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WO2007063839A1 - Derives de cyclohexane - Google Patents

Derives de cyclohexane Download PDF

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Publication number
WO2007063839A1
WO2007063839A1 PCT/JP2006/323693 JP2006323693W WO2007063839A1 WO 2007063839 A1 WO2007063839 A1 WO 2007063839A1 JP 2006323693 W JP2006323693 W JP 2006323693W WO 2007063839 A1 WO2007063839 A1 WO 2007063839A1
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general formula
ΐνυ
compound represented
people
compound
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English (en)
Japanese (ja)
Inventor
Moriyasu Masui
Hidenori Mikamiyama
Naoki Tsuno
Akira Matsumura
Hiroyuki Kai
Kousuke Anan
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to JP2007547945A priority Critical patent/JPWO2007063839A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention shows a specific antagonistic action on a central nerve cell glutamate receptor, particularly NR1ZNR2B receptor, which is one of NMDA receptors, preferably motor function (eg, sensory abnormality), mental
  • NR1ZNR2B receptor which is one of NMDA receptors, preferably motor function (eg, sensory abnormality), mental
  • the present invention relates to a cyclohexane derivative that has few side effects on symptoms (eg, schizophrenia) and is useful as a medicine for analgesics.
  • Amino acids such as L-glutamic acid and L-aspartic acid are important for neuronal activity as neurotransmitters in the central nervous system.
  • the extracellular accumulation of these excitatory amino acids is due to various neurological disorders such as Parkinson's disease, senile dementia, Huntington's chorea, epilepsy, as well as oxygen deficiency, ischemia, hypoglycemia It is thought to cause a loss of mental and motor function, such as that seen during conditions, head or spinal cord injury.
  • a glutamate receptor antagonist is a therapeutic agent for the above diseases and symptoms, For example, it is considered useful as an antiepileptic drug, an ischemic brain injury preventive drug, or an antiparkinsonian drug.
  • the NMDA receptor one of the glutamate receptors mentioned above, is composed of two subunits, NR1 and NR2, and there are four additional subfamily (NR2A, 2B, 2C, 2D) in the NR2 subunit. To do.
  • the NR1ZNR2A receptor is exclusively involved in memory formation and learning acquisition, and the NR1ZNR2B receptor is said to be involved in neurodegenerative cell death and pain transmission during cerebral ischemia. Therefore, a drug having high affinity for the NR1ZNR2B receptor is likely to be an effective analgesic with few side effects.
  • Patent Document 1 International Publication No. 2005Z080317 Pamphlet
  • Patent Document 2 US Patent Application Publication 2002Z0032207 Specification
  • Patent Document 3 US Patent Application Publication US2002Z055519 Specification
  • Patent Document 4 International Publication No. 01Z32634 Pamphlet
  • Patent Document 5 International Publication No. 2005Z19221 Pamphlet
  • Patent Document 6 International Publication No. 01Z94321 Pamphlet
  • Patent Document 7 International Publication 2004Z054579 Pamphlet
  • An NMDA receptor antagonist particularly an analgesic for cancer pain or the like, which is highly active and more preferably exhibits a high affinity for subtypes, particularly the NR1ZNR2B receptor.
  • the present invention provides the following.
  • a 1 may have a substituent, or may be a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group which may have a substituent,
  • the nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensed cyclic group has the following conditions:
  • optionally protected hydroxy, optionally protected amino and optionally substituted aminoxica also have at least one group selected
  • Satisfying at least one of A 2 may have a substituent, may be an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group which may have a substituent,
  • R ⁇ R 2a , R 2b and R 2e are each independently hydrogen, hydroxy or lower alkyl, and R 1 and R 2a or R 2b and R 2e may be joined together to form a single bond R 2a and R 2b may be joined together to form one O or OCH 2-
  • n 0 or 1
  • n and r are each independently an integer of 0 to 4
  • q is an integer of 1 to 4
  • a 3 may have a substituent, may be an aromatic hydrocarbon cyclic group, or may have a substituent! /, Or may have an aromatic heterocyclic group or a substituent. Is a good non-aromatic heterocyclic group,
  • Y is a single bond, lower alkylene, lower alkylene, lower alkylene, -O-, -S- NR 15 CR 12 R 13 0 CR 12 R 13 S or one CR 12 R 13 NR 15 , where When —X— (CO) m— is — CONR 5 CR 3 R 4 — Y is a single bond,
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R n , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen or substituent Or a lower alkyl, and when there are a plurality of each of R 3 and R 4 , they are different from each other! /.
  • a 1 is protected, may be hydroxy, protected !, may be amino or substituted V, may have at least one aminooxy, and is further substituted with another group;
  • ring — containing NH and other ring atoms may be protected, protected, protected, amino and substituted, may be substituted other than aminooxy , May be !, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,
  • a 2 may have a substituent, may be an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group which may have a substituent,
  • R 2a , R 2b and R 2e are each independently hydrogen, hydroxy or lower alkyl, and R 1 and R 2a or R 2b and R 2e may be joined together to form a single bond R 2a And R 2b together may form a single O or OCH-
  • n 0 or 1
  • n and r are each independently an integer of 0 to 4
  • q is an integer of 1 to 4
  • a 3 may have a substituent, may be an aromatic hydrocarbon cyclic group, has a substituent! /, Or may! An aromatic heterocyclic group or a non-aromatic heterocyclic group which may have a substituent,
  • Y is a single bond, lower alkylene, lower alkylene, lower alkylene, —O—, — S— ⁇ one NR 15 —, one CR 12 R 13 0—, one CR 12 R 13 S— or one CR 12 R 13 NR 15 — where —X— (CO) m— is — CONR 5 CR 3 R 4 — Y is a single bond,
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R n , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen or substituent Or a lower alkyl, and when there are a plurality of each of R 3 and R 4 , they are different from each other! /.
  • a 1 is protected, may be hydroxy, protected !, may be amino or substituted V, may have at least one aminooxy, and is further substituted with another group;
  • -NH- in the ring and other ring atoms may be protected hydroxy, protected, may, amino and substituted! /, May !, other than aminooxy Substituted with any of the above substituents !, may !, a nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,
  • a 2 may have a substituent, may be an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group which may have a substituent, R ⁇ R 2a , R 2b and R 2e are each independently hydrogen, hydroxy or lower alkyl, and R 1 and R 2a or R 2b and R 2e may be joined together to form a single bond m is 0 or 1,
  • n and r are each independently an integer of 0 to 4
  • q is an integer of 1 to 4
  • Y is a single bond, lower alkylene, lower alkylene, lower alkylene, —O—, —S—NR 15 — CR 12 R 13 0 CR 12 R 13 S— or one CR 12 R 13 NR 15 —.
  • X— (CO) m— is —CONR 5 CR 3 R 4 —
  • Y is a single bond
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 and R 16 each independently have hydrogen or a substituent. Or lower alkyl, and each of R 3 and R 4 is If there are several, they are different!
  • pyridyl A 1 is substituted with at least hydroxy, quinolyl substituted with at least hydroxy, downy substituted with at least hydroxy Nzuokisazoriru, downy substituted with at least hydroxy Nzuimidazoriru, at least protected, even in good ⁇ Amino Substituted pyridyl, imidazolyl optionally substituted with a ring atom other than —NH, substituted with a ring atom other than —NH, substituted with a ring atom other than pyrrolyl and NH
  • ring atoms other than virazolyl and NH— may be substituted !
  • benzopyrazolyl and benzimidazolyl or ring atoms other than NH— in which the ring atom may be substituted may be substituted.
  • the compound according to the above (1) or a pharmaceutically acceptable salt thereof, which is an indolyl in which a ring member atom other than NH may be
  • R 2b and R 2e are both hydrogen forces, R 2b and R 2e join together to form a single bond, or m is 0, n is 1 or more, and R 2b is A compound of any one of (1) to (6) above, which forms a single bond with R 3 on adjacent CR 3 R 4 together with the carbon atom to which R 2b is bonded, The pharmaceutically acceptable salt or solvate thereof.
  • a 2 is a phenyl optionally substituted with one or more groups selected from a nonogen, a sheared lower alkyl, a halogeno lower alkyl, a lower alkoxy and a halogeno lower alkoxy force.
  • (12) is a nitrogen-containing aromatic monocyclic group which may have a substituent, and the group may be protected! /, Hydroxy or protected! Hey! /,
  • (13) is a nitrogen-containing aromatic condensed cyclic group which may have a substituent, and the group may be protected, hydroxy, or protected, and may contain at least one amino Or a compound or a pharmaceutically acceptable salt thereof according to any one of (1) or (6) to (11) above, wherein X is —NR 5 CO (CR 3 R 4 ) n— Their solvates.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • composition according to (14) above which is a therapeutic agent for tinnitus, epilepsy, Huntington's disease, movement disorder or alcoholism.
  • a method for alleviating pain or migraine, stroke, head trauma, Alzheimer's disease, Parkinson's disease, tinnitus, epilepsy characterized by administering the compound according to any one of (1) to (13) above , Treatment for Huntington's disease, movement disorders or alcoholism.
  • the compound of the present invention is also useful as an analgesic (eg, cancer pain analgesic) having few side effects with force and used for the treatment of neurodegeneration such as stroke and brain trauma.
  • an analgesic eg, cancer pain analgesic
  • protected and optionally hydroxy means, for example, lower alkyl (methyl, tert-butyl, etc.), aryl lower alkyl (trifluoromethyl, benzyl, etc.), tri-lower alkylsilyl, etc.
  • Preferred protecting groups are lower alkyl, aryl lower alkyl, lower alkylsulfonyl and the like.
  • “Protected but optionally amino” means, for example, a lower alkoxy carbo yl (tert-butyloxy carbol etc.), a lower alkoxy carbo bol (buluoxy carbol, allyloxy) Carbon, etc.), halogeno lower alkoxy carbo yl (2-iodinated carbo carbonyl, 2, 2, 2-trichloro ethoxy carbo ol, etc.), aryl lower alkoxy carbonyl (benzyloxycarbonyl, p- Methoxybenzyloxycarbonyl, o-nitrobenzenoreoxycanoleboninole, p-nitrobenenoxoxynoleboninole, pheninore xycarbonyl, etc., tri-lower alkylsilyl (trimethylsilyl, triethylsilyl, tert-butyl) Dimethylsilyl), diazo, acyl (formyl, acetyl, bivaloyl),
  • substituents of “substituted and optionally aminooxy” include lower alkyl and acyl.
  • the "nitrogen-containing aromatic monocyclic group” is a 5- to 6-membered aromatic cyclic group having at least one N in the ring and optionally having O or S. Include. For example,
  • the “nitrogen-containing aromatic fused cyclic group” means that it has at least one N in the ring and further has O or S, and may be a 5- to 6-membered aromatic cyclic group, Includes a group in which one or two benzene rings or aromatic heterocycles are condensed.
  • [ooio] satisfies the condition “0 protected !, may, hydroxy, protected !, may, amino, and optionally substituted aminoxica are also selected” “A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group which may have a substituent, a nitrogen-containing aromatic monocyclic group” or “an optionally protected hydroxy group” May be protected
  • V amino or substituted, may have at least one aminooxy group, and may be further substituted with another group.
  • ⁇ Means that the above ⁇ nitrogen-containing aromatic monocyclic group '' or ⁇ nitrogen-containing aromatic condensed cyclic group '' is protected on the ring !, may! /, Hydroxy, protected! Moly! /, Amino and substituted !, optionally an aminoxica, also has at least one group selected and is further selected from the substituent group a. It may be substituted with one or more groups which include cyclic groups.
  • the substituent group a is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, lower alkylamino-containing carboxy, lower alkoxycarbole, sia-containing nitro.
  • At least one optionally protected amino-substituted pyridyl refers to one or more groups having at least one amino group or protected amino group as a substituent, and further selected from substituent group a. Substituted with !, which includes pyridyl.
  • It may have a nitrogen-containing aromatic monocyclic group or a substituent which may have a substituent satisfying the condition of "ii) containing -NH- in the ring". ⁇ ⁇ "Nitrogen-containing aromatic condensed cyclic group", "in the ring-containing NH, and other ring atoms may be protected hydroxy, protected, amino and substituted.
  • the nitrogen-containing aromatic monocyclic group or the nitrogen-containing aromatic condensed cyclic group ” may be substituted with a substituent other than aminooxy!
  • Monocyclic group "and” nitrogen-containing aromatic fused cyclic group That is, it includes a group containing an NH group in the ring.
  • the bond may be present in any ring, and any ring member other than NH may be substituted with one or more groups selected from the substituent group ⁇ force.
  • the substituent group ⁇ is halogen, lower alkyl, halogeno lower alkyl, acyl, carboxy, lower alkoxy carbo, cyan and -tro.
  • a ring atom other than 1 ⁇ may be substituted, imidazolyl”, “A ring atom other than 1 ⁇ may be substituted, pyrrolyl”, “A ring atom other than 1 ⁇ may be placed. May be substituted with virazolyl ",” other than one ring atom is substituted !, may be benzopyrazolyl "," other than one ring atom may be substituted. "N-midazolyl” and “-ring atoms other than - ⁇ are substituted !, but indolyl” means that each ring atom other than - ⁇ - is selected from the substituent group ⁇ . Includes imidazolyl, pyrrolyl, pyrazolyl, benzpyrazolyl, benzimidazolyl and indolyl optionally substituted with groups.
  • aromatic hydrocarbon cyclic group includes phenyl, naphthyl, phenanthryl and the like.
  • substituent of the “aromatic hydrocarbon cyclic group which may have a substituent” examples include halogen, hydroxy, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkyl.
  • Aromatic hydrocarbon cyclic group, substituent group ⁇ force is also selected Arylthio, optionally substituted with one or more groups A group selected from the group of ⁇ groups, such as aryloxy, which may be substituted with one or more groups, and a group of ⁇ forces
  • the substituent group ⁇ is halogen, hydroxy, lower alkyl, halogeno-lower alkyl, lower alkoxy, halogeno-lower alkoxy, acyl, acyloxy, amino-containing lower alkylamino, acylamino, carboxy, lower alkoxycarbonyl, silane-containing nitro.
  • Arylsulfol “Arylsulfoxy”, “Aryloxy”, “ArylChio”, “Arylamino”, “ArylLoweralkyl”, “Loweralkyldiarylsilyl”, “TriarylLoweralkylsilyl”, “Aryl”
  • the aryl moiety of “lower alkoxy lower alkyl”, “lower alkyl aryl sulfo”, and “aryl lower alkoxy carbo” is the same as the above “aromatic hydrocarbon cyclic group”. Preferred is phenyl.
  • aromatic heterocyclic group is a 5- to 6-membered aromatic monocyclic group containing 1 to 4 heteroatoms (eg, pyrrolyl, imidazolyl, pyrazolyl) that also has a group power consisting of ⁇ , ⁇ , and S.
  • Non-aromatic heterocyclic group means a 5- to 6-membered aromatic monocyclic group containing 1 to 4 heteroatoms (for example, thials, N, O and S).
  • the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” in A 3 include the divalent groups of the above “aromatic heterocyclic group” and “non-aromatic heterocyclic group”. To do. Bonding hands are acceptable
  • “Having a substituent, may be an aromatic heterocyclic group”, “having a substituent, may be a 5- to 6-membered aromatic monocyclic group” and “having a substituent.
  • the substituents for “! /, May !, non-aromatic heterocyclic groups” are the same as the substituents for the above-mentioned “having substituents, may be aromatic hydrocarbon cyclic groups”. It is. “Halogen” includes F, Cl, Br and the like.
  • Halogeno Lower Alkyl “Halogeno Lower Alkoxy”, “Halogeno Lower Alkoxy Power Lol”, “Halogenoacyl”, “Halogeno Lower Alkyl Sulfo”, “Halogeno Lower Alkyl Sulfo-Luoxy” Lower Alkyl and Halogen Part Is the same as the above “halogen”.
  • “Lower alkyl” includes linear or branched alkyl having 1 to LO, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such as methyl, ethyl, n — Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n— Examples thereof include nol and n-decyl. Particularly preferred is methyl or ethyl.
  • lower alkyl part of “lower alkyl which may have a substituent” is the same as the above “lower alkyl”.
  • substituents include halogen, hydroxy, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, amino-containing lower alkylamino-containing amino carboxy, lower alkoxycarbol, cyanated nitro and the like.
  • Preferred examples of alkyl include trihalogeno lower alkyl.
  • Halogeno lower alkyl “lower alkoxy lower alkyl”, “lower alkoxy lower alkoxy lower alkyl”, “lower alkoxy lower alkoxy lower alkyl”, “lower alkylthio lower alkyl”, “aryl aryl lower alkyl lower alkyl”, “lower alkoxy”, “halogeno lower alkoxy”, “ “Lower Alkoxy Carbon”, “Halogeno Lower Alkoxy Carbon”, “Aryl Lower Alkoxy Carbon”, “Lower Alkyl Force Rubamoyl”, “Lower Alkyl Sulfonyl", “Lower Alkyl Carylol” , “Lower alkyl sulfo-oxy”, “halogeno lower alkyl sulfo”, “halogen lower alkyl sulfo-oxy”, “lower alkyl amino”, “aryl lower alkyl”, “tri-lower alkyl silyl”, “lower alkyl di” Reel reel, triary The lower al
  • the "lower alcohol” is a straight chain having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, having one or more double bonds at an arbitrary position. Branched arche -Including le. Specifically, bur, aryl, probe, isoprobe, butur, isobutenyl, prennore, butagenyl, pentenyl, isopentenyl, pentageninore, hexeninore, isohexenore, hexageninore, hepteninole, otatenore, none Including dill and desalin.
  • the lower alkenyl portion of the “lower alkyloxyball” is the same as the above “lower alkell”.
  • the “lower alkylene” includes a divalent carbon chain having 1 to 6 carbon atoms, preferably alkylene having 1 to 3 carbon atoms, more preferably 1 or 2 carbon atoms.
  • the “lower alkenylene” includes a straight or branched divalent carbon chain having 2 to 6 carbon atoms having a double bond at an arbitrary position. Preferably, it has 2 to 4 carbon atoms, more preferably 2 or 3 carbon atoms. Specific examples include beylene, probelene, buterene, butadiene, methylpropylene, pentylene and hexylene, with beylene being preferred.
  • substituent of “having a substituent and may be a lower alkylene” include the same substituents as the above-mentioned “lower alkyl optionally having a substituent”, preferably halogen, It is hydroxy.
  • “Lower alkylene” is a straight or branched divalent carbon chain having 2 to 6 carbon atoms which has a triple bond at an arbitrary position and may further have a double bond. Include. Preferably, it has 2 to 4 carbon atoms, more preferably 2 or 3 carbon atoms. Specific examples include ethylene, propylene, petitylene, pentylene and hexylene.
  • substituent of “may be substituted or lower alkylene” include the same substituents as the above-mentioned “lower alkyl optionally having substituent”, preferably halogen, hydroxy It is.
  • Acyl includes aliphatic asil and Caroyl having 1 to 7 carbon atoms. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, bivaloyl, hexanoyl, attalyloyl, propioroyl, methacryloyl, crotonol and benzoyl.
  • acyloxy “acylamino”, and “halogenoacyl” acyl moieties are It is the same.
  • rR 1 and R 2a or R 2b and R together form a single bond.
  • R 2b forms a single bond with R 3 on the adjacent CR 4 with the carbon atom to which is bonded.”
  • x a is an optionally substituted lower alkylene, an optionally substituted lower alkylene, —CO CONR ′ NR “CO NR” CONR.
  • the compound (I) of the present invention includes all possible isomers and racemates, not limited to specific isomers. For example, it contains tautomers as follows.
  • a ketone represented by general formula ( ⁇ ) and an organic phosphorus compound represented by general formula ( ⁇ ) or (IV) are condensed to synthesize a compound represented by general formula (I—a). be able to.
  • R 3 R 4 ) s, 1 A 3 — (CR 3 R 4 ) s, 1 A 3 — NR 6 (CR 3 R 4 ) s, or 1 A 3 scale 1 . : ! ⁇ 1 . R 3 R 4 ) s, R 17 is C alkyl, s is an integer of 0 to 3, Z is a chlorine atom or bromine source
  • a wavy line indicates a cis or trans form, and other symbols are as defined above
  • the ketone represented by the general formula ( ⁇ ) can be synthesized by the method described in Reference Examples 1 to 4 described later and a method analogous thereto.
  • the carboxylic acid compound represented by the general formula (III) can be synthesized by the method described in New Experimental Chemistry Course 14, Maruzen Co., Ltd. (1977) and a method analogous thereto.
  • organic phosphorus compound represented by the general formula (III) or (IV) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (II).
  • reaction solvent examples include tetrahydrofuran, jetyl ether, acetonitrile, N, N dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium Examples include oxamethyl disilazide, potassium hexamethyl disilazide, sodium amide and the like.
  • the base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula ( ⁇ ).
  • reaction temperature 70 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Ia) can be obtained by known means (for example, chromatography 1 and recrystallization).
  • Method B Synthesis of (I b) from (I a)
  • the compound represented by the general formula (Ib) can be synthesized.
  • reaction solvent examples include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
  • the metal catalyst examples include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, and chlorotris (triphenylphosphine) rhodium (I).
  • chlorotris triphenylphosphine
  • rhodium I
  • 0.01 to 0.5 weight percent can be used.
  • the hydrogen pressure is 1 to 50 atm.
  • reaction temperature examples include 20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Ib) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (Ic) can be synthesized by reacting a ketone represented by the general formula (II) with an organometallic compound represented by the general formula (V).
  • L 1 is lithium, MgCl, MgBr or Mgl
  • the compound represented by the general formula (V) can be used in an amount of 1 to 3 mole equivalent to the ketone represented by the general formula ( ⁇ ).
  • reaction solvent examples include jetyl ether and tetrahydrofuran.
  • the reaction temperature is -70 to 50 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (Ic) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).
  • R 18 is C alkyl
  • the compounds represented by the general formulas (VI) and (VII) can be synthesized by the methods described in Reference Examples 5 to 6 described later and a method analogous thereto.
  • the carboxylic acid represented by the general formula (VII) can be synthesized.
  • Lithium hydroxide, sodium hydroxide or water for the compound represented by the general formula (VI) 1 to 5 molar equivalents of potassium oxide can be used.
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
  • reaction temperature examples include 0 ° C to the reflux temperature of the solvent.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (VII) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • a carboxylic acid represented by general formula (VII) and an amine compound represented by general formula (VIII) can be condensed to synthesize an amidy compound represented by general formula (Id). it can.
  • the compound represented by the general formula (VIII) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (VII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol, salt oxalyl and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (VII).
  • 1-Hydroxybenzotriazole may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula (VII).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Id) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • the compound represented by the general formula (VII) can be reduced to synthesize the alcohol represented by the general formula (IX).
  • reaction solvent examples include jetyl ether, tetrahydrofuran, toluene, ethanol and the like, and these can be used alone or in combination.
  • Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like, and 0.5 to 6 moles relative to the compound represented by the general formula (VI). An equivalent amount can be used.
  • reaction temperature examples include 0 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (IX) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • an alcohol represented by general formula (IX) and a carboxylic acid represented by general formula (X) may be condensed to synthesize an ester compound represented by general formula (I-e). it can.
  • the compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (IX).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agent examples include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethyl carpositimide hydrochloride, and the like.
  • compound represented by the general formula (IX) 0.5 to Two molar equivalents can be used. 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.
  • Examples of the base include triethylamine, 4-dimethylaminopyridine, and the like. Can be used as a mixture. Each of them can be used at 0.05 to 2 mole equivalents relative to the compound represented by the general formula (IX).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I e) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • Phthalimide can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (IX).
  • reaction solvent examples include tetrahydrofuran, jetyl ether, and acetonitrile.
  • azo compound examples include jetyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (IX).
  • trivalent phosphorus compounds examples include triphenylphosphine and tributylphosphine. In addition, it can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (IX).
  • reaction temperature examples include 0 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XI) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).
  • an amine compound represented by the general formula (XII) can be synthesized.
  • Hydrazine hydrate can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XI).
  • reaction solvent examples include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.
  • reaction temperature is 0 to 100 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • an amin compound represented by the general formula (If) is synthesized by condensing the amine compound represented by the general formula (XII) and the carboxylic acid represented by the general formula (X). Can do.
  • the compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • the condensing agent examples include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like.
  • the base can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula ( ⁇ ). 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole may be used as a condensation aid.
  • the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XII).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I f) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (I-g) can be synthesized by reacting an amine represented by the general formula (XII) with an isocyanate represented by the general formula ( ⁇ ) or a carbamate represented by (XI V). I'll do it.
  • the compound represented by the general formula ( ⁇ ) or (XIV) can be used at 0.5 to 3 mole equivalents relative to the compound represented by the general formula (XII).
  • reaction solvent examples include methylene chloride, 1,2-dichloroethane, toluene, acetonitrile, and tetrahydrofuran.
  • an amine such as triethylamine or diisopropylethylamine can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XX).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Ig) can be obtained by known means (for example, chromatography 1 and recrystallization).
  • An amide compound represented by the general formula (XV) can be synthesized by condensing a carboxylic acid represented by the general formula (VII) and N, O dimethylhydroxylamine hydrochloride in the presence of a condensing agent.
  • N, O dimethylhydroxylamine hydrochloride can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (VII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like, and these can be used alone or in combination.
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (VII).
  • 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 3 molar equivalents relative to the compound represented by the general formula (VII).
  • reaction temperature examples include 0 to 80 ° C.
  • reaction time is 0.5 to 72 hours.
  • the compound represented by the general formula (Ih) can be synthesized by reacting the amide compound represented by the general formula (XV) with the organometallic compound represented by the general formula (V).
  • the compound represented by the general formula (V) can be used in an amount of 1 to 3 mole equivalent to the ketone represented by the general formula ( ⁇ ).
  • reaction solvent examples include jetyl ether and tetrahydrofuran.
  • the reaction temperature is -70 to 50 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (I h) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (XVIII) can be synthesized by condensing a ketone represented by the general formula ( ⁇ ) and an organophosphorus compound represented by the general formula (XVI) or (XVII) in the presence of a base. .
  • organic phosphorus compound represented by the general formula (XVI) or (XVII) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (II).
  • Reaction solvents include tetrahydrofuran, jetyl ether, acetonitrile, N, N di- Examples include methylformamide, dimethyl sulfoxide, and liquid ammonia.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride
  • the base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula ( ⁇ ).
  • reaction temperature 70 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XVIII) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • a carboxylic acid represented by the general formula (XIX) can be synthesized by hydrolyzing the compound represented by the general formula (XVIII).
  • Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (XVIII).
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
  • reaction temperature examples include o ° c to the reflux temperature of the solvent.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XIX) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).
  • a carboxylic acid represented by general formula (XIX) and an amine compound represented by general formula (XX) can be condensed to synthesize an amidy compound represented by general formula (I i). it can.
  • the compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XIX).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate,
  • Examples of the compound represented by the general formula (XIX) examples include 0.5 to 2 molar equivalents. 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XIX).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I i) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (XXI) can be synthesized by reducing a compound represented by the general formula (XVIII) with hydrogen in the presence of a metal catalyst.
  • reaction solvent examples include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
  • metal catalyst examples include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, chlorotris (trifluorophosphine) rhodium (I), and the like, and 0 for the compound represented by the general formula (XVIII) 01 to 0.5 weight percent can be used.
  • Examples of the hydrogen pressure include 1 to 50 atmospheres.
  • reaction temperature examples include 20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXI) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (XXI).
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
  • reaction temperature examples include o ° c to the reflux temperature of the solvent.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula ( ⁇ ) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • the amide acid compound represented by the general formula (I j) can be synthesized by condensing the carboxylic acid represented by the general formula (XXII) and the amine compound represented by the general formula (XX). it can.
  • the compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • Condensation agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, black carbonic acid Ethyl, isoptil carbonate, salt and salt, oxalyl and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula (XXII).
  • 1-Hydroxybenzotriazole or the like may be used at 0.5 to 2 molar equivalents as a condensation aid.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula ( ⁇ ).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Ij) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).
  • Method K Compound (XVIII-a), (XXI-a), (XIX-a) or (XXII-a) to (I-k)
  • reaction solvent examples include jetyl ether, tetrahydrofuran, toluene, ethanol and the like, and these can be used alone or in combination.
  • Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, etc., and are represented by the general formulas (XVIII—a), (X XI—a), ( ⁇ — a) or 0.5 to 6 molar equivalents of the compound represented by (XXII—a) can be used.
  • reaction temperature examples include 0 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula ( ⁇ ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • an alcohol represented by the general formula (I) and a carboxylic acid represented by the general formula (X) can be condensed to synthesize an ester compound represented by the general formula (I—k).
  • the compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXIII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agent examples include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethyl carpositimide hydrochloride, and the like.
  • ⁇ 0.5 to Two molar equivalents can be used.
  • 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole or the like may be used as a condensation aid.
  • Examples of the base include triethylamine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination.
  • the compound represented by the general formula ( ⁇ ⁇ ⁇ ) can be used at 0.05 to 2 mole equivalents.
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I k) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (XXIV) can be synthesized by condensing an alcohol represented by the general formula ( ⁇ ) and aphthalimide in the presence of a azo compound and a trivalent phosphorus compound.
  • One to three molar equivalents of phthalimide can be used with respect to the compound represented by the general formula ( ⁇ ).
  • reaction solvent examples include tetrahydrofuran, jetyl ether, and acetonitrile.
  • azo compound examples include jetyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula ( ⁇ ).
  • Examples of the trivalent phosphorus compound include triphenylphosphine and tributylphosphine, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula ( ⁇ ).
  • Examples of the reaction temperature include 0 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXIV) is obtained by known means (for example, chromatograph And recrystallization).
  • an amine compound represented by the general formula (XXV) can be synthesized.
  • Hydrazine hydrate can be used in an amount of 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XXIV).
  • reaction solvent examples include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.
  • reaction temperature is 0 to 100 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XXV) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • an amin compound represented by the general formula (1-1) is synthesized by condensing the amine compound represented by the general formula (XXV) and the force rubonic acid represented by the general formula (X). Can do.
  • the compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXV).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like.
  • the base can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXV).
  • 1-Hydroxybenzotriazole may be used at 0.5 to 2 molar equivalents as a condensation aid.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula (XXV).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I 1) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • the amine represented by the general formula (XXV) can be reacted with the isocyanate represented by the general formula ( ⁇ ) or the carbamate represented by (XIV) to synthesize the compound represented by the general formula (I-m). Monkey.
  • the compound represented by the general formula ( ⁇ ) or (XIV) can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (XXV).
  • reaction solvent examples include methylene chloride, 1,2-dichloroethane, toluene, acetonitrile, and tetrahydrofuran.
  • an amine such as triethylamine or diisopropylethylamine can be used in an amount of 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XXV).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Im) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • N, O dimethylhydroxylamine hydrochloride or the like can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (XIX) or ( ⁇ ).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like, and these can be used alone or in combination.
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate,
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate,
  • Examples include thiol and salt oxalyl, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (XIX) or (XXII). 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole or the like may be used as a condensation aid.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination.
  • the base can be used at 0.05 to 3 molar equivalents relative to the compound represented by the general formula (XIX) or ( ⁇ ).
  • reaction temperature examples include 0 to 80 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXVI) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • a compound represented by the general formula (In) can be synthesized by reacting an amidy compound represented by the general formula (XXVI) with an organometallic compound represented by the general formula (XXVII).
  • the compound represented by the general formula (XXVII) can be used at 1 to 3 molar equivalents relative to the amido compound represented by the general formula (XXVI).
  • reaction solvent examples include jetyl ether and tetrahydrofuran.
  • the reaction temperature is -70 to 50 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (In) can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).
  • An oxime compound represented by the general formula (I-o) can be synthesized by reacting a ketone represented by the general formula (In) with a compound represented by the general formula (XXVIII).
  • the compound represented by the general formula (XXVIII) can be used at 0.5 to 3 molar equivalents relative to the ketone represented by the general formula (In). Hydrochloride or sulfate of the compound represented by the general formula (XXVIII) may be used.
  • reaction solvent examples include methanol, ethanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
  • Bases such as triethylamine and salts such as sodium acetate and potassium acetate have the general formula (I—n) 0.5 to 5 molar equivalents may be used with respect to the ketone represented by!
  • reaction temperature examples include 0 to 80 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I o) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • the compound represented by the general formula (XVIII-a) or (XIX-a) is reacted with a borane compound and then reacted with a peroxide to combine the diol represented by the general formula (XXIX). Can be made.
  • reaction solvent examples include jetyl ether and tetrahydrofuran.
  • borane compounds include borane-tetrahydrofuran complex and borane-dimethylsulfide complex, and 2 to 20 molar equivalents are used with respect to the compound represented by the general formula (XVIII-a) or (XIX-a). be able to.
  • reaction temperature is 0 to 50 ° C.
  • reaction time is 0.5 to 72 hours. After performing the above reaction with a borane compound, the reaction is performed by adding a peroxide to the reaction system.
  • reaction solvent examples include jetyl ether, tetrahydrofuran, water and the like, and these can be used alone or in combination.
  • peroxide examples include 5 to 35% hydrogen peroxide solution, and 3 to 30 molar equivalents of the compound represented by the general formula (XVIII-a) or (XIX-a) can be used. it can.
  • a salt of sodium acetate, potassium acetate, sodium hydrogen carbonate, sodium carbonate, potassium carbonate or the like may be used in an amount of 3 to 50 molar equivalents relative to the compound represented by the general formula (XVIII-a) or (XIX-a).
  • reaction temperature is 0 to 50 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXIX) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • a carboxylic acid represented by the general formula (XXX) can be synthesized by oxidizing the diol represented by the general formula (XXIX).
  • reaction solvent examples include acetone, N, N dimethylformamide and the like.
  • oxidizing agent examples include Diyons reagent and chromium oxide.
  • the oxidizing agent can be used in an amount of 2 to 10 molar equivalents relative to the compound represented by the general formula (XXIX).
  • reaction temperature is 0 to 50 ° C.
  • the reaction time includes 0.5 to 5 hours.
  • the resulting compound represented by the general formula (XXX) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • the carboxylic acid represented by the general formula (XXX) and the amine compound represented by the general formula (XX) are condensed to synthesize an amidy compound represented by the general formula (I—P). Can do.
  • the compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXX).
  • the reaction solvent include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agent examples include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and the compound can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXX). 1-Hydroxybenzotriazole or the like may be used at 0.5 to 2 molar equivalents as a condensation aid.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. 0.05 to 2 molar equivalents can be used for each compound represented by the general formula (XXX).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (IP) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (XXXI) can be synthesized by reacting a compound represented by the general formula (XXX) with diphenyl phosphate azide in the presence of a base.
  • An example of the reaction solvent is tert butanol.
  • Diphenol phosphate azide can be used in an amount of 1 to 2 molar equivalents relative to the compound represented by the general formula (XXX).
  • Examples of the base include triethylamine and diisopropylethylamine, and the base can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula (XX X).
  • reaction temperature examples include 0 to 80 ° C.
  • the reaction time is 1 to 24 hours.
  • the resulting compound represented by the general formula (XXXI) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (XXXII) can be synthesized by reacting a compound represented by the general formula (XXXI) with an acid.
  • reaction solvent examples include methanol, ethanol, and no solvent.
  • Examples of the acid include hydrochloric acid hydrogen, trifluoroacetic acid and the like, and 1 to 30 molar equivalents can be used with respect to the compound represented by the general formula (XXXI).
  • reaction temperature is 0 to 50 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XXXII) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • an amin compound represented by the general formula (I q) can be synthesized by condensing the amine compound represented by the general formula (XXXII) and the force rubonic acid represented by the general formula (X). it can.
  • the compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, chloride Examples thereof include thionyl, salt oxalyl and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula ( ⁇ ⁇ ⁇ ). 1-hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 molar equivalents relative to the compound represented by the general formula (XXXII).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I q) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (IX) can be synthesized by reacting a compound represented by the general formula (IX) with an oxidizing agent.
  • reaction solvent examples include ethyl acetate, methylene chloride, dimethyl sulfoxide and the like.
  • reaction temperature is 0 to 50 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula ( ⁇ ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (XXXV) can be synthesized by condensing a compound represented by the general formula (XXXIII) and an organophosphorus compound represented by the general formula (XXXIV) in the presence of a base.
  • organophosphorus compound represented by the general formula (XXXIV) can be used at 1 to 5 molar equivalents relative to the compound represented by the general formula ( ⁇ ).
  • reaction solvent examples include tetrahydrofuran, jetyl ether, acetonitrile, N, N dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride
  • the base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula ( ⁇ ).
  • reaction temperature 70 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXXV) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (XXXVI) can be synthesized by reducing the compound represented by the general formula (XXXV).
  • reaction solvent examples include methanol, ethanol, N, N dimethylformamide and the like. Can be used alone or in combination.
  • Examples of the reducing agent include sodium borohydride, and 1.0 to 6 molar equivalents can be used with respect to the compound represented by the general formula (XXXV).
  • Metal salts such as cobalt chloride, nickel chloride, and hydrates thereof may be used in an amount of 0.1 to 6 molar equivalents relative to the compound represented by the general formula (XXXV).
  • reaction temperature is 0 to 50 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XXXVI) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • a carboxylic acid represented by the general formula (XXXVII) can be synthesized by hydrolyzing the compound represented by the general formula (XXXVI).
  • Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (XXXVI).
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
  • reaction temperature examples include o ° c to the reflux temperature of the solvent.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XXXVII) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • the amide compound represented by the general formula (Ir) can be synthesized by condensing the carboxylic acid represented by the general formula (XXXVII) and the amine compound represented by the general formula (XX).
  • the compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXVII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and the compound can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXVII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination.
  • the base can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXVII).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I r) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • the compound represented by the general formula (II) can be reduced to synthesize the alcohol represented by the general formula (XXXVIII).
  • reaction solvent examples include jetyl ether, tetrahydrofuran, toluene, ethanol and the like. They can be used alone or in combination.
  • Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, and the like.
  • the compound represented by the general formula ( ⁇ ) 0.5 to 6 molar equivalents can be used.
  • reaction temperature examples include 0 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXXVIII) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • an alcohol represented by the general formula (XXXVIII) and phthalimide can be condensed to synthesize a compound represented by the general formula (XXIV).
  • Phthalimide can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (XXXVIII).
  • reaction solvent examples include tetrahydrofuran, jetyl ether, and acetonitrile.
  • azo compound examples include jetyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and can be used in an amount of ⁇ to 3 molar equivalents relative to the compound represented by the general formula (xxxvm).
  • trivalent phosphorus compound examples include triphenylphosphine, tributylphosphine and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (XXXVIII). c to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXXIX) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • an amine compound represented by the general formula (XXXX) can be synthesized.
  • Hydrazine hydrate can be used in an amount of 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XXXIX).
  • reaction solvent examples include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.
  • reaction temperature is 0 to 100 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XXXX) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • an amin compound represented by the general formula (I s) can be synthesized by condensing the amine compound represented by the general formula (XXXX) and the force rubonic acid represented by the general formula (X). it can.
  • the compound represented by the general formula (X) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXX).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like.
  • the base can be used at 0.5 to 2 mole equivalent based on the compound represented by the general formula (XXXX). 1-hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalent based on the compound represented by the general formula (XXXX).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (I s) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Method T Synthesis of (I t) from compound (XXXX)
  • the compound represented by the general formula (It) can be synthesized by reacting the amine represented by the general formula (XXXX) with the isocyanate represented by the general formula ( ⁇ ) or the carbamate represented by (XIV). .
  • the compound represented by the general formula (XIII) or (XIV) can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (XXXX).
  • reaction solvent examples include methylene chloride, 1,2-dichloroethane, toluene, acetonitrile, and tetrahydrofuran.
  • an amine such as triethylamine or diisopropylethylamine can be used in an amount of 0.05 to 2 mole equivalents relative to the compound represented by the general formula (XXXX).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (It) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • the compound represented by the general formula (XXXXI) can be synthesized by the method described in JP-A-62-258342 and a method analogous thereto.
  • the compound represented by the general formula (II) is condensed with the organic phosphorus compound represented by the general formula (XXXXI), and then treated with an acid to synthesize the compound represented by the general formula (XXXXII). Can do.
  • organic phosphorus compound represented by the general formula (XXXXI) can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by the general formula (II).
  • reaction solvent examples include tetrahydrofuran, jetyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium Examples include oxamethyl disilazide, potassium hexamethyl disilazide, sodium amide and the like.
  • the base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula ( ⁇ ).
  • reaction temperature 70 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • Examples of the acid used in the acid treatment include p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid, and sulfuric acid, and 0.1 to 10 molar equivalents can be used with respect to the compound represented by ( ⁇ ). wear.
  • reaction solvent examples include methanol, ethanol, toluene, water and the like, and these can be used alone or in combination.
  • reaction temperature 20 to 100 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula ( ⁇ ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • the carboxylic acid represented by the general formula ( ⁇ ) can be synthesized.
  • Lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used at 1.0 to 5 molar equivalents with respect to the compound represented by the general formula (xxxxn).
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, water and the like, and these can be used alone or in combination.
  • reaction temperature examples include o ° c to the reflux temperature of the solvent.
  • reaction time examples include 0.5 to 24 hours.
  • the obtained compound represented by the general formula ( ⁇ ) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • the carboxylic acid represented by the general formula (XXXXIII) and the amine compound represented by the general formula (XX) are condensed to synthesize the amide compound represented by the general formula (Iu). Is possible.
  • the compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXXIII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • Condensation agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, black carbonic acid Ethyl, isoptil carbonate, salt, salt, oxalyl, and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound represented by the general formula ( ⁇ ).
  • 1-Hydroxybenzotriazole or the like may be used in an amount of 0.5 to 2 molar equivalents as a condensation aid.
  • the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine, and the like. be able to. Each of them can be used at 0.05 to 2 mole equivalents relative to the compound represented by the general formula ( ⁇ ).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Iu) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • the compound represented by the general formula (XXXXIV) can be synthesized by the method described in Reference Example 4 described later and a method analogous thereto.
  • a compound represented by the general formula (XXXXIV) is represented by the general formula (XVI) or (XVII). 1 to 5 molar equivalents of the organic phosphorus compound can be used.
  • reaction solvent examples include tetrahydrofuran, jetyl ether, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium Examples include oxamethyl disilazide, potassium hexamethyl disilazide, sodium amide and the like.
  • the base can be used at 1.0 to 5 molar equivalents relative to the compound represented by the general formula (XXXXIV).
  • reaction temperature 70 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXXXV) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (XXXXVI) can be synthesized.
  • reaction solvent examples include methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
  • metal catalyst examples include 5% palladium-carbon, 10% palladium-carbon, platinum oxide, chlorotris (trifluorophosphine) rhodium (I), etc., and 0% of the compound represented by the general formula (XXXXVI) 01 to 0.5 weight percent can be used.
  • the hydrogen pressure is 1 to 50 atm.
  • reaction temperature examples include 20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXXXVI) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a carboxylic acid represented by the general formula ( ⁇ ) can be synthesized by treating the compound represented by the general formula (XXXXVI) with thionyl chloride and then reacting with a base.
  • the compound represented by the general formula (XXXXVI) can be used in an amount of 1 to 30 molar equivalents of thiol chloride.
  • reaction solvent examples include tetrahydrofuran, jetyl ether, toluene and the like.
  • reaction temperature examples include o ° c to the reflux temperature of the solvent.
  • reaction time examples include 0.5 to 24 hours.
  • Examples of the base used in the base treatment include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and they can be used at 0.1 to 10 molar equivalents relative to the compound represented by (XXXXVI).
  • reaction solvent examples include methanol, ethanol, toluene, water and the like, and these can be used alone or in combination.
  • reaction temperature 20 to 100 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (XXXXVII) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • the carboxylic acid represented by the general formula (XXXXVII) and the amine compound represented by the general formula (XX) are condensed to synthesize the amido compound represented by the general formula (Iv). can do.
  • the compound represented by the general formula (XX) can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXXVII).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • condensing agents include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, N, N, monocarbodiimidazole, chloroethyl carbonate, isoptil carbonate, Examples include thiol and salt oxalyl, and the compound can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (XXXXVII). 1-Hydroxybenzotriazole or the like may be used as a condensation aid in an amount of 0.5 to 2 molar equivalents.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination.
  • 0.052 molar equivalents can be used for each of the compounds represented by the general formula (XXXXVII).
  • reaction temperature is 0 100 ° C.
  • the reaction time is 0.5 72 hours.
  • the resulting compound represented by the general formula (IV) can be isolated and purified by known means (for example, chromatography recrystallization and the like).
  • reaction solvent examples include jetyl ether, tetrahydrofuran, toluene, ethanol and the like, and these can be used alone or in combination.
  • Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, etc., and 0.5 6 for the compound represented by the general formula (XXXXVII-a) A molar equivalent can be used.
  • reaction temperature examples include 0 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (xxxxvm) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • an alcohol represented by the general formula (XXXXVIII) and phthalimide can be condensed to synthesize a compound represented by the general formula (XXXXIX).
  • reaction solvent examples include tetrahydrofuran, jetyl ether, and acetonitrile.
  • azo compounds include jetyl azodicarboxylate, diisopropyl azodicarboxylate, and the like, and 1 to 3 molar equivalents can be used with respect to the compound represented by the general formula (xxxxvm).
  • trivalent phosphorus compound examples include triphenylphosphine and tributylphosphine, and can be used at 1 to 3 molar equivalents relative to the compound represented by the general formula (XXXXVIII).
  • reaction temperature examples include o ° c to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (XXXXIX) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • an amine compound represented by the general formula (L) can be synthesized.
  • Hydrazine hydrate can be used in an amount of 1.0 to 5 mole equivalent to the compound represented by the general formula (XXXXIX).
  • reaction solvent examples include methanol, ethanol, dichloromethane, N, N-dimethylformamide and the like.
  • reaction temperature is 0 to 100 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the resulting compound represented by the general formula (L) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • An amide compound represented by the general formula (Iw) can be synthesized by condensing the amine compound represented by the general formula (L) and the carboxylic acid represented by the general formula (X) in the presence of a condensing agent. .
  • the compound represented by the general formula (X) can be used at 0.5 to 2 mole equivalents relative to the compound represented by the general formula (L).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N dimethylformamide and the like.
  • Examples of the condensing agent include dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride, chloroethyl carbonate, isobutyl carbonate, thionyl chloride, chlorooxalyl, and the like.
  • the base can be used at 0.5 to 2 molar equivalents relative to the compound represented by the general formula (L). 0.5 to 2 molar equivalents of 1-hydroxybenzotriazole or the like as a condensation aid may be used.
  • Examples of the base include triethylamine, N-methylmorpholine, 4-dimethylaminopyridine and the like, and these can be used alone or in combination. Each of them can be used at 0.05 to 2 mole equivalents relative to the compound represented by the general formula (L).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Iw) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (IX) can be synthesized by reacting an amine represented by the general formula (L) with an isocyanate represented by the general formula ( ⁇ ) or a carbamate represented by (XIV).
  • the compound represented by the general formula (XIII) or (XIV) can be used at 0.5 to 3 molar equivalents relative to the compound represented by the general formula (L).
  • reaction solvent examples include methylene chloride, 1,2-dichloroethane, toluene, acetonitrile, and tetrahydrofuran.
  • an amine such as triethylamine or diisopropylethylamine can be used in an amount of 0.05 to 2 molar equivalents relative to the compound represented by the general formula (L).
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (IX) can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (I z) can be synthesized by reacting a compound represented by the general formula (I y) with a base.
  • the compound represented by the general formula (I y) can be synthesized by the methods shown in Method A, Method I, Method K, Method L, Method M, Method N, and Method O.
  • a base such as N can be used at 0.1 to 10 molar equivalents.
  • reaction solvent examples include tetrahydrofuran, jetyl ether, toluene and the like.
  • Reaction temperature includes ⁇ 70 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (Iz) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • R 2a and R 2b are combined to form one O or one OCH—.
  • the product can be synthesized by subjecting it to the following crosslinking reaction at an appropriate stage.
  • a compound represented by the general formula (LIII) can be synthesized by condensing a ketone represented by the general formula (LI) and an organic phosphorus compound represented by the general formula (LII) in the presence of a base.
  • An organophosphorus compound represented by the general formula (LII) is added to the compound represented by the general formula (LI).
  • the reaction solvent include tetrahydrofuran, jetyl ether, acetonitrile, N, N dimethylformamide, dimethyl sulfoxide, liquid ammonia and the like.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium Examples include oxamethyl disilazide, potassium hexamethyl disilazide, sodium amide and the like.
  • the compound represented by the general formula (LI) can be used at 2.0 to 20 molar equivalents.
  • reaction temperature 70 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound represented by the general formula (LIII) can be isolated and purified by the known means (eg, chromatography, recrystallization, etc.).
  • a 1 may have a substituent, or may have a nitrogen-containing aromatic monocyclic group or a substituent! / A nitrogen-containing aromatic condensed cyclic group
  • the nitrogen-containing aromatic monocyclic group or the nitrogen-containing aromatic condensed cyclic group has the following conditions:
  • the compound of the present invention contains an optical isomer, a stereoisomer, a positional isomer, or a rotational isomer, these are also included as the compound of the present invention, and are synthesized by a known synthesis method or separation method. Each can be obtained as a single item.
  • an optical isomer exists in the compound of the present invention
  • an optical isomer resolved from the compound is also included in the compound of the present invention.
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving a final racemic mixture according to a conventional method.
  • As the optical resolution method a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method and the like described in detail below are used.
  • Racemates and optically active compounds for example, (+) mandelic acid, (1) mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-1-phenethylamine, (-)-1-phenethylamine, Cinchonine, (1) -cinco-zine, brucine, etc.
  • optically active compounds for example, (+) mandelic acid, (1) mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-1-phenethylamine, (-)-1-phenethylamine, Cinchonine, (1) -cinco-zine, brucine, etc.
  • a method in which a racemate or a salt thereof is separated on a column for chiral separation (chiral column).
  • a mixture of optical isomers is added to a chiral column such as ENANTIO- OVM (manufactured by Toso Co., Ltd.) or CHIRAL series manufactured by Daicel, and water, various buffers (for example, phosphate buffer),
  • Optical isomers are separated by developing an organic solvent (for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, jetylamine, etc.) as a single solution or a mixed solution.
  • separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • the racemic mixture is converted into a diastereomer mixture by chemical reaction with an optically active reagent, and this is converted into a single substance through normal separation means (for example, fractional recrystallization, chromatography, etc.), followed by a hydrolysis reaction.
  • normal separation means for example, fractional recrystallization, chromatography, etc.
  • a method of obtaining optical isomers by separating optically active reagent sites by chemical treatment such as
  • the compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecule
  • the compound and an optically active organic acid for example, MTP ⁇ [ ⁇ -methoxy-ex (trifluoromethyl) furacetic acid], (1) -menthoxyacetic acid etc.
  • MTP ⁇ [ ⁇ -methoxy-ex (trifluoromethyl) furacetic acid], (1) -menthoxyacetic acid etc.
  • a condensation reaction to obtain diastereomers of ester or amide, respectively.
  • an amide diester or an ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction.
  • the separated diastereomer is subjected to an acid hydrolysis or basic hydrolysis reaction to produce a photocatalyst of the original compound. Converted to an academic isomer.
  • a pharmaceutically acceptable salt can be used.
  • basic carbonates include alkali metal salts such as sodium salt and potassium salt; for example calcium salt and magnesium salt.
  • Alkaline earth metal salts such as ammonium salts; trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine, ethanolamine salts, ethanolamine salts, triethanolamine salts, brocaine salts; N, N —Aralkylamine salts such as dibenzylethylenediamine; heterocyclic aromatic amines such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt, etc .; eg tetramethyl ammonium salt, tetraethyl ammonium salt Salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzil Examples include quaternary ammonium salts such as tribut
  • acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, oxalate, acetate, propionate, and lactate. , Maleate, fumarate, tartrate, malate, citrate, ascorbate, etc .; for example, methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, etc. Examples thereof include acidic amino acids such as aspartate and dartamate.
  • Compound (I) may be a solvate such as water, acetonitrile, ethyl acetate, methanol or ethanol.
  • the solvation number of the solvate of the compound of the present invention can usually vary depending on the synthesis method, purification method, crystallization conditions, etc., but is, for example, in the range of 1 to 5 molecules per molecule.
  • a 1 is substituted with at least hydroxy, at least hydroxy substituted benz O hexa benzisoxazolyl, downy substituted with at least hydroxy Nzuimidazoriru, pyridyl substituted with Amino which may be at least protected, -NH Other ring member atoms may be substituted, or ring member atoms other than imidazolyl and NH may be substituted.
  • a 1 is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, aminobilidyl, lower alkylsulfo-laminopyridyl, unsubstituted ⁇ midazolyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl or unsubstituted benzimidazolyl.
  • a 1 is hydroxypyridyl, hydroxybenzoxazolyl, hydroxybenzimidazolyl, unsubstituted midazolyl unsubstituted pyrazolyl or unsubstituted pyrrolyl (hereinafter A 1 is a3),
  • a compound wherein A 1 is hydroxypyridyl, hydroxybenzoxazolyl, unsubstituted imidazolyl or unsubstituted pyrrolyl (hereinafter, A1 is a4),
  • X is lower alkylene, CO (CHR 3 ) n- CONH (CHR 3 ) n- NHCO (CHR 3 ) n 0 (CHR 3 ) n S (CHR 3 ) n SO (CHR 3 ) n SO (CH
  • X is one CO (CHR 3 ) CONH (CHR 3 ) NHCO (CHR 3 ) A 3 —
  • R 3 is hydrogen or methyl
  • a 3 is phenylene or a 56-membered aromatic monocyclic group (Each R 3 is different!)
  • a compound (hereinafter, X is assumed to be x4)
  • R 1 is hydrogen
  • R 2a is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2 a may be combined to form a single bond (hereinafter referred to as RR) 2a and R 2b are rl)
  • RR 2a and R 2b are assumed to be r3
  • m is 0 and Y is a single bond, CH—, 1O, 1S— or NH, or R
  • a compound that forms CH with 2a (hereinafter, m and Y are yl),
  • Y is assumed to be y3)
  • m is 1, Y is a single bond, CH —, — O—, —S or — NH or R
  • a 2 is phenyl optionally substituted with one or more groups selected from halogen, halogenated halogeno lower alkyl, and halogeno lower alkoxy (hereinafter A 2 is a 5 And)
  • a 2 is halogen, triflate Ruo Russia methyl and triflusulfuron Ruo b methoxy mosquitoes be substituted with one or more groups selected, even I, Hue - Le, compound (hereinafter, the A 2 is a a6 )
  • a 2 is para halogen, triflate Ruo Russia methyl and triflusulfuron Ruo b methoxy mosquitoes also full alkenyl substituted with one or more groups selected compounds (hereinafter, A 2 is assumed to be a7) ,
  • a 1 may have a substituent, or may be a nitrogen-containing aromatic monocyclic group, which is protected! /, Hydroxy or protected! Hey! /, With at least one amino, X— ⁇ ()) 3 ⁇ 4 / $ ⁇ ⁇ ⁇ 3 ⁇ 3003 3 ⁇ 3 ⁇ . ' ⁇ ⁇ , ,,
  • yyyyyyy ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, a7a4x3r35a5a4x3r35a6a4x3r35a7a4x4rlla5a4x4rll yyyyy ,,,,,,,,,,,,, 3a5a4x4x3r3a3r4 A 3 may have a substituent, may be a phenol or a substituent, and may be a 5- to 6-membered aromatic monocyclic group,
  • R is a substituent of “aromatic hydrocarbon cyclic group having a substituent,”
  • R ⁇ R 2a , R 2b , R 2c , R 3 , R 4 , R 12 , R 13 and R 14 are compounds as defined above (1), and [0060] R A is hydroxy, ami-substituted lower alkylamino or Is an asilamino,
  • Lower alkylene which X may have a substituent, CO (CR 3 R 4 ) n—, — CONR 5 (CR 3 R 4 ) n—, — NR 5 CO (CR 3 R 4 ) n— , — 0 (CR 3 R 4 ) n—, — S (CR 3 R 4 ) n—, —SO (CR 3 R 4 ) n—, 1 SO (CR 3 R 4 ) n—, 1 A 3 — CHR 3- , 1 A 3 -CHR 3 NR 6 or
  • n is an integer from 0 to 4,
  • R 1 is hydrogen
  • R 2a is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b and R 2e may both be hydrogen and may be joined together to form a single bond.
  • R 3 , R 4 and R 6 are each independently hydrogen or lower alkyl
  • R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl, halogeno lower alkoxy or cyan;
  • R A is hydroxy
  • X is — CONR 5 (CR 3 R 4 ) n—, — NR 5 CO (CR 3 R 4 ) n—, — A 3 — CR 3 R 4 —, — A 3 — C HR 3 NR 6 , 1 A 3 — NR 6 or NR 5 CONR 6 ,
  • n is an integer from 0 to 4,
  • R 1 and R 2a may be hydrogen together, and they may be joined together to form a single bond
  • R 2b and R 2e are both hydrogen together, and they are joined together to form a single bond
  • R 4 and R 6 are each independently hydrogen or lower alkyl
  • Y is a single bond or CH—
  • R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl, halogeno lower alkoxy or cyan;
  • R A is hydroxy or amino
  • X is lower alkylene, CO (CHR 3 ) n ⁇ CONR 5 (CHR 3 ) n ⁇ NR 5 CO (C HR 3 ) n A 3 — CHR 3 or NR ONR 6
  • n is an integer of 1 3
  • R 1 is hydrogen
  • R 2 is hydrogen, hydroxy or methyl
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b is hydrogen or hydroxy
  • R 2e is hydrogen or joined together to form a single bond.
  • R 3 is hydrogen or lower alkyl (each R 3 is different! /, May! /),
  • R 5 is hydrogen or lower alkyl
  • R is hydrogen, halogen, halogeno lower alkyl or halogeno lower alkoxy object
  • R A is hydroxy or amino
  • Q 1 is O or NH
  • X is one NR 5 CO (CHR 3 ) A 3 — CHR 3 or one NR 5 CONR 6 ;
  • n 2 or 3
  • R 1 is hydrogen
  • R 2 is hydrogen or hydroxy
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b is hydrogen or hydroxy
  • R 2e is hydrogen or joined together to form a single bond.
  • R 3 is hydrogen or lower alkyl (each R 3 may be different), R 5 is hydrogen or lower alkyl,
  • Y is a single bond or CH—
  • R is hydrogen, halogen, lower alkoxy, halogeno lower alkyl or halogeno lower alkoxy
  • Q 2 is N or CH
  • X is — CO (CHR 3 ) —, — CONR 5 (CHR 3 ) —, — NR 5 CO (CH) —, — A 3 — CH
  • R 1 is hydrogen
  • R 2a is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b is hydrogen or hydroxy
  • R 2e is hydrogen or joined together to form a single bond.
  • R 3 is hydrogen or lower alkyl (each R 3 may be different), R 5 is hydrogen or lower alkyl,
  • Y is a single bond or CH—
  • R is hydrogen, halogen, halogeno lower alkyl or halogeno lower alkoxy
  • Q 3 is N or CH
  • X is one CONR 5 (CHR 3 ) NR 5 CO (CHR 3 ) A 3 — CHR 3 or one NR 5
  • R 1 is hydrogen
  • R 2a is hydrogen or hydroxy
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b is hydrogen or hydroxy
  • R 2e is hydrogen or may be joined together to form a single bond
  • R 3 is hydrogen or lower alkyl (each R 3 may be different), R 5 is hydrogen or lower alkyl,
  • Y is a single bond or CR 12 R 13
  • R is hydrogen, halogen, halogeno lower alkyl, lower alkoxy or halogeno lower alkoxy
  • Q 2 is N or CH
  • X is — CO (CHR 3 ) —, — CONR 5 (CHR 3 ) —, — NR 5 CO (CH) —, — A 3 — CH
  • R 1 is hydrogen
  • R 2a is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b is hydrogen or hydroxy
  • R 2e is hydrogen or may be joined together to form a single bond
  • R 3 is hydrogen or lower alkyl (each R 3 may be different), R 5 is hydrogen or lower alkyl,
  • Y is a single bond or CH—
  • R is hydrogen, halogen, halogeno lower alkyl or halogeno lower alkoxy
  • R A is hydroxy or amino
  • n 0 3
  • a 3 is phenylene
  • R 1 is hydrogen
  • R 2a is hydrogen or hydroxy
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b and R 2e may both be hydrogen and may be joined together to form a single bond.
  • R 3 is hydrogen or lower alkyl (each R 3 is different! /, May! /),
  • R 5 is hydrogen or lower alkyl
  • R is hydrogen, halogen, halogeno lower alkyl or cyan
  • R A is hydroxy or amino
  • Q 1 is 0 NH or CH
  • X is one CO (CHR 3 ) n CONR 5 (CHR 3 ) n NR 5 CO (CHR 3 ) n— or one A 3 —CHR 3 —;
  • n 1 or 2
  • R 1 is hydrogen
  • R 2a is hydrogen or hydroxy
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b and R 2e are both hydrogen and may be combined to form a single bond! / R 3 may be hydrogen or lower alkyl (each R 3 may be different! /, Moyo! /)),
  • R 5 is hydrogen or lower alkyl
  • Y is a single bond or lower alkylene
  • R is hydrogen, halogen or halogeno lower alkyl
  • Q 2 is N or CH
  • X is one CO (CHR 3 ) n CONR 5 (CHR 3 ) n NR 5 CO (CHR 3 ) n— or one A 3 —CHR 3 —;
  • n 0 2
  • R 1 is hydrogen
  • R 2a is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2a may be joined together to form a single bond
  • R 2b and R 2e may be both hydrogen and may be joined together to form a single bond
  • R 3 is hydrogen or lower alkyl (each R 3 may be different! /) ! /))
  • R 5 is hydrogen or lower alkyl
  • Y is a single bond or lower alkylene
  • R is hydrogen, halogen or halogeno lower alkyl
  • Q 3 is N or CH
  • X is one CO (CHR 3 ) n- CONR 5 (CHR 3 ) n- NR 5 CO (CHR 3 ) n, one or one A 3 — CHR 3 —
  • n 1 or 2
  • R 1 is hydrogen
  • R 2a is hydrogen or hydroxy; R 1 and R 2a may be joined together to form a single bond
  • R 2b and R 2e are both hydrogen, and together they can form a single bond!
  • R 3 is hydrogen or lower alkyl (each R 3 is different! /, May! /),
  • R 5 is hydrogen or lower alkyl
  • Y is a single bond or lower alkylene
  • R is hydrogen, halogen, halogeno lower alkyl or lower alkoxy, or a pharmaceutically acceptable salt thereof or a solvate thereof.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

L’invention concerne un dérivé de cyclohexane représenté par la formule (I), capable de se lier spécifiquement à un récepteur NR1/NR2B et pouvant ainsi être utilisé en tant qu’analgésique (agent thérapeutique contre la douleur) : (I) dans laquelle A1 représente un groupement cyclique aromatique (substitué) comportant -NH- dans le cycle ou analogue ; A2 représente un phényle (substitué) ou analogue ; R1, R2a, R2b et R2c représentent indépendamment un hydrogène, un hydroxy ou analogue ; m représente 0 ou 1 ; X représente -CONH(CR3R4)n-, -NHCO(CR3R4)n-, -A3-(CR3R4)n- ou analogue ; R3 et R4 représentent indépendamment un hydrogène ou un alkyle inférieur (substitué) ; n représente un entier compris entre 0 et 4 ; A3 représente un phénylène ou analogue ; et Y représente une liaison simple, un alkylène inférieur ou analogue.
PCT/JP2006/323693 2005-11-30 2006-11-28 Derives de cyclohexane Ceased WO2007063839A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
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US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson
EP2345328A4 (fr) * 2008-09-19 2014-06-25 Sumitomo Chemical Co Composition utilisée en milieu agricole
EP3215141A4 (fr) * 2014-11-05 2018-06-06 Flexus Biosciences, Inc. Agents immunorégulateurs
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
WO2019196780A1 (fr) * 2018-04-09 2019-10-17 信达生物制药(苏州)有限公司 Nouvel inhibiteur de l'indoléamine 2,3-dioxygénase, son procédé de préparation et son utilisation
AU2019202773B2 (en) * 2015-01-20 2020-07-02 Boehringer Ingelheim Animal Health USA Inc. Anthelmintic Compounds, Compositions And Method Of Using Thereof

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WO1998004534A1 (fr) * 1996-07-31 1998-02-05 Nikken Chemicals Co., Ltd. Derives de 6-phenyltetrahydro-1,3-oxazine-2-one et compositions medicinales a base de ces composes
JP2003513080A (ja) * 1999-10-29 2003-04-08 メルク エンド カムパニー インコーポレーテッド ２−シクロヘキシルベンズイミダゾールｎｍｄａｎｒ２ｂアンタゴニスト
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US8614213B2 (en) 2008-08-07 2013-12-24 Novartis Ag Cyclohexyl amide derivatives and their use as CRF-1 receptor antagonists
EP2345328A4 (fr) * 2008-09-19 2014-06-25 Sumitomo Chemical Co Composition utilisée en milieu agricole
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson
EP3215141A4 (fr) * 2014-11-05 2018-06-06 Flexus Biosciences, Inc. Agents immunorégulateurs
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
US10533014B2 (en) 2014-11-05 2020-01-14 Flexus Biosciences, Inc. Immunoregulatory agents
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US11932601B2 (en) 2014-11-05 2024-03-19 Flexus Biosciences, Inc. Immunoregulatory agents
AU2019202773B2 (en) * 2015-01-20 2020-07-02 Boehringer Ingelheim Animal Health USA Inc. Anthelmintic Compounds, Compositions And Method Of Using Thereof
WO2019196780A1 (fr) * 2018-04-09 2019-10-17 信达生物制药(苏州)有限公司 Nouvel inhibiteur de l'indoléamine 2,3-dioxygénase, son procédé de préparation et son utilisation
CN112004790A (zh) * 2018-04-09 2020-11-27 信达生物制药(苏州)有限公司 一种新型吲哚胺2,3-双加氧酶抑制剂及其制备方法和用途

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