WO2020090700A1 - Novel ynone compound and use thereof - Google Patents

Novel ynone compound and use thereof Download PDF

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WO2020090700A1
WO2020090700A1 PCT/JP2019/042086 JP2019042086W WO2020090700A1 WO 2020090700 A1 WO2020090700 A1 WO 2020090700A1 JP 2019042086 W JP2019042086 W JP 2019042086W WO 2020090700 A1 WO2020090700 A1 WO 2020090700A1
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group
formula
alkyl group
hydrogen atom
compound
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PCT/JP2019/042086
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French (fr)
Japanese (ja)
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中山　淳
順平 寺町
正博 安倍
康祐 難波
伊藤　孝司
大輔 辻
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国立大学法人徳島大学
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
    • 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 inone compound and its use.
  • Non-Patent Document 1 The following formula, obtained from the fermentation broth of the fungus Curvularia verruculosa: The enone compound represented by is known to have a strong anti-inflammatory action (Non-Patent Document 1).
  • An object of the present invention is to provide a novel inone compound useful for inducing endoplasmic reticulum stress response and the like.
  • the inventors of the present invention have conducted extensive studies to achieve the above-mentioned object, and as a result, found that a compound having an inone skeleton induces an endoplasmic reticulum stress response.
  • the present inventors have completed the present invention through further studies based on such findings.
  • the present invention includes the following aspects. Item 1.
  • a 1 is an aromatic ring which may have a substituent
  • X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) —
  • R X1 is a hydrogen atom or an alkyl group
  • X 2 is a single bond or a double bond
  • R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group
  • R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms.
  • Item 2 The compound according to Item 1, wherein A 1 is a C 6-10 aromatic hydrocarbon ring which may have a substituent, or a 5- to 10-membered aromatic heterocycle which may have a substituent. Or its salt.
  • R 5 is —OR 5a or —NR 5b R 5c
  • R 5a is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group
  • R 5b and R 5c are each independently a hydrogen atom, an alkyl group, or an aryl group
  • n is an integer of 0 to 4, If n is an integer of 2 or more, the plurality of R 5, may be the same or different from each other.
  • X 3 is a single bond, a double bond, or a triple bond
  • R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent
  • R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or R 7 O and R 8 O may form a ring with two adjacent carbon atoms
  • R 9 is a hydrogen atom, an alkyl group, or an aryl group.
  • the compounds represented by are excluded.
  • Item 11. Item 11.
  • a 1 is an aromatic ring which may have a substituent
  • X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) —
  • R X1 is a hydrogen atom or an alkyl group
  • X 2 is a single bond or a double bond
  • R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group
  • R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms.
  • X 3 is a single bond, a double bond, or a triple bond
  • R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent
  • R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or R 7 O and R 8 O may form a ring with two adjacent carbon atoms
  • R 9 is a hydrogen atom, an alkyl group, or an aryl group.
  • a pharmaceutical composition comprising at least one selected from: Item 16.
  • Item 16. The pharmaceutical composition according to Item 15, which is an endoplasmic reticulum stress response inducer.
  • Item 18. The pharmaceutical composition according to any one of Items 15 to 17, which is at least one prophylactic or therapeutic agent selected from cancer, bone disease, and rheumatism.
  • the compound of the present invention is capable of inducing an endoplasmic reticulum stress response, and is useful for the prevention or treatment of diseases associated with endoplasmic reticulum stress. Moreover, the compound of the present invention can inhibit the activity of protein disulfide isomerase (PDI), and is useful for the prevention or treatment of diseases associated with PDI. Furthermore, the compound of the present invention is useful for the prevention or treatment of at least one disease selected from cancer, bone disease, and rheumatism. Moreover, since the compound of the present invention does not inhibit normal hematopoiesis, it has few side effects.
  • PDI protein disulfide isomerase
  • FIG. 1 is a diagram showing expression levels of CHOP relating to endoplasmic reticulum stress response in Examples 2, 8 and 9.
  • FIG. 2 is a diagram showing the inhibition of tumor progression of the compound of Example 2 in myeloma model mice.
  • FIG. 3 is a diagram showing the inhibition of tumor progression by the compound of Example 8 in myeloma model mice.
  • FIG. 4 is a graph showing the effect of the compound of Example 2 on cytotoxic activity on hematopoietic stem cells.
  • FIG. 5 is a graph showing the effect of the compound of Example 8 on the cytotoxic activity on hematopoietic stem cells.
  • FIG. 6 shows the inhibition of osteoclast formation by the compound of Example 8.
  • 7 is a figure which shows the osteoclast formation suppression of the compound of Example 2.
  • FIG. 8 is a figure which shows the cancer bone lesion formation suppression of the compound of Example 8.
  • FIG. 9 is a graph showing the antirheumatic effect of the compound of Example 2.
  • C ab means that the target carbon number is an integer of a or more and b or less.
  • aromatic ring is a concept including an aromatic hydrocarbon ring and an aromatic heterocycle.
  • the aromatic hydrocarbon ring means an aromatic ring in which the ring-constituting atoms consist of carbon atoms only.
  • the number of constituent atoms of the aromatic hydrocarbon ring is not particularly limited, but can be, for example, 6 to 20.
  • the aromatic hydrocarbon ring can be monocyclic or fused polycyclic. Examples of the monocyclic aromatic hydrocarbon ring include benzene.
  • the condensed polycyclic aromatic hydrocarbon ring examples include two rings (eg, indene, naphthalene), three rings (eg, fluorene, anthracene, phenanthrene), and four rings (eg, pyrene).
  • the aromatic heterocycle means an aromatic ring containing carbon atoms and heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as the constituent atoms of the ring.
  • the number of constituent atoms of the aromatic heterocycle is not particularly limited, but can be, for example, 5 to 20.
  • the number of heteroatoms among the constituent atoms of the aromatic heterocycle is not particularly limited, but can be, for example, 1 to 4.
  • the aromatic heterocycle can be monocyclic or fused polycyclic.
  • monocyclic aromatic heterocycles examples include 5-membered rings (eg, furan, isoxazole, oxazole, thiophene, isothiazole, thiazole, pyrrole, pyrazole, imidazole, triazole), 6-membered rings (eg, pyridine, pyridazine). , Pyrimidine, pyrazine, triazine).
  • the condensed ring aromatic heterocycle examples include two rings (eg, benzofuran, benzothiophene, indole, indazole, benzimidazole, purine, quinoline, isoquinoline, cinoline, quinoxaline, phthalazine, 1,8-naphthyridine, putediline), There are three rings (eg, carbazole, acridine, phenazine, phenanthridine, phenanthroline, phenoxazine, phenothiazine).
  • the “aromatic ring group” refers to a group obtained by removing one hydrogen atom from the aromatic ring.
  • the aromatic ring group examples include aryl groups such as phenyl group and naphthyl group; and heteroaryl groups such as furanyl group, thienyl group and pyridyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • alkyl group is a concept including a linear alkyl group and a branched alkyl group.
  • linear alkyl group examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • the straight-chain C 1-10 alkyl group of Examples of the branched chain alkyl group include a branched chain C 3-10 alkyl group such as isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, 2-ethylhexyl and the like.
  • examples of the “cycloalkyl group” include C 3-10 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • aryl group refers to a monovalent group derived from an aromatic hydrocarbon ring.
  • aryl group include C 6-10 aryl groups such as phenyl and naphthyl.
  • examples of the “aralkyl group” include a C 6-10 aryl C 1-4 alkyl group such as benzyl and phenethyl.
  • alkoxy group refers to a group represented by the formula: R A O— (in the formula, R A is an alkyl group).
  • R A is an alkyl group.
  • alkoxy group include C 1-4 alkoxy groups such as methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), butoxy (n-butoxy, isobutoxy, s-butoxy, t-butoxy).
  • examples of the “alkoxyalkyl group” include groups represented by the formula: (C 1-4 alkyl) -O— (C 1-4 alkylene) -O—.
  • Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl.
  • examples of the “alkoxyalkoxy group” include groups represented by the formula: formula: (C 1-4 alkyl) -O— (C 1-4 alkylene)-.
  • Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkyl groups such as methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.
  • alkoxyalkoxyalkyl group is represented by, for example, the formula: (C 1-6 alkyl) -O- (C 1-4 alkylene) -O- (C 1-4 alkylene)-.
  • Groups. Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkoxy C 1 -such as methoxymethoxyethyl, methoxyethoxymethyl, ethoxymethoxymethyl, ethoxymethoxyethyl, ethoxyethoxymethyl, and ethoxyethoxyethyl. 3 alkyl groups are mentioned.
  • alkoxyalkoxyalkoxy group is represented by, for example, the formula: (C 1-6 alkyl) -O- (C 1-4 alkylene) -O- (C 1-4 alkylene) -O-. And the groups mentioned below.
  • Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkoxy C 1- such as methoxymethoxyethoxy, methoxyethoxymethoxy, ethoxymethoxymethoxy, ethoxymethoxyethoxy, ethoxyethoxymethoxy, and ethoxyethoxyethoxy.
  • 3 alkoxy groups can be mentioned.
  • acyl group means a group represented by the formula: —C ( ⁇ O) —R B1 (in the formula, R B1 is a hydrocarbon group), and —C ( ⁇ O).
  • a group represented by —O—R B2 (in the formula, R B2 is a hydrocarbon group) is included.
  • the hydrocarbon group represented by R B1 and R B2 may be a chain hydrocarbon group (eg, alkyl), a saturated or unsaturated cyclic hydrocarbon group (eg, cycloalkyl, aryl), a combination thereof ( Example: aralkyl).
  • Acyl groups include alkylcarbonyl, arylcarbonyl, and aralkylcarbonyl groups.
  • alkylcarbonyl group examples include (C 1-10 alkyl) carbonyl groups such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl and decanoyl.
  • Arylcarbonyl groups include, for example, benzoyl or (C 6-14 aryl) carbonyl groups such as naphthoyl (ie, ⁇ -naphthoyl or ⁇ -naphthoyl).
  • aralkylcarbonyl group examples include (C 6-14 aryl C 1-4 alkyl) carbonyl groups such as benzylcarbonyl.
  • alkylthio group refers to a group represented by the formula: R C —S— (wherein R C is an alkyl group).
  • R C is an alkyl group.
  • alkylthio group include C 1-4 alkylthio groups such as methylthio, ethylthio, propylthio (n-propylthio, isopropylthio) and butylthio (n-butylthio, isobutylthio, s-butylthio, t-butylthio).
  • the “monoalkylamino group” refers to a group represented by the formula: R D1 —NH— (in the formula, R D1 is an alkyl group).
  • the monoalkylamino group for example, monomethyl amino, mono-ethylamino, monopropyl amino (mono n- propylamino, mono isopropylamino) include mono C 1-4 alkylamino group or the like.
  • dialkylamino group refers to a group represented by the formula: R D2 R D3 N— (in the formula, R D1 and R D3 are the same or different and each is an alkyl group).
  • examples of the dialkylamino group include diC 1-4 alkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, propylmethylamino and the like.
  • the compound of the present invention or a salt thereof is a compound represented by formula (1) or a salt thereof (hereinafter, referred to as “compound (1)”): (In the formula, A 1 , X 1 , X 2 , R 1 , R 2 , R 3 , and R 4 are the same as above.)
  • a 1 is preferably a C 6-10 aromatic hydrocarbon ring which may have a substituent, or a 5- to 10-membered aromatic heterocycle which may have a substituent, and more preferably A C 6-10 aromatic hydrocarbon ring which may have a substituent, a 5- to 10-membered nitrogen-containing aromatic heterocycle which may have a substituent, and a substituent which may have 5 To 10-membered oxygen-containing aromatic heterocycle, or 5- to 10-membered sulfur-containing aromatic heterocycle which may have a substituent, more preferably C 6-10 aromatic hydrocarbon ring, particularly preferably Is a benzene ring which may have a substituent.
  • substituents examples include a halogen atom, a hydroxyl group, a mercapto group, an amino group, an alkyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxyalkoxyalkoxy group, an acyl group, an alkylthio group, a monoalkylamino group and a dialkylamino group.
  • the number of substituents is not particularly limited, but is, for example, an integer of 0 to 4, preferably an integer of 1 to 4, and more preferably an integer of 1 to 3.
  • a 1 is the following formula: (In the formula, R 5 and n are the same as above.)
  • the ring represented by is preferable. -OR 5a or -NR 5b R 5c ,
  • R 5a is preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, more preferably a hydrogen atom, a C 1-4 alkyl group, C 1-4 alkoxy C 1-4 alkyl group or C 1-4 alkoxy C 1-4 alkoxy C 1-4 alkyl group, particularly preferably hydrogen atom, C 1-2 alkyl group, C 1-2 alkoxy A C 1-2 alkyl group or a C 1-2 alkoxy C 1-2 alkoxy C 1-2 alkyl group.
  • R 5b and R 5c are preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-12 aryl group.
  • Examples of the combination of R 5b and R 5c include a combination in which R 5b and R 5c are hydrogen atoms, a combination in which one of R 5b and R 5c is a hydrogen atom and the other is an alkyl group, and a combination of R 5b and R 5c is an alkyl group.
  • a combination which is a group, a combination in which one of R 5b and R 5c is a hydrogen atom and the other is an aryl group, a combination in which R 5b and R 5c are an aryl group and the like are preferable.
  • n is preferably an integer of 1 to 4, more preferably an integer of 1 to 3.
  • a plurality of R 5 may be the same or different from each other, for example, a plurality of R 5 may be all —OR 5a , or —OR 5a and It may be a combination of —NR 5b R 5c .
  • a 1 is the following formula: (In the formula, R 51 , R 52 , R 53 , R 54 , and R 55 are the same as the above.)
  • the ring represented by is preferable.
  • a preferable combination of R 51 and R 52 is a combination in which R 51 is a hydrogen atom and R 52 is an alkyl group, R 51 is an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, and , R 52 is an alkyl group.
  • Suitable combinations of R 53 , R 54 , and R 55 include a combination in which R 51 is a hydrogen atom, R 54 is a hydrogen atom, and R 55 is an alkyl group.
  • X 1 is preferably an oxygen atom, a sulfur atom, or a formula: —N (R X11 ) — (wherein R X11 is a hydrogen atom or a C 1-4 alkyl group), and more preferably an oxygen atom or It is a sulfur atom, and particularly preferably an oxygen atom.
  • X 2 is a single bond or a double bond as described above. Specifically, it is as follows. (In the formula, * indicates a bonding position with A 1. ) When X 2 is a double bond, compound (1) can be in cis form or trans form. X 2 is preferably a double bond.
  • R 1 is preferably an alkyl group, more preferably a C 1-4 alkyl group, and particularly preferably a C 1-2 alkyl group.
  • R 1 is an alkyl group
  • the carbon atom to which R 1 is attached is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably S configuration.
  • R 2 is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and particularly preferably a hydrogen atom.
  • R 2 is an alkyl group
  • the carbon atom to which R 2 is attached is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably R configuration.
  • R 3 and R 4 are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, and more preferably a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkoxyC. 1-4 alkyl group, or C 1-4 alkoxy C 1-4 alkoxy C 1-4 alkyl group, particularly preferably hydrogen atom, C 1-2 alkyl group, C 1-2 alkoxy C 1-2 alkyl. Or a C 1-2 alkoxy C 1-2 alkoxy C 1-2 alkyl group.
  • Suitable combinations of R 3 and R 4, combined combined R 3 and R 4 are both hydrogen atoms, R 3 and R 4 are both alkyl groups, R 3 and R 4 are both an alkoxyalkyl group Combinations can be mentioned.
  • R 3 O and R 4 O may form a ring with two adjacent carbon atoms, and the ring has the following formula: (In the formula, R 3a and R 4a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group.) It may be a ring represented by. Each of R 3a and R 4a is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group. Suitable combinations of R 3a and R 4a, the combination R 3a and R 4a are both alkyl groups, R 3a is a hydrogen atom, and, as combinations R 4a is an aryl group.
  • the carbon atom to which R 3 O and R 4 O are bonded is an asymmetric carbon atom.
  • the configuration of the asymmetric carbon atom to which R 3 O and R 4 O are bonded may be either the R configuration or the S configuration, but both are preferably the S configuration.
  • R 11 is an alkyl group, and R 31 and R 41 are the same or different and are a hydrogen atom, an alkyl group, or an alkoxyalkyl group.
  • R 11 is preferably a C 1-4 alkyl group, and more preferably a C 1-2 alkyl group.
  • R 31 and R 41 are each preferably a hydrogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy C 1-4 alkyl group, more preferably a hydrogen atom, a C 1-2 alkyl group. Or a C 1-2 alkoxy C 1-2 alkyl group.
  • the compound (1) has at least two asymmetric carbon atoms (carbon atoms to which R 3 O and R 4 O are bonded), and includes both enantiomers and diastereomers.
  • the compound (1) may be a mixture containing two kinds of enantiomers.
  • the mixture may be a mixture in which one enantiomer is contained in an excessive amount, or may be an equivalent mixture (racemate) of two kinds of enantiomers.
  • the compound (1) is preferably a compound represented by the following formula (1A) or a salt thereof. (In the formula, A 1 , X 1 , X 2 , R 1 , R 2 , R 3 , and R 4 are the same as described above. However, the following formula: The compounds represented by are excluded. )
  • the compound (1) is preferably a compound selected from the following group or a salt thereof:
  • a compound in which the methoxy group bonded to the benzene ring is changed to a monoalkylamino group such as a monomethylamino group or a salt thereof is also preferable.
  • the salt is preferably a pharmaceutically acceptable salt.
  • the salt can be an inorganic salt or an organic salt.
  • examples of the salt include inorganic acid salts (eg, hydrofluoric acid salts, hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, nitrates, perchloric acid salts, sulfuric acid salts, phosphoric acid salts), organic acids.
  • Acid salts eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citric acid
  • salts tartrates, oxalates, maleates
  • amino acid salts eg, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate.
  • the compound can be produced, for example, according to the following reaction scheme.
  • Z 1 is a leaving group
  • Z 2 is a hydrogen atom, an alkyl group, or an acyl group, or the group represented by the formula: Z 2 OC ( ⁇ O) — and the hydroxyl group which may be substituted at the ortho position are the same as those of the adjacent A 1 It may form a ring with the constituent atoms
  • Z 3 is a silyl group
  • M is an alkali metal
  • L is a leaving group
  • a 1 , X 1 , X 2 , and R 1 to R 4 are the same as above.
  • Step (A) is a step of reacting the compound represented by formula (1-1) with the compound represented by formula (3) to obtain the compound represented by formula (1-2).
  • the leaving group represented by Z 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), alkylsulfonyloxy (eg, C 1-4 alkyl such as mesyloxy).
  • Z 2 is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 1-4 alkylcarbonyl group.
  • the compound is preferably a compound represented by the following formula (1-1-1):
  • Z 21 and Z 22 are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and A 1 and Z 1 are the same as the above.
  • Z 21 and Z 22 are each preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group. Suitable combinations of Z 21 and Z 22, a combination combinations Z 21 and Z 22 are both hydrogen atoms, Z 21 and Z 22 are both alkyl groups, Z 21 is a hydrogen atom, and, Z 22 Is an aryl group.
  • examples of the alkali metal represented by M include lithium, sodium, and potassium.
  • the amount of the compound represented by the formula (3) used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and further 1 mol with respect to 1 mol of the compound represented by the formula (1-1). It is preferably 1.5 to 2.0 mol.
  • the reaction of step (A) is preferably performed in the presence of a base.
  • the base include trialkylamine (eg, triC 1-4 alkylamine such as triethylamine) and carbonate (eg, alkali metal carbonate such as Na 2 CO 3 and K 2 CO 3 ). These bases can be used alone or in combination of two or more. Of these, trialkylamines are preferred.
  • the amount of the base used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and more preferably 1.5 to 2 with respect to 1 mol of the compound represented by the formula (1-1). 0.0 mol.
  • the reaction of step (A) is preferably carried out in the presence of a catalyst.
  • the catalyst examples include a palladium catalyst [eg: tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), palladium carbon, dichloro [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II), trans-dichlorobis (tricyclohexylphosphine) palladium (II), dichlorobis (tri-o-tolylphosphine) palladium (II), dichlorobis (triphenylphosphine) palladium (II), palladium acetate (II) )], A nickel catalyst [eg: dichloro [1,1′-bis (diphenylphosphino) ferrocene] nickel (II), dichlorobis (triphenylphosphine) nickel (II)], and a ruthenium catalyst.
  • a palladium catalyst
  • the catalysts can be used alone or in combination of two or more. Of these, palladium catalysts are preferred.
  • the amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.1 to 0.5 mol, and more preferably 0.1 to 1.0 mol with respect to 1 mol of the compound represented by the formula (1-1). It is 1 to 0.2 mol.
  • the reaction of step (A) is preferably performed in the presence of a solvent.
  • the solvent include water, alcohol solvents (eg methanol, ethanol), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, 20 to 200 ° C., preferably 30 to 150 ° C.
  • the reaction time is, for example, 12 to 24 hours, preferably 12 to 14 hours.
  • Step (B) is a step of reacting the compound represented by formula (1-2) with the compound represented by formula (4) to obtain the compound represented by formula (1-3).
  • the silyl group represented by Z 3 is not particularly limited, and examples thereof include trialkylsilyl (eg, triC 1-4 such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl and the like).
  • Alkylsilyl) and alkyldiarylsilyl eg, C 1-4 alkyldiC 6-10 arylsilyl such as t-butyldiphenylsilyl.
  • the amount of the compound represented by the formula (4) to be used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (1-2). It is 2 mol, and more preferably 1.0 to 1.1 mol.
  • the reaction of step (B) is preferably performed in the presence of a base.
  • the base include alkali metal amides such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), sodium hexamethyldisilazide (NaHMDS) and potassium hexamethyldisilazide (KHMDS). .. These bases can be used alone or in combination of two or more.
  • the amount of the base used is usually 1 to 3 mol, preferably 1.5 to 2.5 mol, and more preferably 2.0 to 2. 1 mol based on 1 mol of the compound represented by the formula (1-2). It is 5 mol.
  • the reaction of step (B) is preferably performed in the presence of a solvent.
  • the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 0.2 to 2.0 hours, preferably 0.5 to 1.0 hours.
  • Step (C) is a step of removing the silyl group Z 3 from the compound represented by formula (1-3) to obtain the compound represented by formula (1-4).
  • the silyl group Z 3 can be removed by a conventional method.
  • a method of reacting the compound represented by the formula (1-3) with a fluorine compound include amine complexes of hydrogen fluoride, metal fluorides (eg, potassium fluoride), ammonium fluoride, and tetrabutylammonium fluoride (TBAF). These fluorine compounds may be used alone or in combination of two or more. Of these, TBAF is preferred.
  • the reaction of step (C) is preferably carried out in the presence of a solvent.
  • the solvent include carboxylic acid solvents (eg acetic acid), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more. Of these, carboxylic acid solvents are preferred.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 5 ° C. to 40 ° C., preferably 0 to 30 ° C.
  • the reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.
  • Step (D) is a step of reacting the compound represented by formula (1-4) with the compound represented by formula (5) to obtain the compound represented by formula (1-5).
  • the leaving group represented by L in the formula (5) include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), alkylsulfonyloxy (eg, C 1-4 alkylsulfonyloxy such as mesyloxy).
  • Haloalkylsulfonyloxy eg, perfluoroC 1-4 alkylsulfonyloxy such as trifluoromethylsulfonyloxy
  • arylsulfonyloxy eg, C 6-10 arylsulfonyloxy such as tosyloxy
  • N (R L1 ) examples thereof include a group represented by (R L2 )-(wherein R L1 and R L2 are the same or different and each is an alkyl group or an alkoxy group).
  • the group represented by the formula: N (R L1 ) (R L2 ) — is preferable.
  • R L1 and R L2 are preferably a C 1-4 alkyl group or a C 1-4 alkoxy group. Suitable combinations of R L1 and R L2 include combinations in which R L1 is an alkyl group and R L2 is an alkoxy group.
  • the amount of the compound represented by the formula (5) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (1-4). It is 2 mol, and more preferably 1.0 to 1.1 mol.
  • the reaction of step (D) is preferably performed in the presence of a base.
  • the base examples include alkyl alkali metal salts (eg: butyl lithium) and alkali metal amides (eg: LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more. Of these bases, alkyl alkali metal salts are preferred.
  • the amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, and more preferably 1. mol to 1 mol of the compound represented by the formula (1-3). It is 0 to 1.1 mol.
  • the reaction of step (D) is preferably performed in the presence of a solvent.
  • the solvent examples include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • ether solvents eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane. These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 0.2 to 1.0 hour, preferably 0.3 to 0.5 hour.
  • Step (E) is a step of reacting the compound represented by formula (1-5) with a triple bond protecting agent to obtain the compound represented by formula (1-6).
  • the triple bond protecting agent include Co 2 CO 8 .
  • the amount of the triple bond protecting agent used is usually 2 to 10 mol, preferably 3 to 6 mol, and more preferably 4 to 5 mol, relative to 1 mol of the compound represented by the formula (1-5). is there.
  • the reaction of step (E) is preferably performed in the presence of a solvent.
  • the solvent include halogen-based solvents (eg, dichloromethane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.
  • Step (F) is a step of obtaining a compound represented by formula (1-7) by cyclizing the compound represented by formula (1-6) and optionally hydrogenating.
  • the cyclization can be performed by a conventional method.
  • the compound represented by formula (1-6) can be cyclized by a metathesis reaction in the presence of a catalyst.
  • the catalyst include a catalyst represented by the following formula (second-generation Pierce-Grubbs catalyst).
  • the amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.2 to 1.0 mol, and more preferably 0.1 to 1.0 mol with respect to 1 mol of the compound represented by the formula (1-6). It is 4 to 1.0 mol.
  • the reaction of step (F) is preferably performed in the presence of a solvent.
  • the solvent include halogen-based solvents (eg, dichloromethane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 96 to 144 hours, preferably 96 to 120 hours.
  • Step (G) is a step of obtaining a compound represented by formula (1) by removing a protective group for triple bond from the compound represented by formula (1-7).
  • Deprotection can be performed by a conventional method.
  • a compound represented by the formula (1-7) is treated with a deprotecting agent [eg, ammonium hexanitratocerium (IV) (CAN), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ ), N-methylmorpholine N-oxide, a combination thereof] to remove the triple bond protecting group.
  • a deprotecting agent eg, ammonium hexanitratocerium (IV) (CAN), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ ), N-methylmorpholine N-oxide, a combination thereof
  • the amount of deprotecting agent used is usually 4 to 10 mol, preferably 4 to 8 mol, and more preferably 4 to 6 mol, relative to 1 mol of the compound represented by the formula (1-7).
  • the reaction of step (G) is preferably performed in the presence of a solvent.
  • the solvent include halogen solvents (eg dichloromethane), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane), ketone solvents (eg acetone, methyl ethyl ketone). Be done. These solvents may be used alone or in combination of two or more. Of these, ketone solvents are preferred.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 1 to 8 hours, preferably 1 to 2 hours.
  • the method for producing the compound (1) may include a step of purifying the intermediate product and / or the final product, if necessary. Purification can be carried out by a conventional method such as filtration or chromatography. In addition, a suitable protecting group may be introduced before the reaction and the protecting group may be removed after the reaction. Protection and deprotection can be performed by a conventional method.
  • the method for producing the compound (1) may include a step of separating isomers if necessary. Separation of isomers can be performed by a conventional method.
  • the compound of the present invention or a salt thereof is a compound represented by formula (2) or a salt thereof (hereinafter, referred to as “compound (2)”): (In the formula, X 3 and R 6 to R 9 are the same as above.)
  • X 3 is a single bond, a double bond, or a triple bond as described above. Specifically, it is as follows. (In the formula, * indicates a bonding position with R 9. ) When X 3 is a double bond and R 9 is an alkyl group or an aryl group, the compound (2) can be in the cis form or the trans form.
  • R 6 is preferably a hydrogen atom, an alkyl group which may have a substituent, or a heteroaryl group which may have a substituent (eg, a furanyl group, a thienyl group, a pyridyl group), and It is preferably an alkyl group which may have a substituent, more preferably a C 1-6 alkyl group which may have a substituent, and particularly preferably a C 1-6 which may have a substituent. It is a 1-4 alkyl group. Examples of the substituent include a hydroxyl group, a mercapto group, an amino group, an alkoxy group, an alkoxyalkoxy group, and an alkoxyalkoxyalkoxy group.
  • R 6 is preferably of the formula: (In the formula, X 4 is a hydroxyl group, a mercapto group, or an amino group, and R 61 and R 62 are the same or different and are a hydrogen atom or an alkyl group.) Is a group represented by.
  • X 4 is preferably a hydroxyl group.
  • R 61 is preferably an alkyl group, more preferably a C 1-4 alkyl group, and particularly preferably a C 1-2 alkyl group.
  • R 61 is an alkyl group
  • the carbon atom to which R 61 is bonded is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably S configuration.
  • R 62 is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and particularly preferably a hydrogen atom.
  • R 62 is an alkyl group
  • the carbon atom to which R 62 is attached is an asymmetric carbon atom.
  • the configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably R configuration.
  • R 7 and R 8 are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an aryl group, more preferably a hydrogen atom, an alkyl group, or an alkoxyalkyl group, and further preferably hydrogen.
  • R 7 O and R 8 O preferably form a ring with two adjacent carbon atoms, and the ring has the following formula: (In the formula, R 7a and R 8a are the same as the above, and * represents the bonding position to the carbonyl carbon).
  • the ring represented by is preferable.
  • Each of R 7a and R 8a is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group. Suitable combinations of R 7a and R 8a, a combination combinations R 7a and R 8a are hydrogen atoms, R 7a and R 8a are both alkyl groups, R 7a is a hydrogen atom, and, R 8a And the combination is an aryl group.
  • the carbon atom to which R 7 O and R 8 O are bonded is an asymmetric carbon atom.
  • the configuration of the asymmetric carbon atom to which R 7 O and R 8 O are bonded may be either the R configuration or the S configuration, but both are preferably the S configuration.
  • R 9 is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or a C 1-4 alkyl group, particularly preferably a hydrogen atom or a C 1-2 alkyl group, and most preferably a hydrogen atom. is there.
  • the compound (2) has at least two asymmetric carbon atoms (carbon atoms to which R 7 O and R 8 O are bonded) and includes both enantiomers and diastereomers.
  • the compound (2) may be a mixture containing two kinds of enantiomers.
  • the mixture may be a mixture in which one enantiomer is contained in an excessive amount, or may be an equivalent mixture (racemate) of two kinds of enantiomers.
  • Compound (2) is, in a preferred embodiment, a compound represented by the following formula (2A) or a salt thereof: . (Wherein, X 3, R 6, R 7, R 8, and R 9 are the same as above except the following formula: The compounds represented by are excluded. )
  • Compound (2) is, in another preferred embodiment, a compound selected from the following group or a salt thereof:
  • the salt is preferably a pharmaceutically acceptable salt.
  • the salt can be an inorganic salt or an organic salt.
  • examples of the salt include inorganic acid salts (eg, hydrofluoric acid salts, hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, nitrates, perchloric acid salts, sulfuric acid salts, phosphoric acid salts), organic acids.
  • Acid salts eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citric acid
  • salts tartrates, oxalates, maleates
  • amino acid salts eg, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate.
  • R 7 and R 8 are the same or different and each is an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group (corresponding to a protective group for a hydroxyl group), or a salt thereof,
  • a compound or a salt thereof in which R 7 O and R 8 O form a ring (corresponding to a protecting group for a hydroxyl group) with two adjacent carbon atoms can be produced, for example, according to the following reaction scheme.
  • Q 1 to Q 3 are the same or different and each is an alkyl group or an aryl group
  • Q 4 is a halide ion
  • Q 5 is a trialkylsilyl group or an alkyldiarylsilyl group
  • R 10 and R 11 are the same or different and each is an alkyl group, an alkoxy group, or an aryl group
  • R 6 to R 9 are the same as above.
  • Step (a) is a step of reacting the compound represented by formula (2-1) with the compound represented by formula (6) to obtain the compound represented by formula (2-2).
  • Q 1 to Q 3 are each preferably an aryl group, and more preferably a C 6-10 aryl group.
  • Q 4 is preferably a bromide ion or a chloride ion.
  • Examples of the compound represented by the formula (6) include methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, propyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide, pentyltriphenylphosphonium bromide, hexyltriphenylphosphonium bromide, Examples include heptyltriphenylphosphonium bromide, benzyltriphenylphosphonium bromide, (1-naphthylmethyl) triphenylphosphonium bromide, and their corresponding chlorides. These compounds can be used alone or in combination of two or more.
  • the amount of the compound represented by the formula (6) used is usually 1 to 5 mol, preferably 2 to 4 mol, and further preferably 3 to 1 mol of the compound represented by the formula (2-1). 4 mol.
  • the reaction of step (a) is preferably performed in the presence of a base.
  • the base include alkyl alkali metal (eg, n-butyl lithium) and alkali metal amide (eg, LDA, LHMDS, NaHMDS, KHMDS).
  • the amount of base used will usually be 1-5 mol, preferably 2-4 mol, and more preferably 3-4 mol, per 1 mol of the compound represented by formula (2-1).
  • the reaction of step (a) is preferably performed in the presence of a solvent.
  • the solvent examples include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • ether solvents eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane. These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 100 to 10 ° C., preferably ⁇ 80 ° C. to 0 ° C.
  • the reaction time is, for example, 1 to 24 hours, preferably 4 to 12 hours.
  • Step (b) is a step of hydrogenating the compound represented by formula (2-2) to obtain the compound represented by formula (2-3).
  • the amount of hydrogen used will usually be 1-50 mol, preferably 2-40 mol, and more preferably 10-20 mol, relative to 1 mol of the compound represented by formula (2-2).
  • the reaction of step (b) is preferably carried out in the presence of a catalyst.
  • the catalyst include catalysts conventionally used in hydrogenation, and examples thereof include palladium carbon and platinum carbon.
  • the amount of the catalyst used is usually 0.01 to 1 mol, preferably 0.1 to 0.5 mol, and more preferably 0.2 to 1 mol with respect to 1 mol of the compound represented by the formula (2-2). It is 0.3 mol.
  • the reaction of step (b) is preferably performed in the presence of a solvent.
  • the solvent include alcohol solvents (eg: methanol, ethanol), ether solvents (eg: chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran, dioxane). These solvents may be used alone or in combination of two or more. Of these, alcohol solvents are preferred.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, 0 to 50 ° C, preferably 5 ° C to 35 ° C.
  • the reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.
  • step (b) is omitted, and before step (e), the compound of formula (2-5) in which X 3 is a double bond is hydrogenated in the same manner as in step (b), Among (2-5), a compound in which X 3 is a single bond may be obtained.
  • Step (c) is a step of reacting the compound represented by formula (2-1) with the compound represented by formula (7) to obtain the compound represented by formula (2-4).
  • the trialkylsilyl group represented by Q 5 include triC 1-4 alkylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, and t-butyldimethylsilyl.
  • the alkyldiarylsilyl group represented by Q 5 include C 1-4 alkyldiC 6-10 arylsilyl such as t-butyldiphenylsilyl.
  • the amount of the compound represented by the formula (7) used is generally 1 to 5 mol, preferably 2 to 4 mol, and more preferably 3 to 1 mol of the compound represented by the formula (2-1). It is 4 mol.
  • the reaction of step (c) is preferably performed in the presence of a base.
  • the base include alkali metal amides (eg, LDA, lithium 2,2,6,6-tetramethylpiperazine, LHMDS, NaHMDS, KHMDS).
  • the amount of the base used is usually 0.8 to 1.2 mol, preferably 0.9 to 1.1 mol, and more preferably 1. mol to 1 mol of the compound represented by the formula (2-1). It is 0 to 1.1 mol.
  • the reaction of step (c) is preferably performed in the presence of a solvent.
  • the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 100 to 10 ° C., preferably ⁇ 80 ° C. to 0 ° C.
  • the reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.
  • step (d) the compound represented by the formula (2-5) is reacted with the compound represented by the formula (2-2), (2-3) or (2-4) to give the compound represented by the formula (2-5). It is a process of obtaining.
  • the oxidizing agent include nitroxy radical type oxidizing agents such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2-azaadamantane-N-oxyl (AZADO).
  • TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl
  • AZADO 2-azaadamantane-N-oxyl
  • the amount of the oxidant used is usually 0.1 to 1.0 mol, preferably 1 to 1.0 mol of the compound represented by the formula (2-2), (2-3) or (2-4). The amount is 0.1 to 0.5 mol, more preferably 0.2 to 0.3 mol.
  • the oxidant can be used with the reoxidant.
  • the reoxidant include sodium hypochlorite and iodobenzene diacetate. These reoxidants can be used alone or in combination of two or more.
  • the amount of the reoxidant used is usually 1 to 3 mol, preferably 1.0, relative to 1 mol of the compound represented by the formula (2-2), (2-3) or (2-4). The amount is up to 2.5 mol, more preferably 2.0 to 2.5 mol.
  • the reaction of step (d) may be carried out in the presence of a base.
  • the reaction of step (d) is preferably carried out in the presence of a solvent.
  • the solvent examples include water, nitrile solvents (eg acetonitrile), and halogen solvents (eg dichloromethane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 20 to 15 ° C., preferably ⁇ 10 ° C. to 10 ° C.
  • the reaction time is, for example, 1 to 5 hours, preferably 3 to 4 hours.
  • Step (e) is a step of reacting the compound represented by formula (2-5) with the compound represented by formula (8) to obtain the compound represented by formula (2-6).
  • R 10 and R 11 are preferably C 1-4 alkyl group, C 1-4 alkoxy group, or C 6-12 aryl group, and preferably C 1-4 alkyl group or C 1 -4 alkoxy group, and more preferably C 1-2 alkyl group or C 1-2 alkoxy group.
  • Suitable combinations of R 10 and R 11 include combinations in which R 10 is an alkyl group and R 11 is an alkoxy group.
  • the amount of the compound represented by the formula (8) used is usually 1 to 2 mol, preferably 1.1 to 1.5 mol, and further 1 mol with respect to 1 mol of the compound represented by the formula (2-5). It is preferably 1.2 to 1.4 mol.
  • the reaction of step (e) is preferably carried out in the presence of a condensing agent.
  • the condensing agent include N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (dimethylaminopropyl) carbodiimide (EDC), 1- [bis (dimethylamino) methylene] -1H-1,2.
  • HATU 3-Triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
  • HBTU 1- [bis (dimethylamino) methylene] -1H-benzotriazolium 3-oxide hexafluorophosphate
  • TATU 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide tetrafluoroborate
  • TBTU dipheni Luphosphoryl azide
  • the condensing agents can be used alone or in combination of two or more.
  • the amount of the condensing agent used is usually 1 to 3 mol, preferably 1.2 to 2.5 mol, more preferably 1.2 to 1 mol, relative to 1 mol of the compound represented by the formula (2-5). 0.5 mol.
  • the reaction of step (e) is preferably performed in the presence of a base.
  • the base include trialkylamine (eg, triC 1-4 alkylamine such as triethylamine), N-methylmorpholine, N, N-dimethylaminopyridine. These bases can be used alone or in combination of two or more kinds.
  • the amount of base used is usually 1 to 5 mol, preferably 1.1 to 2.0 mol, and more preferably 1.2 to 1.
  • the reaction of step (e) is preferably carried out in the presence of a solvent.
  • the solvent include halogen-based solvents (eg: dichloromethane) and ether-based solvents (eg: chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, ⁇ 20 to 15 ° C., preferably ⁇ 10 ° C. to 10 ° C.
  • the reaction time is, for example, 12 to 24 hours, preferably 12 to 20 hours.
  • Step (f) is a step of reacting the compound represented by formula (2-6) with the compound represented by formula (9) to obtain the compound represented by formula (2).
  • the amount of the compound represented by the formula (9) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (2-6). It is 3 mol, and more preferably 1.0 to 1.1 mol.
  • the reaction of step (f) is preferably carried out in the presence of a base.
  • the base include alkyl alkali metal salts (eg: butyl lithium) and alkali metal amides (eg: LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more.
  • alkyl alkali metal salts are preferred.
  • the amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.3 mol, and more preferably 1. to 1 mol of the compound represented by the formula (2-6). It is 0 to 1.1 mol.
  • the reaction of step (f) is preferably performed in the presence of a solvent.
  • the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
  • the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds.
  • the reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C.
  • the reaction time is, for example, 1 to 5 hours, preferably 2 to 3 hours.
  • the compound in which R 7 and R 8 are hydrogen atoms is a compound obtained by following the above reaction scheme, in which R 7 and R 8 are hydroxyl-protecting groups, is deprotected by a conventional method. By doing so, it can be manufactured.
  • the method for producing the compound (2) may include a step of purifying the intermediate product and / or the final product, if necessary. Purification can be carried out by a conventional method such as filtration or chromatography. In addition, a suitable protecting group may be introduced before the reaction and the protecting group may be removed after the reaction. Protection and deprotection can be performed by a conventional method.
  • the method for producing the compound (2) may include a step of separating isomers if necessary. Separation of isomers can also be performed by a conventional method.
  • the pharmaceutical composition contains at least one selected from compounds (1) and (2) (hereinafter referred to as "active ingredient").
  • the lower limit of the content of the active ingredient is, for example, 0.001% by mass, preferably 0.01% by mass, more preferably 0.05% by mass, based on the total mass of the pharmaceutical composition. is there.
  • the upper limit of the content of the active ingredient is not particularly limited, but is, for example, 99% by mass, 95% by mass, or 90% by mass with respect to the total mass of the pharmaceutical composition.
  • the content of the active ingredient is within a range in which the lower limit value and the upper limit value are arbitrarily selected, for example, 0.001 to 99% by mass, preferably 0.01 to 95% by mass, more preferably 0.05 to 90% by mass. %.
  • the pharmaceutical composition may further contain additives, preferably pharmaceutically acceptable additives.
  • the pharmaceutical composition may be in the form of solid preparations (eg granules, powders, tablets, capsules, dry syrups), semisolid preparations (eg creams, ointments, gels), and liquid preparations (eg injections). Agent).
  • the solid preparation is prepared by, for example, mixing active ingredients and additives (eg, excipients, binders, disintegrating agents, lubricants, coloring agents), and if desired, granulating, sizing, compressing, and / or Alternatively, it can be produced by coating.
  • the semi-solid preparation can be produced, for example, by mixing the active ingredient, the semi-solid carrier, and optionally other additives.
  • the liquid preparation includes, for example, an active ingredient, a liquid carrier [eg, an aqueous carrier (eg, purified water), an oil carrier], and optionally other additives (eg, an emulsifier, a dispersant, a suspending agent, a buffering agent, It can be produced by mixing an antioxidant, a surfactant, an osmotic pressure adjusting agent, a chelating agent, an antibacterial agent), and sterilizing if necessary.
  • a liquid carrier eg, an aqueous carrier (eg, purified water), an oil carrier
  • additives eg, an emulsifier, a dispersant, a suspending agent, a buffering agent, It can be produced by mixing an antioxidant, a surfactant, an osmotic pressure adjusting agent, a chelating agent, an antibacterial agent), and sterilizing if necessary.
  • the method for administering the pharmaceutical composition may be either oral administration or parenteral administration (eg, intravenous administration, intramuscular administration, subcutaneous administration).
  • the method of administration of the pharmaceutical composition may be local administration.
  • the subject of administration of the pharmaceutical composition may be any of humans, non-human mammals (eg, monkey, sheep, dog, mouse, rat) and non-mammals.
  • the endoplasmic reticulum stress response inducer contains at least one (active ingredient) selected from compounds (1) and (2).
  • the content of the active ingredient, the type of any additive, the dosage form, and the dosage form in the endoplasmic reticulum stress response-inducing agent can be the same as those described for the pharmaceutical composition.
  • the protein disulfide isomerase inhibitor contains at least one (active ingredient) selected from the compounds (1) and (2).
  • the content of the active ingredient the type of any additive, the dosage form, and the dosage form in the PDI inhibitor, the same as those described for the pharmaceutical composition can be adopted.
  • the preventive or therapeutic agent for diseases contains at least one (active ingredient) selected from compounds (1) and (2). Since the compound of the present invention can induce an endoplasmic reticulum stress response, the disease may be a disease involving endoplasmic reticulum stress. Moreover, since the compound of the present invention can inhibit the activity of PDI, the disease may be a disease associated with PDI.
  • the disease examples include cancer (eg, blood cancer such as multiple myeloma), diabetes (eg, type 1 diabetes, type 2 diabetes), inflammatory disease (eg, inflammatory bowel disease, rheumatism), neurodegeneration Diseases (eg, Parkinson's disease, Huntington's disease, Alzheimer's disease) and diseases associated with these diseases (eg, bone disease associated with multiple myeloma) are mentioned.
  • the disease is preferably at least one selected from cancer, bone disease, and rheumatism.
  • the content of the active ingredient, the type of any additive, the dosage form, and the dosage form in the preventive or therapeutic agent for diseases can be the same as those described for the pharmaceutical composition.
  • Example 1 11 E-inone macrolide A (1-1) (2S, 3S) -N-methoxy-2,3-bis (methoxymethoxy) -N-methylhex-5-enamide was synthesized as follows.
  • Known compound ((4R, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) After dissolving 4.07 g (23.6 mmo) of methanol in 80 mL of acetonitrile and 40 mL of purified water, , 17.0 g (52.0 mmol) of iodobenzene diacetate and 734 mg (4.70 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical were added at room temperature.
  • the obtained crude product was dissolved in 192 mL of acetic acid and 48 mL of purified water, and then stirred at 60 ° C for 12 hours. After the solvent was distilled off under reduced pressure, acetic acid was removed by an azeotropic operation with the addition of toluene.
  • the composition organism thus obtained was dissolved in 118 mL of dichloromethane and then cooled to 0 ° C.
  • 611 mL (354 mmol) of N, N-diisopropylethylamine, 18.8 mL (236 mmol) of chloromethyl methyl ether, and 26.0 g (71.0 mmol) of tetrabutylammonium iodide were added at 0 degrees.
  • (1-2) (S) -Pent-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy) methoxy) -6-vinylbenzoate was synthesized as follows. After dissolving 1.26 g (8.08 mmol) of the known compound (S) -5- (trimethylsilyl) pent-4-yn-2-ol in 108 mL of tetrahydrofuran, 16.2 mL (16.2 mmol) of sodium bis (trimethylsilyl) amide solution was dissolved in 0 mL. Added in degrees.
  • the obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • 11E-Inone macrolide A was synthesized as follows. 86.0 mg (0.105 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-5) was dissolved in 2.0 mL of acetone, and 57 mg (0.105 mmol) of cerium ammonium nitrate was added at 0 degrees. After stirring at 0 ° C for 15 minutes, the same amount of ceriam ammonium nitrate was added, and the mixture was stirred at 0 ° C for 15 minutes. The same work was repeated 3 times. After confirming the disappearance of the raw materials by thin layer chromatography, 1.0 mL of purified water was added, and the solution was separated with dichloromethane three times.
  • Example 2 11 E-inone macrolide A ' 11E-inone macrolide A' was synthesized as follows. 1.9 mL (4.14 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 11E-inone macrolide A 4.04 mg (0.00753 mmol) produced in (1-6). After stirring at room temperature for 5 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 3 11Z-inone macrolide B 11Z-inone macrolide B was synthesized as follows. 87.0 mg (0.106 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-6) was dissolved in 2.0 mL of acetone, and 57.7 mg (0.106 mmol) of cerium ammonium nitrate was added at 0 °. After stirring at 0 ° C for 15 minutes, the same amount of ceriam ammonium nitrate was added, and the mixture was stirred at 0 ° C for 15 minutes. The same work was repeated 3 times.
  • Example 4 11Z-Inone Macrolide C 11Z-inone macrolide C was synthesized as follows. 2.3 mL (4.92 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 4.8 mg (0.00975 mmol) of 11Z-inone macrolide B produced in Example 3. After stirring at room temperature for 1 hour, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the solution was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 5 11Z-Inone Macrolide D 11Z-inone macrolide D was synthesized as follows. 2.4 mL (5.0 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 4.9 mg (0.00975 mmol) of 11Z-inone macrolide B produced in Example 3. After stirring at room temperature for 8 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 6 11 Saturated-Inone Macrolide A (6-1) 11-saturated-cyclized dicobalt hexacarbonyl was synthesized as follows. After dissolving 2.9 mg (0.00353 mmol) of the 11Z-cyclized dicobalt hexacarbonyl produced in (1-5) in 0.7 mL of methanol, 16 mg (0.00353 mmol) of rhodium carbon was added, and the mixture was cooled to -40 degrees. Then, the inside was replaced with hydrogen gas, and the mixture was stirred at -40 ° C for 3 days. After confirming the progress of the reaction by mass spectrometry, filter filtration was performed to remove rhodium carbon.
  • Example 7 11 Saturated-Inone Macrolide B 11 Saturated-Inone macrolide B was synthesized as follows. 0.4 mL (0.8 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 0.8 mg (0.00146 mmol) of 11-saturated-inone macrolide A prepared in Example 6. After stirring at room temperature for 8 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
  • Example 8 (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one (8-1)
  • the known compound (3aR, 7aS) -2,2-dimethyltetrahydro-4H- [1,3] dioxolo [4,5-c] pyran-6-ol was synthesized as follows. After dissolving 6.0 g (44.7 mmol) of 2-deoxy-D-ribose in 90 mL of acetone, 18.8 mL of 2,2-dimethoxypropane was added, and the mixture was stirred at room temperature for 15 minutes.
  • Example 10 1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) hex-2-yn- 1 -one
  • 1-((4S, 5R)- 5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) hex-2-yn-1-one was synthesized as follows. 4.3 ⁇ L (0.0436 mmol) of 1-pentyne was dissolved in 0.4 mL of tetrahydrofuran, cooled to ⁇ 78 ° C., and 16 ⁇ L (0.0436 mmol) of normal butyllithium was added.
  • Example 11 (S) -1-((4S, 5R) -2,2-Dimethyl-5-propyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one (11-1) (4S, 5R) -N-Methoxy-N, 2,2-trimethyl-5-propyl-1,3-dioxolane-4-carboxamide was synthesized as follows. 20 mg (0.0872 mmol) of (4S, 5R) -5-allyl-N-methoxy-N, 2,2-trimethyl-1,3-dioxolane-4-carboxamide prepared in (8-3) was added to 0.4 mL of methanol.
  • Test Example 2 Anti-cancer activity (1) Anti-cancer activity against human multiple myeloma cell line RPMI8226 Human multiple myeloma cell line RPMI8226 was seeded on a 96-well plate at a density of 1 ⁇ 10 4 cells / well, and 5 Incubated overnight at 37 ° C. in a% carbon dioxide atmosphere. Separately, the compound of Example was dissolved in dimethyl sulfoxide and added to each well so that the final concentration of the compound was 0.78125 ⁇ M, 1.5625 ⁇ M, 3.125 ⁇ M, 6.25 ⁇ M, 12.5 ⁇ M, 25 ⁇ M or 50 ⁇ M. . Then, after culturing at 37 ° C.
  • a cell culture / cytotoxicity measuring reagent (Cell Counting Kit-8, manufactured by Dojindo Co., Ltd.) was used to produce an orange dye (produced from living cells). The absorbance (420 nm) of formazan) was measured. The IC 50 value was determined from the relative absorbance when the absorbance without addition of the compound of the present invention or melphalan was 100.
  • Human cancer cell lines HCT116, A549, HeLa or human embryonic kidney-derived cells (HEK293) were seeded on a 96-well plate at a density of 1 ⁇ 10 4 cells / well.
  • Test Example 3 PDI activity measurement PDI activity measurement was carried out using Abcam's PDI Inhibitor Screening Assay Kit (detection sensitivity> 37 ⁇ M). First, was added Insulin solution diluted with Mill-Q H 2 O in 96well plates each Well (320 ⁇ M) or Mill-Q H 2 O (Blank ) so that 50 [mu] L / well. Next, PDI working solution or Mill-Q H 2 O (Negative control) was added to each well at 10 ⁇ L / well.
  • the diluted compound (a solution having a concentration of 8 times the final concentration) was added to each well so that the concentration was 10 ⁇ L / well (Mill-Q H 2 O was 10 ⁇ L / well for Untreated, Negative control, and Blank). Then, DTT was added to each well at 10 ⁇ L / well, and the plate was gently tapped to mix. Then, the mixture was incubated at room temperature for 30 minutes in the dark, and Stop Reagent working solution was added to each well at 10 ⁇ L / well. Furthermore, PDI Detection Reagent working solution was added to each well so that the concentration was 10 ⁇ L / well.
  • mice Mouse myeloma cell line 5TGM-1, which constantly expresses anti-cancer active luciferase in a mouse model , was transplanted into the right tibia bone marrow of a 6-week-old female ICR mouse by 10 6 cells, and 1 week later, engraftment was confirmed. After that, the mice were intraperitoneally administered every other day so that the final concentration of the compound of Example was 20 mg / kg. After administration for 2 weeks, in order to observe the proliferation of tumor cells in the body, luciferin was intraperitoneally administered and detected by the IVIS imaging system. The results are shown in FIGS. As shown in FIGS. 2-3, the compounds of Example 2 and Example 8 suppressed tumor progression in myeloma model mice.
  • Test Example 5 Effect on cytotoxic activity on hematopoietic stem cells
  • Human peripheral blood stem cells were seeded on a 12-well plate at a density of 2 ⁇ 10 6 cells / well, and the compound of the Example was separately dissolved in dimethyl sulfoxide to give a final concentration of 10 ⁇ M.
  • Each well was added as described above and cultured for 24 hours.
  • the cells were collected, and the collected cells were mixed in human hematopoietic stem cell colony measurement medium MethoCult at 2 ⁇ 10 5 cells / ml, seeded in 1 ml on a 35 mm dish, and cultured at 37 ° C. for 14 days in a 5% carbon dioxide atmosphere. .
  • CFU-GM leukocyte colonies
  • BFU-E erythroid colonies
  • Results are shown in FIG. As shown in FIG. 6, the compound of Example 8 suppressed osteoclast formation.
  • Test Example 7 Antirheumatic effect Bovine type II collagen was dissolved in 10 mM acetic acid to prepare a 2 mg / ml solution, which was then mixed with equal amounts of Complete Freund's adjuvant to prepare an emulsion. 100 ⁇ l of the prepared emulsion was intradermally injected into the base of the tail of 6-week-old male DBA / 1J mice. After 3 weeks, booster immunization was carried out in the same manner, and after 2 days, it was confirmed that arthritis was induced. After that, the mice were intraperitoneally administered every other day so that the final concentration of the compound was 20 mg / kg. To evaluate arthritis, clinical scores were measured every other day after the booster immunization.

Abstract

The present invention addresses the problem of providing an ynone compound useful for the inducement of an endoplasmic reticulum stress response. The problem can be solved by an ynone compound represented by formula (1) [in the formula, A1 is an aromatic ring which may have a substituent, X1 is an oxygen atom, a sulfur atom, or a group represented by the formula: -N-(RX1)- (where, RX 1 is a hydrogen atom or an alkyl group), X2 is a single bond or a double bond, R1 and R2 are the same or different and are a hydrogen atom or an alkyl group, R3 and R4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxy alkyl group, or an alkoxy-alkoxy-alkyl group, and R3O and R4O may be bonded to two adjacent carbon atoms to form a ring.].

Description

新規イノン化合物及びその用途Novel inone compound and its use
　本発明は、新規イノン化合物及びその用途に関する。 The present invention relates to a novel inone compound and its use.
　真菌のカーブラリア・ベルクロサ（Curvularia verruculosa）の発酵ブロスから得られる、下記式：
Figure JPOXMLDOC01-appb-C000013
 で表されるエノン化合物が、強力な抗炎症作用を有することが知られている（非特許文献１）。 The following formula, obtained from the fermentation broth of the fungus Curvularia verruculosa:
Figure JPOXMLDOC01-appb-C000013
 The enone compound represented by is known to have a strong anti-inflammatory action (Non-Patent Document 1).
　本発明の目的は、小胞体ストレス応答の誘起等に有用な新規イノン化合物を提供することにある。 An object of the present invention is to provide a novel inone compound useful for inducing endoplasmic reticulum stress response and the like.
　本発明者らは、前記課題を達成するため鋭意検討した結果、イノン骨格を有する化合物が、小胞体ストレス応答を誘起することを見出した。本発明者らは、かかる知見に基づいて更に検討を重ねて本発明を完成した。
　本発明は、以下の態様を包含する。
項１．
下記式（１Ａ）で表される化合物又はその塩：
Figure JPOXMLDOC01-appb-C000014
 ［式中、
Ａ１は、置換基を有していてもよい芳香環であり、
Ｘ１は、酸素原子、硫黄原子、又は式：－Ｎ(ＲＸ１)－（式中、ＲＸ１は、水素原子又はアルキル基である）で表される基であり、
Ｘ２は、単結合又は二重結合であり、
Ｒ１及びＲ２は、同一又は異なって、水素原子、又はアルキル基であり、
Ｒ３及びＲ４は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基である、或いは
Ｒ３Ｏ及びＲ４Ｏは、隣接する２つの炭素原子と共に環を形成していてもよい。
但し、下記式：
Figure JPOXMLDOC01-appb-C000015
 で表される化合物を除く。］
項２．
Ａ１が、置換基を有していてもよいＣ６－１０芳香族炭化水素環、又は置換基を有していてもよい５～１０員芳香族複素環である、項１に記載の化合物又はその塩。
項３．
Ａ１が、下記式で表される環である、項１又は２に記載の化合物又はその塩：
Figure JPOXMLDOC01-appb-C000016
 （式中、
Ｒ５は、－ＯＲ５ａ又は－ＮＲ５ｂＲ５ｃであり、
Ｒ５ａは、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
Ｒ５ｂ及びＲ５ｃは、それぞれ独立して、水素原子、アルキル基、又はアリール基であり、
ｎは、０～４の整数であり、
ｎが２以上の整数である場合、複数のＲ５は、互いに同一であっても異なっていてもよい。）
項４．
Ａ１が、下記式で表される環である、項１～３のいずれか一項に記載の化合物又はその塩：
Figure JPOXMLDOC01-appb-C000017
 （式中、
Ｒ５１及びＲ５２は、同一又は異なって、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
Ｒ５３は、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
Ｒ５４及びＲ５５は、同一又は異なって、水素原子、アルキル基、又はアリール基である。）
項５．
Ｘ１が、酸素原子である、項１～４のいずれか一項に記載の化合物又はその塩。
項６．
Ｘ２が、二重結合である、項１～５のいずれか一項に記載の化合物又はその塩。
項７．
Ｒ１がアルキル基であり、Ｒ２が水素原子である、項１～６のいずれか一項に記載の化合物又はその塩。
項８．
Ｒ３及びＲ４が、同一又は異なって、水素原子、アルキル基、又はアルコキシアルキル基である、項１～７のいずれか一項に記載の化合物又はその塩。
項９．
項１に記載の式（１Ａ）で表される化合物又はその塩の製造方法であって、
（１）下記式（１－５）：
Figure JPOXMLDOC01-appb-C000018
 （式中、Ａ１、Ｘ１、Ｒ１、Ｒ２、Ｒ３、及びＲ４は前記と同じである）
で表される化合物を、三重結合の保護化剤と反応させる工程、
（２）前記工程（１）で得られる生成物を環化し、必要に応じて二重結合を還元する工程、及び
（３）前記工程（２）で得られる生成物から三重結合の保護基を除去する工程
を含む、方法。
項１０．
下記式（２Ａ）で表される化合物又はその塩：
Figure JPOXMLDOC01-appb-C000019
 ［式中、
Ｘ３は、単結合、二重結合、又は三重結合であり、
Ｒ６は、水素原子、置換基を有していてもよいアルキル基、又は置換基を有していてもよい芳香環基であり、
Ｒ７及びＲ８は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアリール基である、或いは、
Ｒ７Ｏ及びＲ８Ｏは、隣接する２つの炭素原子と共に環を形成していてもよく、
Ｒ９は、水素原子、アルキル基、又はアリール基である。
但し、下記式：
Figure JPOXMLDOC01-appb-C000020
 で表される化合物を除く。］
項１１．
Ｒ６が、置換基としてヒドロキシル基を有していてもよいＣ１－４アルキル基である、項１０に記載の化合物又はその塩。
項１２．
Ｒ７Ｏ及びＲ８Ｏが、隣接する２つの炭素原子と共に、下記式：
Figure JPOXMLDOC01-appb-C000021
 （式中、Ｒ７ａ及びＲ８ａは、同一又は異なって、水素原子、アルキル基、又はアリール基であり、＊は、カルボニル炭素との結合位置を示す）
で表される環を形成している、項１０又は１１に記載の化合物又はその塩。
項１３．
Ｒ９が、水素原子である、項１０～１２のいずれか一項に記載の化合物又はその塩。
項１４．
項１０に記載の式（２Ａ）で表される化合物又はその塩の製造方法であって、
塩基の存在下、下記式（２－６）：
Figure JPOXMLDOC01-appb-C000022
 （式中、Ｒ１０及びＲ１１は、同一又は異なって、アルキル基、アルコキシ基、又はアリール基であり、Ｘ３、Ｒ７、Ｒ８、及びＲ９は前記と同じである）
で表される化合物を、下記式（９）：
Figure JPOXMLDOC01-appb-C000023
 （式中、Ｒ６は、前記と同じである）
で表される化合物と反応させる工程を含む、方法。
項１５．
下記式（１）で表される化合物又はその塩：
Figure JPOXMLDOC01-appb-C000024
 ［式中、
Ａ１は、置換基を有していてもよい芳香環であり、
Ｘ１は、酸素原子、硫黄原子、又は式：－Ｎ(ＲＸ１)－（式中、ＲＸ１は、水素原子又はアルキル基である）で表される基であり、
Ｘ２は、単結合又は二重結合であり、
Ｒ１及びＲ２は、同一又は異なって、水素原子、又はアルキル基であり、
Ｒ３及びＲ４は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基である、或いは
Ｒ３Ｏ及びＲ４Ｏは、隣接する２つの炭素原子と共に環を形成していてもよい。］及び下記式（２）で表される化合物又はその塩：
Figure JPOXMLDOC01-appb-C000025
 ［式中、
Ｘ３は、単結合、二重結合、又は三重結合であり、
Ｒ６は、水素原子、置換基を有していてもよいアルキル基、又は置換基を有していてもよい芳香環基であり、
Ｒ７及びＲ８は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアリール基である、或いは、
Ｒ７Ｏ及びＲ８Ｏは、隣接する２つの炭素原子と共に環を形成していてもよく、
Ｒ９は、水素原子、アルキル基、又はアリール基である。］
から選択される少なくとも一種を含む、医薬組成物。
項１６．
小胞体ストレス応答誘起剤である、項１５に記載の医薬組成物。
項１７．
プロテインジスルフィドイソメラーゼ阻害剤である、項１５又は１６に記載の医薬組成物。
項１８．
癌、骨疾患、及びリウマチから選択される少なくとも一種の予防又は治療剤である、項１５～１７のいずれか一項に記載の医薬組成物。 The inventors of the present invention have conducted extensive studies to achieve the above-mentioned object, and as a result, found that a compound having an inone skeleton induces an endoplasmic reticulum stress response. The present inventors have completed the present invention through further studies based on such findings.
The present invention includes the following aspects.
Item 1.
A compound represented by the following formula (1A) or a salt thereof:
Figure JPOXMLDOC01-appb-C000014
 [In the formula,
A 1 is an aromatic ring which may have a substituent,
X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) — (wherein, R X1 is a hydrogen atom or an alkyl group),
X 2 is a single bond or a double bond,
R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group,
R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms. It may form a ring.
However, the following formula:
Figure JPOXMLDOC01-appb-C000015
 The compounds represented by are excluded. ]
Item 2.
Item 2. The compound according to Item 1, wherein A 1 is a C 6-10 aromatic hydrocarbon ring which may have a substituent, or a 5- to 10-membered aromatic heterocycle which may have a substituent. Or its salt.
Item 3.
A compound or a salt thereof according to item 1 or 2, wherein A 1 is a ring represented by the following formula:
Figure JPOXMLDOC01-appb-C000016
 (In the formula,
R 5 is —OR 5a or —NR 5b R 5c ,
R 5a is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group,
R 5b and R 5c are each independently a hydrogen atom, an alkyl group, or an aryl group,
n is an integer of 0 to 4,
If n is an integer of 2 or more, the plurality of R 5, may be the same or different from each other. )
Item 4.
A compound or salt thereof according to any one of items 1 to 3, wherein A 1 is a ring represented by the following formula:
Figure JPOXMLDOC01-appb-C000017
 (In the formula,
R 51 and R 52 are the same or different and each is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group,
R 53 is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group,
R 54 and R 55 are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group. )
Item 5.
Item 5. The compound or salt thereof according to any one of Items 1 to 4, wherein X 1 is an oxygen atom.
Item 6.
Item 6. The compound or a salt thereof according to any one of Items 1 to 5, wherein X 2 is a double bond.
Item 7.
Item 7. The compound or salt thereof according to any one of Items 1 to 6, wherein R 1 is an alkyl group, and R 2 is a hydrogen atom.
Item 8.
Item 8. The compound or salt thereof according to any one of Items 1 to 7, wherein R 3 and R 4 are the same or different and each is a hydrogen atom, an alkyl group, or an alkoxyalkyl group.
Item 9.
A method for producing a compound represented by the formula (1A) or a salt thereof according to item 1,
(1) The following formula (1-5):
Figure JPOXMLDOC01-appb-C000018
 (In the formula, A 1 , X 1 , R 1 , R 2 , R 3 , and R 4 are the same as above)
A step of reacting the compound represented by with a triple bond protecting agent,
(2) a step of cyclizing the product obtained in the step (1) and optionally reducing a double bond, and (3) a protecting group for a triple bond from the product obtained in the step (2). A method comprising the step of removing.
Item 10.
A compound represented by the following formula (2A) or a salt thereof:
Figure JPOXMLDOC01-appb-C000019
 [In the formula,
X 3 is a single bond, a double bond, or a triple bond,
R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent,
R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or
R 7 O and R 8 O may form a ring with two adjacent carbon atoms,
R 9 is a hydrogen atom, an alkyl group, or an aryl group.
However, the following formula:
Figure JPOXMLDOC01-appb-C000020
 The compounds represented by are excluded. ]
Item 11.
Item 11. The compound or a salt thereof according to Item 10, wherein R 6 is a C 1-4 alkyl group optionally having a hydroxyl group as a substituent.
Item 12.
R 7 O and R 8 O together with two adjacent carbon atoms have the formula:
Figure JPOXMLDOC01-appb-C000021
 (In the formula, R 7a and R 8a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and * represents a bonding position with the carbonyl carbon.)
Item 12. The compound or salt thereof according to item 10 or 11, which forms a ring represented by.
Item 13.
Item 13. The compound or salt thereof according to any one of items 10 to 12, wherein R 9 is a hydrogen atom.
Item 14.
Item 10. A method for producing a compound represented by formula (2A) or a salt thereof according to item 10,
In the presence of a base, the following formula (2-6):
Figure JPOXMLDOC01-appb-C000022
 (In the formula, R 10 and R 11 are the same or different and are an alkyl group, an alkoxy group or an aryl group, and X 3 , R 7 , R 8 and R 9 are the same as the above)
The compound represented by the following formula (9):
Figure JPOXMLDOC01-appb-C000023
 (In the formula, R 6 is the same as above)
A method comprising reacting with a compound represented by:
Item 15.
A compound represented by the following formula (1) or a salt thereof:
Figure JPOXMLDOC01-appb-C000024
 [In the formula,
A 1 is an aromatic ring which may have a substituent,
X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) — (wherein, R X1 is a hydrogen atom or an alkyl group),
X 2 is a single bond or a double bond,
R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group,
R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms. It may form a ring. ] And a compound represented by the following formula (2) or a salt thereof:
Figure JPOXMLDOC01-appb-C000025
 [In the formula,
X 3 is a single bond, a double bond, or a triple bond,
R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent,
R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or
R 7 O and R 8 O may form a ring with two adjacent carbon atoms,
R 9 is a hydrogen atom, an alkyl group, or an aryl group. ]
A pharmaceutical composition comprising at least one selected from:
Item 16.
Item 16. The pharmaceutical composition according to Item 15, which is an endoplasmic reticulum stress response inducer.
Item 17.
Item 17. The pharmaceutical composition according to Item 15 or 16, which is a protein disulfide isomerase inhibitor.
Item 18.
Item 18. The pharmaceutical composition according to any one of Items 15 to 17, which is at least one prophylactic or therapeutic agent selected from cancer, bone disease, and rheumatism.
　本発明の化合物は、例えば、小胞体ストレス応答を誘起することができ、小胞体ストレスが関与する疾患の予防又は治療に有用である。また、本発明の化合物は、プロテインジスルフィドイソメラーゼ（ＰＤＩ）の活性を阻害することができ、ＰＤＩが関与する疾患の予防又は治療に有用である。さらに、本発明の化合物は、癌、骨疾患、及びリウマチから選択される少なくとも一種の疾患の予防又は治療に有用である。また、本発明の化合物は、正常造血を阻害しないため、副作用が少ない。 The compound of the present invention is capable of inducing an endoplasmic reticulum stress response, and is useful for the prevention or treatment of diseases associated with endoplasmic reticulum stress. Moreover, the compound of the present invention can inhibit the activity of protein disulfide isomerase (PDI), and is useful for the prevention or treatment of diseases associated with PDI. Furthermore, the compound of the present invention is useful for the prevention or treatment of at least one disease selected from cancer, bone disease, and rheumatism. Moreover, since the compound of the present invention does not inhibit normal hematopoiesis, it has few side effects.
図１は、実施例２、８、及び９の小胞体ストレス応答に関するＣＨＯＰの発現量を示す図である。FIG. 1 is a diagram showing expression levels of CHOP relating to endoplasmic reticulum stress response in Examples 2, 8 and 9. 図２は、骨髄腫モデルマウスにおける実施例２の化合物の腫瘍進展抑制を示す図である。FIG. 2 is a diagram showing the inhibition of tumor progression of the compound of Example 2 in myeloma model mice. 図３は、骨髄腫モデルマウスにおける実施例８の化合物の腫瘍進展抑制を示す図である。FIG. 3 is a diagram showing the inhibition of tumor progression by the compound of Example 8 in myeloma model mice. 図４は、実施例２の化合物の造血幹細胞への細胞障害活性への影響を示す図である。FIG. 4 is a graph showing the effect of the compound of Example 2 on cytotoxic activity on hematopoietic stem cells. 図５は、実施例８の化合物の造血幹細胞への細胞障害活性への影響を示す図である。FIG. 5 is a graph showing the effect of the compound of Example 8 on the cytotoxic activity on hematopoietic stem cells. 図６は、実施例８の化合物の破骨細胞形成抑制を示す図である。FIG. 6 shows the inhibition of osteoclast formation by the compound of Example 8. 図７は、実施例２の化合物の破骨細胞形成抑制を示す図である。7: is a figure which shows the osteoclast formation suppression of the compound of Example 2. FIG. 図８は、実施例８の化合物のがん骨病変形成抑制を示す図である。8: is a figure which shows the cancer bone lesion formation suppression of the compound of Example 8. FIG. 図９は、実施例２の化合物の抗リウマチ効果を示す図である。FIG. 9 is a graph showing the antirheumatic effect of the compound of Example 2.
＜用語の定義＞
　本明細書において、「Ｃａ－ｂ」とは、対象の炭素数がａ以上ｂ以下の整数であることを意味する。
　本明細書において、「芳香環」とは、芳香族炭化水素環及び芳香族複素環を包含する概念である。
　芳香族炭化水素環とは、環の構成原子が炭素原子のみからなる芳香環をいう。
　芳香族炭化水素環の構成原子の数は、特に限定されるものではないが、例えば、６～２０であることができる。
　芳香族炭化水素環は、単環式又は縮合多環式であることができる。
　単環式芳香族炭化水素環としては、例えば、ベンゼンが挙げられる。
　縮合多環式芳香族炭化水素環としては、例えば、２環（例：インデン、ナフタレン）、３環（例：フルオレン、アントラセン、フェナントレン）、４環（例：ピレン）が挙げられる。
　芳香族複素環とは、環の構成原子として、炭素原子、及び、酸素原子、硫黄原子、窒素原子等から選択されるヘテロ原子を含む芳香環をいう。
　芳香族複素環の構成原子の数は、特に限定されるものではないが、例えば、５～２０であることができる。また、芳香族複素環の構成原子のうち、ヘテロ原子の数は、特に限定されるものではないが、例えば、１～４であることができる。
　芳香族複素環は、単環式又は縮合多環式であることができる。
　単環式芳香族複素環としては、例えば、５員環（例：フラン、イソオキサゾール、オキサゾール、チオフェン、イソチアゾール、チアゾール、ピロール、ピラゾール、イミダゾール、トリアゾール）、６員環（例：ピリジン、ピリダジン、ピリミジン、ピラジン、トリアジン）が挙げられる。
　縮合環式芳香族複素環としては、例えば、２環（例：ベンゾフラン、ベンゾチオフェン、インドール、インダゾール、ベンゾイミダゾール、プリン、キノリン、イソキノリン、シノリン、キノキサリン、フタラジン、１，８－ナフチリジン、プテジリン）、３環（例：カルバゾール、アクリジン、フェナジン、フェナントリジン、フェナントロリン、フェノキサジン、フェノチアジン）が挙げられる。
　本明細書において、「芳香環基」とは、前記芳香環から１個の水素原子を除去した基をいう。芳香環基としては、例えば、フェニル基、ナフチル基などのアリール基；フラニル基、チエニル基、ピリジル基などのヘテロアリール基が挙げられる。 <Definition of terms>
In the present specification, “C ab ” means that the target carbon number is an integer of a or more and b or less.
In the present specification, the “aromatic ring” is a concept including an aromatic hydrocarbon ring and an aromatic heterocycle.
The aromatic hydrocarbon ring means an aromatic ring in which the ring-constituting atoms consist of carbon atoms only.
The number of constituent atoms of the aromatic hydrocarbon ring is not particularly limited, but can be, for example, 6 to 20.
The aromatic hydrocarbon ring can be monocyclic or fused polycyclic.
Examples of the monocyclic aromatic hydrocarbon ring include benzene.
Examples of the condensed polycyclic aromatic hydrocarbon ring include two rings (eg, indene, naphthalene), three rings (eg, fluorene, anthracene, phenanthrene), and four rings (eg, pyrene).
The aromatic heterocycle means an aromatic ring containing carbon atoms and heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as the constituent atoms of the ring.
The number of constituent atoms of the aromatic heterocycle is not particularly limited, but can be, for example, 5 to 20. The number of heteroatoms among the constituent atoms of the aromatic heterocycle is not particularly limited, but can be, for example, 1 to 4.
The aromatic heterocycle can be monocyclic or fused polycyclic.
Examples of monocyclic aromatic heterocycles include 5-membered rings (eg, furan, isoxazole, oxazole, thiophene, isothiazole, thiazole, pyrrole, pyrazole, imidazole, triazole), 6-membered rings (eg, pyridine, pyridazine). , Pyrimidine, pyrazine, triazine).
Examples of the condensed ring aromatic heterocycle include two rings (eg, benzofuran, benzothiophene, indole, indazole, benzimidazole, purine, quinoline, isoquinoline, cinoline, quinoxaline, phthalazine, 1,8-naphthyridine, putediline), There are three rings (eg, carbazole, acridine, phenazine, phenanthridine, phenanthroline, phenoxazine, phenothiazine).
In the present specification, the “aromatic ring group” refers to a group obtained by removing one hydrogen atom from the aromatic ring. Examples of the aromatic ring group include aryl groups such as phenyl group and naphthyl group; and heteroaryl groups such as furanyl group, thienyl group and pyridyl group.
　本明細書において、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
　本明細書において、「アルキル基」とは、直鎖状アルキル基及び分岐鎖状アルキル基を包含する概念である。
　直鎖状アルキル基としては、例えば、メチル、エチル、ｎ－プロピル、ｎ－ブチル、ｎ－ペンチル、ｓ－ペンチル、ｎ－ヘキシル、ｎ－ヘプチル、ｎ－オクチル、ｎ－ノニル、ｎ－デシル等の直鎖状Ｃ１－１０アルキル基が挙げられる。
　分岐鎖状アルキル基としては、例えば、イソプロピル、イソブチル、ｓ－ブチル、ｔ－ブチル、イソペンチル、ネオペンチル、イソヘキシル、イソヘプチル、イソオクチル、２－エチルヘキシル等の分岐鎖状Ｃ３－１０アルキル基が挙げられる。 In the present specification, the “alkyl group” is a concept including a linear alkyl group and a branched alkyl group.
Examples of the linear alkyl group include methyl, ethyl, n-propyl, n-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. The straight-chain C 1-10 alkyl group of
Examples of the branched chain alkyl group include a branched chain C 3-10 alkyl group such as isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, 2-ethylhexyl and the like.
　本明細書において、「シクロアルキル基」としては、シクロプロピル、シクロペンチル、シクロヘキシル等のＣ３－１０シクロアルキル基が挙げられる。 In the present specification, examples of the “cycloalkyl group” include C 3-10 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl and the like.
　本明細書において、「アリール基」とは、芳香族炭化水素環に由来する一価の基をいう。アリール基としては、例えば、フェニル、ナフチル等のＣ６－１０アリール基が挙げられる。 In the present specification, the “aryl group” refers to a monovalent group derived from an aromatic hydrocarbon ring. Examples of the aryl group include C 6-10 aryl groups such as phenyl and naphthyl.
　本明細書において、「アラルキル基」としては、例えば、ベンジル、フェネチル等のＣ６－１０アリールＣ１－４アルキル基が挙げられる。 In the present specification, examples of the “aralkyl group” include a C 6-10 aryl C 1-4 alkyl group such as benzyl and phenethyl.
　本明細書において、「アルコキシ基」とは、式：ＲＡＯ－（式中、ＲＡは、アルキル基である）で表される基をいう。アルコキシ基としては、例えば、メトキシ、エトキシ、プロポキシ（ｎ－プロポキシ、イソプロポキシ）、ブトキシ（ｎ－ブトキシ、イソブトキシ、ｓ－ブトキシ、ｔ－ブトキシ）等のＣ１－４アルコキシ基が挙げられる。 In the present specification, the “alkoxy group” refers to a group represented by the formula: R A O— (in the formula, R A is an alkyl group). Examples of the alkoxy group include C 1-4 alkoxy groups such as methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), butoxy (n-butoxy, isobutoxy, s-butoxy, t-butoxy).
　本明細書において、「アルコキシアルキル基」としては、例えば、式：(C１－４アルキル)－Ｏ－(C１－４アルキレン)－Ｏ－で表される基が挙げられる。当該式で表される基としては、例えば、メトキシメチル、メトキシエチル、エトキシメチル、エトキシエチル等のＣ１－３アルコキシＣ１－３アルキル基が挙げられる。 In the present specification, examples of the “alkoxyalkyl group” include groups represented by the formula: (C 1-4 alkyl) -O— (C 1-4 alkylene) -O—. Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl.
　本明細書において、「アルコキシアルコキシ基」としては、例えば、式：式：(C１－４アルキル)－Ｏ－(C１－４アルキレン)－で表される基が挙げられる。当該式で表される基としては、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のＣ１－３アルコキシＣ１－３アルキル基が挙げられる。 In the present specification, examples of the “alkoxyalkoxy group” include groups represented by the formula: formula: (C 1-4 alkyl) -O— (C 1-4 alkylene)-. Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkyl groups such as methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.
　本明細書において、「アルコキシアルコキシアルキル基」としては、例えば、式：(C１－６アルキル)－Ｏ－(C１－４アルキレン)－Ｏ－(C１－４アルキレン)－で表される基が挙げられる。当該式で表される基としては、例えば、メトキシメトキシエチル、メトキシエトキシメチル、エトキシメトキシメチル、エトキシメトキシエチル、エトキシエトキシメチル、エトキシエトキシエチル等のＣ１－３アルコキシＣ１－３アルコキシＣ１－３アルキル基が挙げられる。 In the present specification, the "alkoxyalkoxyalkyl group" is represented by, for example, the formula: (C 1-6 alkyl) -O- (C 1-4 alkylene) -O- (C 1-4 alkylene)-. Groups. Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkoxy C 1 -such as methoxymethoxyethyl, methoxyethoxymethyl, ethoxymethoxymethyl, ethoxymethoxyethyl, ethoxyethoxymethyl, and ethoxyethoxyethyl. 3 alkyl groups are mentioned.
　本明細書において、「アルコキシアルコキシアルコキシ基」としては、例えば、式：(C１－６アルキル)－Ｏ－(C１－４アルキレン)－Ｏ－(C１－４アルキレン)－Ｏ－で表される基が挙げられる。当該式で表される基としては、例えば、メトキシメトキシエトキシ、メトキシエトキシメトキシ、エトキシメトキシメトキシ、エトキシメトキシエトキシ、エトキシエトキシメトキシ、エトキシエトキシエトキシ等のＣ１－３アルコキシＣ１－３アルコキシＣ１－３アルコキシ基が挙げられる。 In the present specification, the "alkoxyalkoxyalkoxy group" is represented by, for example, the formula: (C 1-6 alkyl) -O- (C 1-4 alkylene) -O- (C 1-4 alkylene) -O-. And the groups mentioned below. Examples of the group represented by the formula include C 1-3 alkoxy C 1-3 alkoxy C 1- such as methoxymethoxyethoxy, methoxyethoxymethoxy, ethoxymethoxymethoxy, ethoxymethoxyethoxy, ethoxyethoxymethoxy, and ethoxyethoxyethoxy. 3 alkoxy groups can be mentioned.
　本明細書において、「アシル基」とは、式：－Ｃ(＝Ｏ)－ＲＢ１（式中、ＲＢ１は、炭化水素基である）で表される基、及び－Ｃ(＝Ｏ)－Ｏ－ＲＢ２（式中、ＲＢ２は、炭化水素基である）で表される基を包含する。ＲＢ１及びＲＢ２で示される炭化水素基は、鎖状炭化水素基（例：アルキル）であってもよく、飽和又は不飽和環状炭化水素基（例：シクロアルキル、アリール）、これらの組合せ（例：アラルキル）であってもよい。
　アシル基は、アルキルカルボニル、アリールカルボニル、及びアラルキルカルボニル基を包含する。
　アルキルカルボニル基としては、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ピバロイル、バレリル、イソバレリル、オクタノイル、ノナノイル、デカノイル等の(Ｃ１－１０アルキル)カルボニル基が挙げられる。
　アリールカルボニル基としては、例えば、ベンゾイル、又はナフトイル（即ち、α－ナフトイル又はβ－ナフトイル）等の(Ｃ６－１４アリール)カルボニル基が挙げられる。　アラルキルカルボニル基としては、例えば、ベンジルカルボニル等の(Ｃ６－１４アリールＣ１－４アルキル)カルボニル基が挙げられる。 In the present specification, the “acyl group” means a group represented by the formula: —C (═O) —R B1 (in the formula, R B1 is a hydrocarbon group), and —C (═O). A group represented by —O—R B2 (in the formula, R B2 is a hydrocarbon group) is included. The hydrocarbon group represented by R B1 and R B2 may be a chain hydrocarbon group (eg, alkyl), a saturated or unsaturated cyclic hydrocarbon group (eg, cycloalkyl, aryl), a combination thereof ( Example: aralkyl).
Acyl groups include alkylcarbonyl, arylcarbonyl, and aralkylcarbonyl groups.
Examples of the alkylcarbonyl group include (C 1-10 alkyl) carbonyl groups such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl and decanoyl.
Arylcarbonyl groups include, for example, benzoyl or (C 6-14 aryl) carbonyl groups such as naphthoyl (ie, α-naphthoyl or β-naphthoyl). Examples of the aralkylcarbonyl group include (C 6-14 aryl C 1-4 alkyl) carbonyl groups such as benzylcarbonyl.
　本明細書において、「アルキルチオ基」とは、式：ＲＣ－Ｓ－（式中、ＲＣは、アルキル基である）で表される基をいう。アルキルチオ基としては、例えば、メチルチオ、エチルチオ、プロピルチオ（ｎ－プロピルチオ、イソプロピルチオ）、ブチルチオ（ｎ－ブチルチオ、イソブチルチオ、ｓ－ブチルチオ、ｔ－ブチルチオ）等のＣ１－４アルキルチオ基が挙げられる。 In the present specification, the “alkylthio group” refers to a group represented by the formula: R C —S— (wherein R C is an alkyl group). Examples of the alkylthio group include C 1-4 alkylthio groups such as methylthio, ethylthio, propylthio (n-propylthio, isopropylthio) and butylthio (n-butylthio, isobutylthio, s-butylthio, t-butylthio).
　本明細書において、「モノアルキルアミノ基」とは、式：ＲＤ１－ＮＨ－（式中、ＲＤ１は、アルキル基である）で表される基をいう。モノアルキルアミノ基としては、例えば、モノメチルアミノ、モノエチルアミノ、モノプロピルアミノ（モノｎ－プロピルアミノ、モノイソプロピルアミノ）等のモノＣ１－４アルキルアミノ基が挙げられる。 In the present specification, the “monoalkylamino group” refers to a group represented by the formula: R D1 —NH— (in the formula, R D1 is an alkyl group). The monoalkylamino group, for example, monomethyl amino, mono-ethylamino, monopropyl amino (mono n- propylamino, mono isopropylamino) include mono C 1-4 alkylamino group or the like.
　本明細書において、「ジアルキルアミノ基」とは、式：ＲＤ２ＲＤ３Ｎ－（式中、ＲＤ１及びＲＤ３は、同一又は異なって、アルキル基である）で表される基をいう。ジアルキルアミノ基としては、例えば、ジメチルアミノ、エチルメチルアミノ、ジエチルアミノ、プロピルメチルアミノ等のジＣ１－４アルキルアミノ基が挙げられる。 In the present specification, the “dialkylamino group” refers to a group represented by the formula: R D2 R D3 N— (in the formula, R D1 and R D3 are the same or different and each is an alkyl group). Examples of the dialkylamino group include diC 1-4 alkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, propylmethylamino and the like.
＜化合物（１）＞
　本発明の化合物又はその塩は、一実施態様において、式（１）で表される化合物又はその塩である（以下、「化合物（１）」と称する）：
Figure JPOXMLDOC01-appb-C000026
 （式中、Ａ１、Ｘ１、Ｘ２、Ｒ１、Ｒ２、Ｒ３、及びＲ４は、前記と同じである。） <Compound (1)>
In one embodiment, the compound of the present invention or a salt thereof is a compound represented by formula (1) or a salt thereof (hereinafter, referred to as “compound (1)”):
Figure JPOXMLDOC01-appb-C000026
 (In the formula, A 1 , X 1 , X 2 , R 1 , R 2 , R 3 , and R 4 are the same as above.)
　Ａ１は、好ましくは、置換基を有していてもよいＣ６－１０芳香族炭化水素環、又は置換基を有していてもよい５～１０員芳香族複素環であり、より好ましくは、置換基を有していてもよいＣ６－１０芳香族炭化水素環、置換基を有していてもよい５～１０員含窒素芳香族複素環、置換基を有していてもよい５～１０員含酸素芳香族複素環、又は置換基を有していてもよい５～１０員含硫黄芳香族複素環であり、さらに好ましくはＣ６－１０芳香族炭化水素環であり、特に好ましくは置換基を有していてもよいベンゼン環である。 A 1 is preferably a C 6-10 aromatic hydrocarbon ring which may have a substituent, or a 5- to 10-membered aromatic heterocycle which may have a substituent, and more preferably A C 6-10 aromatic hydrocarbon ring which may have a substituent, a 5- to 10-membered nitrogen-containing aromatic heterocycle which may have a substituent, and a substituent which may have 5 To 10-membered oxygen-containing aromatic heterocycle, or 5- to 10-membered sulfur-containing aromatic heterocycle which may have a substituent, more preferably C 6-10 aromatic hydrocarbon ring, particularly preferably Is a benzene ring which may have a substituent.
　前記置換基としては、例えば、ハロゲン原子、ヒドロキシル基、メルカプト基、アミノ基、アルキル基、アルコキシ基、アルコキシアルコキシ基、アルコキシアルコキシアルコキシ基、アシル基、アルキルチオ基、モノアルキルアミノ基、ジアルキルアミノ基が挙げられる。置換基の数は、特に限定されないが、例えば、０～４の整数であり、好ましくは１～４の整数であり、さらに好ましくは１～３の整数である。 Examples of the substituent include a halogen atom, a hydroxyl group, a mercapto group, an amino group, an alkyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxyalkoxyalkoxy group, an acyl group, an alkylthio group, a monoalkylamino group and a dialkylamino group. Can be mentioned. The number of substituents is not particularly limited, but is, for example, an integer of 0 to 4, preferably an integer of 1 to 4, and more preferably an integer of 1 to 3.
　また、Ａ１は、下記式：
Figure JPOXMLDOC01-appb-C000027
 （式中、Ｒ５及びｎは、前記と同じである。）
で表される環が好ましい。－ＯＲ５ａ又は－ＮＲ５ｂＲ５ｃであり、
　Ｒ５が－ＯＲ５ａである場合、Ｒ５ａは、好ましくは、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、さらに好ましくは、水素原子、Ｃ１－４アルキル基、Ｃ１－４アルコキシＣ１－４アルキル基、又はＣ１－４アルコキシＣ１－４アルコキシＣ１－４アルキル基であり、特に好ましくは、水素原子、Ｃ１－２アルキル基、Ｃ１－２アルコキシＣ１－２アルキル基、又はＣ１－２アルコキシＣ１－２アルコキシＣ１－２アルキル基である。
　Ｒ５が－ＮＲ５ｂＲ５ｃである場合、Ｒ５ｂ及びＲ５ｃは、好ましくは、水素原子、Ｃ１－４アルキル基、又はＣ６－１２アリール基である。Ｒ５ｂ及びＲ５ｃの組合せとしては、Ｒ５ｂ及びＲ５ｃが水素原子である組合せ、Ｒ５ｂ及びＲ５ｃの一方が水素原子であり、他方がアルキル基である組合せ、Ｒ５ｂ及びＲ５ｃがアルキル基である組合せ、Ｒ５ｂ及びＲ５ｃの一方が水素原子であり、他方がアリール基である組合せ、Ｒ５ｂ及びＲ５ｃがアリール基である組合せなどが好ましい。
　ｎは、好ましくは１～４の整数であり、さらに好ましくは１～３の整数である。
　ｎが２以上の整数である場合、複数のＲ５は、互いに同一であっても異なっていてもよく、例えば、複数のＲ５は、すべて－ＯＲ５ａであってもよく、－ＯＲ５ａ及び－ＮＲ５ｂＲ５ｃの組合せであってもよい。 A 1 is the following formula:
Figure JPOXMLDOC01-appb-C000027
 (In the formula, R 5 and n are the same as above.)
The ring represented by is preferable. -OR 5a or -NR 5b R 5c ,
When R 5 is —OR 5a , R 5a is preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, more preferably a hydrogen atom, a C 1-4 alkyl group, C 1-4 alkoxy C 1-4 alkyl group or C 1-4 alkoxy C 1-4 alkoxy C 1-4 alkyl group, particularly preferably hydrogen atom, C 1-2 alkyl group, C 1-2 alkoxy A C 1-2 alkyl group or a C 1-2 alkoxy C 1-2 alkoxy C 1-2 alkyl group.
When R 5 is —NR 5b R 5c , R 5b and R 5c are preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-12 aryl group. Examples of the combination of R 5b and R 5c include a combination in which R 5b and R 5c are hydrogen atoms, a combination in which one of R 5b and R 5c is a hydrogen atom and the other is an alkyl group, and a combination of R 5b and R 5c is an alkyl group. A combination which is a group, a combination in which one of R 5b and R 5c is a hydrogen atom and the other is an aryl group, a combination in which R 5b and R 5c are an aryl group and the like are preferable.
n is preferably an integer of 1 to 4, more preferably an integer of 1 to 3.
When n is an integer of 2 or more, a plurality of R 5 may be the same or different from each other, for example, a plurality of R 5 may be all —OR 5a , or —OR 5a and It may be a combination of —NR 5b R 5c .
　さらに、Ａ１は、下記式：
Figure JPOXMLDOC01-appb-C000028
 （式中、Ｒ５１、Ｒ５２、Ｒ５３、Ｒ５４、及びＲ５５は、前記と同じである。）
で表される環が好ましい。
　Ｒ５１及びＲ５２の好適な組合せとしては、Ｒ５１が水素原子であり、且つ、Ｒ５２がアルキル基である組合せ、Ｒ５１がアルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、且つ、Ｒ５２がアルキル基である組合せが挙げられる。
　Ｒ５３、Ｒ５４、及びＲ５５の好適な組合せとしては、Ｒ５１が水素原子であり、Ｒ５４が水素原子であり、且つ、Ｒ５５がアルキル基である組合せが挙げられる。 Furthermore, A 1 is the following formula:
Figure JPOXMLDOC01-appb-C000028
 (In the formula, R 51 , R 52 , R 53 , R 54 , and R 55 are the same as the above.)
The ring represented by is preferable.
A preferable combination of R 51 and R 52 is a combination in which R 51 is a hydrogen atom and R 52 is an alkyl group, R 51 is an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, and , R 52 is an alkyl group.
Suitable combinations of R 53 , R 54 , and R 55 include a combination in which R 51 is a hydrogen atom, R 54 is a hydrogen atom, and R 55 is an alkyl group.
　Ｘ１は、好ましくは、酸素原子、硫黄原子、又は式：－Ｎ(ＲＸ１１)－（式中、ＲＸ１１は、水素原子又はＣ１－４アルキル基）であり、さらに好ましくは酸素原子又は硫黄原子であり、特に好ましくは酸素原子である。 X 1 is preferably an oxygen atom, a sulfur atom, or a formula: —N (R X11 ) — (wherein R X11 is a hydrogen atom or a C 1-4 alkyl group), and more preferably an oxygen atom or It is a sulfur atom, and particularly preferably an oxygen atom.
　Ｘ２は、前記のとおり、単結合又は二重結合である。具体的には、以下のとおりである。
Figure JPOXMLDOC01-appb-C000029
 （式中、＊は、Ａ１との結合位置を示す）
　Ｘ２が二重結合である場合、化合物（１）は、シス体又はトランス体であることができる。Ｘ２は、好ましくは、二重結合である。 X 2 is a single bond or a double bond as described above. Specifically, it is as follows.
Figure JPOXMLDOC01-appb-C000029
 (In the formula, * indicates a bonding position with A 1. )
When X 2 is a double bond, compound (1) can be in cis form or trans form. X 2 is preferably a double bond.
　Ｒ１は、好ましくはアルキル基であり、さらに好ましくはＣ１－４アルキル基であり、特に好ましくはＣ１－２アルキル基である。
　なお、Ｒ１がアルキル基である場合、Ｒ１が結合する炭素原子は、不斉炭素原子である。この不斉炭素原子の立体配置は、Ｒ配置又はＳ配置のいずれであってもよいが、Ｓ配置であるのが好ましい。 R 1 is preferably an alkyl group, more preferably a C 1-4 alkyl group, and particularly preferably a C 1-2 alkyl group.
When R 1 is an alkyl group, the carbon atom to which R 1 is attached is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably S configuration.
　Ｒ２は、好ましくは水素原子又はＣ１－４アルキル基であり、さらに好ましくは水素原子又はＣ１－２アルキル基であり、特に好ましくは水素原子である。
　なお、Ｒ２がアルキル基である場合、Ｒ２が結合する炭素原子は、不斉炭素原子である。この不斉炭素原子の立体配置は、Ｒ配置又はＳ配置のいずれであってもよいが、Ｒ配置であるのが好ましい。 R 2 is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and particularly preferably a hydrogen atom.
When R 2 is an alkyl group, the carbon atom to which R 2 is attached is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably R configuration.
　Ｒ３及びＲ４は、それぞれ、好ましくは、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、さらに好ましくは、水素原子、Ｃ１－４アルキル基、Ｃ１－４アルコキシＣ１－４アルキル基、又はＣ１－４アルコキシＣ１－４アルコキシＣ１－４アルキル基であり、特に好ましくは、水素原子、Ｃ１－２アルキル基、Ｃ１－２アルコキシＣ１－２アルキル基、又はＣ１－２アルコキシＣ１－２アルコキシＣ１－２アルキル基である。
　Ｒ３及びＲ４の好適な組合せとしては、Ｒ３及びＲ４が共に水素原子である組合せ、Ｒ３及びＲ４が共にアルキル基である組合せ、Ｒ３及びＲ４が共にアルコキシアルキル基である組合せが挙げられる。 R 3 and R 4 are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, and more preferably a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkoxyC. 1-4 alkyl group, or C 1-4 alkoxy C 1-4 alkoxy C 1-4 alkyl group, particularly preferably hydrogen atom, C 1-2 alkyl group, C 1-2 alkoxy C 1-2 alkyl. Or a C 1-2 alkoxy C 1-2 alkoxy C 1-2 alkyl group.
Suitable combinations of R 3 and R 4, combined combined R 3 and R 4 are both hydrogen atoms, R 3 and R 4 are both alkyl groups, R 3 and R 4 are both an alkoxyalkyl group Combinations can be mentioned.
　Ｒ３Ｏ及びＲ４Ｏは、隣接する２つの炭素原子と共に環を形成していてもよく、当該環は、下記式：
Figure JPOXMLDOC01-appb-C000030
 （式中、Ｒ３ａ及びＲ４ａは、同一又は異なって、水素原子、アルキル基、又はアリール基である。）
で表される環であってもよい。
　Ｒ３ａ及びＲ４ａは、それぞれ、好ましくは、水素原子、Ｃ１－４アルキル基、又はＣ６－１０アリール基である。
　Ｒ３ａ及びＲ４ａの好適な組合せとしては、Ｒ３ａ及びＲ４ａが共にアルキル基である組合せ、Ｒ３ａが水素原子であり、且つ、Ｒ４ａがアリール基である組合せが挙げられる。 R 3 O and R 4 O may form a ring with two adjacent carbon atoms, and the ring has the following formula:
Figure JPOXMLDOC01-appb-C000030
 (In the formula, R 3a and R 4a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group.)
It may be a ring represented by.
Each of R 3a and R 4a is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group.
Suitable combinations of R 3a and R 4a, the combination R 3a and R 4a are both alkyl groups, R 3a is a hydrogen atom, and, as combinations R 4a is an aryl group.
　なお、Ｒ３Ｏ及びＲ４Ｏが結合する炭素原子は、不斉炭素原子である。Ｒ３Ｏ及びＲ４Ｏが結合する不斉炭素原子の立体配置は、それぞれ、Ｒ配置又はＳ配置のいずれであってもよいが、共にＳ配置であることが好ましい。 The carbon atom to which R 3 O and R 4 O are bonded is an asymmetric carbon atom. The configuration of the asymmetric carbon atom to which R 3 O and R 4 O are bonded may be either the R configuration or the S configuration, but both are preferably the S configuration.
　Ｒ１、Ｒ２、Ｒ３Ｏ、及びＲ４Ｏを含む構造部分は、好ましくは、下記式：
Figure JPOXMLDOC01-appb-C000031
 （式中、Ｒ１１は、アルキル基であり、Ｒ３１及びＲ４１は、同一又は異なって、水素原子、アルキル基、又はアルコキシアルキル基である）
で表される構造部分である。
　Ｒ１１は、好ましくはＣ１－４アルキル基であり、さらに好ましくはＣ１－２アルキル基である。
　Ｒ３１及びＲ４１は、それぞれ、好ましくは、水素原子、Ｃ１－４アルキル基、又はＣ１－４アルコキシＣ１－４アルキル基であり、さらに好ましくは、水素原子、Ｃ１－２アルキル基、又はＣ１－２アルコキシＣ１－２アルキル基である。 The structural moiety comprising R 1 , R 2 , R 3 O, and R 4 O is preferably of the formula:
Figure JPOXMLDOC01-appb-C000031
 (In the formula, R 11 is an alkyl group, and R 31 and R 41 are the same or different and are a hydrogen atom, an alkyl group, or an alkoxyalkyl group.)
It is a structural part represented by.
R 11 is preferably a C 1-4 alkyl group, and more preferably a C 1-2 alkyl group.
R 31 and R 41 are each preferably a hydrogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy C 1-4 alkyl group, more preferably a hydrogen atom, a C 1-2 alkyl group. Or a C 1-2 alkoxy C 1-2 alkyl group.
　化合物（１）は、少なくとも２つの不斉炭素原子（Ｒ３Ｏ及びＲ４Ｏが結合する炭素原子）を有しており、エナンチオマー及びジアステレオマーのいずれも含む。化合物（１）は、２種類のエナンチオマーを含む混合物であってもよい。当該混合物は、一方のエナンチオマーが過剰量含まれる混合物であってもよく、２種類のエナンチオマーの当量混合物（ラセミ体）であってもよい。 The compound (1) has at least two asymmetric carbon atoms (carbon atoms to which R 3 O and R 4 O are bonded), and includes both enantiomers and diastereomers. The compound (1) may be a mixture containing two kinds of enantiomers. The mixture may be a mixture in which one enantiomer is contained in an excessive amount, or may be an equivalent mixture (racemate) of two kinds of enantiomers.
　化合物（１）は、好ましくは、下記式（１Ａ）で表される化合物又はその塩である。
Figure JPOXMLDOC01-appb-C000032
 （式中、Ａ１、Ｘ１、Ｘ２、Ｒ１、Ｒ２、Ｒ３、及びＲ４は前記と同じである。
但し、下記式：
Figure JPOXMLDOC01-appb-C000033
 で表される化合物を除く。） The compound (1) is preferably a compound represented by the following formula (1A) or a salt thereof.
Figure JPOXMLDOC01-appb-C000032
 (In the formula, A 1 , X 1 , X 2 , R 1 , R 2 , R 3 , and R 4 are the same as described above.
However, the following formula:
Figure JPOXMLDOC01-appb-C000033
 The compounds represented by are excluded. )
　化合物（１）は、好ましくは、下記群から選択される化合物又はその塩である：
Figure JPOXMLDOC01-appb-C000034
 　なお、上記において、ベンゼン環に結合するメトキシ基が、モノメチルアミノ基などのモノアルキルアミノ基に変更された化合物又はその塩も好ましい。 The compound (1) is preferably a compound selected from the following group or a salt thereof:
Figure JPOXMLDOC01-appb-C000034
 In the above, a compound in which the methoxy group bonded to the benzene ring is changed to a monoalkylamino group such as a monomethylamino group or a salt thereof is also preferable.
　化合物（１）が塩の形態である場合、当該塩は、好ましくは薬学上許容される塩である。
　当該塩は、無機塩又は有機塩であることができる。
　当該塩としては、例えば、無機酸塩（例：フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、リン酸塩）、有機酸塩（例：メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、酢酸塩、リンゴ酸塩、フマル酸塩、コハク酸塩、クエン酸塩、酒石酸塩、シュウ酸塩、マレイン酸塩）、アミノ酸塩（例：グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩）が挙げられる。 When the compound (1) is in the form of a salt, the salt is preferably a pharmaceutically acceptable salt.
The salt can be an inorganic salt or an organic salt.
Examples of the salt include inorganic acid salts (eg, hydrofluoric acid salts, hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, nitrates, perchloric acid salts, sulfuric acid salts, phosphoric acid salts), organic acids. Acid salts (eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citric acid) Examples thereof include salts, tartrates, oxalates, maleates), and amino acid salts (eg, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate).
＜化合物（１）の製造方法＞
　化合物は、例えば、以下の反応スキームに従って製造することができる。
Figure JPOXMLDOC01-appb-C000035
 ［式中、
Ｚ１は、脱離基であり、
Ｚ２は、水素原子、アルキル基、又はアシル基である、或いは、式：Ｚ２ＯＣ(＝Ｏ)－で表される基及びそのオルト位に置換し得るヒドロキシル基は、隣接するＡ１の構成原子と共に環を形成していてもよく、
Ｚ３は、シリル基であり、
Ｍは、アルカリ金属であり、
Ｌは、脱離基であり、
Ａ１、Ｘ１、Ｘ２、及びＲ１～Ｒ４は、前記と同じである。］ <Method for producing compound (1)>
The compound can be produced, for example, according to the following reaction scheme.
Figure JPOXMLDOC01-appb-C000035
 [In the formula,
Z 1 is a leaving group,
Z 2 is a hydrogen atom, an alkyl group, or an acyl group, or the group represented by the formula: Z 2 OC (═O) — and the hydroxyl group which may be substituted at the ortho position are the same as those of the adjacent A 1 It may form a ring with the constituent atoms,
Z 3 is a silyl group,
M is an alkali metal,
L is a leaving group,
A 1 , X 1 , X 2 , and R 1 to R 4 are the same as above. ]
＜工程（Ａ）＞
　工程（Ａ）は、式（１－１）で表される化合物を、式（３）で表される化合物と反応させて、式（１－２）で表される化合物を得る工程である。
　式（１－１）において、Ｚ１で示される脱離基としては、例えば、ハロゲン原子（例：塩素原子、臭素原子、ヨウ素原子）、アルキルスルホニルオキシ（例：メシルオキシ等のＣ１－４アルキルスルホニルオキシ）、ハロアルキルスルホニルオキシ（例：トリフルオロメチルスルホニルオキシ等のパーフルオロＣ１－４アルキルスルホニルオキシ）、アリールスルホニルオキシ（例：トシルオキシ等のＣ６－１０アリールスルホニルオキシ）が挙げられる。
　Ｚ２は、好ましくは、水素原子、Ｃ１－４アルキル基、又はＣ１－４アルキルカルボニル基である。
　式：Ｚ２ＯＣ(＝Ｏ)－で表される基及びそのオルト位に置換し得るヒドロキシル基が、隣接するＡ１の構成原子と共に環を形成する場合、式（１－１）で表される化合物は、好ましくは、下記式（１－１－１）で表される化合物である：
Figure JPOXMLDOC01-appb-C000036
 （式中、Ｚ２１及びＺ２２は、同一又は異なって、水素原子、アルキル基、又はアリール基であり、Ａ１及びＺ１は、前記と同じである。）
　Ｚ２１及びＺ２２は、それぞれ、好ましくは、水素原子、Ｃ１－４アルキル基、又はＣ６－１０アリール基である。
　Ｚ２１及びＺ２２の好適な組合せとしては、Ｚ２１及びＺ２２が共に水素原子である組合せ、Ｚ２１及びＺ２２が共にアルキル基である組合せ、Ｚ２１が水素原子であり、且つ、Ｚ２２がアリール基である組合せが挙げられる。
　式（３）において、Ｍで示されるアルカリ金属としては、例えば、リチウム、ナトリウム、カリウムが挙げられる。
　式（３）で表される化合物の使用量は、式（１－１）で表される化合物１モルに対して、通常、１～５モル、好ましくは１．５～３．０モル、さらに好ましくは１．５～２．０モルである。
　工程（Ａ）の反応は、塩基の存在下で行うことが好ましい。
　当該塩基としては、例えば、トリアルキルアミン（例：トリエチルアミン等のトリＣ１－４アルキルアミン）、炭酸塩（例：Ｎａ２ＣＯ３、Ｋ２ＣＯ３等のアルカリ金属炭酸塩）が挙げられる。これらの塩基は単独で又は二種以上組み合わせて使用することができる。これらのうち、トリアルキルアミンが好ましい。
　当該塩基の使用量は、式（１－１）で表される化合物１モルに対して、通常、１～５モル、好ましくは１．５～３．０モル、さらに好ましくは１．５～２．０モルである。
　工程（Ａ）の反応は、触媒の存在下で行うことが好ましい。
　当該触媒としては、例えば、パラジウム触媒［例：テトラキス(トリフェニルホスフィン)パラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、パラジウム炭素、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)、トランス-ジクロロビス(トリシクロヘキシルホスフィン)パラジウム(II)、ジクロロビス(トリ-o-トリルホスフィン)パラジウム(II)、ジクロロビス(トリフェニルホスフィン)パラジウム(II)、酢酸パラジウム(II)］、ニッケル触媒［例：ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ニッケル(II)、ジクロロビス(トリフェニルホスフィン)ニッケル(II)］、ルテニウム触媒が挙げられる。これらの触媒は単独で又は二種以上組み合わせて使用することができる。これらのうち、パラジウム触媒が好ましい。
　触媒の使用量は、式（１－１）で表される化合物１モルに対して、通常、０．１～１．０モル、好ましくは０．１～０．５モル、さらに好ましくは０．１～０．２モルである。　工程（Ａ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、水、アルコール系溶媒（例：メタノール、エタノール）、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。これらのうち、アルコール系溶媒が好ましい。
　工程（Ａ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、２０～２００℃、好ましくは３０～１５０℃である。反応時間は、例えば、１２～２４時間、好ましくは１２～１４時間である。 <Process (A)>
Step (A) is a step of reacting the compound represented by formula (1-1) with the compound represented by formula (3) to obtain the compound represented by formula (1-2).
In formula (1-1), examples of the leaving group represented by Z 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), alkylsulfonyloxy (eg, C 1-4 alkyl such as mesyloxy). Sulfonyloxy), haloalkylsulfonyloxy (eg, perfluoroC 1-4 alkylsulfonyloxy such as trifluoromethylsulfonyloxy), and arylsulfonyloxy (eg, C 6-10 arylsulfonyloxy such as tosyloxy).
Z 2 is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 1-4 alkylcarbonyl group.
When the group represented by the formula: Z 2 OC (═O) — and the hydroxyl group which may be substituted at the ortho position form a ring with the adjacent constituent atom of A 1 , the group represented by the formula (1-1) is represented. The compound is preferably a compound represented by the following formula (1-1-1):
Figure JPOXMLDOC01-appb-C000036
 (In the formula, Z 21 and Z 22 are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and A 1 and Z 1 are the same as the above.)
Z 21 and Z 22 are each preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group.
Suitable combinations of Z 21 and Z 22, a combination combinations Z 21 and Z 22 are both hydrogen atoms, Z 21 and Z 22 are both alkyl groups, Z 21 is a hydrogen atom, and, Z 22 Is an aryl group.
In formula (3), examples of the alkali metal represented by M include lithium, sodium, and potassium.
The amount of the compound represented by the formula (3) used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and further 1 mol with respect to 1 mol of the compound represented by the formula (1-1). It is preferably 1.5 to 2.0 mol.
The reaction of step (A) is preferably performed in the presence of a base.
Examples of the base include trialkylamine (eg, triC 1-4 alkylamine such as triethylamine) and carbonate (eg, alkali metal carbonate such as Na 2 CO 3 and K 2 CO 3 ). These bases can be used alone or in combination of two or more. Of these, trialkylamines are preferred.
The amount of the base used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and more preferably 1.5 to 2 with respect to 1 mol of the compound represented by the formula (1-1). 0.0 mol.
The reaction of step (A) is preferably carried out in the presence of a catalyst.
Examples of the catalyst include a palladium catalyst [eg: tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), palladium carbon, dichloro [1,1′-bis (diphenylphosphino) ) Ferrocene] palladium (II), trans-dichlorobis (tricyclohexylphosphine) palladium (II), dichlorobis (tri-o-tolylphosphine) palladium (II), dichlorobis (triphenylphosphine) palladium (II), palladium acetate (II) )], A nickel catalyst [eg: dichloro [1,1′-bis (diphenylphosphino) ferrocene] nickel (II), dichlorobis (triphenylphosphine) nickel (II)], and a ruthenium catalyst. These catalysts can be used alone or in combination of two or more. Of these, palladium catalysts are preferred.
The amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.1 to 0.5 mol, and more preferably 0.1 to 1.0 mol with respect to 1 mol of the compound represented by the formula (1-1). It is 1 to 0.2 mol. The reaction of step (A) is preferably performed in the presence of a solvent.
Examples of the solvent include water, alcohol solvents (eg methanol, ethanol), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more. Of these, alcohol solvents are preferred.
In the reaction of step (A), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 20 to 200 ° C., preferably 30 to 150 ° C. The reaction time is, for example, 12 to 24 hours, preferably 12 to 14 hours.
＜工程（Ｂ）＞
　工程（Ｂ）は、式（１－２）で表される化合物を、式（４）で表される化合物と反応させて、式（１－３）で表される化合物を得る工程である。
　式（４）に
おいて、Ｚ３で示されるシリル基としては、特に制限されず、例えば、トリアルキルシリル（例：トリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ｔ－ブチルジメチルシリル等のトリＣ１－４アルキルシリル）、アルキルジアリールシリル（例：ｔ－ブチルジフェニルシリル等のＣ１－４アルキルジＣ６－１０アリールシリル）が挙げられる。
　式（４）で表される化合物の使用量は、式（１－２）で表される化合物１モルに対して、通常、１．０～１．５モル、好ましくは１．０～１．２モル、さらに好ましくは１．０～１．１モルである。
　工程（Ｂ）の反応は、塩基の存在下で行うことが好ましい。
　塩基としては、アルカリ金属アミド、例えば、リチウムジイソプロピルアミド（ＬＤＡ）、リチウムヘキサメチルジシラジド（ＬＨＭＤＳ）、ナトリウムヘキサメチルジシラジド（ＮａＨＭＤＳ）、カリウムヘキサメチルジシラジド（ＫＨＭＤＳ）等が挙げられる。これらの塩基は単独で又は二種以上組み合わせて使用することができる。
　塩基の使用量は、式（１－２）で表される化合物１モルに対して、通常、１～３モル、好ましくは１．５～２．５モル、さらに好ましくは２．０～２．５モルである。
　工程（Ｂ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（Ｂ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１０℃～１０℃、好ましくは－５℃～５℃である。反応時間は、例えば、０．２～２．０時間、好ましくは０．５～１．０時間である。 <Process (B)>
Step (B) is a step of reacting the compound represented by formula (1-2) with the compound represented by formula (4) to obtain the compound represented by formula (1-3).
In formula (4), the silyl group represented by Z 3 is not particularly limited, and examples thereof include trialkylsilyl (eg, triC 1-4 such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl and the like). Alkylsilyl) and alkyldiarylsilyl (eg, C 1-4 alkyldiC 6-10 arylsilyl such as t-butyldiphenylsilyl).
The amount of the compound represented by the formula (4) to be used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (1-2). It is 2 mol, and more preferably 1.0 to 1.1 mol.
The reaction of step (B) is preferably performed in the presence of a base.
Examples of the base include alkali metal amides such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), sodium hexamethyldisilazide (NaHMDS) and potassium hexamethyldisilazide (KHMDS). .. These bases can be used alone or in combination of two or more.
The amount of the base used is usually 1 to 3 mol, preferably 1.5 to 2.5 mol, and more preferably 2.0 to 2. 1 mol based on 1 mol of the compound represented by the formula (1-2). It is 5 mol.
The reaction of step (B) is preferably performed in the presence of a solvent.
Examples of the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
In the reaction of step (B), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C. The reaction time is, for example, 0.2 to 2.0 hours, preferably 0.5 to 1.0 hours.
＜工程（Ｃ）＞
　工程（Ｃ）は、式（１－３）で表される化合物からシリル基Ｚ３を除去し、式（１－４）で表される化合物を得る工程である。
　シリル基Ｚ３の除去は、慣用の方法により行うことができる。例えば、式（１－３）で表される化合物をフッ素化合物と反応させる方法が挙げられる。
　フッ素化合物としては、例えば、フッ化水素のアミン錯体、金属フッ化物（例：フッ化カリウム）、フッ化アンモニウム、テトラブチルアンモニウムフロリド（ＴＢＡＦ）が挙げられる。これらのフッ素化合物は単独で又は二種以上組み合わせて使用することができる。これらのうち、ＴＢＡＦが好ましい。
　工程（Ｃ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、カルボン酸系溶媒（例：酢酸）、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。これらのうち、カルボン酸系溶媒が好ましい。
　工程（Ｃ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば－５℃～４０℃、好ましくは０～３０℃である。反応時間は、例えば、６～２４時間、好ましくは１２～１５時間である。 <Process (C)>
Step (C) is a step of removing the silyl group Z 3 from the compound represented by formula (1-3) to obtain the compound represented by formula (1-4).
The silyl group Z 3 can be removed by a conventional method. For example, there may be mentioned a method of reacting the compound represented by the formula (1-3) with a fluorine compound.
Examples of the fluorine compound include amine complexes of hydrogen fluoride, metal fluorides (eg, potassium fluoride), ammonium fluoride, and tetrabutylammonium fluoride (TBAF). These fluorine compounds may be used alone or in combination of two or more. Of these, TBAF is preferred.
The reaction of step (C) is preferably carried out in the presence of a solvent.
Examples of the solvent include carboxylic acid solvents (eg acetic acid), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more. Of these, carboxylic acid solvents are preferred.
In the reaction of step (C), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −5 ° C. to 40 ° C., preferably 0 to 30 ° C. The reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.
＜工程（Ｄ）＞
　工程（Ｄ）は、式（１－４）で表される化合物を、式（５）で表される化合物と反応させて、式（１－５）で表される化合物を得る工程である。
　式（５）において、Ｌで示される脱離基としては、例えば、ハロゲン原子（例：塩素原子、臭素原子、ヨウ素原子）、アルキルスルホニルオキシ（例：メシルオキシ等のＣ１－４アルキルスルホニルオキシ）、ハロアルキルスルホニルオキシ（例：トリフルオロメチルスルホニルオキシ等のパーフルオロＣ１－４アルキルスルホニルオキシ）、アリールスルホニルオキシ（例：トシルオキシ等のＣ６－１０アリールスルホニルオキシ）、式：Ｎ(ＲＬ１)(ＲＬ２)－（式中、ＲＬ１及びＲＬ２は、同一又は異なって、アルキル基又はアルコキシ基である）で表される基が挙げられる。
　これらのうち、式：Ｎ(ＲＬ１)(ＲＬ２)－で表される基が好ましい。ＲＬ１及びＲＬ２は、それぞれ、好ましくはＣ１－４アルキル基又はＣ１－４アルコキシ基である。ＲＬ１及びＲＬ２の好適な組合せとしては、ＲＬ１がアルキル基であり、且つ、ＲＬ２がアルコキシ基である組合せが挙げられる。
　式（５）で表される化合物の使用量は、式（１－４）で表される化合物１モルに対して、通常、１．０～１．５モル、好ましくは１．０～１．２モル、さらに好ましくは１．０～１．１モルである。
　工程（Ｄ）の反応は、塩基の存在下で行うことが好ましい。
　塩基としては、例えば、アルキルアルカリ金属塩（例：ブチルリチウム）、アルカリ金属アミド（例：ＬＤＡ、ＬＨＭＤＳ、ＮａＨＭＤＳ、ＫＨＭＤＳ）が挙げられる。これらの塩基は単独で又は二種以上組み合わせて使用することができる。これらの塩基のうち、アルキルアルカリ金属塩が好ましい。
　塩基の使用量は、式（１－３）で表される化合物１モルに対して、通常、１．０～１．５モル、好ましくは１．０～１．２モル、さらに好ましくは１．０～１．１モルである。　工程（Ｄ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（Ｄ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１０℃～１０℃、好ましくは－５℃～５℃である。反応時間は、例えば、０．２～１．０時間、好ましくは０．３～０．５時間である。 <Process (D)>
Step (D) is a step of reacting the compound represented by formula (1-4) with the compound represented by formula (5) to obtain the compound represented by formula (1-5).
Examples of the leaving group represented by L in the formula (5) include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), alkylsulfonyloxy (eg, C 1-4 alkylsulfonyloxy such as mesyloxy). , Haloalkylsulfonyloxy (eg, perfluoroC 1-4 alkylsulfonyloxy such as trifluoromethylsulfonyloxy), arylsulfonyloxy (eg, C 6-10 arylsulfonyloxy such as tosyloxy), formula: N (R L1 ). Examples thereof include a group represented by (R L2 )-(wherein R L1 and R L2 are the same or different and each is an alkyl group or an alkoxy group).
Among these, the group represented by the formula: N (R L1 ) (R L2 ) — is preferable. Each of R L1 and R L2 is preferably a C 1-4 alkyl group or a C 1-4 alkoxy group. Suitable combinations of R L1 and R L2 include combinations in which R L1 is an alkyl group and R L2 is an alkoxy group.
The amount of the compound represented by the formula (5) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (1-4). It is 2 mol, and more preferably 1.0 to 1.1 mol.
The reaction of step (D) is preferably performed in the presence of a base.
Examples of the base include alkyl alkali metal salts (eg: butyl lithium) and alkali metal amides (eg: LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more. Of these bases, alkyl alkali metal salts are preferred.
The amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, and more preferably 1. mol to 1 mol of the compound represented by the formula (1-3). It is 0 to 1.1 mol. The reaction of step (D) is preferably performed in the presence of a solvent.
Examples of the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
In the reaction of step (D), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C. The reaction time is, for example, 0.2 to 1.0 hour, preferably 0.3 to 0.5 hour.
＜工程（Ｅ）＞
　工程（Ｅ）は、式（１－５）で表される化合物を三重結合の保護化剤と反応させて、式（１－６）で表される化合物を得る工程である。
　三重結合の保護化剤としては、例えば、Ｃｏ２ＣＯ８が挙げられる。
　三重結合の保護化剤の使用量は、式（１－５）で表される化合物１モルに対して、通常、２～１０モル、好ましくは３～６モル、さらに好ましくは４～５モルである。
　工程（Ｅ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、ハロゲン系溶媒（例：ジクロロメタン）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（Ｅ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１０℃～１０℃、好ましくは－５℃～５℃である。反応時間は、例えば、６～２４時間、好ましくは１２～１５時間である。 <Process (E)>
Step (E) is a step of reacting the compound represented by formula (1-5) with a triple bond protecting agent to obtain the compound represented by formula (1-6).
Examples of the triple bond protecting agent include Co 2 CO 8 .
The amount of the triple bond protecting agent used is usually 2 to 10 mol, preferably 3 to 6 mol, and more preferably 4 to 5 mol, relative to 1 mol of the compound represented by the formula (1-5). is there.
The reaction of step (E) is preferably performed in the presence of a solvent.
Examples of the solvent include halogen-based solvents (eg, dichloromethane). These solvents may be used alone or in combination of two or more.
In the reaction of step (E), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C. The reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.
＜工程（Ｆ）＞
　工程（Ｆ）は、式（１－６）で表される化合物を環化し、必要により水素添加することにより、式（１－７）で表される化合物を得る工程である。
　環化は、慣用の方法により行うことができる。例えば、式（１－６）で表される化合物を、触媒の存在下、メタセシス反応により環化することができる。
　触媒としては、例えば、下記式で表される触媒（第２世代ピアース-グラブス触媒）等が挙げられる。
Figure JPOXMLDOC01-appb-C000037
 　触媒の使用量は、式（１－６）で表される化合物１モルに対して、通常、０．１～１．０モル、好ましくは０．２～１．０モル、さらに好ましくは０．４～１．０モルである。　工程（Ｆ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、ハロゲン系溶媒（例：ジクロロメタン）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（Ｆ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１０℃～１０℃、好ましくは－５℃～５℃である。反応時間は、例えば、９６～１４４時間、好ましくは９６～１２０時間である。 <Process (F)>
Step (F) is a step of obtaining a compound represented by formula (1-7) by cyclizing the compound represented by formula (1-6) and optionally hydrogenating.
The cyclization can be performed by a conventional method. For example, the compound represented by formula (1-6) can be cyclized by a metathesis reaction in the presence of a catalyst.
Examples of the catalyst include a catalyst represented by the following formula (second-generation Pierce-Grubbs catalyst).
Figure JPOXMLDOC01-appb-C000037
 The amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.2 to 1.0 mol, and more preferably 0.1 to 1.0 mol with respect to 1 mol of the compound represented by the formula (1-6). It is 4 to 1.0 mol. The reaction of step (F) is preferably performed in the presence of a solvent.
Examples of the solvent include halogen-based solvents (eg, dichloromethane). These solvents may be used alone or in combination of two or more.
In the reaction of step (F), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C. The reaction time is, for example, 96 to 144 hours, preferably 96 to 120 hours.
＜工程（Ｇ）＞
　工程（Ｇ）は、式（１－７）で表される化合物から三重結合の保護基を除去することにより、式（１）で表される化合物を得る工程である。
　脱保護は、慣用の方法により行うことができる。例えば、式（１－７）で表される化合物を脱保護剤［例：ヘキサニトラトセリウム(IV)酸アンモニウム（ＣＡＮ）、２，３－ジクロロ－５，６－ジシアノ－ｐ－ベンゾキノン（ＤＤＱ）、Ｎ－メチルモルホリンＮ－オキシド、これらの組合せ］と反応させることにより、三重結合の保護基を除去することができる。
　脱保護剤の使用量は、式（１－７）で表される化合物１モルに対して、通常、４～１０モル、好ましくは４～８モル、さらに好ましくは４～６モルである。
　工程（Ｇ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、ハロゲン系溶媒（例：ジクロロメタン）、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）、ケトン系溶媒（例：アセトン、メチルエチルケトン）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。これらのうち、ケトン系溶媒が好ましい。
　工程（Ｇ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１０℃～１０℃、好ましくは－５℃～５℃である。反応時間は、例えば、１～８時間、好ましくは１～２時間である。 <Process (G)>
Step (G) is a step of obtaining a compound represented by formula (1) by removing a protective group for triple bond from the compound represented by formula (1-7).
Deprotection can be performed by a conventional method. For example, a compound represented by the formula (1-7) is treated with a deprotecting agent [eg, ammonium hexanitratocerium (IV) (CAN), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ ), N-methylmorpholine N-oxide, a combination thereof] to remove the triple bond protecting group.
The amount of deprotecting agent used is usually 4 to 10 mol, preferably 4 to 8 mol, and more preferably 4 to 6 mol, relative to 1 mol of the compound represented by the formula (1-7).
The reaction of step (G) is preferably performed in the presence of a solvent.
Examples of the solvent include halogen solvents (eg dichloromethane), ether solvents (eg chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane), ketone solvents (eg acetone, methyl ethyl ketone). Be done. These solvents may be used alone or in combination of two or more. Of these, ketone solvents are preferred.
In the reaction of step (G), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C. The reaction time is, for example, 1 to 8 hours, preferably 1 to 2 hours.
　化合物（１）の製造方法は、必要に応じて中間性生物及び／又は最終生成物を精製する工程を含んでいてもよい。精製は、慣用の方法、例えば、濾過、クロマトグラフィーにより行うことができる。
　また、反応の前に適当な保護基を導入し、反応の後に保護基を除去してもよい。保護及び脱保護は、慣用の方法により行うことができる。 The method for producing the compound (1) may include a step of purifying the intermediate product and / or the final product, if necessary. Purification can be carried out by a conventional method such as filtration or chromatography.
In addition, a suitable protecting group may be introduced before the reaction and the protecting group may be removed after the reaction. Protection and deprotection can be performed by a conventional method.
　化合物（１）の製造方法は、必要に応じて異性体を分離する工程を含んでいてもよい。異性体の分離は、慣用の方法により行うことができる。 The method for producing the compound (1) may include a step of separating isomers if necessary. Separation of isomers can be performed by a conventional method.
＜化合物（２）＞
　本発明の化合物又はその塩は、他の実施態様において、式（２）で表される化合物又はその塩である（以下、「化合物（２）」と称する）：
Figure JPOXMLDOC01-appb-C000038
 （式中、Ｘ３及びＲ６～Ｒ９は、前記と同じである。） <Compound (2)>
In another embodiment, the compound of the present invention or a salt thereof is a compound represented by formula (2) or a salt thereof (hereinafter, referred to as “compound (2)”):
Figure JPOXMLDOC01-appb-C000038
 (In the formula, X 3 and R 6 to R 9 are the same as above.)
　Ｘ３は、前記のとおり、単結合、二重結合、又は三重結合である。具体的には、以下のとおりである。
Figure JPOXMLDOC01-appb-C000039
 （式中、＊は、Ｒ９との結合位置を示す）
　Ｘ３が二重結合であり、且つ、Ｒ９がアルキル基又はアリール基である場合、化合物（２）は、シス体又はトランス体であることができる。 X 3 is a single bond, a double bond, or a triple bond as described above. Specifically, it is as follows.
Figure JPOXMLDOC01-appb-C000039
 (In the formula, * indicates a bonding position with R 9. )
When X 3 is a double bond and R 9 is an alkyl group or an aryl group, the compound (2) can be in the cis form or the trans form.
　Ｒ６は、好ましくは水素原子、置換基を有していてもよいアルキル基、又は置換基を有していてもよいヘテロアリール基（例：フラニル基、チエニル基、ピリジル基）であり、より好ましくは置換基を有していてもよいアルキル基であり、さらに好ましくは置換基を有していてもよいＣ１－６アルキル基であり、特に好ましくは置換基を有していてもよいＣ１－４アルキル基である。
　前記置換基としては、例えば、ヒドロキシル基、メルカプト基、アミノ基、アルコキシ基、アルコキシアルコキシ基、アルコキシアルコキシアルコキシ基が挙げられる。これらのうち、ヒドロキシル基、メルカプト基、又はアミノ基が好ましい。
　前記置換基の数は、好ましくは１～３の整数であり、さらに好ましくは１又は２である。
　Ｒ６は、好ましくは、下記式：
Figure JPOXMLDOC01-appb-C000040
 （式中、Ｘ４は、ヒドロキシル基、メルカプト基、又はアミノ基であり、Ｒ６１及びＲ６２は、同一又は異なって、水素原子又はアルキル基である）
で表される基である。
　Ｘ４は、好ましくはヒドロキシル基である。
　Ｒ６１は、好ましくはアルキル基であり、さらに好ましくはＣ１－４アルキル基であり、特に好ましくはＣ１－２アルキル基である。
　なお、Ｒ６１がアルキル基である場合、Ｒ６１が結合する炭素原子は、不斉炭素原子である。この不斉炭素原子の立体配置は、Ｒ配置又はＳ配置のいずれであってもよいが、Ｓ配置であるのが好ましい。 R 6 is preferably a hydrogen atom, an alkyl group which may have a substituent, or a heteroaryl group which may have a substituent (eg, a furanyl group, a thienyl group, a pyridyl group), and It is preferably an alkyl group which may have a substituent, more preferably a C 1-6 alkyl group which may have a substituent, and particularly preferably a C 1-6 which may have a substituent. It is a 1-4 alkyl group.
Examples of the substituent include a hydroxyl group, a mercapto group, an amino group, an alkoxy group, an alkoxyalkoxy group, and an alkoxyalkoxyalkoxy group. Of these, a hydroxyl group, a mercapto group, or an amino group is preferable.
The number of the substituents is preferably an integer of 1 to 3, more preferably 1 or 2.
R 6 is preferably of the formula:
Figure JPOXMLDOC01-appb-C000040
 (In the formula, X 4 is a hydroxyl group, a mercapto group, or an amino group, and R 61 and R 62 are the same or different and are a hydrogen atom or an alkyl group.)
Is a group represented by.
X 4 is preferably a hydroxyl group.
R 61 is preferably an alkyl group, more preferably a C 1-4 alkyl group, and particularly preferably a C 1-2 alkyl group.
When R 61 is an alkyl group, the carbon atom to which R 61 is bonded is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably S configuration.
　Ｒ６２は、好ましくは水素原子又はＣ１－４アルキル基であり、さらに好ましくは水素原子又はＣ１－２アルキル基であり、特に好ましくは水素原子である。
　なお、Ｒ６２がアルキル基である場合、Ｒ６２が結合する炭素原子は、不斉炭素原子である。この不斉炭素原子の立体配置は、Ｒ配置又はＳ配置のいずれであってもよいが、Ｒ配置であるのが好ましい。 R 62 is preferably a hydrogen atom or a C 1-4 alkyl group, more preferably a hydrogen atom or a C 1-2 alkyl group, and particularly preferably a hydrogen atom.
When R 62 is an alkyl group, the carbon atom to which R 62 is attached is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either R configuration or S configuration, but it is preferably R configuration.
　Ｒ７及びＲ８は、それぞれ、好ましくは、水素原子、アルキル基、アルコキシアルキル基、又はアリール基であり、より好ましくは、水素原子、アルキル基、又はアルコキシアルキル基であり、さらに好ましくは、水素原子、Ｃ１－４アルキル基、又はＣ１－４アルコキシＣ１－４アルキル基であり、特に好ましくは、水素原子、Ｃ１－２アルキル基、又はＣ１－２アルコキシＣ１－２アルキル基である。 R 7 and R 8 are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an aryl group, more preferably a hydrogen atom, an alkyl group, or an alkoxyalkyl group, and further preferably hydrogen. An atom, a C 1-4 alkyl group, or a C 1-4 alkoxy C 1-4 alkyl group, particularly preferably a hydrogen atom, a C 1-2 alkyl group, or a C 1-2 alkoxy C 1-2 alkyl group. Is.
　Ｒ７Ｏ及びＲ８Ｏは、隣接する２つの炭素原子と共に環を形成しているのが好ましく、当該環は、下記式：
Figure JPOXMLDOC01-appb-C000041
 （式中、Ｒ７ａ及びＲ８ａは、前記と同じであり、＊は、カルボニル炭素との結合位置を示す）
で表される環が好ましい。
　Ｒ７ａ及びＲ８ａは、それぞれ、好ましくは、水素原子、Ｃ１－４アルキル基、又はＣ６－１０アリール基である。
　Ｒ７ａ及びＲ８ａの好適な組合せとしては、Ｒ７ａ及びＲ８ａが共に水素原子である組合せ、Ｒ７ａ及びＲ８ａが共にアルキル基である組合せ、Ｒ７ａが水素原子であり、且つ、Ｒ８ａがアリール基である組合せが挙げられる。
　なお、Ｒ７Ｏ及びＲ８Ｏが結合する炭素原子は、不斉炭素原子である。Ｒ７Ｏ及びＲ８Ｏが結合する不斉炭素原子の立体配置は、それぞれ、Ｒ配置又はＳ配置のいずれであってもよいが、共にＳ配置であることが好ましい。 R 7 O and R 8 O preferably form a ring with two adjacent carbon atoms, and the ring has the following formula:
Figure JPOXMLDOC01-appb-C000041
 (In the formula, R 7a and R 8a are the same as the above, and * represents the bonding position to the carbonyl carbon).
The ring represented by is preferable.
Each of R 7a and R 8a is preferably a hydrogen atom, a C 1-4 alkyl group, or a C 6-10 aryl group.
Suitable combinations of R 7a and R 8a, a combination combinations R 7a and R 8a are hydrogen atoms, R 7a and R 8a are both alkyl groups, R 7a is a hydrogen atom, and, R 8a And the combination is an aryl group.
The carbon atom to which R 7 O and R 8 O are bonded is an asymmetric carbon atom. The configuration of the asymmetric carbon atom to which R 7 O and R 8 O are bonded may be either the R configuration or the S configuration, but both are preferably the S configuration.
　Ｒ９は、好ましくは水素原子又はアルキル基であり、さらに好ましくは水素原子又はＣ１－４アルキル基であり、特に好ましくは水素原子又はＣ１－２アルキル基であり、最も好ましくは水素原子である。 R 9 is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or a C 1-4 alkyl group, particularly preferably a hydrogen atom or a C 1-2 alkyl group, and most preferably a hydrogen atom. is there.
　化合物（２）は、少なくとも２つの不斉炭素原子（Ｒ７Ｏ及びＲ８Ｏが結合する炭素原子）を有しており、エナンチオマー及びジアステレオマーのいずれも含む。化合物（２）は、２種類のエナンチオマーを含む混合物であってもよい。当該混合物は、一方のエナンチオマーが過剰量含まれる混合物であってもよく、２種類のエナンチオマーの当量混合物（ラセミ体）であってもよい。 The compound (2) has at least two asymmetric carbon atoms (carbon atoms to which R 7 O and R 8 O are bonded) and includes both enantiomers and diastereomers. The compound (2) may be a mixture containing two kinds of enantiomers. The mixture may be a mixture in which one enantiomer is contained in an excessive amount, or may be an equivalent mixture (racemate) of two kinds of enantiomers.
　化合物（２）は、好適な一実施態様において、下記式（２Ａ）で表される化合物又はその塩である：
Figure JPOXMLDOC01-appb-C000042
 （式中、Ｘ３、Ｒ６、Ｒ７、Ｒ８、及びＲ９は、前記と同じである。但し、下記式：
Figure JPOXMLDOC01-appb-C000043
 で表される化合物を除く。） Compound (2) is, in a preferred embodiment, a compound represented by the following formula (2A) or a salt thereof:
Figure JPOXMLDOC01-appb-C000042
 . (Wherein, X 3, R 6, R 7, R 8, and R 9 are the same as above except the following formula:
Figure JPOXMLDOC01-appb-C000043
 The compounds represented by are excluded. )
　化合物（２）は、好適な別の実施態様において、下記群から選択される化合物又はその塩である：
Figure JPOXMLDOC01-appb-C000044
 Compound (2) is, in another preferred embodiment, a compound selected from the following group or a salt thereof:
Figure JPOXMLDOC01-appb-C000044
　化合物（２）が塩の形態である場合、当該塩は、好ましくは薬学上許容される塩である。
　当該塩は、無機塩又は有機塩であることができる。
　当該塩としては、例えば、無機酸塩（例：フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、リン酸塩）、有機酸塩（例：メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、酢酸塩、リンゴ酸塩、フマル酸塩、コハク酸塩、クエン酸塩、酒石酸塩、シュウ酸塩、マレイン酸塩）、アミノ酸塩（例：グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩）が挙げられる。 When the compound (2) is in the form of a salt, the salt is preferably a pharmaceutically acceptable salt.
The salt can be an inorganic salt or an organic salt.
Examples of the salt include inorganic acid salts (eg, hydrofluoric acid salts, hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid salts, nitrates, perchloric acid salts, sulfuric acid salts, phosphoric acid salts), organic acids. Acid salts (eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citric acid) Examples thereof include salts, tartrates, oxalates, maleates), and amino acid salts (eg, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate).
＜化合物（２）の製造方法＞
　式（２）のうち、Ｒ７及びＲ８が、同一又は異なって、アルキル基、アシル基、アルコキシアルキル基、又はアリール基（ヒドロキシル基の保護基に相当する）である化合物又はその塩、或いはＲ７Ｏ及びＲ８Ｏが、隣接する２つの炭素原子と共に環（ヒドロキシル基の保護基に相当する）を形成する化合物又はその塩は、例えば、以下の反応スキームに従って製造することができる。
Figure JPOXMLDOC01-appb-C000045
 ［式中、
Ｑ１～Ｑ３は、同一又は異なって、アルキル基又はアリール基であり、
Ｑ４は、ハロゲン化物イオンであり、
Ｑ５は、トリアルキルシリル基又はアルキルジアリールシリル基であり、
Ｒ１０及びＲ１１は、同一又は異なって、アルキル基、アルコキシ基、又はアリール基であり、
Ｒ６～Ｒ９は、前記と同じである。］ <Method for producing compound (2)>
In the formula (2), R 7 and R 8 are the same or different and each is an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group (corresponding to a protective group for a hydroxyl group), or a salt thereof, A compound or a salt thereof in which R 7 O and R 8 O form a ring (corresponding to a protecting group for a hydroxyl group) with two adjacent carbon atoms can be produced, for example, according to the following reaction scheme.
Figure JPOXMLDOC01-appb-C000045
 [In the formula,
Q 1 to Q 3 are the same or different and each is an alkyl group or an aryl group,
Q 4 is a halide ion,
Q 5 is a trialkylsilyl group or an alkyldiarylsilyl group,
R 10 and R 11 are the same or different and each is an alkyl group, an alkoxy group, or an aryl group,
R 6 to R 9 are the same as above. ]
＜工程（ａ）＞
　工程（ａ）は、式（２－１）で表される化合物を、式（６）で表される化合物と反応させて、式（２－２）で表される化合物を得る工程である。
　式（６）において、Ｑ１～Ｑ３は、それぞれ、好ましくはアリール基であり、さらに好ましくはＣ６－１０アリール基である。
　Ｑ４は、好ましくは臭化物イオン又は塩化物イオンである。
　式（６）で表される化合物としては、例えば、メチルトリフェニルホスホニウムブロミド、エチルトリフェニルホスホニウムブロミド、プロピルトリフェニルホスホニウムブロミド、ブチルトリフェニルホスホニウムブロミド、ペンチルトリフェニルホスホニウムブロミド、ヘキシルトリフェニルホスホニウムブロミド、ヘプチルトリフェニルホスホニウムブロミド、ベンジルトリフェニルホスホニウムブロミド、(1-ナフチルメチル)トリフェニルホスホニウムブロミド、これらに相応するクロリドが挙げられる。これらの化合物は単独で又は二種以上組み合わせて使用することができる。
　式（６）で表される化合物の使用量は、式（２－１）で表される化合物１モルに対して、通常、１～５モル、好ましくは２～４モル、さらに好ましくは３～４モルである。
　工程（ａ）の反応は、塩基の存在下で行うことが好ましい。
　塩基としては、例えば、アルキルアルカリ金属（例：ｎ－ブチルリチウム）、アルカリ金属アミド（例：ＬＤＡ、ＬＨＭＤＳ、ＮａＨＭＤＳ、ＫＨＭＤＳ）が挙げられる。
　塩基の使用量は、式（２－１）で表される化合物１モルに対して、通常、１～５モル、好ましくは２～４モル、さらに好ましくは３～４モルである。
　工程（ａ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（ａ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１００～１０℃、好ましくは－８０℃～０℃である。反応時間は、例えば、１～２４時間、好ましくは４～１２時間である。 <Step (a)>
Step (a) is a step of reacting the compound represented by formula (2-1) with the compound represented by formula (6) to obtain the compound represented by formula (2-2).
In formula (6), Q 1 to Q 3 are each preferably an aryl group, and more preferably a C 6-10 aryl group.
Q 4 is preferably a bromide ion or a chloride ion.
Examples of the compound represented by the formula (6) include methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, propyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide, pentyltriphenylphosphonium bromide, hexyltriphenylphosphonium bromide, Examples include heptyltriphenylphosphonium bromide, benzyltriphenylphosphonium bromide, (1-naphthylmethyl) triphenylphosphonium bromide, and their corresponding chlorides. These compounds can be used alone or in combination of two or more.
The amount of the compound represented by the formula (6) used is usually 1 to 5 mol, preferably 2 to 4 mol, and further preferably 3 to 1 mol of the compound represented by the formula (2-1). 4 mol.
The reaction of step (a) is preferably performed in the presence of a base.
Examples of the base include alkyl alkali metal (eg, n-butyl lithium) and alkali metal amide (eg, LDA, LHMDS, NaHMDS, KHMDS).
The amount of base used will usually be 1-5 mol, preferably 2-4 mol, and more preferably 3-4 mol, per 1 mol of the compound represented by formula (2-1).
The reaction of step (a) is preferably performed in the presence of a solvent.
Examples of the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
In the reaction of step (a), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −100 to 10 ° C., preferably −80 ° C. to 0 ° C. The reaction time is, for example, 1 to 24 hours, preferably 4 to 12 hours.
＜工程（ｂ）＞
　工程（ｂ）は、式（２－２）で表される化合物に水素添加し、式（２－３）で表される化合物を得る工程である。
　水素の使用量は、式（２－２）で表される化合物１モルに対して、通常、１～５０モル、好ましくは２～４０モル、さらに好ましくは１０～２０モルである。
　工程（ｂ）の反応は、触媒の存在下で行うことが好ましい。
　触媒としては、水素添加で慣用的に用いられる触媒が挙げられ、例えば、パラジウム炭素、白金炭素が挙げられる。
　触媒の使用量は、式（２－２）で表される化合物１モルに対して、通常、０．０１～１モル、好ましくは０．１～０．５モル、さらに好ましくは０．２～０．３モルである。　工程（ｂ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、アルコール系溶媒（例：メタノール、エタノール）、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。これらのうち、アルコール系溶媒が好ましい。
　工程（ｂ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、０～５０℃、好ましくは５℃～３５℃である。反応時間は、例えば、１～２４時間、好ましくは１０～１２時間である。
　なお、工程（ｂ）を省略し、工程（ｅ）の前に、式（２－５）のうち、Ｘ３が二重結合である化合物を、工程（ｂ）と同様に水素添加し、式（２－５）のうち、Ｘ３が単結合である化合物を得てもよい。 <Step (b)>
Step (b) is a step of hydrogenating the compound represented by formula (2-2) to obtain the compound represented by formula (2-3).
The amount of hydrogen used will usually be 1-50 mol, preferably 2-40 mol, and more preferably 10-20 mol, relative to 1 mol of the compound represented by formula (2-2).
The reaction of step (b) is preferably carried out in the presence of a catalyst.
Examples of the catalyst include catalysts conventionally used in hydrogenation, and examples thereof include palladium carbon and platinum carbon.
The amount of the catalyst used is usually 0.01 to 1 mol, preferably 0.1 to 0.5 mol, and more preferably 0.2 to 1 mol with respect to 1 mol of the compound represented by the formula (2-2). It is 0.3 mol. The reaction of step (b) is preferably performed in the presence of a solvent.
Examples of the solvent include alcohol solvents (eg: methanol, ethanol), ether solvents (eg: chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran, dioxane). These solvents may be used alone or in combination of two or more. Of these, alcohol solvents are preferred.
In the reaction of step (b), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 0 to 50 ° C, preferably 5 ° C to 35 ° C. The reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.
It should be noted that step (b) is omitted, and before step (e), the compound of formula (2-5) in which X 3 is a double bond is hydrogenated in the same manner as in step (b), Among (2-5), a compound in which X 3 is a single bond may be obtained.
＜工程（ｃ）＞
　工程（ｃ）は、式（２－１）で表される化合物を、式（７）で表される化合物と反応させて、式（２－４）で表される化合物を得る工程である。
　式（７）において、Ｑ５で示されるトリアルキルシリル基としては、例えば、トリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ｔ－ブチルジメチルシリル等のトリＣ１－４アルキルシリルが挙げられる。Ｑ５で示されるアルキルジアリールシリル基としては、例えば、ｔ－ブチルジフェニルシリル等のＣ１－４アルキルジＣ６－１０アリールシリルが挙げられる。
　式（７）で表される化合物の使用量は、式（２－１）で表される化合物１モルに対して、通常、１～５モル、好ましくは２～４モル、さらに好ましくは３～４モルである。
　工程（ｃ）の反応は、塩基の存在下で行うことが好ましい。
　塩基としては、例えば、アルカリ金属アミド（例：ＬＤＡ、リチウム ２，２，６，６－テトラメチルピペラジン、ＬＨＭＤＳ、ＮａＨＭＤＳ、ＫＨＭＤＳ）が挙げられる。　塩基の使用量は、式（２－１）で表される化合物１モルに対して、通常、０．８～１．２モル、好ましくは０．９～１．１モル、さらに好ましくは１．０～１．１モルである。　工程（ｃ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（ｃ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１００～１０℃、好ましくは－８０℃～０℃である。反応時間は、例えば、１～２４時間、好ましくは１０～１２時間である。 <Step (c)>
Step (c) is a step of reacting the compound represented by formula (2-1) with the compound represented by formula (7) to obtain the compound represented by formula (2-4).
In formula (7), examples of the trialkylsilyl group represented by Q 5 include triC 1-4 alkylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, and t-butyldimethylsilyl. Examples of the alkyldiarylsilyl group represented by Q 5 include C 1-4 alkyldiC 6-10 arylsilyl such as t-butyldiphenylsilyl.
The amount of the compound represented by the formula (7) used is generally 1 to 5 mol, preferably 2 to 4 mol, and more preferably 3 to 1 mol of the compound represented by the formula (2-1). It is 4 mol.
The reaction of step (c) is preferably performed in the presence of a base.
Examples of the base include alkali metal amides (eg, LDA, lithium 2,2,6,6-tetramethylpiperazine, LHMDS, NaHMDS, KHMDS). The amount of the base used is usually 0.8 to 1.2 mol, preferably 0.9 to 1.1 mol, and more preferably 1. mol to 1 mol of the compound represented by the formula (2-1). It is 0 to 1.1 mol. The reaction of step (c) is preferably performed in the presence of a solvent.
Examples of the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
In the reaction of step (c), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −100 to 10 ° C., preferably −80 ° C. to 0 ° C. The reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.
＜工程（ｄ）＞
　工程（ｄ）は、式（２－２）、（２－３）、又は（２－４）で表される化合物を酸化剤と反応させて、式（２－５）で表される化合物を得る工程である。
　酸化剤としては、ニトロキシラジカル系酸化剤、例えば、2,2,6,6-テトラメチルピペリジン-1-オキシル（ＴＥＭＰＯ）、２－アザアダマンタン－Ｎ－オキシル（ＡＺＡＤＯ）等が挙げられる。
　酸化剤の使用量は、式（２－２）、（２－３）、又は（２－４）で表される化合物１モルに対して、通常、０．１～１．０モル、好ましくは０．１～０．５モル、さらに好ましくは０．２～０．３モルである。
　酸化剤は、再酸化剤と共に使用することができる。
　再酸化剤としては、例えば、次亜塩素酸ナトリウム、ヨードベンゼンジアセタートが挙げられる。これらの再酸化剤は単独で又は二種以上組み合わせて使用することができる。　再酸化剤の使用量は、式（２－２）、（２－３）、又は（２－４）で表される化合物１モルに対して、通常、１～３モル、好ましくは１．０～２．５モル、さらに好ましくは２．０～２．５モルである。
　工程（ｄ）の反応は、塩基の存在下で行ってもよい。
　工程（ｄ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、水、ニトリル系溶媒（例：アセトニトリル）、ハロゲン系溶媒（例：ジクロロメタン）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（ｄ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－２０～１５℃、好ましくは－１０℃～１０℃である。反応時間は、例えば、１～５時間、好ましくは３～４時間である。 <Process (d)>
In step (d), the compound represented by the formula (2-5) is reacted with the compound represented by the formula (2-2), (2-3) or (2-4) to give the compound represented by the formula (2-5). It is a process of obtaining.
Examples of the oxidizing agent include nitroxy radical type oxidizing agents such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2-azaadamantane-N-oxyl (AZADO).
The amount of the oxidant used is usually 0.1 to 1.0 mol, preferably 1 to 1.0 mol of the compound represented by the formula (2-2), (2-3) or (2-4). The amount is 0.1 to 0.5 mol, more preferably 0.2 to 0.3 mol.
The oxidant can be used with the reoxidant.
Examples of the reoxidant include sodium hypochlorite and iodobenzene diacetate. These reoxidants can be used alone or in combination of two or more. The amount of the reoxidant used is usually 1 to 3 mol, preferably 1.0, relative to 1 mol of the compound represented by the formula (2-2), (2-3) or (2-4). The amount is up to 2.5 mol, more preferably 2.0 to 2.5 mol.
The reaction of step (d) may be carried out in the presence of a base.
The reaction of step (d) is preferably carried out in the presence of a solvent.
Examples of the solvent include water, nitrile solvents (eg acetonitrile), and halogen solvents (eg dichloromethane). These solvents may be used alone or in combination of two or more.
In the reaction of step (d), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −20 to 15 ° C., preferably −10 ° C. to 10 ° C. The reaction time is, for example, 1 to 5 hours, preferably 3 to 4 hours.
＜工程（ｅ）＞
　工程（ｅ）は、式（２－５）で表される化合物を、式（８）で表される化合物と反応させて、式（２－６）で表される化合物を得る工程である。
　式（８）において、Ｒ１０及びＲ１１は、好ましくはＣ１－４アルキル基、Ｃ１－４アルコキシ基、又はＣ６－１２アリール基であり、好ましくはＣ１－４アルキル基又はＣ１－４アルコキシ基であり、さらに好ましくはＣ１－２アルキル基又はＣ１－２アルコキシ基である。
　Ｒ１０及びＲ１１の好適な組合せとしては、Ｒ１０がアルキル基であり、且つ、Ｒ１１がアルコキシ基である組合せが挙げられる。
　式（８）で表される化合物の使用量は、式（２－５）で表される化合物１モルに対して、通常、１～２モル、好ましくは１．１～１．５モル、さらに好ましくは１．２～１．４モルである。
　工程（ｅ）の反応は、縮合剤の存在下で行うことが好ましい。
　縮合剤としては、例えば、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ）、１－エチル－３－（ジメチルアミノプロピル）カルボジイミド（ＥＤＣ）、１－［ビス（ジメチルアミノ）メチレン］－１Ｈ－１，２，３－トリアゾロ［４，５－ｂ］ピリジニウム３－オキシドヘキサフルオロホスファート（ＨＡＴＵ）、１－［ビス（ジメチルアミノ）メチレン］－１Ｈ－ベンゾトリアゾリウム３－オキシドヘキサフルオロホスファート（ＨＢＴＵ）、１－［ビス（ジメチルアミノ）メチレン］-１Ｈ-１，２，３-トリアゾロ［４，５－ｂ］ピリジニウム３－オキシドテトラフルオロボラート（ＴＡＴＵ）、１－［ビス（ジメチルアミノ）メチレン］－１Ｈ－ベンゾトリアゾリウム３－オキシドテトラフルオロボラート（ＴＢＴＵ）、ジフェニルホスホリルアジド（ＤＰＰＡ）が挙げられる。これらの縮合剤は、単独で又は二種以上組み合わせて使用することができる。
　縮合剤の使用量は、式（２－５）で表される化合物１モルに対して、通常、１～３モル、好ましくは１．２～２．５モル、さらに好ましくは１．２～１．５モルである。
　工程（ｅ）の反応は、塩基の存在下で行うことが好ましい。
　塩基としては、トリアルキルアミン（例：トリエチルアミン等のトリＣ１－４アルキルアミン）、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジメチルアミノピリジンが挙げられる。これらの塩基は、単独で又は二種以上組み合わせて使用することができる。
　塩基の使用量は、式（２－５）で表される化合物１モルに対して、通常、１～５モル、好ましくは１．１～２．０モル、さらに好ましくは１．２～１．５モルである。
　工程（ｅ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、ハロゲン系溶媒（例：ジクロロメタン）、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（ｅ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－２０～１５℃、好ましくは－１０℃～１０℃である。反応時間は、例えば、１２～２４時間、好ましくは１２～２０時間である。 <Process (e)>
Step (e) is a step of reacting the compound represented by formula (2-5) with the compound represented by formula (8) to obtain the compound represented by formula (2-6).
In the formula (8), R 10 and R 11 are preferably C 1-4 alkyl group, C 1-4 alkoxy group, or C 6-12 aryl group, and preferably C 1-4 alkyl group or C 1 -4 alkoxy group, and more preferably C 1-2 alkyl group or C 1-2 alkoxy group.
Suitable combinations of R 10 and R 11 include combinations in which R 10 is an alkyl group and R 11 is an alkoxy group.
The amount of the compound represented by the formula (8) used is usually 1 to 2 mol, preferably 1.1 to 1.5 mol, and further 1 mol with respect to 1 mol of the compound represented by the formula (2-5). It is preferably 1.2 to 1.4 mol.
The reaction of step (e) is preferably carried out in the presence of a condensing agent.
Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (dimethylaminopropyl) carbodiimide (EDC), 1- [bis (dimethylamino) methylene] -1H-1,2. , 3-Triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium 3-oxide hexafluorophosphate (HBTU) , 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide tetrafluoroborate (TATU), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium 3-oxide tetrafluoroborate (TBTU), dipheni Luphosphoryl azide (DPPA). These condensing agents can be used alone or in combination of two or more.
The amount of the condensing agent used is usually 1 to 3 mol, preferably 1.2 to 2.5 mol, more preferably 1.2 to 1 mol, relative to 1 mol of the compound represented by the formula (2-5). 0.5 mol.
The reaction of step (e) is preferably performed in the presence of a base.
Examples of the base include trialkylamine (eg, triC 1-4 alkylamine such as triethylamine), N-methylmorpholine, N, N-dimethylaminopyridine. These bases can be used alone or in combination of two or more kinds.
The amount of base used is usually 1 to 5 mol, preferably 1.1 to 2.0 mol, and more preferably 1.2 to 1. mol, relative to 1 mol of the compound represented by the formula (2-5). It is 5 mol.
The reaction of step (e) is preferably carried out in the presence of a solvent.
Examples of the solvent include halogen-based solvents (eg: dichloromethane) and ether-based solvents (eg: chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
In the reaction of step (e), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −20 to 15 ° C., preferably −10 ° C. to 10 ° C. The reaction time is, for example, 12 to 24 hours, preferably 12 to 20 hours.
＜工程（ｆ）＞
　工程（ｆ）は、式（２－６）で表される化合物を、式（９）で表される化合物と反応させて、式（２）で表される化合物を得る工程である。
　式（９）で表される化合物の使用量は、式（２－６）で表される化合物１モルに対して、通常、１．０～１．５モル、好ましくは１．０～１．３モル、さらに好ましくは１．０～１．１モルである。
　工程（ｆ）の反応は、塩基の存在下で行うことが好ましい。
　塩基としては、例えば、アルキルアルカリ金属塩（例：ブチルリチウム）、アルカリ金属アミド（例：ＬＤＡ、ＬＨＭＤＳ、ＮａＨＭＤＳ、ＫＨＭＤＳ）が挙げられる。これらの塩基は単独で又は二種以上組み合わせて使用することができる。これらの塩基のうち、アルキルアルカリ金属塩が好ましい。
　塩基の使用量は、式（２－６）で表される化合物１モルに対して、通常、１．０～１．５モル、好ましくは１．０～１．３モル、さらに好ましくは１．０～１．１モルである。　工程（ｆ）の反応は、溶媒の存在下で行うことが好ましい。
　溶媒としては、例えば、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
　工程（ｆ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１０℃～１０℃、好ましくは－５℃～５℃である。反応時間は、例えば、１～５時間、好ましくは２～３時間である。 <Step (f)>
Step (f) is a step of reacting the compound represented by formula (2-6) with the compound represented by formula (9) to obtain the compound represented by formula (2).
The amount of the compound represented by the formula (9) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1. mol, relative to 1 mol of the compound represented by the formula (2-6). It is 3 mol, and more preferably 1.0 to 1.1 mol.
The reaction of step (f) is preferably carried out in the presence of a base.
Examples of the base include alkyl alkali metal salts (eg: butyl lithium) and alkali metal amides (eg: LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more. Of these bases, alkyl alkali metal salts are preferred.
The amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.3 mol, and more preferably 1. to 1 mol of the compound represented by the formula (2-6). It is 0 to 1.1 mol. The reaction of step (f) is preferably performed in the presence of a solvent.
Examples of the solvent include ether solvents (eg, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents may be used alone or in combination of two or more.
In the reaction of step (f), the reaction temperature and the reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C. The reaction time is, for example, 1 to 5 hours, preferably 2 to 3 hours.
　式（２）のうち、Ｒ７及びＲ８が水素原子である化合物は、上記反応スキームに従って得られた、Ｒ７及びＲ８がヒドロキシル基の保護基である化合物を、慣用の方法により脱保護することにより、製造することができる。 In formula (2), the compound in which R 7 and R 8 are hydrogen atoms is a compound obtained by following the above reaction scheme, in which R 7 and R 8 are hydroxyl-protecting groups, is deprotected by a conventional method. By doing so, it can be manufactured.
　化合物（２）の製造方法は、必要に応じて中間性生物及び／又は最終生成物を精製する工程を含んでいてもよい。精製は、慣用の方法、例えば、濾過、クロマトグラフィーにより行うことができる。
　また、反応の前に適当な保護基を導入し、反応の後に保護基を除去してもよい。保護及び脱保護は、慣用の方法により行うことができる。 The method for producing the compound (2) may include a step of purifying the intermediate product and / or the final product, if necessary. Purification can be carried out by a conventional method such as filtration or chromatography.
In addition, a suitable protecting group may be introduced before the reaction and the protecting group may be removed after the reaction. Protection and deprotection can be performed by a conventional method.
　化合物（２）の製造方法は、必要に応じて異性体を分離する工程を含んでいてもよい。異性体の分離も、慣用の方法により行うことができる。 The method for producing the compound (2) may include a step of separating isomers if necessary. Separation of isomers can also be performed by a conventional method.
＜医薬組成物＞
　医薬組成物は、化合物（１）及び（２）から選択される少なくとも一種（以下、「有効成分」と称する）を含有する。
　有効成分の含有量の下限値は、活性の点から、医薬組成物の全質量に対して、例えば、０．００１質量％、好ましくは０．０１質量％、さらに好ましくは０．０５質量％である。有効成分の含有量の上限値は、特に限定されないが、医薬組成物の全質量に対して、例えば、９９質量％、９５質量％、又は９０質量％である。有効成分の含有量は、前記下限値及び上限値を任意に選択した範囲内、例えば、０．００１～９９質量％、好ましくは０．０１～９５質量％、さらに好ましくは０．０５～９０質量％である。 <Pharmaceutical composition>
The pharmaceutical composition contains at least one selected from compounds (1) and (2) (hereinafter referred to as "active ingredient").
From the viewpoint of activity, the lower limit of the content of the active ingredient is, for example, 0.001% by mass, preferably 0.01% by mass, more preferably 0.05% by mass, based on the total mass of the pharmaceutical composition. is there. The upper limit of the content of the active ingredient is not particularly limited, but is, for example, 99% by mass, 95% by mass, or 90% by mass with respect to the total mass of the pharmaceutical composition. The content of the active ingredient is within a range in which the lower limit value and the upper limit value are arbitrarily selected, for example, 0.001 to 99% by mass, preferably 0.01 to 95% by mass, more preferably 0.05 to 90% by mass. %.
　医薬組成物は、さらに、添加剤、好ましくは、薬学的に許容される添加剤を含有することができる。
　医薬組成物の形態としては、固形製剤（例：顆粒剤、散剤、錠剤、カプセル剤、ドライシロップ剤）、半固形製剤（例：クリーム剤、軟膏剤、ゲル剤）、及び液体製剤（例：注射剤）が挙げられる。
　前記固形製剤は、例えば、有効成分及び添加剤（例：賦形剤、結合剤、崩壊剤、滑沢剤、着色剤）を混合し、及び所望により、造粒、整粒、圧縮、及び／又はコーティングすることにより製造することができる。
　前記半固形製剤は、例えば、有効成分、半固形担体、及び所望による他の添加剤を混合することにより製造することができる。
　前記液体製剤は、例えば、有効成分、液状担体［例：水性担体（例：精製水）、油性担体］、及び所望による他の添加剤（例：乳化剤、分散剤、懸濁剤、緩衝剤、抗酸化剤、界面活性剤、浸透圧調節剤、キレート剤、抗菌剤）を混合し、及び必要により滅菌することにより、製造できる。 The pharmaceutical composition may further contain additives, preferably pharmaceutically acceptable additives.
The pharmaceutical composition may be in the form of solid preparations (eg granules, powders, tablets, capsules, dry syrups), semisolid preparations (eg creams, ointments, gels), and liquid preparations (eg injections). Agent).
The solid preparation is prepared by, for example, mixing active ingredients and additives (eg, excipients, binders, disintegrating agents, lubricants, coloring agents), and if desired, granulating, sizing, compressing, and / or Alternatively, it can be produced by coating.
The semi-solid preparation can be produced, for example, by mixing the active ingredient, the semi-solid carrier, and optionally other additives.
The liquid preparation includes, for example, an active ingredient, a liquid carrier [eg, an aqueous carrier (eg, purified water), an oil carrier], and optionally other additives (eg, an emulsifier, a dispersant, a suspending agent, a buffering agent, It can be produced by mixing an antioxidant, a surfactant, an osmotic pressure adjusting agent, a chelating agent, an antibacterial agent), and sterilizing if necessary.
　医薬組成物の投与方法は、経口投与又は非経口投与（例：静脈投与、筋肉投与、皮下投与）のいずれであってもよい。医薬組成物の投与方法は、局所投与であってもよい。
　医薬組成物の投与対象は、ヒト、非ヒト哺乳動物（例：サル、ヒツジ、イヌ、マウス、ラット）、及び非哺乳動物のいずれであってもよい。 The method for administering the pharmaceutical composition may be either oral administration or parenteral administration (eg, intravenous administration, intramuscular administration, subcutaneous administration). The method of administration of the pharmaceutical composition may be local administration.
The subject of administration of the pharmaceutical composition may be any of humans, non-human mammals (eg, monkey, sheep, dog, mouse, rat) and non-mammals.
＜小胞体ストレス応答誘起剤＞
　小胞体ストレス応答誘起剤は、化合物（１）及び（２）から選択される少なくとも一種（有効成分）を含有する。小胞体ストレス応答誘起剤における、有効成分の含有量、任意の添加剤の種類、剤形、及び投与形態は、前記医薬組成物について記載されたものと同様のものを採用することができる。 <ER stress response inducer>
The endoplasmic reticulum stress response inducer contains at least one (active ingredient) selected from compounds (1) and (2). The content of the active ingredient, the type of any additive, the dosage form, and the dosage form in the endoplasmic reticulum stress response-inducing agent can be the same as those described for the pharmaceutical composition.
＜プロテインジスルフィドイソメラーゼ阻害剤＞
　プロテインジスルフィドイソメラーゼ阻害剤（ＰＤＩ阻害剤）は、化合物（１）及び（２）から選択される少なくとも一種（有効成分）を含有する。ＰＤＩ阻害剤における、有効成分の含有量、任意の添加剤の種類、剤形、及び投与形態は、前記医薬組成物について記載されたものと同様のものを採用することができる。 <Protein disulfide isomerase inhibitor>
The protein disulfide isomerase inhibitor (PDI inhibitor) contains at least one (active ingredient) selected from the compounds (1) and (2). Regarding the content of the active ingredient, the type of any additive, the dosage form, and the dosage form in the PDI inhibitor, the same as those described for the pharmaceutical composition can be adopted.
＜疾患の予防又は治療剤＞
　疾患の予防又は治療剤は、化合物（１）及び（２）から選択される少なくとも一種（有効成分）を含有する。
　本発明の化合物は、小胞体ストレス応答を誘起することができるため、前記疾患は、小胞体ストレスが関与する疾患であってもよい。また、本発明の化合物は、ＰＤＩの活性を阻害することができるため、前記疾患は、ＰＤＩが関与する疾患であってもよい。
　前記疾患としては、例えば、癌（例：多発性骨髄腫等の血液癌）、糖尿病（例：１型糖尿病、２型糖尿病）、炎症性疾患（例：炎症性腸疾患、リウマチ）、神経変性疾患（例：パーキンソン病、ハンチントン病、アルツハイマー病）、これらの疾患と関連する疾患（例：多発性骨髄腫に関連する骨疾患）が挙げられる。
　前記疾患は、好ましくは、癌、骨疾患、及びリウマチから選択される少なくとも一種である。
　疾患の予防又は治療剤における、有効成分の含有量、任意の添加剤の種類、剤形、及び投与形態は、前記医薬組成物について記載されたものと同様のものを採用することができる。 <Prophylactic or therapeutic agent for diseases>
The preventive or therapeutic agent for diseases contains at least one (active ingredient) selected from compounds (1) and (2).
Since the compound of the present invention can induce an endoplasmic reticulum stress response, the disease may be a disease involving endoplasmic reticulum stress. Moreover, since the compound of the present invention can inhibit the activity of PDI, the disease may be a disease associated with PDI.
Examples of the disease include cancer (eg, blood cancer such as multiple myeloma), diabetes (eg, type 1 diabetes, type 2 diabetes), inflammatory disease (eg, inflammatory bowel disease, rheumatism), neurodegeneration Diseases (eg, Parkinson's disease, Huntington's disease, Alzheimer's disease) and diseases associated with these diseases (eg, bone disease associated with multiple myeloma) are mentioned.
The disease is preferably at least one selected from cancer, bone disease, and rheumatism.
The content of the active ingredient, the type of any additive, the dosage form, and the dosage form in the preventive or therapeutic agent for diseases can be the same as those described for the pharmaceutical composition.
　以下に、実施例に基づいて本発明をより詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
　下記実施例において、反応の進行は薄層クロマトグラフィーにて確認し、化合物の同定には1H-NMRを使用した。 In the following examples, the progress of the reaction was confirmed by thin layer chromatography, and 1H-NMR was used to identify the compound.
実施例１　11E-イノンマクロライドA
（1-1）(2S,3S)-N-メトキシ-2,3-ビス (メトキシメトキシ)-N-メチルヘキセ-5-エナミドを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000046
 　既知化合物((4R,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)メタノール 4.07 g (23.6 mmo)にアセトニトリル 80 mLと精製水 40 mLに溶解させた後、ヨードベンゼンジアセテート 17.0 g (52.0 mmol)と2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル 734 mg (4.70 mmol)を室温で加えた。室温で2時間撹拌した後、精製水を加え、酢酸で反応液を酸性にしてから、酢酸エチルで分液を5回行った。得られた有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去して(4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-カルボン酸の粗生成物を得た。
　この粗生成物をジクロロメタン 118 mLに溶解させた後、0度に冷却し、N-メチルモルホリン 2.9 mL (26.0 mmol)、N,O-ジメチルヒドロキシアミン塩酸塩 2.50 g (26.0 mmol)と1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド 5.00 g (26.0 mmol)を加えた。0度で1時間撹拌した後、精製水を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物を酢酸 192 mLと精製水 48 mLに溶解させた後、60度で12時間撹拌した。溶媒を減圧留去した後、トルエンを加えた共沸操作により酢酸を除去した。
　得られた組成生物をジクロロメタン118 mLに溶解した後、0度に冷却した。ここにN,N-ジイソプロピルエチルアミン 611 mL (354 mmol)とクロロメチルメチルエーテル 18.8 mL (236 mmol)、テトラブチルアンモニウムヨージド 26.0 g (71.0 mmol)を0度で加えた。30度で20時間撹拌した後、0度に冷却し、飽和塩化アンモニウム水溶液を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 4 : 6 から 2 : 8)にて精製し、(2S,3S)-N-メトキシ-2,3-ビス (メトキシメトキシ)-N-メチルヘキセ-5-エナミドを得た (5.20 g、収率79%)。
1H-NMR (CDCl3, 400 MHz) δppm: 5.90 (m, 1H), 5.13 (d, J = 17.6 Hz, 1H), 5.10 (d, J = 9.2 Hz, 1H), 4.69-4.61 (overlapped, 5H), 3.96 (m, 1H), 3.75 (s, 3H), 3.37 (s, 3H), 3.36 (s, 3H), 3.22 (s, 3H), 2.52-2.42 (overlapped, 2H) Example 1 11 E-inone macrolide A
(1-1) (2S, 3S) -N-methoxy-2,3-bis (methoxymethoxy) -N-methylhex-5-enamide was synthesized as follows.
Figure JPOXMLDOC01-appb-C000046
 Known compound ((4R, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) After dissolving 4.07 g (23.6 mmo) of methanol in 80 mL of acetonitrile and 40 mL of purified water, , 17.0 g (52.0 mmol) of iodobenzene diacetate and 734 mg (4.70 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical were added at room temperature. After stirring at room temperature for 2 hours, purified water was added, the reaction solution was made acidic with acetic acid, and the solution was separated with ethyl acetate five times. Sodium sulfate was added to the obtained organic layer to remove water. The solvent was distilled off under reduced pressure to obtain a crude product of (4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid.
This crude product was dissolved in 118 mL of dichloromethane, cooled to 0 ° C., and 2.9 mL (26.0 mmol) of N-methylmorpholine, 2.50 g (26.0 mmol) of N, O-dimethylhydroxyamine hydrochloride and 1- ( 5.00 g (26.0 mmol) of 3-dimethylaminopropyl) -3-ethylcarbodiimide was added. After stirring at 0 ° C for 1 hour, purified water was added, and the solution was separated with dichloromethane three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in 192 mL of acetic acid and 48 mL of purified water, and then stirred at 60 ° C for 12 hours. After the solvent was distilled off under reduced pressure, acetic acid was removed by an azeotropic operation with the addition of toluene.
The composition organism thus obtained was dissolved in 118 mL of dichloromethane and then cooled to 0 ° C. Here, 611 mL (354 mmol) of N, N-diisopropylethylamine, 18.8 mL (236 mmol) of chloromethyl methyl ether, and 26.0 g (71.0 mmol) of tetrabutylammonium iodide were added at 0 degrees. After stirring at 30 ° C. for 20 hours, the mixture was cooled to 0 ° C., a saturated aqueous ammonium chloride solution was added, and liquid separation was performed three times with dichloromethane. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 6 to 2: 8), (2S, 3S) -N-methoxy-2,3-bis (methoxymethoxy)- N-methylhex-5-enamide was obtained (5.20 g, yield 79%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 5.90 (m, 1H), 5.13 (d, J = 17.6 Hz, 1H), 5.10 (d, J = 9.2 Hz, 1H), 4.69-4.61 (overlapped, 5H), 3.96 (m, 1H), 3.75 (s, 3H), 3.37 (s, 3H), 3.36 (s, 3H), 3.22 (s, 3H), 2.52-2.42 (overlapped, 2H)
（1-2）(S)-ペント-4-イン-2-イル4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエートを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000047
 　既知化合物(S)-5-(トリメチルシリル)ペント-4-イン-2-オール1.26 g (8.08 mmol)をテトラヒドロフラン108 mLに溶解した後、ナトリウムビス（トリメチルシリル）アミド溶液16.2 mL (16.2 mmol)を0度で加えた。0度で15分間撹拌した後、既知化合物7-メトキシ-2,2-ジメチル-5-ビニル-4H-ベンゾ[d][1,3]ジオキシン-4-オン 1.26 g (5.39 mmol)をテトラヒドロフランに溶解させて反応液に加えた。0度で20分間撹拌した後、酢酸 0.97 mL (16.2 mmol)とテトラブチルアンモニウムフルオリド 8.08 mL (8.08 mmol)を加え、室温で12時間撹拌した。0度に冷却後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。
　得られた粗生成物をジクロロメタン 53.9 mLに溶解させた後、N,N-ジイソプロピルエチルアミン 9.4 mL (53.9 mmol)と2-メトキシエトキシメチルクロリド 3.07 mL (26.9 mmol)、テトラブチルアンモニウムヨージド 6.0 g (16.2 mmol)を加えた。40度で5時間撹拌した後、0度に冷却し、飽和塩化アンモニウム水溶液を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 4 : 6 から 2 : 8)にて精製し、(S)-ペント-4-イン-2-イル4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエートを得た (563 mg、収率30%)。
1H-NMR (CDCl3, 400 MHz) δppm: 6.41 (dd, J = 17.6, 10.8 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.70 (dd, J = 17.2, 1.2 Hz), 5.33-5.23 (overlapped, 4H), 3.83-3.81 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 3H), 2.60 (ddd, J = 16.8, 5.6, 2.8 Hz, 1H), 2.54 (ddd, J = 16.8, 5.6, 2.8 Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.44 (d, J = 6.4 Hz, 3H) (1-2) (S) -Pent-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy) methoxy) -6-vinylbenzoate was synthesized as follows.
Figure JPOXMLDOC01-appb-C000047
 After dissolving 1.26 g (8.08 mmol) of the known compound (S) -5- (trimethylsilyl) pent-4-yn-2-ol in 108 mL of tetrahydrofuran, 16.2 mL (16.2 mmol) of sodium bis (trimethylsilyl) amide solution was dissolved in 0 mL. Added in degrees. After stirring for 15 minutes at 0 degree, 1.26 g (5.39 mmol) of known compound 7-methoxy-2,2-dimethyl-5-vinyl-4H-benzo [d] [1,3] dioxin-4-one in tetrahydrofuran was added to tetrahydrofuran. It was dissolved and added to the reaction solution. After stirring at 0 ° C for 20 minutes, 0.97 mL (16.2 mmol) of acetic acid and 8.08 mL (8.08 mmol) of tetrabutylammonium fluoride were added, and the mixture was stirred at room temperature for 12 hours. After cooling to 0 ° C., a saturated ammonium chloride aqueous solution was added, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure.
The obtained crude product was dissolved in 53.9 mL of dichloromethane, and then 9.4 mL (53.9 mmol) of N, N-diisopropylethylamine and 3.07 mL (26.9 mmol) of 2-methoxyethoxymethyl chloride and 6.0 g of tetrabutylammonium iodide ( 16.2 mmol) was added. After stirring at 40 ° C. for 5 hours, the mixture was cooled to 0 ° C., a saturated aqueous solution of ammonium chloride was added, and liquid separation was performed three times with dichloromethane. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 6 to 2: 8), and (S) -pent-4-yn-2-yl 4-methoxy-2- ( (2-Methoxyethoxy) methoxy) -6-vinylbenzoate was obtained (563 mg, yield 30%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 6.41 (dd, J = 17.6, 10.8 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H) , 5.70 (dd, J = 17.2, 1.2 Hz), 5.33-5.23 (overlapped, 4H), 3.83-3.81 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 3H), 2.60 (ddd, J = 16.8, 5.6, 2.8 Hz, 1H), 2.54 (ddd, J = 16.8, 5.6, 2.8 Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.44 (d, J = 6.4 Hz, 3H)
（1-3）(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエートを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000048
 　（1-2）で製造した(S)-ペント-4-イン-2-イル4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート106 mg (0.23 mmol)をテトラヒドロフラン4.7 mLに溶解した後、－78度に冷却し、ノルマルブチルリチウム0.17 mL (0.260 mmol)を滴下した。-78度で15分間撹拌した後、（1-1）で製造した(2S,3S)-N-メトキシ-2,3-ビス (メトキシメトキシ)-N-メチルヘキサ-5-エナミド 71.0 mg (0.260 mmol)をテトラヒドロフラン 1.0 mLに溶解させ、反応液に加えた。-78度で10分間撹拌した後、飽和塩化アンモニウム水溶液を加えて0度に昇温し、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 4 : 6 から 1 : 1)にて精製し、(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエートを透明の液体として得た (86 mg、収率55%)。
1H-NMR (CDCl3, 400 MHz) δppm: 6.76-6.69 (overlapped, 3H), 5.82 (m, 1H), 5.69 (dd, J = 17.2, 0.8 Hz, 1H), 5.36-5.28 (overlapped, 2H), 5.25 (s, 2H), 5.10 (m, 1H), 4.71-4.65 (overlapped, 4H), 4.21 (d, J = 4.8 Hz, 1H), 4.08 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 6H), 3.33 (s, 3H), 2.81 (m, 2H), 2.43 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H) (1-3) (2S, 7S, 8S) -7,8-Bis (methoxymethoxy) -6-ocisoundec-10-en-4-in-2-yl 4-methoxy-2-((2-methoxyethoxy ) Methoxy) -6-vinylbenzoate was synthesized as follows.
Figure JPOXMLDOC01-appb-C000048
 (S) -Pent-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy) methoxy) -6-vinylbenzoate 106 mg (0.23 mmol) produced in (1-2) was added to tetrahydrofuran 4.7 After dissolving in mL, the mixture was cooled to −78 ° C. and 0.17 mL (0.260 mmol) of normal butyl lithium was added dropwise. After stirring at -78 degrees for 15 minutes, (2S, 3S) -N-methoxy-2,3-bis (methoxymethoxy) -N-methylhex-5-enamide prepared in (1-1) 71.0 mg (0.260 mmol Was dissolved in 1.0 mL of tetrahydrofuran and added to the reaction solution. After stirring at -78 ° C for 10 minutes, a saturated aqueous solution of ammonium chloride was added, the temperature was raised to 0 ° C, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 6 to 1: 1), (2S, 7S, 8S) -7,8-bis (methoxymethoxy) -6- Ossoundec-10-en-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy) methoxy) -6-vinylbenzoate was obtained as a clear liquid (86 mg, yield 55%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 6.76-6.69 (overlapped, 3H), 5.82 (m, 1H), 5.69 (dd, J = 17.2, 0.8 Hz, 1H), 5.36-5.28 (overlapped, 2H ), 5.25 (s, 2H), 5.10 (m, 1H), 4.71-4.65 (overlapped, 4H), 4.21 (d, J = 4.8 Hz, 1H), 4.08 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 6H), 3.33 (s, 3H), 2.81 (m, 2H), 2.43 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H)
（1-4）環化前駆体[(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート] ジコバルトヘキサカルボニルを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000049
 　（1-3）で製造した(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート 283 mg (0.50 mmol)をジクロロメタン10 mLに溶解した後、ジコバルトオクタカルボニル1.80 g (5.00 mmol)を0度で加えた。4度で12時間撹拌した後、反応溶液を減圧留去し、粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 4から2 : 3)にて精製を行い、環化前駆体[(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート] ジコバルトヘキサカルボニルを褐色の液体として得た (355 mg、収率82%)。1H-NMR (CDCl3, 400 MHz) δppm: 6.78 (dd, J = 17.3, 10.8 Hz, 1H), 6.72 (s, 2H), 5.87 (m, 1H), 5.69 (d J = 17.3 Hz, 1H), 5.32-5.21 (overlapped, 4H), 5.14 (m, 1H), 5.11 (m, 1H), 4.67 (overlapped, 3H), 4.57 (d, J = 6.8 Hz, 1H), 4.21 (d, J = 7.6 Hz, 1H), 4.04 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.54 (m, 2H), 3.37 (s, 3H), 3.30 (s, 6H), 3.05 (dd, J = 16.2, 7.0 Hz, 1H), 3.05 (dd, J = 16.2, 7.0 Hz, 1H), 2.59 (m, 1H), 2.47 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H) (1-4) Cyclization precursor [(2S, 7S, 8S) -7,8-Bis (methoxymethoxy) -6-ocisoundec-10-en-4-yn-2-yl-4-methoxy-2- ( (2-Methoxyethoxy) methoxy) -6-vinylbenzoate] Dicobalt hexacarbonyl was synthesized as follows.
Figure JPOXMLDOC01-appb-C000049
 (2S, 7S, 8S) -7,8-bis (methoxymethoxy) -6-ocisoundec-10-en-4-in-2-yl 4-methoxy-2-((2 After dissolving 283 mg (0.50 mmol) of -methoxyethoxy) methoxy) -6-vinylbenzoate in 10 mL of dichloromethane, 1.80 g (5.00 mmol) of dicobalt octacarbonyl was added at 0 °. After stirring at 4 degrees for 12 hours, the reaction solution was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 2: 3) to give a cyclization precursor [ (2S, 7S, 8S) -7,8-Bis (methoxymethoxy) -6-ocisoundec-10-en-4-in-2-yl 4-methoxy-2-((2-methoxyethoxy) methoxy) -6 -Vinylbenzoate] Dicobalt hexacarbonyl was obtained as a brown liquid (355 mg, 82% yield). 1 H-NMR (CDCl 3 , 400 MHz) δppm: 6.78 (dd, J = 17.3, 10.8 Hz, 1H), 6.72 (s, 2H), 5.87 (m, 1H), 5.69 (d J = 17.3 Hz, 1H ), 5.32-5.21 (overlapped, 4H), 5.14 (m, 1H), 5.11 (m, 1H), 4.67 (overlapped, 3H), 4.57 (d, J = 6.8 Hz, 1H), 4.21 (d, J = 7.6 Hz, 1H), 4.04 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.54 (m, 2H), 3.37 (s, 3H), 3.30 (s, 6H), 3.05 (dd, J = 16.2 , 7.0 Hz, 1H), 3.05 (dd, J = 16.2, 7.0 Hz, 1H), 2.59 (m, 1H), 2.47 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H)
（1-5）11E-環化体ジコバルトヘキサカルボニルと11Z-環化体ジコバルトヘキサカルボニルを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000050
 　（1-4）で製造した環化前駆体[(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート] ジコバルトヘキサカルボニル551 mg (0.640 mmol)をジクロロメタン127mLに溶解した後、第2世代ピアース-グラブス触媒219 mg (0.246 mmol)をジクロロメタン5.0 mLに溶解させ反応液に0度で加えた。4度で7日間撹拌した後、反応溶液の溶媒を減圧留去し、粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 3 : 7から1 : 1)にて精製を行い、11E-環化体ジコバルトヘキサカルボニル (163 mg、収率31%)と11Z-環化体ジコバルトヘキサカルボニル (312 mg、収率58%)で、それぞれ褐色の液体として得た。
11E-環化体ジコバルトヘキサカルボニル, 1H-NMR (CDCl3, 400 MHz) δ ppm: 6.64 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 5.91 (m, 1H), 5.37 (sext, J = 5.6 Hz, 1H), 5.26 (m, 2H), 5.01 (d, J = 7.2 Hz, 1H), 4.71-4.66 (overlapped, 2H), 4.33 (d, J = 7.2 Hz, 1H), 4.27 (d, J = 8.4 Hz, 4.11 (m, 1H), 3.83 (m, 2H), 3.79 (s, 3H), 3.62 (dd, J = 16.0, 6.0 Hz, 1H), 3.56 (m, 2H), 3.38 (s, 3H), 3.30 (s, 3H), 3.27 (s, 3H), 3.23 (dd, J = 16.2, 6.0 Hz, 1H)2.77 (m, 1H), 2.54 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H)11Z-環化体ジコバルトヘキサカルボニル, 1H-NMR (CDCl3, 400 MHz) δ ppm: 6.75 (br-s, 1H), 6.63 (d, J = 11.6 Hz, 1H), 6.44 (br-s, 1H), 5.79 (m, 1H), 5.19 (q, J = 7.2 Hz, 2H), 4.93 (m, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.49 (d, J = 7.2 Hz, 1H), 4.39 (d, J = 8.8 Hz, 1H), 3.98-3.93 (overlapped, 2H), 3.83-3.73 (overlapped, 4H), 3.80 (s, 3H), 3.62 (dd, J = 14.8, 10.8 Hz, 1H), 3.53 (m, 2H), 3.37 (s, 3H), 3.31 (s, 3H), 3.11 (s, 3H), 3.05 (m, 1H), 2.37 (m, 1H), 1.66 (d, J = 6.0 Hz, 1H) (1-5) 11E-cyclized dicobalt hexacarbonyl and 11Z-cyclized dicobalt hexacarbonyl were synthesized as follows.
Figure JPOXMLDOC01-appb-C000050
 The cyclization precursor prepared in (1-4) [(2S, 7S, 8S) -7,8-Bis (methoxymethoxy) -6-ocisoundec-10-en-4-in-2-yl 4-methoxy- 2-((2-Methoxyethoxy) methoxy) -6-vinylbenzoate] Dicobalt hexacarbonyl 551 mg (0.640 mmol) was dissolved in 127 mL of dichloromethane, and then 219 mg (0.246 mmol) of 2nd generation Pierce-Grubbs catalyst was added to dichloromethane. It was dissolved in 5.0 mL and added to the reaction solution at 0 degree. After stirring at 4 ° C for 7 days, the solvent of the reaction solution was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1) to give 11E-ring. The compound dicobalt hexacarbonyl (163 mg, yield 31%) and the 11Z-cyclized dicobalt hexacarbonyl (312 mg, yield 58%) were obtained as brown liquids.
11E-cyclized dicobalt hexacarbonyl, 1 H-NMR (CDCl 3 , 400 MHz) δ ppm: 6.64 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.39 ( d, J = 2.0 Hz, 1H), 5.91 (m, 1H), 5.37 (sext, J = 5.6 Hz, 1H), 5.26 (m, 2H), 5.01 (d, J = 7.2 Hz, 1H), 4.71- 4.66 (overlapped, 2H), 4.33 (d, J = 7.2 Hz, 1H), 4.27 (d, J = 8.4 Hz, 4.11 (m, 1H), 3.83 (m, 2H), 3.79 (s, 3H), 3.62 (dd, J = 16.0, 6.0 Hz, 1H), 3.56 (m, 2H), 3.38 (s, 3H), 3.30 (s, 3H), 3.27 (s, 3H), 3.23 (dd, J = 16.2, 6.0 Hz, 1H) 2.77 (m, 1H), 2.54 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H) 11Z-cyclized dicobalt hexacarbonyl, 1 H-NMR (CDCl 3 , 400 MHz) δ ppm: 6.75 (br-s, 1H), 6.63 (d, J = 11.6 Hz, 1H), 6.44 (br-s, 1H), 5.79 (m, 1H), 5.19 (q, J = 7.2 Hz, 2H ), 4.93 (m, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.49 (d, J = 7.2 Hz, 1H), 4.39 (d, J = 8.8 Hz, 1H), 3.98-3.93 (overlapped , 2H), 3.83-3.73 (overlapped, 4H), 3.80 (s, 3H), 3.62 (dd, J = 14.8, 10.8 Hz, 1H), 3.53 (m, 2H), 3.37 (s, 3H), 3.31 ( s, 3H), 3.11 (s, 3H), 3.05 (m, 1H), 2.37 (m, 1H), 1.66 (d, J = 6.0 Hz, 1H)
（1-6）11E-イノンマクロライドAを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000051
 　（1-5）で製造した11E-環化体ジコバルトヘキサカルボニル86.0 mg (0.105 mmol)をアセトン2.0 mLに溶解し、セリウムアンモニウムナイトレート57 mg (0.105 mmol)を0度で加えた。0度で15分間撹拌した後、同量のセリアムアンモニウムナイトレートを加え、0度で15分間攪拌した。同じ作業を3回繰り返し行なった。薄層クロマトグラフィーにて原料の消失を確認後、精製水を1.0 mL加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 1)にて精製し、11E-イノンマクロライドAを透明の液体として得た(41 mg、収率74%)。
1H-NMR (CDCl3, 400 MHz) δppm: 6.78 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.15 (m, 1H), 5.32-5.25 (overlapped, 3H), 4.80 (d, J = 7.2Hz, 1H), 4.74-4.65 (overlapped, 3H), 4.47 (d, J = 2.8 Hz, 1H), 4.37 (m, 1H), 3.83-3.80 (overlapped, 2H), 3.81 (s, 3H), 3.56 (m, 2H), 3.40 (s, 3H), 3.35 (s, 6H), 2.88 (dd, J = 17.4, 3.2 Hz, 1H), 2.74-2.61 (overlapped, 2H), 2.29 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H) (1-6) 11E-Inone macrolide A was synthesized as follows.
Figure JPOXMLDOC01-appb-C000051
 86.0 mg (0.105 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-5) was dissolved in 2.0 mL of acetone, and 57 mg (0.105 mmol) of cerium ammonium nitrate was added at 0 degrees. After stirring at 0 ° C for 15 minutes, the same amount of ceriam ammonium nitrate was added, and the mixture was stirred at 0 ° C for 15 minutes. The same work was repeated 3 times. After confirming the disappearance of the raw materials by thin layer chromatography, 1.0 mL of purified water was added, and the solution was separated with dichloromethane three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain 11E-inone macrolide A as a transparent liquid (41 mg, yield 74%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 6.78 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.15 (m, 1H), 5.32-5.25 (overlapped, 3H), 4.80 (d, J = 7.2Hz, 1H), 4.74-4.65 (overlapped, 3H), 4.47 (d, J = 2.8 Hz, 1H), 4.37 ( m, 1H), 3.83-3.80 (overlapped, 2H), 3.81 (s, 3H), 3.56 (m, 2H), 3.40 (s, 3H), 3.35 (s, 6H), 2.88 (dd, J = 17.4, 3.2 Hz, 1H), 2.74-2.61 (overlapped, 2H), 2.29 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H)
実施例２　11E-イノンマクロライドA’
　11E-イノンマクロライドA’を次のようにして合成した。
Figure JPOXMLDOC01-appb-C000052
 　（1-6）で製造した11E-イノンマクロライドA 4.04 mg (0.00753 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を1.9mL (4.14 mmol)加えた。室温で5時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をプレパラティブTLCで精製を行い、Compound #13を白色の固体として得た (1.10 mg、収率40%)。
1H-NMR (CDCl3, 500 MHz) δppm: 11.5 (s, 1H), 7.27 (d, J = 13.9 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 6.07 (ddd, J = 14.7, 9.9, 4.4 Hz, 1H), 5.41 (m, 1H), 4.44 (d, J = 2.9 Hz, 1H), 4.32 (td, J = 8.4, 2.9 Hz, 1H), 2.94 (dd, J = 17.4, 3.5 Hz, 1H), 2.80 (dd, J = 17.4, 5.6 Hz, 1H), 2.56-2.50 (overlapped, 2H), 1.54 (d, J = 6.3 Hz, 1H) Example 2 11 E-inone macrolide A '
11E-inone macrolide A'was synthesized as follows.
Figure JPOXMLDOC01-appb-C000052
 1.9 mL (4.14 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 11E-inone macrolide A 4.04 mg (0.00753 mmol) produced in (1-6). After stirring at room temperature for 5 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The crude product was purified by preparative TLC to give Compound # 13 as a white solid (1.10 mg, 40% yield).
1 H-NMR (CDCl 3 , 500 MHz) δppm: 11.5 (s, 1H), 7.27 (d, J = 13.9 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 6.07 (ddd, J = 14.7, 9.9, 4.4 Hz, 1H), 5.41 (m, 1H), 4.44 (d, J = 2.9 Hz, 1H), 4.32 (td, J = 8.4, 2.9 Hz, 1H), 2.94 (dd, J = 17.4, 3.5 Hz, 1H), 2.80 (dd, J = 17.4, 5.6 Hz, 1H), 2.56-2.50 (overlapped, 2H), 1.54 (d, J = 6.3 Hz , 1H)
実施例３　11Z-イノンマクロライドB
　11Z-イノンマクロライドBを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000053
 　（1-6）で製造した11E-環化体ジコバルトヘキサカルボニル87.0 mg (0.106 mmol)をアセトン2.0 mLに溶解し、セリウムアンモニウムナイトレート57.7 mg (0.106 mmol)を0度で加えた。0度で15分間撹拌した後、同量のセリアムアンモニウムナイトレートを加え、0度で15分間攪拌した。同じ作業を3回繰り返し行なった。薄層クロマトグラフィーにて原料の消失を確認後、精製水を1.0 mL加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 1)にて精製し、11Z-イノンマクロライドBを透明の液体として得た(45 mg、収率81%)。
1H-NMR (CDCl3, 400 MHz) δppm: 6.67 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 11.6 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 5.53 (m, 1H), 5.30-5.17 (overlapped, 3H), 4.69-4.64 (overlapped, 3H), 4.60 (d, J = 6.8 Hz, 1H), 4.30 (d, J = 2.4 Hz, 1H), 4.20 (m, 1H), 3.84-3.79 (overlapped, 2H), 3.80 (s, 3H), 3.57 (m, 2H), 3.38 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 2.88-2.80 (overlapped, 2H), 2.61 (dd, J = 17.4, 8.4 Hz, 1H), 2.50 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H) Example 3 11Z-inone macrolide B
11Z-inone macrolide B was synthesized as follows.
Figure JPOXMLDOC01-appb-C000053
 87.0 mg (0.106 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-6) was dissolved in 2.0 mL of acetone, and 57.7 mg (0.106 mmol) of cerium ammonium nitrate was added at 0 °. After stirring at 0 ° C for 15 minutes, the same amount of ceriam ammonium nitrate was added, and the mixture was stirred at 0 ° C for 15 minutes. The same work was repeated 3 times. After confirming the disappearance of the raw materials by thin layer chromatography, 1.0 mL of purified water was added, and the solution was separated with dichloromethane three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain 11Z-inone macrolide B as a transparent liquid (45 mg, yield 81%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 6.67 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 11.6 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 5.53 (m, 1H), 5.30-5.17 (overlapped, 3H), 4.69-4.64 (overlapped, 3H), 4.60 (d, J = 6.8 Hz, 1H), 4.30 (d, J = 2.4 Hz, 1H), 4.20 ( m, 1H), 3.84-3.79 (overlapped, 2H), 3.80 (s, 3H), 3.57 (m, 2H), 3.38 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 2.88 -2.80 (overlapped, 2H), 2.61 (dd, J = 17.4, 8.4 Hz, 1H), 2.50 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H)
実施例４　11Z-イノンマクロライドC
　11Z-イノンマクロライドCを次のように合成した。
Figure JPOXMLDOC01-appb-C000054
 　実施例３で製造した11Z-イノンマクロライドB 4.8 mg (0.00975 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を2.3 mL (4.92 mmol)加えた。室温で1時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 2 : 8から1 : 1)にて精製し、11Z-イノンマクロライドCを得た(1.6 mg、収率50%)。
1H-NMR (CDCl3, 500 MHz) δppm: 11.70 (s, 1H), 6.73 (d, J = 11.6 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 5.54 (m, 1H), 5.40 (m, 1H), 4.75-4.71 (overlapped, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.35 (d, J = 2.8 Hz, 1H), 4.30 (d, J = 6.8 Hz, 1H), 4.16 (dt, J = 10.8, 3.2 Hz, 1H), 3.81 (s, 3H), 3.40 (s, 3H), 3.15 (s, 3H), 3.12 (m, 1H), 2.62-2.45 (over;apped, 3H), 1.53 (d, J = 6.4 Hz, 3H) Example 4 11Z-Inone Macrolide C
11Z-inone macrolide C was synthesized as follows.
Figure JPOXMLDOC01-appb-C000054
 2.3 mL (4.92 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 4.8 mg (0.00975 mmol) of 11Z-inone macrolide B produced in Example 3. After stirring at room temperature for 1 hour, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the solution was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 8 to 1: 1) to obtain 11Z-inone macrolide C (1.6 mg, yield 50%).
1 H-NMR (CDCl 3 , 500 MHz) δppm: 11.70 (s, 1H), 6.73 (d, J = 11.6 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 5.54 (m, 1H), 5.40 (m, 1H), 4.75-4.71 (overlapped, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.35 (d, J = 2.8 Hz, 1H), 4.30 (d, J = 6.8 Hz, 1H), 4.16 (dt, J = 10.8, 3.2 Hz, 1H), 3.81 (s, 3H), 3.40 (s, 3H), 3.15 (s, 3H), 3.12 (m, 1H), 2.62-2.45 (over; apped, 3H), 1.53 (d, J = 6.4 Hz, 3H)
実施例５　11Z-イノンマクロライドD
　11Z-イノンマクロライドDを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000055
 　実施例３で製造した11Z-イノンマクロライドB 4.9 mg (0.00975 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を2.4 mL (5.0 mmol)加えた。室温で8時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をHPLCにて精製を行い、Compound #26を白色の固体として得た(0.3 mg、収率9.1%)。
1H-NMR (CDCl3, 500 MHz) δppm: 11.60 (s, 1H), 6.72 (d, J = 11.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.50 (m, 1H), 5.20 (td, J = 11.2, 5.5 Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.82 (s, 3H), 3.64 (m, 1H), 3.08 (dd, J = 17.1, 14.8 Hz, 1H), 2.67 (m, 1H), 2.57 (dd, J = 17.1, 2.8 Hz, 1H), 2.26 (td, J = 11.8, 5.8 Hz, 1H), 1.52 (d, J = 6.4 Hz, 3H) Example 5 11Z-Inone Macrolide D
11Z-inone macrolide D was synthesized as follows.
Figure JPOXMLDOC01-appb-C000055
 2.4 mL (5.0 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 4.9 mg (0.00975 mmol) of 11Z-inone macrolide B produced in Example 3. After stirring at room temperature for 8 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The crude product was purified by HPLC to obtain Compound # 26 as a white solid (0.3 mg, yield 9.1%).
1 H-NMR (CDCl 3 , 500 MHz) δppm: 11.60 (s, 1H), 6.72 (d, J = 11.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.50 (m, 1H), 5.20 (td, J = 11.2, 5.5 Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.82 (s, 3H), 3.64 ( m, 1H), 3.08 (dd, J = 17.1, 14.8 Hz, 1H), 2.67 (m, 1H), 2.57 (dd, J = 17.1, 2.8 Hz, 1H), 2.26 (td, J = 11.8, 5.8 Hz , 1H), 1.52 (d, J = 6.4 Hz, 3H)
実施例６　11飽和-イノンマクロライドA
（6-1）11飽和-環化体ジコバルトヘキサカルボニルを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000056
 　（1-5）で製造した11Z-環化体ジコバルトヘキサカルボニル2.9 mg (0.00353 mmol)をメタノール0.7 mLに溶解した後、ロジウムカーボン16 mg (0.00353 mmol)を加え、－40度に冷却した。その後、内部を水素ガスで置換し、－40度で3日間撹拌した。質量分析にて反応の進行を確認後、フィルターろ過を行い、ロジウムカーボンを除去した。溶媒を減圧留去した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 1から2 : 1)にて精製し、11飽和-環化体ジコバルトヘキサカルボニルを透明の液体として得た(1.2 mg、収率42%)。
1H-NMR (CDCl3, 500 MHz) δppm: 6.54 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 5.28 (m, 1H), 5.20 (s, 2H), 4.73-4.61 (overlapped, 5H), 4.08 (m, 1H), 3.82-3.77 (overlapped, 2H), 3.77 (s, 3H), 3.55 (m, 2H), 3.37 (s, 6H), 3.32-3.26 (overlapped, 2H), 2.62 (m, 2H), 1.75-1.63 (overlapped, 4H), 1.57 (d, J = 6.0 Hz, 3H) Example 6 11 Saturated-Inone Macrolide A
(6-1) 11-saturated-cyclized dicobalt hexacarbonyl was synthesized as follows.
Figure JPOXMLDOC01-appb-C000056
 After dissolving 2.9 mg (0.00353 mmol) of the 11Z-cyclized dicobalt hexacarbonyl produced in (1-5) in 0.7 mL of methanol, 16 mg (0.00353 mmol) of rhodium carbon was added, and the mixture was cooled to -40 degrees. Then, the inside was replaced with hydrogen gas, and the mixture was stirred at -40 ° C for 3 days. After confirming the progress of the reaction by mass spectrometry, filter filtration was performed to remove rhodium carbon. After the solvent was distilled off under reduced pressure, the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 2: 1) to obtain 11 saturated-cyclized dicobalt hexacarbonyl. Was obtained as a liquid (1.2 mg, yield 42%).
1 H-NMR (CDCl 3 , 500 MHz) δppm: 6.54 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 5.28 (m, 1H), 5.20 (s, 2H) , 4.73-4.61 (overlapped, 5H), 4.08 (m, 1H), 3.82-3.77 (overlapped, 2H), 3.77 (s, 3H), 3.55 (m, 2H), 3.37 (s, 6H), 3.32-3.26 (overlapped, 2H), 2.62 (m, 2H), 1.75-1.63 (overlapped, 4H), 1.57 (d, J = 6.0 Hz, 3H)
（6-2）11飽和-イノンマクロライドAを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000057
 　（6-1）で製造した11飽和-環化体ジコバルトヘキサカルボニル1.2 mg (0.00146 mmol)をアセトン0.15 mLに溶解しセリウムアンモニウムナイトレート0.8 mg (0.00146 mmol)を0度で加えた。0度で15分間撹拌した後、同量のセリアムアンモニウムナイトレートを加え、0度で15分間攪拌した。同じ作業を3回繰り返し行なった。薄層クロマトグラフィーにて原料の消失を確認後、精製水を1.0 mL加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン= 2 : 1)にて精製し、11飽和-イノンマクロライドAを透明の液体として得た(0.8 mg、収率99%)。
1H-NMR (CDCl3, 500 MHz) δppm: 6.62 (d, J = 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 5.32 (m, 1H), 5.25 (s, 2H), 4.82 (d, J = 6.8 Hz, 1H), 4.66-4.62 (overlapped, 3H), 4.47 (d, J = 2.4 Hz, 1H), 4.05 (m, 1H), 3.84-3.79 (overlapped, 2H), 3.79 (s, 3H), 3.58-3.55 (overlapped, 2H), 3.40 (s, 3H), 3.39-3.32 (overlapped, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.73-2.58 (overlapped, 3H), 1.80-1.78 (overlapped, 4H), 1.48 (d, J = 6.4 Hz, 3H) (6-2) 11 Saturated-Inone macrolide A was synthesized as follows.
Figure JPOXMLDOC01-appb-C000057
 1.2 mg (0.00146 mmol) of 11-saturated-cyclized dicobalt hexacarbonyl produced in (6-1) was dissolved in 0.15 mL of acetone, and 0.8 mg (0.00146 mmol) of cerium ammonium nitrate was added at 0 °. After stirring at 0 ° C for 15 minutes, the same amount of ceriam ammonium nitrate was added, and the mixture was stirred at 0 ° C for 15 minutes. The same work was repeated 3 times. After confirming the disappearance of the raw materials by thin layer chromatography, 1.0 mL of purified water was added, and the solution was separated with dichloromethane three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 11 saturated-inone macrolide A as a transparent liquid (0.8 mg, yield 99%).
1 H-NMR (CDCl 3 , 500 MHz) δppm: 6.62 (d, J = 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 5.32 (m, 1H), 5.25 (s, 2H) , 4.82 (d, J = 6.8 Hz, 1H), 4.66-4.62 (overlapped, 3H), 4.47 (d, J = 2.4 Hz, 1H), 4.05 (m, 1H), 3.84-3.79 (overlapped, 2H), 3.79 (s, 3H), 3.58-3.55 (overlapped, 2H), 3.40 (s, 3H), 3.39-3.32 (overlapped, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.73-2.58 ( overlapped, 3H), 1.80-1.78 (overlapped, 4H), 1.48 (d, J = 6.4 Hz, 3H)
実施例７　11飽和-イノンマクロライドB
　11飽和-イノンマクロライドBを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000058
 　実施例６で製造した11飽和-イノンマクロライドA 0.8 mg (0.00146 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を0.4 mL (0.8 mmol) 加えた。室温で8時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。溶媒を減圧留去した後、HPLCにて精製を行い、11飽和-イノンマクロライドBを白色の固体として得た(0.05 mg、収率9.3%)。
1H-NMR (CDCl3, 500 MHz) δppm: 11.95 (s, 1H), 6.37 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 5.41 (m, 1H), 4.39 (d, J = 2.5 Hz, 1H), 4.05 (m, 1H), 3.82 (s, 3H), 3.45 (td, J = 12.6, 2.5 Hz, 1H), 3.19 (dd, J = 17.5, 4.1 Hz, 1H), 2.75 (dd, J = 17.5, 4.1 Hz, 1H), 2.49 (m, 1H), 2.14-1.97 (overlapped, 4H), 1.55 (d, J = 6.7 Hz, 3H) Example 7 11 Saturated-Inone Macrolide B
11 Saturated-Inone macrolide B was synthesized as follows.
Figure JPOXMLDOC01-appb-C000058
 0.4 mL (0.8 mmol) of a mixed solution (1:10) of 47% hydrogen fluoride aqueous solution and acetonitrile was added to 0.8 mg (0.00146 mmol) of 11-saturated-inone macrolide A prepared in Example 6. After stirring at room temperature for 8 hours, an aqueous solution of sodium hydrogen carbonate was added at 0 ° C, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated brine, sodium sulfate was added to the organic layer to remove water, and the solvent was evaporated under reduced pressure. After the solvent was distilled off under reduced pressure, purification was performed by HPLC to obtain 11 saturated-inone macrolide B as a white solid (0.05 mg, yield 9.3%).
1 H-NMR (CDCl 3 , 500 MHz) δppm: 11.95 (s, 1H), 6.37 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 5.41 (m, 1H) , 4.39 (d, J = 2.5 Hz, 1H), 4.05 (m, 1H), 3.82 (s, 3H), 3.45 (td, J = 12.6, 2.5 Hz, 1H), 3.19 (dd, J = 17.5, 4.1 Hz, 1H), 2.75 (dd, J = 17.5, 4.1 Hz, 1H), 2.49 (m, 1H), 2.14-1.97 (overlapped, 4H), 1.55 (d, J = 6.7 Hz, 3H)
実施例８　(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキシ-2-イン-1-オン
（8-1）既知化合物(3aR,7aS)-2,2-ジメチルテトラヒドロ-4H-[1,3]ジオキソロ [4,5-c]ピラン-6-オールを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000059
 　2-デオキシ-D-リボース6.0 g (44.7 mmol)をアセトン90 mL に溶解した後、2,2-ジメトキシプロパン18.8 mLを加え、室温で１５分間撹拌した。その後、p－トシル酸170 mg ( 1.00 mmol)を加え、室温で2時間撹拌した。0度に冷却後、炭酸水素ナトリウム水溶液を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン= 1 : 2から4 : 1)にて精製し、(3aR,7aS)-2,2-ジメチルテトラヒドロ-4H-[1,3]ジオキソロ [4,5-c]ピラン-6-オールを透明の液体として得た(5.9 g、収率76%)。 Example 8 (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one (8-1) The known compound (3aR, 7aS) -2,2-dimethyltetrahydro-4H- [1,3] dioxolo [4,5-c] pyran-6-ol was synthesized as follows.
Figure JPOXMLDOC01-appb-C000059
 After dissolving 6.0 g (44.7 mmol) of 2-deoxy-D-ribose in 90 mL of acetone, 18.8 mL of 2,2-dimethoxypropane was added, and the mixture was stirred at room temperature for 15 minutes. Then, 170 mg (1.00 mmol) of p-tosylic acid was added, and the mixture was stirred at room temperature for 2 hours. After cooling to 0 ° C., an aqueous sodium hydrogen carbonate solution was added, and the solution was separated with dichloromethane three times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2 to 4: 1), (3aR, 7aS) -2,2-dimethyltetrahydro-4H- [1,3 ] Dioxolo [4,5-c] pyran-6-ol was obtained as a clear liquid (5.9 g, yield 76%).
（8-2）既知化合物((4R,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)メタノールを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000060
 　メチルトリフェニルホスホニウムブロミド 370 mg (1.04 mmol)をテトラヒドロフラン 2.5 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 0.74 mL (0.888 mmol)を加えた。-78度で15分間撹拌した後、0度に昇温して30分間撹拌した。再度、-78度に反応液を冷却した後、（8-1）で製造した(3aR,7aS)-2,2-ジメチルテトラヒドロ-4H-[1,3]ジオキソロ [4,5-c]ピラン-6-オール 52 mg (0.296 mmol)をテトラヒドロフラン 0.5 mLに溶解させて反応液に加えた。室温で4時間撹拌した後、0度に冷却し、飽和塩化アンモニウム水溶液を加え、クロロホルムで分液を３回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝3:7から1:1)にて精製し、((4R,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)メタノールを透明な液体として得た (44.4 mg、収率87%)。 (8-2) A known compound ((4R, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) methanol was synthesized as follows.
Figure JPOXMLDOC01-appb-C000060
 370 mg (1.04 mmol) of methyltriphenylphosphonium bromide was dissolved in 2.5 mL of tetrahydrofuran, cooled to -78 ° C, and 0.74 mL (0.888 mmol) of normal butyllithium was added. After stirring at -78 degrees for 15 minutes, the temperature was raised to 0 degrees and stirring was performed for 30 minutes. After cooling the reaction solution to -78 degrees again, the (3aR, 7aS) -2,2-dimethyltetrahydro-4H- [1,3] dioxolo [4,5-c] pyran prepared in (8-1) was prepared. 52 mg (0.296 mmol) of -6-ol was dissolved in 0.5 mL of tetrahydrofuran and added to the reaction solution. After stirring at room temperature for 4 hours, the mixture was cooled to 0 ° C., saturated aqueous ammonium chloride solution was added, and the solution was separated with chloroform three times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1), and ((4R, 5R) -5-allyl-2,2-dimethyl-1, 3-Dioxolan-4-yl) methanol was obtained as a transparent liquid (44.4 mg, yield 87%).
（8-3）(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミドは次のようにして合成した。
Figure JPOXMLDOC01-appb-C000061
 　（8-2）で製造した((4R,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)メタノール 2.99 g (17.4 mmo)にアセトニトリル 60 mLと精製水 30 mLに溶解させた後、ヨードベンゼンジアセテート 12.3 g (38.2 mmol)と2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル 543 mg (3.47 mmol)を室温で加えた。室温で2時間撹拌した後、精製水を加え、酢酸で反応液を酸性にしてから、酢酸エチルで分液を5回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去して(4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-カルボン酸の粗生成物を得た。
　この粗生成物をジクロロメタン 90 mLに溶解させた後、0度に冷却し、N-メチルモルホリン 2.3 mL (20.8 mmol)、N,O-ジメチルヒドロキシアミン塩酸塩 1.87 g (19.1 mmol)と1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド 4.00 g (20.8 mmol)を加えた。0度で2時間撹拌した後、精製水を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝3:7から1:1)にて精製し、(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミドを白色な固体として得た (3.37 g、二工程収率85%)。
1H-NMR (CDCl3, 400 MHz) δppm: 5.83 (m, 1H), 5.12 (dd, J = 16.8, 2.0 Hz, 1H), 5.10 (d, J = 10.0, 2.0 Hz, 1H), 4.96 (d, J = 6.4 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.20 (s, 3H), 2.25 (t, J = 6.8 Hz, 2H), 1.66 (s, 3H), 1.43 (s, 3H)  (8-3) (4S, 5R) -5-allyl-N-methoxy-N, 2,2-trimethyl-1,3-dioxolane-4-carboxamide was synthesized as follows.
Figure JPOXMLDOC01-appb-C000061
 To ((4R, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) methanol 2.99 g (17.4 mmo) produced in (8-2), 60 mL of acetonitrile and 30 mL of purified water were added. After dissolving in mL, 12.3 g (38.2 mmol) of iodobenzene diacetate and 543 mg (3.47 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical were added at room temperature. After stirring at room temperature for 2 hours, purified water was added, the reaction solution was made acidic with acetic acid, and the solution was separated with ethyl acetate five times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. The solvent was distilled off under reduced pressure to obtain a crude product of (4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid.
This crude product was dissolved in 90 mL of dichloromethane, cooled to 0 ° C., and 2.3 mL (20.8 mmol) of N-methylmorpholine, 1.87 g (19.1 mmol) of N, O-dimethylhydroxyamine hydrochloride and 1- ( 4.00 g (20.8 mmol) of 3-dimethylaminopropyl) -3-ethylcarbodiimide was added. After stirring at 0 ° C for 2 hours, purified water was added, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1) and (4S, 5R) -5-allyl-N-methoxy-N, 2,2 -Trimethyl-1,3-dioxolane-4-carboxamide was obtained as a white solid (3.37 g, two-step yield 85%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 5.83 (m, 1H), 5.12 (dd, J = 16.8, 2.0 Hz, 1H), 5.10 (d, J = 10.0, 2.0 Hz, 1H), 4.96 ( d, J = 6.4 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.20 (s, 3H), 2.25 (t, J = 6.8 Hz, 2H), 1.66 ( s, 3H), 1.43 (s, 3H)
（8-4）(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オンを次のように合成した。
Figure JPOXMLDOC01-appb-C000062
 　既知化合物(S)-t-ブチル (ペント-4-イン-2-イロキシ)ジフェニルシラン 4.90g (15.2 mmol)をテトラヒドロフラン 70 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 5.8 mL (15.2 mmol)を加えた。-78度で1時間撹拌した後、（8-3）で製造した(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミド 3.16 g (11.4 mmol)をテトラヒドロフラン 20 mLに溶解させて反応液に-78度で加えた。0度で1時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オンを薄黄色の液体として得た (6.14 g、収率100%)。
1H-NMR (CDCl3, 400 MHz) δppm: 7.72-7.66 (overlapped, 4H), 7.43-7.35 (overlapped, 6H), 5.80 (m, 1H), 5.11 (d, J = 10.8 Hz, 1H), 5.09 (d, J = 9.2 Hz, 1H), 4.95 (d, J = 6.4 Hz, 1H), 4.45 (q, J = 6.8 Hz, 1H), 3.99 (sext, J = 6.0 Hz, 1H), 2.37-2.22 (overlapped, 4H), 1.62 (s, 3H), 1.49 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.07 (s, 9H) (8-4) (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) -5-((t-butyldiphenylsilyl) oxy ) Hex-2-yn-1-one was synthesized as follows.
Figure JPOXMLDOC01-appb-C000062
 Dissolve 4.90 g (15.2 mmol) of known compound (S) -t-butyl (pent-4-yn-2-yloxy) diphenylsilane in 70 mL of tetrahydrofuran, and after cooling to -78 degrees, 5.8 mL of normal butyl lithium ( 15.2 mmol) was added. After stirring at -78 ° C for 1 hour, (4S, 5R) -5-allyl-N-methoxy-N, 2,2-trimethyl-1,3-dioxolane-4-carboxamide prepared in (8-3) 3.16 g (11.4 mmol) was dissolved in tetrahydrofuran (20 mL) and added to the reaction solution at -78 degrees. After stirring at 0 ° C. for 1 hour, a saturated ammonium chloride aqueous solution was added, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) and (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl- 1,3-Dioxolan-4-yl) -5-((t-butyldiphenylsilyl) oxy) hex-2-yn-1-one was obtained as a pale yellow liquid (6.14 g, 100% yield).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 7.72-7.66 (overlapped, 4H), 7.43-7.35 (overlapped, 6H), 5.80 (m, 1H), 5.11 (d, J = 10.8 Hz, 1H), 5.09 (d, J = 9.2 Hz, 1H), 4.95 (d, J = 6.4 Hz, 1H), 4.45 (q, J = 6.8 Hz, 1H), 3.99 (sext, J = 6.0 Hz, 1H), 2.37- 2.22 (overlapped, 4H), 1.62 (s, 3H), 1.49 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.07 (s, 9H)
（8-5）(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキシ-2-イン-1-オンを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000063
 　（8-4）で製造した(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オン 5.6 mg (0.0114 mmol)をテトラヒドロフラン 0.17 mLに溶解させ、酢酸 7.0 μL (0.114 mmol)とn-テトラブチルアンモニウムフロリド溶液 0.17 mL (0.171 mmol)を室温で加えた。室温で9時間撹拌した後、0度で飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オンを薄黄色の液体として得た (1.3 mg、収率45%)。
1H-NMR (CDCl3, 400 MHz) δppm: 5.84 (m, 1H), 5.15 (d, J = 14.8 Hz, 1H), 5.12 (d, J = 8.0 Hz, 1H), 4.52 (d, J = 7.6 Hz), 4.44 (m, 1H), 4.08 (m, 1H), 2.65-2.54 (overlapped, 1H), 2.40 (m, 1H), 2.29 (m, 1H), 1.65 (s, 3H), 1.40 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H) (8-5) (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1 -On was synthesized as follows.
Figure JPOXMLDOC01-appb-C000063
 (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) -5-((t-butyldiphenyl) produced in (8-4) (Silyl) oxy) hex-2-yn-1-one 5.6 mg (0.0114 mmol) was dissolved in tetrahydrofuran 0.17 mL, and acetic acid 7.0 μL (0.114 mmol) and n-tetrabutylammonium fluoride solution 0.17 mL (0.171 mmol) were dissolved. Added at room temperature. After stirring at room temperature for 9 hours, a saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the solution was separated with chloroform three times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl- 1,3-Dioxolan-4-yl) -5-((t-butyldiphenylsilyl) oxy) hex-2-yn-1-one was obtained as a pale yellow liquid (1.3 mg, 45% yield).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 5.84 (m, 1H), 5.15 (d, J = 14.8 Hz, 1H), 5.12 (d, J = 8.0 Hz, 1H), 4.52 (d, J = 7.6 Hz), 4.44 (m, 1H), 4.08 (m, 1H), 2.65-2.54 (overlapped, 1H), 2.40 (m, 1H), 2.29 (m, 1H), 1.65 (s, 3H), 1.40 ( s, 3H), 1.31 (d, J = 6.8 Hz, 3H)
実施例９　(S)-1-((4S,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキセ-2-イン-1-オン
（9-1）既知化合物((4R,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)メタノールを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000064
 　テトラヒドロフラン1.5 mLにジイソプロピルアミン105 μL (0.755 mmol)を加え、0度に冷却した後、ノルマルブチルリチウム281 μL (0.755 mmol)を加えた。0度で15分間撹拌した後、－78度に冷却し15分間撹拌した。調製したリチウムジイソプロピルアミドに対し、トリメチルシリルジアゾメタン187 μL (0.374 mmol)を加え、－78度で30分間撹拌した。ここに、実施例1で得られた(3aR,7aS)-2,2-ジメチルテトラヒドロ-4H-[1,3]ジオキソロ [4,5-c]ピラン-6-オール 50.0 mg (0.287 mmol)をテトラヒドロフラン 0.3 mLに溶解した溶液を加え、－78度で30分間撹拌した。室温まで昇温させ、2時間撹拌した後、0度に冷却し、塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 4から2 : 3)にて精製し、((4R,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)メタノールを得た(32.1 mg、収率66%)。 Example 9 (S) -1-((4S, 5R) -2,2-Dimethyl-5- (prop-2-yn-1-yl) -1,3-dioxolan-4-yl) -5-hydroxy Hexe-2-yn-1-one (9-1) known compound ((4R, 5R) -2,2-dimethyl-5- (prop-2-yn-1-yl) -1,3-dioxolane- 4-yl) methanol was synthesized as follows.
Figure JPOXMLDOC01-appb-C000064
 To 1.5 mL of tetrahydrofuran, 105 μL (0.755 mmol) of diisopropylamine was added, and after cooling to 0 ° C, 281 μL (0.755 mmol) of normal butyl lithium was added. After stirring at 0 ° C for 15 minutes, the mixture was cooled to -78 ° C and stirred for 15 minutes. Trimethylsilyldiazomethane (187 μL, 0.374 mmol) was added to the prepared lithium diisopropylamide, and the mixture was stirred at −78 ° C. for 30 minutes. Here, 50.0 mg (0.287 mmol) of (3aR, 7aS) -2,2-dimethyltetrahydro-4H- [1,3] dioxolo [4,5-c] pyran-6-ol obtained in Example 1 was added. A solution dissolved in 0.3 mL of tetrahydrofuran was added, and the mixture was stirred at -78 ° C for 30 minutes. The temperature was raised to room temperature, the mixture was stirred for 2 hours, cooled to 0 ° C., an aqueous solution of ammonium chloride was added, and the mixture was separated with ethyl acetate three times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 2: 3), and ((4R, 5R) -2,2-dimethyl-5- (propy-2 -In-1-yl) -1,3-dioxolan-4-yl) methanol was obtained (32.1 mg, 66% yield).
（9-2）(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-カルボキサミドを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000065
 　（9-1）で製造した((4R,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)メタノール 1.43 g (8.43 mmo)にアセトニトリル 30 mLと精製水 15 mLに溶解させた後、ヨードベンゼンジアセテート 5.97 g (18.5 mmol)と2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル 263 mg (1.69 mmol)を室温で加えた。室温で2時間撹拌した後、精製水を加え、酢酸で反応液を酸性にしてから、酢酸エチルで分液を5回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去して(4S,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-カルボン酸の粗生成物を得た。
　この粗生成物をジクロロメタン 90 mLに溶解させた後、0度に冷却し、N-メチルモルホリン 1.86 mL (18.5 mmol)、N,O-ジメチルヒドロキシアミン塩酸塩 1.64 g (16.9 mmol)と1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド 3.23 g (18.5 mmol)を加えた。0度で20時間撹拌した後、精製水を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝3:7から1:1)にて精製し、(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-カルボキサミドを透明な液体として得た (1.11 g、二工程収率58%)。1H-NMR (CDCl3, 400 MHz) δppm: 4.96 (d, J = 6.4 Hz, 1H), 4.56 (q, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.19 (s, 3H), 2.42-2.39 (overlapped, 2H), 2.01 (t, J = 2.8 Hz, 1H), 1.61 (s, 3H), 1.41 (s, 3H) (9-2) (4S, 5R) -N-Methoxy-N, 2,2-trimethyl-5- (prop-2-yn-1-yl) -1,3-dioxolane-4-carboxamide Was synthesized.
Figure JPOXMLDOC01-appb-C000065
 (9-4) ((4R, 5R) -2,2-dimethyl-5- (prop-2-yn-1-yl) -1,3-dioxolan-4-yl) methanol 1.43 g (8.43 mmo) in 30 mL of acetonitrile and 15 mL of purified water, and then 5.97 g (18.5 mmol) of iodobenzene diacetate and 2,2,6,6-tetramethylpiperidine 1-oxyl free radical 263 mg (1.69 mmol). Was added at room temperature. After stirring at room temperature for 2 hours, purified water was added, the reaction solution was made acidic with acetic acid, and the solution was separated with ethyl acetate five times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. The solvent was distilled off under reduced pressure to obtain a crude product of (4S, 5R) -2,2-dimethyl-5- (prop-2-yn-1-yl) -1,3-dioxolane-4-carboxylic acid. ..
This crude product was dissolved in 90 mL of dichloromethane, then cooled to 0 ° C., 1.86 mL (18.5 mmol) of N-methylmorpholine, 1.64 g (16.9 mmol) of N, O-dimethylhydroxyamine hydrochloride and 1- ( 3.23 g (18.5 mmol) of 3-dimethylaminopropyl) -3-ethylcarbodiimide was added. After stirring at 0 ° C for 20 hours, purified water was added, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1) and (4S, 5R) -N-methoxy-N, 2,2-trimethyl-5. -(Prop-2-yn-1-yl) -1,3-dioxolane-4-carboxamide was obtained as a clear liquid (1.11 g, two-step yield 58%). 1 H-NMR (CDCl 3 , 400 MHz) δppm: 4.96 (d, J = 6.4 Hz, 1H), 4.56 (q, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.19 (s, 3H) , 2.42-2.39 (overlapped, 2H), 2.01 (t, J = 2.8 Hz, 1H), 1.61 (s, 3H), 1.41 (s, 3H)
（9-3）(S)-5-((t-ブチルジフェニルシリル)オキシ)-1-((4S,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オンは次のようにして合成した。
Figure JPOXMLDOC01-appb-C000066
 　既知化合物(S)-t-ブチル (ペント-4-イン-2-イロキシ)ジフェニルシラン 92.3 mg (0.286 mmol)をテトラヒドロフラン 0.9 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 174 μL (0.286 mmol)を加えた。-78度で1時間撹拌した後、実施例19で製造した(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-カルボキサミド 50.0 mg (0.220 mmol)をテトラヒドロフラン 0.2 mLに溶解させて反応液に-78度で加えた。0度で10分間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オンを薄黄色の液体として得た (51.3 mg、収率48%)。
1H-NMR (CDCl3, 400 MHz) δppm: 7.68-7.65 (overlapped, 4H), 7.46-7.36 (overlapped), 4.57-4.50 (overlapped, 2H), 4.03 (sext, J = 6.0 Hz, 1H), 2.56-2.50 (overlapped, 2H), 2.42 (ddd, J = 17.2, 7.6, 2.4 Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.59 (s, 3H), 1.39 (s, 3H), 1.24 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H) (9-3) (S) -5-((t-Butyldiphenylsilyl) oxy) -1-((4S, 5R) -2,2-dimethyl-5- (prop-2-yn-1-yl) -1,3-Dioxolan-4-yl) hex-2-yn-1-one was synthesized as follows.
Figure JPOXMLDOC01-appb-C000066
 The known compound (S) -t-butyl (pent-4-yn-2-yloxy) diphenylsilane 92.3 mg (0.286 mmol) was dissolved in 0.9 mL of tetrahydrofuran and cooled to -78 ° C., and then normal butyl lithium 174 μL ( 0.286 mmol) was added. After stirring for 1 hour at -78 degrees, (4S, 5R) -N-methoxy-N, 2,2-trimethyl-5- (prop-2-yn-1-yl) -1, produced in Example 19. 5-Dioxolane-4-carboxamide (50.0 mg, 0.220 mmol) was dissolved in tetrahydrofuran (0.2 mL) and added to the reaction solution at -78 ° C. After stirring at 0 ° C for 10 minutes, a saturated aqueous solution of ammonium chloride was added, and the solution was separated three times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) and (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl- 1,3-Dioxolan-4-yl) -5-((t-butyldiphenylsilyl) oxy) hex-2-yn-1-one was obtained as a pale yellow liquid (51.3 mg, 48% yield).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 7.68-7.65 (overlapped, 4H), 7.46-7.36 (overlapped), 4.57-4.50 (overlapped, 2H), 4.03 (sext, J = 6.0 Hz, 1H), 2.56-2.50 (overlapped, 2H), 2.42 (ddd, J = 17.2, 7.6, 2.4 Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.59 (s, 3H), 1.39 (s, 3H) , 1.24 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H)
（9-4）(S)-1-((4S,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキセ-2-イン-1-オンを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000067
 　（9-3）で製造した(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オン 5.0 mg (0.0103 mmol)をテトラヒドロフラン 0.1 mLに溶解させ、酢酸 3.7 μL (0.102 mmol)とn-テトラブチルアンモニウムフロリド溶液 150 μL (0.150 mmol)を室温で加えた。室温で10時間撹拌した後、0度で飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキセ-2-イン-1-オンを薄黄色の液体として得た (0.64 mg、収率25%)。
1H-NMR (CDCl3, 400 MHz) δppm: 4.57 (overlapped, 2H), 4.06 (sext, J = 6.0 Hz, 1H), 2.65-2.53 (overlapped, 3H), 2.47 (ddd, J = 16.4, 6.8, 2.4 Hz, 1H), 2.06 (t, J = 2.8 Hz, 1H), 1.65 (s, 3H), 1.41 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H) (9-4) (S) -1-((4S, 5R) -2,2-Dimethyl-5- (prop-2-yn-1-yl) -1,3-dioxolan-4-yl) -5 -Hydroxyhexe-2-yn-1-one was synthesized as follows.
Figure JPOXMLDOC01-appb-C000067
 (S) -1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) -5-((t-butyldiphenyl) produced in (9-3) 5.0 mg (0.0103 mmol) of (silyl) oxy) hex-2-yn-1-one was dissolved in 0.1 mL of tetrahydrofuran, and 3.7 μL (0.102 mmol) of acetic acid and 150 μL (0.150 mmol) of n-tetrabutylammonium fluoride solution were added. Added at room temperature. After stirring at room temperature for 10 hours, a saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the solution was separated with chloroform three times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and (S) -1-((4S, 5R) -2,2-dimethyl-5- (propene 2-In-1-yl) -1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one was obtained as a pale yellow liquid (0.64 mg, yield 25%). ).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 4.57 (overlapped, 2H), 4.06 (sext, J = 6.0 Hz, 1H), 2.65-2.53 (overlapped, 3H), 2.47 (ddd, J = 16.4, 6.8 , 2.4 Hz, 1H), 2.06 (t, J = 2.8 Hz, 1H), 1.65 (s, 3H), 1.41 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H)
実施例１０　1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オン
　1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オンは次のようにして合成した。
Figure JPOXMLDOC01-appb-C000068
 1-ペンチン 4.3 μL (0.0436 mmol)をテトラヒドロフラン 0.4 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 16 μL (0.0436 mmol)を加えた。-78度で1時間撹拌した後、（8-3）で製造した(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミド 10.0 mg (0.0436 mmol)をテトラヒドロフラン 0.1 mLに溶解させて反応液に-78度で加えた。0度で3時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オンを薄黄色の液体として得た (5.0 mg、収率45%)。
1H-NMR (CDCl3, 400 MHz) δppm: 5.82 (m, 1H), 5.20-5.02 (overlapped, 2H), 4.53 (d, J = 7.4 Hz), 4.44 (m, 1H), 2.40-2.30 (overlapped, 3H), 2.28 (m, 1H), 1.70-1.63 (overlapped, 2H), 1.65 (s, 3H), 1.38 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H) Example 10 1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) hex-2-yn- 1 -one 1-((4S, 5R)- 5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl) hex-2-yn-1-one was synthesized as follows.
Figure JPOXMLDOC01-appb-C000068
 4.3 μL (0.0436 mmol) of 1-pentyne was dissolved in 0.4 mL of tetrahydrofuran, cooled to −78 ° C., and 16 μL (0.0436 mmol) of normal butyllithium was added. After stirring at -78 degrees for 1 hour, (4S, 5R) -5-allyl-N-methoxy-N, 2,2-trimethyl-1,3-dioxolane-4-carboxamide prepared in (8-3) 10.0 mg (0.0436 mmol) was dissolved in 0.1 mL of tetrahydrofuran and added to the reaction solution at -78 degrees. After stirring at 0 ° C. for 3 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was partitioned with ethyl acetate three times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and 1-((4S, 5R) -5-allyl-2,2-dimethyl-1,3- Dioxolan-4-yl) hex-2-yn-1-one was obtained as a pale yellow liquid (5.0 mg, yield 45%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 5.82 (m, 1H), 5.20-5.02 (overlapped, 2H), 4.53 (d, J = 7.4 Hz), 4.44 (m, 1H), 2.40-2.30 ( overlapped, 3H), 2.28 (m, 1H), 1.70-1.63 (overlapped, 2H), 1.65 (s, 3H), 1.38 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H)
実施例１１　(S)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキシ-2-イン-1-オン
（11-1）(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-プロピル-1,3-ジオキソラン-4-カルボキサミドは次のようにして合成した。
Figure JPOXMLDOC01-appb-C000069
 　（8-3）で製造した(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミド 20 mg (0.0872 mmol)をメタノール 0.4 mLに溶解させた後、パラジウム/カーボン 9.3 mg (0.00872 mmol)を加えた。水素雰囲気下、室温で12時間撹拌した後、セライト濾過でパラジウム/カーボンを除去した。溶媒を留去した後、粗生成物をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-プロピル-1,3-ジオキソラン-4-カルボキサミドを薄黄色の液体として得た (19.8 g、収率99%)。
1H-NMR (CDCl3, 400 MHz) δppm: 4.92 (d, J = 6.8 Hz, 1H), 4.38 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 3.69 (s, 3H), 3.18 (s, 3H), 1.60 (s, 3H), 1.58-1.31 (overlapped, 4H), 1.38 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H) Example 11 (S) -1-((4S, 5R) -2,2-Dimethyl-5-propyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one (11-1) (4S, 5R) -N-Methoxy-N, 2,2-trimethyl-5-propyl-1,3-dioxolane-4-carboxamide was synthesized as follows.
Figure JPOXMLDOC01-appb-C000069
 20 mg (0.0872 mmol) of (4S, 5R) -5-allyl-N-methoxy-N, 2,2-trimethyl-1,3-dioxolane-4-carboxamide prepared in (8-3) was added to 0.4 mL of methanol. After dissolution, 9.3 mg (0.00872 mmol) of palladium / carbon was added. After stirring for 12 hours at room temperature in a hydrogen atmosphere, palladium / carbon was removed by Celite filtration. After distilling off the solvent, the crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and (4S, 5R) -N-methoxy-N, 2,2-trimethyl-5- Propyl-1,3-dioxolane-4-carboxamide was obtained as a pale yellow liquid (19.8 g, yield 99%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 4.92 (d, J = 6.8 Hz, 1H), 4.38 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 3.69 (s, 3H), 3.18 ( s, 3H), 1.60 (s, 3H), 1.58-1.31 (overlapped, 4H), 1.38 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H)
（11-2）(S)-5-((t-ブチルジフェニルシリル)オキシ)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オンは次のようにして合成した。
Figure JPOXMLDOC01-appb-C000070
 　既知化合物(S)-t-ブチル (ペント-4-イン-2-イロキシ)ジフェニルシラン 27.6 mg (0.0856 mmol)をテトラヒドロフラン 0.8 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 31 μL (0.0856 mmol)を加えた。-78度で1時間撹拌した後、（11-1）で製造した(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-プロピル-1,3-ジオキソラン-4-カルボキサミド 19.8 mg (0.0856 mmol)をテトラヒドロフラン 0.2 mLに溶解させて反応液に-78度で加えた。0度で1時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:4から1:1)にて精製し、(S)-5-((t-ブチルジフェニルシリル)オキシ)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オンを薄黄色の液体として得た (16.9 mg、収率40%)。
1H-NMR (CDCl3, 400 MHz) δppm: 7.68-7.64 (overlapped, 4H), 7.47-7.33 (overlapped, 6H), 4.94 (d, J = 6.8 Hz, 1H), 4.57-4.50 (overlapped, 2H), 4.33 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 4.03 (sext, J = 6.0 Hz, 1H), 1.62 (s, 3H), 1.58-1.31 (overlapped, 4H), 1.38 (s, 3H), 1.22 (t, J = 6.4 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H) (11-2) (S) -5-((t-Butyldiphenylsilyl) oxy) -1-((4S, 5R) -2,2-dimethyl-5-propyl-1,3-dioxolan-4-yl ) Hex-2-yn-1-one was synthesized as follows.
Figure JPOXMLDOC01-appb-C000070
 Known compound (S) -t-butyl (pent-4-yn-2-yloxy) diphenylsilane 27.6 mg (0.0856 mmol) was dissolved in 0.8 mL of tetrahydrofuran, and after cooling to -78 degrees, normal butyl lithium 31 μL ( 0.0856 mmol) was added. After stirring at -78 degrees for 1 hour, (4S, 5R) -N-methoxy-N, 2,2-trimethyl-5-propyl-1,3-dioxolane-4-carboxamide prepared in (11-1) 19.8 mg (0.0856 mmol) was dissolved in 0.2 mL of tetrahydrofuran and added to the reaction solution at -78 degrees. After stirring at 0 ° C. for 1 hour, a saturated ammonium chloride aqueous solution was added, and the mixture was partitioned 3 times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1) and (S) -5-((t-butyldiphenylsilyl) oxy) -1- ((4S, 5R) -2,2-Dimethyl-5-propyl-1,3-dioxolan-4-yl) hex-2-yn-1-one was obtained as a pale yellow liquid (16.9 mg, yield 40%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 7.68-7.64 (overlapped, 4H), 7.47-7.33 (overlapped, 6H), 4.94 (d, J = 6.8 Hz, 1H), 4.57-4.50 (overlapped, 2H ), 4.33 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 4.03 (sext, J = 6.0 Hz, 1H), 1.62 (s, 3H), 1.58-1.31 (overlapped, 4H), 1.38 (s, 3H), 1.22 (t, J = 6.4 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H)
（11-3）(S)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキシ-2-イン-1-オンを次のようにして合成した。
Figure JPOXMLDOC01-appb-C000071
 　（11-2）で製造した(S)-5-((t-ブチルジフェニルシリル)オキシ)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オン 6.0 mg (0.0122 mmol)をテトラヒドロフラン 0.18 mLに溶解させ、酢酸 7.0 μL (0.114 mmol)とn-テトラブチルアンモニウムフロリド溶液 0.17 mL (0.171 mmol)を室温で加えた。室温で9時間撹拌した後、0度で飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:4から1:1)にて精製し、(S)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキシ-2-イン-1-オンを薄黄色の液体として得た (1.1 mg、収率35%)。
1H-NMR (CDCl3, 400 MHz) δppm: 4.90 (d, J = 6.8 Hz, 1H), 4.30 (m, 1H), 1.62 (s, 3H), 1.59-1.29 (overlapped, 4H), 1.37 (s, 3H), 1.27 (t, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H) (11-3) (S) -1-((4S, 5R) -2,2-Dimethyl-5-propyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1 -On was synthesized as follows.
Figure JPOXMLDOC01-appb-C000071
 (S) -5-((t-Butyldiphenylsilyl) oxy) -1-((4S, 5R) -2,2-dimethyl-5-propyl-1,3-dioxolane-prepared in (11-2) 4-yl) hex-2-yn-1-one 6.0 mg (0.0122 mmol) was dissolved in tetrahydrofuran 0.18 mL, and acetic acid 7.0 μL (0.114 mmol) and n-tetrabutylammonium fluoride solution 0.17 mL (0.171 mmol) were dissolved. Added at room temperature. After stirring at room temperature for 9 hours, a saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the solution was separated with chloroform three times. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1), and (S) -1-((4S, 5R) -2,2-dimethyl- 5-Propyl-1,3-dioxolan-4-yl) -5-hydroxyhex-2-yn-1-one was obtained as a pale yellow liquid (1.1 mg, yield 35%).
1 H-NMR (CDCl 3 , 400 MHz) δppm: 4.90 (d, J = 6.8 Hz, 1H), 4.30 (m, 1H), 1.62 (s, 3H), 1.59-1.29 (overlapped, 4H), 1.37 ( s, 3H), 1.27 (t, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H)
試験例１　ヒト多発性骨髄腫細胞株RPMI８２２６に対する小胞体ストレス
　ヒト多発性骨髄腫細胞株RPMI８２２６を、3.5cm　dishに10000細胞／ｗｅｌｌの密度で播種し、５％二酸化炭素雰囲気下、３７℃で一晩インキュベートした。別途、実施例の化合物 (実施例７、１８)をジメチルスルホキシドに溶解し、化合物の最終濃度が10μＭとなるように各ｗｅｌｌへ添加した。
　次いで、５％二酸化炭素雰囲気下、３７℃で２４時間間培養した後、細胞を回収し、PBSバッファーを用いて細胞抽出液を調製し、SDS-PAGEにて泳動し、セミドライの転写装置でPVDF膜に転写した。 
＜抗体処理＞
　１次抗体：抗ＣＨＯＰ　＃２８９５　Ｌｏｔ：４［ＣＳＴ］
　２次抗体：抗マウスＩｇＧ　＃７０７６　Ｌｏｔ：３２［ＣＳＴ］
　　　　　　＋抗ビオチン　　＃７０７５　Ｌｏｔ：３２［ＣＳＴ］
＜検出条件＞
　検出試薬：Ｕｌｔｒａ
　検出強度：Ｓｔａｎｄａｒｄ
　露光時間：４秒
　ゲル濃度：１５％
　タンパク量：５０μｇ／レーン
　結果を図１に示す。図１に示されるように、実施例２、８、及び９の化合物は、小胞体ストレス応答を誘起した。 Test Example 1 Endoplasmic Reticulum Stress on Human Multiple Myeloma Cell Line RPMI8226 Human multiple myeloma cell line RPMI8226 was seeded in a 3.5 cm dish at a density of 10,000 cells / well and incubated at 37 ° C. in a 5% carbon dioxide atmosphere at 37 ° C. Incubated overnight. Separately, the compound of Example (Examples 7 and 18) was dissolved in dimethylsulfoxide and added to each well so that the final concentration of the compound was 10 μM.
Then, after culturing at 37 ° C for 24 hours in a 5% carbon dioxide atmosphere, cells are collected, a cell extract is prepared using PBS buffer, electrophoresed on SDS-PAGE, and PVDF is applied on a semi-dry transcription device. Transferred to a membrane.
<Antibody treatment>
Primary antibody: Anti-CHOP # 2895 Lot: 4 [CST]
Secondary antibody: anti-mouse IgG # 7076 Lot: 32 [CST]
+ Anti-biotin # 7075 Lot: 32 [CST]
<Detection conditions>
Detection reagent: Ultra
Detection intensity: Standard
Exposure time: 4 seconds Gel concentration: 15%
Protein amount: 50 μg / lane The results are shown in FIG. As shown in FIG. 1, the compounds of Examples 2, 8 and 9 elicited an endoplasmic reticulum stress response.
試験例２　抗がん活性
（１）ヒト多発性骨髄腫細胞株RPMI８２２６に対する抗がん活性
　ヒト多発性骨髄腫細胞株RPMI８２２６を、９６ｗｅｌｌプレートに１×１０4細胞／ｗｅｌｌの密度で播種し、５％二酸化炭素雰囲気下、３７℃で一晩インキュベートした。別途、実施例の化合物をジメチルスルホキシドに溶解し、化合物の最終濃度が０．７８１２５μＭ、１．５６２５μＭ、３．１２５μＭ、６．２５μＭ、１２．５μＭ、２５μＭまたは５０μＭとなるように各ｗｅｌｌへ添加した。 
　次いで、５％二酸化炭素雰囲気下、３７℃で３日間培養した後、細胞培養／細胞毒性測定用試薬（同仁化学社製，Ｃｅｌｌ　Ｃｏｕｎｔｉｎｇ　Ｋｉｔ－８）を用い、生細胞から産生される橙色色素（ホルマザン）の吸光度（４２０ｎｍ）を測定した。本発明化合物やメルファランを添加しない場合の吸光度を１００とした場合の相対吸光度からＩＣ50値を求めた。 
（２）各ヒトがん細胞株に対する抗がん活性
　ヒトがん細胞株HCT１１６、A５４９、HeLaまたはヒト胎児腎由来細胞（HEK２９３）を、９６ｗｅｌｌプレートに１×１０4細胞／ｗｅｌｌの密度で播種し、５％二酸化炭素雰囲気下、３７℃で一晩インキュベートした。別途、実施例の化合物をジメチルスルホキシドに溶解し、化合物の最終濃度が０．７８１２５μＭ、１．５６２５μＭ、３．１２５μＭ、６．２５μＭ、１２．５μＭ、２５μＭまたは５０μＭとなるように各ｗｅｌｌへ添加した。 
　次いで、５％二酸化炭素雰囲気下、３７℃で３日間培養した後、細胞培養／細胞毒性測定用試薬（同仁化学社製，Ｃｅｌｌ　Ｃｏｕｎｔｉｎｇ　Ｋｉｔ－８）を用い、生細胞から産生される橙色色素（ホルマザン）の吸光度（４２０ｎｍ）を測定した。本発明化合物やメルファランを添加しない場合の吸光度を１００とした場合の相対吸光度からＩＣ50値を求めた。
　これらの結果を表１に示す。
Figure JPOXMLDOC01-appb-T000072
 Test Example 2 Anti-cancer activity (1) Anti-cancer activity against human multiple myeloma cell line RPMI8226 Human multiple myeloma cell line RPMI8226 was seeded on a 96-well plate at a density of 1 × 10 4 cells / well, and 5 Incubated overnight at 37 ° C. in a% carbon dioxide atmosphere. Separately, the compound of Example was dissolved in dimethyl sulfoxide and added to each well so that the final concentration of the compound was 0.78125 μM, 1.5625 μM, 3.125 μM, 6.25 μM, 12.5 μM, 25 μM or 50 μM. .
Then, after culturing at 37 ° C. for 3 days in a 5% carbon dioxide atmosphere, a cell culture / cytotoxicity measuring reagent (Cell Counting Kit-8, manufactured by Dojindo Co., Ltd.) was used to produce an orange dye (produced from living cells). The absorbance (420 nm) of formazan) was measured. The IC 50 value was determined from the relative absorbance when the absorbance without addition of the compound of the present invention or melphalan was 100.
(2) Anti-cancer activity against each human cancer cell line Human cancer cell lines HCT116, A549, HeLa or human embryonic kidney-derived cells (HEK293) were seeded on a 96-well plate at a density of 1 × 10 4 cells / well. Incubated overnight at 37 ° C in a 5% carbon dioxide atmosphere. Separately, the compound of Example was dissolved in dimethyl sulfoxide and added to each well so that the final concentration of the compound was 0.78125 μM, 1.5625 μM, 3.125 μM, 6.25 μM, 12.5 μM, 25 μM or 50 μM. .
Then, after culturing at 37 ° C. for 3 days in a 5% carbon dioxide atmosphere, a cell culture / cytotoxicity measuring reagent (Cell Counting Kit-8, manufactured by Dojindo Co., Ltd.) was used to produce an orange dye (produced from living cells). The absorbance (420 nm) of formazan) was measured. The IC 50 value was determined from the relative absorbance when the absorbance without addition of the compound of the present invention or melphalan was 100.
The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000072
試験例３　ＰＤＩ活性測定
　Abcam製のPDI Inhibitor Screening Assay Kitを用いてPDI活性測定を行った (検出感度>37μM)。まず、96wellプレート各WellにMill-Q H2Oで希釈したInsulin solution (320μM)或いはMill-Q H2O（Blank）を50μL/wellとなるように加えた。次に、各WellにPDI working solution或いはMill-Q H2O（Negative control）を10μL/wellとなるように加えた。さらに、各Wellに希釈した化合物（最終濃度の8倍濃度の溶液）を10μL/wellとなるように加えた（Untreated, Negative control, BlankにはMill-Q H2Oを10μL/well）。次いで、各WellにDTTを10μL/wellとなるように加え、軽くプレートをたたいて混和した。その後、室温で30分間、遮光下でインキュベートし、各WellにStop Reagent working solutionを10μL/wellとなるように加えた。さらに各WellにPDI Detection Reagent working solutionを10μL/wellとなるように加えた。室温で15分間インキュベート後に励起波長500nm、蛍光波長603nmで蛍光をプレートリーダーで測定した。
　Positive controlであるBacitracinのIC50は169.7μM、実施例2及び実施例9はそれぞれ24.1μM及び164.4μMであった。 Test Example 3 PDI activity measurement PDI activity measurement was carried out using Abcam's PDI Inhibitor Screening Assay Kit (detection sensitivity> 37 μM). First, was added Insulin solution diluted with Mill-Q H 2 O in 96well plates each Well (320μM) or Mill-Q H 2 O (Blank ) so that 50 [mu] L / well. Next, PDI working solution or Mill-Q H 2 O (Negative control) was added to each well at 10 μL / well. Furthermore, the diluted compound (a solution having a concentration of 8 times the final concentration) was added to each well so that the concentration was 10 μL / well (Mill-Q H 2 O was 10 μL / well for Untreated, Negative control, and Blank). Then, DTT was added to each well at 10 μL / well, and the plate was gently tapped to mix. Then, the mixture was incubated at room temperature for 30 minutes in the dark, and Stop Reagent working solution was added to each well at 10 μL / well. Furthermore, PDI Detection Reagent working solution was added to each well so that the concentration was 10 μL / well. After incubating at room temperature for 15 minutes, fluorescence was measured with a plate reader at an excitation wavelength of 500 nm and a fluorescence wavelength of 603 nm.
The IC50 of Bacitracin, which is positive control, was 169.7 μM, and Example 2 and Example 9 were 24.1 μM and 164.4 μM, respectively.
試験例４　マウスモデルにおける抗がん活性
　ルシフェラーゼを恒常的に発現するマウス骨髄腫細胞株５ＴＧＭ－１を６週齢雌ＩＣＲマウス右側脛骨骨髄内に１０６細胞移植し、１週間後に生着を確認後、実施例の化合物の最終濃度が２０ｍｇ／ｋｇとなるようマウスに腹腔内投与を隔日行った。２週間投与を行った後、腫瘍細胞の体内での増殖を観察するため、ルシフェリンを腹腔内投与しＩＶＩＳイメージングシステムにより検出した。
　結果を図２～３に示す。図２～３に示されるように、実施例２及び実施例８の化合物は、骨髄腫モデルマウスにおいて腫瘍進展を抑制した。 Test Example 4 Mouse myeloma cell line 5TGM-1, which constantly expresses anti-cancer active luciferase in a mouse model , was transplanted into the right tibia bone marrow of a 6-week-old female ICR mouse by 10 6 cells, and 1 week later, engraftment was confirmed. After that, the mice were intraperitoneally administered every other day so that the final concentration of the compound of Example was 20 mg / kg. After administration for 2 weeks, in order to observe the proliferation of tumor cells in the body, luciferin was intraperitoneally administered and detected by the IVIS imaging system.
The results are shown in FIGS. As shown in FIGS. 2-3, the compounds of Example 2 and Example 8 suppressed tumor progression in myeloma model mice.
試験例５　造血幹細胞への細胞障害活性への影響
　ヒト末梢血幹細胞を１２ｗｅｌｌプレートに２Ｘ１０６細胞／ｗｅｌｌの密度で播種し別途、実施例の化合物をジメチルスルホキシドに溶解し、最終濃度が１０μＭとなるように各ｗｅｌｌへ添加し、２４時間培養した。細胞を回収し、ヒト造血幹細胞コロニー測定用培地MethoCultに回収した細胞を２Ｘ１０５細胞／ｍｌとなるよう混和後、３５ｍｍディッシュに１ｍｌ播種し、５％二酸化炭素雰囲気下、３７℃で１４日間培養した。培養後、白血球コロニー（ＣＦＵ－ＧＭ）および赤血球コロニー（ＢＦＵ－Ｅ）形成を明視野顕微鏡で観察し、数をカウントした。
　結果を図４～５に示す。図４～５に示されるように、実施例２及び８の化合物は、正常造血には影響を与えなかった。 Test Example 5 Effect on cytotoxic activity on hematopoietic stem cells Human peripheral blood stem cells were seeded on a 12-well plate at a density of 2 × 10 6 cells / well, and the compound of the Example was separately dissolved in dimethyl sulfoxide to give a final concentration of 10 μM. Each well was added as described above and cultured for 24 hours. The cells were collected, and the collected cells were mixed in human hematopoietic stem cell colony measurement medium MethoCult at 2 × 10 5 cells / ml, seeded in 1 ml on a 35 mm dish, and cultured at 37 ° C. for 14 days in a 5% carbon dioxide atmosphere. . After culturing, the formation of leukocyte colonies (CFU-GM) and erythroid colonies (BFU-E) was observed with a bright field microscope, and the numbers were counted.
The results are shown in FIGS. As shown in FIGS. 4-5, the compounds of Examples 2 and 8 had no effect on normal hematopoiesis.
試験例６　骨病変形成抑制活性
（１）マウス破骨前駆細胞株を用いた破骨細胞形成抑制活性
　マウス破骨前駆細胞株ＲＡＷ２６４．７細胞を９６ｗｅｌｌプレートに１０３細胞／ｗｅｌｌの密度で播種し、リコンビナントヒトＭ－ＣＳＦ（１０ｎｇ／ｍｌ）およびリコンビナントヒトＲＡＮＫＬ（２５ｎｇ／ｍｌ）存在下で化合物の最終濃度が５μＭとなるよう添加し、５％二酸化炭素雰囲気下、３７℃で４日間培養した。培養後、ＴＲＡＰ染色を行い、３核以上のＴＲＡＰ陽性破骨細胞数をカウントした。
　結果を図６に示す。図６に示されるように、実施例８の化合物は、破骨細胞形成を抑制した。
（２）マウス初代培養細胞を用いた破骨細胞形成抑制活性
　６週齢Ｃ５７ＢＬ６マウス脛骨及び大腿骨より取り出した骨髄細胞を、５％二酸化炭素雰囲気下、３７℃で一晩インキュベートし、浮遊細胞のみ分離し、細胞を９６ｗｅｌｌプレートに４×１０５細胞／ｗｅｌｌの密度で播種した。これにリコンビナントヒトＭ－ＣＳＦ（１０ｎｇ／ｍｌ）を３日間処理し、その後リコンビナントヒトＭ－ＣＳＦ（１０ｎｇ／ｍｌ）およびリコンビナントヒトＲＡＮＫＬ（２５ｎｇ／ｍｌ）存在下で化合物の最終濃度が５μＭとなるよう添加し、４日間培養した。培養後、ＴＲＡＰ染色を行い、３核以上のＴＲＡＰ陽性破骨細胞数をカウントした。
　結果を図７に示す。図７に示されるように、実施例２の化合物は、破骨細胞形成を抑制した。
（３）がん骨病変形成抑制活性
　ルシフェラーゼを恒常的に発現するマウス骨髄腫細胞株５ＴＧＭ－１を６週齢雌ＩＣＲマウス脛骨骨髄内に１０６細胞移植し、１週間後に生着を確認後、化合物の最終濃度が２０ｍｇ／ｋｇとなるようマウスに腹腔内投与を隔日行った。２週間投与を行い、脛骨を取り出し、軟Ｘ線写真撮影を行った。
　結果を図８に示す。図８に示されるように、実施例８の化合物は、骨病変形成を抑制した。 Test Example 6 Bone Lesion Formation Inhibitory Activity (1) Osteoclast Formation Inhibitory Activity Using Mouse Osteoclast Progenitor Cell Line Mouse osteoclast precursor cell line RAW264.7 cells were seeded on 96-well plate at a density of 10 3 cells / well. , Recombinant human M-CSF (10 ng / ml) and recombinant human RANKL (25 ng / ml) were added so that the final concentration of the compound was 5 μM, and the mixture was cultured at 37 ° C. for 4 days in a 5% carbon dioxide atmosphere. After culturing, TRAP staining was performed to count the number of TRAP-positive osteoclasts of 3 or more nuclei.
Results are shown in FIG. As shown in FIG. 6, the compound of Example 8 suppressed osteoclast formation.
(2) Osteoclast formation inhibitory activity using mouse primary cultured cells Bone marrow cells taken out from 6-week-old C57BL6 mouse tibia and femur were incubated overnight at 37 ° C in a 5% carbon dioxide atmosphere, and only floating cells were present. The cells were separated, and the cells were seeded on a 96-well plate at a density of 4 × 10 5 cells / well. This was treated with recombinant human M-CSF (10 ng / ml) for 3 days, and then the final concentration of the compound was 5 μM in the presence of recombinant human M-CSF (10 ng / ml) and recombinant human RANKL (25 ng / ml). It was added and cultured for 4 days. After culturing, TRAP staining was performed to count the number of TRAP-positive osteoclasts of 3 or more nuclei.
The results are shown in Fig. 7. As shown in FIG. 7, the compound of Example 2 suppressed osteoclast formation.
(3) Cancer bone lesion formation inhibitory activity Mouse myeloma cell line 5TGM-1, which constantly expresses luciferase, was transplanted into 6- week-old female ICR mouse tibia bone marrow by 10 6 cells, and after 1 week, engraftment was confirmed. The mice were intraperitoneally administered every other day so that the final concentration of the compound would be 20 mg / kg. After administration for 2 weeks, the tibia was taken out and a soft X-ray photograph was taken.
The results are shown in Fig. 8. As shown in FIG. 8, the compound of Example 8 suppressed bone lesion formation.
試験例７　抗リウマチ効果
　ウシII型コラーゲンを１０ｍＭ酢酸に溶解し、２ｍｇ／ｍｌの溶液を作成後、Complete Freund's adjuvantと等量混ぜ合わせ、エマルジョンを作成した。作成したエマルジョンを６週齢雄ＤＢＡ／１Ｊマウス尾基部皮内に１００μｌ注射した。３週後、同様の方法で追加免疫を行い、２日後関節炎が誘発されたのを確認後、化合物の最終濃度が２０ｍｇ／ｋｇとなるようマウスに腹腔内投与を隔日行った。関節炎の評価は追加免疫後隔日Clinical Scoreを計測した。Clinical Scoreの判定は以下の基準を用い、四肢ごとに計測し、合計点を１匹の個体の測定値とした。
０：正常
１：１指に発赤・腫脹・変形が観察される
２：２指以上に発赤・腫脹・変形が観察される
３：足全体に発赤・腫脹・変形が観察される
　結果を図９に示す。図９に示されるように、実施例２の化合物は抗リウマチ効果を奏した。 Test Example 7 Antirheumatic effect Bovine type II collagen was dissolved in 10 mM acetic acid to prepare a 2 mg / ml solution, which was then mixed with equal amounts of Complete Freund's adjuvant to prepare an emulsion. 100 μl of the prepared emulsion was intradermally injected into the base of the tail of 6-week-old male DBA / 1J mice. After 3 weeks, booster immunization was carried out in the same manner, and after 2 days, it was confirmed that arthritis was induced. After that, the mice were intraperitoneally administered every other day so that the final concentration of the compound was 20 mg / kg. To evaluate arthritis, clinical scores were measured every other day after the booster immunization. The following criteria were used for the determination of the Clinical Score, each limb was measured, and the total score was used as the measurement value of one individual.
0: Normal 1: Redness / swelling / deformation was observed on one finger 2: Redness / swelling / deformation was observed on two or more fingers 3: Redness / swelling / deformation was observed on the entire foot Figure 9 shows the results. Shown in. As shown in FIG. 9, the compound of Example 2 exhibited an antirheumatic effect.

Claims (18)

  1. 下記式（１Ａ）で表される化合物又はその塩：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    Ａ１は、置換基を有していてもよい芳香環であり、
    Ｘ１は、酸素原子、硫黄原子、又は式：－Ｎ(ＲＸ１)－（式中、ＲＸ１は、水素原子又はアルキル基である）で表される基であり、
    Ｘ２は、単結合又は二重結合であり、
    Ｒ１及びＲ２は、同一又は異なって、水素原子、又はアルキル基であり、
    Ｒ３及びＲ４は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基である、或いは
    Ｒ３Ｏ及びＲ４Ｏは、隣接する２つの炭素原子と共に環を形成していてもよい。
    但し、下記式：
    Figure JPOXMLDOC01-appb-C000002
     で表される化合物を除く。］     A compound represented by the following formula (1A) or a salt thereof:
    Figure JPOXMLDOC01-appb-C000001
     [In the formula,
    A 1 is an aromatic ring which may have a substituent,
    X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) — (wherein, R X1 is a hydrogen atom or an alkyl group),
    X 2 is a single bond or a double bond,
    R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group,
    R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms. It may form a ring.
    However, the following formula:
    Figure JPOXMLDOC01-appb-C000002
     The compounds represented by are excluded. ]
  2. Ａ１が、置換基を有していてもよいＣ６－１０芳香族炭化水素環、又は置換基を有していてもよい５～１０員芳香族複素環である、請求項１に記載の化合物又はその塩。 The A 1 is a C 6-10 aromatic hydrocarbon ring which may have a substituent or a 5- to 10-membered aromatic heterocycle which may have a substituent. A compound or salt thereof.
  3. Ａ１が、下記式で表される環である、請求項１又は２に記載の化合物又はその塩：
    Figure JPOXMLDOC01-appb-C000003
     （式中、
    Ｒ５は、－ＯＲ５ａ又は－ＮＲ５ｂＲ５ｃであり、
    Ｒ５ａは、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
    Ｒ５ｂ及びＲ５ｃは、それぞれ独立して、水素原子、アルキル基、又はアリール基であり、
    ｎは、０～４の整数であり、
    ｎが２以上の整数である場合、複数のＲ５は、互いに同一であっても異なっていてもよい。）     The compound or salt thereof according to claim 1 or 2, wherein A 1 is a ring represented by the following formula:
    Figure JPOXMLDOC01-appb-C000003
     (In the formula,
    R 5 is —OR 5a or —NR 5b R 5c ,
    R 5a is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group,
    R 5b and R 5c are each independently a hydrogen atom, an alkyl group, or an aryl group,
    n is an integer of 0 to 4,
    If n is an integer of 2 or more, the plurality of R 5, may be the same or different from each other. )
  4. Ａ１が、下記式で表される環である、請求項１～３のいずれか一項に記載の化合物又はその塩：
    Figure JPOXMLDOC01-appb-C000004
     （式中、
    Ｒ５１及びＲ５２は、同一又は異なって、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
    Ｒ５３は、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
    Ｒ５４及びＲ５５は、同一又は異なって、水素原子、アルキル基、又はアリール基である。）     The compound or salt thereof according to any one of claims 1 to 3, wherein A 1 is a ring represented by the following formula:
    Figure JPOXMLDOC01-appb-C000004
     (In the formula,
    R 51 and R 52 are the same or different and each is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group,
    R 53 is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group,
    R 54 and R 55 are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group. )
  5. Ｘ１が、酸素原子である、請求項１～４のいずれか一項に記載の化合物又はその塩。 The compound or salt thereof according to any one of claims 1 to 4, wherein X 1 is an oxygen atom.
  6. Ｘ２が、二重結合である、請求項１～５のいずれか一項に記載の化合物又はその塩。 The compound or salt thereof according to any one of claims 1 to 5, wherein X 2 is a double bond.
  7. Ｒ１がアルキル基であり、Ｒ２が水素原子である、請求項１～６のいずれか一項に記載の化合物又はその塩。 The compound or salt thereof according to any one of claims 1 to 6, wherein R 1 is an alkyl group and R 2 is a hydrogen atom.
  8. Ｒ３及びＲ４が、同一又は異なって、水素原子、アルキル基、又はアルコキシアルキル基である、請求項１～７のいずれか一項に記載の化合物又はその塩。 The compound or salt thereof according to any one of claims 1 to 7, wherein R 3 and R 4 are the same or different and each is a hydrogen atom, an alkyl group, or an alkoxyalkyl group.
  9. 請求項１に記載の式（１Ａ）で表される化合物又はその塩の製造方法であって、
    （１）下記式（１－５）：
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ａ１、Ｘ１、Ｒ１、Ｒ２、Ｒ３、及びＲ４は前記と同じである）
    で表される化合物を、三重結合の保護化剤と反応させる工程、
    （２）前記工程（１）で得られる生成物を環化し、必要に応じて二重結合を還元する工程、及び
    （３）前記工程（２）で得られる生成物から三重結合の保護基を除去する工程
    を含む、方法。     A method for producing a compound represented by the formula (1A) according to claim 1 or a salt thereof, comprising:
    (1) The following formula (1-5):
    Figure JPOXMLDOC01-appb-C000005
     (In the formula, A 1 , X 1 , R 1 , R 2 , R 3 , and R 4 are the same as above)
    A step of reacting the compound represented by with a triple bond protecting agent,
    (2) a step of cyclizing the product obtained in the step (1) and optionally reducing a double bond, and (3) a protecting group for a triple bond from the product obtained in the step (2). A method comprising the step of removing.
  10. 下記式（２Ａ）で表される化合物又はその塩：
    Figure JPOXMLDOC01-appb-C000006
     ［式中、
    Ｘ３は、単結合、二重結合、又は三重結合であり、
    Ｒ６は、水素原子、置換基を有していてもよいアルキル基、又は置換基を有していてもよい芳香環基であり、
    Ｒ７及びＲ８は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアリール基である、或いは、
    Ｒ７Ｏ及びＲ８Ｏは、隣接する２つの炭素原子と共に環を形成していてもよく、
    Ｒ９は、水素原子、アルキル基、又はアリール基である。
    但し、下記式：
    Figure JPOXMLDOC01-appb-C000007
     で表される化合物を除く。］     A compound represented by the following formula (2A) or a salt thereof:
    Figure JPOXMLDOC01-appb-C000006
     [In the formula,
    X 3 is a single bond, a double bond, or a triple bond,
    R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent,
    R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or
    R 7 O and R 8 O may form a ring with two adjacent carbon atoms,
    R 9 is a hydrogen atom, an alkyl group, or an aryl group.
    However, the following formula:
    Figure JPOXMLDOC01-appb-C000007
     The compounds represented by are excluded. ]
  11. Ｒ６が、置換基としてヒドロキシル基を有していてもよいＣ１－４アルキル基である、請求項１０に記載の化合物又はその塩。 The compound or a salt thereof according to claim 10, wherein R 6 is a C 1-4 alkyl group which may have a hydroxyl group as a substituent.
  12. Ｒ７Ｏ及びＲ８Ｏが、隣接する２つの炭素原子と共に、下記式：
    Figure JPOXMLDOC01-appb-C000008
     （式中、Ｒ７ａ及びＲ８ａは、同一又は異なって、水素原子、アルキル基、又はアリール基であり、＊は、カルボニル炭素との結合位置を示す）
    で表される環を形成している、請求項１０又は１１に記載の化合物又はその塩。     R 7 O and R 8 O together with two adjacent carbon atoms have the formula:
    Figure JPOXMLDOC01-appb-C000008
     (In the formula, R 7a and R 8a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and * represents a bonding position with the carbonyl carbon.)
    The compound or a salt thereof according to claim 10 or 11, which forms a ring represented by.
  13. Ｒ９が、水素原子である、請求項１０～１２のいずれか一項に記載の化合物又はその塩。 The compound or salt thereof according to any one of claims 10 to 12, wherein R 9 is a hydrogen atom.
  14. 請求項１０に記載の式（２Ａ）で表される化合物又はその塩の製造方法であって、
    塩基の存在下、下記式（２－６）：
    Figure JPOXMLDOC01-appb-C000009
     （式中、Ｒ１０及びＲ１１は、同一又は異なって、アルキル基、アルコキシ基、又はアリール基であり、Ｘ３、Ｒ７、Ｒ８、及びＲ９は前記と同じである）
    で表される化合物を、下記式（９）：
    Figure JPOXMLDOC01-appb-C000010
     （式中、Ｒ６は、前記と同じである）
    で表される化合物と反応させる工程を含む、方法。     A method for producing a compound represented by formula (2A) or a salt thereof according to claim 10,
    In the presence of a base, the following formula (2-6):
    Figure JPOXMLDOC01-appb-C000009
     (In the formula, R 10 and R 11 are the same or different and are an alkyl group, an alkoxy group or an aryl group, and X 3 , R 7 , R 8 and R 9 are the same as the above)
    The compound represented by the following formula (9):
    Figure JPOXMLDOC01-appb-C000010
     (In the formula, R 6 is the same as above)
    A method comprising reacting with a compound represented by:
  15. 下記式（１）で表される化合物又はその塩：
    Figure JPOXMLDOC01-appb-C000011
     ［式中、
    Ａ１は、置換基を有していてもよい芳香環であり、
    Ｘ１は、酸素原子、硫黄原子、又は式：－Ｎ(ＲＸ１)－（式中、ＲＸ１は、水素原子又はアルキル基である）で表される基であり、
    Ｘ２は、単結合又は二重結合であり、
    Ｒ１及びＲ２は、同一又は異なって、水素原子、又はアルキル基であり、
    Ｒ３及びＲ４は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基である、或いは
    Ｒ３Ｏ及びＲ４Ｏは、隣接する２つの炭素原子と共に環を形成していてもよい。］及び下記式（２）で表される化合物又はその塩：
    Figure JPOXMLDOC01-appb-C000012
     ［式中、
    Ｘ３は、単結合、二重結合、又は三重結合であり、
    Ｒ６は、水素原子、置換基を有していてもよいアルキル基、又は置換基を有していてもよい芳香環基であり、
    Ｒ７及びＲ８は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアリール基である、或いは、
    Ｒ７Ｏ及びＲ８Ｏは、隣接する２つの炭素原子と共に環を形成していてもよく、
    Ｒ９は、水素原子、アルキル基、又はアリール基である。］
    から選択される少なくとも一種を含む、医薬組成物。     A compound represented by the following formula (1) or a salt thereof:
    Figure JPOXMLDOC01-appb-C000011
     [In the formula,
    A 1 is an aromatic ring which may have a substituent,
    X 1 is an oxygen atom, a sulfur atom, or a group represented by the formula: —N (R X1 ) — (wherein, R X1 is a hydrogen atom or an alkyl group),
    X 2 is a single bond or a double bond,
    R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group,
    R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R 3 O and R 4 O are together with two adjacent carbon atoms. It may form a ring. ] And a compound represented by the following formula (2) or a salt thereof:
    Figure JPOXMLDOC01-appb-C000012
     [In the formula,
    X 3 is a single bond, a double bond, or a triple bond,
    R 6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent,
    R 7 and R 8 are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group, or
    R 7 O and R 8 O may form a ring with two adjacent carbon atoms,
    R 9 is a hydrogen atom, an alkyl group, or an aryl group. ]
    A pharmaceutical composition comprising at least one selected from:
  16. 小胞体ストレス応答誘起剤である、請求項１５に記載の医薬組成物。 The pharmaceutical composition according to claim 15, which is an endoplasmic reticulum stress response inducer.
  17. プロテインジスルフィドイソメラーゼ阻害剤である、請求項１５又は１６に記載の医薬組成物。 The pharmaceutical composition according to claim 15 or 16, which is a protein disulfide isomerase inhibitor.
  18. 癌、骨疾患、及びリウマチから選択される少なくとも一種の予防又は治療剤である、請求項１５～１７のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 15 to 17, which is at least one prophylactic or therapeutic agent selected from cancer, bone disease, and rheumatism.
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