WO2001007031A1 - Derives de benzene, compositions immunostimulantes ou agents de retablissement de la pharmacosensibilite les contenant - Google Patents

Derives de benzene, compositions immunostimulantes ou agents de retablissement de la pharmacosensibilite les contenant Download PDF

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Publication number
WO2001007031A1
WO2001007031A1 PCT/JP2000/005001 JP0005001W WO0107031A1 WO 2001007031 A1 WO2001007031 A1 WO 2001007031A1 JP 0005001 W JP0005001 W JP 0005001W WO 0107031 A1 WO0107031 A1 WO 0107031A1
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group
optionally substituted
prodrug
pharmaceutically acceptable
substituted
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PCT/JP2000/005001
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English (en)
Japanese (ja)
Inventor
Kazuo Ueda
Moriyasu Masui
Akira Ino
Ken Yasui
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Shionogi & Co., Ltd.
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Priority to AU63153/00A priority Critical patent/AU6315300A/en
Publication of WO2001007031A1 publication Critical patent/WO2001007031A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/64—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with oxygen atoms directly attached in position 8

Definitions

  • the present invention relates to the fields of medicine, veterinary medicine (livestock medicine, marine medicine, etc.). More specifically, the present invention relates to a benzene derivative and an immunostimulatory active composition containing the same for preventing or treating a disease associated with insufficiency of immune function. The present invention also relates to the use of the immunostimulatory active compounds for producing these compositions and to the therapeutic methods using these compositions.
  • the present invention also relates to a compound capable of overcoming the resistance acquired by a pathogenic microorganism and restoring the action of an antipathogenic microbial agent to a drug susceptibility level and a drug susceptibility restorer.
  • the present invention relates to an agent for restoring the sensitivity of pathogenic microorganisms, particularly Pseudomonas aeruginosa, which exhibit multidrug resistance to antibacterial agents.
  • the present invention particularly relates to a drug sensitivity restoring agent comprising a compound represented by the following general formula (I) or a salt thereof.
  • the present invention provides a drug sensitivity restoring agent comprising a compound represented by the formula (M) or a salt thereof.
  • the present invention provides a pharmaceutical composition comprising the agent for restoring drug sensitivity and an antibacterial agent.
  • the present invention also relates to a compound of the general formula (I) for producing these drug sensitizers. And therapeutic methods using a drug-sensitizing agent.
  • the mechanism of drug resistance in Pseudomonas aeruginosa includes a decrease in membrane permeability (mutation of LPS and porin), a change in the site of action (change in drug affinity of Benicillin-binding protein PBP: peptide darican biosynthetic enzyme), drugs Inactivation enzyme () Production of 3-lactamase, aminoglycoside-modifying enzyme), mutation of DNA gyrase, elimination of intracellular drug by drug efflux system, etc. are known. You. In recent years, attention has been paid to the drug efflux system, that is, the production of drug transporters, as a mechanism for making multidrug resistance, and research at the molecular level has been actively conducted.
  • Examples of the compound having an activity of inhibiting a drug efflux transporter include the compound L-phenylalanine-arginyl- ⁇ -naphthylamide described in WO96 / 33285. This is a dipeptide compound that has the effect of lowering the MIC against 7 new quinolones such as chloramphenicol, tetracycline, ofloxacin, etc., piramacillin, and ceftazidime, a mutant strain of the OprM high-production laboratory (K385) and the standard strain (PA01). is there. As a compound having a similar effect, the compound Micacoc idin described in W099 / 61021 has also been reported.
  • the present invention solves the above-mentioned problems, and has an object to provide a compound and a composition having an immunostimulating effect.
  • An object of the present invention is to provide a drug-sensitivity restoring agent capable of restoring the action of an agent to the level of a drug-sensitive strain. Disclosure of the invention
  • the present invention relates to an immunostimulatory composition
  • an immunostimulatory composition comprising the compound represented by the general formula (I) or a salt thereof.
  • the present invention relates to a drug sensitivity-restoring agent containing the compound represented by the general formula (I) or a salt thereof.
  • the compound represented by the following formula (M) is also referred to as “compound (M)”. More specifically, according to the present invention, the following compositions and compounds and methods are provided.
  • X is independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy Group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted alkynyloxy group, an optionally substituted aryloxy group, an optionally substituted acyloxy group A tri-substituted silyloxy group, a mercapto group, an optionally substituted alkylthio group, an optionally substituted arylthio group, a monosubstituted sulfinyl group, a monosubstituted sulfonyl group, an optionally substituted amino group, Group, aminocarbonyl group which may be substituted, hydroxycarbonyl group Optionally substituted alkoxycarbonyl group, Shiano group, a nitro group or Bok Li substituted si
  • R 2 and R 3 are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a trisubstituted silyl group, an optionally substituted acyl group An optionally substituted aminocarbonyl group or a monosubstituted sulfonyl group;
  • n is an integer of 0 to 4.
  • Y is each independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy group, Optionally substituted alkoxy group, optionally substituted alkenyloxy group, optionally substituted alkynyloxy group, optionally substituted aryloxy group, optionally substituted alkoxy group, tri Substituted silyloxy group, mercapto group, optionally substituted alkylthio group, optionally substituted arylthio group, monosubstituted sulfinyl group, monosubstituted sulfonyl group, optionally substituted amino group, substituted Optionally substituted acyl group, optionally substituted aminocarbonyl group, hydroxycarbonyl group, substituted An optionally substituted alkoxycarbonyl, cyano, nitro, or trisubstituted silyl group;
  • n is an integer from 0 to 5;
  • X, Y, m, and n have the same meanings as in the above item (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a composition having an immunostimulating effect comprising a substance.
  • composition having an immunostimulating effect comprising a solvate thereof.
  • a composition having an immunostimulatory action comprising a Japanese product.
  • a composition having an immunostimulatory action comprising:
  • composition having an immunostimulatory action comprising a Japanese product.
  • a composition having an immunostimulating effect comprising a compound, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a composition having an immunostimulatory action comprising a Japanese product.
  • X, Y, m, and n have the same meanings as in the above item (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • X is each independently a halogen atom, an alkyl group, an alkenyl group, a hydroxy group, or an optionally substituted alkoxy group
  • Y is each independently a halogen atom, an alkyl group, an octaalkyl group, An aryl group, a hydroxy group, an optionally substituted alkoxy group, an alkenyloxy group, a trisubstituted silyloxy group, or a nitro group
  • m is an integer of 0 to 3 and n is an integer of 0 to 2; The composition according to 1).
  • X is each independently a nitrogen atom, a methyl group, a hydroxy group, a methoxy group, or a prenyloxy group
  • Y is each independently a fluoro atom, a methyl group, a trifluoromethyl group, a phenyl group, or a hydroxy group.
  • m is an integer of 0 to 3
  • n is an integer of 0 to 2.
  • X is independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy Group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted alkynyloxy group, an optionally substituted aryloxy group, an optionally substituted acyloxy group Tri-substituted silyloxy group, mercapto group, optionally substituted alkylthio group, optionally substituted arylthio group, monosubstituted sulfinyl group, monosubstituted sulfonyl group, optionally substituted amino group, substituted Optionally substituted acyl group, optionally substituted aminocarbonyl group, hydroxycarbonyl group Optionally substituted alkoxycarbonyl group, Shiano group, a nitro group or Application Benefits substituted silyl
  • Y is each independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy group, Optionally substituted alkoxy group, optionally substituted alkenyloxy group, optionally substituted alkynyloxy group, optionally substituted aryloxy group, optionally substituted alkoxy group, tri Substituted silyloxy group, mercapto group, optionally substituted alkylthio group, optionally substituted arylthio group, monosubstituted sulfinyl group, monosubstituted sulfonyl group, optionally substituted amino group, substituted Group, aminocarbonyl group which may be substituted, hydroxycarbonyl group, substitution Optionally substituted alkoxycarbonyl, cyano, nitro, or tri-substituted A substituted silyl group;
  • n is an integer of 1 to 5
  • a prodrug thereof or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 1 ′ is a hydrogen atom or an alkyl group, provided that the 5-position and 7-position of Xm in the formula (IE) And all of the 2- and 4-positions of Yn are the same or different, and each represents a hydroxy group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted alkynyloxy group When substituted with an optionally substituted aryloxy group, an optionally substituted acyloxy group, or a tri-substituted silyloxy group, R 1 ′ is not a hydrogen atom), or a prodrug thereof, or Their pharmaceutically acceptable salts, or their solvates.
  • R 1 is a hydrogen atom or an alkyl group
  • X, Y, m, and n are as defined in the above item (15)
  • R 1 is a hydrogen atom or an alkyl group
  • a prodrug thereof or a pharmaceutical product thereof.
  • R 2 is an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted Alkynyl group, trisubstituted silyl group, optionally substituted acyl group, optionally substituted aminocarbonyl group, or monosubstituted sulfonyl group), a prodrug thereof, or a pharmaceutically acceptable compound thereof. Salts or solvates thereof.
  • X is each independently a halogen atom, an alkyl group, an alkenyl group, a hydroxy group, or an optionally substituted alkoxy group;
  • Y is each independently a halogen atom, an alkyl group, a haloalkyl group, an aryl group, a hydroxy group, an optionally substituted alkoxy group, an alkenyloxy group, a tri-substituted silyloxy group, or a nitro group;
  • n is an integer from 0 to 3;
  • n is an integer from 0 to 2;
  • R 1 ′ is a hydrogen atom or an alkyl group, provided that the 5-position, 7-position of Xm and the 2- and 4-positions of Yn in the formula (I-E) are the same or different, and a hydroxy group,
  • R 1 ' is not a hydrogen atom;
  • R 1 is a hydrogen atom or an alkyl group
  • R 2 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a trisubstituted silyl group, an optionally substituted acryl group, an optionally substituted An aminocarbonyl group or a monosubstituted sulfonyl group;
  • Y n is not 2,4-dihydroxy.
  • X is each independently a nitrogen atom, a methyl group, a hydroxy group, a methoxy group, or a prenyloxy group
  • ⁇ is each independently a fluorine atom, a methyl group, a trifluoromethyl group, a phenyl group, a hydroxy group.
  • m Is an integer of 0 to 3
  • n is an integer of 0 to 2.
  • Xm is 4-chloro, 3-methoxy, 4-methoxy, 5-methoxy, 3,5-dimethoxy, or 3,5-dimethoxy-4-prenyloxy
  • Yn is 4-fluoro, 4 —Methyl, 2-trifluoromethyl, 2,4-dimethyl, 2-phenyl, 4-phenyl, 2-hydroxy, 2,4-dihydroxy, 2-prenyloxy, 2-n-hexyloxy, 2-benzyloxy, 3 _Benzyloxy, 4-benzyloxy, 2-benzyloxy-4-hydroxy, 2,4-dibenzyl Benzyloxy, 3- (1,3-dioxolan-2-yl) ethoxy, 3-phenoxyethoxy, or 3-nitro (however, each substitution position is named after the substitution position in the general formula (I-A)).
  • composition containing as: °
  • X is independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy Group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted alkynyloxy group, an optionally substituted aryloxy group, an optionally substituted Siloxy group, tri-substituted silyloxy group, mercapto group, optionally substituted alkylthio group, optionally substituted arylthio group, monosubstituted sulfinyl group, monosubstituted sulfonyl group, optionally substituted amino group
  • Y is each independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy group, Optionally substituted alkoxy group, optionally substituted alkenyloxy group, optionally substituted alkynyloxy group, optionally substituted aryloxy group, optionally substituted alkoxy group, tri Substituted silyloxy group, mercapto group, optionally substituted alkylthio group, optionally substituted arylthio group, monosubstituted sulfinyl group, monosubstituted sulfonyl group, optionally substituted amino group, substituted Group, aminocarbonyl group which may be substituted, hydroxycarbonyl group, substitution An optionally substituted alkoxycarbonyl group, a cyano group, a nitro group, or a tri-substituted silyl group;
  • n is an integer from 1 to 4.
  • n is an integer from 1 to 5;
  • R 1 ′ is a hydrogen atom or an alkyl group, provided that the 5-position, 7-position of Xm and the 2- and 4-positions of Yn in the formula (I-E) are the same or different, and a hydroxy group or a substituted group; Alkoxy group, alkenyloxy group which may be substituted, alkynyloxy group which may be substituted, aryloxy group which may be substituted, acyloxy group which may be substituted, trisubstituted silyloxy group R 1 ′ is not a hydrogen atom when substituted with
  • R 1 is a hydrogen atom or an alkyl group
  • R 2 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a trisubstituted silyl group, an optionally substituted acryl group, an optionally substituted Aminocarbonyl group or monosubstituted sulfonyl
  • a method for activating immunity of a subject comprising a step of administering the composition according to the above (1) to the subject.
  • X is independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy Group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted alkynyloxy group, an optionally substituted aryloxy group, an optionally substituted acyloxy group A tri-substituted silyloxy group, a mercapto group, an optionally substituted alkylthio group, an optionally substituted arylthio group, a monosubstituted sulfinyl group, a monosubstituted sulfonyl group, an optionally substituted amino group, Group, aminocarbyl group which may be substituted, hydroxycarbonyl group Optionally substituted alkoxycarbonyl group, Shiano group, a nitro group or Application Benefits substituted si
  • R 2 and R 3 are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a trisubstituted silyl group, an optionally substituted acyl group An optionally substituted aminocarbonyl group or a monosubstituted sulfonyl group;
  • n is an integer of 0 to 4.
  • Y is each independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy group, Optionally substituted alkoxy group, optionally substituted alkenyloxy group, optionally substituted alkynyloxy group, optionally substituted aryloxy group, optionally substituted alkoxy group, tri Substituted silyloxy group, mercapto group, optionally substituted alkylthio group, optionally substituted arylthio group, monosubstituted sulfinyl group, monosubstituted sulfonyl group, optionally substituted amino group, substituted Group, aminocarbonyl group which may be substituted, hydroxycarbonyl group, substitution An optionally substituted alkoxycarbonyl, cyano, nitro, or trisubstituted silyl group;
  • n is an integer of 0 to 5; provided that all of the 5-position, 7-position of Xm and 2- and 4-positions of Yn in the formula (E) are the same or different, and a hydroxy group or an optionally substituted alkoxy group; Group, an optionally substituted alkenyloxy group, an optionally substituted alkynyloxy group, an optionally substituted aryloxy group, an optionally substituted acyloxy group, and a trisubstituted silyloxy group.
  • R 1 ' is not a hydrogen atom
  • the compound represented by the formula (I), a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof is used.
  • a drug-sensitivity-restoring agent comprising:
  • X, Y, RR 2 , R 3 , m, and n have the same meanings as in the above item (30)
  • a prodrug thereof, or a pharmaceutically acceptable salt thereof Or a drug sensitizer containing a solvate thereof.
  • X, Y, R 1 , m, and n have the same meanings as in the above item (30)
  • a prodrug thereof or a pharmaceutically acceptable salt thereof, or a solvent thereof.
  • X is each independently a halogen atom, an alkyl group, an alkenyl group, a hydroxy group, or an optionally substituted alkoxy group
  • Y is each independently a halogen atom, an alkyl group, a haloalkyl group, an aryl group.
  • m is an integer of 0 to 3
  • n is an integer of 0 to 2.
  • X is each independently a nitrogen atom, a methyl group, a hydroxy group, a methoxy group, or a prenyloxy group
  • Y is each independently a fluorine atom, a methyl group, a trifluoromethyl group, a phenyl group, or a hydroxy group , Methoxy, prenyloxy, n-hexyloxy, 2-phenoxyethoxy, 2- (1,3-dioxolan-2-yl) ethoxy, benzyloxy, or nitro
  • m is The drug sensitivity recovery agent according to the above item (30), wherein an integer of 0 to 3 and n is an integer of 0 to 2.
  • X is independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, a hydroxy Group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted alkynyloxy group, an optionally substituted aryloxy group, an optionally substituted acyloxy group A tri-substituted silyloxy group, a mercapto group, an optionally substituted alkylthio group, an optionally substituted arylthio group, a monosubstituted sulfier group, a monosubstituted sulfonyl group, an optionally substituted amino group, Group, aminocarbonyl group which may be substituted, hydroxycarbonyl group Optionally substituted alkoxycarbonyl group, Shiano group, a nitro group or Application Benefits substituted silyl
  • n is an integer from 1 to 5;
  • R 1 is a hydrogen atom or an alkyl group
  • alkyl includes straight or branched chain monovalent hydrocarbon radicals having 1 to 20 carbon atoms. I do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n_pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n—octyl and the like. Preferably, C 1 -C 6 alkyl is used.
  • alkenyl As used herein, the term ⁇ alkenyl, '' used alone or in combination with other terms, refers to a straight or linear chain having from 2 to 12 carbon atoms and one or more double bonds. Includes branched monovalent hydrocarbon groups. For example, vinyl, aryl, probenyl, crotonyl, prenyl, various butenyl isomers and the like can be mentioned. Preferably, C2-C6 alkenyl is used.
  • alkynyl refers to a straight or branched chain having 2 to 12 carbon atoms and one or more triple bonds. Includes monovalent hydrocarbon groups in the chain. Further, it may have a double bond. For example, ethynyl, propynyl, 6-heptynyl, 7-octynyl and the like can be mentioned. Preferably, C 2 _C 6 alkynyl is used.
  • aryl as used herein, alone or in combination with other terms, includes monocyclic or fused cyclic aromatic hydrocarbon groups.
  • phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned.
  • phenyl, 11-naphthyl and 2-naphthyl are mentioned. More preferably, phenyl is used.
  • examples of the substituent in the “optionally substituted aryl” preferably include a halogen atom, an alkyl group, a haloalkyl group, and an alkoxy group.
  • examples of the substituent in the “optionally substituted aryloxy” preferably include a halogen atom, an alkyl group, a haloalkyl group, and an alkoxy group. And the like.
  • examples of the substituent in the “optionally substituted arylthio” preferably include a halogen atom, an alkyl group, a haloalkyl group, and an alkoxy group.
  • the “monosubstituted sulfinyl” refers to a monovalent substituent bonded to a sulfinyl group.
  • substituent in the “monosubstituted sulfinyl” preferably include an alkyl group, a haloalkyl group, and a phenyl group which may be substituted. More preferably, a methyl group, a trifluoromethyl group, a phenyl group, a 4-chlorophenyl group and the like can be mentioned.
  • “monosubstituted sulfonyl” refers to a monovalent substituent bonded to a sulfonyl group.
  • substituent in the “monosubstituted sulfonyl” preferably include an alkyl group, a haloalkyl group, an optionally substituted phenyl group and the like. More preferably, a methyl group, a trifluoromethyl group, a phenyl group, a 4-chlorophenyl group and the like can be mentioned.
  • examples of the substituent in the “optionally substituted aminocarbonyl” preferably include an alkyl group, a haloalkyl group, an optionally substituted phenyl group and the like. More preferred examples include a methyl group, a trifluoromethyl group, a phenyl group, and a 4-chlorophenyl group.
  • acyl used alone or in combination with other terms refers to an alkylcarbonyl in which the alkyl moiety is the above “alkyl” or an arylcarbonyl in which the aryl moiety is the above “aryl”. Include. For example, acetyl, propionyl, butyryl, benzoyl and the like can be mentioned.
  • examples of the substituent in the “optionally substituted acyl” preferably include an alkyl group, a haloalkyl group, and an optionally substituted phenyl group. More preferably, a methyl group, a trifluoromethyl group, a phenyl group, a 4-chlorophenyl group and the like can be mentioned.
  • examples of the substituent in the “optionally substituted acyloxy” preferably include an alkyl group, a haloalkyl group, and an optionally substituted phenyl group. More preferably, a methyl group, a trifluoromethyl group, a phenyl group, a 4-chlorophenyl group and the like can be mentioned.
  • halogen means fluorine, chlorine, bromine, and iodine.
  • alkoxy J as used herein, alone or in combination with other terms, includes straight-chain or branched alkyloxy having 1 to 20 carbon atoms.
  • methoxy, ethoxy, n-propoxy, isopropoxy is mentioned.
  • examples of the substituent in the “optionally substituted alkoxy” preferably include a halogen atom and an aryl group. More preferably, a fluorine atom, a phenyl group and the like are mentioned.
  • alkylthio examples include methylthio, ethylthio, n_propylthio, isopropylthio, n-butylthio, isopropylthio, sec-butylthio, tert-butylthio, and the like.
  • methylthio, ethylthio, ⁇ -propylthio, and isopropylthio are mentioned.
  • alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, ⁇ -propoxycarbonyl and the like.
  • examples of the substituent in the “optionally substituted alkoxycarbonyl” preferably include a halogen atom and an aryl group. More preferably, a fluorine atom, a phenyl group and the like are mentioned.
  • the “optionally substituted amino” refers to the above “alkyl”, “aralkyl”, “acyl”, optionally substituted arylsulfonyl (eg, alkoxyphenylsulfonyl), a Reel alkylene (eg, benzylide ), Amino or unsubstituted amino substituted at one or two places by alkylsulfonyl, carbamoyl or the like.
  • amino, methylamino, dimethylamino, getylamino, and acetylamino are preferable.
  • examples of the substituent in the “optionally substituted aminocarbonyl” preferably include an alkyl group optionally substituted by halogen, a phenyl group optionally substituted and the like. More preferably, a methyl group, a trifluoromethyl group, a phenyl group, a 4-chlorophenyl group and the like can be mentioned.
  • substituents in “optionally substituted alkyl”, “optionally substituted alkylthio”, “optionally substituted alkoxy”, and “optionally substituted alkoxycarbonyl” examples include hydroxy, alkoxy (for example, methoxy, ethoxy), mercapto, alkylthio (for example, methylthio), cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (for example, fluorine, Chlorine, bromine, iodine), alkoxy, alkoxycarbonyl (eg, methoxycarbonyl, ethoxycalponyl), nitro, cyano, haloalkyl (eg, trifluoromethyl), optionally substituted amino (eg, amino, methyla) Bruno, Jimechiruamino force Rubamoiruamino, t e r t - butoxycarbonyl
  • the number of substituents in the “optionally substituted alkyl group” is preferably 1-5, more preferably 1-3.
  • the position of the substituent is not particularly limited. Particularly preferred are halogen, hydroxyl, lower alkoxy, lower alkenyloxy and acyl groups.
  • various groups are "lower" when the number of carbon atoms in the groups is 1 to 10, preferably 1 to 8, and more preferably 1 to 6.
  • alkenyl “optionally substituted alkenyloxy”, “optionally substituted alkynyl” and “optionally substituted alkynyloxy” are hydroxy, alkoxy (eg, methoxy, ethoxy), mercapto, alkylthio (eg, methylthio), cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (eg, fluorine, chlorine, bromine) , Iodine), carboxy, alkoxycarbonyl (eg, methoxycarbonyl, ethoxycalponyl), nitro, cyano, haloalkyl (eg, trifluoromethyl), optionally substituted amino (eg, amino, methylamino, Dimethylamino, carbamoylamino, tert-butoxycarbonylamino), acyl
  • the number of substituents in the “optionally substituted alkenyl group” and the “optionally substituted alkynyl group” is preferably 1 to 5, more preferably 1 to 3.
  • the position of the substituent is not particularly limited. Preferred among the above substituents are halogen, hydroxyl, lower alkoxy, lower alkenyloxy, and acyl.
  • Optionally substituted alkyl includes straight-chain or branched C 1 to C 20 alkyl.
  • C1 to C10 alkyl are exemplified. More preferably, C 1 to C 6 alkyl is used.
  • optionally substituted alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyclohexylmethyl Carboxyethyl, acetyloxyl, benzyloxymethyl.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl and 2,2,2-trifluoroethyl are particularly preferred.
  • the “optionally substituted alkenyl group” includes a linear or branched C 2 to C 12 alkenyl. They can have as many double bonds as possible at the possible positions, and the configuration at those double bonds can be in the (E) or (Z) configuration, for example, vinyl, aryl, isopropyl, 1-Propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-hexenyl 1-octenyl, geranyl, 1-decenyl, 1-octenyl Includes tetradecenyl, 1-octane dec
  • C2 to C8 alkenyl Preference is given to C2 to C8 alkenyl. More preferred are C2 to C6 alkenyl. Of these, vinyl, aryl, isoprobenyl, 1-butenyl, 2-methyl-1-probenyl, 1-butenyl, 2-butenyl, and 3-methyl-2-butenyl are particularly preferred.
  • the “optionally substituted alkynyl group” includes a linear or branched C2 to C12 alkynyl. These can have a possible number of triple bonds at possible positions. For example, ethynyl, 1_propynyl, 2-propynyl (propargyl), 2-butynyl, 2-pentene_4_ynyl, etc. And alkynyl groups which may have 20 double bonds. Preferably, C2 to C8 alkynyl is used. More preferred are C2 to C6 alkynyl.
  • a substituted or unsubstituted acyl group refers to a carboxylic acid which may be substituted, an oxycarboxylic acid which may be substituted, a sulfonic acid which may be substituted, a sulfinic acid which may be substituted, and the like. And the like. Specifically, the expression
  • Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group or heterocyclic group” represented by R 9 , R 1Q , R 11 and R 12 include, for example, a linear group as an acyclic group Or a branched aliphatic hydrocarbon group (such as an alkyl group, an alkenyl group, and an alkynyl group).
  • the cyclic group is a saturated or unsaturated alicyclic hydrocarbon group (a cycloalkyl group, a cycloalkenyl group). Group, cycloalkadienyl group, etc.), monocyclic or Is a fused polycyclic aryl group.
  • alkyl group, alkenyl group and alkynyl group of the above “hydrocarbon group” examples include the same as the above-mentioned alkyl group, alkenyl group and alkynyl group.
  • substituent in the “optionally substituted acyl group” include, for example, halogen, hydroxyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkenyloxy, substituted and unsubstituted lower.
  • Alkyl radicals carboxy groups, substituted or unsubstituted radicals, cyano groups, substituted or unsubstituted amino groups, substituted or unsubstituted amidino groups, azide groups, nitro groups, nitroso groups, mercapto groups
  • the number of substituents in the “optionally substituted acyl group” is 1 ⁇ to 5 ⁇ , preferably 1 to 3.
  • the position of the substituent is not particularly limited. Among the above substituents, preferred are a halogen, a hydroxyl group, a lower alkoxy, a lower alkenyloxy and an acyl group.
  • optionally substituted acyl group include an optionally substituted acetyl group and an optionally substituted benzoyl group, wherein the benzene ring hydrogen of the benzoyl group is substituted.
  • substituent and the substitution position include, for example, 2—, 3—, or 4-fluoro; 2 _, 3—, or 4_ black; 2_, 3—, or 4 bromo; Or 4-chloride; 2-, 3_, or 4-methyl; 2, 3-, 2, 4-, or 2,5-dimethyl; 2, 6_, 3, 4_, or 3,5-dimethyl: 2 , 3, 4_, 2, 3, 5-, 2, 3, 6-, 2, 4, 5—, 2, 4, 6—, or 3, 4, 5—trimethyl; 2—, 3—, or 4 —Ethyl; 2-, 3-, or 4-monopropyl; 2-, 3 _, or 4-trifluoromethyl; 2,3-, or 4-methoxy; 2,3-, 2,4-, 2,5-, 2,6-,
  • the tri-substituted silyl group is preferably an optionally substituted trialkylsilyl, dialkylmonoarylsilyl, or monoalkyldiarylsilyl.
  • Specific examples of trialkylsilyl include trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.
  • Examples of monoalkyldiarylsilyl include tert-butyldiphenylsilyl and the like.
  • examples of the substituent in the “optionally substituted trisubstituted silyloxy” preferably include halogen, alkoxy and the like.
  • symbol (*) indicates the presence of an asymmetric carbon, and indicates any of stereoisomeric R-form, S-form, or a mixture thereof.
  • any of the R-form, the S-form, and a mixture thereof can be used.
  • a stereoisomer in which the 3-position of 2H-1-benzopyran has the R configuration is preferred.
  • a geometric isomer When a geometric isomer is present, it may be either cis or trans.
  • the compound used in the present invention is preferably a compound represented by the following compound number described in the tables and examples:
  • the compound represented by the general formula (I) and its use such as immunostimulatory activity are novel.
  • Preferred examples thereof include compounds in which each substituent is a combination of any one of the following Tables 1 to 11. And the like.
  • the column of “No.” among the symbols in the table indicates the compound number.
  • H is hydrogen, OH is a hydroxyl group, Me is methyl, Et is ethyl, i-Pr is isopropyl, TBS is tert-butyldimethylsilyl, and SEM is 2- (trimethylsilyl) ethoxymethyl.
  • Bz 1 is benzyl group, Me is methyl group, Ph is phenyl group, MOM is methoxymethyl, TMS is trimethylsilyl, preny 1 is prenyl group (that is, 3-methyl-2-butenyl group), preny 1 o X y is Pureniruokishi group, " ⁇ _C 6 H u _c" is Kishiruokishi group cycloheteroalkyl, "OC 6 Hu-n” includes straight-chain to the Kishiruokishi group, Ts is p - toluenesulfonyl group, TBDPS is , tert- butyl diphenyl silyl group, Bu l is, tert- heptyl group, '[rho r is an isopropyl group, pico 1 y 1 oxy shows Pikoriruokishi. “() 2 ” indicates di-substitution. For example, “5,6- (OMe)
  • a prodrug is a derivative of a compound of the present invention that has a chemically or metabolically degradable group and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions.
  • Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.
  • an ester derivative produced by reacting a base acidic compound with a suitable alcohol, or a base amine and a suitable amine are reacted.
  • Prodrugs such as amide derivatives produced by the above method are exemplified.
  • esters as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, N, N-getyl dalicholamide ester And so on.
  • a prodrug such as an acyloxy derivative produced by reacting a compound having a hydroxy group with a suitable acyl halide or a suitable acid anhydride is exemplified.
  • Particularly preferred acyloxy as a prodrug include _OCOC 2 H 5 , -OCO (tert-Bu), one OCOC 15 H 3 or one C (m-COON a -P h), one O COCH 2 CH 2 COON a, one OCOCH (NH 2 ) CH 3 , —OCOCH 2 N (CH 3 ) 2 and the like.
  • a prodrug such as an amide derivative produced by reacting a compound having an amino group with a suitable acid octogenate or a suitable mixed acid anhydride is exemplified. Is done.
  • Particularly preferred amides as prodrugs are —NHCO (CH 2 ) 2 . CH 3 , one NHCOCH (NH 2 ) CH 3 and the like.
  • the “salt” of the target compound of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, basic Or with an acidic amino salt.
  • a salt with an inorganic base sodium Alkali metal salts such as calcium salts, potassium salts, etc .; alkaline earth metal salts such as calcium salts, magnesium salts, and balium salts; and aluminum salts, ammonium salts, and the like.
  • Salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triene-lamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like.
  • Examples of salts with inorganic acids include salts with hydrochloric acid, hydrofluoric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, perchloric acid, hydroiodic acid, and the like.
  • Salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, cunic acid, succinic acid, malic acid, mandelic acid, ascorbic acid, lactic acid, dalconic acid, methanesulfonic acid And p-toluenesulfonic acid, benzenesulfonic acid and the like.
  • Salts with basic amino acids include salts with arginine, lysine, orditin and the like, and salts with acidic amino acids include salts with aspartic acid, dalminic acid and the like.
  • solvate includes, for example, solvates with organic solvents, hydrates, and the like. Those solvated in a pharmacologically acceptable solvent are preferred. Hydrates are more preferred.
  • the “hydrate” of the target compound of the present invention is preferably a pharmacologically acceptable hydrate, and also includes a hydrate. Specific examples include monohydrate, dihydrate, hexahydrate and the like.
  • Immunosanostimulatory action refers to the enhancement of immune function, that is, the ability of a living body to protect against the infection of viruses and bacteria (including secondary ones) (eg, opportunistic infections, intractable infections, etc.). Improve or enhance the immune capacity of malignant tumor patients with reduced immune capacity to immunologically attack and treat cancer cells, and to protect the body from responses to other disorders associated with immune dysfunction, such as radiation damage. It refers to activation. It is also effective in reducing immunity caused by administration of an anticancer drug, and the compound of the present invention can be preferably used as an immunostimulant (excluding an anticancer drug). “Immunostimulatory activity” refers to the activity of the above immunostimulatory action.
  • a quantitative method for measuring the immunostimulatory effect can be measured, for example, by measuring the blastogenesis rate or cell metabolic activity.
  • the blast transformation rate can be measured, for example, by measuring the effect of mouse spleen cells on the blast transformation.
  • the following measurement methods can be used: A test sample dissolved in a dimethylsulfoxide (DMSO) solution is serially diluted two-fold with a 96-well microplate using 10% FBS (1). ⁇ The sample subjected to Erno 100 ⁇ 1) shall be the test sample.
  • DMSO dimethylsulfoxide
  • the spleen of a BALB / c mouse is aseptically removed, gently ground while dropping sterile saline on a wire-mesh, and the filtrate is nylon mesh (Bectondixon: pore size 70 ⁇ m). To prepare a single cell suspension.
  • Splenocytes are washed twice with sterile physiological saline, then contain 1 gZm of concanapalin A (Short name: ConA, manufactured by Sigma, USA) and contain antibiotics (Sigma: anti-biotic, anti-mycotic) 10% —float in RPMI 1640 with FCS, dilute the test sample in advance, and dilute 100 l into a 96-well microplate that has been dispensed so that it will be 3 X l 05 cel 1Z100 / 1Z well. Note.
  • the blast conversion rate can be quantified as a ratio when the blast conversion reaction in the sample-free group was set to 1. When the immature transformation rate exceeds 1, it can be determined that there is an immunostimulatory effect.
  • Cell metabolic activity can be determined, for example, by assaying the test compound in RPMI 1640 medium containing BALBZc mouse bone marrow cells 2 ⁇ 10 6 ce 11 / m antibiotic, 10% fetal calf serum. 12.Add 5 t gZm 1 and incubate at 37 ° C, 5% carbon dioxide for 5 days, then mitochondrial metabolic activity of bone marrow cells by MTT reduction method. Is measured. If the metabolic rate when the cell metabolic rate when no sample is added is 1 exceeds 1, it can be determined that there is an immunostimulatory effect.
  • “Bone marrow cell metabolism promoting action” broadly includes the following leukocyte proliferating action and lymphocyte function regulating action, and refers to an action of promoting the proliferation of bone marrow cells via various mechanisms of action.
  • Lymphocytes are cells that have the function of recognizing foreign antigens with surface receptors, and turn into cells that play the most important role in the immune phenomenon through cell division and maturation. Antigen lectins and the like are known as substances that cause lymphocyte activation. These activations cause biochemical changes in the cell membrane and cytoplasm. The action of regulating lymphocyte-based immune phenomena is referred to herein as “lymphocyte function regulating action”.
  • Leukocytes are one of the blood cell components and are composed of neutrophils, eosinophils, basophils, monocytes, and lymphocytes (T lymphocytes and B lymphocytes). Leukocytes other than T lymphocytes proliferate, differentiate and mature in the bone marrow, and T lymphocytes proliferate in the bone marrow and then proliferate, differentiate and mature in the thymus. It can be used as a therapeutic or prophylactic agent for leukopenia caused by various causes, for example, cancer radiotherapy or chemotherapy, due to its leukocyte proliferation action. In addition, it can be used as a hematopoietic promoter at the time of bone marrow transplantation and as a drug that rapidly recovers the white blood cell count.
  • the compound of the present invention has an effect of increasing other substances having an immunostimulating effect, for example, G—CSF, and is expected to have a synergistic effect. It can also be used in the field of treatment of thrombocytopenia after bone marrow transplantation and autoimmune diseases associated with thrombocytopenia, such as aplastic anemia and idiopathic thrombocytopenic purpura.
  • compositions examples include pharmaceutical compositions (including quasi-drugs), veterinary drugs (livestock drugs, marine drugs, etc.), and food compositions, cosmetic compositions, and the like. Therefore, the product of the present invention can be used for various applications.
  • quasi-drugs that are formulated as immune function stimulants in humans or animals or that are expected to have their immune function stimulating effects Cosmetics, foods, foods for specified insurance, beverages and feed for livestock.
  • the compound, a salt thereof, a prodrug thereof or a hydrate thereof used in the present invention can be easily produced by a method known per se. Specific examples of the method include the following method.
  • the compound of the formula (I-A) can be obtained, for example, by reacting a compound of the formula II with a compound of the formula III in the presence of a base. Specifically, for example, it can be obtained by a method similar to the method described in Example 1.
  • the base that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is an inorganic base or an organic base.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. Preferred Or 0 to 100.
  • the reaction time varies depending mainly on the solvent used, the reaction temperature, the type of the starting compound or the reaction reagent, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • the amount of the compound of the formula II used is preferably 0.5 to 4 equivalents, more preferably 0.9 to 1.5 equivalents to the compound of the formula III.
  • the compound of the formula (I_B) is obtained, for example, by reacting the compound of the formula (I-A) with the compound RCH 2 PPh 3 Ha 1. Specifically, for example, it can be obtained by a method similar to the method described in Example 2.
  • the base that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is an inorganic base or an organic base.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. Preferably-20 ° C to 50 ° C.
  • the reaction time varies depending mainly on the solvent used, the reaction temperature, the type of the starting compound or the reaction reagent, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • the amount of RCH 2 PPH 3 Ha 1 used is preferably 0.5 to 4 equivalents, more preferably 0.9 to 1.5 equivalents, to the compound of the formula (I-A).
  • the compound of the formula (I-C) can be obtained, for example, by rearranging the compound of the formula (I-B). Specifically, for example, it is obtained by a method similar to the method described in Example 3.
  • the above rearrangement reaction can be carried out by heating or adding a reagent, but when a reagent is used, it is appropriately selected according to the type of the raw material compound, and the normal rearrangement reaction is performed. There is no particular limitation as long as it is used as a drug. For example, an acid or a base can be used.
  • the acid examples include an inorganic acid (eg, hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, etc.) or an organic acid (eg, acetic acid, formic acid, Bronsted acids such as oxalic acid, methanesulfonate, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonate and the like, and Lewis acids such as boron trichloride, boron trifluoride and boron tripromide.
  • an inorganic acid eg, hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, etc.
  • an organic acid eg, acetic acid, formic acid, Bronsted acids such as oxalic acid, methanesulfonate, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonate and the like
  • Examples of the base include alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, etc.), alkali metal hydrides (Eg, sodium hydride, lithium hydride, potassium hydride, etc.), alkali metal water Oxides (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.), alkali metal fluorides (eg, sodium fluoride, potassium fluoride, etc.), alkali metal alkoxides (eg, sodium hydroxide) Methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide, etc.), lithium disopyramide, tetra-n-butylammonium, anhydrous sodium acetate, aqueous silver sulfate and the like. .
  • the solvent that can be used is not particularly limited as long as it does not adversely affect the reaction and dissolves the starting materials to such an extent that the reaction is not hindered, but is preferably an alcohol solvent (e.g., methanol, ethanol, n_propanol, Isopropanol, etc.), ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, diisopropyl ether, dimethoxyethane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (eg, tetrachloromethane, dichloromethane, dichlorobenzene, chlorobenzene) Benzene, dichloroethane, methylene chloride, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), saturated hydrocarbons (eg, heptane, hexane, etc.), nitriles (
  • the reaction temperature is preferably from 178 ° C to 350 ° C, more preferably from -20 ° C to 300 ° C.
  • the reaction time varies depending on the type of the solvent, the reaction temperature, the starting compound or the reaction reagent used, but is preferably from 0.33 to 48 hours, more preferably from 0.5 to 10 hours. .
  • the reaction can also be performed in the presence of argon or nitrogen.
  • the compound of the formula (I-D) is obtained, for example, by adding water to the compound of the formula (I_C). Specifically, for example, it can be obtained by a method similar to the method described in Example 4.
  • the compound of the formula (I-D) can be produced, for example, by oxidizing the compound of the formula (I-C) with an oxidizing agent in a suitable solvent under the condition of using or not using a hydroborating agent. it can.
  • hydroborating agent examples include borane, dipolane, 9-porabicyclo [3.3.1] nonane (9-BBN), borohydride salts (eg, borohydride Sodium, etc.), Lewis acids and the like, which are appropriately selected according to the type of compound (VI).
  • the oxidizing agent to be used is not particularly limited as long as it is a normal oxidizing agent, and examples thereof include hydrogen peroxide and peroxide (eg, tert-butyl peroxide and the like).
  • the solvent used in the case of using the hydroborating agent is not particularly limited as long as it does not adversely affect the reaction and dissolves the starting material to such an extent that the reaction is not hindered.
  • Tetrahydrofuran getyl ether, dioxane, diisopropyl ether, dimethoxyethane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (eg, tetrachloromethane, dichloromethane, dichlorobenzene, benzene, dichloroethane, methylene chloride, etc.) ), Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), saturated hydrocarbons (eg, heptane, hexane, etc.), alcohols (eg, methanol, ethanol, n-propanol, isopropanol, etc.) ), Water etc. or these Mixed solvent and the like, is appropriately selected in consideration of the type of solubility or reagent compounds.
  • the reaction temperature is preferably between -78 ° C and 70 ° C, more preferably between 110 ° C and 35 ° C.
  • the reaction time varies depending on the type of the solvent, reaction temperature, starting compound, or reaction reagent used, but is preferably from 0.3 to 48 hours, more preferably from 1 to 6 hours. .
  • oxidizing agent examples include, in addition to the above-mentioned peroxides, osmium compounds (eg, potassium osmate / dihydrate, osmium tetroxide), ruthenium oxides (eg, ruthenium oxide (IV), etc.) , Selenium compounds (eg, selenium dioxide, etc.), manganese oxides (eg, manganese peroxide, manganese dioxide, etc.), ferricyanide metals (eg, potassium ferricyanide, etc.), nitrites (eg, ethyl nitrite) Etc.), hypochlorous acid compounds (eg, ethyl hypochlorite, etc.), and persulfate compounds (eg, potassium persulfate, etc.).
  • osmium compounds eg, potassium osmate / dihydrate, osmium tetroxide
  • ruthenium oxides eg, ruthenium oxide (IV
  • oxidizing agents are preferably used in the presence of an acid or a base.
  • the acid include Lewis acids (eg, aluminum chloride), and bases include alkali metal hydroxides (eg, sodium hydroxide, etc.). ) And organic bases (eg, tetramethylethylenediamine and the like).
  • the starting material is used for the reaction without adversely affecting the reaction.
  • an ether solvent eg, tetrahydrofuran, getyl ether, dioxane, diisopropyl ether, dimethoxyethane, diethylene glycol dimethyl ether, etc.
  • halogenated carbonized Hydrogens eg, tetrachloromethane, dichloromethane, dichlorobenzene, benzene, dichloroethane, methylene chloride, etc.
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • saturated hydrocarbons eg, heptane
  • nitriles eg, acetonitrile, isobutyryl nitrile, etc.
  • amides eg,
  • the reaction temperature is preferably from ⁇ 78 ° C. to 70 ° C., more preferably from ⁇ 10 ° C. to 35 ° C.
  • the reaction time varies depending on the type of the solvent, reaction temperature, starting compound, or reaction reagent used, but is preferably from 0.3 to 48 hours, more preferably from 1 to 6 hours. .
  • the step of using the above-mentioned hydroborating agent and the step of using the oxidizing agent may be carried out stepwise. No.
  • the compound of the formula (I-D) can be obtained depending on the reaction conditions only by using the oxidizing agent alone.
  • the compound of the formula (I-E) is obtained, for example, by subjecting the compound of the formula (I-D) to cyclodehydration. Specifically, for example, it can be obtained by a method similar to the method described in Example 5. Alternatively, as described in Example 9, the compound of formula (I_J) may be obtained by hydrogenation.
  • the compound of the formula (I-E) is subjected to a dehydration reaction from the compound of the formula (I-D) in the presence or absence of a solvent, in the presence or absence of an acid or a base, for example, to effect ring closure.
  • a dehydration reaction from the compound of the formula (I-D) in the presence or absence of a solvent, in the presence or absence of an acid or a base, for example, to effect ring closure.
  • the acid to be used is not particularly limited as long as it is used as an acid in a usual reaction, but is preferably an inorganic acid (eg, hydrogen chloride, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, etc. ) Or organic acids (eg, acetic acid, formic acid, oxalic acid, methanesulphonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulphonic acid, etc.) or boron trichloride, boron trifluoride, Polontriol Lewis acids such as bromide, phosphine and a combination of dialkyl azodicarboxylates or tetraalkyl azodicarboxamides (eg, 1: 1 triphenylphosphine getyl azodicarboxylate (TPP-DEAD), etc.) No.
  • inorganic acid eg, hydrogen chloride, hydrobromic acid, sulfuric
  • the base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably an alkali metal carbonate (eg, sodium carbonate, etc.) or an organic base (eg, pyridine, etc.) ).
  • an alkali metal carbonate eg, sodium carbonate, etc.
  • an organic base eg, pyridine, etc.
  • the solvent that can be used is not particularly limited as long as it does not adversely affect the reaction and dissolves the starting material to such an extent that the reaction is not hindered.
  • Examples thereof include pyridine, acetone, and the like, and a mixed solvent thereof, and are appropriately selected in consideration of the solubility of the compound, the type of reaction, and the like.
  • an acid or a base itself can be used as a solvent.
  • the reaction temperature is preferably between -78 ° C and 250 ° C, more preferably between 0 ° C and 10 ° C.
  • the reaction time varies depending on the type of the solvent, reaction temperature, starting compound, or reaction reagent used, but it is preferably from 0.03 to 48 hours, more preferably from 1 to 25 hours. is there.
  • the amount of the acid to be used is preferably 0.8 to 2.0 equivalents to the compound of the formula (ID).
  • the reaction can also be performed in the presence of argon or nitrogen.
  • reaction scheme 2 illustrates a method for synthesizing the compound of the formula (IF).
  • the compound of the formula (I-F) can be obtained, for example, by treating a compound of the formula (I-B) with an acid.
  • the acid that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is an inorganic acid or an organic acid.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. It is preferably between 0 and 100 ° C.
  • the reaction time varies depending mainly on the solvent used, the reaction temperature, the type of the starting compound or the reaction reagent, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • the amount of the acid to be used is preferably 0.1 to 20 equivalents, more preferably 0.5 to 5 equivalents, relative to the compound of the formula (I_B).
  • the obtained compound can be purified, if necessary, by a conventional method (eg, column chromatography, recrystallization, etc.).
  • a conventional method eg, column chromatography, recrystallization, etc.
  • the following scheme illustrates a method for synthesizing the compounds of formulas (I-G) and (I-H).
  • the base that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is an inorganic base or an organic base.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. Preferably-20 to ⁇ 50 ° C.
  • the reaction time varies depending mainly on the solvent, reaction temperature, starting material compound or type of reaction reagent used, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • CH 3 PP h 3 Ha 1 is preferably 0.5 to: L 0 equivalent, more preferably 0.9 to 2 equivalent, based on the compound of the formula (I-C).
  • the obtained compound can be purified, if necessary, by a conventional method (eg, column chromatography, recrystallization, etc.).
  • the compound of the formula (IH) can be obtained, for example, by treating a compound of the formula (IC) with an acid.
  • the acid that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is an inorganic acid or an organic acid.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. It is preferably between 0 ° C and 100 ° C.
  • the reaction time varies depending mainly on the solvent, reaction temperature, starting material compound or type of reaction reagent used, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • the amount of the acid to be used is preferably 0.1 to 20 equivalents, more preferably 0.5 to 5 equivalents, to the compound of the formula (I-C).
  • the obtained compound can be purified, if necessary, by a conventional method (eg, column chromatography, recrystallization, etc.). Then, the following scheme illustrates a method of synthesizing the compound of formula (I-J) ⁇ (Reaction Scheme 4)
  • the compound of formula (I-J) can be obtained, for example, by working a compound of formula IX on a compound of formula VIII. Specifically, for example, it is obtained by a method similar to the method described in Example 2.
  • the base that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is an inorganic base or an organic base.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. Preferably it is between 0 ° C and 150 ° C.
  • the reaction time varies depending mainly on the solvent used, the reaction temperature, the type of the starting compound or the reaction reagent, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • the amount of the IX compound to be used is preferably 0.5 to 10 equivalents, more preferably 0.9 to 2 equivalents, relative to the VIII compound.
  • the obtained compound may be used in a conventional manner (for example, column chromatography, (For example, recrystallization).
  • a conventional manner for example, column chromatography, (For example, recrystallization).
  • the compound of the formula (I- ⁇ ) is obtained, for example, by reacting the compound of the formula XIII with the compound of the formula XIII. Specifically, for example, it can be obtained by a method similar to the method described in Example 10.
  • the base that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is an inorganic base or an organic base.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. Preferably it is 0 to 150 ° C.
  • the reaction time varies depending mainly on the solvent, reaction temperature, starting material compound or type of reaction reagent used, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • the amount of the compound XIII used is 0.1 to 10 equivalents to the compound XII. It is preferably 0.9 to 2 equivalents.
  • the compound of the formula (I-L) is obtained, for example, by hydrogenating a compound of the formula (I-K). Specifically, for example, it can be obtained by a method similar to the method described in Example 9.
  • the catalyst that can be used is not particularly limited as long as the reaction can proceed favorably.
  • it is palladium carbon or platinum dioxide.
  • the reaction temperature is not particularly limited as long as the reaction can proceed sufficiently. It is preferably 0 ° C to 100 ° C.
  • the reaction time varies depending mainly on the solvent, reaction temperature, starting material compound or type of reaction reagent used, but is preferably 0.5 hours to 48 hours, more preferably 1 hour to 24 hours.
  • the amount of the catalyst to be used is preferably 0.01 to 1 equivalent, more preferably 0.02 to 0.5 equivalent, relative to the compound of the formula (I_K).
  • the obtained compound can be purified, if necessary, by a conventional method (eg, column chromatography, recrystallization, etc.). (Protecting group)
  • protecting group for the amino group examples include, for example, an amide-forming protecting group (eg, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, acetoacetyl, 0-nitrophenylacetyl), and the like.
  • an amide-forming protecting group eg, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, acetoacetyl, 0-nitrophenylacetyl
  • hydroxyl-protecting group examples include ether-type protecting groups (eg, methoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, methylthiomethyl) , 2-tetrahydropyranyl, 4-methoxy-14-tetrahydrobiranyl, 2-tetrahydroviranyl, benzyl, p-methoxybenzyl, P-nitrobenzyl, 0-nitrobenzyl, 2,6-dichloromouth benzyl, trityl, etc.) , A protective group of the type that forms a silyl ether (eg, trimethylsilyl, triethylsilyl, trisopropylsilyl, isopropyldimethylsilyl, getylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl
  • carboxy-protecting group examples include, for example, an ester-forming protecting group (eg, methyl, ethyl, tert-butyl, methoxymethyl, methoxyethoxymethyl, 2,2,2-trichloroethyl) , Benzyloxymethyl, 2-trimethylsilylethyl, aryl, benzyl, P-methoxybenzyl, 0-nitro Benzyl, p-nitrobenzyl, benzhydryl, trityl, cyclohexyl, cyclopentyl, phenacyl, etc.), a protective group that forms silyl esters
  • the protecting group for the carbonyl group include, for example, a protecting group of a type that forms an acetal-dialkyl or dithioacetal-dithioketal (eg, dimethyl, dimethyl, diacetyl, dibenzyl, etc.), which may be substituted 1 , 3—dioxane or 1,3-dioxolane-forming type, 1,3-dithiane or 1,3-dithiolane-forming type, and substituted hydrazone-forming type (eg, N, N-dimethyl, 2, 4-dinitrophenyl) and the like.
  • a protecting group of a type that forms an acetal-dialkyl or dithioacetal-dithioketal eg, dimethyl, dimethyl, diacetyl, dibenzyl, etc.
  • substituted hydrazone-forming type eg, N, N-dimethyl, 2, 4-dinitrophenyl
  • a method for removing the above protecting group for an amino group a protecting group for a hydroxyl group, a protecting group for a carbonyl group and a protecting group for a carboxyl group, for example, a method using a base, a method using an acid, a method using reduction, and a method using ultraviolet light Method, a method using hydrazine, a method using phenylhydrazine, a method using sodium N-methyldithiophosphate, a method using tetrabutylammonium fluoride, a method using palladium acetate, a method using mercuric chloride, a method using a Lewis acid, and the like.
  • These general methods or other known means can be appropriately selected and used.
  • the method using a base is one of the general methods for hydrolyzing amides, esters, and the like, similar to the method using an acid, and is applied to the elimination of the corresponding protecting group.
  • organic bases are effectively used for deprotection of an amino group protected by 9-fluorenylmethoxycarbonyl.
  • Preferred examples of the base used include, for example, inorganic bases such as alkali metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) and alkaline earth metal hydroxides (eg, hydroxide Magnesium, hydroxylating power, etc.), alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (eg, magnesium carbonate, calcium carbonate, etc.), hydrogen carbonate Lucari metal (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal acetate (eg, sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (eg, calcium phosphate, magnesium phosphate, etc.), Alkali metal hydrogen phosphates (eg, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.) and aqueous ammonia, and organic bases include, for example, trimethylamine, triethylamine,
  • the acid method is one of the general methods for hydrolyzing amides, esters, silyl esters, silyl ethers, etc., and is applied to the elimination of the corresponding protecting group.
  • Protected amino groups eg, tert-butoxycarbonyl, P-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, benzhydryloxycarbonyl, 9-anthrylmethoxycarbonyl, 1-methyl-1- (4 —Bifenylyl) ethoxycarponyl, 1—Adamantyloxycarbonyl, amino group protected with trityl, etc., protected hydroxyl group (eg, methoxymethyl, tert-butoxymethyl, 2-tetrahydrovinylanyl, 4 -Methoxy-4-tetrahydrovilanyl, 2-tetrahydroviranyl, 2-tetrahydrofuranyl, hydroxyl group protected with trityl, etc.).
  • Preferred examples of the acid used include organic acids (eg, formic acid, trifluoroacetic acid, benzenesulfonic acid, P-toluenesulfonic acid, etc.), and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).
  • organic acids eg, formic acid, trifluoroacetic acid, benzenesulfonic acid, P-toluenesulfonic acid, etc.
  • inorganic acids eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the method by reduction may be a protected amino group (eg, trichloroacetyl, trifluoroacetyl, 0-nitrophenylacetyl, 2,2,2-trichloromouth ethoxycarbonyl, benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, 2 , 4 dichloro mouth benzyloxycarbonyl, isonicotinyloxycarbonyl, triamino protected amino group, etc., protected hydroxyl group (eg, benzyl, p-Nitrobenzyl protected hydroxyl group, etc.), protected carboxyl group
  • a protected amino group eg, trichloroacetyl, trifluoroacetyl, 0-nitrophenylacetyl, 2,2,2-trichloromouth ethoxycarbonyl, benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, 2 , 4 dichloro mouth benzyloxycarbonyl, isonicot
  • benzyloxymethyl, benzyl, P-nitrobenzyl, phenacyl, 2,2,2-trichloroethyl, benzhydryl protected carboxyl group, etc. Preferred examples of the reduction method used include, for example, reduction with sodium borohydride, reduction with zinc / acetic acid, and catalytic reduction.
  • the method using ultraviolet light is used for, for example, deprotection of a hydroxyl group and a carboxyl group protected with 0-nitrobenzyl.
  • the method using hydrazine is used for, for example, deprotection of an amino group protected with phthaloyl (for example, a phthalimide group).
  • the method using phenylhydrazine is used, for example, for deprotection of an amino group protected with acetoacetyl.
  • the method using sodium N-methyldithiolrubinate is used, for example, for deprotection of chloroacetyl-protected amino and hydroxyl groups.
  • the method using tetrabutylammonium fluoride is, for example, a method in which a protecting group is removed from 2-trimethylsilylethyl carbamate, silyl ethers and silyl esters to obtain an amino group, a hydroxyl group and a hydroxyl group, respectively.
  • mercury chloride As a method using mercury chloride, for example, it is used for deprotection of a hydroxy group protected by methylthiomethyl.
  • the method using a Lewis acid is used, for example, for deprotection of a hydroxyl group protected with 2-methoxyethoxymethyl.
  • Preferred examples of the Lewis acid used include, for example, mercury bromide, titanium tetrachloride and the like.
  • the compound of the present invention is compounded with a pharmacologically acceptable carrier to prepare tablets, capsules, granules, powders, powders, suppositories, and other solid preparations, or syrups, injections, suspensions, and solutions. It can be administered orally or parenterally as a liquid preparation such as a spray.
  • Pharmaceutically acceptable carriers include excipients, lubricants, binders, disintegrants, disintegration inhibitors, absorption enhancers, adsorbents, humectants, solubilizing agents, stabilizing agents, Examples include a solvent, a dissolution aid, a suspending agent, a tonicity agent, a buffer, a soothing agent and the like in a liquid preparation.
  • composition of the present invention may contain a compound having an immunostimulatory action other than the compound represented by the general formula (I), a salt thereof or a hydrate thereof.
  • Parenteral routes of administration include intravenous injection, intramuscular injection, nasal, rectal, vaginal and transdermal.
  • excipient in the solid preparation examples include glucose, lactose, sucrose, D_mannitol, crystalline cellulose, starch, calcium carbonate, light anhydrous calcium acid, sodium chloride, kaolin and urea.
  • Lubricants in solid preparations include, for example, magnesium stearate, calcium stearate, powdered boric acid, colloidal keic acid, talc, polyethylene glycol and the like.
  • Examples of a binder in a solid preparation include water, ethanol, propanol, sucrose, D-mannitol, crystalline cellulose, dextrin, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, starch solution, gelatin solution, polyvinylpyrrolidone, Examples include calcium phosphate, potassium phosphate, and shellac.
  • Disintegrants in solid preparations include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, agar powder, laminaran powder, croscarmellose sodium, carboxymethyl starch sodium, algi
  • examples include sodium phosphate, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, starch, stearic acid monodaliseride, lactose, and calcium cellulose glycolate.
  • Preferred examples of the disintegration inhibitor in the solid preparation include hydrogenated oil, sucrose, stearin, cocoa butter, and hardened oil.
  • absorption enhancer in a solid preparation examples include quaternary ammonium bases and sodium lauryl sulfate.
  • adsorbent in the solid preparation examples include starch, lactose, kaolin, bentonite, and colloidal citric acid.
  • humectant in the solid preparation examples include glycerin, starch and the like.
  • solubilizer in a solid preparation examples include arginine, glutamic acid, and aspartic acid.
  • Examples of the stabilizer in the solid preparation include human serum albumin, lactose and the like.
  • tablets, pills and the like When preparing tablets, pills and the like as solid preparations, they may be coated with a film of a gastric or enteric substance (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) as necessary.
  • Tablets include tablets coated with ordinary skin as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets, and multilayer tablets.
  • Capsules include hard capsules and soft capsules.
  • Preferable examples of the solvent in the liquid preparation include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • Preferred examples of solubilizers in liquid formulations include polyethylene glycol, propylene glycol, D-manni! Yl, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and quencher. Acid sodium and the like.
  • the suspending agent in the liquid preparation include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate.
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium propyloxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Preferable examples of the tonicity agent in the liquid preparation include sodium chloride, glycerin, D-mannitol and the like.
  • buffers such as phosphate, acetate, carbonate, and citrate.
  • the soothing agent in the liquid preparation include benzyl alcohol, benzalkonium chloride and procaine hydrochloride.
  • preservative in the liquid preparation include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, 2-phenylethyl alcohol, acetic acid, acetic acid and sorbic acid.
  • antioxidant in the liquid preparation include sulfite, ascorbic acid, sodium tocopherol and cysteine.
  • the solutions and suspensions are preferably sterilized and isotonic with blood and blood.
  • these are sterilized by filtration using a bacteria-retaining filter or the like, blending of a bactericide or irradiation. Further, after these treatments, solidify by freeze-drying etc., and use sterile water or sterile injectable diluent immediately before use.
  • aqueous solution of lidocaine hydrochloride, physiological saline, aqueous glucose solution, ethanol or a mixed solution thereof may be added.
  • compositions may contain coloring agents, preservatives, flavors, flavors, sweeteners and the like, as well as other agents.
  • the immunostimulation method of the present invention is a method for activating immunity of a subject, which comprises a step of administering the above-described composition of the present invention to the subject.
  • the route of administration and the type of carrier and preparation used for administration are as described above for the preparation of the pharmaceutical composition.
  • the subject refers to a human or a non-human animal.
  • the animal may be a mammal or a non-mammalian animal.
  • it may be fish.
  • the dosage of the active ingredient varies depending on the disease state, administration route, patient age, and body weight. Is in the range of 1-5 O m gZ k gZ days.
  • the compound represented by the general formula (I) and a salt thereof in particular, the compound represented by the following formula (M) and a salt thereof have a drug sensitivity restoring action. That is, the present invention relates to a drug sensitivity-restoring agent containing the compound represented by the general formula (I) or a salt thereof.
  • the “drug-sensitizing agent” refers to a substance having an effect of restoring the drug sensitivity of drug-resistant pathogenic microorganisms when used in combination with an antibacterial agent.
  • the drug-sensitivity-restoring agent of the present invention is particularly excellent in the action of restoring the drug-sensitivity of Pseudomonas aeruginosa, which has become less sensitive to drugs due to overproduction of OprM.
  • antibacterial agent used in combination with the drug sensitivity restoring agent various antibacterial agents described in Examples described later can be used.
  • antibacterial agents that can be used in addition to antibacterial agents include, for example, b-lactam antibiotics, such as cizop (CZOP) and piperacillin (PIPC), and merubenem (MEP M) -type potash antibiotics And the like.
  • 0prM is one of the Pseudomonas aeruginosa efflux pumps that provides P. aeruginosa drug resistance. More specifically, “0prM” is caused by high expression of the drug excretion system (MexAB-OprM), which is encoded on the P. aeruginosa chromosome and is encoded on the chromosome by mutation of the nalB locus. Things.
  • MexAB-OprM drug excretion system
  • OprM and OprJ are known as Pseudomonas aeruginosa efflux pumps that provide drug resistance of Pseudomonas aeruginosa.
  • composition having excellent antibacterial properties is provided by combining various antibacterial agents with the drug sensitivity restoring agent of the present invention.
  • the method for restoring drug sensitivity of the present invention is a method for restoring the sensitivity of a subject to a drug, and includes the step of administering the drug sensitivity restoring agent of the present invention to the subject.
  • the route of administration, the type of carrier and formulation used for administration, and the like are as described above for the preparation of the pharmaceutical composition.
  • the subject refers to a human or a non-human animal.
  • the animal may be a mammal or a non-mammalian animal.
  • it may be fish.
  • the dose of the active ingredient varies depending on the disease state, administration route, patient age, or body weight.When orally administered to an adult, it is usually 0.1 to 10 OmgZg gZ days, preferably 1 to 10 mg / kg. Within 5 OmgZk days.
  • the obtained 2- (3,5-dimethoxyphenoxy) acetate was dissolved in ethanol (10 ml) without purification, and a 1N aqueous sodium hydroxide solution (13 ml, 13 mmol) was added at room temperature to obtain a solution. Stirred for hours.
  • the reaction solution was acidified with a 5% aqueous solution of sodium hydrogen sulfate and extracted with ethyl acetate.
  • the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of 2- (3,5-dimethoxyphenoxy) acetic acid.
  • N, O-dimethylhydroxylamine hydrochloride (1.1 g, llmmol), N, N-dimethylformamide (2 Om 1), N- (3,5-dimethoxyphenoxy) acetic acid
  • Triethylamine (3.4 m 1, 24 mmo 1) was added, and chilled ice-cooled getyl cyanophosphate (1.9 ml, 13 mmol) was added, followed by stirring at room temperature for 14.5 hours.
  • Jethyl cyanophosphate (0.3 ml, 2 mMol) was added, and the mixture was further stirred for 4.5 hours.
  • Ethyl acetate-getyl ether (1: 1) was added, and the mixture was washed successively with water and saturated saline.
  • the obtained Grignard reagent was cooled with dry ice-acetone and a solution of 2- (3,5-dimethoxyphenoxy) -N-methoxy-1-N-methylacetoamide (1.7 g, 6.7 mmol) in tetrahydrofuran (5 ml), and the mixture was further stirred at room temperature for 1.5 hours and cooled with ice.
  • To the reaction solution was added 1N hydrochloric acid (20 ml), and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Getyl ether was added to the obtained crude product, and the crystals were collected by filtration to obtain the desired product (1.6 g, 70%).
  • Tetrahydrofuran (6 ml) was added to methyltriphenylphosphonium methoxide (800 mg, 2.Ommo 1) and stirred at room temperature with 0.5 M potassium hexamethyldisilazane in toluene (3.7 ml, 1.9 mmol). Was added dropwise. After stirring for 20 minutes, a tetrahedron solution (7 ml) of 2-benzyloxy_2,-(3,5-dimethoxyphenoxy) acetophenone (50 Omg, 1.3 mmo 1) was added. After stirring for additional 1.4 hours, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • the obtained crude product was subjected to silica gel column chromatography (n-hexane to 10% getyl ether Zn-hexane) to obtain the desired product (37 mg, 54%) containing a small amount of impurities.
  • the product was further purified using HPLC (silica gel column, 5% ethyl ether Zn-hexane), and the desired product, 3- (2-benzyloxyphenyl) -1,2, was extracted from dimethyl ether-n-hexane. Crystals of 3-dihydro-4,6-dimethoxy-3-methylbenzofuran were obtained. Melting point: 117-118 ° C
  • the reaction solution was ice-cooled without post-treatment, a 0.5 M methanolic sulfuric acid solution (1.5 ml, 0.75 mmol) was added, and the mixture was stirred at room temperature for 4 hours.
  • the reaction solution was ice-cooled again, concentrated sulfuric acid (0.04 ml, 0.75 mmol 1) was added, and the mixture was gradually heated to 60 ° C. After stirring at 60 for 14 hours, the mixture was allowed to cool.
  • the reaction solution was made basic by adding a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • 3,5-Dimethoxyphenol (15.42 g, 0.1 mol 1) was dissolved in 50 ml of DMF, and 2-bromoacetaldehyde dimethyl acetate (20.28 g, 0.12 mol 1), potassium carbonate (20. 73 g, 0.15mol), iodine Potassium iodide (0.1 lg) was added, and the mixture was heated and stirred at 140 for 18 hours. After cooling to room temperature, water was added, extracted with getyl ether, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • n-Butyllithium (12.6 ml, 1.53 M hexane solution, 19.2 mm 01) was added dropwise, and the mixture was stirred at room temperature for 2 hours. THF (20 ml) was added, and the mixture was further stirred at room temperature for 0.5 hours. did. This reaction solution was added dropwise at ⁇ 78 ° C. to a 40 ml 1 THF solution of triisopropylporate (3.62 g, 19.2 mmo), and the mixture was stirred at —78 ° C. for 1.5 hours and at room temperature for 0.5 hours. .
  • Table 13 shows the metabolic promoting effects of the compounds of the present invention on mouse bone marrow cells.
  • the data in the table are the metabolic rates when the cell metabolism when no sample is added is defined as 1. “NT” in the table indicates that the test was not performed.
  • Compound (M) was dissolved in 0.5% carboxymethylcellulose aqueous solution and orally administered to 5-week-old CD-1 mice at a maximum dose of 1000 mg / kg, and the safety of single administration was examined. Observations were made for 20 days after administration. No deaths were observed at the highest dose. Therefore, the safety of this compound is considered to be high.
  • Compound (M) was dissolved in dimethyl sulfoxide and added to the medium to a concentration of 20 / z g / ml. Each antibacterial agent was serially diluted 2-fold, and the final concentration at which bacterial growth was completely inhibited was defined as MIC. Aztreonam (AZT), ceftazidime (CAZ), cefpirome (CPR), ratamoxef (LM0X), cefsulosin (CFS), ofloxacin (0FLX), tetracycline (TC), and chloramphenicol (CP) were used as antibacterial agents. The results are shown in Table 14. As evident from Table 14, compound (M) restored drug sensitivity of OprM overproduction-resistant Pseudomonas aeruginosa when used with any of the drugs.
  • compound (M) has a susceptibility-restoring effect on a drug involved in reducing sensitivity due to OprM overproduction.
  • Compound (M) is NalB No antibacterial activity at 100 g / ml at 3 strains or 0FR504 strain described below c
  • the activity of compound (M) against various Pseudomonas aeruginosa was tested as described in Example 11.
  • the strains used were the P. aeruginosa standard strain PA01 and the laboratory mutants of the P. aeruginosa strains OFR504 and SLR-09, which are commonly used in genetic experiments.
  • the 0FR504 strain expresses OprJ among the three types of Pseudomonas aeruginosa drug efflux pumps (0prM, OprJ and OprN), and is thus a strain exhibiting 0PR, 0FLX and CP resistance.
  • the SLR-09 strain is a strain showing CAZ, CPR and LM0X resistance by producing j8-lactamase at a high level. Table 15 shows the properties of the strains tested. (Table 15)
  • the activity levels are “-”, “soil”, “ten”, “++”, and “+++” (the results are shown in Table 16).
  • the “None” column shows the results when no compound (M) is present.
  • Table 16 in the NalB3 strain that had been made resistant by OprM overproduction, MIC recovery was observed by adding the compound (M). That is, compound (M) Had the effect of restoring drug sensitivity.
  • CPR and 0FLX resistance of OFR504 strain which is an OprJ production resistant strain
  • CAZ, CPR, and LM0X resistance of SLR09 strain which is a highly resistant strain of / 3-lactamase. This suggests that compound (M) is specific for inhibiting the drug efflux pump OprM.
  • Example 11 In the same manner as in Example 11, the action of various compounds of the present invention to restore drug sensitivity was examined. Mic was measured using aztreonam (aztreonam, AZT) as a drug under conditions in which various compounds were present at 20 g / ml. As a result, as shown in the following Tables 17 to 21, it was confirmed that each compound had an effect of restoring drug sensitivity.
  • the MIC of the control using only aztreonam (AZT) without using a sensitizer was 12.5 zg / ml.
  • the MIC of compound (M) (compound K-59) was measured and found to be 3.13 g / ml.
  • the measured MIC is shown in the column of “TI activity” as an index of the drug sensitivity recovery effect.
  • ⁇ activity is an abbreviation for Transporter Inhibitor activity.
  • novel benzene derivatives are provided, and by using them, an effect as a biological defense enhancing agent can be expected through a lymphocyte function enhancing action and a bone marrow function enhancing action. Further, according to these novel benzene derivatives, useful drug sensitizing agents are provided.
  • the drug sensitivity-restoring agent of the present invention exhibits an excellent drug sensitivity-restoring effect and is highly safe, and thus is extremely useful for infections caused by multidrug-resistant Pseudomonas aeruginosa.

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Abstract

L'invention concerne des composés et des compositions spécifiques pour prévenir ou traitement des maladies associées à des anomalies de la fonction immunitaire. L'invention porte également sur des composés dérivés du benzène, sur des sels ou sur des hydrates de ceux-ci, ayant des effets immunostimulants et efficaces en tant qu'accélérateurs du mécanisme de défense biologique par la stimulation de la fonction lymphocytaire et de la moelle osseuse.
PCT/JP2000/005001 1999-07-26 2000-07-26 Derives de benzene, compositions immunostimulantes ou agents de retablissement de la pharmacosensibilite les contenant WO2001007031A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006504764A (ja) * 2002-10-30 2006-02-09 コビオン オーガニック セミコンダクターズ ゲーエムベーハー 半導体高分子製品に有用な単量体の新規な製造
JP2006193517A (ja) * 2004-12-21 2006-07-27 Chisso Corp クロマン環を有する液晶化合物、液晶組成物、およびこの液晶組成物を含有する液晶表示素子
JP2012500809A (ja) * 2008-08-29 2012-01-12 ノボゲン リサーチ ピーティーワイ リミテッド 免疫調節活性
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