from the above “cycloalkyl”.
「炭素環式基」とは、上記「芳香族炭素環式基」および「非芳香族炭素環式基」を包含する。「炭素環」とは、上記「炭素環式基」から導かれる環を意味する。「炭素環ジイル」とは、上記「炭素環式基」から導かれる二価の基を意味する。 The “carbocyclic group” includes the above “aromatic carbocyclic group” and “non-aromatic carbocyclic group”. “Carbocycle” means a ring derived from the above “carbocyclic group”. “Carbocyclic diyl” means a divalent group derived from the above “carbocyclic group”.
「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環式基を意味する。２環以上の芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
単環の芳香族複素環式基としては、５～８員が好ましく、より好ましくは５員または６員である。例えば、５員の単環の芳香族複素環式基としては、ピロリル、イミダゾリル、ピラゾリル、フリル、チエニル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル等が挙げられ、６員の単環の芳香族複素環式基としては、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル等が挙げられる。
２環の芳香族複素環式基としては、例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンズイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等が挙げられる。
３環以上の芳香族複素環式基としては、例えば、カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、ジベンゾフリル等が挙げられる。 “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do. The aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. For example, the 5-membered monocyclic aromatic heterocyclic group includes pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like, and includes a 6-membered monocyclic aromatic group. Examples of group heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl and the like.
Examples of the bicyclic aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
Examples of the aromatic heterocyclic group having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、環状非芳香族環式基を意味する。２環以上の非芳香族複素環式基は、単環または２環以上の非芳香族複素環式基に、上記「芳香族炭素環式基」、「非芳香族炭素環式基」、および／または「芳香族複素環式基」におけるそれぞれの環が縮合したものも包含する。
さらに、「非芳香族複素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000076
単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。例えば、ジオキサニル、チイラニル、オキシラニル、オキセタニル、オキサチオラニル、アゼチジニル、チアニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジニル、ピペラジニル、テトラヒドロピリジル、テトラヒドロフリル、テトラヒドロピラニル、ジヒドロチアゾリル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル、アゼパン－１－イル等が挙げられる。
２環以上の非芳香族複素環式基としては、例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル、オクタヒドロ－７Ｈ－ピラノ［２，３－ｃ］ピリジン－７－イル、ヘキサヒドロ－２Ｈ－ピラノ［３，２－ｃ］ピリジン－６（５Ｈ）－イル、７，８－ジヒドロピリド［４，３－ｄ］ピリミジン－６（５Ｈ）－イル等が挙げられる。 “Non-aromatic heterocyclic group” means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group. The non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000076
The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. For example, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyryl, Thiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl, aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thiynyl, thiazinyl Azepan-1-yl and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include, for example, indolinyl, isoindolinyl, chromanyl, isochromanyl, octahydro-7H-pyrano [2,3-c] pyridin-7-yl, hexahydro-2H-pyrano [3, 2-c] pyridin-6 (5H) -yl, 7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -yl and the like.
「芳香族複素環」とは、上記「芳香族複素環式基」から導かれる環を意味する。「非芳香族複素環」とは、上記「非芳香族複素環式基」から導かれる環を意味する。 “Aromatic heterocycle” means a ring derived from the above “aromatic heterocyclic group”. The “non-aromatic heterocyclic ring” means a ring derived from the above “non-aromatic heterocyclic group”.
「複素環式基」とは、上記「芳香族複素環式基」および「非芳香族複素環式基」を包含する。「複素環」とは、上記「複素環式基」から導かれる環を意味する。「複素環ジイル」とは、上記「複素環式基」から導かれる二価の基を意味する。 The “heterocyclic group” includes the above “aromatic heterocyclic group” and “non-aromatic heterocyclic group”. “Heterocycle” means a ring derived from the above “heterocyclic group”. “Heterocyclic diyl” means a divalent group derived from the above “heterocyclic group”.
「アシル」とは、ホルミルおよび置換基を有するカルボニルを意味する。
「置換基を有するカルボニル」とは、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル等が挙げられる。 “Acyl” means formyl and substituted carbonyl.
“Substituted carbonyl” means substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic Examples thereof include carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl and the like.
「アシルで置換されたアミノ」とは、「アミノ」の窒素原子に結合している１または２つの水素原子が、上記「アシル」に置き換わった基、すなわち、モノアシルアミノまたはジアシルアミノを意味する。好ましくは、モノアシルアミノである。「ジアシルアミノ」の２つの「アシル」は、同一でも異なっていても良い。該「アシル」の好ましい態様としては、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル等であり、より好ましくは置換もしくは非置換のアルキルカルボニルである。 “Acyl-substituted amino” means a group in which one or two hydrogen atoms bonded to the nitrogen atom of “amino” are replaced with the above “acyl”, that is, monoacylamino or diacylamino. . Preferably, it is monoacylamino. Two “acyl” of “diacylamino” may be the same or different. Preferred examples of the “acyl” include substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, etc., more preferably substituted or unsubstituted. Of alkylcarbonyl.
「アルキルカルボニル」とは、上記「アルキル」がカルボニル基に結合した基を意味する。例えば、メチルカルボニル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ｔｅｒｔ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ペンチルカルボニル、イソペンチルカルボニル、へキシルカルボニル等が挙げられる。
　「アルキルカルボニル」の好ましい態様として、メチルカルボニル、エチルカルボニル、ｎ－プロピルカルボニルが挙げられる。 “Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
　「アルケニルカルボニル」とは、上記「アルケニル」がカルボニル基に結合した基を意味する。例えば、エチレニルカルボニル、プロペニルカルボニル等が挙げられる。 “Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
　「アルキニルカルボニル」とは、上記「アルキニル」がカルボニル基に結合した基を意味する。例えば、エチニルカルボニル、プロピニルカルボニル等が挙げられる。 “Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
「ヒドロキシアルキル」とは、１以上のヒドロキシ基が、上記「アルキル」の炭素原子に結合している水素原子と置き換わった基を意味する。例えば、ヒドロキシメチル、１－ヒドロキシエチル、２－ヒドロキシエチル、１－ヒドロキシプロピル、２－ヒドロキシプロピル、１，２－ヒドロキシエチル等が挙げられる。
「ヒドロキシアルキル」の好ましい態様として、ヒドロキシメチルが挙げられる。 “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
「アルキルオキシ」とは、上記「アルキル」が酸素原子に結合した基を意味する。例えば、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｎ－ブチルオキシ、ｔｅｒｔ－ブチルオキシ、イソブチルオキシ、ｓｅｃ－ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、ヘキシルオキシ等が挙げられる。
「アルキルオキシ」の好ましい態様として、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ヘキシルオキシ等が挙げられる。 “Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, hexyloxy and the like.
「アルケニルオキシ」とは、上記「アルケニル」が酸素原子に結合した基を意味する。例えば、ビニルオキシ、アリルオキシ、１－プロペニルオキシ、２－ブテニルオキシ、２－ペンテニルオキシ、２－ヘキセニルオキシ、２－ヘプテニルオキシ、２－オクテニルオキシ等が挙げられる。 “Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
「アルキニルオキシ」とは、上記「アルキニル」が酸素原子に結合した基を意味する。例えば、エチニルオキシ、１－プロピニルオキシ、２－プロピニルオキシ、２－ブチニルオキシ、２－ペンチニルオキシ、２－ヘキシニルオキシ、２－ヘプチニルオキシ、２－オクチニルオキシ等が挙げられる。 “Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
「ハロアルキル」とは、１以上の上記「ハロゲン」が上記「アルキル」に結合した基を意味する。例えば、モノフルオロメチル、モノフルオロエチル、モノフルオロプロピル、２，２，３，３，３－ペンタフルオロプロピル、モノクロロメチル、トリフルオロメチル、トリクロロメチル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチル、１，２－ジブロモエチル、１，１，１－トリフルオロプロパン－２－イル等が挙げられる。
「ハロアルキル」の好ましい態様として、トリフルオロメチル、トリクロロメチルが挙げられる。 “Haloalkyl” means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
「ハロアルキルオキシ」とは、上記「ハロアルキル」が酸素原子に結合した基を意味する。例えば、モノフルオロメトキシ、モノフルオロエトキシ、トリフルオロメトキシ、トリクロロメトキシ、トリフルオロエトキシ、トリクロロエトキシ等が挙げられる。
「ハロアルキルオキシ」の好ましい態様として、トリフルオロメトキシ、トリクロロメトキシ等が挙げられる。 “Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
Preferable embodiments of “haloalkyloxy” include trifluoromethoxy, trichloromethoxy and the like.
「アシルオキシ」とは、ホルミルオキシおよび置換基を有するカルボニルオキシを意味する。「置換基を有するカルボニルオキシ」とは、上記「置換基を有するカルボニル」が酸素原子に結合した基を意味する。例えば、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ等が挙げられる。 “Acyloxy” means formyloxy and carbonyloxy having a substituent. “Carbonyloxy having a substituent” means a group in which the above “carbonyl having a substituent” is bonded to an oxygen atom. For example, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted nonaromatic carbon Ring carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy and the like.
「アルキルカルボニルオキシ」とは、上記「アルキルカルボニル」が酸素原子に結合した基を意味する。例えば、メチルカルボニルオキシ、エチルカルボニルオキシ、プロピルカルボニルオキシ、イソプロピルカルボニルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ、イソブチルカルボニルオキシ、ｓｅｃ－ブチルカルボニルオキシ等が挙げられる。
「アルキルカルボニルオキシ」の好ましい態様としては、メチルカルボニルオキシ、エチルカルボニルオキシが挙げられる。 “Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. For example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
「アルケニルカルボニルオキシ」とは、上記「アルケニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチレニルカルボニルオキシ、プロペニルカルボニルオキシ等が挙げられる。 “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
「アルキニルカルボニルオキシ」とは、上記「アルキニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチニルカルボニルオキシ、プロピニルカルボニルオキシ等が挙げられる。 “Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
「アルキルオキシアルキル」とは、上記「アルキルオキシ」が上記「アルキル」に結合した基を意味する。例えば、メトキシメチル、メトキシエチル、エトキシメチル等が挙げられる。 “Alkyloxyalkyl” means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
「アルキルオキシアルキルオキシ」とは、上記「アルキルオキシ」が上記「アルキルオキシ」に結合した基を意味する。例えば、メトキシメトキシ、メトキシエトキシ、エトキシメトキシ、エトキシエトキシ等が挙げられる。 “Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
　「アルキルスルホニル」とは、上記「アルキル」がスルホニル基に結合した基を意味する。例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ｔｅｒｔ－ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル等が挙げられる。
「アルキルスルホニル」の好ましい態様として、メチルスルホニル、エチルスルホニル等が挙げられる。 “Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
Preferable embodiments of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like.
「アルケニルスルホニル」とは、上記「アルケニル」がスルホニル基に結合した基を意味する。例えば、エチレニルスルホニル、プロペニルスルホニル等が挙げられる。 “Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
　「アルキニルスルホニル」とは、上記「アルキニル」がスルホニル基に結合した基を意味する。例えば、エチニルスルホニル、プロピニルスルホニル等が挙げられる。 “Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
　「アルキルイミノ」とは、上記「アルキル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルイミノ、エチルイミノ、ｎ－プロピルイミノ、イソプロピルイミノ等が挙げられる。 “Alkylimino” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
　「アルケニルイミノ」とは、上記「アルケニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルイミノ、プロペニルイミノ等が挙げられる。 “Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
　「アルキニルイミノ」とは、上記「アルキニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルイミノ、プロピニルイミノ等が挙げられる。 “Alkynylimino” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.
　「アルキルカルボニルイミノ」とは、上記「アルキルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えばメチルカルボニルイミノ、エチルカルボニルイミノ、ｎ－プロピルカルボニルイミノ、イソプロピルカルボニルイミノ等が挙げられる。 “Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
　「アルケニルカルボニルイミノ」とは、上記「アルケニルカルボニル」がイミノ基の窒素原子と結合している水素原子を置き換わった基を意味する。例えば、エチレニルカルボニルイミノ、プロペニルカルボニルイミノ等が挙げられる。 “Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” replaces the hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
「アルキニルカルボニルイミノ」とは、上記「アルキニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルカルボニルイミノ、プロピニルカルボニルイミノ等が挙げられる。 “Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
「アルキルオキシイミノ」とは、上記「アルキルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルオキシイミノ、エチルオキシイミノ、ｎ－プロピルオキシイミノ、イソプロピルオキシイミノ等が挙げられる。 “Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
「アルケニルオキシイミノ」とは、上記「アルケニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルオキシイミノ、プロペニルオキシイミノ等が挙げられる。 “Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
「アルキニルオキシイミノ」とは、上記「アルキニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルオキシイミノ、プロピニルオキシイミノ等が挙げられる。 “Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.
「アルキルオキシカルボニル」とは、上記「アルキルオキシ」がカルボニル基に結合した基を意味する。例えば、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｔｅｒｔ－ブチルオキシカルボニル、イソブチルオキシカルボニル、ｓｅｃ－ブチルオキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、ヘキシルオキシカルボニル等が挙げられる。
「アルキルオキシカルボニル」の好ましい態様としては、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニルが挙げられる。 “Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl and the like. .
Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
「アルケニルオキシカルボニル」とは、上記「アルケニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチレニルオキシカルボニル、プロペニルオキシカルボニル等が挙げられる。 “Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
「アルキニルオキシカルボニル」とは、上記「アルキニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチニルオキシカルボニル、プロピニルオキシカルボニル等が挙げられる。 “Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
「アルキルスルファニル」とは、上記「アルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル等が挙げられる。「アルキルスルファニル」の好ましい態様として、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル、ヘキシルスルファニル等が挙げられる。 “Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned. Preferable embodiments of “alkylsulfanyl” include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, hexylsulfanyl and the like.
「アルケニルスルファニル」とは、上記「アルケニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルスルファニル、プロペニルスルファニル等が挙げられる。 “Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
「アルキニルスルファニル」とは、上記「アルキニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルスルファニル、プロピニルスルファニル等が挙げられる。 “Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
「ハロアルキルスルファニル」とは、上記「ハロアルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、モノフルオロメチルスルファニル、モノフルオロエチルスルファニル、トリフルオロメチルスルファニル、トリクロロメチルスルファニル、トリフルオロエチルスルファニル、トリクロロエチルスルファニル等が挙げられる。
「ハロアルキルスルファニル」の好ましい態様として、トリフルオロメチルスルファニル、トリクロロメチルスルファニル等が挙げられる。 “Haloalkylsulfanyl” means a group in which the above “haloalkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like can be mentioned.
Preferable embodiments of “haloalkylsulfanyl” include trifluoromethylsulfanyl, trichloromethylsulfanyl and the like.
「アルキルスルフィニル」とは、上記「アルキル」がスルフィニル気に結合した基を意味する。例えば、メチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル等が挙げられる。 “Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
「アルケニルスルフィニル」とは、上記「アルケニル」がスルフィニル基に結合した基を意味する。例えば、エチレニルスルフィニル、プロペニルスルフィニル等が挙げられる。 “Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
「アルキニルスルフィニル」とは、上記「アルキニル」がスルフィニル基に結合した基を意味する。例えば、エチニルスルフィニル、プロピニルスルフィニル等が挙げられる。 “Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
「トリアルキルシリル」とは、上記「アルキル」3個がケイ素原子に結合している基を意味する。3個のアルキル基は同一でも異なっていてもよい。例えば、トリメチルシリル、トリエチルシリル、ｔｅｒｔ－ブチルジメチルシリル等が挙げられる。 “Trialkylsilyl” means a group in which three of the above “alkyl” are bonded to a silicon atom. The three alkyl groups may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
「炭素環アルキル」、「芳香族炭素環アルキル」、「非芳香族炭素環アルキル」、「複素環アルキル」、「芳香族複素環アルキル」、「非芳香族複素環アルキル」、「炭素環アルキルオキシ」、「芳香族炭素環アルキルオキシ」、「非芳香族炭素環アルキルオキシ」、「複素環アルキルオキシ」、「芳香族複素環アルキルオキシ」、「非芳香族複素環アルキルオキシ」、「炭素環アルキルオキシカルボニル」、「芳香族炭素環アルキルオキシカルボニル」、「非芳香族炭素環アルキルオキシカルボニル」、「複素環アルキルオキシカルボニル」、「芳香族複素環オキシカルボニル」、「非芳香族複素環オキシカルボニル」、「炭素環アルキルオキシアルキル」、「芳香族炭素環アルキルオキシアルキル」、「非芳香族炭素環アルキルオキシアルキル」、「複素環アルキルオキシアルキル」、「芳香族複素環アルキルオキシアルキル」、「非芳香族複素環アルキルオキシアルキル」、「炭素環アルキルアミノ」、「芳香族炭素環アルキルアミノ」、「非芳香族炭素環アルキルアミノ」、「複素環アルキルアミノ」、「芳香族複素環アルキルアミノ」、および「非芳香族複素環アルキルアミノ」のアルキル部分も、上記「アルキル」と同様である。 “Carbocyclic alkyl”, “Aromatic carbocyclic alkyl”, “Non-aromatic carbocyclic alkyl”, “Heterocyclic alkyl”, “Aromatic heterocyclic alkyl”, “Non-aromatic heterocyclic alkyl”, “Carbocyclic alkyl” "Oxy", "aromatic carbocyclic alkyloxy", "non-aromatic carbocyclic alkyloxy", "heterocyclic alkyloxy", "aromatic heterocyclic alkyloxy", "non-aromatic heterocyclic alkyloxy", "carbon" Ring alkyloxycarbonyl "," aromatic carbocyclic alkyloxycarbonyl "," non-aromatic carbocyclic alkyloxycarbonyl "," heterocyclic alkyloxycarbonyl "," aromatic heterocyclic oxycarbonyl "," non-aromatic heterocyclic " "Oxycarbonyl", "carbocyclic alkyloxyalkyl", "aromatic carbocyclic alkyloxyalkyl", "non-aromatic carbocyclic alkyloxya" "Kil", "heterocyclic alkyloxyalkyl", "aromatic heterocyclic alkyloxyalkyl", "non-aromatic heterocyclic alkyloxyalkyl", "carbocyclic alkylamino", "aromatic carbocyclic alkylamino", "non The alkyl part of “aromatic carbocyclic alkylamino”, “heterocyclic alkylamino”, “aromatic heterocyclic alkylamino”, and “non-aromatic heterocyclic alkylamino” is the same as the above “alkyl”.
「芳香族炭素環アルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルを意味する。例えば、ベンジル、フェネチル、フェニルプロピル、ベンズヒドリル、トリチル、ナフチルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000077
等が挙げられる。
「芳香族炭素環アルキル」の好ましい態様としては、ベンジル、フェネチル、ベンズヒドリル等が挙げられる。 “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below:
Figure JPOXMLDOC01-appb-C000077
Etc.
Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl, benzhydryl and the like.
「非芳香族炭素環アルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルを意味する。また、「非芳香族炭素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキル」も包含する。例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000078
等が挙げられる。 “Non-aromatic carbocyclic alkyl” means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below:
Figure JPOXMLDOC01-appb-C000078
Etc.
「炭素環アルキル」とは、「芳香族炭素環アルキル」および「非芳香族炭素環アルキル」を包含する。「炭素環アルキル」の好ましい態様としては、ベンジル、フェネチル、ベンズヒドリル、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000079
等が挙げられる。 “Carbocyclic alkyl” includes “aromatic carbocyclic alkyl” and “non-aromatic carbocyclic alkyl”. Preferable embodiments of “carbocycle alkyl” include benzyl, phenethyl, benzhydryl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and groups shown below:
Figure JPOXMLDOC01-appb-C000079
Etc.
「芳香族複素環アルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルを意味する。また、「芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキル」も包含する。例えば、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000080
等が挙げられる。 “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. . For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below
Figure JPOXMLDOC01-appb-C000080
Etc.
「非芳香族複素環アルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルを意味する。また、「非芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキル」も包含する。例えば、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000081
等が挙げられる。 “Non-aromatic heterocyclic alkyl” means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyl”, the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000081
Etc.
「複素環アルキル」とは、「芳香族複素環アルキル」および「非芳香族複素環アルキル」を包含する。「複素環アルキル」の好ましい態様としては、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基：
Figure JPOXMLDOC01-appb-C000082
等が挙げられる。 “Heterocyclic alkyl” includes “aromatic heterocyclic alkyl” and “non-aromatic heterocyclic alkyl”. Preferred embodiments of “heterocyclic alkyl” include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, iso Pyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below:
Figure JPOXMLDOC01-appb-C000082
Etc.
「芳香族炭素環アルキルオキシ」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシを意味する。例えば、ベンジルオキシ、フェネチルオキシ、フェニルプロピルオキシ、ベンズヒドリルオキシ、トリチルオキシ、ナフチルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000083
等が挙げられる。 “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below:
Figure JPOXMLDOC01-appb-C000083
Etc.
　「非芳香族炭素環アルキルオキシ」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族炭素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシ」も包含する。例えば、シクロプロピルメチルオキシ、シクロブチルメチルオキシ、シクロペンチルメチルオキシ、シクロヘキシルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000084
等が挙げられる。 “Non-aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below:
Figure JPOXMLDOC01-appb-C000084
Etc.
　「芳香族複素環アルキルオキシ」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシ」も包含する。例えば、ピリジルメチルオキシ、不らニルメチルオキシ、イミダゾリルメチルオキシ、インドリルメチルオキシ、ベンゾチオフェニルメチルオキシ、イソチアゾリルメチルオキシ、ピラゾリルメチルオキシ、イソピラゾリルメチルオキシ、ピロリジニルメチルオキシ、ベンズオキサゾリルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000085
等が挙げられる。 “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include. For example, pyridylmethyloxy, nonylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxa Zolylmethyloxy, the group shown below:
Figure JPOXMLDOC01-appb-C000085
Etc.
　「非芳香族複素環アルキルオキシ」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシ」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基：
Figure JPOXMLDOC01-appb-C000086
等が挙げられる。 “Non-aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below:
Figure JPOXMLDOC01-appb-C000086
Etc.
　「芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル、フェニルプロピルオキシカルボニル、ベンズヒドリルオキシカルボニル、トリチルオキシカルボニル、ナフチルメチルオキシカルボニル、以下に示される基：
Figure JPOXMLDOC01-appb-C000087
等が挙げられる。 “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below:
Figure JPOXMLDOC01-appb-C000087
Etc.
　「非芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族炭素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシカルボニル」も包含する。例えば、シクロプロピルメチルオキシカルボニル、シクロブチルメチルオキシカルボニル、シクロペンチルメチルオキシカルボニル、シクロヘキシルメチルオキシカルボニル、以下に示される基：
Figure JPOXMLDOC01-appb-C000088
等が挙げられる。 “Non-aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below:
Figure JPOXMLDOC01-appb-C000088
Etc.
　「芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシカルボニル」も包含する。例えば、ピリジルメチルオキシカルボニル、フラニルメチルオキシカルボニル、イミダゾリルメチルオキシカルボニル、インドリルメチルオキシカルボニル、ベンゾチオフェニルメチルオキシカルボニル、オキサゾリルメチルオキシカルボニル、イソキサゾリルメチルオキシカルボニル、チアゾリルメチルオキシカルボニル、イソチアゾリルメチルオキシカルボニル、ピラゾリルメチルオキシカルボニル、イソピラゾリルメチルオキシカルボニル、ピロリジニルメチルオキシカルボニル、ベンズオキサゾリルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000089
等が挙げられる。 “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000089
Etc.
　「非芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシカルボニル」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000090
等が挙げられる。 “Non-aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxycarbonyl”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. And “non-aromatic heterocyclic alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000090
Etc.
　「芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。例えば、ベンジルオキシメチル、フェネチルオキシメチル、フェニルプロピルオキシメチル、ベンズヒドリルオキシメチル、トリチルオキシメチル、ナフチルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000091
等が挙げられる。 “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000091
Etc.
　「非芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族炭素環アルキルオキシアルキル」は、非芳香族炭素環が結合しているアルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシアルキル」も包含する。例えば、シクロプロピルメチルオキシメチル、シクロブチルメチルオキシメチル、シクロペンチルメチルオキシメチル、シクロへキシルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000092
等が挙げられる。 “Non-aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000092
Etc.
　「芳香族複素環アルキルオキシアルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「芳香族複素環アルキルオキシアルキル」は、芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシアルキル」も包含する。例えば、ピリジルメチルオキシメチル、フラニルメチルオキシメチル、イミダゾリルメチルオキシメチル、インドリルメチルオキシメチル、ベンゾチオフェニルメチルオキシメチル、オキサゾリルメチルオキシメチル、イソキサゾリルメチルオキシメチル、チアゾリルメチルオキシメチル、イソチアゾリルメチルオキシメチル、ピラゾリルメチルオキシメチル、イソピラゾリルメチルオキシメチル、ピロリジニルメチルオキシメチル、ベンズオキサゾリルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000093
等が挙げられる。 “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. In addition, the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000093
Etc.
　「非芳香族複素環アルキルオキシアルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族複素環アルキルオキシアルキル」は、非芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシアルキル」も包含する。例えば、テトラヒドロピラニルメチルオキシメチル、モルホリニルエチルオキシメチル、ピペリジニルメチルオキシメチル、ピペラジニルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000094
等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. The “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000094
Etc.
「芳香族炭素環オキシ」「芳香族炭素環カルボニル」、「芳香族炭素環オキシカルボニル」、「芳香族炭素環スルファニル」、「芳香族炭素環スルフィニル」および「芳香族炭素環スルホニル」の「芳香族炭素環」部分も、上記「芳香族炭素環式基」と同様である。 "Aromatic carbocyclic oxy" "aromatic carbocyclic carbonyl", "aromatic carbocyclic oxycarbonyl", "aromatic carbocyclic sulfanyl", "aromatic carbocyclic sulfinyl" and "aromatic carbocyclic sulfonyl" The “aromatic carbocyclic” moiety is the same as the above “aromatic carbocyclic group”.
　「芳香族炭素環オキシ」とは、上記「芳香族炭素環」が酸素原子に結合した基を意味する。例えば、フェニルオキシ、ナフチルオキシ等が挙げられる。 “Aromatic carbocyclic oxy” means a group in which the above “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
　「芳香族炭素環カルボニル」とは、上記「芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、ベンゾイル、ナフチルカルボニル等が挙げられる。 “Aromatic carbocyclic carbonyl” means a group in which the above “aromatic carbocycle” is bonded to a carbonyl group. Examples include benzoyl and naphthylcarbonyl.
「芳香族炭素環オキシカルボニル」とは、「芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、フェニルオキシカルボニル、ナフチルオキシカルボニル等が挙げられる。 “Aromatic carbocyclic oxycarbonyl” means a group in which “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
「芳香族炭素環スルファニル」とは、「芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、フェニルスルファニル、ナフチルスルファニル等が挙げられる。 “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
「芳香族炭素環スルフィニル」とは、「芳香族炭素環」がスルフィニル基に結合した基を意味する。例えば、フェニルスルフィニル、ナフチルスルフィニル等が挙げられる。 “Aromatic carbocyclic sulfinyl” means a group in which an “aromatic carbocyclic ring” is bonded to a sulfinyl group. Examples thereof include phenylsulfinyl and naphthylsulfinyl.
「芳香族炭素環スルホニル」とは、「芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、フェニルスルホニル、ナフチルスルホニル等が挙げられる。 “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
「非芳香族炭素環オキシ」、「非芳香族炭素環カルボニル」、「非芳香族炭素環オキシカルボニル」、「非芳香族炭素環スルファニル」、「非芳香族炭素環スルフィニル」、および「非芳香族炭素環スルホニル」の「非芳香族炭素環」部分も、上記「非芳香族炭素環式基」と同様である。 “Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic sulfinyl”, and “non-aromatic The “non-aromatic carbocyclic” portion of the “aromatic carbocyclic sulfonyl” is the same as the above “non-aromatic carbocyclic group”.
「非芳香族炭素環オキシ」とは、上記「非芳香族炭素環」が酸素原子に結合した基を意味する。例えば、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシ、シクロプロペニルオキシ、シクロブテニルオキシ、シクロペンテニルオキシ、シクロヘキセニルオキシ、シクロヘプテニルオキシ、シクロヘキサジエニルオキシ、インダニルオキシ、テトラヒドロナフチルオキシ、フルオレニルオキシ、アダマンチルオキシ等が挙げられる。 “Non-aromatic carbocyclic oxy” means a group in which the “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclohexadienyloxy , Indanyloxy, tetrahydronaphthyloxy, fluorenyloxy, adamantyloxy and the like.
　「非芳香族炭素環カルボニル」とは、上記「非芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロプロペニルカルボニル、インダニルカルボニル等が挙げられる。 “Non-aromatic carbocyclic carbonyl” means a group in which the above “non-aromatic carbocycle” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclopropenylcarbonyl, indanylcarbonyl and the like can be mentioned.
「非芳香族炭素環オキシカルボニル」とは、「非芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロヘキセニルカルボニル等が挙げられる。 “Non-aromatic carbocyclic oxycarbonyl” means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. Examples thereof include cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like.
「非芳香族炭素環オキシカルボニル」とは、上記「非芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、シクロプロピルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロヘキセニルオキシカルボニル等が挙げられる。 The “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
「非芳香族炭素環スルファニル」とは、上記「非芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、シクロプロピルスルファニル、シクロブチルスルファニル、シクロペンチルスルファニル、シクロヘキシルスルファニル、シクロヘプチルスルファニル、シクロオクチルスルファニル、シクロプロペニルスルファニル、シクロブテニルスルファニル、シクロペンテニルスルファニル、シクロヘキセニルスルファニル、シクロヘプテニルスルファニル、シクロヘキサジエニルスルファニル、インダニルスルファニル、テトラヒドロナフチルスルファニル、フルオレニルスルファニル、アダマンチルスルファニル等が挙げられる。 The “non-aromatic carbocyclic sulfanyl” means a group in which the “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl, cyclopropenylsulfanyl, cyclobutenylsulfanyl, cyclopentenylsulfanyl, cyclohexenylsulfanyl, cycloheptenylsulfanyl, cyclohexadienylsulfanyl , Indanylsulfanyl, tetrahydronaphthylsulfanyl, fluorenylsulfanyl, adamantylsulfanyl and the like.
「非芳香族炭素環スルフィニル」とは、上記「非芳香族炭素環」がスルフィニル基に結合した基を意味する。例えば、シクロプロピルスルフィニル、シクロブチルスルフィニル、シクロペンチルスルフィニル、シクロヘキシルスルフィニル、シクロヘプチルスルフィニル、シクロヘキセニルスルフィニル、テトラヒドロナフチルスルフィニル、アダマンチルスルフィニル等が挙げられる。 The “non-aromatic carbocyclic sulfinyl” means a group in which the “non-aromatic carbocyclic ring” is bonded to a sulfinyl group. Examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, cyclohexenylsulfinyl, tetrahydronaphthylsulfinyl, adamantylsulfinyl and the like.
「非芳香族炭素環スルホニル」とは、上記「非芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、シクロプロピルスルホニル、シクロヘキシルスルホニル、シクロヘキセニルスルホニル等が挙げられる。 The “non-aromatic carbocycle sulfonyl” means a group in which the above “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
「芳香族複素環オキシ」、「芳香族複素環カルボニル」、「芳香族複素環オキシカルボニル」、「芳香族複素環スルファニル」、「芳香族複素環スルフィニル」、および「芳香族複素環スルホニル」の「芳香族複素環」部分も、上記「芳香族複素環式基」と同様である。 “Aromatic heterocyclic oxy”, “aromatic heterocyclic carbonyl”, “aromatic heterocyclic oxycarbonyl”, “aromatic heterocyclic sulfanyl”, “aromatic heterocyclic sulfinyl”, and “aromatic heterocyclic sulfonyl” The “aromatic heterocyclic ring” moiety is the same as the above “aromatic heterocyclic group”.
　「芳香族複素環オキシ」とは、上記「芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピリジルオキシ、オキサゾリルオキシ等が挙げられる。 “Aromatic heterocycle oxy” means a group in which the above “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
　「芳香族複素環カルボニル」とは、上記「芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピロリルカルボニル、ピラゾリルカルボニル、ピリジルカルボニル、オキサゾリルカルボニル、インドリルカルボニル等が挙げられる。 “Aromatic heterocycle carbonyl” means a group in which the above “aromatic heterocycle” is bonded to a carbonyl group. For example, pyrrolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, oxazolylcarbonyl, indolylcarbonyl and the like can be mentioned.
「芳香族複素環オキシカルボニル」とは、上記「芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピリジルオキシカルボニル、オキサゾリルオキシカルボニル等が挙げられる。 “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
「芳香族複素環スルファニル」とは、上記「芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピリジルスルファニル、オキサゾリルスルファニル等が挙げられる。 “Aromatic heterocycle sulfanyl” means a group in which the above “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
「芳香族複素環スルフィニル」とは、上記「芳香族複素環」がスルフィニル基に結合した基を意味する。例えば、ピリジルスルフィニル、オキサゾリルスルフィニル等が挙げられる。 “Aromatic heterocycle sulfinyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfinyl group. For example, pyridylsulfinyl, oxazolylsulfinyl and the like can be mentioned.
「芳香族複素環スルホニル」とは、上記「芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピリジルスルホニル、オキサゾリルスルホニル等が挙げられる。 “Aromatic heterocycle sulfonyl” means a group in which the above “aromatic heterocycle” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
「非芳香族複素環オキシ」、「非芳香族複素環カルボニル」、「非芳香族複素環オキシカルボニル」、「非芳香族複素環スルファニル」、「非芳香族複素環スルフィニル」、および「非芳香族複素環スルホニル」の「非芳香族複素環」部分も、上記「非芳香族複素環式基」と同様である。 “Non-aromatic heterocyclic oxy”, “Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic oxycarbonyl”, “Non-aromatic heterocyclic sulfanyl”, “Non-aromatic heterocyclic sulfinyl”, and “Non-aromatic” The “non-aromatic heterocyclic” part of the “aromatic heterocyclic sulfonyl” is the same as the above “non-aromatic heterocyclic group”.
　「非芳香族複素環オキシ」とは、上記「非芳香族複素環」が酸素原子に結合した基を意味する。例えば、ジオキサニルオキシ、チイラニルオキシ、オキシラニルオキシ、オキセタニルオキシ、オキサチオラニルオキシ、アゼチジニルオキシ、チアニルオキシ、チアゾリジニルオキシ、ピロリジニルオキシ、ピロリニルオキシ、イミダゾリジニルオキシ、イミダゾリニルオキシ、ピラゾリジニルオキシ、ピラゾリニルオキシ、ピペリジルオキシ、ピペラジニルオキシ、モルホリニルオキシ、インドリニルオキシ、クロマニルオキシ等が挙げられる。 “Non-aromatic heterocyclic oxy” means a group in which the above “non-aromatic heterocyclic” is bonded to an oxygen atom. For example, dioxanyloxy, thiranyloxy, oxiranyloxy, oxetanyloxy, oxathiolanyloxy, azetidinyloxy, thianyloxy, thiazolidinyloxy, pyrrolidinyloxy, pyrrolinyloxy, imidazolidinyloxy, imidazo Examples include linyloxy, pyrazolidinyloxy, pyrazolinyloxy, piperidyloxy, piperazinyloxy, morpholinyloxy, indolinyloxy, chromanyloxy and the like.
「非芳香族複素環カルボニル」とは、上記「非芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ジオキサニルカルボニル、オキセタニルカルボニル、ピラゾリニルカルボニル、モルホリノカルボニル、モルホリニルカルボニル、インドリニルカルボニル等が挙げられる。 The “non-aromatic heterocyclic carbonyl” means a group in which the above “non-aromatic heterocyclic” is bonded to a carbonyl group. Examples include dioxanylcarbonyl, oxetanylcarbonyl, pyrazolinylcarbonyl, morpholinocarbonyl, morpholinylcarbonyl, indolinylcarbonyl and the like.
「非芳香族複素環オキシカルボニル」とは、上記「非芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピペリジニルオキシカルボニル、テトラヒドロフリルオキシカルボニル等が挙げられる。 The “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
「非芳香族複素環スルファニル」とは、上記「非芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ジオキサニルスルファニル、チイラニルスルファニル、オキシラニルスルファニル、オキセタニルスルファニル、オキサチオラニルスルファニル、アゼチジニルスルファニル、チアニルスルファニル、チアゾリジニルスルファニル、ピロリジニルスルファニル、ピロリニルスルファニル、イミダゾリジニルスルファニル、イミダゾリニルスルファニル、ピラゾリジニルスルファニル、ピラゾリニルスルファニル、ピペリジルスルファニル、ピペラジニルスルファニル、モルホリニルスルファニル、インドリニルスルファニル、クロマニルスルファニル等が挙げられる。 “Non-aromatic heterocyclic sulfanyl” means a group in which the “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, dioxanylsulfanyl, thiylylsulfanyl, oxiranylsulfanyl, oxetanylsulfanyl, oxathiolanylsulfanyl, azetidinylsulfanyl, thianylsulfanyl, thiazolidinylsulfanyl, pyrrolidinylsulfanyl, pyrrolinylsulfanyl, imidazolidinini Examples include sulfanyl, imidazolinylsulfanyl, pyrazolidinylsulfanyl, pyrazolinylsulfanyl, piperidylsulfanyl, piperazinylsulfanyl, morpholinylsulfanyl, indolinylsulfanyl, chromanylsulfanyl and the like.
「非芳香族複素環スルフィニル」とは、上記「非芳香族複素環」がスルフィニル基に結合した基を意味する。例えば、ピペリジニルスルフィニル、テトラヒドロフリルスルフィニル等が挙げられる。 The “non-aromatic heterocyclic sulfinyl” means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfinyl group. For example, piperidinylsulfinyl, tetrahydrofurylsulfinyl and the like can be mentioned.
「非芳香族複素環スルホニル」とは、上記「非芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピペリジニルスルホニル、テトラヒドロフリルスルホニル等が挙げられる。 The “non-aromatic heterocyclic sulfonyl” means a group in which the “non-aromatic heterocyclic ring” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
「カルバモイルオキシ」とは、カルバモイルに酸素原子が結合した基を意味する。 “Carbamoyloxy” means a group in which an oxygen atom is bonded to carbamoyl.
　「置換若しくは非置換のアルキル」、「置換若しくは非置換のアルケニル」、「置換若しくは非置換のアルキニル」、「置換若しくは非置換のアルキルオキシ」、「置換若しくは非置換のアルケニルオキシ」、「置換若しくは非置換のアルキニルオキシ」、「置換若しくは非置換のアルキルカルボニル」、「置換若しくは非置換のアルケニルカルボニル」、「置換若しくは非置換のアルキニルカルボニル」、「置換若しくは非置換のモノアルキルアミノ」、「置換若しくは非置換のジアルキルアミノ」、「置換若しくは非置換のアルキルスルホニル」、「置換若しくは非置換のアルケニルスルホニル」、「置換若しくは非置換のアルキニルスルホニル」、「置換若しくは非置換のモノアルキルカルボニルアミノ」、「置換若しくは非置換のジアルキルカルボニルアミノ」、「置換若しくは非置換のモノアルキルスルホニルアミノ」、「置換若しくは非置換のジアルキルスルホニルアミノ」、「置換若しくは非置換のアルキルイミノ」、「置換若しくは非置換のアルケニルイミノ」、「置換若しくは非置換のアルキニルイミノ」、「置換若しくは非置換のアルキルカルボニルイミノ」、「置換若しくは非置換のアルケニルカルボニルイミノ」、「置換若しくは非置換のアルキニルカルボニルイミノ」、「置換若しくは非置換のアルキルオキシイミノ」、「置換若しくは非置換のアルケニルオキシイミノ」、「置換若しくは非置換のアルキニルオキシイミノ」、「置換若しくは非置換のアルキルカルボニルオキシ」、「置換若しくは非置換のアルケニルカルボニルオキシ」、「置換若しくは非置換のアルキニルカルボニルオキシ」、「置換若しくは非置換のアルキルオキシカルボニル」、「置換若しくは非置換のアルケニルオキシカルボニル」、「置換若しくは非置換のアルキニルオキシカルボニル」、「置換若しくは非置換のアルキルスルファニル」、「置換若しくは非置換のアルケニルスルファニル」、「置換若しくは非置換のアルキニルスルファニル」、「置換若しくは非置換のアルキルスルフィニル」、「置換若しくは非置換のアルケニルスルフィニル」、「置換若しくは非置換のアルキニルスルフィニル」、「置換若しくは非置換のモノアルキルカルバモイル」、「置換若しくは非置換のジアルキルカルバモイル」、「置換若しくは非置換のモノアルキルスルファモイル」、「置換若しくは非置換のジアルキルスルファモイル」、「置換もしくは非置換のアルキレン」、「置換もしくは非置換のアルケニレン」および「置換もしくは非置換のアルキニレン」の置換基としては、次の置換基群Ａが挙げられる。任意の位置の炭素原子が次の置換基群Ａから選択される１以上の基と結合していてもよい。
置換基群Ａ：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。 “Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, “substituted or "Unsubstituted alkynyloxy", "substituted or unsubstituted alkylcarbonyl", "substituted or unsubstituted alkenylcarbonyl", "substituted or unsubstituted alkynylcarbonyl", "substituted or unsubstituted monoalkylamino", "substituted Or “unsubstituted dialkylamino”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted or unsubstituted monoalkylcarbonylamino”, "Substituted or unsubstituted di- ”Alkylcarbonylamino”, “substituted or unsubstituted monoalkylsulfonylamino”, “substituted or unsubstituted dialkylsulfonylamino”, “substituted or unsubstituted alkylimino”, “substituted or unsubstituted alkenylimino”, “substituted” Or “substituted alkynylimino”, “substituted or unsubstituted alkylcarbonylimino”, “substituted or unsubstituted alkenylcarbonylimino”, “substituted or unsubstituted alkynylcarbonylimino”, “substituted or unsubstituted alkyloxyimino” , “Substituted or unsubstituted alkenyloxyimino”, “substituted or unsubstituted alkynyloxyimino”, “substituted or unsubstituted alkylcarbonyloxy”, “substituted or unsubstituted alkenylcarbonyloxy”, “substituted Is “unsubstituted alkynylcarbonyloxy”, “substituted or unsubstituted alkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”, “substituted or unsubstituted alkynyloxycarbonyl”, “substituted or unsubstituted alkylsulfanyl” ”,“ Substituted or unsubstituted alkenylsulfanyl ”,“ substituted or unsubstituted alkynylsulfanyl ”,“ substituted or unsubstituted alkylsulfinyl ”,“ substituted or unsubstituted alkenylsulfinyl ”,“ substituted or unsubstituted alkynylsulfinyl ” , “Substituted or unsubstituted monoalkylcarbamoyl”, “substituted or unsubstituted dialkylcarbamoyl”, “substituted or unsubstituted monoalkylsulfamoyl”, “substituted or unsubstituted dialkylsulfamoyl” Examples of the substituent of “amoyl”, “substituted or unsubstituted alkylene”, “substituted or unsubstituted alkenylene” and “substituted or unsubstituted alkynylene” include the following substituent group A. The carbon atom at any position may be bonded to one or more groups selected from the following substituent group A.
Substituent group A: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl , Alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfo Ruamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic Group carbocyclic , Non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, Aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic Aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyl Oxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkylamino , Non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, Non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.
　　「置換若しくは非置換の芳香族炭素環式基」、「置換若しくは非置換の非芳香族炭素環式基」、「置換若しくは非置換の芳香族複素環式基」、「置換若しくは非置換の非芳香族複素環式基」、「置換若しくは非置換の芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の芳香族複素環オキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換の芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の芳香族複素環カルボニル」、「置換若しくは非置換の非芳香族複素環カルボニル」、「置換若しくは非置換の芳香族炭素環オキシカルボニル」、「置換若しくは非置換の非芳香族炭素環オキシカルボニル」、「置換若しくは非置換の芳香族複素環オキシカルボニル」、「置換若しくは非置換の非芳香族複素環オキシカルボニル」、「置換若しくは非置換の芳香族炭素環カルボニルオキシ」、「置換若しくは非置換の非芳香族炭素環カルボニルオキシ」、「置換若しくは非置換の芳香族複素環カルボニルオキシ」、「置換若しくは非置換の非芳香族複素環カルボニルオキシ」、「置換若しくは非置換の芳香族炭素環スルファニル」、「置換若しくは非置換の非芳香族炭素環スルファニル」、「置換若しくは非置換の芳香族複素環スルファニル」、「置換若しくは非置換の非芳香族複素環スルファニル」、「置換もしくは非置換の芳香族炭素環スルフィニル」、「置換もしくは非置換の非芳香族炭素環スルフィニル」、「置換もしくは非置換の芳香族複素環スルフィニル」、「置換もしくは非置換の非芳香族複素環スルフィニル」、
「置換若しくは非置換の芳香族炭素環スルホニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、「置換若しくは非置換の芳香族複素環スルホニル」、「置換若しくは非置換の非芳香族複素環スルホニル」、「置換もしくは非置換の非芳香族炭素環」、「置換もしくは非置換の非芳香族複素環」、「置換もしくは非置換の炭素環式基」、「置換もしくは非置換の複素環式基」、「置換もしくは非置換の炭素環ジイル」および「置換もしくは非置換の複素環ジイル」の「芳香族炭素環」、「非芳香族炭素環」、「芳香族複素環」、「非芳香族複素環」、「炭素環」および「複素環」の環上の置換基としては、次の置換基群Ｂが挙げられる。環上の任意の位置の原子が次の置換基群Ｂから選択される１以上の基と結合していてもよい。
　置換基群Ｂ：オキソ、ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、シアノアルキル、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、ヒドロキシアルキルオキシ、アルキルオキシアルキル、アルキルオキシアルキルオキシ、ヒドロキシアルキル、ヒドロキシアルケニル、ヒドロキシアルキニル、シアノアルキル、アルキルオキシアルキル、アルキルオキシアルキルオキシアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、ハロアルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルオキシアルキルオキシイミノ、メチリデン、アルキルメチリデン、アルキルオキシカルボニルメチリデン、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルオキシカルボニルアルキルオキシ、アルキルオキシカルボニルアルキル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、芳香族炭素環式基、ハロゲンもしくはシアノもしくはアルキルもしくはハロアルキルもしくはヒドロキシで置換された芳香族炭素環式基、非芳香族炭素環式基、ハロゲンもしくはシアノで置換された非芳香族炭素環式基、芳香族複素環式基、アルキルで置換された芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、ハロアルキルで置換された芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキル、ハロゲンもしくはアルキルもしくはハロアルキルもしくはヒドロキシで置換された芳香族炭素環アルキル、非芳香族炭素環アルキル、アルキルで置換された非芳香族炭素環アルキル、芳香族複素環アルキル、非芳香族複素環アルキル、芳香族炭素環アルケニル、非芳香族炭素環アルケニル、芳香族炭素環アルキルオキシ、ハロゲンもしくはアルキルもしくはハロアルキルもしくはアルキルオキシもしくはヒドロキシで置換された芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシアルキルオキシ、芳香族炭素環オキシアルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環オキシアルキル、ハロゲンもしくはシアノもしくはヒドロキシで置換された芳香族炭素環オキシアルキル、非芳香族炭素環オキシアルキル、芳香族複素環オキシアルキル、非芳香族複素環オキシアルキル、芳香族炭素環アルキルオキシアルキル、非芳香族炭素環アルキルオキシアルキル、芳香族複素環アルキルオキシアルキル、非芳香族複素環アルキルオキシアルキル、芳香族炭素環オキシイミノ、非芳香族炭素環オキシイミノ、アルキルオキシ芳香族炭素環アルキルオキシ、芳香族炭素環スルファモイル、非芳香族炭素環スルファモイル、芳香族複素環スルファモイル、非芳香族複素環スルファモイル、芳香族炭素環アルキルスルファモイル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。 “Substituted or unsubstituted aromatic carbocyclic group”, “substituted or unsubstituted non-aromatic carbocyclic group”, “substituted or unsubstituted aromatic heterocyclic group”, “substituted or unsubstituted non-substituted aromatic carbocyclic group” "Aromatic heterocyclic group", "Substituted or unsubstituted aromatic carbocyclic oxy", "Substituted or unsubstituted non-aromatic carbocyclic oxy", "Substituted or unsubstituted aromatic heterocyclic oxy", "Substituted Or “unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted aromatic carbocyclic carbonyl”, “substituted or unsubstituted non-aromatic carbocyclic carbonyl”, “substituted or unsubstituted aromatic heterocyclic carbonyl” , “Substituted or unsubstituted non-aromatic heterocyclic carbonyl”, “substituted or unsubstituted aromatic carbocyclic oxycarbonyl”, “substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl”, “substituted Or unsubstituted aromatic heterocyclic oxycarbonyl "," substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl "," substituted or unsubstituted aromatic carbocyclic oxycarbonyl "," substituted or unsubstituted non-aromatic Aromatic carbocyclic oxy ”,“ substituted or unsubstituted aromatic heterocyclic carbonyloxy ”,“ substituted or unsubstituted non-aromatic heterocyclic carbonyloxy ”,“ substituted or unsubstituted aromatic carbocyclic sulfanyl ”,“ "Substituted or unsubstituted non-aromatic carbocyclic sulfanyl", "Substituted or unsubstituted aromatic heterocyclic sulfanyl", "Substituted or unsubstituted non-aromatic heterocyclic sulfanyl", "Substituted or unsubstituted aromatic carbocyclic ring" Sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulf Iniru "," non-aromatic heterocyclic sulfinyl substituted or unsubstituted "
“Substituted or unsubstituted aromatic carbocyclic sulfonyl”, “Substituted or unsubstituted non-aromatic carbocyclic sulfonyl”, “Substituted or unsubstituted aromatic heterocyclic sulfonyl”, “Substituted or unsubstituted non-aromatic heterocyclic” Ring sulfonyl "," substituted or unsubstituted non-aromatic carbocycle "," substituted or unsubstituted non-aromatic heterocycle "," substituted or unsubstituted carbocyclic group "," substituted or unsubstituted heterocycle ""Aromaticcarbocycle","non-aromaticcarbocycle","aromaticheterocycle","non-substituted carbocycle diyl" and "substituted or unsubstituted heterocycle diyl" Examples of the substituent on the ring of “aromatic heterocycle”, “carbocycle” and “heterocycle” include the following substituent group B. The atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B.
Substituent group B: oxo, halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano , Cyanoalkyl, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, hydroxyalkyloxy, alkyloxyalkyl, Alkyloxyalkyloxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, cyanoalkyl, alkyloxy Cialkyl, alkyloxyalkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonyl Amino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, haloalkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkyloxyalkyloxyimino, methylidene, alkylmethylidene , Alkyloxycarbonylmethyl Den, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkyloxycarbonylalkyloxy, alkyloxycarbonylalkyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenyl Sulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, aromatic carbocyclic group substituted with halogen or cyano or alkyl or haloalkyl or hydroxy, Non-aromatic carbocyclic group, substituted with halogen or cyano Non-aromatic carbocyclic group, aromatic heterocyclic group, aromatic heterocyclic group substituted with alkyl, non-aromatic heterocyclic group, aromatic carbocyclic oxy, aromatic carbocycle substituted with haloalkyl Oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic Carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, halogen or alkyl or haloalkyl or hydroxy substituted aromatic carbocyclic alkyl Non-aromatic carbocyclic alkyl, alkyl-substituted non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, non-aromatic Ring alkyl, aromatic carbocyclic alkenyl, non-aromatic carbocyclic alkenyl, aromatic carbocyclic alkyloxy, aromatic carbocyclic alkyloxy substituted with halogen or alkyl or haloalkyl or alkyloxy or hydroxy, non-aromatic carbocyclic alkyl Oxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxyalkyloxy, aromatic carbocyclic oxyalkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl , Aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic oxyalkyl, aromatic carbocyclic oxyalkyl substituted with halogen or cyano or hydroxy, non-aromatic carbocyclic oxia Kill, aromatic heterocyclic oxyalkyl, non-aromatic heterocyclic oxyalkyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl , Aromatic carbocyclic oxyimino, non-aromatic carbocyclic oxyimino, alkyloxy aromatic carbocyclic alkyloxy, aromatic carbocyclic sulfamoyl, non-aromatic carbocyclic sulfamoyl, aromatic heterocyclic sulfamoyl, non-aromatic heterocyclic sulfamoyl, aromatic Aromatic carbocyclic alkylsulfamoyl, aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl , Aromatic heterocyclic sulfanyl, non-aromatic compounds Prime ring sulfanyl, non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.
　「置換もしくは非置換の炭素環アルキル」および「置換もしくは非置換の複素環アルキル」の「炭素環」および「複素環」の環上の置換基としても、置換基群Ｂが挙げられる。環上の任意の位置の原子が置換基群Ｂから選択される１以上の基と結合していてもよい。該置換基が２つ以上存在する場合は同一でも異なっていても良い。また、「置換もしくは非置換の炭素環アルキル」および「置換もしくは非置換の複素環アルキル」の「アルキル」部分の置換基としても、置換基群Ａが挙げられる。任意の位置の水素原子が置換基群Ａから選択される１以上の基と置換していてもよい。該置換基が２つ以上存在する場合は同一でも異なっていても良い。 Substituent group B can also be mentioned as substituents on the “carbocycle” and “heterocycle” rings of “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl”. The atom at any position on the ring may be bonded to one or more groups selected from the substituent group B. When two or more substituents are present, they may be the same or different. Moreover, the substituent group A can be exemplified as the substituent of the “alkyl” part of “substituted or unsubstituted carbocyclic alkyl” and “substituted or unsubstituted heterocyclic alkyl”. The hydrogen atom at any position may be substituted with one or more groups selected from the substituent group A. When two or more substituents are present, they may be the same or different.
　「置換もしくは非置換のアミノ」、「置換もしくは非置換のカルバモイル」、「置換もしくは非置換のスルファモイル」および「置換もしくは非置換のカルバモイルオキシ」の置換基としては、次の置換基群Ｃが挙げられる。該置換基が２つ存在する場合は同一でも異なっていてもよい。
置換基群Ｃ：ヒドロキシ、アミノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシアルキル、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキル、非芳香族炭素環アルキル、芳香族複素環アルキル、非芳香族複素環アルキル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルオキシアルキル、非芳香族炭素環アルキルオキシアルキル、芳香族複素環アルキルオキシアルキル、非芳香族複素環アルキルオキシアルキル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。 Examples of the substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted sulfamoyl” and “substituted or unsubstituted carbamoyloxy” include the following substituent group C: It is done. When two substituents are present, they may be the same or different.
Substituent group C: hydroxy, amino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic Aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl , Fool Aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, aromatic carbon Ring alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxy Carbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl, non-aromatic carbocyclic Sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic ring Honiru, and non-aromatic heterocyclic sulfonyl.
また、「置換もしくは非置換の非芳香族炭素環式基」および「置換もしくは非置換の非芳香族複素環式基」は「オキソ」で置換されていてもよい。この場合、以下のように炭素原子上の2個の水素原子がオキソで置換されている基を意味する。
Figure JPOXMLDOC01-appb-C000095
　上記、「置換もしくは非置換の非芳香族炭素環」、「置換もしくは非置換の非芳香族複素環」、「置換もしくは非置換の非芳香族炭素環アルキル」、「置換もしくは非置換の芳香族複素環アルキル」、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族複素環カルボニル」、「置換若しくは非置換の非芳香族炭素環オキシカルボニル」、「置換若しくは非置換の非芳香族複素環オキシカルボニル」、「置換もしくは非置換の非芳香族炭素環カルボニルオキシ」、「置換もしくは非置換の非芳香族複素環カルボニルオキシ」、「置換若しくは非置換の非芳香族炭素環スルファニル」、「置換若しくは非置換の非芳香族複素環スルファニル」、「置換もしくは非置換の非芳香族炭素環スルフィニル」、「置換もしくは非置換の非芳香族複素環スルフィニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、および「置換若しくは非置換の非芳香族複素環スルホニル」の非芳香族炭素環、および非芳香族複素環部分も上記と同様に「オキソ」で置換されていてもよい。 Further, the “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted with oxo as follows.
Figure JPOXMLDOC01-appb-C000095
"Substituted or unsubstituted non-aromatic carbocycle", "Substituted or unsubstituted non-aromatic heterocycle", "Substituted or unsubstituted non-aromatic carbocyclic alkyl", "Substituted or unsubstituted aromatic "Heterocyclic alkyl", "substituted or unsubstituted non-aromatic carbocyclic oxy", "substituted or unsubstituted non-aromatic heterocyclic oxy", "substituted or unsubstituted non-aromatic carbocyclic carbonyl", "substituted or "Unsubstituted non-aromatic heterocyclic carbonyl", "substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl", "substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl", "substituted or unsubstituted non-aromatic “Carbocyclic carbonyloxy”, “substituted or unsubstituted non-aromatic heterocyclic carbonyloxy”, “substituted or unsubstituted non-aromatic carbocyclic sulfanyl”, “substituted or unsubstituted Non-aromatic heterocyclic sulfanyl ”,“ substituted or unsubstituted non-aromatic carbocyclic sulfinyl ”,“ substituted or unsubstituted non-aromatic heterocyclic sulfinyl ”,“ substituted or unsubstituted non-aromatic carbocyclic sulfonyl ” And the non-aromatic carbocyclic ring and the non-aromatic heterocyclic part of the “substituted or unsubstituted non-aromatic heterocyclic sulfonyl” may be substituted with “oxo” in the same manner as described above.
「置換もしくは非置換のメチリデン」および「置換もしくは非置換のヒドロキシイミノ」の置換基としては、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の炭素環式基、置換もしくは非置換の複素環式基等が挙げられる。複数の置換基で置換される場合は、置換基は同一でも異なっていても良い。 Examples of the substituent of “substituted or unsubstituted methylidene” and “substituted or unsubstituted hydroxyimino” include a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or An unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, etc. are mentioned. When substituted with a plurality of substituents, the substituents may be the same or different.
「脱離基」としては、たとえば、ハロゲン、Ｃ１－６アルキルスルホニルオキシ、ハロＣ１－６アルキルスルホニルオキシまたは置換もしくは非置換のアリールスルホニルオキシ等が挙げられる。 Examples of the “leaving group” include halogen, C 1-6 alkylsulfonyloxy, halo C 1-6 alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy and the like.
式（Ｉ），（ＩＡ）または（ＩＩ）で示される化合物における、Ｒ１，Ｒ２Ａ，Ｒ２Ｂ，Ｒ３，Ｚ，Ｙ，Ｗ，Ｔ，Ｒ７Ａ，Ｒ７Ｂ，Ｒ４Ａ，Ｒ４Ｂ，Ｒ５Ａ，Ｒ５Ｂ，Ｒ６Ａ，Ｘ，Ｒ８，Ｒ９，Ｑ，ｍ，Ｒ１０，Ｒ１１，Ｒ１２，Ｒ１３，Ｒ１４，Ｒ１５，Ｒ１６，Ｒ１７，Ｒ１’，Ｒ２’Ａ，Ｒ２’Ｂ，Ｘ’，Ｒ８’，Ｒ９’， Ｒ１０’およびＵの例または好ましい態様を示すが、本発明の範囲は下記に記載されるものに限定されない。 下記の可能な組み合わせの化合物が好ましい。 R 1 , R 2A , R 2B , R 3 , Z, Y, W, T, R 7A , R 7B , R 4A , R 4B , in the compound represented by the formula (I), (IA) or (II) R 5A, R 5B, R 6A , X, R 8, R 9, Q, m, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 1 ', R Examples or preferred embodiments of 2′A , R 2′B , X ′, R 8 ′ , R 9 ′ , R 10 ′ and U are shown, but the scope of the present invention is not limited to those described below. The following possible combinations of compounds are preferred:
Ｒ１およびＲ１’の「置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基」の該環の好ましい態様は５～６員環であり、より好ましい態様としては、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基である。炭素環式基の好ましい例としては、フェニル、ヒドロキシフェニル、ジヒドロキシフェニル、置換基としてハロゲンを有するフェニル、置換基としてハロゲンおよびヒドロキシを有するフェニルなどが挙げられる。複素環式基の好ましい例としては、アミノチアゾール、置換基としてハロゲンを有するアミノチアゾール、アミノチアジアゾール、チオフェン、フラン、ベンゾチアゾール、ピリジン、ピリミジン、ピリダジン、アミノピリジンなどが挙げられる。炭素環式基のより好ましい例としては、フェニル、ヒドロキシフェニル、ジヒドロキシフェニル、クロロジヒドロキシフェニルなどが挙げられる。複素環式基のより好ましい例としては、アミノチアゾール、置換基としてハロゲンを有するアミノチアゾールまたはアミノチアジアゾールなどである。複素環式基のさらに好ましい例としては、アミノチアゾール、アミノクロロチアゾール、アミノフルオロチアゾール、アミノブロモチアゾールまたはアミノチアジアゾールである。
炭素環式基の特に好ましい例としては、以下に示される基が挙げられる。
Figure JPOXMLDOC01-appb-C000096
 複素環式基の特に好ましい例としては、以下に示される基が挙げられる。
Figure JPOXMLDOC01-appb-C000097

複素環式基の別の好ましい例としては、以下に示される基が挙げられる。
Figure JPOXMLDOC01-appb-C000098
複素環式基のより好ましい例としては、以下に示される基が挙げられる。
Figure JPOXMLDOC01-appb-C000099
 A preferred embodiment of the ring of the “substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group” of R 1 and R 1 ′ is a 5- to 6-membered ring, and a more preferred embodiment is substituted Or an unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group. Preferable examples of the carbocyclic group include phenyl, hydroxyphenyl, dihydroxyphenyl, phenyl having halogen as a substituent, and phenyl having halogen and hydroxy as a substituent. Preferable examples of the heterocyclic group include aminothiazole, aminothiazole having halogen as a substituent, aminothiadiazole, thiophene, furan, benzothiazole, pyridine, pyrimidine, pyridazine, aminopyridine and the like. More preferred examples of the carbocyclic group include phenyl, hydroxyphenyl, dihydroxyphenyl, chlorodihydroxyphenyl and the like. More preferable examples of the heterocyclic group include aminothiazole, aminothiazole having a halogen as a substituent, and aminothiadiazole. Further preferred examples of the heterocyclic group are aminothiazole, aminochlorothiazole, aminofluorothiazole, aminobromothiazole or aminothiadiazole.
Particularly preferred examples of the carbocyclic group include the groups shown below.
Figure JPOXMLDOC01-appb-C000096
 Particularly preferred examples of the heterocyclic group include the groups shown below.
Figure JPOXMLDOC01-appb-C000097

Other preferred examples of the heterocyclic group include the groups shown below.
Figure JPOXMLDOC01-appb-C000098
More preferable examples of the heterocyclic group include the groups shown below.
Figure JPOXMLDOC01-appb-C000099
　Ｒ２ＡおよびＲ２Ｂ、ならびにＲ２’ＡおよびＲ２’Ｂについて、ａ）Ｒ２ＡおよびＲ２Ｂ、またはＲ２’ＡおよびＲ２’Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、スルホ、置換もしくは非置換のスルファモイル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシである場合、例えば下式：
Figure JPOXMLDOC01-appb-C000100
の好ましい例としては、下式：
Figure JPOXMLDOC01-appb-C000101
以下に示す置換アミノ：
Figure JPOXMLDOC01-appb-C000102
以下に示す、置換スルファモイル：
Figure JPOXMLDOC01-appb-C000103
（式中、環Ｃは置換もしくは非置換の複素環式基を表す）；
以下に示す、置換カルバモイル：
Figure JPOXMLDOC01-appb-C000104
（式中、環Ｂは置換もしくは非置換の複素環式基を表す）；または
以下に示す、置換カルボニルオキシ：
Figure JPOXMLDOC01-appb-C000105
（式中、環Ｃは置換もしくは非置換の複素環式基を表す）などが挙げられる。 For R 2A and R 2B and R 2′A and R 2′B , a) R 2A and R 2B , or R 2′A and R 2′B are each independently a hydrogen atom, substituted or unsubstituted When it is amino, sulfo, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, for example:
Figure JPOXMLDOC01-appb-C000100
Preferred examples of are:
Figure JPOXMLDOC01-appb-C000101
The substituted amino shown below:
Figure JPOXMLDOC01-appb-C000102
Substituted sulfamoyl, shown below:
Figure JPOXMLDOC01-appb-C000103
(Wherein ring C represents a substituted or unsubstituted heterocyclic group);
Substituted carbamoyl shown below:
Figure JPOXMLDOC01-appb-C000104
(Wherein ring B represents a substituted or unsubstituted heterocyclic group); or substituted carbonyloxy as shown below:
Figure JPOXMLDOC01-appb-C000105
(Wherein, ring C represents a substituted or unsubstituted heterocyclic group).
　あるいは、Ｒ２ＡおよびＲ２Ｂ、またはＲ２’ＡおよびＲ２’Ｂは、一緒になって置換もしくは非置換のメチリデンを形成する場合、好ましくは式：
Figure JPOXMLDOC01-appb-C000106
（Ｒ２１は置換もしくは非置換のアルキルである。）
で示される基である。ここで、二重結合を形成する炭素原子とＲ２１の間の波線は、シス結合、トランス結合またはその混合であることを意味する。
　　　　　　　好ましくは、
Figure JPOXMLDOC01-appb-C000107
（式中、二重結合を形成する炭素原子とカルボキシ基またはアルキル基との間の波線は、シス結合、トランス結合またはその混合であることを意味する）
である。　　　　　　　
より好ましくは、
Figure JPOXMLDOC01-appb-C000108
 である。 Alternatively, when R 2A and R 2B , or R 2′A and R 2′B together form a substituted or unsubstituted methylidene, preferably the formula:
Figure JPOXMLDOC01-appb-C000106
(R 21 is substituted or unsubstituted alkyl.)
It is group shown by these. Here, the wavy line between the carbon atom forming a double bond and R 21 means a cis bond, a trans bond, or a mixture thereof.
Preferably,
Figure JPOXMLDOC01-appb-C000107
(In the formula, a wavy line between a carbon atom forming a double bond and a carboxy group or an alkyl group means a cis bond, a trans bond or a mixture thereof)
It is.
More preferably,
Figure JPOXMLDOC01-appb-C000108
 It is.
　あるいは、Ｒ２ＡおよびＲ２Ｂは一緒になって、置換もしくは非置換のヒドロキシイミノを形成していてもよく、好ましくは、式：
Figure JPOXMLDOC01-appb-C000109
（式中Ｒ１０は水素原子または置換基群Ｄから選択される１以上の基で置換されていてもよいアルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、カルバモイルアルキルである。ここで置換基群Ｄはハロゲン、ヒドロキシ、アミノ、カルバモイル、アルキルオキシカルボニルアミノおよびフェニルからなる群である。）で示される基であるか、または
式：
Figure JPOXMLDOC01-appb-C000110
（式中、Ｒ８およびＲ９はそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換の炭素環式基、もしくは置換もしくは非置換の複素環式基であるか、Ｒ８およびＲ９が一緒になって置換もしくは非置換のメチリデンを形成するか、またはＲ８およびＲ９は隣接原子と一緒になって置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基を形成していてもよく；Ｑは単結合、置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；ｍは０～３の整数である）である。
より好ましくは、
Figure JPOXMLDOC01-appb-C000111
（式中、各定義は上記と同意義である）である。 Alternatively, R 2A and R 2B may be taken together to form a substituted or unsubstituted hydroxyimino, preferably having the formula:
Figure JPOXMLDOC01-appb-C000109
(Wherein R 10 is a hydrogen atom or an alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carbamoylalkyl optionally substituted with one or more groups selected from substituent group D. Here, substituent group D is A group consisting of halogen, hydroxy, amino, carbamoyl, alkyloxycarbonylamino and phenyl), or a group represented by the formula:
Figure JPOXMLDOC01-appb-C000110
Wherein R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic R 8 and R 9 together form a substituted or unsubstituted methylidene, or R 8 and R 9 together with adjacent atoms are substituted or unsubstituted carbocyclic groups or May be a substituted or unsubstituted heterocyclic group; Q is a single bond, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; m is 0-3 Is an integer).
More preferably,
Figure JPOXMLDOC01-appb-C000111
Wherein each definition is as defined above.
　「Ｒ８およびＲ９がそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換の炭素環式基、もしくは置換もしくは非置換の複素環式基である」場合の例としては、水素原子、フッ素原子、塩素原子、ヒドロキシ、カルボキシ、メチル、エチル、イソプロピル、ｔｅｒｔ－ブチル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、カルボキシメチル、ヒドロキシエチル、カルバモイルメチル、カルバモイルエチル、ヒドロキシメチル、ヒドロキシエチル、メトキシメチル、エトキシメチル、メトキシエチル、エトキシエチル、メチルチオメチル、エチルチオメチル、アリルオキシカルボニルアミノメチル、ベンジル、４－ヒドロキシベンジル、４－メトキシベンジル、４－カルボキシベンジル、３，４－ジヒドロキシフェニル、ナフチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル、フリル、およびチエニル等が挙げられる。Ｒ８およびＲ９の好ましい組み合わせとしては、（Ｒ８、Ｒ９）が（水素原子、水素原子）、（水素原子、フッ素原子）、（フッ素原子、水素原子）、（水素原子、メチル）、（メチル、水素原子）、）、（水素原子、エチル）、（エチル、水素原子）（水素原子、イソプロピル）、（イソプロピル、水素原子）、（水素原子、フェニル）、（フェニル、水素原子）、（水素原子、カルボキシメチル）、（カルボキシメチル、水素原子）、（水素原子、ヒドロキシメチル）、（ヒドロキシメチル、水素原子）、（水素原子、アミノメチル）、（アミノメチル、水素原子）、(メチル、メチル)等が挙げられる。 “R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group. Examples of the case include a hydrogen atom, a fluorine atom, a chlorine atom, hydroxy, carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, hydroxyethyl, carbamoylmethyl, Carbamoylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, allyloxycarbonylaminomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybe Zyl, 4-carboxybenzyl, 3,4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl , Isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like. As a preferable combination of R 8 and R 9 , (R 8 , R 9 ) is (hydrogen atom, hydrogen atom), (hydrogen atom, fluorine atom), (fluorine atom, hydrogen atom), (hydrogen atom, methyl), (Methyl, hydrogen atom),), (hydrogen atom, ethyl), (ethyl, hydrogen atom) (hydrogen atom, isopropyl), (isopropyl, hydrogen atom), (hydrogen atom, phenyl), (phenyl, hydrogen atom), (Hydrogen atom, carboxymethyl), (carboxymethyl, hydrogen atom), (hydrogen atom, hydroxymethyl), (hydroxymethyl, hydrogen atom), (hydrogen atom, aminomethyl), (aminomethyl, hydrogen atom), (methyl , Methyl) and the like.
　あるいは、Ｒ２’ＡおよびＲ２’Ｂは一緒になって、置換もしくは非置換のヒドロキシイミノを形成していてもよく、好ましくは、式：
Figure JPOXMLDOC01-appb-C000112
（式中Ｒ１０’は水素原子またはアルキルである）で示される基であるか、または、式：
Figure JPOXMLDOC01-appb-C000113
（式中、Ｒ８’およびＲ９’はそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換の炭素環式基、もしくは置換もしくは非置換の複素環式基であるか、Ｒ８’およびＲ９’が一緒になって置換もしくは非置換のメチリデンを形成するか、またはＲ８’およびＲ９’は隣接原子と一緒になって置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基を形成していてもよく；Ｑ’は単結合、置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；ｍ’は０～３の整数である）である。
好ましくは、
Figure JPOXMLDOC01-appb-C000114
（式中、各定義は上記と同意義である）である。 Alternatively, R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino, preferably having the formula:
Figure JPOXMLDOC01-appb-C000112
(Wherein R 10 ′ is a hydrogen atom or alkyl), or a group represented by the formula:
Figure JPOXMLDOC01-appb-C000113
Wherein R 8 ′ and R 9 ′ are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted A cyclic group, R 8 ′ and R 9 ′ together form a substituted or unsubstituted methylidene, or R 8 ′ and R 9 ′ together with adjacent atoms are substituted or unsubstituted Or a substituted or unsubstituted heterocyclic group; Q ′ is a single bond, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group M ′ is an integer of 0 to 3).
Preferably,
Figure JPOXMLDOC01-appb-C000114
Wherein each definition is as defined above.
　「Ｒ８’およびＲ９’がそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換の炭素環式基、もしくは置換もしくは非置換の複素環式基である」場合の例としては、水素原子、フッ素原子、塩素原子、ヒドロキシ、カルボキシ、メチル、エチル、イソプロピル、ｔｅｒｔ－ブチル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、カルボキシメチル、ヒドロキシエチル、カルバモイルメチル、カルバモイルエチル、ヒドロキシメチル、ヒドロキシエチル、メトキシメチル、エトキシメチル、メトキシエチル、エトキシエチル、メチルチオメチル、エチルチオメチル、ベンジル、４－ヒドロキシベンジル、４－メトキシベンジル、４－カルボキシベンジル、３，４－ジヒドロキシフェニル、ナフチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル、フリル、およびチエニル等が挙げられる。
「Ｒ８’およびＲ９’がそれぞれ独立して、水素原子またはアルキルである」場合の例としては、水素原子、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチル等が挙げられる。Ｒ８’およびＲ９’の好ましい組み合わせとしては、（Ｒ８’、Ｒ９’）が（水素原子、水素原子）、（水素原子、メチル）、（メチル、水素原子）、または(メチル、メチル)が挙げられる。 “R 8 ′ and R 9 ′ are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group. Examples of the case of `` is a hydrogen atom, fluorine atom, chlorine atom, hydroxy, carboxy, methyl, ethyl, isopropyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, carboxymethyl, hydroxyethyl, carbamoyl '' Methyl, carbamoylethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methylthiomethyl, ethylthiomethyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-carboxybenzyl, 3, 4-dihydroxyphenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiazolyl, fur And thienyl and the like.
Examples of the case where “R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl” include a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, tert-butyl and the like. As a preferred combination of R 8 ′ and R 9 ′ , (R 8 ′ , R 9 ′ ) is (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (methyl, hydrogen atom), or (methyl, methyl) ).
　「Ｒ８およびＲ９、またはＲ８’およびＲ９’が一緒になって置換もしくは非置換のメチリデンを形成する」場合の例としては、下式
Figure JPOXMLDOC01-appb-C000115
（式中、Ｒ２２およびＲ２３はそれぞれ独立して、水素原子または置換もしくは非置換のアルキルである。）が挙げられる。Ｒ２２およびＲ２３の好ましい例としては、それぞれ独立して水素原子、メチル、フルオロメチル、トリフルオロメチル、エチル等であり、より好ましくは同時に水素原子である。 Examples of “R 8 and R 9 , or R 8 ′ and R 9 ′ together form a substituted or unsubstituted methylidene” include:
Figure JPOXMLDOC01-appb-C000115
(Wherein R 22 and R 23 are each independently a hydrogen atom or substituted or unsubstituted alkyl). Preferable examples of R 22 and R 23 are each independently a hydrogen atom, methyl, fluoromethyl, trifluoromethyl, ethyl or the like, more preferably a hydrogen atom at the same time.
　「Ｒ８およびＲ９、またはＲ８’およびＲ９’は隣接原子と一緒になって置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成する」場合、好ましくは３～６員の単環であり、より好ましくは３または４員環である。好ましい例としては、シクロプロパン、シクロブタン、シクロヘプタン、シクロヘキサン、アジリジン、オキシラン、チイラン、アジリン、チイレン、アゼチジン、オキセタン、チエタン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、テトラヒドロピラン、テトラヒドロチオピラン等が挙げられる。より好ましい例としては、シクロプロパンである。 “R 8 and R 9 , or R 8 ′ and R 9 ′ together with adjacent atoms form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle” A 3- to 6-membered monocycle is preferable, and a 3- or 4-membered ring is more preferable. Preferred examples include cyclopropane, cyclobutane, cycloheptane, cyclohexane, aziridine, oxirane, thiirane, azirine, thylene, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran and the like. . A more preferred example is cyclopropane.
　Ｒ３は水素原子、ＯＣＨ３またはＮＨ－ＣＨ（＝Ｏ）であり、好ましくは水素原子である。 R 3 is a hydrogen atom, OCH 3 or NH—CH (═O), preferably a hydrogen atom.
　Ｒ１６はカルボキシ、テトラゾリルまたは置換もしくは非置換のカルバモイルであり、好ましくはカルボキシ、カルバモイル、または下式：
Figure JPOXMLDOC01-appb-C000116
である。より好ましくは、カルボキシである。Ｒ１６の別の好ましい態様としては、テトラゾリルである。 R 16 is carboxy, tetrazolyl or substituted or unsubstituted carbamoyl, preferably carboxy, carbamoyl or the following formula:
Figure JPOXMLDOC01-appb-C000116
It is. More preferably, it is carboxy. Another preferred embodiment of R 16 is tetrazolyl.
　Ｒ１７は水素原子または置換もしくは非置換のアルキルであり、好ましくは水素原子またはアルキルである。より好ましくは、水素原子である。 R 17 is a hydrogen atom or substituted or unsubstituted alkyl, preferably a hydrogen atom or alkyl. More preferably, it is a hydrogen atom.
　－Ｚ－は単結合または－ＣＲ７ＡＲ７Ｂ－である。Ｒ７ＡおよびＲ７Ｂの好ましい例としては、それぞれ独立して、水素原子、ヒドロキシ、カルボキシ、カルバモイル、モノアルキルカルバモイル、ジアルキルカルバモイル、スルファモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシが挙げられる。より好ましくは、Ｒ７Ａが水素原子またはメチルであり、かつＲ７Ｂが水素原子、メチル、トリフルオロメチル、ヒドロキシまたはメトキシである。－Ｚ－の好ましい態様としては、単結合、－ＣＨ２－、－Ｃ（ＣＨ３）Ｈ－または－（ＣＨ３）２－であり、より好ましい態様としては、単結合または－ＣＨ２－である。 —Z— is a single bond or —CR 7A R 7B —. Preferable examples of R 7A and R 7B are each independently a hydrogen atom, hydroxy, carboxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkyl, haloalkyl, alkyl Examples include oxy and haloalkyloxy. More preferably, R7A is a hydrogen atom or methyl, and R7B is a hydrogen atom, methyl, trifluoromethyl, hydroxy or methoxy. A preferred embodiment of —Z— is a single bond, —CH 2 —, —C (CH 3 ) H— or — (CH 3 ) 2 —, and a more preferred embodiment is a single bond or —CH 2 —. is there.
　－Ｗ－は－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－である。好ましくは、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－Ｓ－である。より好ましくは、－Ｓ－ＣＨ２－である。 -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -. Preferred is —S—CH 2 —, —CH 2 —S— or —S—. More preferred is —S—CH 2 —.
　－Ｔ－は－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－である。Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂの好ましい例としては、それぞれ独立して水素原子、ハロゲン、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、カルボキシ、スルファモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、アルキル、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アシル、アシルオキシ、シアノ、アミジノ、グアニジノ、カルバモイルオキシ、アルキルカルボニルオキシ等が挙げられる。Ｒ４ＡおよびＲ４Ｂの好ましい態様としては、それぞれ独立して、水素原子、ヒドロキシ、アミノ、カルボキシ、メチル、メトキシ、トリフルオロメチル、トリフルオロメトキシ、シアノ、カルバモイルオキシ、アセチルオキシ等であり、さらに好ましくは、Ｒ４Ａが水素原子またはメチルであり、Ｒ４Ｂが水素原子、メチル、ヒドロキシ、カルバモイルオキシまたはアセチルオキシである。より好ましくは、Ｒ４Ａが水素原子またはメチルであり、Ｒ４Ｂが水素原子またはメチルである。Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂの好ましい態様としては、それぞれ独立して水素原子、ヒドロキシ、アミノ、カルボキシ、メチル、メトキシ、トリフルオロメチル、トリフルオロメトキシ、シアノである。より好ましい態様としては、Ｒ５ＡおよびＲ６Ａが水素原子であり、かつＲ５ＢおよびＲ６Ｂがそれぞれ独立して、水素原子、ヒドロキシである。さらに好ましくは、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂが水素原子である。好ましくは、－Ｔ－は－ＣＲ４ＡＲ４Ｂ－であり、より好ましくは、－ＣＨ２－、－Ｃ（ＣＨ３）Ｈ－、－Ｃ（ＣＨ３）２－または－Ｃ（ＯＨ）Ｈ－である。 —T— is —CR 4A R 4B —, —CR 5A R 5B —CR 6A R 6B — or —O—. Preferred examples of R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, halogen, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, carboxy, sulfamoyl, mono Examples include alkylsulfamoyl, dialkylsulfamoyl, alkyl, haloalkyl, haloalkyloxy, alkyloxy, acyl, acyloxy, cyano, amidino, guanidino, carbamoyloxy, alkylcarbonyloxy and the like. Preferred embodiments of R 4A and R 4B are each independently a hydrogen atom, hydroxy, amino, carboxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, carbamoyloxy, acetyloxy, and the like, and more preferably R 4A is a hydrogen atom or methyl, and R 4B is a hydrogen atom, methyl, hydroxy, carbamoyloxy or acetyloxy. More preferably, R 4A is a hydrogen atom or methyl, and R 4B is a hydrogen atom or methyl. Preferable embodiments of R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, hydroxy, amino, carboxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyano. In a more preferred embodiment, R 5A and R 6A are hydrogen atoms, and R 5B and R 6B are each independently a hydrogen atom and hydroxy. More preferably, R 5A , R 5B , R 6A and R 6B are hydrogen atoms. Preferably, -T- is -CR 4A R 4B -, more preferably an, -CH 2 -, - C ( CH 3) H -, - C (CH 3) 2 - or -C (OH) H- It is.
　式（Ｉ）において、－Ｚ－、Ｙ，－Ｗ－および－Ｔ－の好ましい組み合わせを以下に示す。
ｉ）－Ｚ－が単結合の時、ＹがＣＨであり、－Ｗ－が－Ｓ－ＣＨ２－であり、かつ－Ｔ－が－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－である。
ｉｉ）－Ｚ－が－ＣＲ７ＡＲ７Ｂ－の時、ＹがＮであり、－Ｗ－が－ＣＨ２－であり、かつ－Ｔ－が－ＣＲ４ＡＲ４Ｂ－である。 In the formula (I), preferred combinations of -Z-, Y, -W- and -T- are shown below.
i) -Z- when is a single bond, Y is CH, -W- is -S-CH 2 - and is, and -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B — or —O—.
ii) -Z- -CR 7A R 7B is - when, Y is N, -W- is -CH 2 - and is, and -T- is -CR 4A R 4B - is.
　式（ＩＩ）において、－Ｕ－は－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である。好ましくは、－Ｓ－ＣＨ２－である。 In the formula (II), —U— is —S—, —S—CH 2 — or —CH 2 —S—. Preferred is —S—CH 2 —.
　Ｒ１１はアミノまたはアシルで置換されたアミノである。好ましくは、置換もしくは非置換のアルキルカルボニルアミノである。Ｒ１１の好ましい態様としては、下式：
Figure JPOXMLDOC01-appb-C000117
（式中、Ｒ１’は置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；
Ｒ２’ＡおよびＲ２’Ｂについては、
ａ）Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、ＳＯ３Ｈ、置換もしくは非置換のスルファモイル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
ｂ）Ｒ２’ＡおよびＲ２’Ｂが一緒になって、置換もしくは非置換のヒドロキシイミノを形成してもよい）
で示される基である。より好ましい態様としては、下式：
Figure JPOXMLDOC01-appb-C000118
（式中、Ｒ１’は置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基であり、Ｒ１０’は水素原子またはアルキルであり、Ｒ８’およびＲ９’はそれぞれ独立して水素原子またはアルキルである）
である。 R 11 is amino or amino substituted with acyl. Preferred is substituted or unsubstituted alkylcarbonylamino. In a preferred embodiment of R 11 , the following formula:
Figure JPOXMLDOC01-appb-C000117
Wherein R 1 ′ is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
For R 2′A and R 2′B ,
a) R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted Or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or
b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
It is group shown by these. As a more preferred embodiment, the following formula:
Figure JPOXMLDOC01-appb-C000118
Wherein R 1 ′ is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, R 10 ′ is a hydrogen atom or alkyl, R 8 ′ and R Each 9 ′ is independently a hydrogen atom or alkyl)
It is.
　Ｒ１２は水素原子、ＯＣＨ３またはＮＨ－ＣＨ（＝Ｏ）であり、好ましくは水素原子である。 R 12 is a hydrogen atom, OCH 3 or NH—CH (═O), preferably a hydrogen atom.
　Ｒ１３は好ましくは水素原子である。 R 13 is preferably a hydrogen atom.
　Ｒ１４およびＲ１５はそれぞれ独立して水素原子または置換もしくは非置換のアルキルである。好ましくは、それぞれ独立して、水素原子またはメチルである。より好ましくは、同時に水素原子または同時にメチルである。 R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl. Preferably, they are each independently a hydrogen atom or methyl. More preferably, they are simultaneously hydrogen atoms or simultaneously methyl.
　本発明化合物の好ましい実施形態を以下に例示する。以下の実施形態で示される化合物としては、これらの具体例の全ての組み合わせが例示される。
（実施形態１）
式（Ｉ）において、
－Ｚ－が単結合であり；
ＹがＣＨであり；
－Ｗ－が－Ｓ－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－または－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、アセチルオキシ、カルバモイルオキシ、メチル、またはアミノであり；
Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂが水素原子であり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000119

（式中、各定義は上記と同意義である）
であり； 
Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000120
または下式：
Figure JPOXMLDOC01-appb-C000121
（式中、各定義は上記と同意義である）
であり；
Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６がカルボキシであり；かつ、Ｒ１７が水素原子である、ただし、以下の化合物を除く。
Figure JPOXMLDOC01-appb-C000122
 Preferred embodiments of the compound of the present invention are exemplified below. As a compound shown by the following embodiment, all the combinations of these specific examples are illustrated.
(Embodiment 1)
In formula (I),
-Z- is a single bond;
Y is CH;
-W- is -S-CH 2- ;
-T- is -CR 4A R 4B - or -CR 5A R 5B -CR 6A R 6B - a and;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, acetyloxy, carbamoyloxy, methyl, or amino;
R 5A , R 5B , CR 6A and R 6B are hydrogen atoms;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000119

(Wherein each definition has the same meaning as above)
Is;
R 2A and R 2B taken together have a methylidene having the substituents shown below:
Figure JPOXMLDOC01-appb-C000120
Or the following formula:
Figure JPOXMLDOC01-appb-C000121
(Wherein each definition has the same meaning as above)
Is;
R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy; and R 17 is a hydrogen atom, except for the following compounds.
Figure JPOXMLDOC01-appb-C000122
（実施形態２）
式（Ｉ）において、
－Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり；
ＹがＮであり；
－Ｗ－が－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルキル、または置換もしくは非置換のアミノであり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000123

（式中、各定義は上記と同意義である）
で示される基であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２Ａがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、スルホ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであり、およびＲ２Ｂが水素原子であり、
ｂ－１）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000124
または、
ｂ－２）下式：
Figure JPOXMLDOC01-appb-C000125

（式中、各定義は上記と同意義である）
であり；
Ｒ３が水素原子であり；Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６はカルボキシ、テトラゾリルまたはカルバモイルでありであり；かつ、Ｒ１７が水素原子またはアルキルである。 (Embodiment 2)
In formula (I),
-Z- is -CR 7A R 7B - a and;
Y is N;
-W- is -CH 2- ;
-T- is -CR 4A R 4B - a and;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000123

(Wherein each definition has the same meaning as above)
A group represented by:
For R 2A and R 2B
a) R 2A each independently has a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituent. Carbonyloxy, and R 2B is a hydrogen atom,
b-1) R 2A and R 2B taken together have a methylidene having the following substituents:
Figure JPOXMLDOC01-appb-C000124
Or
b-2) The following formula:
Figure JPOXMLDOC01-appb-C000125

(Wherein each definition has the same meaning as above)
Is;
R 3 is a hydrogen atom; R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy, tetrazolyl or carbamoyl; and R 17 is a hydrogen atom or alkyl.
（実施形態２－１）
式（Ｉ）が下式：
Figure JPOXMLDOC01-appb-C000126
（式中、－Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり；
ＹがＮであり；
－Ｗ－が－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルキル、または置換もしくは非置換のアミノであり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000127

（式中、各定義は上記と同意義である）
で示される基であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２ＡおよびＲ２Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、スルホ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、
ｂ－１）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000128
または、
ｂ－２）下式：
Figure JPOXMLDOC01-appb-C000129

（式中、各定義は上記と同意義である）
であり；
Ｒ３が水素原子であり；Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６はカルボキシ、テトラゾリルまたはカルバモイルでありであり；かつ、Ｒ１７が水素原子またはアルキルである。）である。 Embodiment 2-1
Formula (I) is:
Figure JPOXMLDOC01-appb-C000126
(Wherein, -Z- is -CR 7A R 7B - is;
Y is N;
-W- is -CH 2- ;
-T- is -CR 4A R 4B - a and;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000127

(Wherein each definition has the same meaning as above)
A group represented by:
For R 2A and R 2B
a) R 2A and R 2B each independently have a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituent. Or carbonyloxy
b-1) R 2A and R 2B taken together have a methylidene having the following substituents:
Figure JPOXMLDOC01-appb-C000128
Or
b-2) The following formula:
Figure JPOXMLDOC01-appb-C000129

(Wherein each definition has the same meaning as above)
Is;
R 3 is a hydrogen atom; R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy, tetrazolyl or carbamoyl; and R 17 is a hydrogen atom or alkyl. ).
（実施形態３）
式（Ｉ）が下式：
Figure JPOXMLDOC01-appb-C000130
 （式中、－Ｚ－が単結合であり；
ＹがＣＨであり；
－Ｗ－が－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、アセチルオキシ、カルバモイルオキシ、メチル、またはアミノであり；
Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂが水素原子であり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000131

（式中、各定義は上記と同意義である）
であり； 
Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000132
または下式：
Figure JPOXMLDOC01-appb-C000133

（式中、各定義は上記と同意義である）
であり；
Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６がカルボキシであり；かつ、Ｒ１７が水素原子である。）
である、ただし、以下の化合物を除く。
Figure JPOXMLDOC01-appb-C000134
 (Embodiment 3)
Formula (I) is:
Figure JPOXMLDOC01-appb-C000130
 Wherein -Z- is a single bond;
Y is CH;
-W- is -S-, -S-CH 2 -or -CH 2 -S-;
-T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, acetyloxy, carbamoyloxy, methyl, or amino;
R 5A , R 5B , CR 6A and R 6B are hydrogen atoms;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000131

(Wherein each definition has the same meaning as above)
Is;
R 2A and R 2B taken together have a methylidene having the substituents shown below:
Figure JPOXMLDOC01-appb-C000132
Or the following formula:
Figure JPOXMLDOC01-appb-C000133

(Wherein each definition has the same meaning as above)
Is;
R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy; and R 17 is a hydrogen atom. )
However, the following compounds are excluded.
Figure JPOXMLDOC01-appb-C000134
（実施形態４）
式（Ｉ）において、
－Ｚ－が単結合であり；
ＹがＣＨであり；
－Ｗ－が－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルキル、または置換もしくは非置換のアミノであり；
Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂが水素原子であり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000135

（式中、ＸはＣＣｌ、ＣＦまたはＣＢｒである）であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２Ａがそれぞれ独立して、置換もしくは非置換のアミノ、スルホ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであり、およびＲ２Ｂが水素原子であり、
ｂ－１）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000136
または、
ｂ－２）下式：
Figure JPOXMLDOC01-appb-C000137

（式中、各定義は上記と同意義である）
であり；
Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６はカルボキシ、テトラゾリルまたはカルバモイルでありであり；かつ、Ｒ１７が水素原子またはアルキルである。 (Embodiment 4)
In formula (I),
-Z- is a single bond;
Y is CH;
-W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -;
-T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino;
R 5A , R 5B , CR 6A and R 6B are hydrogen atoms;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000135

Where X is CCl, CF or CBr;
For R 2A and R 2B
a) each R 2A is independently substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy And R 2B is a hydrogen atom,
b-1) R 2A and R 2B taken together have a methylidene having the following substituents:
Figure JPOXMLDOC01-appb-C000136
Or
b-2) The following formula:
Figure JPOXMLDOC01-appb-C000137

(Wherein each definition has the same meaning as above)
Is;
R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy, tetrazolyl or carbamoyl; and R 17 is a hydrogen atom or alkyl.
（実施形態５）
式（Ｉ）において、
－Ｚ－が単結合であり；
ＹがＣＨであり；
－Ｗ－が－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－でありであり；
－Ｔ－が－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－であり；
Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂがそれぞれ独立して水素原子、ヒドロキシ、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルキル、または置換もしくは非置換のアミノであり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000138

（式中、各定義は上記と同意義である）
であり； 
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２Ａがそれぞれ独立して、置換もしくは非置換のアミノ、スルホ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであり、およびＲ２Ｂが水素原子であり、
ｂ－１）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000139
または、
ｂ－２）下式：
Figure JPOXMLDOC01-appb-C000140

（式中、各定義は上記と同意義である）
であり；Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６がカルボキシであり；かつ、Ｒ１７が水素原子である。 (Embodiment 5)
In formula (I),
-Z- is a single bond;
Y is CH;
-W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 - is the be;
-T- is -CR 5A R 5B -CR 6A R 6B -or -O-;
R 5A , R 5B , CR 6A and R 6B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted Of amino;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000138

(Wherein each definition has the same meaning as above)
Is;
For R 2A and R 2B
a) each R 2A is independently substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy And R 2B is a hydrogen atom,
b-1) R 2A and R 2B taken together have a methylidene having the following substituents:
Figure JPOXMLDOC01-appb-C000139
Or
b-2) The following formula:
Figure JPOXMLDOC01-appb-C000140

(Wherein each definition has the same meaning as above)
R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy; and R 17 is a hydrogen atom.
（実施形態６）
式（Ｉ）において、
－Ｚ－が単結合であり；
ＹがＣＨであり；
－Ｗ－が－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－であり；
－Ｔ－が－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－であり；
Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルキル、または置換もしくは非置換のアミノであり；
Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂが水素原子であり；
Ｒ１が下式：
Figure JPOXMLDOC01-appb-I000141

（式中、各定義は上記と同意義である）であり；
Ｒ２ＡおよびＲ２Ｂについては、
ａ）Ｒ２Ａがそれぞれ独立して、置換もしくは非置換のアミノ、スルホ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであり、およびＲ２Ｂが水素原子であり、
ｂ－１）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
Figure JPOXMLDOC01-appb-C000142
または、
ｂ－２）下式：
Figure JPOXMLDOC01-appb-C000143
（式中、各定義は上記と同意義である）
であり；
Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６はテトラゾリルまたはカルバモイルでありであり；かつ、Ｒ１７が水素原子である。 (Embodiment 6)
In formula (I),
-Z- is a single bond;
Y is CH;
-W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -;
-T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is;
R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino;
R 5A , R 5B , CR 6A and R 6B are hydrogen atoms;
R 1 is the following formula:
Figure JPOXMLDOC01-appb-I000141

Where each definition is as defined above;
For R 2A and R 2B
a) each R 2A is independently substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy And R 2B is a hydrogen atom,
b-1) R 2A and R 2B taken together have a methylidene having the following substituents:
Figure JPOXMLDOC01-appb-C000142
Or
b-2) The following formula:
Figure JPOXMLDOC01-appb-C000143
(Wherein each definition has the same meaning as above)
Is;
R 3 is a hydrogen atom or OCH 3 ; R 16 is tetrazolyl or carbamoyl; and R 17 is a hydrogen atom.
　本発明化合物（Ｉ）および（ＩＡ）は、特定の異性体に限定するものではなく、すべての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体、幾何異性体等）、ラセミ体またはそれらの混合物を含む。 The compounds (I) and (IA) of the present invention are not limited to specific isomers, but all possible isomers (for example, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical Isomers, rotamers, geometric isomers, etc.), racemates or mixtures thereof.
　式（ＩＩ）は、立体表記を特定している箇所を除き、すべての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体、幾何異性体等）、ラセミ体またはそれらの混合物を含む。 Formula (II) has all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, except where stereo designations are specified) , Geometric isomers, etc.), racemates or mixtures thereof.
　例えば、式（Ｉ）における
Figure JPOXMLDOC01-appb-C000144
は、
Figure JPOXMLDOC01-appb-C000145
等を包含する。
好ましくは、
Figure JPOXMLDOC01-appb-C000146
である。より好ましくは、
Figure JPOXMLDOC01-appb-C000147
である。 For example, in formula (I)
Figure JPOXMLDOC01-appb-C000144
Is
Figure JPOXMLDOC01-appb-C000145
Etc.
Preferably,
Figure JPOXMLDOC01-appb-C000146
It is. More preferably,
Figure JPOXMLDOC01-appb-C000147
It is.
　例えば、式（ＩＩ）における
Figure JPOXMLDOC01-appb-C000148
は
Figure JPOXMLDOC01-appb-C000149
等を包含する。
好ましくは、
Figure JPOXMLDOC01-appb-C000150
である。 For example, in formula (II)
Figure JPOXMLDOC01-appb-C000148
Is
Figure JPOXMLDOC01-appb-C000149
Etc.
Preferably,
Figure JPOXMLDOC01-appb-C000150
It is.
　式（Ｉ）および式（ＩＩ）の骨格上の置換位置の命名は、以下のとおりとする。本明細書中におけるα位側鎖およびβ位側鎖とは、下記母核のα位およびβ位に結合している基を示す。 The names of substitution positions on the skeletons of formula (I) and formula (II) are as follows. In the present specification, the α-position side chain and the β-position side chain represent groups bonded to the α-position and β-position of the following mother nucleus.
Figure JPOXMLDOC01-appb-I000151
Figure JPOXMLDOC01-appb-I000151
式（Ｉ）、（ＩＡ）または（ＩＩ）のエステル体とは、好ましくはα位のカルボキシおよび／またはβ位側鎖上におけるカルボキシのエステル体を包含する。β位側鎖上のカルボキシにおけるエステル体は、式：
Figure JPOXMLDOC01-appb-C000152
（式中、各記号は前記と同意義である。）
で示されるＲ1またはＲ2AもしくはＲ2Bの末端において、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、カルボキシ、置換もしくは非置換の低級アルキルオキシカルボニル、置換もしくは非置換のカルバモイル、置換基を有しているカルボニルオキシ等におけるカルボキシがエステル構造を有しているもの（例えば、カルボキシ（－ＣＯＯＨ）の場合、カルボキシ保護基等のエステル残基を示すＲＰ１とともに示される－ＣＯＯＲＰ１という構造で示される。）などを挙げることができ、体内で容易に代謝されてカルボキシの状態になるエステルを包含する。 The ester form of the formula (I), (IA) or (II) preferably includes an ester form of carboxy on the α-position and / or carboxy on the β-position side chain. Esters in carboxy on the β-position side chain have the formula:
Figure JPOXMLDOC01-appb-C000152
(In the formula, each symbol is as defined above.)
Substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, carboxy, substituted or unsubstituted lower alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituent at the end of R 1 or R 2A or R 2B represented by In which carboxy in carbonyloxy or the like having an ester structure has an ester structure (for example, in the case of carboxy (—COOH), a structure of —COOR P1 shown together with R P1 indicating an ester residue such as a carboxy protecting group) And esters that are easily metabolized in the body to form a carboxy state.
　上記のカルボキシ等の保護基としては、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ、Ｔ．Ｗ．Ｇｒｅｅｎｅ著、Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．（１９９１年）等に記載の方法で保護および／または脱保護できる基であればよく、例えば、低級アルキル（例：メチル、エチル、ｔ－ブチル）、低級アルキルカルボニルオキシメチル（例：ピバロイル）、置換されていてもよいアリールアルキル（例：ベンジル、ベンズヒドリル、フェネチル、ｐ－メトキシベンジル、ｐ－ニトロベンジル）、シリル基（例：ｔ－ブチルジメチルシリル、ジフェニルｔ－ブチルシリル）等が挙げられる。 Protecting groups such as carboxy described above include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected, such as lower alkyl (eg, methyl, ethyl, t-butyl), lower alkylcarbonyloxymethyl (eg, pivaloyl), An optionally substituted arylalkyl (eg, benzyl, benzhydryl, phenethyl, p-methoxybenzyl, p-nitrobenzyl), a silyl group (eg, t-butyldimethylsilyl, diphenyl t-butylsilyl) and the like can be mentioned.
　アミノ基の保護基としては、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ、Ｔ．Ｗ．Ｇｒｅｅｎｅ著、Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．（１９９１年）等に記載の方法で保護および／または脱保護できる基であればよく、例えば、低級アルキルオキシカルボニル（例：ｔ－ブトキシカルボニル、ベンジルオキシカルボニル、ｐ－ニトロベンジルオキシカルボニル）、置換されていてもよいアラルカノイル（例：ベンゾイル、ｐ－ニトロベンゾイル）、アシル（例：ホルミル、クロロアセチル）等が挙げられる。該アミノ基の保護基は、体内で容易に代謝されてアミノになる基も包含する。 Protecting groups for amino groups include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like, and any group that can be protected and / or deprotected, such as lower alkyloxycarbonyl (eg, t-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), substituted Aralkylanoyl (eg: benzoyl, p-nitrobenzoyl), acyl (eg: formyl, chloroacetyl) and the like which may be used may be mentioned. The amino-protecting group also includes a group that is easily metabolized in the body to become amino.
　式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ2Ｈ、3Ｈ、11Ｃ、13Ｃ、14Ｃ、15Ｎ、18Ｏ、17Ｏ、31Ｐ、32Ｐ、35Ｓ、18Ｆ、123Ｉおよび36Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), (IA) or (II) may be replaced by hydrogen, carbon and / or isotopes of other atoms, respectively. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compounds of formula (I), (IA) or (II) also include compounds substituted with such isotopes. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I), (IA) or (II). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
　式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）、（ＩＡ）または（ＩＩ）で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。他のトリチウム標識化合物を調製するための適切な方法としては、文書Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）を参照にできる。14Ｃ－標識化合物は、14Ｃ炭素を有する原料を用いることによって調製できる。 Radiolabeled compounds of the compounds represented by formula (I), (IA) or (II) can be prepared by methods well known in the art. For example, a tritium-labeled compound represented by the formula (I), (IA) or (II) is represented by the formula (I), (IA) or (II) by, for example, catalytic dehalogenation reaction using tritium. It can be prepared by introducing tritium into a specific compound. This method is a precursor in which a compound of formula (I), (IA) or (II) is appropriately halogen-substituted in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. It includes reacting the body with tritium gas. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
　式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物の塩とは、α位のカルボキシ基および／またはβ位のカルボキシ基および／またはβ位側鎖アミノ基が無機酸や有機酸と塩を形成しているものを包含する。 The salt of the compound represented by the formula (I), (IA) or (II) means that the α-position carboxy group and / or the β-position carboxy group and / or the β-position side chain amino group is an inorganic acid or an organic acid. Includes those forming a salt.
　式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物の製薬上許容される塩としては、例えば、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、ジエタノールアミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）およびアミノ酸との塩、または無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、および有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸等）との塩が挙げられる。特に塩酸、硫酸、リン酸、酒石酸、メタンスルホン酸との塩等が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 As the pharmaceutically acceptable salt of the compound represented by the formula (I), (IA) or (II), for example, a compound represented by the formula (I), (IA) or (II) and an alkali metal (for example, Lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanol) Amine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, iodine) Hydrofluoric acid etc.) and organic acids (eg formic acid, acetic acid) Propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid , Methanesulfonic acid, ethanesulfonic acid and the like). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
　式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物および結晶多形も包含する。「溶媒和物」は、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）または（ＩＡ）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物またはその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。 The compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystalline polymorph. The present invention also encompasses such various solvates and polymorphs. The “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I), (IA) or (II). When the compound represented by formula (I) or (IA) or a pharmaceutically acceptable salt thereof is left in the atmosphere to absorb moisture and adsorbed water adheres or forms a hydrate There is. In addition, a crystal polymorph may be formed by recrystallizing a compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof.
　式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解などを受けて式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物に変換される化合物、胃酸などにより加水分解されて式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばＤｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ　１９８５に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is hydrolyzed by a compound, gastric acid, etc., which is enzymatically oxidized, reduced, hydrolyzed and converted to a compound represented by the formula (I), (IA) or (II) under physiological conditions in vivo. The compound etc. which are decomposed | disassembled and converted into the compound shown by a formula (I), (IA) or (II) are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
　式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物またはその製薬上許容される塩がヒドロキシ基を有する場合は、例えばヒドロキシ基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることによりあるいは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えばＣＨ3ＣＯＯ－、Ｃ2Ｈ5ＣＯＯ－、ｔ－ＢｕＣＯＯ－、Ｃ15Ｈ31ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ2ＣＨ2ＣＯＯ－、ＣＨ3ＣＨ（ＮＨ2）ＣＯＯ－、ＣＨ2Ｎ（ＣＨ3）2ＣＯＯ－、ＣＨ3ＳＯ3－、ＣＨ3ＣＨ2ＳＯ3－、ＣＦ3ＳＯ3－、ＣＨ2ＦＳＯ3－、ＣＦ3ＣＨ2ＳＯ3－、ｐ－ＣＨ3－Ｏ－ＰｈＳＯ3－、ＰｈＳＯ3－、ｐ－ＣＨ3ＰｈＳＯ3－が挙げられる。 When the compound represented by the formula (I), (IA) or (II) or a pharmaceutically acceptable salt thereof has a hydroxy group, for example, a compound having a hydroxy group and an appropriate acyl halide, an appropriate acid anhydride, Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride and a mixed anhydride, or reacting with a condensing agent. For example, CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p— CH 3 —O—PhSO 3 —, PhSO 3 —, and p—CH 3 PhSO 3 — can be mentioned.
　本発明は、（Ａ）式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物と、（Ｂ）β－ラクタマーゼ阻害作用を有する化合物、その製薬上許容される塩、またはそれらの溶媒和物を組み合わせることを特徴とする医薬を提供する。β―ラクタマーゼ阻害作用を有する化合物としては、メタロβ－ラクタマーゼ阻害作用を有する化合物やセリンβ－ラクタマーゼ阻害作用を有する化合物等が挙げられ、好ましくはセリンβ－ラクタマーゼ阻害作用を有する化合物である。より好ましくは、クラスＣのβ－ラクタマーゼ阻害作用を有する化合物である。β－ラクタマーゼ阻害作用を有する化合物の具体例としては、クラブラン酸、スルバクタム、タゾバクタム、ジピコリン酸（ＤＰＡ）、３－アミノフェニルボロン酸（ＡＰＢ）、エチレンジアミン四酢酸（ＥＤＴＡ）、アビバクタム（ＡＶＩ）等が挙げられ、その他にもＥｘｐｅｒｔ Ｏｐｉｎｉｏｎ Ｔｈｅｒａｐｅｕｔｉｃ Ｐａｔｅｎｔｓ （２０１３）， ２３（１１），１４６９－１４８１に記載されているβ－ラクタマーゼ阻害作用を有する化合物が挙げられる。好ましくは、アビバクタム、３－アミノフェニルボロン酸等である。 The present invention relates to (A) a compound represented by formula (I), (IA) or (II), an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (B) β- There is provided a medicament characterized by combining a compound having a lactamase inhibitory action, a pharmaceutically acceptable salt thereof, or a solvate thereof. Examples of the compound having a β-lactamase inhibitory action include a compound having a metallo β-lactamase inhibitory action and a compound having a serine β-lactamase inhibitory action, and a compound having a serine β-lactamase inhibitory action is preferable. More preferred are compounds having class C β-lactamase inhibitory action. Specific examples of the compound having β-lactamase inhibitory action include clavulanic acid, sulbactam, tazobactam, dipicolinic acid (DPA), 3-aminophenylboronic acid (APB), ethylenediaminetetraacetic acid (EDTA), abibactam (AVI) and the like. In addition, compounds having β-lactamase inhibitory activity described in Expert Opinion Therapeutic Patents (2013), 23 (11), 1469-1481 can be mentioned. Preferred are abibactam and 3-aminophenylboronic acid.
　下記の一般的合成法および実施例に記載するように、式（Ｉ）および（ＩＡ）で示される本発明の化合物は、下記中間体の骨格のα位およびβ位にそれぞれ側鎖部位を結合することにより得られる。上記保護基Ｐとしては、以下の一般的合成において記載する保護基が挙げられるが、好ましい例としては、ベンズヒドリル基、パラメトキシベンジル基、トリチル基、２，６－ジメトキシベンジル基、メトキシメチル基、ベンジルオキシメチル基または２-（トリメチルシリル）エトキシメチル基などが挙げられる。また、脱離基としては、ハロゲン（Ｃｌ、Ｂｒ、Ｉ、Ｆ）、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等が例示される。 As described in the following general synthetic methods and examples, the compounds of the present invention represented by the formulas (I) and (IA) have side chain sites bonded to the α-position and β-position of the skeleton of the intermediate shown below Can be obtained. Examples of the protecting group P include protecting groups described in the following general synthesis. Preferred examples include a benzhydryl group, a paramethoxybenzyl group, a trityl group, a 2,6-dimethoxybenzyl group, a methoxymethyl group, Examples thereof include a benzyloxymethyl group and a 2- (trimethylsilyl) ethoxymethyl group. Examples of the leaving group include halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like.
（製法Ａ）
Figure JPOXMLDOC01-appb-C000153
（式中、Ｚ，Ｗ、Ｙ、ＴおよびＲ３は前記と同意義であり、－Ｗ１は－Ｈ，－ＳＨまたは－ＣＨ２－ＳＨであり、Ａは脱離基（たとえば、ハロゲン（Ｃｌ、Ｂｒ、Ｉ、Ｆ）、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）を示し、Ｐ１はアミノ基の保護基を示し、Ｐ２およびＰ３はそれぞれ独立してカルボキシの保護基を示す。）
工程１
化合物（ＩＩＩ）と化合物（ＩＶ）を付加反応及び分子内環化反応に付すことにより化合物（Ｖ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。
好ましくはアセトンとＨＭＰＡである。反応温度は通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約１０～３０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程２
化合物（Ｖ）の保護基Ｐ３を酸性条件下脱保護反応に付し、続いて縮合剤存在下で分子内環化反応に付すことにより化合物（ＶＩ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。脱保護反応に用いる酸としては、有機酸または無機酸が挙げられる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸等が挙げられる。好ましくはトリフルオロ酢酸である。縮合剤としては、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール等が挙げられる。反応温度は通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約０～２０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程３
化合物（ＶＩ）のアシル基を含むカルボキシ保護基Ｐ１を塩基存在下の加アルコール分解反応または酸性条件下での脱保護反応を行うことにより化合物（ＶＩＩ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。加アルコール分解反応としては、五塩化リン、五臭化リン、オキシ塩化リン、チオニルクロライド等によって活性化することができる。好ましくは、五塩化リンである。塩基としては有機塩基等が挙げられる。例えば、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、Ｎ－メチルイミダゾール、Ｎ－メチルモルホリン等が挙げられる。好ましくはピリジンである。その後アルコールを加える。該アルコールとしては、メタノール、エタノール、プロパノール等を用いることができる。好ましくは、エタノールである。酸性条件下での脱保護反応の際に用いる酸としては、有機酸または無機酸が挙げられる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸等が挙げられる。反応温度は通常、加アルコール分解反応としては約－１００～１００℃、好ましくは約－７０～２０℃であり、より好ましくは約－７０～－３０℃である。酸性条件下での脱保護反応としては、通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約－２０～２０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
Figure JPOXMLDOC01-appb-C000154
 （式中、Ｚ，Ｙ、Ｗ，Ｔ、Ｒ１、Ｒ２Ａ、Ｒ２ＢおよびＲ３は前記と同意義であり、Ｐ２はカルボキシの保護基を示す。）
工程４
化合物（ＶＩＩ）を、化合物（ＶＩＩＩ）と塩基存在下で縮合反応に付すことにより、化合物（ＩＸ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。縮合剤としては、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩、オキシ塩化リン、メタンスルホニルクロライド、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール、フェニルリン酸ジクロライド等が挙げられる。用いる塩基としては、有機塩基等が挙げられる。例えば、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、Ｎ－メチルイミダゾール、Ｎ－メチルモルホリン等が挙げられる。好ましくは、ピリジンである。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。
工程５
化合物（ＩＸ）の全ての保護基を酸性条件下脱保護反応に付し、化合物（Ｉ）を得る。反応溶媒としては、例えば、反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。酸としては、有機酸または無機酸を用いることができる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸、ギ酸、塩化アルミニウム、塩化チタニウム等が挙げられる。好ましくは、トリフルオロ酢酸または塩化アルミニウムである。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。 (Manufacturing method A)
Figure JPOXMLDOC01-appb-C000153
Wherein Z, W, Y, T and R 3 are as defined above, -W 1 is -H, -SH or -CH 2 -SH, and A is a leaving group (for example, halogen ( Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.), P 1 represents an amino-protecting group, and P 2 and P 3 independently represent carboxy Represents a protecting group.)
Process 1
Compound (V) is obtained by subjecting compound (III) and compound (IV) to an addition reaction and an intramolecular cyclization reaction. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more.
Acetone and HMPA are preferred. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 10 to 30 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 2
It subjected the compound protecting group P 3 of (V) under acidic conditions deprotection reaction to obtain subsequently a compound by subjecting the intramolecular cyclization reaction under condensing agent present in the (VI). Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. Examples of the acid used for the deprotection reaction include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned. Trifluoroacetic acid is preferred. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 0 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 3
Compound (VII) is obtained by subjecting the carboxy protecting group P 1 containing an acyl group of compound (VI) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride. Examples of the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred. Then add alcohol. As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable. Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned. The reaction temperature is usually about −100 to 100 ° C., preferably about −70 to 20 ° C., more preferably about −70 to −30 ° C. for the alcoholysis reaction. The deprotection reaction under acidic conditions is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Figure JPOXMLDOC01-appb-C000154
 (In the formula, Z, Y, W, T, R 1 , R 2A , R 2B and R 3 are as defined above, and P 2 represents a protecting group for carboxy.)
Process 4
Compound (IX) is obtained by subjecting Compound (VII) to a condensation reaction with Compound (VIII) in the presence of a base. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, phosphorus oxychloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, carbonyldiimidazole, phenyl phosphate dichloride, and the like. Examples of the base used include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferable. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process 5
All protecting groups of compound (IX) are subjected to a deprotection reaction under acidic conditions to give compound (I). Examples of the reaction solvent include, for example, ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-acetate). -Butyl), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg acetonitrile, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, Water It is shown. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. As the acid, an organic acid or an inorganic acid can be used. Examples thereof include trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride and the like. Preferred is trifluoroacetic acid or aluminum chloride. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
（製法Ｂ）
Figure JPOXMLDOC01-appb-C000155
（Ｒ１６ａおよびＲ１６ｂはそれぞれ独立して、水素原子または置換もしくは非置換のアルキルであり、Ｒ１６Ａはシアノまたは保護基を有していてもよいテトラゾリルであり、その他の記号は前記と同意義である）
工程１
化合物（ＶＩ）のＰ２は、保護基によって接触還元または酸性条件下によって脱保護できる。接触還元は、常圧水素存在下、触媒としてパラジウム-炭素を用い、反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはエタノールまたはテトラヒドロフランである。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。酸性条件下による脱保護は、酸としては、有機酸または無機酸を用いることができる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸、ギ酸、塩化アルミニウム、塩化チタニウム等が挙げられる。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。
工程２
化合物（ＶＩＩ）のカルボン酸は、アミドに変換できる。カルボン酸の活性化試薬として、塩化チオニル、オキザリルクロリド、クロロ炭酸エチル、二炭酸ジ-tert-ブチル、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミドなどが挙げられる。好ましくは二炭酸ジ-tert-ブチルである。アミド化剤として、アンモニア、塩化アンモニウム、ギ酸アンモニウム、炭酸アンモニウムなどが挙げられる。好ましくは炭酸アンモニウムである。塩基として、ピリジン、ジメチルアミノピリジン、ピコリン、トリエチルアミン、ジイソプロピルエチルアミンなどが挙げられる。好ましくはピリジンである。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。
工程３
化合物（ＶＩＩ）のアミド基は、シアノ基またはシアノ基を経由して保護基を有していてもよいテトラゾリルに変換可能である。シアノ基への変換は、脱水試薬を用いて行うことができる。脱水試薬としては、塩化チオニル、オギザリルクロリド、トリフルオロ酢酸無水物、酢酸無水物、五塩化リン、五酸化二リンなどが挙げられる。好ましくはトリフルオロ酢酸無水物である。反応には塩基を共存させても良い。塩基としては、ピリジン、ピコリン、トリエチルアミン、ルチジン、ジイソプロピルエチルアミンなどが挙げられる。好ましくは、ピリジンである。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。続いてテトラゾリルに変換する場合、トリメチルシリルアジド、アジ化ナトリウム、アジ化水素酸、ジフェニルリン酸アジドを用いて変換できる。好ましくはトリメチルシリルアジドである。触媒としてジブチルスズオキシドを共存させることができる。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジオキサンである。反応温度は通常、約－５０～１５０℃、好ましくは約２０～１２０℃、より好ましくは約６０～１００℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。該テトラゾリル基は必要に応じて保護することができる。該保護基としては、カルボキシ基の保護基と同様の保護基を用いることができる。好ましい保護基としては、ベンズヒドリル、p－メトキシベンジルなどが挙げられる。
工程４
化合物（ＩX）のアシル基を含むカルボキシ保護基Ｐ１を塩基存在下の加アルコール分解反応または酸性条件下での脱保護反応を行うことにより化合物（ＶＩＩ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。加アルコール分解反応としては、五塩化リン、五臭化リン、オキシ塩化リン、チオニルクロライド等によって活性化することができる。好ましくは、五塩化リンである。塩基としては有機塩基等が挙げられる。例えば、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、Ｎ－メチルイミダゾール、Ｎ－メチルモルホリン等が挙げられる。好ましくはピリジンである。その後アルコールを加える。該アルコールとしては、メタノール、エタノール、プロパノール等を用いることができる。好ましくは、エタノールである。酸性条件下での脱保護反応の際に用いる酸としては、有機酸または無機酸が挙げられる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸等が挙げられる。反応温度は通常、加アルコール分解反応としては約－１００～１００℃、好ましくは約－７０～２０℃であり、より好ましくは約－７０～－３０℃である。酸性条件下での脱保護反応としては、通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約－２０～２０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。 (Manufacturing method B)
Figure JPOXMLDOC01-appb-C000155
(R 16a and R 16b are each independently a hydrogen atom or substituted or unsubstituted alkyl, R 16A is cyano or tetrazolyl optionally having a protecting group, and other symbols are as defined above. Is)
Process 1
P 2 of compound (VI) can be deprotected by catalytic reduction or acidic conditions with a protecting group. For catalytic reduction, palladium-carbon is used as a catalyst in the presence of atmospheric pressure hydrogen, and examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (Eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides ( Examples: formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, : Nitromethane, nitroethane, nitrobenzene ), Dimethyl sulfoxide, water and the like. These solvents may be used alone or in combination of two or more. Ethanol or tetrahydrofuran is preferred. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours. For deprotection under acidic conditions, an organic acid or an inorganic acid can be used as the acid. Examples thereof include trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process 2
The carboxylic acid of compound (VII) can be converted to an amide. Examples of the activating agent for carboxylic acid include thionyl chloride, oxalyl chloride, ethyl chlorocarbonate, di-tert-butyl dicarbonate, carbonyldiimidazole, dicyclohexylcarbodiimide and the like. Preferred is di-tert-butyl dicarbonate. Examples of the amidating agent include ammonia, ammonium chloride, ammonium formate, and ammonium carbonate. Ammonium carbonate is preferred. Examples of the base include pyridine, dimethylaminopyridine, picoline, triethylamine, diisopropylethylamine and the like. Pyridine is preferred. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process 3
The amide group of compound (VII) can be converted to a tetrazolyl optionally having a protecting group via a cyano group or a cyano group. Conversion to a cyano group can be performed using a dehydrating reagent. Examples of the dehydrating reagent include thionyl chloride, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, phosphorus pentachloride, diphosphorus pentoxide, and the like. Preferred is trifluoroacetic anhydride. A base may coexist in the reaction. Examples of the base include pyridine, picoline, triethylamine, lutidine, diisopropylethylamine and the like. Pyridine is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours. Subsequent conversion to tetrazolyl can be done using trimethylsilyl azide, sodium azide, hydrazoic acid, diphenylphosphoric acid azide. Trimethylsilyl azide is preferred. Dibutyltin oxide can coexist as a catalyst. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Dioxane is preferred. The reaction temperature is usually about −50 to 150 ° C., preferably about 20 to 120 ° C., more preferably about 60 to 100 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours. The tetrazolyl group can be protected as necessary. As the protecting group, a protecting group similar to the protecting group for carboxy group can be used. Preferred protecting groups include benzhydryl, p-methoxybenzyl and the like.
Process 4
Compound (VII) is obtained by subjecting carboxy protecting group P 1 containing an acyl group of compound (IX) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride. Examples of the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred. Then add alcohol. As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable. Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned. The reaction temperature is usually about −100 to 100 ° C., preferably about −70 to 20 ° C., more preferably about −70 to −30 ° C. for the alcoholysis reaction. The deprotection reaction under acidic conditions is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
（製法Ｃ）
Figure JPOXMLDOC01-appb-C000156
（Ｐ１‘は置換もしくは非置換のアルキル等であり、脱離基（たとえば、ハロゲン（Ｃｌ、Ｂｒ、Ｉ、Ｆ）、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）であり、、その他の記号は前記と同意義である）
工程１
化合物（XＩ）を酸化することによって化合物（XII）に導くことができる。酸化剤としては、二酸化セレン、オクソンなどが挙げられる。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。反応温度は通常、約－５０～１５０℃、好ましくは約２０～１２０℃、より好ましくは約６０～１００℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。
工程２
化合物（XＩI）と化合物（XIII）のアルキル化反応及び続く環化反応によって化合物（XIV）に導くことができる。塩基としてトリエチルアミン、ジイソプロピルエチルアミン、ピリジン、モルホリン、ルチジンが挙げられる。好ましくは、トリエチルアミンである。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはアセトンとHMPAである。反応温度は通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約１０～３０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程３
化合物（XIV）にα―ハロ酢酸ハライドを反応させることにより、化合物（XV）へ導くことができる。用いる塩基として、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、モルホリン、ルチジンが挙げられる。好ましくは、トリエチルアミンである。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。反応温度は通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約０～２０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程４
化合物（XV）のハライドをホスホニウム塩に変換し、続いて塩基存在下起こる分子内環化によって化合物（XV）に導くことができる。ホスホニウム塩形成には、トリフェニルホスフィン、トリエチルホスフィン、トリブチルホスフィンなどが挙げられ、好ましくはトリフェニルホスフィンである。塩基としては、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、トリエチルアミン、ジイソプロピルエチルアミン、ナトリウムメトキシド、ナトリウムエトキシド、カリウム-tert-ブトキシドが挙げられる。好ましくは炭酸水素ナトリウムである。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジメチルホルムアミドである。反応温度は通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約１０～３０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程５
化合物（XVI）の二重結合を還元することによって、化合物（XVII）に導くことができる。還元は接触水素化または還元剤を用いて行い、還元剤としては水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化ホウ素が挙げられる。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジメチルホルムアミドである。反応温度は通常、約－１００～５０℃、好ましくは約－６０～０℃、より好ましくは約－５０～－２０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程６
化合物（ＩX）のカルボニル基を含むアミノ保護基Ｐ１を塩基存在下の加アルコール分解反応または酸性条件下での脱保護反応を行うことにより化合物（ＶＩＩ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。加アルコール分解反応としては、五塩化リン、五臭化リン、オキシ塩化リン、チオニルクロライド等によって活性化することができる。好ましくは、五塩化リンである。塩基としては有機塩基等が挙げられる。例えば、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、Ｎ－メチルイミダゾール、Ｎ－メチルモルホリン等が挙げられる。好ましくはピリジンである。その後アルコールを加える。該アルコールとしては、メタノール、エタノール、プロパノール等を用いることができる。好ましくは、エタノールである。酸性条件下での脱保護反応の際に用いる酸としては、有機酸または無機酸が挙げられる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸等が挙げられる。反応温度は通常、加アルコール分解反応としては約－１００～１００℃、好ましくは約－７０～２０℃であり、より好ましくは約－７０～－３０℃である。酸性条件下での脱保護反応としては、通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約－２０～２０℃である。 (Manufacturing method C)
Figure JPOXMLDOC01-appb-C000156
(P1 ′ is substituted or unsubstituted alkyl or the like, and is a leaving group (for example, halogen (Cl, Br, I, F), methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.), And other symbols are as defined above)
Process 1
Compound (XI) can be led to compound (XII) by oxidation. Examples of the oxidizing agent include selenium dioxide and oxon. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually about −50 to 150 ° C., preferably about 20 to 120 ° C., more preferably about 60 to 100 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process 2
Compound (XIV) can be led to compound (XIV) by alkylation reaction of compound (XII) and compound (XIII) and subsequent cyclization reaction. Examples of the base include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Acetone and HMPA are preferred. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 10 to 30 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 3
By reacting compound (XIV) with α-haloacetic acid halide, compound (XV) can be derived. Examples of the base used include triethylamine, diisopropylethylamine, pyridine, morpholine, and lutidine. Triethylamine is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 0 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 4
The halide of compound (XV) can be converted to a phosphonium salt and subsequently led to compound (XV) by intramolecular cyclization that occurs in the presence of a base. Examples of the phosphonium salt formation include triphenylphosphine, triethylphosphine, tributylphosphine, and the like, and triphenylphosphine is preferable. Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, and potassium tert-butoxide. Sodium bicarbonate is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dimethylformamide. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about 10 to 30 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 5
Reduction of the double bond of compound (XVI) can lead to compound (XVII). The reduction is performed using catalytic hydrogenation or a reducing agent, and examples of the reducing agent include sodium borohydride, lithium borohydride, and borohydride. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dimethylformamide. The reaction temperature is usually about −100 to 50 ° C., preferably about −60 to 0 ° C., more preferably about −50 to −20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Step 6
Compound (VII) is obtained by subjecting amino protecting group P 1 containing a carbonyl group of compound (IX) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride. Examples of the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred. Then add alcohol. As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable. Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned. The reaction temperature is usually about −100 to 100 ° C., preferably about −70 to 20 ° C., more preferably about −70 to −30 ° C. for the alcoholysis reaction. The deprotection reaction under acidic conditions is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about −20 to 20 ° C.
（製法D）
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000158
（式中、Ｒ１８は置換もしくは非置換のアルキルであり、Ｒ１７は水素原子または置換もしくは非置換のアルキルであり、その他の記号は前記と同意義である。）
工程１－１
化合物（XIX）または化合物（XX）の環状アミド窒素原子を塩基存在下でアシル化することによって化合物（XXI）または化合物（XXII）に導くことができる。アシル化剤としてはｔｅｒｔ－ブチル　２－クロロ－２－オキソアセテートなどが挙げられる。塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ルチジンなどが挙げられる。好ましくは、ジイソプロピルエチルアミンである。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。反応温度は通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約－２０～２０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程１－２
化合物（XXII）の二重結合をオゾン分解することにより、化合物（XXIII）に導くことができる。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。反応温度は通常、約－１００～０℃、好ましくは約－７０～－４０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程２
化合物（XXI）や化合物（XXIII）に代表される化合物（XXIV）を還元剤によって環化させ化合物（XXV）に導くことができる。還元剤としては、ヨウ化サマリウムなどが挙げられる。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはテトラヒドロフランである。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。反応温度は通常、約－１００～０℃、好ましくは約－７０～－４０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程３
化合物（XXV）のジヒドロキシ基は、アシル化剤によって環状カーボネート構造に導くことができる。アシル化剤としては、カルボニルジイミダゾール、トリホスゲンなどが挙げられる。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。反応温度は通常、約－１００～１００℃、好ましくは約－４０～０℃である。反応時間は、溶媒や反応温度により異なるが、通常０．５～４８時間である。
工程４
化合物（ＸＸＶＩ）のカルボニル基を含むアミノ保護基Ｐ１を塩基存在下の加アルコール分解反応または酸性条件下での脱保護反応を行うことにより化合物（ＶＩＩ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：アセトニトリル、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくはジクロロメタンである。加アルコール分解反応としては、五塩化リン、五臭化リン、オキシ塩化リン、チオニルクロライド等によって活性化することができる。好ましくは、五塩化リンである。塩基としては有機塩基等が挙げられる。例えば、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、Ｎ－メチルイミダゾール、Ｎ－メチルモルホリン等が挙げられる。好ましくはピリジンである。その後アルコールを加える。該アルコールとしては、メタノール、エタノール、プロパノール等を用いることができる。好ましくは、エタノールである。酸性条件下での脱保護反応の際に用いる酸としては、有機酸または無機酸が挙げられる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸等が挙げられる。反応温度は通常、加アルコール分解反応としては約－１００～１００℃、好ましくは約－７０～２０℃であり、より好ましくは約－７０～－３０℃である。酸性条件下での脱保護反応としては、通常、約－１００～１００℃、好ましくは約－２０～４０℃、より好ましくは約－２０～２０℃である。 (Manufacturing method D)
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000158
(Wherein R 18 is substituted or unsubstituted alkyl, R 17 is a hydrogen atom or substituted or unsubstituted alkyl, and other symbols are as defined above.)
Step 1-1
The compound (XIX) or compound (XXII) can be derived by acylating the cyclic amide nitrogen atom of the compound (XIX) or compound (XX) in the presence of a base. Examples of the acylating agent include tert-butyl 2-chloro-2-oxoacetate. Examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine and the like. Diisopropylethylamine is preferable. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours. The reaction temperature is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Step 1-2
Ozonolysis of the double bond of compound (XXII) can lead to compound (XXIII). Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours. The reaction temperature is usually about −100 to 0 ° C., preferably about −70 to −40 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 2
The compound (XXIV) typified by the compound (XXI) or the compound (XXIII) can be cyclized with a reducing agent to lead to the compound (XXV). Examples of the reducing agent include samarium iodide. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Tetrahydrofuran is preferred. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours. The reaction temperature is usually about −100 to 0 ° C., preferably about −70 to −40 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 3
The dihydroxy group of compound (XXV) can be led to a cyclic carbonate structure by an acylating agent. Examples of the acylating agent include carbonyldiimidazole and triphosgene. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours. The reaction temperature is usually about −100 to 100 ° C., preferably about −40 to 0 ° C. The reaction time varies depending on the solvent and reaction temperature, but is usually 0.5 to 48 hours.
Process 4
Compound (VII) is obtained by subjecting amino protecting group P 1 containing a carbonyl group of compound (XXVI) to an alcoholysis reaction in the presence of a base or a deprotection reaction under acidic conditions. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, acetonitrile, propionitrile), nitros (eg, nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like are exemplified. These solvents may be used alone or in combination of two or more. Preferred is dichloromethane. The alcoholysis decomposition reaction can be activated by phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or the like. Preferably, it is phosphorus pentachloride. Examples of the base include organic bases. For example, triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Pyridine is preferred. Then add alcohol. As the alcohol, methanol, ethanol, propanol or the like can be used. Ethanol is preferable. Examples of the acid used in the deprotection reaction under acidic conditions include organic acids and inorganic acids. For example, trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be mentioned. The reaction temperature is usually about −100 to 100 ° C., preferably about −70 to 20 ° C., more preferably about −70 to −30 ° C. for the alcoholysis reaction. The deprotection reaction under acidic conditions is usually about −100 to 100 ° C., preferably about −20 to 40 ° C., more preferably about −20 to 20 ° C.
（製法Ｅ）
Figure JPOXMLDOC01-appb-C000159
（式中、各記号は前記と同意義である）
工程１
アミン体を、化合物（ＶＩＩ）と塩基存在下で縮合反応に付すことにより、化合物（ＸＸＶＩＩＩ）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：ＭｅＣＮ、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。縮合剤としては、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩、オキシ塩化リン、メタンスルホニルクロライド、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール、フェニルリン酸ジクロライド等が挙げられる。塩基としては、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、Ｎ－メチルイミダゾール、Ｎ－メチルモルホリン等が挙げられる。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。
工程２
化合物（ＸＸＶＩＩＩ）を酸化することにより、化合物（ＸＸＩX）を得る。反応溶媒としては、例えばエーテル類（例：アニソール、ジオキサン、テトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル）、エステル類（例：ギ酸エチル、酢酸エチル、酢酸ｎ－ブチル）、ハロゲン化炭化水素類（例：ジクロロメタン、クロロホルム、四塩化炭素）、炭化水素類（例：ｎ－ヘキサン、ベンゼン、トルエン）、アミド類（例：ホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン）、ケトン類（例：アセトン、メチルエチルケトン）、ニトリル類（例：ＭｅＣＮ、プロピオニトリル）、ニトロ類（例：ニトロメタン、ニトロエタン、ニトロベンゼン）、ジメチルスルホキシド、水などが例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。酸化剤としては、過酢酸、m－クロロ過安息香酸、過酸化水素、タングステン酸ナトリウム等が挙げられる。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。
工程３
化合物（ＸＸIX）の全ての保護基を酸性条件下脱保護反応に付し、化合物（I）を得る。酸としては、有機酸または無機酸を用いることができる。例えば、トリフルオロ酢酸、トシル酸、塩酸、硫酸、リン酸、ギ酸、塩化アルミニウム、塩化チタニウム等が挙げられる。反応温度は通常、約－１００～１００℃、好ましくは約－８０～２０℃、より好ましくは約－２０～２０℃である。反応時間は、用いる試薬や溶媒や反応温度により異なるが、通常０．５～２４時間である。 (Manufacturing method E)
Figure JPOXMLDOC01-appb-C000159
(Wherein each symbol is as defined above)
Process 1
Compound (XXVIII) is obtained by subjecting the amine body to a condensation reaction with compound (VII) in the presence of a base. Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like. These solvents may be used alone or in combination of two or more. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, phosphorus oxychloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, carbonyldiimidazole, and phenyl phosphate dichloride. Examples of the base include triethylamine, pyridine, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process 2
Compound (XXIX) is obtained by oxidizing compound (XXVIII). Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), halogenated carbonization Hydrogens (eg, dichloromethane, chloroform, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitroethane, nitrobenzene), dimethyl sulfoxide, water and the like. These solvents may be used alone or in combination of two or more. Examples of the oxidizing agent include peracetic acid, m-chloroperbenzoic acid, hydrogen peroxide, sodium tungstate, and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
Process 3
All protecting groups of compound (XXIX) are subjected to a deprotection reaction under acidic conditions to give compound (I). As the acid, an organic acid or an inorganic acid can be used. Examples thereof include trifluoroacetic acid, tosylic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aluminum chloride, titanium chloride and the like. The reaction temperature is usually about −100 to 100 ° C., preferably about −80 to 20 ° C., more preferably about −20 to 20 ° C. The reaction time varies depending on the reagent, solvent and reaction temperature used, but is usually 0.5 to 24 hours.
　なお、得られた化合物（Ｉ）または（ＩＡ）をさらに化学修飾してエステル体、またはそれらの製薬上許容される塩もしくは溶媒和物を合成することもできる。 The obtained compound (I) or (IA) can be further chemically modified to synthesize ester forms, or pharmaceutically acceptable salts or solvates thereof.
　本発明化合物は、スペクトルの広い抗菌活性を有し、ヒトを含む各種哺乳動物における病原性細菌により生ずる種々の疾病、例えば気道感染症、***症、呼吸器感染症、敗血症、腎炎、胆嚢炎、口腔内感染症、心内膜炎、肺炎、骨髄膜炎、中耳炎、腸炎、蓄膿、創傷感染、日和見感染等の予防または治療のために使用され得る。 The compound of the present invention has a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, gallbladder It can be used for the prevention or treatment of inflammation, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.
　本発明化合物は、特にグラム陰性菌、好ましくは、腸内細菌科のグラム陰性菌（大腸菌、クレブシエラ、セラチア、エンテロバクター、シトロバクター、モルガネラ、プロビデンシア、プロテウス等）、呼吸器に定着するグラム陰性菌（ヘモフィルス、モラキセラ等）およびブドウ糖非発酵のグラム陰性菌（緑膿菌以外のシュードモナス、ステノトロフォモナス、バークホルデリア、アシネトバクター等）に対して高い抗菌活性を示す。本発明化合物は、これらのグラム陰性菌が産生するクラスＡ，Ｂ，ＣおよびＤに属するβ－ラクタマーゼに対して安定である。特にクラスＡ、ＢおよびＤに属するβ－ラクタマーゼに対して高い安定性を示す。それにより、ＴＥＭ型、ＳＨＶ型、ＫＰＣ型などに代表されるＥＳＢＬ産生菌などの各種β－ラクタム薬耐性グラム陰性菌に高い抗菌活性を有する。特にＮＤＭ型、ＩＭＰ型、ＶＩＭ型、Ｌ－１型などを含むクラスＢに属するメタロ－β－ラクタマーゼに対しても極めて安定であるので、セフェムやカルバペネムを含む各種β－ラクタム薬耐性グラム陰性菌に対しても有効である。さらに、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される本発明化合物はβ－ラクタマーゼ阻害剤を組み合わせることにより、クラスＣに属するβ－ラクタマーゼに対する安定性が向上するため、クラスＡ，Ｂ，Ｃおよび／またはＤに属するβ－ラクタマーゼを産生する各種β－ラクタム薬耐性グラム陰性菌に対して幅広く有効である。また本発明化合物は、メチシリン感受性黄色ブドウ球菌（ＭＲＳＡ）、ペニシリン耐性肺炎ブドウ球菌（ＰＲＳＰ）等を含むグラム陽性菌に対しても抗菌活性を有している。さらに好ましい化合物は、体内動態として、血中濃度が高い、効果の持続時間が長い、および／または組織移行性が顕著である等の特徴も有している。また好ましい化合物は発熱を示さない、腎毒性を示さないなど副作用の点で安全である。また好ましい化合物は、水溶性が高く、体内動態が良好であり、注射薬および経口薬として好適である。 The compound of the present invention is a gram-negative bacterium, preferably a gram-negative bacterium of the family Enterobacteriaceae (E. coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.) (Hemophilus, Moraxella, etc.) and glucose non-fermenting Gram-negative bacteria (Pseudomonas other than Pseudomonas aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.). The compounds of the present invention are stable against β-lactamases belonging to classes A, B, C and D produced by these gram-negative bacteria. In particular, it exhibits high stability against β-lactamases belonging to classes A, B and D. Thereby, it has high antibacterial activity against various β-lactam drug-resistant gram-negative bacteria such as ESBL-producing bacteria represented by TEM type, SHV type, KPC type and the like. In particular, it is extremely stable against metallo-β-lactamases belonging to class B including NDM type, IMP type, VIM type, L-1 type, etc., so various β-lactam drug resistant gram-negative bacteria including cephem and carbapenem It is also effective against Furthermore, since the compounds of the present invention represented by the formula (I), (IA) or (II) are combined with a β-lactamase inhibitor, the stability to β-lactamases belonging to class C is improved. , C and / or D are effective against various β-lactam drug-resistant gram-negative bacteria that produce β-lactamases belonging to D. The compound of the present invention also has antibacterial activity against gram-positive bacteria including methicillin-sensitive Staphylococcus aureus (MRSA), penicillin-resistant pneumococcus (PRSP) and the like. Further preferable compounds have characteristics such as high blood concentration, long duration of effect, and / or remarkable tissue transferability as pharmacokinetics. Preferred compounds are safe in terms of side effects such as no fever and no nephrotoxicity. Further, preferred compounds have high water solubility and good pharmacokinetics, and are suitable as injections and oral drugs.
　本発明化合物は、経口的又は非経口的に投与することができる。経口投与による場合、本発明化合物は通常の製剤、例えば、錠剤、散剤、顆粒剤、カプセル剤等の固形剤、水剤、油性懸濁剤、又はシロップ剤もしくはエリキシル剤等の液剤のいずれかの剤形としても用いることができる。非経口投与による場合、本発明化合物は、水性又は油性懸濁注射剤、点鼻液として用いることができる。その調製に際しては、慣用の賦形剤、結合剤、滑沢剤、水性溶剤、油性溶剤、乳化剤、懸濁化剤、保存剤、安定剤等を任意に用いることができる。本発明の製剤は、治療有効量の本発明化合物を製薬上許容される担体又は希釈剤とともに組み合わせる（例えば混合する）ことによって製造される。 The compound of the present invention can be administered orally or parenterally. In the case of oral administration, the compound of the present invention is any of ordinary preparations, for example, solid preparations such as tablets, powders, granules and capsules, liquid preparations, oil suspensions, or liquid preparations such as syrups and elixirs. It can also be used as a dosage form. In the case of parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used. The formulations of the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent.
　本発明化合物は、注射剤、カプセル剤、錠剤、顆粒剤として非経口または経口的に投与できるが、好ましくは注射剤として投与される。投与量は、通常、患者または動物の体重１ｋｇ当たり、約０．１～１００ｍｇ／日、好ましくは約０．５～５０ｍｇ／日を、所望により１日２～４回に分割して投与すればよい。注射剤として用いられる場合の担体は、たとえば蒸留水、生理食塩水などであり、またｐＨ調節のための塩基等を使用してもよい。カプセル剤、顆粒剤、錠剤として用いられる場合の担体は、公知の賦形剤(例：デンプ
ン、乳糖、白糖、炭酸カルシウム、リン酸カルシウムなど)、結合剤(例：デンプン、アラビアゴム、カルボキシメチルセルロ－ス、ヒドロキシプロピルセルロ－ス、結晶セルロ－スなど)、滑沢剤(例：ステアリン酸マグネシウム、タルクなど)等である。 The compound of the present invention can be administered parenterally or orally as an injection, capsule, tablet or granule, but is preferably administered as an injection. The dose is usually about 0.1 to 100 mg / day, preferably about 0.5 to 50 mg / day per kg of the body weight of the patient or animal, if desired divided into 2 to 4 times a day. Good. When used as an injection, the carrier is, for example, distilled water, physiological saline or the like, and a base for adjusting pH may be used. Carriers when used as capsules, granules, tablets are known excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose) , Hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.).
　以下に、実施例、参考例、試験例および製剤例を挙げて本発明をさらに詳しく説明するが、本発明はこれに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and Preparation Examples, but the present invention is not limited thereto.
　また、本明細書中で用いる略語は以下の意味を表す。
Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル
Ｂｔ：１－ベンゾトリアゾリル
ＢＨ：ベンゾヒドリル
ＤＩＡＤ：アゾジカルボン酸ジイソプロピル
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＭＡ：Ｎ，Ｎ－ジメチルアセトアミド
ＤＭＡＰ：Ｎ，Ｎ－ジメチル－４－アミノピリジン
ＥＤＣ：１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩
ＨＭＰＡ：ヘキサメチルリン酸トリアミド
ＨＯＢｔ：１－ヒドロキシベンゾトリアゾール
ｍＣＰＢＡ：ｍ－クロロ過安息香酸
Ｍｅ：メチル
ＯＤＳ：オクタデシルシリル
ｔ－Ｂｕ：ｔｅｒｔ－ブチル
Ｐｈ：フェニル
ＰＭＢ：パラメトキシベンジル
ＴＢＡＦ：フッ化テトラ－ｎ－ブチルアンモニウム
ＴＢＳ：ｔｅｒｔ－ブチルジメチルシリル
ＴＦＡ：トリフルオロ酢酸
ＴＨＦ：テトラヒドロフラン
Ｔｒｔ：トリチル Moreover, the abbreviation used in this specification represents the following meaning.
Boc: tert-butoxycarbonyl Bt: 1-benzotriazolyl BH: benzohydryl DIAD: diisopropyl azodicarboxylate DMF: N, N-dimethylformamide DMA: N, N-dimethylacetamide DMAP: N, N-dimethyl-4-amino Pyridine EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HMPA: hexamethylphosphoric triamide HOBt: 1-hydroxybenzotriazole mCPBA: m-chloroperbenzoic acid Me: methyl ODS: octadecylsilyl t- Bu: tert-butyl Ph: phenyl PMB: paramethoxybenzyl TBAF: tetra-n-butylammonium fluoride TBS: tert-butyldimethylsilyl TFA: trifluoroacetic acid THF: tetrahydrofura Trt: trityl
実施例で得られたＮＭＲ分析は４００ＭＨｚで行い、ＤＭＳＯ－ｄ６、ＣＤＣｌ３等を用いて測定した。 The NMR analysis obtained in the examples was performed at 400 MHz and measured using DMSO-d 6 , CDCl 3 and the like.
実施例で得られたＬＣＭＳ分析は、以下の条件下で測定した。
測定条件１：
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（登録商標）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：０．８ ｍＬ／分
ＰＤＡ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行った後、０．５分間、１００％溶媒［Ｂ］を維持した。
測定条件２：
カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）　
流速：１．６ ｍＬ／分
ＰＤＡ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０.５分間、１００％溶媒［Ｂ］を維持した。 The LCMS analysis obtained in the examples was measured under the following conditions.
Measurement condition 1:
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, [B] was 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 5% -100% solvent [B] was performed in 3.5 minutes Thereafter, 100% solvent [B] was maintained for 0.5 minutes.
Measurement condition 2:
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm)
Flow rate: 1.6 mL / min PDA detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution for 3 minutes, and a linear gradient of 10% -100% solvent [B] is performed for 0.5 minutes. 100% solvent [B] was maintained.
化合物Ｉ－００３の合成　
Figure JPOXMLDOC01-appb-C000160
工程１　化合物３ｂの合成
特許ＥＰ２５３３３７Ａ２に記載の方法で合成した化合物３ａ（７．１６ｇ、１４ｍｍｏｌ）の酢酸エチル（１４３ｍＬ）溶液に、０．１ｍｏｌ／Ｌリン酸緩衝液（１４３ｍＬ）、１０％パラジウム／炭素（５０％含水）（５．９６ｇ、２．８ｍｍｏｌ）を加えた。水素１気圧下、室温で２時間攪拌した後、不溶物をセライトろ過により除いた。水層を分取し、有機層を再度水で抽出した後、すべての水層を合せ、塩酸水をｐＨ＝３まで加えた。次いで、ＨＰ２０－ＳＳ樹脂を加え減圧濃縮した。得られた混合液をＨＰ２０－ＳＳカラムクロマトグラフィ（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することにより化合物３ｂ（４．７９ｇ、収率９１％）を淡黄色粉末として得た。
1H-NMR (D2O)δ: 2.64-3.12 (5H, m), 3.72 (2H, d, J = 7.5 Hz), 5.15 (1H, d, J = 4.5 Hz), 5.38 (1H, d, J = 4.5 Hz), 7.35-7.44 (5H, m).
MS (m+1) = 377.07
Synthesis of Compound I-003
Figure JPOXMLDOC01-appb-C000160
Step 1 Synthesis of Compound 3b To a solution of Compound 3a (7.16 g, 14 mmol) synthesized in the manner described in Patent EP253337A2 in ethyl acetate (143 mL), 0.1 mol / L phosphate buffer (143 mL), 10% palladium / Carbon (50% water content) (5.96 g, 2.8 mmol) was added. After stirring at room temperature for 2 hours under 1 atmosphere of hydrogen, insoluble matters were removed by Celite filtration. The aqueous layer was separated, and the organic layer was extracted again with water. All the aqueous layers were combined, and aqueous hydrochloric acid was added to pH = 3. Next, HP20-SS resin was added and concentrated under reduced pressure. The resulting mixture was purified by HP20-SS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to give compound 3b (4.79 g, yield 91%) as a pale yellow powder.
1 H-NMR (D 2 O) δ: 2.64-3.12 (5H, m), 3.72 (2H, d, J = 7.5 Hz), 5.15 (1H, d, J = 4.5 Hz), 5.38 (1H, d, J = 4.5 Hz), 7.35-7.44 (5H, m).
MS (m + 1) = 377.07
工程２　化合物３ｃの合成
化合物３ｂ（４．７９ｇ、１２．７ｍｍｏｌ）のテトラヒドロフラン（２４ｍＬ）溶液に、ジフェニルジアゾメタン（２．６０ｇ、１３．４ｍｍｏｌ）のテトラヒドロフラン（２４ｍＬ）溶液を２０分間かけて滴下した。室温で２時間攪拌した後、反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製することにより、化合物３ｃ（３．３７ｇ、収率４９％）を白色固体として得た。
1H-NMR (CDCl3)δ: 2.52 (2H, d, J = 5.6 Hz), 2.61 (1H, dd, J = 14.5, 9.6 Hz), 2.90 (1H, dd, J = 14.5, 4.5 Hz), 3.08-3.15 (1H, m), 3.63 (2H, dd, J = 22.1, 16.1 Hz), 4.99 (1H, d, J = 4.7 Hz), 5.54 (1H, dd, J = 8.7, 4.7 Hz), 6.11 (1H, d, J = 8.7 Hz), 6.94 (1H, s), 7.25-7.38 (15H, m).
MS (m+1) = 543.21
Step 2 Synthesis of Compound 3c To a solution of Compound 3b (4.79 g, 12.7 mmol) in tetrahydrofuran (24 mL) was added dropwise a solution of diphenyldiazomethane (2.60 g, 13.4 mmol) in tetrahydrofuran (24 mL) over 20 minutes. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 3c (3.37 g, yield 49%) as a white solid. .
1 H-NMR (CDCl 3 ) δ: 2.52 (2H, d, J = 5.6 Hz), 2.61 (1H, dd, J = 14.5, 9.6 Hz), 2.90 (1H, dd, J = 14.5, 4.5 Hz), 3.08-3.15 (1H, m), 3.63 (2H, dd, J = 22.1, 16.1 Hz), 4.99 (1H, d, J = 4.7 Hz), 5.54 (1H, dd, J = 8.7, 4.7 Hz), 6.11 (1H, d, J = 8.7 Hz), 6.94 (1H, s), 7.25-7.38 (15H, m).
MS (m + 1) = 543.21
工程３　化合物３ｆの合成
五塩化リン（１．０４ｇ、５．０ｍｍｏｌ）のジクロロメタン（６．８ｍＬ）懸濁液を－７８℃まで冷却した後、ピリジン（０．４４４ｍＬ、５．５ｍｍｏｌ）を加え、次いで化合物３ｃ（１．３６ｇ、２．５ｍｍｏｌ）のジクロロメタン（６．８ｍＬ）溶液を滴下した。－１０℃で１時間攪拌した後、反応混合物を－７８℃まで冷却し、メタノール（６．８ｍＬ）を加えた。－３０℃で２時間攪拌した後、反応混合物に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥した後、無機物をろ過により除去した。ろ液に酢酸エチルを加え、ジクロロメタン及びメタノールを減圧留去することにより化合物３ｄの酢酸エチル溶液を得た。
化合物３ｅ（３１５ｍｇ、０．６０ｍｍｏｌ）のジメチルアセトアミド（１．１ｍＬ）溶液を－２０℃まで冷却した後、トリエチルアミン（０．１０４ｍＬ、０．７５ｍｍｏｌ）メタンスルホニルクロリド（０．０５５ｍＬ、０．７０ｍｍｏｌ）を加えた。－２０℃で３０分間攪拌することで、溶液Ｂを得た。
化合物３ｄ（２１２ｍｇ、０．５０ｍｍｏｌ）を含む酢酸エチル溶液に、氷冷下でピリジン（０．０４８ｍＬ、０．６ｍｍｏｌ）、溶液Ｂを加えた。氷冷下で３０分間攪拌した後、希塩酸水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物３ｆ（３６７ｍｇ、収率７９％）を白色フォームとして得た。
1H-NMR (CDCl3)δ: 1.53 (9H, s), 1.64 (3H, d, J = 7.3 Hz), 2.29 (1H, dd, J = 14.7, 7.2 Hz), 2.52-2.70 (2H, m), 2.83 (1H, dd, J = 14.7, 4.0 Hz), 3.14-3.18 (1H, m), 5.01 (1H, d, J = 4.8 Hz), 5.15 (1H, q, J = 7.3 Hz), 5.62 (1H, dd, J = 8.7, 4.8 Hz), 6.87 (1H, s), 6.92 (1H, s), 7.29-7.36 (21H, m), 8.08 (1H, s), 8.25 (1H, d, J = 8.7 Hz).
MS (m+1) = 932.14
Step 3 Synthesis of Compound 3f After cooling a suspension of phosphorus pentachloride (1.04 g, 5.0 mmol) in dichloromethane (6.8 mL) to −78 ° C., pyridine (0.444 mL, 5.5 mmol) was added, Then, a solution of compound 3c (1.36 g, 2.5 mmol) in dichloromethane (6.8 mL) was added dropwise. After stirring at −10 ° C. for 1 hour, the reaction mixture was cooled to −78 ° C. and methanol (6.8 mL) was added. After stirring at −30 ° C. for 2 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then inorganic substances were removed by filtration. Ethyl acetate was added to the filtrate, and dichloromethane and methanol were distilled off under reduced pressure to obtain an ethyl acetate solution of compound 3d.
A solution of compound 3e (315 mg, 0.60 mmol) in dimethylacetamide (1.1 mL) was cooled to −20 ° C., and then triethylamine (0.104 mL, 0.75 mmol) methanesulfonyl chloride (0.055 mL, 0.70 mmol) was added. added. Solution B was obtained by stirring at −20 ° C. for 30 minutes.
To an ethyl acetate solution containing compound 3d (212 mg, 0.50 mmol), pyridine (0.048 mL, 0.6 mmol) and solution B were added under ice cooling. The mixture was stirred for 30 minutes under ice-cooling, diluted aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 3f (367 mg, yield 79%) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.53 (9H, s), 1.64 (3H, d, J = 7.3 Hz), 2.29 (1H, dd, J = 14.7, 7.2 Hz), 2.52-2.70 (2H, m ), 2.83 (1H, dd, J = 14.7, 4.0 Hz), 3.14-3.18 (1H, m), 5.01 (1H, d, J = 4.8 Hz), 5.15 (1H, q, J = 7.3 Hz), 5.62 (1H, dd, J = 8.7, 4.8 Hz), 6.87 (1H, s), 6.92 (1H, s), 7.29-7.36 (21H, m), 8.08 (1H, s), 8.25 (1H, d, J = 8.7 Hz).
MS (m + 1) = 932.14
工程４　化合物Ｉ－００３の合成
化合物３ｆ（３６７ｍｇ、０．３９ｍｍｏｌ）のジクロロメタン（３．７ｍＬ）溶液を－４０℃まで冷却した後、アニソール（０．３４４ｍＬ、３．１５ｍｍｏｌ）と２ｍｏｌ／Ｌ塩化アルミニウム／ニトロメタン溶液（１．５８ｍＬ、３．１５ｍｍｏｌ）を順に加え、氷冷下で３０分間攪拌した。反応液にジイソプロピルエーテル、氷、アセトニトリルを順に加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィ（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することにより化合物Ｉ－００３（１２０ｍｇ、収率６１％）を白色粉末として得た。
1H-NMR (DMSO-D6)δ: 1.05 (3H, d, J = 7.1 Hz), 1.36 (3H, s), 1.38 (3H, s), 3.78 (1H, q, J = 7.1 Hz), 4.91 (2H, s), 5.17 (1H, d, J = 5.1 Hz), 5.60 (1H, dd, J = 8.0, 5.1 Hz), 6.60-6.68 (3H, m), 6.82-6.84 (1H, m), 6.92 (1H, d, J = 7.1 Hz), 7.18 (2H, s), 8.25-8.29 (2H, m), 8.44 (1H, d, J = 7.1 Hz), 8.77 (1H, s), 9.43 (1H, s).
MS (m+1) = 499.98 (0.67min)
元素分析：C17H17N5O9S2(H2O)3.1
計算値：C,36.77; H,4.21; N,12.61; S,11.55 (%)
実測値：C,36.65; H,4.09; N,12.88; S,11.40 (%)
Step 4 Synthetic compound 3f (367 mg, 0.39 mmol) in dichloromethane (3.7 mL) was cooled to −40 ° C., then anisole (0.344 mL, 3.15 mmol) and 2 mol / L aluminum chloride were used. / Nitromethane solution (1.58 mL, 3.15 mmol) was sequentially added, and the mixture was stirred for 30 minutes under ice cooling. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to give Compound I-003 (120 mg, 61% yield) as a white powder.
1 H-NMR (DMSO-D 6 ) δ: 1.05 (3H, d, J = 7.1 Hz), 1.36 (3H, s), 1.38 (3H, s), 3.78 (1H, q, J = 7.1 Hz), 4.91 (2H, s), 5.17 (1H, d, J = 5.1 Hz), 5.60 (1H, dd, J = 8.0, 5.1 Hz), 6.60-6.68 (3H, m), 6.82-6.84 (1H, m) , 6.92 (1H, d, J = 7.1 Hz), 7.18 (2H, s), 8.25-8.29 (2H, m), 8.44 (1H, d, J = 7.1 Hz), 8.77 (1H, s), 9.43 ( 1H, s).
MS (m + 1) = 499.98 (0.67min)
Elemental analysis: C17H17N5O9S2 (H2O) 3.1
Calculated value: C, 36.77; H, 4.21; N, 12.61; S, 11.55 (%)
Found: C, 36.65; H, 4.09; N, 12.88; S, 11.40 (%)
化合物Ｉ－００４の合成
Figure JPOXMLDOC01-appb-C000161
工程１　化合物４ａの合成
化合物３ｄ（２１２ｍｇ、０．５０ｍｍｏｌ）を含む酢酸エチル溶液を減圧濃縮し、残渣をジクロロメタン（２．１ｍＬ）に溶解させた後、化合物１ｉ（Ｅ体／Ｚ体混合物）（３０１ｍｇ、０．７０ｍｍｏｌ）を加えた。次いで、氷冷下でＥＤＣ塩酸塩（１３４ｍｇ、０．７０ｍｍｏｌ）を加えた。室温で１時間半攪拌した後、減圧濃縮し、残渣に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４ａ（Ｅ体／Ｚ体混合物）（２９５ｍｇ、収率７１％）を白色フォームとして得た。
1H-NMR (CDCl3)δ: 1.70 (3H, s), 1.76 (3H, s), 2.49-2.64 (3H, m), 2.88-3.02 (1H, m), 3.12-3.19 (1H, m), 3.32-3.64 (2H, m), 4.61 (2H, d, J = 7.3 Hz), 5.06 (1H, dd, J = 7.3, 4.5 Hz), 5.27-5.34 (3H, m), 5.53-5.59 (1H, m), 6.66-7.20 (3H, m), 7.29-7.38 (15H, m), 8.27-8.42 (1H, m).
MS (m+1) = 837.17
Synthesis of Compound I-004
Figure JPOXMLDOC01-appb-C000161
Step 1 Synthesis of Compound 4a An ethyl acetate solution containing Compound 3d (212 mg, 0.50 mmol) was concentrated under reduced pressure, the residue was dissolved in dichloromethane (2.1 mL), and then Compound 1i (E-form / Z-form mixture) ( 301 mg, 0.70 mmol) was added. Then, EDC hydrochloride (134 mg, 0.70 mmol) was added under ice cooling. After stirring at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 4a (E-form / Z-form mixture) (295 mg, 71% yield) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.70 (3H, s), 1.76 (3H, s), 2.49-2.64 (3H, m), 2.88-3.02 (1H, m), 3.12-3.19 (1H, m) , 3.32-3.64 (2H, m), 4.61 (2H, d, J = 7.3 Hz), 5.06 (1H, dd, J = 7.3, 4.5 Hz), 5.27-5.34 (3H, m), 5.53-5.59 (1H , m), 6.66-7.20 (3H, m), 7.29-7.38 (15H, m), 8.27-8.42 (1H, m).
MS (m + 1) = 837.17
工程２　化合物Ｉ－００４の合成
化合物４ａ（２９５ｍｇ、０．３５ｍｍｏｌ）のジクロロメタン（３．０ｍＬ）溶液を－２０℃まで冷却した後、アニソール（０．３８５ｍＬ、３．５ｍｍｏｌ）と２ｍｏｌ／Ｌ塩化チタン／ジクロロメタン溶液（１．２３ｍＬ、２．４７ｍｍｏｌ）を順に加え、氷冷下で４０分間攪拌した。反応液にジイソプロピルエーテル、氷、アセトニトリルを順に加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィ（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することにより化合物Ｉ－００４（Ｅ体／Ｚ体混合物、Ｅ：Ｚ＝３：２）（４５ｍｇ、収率２７％）を淡黄色粉末として得た。
1H-NMR (D2O)δ: 2.67-2.93 (3H, m), 3.05-3.19 (2H, m), 3.33-3.36 (1H, m), 3.47 (1H, d, J = 7.6 Hz), 5.23-5.26 (1H, m), 5.49-5.51 (1H, m), 6.50-7.14 (2H, m).
MS (m+1) = 468.94 (0.50min)
元素分析：C17H16N4O8S2(H2O)2.4
計算値：C,39.90; H,4.10; N,10.95; S,12.53 (%)
実測値：C,39.86; H,4.08; N,11.36; S,12.56 (%)
Step 2 Synthesis of Compound I-004 Compound 4a (295 mg, 0.35 mmol) in dichloromethane (3.0 mL) was cooled to −20 ° C., then anisole (0.385 mL, 3.5 mmol) and 2 mol / L titanium chloride. / Dichloromethane solution (1.23 mL, 2.47 mmol) was sequentially added, and the mixture was stirred for 40 minutes under ice cooling. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and then lyophilized to obtain Compound I-004 (E-form / Z-form mixture, E: Z = 3: 2) (45 mg, 27% yield) lightly. Obtained as a yellow powder.
1 H-NMR (D 2 O) δ: 2.67-2.93 (3H, m), 3.05-3.19 (2H, m), 3.33-3.36 (1H, m), 3.47 (1H, d, J = 7.6 Hz), 5.23-5.26 (1H, m), 5.49-5.51 (1H, m), 6.50-7.14 (2H, m).
MS (m + 1) = 468.94 (0.50min)
Elemental analysis: C17H16N4O8S2 (H2O) 2.4
Calculated values: C, 39.90; H, 4.10; N, 10.95; S, 12.53 (%)
Found: C, 39.86; H, 4.08; N, 11.36; S, 12.56 (%)
化合物Ｉ－００７および化合物Ｉ－００８の合成
Figure JPOXMLDOC01-appb-C000162
工程１　化合物３の合成
化合物１（８．７６ｇ、４３．５ｍｍｏｌ）をメタノール（１００ｍＬ）に溶解し、酢酸（２．４９ｍＬ、４３．５ｍｍｏｌ）と化合物２（２０．０ｇ、４３．５ｍｍｏｌ）を加え室温で撹拌した。反応終了後、反応液を精製水で希釈し、酢酸エチルで目的物を抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去した。得られた残渣をシリカゲルクロマトグラフィーに付し、化合物３（１８．０ｇ、１．２７．３ｍｍｏｌ）を分離不能な混合物として得た。
1H-NMR (CDCl3)δ: 8.24-8.14 (m, 2H), 7.58-7.43 (m, 2H), 7.37-7.27 (m, 10H), 6.87-6.75 (m, 1H), 5.37-4.58 (m, 5H), 4.16-4.06 (m, 1H), 3.82-3.38 (m, 2H), 3.06-2.35 (m, 4H), 1.44 (s, 9H).
Synthesis of Compound I-007 and Compound I-008
Figure JPOXMLDOC01-appb-C000162
Step 1 Synthesis of Compound 3 Compound 1 (8.76 g, 43.5 mmol) was dissolved in methanol (100 mL), and acetic acid (2.49 mL, 43.5 mmol) and compound 2 (20.0 g, 43.5 mmol) were added. Stir at room temperature. After completion of the reaction, the reaction solution was diluted with purified water, and the target product was extracted with ethyl acetate. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain compound 3 (18.0 g, 1.27.3 mmol) as an inseparable mixture.
1 H-NMR (CDCl 3 ) δ: 8.24-8.14 (m, 2H), 7.58-7.43 (m, 2H), 7.37-7.27 (m, 10H), 6.87-6.75 (m, 1H), 5.37-4.58 ( m, 5H), 4.16-4.06 (m, 1H), 3.82-3.38 (m, 2H), 3.06-2.35 (m, 4H), 1.44 (s, 9H).
工程２　化合４の合成
化合物３（１８．０ｇ、２７．２ｍｍｏｌ）をジクロロメタン（１８０ｍＬ）に溶解し、氷点下５０度に冷却し、アニソール（１１．９ｍＬ、１０９ｍｍｏｌ）と２ｍｏｌ／Ｌ塩化アルミニウム‐ニトロメタン溶液（４７．７ｍＬ、９５．０ｍｍｏｌ）を滴下し、同温度で２０分間撹拌した。反応液に精製水を加え、ジクロロメタンで目的物を抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去し、化合物４を得た。得られた全量を精製せずそのまま次の反応に用いた。
Step 2 Compound 4 of Compound 4 (18.0 g, 27.2 mmol) was dissolved in dichloromethane (180 mL), cooled to 50 ° C. below freezing, and anisole (11.9 mL, 109 mmol) and 2 mol / L aluminum chloride-nitromethane solution (47.7 mL, 95.0 mmol) was added dropwise and stirred at the same temperature for 20 minutes. Purified water was added to the reaction solution, and the target product was extracted with dichloromethane. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to obtain Compound 4. The entire amount obtained was used in the next reaction without purification.
工程３　化合物５の合成
全反応で得られた残渣をジクロロメタン（１３０ｍＬ）に溶解し、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（５．２１ｇ、２７．２ｍｍｏｌ）を加え室温で1時間３０分間撹拌した。この溶液に再度１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（２．６１ｇ、１３．６ｍｍｏｌ）を加え室温で1時間撹拌した。反応液に精製水を加え、ジクロロメタンで目的物を抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去し、得られた残渣をシリカゲルクロマトグラフィーに付し化合物５（２．８ｇ、５．８８ｍｍｏｌ）を分離不能な混合物として得た。
1H-NMR (CDCl3)δ: 8.25 (d, J = 9.4 Hz, 2H), 7.62-7.52 (m, 2H), 5.49-5.30 (m, 2H), 5.22-5.04 (br m, 1H), 4.80-4.61 (br m, 1H), 3.81-3.47 (m, 2H), 2.99-2.58 (m, 3H), 1.45 (s, 9H).
Step 3 Synthesis of Compound 5 The residue obtained in the entire reaction was dissolved in dichloromethane (130 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.21 g, 27.2 mmol) was added thereto at room temperature. For 1 hour 30 minutes. To this solution was again added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.61 g, 13.6 mmol), and the mixture was stirred at room temperature for 1 hour. Purified water was added to the reaction solution, and the target product was extracted with dichloromethane. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography to give a compound. 5 (2.8 g, 5.88 mmol) was obtained as an inseparable mixture.
1 H-NMR (CDCl 3 ) δ: 8.25 (d, J = 9.4 Hz, 2H), 7.62-7.52 (m, 2H), 5.49-5.30 (m, 2H), 5.22-5.04 (br m, 1H), 4.80-4.61 (br m, 1H), 3.81-3.47 (m, 2H), 2.99-2.58 (m, 3H), 1.45 (s, 9H).
工程４　化合物６の合成
化合物６（２．８０ｇ、５．８８ｍｍｏｌ）をジクロロメタン（３０．０ｍＬ）に懸濁させ、４ｍｏｌ／Ｌ塩酸‐酢酸エチル（２２．０ｍＬ，８８．０ｍｍｏｌ）を加え室温で40分間撹拌した。生じた個体をろ取し酢酸エチルで洗浄し、化合物８を分離不能な混合物として得た。（２．６７ｇ）
1H-NMR (D2O)δ: 8.28 (d, J = 8.6 Hz, 2.0H), 7.70-7.60 (m, 2.0H), 5.48 (s, 1.7H), 4.71-4.61 (m, 0.8H), 4.20-2.65 (m, 7.0H).
Step 4 Synthesis of Compound 6 Compound 6 (2.80 g, 5.88 mmol) was suspended in dichloromethane (30.0 mL), 4 mol / L hydrochloric acid-ethyl acetate (22.0 mL, 88.0 mmol) was added, and the mixture was stirred at room temperature. Stir for minutes. The resulting solid was collected by filtration and washed with ethyl acetate to obtain Compound 8 as an inseparable mixture. (2.67 g)
1 H-NMR (D 2 O) δ: 8.28 (d, J = 8.6 Hz, 2.0H), 7.70-7.60 (m, 2.0H), 5.48 (s, 1.7H), 4.71-4.61 (m, 0.8H ), 4.20-2.65 (m, 7.0H).
工程５　化合物８の合成
化合物８（２０２ｍｇ）をジクロロメタンに懸濁させ、0度に冷却し、化合物９（１８９ｍｇ、０．５３８ｍｍｏｌ）とＮ－メチルモルホリン（０．１１８ｍＬ、１．０８ｍｍｏｌ）を加え終夜で撹拌した。反応液に5%重層水とテトラヒドロフランを加え、水層から目的物をジクロロメタンで抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去し、得られた残渣をシリカゲルクロマトグラフィーに付し化合物８（２８３ｍｇ、０．５０５ｍｍｏｌ）を分離不能な混合物として得た。
1H-NMR (DMSO-D6)δ: 9.19 (t, J = 7.3 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.70 (dd, J = 8.7, 2.0 Hz, 2H), 7.22 (s, 2H), 6.94-6.84 (m, 1H), 5.47-5.31 (m, 2H), 5.08-4.91 (m, 1H), 3.89-3.81 (m, 5H), 3.58-3.42 (m, 1H), 3.10-2.89 (m, 2H), 2.81-2.65 (m, 2H).
Step 5 Synthesis of Compound 8 Compound 8 (202 mg) was suspended in dichloromethane, cooled to 0 ° C., compound 9 (189 mg, 0.538 mmol) and N-methylmorpholine (0.118 mL, 1.08 mmol) were added overnight. Stir with. 5% multistory water and tetrahydrofuran were added to the reaction solution, and the target product was extracted from the aqueous layer with dichloromethane. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography to give a compound. 8 (283 mg, 0.505 mmol) was obtained as an inseparable mixture.
1 H-NMR (DMSO-D 6 ) δ: 9.19 (t, J = 7.3 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.70 ( dd, J = 8.7, 2.0 Hz, 2H), 7.22 (s, 2H), 6.94-6.84 (m, 1H), 5.47-5.31 (m, 2H), 5.08-4.91 (m, 1H), 3.89-3.81 ( m, 5H), 3.58-3.42 (m, 1H), 3.10-2.89 (m, 2H), 2.81-2.65 (m, 2H).
工程６　化合物Ｉ－００７および化合物Ｉ－００８の合成
化合物８（２７５ｍｇ、０．４９２ｍｍｏｌ）をテトラヒドロフラン（６．００ｍＬ）に溶解させ、０．１ｍｏｌ／Ｌ　ｐＨ６リン酸緩衝液（６．００ｍＬ）と５％パラジウム‐活性炭素（４１８ｍｇ、０．１９７ｍｍｏｌ）を加え、水素雰囲気化、0度で２時間撹拌した。反応液に、再度５％パラジウム‐活性炭素（２０９ｍｇ、０．０９８ｍｍｏｌ）を加え、水素雰囲気化、0度で１時間撹拌した。反応液に、再度５％パラジウム‐活性炭素（２０９ｍｇ、０．０９８ｍｍｏｌ）を加え、水素雰囲気化、0度で３０分間撹拌した。懸濁液をセライト濾過し、テトラヒドロフランを減圧下留去した。得られた水溶液をＨＰ２０ＳＳとＯＤＳを連結したカラムクロマトグラフィーに付し、水－アセトニトリルで溶離し、目的物を含む分画を集め、減圧濃縮し、濃縮液を凍結乾燥することによって化合物Ｉ－００７（２６．３ｍｇ、０．０５９ｍｍｏｌ）, 化合物Ｉ－００８（２２．０ｍｇ、０．０４９ｍｍｏｌ）を得た。
化合物Ｉ－００７：
1H-NMR (D2O)δ: 7.01 (br s, 1H), 5.21-5.12 (br m, 1H), 3.98 (s, 3H), 3.79-2.75 (m, 7H).
MS  (m+1) =  425.11   0.41min

化合物Ｉ－００８：
1H-NMR (D2O)δ: 7.08 (s, 1H), 5.32 (dd, J = 12.4, 8.5 Hz, 1H), 4.12 (t, J = 8.2 Hz, 1H), 3.98 (s, 3H), 3.74-3.68 (m, 1H), 3.58-3.44 (br m, 1H), 3.16 (dd, J = 19.3, 11.1 Hz, 1H), 3.07-2.98 (br m, 2H), 2.80 (dd, J = 19.3, 5.9 Hz, 1H).
MS  (m+1) =  425.11  0.53min
Step 6 Synthesis of Compound I-007 and Compound I-008 Compound 8 (275 mg, 0.492 mmol) was dissolved in tetrahydrofuran (6.00 mL), 0.1 mol / L pH 6 phosphate buffer (6.00 mL) and 5 % Palladium-activated carbon (418 mg, 0.197 mmol) was added, and the mixture was placed in a hydrogen atmosphere and stirred at 0 ° C. for 2 hours. To the reaction solution was added 5% palladium-activated carbon (209 mg, 0.098 mmol) again, and the mixture was stirred in a hydrogen atmosphere at 0 ° C. for 1 hour. To the reaction solution, 5% palladium-activated carbon (209 mg, 0.098 mmol) was added again, and the mixture was placed in a hydrogen atmosphere and stirred at 0 ° C. for 30 minutes. The suspension was filtered through celite, and tetrahydrofuran was distilled off under reduced pressure. The obtained aqueous solution was subjected to column chromatography in which HP20SS and ODS were linked, eluted with water-acetonitrile, fractions containing the desired product were collected, concentrated under reduced pressure, and the concentrated solution was lyophilized to give compound I-007. (26.3 mg, 0.059 mmol), Compound I-008 (22.0 mg, 0.049 mmol) was obtained.
Compound I-007:
1 H-NMR (D 2 O) δ: 7.01 (br s, 1H), 5.21-5.12 (br m, 1H), 3.98 (s, 3H), 3.79-2.75 (m, 7H).
MS (m + 1) = 425.11 0.41min

Compound I-008:
1 H-NMR (D 2 O) δ: 7.08 (s, 1H), 5.32 (dd, J = 12.4, 8.5 Hz, 1H), 4.12 (t, J = 8.2 Hz, 1H), 3.98 (s, 3H) , 3.74-3.68 (m, 1H), 3.58-3.44 (br m, 1H), 3.16 (dd, J = 19.3, 11.1 Hz, 1H), 3.07-2.98 (br m, 2H), 2.80 (dd, J = (19.3, 5.9 Hz, 1H).
MS (m + 1) = 425.11 0.53min
化合物Ｉ－００９の合成　
Figure JPOXMLDOC01-appb-C000163
工程１　化合物１ｂの合成
化合物１ａ（２０．１ｇ、１２６ｍｍｏｌ、合成法はThe Journal of Biological　Chemistry　VOLUME 283・NUMBER 43・２００８・２８８８８～２８８９６に記載。）を化合物Ｉ－０１６の合成実施例の工程１と同様に処理し、化合物１ｂ（１３．８７ｇ、収率２８．０％）を黄色オイルとして得た。
1H-NMR (CDCl3)δ: 1.73 (s, 3H), 1.77 (s, 3H), 1.92-2.00 (m, 2H), 2.50 (t, J = 7.3 Hz, 2H), 2.87 (t, J = 7.1 Hz, 2H), 4.71 (d, J = 7.6 Hz, 2H), 5.37-5.39 (m, 1H), 6.88 (s, 1H), 7.27-7.37 (m, 10H).
Synthesis of Compound I-009
Figure JPOXMLDOC01-appb-C000163
Step 1 Synthesis of Compound 1b Compound 1a (20.1 g, 126 mmol, the synthesis method is described in The Journal of Biological Chemistry VOLUME 283, NUMBER 43, 2008, 28888-28896) was synthesized in Step 1 of the synthesis example of Compound I-016. The compound 1b (13.87 g, yield 28.0%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.73 (s, 3H), 1.77 (s, 3H), 1.92-2.00 (m, 2H), 2.50 (t, J = 7.3 Hz, 2H), 2.87 (t, J = 7.1 Hz, 2H), 4.71 (d, J = 7.6 Hz, 2H), 5.37-5.39 (m, 1H), 6.88 (s, 1H), 7.27-7.37 (m, 10H).
工程２　化合物１ｃの合成
化合物１ｂ（１３．８７ｇ、３５．２ｍｍｏｌ）を化合物Ｉ－０３１の合成実施例の工程２と同様に処理し、化合物１ｃ（９．６４ｇ、収率６７．４％）を無色透明オイルとして得た。
1H-NMR (CDCl3)δ: 1.74 (s, 3H), 1.78 (s, 3H), 2.62-2.67 (m, 4H), 4.78 (d, J = 7.3 Hz, 2H), 5.39-5.41 (m, 1H), 6.07 (s, 2H), 6.88 (s, 1H), 7.30-7.35 (m, 10H).
Step 2 Synthesis of Compound 1c Compound 1b (13.87 g, 35.2 mmol) was treated in the same manner as in Step 2 of Synthesis Example of Compound I-031 to give Compound 1c (9.64 g, yield 67.4%). Obtained as a clear colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.74 (s, 3H), 1.78 (s, 3H), 2.62-2.67 (m, 4H), 4.78 (d, J = 7.3 Hz, 2H), 5.39-5.41 (m , 1H), 6.07 (s, 2H), 6.88 (s, 1H), 7.30-7.35 (m, 10H).
工程３　化合物１ｅの合成
化合物１ｃ（８．６４ｇ、２１．２６ｍｍｏｌ）のアセトン（５０．２ｍＬ）懸濁溶液に、化合物１ｄ（５．０２ｇ、２１．２６ｍｍｏｌ）およびヘキサメチルリン酸トリアミド（１２．９５ｍＬ）を加え、室温で２４時間撹拌した。水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製することにより、白色フォーム状の化合物１ｅ（１１．３５ｇ、収率８３．１％）を3種の異性体の混合物(異性体Ａ，異性体Ｂ、異性体Ｃ)として得た。
1H-NMR (CDCl3)δ: 1.63-1.75 (m, 6H), 2.14-2.97 (m, 6H), 3.57-3.67 (m, 2H), 3.80 (s, 0.48H), 4.35 (s, 0.13H), 4.59 (s, 0.30H), 4.63-4.74 (m, 1.33H), 4.84-4.87 (m, 0.66H), 4.97 (d, J = 4.4 Hz, 0.32H), 5.10 (d, J = 4.5 Hz, 0.67H), 5.28-5.34 (m, 1H), 5.44-5.48 (m, 1H), 6.08 (d, J = 9.5 Hz, 0.56H), 6.22 (d, J = 9.3 Hz, 0.13H), 6.26 (d, J = 9.4 Hz, 0.31H), 6.86-6.87 (m, 1H), 7.30-7.35 (m, 15H).
Step 3 Synthesis of Compound 1e To a suspension of Compound 1c (8.64 g, 21.26 mmol) in acetone (50.2 mL), Compound 1d (5.02 g, 21.26 mmol) and hexamethylphosphoric triamide (12.95 mL) were prepared. ) And stirred at room temperature for 24 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give white foam-like compound 1e (11.35 g, yield 83.1%) as three kinds of isomers. As a mixture of isomers (isomer A, isomer B, isomer C).
1 H-NMR (CDCl 3 ) δ: 1.63-1.75 (m, 6H), 2.14-2.97 (m, 6H), 3.57-3.67 (m, 2H), 3.80 (s, 0.48H), 4.35 (s, 0.13 H), 4.59 (s, 0.30H), 4.63-4.74 (m, 1.33H), 4.84-4.87 (m, 0.66H), 4.97 (d, J = 4.4 Hz, 0.32H), 5.10 (d, J = 4.5 Hz, 0.67H), 5.28-5.34 (m, 1H), 5.44-5.48 (m, 1H), 6.08 (d, J = 9.5 Hz, 0.56H), 6.22 (d, J = 9.3 Hz, 0.13H) , 6.26 (d, J = 9.4 Hz, 0.31H), 6.86-6.87 (m, 1H), 7.30-7.35 (m, 15H).
工程４　化合物１ｆの合成
化合物１ｅ（１１．３５ｇ、１７．６６ｍｍｏｌ）を化合物Ｉ－０３１の合成実施例の工程６と同様に処理し、化合物１ｆを３種の異性体として得て、異性体Ａ（３３６．６ｍｇ、収率４．１６％）、異性体Ｂと異性体Ｃの混合物（Ｂ：Ｃ＝２：１、３．３８ｇ、収率４１．７％）をそれぞれ白色フォームとして得た。
異性体A
1H-NMR (CDCl3)δ: 1.45-1.51 (m, 1H), 1.71 (s, 3H), 1.77 (s, 3H), 1.88-1.94 (m, 1H), 2.34-2.37 (m, 1H), 2.63-2.82 (m, 3H), 2.90-2.93 (m, 1H), 3.62-3.67 (m, 2H), 4.73-4.82 (m, 2H), 5.27 (d, J = 4.3 Hz, 1H), 5.32 (t, J = 7.5 Hz, 1H), 5.60 (dd, J = 9.3, 4.5 Hz, 1H), 6.25 (d, J = 9.1 Hz, 1H), 7.29-7.36 (m, 5H).
異性体Bと異性体Cの混合物
1H-NMR (CDCl3)δ: 1.62-1.69 (m, 1H), 1.69-1.78 (m, 6H), 2.10-2.18 (m, 1H), 2.38-2.41 (m, 1H), 2.47-2.52 (m, 0.66H), 2.59-2.63 (m, 1.35H), 2.74-2.80 (m, 1.30H), 2.97-3.01 (m, 0.64H), 3.61-3.66 (m, 2H), 4.75-4.82 (m, 2H), 5.11 (d, J = 4.8 Hz, 0.65H), 5.25 (d, J = 4.5 Hz, 0.32H), 5.34-5.36 (m, 1H), 5.57 (dd, J = 9.2, 4.8 Hz, 0.65H), 5.66 (dd, J = 9.0, 4.6 Hz, 0.35H), 6.10 (d, J = 8.8 Hz, 0.67H), 6.24 (d, J = 8.8 Hz, 0.33H), 7.26-7.39 (m, 5H). Step 4 Synthesis of Compound If If Compound 1e (11.35 g, 17.66 mmol) was treated in the same manner as in Step 6 of the Synthesis Example of Compound I-031, compound 1f was obtained as three isomers, and isomer A (336.6 mg, yield 4.16%) and a mixture of isomer B and isomer C (B: C = 2: 1, 3.38 g, yield 41.7%) were obtained as white foams, respectively.
Isomer A
1 H-NMR (CDCl 3 ) δ: 1.45-1.51 (m, 1H), 1.71 (s, 3H), 1.77 (s, 3H), 1.88-1.94 (m, 1H), 2.34-2.37 (m, 1H) , 2.63-2.82 (m, 3H), 2.90-2.93 (m, 1H), 3.62-3.67 (m, 2H), 4.73-4.82 (m, 2H), 5.27 (d, J = 4.3 Hz, 1H), 5.32 (t, J = 7.5 Hz, 1H), 5.60 (dd, J = 9.3, 4.5 Hz, 1H), 6.25 (d, J = 9.1 Hz, 1H), 7.29-7.36 (m, 5H).
Mixture of isomer B and isomer C
1 H-NMR (CDCl 3 ) δ: 1.62-1.69 (m, 1H), 1.69-1.78 (m, 6H), 2.10-2.18 (m, 1H), 2.38-2.41 (m, 1H), 2.47-2.52 ( m, 0.66H), 2.59-2.63 (m, 1.35H), 2.74-2.80 (m, 1.30H), 2.97-3.01 (m, 0.64H), 3.61-3.66 (m, 2H), 4.75-4.82 (m , 2H), 5.11 (d, J = 4.8 Hz, 0.65H), 5.25 (d, J = 4.5 Hz, 0.32H), 5.34-5.36 (m, 1H), 5.57 (dd, J = 9.2, 4.8 Hz, 0.65H), 5.66 (dd, J = 9.0, 4.6 Hz, 0.35H), 6.10 (d, J = 8.8 Hz, 0.67H), 6.24 (d, J = 8.8 Hz, 0.33H), 7.26-7.39 (m , 5H).
工程５　化合物１ｈの合成
化合物１ｆ―異性体Ｂと化合物１ｆ－異性体Ｃの混合物（５００ｍｇ、１．０９ｍｍｏｌ）と化合物１ｇ（５２５ｍｇ、１．３１ｍｍｏｌ）を化合物Ｉ－０３１の合成の工程７と同様に処理し、白色フォーム状の化合物１ｈ―異性体Ｃ（９６．７ｍｇ、収率１２．３％）を単一の異性体として得た。
1H-NMR (CDCl3)δ: 1.52 (s, 9H), 1.57 (s, 9H), 1.74 (s, 3H), 1.80 (s, 3H), 2.64-2.68 (m, 3H), 2.78-2.83 (m, 2H), 3.22-3.25 (m, 1H), 3.65-3.67 (m, 1H), 4.73-4.78 (m, 4H), 5.37-5.38 (m, 2H), 5.80-5.82 (m, 1H), 7.37 (s, 1H), 8.07 (s, 1H), 8.82 (d, J = 8.8 Hz, 1H). Step 5 Synthesis of Compound 1h Compound 1f-isomer B and Compound 1f-isomer C mixture (500 mg, 1.09 mmol) and compound 1g (525 mg, 1.31 mmol) were used in the same manner as in step 7 of the synthesis of compound I-031. To give compound 1h-isomer C (96.7 mg, 12.3% yield) as a single isomer.
1 H-NMR (CDCl 3 ) δ: 1.52 (s, 9H), 1.57 (s, 9H), 1.74 (s, 3H), 1.80 (s, 3H), 2.64-2.68 (m, 3H), 2.78-2.83 (m, 2H), 3.22-3.25 (m, 1H), 3.65-3.67 (m, 1H), 4.73-4.78 (m, 4H), 5.37-5.38 (m, 2H), 5.80-5.82 (m, 1H) , 7.37 (s, 1H), 8.07 (s, 1H), 8.82 (d, J = 8.8 Hz, 1H).
工程６　化合物Ｉ－００９の合成
化合物１ｈ―異性体Ｃ（９０．２ｍｇ、０．１２５ｍｍｏｌ）を化合物Ｉ－０３１の合成の工程７と同様に処理し、化合物Ｉ－００９（１４．２ｍｇ、収率２１．０％）を褐色固体として得た。
1H-NMR (D2O)δ: 1.87-1.90 (m, 1H), 2.40-2.51 (m, 1H), 2.71-2.73 (m, 1H), 2.78-2.80 (m, 2H), 2.96-3.00 (m, 1H), 3.30-3.33 (m, 1H), 4.58 (s, 2H), 5.52 (d, J = 4.3 Hz, 1H), 5.59 (d, J = 4.3 Hz, 1H), 7.08 (s, 1H).
［Ｍ＋Ｈ］＝４９９．９０
Step 6 Synthesis of Compound I-009 Compound 1h—isomer C (90.2 mg, 0.125 mmol) was treated in the same manner as in Step 7 of the synthesis of Compound I-031 to give compound I-009 (14.2 mg, yield). 21.0%) was obtained as a brown solid.
1 H-NMR (D 2 O) δ: 1.87-1.90 (m, 1H), 2.40-2.51 (m, 1H), 2.71-2.73 (m, 1H), 2.78-2.80 (m, 2H), 2.96-3.00 (m, 1H), 3.30-3.33 (m, 1H), 4.58 (s, 2H), 5.52 (d, J = 4.3 Hz, 1H), 5.59 (d, J = 4.3 Hz, 1H), 7.08 (s, 1H).
[M + H] = 499.90
化合物Ｉ－０１８の合成
Figure JPOXMLDOC01-appb-C000164
工程１
化合物２（４４２ｍｇ、１．１０ｍｍｏｌ）をジメチルアセトアミド（５．００ｍＬ）に溶解し、氷点下１０度に冷却した。この溶液に塩化メタンスルホニル（０．０８６ｍＬ、１．１０ｍｍｏｌ）を加え、次いでトリエチルアミン（０．１５２ｍＬ。１．１０ｍｍｏｌ）を滴下し、氷点下１０度で１５分間撹拌した。この反応液に化合物１（４１３ｍｇ、１．００ｍｍｏｌ）とＮ－メチルモルホリン（０．２２０ｍＬ、２．００ｍｍｏｌ）を加え０度で８０分間撹拌した。この反応液に精製水を加え、水層から目的物を酢酸エチルで抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去した。得られた残渣をシリカゲルクロマトグラフィーに付し、化合物３（３５８ｍｇ、０．４７２ｍｍｏｌ）を分離不能な混合物として得た。
1H-NMR (CDCl3)δ: 8.45 (d, J = 7.3 Hz, 0.8H), 8.26 (d, J = 7.8 Hz, 2.2H), 8.04 (s, 0.9H), 7.58 (d, J = 8.6 Hz, 2.1H), 7.39 (s, 1.0H), 5.44 (d, J = 12.9 Hz, 1.0H), 5.38-5.31 (m, 1.0H), 5.17 (dd, J = 16.4, 8.3 Hz, 0.9H), 4.74 (dd, J = 25.5, 16.9 Hz, 2.0H), 3.66-3.53 (m, 2.1H), 2.97-2.86 (m, 1.0H), 2.77-2.64 (m, 0.8H), 1.54 (s, 9.0H), 1.46 (s, 9.3H), 1.26 (t, J = 7.2 Hz, 1.9H). Synthesis of Compound I-018
Figure JPOXMLDOC01-appb-C000164
Process 1
Compound 2 (442 mg, 1.10 mmol) was dissolved in dimethylacetamide (5.00 mL) and cooled to 10 degrees below freezing. To this solution was added methanesulfonyl chloride (0.086 mL, 1.10 mmol), then triethylamine (0.152 mL. 1.10 mmol) was added dropwise, and the mixture was stirred at 10 ° C. for 15 minutes at freezing. To this reaction solution, Compound 1 (413 mg, 1.00 mmol) and N-methylmorpholine (0.220 mL, 2.00 mmol) were added and stirred at 0 ° C. for 80 minutes. Purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with ethyl acetate. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain compound 3 (358 mg, 0.472 mmol) as an inseparable mixture.
1 H-NMR (CDCl 3 ) δ: 8.45 (d, J = 7.3 Hz, 0.8H), 8.26 (d, J = 7.8 Hz, 2.2H), 8.04 (s, 0.9H), 7.58 (d, J = 8.6 Hz, 2.1H), 7.39 (s, 1.0H), 5.44 (d, J = 12.9 Hz, 1.0H), 5.38-5.31 (m, 1.0H), 5.17 (dd, J = 16.4, 8.3 Hz, 0.9 H), 4.74 (dd, J = 25.5, 16.9 Hz, 2.0H), 3.66-3.53 (m, 2.1H), 2.97-2.86 (m, 1.0H), 2.77-2.64 (m, 0.8H), 1.54 ( s, 9.0H), 1.46 (s, 9.3H), 1.26 (t, J = 7.2 Hz, 1.9H).
工程２
化合物３（１．０５３ｇ、１．３８６ｍｍｏｌ）をテトラヒドロフラン（１０．０ｍＬ）に溶解させ、０．１ｍｏｌ／Ｌ　ｐＨ６リン酸緩衝液（１０．０ｍＬ）と５％パラジウム‐活性炭素（１．１８ｍｇ、０．５５４ｍｍｏｌ）を加え、水素雰囲気化、室温で80分間撹拌した。懸濁液をセライト濾過し、２ｍｏｌ／Ｌ塩酸を用いｐＨを１．３５とし飽和食塩水を加え、水層から酢酸エチルで抽出した。集めた有機層を無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去し化合物４（５９０ｍｇ、０．９４４ｍｍｏｌ）を得た。これ以上の精製は行わず次の反応に使用した。 Process 2
Compound 3 (1.053 g, 1.386 mmol) was dissolved in tetrahydrofuran (10.0 mL), 0.1 mol / L pH 6 phosphate buffer (10.0 mL) and 5% palladium-activated carbon (1.18 mg, 0 .554 mmol) was added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 80 minutes. The suspension was filtered through celite, the pH was adjusted to 1.35 using 2 mol / L hydrochloric acid, saturated brine was added, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure to obtain Compound 4 (590 mg, 0.944 mmol). It was used in the next reaction without further purification.
工程3
化合物４（５９０ｍｇ）をジクロロメタン（６．０ｍＬ）に溶解し氷点下２０度に冷却し、アニソール（１．０３ｍＬ、９．４５ｍｍｏｌ）と、２ｍｏｌ／Ｌ塩化アルミニウム‐ニトロメタン溶液（４．７２ｍＬ、９．４５ｍｍｏｌ）を加え、－２０度で３０分間撹拌した。反応液に精製水とジイソプロピルエーテルを加えた。反応液にアセトニトリルを加え水層を分離した。有機層を水/アセトニトリル/希塩酸混液で抽出し、２ｍｏｌ／Ｌ塩酸を用いｐＨを１．３に合わせた。この水層にＨＰ２０ＳＳを加えて濃縮した。濃縮した懸濁液をＨＰ２０ＳＳとＯＤＳを連結したカラムクロマトグラフィーに付し、水－アセトニトリルで溶離し、目的物を含む分画を集めた。この水溶液を２ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いｐＨを９．０に合わせ、ドライアイスを一片加えｐＨを５．２とした。この水溶液を減圧濃縮し、濃縮液を凍結乾燥することによって化合物Ｉ－０１８を粉末として得た。（収量２０５ｍｇ, 収率４２％）
1H-NMR (D2O)δ: 7.04 (s, 1H), 5.23-5.12 (m, 1H), 4.56 (s, 2H), 3.68-2.75 (m, 7H).
MS  (m+1) =  468.94   0.57min

Process 3
Compound 4 (590 mg) was dissolved in dichloromethane (6.0 mL), cooled to 20 degrees below freezing, and anisole (1.03 mL, 9.45 mmol) and a 2 mol / L aluminum chloride-nitromethane solution (4.72 mL, 9.45 mmol). ) And stirred at -20 degrees for 30 minutes. Purified water and diisopropyl ether were added to the reaction solution. Acetonitrile was added to the reaction solution, and the aqueous layer was separated. The organic layer was extracted with a water / acetonitrile / dilute hydrochloric acid mixture, and the pH was adjusted to 1.3 using 2 mol / L hydrochloric acid. HP20SS was added to the aqueous layer and concentrated. The concentrated suspension was subjected to column chromatography connecting HP20SS and ODS and eluted with water-acetonitrile, and fractions containing the desired product were collected. The aqueous solution was adjusted to pH 9.0 using a 2 mol / L aqueous sodium hydroxide solution, and a piece of dry ice was added to adjust the pH to 5.2. This aqueous solution was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound I-018 as a powder. (Yield 205 mg, 42% yield)
1 H-NMR (D 2 O) δ: 7.04 (s, 1H), 5.23-5.12 (m, 1H), 4.56 (s, 2H), 3.68-2.75 (m, 7H).
MS (m + 1) = 468.94 0.57min

化合物Ｉ－０２９の合成
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-I000166
工程１　化合物２９ｂの合成
化合物２９ａ（１５ｇ、１１２ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液に、無水トリフルオロ酢酸（３３．１ｍＬ、２３５ｍｍｏｌ）を内温が４０℃になるように滴下した。室温で２時間攪拌した後、パラメトキシベンジルアルコール（４６．４ｇ、３３６ｍｍｏｌ）を加えた。さらに室温で終夜攪拌した後、氷冷下で１０％炭酸ナトリウム水溶液をｐＨ＝９になるまで滴下した。次いで、酢酸エチルを加え、水層を分取した後、さらに水層を酢酸エチルで洗浄した。得られた水層に２ｍｏｌ／Ｌ塩酸水をｐＨ＝２になるまで加えた後、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮することにより、化合物２９ｂ（２７．８７ｇ、収率９８％）を無色オイルとして得た。
1H-NMR (DMSO-D6)δ: 2.46 (1H, d, J = 7.6 Hz), 2.63 (1H, dd, J = 15.9, 5.1 Hz), 3.75 (3H, s), 4.36 (1H, t, J = 6.2 Hz), 5.05 (2H, s), 6.93 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.3 Hz). Synthesis of Compound I-029
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-I000166
Step 1 Synthesis of Compound 29b To a solution of Compound 29a (15 g, 112 mmol) in tetrahydrofuran (30 mL) was added dropwise trifluoroacetic anhydride (33.1 mL, 235 mmol) so that the internal temperature was 40 ° C. After stirring at room temperature for 2 hours, paramethoxybenzyl alcohol (46.4 g, 336 mmol) was added. Further, after stirring overnight at room temperature, a 10% aqueous sodium carbonate solution was added dropwise under ice cooling until pH = 9. Next, ethyl acetate was added, the aqueous layer was separated, and the aqueous layer was further washed with ethyl acetate. 2 mol / L hydrochloric acid water was added to the obtained aqueous layer until pH = 2, and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure to obtain Compound 29b (27.87 g, yield 98%) as a colorless oil.
1 H-NMR (DMSO-D 6 ) δ: 2.46 (1H, d, J = 7.6 Hz), 2.63 (1H, dd, J = 15.9, 5.1 Hz), 3.75 (3H, s), 4.36 (1H, t , J = 6.2 Hz), 5.05 (2H, s), 6.93 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.3 Hz).
工程２　化合物２９ｃの合成
化合物２９ｂ（２７．８７ｇ、１１０ｍｍｏｌ）のジメチルホルムアミド（１３９ｍＬ）溶液に、氷冷下でイミダゾール（２２．３９ｇ、３２９ｍｍｏｌ）、ＴＢＳクロライド（４１．３ｇ、２７４ｍｍｏｌ）を加えた。室温で１時間攪拌した後、氷冷下で２ｍｏｌ／Ｌ塩酸水をｐＨ＝５．５になるまで加えた。さらに氷冷下で４０分間攪拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物２９ｃ（３２．６９ｇ、収率８１％）を無色オイルとして得た。
1H-NMR (CDCl3)δ: 0.04 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 2.74 (1H, dd, J = 15.8, 7.7 Hz), 2.84 (1H, dd, J = 15.8, 4.6 Hz), 3.81 (3H, s), 4.62 (1H, dd, J = 7.7, 4.6 Hz), 5.11 (2H, dd, J = 22.3, 11.9 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz). Step 2 Synthesis of Compound 29c Imidazole (22.39 g, 329 mmol) and TBS chloride (41.3 g, 274 mmol) were added to a solution of compound 29b (27.87 g, 110 mmol) in dimethylformamide (139 mL) under ice cooling. After stirring at room temperature for 1 hour, 2 mol / L aqueous hydrochloric acid was added under ice cooling until pH = 5.5. The mixture was further stirred for 40 minutes under ice cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 29c (32.69 g, yield 81%) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.04 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 2.74 (1H, dd, J = 15.8, 7.7 Hz), 2.84 (1H, dd , J = 15.8, 4.6 Hz), 3.81 (3H, s), 4.62 (1H, dd, J = 7.7, 4.6 Hz), 5.11 (2H, dd, J = 22.3, 11.9 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz).
工程３　化合物２９ｄの合成
化合物２９ｃ（３２．６９ｇ、８９ｍｍｏｌ）のジクロロメタン（６５４ｍＬ）溶液に、トリフェニルホスホラニリデンアセトニトリル（２６．７ｇ、８９ｍｍｏｌ）、ＤＭＡＰ（１．０８ｇ、８．９ｍｍｏｌ）、ＥＤＣ塩酸塩（１８．７１ｇ、９８ｍｍｏｌ）を順に加えた。室温で２時間攪拌した後、減圧濃縮し、残渣に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物２９ｄ（４７．０１ｇ、収率８１％）を黄色オイルとして得た。
1H-NMR (CDCl3)δ: -0.03 (3H, s), 0.01 (3H, s), 0.85 (9H, s), 3.12 (1H, dd, J = 15.5, 6.4 Hz), 3.23 (1H, dd, J = 15.5, 5.3 Hz), 3.80 (3H, s), 4.72 (1H, t, J = 5.9 Hz), 5.06 (2H, dd, J = 13.4, 12.4 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 7.6 Hz), 7.47-7.62 (15H, m). Step 3 Synthesis of Compound 29d To a solution of Compound 29c (32.69 g, 89 mmol) in dichloromethane (654 mL), triphenylphosphoranylideneacetonitrile (26.7 g, 89 mmol), DMAP (1.08 g, 8.9 mmol), EDC hydrochloric acid Salt (18.71 g, 98 mmol) was added in order. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 29d (47.01 g, yield 81%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: -0.03 (3H, s), 0.01 (3H, s), 0.85 (9H, s), 3.12 (1H, dd, J = 15.5, 6.4 Hz), 3.23 (1H, dd, J = 15.5, 5.3 Hz), 3.80 (3H, s), 4.72 (1H, t, J = 5.9 Hz), 5.06 (2H, dd, J = 13.4, 12.4 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 7.6 Hz), 7.47-7.62 (15H, m).
工程４　化合物２９ｆの合成
化合物２９ｄ（２２．８１ｇ、３５ｍｍｏｌ）のジクロロメタン（４５６ｍＬ）溶液を、－７８℃でオゾンガスをバブリングしながら２時間半攪拌した。系内を窒素ガスで置換した後、ジメチルスルフィド（７．７７ｍＬ、１０５ｍｍｏｌ）を加え、－７８℃で５分間攪拌した。次いで、プレニルアルコール（５．３３ｍＬ、５３ｍｍｏｌ）を加え、－７８℃で１時間半攪拌した。反応混合物を０℃程度まで昇温した後、５％炭酸ナトリウム水溶液を加え、室温で５分間攪拌した。ジクロロメタンを減圧留去した後、酢酸エチルで抽出し、有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物２９ｆ（６．６７ｇ、収率４１％）を無色オイルとして得た。
1H-NMR (CDCl3)δ: 0.03 (3H, s), 0.04 (3H, s), 0.83 (9H, s), 1.73 (3H, s), 1.76 (3H, s), 3.24 (2H, d, J = 6.6 Hz), 3.81 (3H, s), 4.73 (3H, d, J = 7.6 Hz), 5.09 (2H, dd, J = 16.3, 12.0 Hz), 5.38 (1H, t, J = 6.8 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.8 Hz). Step 4 Synthesis of Compound 29f A solution of compound 29d (22.81 g, 35 mmol) in dichloromethane (456 mL) was stirred at −78 ° C. for 2 hours and a half while bubbling ozone gas. The system was replaced with nitrogen gas, dimethyl sulfide (7.77 mL, 105 mmol) was added, and the mixture was stirred at −78 ° C. for 5 minutes. Next, prenyl alcohol (5.33 mL, 53 mmol) was added, and the mixture was stirred at −78 ° C. for 1.5 hours. The temperature of the reaction mixture was raised to about 0 ° C., 5% aqueous sodium carbonate solution was added, and the mixture was stirred at room temperature for 5 minutes. Dichloromethane was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 29f (6.67 g, yield 41%) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.03 (3H, s), 0.04 (3H, s), 0.83 (9H, s), 1.73 (3H, s), 1.76 (3H, s), 3.24 (2H, d , J = 6.6 Hz), 3.81 (3H, s), 4.73 (3H, d, J = 7.6 Hz), 5.09 (2H, dd, J = 16.3, 12.0 Hz), 5.38 (1H, t, J = 6.8 Hz ), 6.88 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.8 Hz).
工程５　化合物２９ｇの合成
化合物２９ｆ（６．６７ｇ、１４．４ｍｍｏｌ）のジクロロメタン（３３ｍＬ）溶液に、氷冷下でＮ，Ｎ，Ｎ’Ｎ’－テトラメチルメタンジアミン（７．８２ｍＬ、５７．４ｍｍｏｌ）を加えた後、無水酢酸（６．７８ｍＬ、７１．８ｍｍｏｌ）、酢酸（５．７５ｍＬ、１００ｍｍｏｌ）を順にゆっくりと加えた。室温で３時間攪拌した後、反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物２９ｇ（３．６４ｇ、収率５３％）を無色オイルとして得た。
1H-NMR (CDCl3)δ: 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.74 (3H, s), 1.78 (3H, s), 3.80 (3H, s), 4.77 (2H, d, J = 7.6 Hz), 5.07 (2H, s), 5.22 (1H, s), 5.39 (1H, t, J = 6.7 Hz), 6.41 (1H, s), 6.48 (1H, s), 6.86 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 9.1 Hz). Step 5 Compound 29g Synthesis compound 29f (6.67 g, 14.4 mmol) in dichloromethane (33 mL) was added with N, N, N′N′-tetramethylmethanediamine (7.82 mL, 57.4 mmol) under ice cooling. ) Was added, and acetic anhydride (6.78 mL, 71.8 mmol) and acetic acid (5.75 mL, 100 mmol) were slowly added in this order. After stirring at room temperature for 3 hours, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 29 g (3.64 g, 53% yield) of compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.05 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.74 (3H, s), 1.78 (3H, s), 3.80 (3H, s ), 4.77 (2H, d, J = 7.6 Hz), 5.07 (2H, s), 5.22 (1H, s), 5.39 (1H, t, J = 6.7 Hz), 6.41 (1H, s), 6.48 (1H , s), 6.86 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 9.1 Hz).
工程６　化合物２９ｉの合成
化合物２９ｇ（３．６４ｇ、７．６ｍｍｏｌ）のアセトン（３６ｍＬ）溶液に、化合物２９ｈ（１．９９ｇ、８．４ｍｍｏｌ）、ヘキサメチルリン酸トリアミド（４．６５ｍＬ、２６．７ｍｍｏｌ）を加えた。室温で３時間半攪拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物２９ｉ（７８０ｍｇ、収率１４％）を白色フォームとして得た。
1H-NMR (CDCl3)δ: -0.05 (3H, s), -0.01 (3H, s), 0.83 (9H, s), 1.69 (3H, s), 1.76 (3H, s), 2.68-2.76 (2H, m), 3.09 (1H, t, J = 12.5 Hz), 3.61 (2H, dd, J = 24.1, 16.0 Hz), 3.82 (3H, s), 4.11 (1H, d, J = 6.6 Hz), 4.19 (1H, s), 4.70 (1H, dd, J = 12.1, 7.6 Hz), 4.85 (1H, dd, J = 12.1, 7.3 Hz), 5.05-5.07 (3H, m), 5.37 (1H, t, J = 6.8 Hz), 5.45 (1H, dd, J = 9.1, 4.5 Hz), 6.09 (1H, d, J = 9.1 Hz), 6.88 (2H, d, J = 8.3 Hz), 7.26-7.39 (7H, m). Step 6 Synthesis of compound 29i To a solution of compound 29g (3.64 g, 7.6 mmol) in acetone (36 mL), compound 29h (1.99 g, 8.4 mmol), hexamethylphosphoric triamide (4.65 mL, 26.7 mmol) were prepared. ) Was added. After stirring at room temperature for 3.5 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 29i (780 mg, yield 14%) as a white foam.
1 H-NMR (CDCl 3 ) δ: -0.05 (3H, s), -0.01 (3H, s), 0.83 (9H, s), 1.69 (3H, s), 1.76 (3H, s), 2.68-2.76 (2H, m), 3.09 (1H, t, J = 12.5 Hz), 3.61 (2H, dd, J = 24.1, 16.0 Hz), 3.82 (3H, s), 4.11 (1H, d, J = 6.6 Hz) , 4.19 (1H, s), 4.70 (1H, dd, J = 12.1, 7.6 Hz), 4.85 (1H, dd, J = 12.1, 7.3 Hz), 5.05-5.07 (3H, m), 5.37 (1H, t , J = 6.8 Hz), 5.45 (1H, dd, J = 9.1, 4.5 Hz), 6.09 (1H, d, J = 9.1 Hz), 6.88 (2H, d, J = 8.3 Hz), 7.26-7.39 (7H , m).
工程７　化合物２９ｋの合成
化合物２９ｉ（７００ｍｇ、０．９８ｍｍｏｌ）のジクロロメタン（３．５ｍＬ）溶液に、－１０℃でトリフルオロ酢酸（３．５ｍＬ）のジクロロメタン（３．５ｍＬ）溶液を１０分間かけて滴下した。－１０℃で３０分間攪拌した後、反応混合物に氷水を加え、ジクロロメタンで抽出した。有機層を水で４回洗浄した後、飽和食塩水で洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮することにより化合物２９ｊを白色フォームとして得た。得られた２９ｊは精製せずにそのまま次の反応に用いた。
得られた２９ｊ全量をジクロロメタン（５．８ｍＬ）溶液に溶解させた後、氷冷下でＥＤＣ塩酸塩（３７７ｍｇ、１．９６ｍｍｏｌ）を加えた。室温で１時間攪拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物２９ｋ（２２３ｍｇ、収率４０％）を白色フォームとして得た。
1H-NMR (CDCl3)δ: 0.11 (3H, s), 0.17 (3H, s), 0.90 (9H, s), 1.71 (3H, s), 1.77 (3H, s), 2.60-2.69 (2H, m), 2.96 (1H, dd, J = 15.3, 3.7 Hz), 3.09-3.15 (1H, m), 3.64 (2H, dd, J = 26.7, 16.3 Hz), 4.46 (1H, d, J = 6.3 Hz), 4.72-4.84 (1H, m), 4.97 (1H, d, J = 3.8 Hz), 5.36 (1H, s), 5.65 (1H, dd, J = 8.6, 4.3 Hz), 6.00 (1H, d, J = 8.8 Hz), 7.31-7.38 (5H, m). Step 7 Synthesis of Compound 29k Compound 29i (700 mg, 0.98 mmol) in dichloromethane (3.5 mL) at −10 ° C. with trifluoroacetic acid (3.5 mL) in dichloromethane (3.5 mL) over 10 minutes It was dripped. After stirring at −10 ° C. for 30 minutes, ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed 4 times with water, then with saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure to obtain Compound 29j as a white foam. The obtained 29j was used in the next reaction without purification.
The total amount of 29j thus obtained was dissolved in a dichloromethane (5.8 mL) solution, and then EDC hydrochloride (377 mg, 1.96 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 29k (223 mg, yield 40%) as a white foam.
1 H-NMR (CDCl 3 ) δ: 0.11 (3H, s), 0.17 (3H, s), 0.90 (9H, s), 1.71 (3H, s), 1.77 (3H, s), 2.60-2.69 (2H , m), 2.96 (1H, dd, J = 15.3, 3.7 Hz), 3.09-3.15 (1H, m), 3.64 (2H, dd, J = 26.7, 16.3 Hz), 4.46 (1H, d, J = 6.3 Hz), 4.72-4.84 (1H, m), 4.97 (1H, d, J = 3.8 Hz), 5.36 (1H, s), 5.65 (1H, dd, J = 8.6, 4.3 Hz), 6.00 (1H, d , J = 8.8 Hz), 7.31-7.38 (5H, m).
工程８　化合物２９ｎの合成
化合物２９ｋ（２１２ｍｇ、０．３７ｍｍｏｌ）と化合物２９ｍ（１７８ｍｇ、０．４４ｍｍｏｌ）から実施例１の工程３と同様にして化合物２９ｎ（２５５ｍｇ、収率８２％）を白色フォームとして得た。
1H-NMR (CDCl3)δ: 0.12 (3H, s), 0.19 (3H, s), 0.91 (9H, s), 1.53 (9H, s), 1.56 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.67-2.74 (1H, m), 3.02 (1H, dd, J = 15.2, 4.3 Hz), 3.10-3.14 (1H, m), 3.77 (2H, s), 4.49 (1H, d, J = 7.1 Hz), 4.76 (2H, d, J = 8.1 Hz), 5.09 (1H, d, J = 5.1 Hz), 5.38 (1H, s), 5.74 (1H, dd, J = 8.3, 5.1 Hz), 7.37 (1H, s), 8.03 (1H, s), 8.65 (1H, d, J = 8.6 Hz). Step 8 Synthesis of Compound 29n Compound 29n (255 mg, 82% yield) was converted into white foam from Compound 29k (212 mg, 0.37 mmol) and Compound 29m (178 mg, 0.44 mmol) in the same manner as in Step 3 of Example 1. Obtained.
1 H-NMR (CDCl 3 ) δ: 0.12 (3H, s), 0.19 (3H, s), 0.91 (9H, s), 1.53 (9H, s), 1.56 (9H, s), 1.73 (3H, s ), 1.77 (3H, s), 2.67-2.74 (1H, m), 3.02 (1H, dd, J = 15.2, 4.3 Hz), 3.10-3.14 (1H, m), 3.77 (2H, s), 4.49 ( 1H, d, J = 7.1 Hz), 4.76 (2H, d, J = 8.1 Hz), 5.09 (1H, d, J = 5.1 Hz), 5.38 (1H, s), 5.74 (1H, dd, J = 8.3 , 5.1 Hz), 7.37 (1H, s), 8.03 (1H, s), 8.65 (1H, d, J = 8.6 Hz).
工程９　化合物Ｉ－０２９の合成
化合物２９ｎ（２５５ｍｇ、０．３０ｍｍｏｌ）から実施例１の工程４と同様にして化合物Ｉ－０２９（２２ｍｇ、収率１４％）を淡黄色粉末として得た。
1H-NMR (D2O)δ: 2.72-3.26 (4H, m), 4.58 (2H, s), 5.28 (1H, d, J = 4.5 Hz), 5.67 (1H, d, J = 4.3 Hz), 7.06 (1H, s).
MS (m+1) = 501.96 (0.71min)
Step 9 Synthesis of Compound I-029 Compound I-029 (22 mg, 14% yield) was obtained as a pale yellow powder from Compound 29n (255 mg, 0.30 mmol) in the same manner as in Step 4 of Example 1.
1 H-NMR (D 2 O) δ: 2.72-3.26 (4H, m), 4.58 (2H, s), 5.28 (1H, d, J = 4.5 Hz), 5.67 (1H, d, J = 4.3 Hz) , 7.06 (1H, s).
MS (m + 1) = 501.96 (0.71min)
化合物Ｉ－０３１の合成
Figure JPOXMLDOC01-appb-C000167
 工程１　化合物１ｂの合成
化合物１ａ（４３．８ｇ、３００ｍｍｏｌ）のＤＭＦ（３０７ｍＬ）溶液を６０℃に昇温した。これに、ジシクロヘキシルアミン（５９．６ｍＬ、３００ｍｍｏｌ）および、1－ブロモ－３－メチル－２－ブテン（３８．１ｍＬ、３００ｍｍｏｌ）を加えた。６０℃下で1時間攪拌した後、析出した固体をろ過除去した。濾液に水を加え、酢酸エチルで抽出した。有機層を水および、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣のテトラヒドロフラン（３２１ｍＬ）溶液に、氷冷下、ジフェニルジアゾメタン（６４．１ｇ、３３０ｍｍｏｌ）を加え、室温で7時間撹拌した。室温で２日間静置した後、溶媒を減圧留去した。得られた粗生成物はシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物１ｂ（１０４ｇ、収率９１％）を得た。
1H-NMR (CDCl3)δ: 1.73 (3H, s), 1.76 (3H, s), 2.79 (2H, t, J = 6.2 Hz), 3.18 (2H, t, J = 6.2 Hz), 4.74 (2H, d, J = 7.3 Hz), 5.38 (1H, t, J = 7.3 Hz), 6.86 (1H, s), 7.26-7.36 (10H, m).
工程２　化合物１ｃの合成
化合物１ｂ（１０４ｇ、２７３ｍｍｏｌ）のジクロロメタン（５２０ｍＬ）溶液に、Ｎ，Ｎ，Ｎ‘，Ｎ’－テトラメチルジアミノメタン（１４９ｍＬ、１０９３ｍｍｏｌ）を加えた。氷冷下で、無水酢酸（１２９ｍＬ、１３６７ｍＬ）、酢酸（１０９ｍＬ、１９１４ｍｍｏｌ）を加え、室温化、１時間撹拌後、溶媒を減圧留去した後、水を加え、酢酸エチルで抽出した。有機層を水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物１ｃ（７９ｇ、７４％）を得た。
1H-NMR (CDCl3)δ: 1.74 (3H, s), 1.77 (3H, s), 3.48 (2H, s), 4.78 (2H, d, J = 7.4 Hz), 5.39 (1H, t, J = 7.4 Hz), 6.25 (1H, s), 6.36 (1H, s), 6.86 (1H, s), 7.26-7.35 (10H, m). Synthesis of Compound I-031
Figure JPOXMLDOC01-appb-C000167
 Step 1 Synthesis of Compound 1b A DMF (307 mL) solution of Compound 1a (43.8 g, 300 mmol) was heated to 60 ° C. To this was added dicyclohexylamine (59.6 mL, 300 mmol) and 1-bromo-3-methyl-2-butene (38.1 mL, 300 mmol). After stirring at 60 ° C. for 1 hour, the precipitated solid was removed by filtration. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diphenyldiazomethane (64.1 g, 330 mmol) was added to a tetrahydrofuran (321 mL) solution of the obtained residue under ice cooling, followed by stirring at room temperature for 7 hours. After standing at room temperature for 2 days, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 1b (104 g, yield 91%).
1 H-NMR (CDCl 3 ) δ: 1.73 (3H, s), 1.76 (3H, s), 2.79 (2H, t, J = 6.2 Hz), 3.18 (2H, t, J = 6.2 Hz), 4.74 ( 2H, d, J = 7.3 Hz), 5.38 (1H, t, J = 7.3 Hz), 6.86 (1H, s), 7.26-7.36 (10H, m).
Step 2 Synthesis of Compound 1c To a solution of Compound 1b (104 g, 273 mmol) in dichloromethane (520 mL) was added N, N, N ′, N′-tetramethyldiaminomethane (149 mL, 1093 mmol). Under ice-cooling, acetic anhydride (129 mL, 1367 mL) and acetic acid (109 mL, 1914 mmol) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain Compound 1c (79 g, 74%).
1 H-NMR (CDCl 3 ) δ: 1.74 (3H, s), 1.77 (3H, s), 3.48 (2H, s), 4.78 (2H, d, J = 7.4 Hz), 5.39 (1H, t, J = 7.4 Hz), 6.25 (1H, s), 6.36 (1H, s), 6.86 (1H, s), 7.26-7.35 (10H, m).
工程３　化合物１ｅの合成
化合物１ｃ（１０．０ｇ、２５．５ｍｍｏｌ）のアセトン（１００ｍＬ）溶液に、化合物１ｄ（６．０２ｇ、２５．５ｍｍｏｌ）およびヘキサメチルリン酸トリアミド（１５．５ｍＬ、８９ｍｍｏｌ）を加え、室温で１時間撹拌した。水を加え、酢酸エチルで抽出した。有機層を水、および飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製することにより、化合物１ｅ（２．１ｇ、収率１３．１％）で得た。
1H-NMR (CDCl3)δ: 1.65 (3H, s), 1.69 (3H, s), 2.34 (2H, t, J = 4.5 Hz), 2.69 (1H, dd, J = 13.6, 2.8 Hz), 2.81 (1H, br s), 2.91-2.98 (1H, m), 3.59 (1H, d, J = 16.1 Hz), 3.65 (1H, d, J = 16.1 Hz), 3.77 (1H, s), 4.67 (1H, dd, J = 12.0, 7.5 Hz), 4.88 (1H, dd, J = 12.0, 7.5 Hz), 5.08 (1H, d, J = 4.7 Hz), 5.33 (1H, t, J = 7.5 Hz), 5.51 (1H, dd, J = 9.5, 4.7 Hz), 6.09 (1H, d, J = 9.5 Hz), 6.86 (1H, s), 7.26-7.40 (17H, m). Step 3 Synthesis of Compound 1e To a solution of Compound 1c (10.0 g, 25.5 mmol) in acetone (100 mL), Compound 1d (6.02 g, 25.5 mmol) and hexamethylphosphoric triamide (15.5 mL, 89 mmol) were added. The mixture was further stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain Compound 1e (2.1 g, yield: 13.1%).
1 H-NMR (CDCl 3 ) δ: 1.65 (3H, s), 1.69 (3H, s), 2.34 (2H, t, J = 4.5 Hz), 2.69 (1H, dd, J = 13.6, 2.8 Hz), 2.81 (1H, br s), 2.91-2.98 (1H, m), 3.59 (1H, d, J = 16.1 Hz), 3.65 (1H, d, J = 16.1 Hz), 3.77 (1H, s), 4.67 ( 1H, dd, J = 12.0, 7.5 Hz), 4.88 (1H, dd, J = 12.0, 7.5 Hz), 5.08 (1H, d, J = 4.7 Hz), 5.33 (1H, t, J = 7.5 Hz), 5.51 (1H, dd, J = 9.5, 4.7 Hz), 6.09 (1H, d, J = 9.5 Hz), 6.86 (1H, s), 7.26-7.40 (17H, m).
工程４　化合物１ｆの合成
窒素雰囲気下、化合物１ｅ（６．８０ｇ、１０．８ｍｍｏｌ）のジクロロメタン（３４ｍＬ）溶液を－１０℃に冷却した。これに、ＴＦＡ（３４ｍＬ、４４１ｍｍｏｌ）のジクロロメタン（３４ｍＬ）溶液を滴下し、－１０℃で３０分間撹拌した。水を加え、ジクロロメタンで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を留去し、得られた残渣のジクロロメタン（５０ｍＬ）溶液を０℃に冷却した。これに、ＥＤＣ塩酸塩（４．１５ｇ、２１．６ｍｍｏｌ）を加え、室温下１時間撹拌した。水を加え、ジクロロメタンで抽出した。有機層を希塩酸および飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残渣をカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物１ｆ（４．０ｇ、８３％）を得た。
1H-NMR (CDCl3)δ: 1.71 (3H, s), 1.77 (3H, s), 2.60-2.67 (2H, m), 2.75 (1H, dd, J = 18.1, 9.0 Hz), 2.94 (1H, dd, J = 14.4, 4.3 Hz), 3.19-3.25 (1H, m), 4.73-4.83 (2H, m), 4.96-4.98 (1H, m), 5.36 (1H, t, J = 6.8 Hz), 5.53 (1H, dd, J = 8.7, 4.7 Hz), 6.16 (1H, d, J = 8.6 Hz), 7.26-7.39 (6H, m). Step 4 Synthesis of Compound 1f Under a nitrogen atmosphere, a solution of compound 1e (6.80 g, 10.8 mmol) in dichloromethane (34 mL) was cooled to −10 ° C. A solution of TFA (34 mL, 441 mmol) in dichloromethane (34 mL) was added dropwise thereto, and the mixture was stirred at −10 ° C. for 30 minutes. Water was added and extracted with dichloromethane. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and a solution of the obtained residue in dichloromethane (50 mL) was cooled to 0 ° C. To this, EDC hydrochloride (4.15 g, 21.6 mmol) was added and stirred at room temperature for 1 hour. Water was added and extracted with dichloromethane. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain Compound 1f (4.0 g, 83%).
1 H-NMR (CDCl 3 ) δ: 1.71 (3H, s), 1.77 (3H, s), 2.60-2.67 (2H, m), 2.75 (1H, dd, J = 18.1, 9.0 Hz), 2.94 (1H , dd, J = 14.4, 4.3 Hz), 3.19-3.25 (1H, m), 4.73-4.83 (2H, m), 4.96-4.98 (1H, m), 5.36 (1H, t, J = 6.8 Hz), 5.53 (1H, dd, J = 8.7, 4.7 Hz), 6.16 (1H, d, J = 8.6 Hz), 7.26-7.39 (6H, m).
Figure JPOXMLDOC01-appb-C000168
工程５　化合物１ｉの合成
化合物１ｇ（５．０ｇ、３３．５ｍｍｏｌ）のテトラヒドロフラン溶液に、トリフェニルホスフィン（８．８０ｇ、３３．５ｍｍｏｌ）を加え、０℃に冷却した。これにＤＩＡＤ（６．５２ｍＬ，３３．５ｍｍｏｌ）およびヒドロキシ酢酸ベンズヒドリルを加え、０℃で１時間撹拌した。反応混合物をヘキサン－酢酸エチル混合液に注ぎ、生じた不溶物を濾過した。濾液を減圧留去し、得られた残渣をカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物１ｈを含む粗生成物１０ｇを得た。この化合物１ｈのＤＭＡ（６０ｍＬ）溶液にチオ尿素（１５．３ｇ、２０１ｍｍｏｌ）を加え、３０℃で２４時間撹拌した。不溶物を濾過し、濾液を減圧留去した。得られた残渣をカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物１ｉ（１．５ｇ、９．５％）を得た。
1H-NMR (CDCl3)δ: 4.78 (2H, d, J = 5.8 Hz), 4.94 (4H, br s), 5.26 (1H, dd, J = 10.4, 1.0 Hz), 5.36 (1H, dd, J = 17.2, 1.3 Hz), 5.90-6.00 (1H, m), 6.96 (1H, s), 7.26-7.33 (10H, m).
Figure JPOXMLDOC01-appb-C000168
Step 5 Synthesis of Compound 1i To a tetrahydrofuran solution of 1 g (5.0 g, 33.5 mmol) of compound 1i was added triphenylphosphine (8.80 g, 33.5 mmol) and cooled to 0 ° C. DIAD (6.52 mL, 33.5 mmol) and hydroxyacetic acid benzhydryl were added thereto, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was poured into a hexane-ethyl acetate mixture, and the resulting insoluble material was filtered. The filtrate was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain 10 g of a crude product containing compound 1h. Thiourea (15.3 g, 201 mmol) was added to a solution of this compound 1h in DMA (60 mL), and the mixture was stirred at 30 ° C. for 24 hours. Insoluble matter was filtered, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain Compound 1i (1.5 g, 9.5%).
1 H-NMR (CDCl 3 ) δ: 4.78 (2H, d, J = 5.8 Hz), 4.94 (4H, br s), 5.26 (1H, dd, J = 10.4, 1.0 Hz), 5.36 (1H, dd, J = 17.2, 1.3 Hz), 5.90-6.00 (1H, m), 6.96 (1H, s), 7.26-7.33 (10H, m).
工程６　化合物１ｊの合成
窒素雰囲気化、化合物１ｉ（８５０ｍｇ、１．８１ｍｍｏｌ）のテトラヒドロフラン（１３ｍＬ）溶液にモルホリン（７８９ｍｇ、９．０５ｍｍｏｌ）および、Ｐｄ（ＰＰｈ３）４（１０５ｍｇ、０．０９１ｍｍｏｌ）を加え、室温下、１時間撹拌した。水を加え、酢酸エチルで抽出した。有機層を希塩酸および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去することで化合物１ｊを得た。
MS (m-1) =428.01  Step 6 Synthesis of Compound 1j in a nitrogen atmosphere, To a solution of Compound 1i (850 mg, 1.81 mmol) in tetrahydrofuran (13 mL) were added morpholine (789 mg, 9.05 mmol) and Pd (PPh 3 ) 4 (105 mg, 0.091 mmol). The mixture was further stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 1j.
MS (m-1) = 428.01
Figure JPOXMLDOC01-appb-C000169
工程７　化合物Ｉ－０３１の合成
五塩化リン（０．７５４ｇ、３．６２ｍｍｏｌ）のジクロロメタン（１０ｍＬ）懸濁液を－４０℃まで冷却した後、ピリジン（０．５８４ｍＬ、７．２４ｍｍｏｌ）を加え、次いで化合物１ｆ（０．８０５ｇ、１．８１ｍｍｏｌ）を加えた。氷冷下で１時間攪拌した後、反応混合物を－７８℃まで冷却し、メタノール（８．１ｍＬ）を加えた。－３０℃で２時間攪拌した後、反応混合物に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥した後、無機物をろ過により除去した。ろ液に酢酸エチルを加え、ジクロロメタン及びメタノールを減圧留去し、酢酸エチル溶液（溶液Ａ）を得た。化合物１ｊ（７７７ｍｇ、１．８１ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、ＨＯＢｔ（０．３６７ｇ、２．７２ｍｍｏｌ）を加え、反応溶液を０℃に冷却した。これに、ＥＤＣ塩酸塩（０．４１６ｇ、２．１７ｍｍｏｌ）を加え、氷冷下、１時間撹拌した。生じた不溶物を濾過し、濾液を、氷冷下、溶液Ａに加え、１時間撹拌した。これに水を加え、酢酸エチルで抽出した。有機層を希塩酸、炭酸水素ナトリウム水、飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物１ｋの粗生成物（１ｇ）を得た。これをジクロロメタン（１０ｍＬ）に溶解させ、アニソール（１．４８ｍＬ、１３．６ｍｍｏｌ）を加え、－３０℃に冷却した。これに、２ｍｏｌ／Ｌ塩化アルミニウム／ニトロメタン溶液（１．４８ｍＬ、１３．６ｍｍｏｌ）を加え－３０℃下、１時間撹拌した。反応液に氷、ジイソプロピルエーテル、アセトニトリルを順に加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィー（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することにより化合物Ｉ－０３１（２７０ｍｇ）を白色粉末として得た。
1H-NMR (D2O)δ: 2.62 (1H, d, J = 18.2 Hz), 2.94-2.78 (2H, m), 3.15-3.06 (2H, m), 4.67 (2H, s), 5.26 (1H, d, J = 4.5 Hz), 5.61 (1H, d, J = 4.5 Hz).
元素分析：C16H14FN5O9S2(H2O)4.2
計算値：C,33.19; H,3.90; F, 3.28; N,12.09; S 11.07 (%)
実測値：C,33.14; H,3.60; F, 3.25; N,12.11; S,11.05 (%)
Figure JPOXMLDOC01-appb-C000169
Step 7 Synthesis of Compound I-031 A suspension of phosphorus pentachloride (0.754 g, 3.62 mmol) in dichloromethane (10 mL) was cooled to −40 ° C., and pyridine (0.584 mL, 7.24 mmol) was added. Compound 1f (0.805 g, 1.81 mmol) was then added. After stirring for 1 hour under ice cooling, the reaction mixture was cooled to −78 ° C., and methanol (8.1 mL) was added. After stirring at −30 ° C. for 2 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then inorganic substances were removed by filtration. Ethyl acetate was added to the filtrate, and dichloromethane and methanol were distilled off under reduced pressure to obtain an ethyl acetate solution (solution A). To a solution of compound 1j (777 mg, 1.81 mmol) in dichloromethane (10 mL) was added HOBt (0.367 g, 2.72 mmol), and the reaction solution was cooled to 0 ° C. To this, EDC hydrochloride (0.416 g, 2.17 mmol) was added and stirred for 1 hour under ice cooling. The resulting insoluble material was filtered, and the filtrate was added to solution A under ice cooling and stirred for 1 hour. Water was added thereto and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain a crude product (1 g) of compound 1k. This was dissolved in dichloromethane (10 mL), anisole (1.48 mL, 13.6 mmol) was added, and the mixture was cooled to −30 ° C. To this was added a 2 mol / L aluminum chloride / nitromethane solution (1.48 mL, 13.6 mmol), and the mixture was stirred at −30 ° C. for 1 hour. Ice, diisopropyl ether and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matters, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to give Compound I-031 (270 mg) as a white powder.
1 H-NMR (D 2 O) δ: 2.62 (1H, d, J = 18.2 Hz), 2.94-2.78 (2H, m), 3.15-3.06 (2H, m), 4.67 (2H, s), 5.26 ( 1H, d, J = 4.5 Hz), 5.61 (1H, d, J = 4.5 Hz).
Elemental analysis: C16H14FN5O9S2 (H2O) 4.2
Calculated values: C, 33.19; H, 3.90; F, 3.28; N, 12.09; S 11.07 (%)
Found: C, 33.14; H, 3.60; F, 3.25; N, 12.11; S, 11.05 (%)
　化合物Ｉ－３３の合成 　
Figure JPOXMLDOC01-appb-C000170
化合物３３ａ（Ｄ－リンゴ酸）から実施例６の工程１～９と同様にして化合物Ｉ－３３を合成した。
1H-NMR (D2O) δ: 2.96 (1H, dd, J = 14.1, 5.3 Hz), 3.08-3.13 (1H, m), 3.41 (1H, dd, J = 14.1, 2.8 Hz), 5.16 (1H, d, J = 8.6 Hz), 5.20 (1H, d, J = 4.3 Hz), 5.43 (1H, d, J = 4.0 Hz), 7.32 (1H, s).
MS (m+1) = 501.92、保持時間：0.65 分、測定条件１)
元素分析：C16H15N5O10S2(H2O)3.1
計算値：C,34.48; H,3.83; N,12.57; S,11.51 (%)
実測値：C,34.37; H,3.68; N,12.71; S,11.81 (%)
Synthesis of Compound I-33
Figure JPOXMLDOC01-appb-C000170
Compound I-33 was synthesized from Compound 33a (D-malic acid) in the same manner as in Steps 1 to 9 of Example 6.
1 H-NMR (D 2 O) δ: 2.96 (1H, dd, J = 14.1, 5.3 Hz), 3.08-3.13 (1H, m), 3.41 (1H, dd, J = 14.1, 2.8 Hz), 5.16 ( 1H, d, J = 8.6 Hz), 5.20 (1H, d, J = 4.3 Hz), 5.43 (1H, d, J = 4.0 Hz), 7.32 (1H, s).
MS (m + 1) = 501.92, retention time: 0.65 minutes, measurement condition 1)
Elemental analysis: C16H15N5O10S2 (H2O) 3.1
Calculated value: C, 34.48; H, 3.83; N, 12.57; S, 11.51 (%)
Found: C, 34.37; H, 3.68; N, 12.71; S, 11.81 (%)
　化合物Ｉ－３４の合成 　
Figure JPOXMLDOC01-appb-C000171
工程１　化合物３４ｂの合成
Ｄ－リンゴ酸から実施例６の工程１～８と同様にして合成した化合物３４ａ（７４３ｍｇ、０．８８ｍｍｏｌ）のテトラヒドロフラン（７．４ｍＬ）溶液に、酢酸（３０４μＬ、５．３ｍｍｏｌ）、１ｍｏｌ／Ｌ　ＴＢＡＦ／テトラヒドロフラン溶液（２．６５ｍＬ、２．６５ｍｍｏｌ）を順に加えた。室温で３０分間攪拌した後、水を加え、酢酸エチルで抽出した。有機層を、炭酸水素ナトリウム水溶液、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物３４ｂ（４３４ｍｇ、収率６８％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.53 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.81 (1H, dd, J = 14.1, 5.1 Hz), 3.26 (2H, br s), 3.34 (1H, d, J = 14.1 Hz), 3.77 (1H, d, J = 6.3 Hz), 4.76 (2H, s), 4.84 (1H, dd, J = 17.3, 9.5 Hz), 4.97 (1H, d, J = 4.3 Hz), 5.08 (1H, d, J = 7.3 Hz), 5.39 (1H, t, J = 6.7 Hz), 5.53 (1H, dd, J = 7.8, 4.3 Hz), 7.42 (1H, s), 8.17 (1H, s), 8.80 (1H, d, J = 8.1 Hz).

工程２　化合物３４ｃの合成
　化合物３４ｂ（２００ｍｇ、０．２８ｍｍｏｌ）のテトラヒドロフラン（２．０ｍＬ）溶液に、イソシアン酸クロロスルホニル（４３μＬ、０．５０ｍｍｏｌ）を－３０℃で加えた。そのまま－３０℃で１時間攪拌した後、炭酸水素ナトリウム（１１６ｍｇ、１．３８ｍｍｏｌ）、水（２００μＬ）を加えた。さらに室温で３０分間攪拌した後、水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物３４ｃ（１５４ｍｇ、収率７３％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.46 (9H, s), 1.53 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.84 (1H, dd, J = 14.5, 5.6 Hz), 3.27 (1H, dd, J = 14.5, 2.9 Hz), 3.52 (1H, s), 3.77 (1H, s), 4.76-4.87 (4H, m), 5.00 (1H, d, J = 4.5 Hz), 5.40 (1H, s), 5.55 (1H, dd, J = 8.2, 4.5 Hz), 5.80 (1H, d, J = 6.3 Hz), 7.42 (1H, s), 8.12 (1H, s), 8.81 (1H, d, J = 8.2 Hz).

工程３　化合物Ｉ－３４の合成
化合物３４ｃ（１５４ｍｇ、０．２０ｍｍｏｌ）のジクロロメタン（１．５ｍＬ）溶液を－４０℃まで冷却した後、アニソール（０．２２ｍＬ、２．０ｍｍｏｌ）、２ｍｏｌ／Ｌ　塩化アルミニウム／ニトロメタン溶液（１．０ｍＬ、２．０ｍｍｏｌ）を順に加え、－３０℃で３０分間攪拌した。反応液にジイソプロピルエーテル、氷水、アセトニトリルを加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去し、２ｍｏｌ／Ｌ　塩酸（１．０ｍＬ）を加えた。得られた混合液をＯＤＳカラムクロマトグラフィ（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することによりＩ－３４（２８ｍｇ、収率２６％）を淡黄色粉末として得た。
1H-NMR (D2O) δ: 2.93 (1H, dd, J = 14.3, 6.2 Hz), 3.32 (1H, dd, J = 14.3, 3.0 Hz), 3.39-3.43 (1H, m), 5.23 (1H, d, J = 4.3 Hz), 5.45 (1H, d, J = 4.0 Hz), 5.82 (1H, d, J = 6.6 Hz), 7.30 (1H, s).
MS (m+1) = 544.94、保持時間：0.74分、測定条件１
元素分析：C17H16N6O11S2(H2O)3.0
計算値：C,34.12; H,3.71; N,14.04; S,10.71 (%)
実測値：C,34.16; H,3.74; N,14.00; S,10.60 (%)
Synthesis of Compound I-34
Figure JPOXMLDOC01-appb-C000171
Step 1 Synthesis of Compound 34b To a solution of Compound 34a (743 mg, 0.88 mmol) synthesized from D-malic acid in the same manner as in Steps 1 to 8 of Example 6 in tetrahydrofuran (7.4 mL), acetic acid (304 μL, 5. 3 mmol), 1 mol / L TBAF / tetrahydrofuran solution (2.65 mL, 2.65 mmol) was added in turn. After stirring at room temperature for 30 minutes, water was added and extracted with ethyl acetate. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 34b (434 mg, 68% yield) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.53 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.81 (1H, dd, J = 14.1, 5.1 Hz ), 3.26 (2H, br s), 3.34 (1H, d, J = 14.1 Hz), 3.77 (1H, d, J = 6.3 Hz), 4.76 (2H, s), 4.84 (1H, dd, J = 17.3 , 9.5 Hz), 4.97 (1H, d, J = 4.3 Hz), 5.08 (1H, d, J = 7.3 Hz), 5.39 (1H, t, J = 6.7 Hz), 5.53 (1H, dd, J = 7.8 , 4.3 Hz), 7.42 (1H, s), 8.17 (1H, s), 8.80 (1H, d, J = 8.1 Hz).

Step 2 Synthesis of Compound 34c To a solution of Compound 34b (200 mg, 0.28 mmol) in tetrahydrofuran (2.0 mL) was added chlorosulfonyl isocyanate (43 μL, 0.50 mmol) at −30 ° C. After stirring as it was at −30 ° C. for 1 hour, sodium hydrogen carbonate (116 mg, 1.38 mmol) and water (200 μL) were added. The mixture was further stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 34c (154 mg, yield 73%) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.53 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.84 (1H, dd, J = 14.5, 5.6 Hz ), 3.27 (1H, dd, J = 14.5, 2.9 Hz), 3.52 (1H, s), 3.77 (1H, s), 4.76-4.87 (4H, m), 5.00 (1H, d, J = 4.5 Hz) , 5.40 (1H, s), 5.55 (1H, dd, J = 8.2, 4.5 Hz), 5.80 (1H, d, J = 6.3 Hz), 7.42 (1H, s), 8.12 (1H, s), 8.81 ( (1H, d, J = 8.2 Hz).

Step 3 Synthesis of Compound I-34 Compound 34c (154 mg, 0.20 mmol) in dichloromethane (1.5 mL) was cooled to −40 ° C., then anisole (0.22 mL, 2.0 mmol), 2 mol / L aluminum chloride / Nitromethane solution (1.0 mL, 2.0 mmol) was sequentially added, and the mixture was stirred at −30 ° C. for 30 minutes. Diisopropyl ether, ice water, and acetonitrile were added to the reaction solution and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, acetonitrile was distilled off under reduced pressure, and 2 mol / L hydrochloric acid (1.0 mL) was added. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to give I-34 (28 mg, 26% yield) as a pale yellow powder.
1 H-NMR (D 2 O) δ: 2.93 (1H, dd, J = 14.3, 6.2 Hz), 3.32 (1H, dd, J = 14.3, 3.0 Hz), 3.39-3.43 (1H, m), 5.23 ( 1H, d, J = 4.3 Hz), 5.45 (1H, d, J = 4.0 Hz), 5.82 (1H, d, J = 6.6 Hz), 7.30 (1H, s).
MS (m + 1) = 544.94, retention time: 0.74 minutes, measurement condition 1
Elemental analysis: C17H16N6O11S2 (H2O) 3.0
Calculated value: C, 34.12; H, 3.71; N, 14.04; S, 10.71 (%)
Found: C, 34.16; H, 3.74; N, 14.00; S, 10.60 (%)
　化合物Ｉ－３５の合成 　
Figure JPOXMLDOC01-appb-C000172
 工程１　化合物３５ａの合成
化合物３４ｂ（１７０ｍｇ、０．２３ｍｍｏｌ）のジクロロメタン（１．７ｍＬ）溶液に、塩化アセチル（２５μＬ、０．３５ｍｍｏｌ）、ピリジン（３４μＬ、０．４２ｍｍｏｌ）を氷冷下で加えた。室温で１時間攪拌した後、希塩酸水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物３５ａ（１６１ｍｇ、収率８７％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.46 (9H, s), 1.54 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.16 (3H, s), 2.78 (1H, dd, J = 14.8, 4.9 Hz), 3.26 (1H, d, J = 11.6 Hz), 3.78 (1H, d, J = 4.8 Hz), 4.77-4.87 (4H, m), 5.01 (1H, d, J = 4.3 Hz), 5.40 (1H, d, J = 7.3 Hz), 5.56 (1H, dd, J = 8.3, 4.7 Hz), 5.82 (1H, d, J = 6.1 Hz), 7.41 (1H, s), 8.12 (1H, s), 8.81 (1H, d, J = 8.3 Hz).

工程２　化合物Ｉ－３５の合成
化合物３５ａ（１６１ｍｇ、０．２１ｍｍｏｌ）から実施例２の工程３と同様にして化合物Ｉ－３５（３７ｍｇ、収率３３％）を白色粉末として得た。
1H-NMR (D2O) δ: 2.17 (3H, s), 2.91 (1H, dd, J = 14.4, 6.1 Hz), 3.32 (1H, dd, J = 14.4, 3.3 Hz), 3.38-3.42 (1H, m), 5.24 (1H, d, J = 4.3 Hz), 5.46 (1H, d, J = 4.3 Hz), 5.92 (1H, d, J = 6.3 Hz), 7.30 (1H, s).
MS (m+1) = 543.97、保持時間：0.71分、測定条件１
元素分析：C18H17N5O11S2(H2O)2.8
計算値：C,36.40; H,3.84; N,11.79; S,10.80 (%)
実測値：C,36.25; H,3.79; N,12.04; S,10.89 (%)
Synthesis of Compound I-35
Figure JPOXMLDOC01-appb-C000172
 Step 1 Synthesis of Compound 35a To a solution of Compound 34b (170 mg, 0.23 mmol) in dichloromethane (1.7 mL), acetyl chloride (25 μL, 0.35 mmol) and pyridine (34 μL, 0.42 mmol) were added under ice cooling. . After stirring at room temperature for 1 hour, dilute aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 35a (161 mg, yield 87%) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.54 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 2.16 (3H, s), 2.78 (1H, dd , J = 14.8, 4.9 Hz), 3.26 (1H, d, J = 11.6 Hz), 3.78 (1H, d, J = 4.8 Hz), 4.77-4.87 (4H, m), 5.01 (1H, d, J = 4.3 Hz), 5.40 (1H, d, J = 7.3 Hz), 5.56 (1H, dd, J = 8.3, 4.7 Hz), 5.82 (1H, d, J = 6.1 Hz), 7.41 (1H, s), 8.12 (1H, s), 8.81 (1H, d, J = 8.3 Hz).

Step 2 Synthesis of Compound I-35 Compound I-35 (37 mg, 33% yield) was obtained as a white powder from Compound 35a (161 mg, 0.21 mmol) in the same manner as in Step 3 of Example 2.
1 H-NMR (D 2 O) δ: 2.17 (3H, s), 2.91 (1H, dd, J = 14.4, 6.1 Hz), 3.32 (1H, dd, J = 14.4, 3.3 Hz), 3.38-3.42 ( 1H, m), 5.24 (1H, d, J = 4.3 Hz), 5.46 (1H, d, J = 4.3 Hz), 5.92 (1H, d, J = 6.3 Hz), 7.30 (1H, s).
MS (m + 1) = 543.97, retention time: 0.71 minutes, measurement condition 1
Elemental analysis: C18H17N5O11S2 (H2O) 2.8
Calculated value: C, 36.40; H, 3.84; N, 11.79; S, 10.80 (%)
Found: C, 36.25; H, 3.79; N, 12.04; S, 10.89 (%)
　化合物Ｉ－３６及びＩ－３７の合成 　
Figure JPOXMLDOC01-appb-C000173
工程１　化合物３６cの合成
化合物３６ａ及び化合物３６ｂを原料として、ＵＳ４８９１４２７Ａ公報に記載の方法と同様の方法により化合物３６ｃを合成した。
工程２　化合物３６ｅの合成
化合物３６ｃ（０．３０ｇ、０．６３ｍｍｏｌ）のジクロロメタン（６ｍＬ）溶液を－７８℃まで冷却した後、Ｎ，Ｎ’－ジメチルアニリン（０．４０ｍＬ、３．１６ｍｍｏｌ）と五塩化リン（０．３３ｇ、１．５８ｍｍｏｌ）を加えた。－６０℃で２時間攪拌した後、メタノール（０．６ｍＬ）を加えた。－２０℃で４時間攪拌した後、反応混合物に水を加え炭酸ナトリウム水溶液でｐＨ６に調整した後、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。無機物をろ過により除去した後、減圧下約５ｍｌまで濃縮しジクロロメタン溶液（溶液Ａ）を得た。化合物３６ｄ（０．５１ｇ、１．２６ｍｍｏｌ）をジクロロメタン（５ｍＬ）に懸濁させ、１－クロロ－Ｎ，Ｎ，２－トリメチル－１－プロペニルアミン（０．１８ｍＬ、１．３９ｍｍｏｌ）を加えた。室温で３時間攪拌することで溶液Ｂを得た。
溶液Ａ（約５ｍｌ、０．６３ｍｍｏｌ相当）に氷冷下でピリジン（０．１５ｍＬ、１．９０ｍｍｏｌ）、溶液Ｂを加えた。氷冷下で１時間攪拌した後、希塩酸水を加え、ジクロロメタンで抽出した。有機層を、水、飽和重曹水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。硫酸マグネシウムをろ過した後、減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、ヘキサン／酢酸エチルで溶離させた。所望の化合物を含むフラクションを減圧下濃縮し、化合物３６ｅを含む混合物（０．４３ｇ）を得た。
［Ｍ＋Ｈ］＝７４０、保持時間：２．６２分、測定条件１

工程３　化合物Ｉ－３６及びＩ－３７の合成
化合物３６ｅ（０．４３ｇ、０．５８ｍｍｏｌ換算）をジクロロメタン（１０ｍｌ）に溶解させ、－４０℃まで冷却した後、アニソール（０．７６ｍｌ、６．９７ｍｍｏｌ）と２ｍｏｌ／Ｌ塩化アルミニウム／ニトロメタン溶液（３．４９ｍｌ、６．９７ｍｍｏｌ）を順次加え、－３０℃で３０分間攪拌した。反応液を水、２ｍｏｌ／Ｌ塩酸、アセトニトリルに溶解させた後、ジイソプロピルエーテルで洗浄した。水層にＨＰ２０‐ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィに付し水／アセトニトリルで溶離させた。所望の化合物を含むフラクションを減圧下濃縮した後、凍結乾燥することにより化合物Ｉ－３６及びＩ－３７を白色粉末として得た。
収量:化合物Ｉ－３６：３０．３ｍｇ、(収率１０％) 化合物Ｉ－３７：１４．４ｍｇ、(収率４．８％)

化合物Ｉ－３６
1H-NMR (D2O) δ: 6.98 (1H, s), 5.33 (1H, s), 4.59 (2H, s), 3.63 (3H, s), 3.19-3.11 (2H, m), 2.96-2.68 (3H, m).
［Ｍ＋Ｈ］＝５１６、保持時間：０．６１分、測定条件１

化合物Ｉ－３７
1H-NMR (D2O) δ: 7.23 (1H, s), 5.41 (1H, s), 4.66 (2H, s), 3.61 (3H, s), 3.41 (1H, dd, J = 14.6, 2.4 Hz), 3.19-2.99 (3H, m), 2.76 (1H, dd, J = 17.2, 7.7 Hz).
［Ｍ＋Ｈ］＝５１６、保持時間：０．４７分、測定条件１
Synthesis of compounds I-36 and I-37
Figure JPOXMLDOC01-appb-C000173
Step 1 Synthesis of Compound 36c Compound 36c was synthesized by the same method as described in US Pat. No. 4,891,427A using compound 36a and compound 36b as raw materials.
Step 2 Synthesis of Compound 36e After cooling a solution of Compound 36c (0.30 g, 0.63 mmol) in dichloromethane (6 mL) to −78 ° C., N, N′-dimethylaniline (0.40 mL, 3.16 mmol) and five Phosphorous chloride (0.33 g, 1.58 mmol) was added. After stirring at −60 ° C. for 2 hours, methanol (0.6 mL) was added. After stirring at −20 ° C. for 4 hours, water was added to the reaction mixture, the pH was adjusted to 6 with an aqueous sodium carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. Inorganic substances were removed by filtration, and then concentrated to about 5 ml under reduced pressure to obtain a dichloromethane solution (solution A). Compound 36d (0.51 g, 1.26 mmol) was suspended in dichloromethane (5 mL) and 1-chloro-N, N, 2-trimethyl-1-propenylamine (0.18 mL, 1.39 mmol) was added. Solution B was obtained by stirring at room temperature for 3 hours.
Pyridine (0.15 mL, 1.90 mmol) and Solution B were added to Solution A (about 5 ml, corresponding to 0.63 mmol) under ice cooling. After stirring for 1 hour under ice cooling, dilute hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was washed sequentially with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered, concentrated under reduced pressure, subjected to silica gel column chromatography, and eluted with hexane / ethyl acetate. The fraction containing the desired compound was concentrated under reduced pressure to obtain a mixture (0.43 g) containing compound 36e.
[M + H] = 740, retention time: 2.62 minutes, measurement condition 1

Step 3 Compound 36e (0.43 g, 0.58 mmol equivalent) of compound I-36 and I-37 was dissolved in dichloromethane (10 ml), cooled to −40 ° C., and then anisole (0.76 ml, 6.97 mmol). ) And 2 mol / L aluminum chloride / nitromethane solution (3.49 ml, 6.97 mmol) were sequentially added, and the mixture was stirred at −30 ° C. for 30 minutes. The reaction solution was dissolved in water, 2 mol / L hydrochloric acid and acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was subjected to ODS column chromatography and eluted with water / acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure and lyophilized to give compounds I-36 and I-37 as white powders.
Yield: Compound I-36: 30.3 mg, (Yield 10%) Compound I-37: 14.4 mg, (Yield 4.8%)

Compound I-36
1H-NMR (D2O) δ: 6.98 (1H, s), 5.33 (1H, s), 4.59 (2H, s), 3.63 (3H, s), 3.19-3.11 (2H, m), 2.96-2.68 (3H , m).
[M + H] = 516, Retention time: 0.61 minutes, Measurement condition 1

Compound I-37
1H-NMR (D2O) δ: 7.23 (1H, s), 5.41 (1H, s), 4.66 (2H, s), 3.61 (3H, s), 3.41 (1H, dd, J = 14.6, 2.4 Hz), 3.19-2.99 (3H, m), 2.76 (1H, dd, J = 17.2, 7.7 Hz).
[M + H] = 516, Retention time: 0.47 minutes, Measurement condition 1
化合物Ｉ－３８の合成 　
Figure JPOXMLDOC01-appb-C000174
工程１　化合物３８ｂの合成
エタノールアミン３８ａ（１．１９ｍＬ、１９．７ｍｍｏｌ）のジクロロメタン（１２ｍＬ）溶液に二炭酸ジメチル（２．６３ｇ、１９．７ｍｍｏｌ）を加えた。室温で１．５時間撹拌した後、反応混合液を減圧下濃縮した。得られた残渣をＴＨＦ（２０ｍＬ）に溶解し、氷冷した後、Ｎ－ヒドロキシフタルイミド（３．８５ｇ、２３．６ｍｍｏｌ）とトリフェニルホスフィン（６．１８ｇ、２３．６ｍｍｏｌ）を加え、次いでジイソプロピルアゾジカルボキシレート（４．５８ｍＬ、２３．６ｍｍｏｌ）を加えた。室温で２３時間撹拌した後、反応混合液を減圧下濃縮した。残渣をメタノールに溶解してから再度減圧下で濃縮すると白色固体が得られ、これを濾取して３８ｂ（１．３４ｇ、２６％）を得た。
1H-NMR (CDCl3) δ: 3.50 (2H, m), 3.72 (3H, s), 4.27 (2H, t, J = 4.8 Hz), 5.91 (1H, brs), 7.78 (2H, m), 7.86 (2H, m).
[M+H]＝264.85、保持時間：1.24分、測定条件２


工程２　化合物３８ｄの合成
３８ｂ（１．３４ｇ、５．０７ｍｍｏｌ）のジクロロメタン（２０ｍＬ）溶液を氷冷し、メチルヒドラジン（０．２８２ｍＬ、５．３２ｍｍｏｌ）を加えた。０℃で５０分間撹拌した後、不溶物をろ過により除去し、ジクロロメタンが１０ｍＬ程度になるまで減圧留去して、ヒドロキシアミンのジクロロメタン溶液を得た。別途調製した２ｃ（１．３８ｇ、５．０７ｍｍｏｌ）のメタノール（２０ｍＬ）溶液を氷冷し、このヒドロキシアミンのジクロロメタン溶液を滴下した。０℃で１時間撹拌した後、ジクロロメタンを減圧留去した。酢酸エチルと水、次いで２ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮して化合物３８ｄ（１．８０ｇ、９１％）を得た。
1H-NMR (CDCl3) δ: 1.47 (9H, s), 3.25 (2H, m), 3.53 (3H, s), 4.08 (2H, t, J = 6.2 Hz), 7.15 (1H, m), 7.42 (1H, s), 11.81 (1H, s), 13.93 (1H, brs).
[M+H]＝389.10、保持時間：1.35分、測定条件２

工程３　化合物３８ｆの合成
　五塩化リン（９３７ｍｇ、４．５０ｍｍｏｌ）のジクロロメタン（１０ｍＬ）懸濁液に氷冷下ピリジン（０．４００ｍＬ、４．９５ｍｍｏｌ）を加えた。反応混合物を－７８℃まで冷却した後、化合物３８ｅ（１．０ｇ、２．２５ｍｍｏｌ）を加えた。氷冷下４０分間攪拌した後、反応混合物を－７８℃まで冷却し、エタノール（１０ｍＬ）を加えた。－３０℃で３５分間攪拌した後、水（２．２５ｍＬ）を加えた。－３０℃で３５分間攪拌した後、反応混合物に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、ろ液をジクロロメタンが１０ｍＬ程度になるまで減圧留去して、ジクロロメタン溶液（溶液Ａ）を得た。化合物３８ｄ（９６１ｍｇ、２．４８ｍｍｏｌ）のＤＭＡ（３．７ｍＬ）溶液を－２０℃に冷却し、トリエチルアミン（０．４３７ｍＬ、３．１５ｍｍｏｌ）およびメタンスルホニルクロリド（０．２２８ｍＬ、２．９３ｍｍｏｌ）を加え、－２０℃で４０分間撹拌し、懸濁液（懸濁液Ｂ）を得た。溶液Ａに氷冷下ピリジン（０．２１８ｍＬ、２．７０ｍｍｏｌ）を加え、次いで懸濁液Ｂを滴下した。０℃で３５分間攪拌した後、水を加え、ジクロロメタンを減圧留去した。酢酸エチルと２ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで抽出し、有機層を水で洗浄した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物３８ｆ（１．１４ｇ、７２％）を得た。
1H-NMR (CDCl3) δ: 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.63-2.75 (2H, m), 2.80 (1H, dd, J = 18.1, 8.3 Hz), 3.13 (1H, dd, J = 14.6, 4.3 Hz), 3.31 (1H, m), 3.52 (2H, m), 3.56 (3H, s), 4.35 (2H, m), 4.81 (2H, m), 5.11 (1H, d, J = 4.6 Hz), 5.33 (1H, m), 5.38 (1H, m), 5.70 (1H, dd, J = 8.7, 4.6 Hz), 7.29 (1H, s), 7.81 (1H, d, J = 8.7 Hz), 8.25 (1H, brs).
[M+H]＝697.25、保持時間：2.00分、測定条件２

工程４　化合物Ｉ－３８の合成
　化合物３８ｆ（５３６ｍｇ、０．７６９ｍｍｏｌ)のジクロロメタン（１０ｍＬ）溶液にアニソール（０．６７２ｍＬ、６．１５ｍｍｏｌ）および２ｍｏｌ／Ｌ塩化アルミニウム／ニトロメタン溶液（３．０８ｍＬ、６．１５ｍｍｏｌ）を加え－３０℃から－１９℃で４５分間撹拌した。反応混合物を氷水、２ｍｏｌ／Ｌ塩酸、アセトニトリルに溶解させた後、ジイソプロピルエーテルで洗浄した。水層にＨＰ２０‐ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィー（水－アセトニトリル）により精製した。所望の化合物を含むフラクションを混合し、ｐＨメーターを用い０．２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２．２ｍＬ）を氷冷下ゆっくり滴下し、ｐＨ４．７６になった時点でドライアイスの小片を加えると、ｐＨは４．５２となった。この混合液を減圧下濃縮した後、凍結乾燥することにより化合物Ｉ－３８（２８６ｍｇ、６８％)を得た。
1H-NMR (D2O) δ: 2.68 (1H, dd, J = 18.3, 2.5 Hz), 2.85 (1H, m), 2.92 (1H, dd, J = 18.3, 7.8 Hz), 3.06-3.19 (2H, m), 3.48 (2H, m), 3.64 (3H, s), 4.29 (2H, m), 5.28 (1H, d, J = 4.5 Hz), 5.58 (1H, d, J = 4.5 Hz), 7.07 (1H, s).
[M+H]＝529.10、保持時間：0.71分、測定条件２
C18H19N6O9S2Na1(H2O)3.6 計算値C : 35.13%, H : 4.29%, N : 13.66%, S : 10.42%, Na : 3.74%. 実測値C : 35.04 %, H : 4.33%, N : 13.80%, S : 10.37%, Na : 3.81%.
Synthesis of Compound I-38
Figure JPOXMLDOC01-appb-C000174
Step 1 Synthesis of Compound 38b To a solution of ethanolamine 38a (1.19 mL, 19.7 mmol) in dichloromethane (12 mL) was added dimethyl dicarbonate (2.63 g, 19.7 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in THF (20 mL), cooled on ice, N-hydroxyphthalimide (3.85 g, 23.6 mmol) and triphenylphosphine (6.18 g, 23.6 mmol) were added, and then diisopropylazo Dicarboxylate (4.58 mL, 23.6 mmol) was added. After stirring at room temperature for 23 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol and concentrated again under reduced pressure to give a white solid that was collected by filtration to give 38b (1.34 g, 26%).
1H-NMR (CDCl 3 ) δ: 3.50 (2H, m), 3.72 (3H, s), 4.27 (2H, t, J = 4.8 Hz), 5.91 (1H, brs), 7.78 (2H, m), 7.86 (2H, m).
[M + H] = 264.85, Retention time: 1.24 minutes, Measurement condition 2


Step 2 Synthesis of Compound 38d A solution of 38b (1.34 g, 5.07 mmol) in dichloromethane (20 mL) was ice-cooled, and methylhydrazine (0.282 mL, 5.32 mmol) was added. After stirring at 0 ° C. for 50 minutes, insoluble matters were removed by filtration, and the solvent was distilled off under reduced pressure until the dichloromethane amounted to about 10 mL, to obtain a solution of hydroxyamine in dichloromethane. A separately prepared solution of 2c (1.38 g, 5.07 mmol) in methanol (20 mL) was ice-cooled, and a dichloromethane solution of hydroxyamine was added dropwise. After stirring at 0 ° C. for 1 hour, dichloromethane was distilled off under reduced pressure. Ethyl acetate and water, then 2 mol / L hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure to obtain compound 38d (1.80 g, 91%).
1H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 3.25 (2H, m), 3.53 (3H, s), 4.08 (2H, t, J = 6.2 Hz), 7.15 (1H, m), 7.42 (1H, s), 11.81 (1H, s), 13.93 (1H, brs).
[M + H] = 389.10, Retention time: 1.35 minutes, Measurement condition 2

Step 3 Synthesis of Compound 38f To a suspension of phosphorus pentachloride (937 mg, 4.50 mmol) in dichloromethane (10 mL) was added pyridine (0.400 mL, 4.95 mmol) under ice cooling. After the reaction mixture was cooled to −78 ° C., compound 38e (1.0 g, 2.25 mmol) was added. After stirring for 40 minutes under ice cooling, the reaction mixture was cooled to −78 ° C., and ethanol (10 mL) was added. After stirring at −30 ° C. for 35 minutes, water (2.25 mL) was added. After stirring at −30 ° C. for 35 minutes, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and the magnesium sulfate was filtered, and then the filtrate was distilled off under reduced pressure until the dichloromethane was about 10 mL to obtain a dichloromethane solution (solution A). A solution of compound 38d (961 mg, 2.48 mmol) in DMA (3.7 mL) is cooled to −20 ° C. and triethylamine (0.437 mL, 3.15 mmol) and methanesulfonyl chloride (0.228 mL, 2.93 mmol) are added. The mixture was stirred at −20 ° C. for 40 minutes to obtain a suspension (suspension B). To solution A, pyridine (0.218 mL, 2.70 mmol) was added under ice-cooling, and then suspension B was added dropwise. After stirring at 0 ° C. for 35 minutes, water was added and dichloromethane was distilled off under reduced pressure. Ethyl acetate and 2 mol / L hydrochloric acid were added, extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 38f (1.14 g, 72%).
1H-NMR (CDCl 3 ) δ: 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.63-2.75 (2H, m), 2.80 (1H, dd, J = 18.1, 8.3 Hz), 3.13 (1H, dd, J = 14.6, 4.3 Hz), 3.31 (1H, m), 3.52 (2H, m), 3.56 (3H, s), 4.35 (2H, m), 4.81 (2H, m ), 5.11 (1H, d, J = 4.6 Hz), 5.33 (1H, m), 5.38 (1H, m), 5.70 (1H, dd, J = 8.7, 4.6 Hz), 7.29 (1H, s), 7.81 (1H, d, J = 8.7 Hz), 8.25 (1H, brs).
[M + H] = 697.25, retention time: 2.00 minutes, measurement condition 2

Step 4 Synthesis of Compound I-38 Compound 38f (536 mg, 0.769 mmol) in dichloromethane (10 mL) in anisole (0.672 mL, 6.15 mmol) and 2 mol / L aluminum chloride / nitromethane solution (3.08 mL, 6. 15 mmol) was added and the mixture was stirred at -30 ° C to -19 ° C for 45 minutes. The reaction mixture was dissolved in ice water, 2 mol / L hydrochloric acid, and acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound are mixed, 0.2 mol / L aqueous sodium hydroxide solution (2.2 mL) is slowly added dropwise under ice cooling using a pH meter, and a small piece of dry ice is added when the pH reaches 4.76. The pH was 4.52. The mixture was concentrated under reduced pressure and lyophilized to give compound I-38 (286 mg, 68%).
1H-NMR (D 2 O) δ: 2.68 (1H, dd, J = 18.3, 2.5 Hz), 2.85 (1H, m), 2.92 (1H, dd, J = 18.3, 7.8 Hz), 3.06-3.19 (2H , m), 3.48 (2H, m), 3.64 (3H, s), 4.29 (2H, m), 5.28 (1H, d, J = 4.5 Hz), 5.58 (1H, d, J = 4.5 Hz), 7.07 (1H, s).
[M + H] = 529.10, Retention time: 0.71 minutes, Measurement condition 2
C18H19N6O9S2Na1 (H 2 O) 3.6 Calculated value C: 35.13%, H: 4.29%, N: 13.66%, S: 10.42%, Na: 3.74%. Measured value C: 35.04%, H: 4.33%, N: 13.80% , S: 10.37%, Na: 3.81%.
化合物Ｉ－３９の合成　
Figure JPOXMLDOC01-appb-C000175
工程１　化合物３９ｂの合成
化合物３９ａ（６５３ｍｇ、１．００ｍｍｏｌ）を１，４－ジオキサン（７．００ｍＬ）に懸濁し、二炭酸ジブチル（２８４ｍｇ、１．３０ｍｍｏｌ）、炭酸アンモニウム（１２０ｍｇ、１．２５ｍｍｏｌ）、ついでピリジン（３９．６ｍｇ、０．５００ｍｍｏｌ）を加え終夜撹拌した。この反応液に、二炭酸ジブチル（２１８ｍｇ、１．００ｍｍｏｌ）、炭酸アンモニウム（９６．０ｍｇ、１．００５ｍｍｏｌ）、ついでピリジン（３９．６ｍｇ、０．５００ｍｍｏｌ）を加え再度終夜撹拌した。この反応液に精製水を加え、水層から目的物を酢酸エチルで抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去した。得られた残渣をシリカゲルクロマトグラフィーに付し、化合物３９ｂ（１３７ｍｇ、０．２１ｍｍｏｌ）を得た。
1H-NMR (CDCl3) δ: 9.38 (br s, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.44 (br s, 1H), 7.32 (s, 1H), 6.87 (s, 1H), 5.21 (dd, J = 14.1, 3.7 Hz, 1H), 3.78-2.85 (br m, 5H), 2.64 (d, J = 18.2 Hz, 1H), 1.58 (s, 3H), 1.54 (s, 3H), 1.52 (s, 9H), 1.44 (d, J = 6.8 Hz, 9H).

工程２　化合物３９ｃの合成
　化合物３９ｂ（１３５ｍｇ、０．２０７ｍｍｏｌ）をジクロロメタン（１．５０ｍＬ）に溶解し、氷点下３０度に冷却した。この溶液にピリジン（０．０５０ｍＬ、０．６２１ｍｍｏｌ）、次いで無水トリフルオロ酢酸（０．０４４ｍＬ。０．３１１ｍｍｏｌ）を加え、氷点下３０度で４５分間撹拌した。この反応液にピリジン（０．０３３ｍＬ、０．４１４ｍｍｏｌ）と無水トリフルオロ酢酸（０．０２９ｍＬ。０．２０７ｍｍｏｌ）を加え、０度で2時間30分間撹拌した。この反応液にピリジン（０．０５０ｍＬ、０．６２１ｍｍｏｌ）と無水トリフルオロ酢酸（０．０４４ｍＬ。０．３１１ｍｍｏｌ）を加え、０度で１時間４５分間撹拌した。この反応液に精製水を加え、水層から目的物を酢酸エチルで抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去した。得られた残渣をシリカゲルクロマトグラフィーに付し、化合物３９ｃ（１２１ｍｇ、０．１９１ｍｍｏｌ）を得た。
1H-NMR (CDCl3) δ: 8.48-8.25 (br m, 2H), 7.33 (s, 1H), 5.15 (dd, J = 15.2, 8.3 Hz, 1H), 3.98-3.89 (m, 1H), 3.74-3.01 (m, 4H), 2.76 (dd, J = 18.4, 5.2 Hz, 1H), 1.60 (s, 3H), 1.58 (s, 3H), 1.53 (s, 9H), 1.43 (s, 9H).

工程３　化合物３９ｄの合成
　化合物３９ｃ（１２０ｍｇ、０．１８９ｍｍｏｌ）を１，４－ジオキサン（１．２０ｍＬ）に溶解し、トリメチルシリルアジド（０．０５０ｍＬ、０．３７９ｍｍｏｌ）とジブチルすずオキシド（４．７１ｍｇ、０．０１８９ｍｍｏｌ）を加え、70度で撹拌した。反応終了後、この反応液に精製水を加え、水層から目的物を酢酸エチルで抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去し、化合物３９ｄを得た。この化合物は精製せずに次の反応に用いた。

工程４
化合物３９ｄ（１２８ｍｇ、０．１８９ｍｍｏｌ）をジクロロメタン（１．０ｍＬ）に溶解し氷点下３０度に冷却し、アニソール（０．１２４ｍＬ、１．１３ｍｍｏｌ）と、２ｍｏｌ／Ｌ塩化アルミニウム‐ニトロメタン溶液（０．５６７ｍＬ、１．１３ｍｍｏｌ）を加え、０度で４５分間撹拌した。反応液に精製水とジイソプロピルエーテルを加えた。反応液にアセトニトリル、２ｍｏｌ／Ｌ塩酸を加え、析出物を溶解させた後、水層を分離した。有機層を水/アセトニトリル/希塩酸混液で抽出し、合わせた水層にＨＰ２０ＳＳを加えて濃縮した。濃縮した懸濁液をＨＰ２０ＳＳとＯＤＳを連結したカラムクロマトグラフィーに付し、水－アセトニトリルで溶離し、目的物を含む分画を集め、０．２ｍｏｌ／Ｌ水酸化ナトリウム水溶液を用いｐＨを6.5とし、ドライアイスを一片加えた。この溶液を減圧濃縮し、濃縮液を凍結乾燥することによって化合物Ｉ－３９を、粉末として得た。（収量２２．０ｍｇ, 収率２１％）
1H-NMR (D2O) δ: 6.96 (s, 1H), 5.22 (s, 1H), 3.85-2.92 (m, 7H), 1.47 (s, 3H), 1.47 (s, 3H).
MS  (m+1) = 521.22、保持時間：0.67分、測定条件１
Synthesis of Compound I-39
Figure JPOXMLDOC01-appb-C000175
Step 1 Synthesis of Compound 39b Compound 39a (653 mg, 1.00 mmol) was suspended in 1,4-dioxane (7.00 mL), dibutyl dicarbonate (284 mg, 1.30 mmol), ammonium carbonate (120 mg, 1.25 mmol) Then, pyridine (39.6 mg, 0.500 mmol) was added and stirred overnight. To this reaction solution, dibutyl dicarbonate (218 mg, 1.00 mmol), ammonium carbonate (96.0 mg, 1.005 mmol) and then pyridine (39.6 mg, 0.500 mmol) were added and stirred again overnight. Purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with ethyl acetate. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain compound 39b (137 mg, 0.21 mmol).
1 H-NMR (CDCl 3 ) δ: 9.38 (br s, 1H), 8.00 (d, J = 7.4 Hz, 1H), 7.44 (br s, 1H), 7.32 (s, 1H), 6.87 (s, 1H ), 5.21 (dd, J = 14.1, 3.7 Hz, 1H), 3.78-2.85 (br m, 5H), 2.64 (d, J = 18.2 Hz, 1H), 1.58 (s, 3H), 1.54 (s, 3H ), 1.52 (s, 9H), 1.44 (d, J = 6.8 Hz, 9H).

Step 2 Synthesis of Compound 39c Compound 39b (135 mg, 0.207 mmol) was dissolved in dichloromethane (1.50 mL) and cooled to 30 degrees below freezing. Pyridine (0.050 mL, 0.621 mmol) was added to this solution, and then trifluoroacetic anhydride (0.044 mL. 0.311 mmol) was added, followed by stirring at 30 ° C. for 45 minutes. To this reaction solution were added pyridine (0.033 mL, 0.414 mmol) and trifluoroacetic anhydride (0.029 mL. 0.207 mmol), and the mixture was stirred at 0 ° C. for 2 hours and 30 minutes. Pyridine (0.050 mL, 0.621 mmol) and trifluoroacetic anhydride (0.044 mL. 0.311 mmol) were added to the reaction solution, and the mixture was stirred at 0 degree for 1 hour and 45 minutes. Purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with ethyl acetate. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain compound 39c (121 mg, 0.191 mmol).
1 H-NMR (CDCl 3 ) δ: 8.48-8.25 (br m, 2H), 7.33 (s, 1H), 5.15 (dd, J = 15.2, 8.3 Hz, 1H), 3.98-3.89 (m, 1H), 3.74-3.01 (m, 4H), 2.76 (dd, J = 18.4, 5.2 Hz, 1H), 1.60 (s, 3H), 1.58 (s, 3H), 1.53 (s, 9H), 1.43 (s, 9H) .

Step 3 Synthesis of Compound 39d Compound 39c (120 mg, 0.189 mmol) was dissolved in 1,4-dioxane (1.20 mL), trimethylsilyl azide (0.050 mL, 0.379 mmol) and dibutyltin oxide (4.71 mg, 0.0189 mmol) was added and stirred at 70 degrees. After completion of the reaction, purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with ethyl acetate. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure to give compound 39d. This compound was used in the next reaction without purification.

Process 4
Compound 39d (128 mg, 0.189 mmol) was dissolved in dichloromethane (1.0 mL), cooled to 30 ° C. below freezing, and anisole (0.124 mL, 1.13 mmol) and 2 mol / L aluminum chloride-nitromethane solution (0.567 mL) were cooled. 1.13 mmol) and stirred at 0 degrees for 45 minutes. Purified water and diisopropyl ether were added to the reaction solution. Acetonitrile, 2 mol / L hydrochloric acid was added to the reaction solution to dissolve the precipitate, and then the aqueous layer was separated. The organic layer was extracted with a water / acetonitrile / dilute hydrochloric acid mixture, and HP20SS was added to the combined aqueous layer and concentrated. The concentrated suspension was subjected to column chromatography in which HP20SS and ODS were connected, and eluted with water-acetonitrile. Fractions containing the target product were collected, and the pH was adjusted to 6.5 using 0.2 mol / L aqueous sodium hydroxide solution. A piece of dry ice was added. This solution was concentrated under reduced pressure, and the concentrate was lyophilized to obtain Compound I-39 as a powder. (Yield 22.0 mg, Yield 21%)
1 H-NMR (D 2 O) δ: 6.96 (s, 1H), 5.22 (s, 1H), 3.85-2.92 (m, 7H), 1.47 (s, 3H), 1.47 (s, 3H).
MS (m + 1) = 521.22, retention time: 0.67 minutes, measurement condition 1
化合物Ｉ－４０の合成 
Figure JPOXMLDOC01-appb-C000176
工程１　化合物４０ｂの合成
五塩化リン（０．９３７ｇ、４．５０ｍｍｏｌ）のジクロロメタン（５ｍＬ）懸濁液を－７８℃まで冷却した後、ピリジン（０．４００ｍＬ、４．９５ｍｍｏｌ）を加え、次いで化合物４０ａ（１．０ｇ、２．２５ｍｍｏｌ）を加えた。氷冷下で４０分間攪拌した後、反応混合物を－７８℃まで冷却し、エタノール（５．０ｍＬ）を加えた。－４０から－２０℃で１時間攪拌した後、反応混合物に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥した後、無機物をろ過により除去した。ろ液をジクロロメタンが１０ｍＬ程度になるまで減圧留去した。この溶液を０℃まで冷却した後、ピリジン（０．２７２ｍＬ、３．３７ｍｍｏｌ）および、クロロギ酸アリル（０．２４０ｍＬ、２．２５ｍｍｏｌ）を加え室温下、１時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を希塩酸および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物４０ｂ（４００ｍｇ、４３％）を得た。MS(M+1) = 411.20.

工程２　化合物４０ｃの合成
化合物４０ｂ（３．８ｇ、　９．２６ｍｍｏｌ）のジクロロメタン（１９ｍＬ）溶液にを－３０℃に冷却した。これにアニソール（４．０５ｍＬ、３７ｍｍｏｌ）および２ｍｏｌ／Ｌ塩化アルミニウム／ニトロメタン溶液（１８．５ｍＬ、３７．０ｍｍｏｌ）を加え－３０℃下、１時間撹拌した。反応液に希塩酸を加え、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液で抽出し、希塩酸を加えｐＨを２とし、再度酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣に１，４－ジオキサン（３２ｍＬ）、炭酸アンモニウム（１．１１ｇ、１１．６ｍｍｏｌ）、二炭酸ジ-tert-ブチル（２．７９ｍＬ，１２．０ｍｍｏｌ）、ピリジン（０．３７４ｍＬ、４．６３ｍｍｏｌ）を加え、室温下終夜撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を希塩酸、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、溶媒を減圧留去し、化合物４０ｃの粗生成物（３．１ｇ）を得た。MS(M+1) = 342.15.

工程３　化合物Ｉ－４０の合成
　化合物４０ｃの組成生物(５００ｍｇ)のＤＭＦ溶液にジメドン（６１６ｍｇ、４．３９ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（１６９ｍｇ、０．１４６ｍｍｏｌ）を加え、室温下、３０分間撹拌した。これに、化合物４０ｄ（７７０ｍｇ、２．２０ｍｍｏｌ）を加え、室温下１時間撹拌した。反応液中の不溶物をセライトろ過により取り除いた。ろ液にジイソプロピルエーテル、アセトニトリル、希塩酸を順に加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィー（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することにより化合物Ｉ－４０（１６０ｍｇ）を白色粉末として得た。
1H-NMR (D2O) δ: 2.91 (1H, dd, J = 14.1, 8.5 Hz), 2.98-3.01 (2H, m), 3.33-3.23 (2H, m), 4.00 (3H, s), 5.31 (1H, d, J = 4.5 Hz), 5.51 (1H, d, J = 4.5 Hz), 7.12 (1H, s).
MS(M+1) = 441.11、保持時間：０．６７分、測定条件１
C15H16N6O6S2(H2O)1.8(C4H8O2)0.1計算値C : 38.40%, H : 4.27%, N : 17.45%, S : 13.31%, 実測値 C :38.34%, H :4.24%, N : 17.65%, S : 13.12%.
Synthesis of Compound I-40
Figure JPOXMLDOC01-appb-C000176
Step 1 Synthesis of Compound 40b After cooling a suspension of phosphorus pentachloride (0.937 g, 4.50 mmol) in dichloromethane (5 mL) to −78 ° C., pyridine (0.400 mL, 4.95 mmol) was added, and then compound 40a (1.0 g, 2.25 mmol) was added. After stirring for 40 minutes under ice cooling, the reaction mixture was cooled to −78 ° C., and ethanol (5.0 mL) was added. After stirring at −40 to −20 ° C. for 1 hour, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then inorganic substances were removed by filtration. The filtrate was distilled off under reduced pressure until dichloromethane became about 10 mL. After cooling this solution to 0 ° C., pyridine (0.272 mL, 3.37 mmol) and allyl chloroformate (0.240 mL, 2.25 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 40b (400 mg, 43%). MS (M + 1) = 411.20.

Step 2 Synthesis of Compound 40c A solution of compound 40b (3.8 g, 9.26 mmol) in dichloromethane (19 mL) was cooled to −30 ° C. To this was added anisole (4.05 mL, 37 mmol) and 2 mol / L aluminum chloride / nitromethane solution (18.5 mL, 37.0 mmol), and the mixture was stirred at −30 ° C. for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was extracted with an aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid was added to adjust the pH to 2, and the mixture was extracted again with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the resulting residue, 1,4-dioxane (32 mL), ammonium carbonate (1.11 g, 11.6 mmol), di-tert-butyl dicarbonate (2.79 mL, 12.0 mmol), pyridine (0.374 mL, 4 .63 mmol) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated under reduced pressure to obtain a crude product of compound 40c (3.1 g). MS (M + 1) = 342.15.

Step 3 Synthesis of Compound I-40 Dimedone (616 mg, 4.39 mmol) and tetrakis (triphenylphosphine) palladium (0) (169 mg, 0.146 mmol) were added to a DMF solution of the composition of compound 40c (500 mg) at room temperature. The mixture was stirred for 30 minutes. To this, compound 40d (770 mg, 2.20 mmol) was added and stirred at room temperature for 1 hour. Insoluble matters in the reaction solution were removed by Celite filtration. Diisopropyl ether, acetonitrile and dilute hydrochloric acid were sequentially added to the filtrate and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to obtain Compound I-40 (160 mg) as a white powder.
1H-NMR (D2O) δ: 2.91 (1H, dd, J = 14.1, 8.5 Hz), 2.98-3.01 (2H, m), 3.33-3.23 (2H, m), 4.00 (3H, s), 5.31 (1H , d, J = 4.5 Hz), 5.51 (1H, d, J = 4.5 Hz), 7.12 (1H, s).
MS (M + 1) = 441.11, retention time: 0.67 minutes, measurement condition 1
C15H16N6O6S2 (H2O) 1.8 (C4H8O2) 0.1 Calculated value C: 38.40%, H: 4.27%, N: 17.45%, S: 13.31%, measured value C: 38.34%, H: 4.24%, N: 17.65%, S: 13.12%.
化合物Ｉ－４１の合成 
Figure JPOXMLDOC01-appb-C000177
 工程１　化合物４１ｆの合成
　化合物４１ｃの組成生物（１．６ｇ）のＴＨＦ（１６ｍＬ）溶液にピリジン（１．１４ｍＬ、１４．１ｍｍｏｌ）を加えた。反応液を－３０℃に冷却後、トリフルオロ酢酸無水物（０．９９ｍＬ、７．０ｍｍｏｌ）を加え、－３０℃下、１時間撹拌した。反応混合物に水をを加え、酢酸エチルで抽出した。有機層を希塩酸、炭酸水素ナトリウム水溶液、および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物４１ｆ（５２０ｍｇ、３４％）を得た。MS(M+1) = 411.20.

工程２　化合物４１ｇの合成
　化合物４１ｆの組成生物（３５０ｍｇ）の１，４－ジオキサン（３．５ｍＬ）溶液にトリメチルシリルアジド（０．２８７ｍＬ、２．１７ｍｍｏｌ）、ジブチルすずオキシドを加えた。反応液を９０℃に昇温後、１．５時間撹拌した。反応混合物にジイソプロピルエーテルを加え、炭酸水素ナトリウム水溶液で抽出した。水層に希塩酸を加えｐＨを２に調節した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去し、化合物４１ｇの組成生物を得た。MS(M+1) = 367.13.

工程４　化合物Ｉ－４１の合成
化合物４１ｇ組成生物(６００ｍｇ)のＤＭＦ溶液にジメドン（６８９ｍｇ、４．９１ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（３７９ｍｇ、０．３２８ｍｍｏｌ）を加え、室温下、１時間撹拌した。これに、化合物１ｄ（８６１ｍｇ、２．４６ｍｍｏｌ）を加え、室温下１時間撹拌した。反応液中の不溶物をセライトろ過により取り除いた。ろ液にジイソプロピルエーテル、アセトニトリル、希塩酸を順に加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィー（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することにより化合物Ｉ－４１（１９０ｍｇ）を白色粉末として得た。
C15H15N9O5S2(H2O)2.2 
計算値C : 35.67%, H : 3.87%, N : 24.96%, S : 12.69%, 
実測値 C :35.49%, H :3.85%, N : 25.14%, S : 12.77%
1H-NMR (D2O) δ: 2.81-2.83 (2H, m), 3.04 (1H, dd, J = 14.6, 9.9 Hz), 3.28 (1H, dd, J = 14.6, 4.6 Hz), 3.44-3.49 (1H, m), 3.98 (3H, s), 5.42 (1H, d, J = 4.6 Hz), 5.57 (1H, d, J = 4.6 Hz), 7.06 (1H, s).
[M+1]= 466.13、保持時間：０．６７分、測定条件１
Synthesis of Compound I-41
Figure JPOXMLDOC01-appb-C000177
 Step 1 Synthesis of Compound 41f Pyridine (1.14 mL, 14.1 mmol) was added to a THF (16 mL) solution of the component organism (1.6 g) of Compound 41c. The reaction mixture was cooled to −30 ° C., trifluoroacetic anhydride (0.99 mL, 7.0 mmol) was added, and the mixture was stirred at −30 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 41f (520 mg, 34%). MS (M + 1) = 411.20.

Step 2 Synthesis of Compound 41g Trimethylsilyl azide (0.287 mL, 2.17 mmol) and dibutyltin oxide were added to a 1,4-dioxane (3.5 mL) solution of the component organism (350 mg) of compound 41f. The reaction solution was heated to 90 ° C. and stirred for 1.5 hours. Diisopropyl ether was added to the reaction mixture, and the mixture was extracted with an aqueous sodium hydrogen carbonate solution. Dilute hydrochloric acid was added to the aqueous layer to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 41 g of a compound organism. MS (M + 1) = 367.13.

Step 4 Synthesis of Compound I-41 Dimedone (689 mg, 4.91 mmol) and tetrakis (triphenylphosphine) palladium (0) (379 mg, 0.328 mmol) were added to a DMF solution of 41 g of the composition compound (600 mg), at room temperature. Stir for 1 hour. To this, compound 1d (861 mg, 2.46 mmol) was added and stirred at room temperature for 1 hour. Insoluble matters in the reaction solution were removed by Celite filtration. Diisopropyl ether, acetonitrile and dilute hydrochloric acid were sequentially added to the filtrate and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to give Compound I-41 (190 mg) as a white powder.
C15H15N9O5S2 (H2O) 2.2
Calculated C: 35.67%, H: 3.87%, N: 24.96%, S: 12.69%,
Measured value C: 35.49%, H: 3.85%, N: 25.14%, S: 12.77%
1H-NMR (D2O) δ: 2.81-2.83 (2H, m), 3.04 (1H, dd, J = 14.6, 9.9 Hz), 3.28 (1H, dd, J = 14.6, 4.6 Hz), 3.44-3.49 (1H , m), 3.98 (3H, s), 5.42 (1H, d, J = 4.6 Hz), 5.57 (1H, d, J = 4.6 Hz), 7.06 (1H, s).
[M + 1] = 466.13, retention time: 0.67 minutes, measurement condition 1
　化合物Ｉ－４２の合成 
Figure JPOXMLDOC01-appb-C000178
工程１　化合４２ｂ及び４２ｃの合成
ＥＰ２５３３３７Ａ公報に記載の方法により得られた粗生成物４２ａ（１．４０ｍｍｏｌ相当）をテトラヒドロフラン（１０ｍｌ）、ジクロロメタン（１０ｍｌ）に溶解し、氷冷下ＥＤＣ（０．５４ｇ，２．８０ｍｍｏｌ）を加えた。
室温で１時間撹拌した後、減圧下溶媒を留去した。残渣を酢酸エチルと塩酸水で希釈した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。硫酸マグネシウムをろ過した後、減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、ヘキサン／酢酸エチルで溶離させた。所望の化合物を含むフラクションを減圧下濃縮し、化合物４２ｂ（０．２６ｇ，３２％）化合物４２ｃ（０．２１ｇ，２６％）を得た。
化合物４２ｂ
1H-NMR (CDCl3) δ: 8.23 (4H, d, J = 7.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.7 Hz), 5.47-5.41 (2H, m), 5.36 (1H, d, J = 12.9 Hz), 5.22 (2H, dd, J = 16.1, 13.4 Hz), 4.96 (1H, dd, J = 7.0, 5.0 Hz), 4.14-4.20 (1H, m), 2.94-2.86 (2H, m), 2.65 (1H, dd, J = 13.4, 3.3 Hz), 2.45 (1H, d, J = 18.1 Hz).
化合物４２ｃ
1H-NMR (CDCl3) δ: 8.24 (2H, d, J = 8.7 Hz), 8.20 (2H, d, J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7 Hz), 6.08 (1H, d, J = 7.3 Hz), 5.43 (1H, d, J = 13.1 Hz), 5.36 (1H, d, J = 13.1 Hz), 5.22 (1H, d, J = 13.4 Hz), 5.18 (1H, d, J = 13.4 Hz), 4.94 (1H, dd, J = 7.2, 4.9 Hz), 4.19-4.14 (1H, m), 3.70 (1H, dd, J = 11.4, 8.5 Hz), 3.09 (1H, dd, J = 17.9, 11.5 Hz), 2.98-2.87 (2H, m), 2.50 (1H, dd, J = 13.9, 3.8 Hz).

工程２　化合物Ｉ－４２の合成
化合物４２ｂ（１００ｍｇ，０．１８ｍｍｏｌ）と化合物４２ｄ（１８４ｍｇ，０．５２ｍｍｏｌ）を用いＥＰ２５３３３７Ａ公報に記載の方法により化合物Ｉ－４２を合成し、ＯＤＳカラムクロマトグラフィにより精製することにより化合物Ｉ－４２（１５ｍｇ，１９％）を得た。
1H-NMR (D2O) δ: 6.98 (1H, s), 5.34 (1H, d, J = 4.8 Hz), 4.33-4.28 (1H, m), 4.12 (1H, d, J = 6.7 Hz), 3.99 (3H, s), 3.13-2.97 (2H, m), 2.73 (1H, dd, J = 13.4, 3.5 Hz), 2.51 (1H, d, J = 18.3 Hz).
［Ｍ＋Ｈ］＝４４２、保持時間：0.73分、測定条件１
Synthesis of Compound I-42
Figure JPOXMLDOC01-appb-C000178
Step 1 Synthesis of Compounds 42b and 42c Crude product 42a (corresponding to 1.40 mmol) obtained by the method described in EP253337A was dissolved in tetrahydrofuran (10 ml) and dichloromethane (10 ml), and EDC (0.54 g) was cooled with ice. , 2.80 mmol).
After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and aqueous hydrochloric acid. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered, concentrated under reduced pressure, subjected to silica gel column chromatography, and eluted with hexane / ethyl acetate. Fractions containing the desired compound were concentrated under reduced pressure to give compound 42b (0.26 g, 32%) and compound 42c (0.21 g, 26%).
Compound 42b
1 H-NMR (CDCl 3 ) δ: 8.23 (4H, d, J = 7.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.7 Hz), 5.47-5.41 ( 2H, m), 5.36 (1H, d, J = 12.9 Hz), 5.22 (2H, dd, J = 16.1, 13.4 Hz), 4.96 (1H, dd, J = 7.0, 5.0 Hz), 4.14-4.20 (1H , m), 2.94-2.86 (2H, m), 2.65 (1H, dd, J = 13.4, 3.3 Hz), 2.45 (1H, d, J = 18.1 Hz).
Compound 42c
1 H-NMR (CDCl 3 ) δ: 8.24 (2H, d, J = 8.7 Hz), 8.20 (2H, d, J = 8.7 Hz), 7.54 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7 Hz), 6.08 (1H, d, J = 7.3 Hz), 5.43 (1H, d, J = 13.1 Hz), 5.36 (1H, d, J = 13.1 Hz), 5.22 (1H, d, J = 13.4 Hz), 5.18 (1H, d, J = 13.4 Hz), 4.94 (1H, dd, J = 7.2, 4.9 Hz), 4.19-4.14 (1H, m), 3.70 (1H, dd, J = 11.4 , 8.5 Hz), 3.09 (1H, dd, J = 17.9, 11.5 Hz), 2.98-2.87 (2H, m), 2.50 (1H, dd, J = 13.9, 3.8 Hz).

Step 2 Synthesis of Compound I-42 Compound I-42 was synthesized by the method described in EP253337A using Compound 42b (100 mg, 0.18 mmol) and Compound 42d (184 mg, 0.52 mmol) and purified by ODS column chromatography. This gave compound I-42 (15 mg, 19%).
1H-NMR (D2O) δ: 6.98 (1H, s), 5.34 (1H, d, J = 4.8 Hz), 4.33-4.28 (1H, m), 4.12 (1H, d, J = 6.7 Hz), 3.99 ( 3H, s), 3.13-2.97 (2H, m), 2.73 (1H, dd, J = 13.4, 3.5 Hz), 2.51 (1H, d, J = 18.3 Hz).
[M + H] = 442, retention time: 0.73 minutes, measurement condition 1
　化合物Ｉ－４３の合成　
Figure JPOXMLDOC01-appb-C000179
工程１　化合物４３ｂ
化合物４３ａ（７．４３ｇ、５１．２ｍｍｏｌ、合成法はＷＯ２００６１２７９６１Ａ１に記載。）のテトラヒドロフラン（３４２ｍＬ）および水（３４．２ｍＬ）溶液に、０℃でアリル（２，５－ジオキシピロリジンー１－イル）カーボネート（１２．２４ｇ、６１．４ｍｍｏｌ）を加え、トリフェニルホスフィン（１７．４６ｇ、６６．６ｍｍｏｌ）を加えた後、室温で３日間撹拌した。得られた溶液を減圧濃縮し、得られた無色透明のオイルに水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物にトリフェニルホスフィンの種晶を加え、ジイソプロピルエーテル（４５ｍＬ）を加え、得られた白色サスペンジョンを濾過した。得られた母液を減圧濃縮し、シリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４３ｂ（６．４４ｇ、収率６１．９％）を無色透明オイルとして得た。
1H-NMR (CDCl3) δ: 3.31 (1H, s), 3.53-3.60 (2H, m), 3.80 (3H, s), 4.29-4.30 (1H, m), 4.56 (2H, d, J = 4.8 Hz), 5.22 (2H, d, J = 10.4 Hz), 5.30 (1H, d, J = 17.2 Hz), 5.88-5.93 (1H, m).

工程２　化合物４３ｃ
イミダゾール（３．４４ｇ、５０．６ｍｍｏｌ）のジクロロメタン（１９２ｍＬ）溶液に、０℃で化合物４３ｂ（６．８５ｇ、３３．７ｍｍｏｌ）およびｔ－ブチルジメチルシリルクロリド（７．６２ｇ、５０．６ｍｍｏｌ）を加え、室温で終夜静置した。水を加え、酢酸エチルで抽出した。有機層は、水、飽和塩化ナトリウム水溶液で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４３ｃ（１０．８１ｇ、収率１００％）を無色透明オイルとして得た。
1H-NMR (CDCl3) δ: 0.00 (3H, s), 0.03 (3H, s), 0.83 (9H, s), 3.38-3.43 (2H, m), 3.66 (3H, s), 4.24 (1H, t, J = 4.8 Hz), 4.49 (2H, br s), 4.97 (1H, br s), 5.13 (1H, d, J = 10.4 Hz), 5.22 (1H, d, J = 17.2 Hz), 5.80-5.86 (1H, m).

工程３　化合物４３ｅ
化合物４３ｃ（１１．３２ｇ、３５．７ｍｍｏｌ）のテトラヒドロフラン（１９２ｍＬ）溶液に、０℃で８Ｎ水酸化ナトリウム水溶液（８．９１ｍＬ、７１．３ｍｍｏｌ）を加え、室温で終夜静置した。０℃で１Ｎ塩酸水溶液（７８ｍＬ、７８ｍｍｏｌ）を加え、減圧濃縮し、飽和食塩水を加え、酢酸エチルで抽出した。有機層は、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮し、化合物４３ｄ（９．０８ｇ、収率８３．９％）を粗生成物として得た。
化合物４３ｄ（９．０８ｇ、２９．９ｍｍｏｌ）のテトラヒドロフラン（５４．５ｍＬ）溶液に、室温でジフェニルジアゾメタン（５．８１ｇ、２９．９ｍｍｏｌ）のテトラヒドロフラン（３６．３ｍＬ）溶液を２０分間かけて加え、室温で終夜静置した。得られた溶液に、室温でジフェニルジアゾメタン（１．７４ｇ、８．９８ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液を２０分間かけて加え、室温で再び終夜静置した。得られた溶液を減圧濃縮し、シリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４３ｅ（５．０ｇ、収率３５．６％）を薄黄色オイルとして得た。
1H-NMR (CDCl3) δ: -0.07 (3H, s), -0.06 (3H, s), 0.74-0.80 (9H, m), 3.34-3.41 (1H, m), 3.45-3.51 (1H, m), 4.31 (1H, t, J = 5.5 Hz), 4.43 (2H, ddd, J = 22.4, 13.3, 5.6 Hz), 4.91 (1H, br s), 5.10 (1H, dd, J = 10.4, 1.4 Hz), 5.19 (1H, dd, J = 17.3, 1.5 Hz), 5.76-5.82 (1H, m), 6.81 (1H, s), 7.18-7.30 (10H, m).

工程４　化合物４３ｆ
化合物４３ｅ（５．０ｇ、１０．６５ｍｍｏｌ）のテトラヒドロフラン（５０ｍＬ）溶液に、０℃で酢酸（０．９１３ｍＬ、１５．９７ｍｍｏｌ）およびテトラブチルアンモニウムフルオリド（１Ｍテトラヒドロフラン溶液、１５．９７ｍＬ、１５．９７ｍｍｏｌ）を加え、室温で２時間撹拌した。水を加え、酢酸エチルで抽出した。有機層は、８．４％炭酸水素ナトリウム水溶液、水、飽和塩化ナトリウム水溶液で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４３ｆ（３．２ｇ、収率８４．６％）を無色透明オイルとして得た。
1H-NMR (CDCl3) δ: 3.24 (1H, d, J = 4.1 Hz), 3.50-3.56 (1H, m), 3.69-3.73 (1H, m), 4.39-4.40 (1H, m), 4.53 (2H, d, J = 5.4 Hz), 5.04 (1H, br s), 5.20 (1H, dd, J = 10.4, 1.1 Hz), 5.28 (1H, dq, J = 17.2, 1.5 Hz), 5.85-5.91 (1H, m), 6.93 (1H, s), 7.27-7.37 (10H, m).

工程５　化合物４３ｇ
化合物４３ｆ（３．２ｇ、９．０ｍｍｏｌ）のテトラヒドロフラン（３２ｍＬ）溶液に、室温で２－ヒドロキシインドリン－１，３－ジオン（１．７６３ｇ、１０．８１ｍｍｏｌ）およびトリフェニルホスフィン（２．８３ｇ、１０．８１ｍｍｏｌ）を加え、ジイソプロピルアゾジカルボキシレート（２．１０ｍＬ、１０．８１ｍｍｏｌ）を滴下しながら加え、室温で１．５時間撹拌した。得られた溶液に、室温で２－ヒドロキシインドリン－１，３－ジオン（１．７６３ｇ、１０．８１ｍｍｏｌ）およびトリフェニルホスフィン（２．８３ｇ、１０．８１ｍｍｏｌ）を加え、ジイソプロピルアゾジカルボキシレート（６．３ｍＬ、３２．４３ｍｍｏｌ）を滴下しながら加え、室温で３日間静置した。得られた溶液を、減圧濃縮し、シリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、減圧乾燥した後、メタノール（５０ｍＬ）を加え、得られた白色スラリーを濾過して、白色固体Ｘ１（３．８７ｇ）と母液Ｍ１を得た。母液Ｍ１を濃縮後、メタノール（５０ｍＬ）を加え、得られた白色スラリーを濾過して、白色固体Ｘ２（２２４．２ｍｇ）と母液Ｍ２を得た。白色固体Ｘ１（３．８７ｇ）とＸ２（２２４．２ｍｇ）をジクロロメタン（１０ｍＬ）に溶かし、メタノール（１０ｍＬ）を加え、２５０Ｔｏｒｒ、３５℃の条件で、ジクロロメタンのみを減圧濃縮し、得られた白色スラリーにメタノールを加え、濾過することで、化合物４３ｇ（２．９６ｇ、収率６５．７％）を白色固体として得た。
1H-NMR (CDCl3) δ: 3.78 (2H, t, J = 5.7 Hz), 4.49-4.59 (2H, m), 4.91 (1H, t, J = 5.3 Hz), 5.20 (1H, d, J = 10.5 Hz), 5.30 (1H, d, J = 17.2 Hz), 5.86-5.95 (2H, m), 6.94 (1H, s), 7.24-7.37 (10H, m), 7.74-7.78 (2H, m), 7.80-7.82 (2H, m).

工程６　化合物４３ｋ
化合物４３ｇ（２．９６ｇ、５．９１ｍｍｏｌ）のジクロロメタン（２０．７ｍＬ）溶液に、０℃でメチルヒドラジン（０．３５１ｍＬ、６．５０ｍｍｏｌ）を一度に加え、０℃で１時間撹拌した。得られた溶液を濾過してジクロロメタン（８．９ｍＬ）で洗浄し、得られたジクロロメタン溶液に、メタノール（１４．８ｍＬ）を加え、０℃で化合物４３ｈ（１．５４５ｇ、５．６７ｍｍｏｌ）を加え、０℃で１時間撹拌した。１Ｎ塩酸水溶液（６０ｍＬ）を加え、酢酸エチルで抽出した。有機層は、水、飽和塩化ナトリウム水溶液で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮し、化合物４３ｉ（３．７７ｇ、収率１００％）を粗生成物として得た。
化合物４３ｉ（３．１１ｇ、４．９８ｍｍｏｌ）のジメチルアセトアミド（６．８ｍＬ）溶液を－２０℃まで冷却した後、トリエチルアミン（０．８６３ｍＬ、６．２３ｍｍｏｌ）メタンスルホニルクロリド（０．４５３ｍＬ、５．８１ｍｍｏｌ）を加えた。－２０℃で３０分間攪拌することで、溶液Ｃを得た。
実施例１２の工程３に記載された方法で合成した化合物４３ｊ（１．３５４ｇ、４．１５ｍｍｏｌ）の酢酸エチル（１３．５ｍＬ）溶液に、氷冷下でピリジン（０．４０２ｍＬ、４．９８ｍｍｏｌ）、溶液Ｃを加えた。氷冷下で９０分間攪拌した後、希塩酸水を加え、酢酸エチルで抽出した。有機層を、８．４％炭酸水素ナトリウム水溶液、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４３ｋ（１．５２６ｇ、収率３９．４％）を黄色フォームとして得た。
1H-NMR (CDCl3) δ: 1.54 (9H, s), 1.70 (3H, s), 1.76 (3H, s), 2.57-2.64 (1H, m), 2.70-2.86 (3H, m), 3.18-3.27 (1H, m), 3.79-3.87 (2H, m), 4.51-4.59 (2H, m), 4.77 (4H, dd, J = 14.3, 8.7 Hz), 4.97 (1H, d, J = 4.8 Hz), 5.14-5.17 (2H, m), 5.28 (1H, dd, J = 17.2, 1.5 Hz), 5.35-5.37 (1H, m), 5.49-5.55 (1H, m), 5.67-5.71 (1H, m), 5.85-5.90 (1H, m), 6.84 (1H, s), 7.29-7.39 (10H, m), 8.12 (1H, s), 8.19 (1H, d, J = 8.9 Hz).

工程７　化合物Ｉ－４３
実施例１の工程４と同様の方法で、化合物４３ｋを用いて、化合物Ｉ－４３（２５２．５ｍｇ、２９．６％）を白色固体として得た。
1H-NMR (DMSO-D6) δ: 2.63-2.67 (1H, m), 2.74 (1H, dd, J = 14.0, 9.0 Hz), 2.85 (2H, dd, J = 18.1, 8.5 Hz), 3.04-3.09 (1H, m), 3.15 (1H, dd, J = 14.1, 4.4 Hz), 3.54-3.60 (1H, m), 4.48 (2H, d, J = 5.3 Hz), 4.61 (1H, dd, J = 8.0, 5.0 Hz), 5.16-5.18 (2H, m), 5.28 (1H, dd, J = 17.1, 1.6 Hz), 5.56 (1H, dd, J = 8.5, 4.6 Hz), 5.90 (1H, ddd, J = 22.6, 10.5, 5.4 Hz), 6.81 (1H, s), 7.25-7.27 (3H, m), 9.64 (1H, d, J = 8.5 Hz).
ＭＳ（Ｍ＋１）＝５９９、保持時間：０．８０分、測定条件１
元素分析：Ｃ２１Ｈ２２Ｎ６Ｏ１１Ｓ２（Ｈ２Ｏ）１．８ ．
計算値C: 39.97%, H: 4.09%, N: 13.32%, S: 10.16%．
実測値C: 40.06%, H: 4.11%, N: 13.22%, S: 10.18%．
Synthesis of Compound I-43
Figure JPOXMLDOC01-appb-C000179
Step 1 Compound 43b
Compound 43a (7.43 g, 51.2 mmol, synthesis method described in WO2006127961A1) in tetrahydrofuran (342 mL) and water (34.2 mL) at 0 ° C. is allyl (2,5-dioxypyrrolidin-1-yl). ) Carbonate (12.24 g, 61.4 mmol) was added, and triphenylphosphine (17.46 g, 66.6 mmol) was added, followed by stirring at room temperature for 3 days. The obtained solution was concentrated under reduced pressure, water was added to the obtained colorless and transparent oil, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. Triphenylphosphine seed crystals were added to the resulting crude product, diisopropyl ether (45 mL) was added, and the resulting white suspension was filtered. The resulting mother liquor was concentrated under reduced pressure and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 43b (6.44 g, yield 61.9%) as a colorless transparent oil.
1H-NMR (CDCl3) δ: 3.31 (1H, s), 3.53-3.60 (2H, m), 3.80 (3H, s), 4.29-4.30 (1H, m), 4.56 (2H, d, J = 4.8 Hz ), 5.22 (2H, d, J = 10.4 Hz), 5.30 (1H, d, J = 17.2 Hz), 5.88-5.93 (1H, m).

Step 2 Compound 43c
Compound 43b (6.85 g, 33.7 mmol) and t-butyldimethylsilyl chloride (7.62 g, 50.6 mmol) were added to a solution of imidazole (3.44 g, 50.6 mmol) in dichloromethane (192 mL) at 0 ° C. And left at room temperature overnight. Water was added and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 43c (10.81 g, yield 100%) as a colorless transparent oil.
1H-NMR (CDCl3) δ: 0.00 (3H, s), 0.03 (3H, s), 0.83 (9H, s), 3.38-3.43 (2H, m), 3.66 (3H, s), 4.24 (1H, t , J = 4.8 Hz), 4.49 (2H, br s), 4.97 (1H, br s), 5.13 (1H, d, J = 10.4 Hz), 5.22 (1H, d, J = 17.2 Hz), 5.80-5.86 (1H, m).

Step 3 Compound 43e
To a solution of compound 43c (11.32 g, 35.7 mmol) in tetrahydrofuran (192 mL) was added 8N aqueous sodium hydroxide solution (8.91 mL, 71.3 mmol) at 0 ° C., and the mixture was allowed to stand overnight at room temperature. A 1N aqueous hydrochloric acid solution (78 mL, 78 mmol) was added at 0 ° C., the mixture was concentrated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Compound 43d (9.08 g, yield 83.9%) as a crude product.
To a solution of compound 43d (9.08 g, 29.9 mmol) in tetrahydrofuran (54.5 mL) was added a solution of diphenyldiazomethane (5.81 g, 29.9 mmol) in tetrahydrofuran (36.3 mL) at room temperature over 20 minutes. And left overnight. To the resulting solution was added a solution of diphenyldiazomethane (1.74 g, 8.98 mmol) in tetrahydrofuran (15 mL) at room temperature over 20 minutes, and the mixture was allowed to stand again at room temperature overnight. The resulting solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 43e (5.0 g, yield 35.6%) as a pale yellow oil.
1H-NMR (CDCl3) δ: -0.07 (3H, s), -0.06 (3H, s), 0.74-0.80 (9H, m), 3.34-3.41 (1H, m), 3.45-3.51 (1H, m) , 4.31 (1H, t, J = 5.5 Hz), 4.43 (2H, ddd, J = 22.4, 13.3, 5.6 Hz), 4.91 (1H, br s), 5.10 (1H, dd, J = 10.4, 1.4 Hz) , 5.19 (1H, dd, J = 17.3, 1.5 Hz), 5.76-5.82 (1H, m), 6.81 (1H, s), 7.18-7.30 (10H, m).

Step 4 Compound 43f
A solution of compound 43e (5.0 g, 10.65 mmol) in tetrahydrofuran (50 mL) was added acetic acid (0.913 mL, 15.97 mmol) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 15.97 mL, 15.97 mmol) at 0 ° C. ) And stirred at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic layer was washed sequentially with an 8.4% aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 43f (3.2 g, yield 84.6%) as a colorless transparent oil.
1H-NMR (CDCl3) δ: 3.24 (1H, d, J = 4.1 Hz), 3.50-3.56 (1H, m), 3.69-3.73 (1H, m), 4.39-4.40 (1H, m), 4.53 (2H , d, J = 5.4 Hz), 5.04 (1H, br s), 5.20 (1H, dd, J = 10.4, 1.1 Hz), 5.28 (1H, dq, J = 17.2, 1.5 Hz), 5.85-5.91 (1H , m), 6.93 (1H, s), 7.27-7.37 (10H, m).

Step 5 Compound 43g
To a solution of compound 43f (3.2 g, 9.0 mmol) in tetrahydrofuran (32 mL) at room temperature was added 2-hydroxyindoline-1,3-dione (1.763 g, 10.81 mmol) and triphenylphosphine (2.83 g, 10 .81 mmol) was added, and diisopropyl azodicarboxylate (2.10 mL, 10.81 mmol) was added dropwise, followed by stirring at room temperature for 1.5 hours. To the obtained solution, 2-hydroxyindoline-1,3-dione (1.763 g, 10.81 mmol) and triphenylphosphine (2.83 g, 10.81 mmol) were added at room temperature, and diisopropyl azodicarboxylate (6 3 mL, 32.43 mmol) was added dropwise and allowed to stand at room temperature for 3 days. The resulting solution was concentrated under reduced pressure, purified by silica gel column chromatography (hexane-ethyl acetate), dried under reduced pressure, methanol (50 mL) was added, and the resulting white slurry was filtered to obtain a white solid X1 (3 .87 g) and mother liquor M1. After concentrating the mother liquor M1, methanol (50 mL) was added, and the resulting white slurry was filtered to obtain a white solid X2 (224.2 mg) and the mother liquor M2. White solids X1 (3.87 g) and X2 (224.2 mg) were dissolved in dichloromethane (10 mL), methanol (10 mL) was added, and only dichloromethane was concentrated under reduced pressure at 250 Torr and 35 ° C. The resulting white slurry Methanol was added to and filtered to obtain 43 g of compound (2.96 g, yield 65.7%) as a white solid.
1H-NMR (CDCl3) δ: 3.78 (2H, t, J = 5.7 Hz), 4.49-4.59 (2H, m), 4.91 (1H, t, J = 5.3 Hz), 5.20 (1H, d, J = 10.5 Hz), 5.30 (1H, d, J = 17.2 Hz), 5.86-5.95 (2H, m), 6.94 (1H, s), 7.24-7.37 (10H, m), 7.74-7.78 (2H, m), 7.80 -7.82 (2H, m).

Step 6 Compound 43k
To a solution of compound 43g (2.96 g, 5.91 mmol) in dichloromethane (20.7 mL), methylhydrazine (0.351 mL, 6.50 mmol) was added at once at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. The obtained solution was filtered and washed with dichloromethane (8.9 mL), methanol (14.8 mL) was added to the obtained dichloromethane solution, and compound 43h (1.545 g, 5.67 mmol) was added at 0 ° C. And stirred at 0 ° C. for 1 hour. A 1N aqueous hydrochloric acid solution (60 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure to obtain Compound 43i (3.77 g, yield 100%) as a crude product.
A solution of compound 43i (3.11 g, 4.98 mmol) in dimethylacetamide (6.8 mL) was cooled to −20 ° C., and then triethylamine (0.863 mL, 6.23 mmol) methanesulfonyl chloride (0.453 mL, 5.81 mmol). ) Was added. Solution C was obtained by stirring at −20 ° C. for 30 minutes.
To a solution of compound 43j (1.354 g, 4.15 mmol) synthesized by the method described in Step 3 of Example 12 in ethyl acetate (13.5 mL) was added pyridine (0.402 mL, 4.98 mmol) under ice-cooling. Solution C was added. After stirring for 90 minutes under ice cooling, dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an 8.4% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 43k (1.526 g, yield 39.4%) as a yellow foam.
1H-NMR (CDCl3) δ: 1.54 (9H, s), 1.70 (3H, s), 1.76 (3H, s), 2.57-2.64 (1H, m), 2.70-2.86 (3H, m), 3.18-3.27 (1H, m), 3.79-3.87 (2H, m), 4.51-4.59 (2H, m), 4.77 (4H, dd, J = 14.3, 8.7 Hz), 4.97 (1H, d, J = 4.8 Hz), 5.14-5.17 (2H, m), 5.28 (1H, dd, J = 17.2, 1.5 Hz), 5.35-5.37 (1H, m), 5.49-5.55 (1H, m), 5.67-5.71 (1H, m), 5.85-5.90 (1H, m), 6.84 (1H, s), 7.29-7.39 (10H, m), 8.12 (1H, s), 8.19 (1H, d, J = 8.9 Hz).

Step 7 Compound I-43
In the same manner as in Step 4 of Example 1, using Compound 43k, Compound I-43 (252.5 mg, 29.6%) was obtained as a white solid.
1H-NMR (DMSO-D6) δ: 2.63-2.67 (1H, m), 2.74 (1H, dd, J = 14.0, 9.0 Hz), 2.85 (2H, dd, J = 18.1, 8.5 Hz), 3.04-3.09 (1H, m), 3.15 (1H, dd, J = 14.1, 4.4 Hz), 3.54-3.60 (1H, m), 4.48 (2H, d, J = 5.3 Hz), 4.61 (1H, dd, J = 8.0 , 5.0 Hz), 5.16-5.18 (2H, m), 5.28 (1H, dd, J = 17.1, 1.6 Hz), 5.56 (1H, dd, J = 8.5, 4.6 Hz), 5.90 (1H, ddd, J = 22.6, 10.5, 5.4 Hz), 6.81 (1H, s), 7.25-7.27 (3H, m), 9.64 (1H, d, J = 8.5 Hz).
MS (M + 1) = 599, retention time: 0.80 minutes, measurement condition 1
Elemental analysis: C21H22N6O11S2 (H2O) 1.8.
Calculated C: 39.97%, H: 4.09%, N: 13.32%, S: 10.16%.
Found C: 40.06%, H: 4.11%, N: 13.22%, S: 10.18%.
　化合物Ｉ－４４の合成　
Figure JPOXMLDOC01-appb-C000180
工程１
化合物Ｉ－４３（２０４．９ｍｇ、０．３４２ｍｍｏｌ）のテトラヒドロフラン（４．１ｍＬ）溶液に、室温でジメドン（１４４ｍｇ、１．０２７ｍｍｏｌ）を加え、溶液を脱気した後、テトラキス（トリフェニルホスフィン）パラジウム（３９．６ｍｇ、０．０３４ｍｍｏｌ）を加え、室温で５時間撹拌した。溶液を脱気した後、テトラキス（トリフェニルホスフィン）パラジウム（３９．６ｍｇ、０．０３４ｍｍｏｌ）を加え、室温で８時間撹拌した。反応液にジイソプロピルエーテル、氷、アセトニトリルを順に加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液に２Ｎ塩酸を加え、ＯＤＳカラムクロマトグラフィ（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、減圧濃縮した後、凍結乾燥することにより化合物Ｉ－４４（７１．９ｍｇ、４４．５％収率）を白色粉末として得た。
1H-NMR (DMSO-D6) δ: 2.41 (1H, d, J = 17.7 Hz), 2.65-2.71 (2H, m), 2.91-2.94 (2H, m), 3.03-3.07 (1H, m), 3.23 (1H, d, J = 10.3 Hz), 4.85 (1H, d, J = 9.7 Hz), 5.11 (1H, d, J = 4.5 Hz), 5.43 (1H, dd, J = 7.7, 4.6 Hz), 6.84 (1H, s), 7.29 (2H, s), 8.19 (2H, br s), 10.30 (1H, s).
ＭＳ（Ｍ＋１）＝５１５、保持時間：０．３８分、測定条件１
元素分析：C17H18N6O9S2(H2O)3.5．
計算値C: 35.55%, H: 4.36%, N: 14.55%, S: 11.10%．
実測値C: 35.34%, H: 4.31%, N: 14.60%, S: 11.21%.
Synthesis of Compound I-44
Figure JPOXMLDOC01-appb-C000180
Process 1
Dimedone (144 mg, 1.027 mmol) was added to a solution of compound I-43 (204.9 mg, 0.342 mmol) in tetrahydrofuran (4.1 mL) at room temperature, the solution was degassed, and then tetrakis (triphenylphosphine) palladium. (39.6 mg, 0.034 mmol) was added and stirred at room temperature for 5 hours. After degassing the solution, tetrakis (triphenylphosphine) palladium (39.6 mg, 0.034 mmol) was added and stirred at room temperature for 8 hours. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. 2N Hydrochloric acid was added to the obtained mixed liquid, and the mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, concentrated under reduced pressure, and lyophilized to give compound I-44 (71.9 mg, 44.5% yield) as a white powder.
1H-NMR (DMSO-D6) δ: 2.41 (1H, d, J = 17.7 Hz), 2.65-2.71 (2H, m), 2.91-2.94 (2H, m), 3.03-3.07 (1H, m), 3.23 (1H, d, J = 10.3 Hz), 4.85 (1H, d, J = 9.7 Hz), 5.11 (1H, d, J = 4.5 Hz), 5.43 (1H, dd, J = 7.7, 4.6 Hz), 6.84 (1H, s), 7.29 (2H, s), 8.19 (2H, br s), 10.30 (1H, s).
MS (M + 1) = 515, retention time: 0.38 minutes, measurement condition 1
Elemental analysis: C17H18N6O9S2 (H2O) 3.5.
Calculated C: 35.55%, H: 4.36%, N: 14.55%, S: 11.10%.
Found C: 35.34%, H: 4.31%, N: 14.60%, S: 11.21%.
　化合物Ｉ－４５の合成 　
Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000182
工程１　化合物４５ｂの合成
　化合物４５ａ（１０ｇ、５８ｍｍｏｌ）のジメチルホルムアミド（７０ｍＬ）溶液に、ジシクロヘキシルアミン（１１．５ｍＬ、５８ｍｍｏｌ）、1－ブロモ－３－メチル－２－ブテン（７．３ｍＬ、６４ｍｍｏｌ）を順に５０℃で加えた。６０℃で１時間攪拌した後、酢酸エチルをを加え、不溶物をろ過により除いた。ろ液に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４５ｂ（８．０７ｇ、収率５８％）を橙色オイルとして得た。
1H-NMR (DMSO-D6) δ: 1.19 (6H, s), 1.69 (3H, s), 1.73 (3H, s), 4.66 (2H, d, J = 7.1 Hz), 5.33 (1H, t, J = 6.4 Hz), 8.17 (1H, s).

工程２　化合物４５ｃの合成
　化合物４５ｂ（８．０７ｇ、３３ｍｍｏｌ）のテトラヒドロフラン（３２ｍＬ）溶液に、ジフェニルジアゾメタン（７．１２ｇ、３７ｍｍｏｌ）のテトラヒドロフラン（２４ｍＬ）溶液を滴下した。室温で５日間攪拌した後、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４５ｃ（４．８０ｇ、収率３５％）を白色固体として得た。
1H-NMR (CDCl3) δ: 1.33 (6H, s), 1.73 (3H, s), 1.77 (3H, s), 3.15 (2H, s), 4.70 (2H, d, J = 7.3 Hz), 5.35-5.38 (1H, m), 6.82 (1H, s), 7.26-7.34 (10H, m).

工程３　化合物４５ｄの合成
化合物４５ｃ（４．８ｇ、１１．７ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、氷冷下でＮ，Ｎ，Ｎ’Ｎ’－テトラメチルメタンジアミン（６．４０ｍＬ、４７ｍｍｏｌ）を加えた後、無水酢酸（５．５５ｍＬ、５９ｍｍｏｌ）、酢酸（４．７０ｍＬ、８２ｍｍｏｌ）を順に滴下した。５０℃で６時間攪拌した後、反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４５ｄ（４．８３ｇ、収率９２％）を無色オイルとして得た。
1H-NMR (CDCl3) δ: 1.41 (6H, s), 1.75 (3H, s), 1.79 (3H, s), 4.77 (2H, d, J = 7.4 Hz), 5.37-5.42 (1H, m), 6.24 (1H, d, J = 1.0 Hz), 6.31 (1H, d, J = 1.0 Hz), 6.81 (1H, s), 7.23-7.32 (10H, m).

工程４　化合物４５ｆ及び４５ｇの合成
化合物４５ｄ（４．８３ｇ、１０．７ｍｍｏｌ）のアセトン（４８ｍＬ）溶液に、化合物４５ｅ（２．７９ｇ、１１．８ｍｍｏｌ）、ヘキサメチルリン酸トリアミド（６．５４ｍＬ、３７．６ｍｍｏｌ）を加えた。室温で終夜攪拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４５ｆ（６７７ｍｇ、収率１０％）を白色フォームとして、化合物４５ｇ（７２２ｍｇ、収率１０％）を白色フォームとして得た。
化合物４５ｆ
1H-NMR (CDCl3) δ: 1.22 (3H, s), 1.27 (3H, s), 1.68 (3H, s), 1.73 (3H, s), 2.41 (1H, d, J = 14.1 Hz), 2.96 (1H, d, J = 11.9 Hz), 3.11 (1H, t, J = 13.0 Hz), 3.62 (2H, dd, J = 24.8, 15.9 Hz), 4.19 (1H, s), 4.66-4.75 (1H, m), 4.91 (1H, dd, J = 11.9, 7.6 Hz), 5.02 (1H, d, J = 4.0 Hz), 5.37-5.45 (2H, m), 6.06 (1H, d, J = 9.3 Hz), 6.81 (1H, s), 7.26-7.39 (15H, m).
化合物４５ｇ
1H-NMR (CDCl3) δ: 1.24 (3H, s), 1.26 (3H, s), 1.73 (3H, s), 1.77 (3H, s), 2.42 (1H, dd, J = 13.7, 2.9 Hz), 2.74 (1H, t, J = 13.1 Hz), 3.61 (2H, d, J = 4.9 Hz), 4.18 (1H, dd, J = 12.4, 2.9 Hz), 4.57 (1H, d, J = 4.6 Hz), 4.73 (2H, t, J = 8.0 Hz), 5.28-5.40 (2H, m), 5.90 (1H, d, J = 8.9 Hz), 6.52 (1H, s), 6.83 (1H, s), 7.24-7.38 (15H, m).

工程５　化合物４５ｉの合成
化合物４５ｆ（６７７ｍｇ、１．０３ｍｍｏｌ）のジクロロメタン（４．７ｍＬ）溶液に、－２０℃でトリフルオロ酢酸（２．４ｍＬ、３０．９ｍｍｏｌ）を１０分間かけて滴下した。－２０℃で１時間攪拌した後、反応混合物を氷冷した炭酸水素ナトリウム水溶液とジクロロメタンの混合液に加えた。続いて、希塩酸をｐＨ＝２になるまで加えた後、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮することにより化合物４５ｈを得た。得られた４５ｈは精製せずにそのまま次の反応に用いた。
得られた４５ｈ全量をジクロロメタン（６．８ｍＬ）溶液に溶解させた後、氷冷下でＥＤＣ塩酸塩（２１７ｍｇ、１．１３ｍｍｏｌ）を加えた。室温で１時間攪拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４５ｉ（３５４ｍｇ、収率７３％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.20 (3H, s), 1.27 (3H, s), 1.71 (3H, s), 1.76 (3H, s), 2.59 (1H, dd, J = 14.2, 10.7 Hz), 2.84-2.94 (2H, m), 3.64 (2H, dd, J = 24.2, 16.1 Hz), 4.73-4.84 (2H, m), 4.96 (1H, d, J = 4.8 Hz), 5.36-5.40 (1H, m), 5.55 (1H, dd, J = 8.8, 4.8 Hz), 6.04 (1H, d, J = 8.8 Hz), 7.28-7.39 (5H, m).

工程６　化合物４５ｌの合成
化合物４５ｋ（３６１ｍｇ、０．９０ｍｍｏｌ）のジメチルアセトアミド（１．８ｍＬ）溶液を－２０℃まで冷却した後、トリエチルアミン（０．１５６ｍＬ、１．１２ｍｍｏｌ）メタンスルホニルクロリド（０．０８２ｍＬ、１．０５ｍｍｏｌ）を加えた。－２０℃で３０分間攪拌することで、溶液Ａを得た。
五塩化リン（３１２ｍｇ、１．５ｍｍｏｌ）のジクロロメタン（１．８ｍＬ）懸濁液を－７８℃まで冷却した後、ピリジン（０．１３３ｍＬ、１．６５ｍｍｏｌ）を加え、次いで化合物４５ｉ（３５４ｍｇ、０．７５ｍｍｏｌ）のジクロロメタン（１．８ｍＬ）溶液を滴下した。－１０℃で１時間攪拌した後、反応混合物を－７８℃まで冷却し、冷却したメタノール（１．８ｍＬ）を加えた。－３０℃で２時間攪拌した後、反応混合物に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥した後、無機物をろ過により除去した。ろ液に酢酸エチルを加え、ジクロロメタン及びメタノールを減圧留去することにより化合物４５ｊの酢酸エチル溶液を得た。得られた化合物４ｊの酢酸エチル溶液に、氷冷下でピリジン（０．０７３ｍＬ、０．９０ｍｍｏｌ）、及び上記で得られた溶液Ａを加えた。氷冷下で３０分間攪拌した後、希塩酸水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４５ｌ（４０７ｍｇ、収率７４％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.23 (3H, s), 1.31 (3H, s), 1.48 (9H, s), 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s), 2.62 (1H, dd, J = 15.9, 11.2 Hz), 2.97-3.02 (2H, m), 4.73-4.88 (4H, m), 5.08 (1H, d, J = 4.6 Hz), 5.37-5.42 (1H, m), 5.67 (1H, dd, J = 8.4, 4.6 Hz), 7.37 (1H, s), 8.06 (1H, s), 8.66 (1H, d, J = 8.4 Hz).

工程７　化合物Ｉ－４５の合成
　化合物４５ｌ（４０７ｍｇ、０．５５ｍｍｏｌ）のジクロロメタン（４ｍＬ）溶液を－４０℃まで冷却した後、アニソール（０．４８ｍＬ、４．４ｍｍｏｌ）、２ｍｏｌ／Ｌ　塩化アルミニウム／ニトロメタン溶液（２．２ｍＬ、４．４ｍｍｏｌ）を順に加え、－３０℃で３０分間攪拌した。反応液にジイソプロピルエーテル、氷水、アセトニトリルを加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去し、２ｍｏｌ／Ｌ塩酸（１．０ｍＬ）を加えた。得られた混合液をＯＤＳカラムクロマトグラフィ（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、０．２ｍｏｌ／Ｌ水酸化ナトリウム水溶液ｐＨ＝５．５まで加えた後、少量のドライアイスを加えた。得られた溶液を減圧濃縮した後、凍結乾燥することによりＩ－４５（１８０ｍｇ、収率５９％）を白色粉末として得た。
1H-NMR (D2O) δ: 1.26 (3H, s), 1.29 (3H, s), 2.84-2.97 (2H, m), 3.13 (1H, dd, J = 13.3, 4.1 Hz), 4.58 (2H, s), 5.24 (1H, d, J = 4.6 Hz), 5.62 (1H, d, J = 4.6 Hz), 7.06 (1H, s).
MS (m+1) = 514.05、保持時間：0.71分、測定条件１
元素分析：C18H17N5Na2O9S2(H2O)3.0
計算値：C,35.36; H,3.79; N,11.45; Na,7.52; S,10.49 (%)
実測値：C,35.34; H,3.83; N,11.62; Na,7.38; S,10.48 (%)
Synthesis of Compound I-45
Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000182
Step 1 Synthesis of Compound 45b To a solution of compound 45a (10 g, 58 mmol) in dimethylformamide (70 mL) was added dicyclohexylamine (11.5 mL, 58 mmol), 1-bromo-3-methyl-2-butene (7.3 mL, 64 mmol). In order at 50 ° C. After stirring at 60 ° C. for 1 hour, ethyl acetate was added, and insoluble matters were removed by filtration. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 45b (8.07 g, yield 58%) as an orange oil.
1 H-NMR (DMSO-D 6 ) δ: 1.19 (6H, s), 1.69 (3H, s), 1.73 (3H, s), 4.66 (2H, d, J = 7.1 Hz), 5.33 (1H, t , J = 6.4 Hz), 8.17 (1H, s).

Step 2 Synthesis of Compound 45c To a solution of Compound 45b (8.07 g, 33 mmol) in tetrahydrofuran (32 mL) was added dropwise a solution of diphenyldiazomethane (7.12 g, 37 mmol) in tetrahydrofuran (24 mL). The mixture was stirred at room temperature for 5 days and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 45c (4.80 g, yield 35%) as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.33 (6H, s), 1.73 (3H, s), 1.77 (3H, s), 3.15 (2H, s), 4.70 (2H, d, J = 7.3 Hz), 5.35-5.38 (1H, m), 6.82 (1H, s), 7.26-7.34 (10H, m).

Step 3 Synthesis of Compound 45d To a solution of Compound 45c (4.8 g, 11.7 mmol) in dichloromethane (10 mL) was added N, N, N′N′-tetramethylmethanediamine (6.40 mL, 47 mmol) under ice cooling. After the addition, acetic anhydride (5.55 mL, 59 mmol) and acetic acid (4.70 mL, 82 mmol) were added dropwise in this order. After stirring at 50 ° C. for 6 hours, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 45d (4.83 g, yield 92%) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.41 (6H, s), 1.75 (3H, s), 1.79 (3H, s), 4.77 (2H, d, J = 7.4 Hz), 5.37-5.42 (1H, m ), 6.24 (1H, d, J = 1.0 Hz), 6.31 (1H, d, J = 1.0 Hz), 6.81 (1H, s), 7.23-7.32 (10H, m).

Step 4 To a solution of compound 45f and 45 g of compound 45d (4.83 g, 10.7 mmol) in acetone (48 mL), compound 45e (2.79 g, 11.8 mmol), hexamethylphosphoric triamide (6.54 mL, 37 .6 mmol) was added. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 45f (677 mg, yield 10%) as a white foam and compound 45 g (722 mg, yield 10%) as a white foam. It was.
Compound 45f
1 H-NMR (CDCl 3 ) δ: 1.22 (3H, s), 1.27 (3H, s), 1.68 (3H, s), 1.73 (3H, s), 2.41 (1H, d, J = 14.1 Hz), 2.96 (1H, d, J = 11.9 Hz), 3.11 (1H, t, J = 13.0 Hz), 3.62 (2H, dd, J = 24.8, 15.9 Hz), 4.19 (1H, s), 4.66-4.75 (1H , m), 4.91 (1H, dd, J = 11.9, 7.6 Hz), 5.02 (1H, d, J = 4.0 Hz), 5.37-5.45 (2H, m), 6.06 (1H, d, J = 9.3 Hz) , 6.81 (1H, s), 7.26-7.39 (15H, m).
Compound 45g
1 H-NMR (CDCl 3 ) δ: 1.24 (3H, s), 1.26 (3H, s), 1.73 (3H, s), 1.77 (3H, s), 2.42 (1H, dd, J = 13.7, 2.9 Hz ), 2.74 (1H, t, J = 13.1 Hz), 3.61 (2H, d, J = 4.9 Hz), 4.18 (1H, dd, J = 12.4, 2.9 Hz), 4.57 (1H, d, J = 4.6 Hz) ), 4.73 (2H, t, J = 8.0 Hz), 5.28-5.40 (2H, m), 5.90 (1H, d, J = 8.9 Hz), 6.52 (1H, s), 6.83 (1H, s), 7.24 -7.38 (15H, m).

Step 5 Synthesis of compound 45i To a solution of compound 45f (677 mg, 1.03 mmol) in dichloromethane (4.7 mL) was added trifluoroacetic acid (2.4 mL, 30.9 mmol) dropwise at −20 ° C. over 10 minutes. After stirring at −20 ° C. for 1 hour, the reaction mixture was added to an ice-cooled mixture of aqueous sodium bicarbonate and dichloromethane. Subsequently, dilute hydrochloric acid was added until pH = 2, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and the compound 45h was obtained by concentrating under reduced pressure. The obtained 45 h was used in the next reaction without purification.
The total amount of the obtained 45 h was dissolved in a dichloromethane (6.8 mL) solution, and then EDC hydrochloride (217 mg, 1.13 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 45i (354 mg, 73% yield) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.20 (3H, s), 1.27 (3H, s), 1.71 (3H, s), 1.76 (3H, s), 2.59 (1H, dd, J = 14.2, 10.7 Hz ), 2.84-2.94 (2H, m), 3.64 (2H, dd, J = 24.2, 16.1 Hz), 4.73-4.84 (2H, m), 4.96 (1H, d, J = 4.8 Hz), 5.36-5.40 ( 1H, m), 5.55 (1H, dd, J = 8.8, 4.8 Hz), 6.04 (1H, d, J = 8.8 Hz), 7.28-7.39 (5H, m).

Step 6 Synthesis of Compound 45l After cooling a solution of Compound 45k (361 mg, 0.90 mmol) in dimethylacetamide (1.8 mL) to −20 ° C., triethylamine (0.156 mL, 1.12 mmol) methanesulfonyl chloride (0.082 mL) 1.05 mmol). Solution A was obtained by stirring at −20 ° C. for 30 minutes.
After cooling a suspension of phosphorus pentachloride (312 mg, 1.5 mmol) in dichloromethane (1.8 mL) to −78 ° C., pyridine (0.133 mL, 1.65 mmol) was added, followed by compound 45i (354 mg, 0. 75 mmol) in dichloromethane (1.8 mL) was added dropwise. After stirring at −10 ° C. for 1 hour, the reaction mixture was cooled to −78 ° C. and cooled methanol (1.8 mL) was added. After stirring at −30 ° C. for 2 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then inorganic substances were removed by filtration. Ethyl acetate was added to the filtrate, and dichloromethane and methanol were distilled off under reduced pressure to obtain an ethyl acetate solution of compound 45j. To an ethyl acetate solution of the obtained compound 4j, pyridine (0.073 mL, 0.90 mmol) and the solution A obtained above were added under ice cooling. The mixture was stirred for 30 minutes under ice-cooling, diluted aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 45l (407 mg, 74% yield) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.23 (3H, s), 1.31 (3H, s), 1.48 (9H, s), 1.54 (9H, s), 1.72 (3H, s), 1.76 (3H, s ), 2.62 (1H, dd, J = 15.9, 11.2 Hz), 2.97-3.02 (2H, m), 4.73-4.88 (4H, m), 5.08 (1H, d, J = 4.6 Hz), 5.37-5.42 ( 1H, m), 5.67 (1H, dd, J = 8.4, 4.6 Hz), 7.37 (1H, s), 8.06 (1H, s), 8.66 (1H, d, J = 8.4 Hz).

Step 7 Synthesis of Compound I-45 After cooling a solution of Compound 45l (407 mg, 0.55 mmol) in dichloromethane (4 mL) to −40 ° C., anisole (0.48 mL, 4.4 mmol), 2 mol / L aluminum chloride / nitromethane The solution (2.2 mL, 4.4 mmol) was added in order and stirred at −30 ° C. for 30 minutes. Diisopropyl ether, ice water, and acetonitrile were added to the reaction solution and stirred to completely dissolve insoluble matters, and then the aqueous layer was separated. After the organic layer was extracted again with water, all aqueous layers were combined, HP20-SS resin was added, acetonitrile was distilled off under reduced pressure, and 2 mol / L hydrochloric acid (1.0 mL) was added. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected and added to a 0.2 mol / L aqueous sodium hydroxide solution pH = 5.5, followed by a small amount of dry ice. The resulting solution was concentrated under reduced pressure and lyophilized to obtain I-45 (180 mg, yield 59%) as a white powder.
1 H-NMR (D 2 O) δ: 1.26 (3H, s), 1.29 (3H, s), 2.84-2.97 (2H, m), 3.13 (1H, dd, J = 13.3, 4.1 Hz), 4.58 ( 2H, s), 5.24 (1H, d, J = 4.6 Hz), 5.62 (1H, d, J = 4.6 Hz), 7.06 (1H, s).
MS (m + 1) = 514.05, retention time: 0.71 minutes, measurement condition 1
Elemental analysis: C18H17N5Na2O9S2 (H2O) 3.0
Calculated values: C, 35.36; H, 3.79; N, 11.45; Na, 7.52; S, 10.49 (%)
Found: C, 35.34; H, 3.83; N, 11.62; Na, 7.38; S, 10.48 (%)
　化合物Ｉ－４６の合成 　
Figure JPOXMLDOC01-appb-C000183
 化合物４６ａを用いて、実施例１９の工程５～７と同様にして化合物Ｉ－４６を合成した。
1H-NMR (D2O) δ: 1.33 (3H, s), 1.34 (3H, s), 2.88 (1H, dd, J = 7.4, 4.5 Hz), 3.00 (1H, dd, J = 14.7, 7.4 Hz), 3.14 (1H, dd, J = 14.7, 4.5 Hz), 4.57 (2H, s), 5.38 (1H, d, J = 4.1 Hz), 5.47 (1H, d, J = 4.1 Hz), 7.14 (1H, s).
MS (m+1) = 514.02、保持時間：0.58分、測定条件１
元素分析：C18H17N5Na2O9S2(H2O)2.5(NaHCO3)0.1
計算値：C,35.59; H,3.65; N,11.46; Na,7.90; S,10.50 (%)
実測値：C,35.53; H,3.70; N,11.55; Na,7.88; S,10.53 (%)
Synthesis of Compound I-46
Figure JPOXMLDOC01-appb-C000183
 Compound I-46 was synthesized in the same manner as in Steps 5 to 7 of Example 19 using Compound 46a.
1 H-NMR (D 2 O) δ: 1.33 (3H, s), 1.34 (3H, s), 2.88 (1H, dd, J = 7.4, 4.5 Hz), 3.00 (1H, dd, J = 14.7, 7.4 Hz), 3.14 (1H, dd, J = 14.7, 4.5 Hz), 4.57 (2H, s), 5.38 (1H, d, J = 4.1 Hz), 5.47 (1H, d, J = 4.1 Hz), 7.14 ( 1H, s).
MS (m + 1) = 514.02, retention time: 0.58 minutes, measurement condition 1
Elemental analysis: C18H17N5Na2O9S2 (H2O) 2.5 (NaHCO3) 0.1
Calculated value: C, 35.59; H, 3.65; N, 11.46; Na, 7.90; S, 10.50 (%)
Found: C, 35.53; H, 3.70; N, 11.55; Na, 7.88; S, 10.53 (%)
　化合物Ｉ－４７の合成 　
Figure JPOXMLDOC01-appb-C000184
工程１　化合物４７ｃの合成
化合物４７ａ（７．３８ｇ、３４ｍｍｏｌ）に、無水酢酸（２４．１ｍＬ、２５５ｍｍｏｌ）を加え、室温で終夜攪拌した。反応混合物を減圧濃縮することにより化合物４７ｂを得た。得られた４７ｂは精製せずにそのまま次の反応に用いた。
　得られた４７ｂ全量にｐ－メトキシベンジルアルコール（２３．５ｇ、１７０ｍｍｏｌ）を加え、５０℃で４時間半攪拌した。反応混合物を氷冷した後、冷却した１０％炭酸ナトリウム水溶液をｐＨ＝９まで滴下した。氷冷下でしばらく攪拌した後、酢酸エチルを加え、水層を分取した。分取した水層に２ｍｏｌ／Ｌ塩酸をｐＨ＝２まで加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮することにより化合物４７ｃ（９．４２ｇ、収率８２％）を無色オイルとして得た。
1H-NMR (DMSO-D6) δ: 2.55-2.85 (2H, m), 3.75 (3H, s), 4.34-4.47 (3H, m), 5.03 (2H, d, J = 7.6 Hz), 5.16 (1H, d, J = 10.1 Hz), 5.27 (1H, d, J = 17.2 Hz), 5.84-5.93 (1H, m), 6.92 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.3 Hz).

工程２　化合物４７ｄの合成
化合物４７ｃ（２０．４ｇ、６０．６ｍｍｏｌ）のジクロロメタン（４００ｍＬ）溶液にトリフェニルホスホラニリデンアセトニトリル（１６．４ｇ、５４．５ｍｍｏｌ）、ＤＭＡＰ（０．７４ｇ、６．１ｍｍｏｌ）、ＥＤＣ塩酸塩（１２．８ｇ、６６．７ｍｍｏｌ）を順に加えた。室温で１時間攪拌した後、減圧濃縮し、残渣に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４７ｄ（１９．９５ｇ、収率５３％）を橙色フォームとして得た。
1H-NMR (CDCl3) δ: 3.07 (1H, dd, J = 16.7, 3.5 Hz), 3.59 (1H, dd, J = 16.5, 4.2 Hz), 3.78 (3H, s), 4.56 (2H, br s), 4.64 (1H, t, J = 4.3 Hz), 5.05 (2H, dd, J = 21.3, 12.0 Hz), 5.17 (1H, d, J = 10.1 Hz), 5.27 (1H, d, J = 17.2 Hz), 5.84-5.92 (1H, m), 5.99 (1H, d, J = 9.1 Hz), 6.82 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 7.8 Hz), 7.50-7.65 (15H, m).

工程３　化合物４７ｅの合成
化合物４７ｄ（２０．８ｇ、３３．５ｍｍｏｌ）のテトラヒドロフラン（２０８ｍＬ）溶液を減圧脱気した後、モルホリン（６．４２ｍＬ、７３．７ｍｍｏｌ）、Ｐｄ（ＰＰｈ３）４（１．９４ｇ、１．６８ｍｍｏｌ）を順に加えた。室温で１時間攪拌した後、Ｂｏｃ２Ｏ（２１．８ｍＬ、９４ｍｍｏｌ）を加えた。さらに室温で１時間半攪拌した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４７ｅ（２０．１２ｇ、収率９４％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.41 (9H, s), 3.03 (1H, d, J = 16.7 Hz), 3.58 (1H, d, J = 16.4 Hz), 3.78 (3H, s), 4.59 (1H, s), 5.04 (2H, s), 5.78 (1H, d, J = 8.6 Hz), 6.82 (2H, d, J = 7.8 Hz), 7.26 (2H, d, J = 7.3 Hz), 7.51-7.65 (15H, m).

工程４　化合物４７ｇの合成
　化合物４７ｅ（１８ｇ、２８．３ｍｍｏｌ）のジクロロメタン（３６０ｍＬ）溶液を、－７８℃でオゾンガスをバブリングしながら２時間半攪拌した。系内を窒素ガスで置換した後、ジメチルスルフィド（６．２７ｍＬ、８５ｍｍｏｌ）を加え、－７８℃で５分間攪拌した。次いで、３－メチル－２－ブテン－１－オール（４．３１ｍＬ、４２．４ｍｍｏｌ）を加え、－７８℃で１時間半攪拌した。反応混合物を０℃程度まで昇温した後、５％炭酸ナトリウム水溶液を加え、室温で５分間攪拌した。ジクロロメタンを減圧留去した後、酢酸エチルで抽出し、有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４７ｇ（４．２７ｇ、収率３４％）を無色オイルとして得た。
1H-NMR (CDCl3) δ: 1.41 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 3.81 (3H, s), 4.11-4.15 (3H, m), 4.66 (1H, s), 4.73 (2H, d, J = 7.3 Hz), 5.36-5.43 (3H, m), 6.87 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.1 Hz).

工程５　化合物Ｉ－４７の合成
化合物４７ｇから実施例１９の工程３～７と同様にして合成し、ジアステレオマー混合物として得た。
1H-NMR (D2O) δ: 2.62 (1H, d, J = 12.9 Hz), 2.98 (1H, dd, J = 14.8, 3.2 Hz), 3.13-3.26 (2H, m), 3.47 (1H, d, J = 14.4 Hz), 3.56 (1H, d, J = 9.9 Hz), 3.75 (1H, s), 4.69 (4H, d, J = 3.0 Hz), 5.19 (1H, d, J = 3.5 Hz), 5.28 (1H, d, J = 9.9 Hz), 5.38 (2H, br s), 5.50 (1H, d, J = 4.0 Hz), 7.13 (1H, s), 7.27 (1H, s).
MS (m+1) = 501.06、保持時間：0.45分、測定条件１
Synthesis of Compound I-47
Figure JPOXMLDOC01-appb-C000184
Step 1 Synthesis of Compound 47c To compound 47a (7.38 g, 34 mmol) was added acetic anhydride (24.1 mL, 255 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give compound 47b. The obtained 47b was used in the next reaction without purification.
P-Methoxybenzyl alcohol (23.5 g, 170 mmol) was added to the total amount of 47b obtained, and the mixture was stirred at 50 ° C. for 4 hours and a half. The reaction mixture was ice-cooled, and a cooled 10% aqueous sodium carbonate solution was added dropwise until pH = 9. After stirring for a while under ice cooling, ethyl acetate was added, and the aqueous layer was separated. 2 mol / L hydrochloric acid was added to the separated aqueous layer until pH = 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure to obtain Compound 47c (9.42 g, yield 82%) as a colorless oil.
1 H-NMR (DMSO-D 6 ) δ: 2.55-2.85 (2H, m), 3.75 (3H, s), 4.34-4.47 (3H, m), 5.03 (2H, d, J = 7.6 Hz), 5.16 (1H, d, J = 10.1 Hz), 5.27 (1H, d, J = 17.2 Hz), 5.84-5.93 (1H, m), 6.92 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.3 Hz).

Step 2 Synthesis of Compound 47d To a solution of Compound 47c (20.4 g, 60.6 mmol) in dichloromethane (400 mL) was added triphenylphosphoranylideneacetonitrile (16.4 g, 54.5 mmol), DMAP (0.74 g, 6.1 mmol). , EDC hydrochloride (12.8 g, 66.7 mmol) was added in turn. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 47d (19.95 g, 53% yield) as an orange foam.
1 H-NMR (CDCl 3 ) δ: 3.07 (1H, dd, J = 16.7, 3.5 Hz), 3.59 (1H, dd, J = 16.5, 4.2 Hz), 3.78 (3H, s), 4.56 (2H, br s), 4.64 (1H, t, J = 4.3 Hz), 5.05 (2H, dd, J = 21.3, 12.0 Hz), 5.17 (1H, d, J = 10.1 Hz), 5.27 (1H, d, J = 17.2 Hz), 5.84-5.92 (1H, m), 5.99 (1H, d, J = 9.1 Hz), 6.82 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 7.8 Hz), 7.50- 7.65 (15H, m).

Step 3 Synthesis of Compound 47e A solution of Compound 47d (20.8 g, 33.5 mmol) in tetrahydrofuran (208 mL) was degassed under reduced pressure, and then morpholine (6.42 mL, 73.7 mmol), Pd (PPh 3 ) 4 (1. 94 g, 1.68 mmol) was added in order. After stirring at room temperature for 1 hour, Boc 2 O (21.8 mL, 94 mmol) was added. The mixture was further stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 47e (20.12 g, 94% yield) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.41 (9H, s), 3.03 (1H, d, J = 16.7 Hz), 3.58 (1H, d, J = 16.4 Hz), 3.78 (3H, s), 4.59 ( 1H, s), 5.04 (2H, s), 5.78 (1H, d, J = 8.6 Hz), 6.82 (2H, d, J = 7.8 Hz), 7.26 (2H, d, J = 7.3 Hz), 7.51- 7.65 (15H, m).

Step 4 Synthesis of Compound 47g A solution of compound 47e (18 g, 28.3 mmol) in dichloromethane (360 mL) was stirred at −78 ° C. while bubbling ozone gas for 2.5 hours. The system was replaced with nitrogen gas, dimethyl sulfide (6.27 mL, 85 mmol) was added, and the mixture was stirred at −78 ° C. for 5 minutes. Subsequently, 3-methyl-2-buten-1-ol (4.31 mL, 42.4 mmol) was added, and the mixture was stirred at −78 ° C. for 1.5 hours. The temperature of the reaction mixture was raised to about 0 ° C., 5% aqueous sodium carbonate solution was added, and the mixture was stirred at room temperature for 5 minutes. Dichloromethane was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 47 g (4.27 g, yield 34%) of the compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.41 (9H, s), 1.73 (3H, s), 1.77 (3H, s), 3.81 (3H, s), 4.11-4.15 (3H, m), 4.66 (1H , s), 4.73 (2H, d, J = 7.3 Hz), 5.36-5.43 (3H, m), 6.87 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.1 Hz).

Step 5 Synthesis of Compound I-47 The compound I-47 was synthesized from 47 g of the compound in the same manner as in Steps 3 to 7 of Example 19 to obtain a diastereomer mixture.
1 H-NMR (D 2 O) δ: 2.62 (1H, d, J = 12.9 Hz), 2.98 (1H, dd, J = 14.8, 3.2 Hz), 3.13-3.26 (2H, m), 3.47 (1H, d, J = 14.4 Hz), 3.56 (1H, d, J = 9.9 Hz), 3.75 (1H, s), 4.69 (4H, d, J = 3.0 Hz), 5.19 (1H, d, J = 3.5 Hz) , 5.28 (1H, d, J = 9.9 Hz), 5.38 (2H, br s), 5.50 (1H, d, J = 4.0 Hz), 7.13 (1H, s), 7.27 (1H, s).
MS (m + 1) = 501.06, Retention time: 0.45 minutes, Measurement condition 1
　化合物Ｉ－４８の合成　
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000186
工程１　化合物４８ｂの合成
ｔｅｒｔ－ブチル　２－クロロ－２－オキソアセテート（３０．４ｇ、１８５ｍｍｏｌ）のジクロロメタン（３００ｍＬ）溶液に、氷冷下で塩化カルシウム（４１．０ｇ、３６９ｍｍｏｌ）を加え、化合物４８ａ（３０．０ｇ、１０３ｍｍｏｌ、合成法はＤＥ２１３８３２０Ａ１に記載。）とジイソプロピルエチルアミン（３２．３ｍＬ、１８５ｍｍｏｌ）のジクロロメタン（１５０ｍＬ）溶液を加えた。－５℃で３０分間攪拌した後、濾過をし、得られた濾液に水を加え、ジクロロメタンで抽出した。有機層を、８．４％炭酸水素ナトリウム水溶液、水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４８ｂ（１４．１３ｇ、収率３２．７％）を黄色フォームとして得た。
1H-NMR (CDCl3) δ: 1.55 (9H, s), 2.24 (3H, s), 3.60 (1H, d, J = 16.7 Hz), 3.68 (2H, s), 3.78 (1H, d, J = 16.6 Hz), 5.40 (1H, d, J = 6.4 Hz), 5.46 (1H, dd, J = 8.3, 6.5 Hz), 6.55 (1H, d, J = 8.4 Hz), 7.29-7.38 (5H, m).

工程２　化合物４８ｄおよび４８ｅの合成
化合物４８ｂ（７ｇ、１６．６５ｍｍｏｌ）のテトラヒドロフラン（３５０ｍＬ）溶液に対して減圧脱気を３回繰り返し行った後、－７８℃で０．１ｍｏｌ／Ｌヨウ化サマリウム（テトラヒドロフラン溶液、３５０ｍＬ，３５０ｍｍｏｌ）を４０分間かけて滴下する。－７８℃で５分間撹拌した後、酢酸エチル（８００ｍＬ）、氷冷した８．４％炭酸水素ナトリウム水溶液（５００ｍＬ）を加え、セライト濾過をし、得られた濾液を酢酸エチルで抽出した。有機層を、水、飽和塩化ナトリウム水溶液で順に洗浄し、無水硫酸ナトリウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４８ｃ（４．０７ｇ、収率５７．９％）を黄色フォームとして得た。
化合物４８ｃ（４．０７ｇ、９．６３ｍｍｏｌ）のジクロロメタン（１５１ｍＬ）溶液に、－２０℃でピリジン（５．４４ｍＬ、６７．４ｍｍｏｌ）を加え、トリホスゲン（２．８６ｇ、９．６３ｍｍｏｌ）をゆっくり投入した。－２０℃で１時間撹拌した後、氷水を加え、酢酸エチルで抽出した。有機層を、１ｍｏｌ／Ｌ塩酸、８．４％炭酸水素ナトリウム水溶液、水、飽和塩化ナトリウム水溶液で順に洗浄し、無水硫酸ナトリウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４８ｄ（６５８．２ｍｇ、収率１５．２％）を黄色フォームとして得、化合物４８ｅ（１．１３ｇ、収率２６．２％）を黄色フォームとして得た。
化合物４８ｄ
1H-NMR (CDCl3) δ: 1.55 (9H, s), 1.58 (3H, s), 2.90 (1H, d, J = 14.6 Hz), 3.18 (1H, d, J = 14.4 Hz), 3.68 (2H, s), 4.98 (1H, d, J = 4.5 Hz), 5.21 (1H, dd, J = 8.2, 4.5 Hz), 6.03 (1H, d, J = 7.9 Hz), 7.31-7.38 (5H, m).
化合物４８ｅ
1H-NMR (CDCl3) δ: 1.54 (3H, s), 1.54 (9H, s), 3.07 (2H, dd, J = 17.9, 15.2 Hz), 3.65 (2H, dd, J = 21.3, 15.8 Hz), 5.09 (1H, d, J = 4.6 Hz), 5.57 (1H, dd, J = 8.4, 4.6 Hz), 6.24 (1H, d, J = 8.3 Hz), 7.27-7.40 (5H, m).

工程３　化合物４８ｇの合成
五塩化リン（６１１ｍｇ、２．９４ｍｍｏｌ）のジクロロメタン（３．３ｍＬ）懸濁液を－７８℃まで冷却した後、ピリジン（０．２６１ｍＬ、３．２ｍｍｏｌ）を加え、次いで化合物４８ｄ（６５８．２ｍｇ、１．４７ｍｍｏｌ）のジクロロメタン（３．３ｍＬ）溶液を滴下した。－１０℃で２時間攪拌した後、反応混合物を－７８℃まで冷却し、エタノール（３．３ｍＬ）を加えた。－３０℃で１．５時間攪拌した後、反応混合物に氷冷した８．４％炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥した後、無機物をろ過により除いた。ろ液に酢酸エチルを加え、ジクロロメタン及びエタノールを減圧留去することにより酢酸エチル溶液Ａを得た。
化合物４８ｆ（７０７ｍｇ、１．７６ｍｍｏｌ）のジメチルアセトアミド（２．４ｍＬ）溶液を－２０℃まで冷却した後、トリエチルアミン（０．３０５ｍＬ、２．２ｍｍｏｌ）メタンスルホニルクロリド（０．１６ｍＬ、２．０６ｍｍｏｌ）を加えた。－２０℃で３０分間攪拌することで、溶液Ｂを得た。
酢酸エチル溶液Ａに、氷冷下でピリジン（０．１４２ｍＬ、１．７６ｍｍｏｌ）、溶液Ｂを加えた。氷冷下で４０分間攪拌した後、希塩酸水を加え、酢酸エチルで抽出した。有機層を、８．４％炭酸水素ナトリウム水溶液、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物４８ｇ（４５３．７ｍｇ、収率４３．４％）を黄色オイルとして得た。
1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.54 (9H, s), 1.58 (9H, s), 1.63 (3H, s), 2.91 (1H, d, J = 14.4 Hz), 3.34 (1H, d, J = 14.6 Hz), 4.78 (2H, s), 5.11 (1H, d, J = 4.5 Hz), 5.37 (1H, dd, J = 7.8, 4.5 Hz), 7.43 (1H, s), 8.11 (1H, s), 8.71 (1H, d, J = 7.8 Hz).

工程４　化合物Ｉ－４８の合成
化合物４８ｇ（４５３．７ｍｇ、０．６４ｍｍｏｌ）のジクロロメタン（６．８ｍＬ）溶液を－３０℃まで冷却した後、アニソール（０．８３３ｍＬ、７．６３ｍｍｏｌ）と２ｍｏｌ／Ｌ塩化アルミニウム／ニトロメタン溶液（３．８１ｍＬ、７．６３ｍｍｏｌ）を順に加え、－３０℃で２０分間攪拌した。反応液にジイソプロピルエーテル、氷、アセトニトリルを順に加えて攪拌し、不溶物を完全に溶解させた後、水層を分取した。有機層を再度水で抽出した後、すべての水層を合せＨＰ２０－ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液に１Ｎ塩酸を加え、ＯＤＳカラムクロマトグラフィ（水－アセトニトリル）により精製した。所望の化合物を含む分画を集め、氷冷下で０．２ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加え、ｐＨが６．０のところでドライアイスをひとかけら加え、減圧濃縮した後、凍結乾燥することにより化合物Ｉ－４８（２１５．８ｍｇ、６２．２％収率）を白色粉末として得た。
1H-NMR (D2O) δ: 1.65 (3H, s), 3.19 (1H, d, J = 14.7 Hz), 3.36 (1H, d, J = 14.7 Hz), 4.58 (2H, s), 5.32 (1H, d, J = 4.4 Hz), 5.45 (1H, d, J = 4.3 Hz), 7.19 (1H, s).
ＭＳ（Ｍ＋１）＝５０２、保持時間：０．５９分、測定条件１
元素分析：C16H13N5Na2O10S2(H2O)4.5．
計算値C: 30.68%, H: 3.54%, N: 11.18%, S: 10.24%, Na: 7.34%．
実測値C: 30.72%, H: 3.45%, N: 11.36%, S: 9.94%, Na: 7.41%.
Synthesis of Compound I-48
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000186
Step 1 Synthesis of Compound 48b To a solution of tert-butyl 2-chloro-2-oxoacetate (30.4 g, 185 mmol) in dichloromethane (300 mL) was added calcium chloride (41.0 g, 369 mmol) under ice-cooling to give compound 48a (30.0 g, 103 mmol, the synthesis method is described in DE2138320A1) and diisopropylethylamine (32.3 mL, 185 mmol) in dichloromethane (150 mL) were added. After stirring at −5 ° C. for 30 minutes, filtration was performed, water was added to the obtained filtrate, and the mixture was extracted with dichloromethane. The organic layer was washed successively with an 8.4% aqueous sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 48b (14.13 g, yield 32.7%) as a yellow foam.
1 H-NMR (CDCl 3 ) δ: 1.55 (9H, s), 2.24 (3H, s), 3.60 (1H, d, J = 16.7 Hz), 3.68 (2H, s), 3.78 (1H, d, J = 16.6 Hz), 5.40 (1H, d, J = 6.4 Hz), 5.46 (1H, dd, J = 8.3, 6.5 Hz), 6.55 (1H, d, J = 8.4 Hz), 7.29-7.38 (5H, m ).

Step 2 Compound 48d and 48e Synthesis Compound 48b (7 g, 16.65 mmol) in tetrahydrofuran (350 mL) was repeatedly degassed under reduced pressure three times, and then at −78 ° C., 0.1 mol / L samarium iodide ( Tetrahydrofuran solution, 350 mL, 350 mmol) is added dropwise over 40 minutes. After stirring at −78 ° C. for 5 minutes, ethyl acetate (800 mL) and ice-cooled 8.4% aqueous sodium hydrogen carbonate solution (500 mL) were added, and the mixture was filtered through celite, and the resulting filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 48c (4.07 g, yield 57.9%) as a yellow foam.
To a solution of compound 48c (4.07 g, 9.63 mmol) in dichloromethane (151 mL) was added pyridine (5.44 mL, 67.4 mmol) at −20 ° C., and triphosgene (2.86 g, 9.63 mmol) was slowly added. . After stirring at −20 ° C. for 1 hour, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid, 8.4% aqueous sodium hydrogen carbonate solution, water, and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 48d (658.2 mg, 15.2% yield) as a yellow foam, compound 48e (1.13 g, yield 26). .2%) as a yellow foam.
Compound 48d
1H-NMR (CDCl3) δ: 1.55 (9H, s), 1.58 (3H, s), 2.90 (1H, d, J = 14.6 Hz), 3.18 (1H, d, J = 14.4 Hz), 3.68 (2H, s), 4.98 (1H, d, J = 4.5 Hz), 5.21 (1H, dd, J = 8.2, 4.5 Hz), 6.03 (1H, d, J = 7.9 Hz), 7.31-7.38 (5H, m).
Compound 48e
1H-NMR (CDCl3) δ: 1.54 (3H, s), 1.54 (9H, s), 3.07 (2H, dd, J = 17.9, 15.2 Hz), 3.65 (2H, dd, J = 21.3, 15.8 Hz), 5.09 (1H, d, J = 4.6 Hz), 5.57 (1H, dd, J = 8.4, 4.6 Hz), 6.24 (1H, d, J = 8.3 Hz), 7.27-7.40 (5H, m).

Step 3 Synthesis of Compound 48g After cooling a suspension of phosphorus pentachloride (611mg, 2.94mmol) in dichloromethane (3.3mL) to -78 ° C, pyridine (0.261mL, 3.2mmol) was added, and then compound A solution of 48d (658.2 mg, 1.47 mmol) in dichloromethane (3.3 mL) was added dropwise. After stirring at −10 ° C. for 2 hours, the reaction mixture was cooled to −78 ° C. and ethanol (3.3 mL) was added. After stirring at −30 ° C. for 1.5 hours, an ice-cooled 8.4% aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then inorganic substances were removed by filtration. Ethyl acetate was added to the filtrate, and dichloromethane and ethanol were distilled off under reduced pressure to obtain an ethyl acetate solution A.
A solution of compound 48f (707 mg, 1.76 mmol) in dimethylacetamide (2.4 mL) was cooled to −20 ° C., and then triethylamine (0.305 mL, 2.2 mmol) methanesulfonyl chloride (0.16 mL, 2.06 mmol) was added. added. Solution B was obtained by stirring at −20 ° C. for 30 minutes.
To ethyl acetate solution A, pyridine (0.142 mL, 1.76 mmol) and solution B were added under ice cooling. After stirring for 40 minutes under ice cooling, dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an 8.4% aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 48 g (453.7 mg, yield 43.4%) of a compound as a yellow oil.
1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.54 (9H, s), 1.58 (9H, s), 1.63 (3H, s), 2.91 (1H, d, J = 14.4 Hz), 3.34 ( 1H, d, J = 14.6 Hz), 4.78 (2H, s), 5.11 (1H, d, J = 4.5 Hz), 5.37 (1H, dd, J = 7.8, 4.5 Hz), 7.43 (1H, s), 8.11 (1H, s), 8.71 (1H, d, J = 7.8 Hz).

Step 4 Synthesis of Compound I-48 48 g (453.7 mg, 0.64 mmol) in dichloromethane (6.8 mL) was cooled to −30 ° C., then anisole (0.833 mL, 7.63 mmol) and 2 mol / L. An aluminum chloride / nitromethane solution (3.81 mL, 7.63 mmol) was sequentially added, and the mixture was stirred at −30 ° C. for 20 minutes. Diisopropyl ether, ice, and acetonitrile were added to the reaction solution in this order and the mixture was stirred to completely dissolve insoluble matter, and then the aqueous layer was separated. The organic layer was extracted again with water, all the aqueous layers were combined, HP20-SS resin was added, and acetonitrile was distilled off under reduced pressure. 1N Hydrochloric acid was added to the obtained mixed liquid, and the mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound were collected, 0.2 mol / L aqueous sodium hydroxide solution was added under ice cooling, a portion of dry ice was added at pH 6.0, the solution was concentrated under reduced pressure, and then freeze-dried. Compound I-48 (215.8 mg, 62.2% yield) was obtained as a white powder.
1H-NMR (D2O) δ: 1.65 (3H, s), 3.19 (1H, d, J = 14.7 Hz), 3.36 (1H, d, J = 14.7 Hz), 4.58 (2H, s), 5.32 (1H, d, J = 4.4 Hz), 5.45 (1H, d, J = 4.3 Hz), 7.19 (1H, s).
MS (M + 1) = 502, retention time: 0.59 minutes, measurement condition 1
Elemental analysis: C16H13N5Na2O10S2 (H2O) 4.5.
Calculated C: 30.68%, H: 3.54%, N: 11.18%, S: 10.24%, Na: 7.34%.
Found C: 30.72%, H: 3.45%, N: 11.36%, S: 9.94%, Na: 7.41%.
　化合物Ｉ－４９の合成　
Figure JPOXMLDOC01-appb-C000187
工程１　化合物Ｉ－４９の合成
実施例２２の工程２で得た化合物４８ｅを用いて、実施例２２の工程３、４と同様にして、化合物Ｉ－４９（１７８．３ｍｇ、１８．２％収率（２工程））を黄色固体として得た。
1H-NMR (D2O) δ: 1.57 (3H, s), 3.41 (2H, s), 4.58 (2H, s), 5.42 (1H, d, J = 4.5 Hz), 5.46 (1H, d, J = 4.4 Hz), 7.08 (1H, s).
ＭＳ（Ｍ＋１）＝５０２、保持時間０．４７分、測定条件１
元素分析：C16H13N5Na2O10S2(H2O)3.8.
計算値C: 31.31%, H: 3.38%, N: 11.41%, S: 10.45%, Na: 7.49%．
実測値C: 31.29%, H: 3.29%, N: 11.56%, S: 10.25%, Na: 7.61%.
Synthesis of Compound I-49
Figure JPOXMLDOC01-appb-C000187
Step 1 Synthesis of Compound I-49 Compound I-49 (178.3 mg, 18.2% yield) was obtained in the same manner as in Steps 3 and 4 of Example 22 using Compound 48e obtained in Step 2 of Example 22. Rate (2 steps)) was obtained as a yellow solid.
1H-NMR (D2O) δ: 1.57 (3H, s), 3.41 (2H, s), 4.58 (2H, s), 5.42 (1H, d, J = 4.5 Hz), 5.46 (1H, d, J = 4.4 Hz), 7.08 (1H, s).
MS (M + 1) = 502, retention time 0.47 minutes, measurement condition 1
Elemental analysis: C16H13N5Na2O10S2 (H2O) 3.8.
Calculated C: 31.31%, H: 3.38%, N: 11.41%, S: 10.45%, Na: 7.49%.
Found C: 31.29%, H: 3.29%, N: 11.56%, S: 10.25%, Na: 7.61%.
　化合物Ｉ－５０の合成　
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000189
工程１　化合物５０ｊの合成
Ｊｏｕｎａｌ　ｏｆ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ，　Ｐｅｒｋｉｎ　Ｔｒａｎｓａｃｔｉｏｎｓ　１：　Ｏｒｇａｎｉｃ ａｎｄ　Ｂｉｏ－Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ　（１９７２－１９９９）　（１９９５），　（５）， ４３２－４３８.に記載されている方法を用いて合成した化合物５０ｉを用いて、実施例２２の工程１と同様にして、化合物５０ｊ（２１．５４ｇ、４０．０％収率）を白色固体として得た。
1H-NMR (CDCl3) δ: 1.56 (9H, s), 3.26 (1H, dd, J = 13.7, 5.9 Hz), 3.56 (1H, dd, J = 13.7, 8.5 Hz), 3.68 (2H, d, J = 5.7 Hz), 5.17 (1H, d, J = 9.8 Hz), 5.24 (1H, dd, J = 16.9, 1.1 Hz), 5.36 (1H, d, J = 6.4 Hz), 5.62 (1H, dd, J = 9.0, 6.5 Hz), 5.66-5.75 (1H, m), 6.01 (1H, d, J = 8.8 Hz), 7.27-7.41 (5H, m).

工程２　化合物５０ｍおよび５０ｎの合成
化合物５０ｊ（２１．０ｇ、５１．９ｍｍｏｌ）のジクロロメタン（４２０ｍＬ）溶液に、－７８℃でオゾンガスを吹き込みながら、４０分間撹拌する。得られた青色溶液に窒素を５分間吹き込み、ジメチルスルフィド（１１．５ｍＬ，１５６ｍｍｏｌ）を加え、－７８℃で１５分間撹拌し、０℃で１時間撹拌し、氷水を加え、酢酸エチルで抽出した。有機層は、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮し、化合物５０ｋ（２２．９８ｇ）を粗生成物として得た。
化合物５０ｋ（２２．９８ｇ）を用いて、実施例２２の工程２と同様にして、化合物５０ｍ（１．０２ｇ、４．７%収率）を黄色フォームとして、化合物５０ｎ（７６５．６ｍｇ、３．５%収率）を黄色フォームとして得た。
化合物５０ｍ
1H-NMR (CDCl3) δ: 1.54 (9H, s), 2.84 (1H, dd, J = 15.2, 5.6 Hz), 2.99 (1H, dd, J = 15.2, 3.0 Hz), 3.68 (2H, s), 4.98 (1H, d, J = 4.3 Hz), 5.25 (1H, dd, J = 5.3, 3.0 Hz), 5.34 (1H, dd, J = 7.8, 4.5 Hz), 6.03 (1H, d, J = 7.6 Hz), 7.28-7.39 (5H, m).
化合物５０ｎ
1H-NMR (CDCl3) δ: 1.56 (9H, s), 3.01-3.08 (2H, m), 3.66 (2H, dd, J = 21.5, 16.2 Hz), 4.77 (1H, dd, J = 5.4, 3.9 Hz), 4.98 (1H, d, J = 4.5 Hz), 5.28-5.32 (1H, m), 5.58 (1H, dd, J = 8.2, 4.7 Hz), 6.18 (1H, d, J = 8.6 Hz), 7.29-7.38 (5H, m).

工程３　化合物Ｉ－５０の合成
実施例２２の工程３～４と同様にして、化合物５０ｍを用いて、化合物Ｉ－５０（１６９．９ｍｇ、２７．３％収率（２工程））を黄色固体として得た。
1H-NMR (D2O) δ: 3.15 (1H, dd, J = 15.2, 5.6 Hz), 3.32 (1H, dd, J = 14.9, 2.8 Hz), 4.58 (2H, s), 5.31 (1H, d, J = 4.3 Hz), 5.40 (1H, dd, J = 5.7, 2.9 Hz), 5.49 (1H, d, J = 4.3 Hz), 7.17 (1H, s).
ＭＳ（Ｍ＋１）＝４８８、保持時間：０．５７分、測定条件１
元素分析：C15H11N5Na2O10S2(H2O)4.1 ．
計算値C: 29.77%, H: 3.20%, N: 11.57%, S: 10.59%, Na: 7.60%．
実測値C: 29.76%, H: 3.16%, N: 11.56%, S: 10.37%, Na: 7.67%．
Synthesis of Compound I-50
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000189
Step 1 Synthesis of Compound 50j Journal of Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1995), (5), 432-438. Compound 50j (21.54 g, 40.0% yield) was obtained as a white solid in the same manner as in Step 1 of Example 22 using 50i.
1H-NMR (CDCl3) δ: 1.56 (9H, s), 3.26 (1H, dd, J = 13.7, 5.9 Hz), 3.56 (1H, dd, J = 13.7, 8.5 Hz), 3.68 (2H, d, J = 5.7 Hz), 5.17 (1H, d, J = 9.8 Hz), 5.24 (1H, dd, J = 16.9, 1.1 Hz), 5.36 (1H, d, J = 6.4 Hz), 5.62 (1H, dd, J = 9.0, 6.5 Hz), 5.66-5.75 (1H, m), 6.01 (1H, d, J = 8.8 Hz), 7.27-7.41 (5H, m).

Step 2 A solution of compound 50m and 50n in 50 ml of synthetic compound 50j (21.0 g, 51.9 mmol) in dichloromethane (420 mL) is stirred for 40 minutes while blowing ozone gas at −78 ° C. Nitrogen was blown into the obtained blue solution for 5 minutes, dimethyl sulfide (11.5 mL, 156 mmol) was added, and the mixture was stirred at −78 ° C. for 15 minutes, stirred at 0 ° C. for 1 hour, added with ice water, and extracted with ethyl acetate. . The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Compound 50k (22.98 g) as a crude product.
Using compound 50k (22.98 g) in the same manner as in Step 2 of Example 22, compound 50m (1.02 g, 4.7% yield) as yellow foam, compound 50n (765.6 mg, 3. 5% yield) was obtained as a yellow foam.
Compound 50m
1H-NMR (CDCl3) δ: 1.54 (9H, s), 2.84 (1H, dd, J = 15.2, 5.6 Hz), 2.99 (1H, dd, J = 15.2, 3.0 Hz), 3.68 (2H, s), 4.98 (1H, d, J = 4.3 Hz), 5.25 (1H, dd, J = 5.3, 3.0 Hz), 5.34 (1H, dd, J = 7.8, 4.5 Hz), 6.03 (1H, d, J = 7.6 Hz) ), 7.28-7.39 (5H, m).
Compound 50n
1H-NMR (CDCl3) δ: 1.56 (9H, s), 3.01-3.08 (2H, m), 3.66 (2H, dd, J = 21.5, 16.2 Hz), 4.77 (1H, dd, J = 5.4, 3.9 Hz ), 4.98 (1H, d, J = 4.5 Hz), 5.28-5.32 (1H, m), 5.58 (1H, dd, J = 8.2, 4.7 Hz), 6.18 (1H, d, J = 8.6 Hz), 7.29 -7.38 (5H, m).

Step 3 Synthesis of Compound I-50 In the same manner as in Steps 3 to 4 of Example 22, using Compound 50m, Compound I-50 (169.9 mg, 27.3% yield (2 steps)) was obtained as a yellow solid. Got as.
1H-NMR (D2O) δ: 3.15 (1H, dd, J = 15.2, 5.6 Hz), 3.32 (1H, dd, J = 14.9, 2.8 Hz), 4.58 (2H, s), 5.31 (1H, d, J = 4.3 Hz), 5.40 (1H, dd, J = 5.7, 2.9 Hz), 5.49 (1H, d, J = 4.3 Hz), 7.17 (1H, s).
MS (M + 1) = 488, retention time: 0.57 minutes, measurement condition 1
Elemental analysis: C15H11N5Na2O10S2 (H2O) 4.1.
Calculated C: 29.77%, H: 3.20%, N: 11.57%, S: 10.59%, Na: 7.60%.
Found C: 29.76%, H: 3.16%, N: 11.56%, S: 10.37%, Na: 7.67%.
　化合物Ｉ－５１の合成　
Figure JPOXMLDOC01-appb-C000190
工程１　化合物Ｉ－５１の合成
実施例２２の工程３～４と同様にして、実施例２４の工程２で得られた化合物５０ｎを用いて、化合物Ｉ－５１（４０．０ｍｇ、８．５％収率（２工程））を黄色固体として得た。
1H-NMR (D2O) δ: 3.42-3.47 (2H, m), 4.58 (2H, s), 5.09 (1H, dd, J = 3.2, 1.6 Hz), 5.34 (1H, d, J = 4.5 Hz), 5.52 (1H, d, J = 4.3 Hz), 7.08 (1H, s).
ＭＳ（Ｍ＋１）＝４８８、保持時間：０．４４分、測定条件１
元素分析：C15H11N5Na2O10S2(H2O)4.3(NaHCO3)0.2 ．
計算値C: 29.18%, H: 3.19%, N: 11.19%, S: 10.25%, Na: 8.08%．
実測値C: 29.43%, H: 3.24%, N: 11.27%, S: 9.96%, Na: 8.19%.
Synthesis of Compound I-51
Figure JPOXMLDOC01-appb-C000190
Step 1 Synthesis of Compound I-51 In the same manner as in Steps 3 to 4 of Example 22, using Compound 50n obtained in Step 2 of Example 24, Compound I-51 (40.0 mg, 8.5%) was prepared. Yield (2 steps)) was obtained as a yellow solid.
1H-NMR (D2O) δ: 3.42-3.47 (2H, m), 4.58 (2H, s), 5.09 (1H, dd, J = 3.2, 1.6 Hz), 5.34 (1H, d, J = 4.5 Hz), 5.52 (1H, d, J = 4.3 Hz), 7.08 (1H, s).
MS (M + 1) = 488, retention time: 0.44 minutes, measurement condition 1
Elemental analysis: C15H11N5Na2O10S2 (H2O) 4.3 (NaHCO3) 0.2.
Calculated C: 29.18%, H: 3.19%, N: 11.19%, S: 10.25%, Na: 8.08%.
Found C: 29.43%, H: 3.24%, N: 11.27%, S: 9.96%, Na: 8.19%.
化合物Ｉ－５２の合成 　
Figure JPOXMLDOC01-appb-C000191
工程１　化合物５２ｂの合成
メルドラム酸５２ａ（３０．０ｇ、２０８ｍｍｏｌ）のジクロロメタン（３００ｍＬ）溶液を氷冷した後、ピリジン（３３．６ｍＬ、４１６ｍｍｏｌ）を加え、次いで２－ブロモプロピオニルブロミド（２４．０ｍＬ、２２９ｍｍｏｌ）を加えた。氷冷下で３０分間攪拌した後、１ｍｏｌ／Ｌ塩酸を加えジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮した。得られた茶色のオイルをｔ－ブチルアルコール（２２５ｍＬ）に溶解し、８０℃で４５分間撹拌したのち溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５２ｂ（４１．５ｇ、８０％）を得た。５２ｂはケト体：エノール体＝４．５：１の混合物として得られた。
ケト体: 1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.77 (3H, d, J = 6.8 Hz), 3.54 (1H, d, J = 15.9 Hz), 3.77 (1H, d, J = 15.9 Hz), 4.62 (1H, q, J = 6.8 Hz).
エノール体: 1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.83 (3H, d, J = 6.8 Hz), 4.43 (1H, q, J = 6.8 Hz), 5.16 (1H, s), 12.23 (1H, s).

工程２　化合物５２ｃの合成
化合物５２ｂ（４１．５ｇ、１６５ｍｍｏｌ）のジオキサン（２１５ｍＬ）溶液に酸化セレン（ＩＶ）（４０．４ｇ、３６４ｍｍｏｌ）を加え、８０℃で１、５時間撹拌した。反応液を室温に冷却後、不溶物をセライトでろ過し、酢酸エチルで洗浄した。溶媒を減圧留去した後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５２ｃ（２１．３ｇ、４６％）を得た。
1H-NMR (CDCl3) δ: 1.52 (9H, s), 1.82 (3H, d, J = 6.8 Hz), 4.77 (1H, s), 4.86 (1H, q, J = 6.8 Hz), 4.99 (1H, s).

工程３　化合物５２ｅ、５２ｆの合成
　化合物５２ｄ (３．１９ｇ、１３．５ｍｍｏｌ)と化合物５２ｃ (３．８２ｇ、１３．５ｍｍｏｌ)をアセトン（３８ｍＬ）に溶解し、ＨＭＰＡ（１５．７ｍＬ、９０．０ｍｍｏｌ）を加えて室温で１５分間撹拌した。反応液を氷冷した後、トリエチルアミン（２．０６ｍＬ、１４．８ｍｍｏｌ）を加え、０℃で３０分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５２ｅ（２．１８ｇ、３８％）、５２ｆ（４８３ｍｇ、８．５％）を得た。
５２ｅ：1H-NMR (CDCl3) δ: 1.26 (3H, d, J = 6.3 Hz), 1.49 (9H, s), 3.74 (2H, s), 4.15 (1H, q, J = 6.3 Hz), 4.42 (1H, s), 4.99-5.08 (2H, m), 5.99 (1H, d, J = 7.1 Hz), 7.31-7.43 (5H, m).
５２ｆ：1H-NMR (CDCl3) δ: 1.36 (3H, d, J = 6.8 Hz), 1.47 (9H, s), 3.64 (1H, d, J = 16.2 Hz), 3.68 (1H, d, J = 16.2 Hz), 4.04 (1H, q, J = 6.8 Hz), 4.70 (1H, s), 5.48 (1H, dd, J = 8.6, 4.5 Hz), 5.52 (1H, d, J = 4.5 Hz), 5.88 (1H, d, J = 8.6 Hz), 7.24-7.41 (5H, m).

工程４　化合物５２ｇの合成
化合物５２ｅ(５．５４ｇ、１３．２ｍｍｏｌ)のジクロロメタン（５５ｍＬ）溶液を氷冷した後、ブロモアセチルブロミド（２．０６ｍＬ、２３．７ｍｍｏｌ）を加え、次いでトリエチルアミン（３．２９ｍＬ、２３．７ｍｍｏｌ）を加えた。氷冷下で２時間攪拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５２ｇ（４．２１ｇ、５９％）を得た。
1H-NMR (CDCl3) δ: 1.32 (3H, d, J = 6.7 Hz), 1.48 (9H, s), 3.73 (2H, s), 4.01 (1H, d, J = 13.6 Hz), 4.02 (1H, d, J = 13.6 Hz), 4.26 (1H, q, J = 6.7 Hz), 5.07-5.13 (2H, m), 6.03 (1H, m), 7.29-7.43 (5H, m).

工程５　化合物５２ｈの合成
化合物５２ｇ（４．２１ｇ、７．７８ｍｍｏｌ）のＤＭＦ（４２ｍＬ）溶液にトリフェニルホスフィン（２．４５ｇ、９．３３ｍｍｏｌ）を加えた。室温下１、５時間撹拌した後、８．４％炭酸水素ナトリウム水溶液（２０．０ｍＬ、２０．０ｍｍｏｌ）を加えた。室温下２０分間撹拌した後、反応混合物に水と酢酸エチルを加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５２ｈ（１．７６ｇ、５１％）を得た。
1H-NMR (CDCl3) δ: 1.44 (9H, s), 1.65 (3H, d, J = 6.6 Hz), 3.65 (1H, d, J = 16.7 Hz), 3.66 (1H, d, J = 16.7 Hz), 4.13 (1H, m), 5.04 (1H, d, J = 4.3 Hz), 5.60 (1H, dd, J = 9.1, 4.3 Hz), 6.10 (1H, m), 6.19 (1H, d, J = 9.1 Hz), 7.24-7.42 (5H, m).
[M+Na]＝467.00

工程６　化合物５２ｉの合成
　化合物５２ｈ（３６０ｍｇ、０．８１０ｍｍｏｌ）のメタノール（１０．５ｍＬ）溶液を－５０℃に冷却し、水素化ホウ素ナトリウム（９２．０ｍｇ、２．４３ｍｍｏｌ）を加えた。－５０℃で４．５時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５２ｉ（２１６ｍｇ、６０％）を得た。
1H-NMR (CDCl3) δ: 1.12 (3H, d, J = 6.9 Hz), 1.53 (9H, s), 2.60 (1H, dd, J = 18.6, 10.2 Hz), 3.12 (1H, dd, J = 18.6, 8.5 Hz), 3.21 (1H, qd, J = 6.9, 2.6 Hz), 3.34 (1H, ddd, J = 10.2, 8.5, 2.6 Hz), 3.69 (2H, s), 4.84 (1H, d, J = 4.4 Hz), 5.35 (1H, dd, J = 8.4, 4.4 Hz), 6.11 (1H, d, J = 8.4 Hz), 7.28-7.41 (5H, m).
[M+Na]＝469.10

工程７　化合物５２ｊの合成
五塩化リン（２１８ｍｇ、１．０５ｍｍｏｌ）のジクロロメタン（２．５ｍＬ）懸濁液に氷冷下ピリジン（０．０９３ｍＬ、１．１５ｍｍｏｌ）を加えた。反応混合物を－７８℃まで冷却した後、化合物５２ｉ（２３４ｍｇ、０．５２４ｍｍｏｌ）のジクロロメタン（２．５ｍＬ）を溶液を加えた。氷冷下３０分間攪拌した後、反応混合物を－７８℃まで冷却し、エタノール（２．５ｍＬ）を加えた。－３０℃で４５分間攪拌した後、水（０．９４４ｍＬ）を加えた。－３０℃で２５分間攪拌した後、反応混合物に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、ろ液をジクロロメタンが１０ｍＬ程度になるまで減圧留去して、５２ｊのジクロロメタン溶液を得た。

工程８　化合物５２ｌの合成
化合物５２ｋ（２１０ｍｇ、０．５２４ｍｍｏｌ）のＤＭＡ（１．５ｍＬ）溶液を－２０℃に冷却し、トリエチルアミン（０．１０２ｍＬ、０．７３４ｍｍｏｌ）およびメタンスルホニルクロリド（０．０５３ｍＬ、０．６８１ｍｍｏｌ）を加え、－２０℃で３０分間撹拌し、反応混合物Ａを得た。工程７で得た５２ｊのジクロロメタン溶液に氷冷下ピリジン（０．０５１ｍＬ、０．６２９ｍｍｏｌ）を加え、次いで反応混合物Ａを滴下した。０℃で４０分間攪拌した後、水を加え、ジクロロメタンを減圧留去した。酢酸エチルと２ｍｏｌ／Ｌ塩酸を加え、酢酸エチルで抽出し、有機層を水で洗浄した。有機層を無水硫酸マグネシウムにより乾燥し、硫酸マグネシウムをろ過した後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５２ｌ（３３４ｍｇ、９０％）を得た。
1H-NMR (CDCl3) δ: 1.19 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 1.54 (9H, s), 1.55 (9H, s), 2.64 (1H, dd, J = 18.4, 10.1 Hz), 3.22 (1H, dd, J = 18.4, 8.3 Hz), 3.38 (1H, m), 3.56 (1H, m), 4.76 (1H, d, J = 16.9 Hz), 4.78 (1H, d, J = 16.9 Hz), 4.97 (1H, d, J = 4.3 Hz), 5.52 (1H, dd, J = 8.1, 4.3 Hz), 7.44 (1H, s), 8.07 (1H, s), 8.69 (1H, d, J = 8.1 Hz).
[M+H]＝712.15

工程９　化合物Ｉ－５２の合成
　化合物５２ｌ（３３４ｍｇ、０．４６９ｍｍｏｌ)のジクロロメタン（７ｍＬ）溶液にアニソール（０．４１０ｍＬ、３．７５ｍｍｏｌ）および２ｍｏｌ／Ｌ塩化アルミニウム／ニトロメタン溶液（１．８８ｍＬ、３．７５ｍｍｏｌ）を加え－３０℃から－２３℃で３０分間撹拌した。反応混合物を氷水、２ｍｏｌ／Ｌ塩酸、アセトニトリルに溶解させた後、ジイソプロピルエーテルで洗浄した。水層にＨＰ２０‐ＳＳ樹脂を加えアセトニトリルを減圧留去した。得られた混合液をＯＤＳカラムクロマトグラフィー（水－アセトニトリル）により精製した。所望の化合物を含むフラクションを混合し、ｐＨメーターを用い０．１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（５．２ｍＬ）を氷冷下ゆっくり滴下し、ｐＨ５．０３になった時点でドライアイスの小片を加えると、ｐＨは４．８６となった。この混合液を減圧下濃縮した後、凍結乾燥することにより化合物Ｉ－５２（１６５ｍｇ、６５％)を得た。
1H-NMR (D2O) δ: 1.21 (3H, d, J = 6.9 Hz), 2.82 (1H, dd, J = 21.6, 12.8 Hz), 3.28-3.37 (2H, m), 3.70 (1H, qd, J = 6.9, 2.4 Hz), 4.59 (2H, s), 5.22 (1H, d, J = 4.1 Hz), 5.42 (1H, d, J = 4.1 Hz), 7.21 (1H, s).
[M+H]＝500、保持時間：０．９２分、測定条件２
C17H15.2N5O9S2Na1.8(H2O)3.6 計算値C : 33.81%, H : 3.74%, N : 11.60%, S : 10.62%, Na : 6.85%. 実測値C : 33.97%, H : 3.78%, N : 11.78%, S : 10.34%, Na : 6.99%.
Synthesis of Compound I-52
Figure JPOXMLDOC01-appb-C000191
Step 1 Synthesis of Compound 52b Meldrum acid 52a (30.0 g, 208 mmol) in dichloromethane (300 mL) was ice-cooled, pyridine (33.6 mL, 416 mmol) was added, and 2-bromopropionyl bromide (24.0 mL, 229 mmol) was added. After stirring for 30 minutes under ice cooling, 1 mol / L hydrochloric acid was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure. The obtained brown oil was dissolved in t-butyl alcohol (225 mL) and stirred at 80 ° C. for 45 minutes, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52b (41.5 g, 80%). 52b was obtained as a mixture of keto form: enol form = 4.5: 1.
Keto: 1H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.77 (3H, d, J = 6.8 Hz), 3.54 (1H, d, J = 15.9 Hz), 3.77 (1H, d, J = 15.9 Hz), 4.62 (1H, q, J = 6.8 Hz).
Enol: 1H-NMR (CDCl 3 ) δ: 1.50 (9H, s), 1.83 (3H, d, J = 6.8 Hz), 4.43 (1H, q, J = 6.8 Hz), 5.16 (1H, s), 12.23 (1H, s).

Step 2 Synthesis of Compound 52c Selenium oxide (IV) (40.4 g, 364 mmol) was added to a solution of compound 52b (41.5 g, 165 mmol) in dioxane (215 mL), and the mixture was stirred at 80 ° C. for 15 hours. The reaction solution was cooled to room temperature, and the insoluble material was filtered through celite and washed with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52c (21.3 g, 46%).
1H-NMR (CDCl 3 ) δ: 1.52 (9H, s), 1.82 (3H, d, J = 6.8 Hz), 4.77 (1H, s), 4.86 (1H, q, J = 6.8 Hz), 4.99 (1H , s).

Step 3 Synthesis of Compounds 52e and 52f Compound 52d (3.19 g, 13.5 mmol) and Compound 52c (3.82 g, 13.5 mmol) were dissolved in acetone (38 mL), and HMPA (15.7 mL, 90.0 mmol) was dissolved. And stirred at room temperature for 15 minutes. The reaction mixture was ice-cooled, triethylamine (2.06 mL, 14.8 mmol) was added, and the mixture was stirred at 0 ° C. for 30 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52e (2.18 g, 38%) and 52f (483 mg, 8.5%).
52e: 1H-NMR (CDCl 3 ) δ: 1.26 (3H, d, J = 6.3 Hz), 1.49 (9H, s), 3.74 (2H, s), 4.15 (1H, q, J = 6.3 Hz), 4.42 (1H, s), 4.99-5.08 (2H, m), 5.99 (1H, d, J = 7.1 Hz), 7.31-7.43 (5H, m).
52f: 1H-NMR (CDCl 3 ) δ: 1.36 (3H, d, J = 6.8 Hz), 1.47 (9H, s), 3.64 (1H, d, J = 16.2 Hz), 3.68 (1H, d, J = 16.2 Hz), 4.04 (1H, q, J = 6.8 Hz), 4.70 (1H, s), 5.48 (1H, dd, J = 8.6, 4.5 Hz), 5.52 (1H, d, J = 4.5 Hz), 5.88 (1H, d, J = 8.6 Hz), 7.24-7.41 (5H, m).

Step 4 Compound 52g Synthetic compound 52e (5.54 g, 13.2 mmol) in dichloromethane (55 mL) was ice-cooled, bromoacetyl bromide (2.06 mL, 23.7 mmol) was added, and then triethylamine (3.29 mL). 23.7 mmol). After stirring for 2 hours under ice cooling, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 52 g (4.21 g, 59%) of a compound.
1H-NMR (CDCl 3 ) δ: 1.32 (3H, d, J = 6.7 Hz), 1.48 (9H, s), 3.73 (2H, s), 4.01 (1H, d, J = 13.6 Hz), 4.02 (1H , d, J = 13.6 Hz), 4.26 (1H, q, J = 6.7 Hz), 5.07-5.13 (2H, m), 6.03 (1H, m), 7.29-7.43 (5H, m).

Step 5 Synthesis of Compound 52h Triphenylphosphine (2.45 g, 9.33 mmol) was added to a DMF (42 mL) solution of compound 52 g (4.21 g, 7.78 mmol). After stirring at room temperature for 1 to 5 hours, 8.4% aqueous sodium hydrogen carbonate solution (20.0 mL, 20.0 mmol) was added. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52h (1.76 g, 51%).
1H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 1.65 (3H, d, J = 6.6 Hz), 3.65 (1H, d, J = 16.7 Hz), 3.66 (1H, d, J = 16.7 Hz ), 4.13 (1H, m), 5.04 (1H, d, J = 4.3 Hz), 5.60 (1H, dd, J = 9.1, 4.3 Hz), 6.10 (1H, m), 6.19 (1H, d, J = 9.1 Hz), 7.24-7.42 (5H, m).
[M + Na] = 467.00

Step 6 Synthesis of Compound 52i A solution of compound 52h (360 mg, 0.810 mmol) in methanol (10.5 mL) was cooled to −50 ° C., and sodium borohydride (92.0 mg, 2.43 mmol) was added. After stirring at −50 ° C. for 4.5 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52i (216 mg, 60%).
1H-NMR (CDCl 3 ) δ: 1.12 (3H, d, J = 6.9 Hz), 1.53 (9H, s), 2.60 (1H, dd, J = 18.6, 10.2 Hz), 3.12 (1H, dd, J = 18.6, 8.5 Hz), 3.21 (1H, qd, J = 6.9, 2.6 Hz), 3.34 (1H, ddd, J = 10.2, 8.5, 2.6 Hz), 3.69 (2H, s), 4.84 (1H, d, J = 4.4 Hz), 5.35 (1H, dd, J = 8.4, 4.4 Hz), 6.11 (1H, d, J = 8.4 Hz), 7.28-7.41 (5H, m).
[M + Na] = 469.10

Step 7 Synthesis of Compound 52j Pyridine (0.093 mL, 1.15 mmol) was added to a suspension of phosphorus pentachloride (218 mg, 1.05 mmol) in dichloromethane (2.5 mL) under ice cooling. After the reaction mixture was cooled to −78 ° C., a solution of compound 52i (234 mg, 0.524 mmol) in dichloromethane (2.5 mL) was added. After stirring for 30 minutes under ice cooling, the reaction mixture was cooled to −78 ° C., and ethanol (2.5 mL) was added. After stirring at −30 ° C. for 45 minutes, water (0.944 mL) was added. After stirring at −30 ° C. for 25 minutes, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the magnesium sulfate was filtered. Then, the filtrate was distilled off under reduced pressure until the dichloromethane amounted to about 10 mL to obtain a 52j dichloromethane solution.

Step 8 Synthesis of Compound 52l Compound 52k (210 mg, 0.524 mmol) in DMA (1.5 mL) was cooled to −20 ° C. and triethylamine (0.102 mL, 0.734 mmol) and methanesulfonyl chloride (0.053 mL, 0.681 mmol) was added, and the mixture was stirred at −20 ° C. for 30 minutes to obtain a reaction mixture A. Pyridine (0.051 mL, 0.629 mmol) was added to the dichloromethane solution of 52j obtained in step 7 under ice-cooling, and then reaction mixture A was added dropwise. After stirring at 0 ° C. for 40 minutes, water was added and dichloromethane was distilled off under reduced pressure. Ethyl acetate and 2 mol / L hydrochloric acid were added, extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 52l (334 mg, 90%).
1H-NMR (CDCl 3 ) δ: 1.19 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 1.54 (9H, s), 1.55 (9H, s), 2.64 (1H, dd, J = 18.4, 10.1 Hz), 3.22 (1H, dd, J = 18.4, 8.3 Hz), 3.38 (1H, m), 3.56 (1H, m), 4.76 (1H, d, J = 16.9 Hz), 4.78 (1H, d, J = 16.9 Hz), 4.97 (1H, d, J = 4.3 Hz), 5.52 (1H, dd, J = 8.1, 4.3 Hz), 7.44 (1H, s), 8.07 (1H, s), 8.69 ( (1H, d, J = 8.1 Hz).
[M + H] = 712.15

Step 9 Synthesis of Compound I-52 To a solution of Compound 52l (334 mg, 0.469 mmol) in dichloromethane (7 mL) was added anisole (0.410 mL, 3.75 mmol) and 2 mol / L aluminum chloride / nitromethane solution (1.88 mL, 3. 75 mmol) was added, and the mixture was stirred at -30 ° C to -23 ° C for 30 minutes. The reaction mixture was dissolved in ice water, 2 mol / L hydrochloric acid, and acetonitrile, and then washed with diisopropyl ether. HP20-SS resin was added to the aqueous layer, and acetonitrile was distilled off under reduced pressure. The resulting mixture was purified by ODS column chromatography (water-acetonitrile). Fractions containing the desired compound are mixed, and 0.1 mol / L aqueous sodium hydroxide solution (5.2 mL) is slowly added dropwise under ice-cooling using a pH meter. When pH 5.03 is reached, a small piece of dry ice is added. The pH was 4.86. The mixture was concentrated under reduced pressure and lyophilized to give Compound I-52 (165 mg, 65%).
1H-NMR (D 2 O) δ: 1.21 (3H, d, J = 6.9 Hz), 2.82 (1H, dd, J = 21.6, 12.8 Hz), 3.28-3.37 (2H, m), 3.70 (1H, qd , J = 6.9, 2.4 Hz), 4.59 (2H, s), 5.22 (1H, d, J = 4.1 Hz), 5.42 (1H, d, J = 4.1 Hz), 7.21 (1H, s).
[M + H] = 500, retention time: 0.92 minutes, measurement condition 2
C17H15.2N5O9S2Na1.8 (H 2 O) 3.6 Calculated value C: 33.81%, H: 3.74%, N: 11.60%, S: 10.62%, Na: 6.85%. Actual value C: 33.97%, H: 3.78%, N: 11.78%, S: 10.34%, Na: 6.99%.
　化合物Ｉ－５３の合成 　
Figure JPOXMLDOC01-appb-C000192
工程１　化合物５３ｃの合成
化合物５３ａ（１３．８ｇ、１０４ｍｍｏｌ）に無水トリフルオロ酢酸（１７．７ｍＬ、１２５ｍｍｏｌ）を氷冷下で加えた。氷冷下で３時間攪拌した後、減圧濃縮した。残渣にトルエンを加え、再び減圧濃縮することにより、化合物５３ｂを得た。得られた５３ｂは精製せずにそのまま次の反応に用いた。
得られた５３ｂ全量のテトラヒドロフラン（６４ｍＬ）溶液にｐ－メトキシベンジルアルコール（２３．２ｇ、１６８ｍｍｏｌ）、ＤＭＡＰ（１．３７ｇ、１１．２ｍｍｏｌ）を加え、６時間加熱還流した。反応混合物を減圧濃縮した後、残渣に炭酸水素ナトリウム水溶液と酢酸エチルを加え、水層を分取した。分取した水層に２ｍｏｌ／Ｌ塩酸をｐＨ＝２まで加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮することにより化合物５３ｃと５３ｃ－ｉｉの混合物（２１ｇ、収率７４％）を無色オイルとして得た。
1H-NMR (DMSO-D6) δ: 1.09-1.12 (6H, m), 2.31-2.46 (2H, m), 2.53-2.63 (2H, m), 2.67-2.80 (2H, m), 3.75 (6H, s), 5.01 (4H, s), 6.92 (4H, d, J = 8.6 Hz), 7.29 (4H, d, J = 8.3 Hz).

工程２　化合物５３ｄの合成
化合物５３ｃと５３ｃ－ｉｉの混合物（２１ｇ、８３ｍｍｏｌ）から実施例６の工程２と同様にして化合物５３ｄと５３ｄ－ｉｉの混合物（２５．８８ｇ、収率５８％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.20 (3H, d, J = 6.8 Hz), 1.25 (3H, d, J = 7.1 Hz), 2.30 (1H, dd, J = 16.5, 4.7 Hz), 2.77-2.85 (2H, m), 3.02 (1H, dd, J = 13.9, 7.1 Hz), 3.22 (1H, dd, J = 16.0, 7.7 Hz), 3.63-3.68 (1H, m), 3.78 (6H, s), 4.98-5.06 (4H, m), 6.84 (4H, d, J = 8.1 Hz), 7.27 (4H, d, J = 14.9 Hz), 7.49-7.61 (30H, m).

工程３　化合物５３ｅの合成
化合物５３ｄと５３ｄ－ｉｉの混合物（２５．９ｇ、４８ｍｍｏｌ）から実施例６の工程４と同様にして化合物５３ｅと５３ｅ－ｉｉの混合物（６．１１ｇ、収率３６％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.19 (3H, d, J = 7.1 Hz), 1.23 (3H, d, J = 7.1 Hz), 1.74 (6H, s), 1.77 (6H, s), 2.49 (1H, dd, J = 16.9, 5.3 Hz), 2.82-2.91 (2H, m), 3.02 (1H, dd, J = 13.4, 7.1 Hz), 3.31 (1H, dd, J = 18.6, 7.7 Hz), 3.63-3.70 (1H, m), 3.81 (6H, s), 4.73-4.76 (4H, m), 5.04 (4H, d, J = 8.8 Hz), 5.39 (2H, s), 6.88 (4H, d, J = 8.1 Hz), 7.26 (4H, br s).

工程４　化合物５３ｇの合成
化合物５３ｅと５３ｅ－ｉｉの混合物（６．１１ｇ、１７．５ｍｍｏｌ）のジクロロメタン（３０ｍＬ）溶液に、氷冷下でＮ，Ｎ，Ｎ’Ｎ’－テトラメチルメタンジアミン（７．１７ｍＬ、５２．６ｍｍｏｌ）を加えた後、無水酢酸（６．３０ｍＬ、６６．６ｍｍｏｌ）、酢酸（５．３２ｍＬ、９３ｍｍｏｌ）を順に滴下した。室温で終夜攪拌した後、反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除くことにより化合物５３ｆと５３ｅ－ｉｉの混合物の酢酸エチル溶液を得た。
得られた化合物５３ｆと５３ｅ－ｉｉの混合物の酢酸エチル溶液に、化合物４ｅ（２．４９ｇ、１０．５ｍｍｏｌ）、ヘキサメチルリン酸トリアミド（９．１６ｍＬ、５２．６ｍｍｏｌ）を加えた。室温で終夜攪拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムにより乾燥した。無機物をろ過により除き、減圧濃縮した。得られた粗生成物はシリカゲルカラムクロマトグラフィ（ヘキサン－酢酸エチル）により精製し、化合物５３ｇ（２．６４ｇ、収率４２％）を白色フォームとして得た。
1H-NMR (CDCl3) δ: 1.13 (3H, d, J = 6.1 Hz), 1.70 (3H, s), 1.76 (3H, s), 2.50-2.54 (2H, m), 2.68 (1H, d, J = 14.7 Hz), 3.12 (1H, dd, J = 14.0, 11.5 Hz), 3.61 (2H, dd, J = 25.0, 15.9 Hz), 3.81 (3H, s), 4.04 (1H, s), 4.69 (1H, dd, J = 11.9, 7.6 Hz), 4.89 (1H, dd, J = 11.9, 7.6 Hz), 5.02 (2H, s), 5.07 (1H, d, J = 4.3 Hz), 5.37 (1H, t, J = 6.8 Hz), 5.46 (1H, dd, J = 9.1, 4.5 Hz), 6.09 (1H, d, J = 9.3 Hz), 6.88 (2H, d, J = 8.3 Hz), 7.24-7.39 (7H, m).

工程５　化合物Ｉ－５３の合成
化合物５３ｇから実施例１９の工程５～７と同様にして合成し、化合物Ｉ－５３を得た。
1H-NMR (D2O) δ: 1.19 (3H, d, J = 5.8 Hz), 2.77 (1H, t, J = 14.0 Hz), 3.03-3.09 (3H, m), 4.58 (2H, s), 5.26 (1H, d, J = 4.5 Hz), 5.65 (1H, d, J = 4.5 Hz), 7.05 (1H, s).
MS (m+1) = 499.94、保持時間：0.69分、測定条件１
元素分析：C17H15N5Na2O9S2(H2O)2.3(NaHCO3)0.2
計算値：C,34.34; H,3.32; N,11.64; Na,8.41; S,10.66 (%)
実測値：C,34.38; H,3.68; N,11.96; Na,8.43; S,10.67 (%)
Synthesis of Compound I-53
Figure JPOXMLDOC01-appb-C000192
Step 1 Synthesis of Compound 53c To compound 53a (13.8 g, 104 mmol) was added trifluoroacetic anhydride (17.7 mL, 125 mmol) under ice cooling. The mixture was stirred for 3 hours under ice cooling and then concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure to obtain Compound 53b. The obtained 53b was used in the next reaction without purification.
P-Methoxybenzyl alcohol (23.2 g, 168 mmol) and DMAP (1.37 g, 11.2 mmol) were added to a solution of the total amount of 53b in tetrahydrofuran (64 mL), and the mixture was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the aqueous layer was separated. 2 mol / L hydrochloric acid was added to the separated aqueous layer until pH = 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration, and the mixture was concentrated under reduced pressure to give a mixture of compound 53c and 53c-ii (21 g, yield 74%) as a colorless oil.
1 H-NMR (DMSO-D 6 ) δ: 1.09-1.12 (6H, m), 2.31-2.46 (2H, m), 2.53-2.63 (2H, m), 2.67-2.80 (2H, m), 3.75 ( 6H, s), 5.01 (4H, s), 6.92 (4H, d, J = 8.6 Hz), 7.29 (4H, d, J = 8.3 Hz).

Step 2 Synthesis of Compound 53d A mixture of Compound 53d and 53d-ii (25.88 g, Yield 58%) was mixed with white from a mixture of Compound 53c and 53c-ii (21 g, 83 mmol) in the same manner as in Step 2 of Example 6. Obtained as a foam.
1 H-NMR (CDCl 3 ) δ: 1.20 (3H, d, J = 6.8 Hz), 1.25 (3H, d, J = 7.1 Hz), 2.30 (1H, dd, J = 16.5, 4.7 Hz), 2.77- 2.85 (2H, m), 3.02 (1H, dd, J = 13.9, 7.1 Hz), 3.22 (1H, dd, J = 16.0, 7.7 Hz), 3.63-3.68 (1H, m), 3.78 (6H, s) , 4.98-5.06 (4H, m), 6.84 (4H, d, J = 8.1 Hz), 7.27 (4H, d, J = 14.9 Hz), 7.49-7.61 (30H, m).

Step 3 Synthesis of Compound 53e A mixture of Compound 53e and 53e-ii (6.11 g, yield 36%) was prepared in the same manner as in Step 4 of Example 6 from a mixture of Compound 53d and 53d-ii (25.9 g, 48 mmol). Was obtained as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.19 (3H, d, J = 7.1 Hz), 1.23 (3H, d, J = 7.1 Hz), 1.74 (6H, s), 1.77 (6H, s), 2.49 ( 1H, dd, J = 16.9, 5.3 Hz), 2.82-2.91 (2H, m), 3.02 (1H, dd, J = 13.4, 7.1 Hz), 3.31 (1H, dd, J = 18.6, 7.7 Hz), 3.63 -3.70 (1H, m), 3.81 (6H, s), 4.73-4.76 (4H, m), 5.04 (4H, d, J = 8.8 Hz), 5.39 (2H, s), 6.88 (4H, d, J = 8.1 Hz), 7.26 (4H, br s).

Step 4 Synthesis of Compound 53g To a solution of a mixture of compound 53e and 53e-ii (6.11 g, 17.5 mmol) in dichloromethane (30 mL) was added N, N, N′N′-tetramethylmethanediamine (7 .17 mL, 52.6 mmol) was added, and acetic anhydride (6.30 mL, 66.6 mmol) and acetic acid (5.32 mL, 93 mmol) were added dropwise in this order. After stirring overnight at room temperature, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration to obtain an ethyl acetate solution of a mixture of compounds 53f and 53e-ii.
Compound 4e (2.49 g, 10.5 mmol) and hexamethylphosphoric triamide (9.16 mL, 52.6 mmol) were added to an ethyl acetate solution of the obtained mixture of Compound 53f and 53e-ii. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The inorganic substance was removed by filtration and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 53g (2.64 g, yield 42%) as a white foam.
1 H-NMR (CDCl 3 ) δ: 1.13 (3H, d, J = 6.1 Hz), 1.70 (3H, s), 1.76 (3H, s), 2.50-2.54 (2H, m), 2.68 (1H, d , J = 14.7 Hz), 3.12 (1H, dd, J = 14.0, 11.5 Hz), 3.61 (2H, dd, J = 25.0, 15.9 Hz), 3.81 (3H, s), 4.04 (1H, s), 4.69 (1H, dd, J = 11.9, 7.6 Hz), 4.89 (1H, dd, J = 11.9, 7.6 Hz), 5.02 (2H, s), 5.07 (1H, d, J = 4.3 Hz), 5.37 (1H, t, J = 6.8 Hz), 5.46 (1H, dd, J = 9.1, 4.5 Hz), 6.09 (1H, d, J = 9.3 Hz), 6.88 (2H, d, J = 8.3 Hz), 7.24-7.39 ( 7H, m).

Step 5 Synthesis of Compound I-53 Synthesis was performed from 53 g of Compound I in the same manner as in Steps 5 to 7 of Example 19 to obtain Compound I-53.
1 H-NMR (D 2 O) δ: 1.19 (3H, d, J = 5.8 Hz), 2.77 (1H, t, J = 14.0 Hz), 3.03-3.09 (3H, m), 4.58 (2H, s) , 5.26 (1H, d, J = 4.5 Hz), 5.65 (1H, d, J = 4.5 Hz), 7.05 (1H, s).
MS (m + 1) = 499.94, retention time: 0.69 minutes, measurement condition 1
Elemental analysis: C17H15N5Na2O9S2 (H2O) 2.3 (NaHCO3) 0.2
Calculated values: C, 34.34; H, 3.32; N, 11.64; Na, 8.41; S, 10.66 (%)
Found: C, 34.38; H, 3.68; N, 11.96; Na, 8.43; S, 10.67 (%)
　化合物Ｉ－５４の合成　
Figure JPOXMLDOC01-appb-C000193
 （式中、波線はシス体およびトランス体の混合体を意味する。）
工程１　化合物５４ｃの合成
化合物５４ａ（５．００ｇ、２８．７ｍｍｏｌ）をメタノール（５０ｍｌ）に溶解し、氷冷下化合物５４ｂ（４．６１ｇ、３０．１ｍｍｏｌ）のジクロロメタン（２５ｍｌ）溶液を加えた。氷冷下で１時間撹拌した後、室温で一晩撹拌した。減圧下濃縮し粗生成物として化合物５４ｃを得た。化合物５４ｃは精製することなく次の反応に用いた。

工程２　化合物５４ｄの合成
得られた化合物５４ｃ（２８．７ｍｍｏｌ相当）をテトラヒドロフラン（３０ｍｌ）に溶解し、酢酸（４．９２ｍｌ、８６ｍｍｏｌ）と１ｍｏｌ／ＬのＴＢＡＦテトラヒドロフラン溶液（８６ｍｌ、８６ｍｍｏｌ）を加えた。３時間撹拌した後水を加え、酢酸エチルで抽出した。有機層を、飽和重曹水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムで乾燥した。硫酸マグネシウムを除去した後、減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、ヘキサン／酢酸エチルで溶離させた。所望の化合物を含むフラクションを減圧下濃縮し、化合物５４ｄ（４．３６ｇ、７８％）を約２：１の混合物として得た。
1H-NMR (CDCl3) δ: 7.55 (1H, t, J = 4.0 Hz), 7.29 (3H, t, J = 7.8 Hz), 6.89 (4H, d, J = 8.1 Hz), 5.04 (1H, s), 5.02 (2H, s), 4.41 (1H, d, J = 3.5 Hz), 4.26 (2H, d, J = 4.0 Hz), 3.81 (5H, s).

工程３　化合物５４ｅの合成
化合物５４ｄ（４．３６ｇ、２２．３３ｍｍｏｌ）、Ｎ－ヒドロキシフタルイミド（４．３７ｇ、２６．８ｍｍｏｌ）、トリフェニルホスフィン（７．０３ｇ、２６．８ｍｍｏｌ）をテトラヒドロフラン（４５ｍｌ）に溶解し、氷冷下アゾジカルボン酸ビス（2-メトキシエチル）（６．２８ｇ、２６．８ｍｍｏｌ）を加えた。氷冷下１時間撹拌した後、減圧下濃縮した。残渣にメタノールを加え固体を析出させ、析出した固体をろ取することで化合物５４ｅ（５．０６ｇ、６７％）を約２：１の混合物として得た。
1H-NMR (CDCl3) δ: 7.85-7.81 (3.0H, m), 7.77-7.75 (3.0H, m), 7.68 (1.0H, t, J = 6.2 Hz), 7.23-7.17 (3.0H, m), 6.84 (1.0H, d, J = 7.8 Hz), 6.76 (2.0H, d, J = 8.3 Hz), 5.03-5.01 (1.0H, m), 5.00 (1.0H, br s), 4.94 (2.0H, br s), 4.75 (2.0H, d, J = 6.3 Hz), 3.79 (1.5H, s), 3.77 (3.0H, s).

工程４　化合物５４ｆの合成
化合物５４ｅ（１．００ｇ、２．９４ｍｍｏｌ）を用いて実施例１２の工程２と同様にして化合物５４ｆ（１．２０ｇ、８８％）の粗生成物約２：１の混合物として得た。
[M+H]＝465、保持時間：１．９８分、測定条件１

Figure JPOXMLDOC01-appb-C000194
工程５　化合物５４ｈの合成
化合物５４ｆ（１．０４ｇ、２．２５ｍｍｏｌ）と化合物５４ｇ（１．００ｇ、２．２５ｍｍｏｌ）を用いて実施例１２の工程３と同様にして化合物５４ｈ（１．６０ｇ、９２％）の粗生成物約１．２：１の混合物として得た。
[M+H]＝773、保持時間：２．６７分、測定条件２

工程６　化合物Ｉ－５４の合成
化合物５４ｈ（７０８ｍｇ、０．９１６ｍｍｏｌ）を用いて実施例１２の工程４と同様にして化合物Ｉ－５４（７５．６ｍｇ、１６％）を１．８：１のオキシムの異性体混合物として得た。
major: 1H-NMR (D2O) δ: 2.68 (1H, dd, J = 18.4, 2.4 Hz), 2.85 (1H, dd, J = 13.1, 9.2 Hz), 2.92 (1H, dd, J = 18.4, 7.8 Hz), 3.07-3.20 (2H, m), 4.79-4.85 (2H, m), 5.28 (1H, d, J = 4.5 Hz), 5.59 (1H, d, J = 4.5 Hz), 7.11 (1H, s), 7.70 (1H, t, J = 5.6 Hz).
minor: 1H-NMR (D2O) δ: 2.68 (1H, dd, J = 18.4, 2.4 Hz), 2.85 (1H, dd, J = 13.1, 9.2 Hz), 2.92 (1H, dd, J = 18.4, 7.8 Hz), 3.07-3.20 (2H, m), 5.07 (2H, d, J = 3.9 Hz), 5.30 (1H, d, J = 4.6 Hz), 5.60 (1H, d, J = 4.6 Hz), 7.13 (1H, s), 7.14 (1H, t, J = 3.9 Hz).
[M+H]＝485、保持時間：０．８３分、測定条件２
C16H15N6O8S2Na1(H2O)2.6(NaHCO3)0.1 計算値C : 34.43%, H : 3.64%, N : 14.96%, S : 11.42%, Na : 4.50%. 実測値C : 34.44%, H : 3.81%, N : 15.09%, S : 11.25%, Na : 4.40%.
Synthesis of Compound I-54
Figure JPOXMLDOC01-appb-C000193
 (In the formula, a wavy line means a mixture of a cis form and a trans form.)
Step 1 Synthesis of Compound 54c Compound 54a (5.00 g, 28.7 mmol) was dissolved in methanol (50 ml), and a solution of compound 54b (4.61 g, 30.1 mmol) in dichloromethane (25 ml) was added under ice cooling. After stirring for 1 hour under ice cooling, the mixture was stirred overnight at room temperature. Concentration under reduced pressure gave Compound 54c as a crude product. Compound 54c was used in the next reaction without purification.

Step 2 Synthesis of Compound 54d Compound 54c (corresponding to 28.7 mmol) obtained was dissolved in tetrahydrofuran (30 ml), and acetic acid (4.92 ml, 86 mmol) and 1 mol / L TBAF tetrahydrofuran solution (86 ml, 86 mmol) were added. . After stirring for 3 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After removing magnesium sulfate, the solution was concentrated under reduced pressure, subjected to silica gel column chromatography, and eluted with hexane / ethyl acetate. Fractions containing the desired compound were concentrated under reduced pressure to provide compound 54d (4.36 g, 78%) as an approximately 2: 1 mixture.
1 H-NMR (CDCl 3 ) δ: 7.55 (1H, t, J = 4.0 Hz), 7.29 (3H, t, J = 7.8 Hz), 6.89 (4H, d, J = 8.1 Hz), 5.04 (1H, s), 5.02 (2H, s), 4.41 (1H, d, J = 3.5 Hz), 4.26 (2H, d, J = 4.0 Hz), 3.81 (5H, s).

Step 3 Synthesis of Compound 54e Compound 54d (4.36 g, 22.33 mmol), N-hydroxyphthalimide (4.37 g, 26.8 mmol) and triphenylphosphine (7.03 g, 26.8 mmol) were added to tetrahydrofuran (45 ml). After dissolution, bis (2-methoxyethyl) azodicarboxylate (6.28 g, 26.8 mmol) was added under ice cooling. The mixture was stirred for 1 hour under ice cooling and then concentrated under reduced pressure. Methanol was added to the residue to precipitate a solid, and the precipitated solid was collected by filtration to obtain Compound 54e (5.06 g, 67%) as an approximately 2: 1 mixture.
1 H-NMR (CDCl 3 ) δ: 7.85-7.81 (3.0H, m), 7.77-7.75 (3.0H, m), 7.68 (1.0H, t, J = 6.2 Hz), 7.23-7.17 (3.0H, m), 6.84 (1.0H, d, J = 7.8 Hz), 6.76 (2.0H, d, J = 8.3 Hz), 5.03-5.01 (1.0H, m), 5.00 (1.0H, br s), 4.94 ( 2.0H, br s), 4.75 (2.0H, d, J = 6.3 Hz), 3.79 (1.5H, s), 3.77 (3.0H, s).

Step 4 Synthesis of Compound 54f A mixture of about 2: 1 crude product of Compound 54f (1.20 g, 88%) using Compound 54e (1.00 g, 2.94 mmol) in the same manner as Step 2 of Example 12. Got as.
[M + H] = 465, retention time: 1.98 minutes, measurement condition 1

Figure JPOXMLDOC01-appb-C000194
Step 5 Synthesis of Compound 54h Compound 54h (1.60 g, 92 g) was obtained in the same manner as in Step 3 of Example 12 using Compound 54f (1.04 g, 2.25 mmol) and Compound 54 g (1.00 g, 2.25 mmol). %) Crude product as a mixture of about 1.2: 1.
[M + H] = 773, retention time: 2.67 minutes, measurement condition 2

Step 6 Synthesis of Compound I-54 Compound I-54 (75.6 mg, 16%) was converted to 1.8: 1 oxime in the same manner as in Step 4 of Example 12 using Compound 54h (708 mg, 0.916 mmol). As a mixture of isomers.
major: 1H-NMR (D2O) δ: 2.68 (1H, dd, J = 18.4, 2.4 Hz), 2.85 (1H, dd, J = 13.1, 9.2 Hz), 2.92 (1H, dd, J = 18.4, 7.8 Hz ), 3.07-3.20 (2H, m), 4.79-4.85 (2H, m), 5.28 (1H, d, J = 4.5 Hz), 5.59 (1H, d, J = 4.5 Hz), 7.11 (1H, s) , 7.70 (1H, t, J = 5.6 Hz).
minor: 1H-NMR (D2O) δ: 2.68 (1H, dd, J = 18.4, 2.4 Hz), 2.85 (1H, dd, J = 13.1, 9.2 Hz), 2.92 (1H, dd, J = 18.4, 7.8 Hz ), 3.07-3.20 (2H, m), 5.07 (2H, d, J = 3.9 Hz), 5.30 (1H, d, J = 4.6 Hz), 5.60 (1H, d, J = 4.6 Hz), 7.13 (1H , s), 7.14 (1H, t, J = 3.9 Hz).
[M + H] = 485, retention time: 0.83 minutes, measurement condition 2
C16H15N6O8S2Na1 (H2O) 2.6 (NaHCO3) 0.1 Calculated value C: 34.43%, H: 3.64%, N: 14.96%, S: 11.42%, Na: 4.50%. Found C: 34.44%, H: 3.81%, N: 15.09%, S: 11.25%, Na: 4.40%.
　化合物Ｉ－５５の合成　
Figure JPOXMLDOC01-appb-C000195
工程1　化合物５５ｂの合成
N-Boc-L-アスパラギン酸（６５．０ｇ、１５３ｍｍｏｌ）をジクロロメタン（６５０ｍＬ）に溶解し、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（３２．３ｇ、１６９ｍｍｏｌ）を加え室温で終夜撹拌した。この反応液を０．１ｍｏｌ／Ｌ塩酸水を加え、目的物をジクロロメタンで抽出した。この有機層を精製水、次いで飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過材をろ過により除去し、溶媒を減圧下留去し、得られた残渣にジイソプロピルエーテル、酢酸イソプロピルを加え結晶化させた。析出した結晶をろ過により集め減圧下乾燥し化合物５５ｂを得た。（収量１９．１ｇ、収率５８％）
1H-NMR (DMSO-D6) δ: 7.74 (d, J = 7.8 Hz, 1H), 4.65-4.55 (m, 1H), 3.22 (dd, J = 9.0, 18.4 Hz, 1H), 2.84 (dd, J = 18.4, 6.2 Hz, 1H), 1.38 (s, 9H).

工程２　化合物５５ｃの合成
化合物５５ｂ（１９．１ｇ、８９．０ｍｍｏｌ）をテトラヒドロフラン（３８ｍＬ）に懸濁させ、４－メトキシフェニルメタノール（３６．８ｇ、２６７ｍｍｏｌ）を加え５０度で１０時間撹拌した。反応終了後、この反応液に精製水を加え、水層から目的物をジクロロメタンで抽出した。集めた有機層を精製水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥材を濾過により除去し、溶媒を減圧下留去した。得られた残渣をシリカゲルクロマトグラフィーに付し、化合物５５ｃを得た。（収量１２．０ｇ、収率３８％）
1H-NMR (DMSO-D6) δ: 12.42 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 9.8 Hz, 2H), 5.03 (s, 2H), 4.39-4.29 (m, 1H), 3.75 (s, 2H), 2.70 (dd, J = 16.6, 5.6 Hz, 1H), 2.60-2.52 (m, 1H), 1.36 (s, 9H).

工程３　化合物５５ｄの合成
化合物５５ｃ（１２．０ｇ、３４．０ｍｍｏｌ）を用い実施例６の工程２と同様の方法で化合物５５ｄを合成した。（収量２０．２ｇ、収率９４％）
1H-NMR (CDCl3) δ: 7.67-7.46 (m, 20H), 7.25 (d, J = 6.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 5.78 (d, J = 9.1 Hz, 1H), 5.04 (dd, J = 15.8, 12.0 Hz, 2H), 4.62-4.53 (m, 1H), 3.78 (s, 3H), 3.58 (dd, J = 16.3, 4.4 Hz, 1H), 3.03 (dd, J = 8.2, 4.1 Hz, 1H), 1.40 (s, 9H).

工程４　化合物５５ｅの合成
化合物５５ｄ（２０．２ｇ、３１．７ｍｍｏｌ）を用い実施例６の工程３と同様の方法で化合物５５ｅを合成した。（収量５．０１ｇ、収率３５％）
1H-NMR (CDCl3) δ: 7.25 (d, J = 7.4 Hz, 2H), 6.91-6.86 (m, 2H), 5.37 (ddd, J = 9.6, 5.3, 2.1 Hz, 2H), 5.10 (dt, J = 23.8, 8.6 Hz, 2H), 4.74 (d, J = 7.4 Hz, 2H), 4.69-4.61 (m, 1H), 3.81 (s, 3H), 3.44-3.39 (m, 2H), 1.77 (s, 3H), 1.73 (s, 3H), 1.41 (s, 9H).

工程５　化合物Ｉ－５５の合成
化合物５５ｅを用いて実施例６の工程５と同様の方法で化合物Ｉ－５５を合成した。
1H-NMR (D2O) δ: 7.09 (s, 1H), 5.70 (d, J = 4.8 Hz, 1H), 5.32 (d, J = 4.8 Hz, 1H), 4.62 (s, 2H), 3.46-3.40 (m, 1H), 3.22-3.09 (m, 1H), 2.97-2.82 (m, 2H).
MS (m+1) = 500.95、保持時間：0.32分、測定条件１
Synthesis of Compound I-55
Figure JPOXMLDOC01-appb-C000195
Step 1 Synthesis of Compound 55b
N-Boc-L-aspartic acid (65.0 g, 153 mmol) is dissolved in dichloromethane (650 mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (32.3 g, 169 mmol) is added to room temperature. And stirred overnight. To this reaction solution was added 0.1 mol / L aqueous hydrochloric acid, and the target product was extracted with dichloromethane. This organic layer was washed with purified water and then with saturated brine, and dried over anhydrous magnesium sulfate. The filter medium was removed by filtration, the solvent was distilled off under reduced pressure, and diisopropyl ether and isopropyl acetate were added to the resulting residue for crystallization. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain Compound 55b. (Yield 19.1 g, Yield 58%)
1 H-NMR (DMSO-D 6 ) δ: 7.74 (d, J = 7.8 Hz, 1H), 4.65-4.55 (m, 1H), 3.22 (dd, J = 9.0, 18.4 Hz, 1H), 2.84 (dd , J = 18.4, 6.2 Hz, 1H), 1.38 (s, 9H).

Step 2 Synthesis of Compound 55c Compound 55b (19.1 g, 89.0 mmol) was suspended in tetrahydrofuran (38 mL), 4-methoxyphenylmethanol (36.8 g, 267 mmol) was added, and the mixture was stirred at 50 ° C. for 10 hours. After completion of the reaction, purified water was added to the reaction solution, and the target product was extracted from the aqueous layer with dichloromethane. The collected organic layer was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain compound 55c. (Yield 12.0 g, Yield 38%)
1 H-NMR (DMSO-D 6 ) δ: 12.42 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 9.8 Hz, 2H), 5.03 (s, 2H), 4.39-4.29 (m, 1H), 3.75 (s, 2H), 2.70 (dd, J = 16.6, 5.6 Hz, 1H), 2.60-2.52 (m, 1H), 1.36 (s, 9H).

Step 3 Synthesis of Compound 55d Compound 55d was synthesized in the same manner as in Step 2 of Example 6 using Compound 55c (12.0 g, 34.0 mmol). (Yield 20.2 g, 94% yield)
1 H-NMR (CDCl 3 ) δ: 7.67-7.46 (m, 20H), 7.25 (d, J = 6.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 5.78 (d, J = 9.1 Hz, 1H), 5.04 (dd, J = 15.8, 12.0 Hz, 2H), 4.62-4.53 (m, 1H), 3.78 (s, 3H), 3.58 (dd, J = 16.3, 4.4 Hz, 1H), 3.03 (dd, J = 8.2, 4.1 Hz, 1H), 1.40 (s, 9H).

Step 4 Synthesis of Compound 55e Compound 55e was synthesized in the same manner as in Step 3 of Example 6 using Compound 55d (20.2 g, 31.7 mmol). (Yield 5.01 g, Yield 35%)
1 H-NMR (CDCl 3 ) δ: 7.25 (d, J = 7.4 Hz, 2H), 6.91-6.86 (m, 2H), 5.37 (ddd, J = 9.6, 5.3, 2.1 Hz, 2H), 5.10 (dt , J = 23.8, 8.6 Hz, 2H), 4.74 (d, J = 7.4 Hz, 2H), 4.69-4.61 (m, 1H), 3.81 (s, 3H), 3.44-3.39 (m, 2H), 1.77 ( s, 3H), 1.73 (s, 3H), 1.41 (s, 9H).

Step 5 Synthesis of Compound I-55 Compound I-55 was synthesized in the same manner as in Step 5 of Example 6 using Compound 55e.
1H-NMR (D2O) δ: 7.09 (s, 1H), 5.70 (d, J = 4.8 Hz, 1H), 5.32 (d, J = 4.8 Hz, 1H), 4.62 (s, 2H), 3.46-3.40 ( m, 1H), 3.22-3.09 (m, 1H), 2.97-2.82 (m, 2H).
MS (m + 1) = 500.95, retention time: 0.32 minutes, measurement condition 1
同様の方法により、以下の化合物を合成した。なお、化合物Ｉ－００１～Ｉ－０３２のＬＣＭＳ分析は測定条件１で分析を行った。
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000214
The following compounds were synthesized by the same method. The LCMS analysis of compounds I-001 to I-032 was performed under measurement condition 1.
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000214
（試験例１）
　本発明化合物のＩｎ　Ｖｉｔｒｏ抗菌活性を確認した。
（試験方法）
最小発育阻止濃度 (MIC) の測定は、CLSI (Clinical and Laboratory Standards Institute) が推奨する方法に準じ、接種菌量は1×105 CFU/mL、試験培地はカチオン調整ミューラーヒントンブロスを用いて、微量液体希釈法により実施した。
使用した菌株は以下の表のとおりである。
Figure JPOXMLDOC01-appb-T000215
（結果）
試験結果を表２０および２１に示す。表中、阻害活性の数値の単位はμｇ／ｍＬである。
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
 (Test Example 1)
In vitro antibacterial activity of the compound of the present invention was confirmed.
(Test method)
The minimum inhibitory concentration (MIC) is measured according to the method recommended by CLSI (Clinical and Laboratory Standards Institute), the inoculum is 1 × 10 5 CFU / mL, the test medium is cation-adjusted Mueller Hinton broth, It was carried out by a micro liquid dilution method.
The strains used are shown in the table below.
Figure JPOXMLDOC01-appb-T000215
(result)
The test results are shown in Tables 20 and 21. In the table, the unit of the numerical value of the inhibitory activity is μg / mL.
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
　以上の結果から、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される化合物が広範な抗菌スペクトルを有し、特にグラム陰性菌に対して強力な抗菌スペクトルを示し、および／または多剤耐性菌、特にクラムＢ型のメタロ－β－ラクタマーゼ産生グラム陰性菌に対し強い抗菌活性を示し、および／または基質特異性拡張型β－ラクタマーゼ（ＥＳＢＬ）産生菌に対し強い抗菌活性を示す。また、カルバペネマーゼ耐性を含む多剤耐性菌に対しても有効であり、β－ラクタマーゼ産生グラム陰性菌に対しても高い安定性を有していることが示される。 From the above results, the compound represented by the formula (I), (IA) or (II) has a broad antibacterial spectrum, particularly a strong antibacterial spectrum against gram-negative bacteria, and / or multidrug resistance. It exhibits strong antibacterial activity against bacteria, particularly crumb B type metallo-β-lactamase producing Gram negative bacteria, and / or strong antibacterial activity against substrate-specific extended β-lactamase (ESBL) producing bacteria. It is also effective against multi-drug resistant bacteria including carbapenemase resistance, and has high stability against β-lactamase producing gram-negative bacteria.
（試験例１－２）
　本発明化合物とβ－ラクタマーゼ阻害作用を有する化合物との併用効果を確認するため、Ｉｎ　Ｖｉｔｒｏ抗菌活性を確認した。
（試験方法）
最小発育阻止濃度 (MIC: ug/mL)の測定は、CLSI（Clinical and Laboratory Standards Institute）法に準じ、接種菌量は10000 cfu/spot、試験培地はミューラーヒントン寒天培地を用いて、微量液体希釈法により実施した。なお、β－ラクタマーゼ阻害作用を有する化合物の使用量は、３－アミノフェニルボロン酸：400 ug/ml、アビバクタム：4 ug/mlであった。
使用した菌株は以下の表のとおりである。
Figure JPOXMLDOC01-appb-T000218
 　試験結果を表２４に示す。表中、阻害活性の数値の単位はug/mlであり、ＡＰＢは３－アミノフェニルボロン酸、ＡＶＩはアビバクタムを意味する。
Figure JPOXMLDOC01-appb-T000219
 (Test Example 1-2)
In vitro antibacterial activity was confirmed in order to confirm the combined effect of the compound of the present invention and a compound having β-lactamase inhibitory action.
(Test method)
Minimum growth inhibitory concentration (MIC: ug / mL) is measured according to the CLSI (Clinical and Laboratory Standards Institute) method. Implemented by law. The amount of the compound having β-lactamase inhibitory action was 3-aminophenylboronic acid: 400 ug / ml and abibactam: 4 ug / ml.
The strains used are shown in the table below.
Figure JPOXMLDOC01-appb-T000218
 The test results are shown in Table 24. In the table, the unit of the numerical value of the inhibitory activity is ug / ml, APB means 3-aminophenylboronic acid, and AVI means abibactam.
Figure JPOXMLDOC01-appb-T000219
　以上の結果から、式（Ｉ）、（ＩＡ）または（ＩＩ）で示される本発明化合物とβ－ラクタマーゼ阻害作用を有する化合物とを組み合わせて使用することにより、さらに広範な抗菌スペクトルを有し、クラスＡ，Ｂ，ＣおよびＤ型全てのβ－ラクタマーゼを産生する菌株に対して強い抗菌活性を示す。すなわち、クラムＢ型のメタロ－β－ラクタマーゼ産生グラム陰性菌に対し強い抗菌活性を示し、および／または基質特異性拡張型β－ラクタマーゼ（ＥＳＢＬ）産生菌に対し強い抗菌活性を示す。また、カルバペネマーゼ耐性を含む多剤耐性菌に対しても有効であり、各種のβ－ラクタマーゼ産生グラム陰性菌に対しても高い安定性を有していることが示される。 From the above results, by using the compound of the present invention represented by the formula (I), (IA) or (II) in combination with a compound having β-lactamase inhibitory activity, it has a broader antibacterial spectrum, It exhibits strong antibacterial activity against strains producing all types of β-lactamases of class A, B, C and D. That is, it exhibits strong antibacterial activity against crumb B-type metallo-β-lactamase-producing gram-negative bacteria and / or strong antibacterial activity against substrate-specific extended β-lactamase (ESBL) -producing bacteria. It is also effective against multidrug-resistant bacteria including carbapenemase resistance, and shows high stability against various β-lactamase-producing gram-negative bacteria.
試験例２：ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価した。 Test Example 2: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
　反応条件は以下のとおり：基質、０．５μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム０．２ｍｇ　タンパク質／ｍＬ；本発明化合物濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .
　９６穴プレートに反応溶液として、５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ緩衝液中に各５種の基質、ヒト肝ミクロソーム、本発明化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始した。３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を添加することで反応を停止した。３０００ｒｐｍ、１５分間の遠心後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで定量し、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量した。 As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction. Started. After reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、溶媒に加えた本発明化合物の各濃度における残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。 The residual activity (%) at each concentration of the compound of the present invention added to the solvent was calculated by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the concentration and inhibition rate were calculated. The IC 50 was calculated by inverse estimation using a logistic model.
試験例３：ＢＡ試験
経口吸収性の検討実験材料と方法
（１）使用動物：マウスあるいはＳＤラットを使用した。
（２）飼育条件：マウスあるいはＳＤラットは、固形飼料および滅菌水道水を自由摂取させた。
（３）投与量、群分けの設定：経口投与、静脈内投与を所定の投与量により投与した。以下のように群を設定した。（化合物ごとで投与量は変更有）
　経口投与　１～３０ｍｇ／ｋｇ（ｎ＝２～３）
　静脈内投与　０．５～１０ｍｇ／ｋｇ（ｎ＝２～３）
（４）投与液の調製：経口投与は溶液または懸濁液として投与した。静脈内投与は可溶化して投与した。
（５）投与方法：経口投与は、経口ゾンデにより強制的に胃内に投与した。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与した。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定した。
（７）統計解析：血漿中本発明化合物濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群のＡＵＣから本発明化合物のバイオアベイラビリティ（ＢＡ）を算出した。
その結果、化合物Ｉ－１２はＢＡ＝５７％、Ｉ－３１はＢＡ＝３８％、Ｉ－１１はＢＡ＝２１％、Ｉ－１７はＢＡ＝１８％であった。 Test Example 3: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats were used.
(2) Breeding conditions: Mice or SD rats were allowed to freely take solid feed and sterilized tap water.
(3) Setting of dose and grouping: Oral administration and intravenous administration were administered at a predetermined dose. Groups were set up as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was forcibly administered into the stomach with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention was calculated from the AUC of the group.
As a result, Compound I-12 had BA = 57%, I-31 had BA = 38%, I-11 had BA = 21%, and I-17 had BA = 18%.
試験例３－１：静脈内投与試験
静脈内投与試験の検討実験材料と方法
（１）使用動物：ＳＤラットを使用した。
（２）飼育条件：ＳＤラットは、固形飼料および滅菌水道水を自由摂取させた。
（３）投与量、群分けの設定：所定の投与量により静脈内に投与した。以下のように群を設定した。（化合物ごとで投与量は変更有）
　静脈内投与　０．５～１ｍｇ／ｋｇ（ｎ＝２～３）
（４）投与液の調製：静脈内投与は可溶化して投与した。
（５）投与方法：静脈内投与は、注射針を付けたシリンジにより尾静脈から投与した。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定した。
（７）統計解析：血漿中本発明化合物濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて全身クリアランス（ＣＬtoｔ）及び消失半減期（ｔ１／２，ｚ）を算出した。 Test Example 3-1: Intravenous administration test Examination of intravenous administration test Experimental materials and methods (1) Animals used: SD rats were used.
(2) Breeding conditions: SD rats were allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: Intravenous administration was carried out at a predetermined dosage. Groups were set up as follows. (Dose may vary for each compound)
Intravenous administration 0.5-1 mg / kg (n = 2-3)
(4) Preparation of administration solution: Intravenous administration was solubilized and administered.
(5) Administration method: Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: Whole body clearance (CLtot) and elimination half-life (t1 / 2, z) were calculated using the non-linear least-squares program WinNonlin (registered trademark) for plasma compound concentration transition.
試験例４：代謝安定性試験
　市販のプールドヒト肝ミクロソームと本発明化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、本発明化合物が肝で代謝される程度を評価した。 Test Example 4: Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
　ヒト肝ミクロソーム０．５ｍｇタンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、１５０ｍｍｏｌ／Ｌ　塩化カリウム、１０ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させた（酸化的反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０μＬを添加、混合し、３０００ｒｐｍで１５分間遠心した。その遠心上清中の本発明化合物をＬＣ／ＭＳ／ＭＳにて定量し、反応後の本発明化合物の残存量を０分反応時の化合物量を１００％として計算した。なお、加水分解反応はＮＡＤＰＨ非存在下で、グルクロン酸抱合反応はＮＡＤＰＨに換えて５ｍｍｏｌ／Ｌ　ＵＤＰ－グルクロン酸の存在下で反応を行い、以後同じ操作を実施することができる。 In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%. The hydrolysis reaction can be carried out in the absence of NADPH, the glucuronic acid conjugation reaction can be carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation can be carried out thereafter.
試験例５：ＣＹＰ３Ａ４蛍光ＭＢＩ試験
　ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による本発明化合物のＣＹＰ３Ａ４阻害の増強を調べる試験である。ＣＹＰ３Ａ４酵素（大腸菌発現酵素）により７－ベンジルオキシトリフルオロメチルクマリン（７－ＢＦＣ）が脱ベンジル化されて、蛍光を発する代謝物７－ハイドロキシトリフルオロメチルクマリン（７－ＨＦＣ）が生じる。７－ＨＦＣ生成反応を指標としてＣＹＰ３Ａ４阻害を評価した。 Test Example 5: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
　反応条件は以下のとおり：基質、５．６μｍｏｌ／Ｌ　７－ＢＦＣ；プレ反応時間、０または３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ、反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；本発明化合物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中に酵素、本発明化合物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止した。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始した。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止した。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７－ＨＦＣの蛍光値を測定した。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ） The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in the K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition. A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction was stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, was measured using a fluorescent plate reader on the plate on which each index reaction was performed. (Ex = 420nm, Em = 535nm)
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。ＩＣ５０値の差が５μｍｏｌ／Ｌ以上の場合を（＋）とし、３μｍｏｌ／Ｌ以下の場合を（－）とした。 A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. The IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 μmol / L or more was designated as (+), and the case where it was 3 μmol / L or less was designated as (−).
試験例６：Ｆｌｕｃｔｕａｔｉｏｎ　Ａｍｅｓ　Ｔｅｓｔ
　本発明化合物の変異原性を評価した。
　凍結保存しているネズミチフス菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ　ＴＡ９８株、ＴＡ１００株）２０μＬを１０ｍＬ液体栄養培地（２．５％　Ｏｘｏｉｄ　ｎｕｔｒｉｅｎｔ　ｂｒｏｔｈ　Ｎｏ．２）に接種し３７℃にて１０時間、振盪前培養した。ＴＡ９８株は９ｍＬの菌液を遠心（２０００×ｇ、１０分間）して培養液を除去した。９ｍＬのＭｉｃｒｏ　Ｆ緩衝液（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／Ｌ）に菌を懸濁し、１１０ｍＬのＥｘｐｏｓｕｒｅ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）に添加した。ＴＡ１００株は３．１６ｍＬ菌液に対しＥｘｐｏｓｕｒｅ培地１２０ｍＬに添加し試験菌液を調製した。本発明化合物ＤＭＳＯ溶液（最高用量５０ｍｇ／ｍＬから２～３倍公比で数段階希釈）、陰性対照としてＤＭＳＯ、陽性対照として非代謝活性化条件ではＴＡ９８株に対しては５０μｇ／ｍＬの４－ニトロキノリン－１－オキシドＤＭＳＯ溶液、ＴＡ１００株に対しては０．２５μｇ／ｍＬの２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミドＤＭＳＯ溶液、代謝活性化条件ではＴＡ９８株に対して４０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液、ＴＡ１００株に対しては２０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液それぞれ１２μＬと試験菌液５８８μＬ（代謝活性化条件では試験菌液４９８μＬとＳ９　ｍｉｘ　９０μＬの混合液）を混和し、３７℃にて９０分間、振盪培養した。本発明化合物を暴露した菌液４６０μＬを、Ｉｎｄｉｃａｔｏｒ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬ、ブロモクレゾールパープル：３７．５μｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）２３００μＬに混和し５０μＬずつマイクロプレート４８ウェル／用量に分注し、３７℃にて３日間、静置培養した。アミノ酸（ヒスチジン）合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、ｐＨ変化により紫色から黄色に変色するため、１用量あたり４８ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価した。変異原性が陰性のものを（－）、陽性のものを（＋）として示す。 Test Example 6: Fluctuation Ames Test
The mutagenicity of the compounds of the present invention was evaluated.
Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L) Buffer). The TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL of the test bacterial solution and S9 under metabolic activation conditions). (mixture of 90 μL of mix) was mixed and incubated at 37 ° C. for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer solution containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each, and dispensed into 48 wells / dose of the microplate, and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation was made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).
試験例７：ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャンネルを発現させたＨＥＫ２９３細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討した。
　全自動パッチクランプシステム（ＰａｔｃｈＸｐｒｅｓｓ　７０００Ａ、ＡｘｏｎＩｎｓｔｒｕｍｅｎｔｓ　Ｉｎｃ．）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持した後、＋４０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録した。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液（ＮａＣｌ：１３５　ｍｍｏｌ／Ｌ、ＫＣｌ：５．４　ｍｍｏｌ／Ｌ、ＮａＨ２ＰＯ４：０．３ｍｍｏｌ／Ｌ、ＣａＣｌ２・２Ｈ２Ｏ：１．８ｍｍｏｌ／Ｌ、ＭｇＣｌ２・６Ｈ２Ｏ：１ｍｍｏｌ／Ｌ、グルコース：１０ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を室温で、１０分間細胞に適用させた。得られたＩＫｒから、解析ソフト（ＤａｔａＸｐｒｅｓｓ　ｖｅｒ．１、Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ　Ｃｏｒｐｏｒａｔｉｏｎ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測した。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群（０．１％ジメチルスルホキシド溶液）と比較して、本発明化合物のＩＫｒへの影響を評価した。 Test Example 7: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using HEK293 cells expressing human ether-a-go-related gene (hERG) channel, it is important for ventricular repolarization process The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role, was investigated.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of −80 mV by whole cell patch clamp, a +40 mV depolarization stimulus was applied for 2 seconds, followed by a −50 mV repolarization. The I Kr elicited when the stimulus was applied for 2 seconds was recorded. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH 2 PO 4 : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl 2 · 2H 2 O: 1.8 mmol / L, MgCl 2 · 6H 2 O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was applied to the cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
試験例８：溶解性試験
　本発明化合物の溶解度は、１％ＤＭＳＯ添加条件下で決定した。ＤＭＳＯにて１０ｍｍｏｌ／Ｌ化合物溶液を調製し、本発明化合物溶液６　μＬをｐＨ６．８人工腸液（０．２ｍｏｌ／Ｌ　リン酸二水素カリウム試液　２５０ｍＬに０．２ｍｏｌ／Ｌ　ＮａＯＨ試液１１８ｍＬ、水を加えて１０００ｍＬとした）５９４μＬに添加した。２５℃で１６時間静置させた後、混液を吸引濾過した。濾液をメタノール／水＝１／１（Ｖ／Ｖ）にて２倍希釈し、絶対検量線法によりＨＰＬＣまたはＬＣ／ＭＳ／ＭＳを用いて濾液中濃度を測定した。 Test Example 8: Solubility test The solubility of the compound of the present invention was determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) Was added to 594 μL. After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate was measured by HPLC or LC / MS / MS using the absolute calibration curve method.
試験例９：粉末溶解度試験
　適当な容器に本発明化合物を適量入れ、各容器にＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとする）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加える）、２０ｍｍｏｌ／Ｌ　タウロコール酸ナトリウム（ＴＣＡ）／ＪＰ－２液（ＴＣＡ１．０８ｇにＪＰ－２液を加え１００ｍＬとする）を２００μＬずつ添加する。試験液添加後に全量溶解した場合には、適宜、本発明化合物を追加する。密閉して３７℃で１時間振とう後に濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡および析出物がないことを確認し、密閉して振とうする。絶対検量線法によりＨＰＬＣを用いて本発明化合物を定量する。 Test Example 9: Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Make sure there are no bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.
試験例１０：目視溶解性試験
化合物約5ｍｇを微量試験管3本に秤量し、各媒体(注射用水、生食注、0.5%ブドウ糖液)を化合物濃度20%になるように添加する。ボルテックスにて撹拌後、目視にて溶解の有無を確認する。溶解していればその媒体での溶解度を>20%とする。それら試験液に各媒体(注射用水、生食注、ブドウ糖液)を更に加えて化合物濃度10%の試験液を調製し、ボルテックスにて撹拌後、目視にて溶解の有無を確認する。溶解していればその媒体での溶解度を20%～10%とする。同様に5%濃度、2.5%濃度、1%濃度まで試験をし、1%濃度で溶解しない場合はその媒体での溶解度を<1%とする。1%濃度の試験液でのpHを測定し、記録する。　 Test Example 10: About 5 mg of visual solubility test compound is weighed into three microscopic test tubes, and each medium (water for injection, saline feed, 0.5% glucose solution) is added to a compound concentration of 20%. After stirring by vortex, visually check for dissolution. If so, the solubility in the medium is> 20%. Each medium (water for injection, raw food injection, glucose solution) is further added to these test solutions to prepare a test solution with a compound concentration of 10%. After stirring by vortexing, the presence or absence of dissolution is visually confirmed. If dissolved, the solubility in the medium should be 20% to 10%. Similarly, test to 5% concentration, 2.5% concentration, 1% concentration, and if not soluble at 1% concentration, the solubility in the medium should be <1%. Measure and record the pH with 1% test solution.
試験例１１：ｐＫａ測定（キャピラリー電気泳動法 (capillary electrophoresis法，CE法)の測定方法）
キャピラリーゾーン電気泳動技術を用いた手法で，電解質を含む緩衝液中での各試料成分の自由泳動を利用した分離方法である。
pH2.5～11.5に調製した緩衝液が充填されたフューズドシリカキャピラリーに、化合物溶液を注入した後、キャピラリーに高電圧 (Inlet側＋，Outlet側－) をかけると、化合物は緩衝液ｐＨにおけるイオン化状態を反映した速度 (＋チャージした化合物は速く、－チャージした化合物は遅く) で移動する。この化合物の移動時間と中性分子 (DMSO) の移動時間との差をpHに対してプロットし、フィッティングをかけてpKaを算出した。測定条件を以下に示す。
使用装置：Beckman P/ACEシステムMDQ　PDA
泳動液：pH2.5～11.5　Buffer (10vol%　MeOH含有)
サンプル溶液：　　　　Blank DMSO 10μL+注用水90μL混合
　　　　　　　　　　　Sample　10mM DMSO stock solution 4μL + DMSO 6μL + 注用水 90μL
（メソッド）
キャピラリー　　　　：Fused silica capillary (BECKMAN COULTER，内径50 μm，全長30.2 cm，有効長20.0 cm)
印加電圧　　　　　：10kV　(331 V/cm)
印加空気圧　　　　：0.7 psi
キャピラリー温度　　　：25°C
電気浸透流マーカー　　：DMSO
検出　　　　　　：紫外部多波長吸光検出 (測定波長；215 nm，238 nm)
試料注入　　　　　：加圧法 (0.5 psi，5 sec) Test Example 11: pKa measurement (capillary electrophoresis method (capillary electrophoresis method, CE method) measurement method)
This is a separation method using capillary zone electrophoresis technology and free migration of each sample component in a buffer solution containing an electrolyte.
After injecting a compound solution into a fused silica capillary filled with a buffer solution adjusted to pH 2.5 to 11.5 and then applying a high voltage (Inlet side +, Outlet side-) to the capillary, the compound is at the buffer pH. It moves at a speed that reflects the ionization state (+ charged compounds are fast, -charged compounds are slow). The difference between the migration time of this compound and the migration time of neutral molecule (DMSO) was plotted against pH, and pKa was calculated by fitting. The measurement conditions are shown below.
Equipment used: Beckman P / ACE system MDQ PDA
Electrophoresis: pH2.5 to 11.5 Buffer (containing 10vol% MeOH)
Sample solution: Blank DMSO 10 μL + Injection water 90 μL Sample 10 mM DMSO stock solution 4 μL + DMSO 6 μL + Injection water 90 μL
(Method)
Capillary: Fused silica capillary (BECKMAN COULTER, inner diameter 50 μm, total length 30.2 cm, effective length 20.0 cm)
Applied voltage: 10 kV (331 V / cm)
Applied air pressure: 0.7 psi
Capillary temperature: 25 ° C
Electroosmotic flow marker: DMSO
Detection: UV multi-wavelength absorption detection (measurement wavelength: 215 nm, 238 nm)
Sample injection: pressurized method (0.5 psi, 5 sec)
製剤例
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例１：　錠剤
　本発明化合物、乳糖およびステアリン酸カルシウムを混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。 Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1: Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
製剤例２：　カプセル剤
　本発明化合物、乳糖およびステアリン酸カルシウムを均一に混合して粉末または細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。 Formulation Example 2: Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
製剤例３：　顆粒剤
　本発明化合物、乳糖およびステアリン酸カルシウムを均一に混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。 Formulation Example 3: Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
製剤例４：　口腔内崩壊錠
　本発明化合物および結晶セルロースを混合し、造粒後打錠して口腔内崩壊錠とする。 Formulation Example 4: Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
製剤例５：　ドライシロップ
　本発明化合物および乳糖を混合し、粉砕、整粒、篩別して適当な大きさのドライシロップとする。 Formulation Example 5: Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
製剤例６：　注射剤
　本発明化合物およびリン酸緩衝液を混合し、注射剤とする。 Formulation Example 6: Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
製剤例７：　点滴剤
　本発明化合物およびリン酸緩衝液を混合し、点滴剤とする。 Formulation Example 7: Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
製剤例８：　吸入剤
　本発明化合物および乳糖を混合し細かく粉砕することにより、吸入剤とする。 Formulation Example 8: Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
製剤例９：　軟膏剤
　本発明化合物およびワセリンを混合し、軟膏剤とする。 Formulation Example 9: Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
製剤例１０： 貼付剤
　本発明化合物および粘着プラスターなどの基剤を混合し、貼付剤とする。 Formulation Example 10: Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
　本発明に係る化合物は、特にグラム陰性菌に対する広範な抗菌スペクトルを有し、β－ラクタマーゼ産生グラム陰性菌に対して高い安定性を有している抗菌薬として有効である。また、体内動態もよく、水溶性も高いため、特に注射薬または経口薬として有効である。 The compound according to the present invention has a broad antibacterial spectrum particularly against gram-negative bacteria and is effective as an antibacterial drug having high stability against β-lactamase-producing gram-negative bacteria. In addition, since it has good pharmacokinetics and high water solubility, it is particularly effective as an injection or oral drug.

Claims (27)

  1. 式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    －Ｚ－は単結合または－ＣＲ７ＡＲ７Ｂ－であり；
    Ｒ７ＡおよびＲ７Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、または置換もしくは非置換の芳香族複素環スルホニルであり；
    ＹはＮまたはＣＨであり；
    －Ｗ－は－Ｓ－、－Ｓ－ＣＨ２－、－ＣＨ２－Ｓ－または－ＣＨ２－であり；
    －Ｔ－は－ＣＲ４ＡＲ４Ｂ－、－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－または－Ｏ－であり；
    Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂはそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、アシル、アシルオキシ、スルファニル、スルホ、シアノ、ニトロ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアミノ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、または置換もしくは非置換の芳香族複素環スルホニルであり；
    Ｒ１６はカルボキシ、シアノ、テトラゾリルまたは置換もしくは非置換のカルバモイルであり；
    Ｒ１７は水素原子または置換もしくは非置換のアルキルであり；
    Ｒ１は置換もしくは非置換の炭素環式基または置換もしくは非置換の複素環式基であり；
    Ｒ２ＡおよびＲ２Ｂについては、
    ａ）Ｒ２ＡおよびＲ２Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、スルホ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
    ｂ）Ｒ２ＡおよびＲ２Ｂが一緒になって、置換もしくは非置換のメチリデン、または置換もしくは非置換のヒドロキシイミノを形成し；
    Ｒ３は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）である。
    ただし、以下の化合物を除く。
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
    Figure JPOXMLDOC01-appb-C000006
    で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (Where
    -Z- is a single bond or -CR 7A R 7B- ;
    R 7A and R 7B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted amino, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, Substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or non-substituted Substituted aromatic heterocyclic oxy, substituted if Or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted non-substituted Aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted Or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic An aromatic carbocyclic sulfonyl, or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
    Y is N or CH;
    -W- is -S -, - S-CH 2 -, - CH 2 -S- or -CH 2 -;
    -T- is -CR 4A R 4B -, - CR 5A R 5B -CR 6A R 6B - or -O- and is;
    R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, halogen, hydroxy, carboxy, acyl, acyloxy, sulfanyl, sulfo, cyano, nitro, ureido, amidino, guanidino, Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynyl Rusulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or Unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted Substituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic Elementary ring oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy Substituted, unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted Aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic Heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or An unsubstituted aromatic carbocyclic sulfonyl, or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
    R 16 is carboxy, cyano, tetrazolyl or substituted or unsubstituted carbamoyl;
    R 17 is a hydrogen atom or substituted or unsubstituted alkyl;
    R 1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
    For R 2A and R 2B
    a) R 2A and R 2B are each independently a hydrogen atom, substituted or unsubstituted amino, sulfo, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl , Hydroxy, or substituted carbonyloxy, or
    b) R 2A and R 2B together form a substituted or unsubstituted methylidene, or a substituted or unsubstituted hydroxyimino;
    R 3 is a hydrogen atom, —OCH 3 or —NH—CH (═O).
    However, the following compounds are excluded.
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
    Figure JPOXMLDOC01-appb-C000006
    Or an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  2. －Ｚ－が単結合であり、ＹがＣＨであり、－Ｗ－が－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である、請求項１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    The compound according to claim 1, an ester thereof, or a pharmaceutically acceptable salt thereof, wherein -Z- is a single bond, Y is CH, and -W- is -S-CH 2 -or -CH 2 -S-. Acceptable salts or hydrates thereof.
  3. －Ｚ－が単結合であり、Ｒ４Ａ、Ｒ４Ｂ、Ｒ５Ａ、Ｒ５Ｂ、Ｒ６ＡおよびＲ６Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアミノ、またはヒドロキシである、請求項２記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    -Z- is a single bond, and R 4A , R 4B , R 5A , R 5B , R 6A and R 6B are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbamoyloxy, The compound according to claim 2, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino, or hydroxy.
  4. －Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり、ＹがＮであり、－Ｗ－が－ＣＨ２－であり、－Ｔ－が－ＣＲ４ＡＲ４Ｂ－である、請求項１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    -Z- is -CR 7A R 7B - is, Y is N, -W- is -CH 2 - and is, -T- is -CR 4A R 4B - is a compound according to claim 1, wherein, An ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  5. Ｒ１が置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基である、請求項１～４のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    The compound according to any one of claims 1 to 4, R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, an ester thereof, or a pharmaceutical thereof Acceptable salts or hydrates thereof.
  6. Ｒ１が下式：
    Figure JPOXMLDOC01-appb-C000007
    （式中、ＸはＣＨ、ＣＣｌ、ＣＦ、ＣＢｒまたはＮである）
    で示される基である、請求項１～５のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    R 1 is the following formula:
    Figure JPOXMLDOC01-appb-C000007
    (Wherein X is CH, CCl, CF, CBr or N)
    The compound according to any one of claims 1 to 5, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a group represented by:
  7. Ｒ１が下式：
    Figure JPOXMLDOC01-appb-C000008
    （式中、ＸはＣＣｌ、ＣＦまたはＣＢｒである）
    で示される基である、請求項１～５のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    R 1 is the following formula:
    Figure JPOXMLDOC01-appb-C000008
    (Wherein X is CCl, CF or CBr)
    The compound according to any one of claims 1 to 5, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a group represented by:
  8. Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
    Figure JPOXMLDOC01-appb-C000009
    または以下に示す置換もしくは非置換のヒドロキシイミノ：
    Figure JPOXMLDOC01-appb-C000010
    （式中、Ｒ１０は水素原子または置換もしくは非置換のアルキルであり、式中、Ｒ８およびＲ９はそれぞれ独立して、水素原子、ハロゲン、ヒドロキシ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換の炭素環式基、もしくは置換もしくは非置換の複素環式基であるか、Ｒ８およびＲ９が一緒になって置換もしくは非置換のメチリデンを形成するか、またはＲ８およびＲ９は隣接原子と一緒になって置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成していてもよく；Ｑは単結合、置換もしくは非置換の炭素環ジイルまたは置換もしくは非置換の複素環ジイルであり；ｍは０～３の整数である）
    である、請求項１～７のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    R 2A and R 2B taken together have a methylidene having the substituents shown below:
    Figure JPOXMLDOC01-appb-C000009
    Or substituted or unsubstituted hydroxyimino:
    Figure JPOXMLDOC01-appb-C000010
    (Wherein R 10 is a hydrogen atom or substituted or unsubstituted alkyl, and in the formula, R 8 and R 9 are each independently a hydrogen atom, halogen, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted Or an unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group, R 8 and R 9 taken together to form a substituted or unsubstituted methylidene, or R 8 and R 9 May be taken together with adjacent atoms to form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle; Q is a single bond, substituted or unsubstituted carbocyclic diyl Or substituted or unsubstituted heterocyclic diyl; m is an integer from 0 to 3)
    The compound according to any one of claims 1 to 7, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  9. Ｒ２ＡおよびＲ２Ｂが一緒になって下式：
    Figure JPOXMLDOC01-appb-C000011
    （式中、各記号は上記と同意義である。）
    で示される基である、請求項１～７のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    R 2A and R 2B together form the following formula:
    Figure JPOXMLDOC01-appb-C000011
    (In the formula, each symbol is as defined above.)
    The compound according to any one of claims 1 to 7, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a group represented by:
  10. Ｒ３が水素原子または－ＯＣＨ３である、請求項１～９のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    10. The compound according to any one of claims 1 to 9, wherein R 3 is a hydrogen atom or —OCH 3 , an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  11. Ｒ１６がカルボキシである、請求項１～１０のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    The compound according to any one of claims 1 to 10, wherein R 16 is carboxy, an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  12. Ｒ１７が水素原子であり、請求項１～１１のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    The compound according to any one of claims 1 to 11, R ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 17 is a hydrogen atom.
  13. Ｔが－ＣＲ４ＡＲ４Ｂ－である、請求項１～１２のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    The compound according to any one of claims 1 to 12, wherein T is -CR 4A R 4B- , an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  14. －Ｚ－が単結合であり；
    ＹがＣＨであり；
    －Ｗ－が－Ｓ－ＣＨ２－であり；
    －Ｔ－が－ＣＲ４ＡＲ４Ｂ－または－ＣＲ５ＡＲ５Ｂ－ＣＲ６ＡＲ６Ｂ－であり；
    Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、アセチルオキシ、カルバモイルオキシ、メチル、またはアミノであり；
    Ｒ５Ａ、Ｒ５Ｂ、ＣＲ６ＡおよびＲ６Ｂが水素原子であり；
    Ｒ１が下式：
    Figure JPOXMLDOC01-appb-C000012
    （式中、各定義は請求項６と同意義である）
    であり；
    Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
    Figure JPOXMLDOC01-appb-C000013
    または下式：
    Figure JPOXMLDOC01-appb-C000014
    （式中、各定義は請求項８と同意義である）
    であり；
    Ｒ３が水素原子または－ＯＣＨ３であり、Ｒ１６がカルボキシであり、Ｒ１７が水素原子である、請求項１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。     -Z- is a single bond;
    Y is CH;
    -W- is -S-CH 2- ;
    -T- is -CR 4A R 4B - or -CR 5A R 5B -CR 6A R 6B - a and;
    R 4A and R 4B are each independently a hydrogen atom, hydroxy, acetyloxy, carbamoyloxy, methyl, or amino;
    R 5A , R 5B , CR 6A and R 6B are hydrogen atoms;
    R 1 is the following formula:
    Figure JPOXMLDOC01-appb-C000012
    (Wherein each definition has the same meaning as in claim 6)
    Is;
    R 2A and R 2B taken together have a methylidene having the substituents shown below:
    Figure JPOXMLDOC01-appb-C000013
    Or the following formula:
    Figure JPOXMLDOC01-appb-C000014
    (Wherein each definition has the same meaning as in claim 8)
    Is;
    The compound according to claim 1, an ester thereof or a pharmaceutically acceptable salt thereof, or a compound thereof, wherein R 3 is a hydrogen atom or —OCH 3 , R 16 is carboxy, and R 17 is a hydrogen atom. Hydrate.
  15. －Ｚ－が－ＣＲ７ＡＲ７Ｂ－であり；
    ＹがＮであり；
    －Ｗ－が－ＣＨ２－であり；
    －Ｔ－が－ＣＲ４ＡＲ４Ｂ－であり；
    Ｒ４ＡおよびＲ４Ｂがそれぞれ独立して水素原子、ヒドロキシ、置換もしくは非置換のカルバモイルオキシ、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルキル、または置換もしくは非置換のアミノであり；
    Ｒ１が下式：
    Figure JPOXMLDOC01-appb-C000015
    （式中、各定義は請求項６と同意義である）
    で示される基であり；
    Ｒ２ＡおよびＲ２Ｂについては、
    ａ）Ｒ２Ａが、水素原子、置換もしくは非置換のアミノ、スルホ、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであり、およびＲ２Ｂが水素原子であり、
    ｂ－１）Ｒ２ＡおよびＲ２Ｂが一緒になって、以下に示す置換基を有するメチリデン：
    Figure JPOXMLDOC01-appb-C000016
    または、
    ｂ－２）下式：
    Figure JPOXMLDOC01-appb-C000017
    （式中、各定義は上記と同意義である）
    であり；
    Ｒ３が水素原子またはＯＣＨ３であり；Ｒ１６はカルボキシ、テトラゾリルまたはカルバモイルであり；かつ、Ｒ１７が水素原子またはアルキルである、請求項１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    -Z- is -CR 7A R 7B - a and;
    Y is N;
    -W- is -CH 2- ;
    -T- is -CR 4A R 4B - a and;
    R 4A and R 4B are each independently a hydrogen atom, hydroxy, substituted or unsubstituted carbamoyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkyl, or substituted or unsubstituted amino;
    R 1 is the following formula:
    Figure JPOXMLDOC01-appb-C000015
    (Wherein each definition has the same meaning as in claim 6)
    A group represented by:
    For R 2A and R 2B
    a) R 2A is a hydrogen atom, substituted or unsubstituted amino, sulfo, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, hydroxy, or carbonyloxy having a substituent And R 2B is a hydrogen atom,
    b-1) R 2A and R 2B taken together have a methylidene having the following substituents:
    Figure JPOXMLDOC01-appb-C000016
    Or
    b-2) The following formula:
    Figure JPOXMLDOC01-appb-C000017
    (Wherein each definition has the same meaning as above)
    Is;
    The compound according to claim 1, its ester or pharmaceutically acceptable thereof, wherein R 3 is a hydrogen atom or OCH 3 ; R 16 is carboxy, tetrazolyl or carbamoyl; and R 17 is a hydrogen atom or alkyl. Salts, or hydrates thereof.
  16. 化合物Ｉ－００２，　Ｉ－００３，　Ｉ－０１１，　Ｉ－０１７，　Ｉ－０１８，　Ｉ－０１９，　Ｉ－０２９，　Ｉ－０３１，　Ｉ－０３９，　Ｉ－０５３，　Ｉ－０５５，　Ｉ－０６３，　Ｉ－０７０，　Ｉ－０７２，　Ｉ－０７５,　Ｉ－０７６,　Ｉ－０７７,　およびＩ－０８６の請求項１記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    Compounds I-002, I-003, I-011, I-017, I-018, I-019, I-029, I-031, I-039, I-053, I-055, I-063, I -070, I-072, I-075, I-076, I-077, and I-086, the ester or pharmaceutically acceptable salt thereof, or the hydrate thereof .
  17. 請求項１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する医薬組成物。
    A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  18. 抗菌作用を有する、請求項１７記載の医薬組成物。
    The pharmaceutical composition according to claim 17, which has an antibacterial action.
  19. 請求項１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を投与することを特徴とする、菌感染に関連する疾患の治療またはその予防法。
    A treatment for a disease associated with a bacterial infection, which comprises administering a compound according to any one of claims 1 to 16, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Its prevention method.
  20. 菌感染に関連する疾患を治療または予防するための、請求項１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物。
    The compound according to any one of claims 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof for treating or preventing a disease associated with bacterial infection.
  21. （Ａ－１）請求項１～１６のいずれかに記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物と、（Ｂ－１）β－ラクタマーゼ阻害作用を有する化合物、その製薬上許容される塩、またはそれらの溶媒和物を組み合わせることを特徴とする医薬。
    (A-1) the compound according to any one of claims 1 to 16, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (B-1) a β-lactamase inhibitory action Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  22. 式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000018
    （式中、
    Ｒ１１はアミノ、またはアシルで置換されたアミノであり；
    Ｒ１２は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）であり；
    Ｒ１３、Ｒ１４およびＲ１５はそれぞれ独立して水素原子または置換もしくは非置換のアルキルであり；
    Ｕは－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である）
    で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。
    Formula (II):
    Figure JPOXMLDOC01-appb-C000018
    (Where
    R 11 is amino or amino substituted with acyl;
    R 12 is a hydrogen atom, —OCH 3 or —NH—CH (═O);
    R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl;
    U is —S—, —S—CH 2 — or —CH 2 —S—)
    A pharmaceutical composition having an antibacterial action against carbapenem-resistant bacteria, comprising a compound represented by the formula:
  23. Ｒ１１が下式：
    Figure JPOXMLDOC01-appb-C000019
    （式中、Ｒ１’は置換もしくは非置換の複素環式基であり；
    Ｒ２’ＡおよびＲ２’Ｂについては、
    ａ）Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、ＳＯ３Ｈ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
    ｂ）Ｒ２’ＡおよびＲ２’Ｂが一緒になって、置換もしくは非置換のヒドロキシイミノを形成してもよい）
    で示される基であり；
    Ｒ１３は水素原子であり；
    Ｒ１４およびＲ１５はそれぞれ独立して水素原子またはメチルである、請求項２２記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。
    R 11 is the following formula:
    Figure JPOXMLDOC01-appb-C000019
    Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
    For R 2′A and R 2′B ,
    a) R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or
    b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
    A group represented by:
    R 13 is a hydrogen atom;
    23. A carbapenem-resistant bacterium comprising the compound according to claim 22, an ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 14 and R 15 are each independently a hydrogen atom or methyl. A pharmaceutical composition having an antibacterial action.
  24. Ｒ１’が下式：
    Figure JPOXMLDOC01-appb-C000020
    （式中、Ｘ’はＣＨまたはＮである）
    で示される基であり、
    Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して水素原子、または下式：
    Figure JPOXMLDOC01-appb-C000021
    で示される基であるか、またはＲ２‘ＡおよびＲ２’Ｂが一緒になって下式：
    Figure JPOXMLDOC01-appb-C000022
    （式中、Ｒ１０’は水素原子またはアルキルであり、Ｒ８’およびＲ９’はそれぞれ独立して水素原子またはアルキルである）
    で示される基であり、Ｒ１２が水素原子またはメトキシである、請求項２２または２３記載の化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物を含有する、カルバペネム耐性菌に対して抗菌作用を有する医薬組成物。
    R 1 ′ is the following formula:
    Figure JPOXMLDOC01-appb-C000020
    (Where X ′ is CH or N)
    A group represented by
    R 2′A and R 2′B each independently represent a hydrogen atom, or the following formula:
    Figure JPOXMLDOC01-appb-C000021
    Or R 2′A and R 2′B together are represented by the following formula:
    Figure JPOXMLDOC01-appb-C000022
    Wherein R 10 ′ is a hydrogen atom or alkyl, and R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl.
    24. A carbapenem containing the compound according to claim 22 or 23, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R 12 is a hydrogen atom or methoxy. A pharmaceutical composition having an antibacterial action against resistant bacteria.
  25. （Ａ－２）式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000023
    （式中、
    Ｒ１１はアミノ、またはアシルで置換されたアミノであり；
    Ｒ１２は水素原子、－ＯＣＨ３または－ＮＨ－ＣＨ（＝Ｏ）であり；
    Ｒ１３、Ｒ１４およびＲ１５はそれぞれ独立して水素原子または置換もしくは非置換のアルキルであり；
    Ｕは－Ｓ－、－Ｓ－ＣＨ２－または－ＣＨ２－Ｓ－である）
    で示される化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物と（Ｂ－１）β－ラクタマーゼ阻害作用を有する化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの溶媒和物を組み合わせることを特徴とする医薬。
    (A-2) Formula (II):
    Figure JPOXMLDOC01-appb-C000023
    (Where
    R 11 is amino or amino substituted with acyl;
    R 12 is a hydrogen atom, —OCH 3 or —NH—CH (═O);
    R 13 , R 14 and R 15 are each independently a hydrogen atom or substituted or unsubstituted alkyl;
    U is —S—, —S—CH 2 — or —CH 2 —S—)
    Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a compound having an inhibitory action on (B-1) β-lactamase, an ester thereof or a pharmaceutically acceptable salt thereof. A pharmaceutical comprising a combination of a salt or a solvate thereof.
  26. （Ａ－２）のＲ１１が下式：
    Figure JPOXMLDOC01-appb-C000024

    （式中、Ｒ１’は置換もしくは非置換の複素環式基であり；
    Ｒ２’ＡおよびＲ２’Ｂについては、
    ａ）Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して、水素原子、置換もしくは非置換のアミノ、ＳＯ３Ｈ、置換もしくは非置換のアミノスルホニル、カルボキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、ヒドロキシ、もしくは置換基を有しているカルボニルオキシであるか、または、
    ｂ）Ｒ２’ＡおよびＲ２’Ｂが一緒になって、置換もしくは非置換のヒドロキシイミノを形成してもよい）
    で示される基であり；
    Ｒ１３は水素原子であり；
    Ｒ１４およびＲ１５はそれぞれ独立して水素原子またはメチルである化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物である、請求項２５記載の医薬。
    R 11 of (A-2) is the following formula:
    Figure JPOXMLDOC01-appb-C000024

    Wherein R 1 ′ is a substituted or unsubstituted heterocyclic group;
    For R 2′A and R 2′B ,
    a) R 2′A and R 2′B each independently represent a hydrogen atom, substituted or unsubstituted amino, SO 3 H, substituted or unsubstituted aminosulfonyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, Substituted or unsubstituted carbamoyl, hydroxy, or substituted carbonyloxy, or
    b) R 2′A and R 2′B may be taken together to form a substituted or unsubstituted hydroxyimino)
    A group represented by:
    R 13 is a hydrogen atom;
    26. The medicament according to claim 25, wherein R 14 and R 15 are each independently a hydrogen atom or a compound, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  27. （Ａ－２）のＲ１’が下式：
    Figure JPOXMLDOC01-appb-C000025

    （式中、Ｘ’はＣＨまたはＮである）
    で示される基であり、
    Ｒ２’ＡおよびＲ２’Ｂがそれぞれ独立して水素原子、または下式：
    Figure JPOXMLDOC01-appb-C000026
    で示される基であるか、またはＲ２’ＡおよびＲ２’Ｂが一緒になって下式：
    Figure JPOXMLDOC01-appb-C000027

    （式中、Ｒ１０’は水素原子またはアルキルであり、Ｒ８’およびＲ９’はそれぞれ独立して水素原子またはアルキルである）
    で示される基であり、Ｒ１２が水素原子またはメトキシである化合物、そのエステル体もしくはそれらの製薬上許容される塩、またはそれらの水和物である、請求項２６記載の医薬。     R 1 ′ in (A-2) is the following formula:
    Figure JPOXMLDOC01-appb-C000025

    (Where X ′ is CH or N)
    A group represented by
    R 2′A and R 2′B each independently represent a hydrogen atom, or the following formula:
    Figure JPOXMLDOC01-appb-C000026
    Or R 2′A and R 2′B together are represented by the following formula:
    Figure JPOXMLDOC01-appb-C000027

    Wherein R 10 ′ is a hydrogen atom or alkyl, and R 8 ′ and R 9 ′ are each independently a hydrogen atom or alkyl.
    27. The medicament according to claim 26, which is a compound represented by the formula: wherein R 12 is a hydrogen atom or methoxy, an ester thereof or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
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