WO2007116901A1 - Nouveau derive d'arylamide - Google Patents

Nouveau derive d'arylamide Download PDF

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Publication number
WO2007116901A1
WO2007116901A1 PCT/JP2007/057537 JP2007057537W WO2007116901A1 WO 2007116901 A1 WO2007116901 A1 WO 2007116901A1 JP 2007057537 W JP2007057537 W JP 2007057537W WO 2007116901 A1 WO2007116901 A1 WO 2007116901A1
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group
methyl
thiazole
amino
tert
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PCT/JP2007/057537
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English (en)
Japanese (ja)
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Wataru Itoh
Atsushi Satoh
Yukari Hirata
Akio Ohno
Hiroshi Kawamoto
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Banyu Pharmaceutical Co., Ltd.
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Publication of WO2007116901A1 publication Critical patent/WO2007116901A1/fr

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    • C07—ORGANIC CHEMISTRY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to arylamide derivatives useful in the field of medicine.
  • This compound acts as an inhibitor of metabotropic glutamate receptor 1 and is used for cerebral disorders such as convulsions, acute pain, inflammatory pain, chronic pain, cerebral infarction or transient ischemic attack, schizophrenia, etc. It is useful as a therapeutic agent for diseases such as mental dysfunction, anxiety and drug dependence, and as a Z or preventive agent.
  • Glutamate is a neurotransmitter that mediates excitatory transmission in the central nervous system. Glutamate, in addition to various neurotransmitter effects, has many important brain functions such as neuronal survival and death, differentiation and proliferation, nerve and glial development, maturation or plastic changes in neurotransmission efficiency of the developing brain. (See, for example, Annual Review of Biophysics and Biomoiecular Structure, 23: 319 (199 4)).
  • mammalian central nervous system glutamate receptors are classified into two types: ion channel glutamate receptors and metabotropic glutamate receptors (hereinafter referred to as “mGluR”!). Being!
  • the ion channel glutamate receptor is an ion channel that is also opened and closed by the binding of a ligand, which also has a complex power of different subunit proteins.
  • mGluR is coupled to GTP-binding protein and acts by regulating intracellular second messenger production or ion channel activity via GTP-binding protein (for example, Brain Research Reviews, 26 ⁇ ). 230 (1998)).
  • mGluR exists as eight different subtypes of mGluRl-8. These fall into three subgroups based on amino acid sequence homology, signal transduction, and pharmacological properties.
  • Group I mGluRl and 5
  • Group II mGluR2 and 3
  • Group III mGluR4, 6, 7, and 8
  • cAMP phosphate
  • Group IV is selectively activated by LY354740 described in the literature (for example, Journal of Medicinal Chemistry, 42ry, page 1027 (1999)), and group IV is L— It is selectively activated by AP4, and various receptors are expressed in a wide range of cranial nervous system, except for mGluR6, which exists specifically in the retina. Each receptor is thought to play a different physiological role (for example, two chemistry internationale (Neurochemistry International), 24 ⁇ , 439 (1994)) and the BIO Journal of Pharmacology ( European Journal of Pharmacology), 375, 277 (1999)).
  • DH PG 5-dihydroxyphenyglycine
  • LY456236 Another selective antagonist, LY456236, has been reported to reduce spasm duration and extent in kindled rat amygdala, known as a model of human convulsions (eg, neurofa -Macophology (Neurophar macology), 43 ⁇ , 308 (2002)). The above suggests the anticonvulsant action of mGluRl antagonists!
  • the pain threshold increases when AIDA is administered into the brain (for example, The Journal of Pharmacology & Experiment al. Therapeutics), 281 ⁇ , 721 (1997), etc.), spinal cord injury hyperalgesia model (eg, Journal of Neurotrauma, 19 ⁇ , 23) Page (2002), etc.) and arthritis models (eg The Journal oi Pharmacology & Experimental Therapeutics, 300 ⁇ , 149 (2002) ), Etc.) are reported to show analgesic activity in models of persistent pain, such as mGluRl antagonists against such Razz inflammatory pain and chronic pain, suggesting the possibility of having an analgesic effect.
  • mGluRl or mGluR5 activates the subthalamic nucleus. It is well known that subthalamic nucleus excitement is characteristic of Parkinson's disease. Therefore, mGluRl selective antagonists may be useful as therapeutic agents for Parkinson's disease.
  • Reflux esophagitis is the most common upper gastrointestinal disorder.
  • Current drug therapies aim to suppress gastric acid secretion or neutralize gastric acid in the esophagus.
  • the main mechanism involved in reflux has been thought to be due to chronic tension decline in the lower esophageal sphincter.
  • TLESRs temporary relaxation of the lower esophageal sphincter muscles
  • TLESRs temporary relaxation of the lower esophageal sphincter muscles
  • TLESRs temporary relaxation of the lower esophageal sphincter muscles
  • relaxations other than swallowing eg, Gastroenterol Tali-Carl North America ( Gastroenterol C1 in. North Am.
  • Gastroenterol C1 in. North Am. 19 ⁇ , pages 517-535 (1990)
  • normal gastric acid secretion in GERD patients has been found to be normal.
  • the lower esophageal sphincter tends to relax intermittently. As a result, the mechanical barrier is temporarily lost when the sphincter is relaxed, and this phenomenon is defined as “reflux” in which gastric fluid can flow into the esophagus.
  • TLESR which indicates the temporary relaxation of the lower esophageal sphincter, is defined according to Gastroenterology, 109 ⁇ (2), p. 601, p. 610 (1995).
  • reflux esophagitis is defined as gastric juice in which gastric forces can also flow into the esophagus. Because in this state, the mechanical barrier is temporarily lost.
  • GERD for reflux esophagitis is defined according to Bailliere's Clinical Gastroenterology, 14ology, 759, 774 (2000).
  • mGluRl antagonists are considered useful for the prevention or treatment of gastrointestinal disorders.
  • Examples of compounds structurally related to the compound according to the present invention include the following compounds described in W096Z36619
  • An object of the present invention is to provide a novel arylamide derivative having an mGluRl inhibitory action.
  • the present inventors have intensively studied to develop a compound having an mGluRl inhibitory action, and found that the compound according to the present invention is effective as a compound having an mGluRl inhibitory action. Based on this, the present invention has been completed.
  • E is a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a cyan group, wherein the lower alkyl group or lower alkoxy group may be the same or different.
  • the 5- or 6-membered aromatic ring represented by (a) above and a heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom may have 1 to 4 in the ring A bicyclic group fused with a 5- or 6-membered aromatic ring, and
  • G1 and G2 are each independently a linear or branched lower alkyl group (the lower alkyl group is substituted by the same or different halogen atom or lower alkoxy group 1 to 3). Or a 4- to 7-membered ring formed together with Gl, G2 and the nitrogen atom or carbon atom to which they are bonded to each other (the 4- to 7-membered ring is the same or different halogen atom) , Substituted with a lower alkyl group, may be
  • ( ⁇ ) has at least one nitrogen atom and may have 1 to 2 heteroatoms in the ring selected from the group consisting of nitrogen, sulfur and oxygen atoms, 5 or 6
  • a heteroaryl group (the heteroaryl group is the same or different with a halogen atom, a lower alkyl group, or a lower alkoxy group, and the lower alkyl group and the lower alkoxy group which may be substituted by 1 to 3 are 1 to 3 substituents may be substituted with the same or different halogen atoms), ( ⁇ 8) formula ( ⁇ )
  • R 1 is a lower alkyl group, a 3- to 7-membered cycloalkyl group (the lower alkyl group and the cycloalkyl group may be substituted with the same or different 1 to 3 halogen atoms)
  • R 2 is a hydrogen atom, a lower alkyl group, a 3- to 7-membered cycloalkyl group (the lower alkyl group and the cycloalkyl group are the same or different) Which may be substituted with 1 to 3 halogen atoms)
  • R 11 is a hydrogen atom, a lower alkyl group, 3 to 7 cycloalkyl groups (the lower alkyl group and the cycloalkyl group are substituted with the same or different 1 to 3 halogen atoms) indicates also be
  • R 21 is a hydrogen atom, or a methyl group or Echiru group, or an aliphatic 3-7 membered ring connexion formed such together with the nitrogen atom to which R 1 1 and R 21 are adjacent to each other
  • the aliphatic 3- to 7-membered ring is substituted with a lower alkyl group (the lower alkyl group may be substituted with the same or different 1 to 3 halogen atoms !, or may be! /), Or a halogen atom!
  • one of the carbon atoms constituting the aliphatic 3- to 7-membered ring is replaced by an oxygen atom! /, Or a group represented by
  • R 3 represents a lower alkyl group or a cycloalkyl group having 3 to 7 carbon atoms (the lower alkyl group or cycloalkyl group having 3 to 7 carbon atoms may be the same or different 1 to 3 halogen atoms).
  • R4 is a group represented by a lower alkoxy group (which may be substituted with the same or different 1 to 3 halogen atoms),
  • Y represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group] or a pharmaceutically acceptable salt thereof
  • Equation (I) becomes Equation (I 1) [0026] [Chemical 11]
  • E is a group selected from the group consisting of (a) and (b) force
  • W is a group of formula (III-1)
  • E is a group selected from the group consisting of (a) and (c) force
  • W is a group selected from the group consisting of ( ⁇ ) and ()
  • X is ( ⁇ ) and ( ⁇ Or a pharmaceutically acceptable salt thereof, which is a group selected from the group consisting of:
  • ⁇ is a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a cyan group, wherein the lower alkyl group or lower alkoxy group is the same or different from 1 to 3 halogen atoms
  • the compound according to the above (3) which is substituted with 1 to 3 with!, May! /, A phenyl group, a pyridyl group, a birazinyl group or a pyrimidinyl group. Or a pharmaceutically acceptable salt thereof,
  • (9) ⁇ is a phenyl group, a 4-fluorophenol group, a 3-fluorophenyl group, a 2-fluorophenol group, a 4-cyanophenol group, a 3-cyanophenol group, a 2-cyanophenol group, a 4-methoxyphenol group Group, 3-methoxyphenyl group, 2-methoxyphenyl group, 4 trifluoromethylphenol group, 3 trifluoromethylphenyl group, 2 trifluoromethylphenyl group, 4-difluoromethyl group Methoxyphenyl group, 3 Difluoromethoxyphenyl group, 2 Difluoromethoxyphenyl group, 4 Pyridyl group, 3 Pyridyl group, 2 Pyridyl group, 6 Fluoro group Rho
  • G represents a hydrogen atom or a lower alkyl group
  • a pharmaceutical composition comprising the compound according to any one of (1) to (13) above and a pharmaceutically acceptable carrier,
  • an mGluRl inhibitor comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof as an active ingredient
  • the present invention relates to a treatment for cerebral disorder such as transient cerebral ischemic attack, mental dysfunction such as schizophrenia, anxiety, drug dependence and Z or Parkinson's disease and Z or preventive agent.
  • cerebral disorder such as transient cerebral ischemic attack, mental dysfunction such as schizophrenia, anxiety, drug dependence and Z or Parkinson's disease and Z or preventive agent.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec butyl group, tert butyl group, pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1 methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2 dimethylbutyl group, 2,2 dimethylbutyl group, 1,3 dimethylbutyl group, 2,3 dimethyl Examples include a rubutyl group, a 3,3 di
  • the “lower alkoxy group” means a group in which a hydrogen atom of a hydroxy group is substituted with the lower alkyl group, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec butoxy group, tert Butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, isohexyloxy group and the like.
  • Cycloalkyl group means a cycloalkyl group having 3 to 7 carbon atoms. Specifically, examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Can be mentioned.
  • E is a group selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a cyan group (the lower alkyl group or lower alkoxy group is substituted with the same or different halogen atoms by 1 to 3 substituents). Or a group selected from the group consisting of (a), (b) and (c), which may be substituted by 1 to 3;
  • a 5- or 6-membered aromatic ring optionally having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom Specifically, for example, a phenyl group, a pyridyl group, a birazinyl group, or a pyrimidyl group, and the like are selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and a cyan group (this group The lower alkyl group or the lower alkoxy group may be substituted by 1 to 3 by the same or different halogen atom), and (a) specifically includes, for example, Phenolic group, 4 Fluorophenol group, 3 Fluorophenol group, 2 —Fluorophenol group, 4 Sianophenol group, 3 Sianophenol group, 2 Sianophenol Group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group
  • (b) indicates, “(5 or 6-membered aromatic ring represented by (N), selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atomic force, and having 1 to 4 heteroatoms in the ring.
  • Examples of the “bicyclic group condensed with a 5- or 6-membered aromatic ring” include a quinolinyl group.
  • W represents a group selected from the group consisting of the above ( ⁇ ), () and ( ⁇ ).
  • W represents (a) having at least one nitrogen atom, and 1 to 2 heteroatoms in the ring selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen nuclear atom.
  • a 5- or 6-membered heteroaryl group (the heteroaryl group is a halogen atom, a lower alkyl group, The lower alkyl group and the lower alkoxy group which may be the same or different in the lower alkoxy group and may be substituted by 1 to 3 may be substituted by the same or different halogen atoms.
  • N in the pyridine ring may be N-oxide.
  • W represents the formula () (111-1)
  • X represents a group selected from the group consisting of the above (A), (B), (C) and (D).
  • the "lower alkyl group" represented by R 1 means the same group as the lower alkyl group defined above. Specific examples include a methyl group, an ethyl group, an isopropyl group, an n-propyl group, a tert-butyl group, and a 2,2-dimethylpropyl group. Of these, the lower alkyl group is preferably an isopropyl group or a tert-butyl group.
  • Examples of the “3- to 7-membered cycloalkyl group” represented by R 1 include the same groups as the cycloalkyl groups defined above.
  • R 1 is a lower alkyl group or a 3- to 7-membered cycloalkyl group, these groups may be substituted with the same or different 1 to 3 halogen atoms.
  • halogen atom examples include the same groups as the “halogen atom” defined above.
  • lower alkyl group substituted with a halogen atom or a 3- to 7-membered cycloalkyl group include, for example, a trifluoromethyl group, a difluoromethyl group, a 2, 2, 2-trifluoroethyl group, and a 4-trifluoro group. Examples thereof include an chloromethylcyclohexyl group.
  • the “lower alkoxy group” represented by R 1 means the same group as the lower alkoxy group defined above, and specifically includes, for example, methoxy group, ethoxy group, isopropyloxy and the like.
  • the “mono-lower alkylamino group” represented by R 1 means an amino group mono-substituted by the lower alkyl group defined above, and specifically includes, for example, a methylamino group, an ethylamino group, an isopropylamino group. Groups and the like.
  • the “di-lower alkylamino group” represented by R 1 means an amino group substituted with the same or different two lower alkyl groups defined above, and specifically includes, for example, a dimethylamino group, a jetylamino group, Examples include tilmethylamino group, isopropylmethylamino group, etc.
  • R 1 is more preferably a lower alkyl group, preferably a lower alkyl group, a 3- to 7-membered cycloalkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group.
  • the “lower alkyl group” represented by R 2 means the same group as the lower alkyl group defined above, specifically, for example, methyl group, ethyl group, isopropyl group, n-propyl group, tert-butyl Group, 2, 2-dibutylpropyl group and the like, and of these, methyl group is preferred.
  • the “3- to 7-membered cycloalkyl group” represented by R 2 means the same group as the cycloalkyl group defined above, and specifically includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclopentyl group, and the like. A hexyl group etc. are mentioned.
  • R 2 is preferably a hydrogen atom or a lower alkyl group, preferably a hydrogen atom or a methyl group.
  • formula (IV) include, for example, (1,1-dimethyl) ethylcarbolamino group, methoxycarbolamamino group, (1,1-dimethyl) ethyloxycarboroamino group, (1,1-dimethyl) ethylaminocarbolamino group, propyloxycarbolamino group, (2,2-dimethylpropyl) carbolamino group, (1-methylethyl) carbolamino group, (1 ethylpropyl) Carbo-lamino group, ethyl carbo-lamino group, ethoxy carbo-lamino group, N-isopropyloxycarbo-lamino group, N- (1,1-dimethylethyl) carbo N-methylamino group, N-isopropylcarbonyl N-methylamino group, N isopropyloxycarbo ol N methylamino
  • the “lower alkyl group” represented by R 11 means the same group as the lower alkyl group defined above, and specifically includes, for example, methyl group, ethyl group, isopropyl group, n propyl group, tert butyl group, etc. Of these, ethyl, isopropyl and tert-butyl are preferred.
  • the "3- to 7-membered cycloalkyl group" represented by R 11 means a group similar to the cycloalkyl group defined above, and specifically includes, for example, a cyclopropyl group, a cyclobutyl group, a cycloalkyl group. Examples include a benzyl group and a cyclohexyl group, and among these, a cyclopropyl group is preferred.
  • the lower alkyl group and the 3- to 7-membered cycloalkyl group may be the same or different. 1 to 3 substitutions with a rogen atom.
  • halogen atom of the substituent means the same group as the "halogen atom" defined above.
  • R 21 represents a hydrogen atom, a methyl group or an ethyl group.
  • R 21 is preferably a hydrogen atom or a methyl group.
  • R 11 and R 21 together with an adjacent nitrogen atom are aliphatic 3- to 7-membered rings (one of the carbon atoms constituting the ring is replaced by an oxygen atom). May also be formed.
  • the aliphatic 3- to 7-membered ring means a cycloalkyl group having 3 to 7 carbon atoms as defined above, or one of the carbon atoms constituting the cycloalkyl group is an oxygen atom.
  • the aliphatic 3- to 7-membered ring may be substituted 1 to 3 with a lower alkyl group or a halogen atom.
  • the lower alkyl group of the substituent means the same group as the “lower alkyl group” defined above, and specifically includes, for example, a methyl group, an ethyl group, an isopropyl group, and the like.
  • the halogen atom of the substituent means a group similar to the above-defined "halogen atom", and includes a fluorine atom, a chlorine atom, a bromine atom and the like.
  • aliphatic 3- to 7-membered ring examples include a piperidine ring, a pyrrolidine ring, a azetidine ring, an aziridine ring, and a morpholine ring, and among these, a pyrrolidine ring is preferable.
  • X is represented by the formula (IV-1)
  • specific examples of the group in the case where X is represented by the formula (IV-1) include, for example, an amino group carbonyl group, a methylaminocarbonyl group, and an ethylaminocarbo- group.
  • tert-butylaminocarbole group isopropylaminocarbol group, cyclopropylaminocarbol group, 2-fluoro- (1,1-dimethyl) ethylaminocarbole group, tert-butylmethylaminocarbole group -Butyl group, tert-butylethylaminocarbol group, ethylmethylaminocarbol group, jetylaminocarbol group, isopropylmethylaminocarbole group, ethylisopropylaminocarbol group, 2— Methyl-1 pyrrolidyl-l-carbonyl group, 2-Methyl-1 aziridyl-l-carbol group, 2, 2-dimethyl-1 aziridyl-luca Examples include luponyl group
  • the lower alkyl group represented by R 3 means a force that means a lower alkyl group as defined above, or a lower alkyl group that is substituted with 1 to 3 halogen atoms.
  • 2-methylpropyl group and 2,2-dimethylpropyl group are preferable.
  • the cycloalkyl group having 3 to 7 carbon atoms represented by R 3 means a cycloalkyl group as defined above, or means a cycloalkyl group substituted with 1 to 3 halogen atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a 4 trifluoromethylcyclohexyl group.
  • Y represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.
  • halogen atom represented by Y means an atom similar to the halogen atom defined above, Specifically, a fluorine atom, a chlorine atom, a bromine atom, etc. are mentioned, for example.
  • the “lower alkyl group” represented by Y means the same group as the lower alkyl group defined above, and specifically includes, for example, methyl group, ethyl group, isopropyl group, n-propyl group and the like.
  • the “lower alkoxy group” represented by Y means the same group as the lower alkoxy group defined above.
  • Y is preferably a hydrogen atom.
  • the compounds according to the present invention also include the compounds shown in Table 1 or pharmaceutically acceptable salts thereof.
  • R 3 represents a lower alkyl group, and other symbols are the same as above]
  • This step is a method for producing compound (2) by reacting compound (I) with a base.
  • the compound (1) used in this step for example, a method described in the literature (for example, JP-A-9-87237), a method according to this, or a compound produced by combining this with a conventional method is used. Examples thereof include ethyl 2-[(tert-butoxycarbol) (methyl) amino] 1,3 thiazole-4-carboxylate.
  • the amount of the base used in this step is generally 0.1 to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (1).
  • Examples of the base include sodium hydroxide, potassium hydroxide and the like.
  • the reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction.
  • water, methanol, ethanol, tetrahydrofuran, 1,4 dioxane and the like can be mentioned.
  • the reaction temperature is usually -30 ° C to the boiling point of the solvent, preferably 0 ° C to 50 ° C.
  • the reaction time is usually 0.1 hour to 96 hours, preferably 0.5 to 24 hours.
  • the compound (1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • This step is a method for producing compound (3) by reacting compound (2) with benzyl alcohol.
  • ester bond-forming reagent examples include salt thiothionyl, salt oxyoxalyl, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridyl-mu-iodide, N, N, monocarbodiimidazole, diphenylphosphoryl.
  • Chloride diphenylphosphoryl azide, N, N, monodisuccimidyl carbonate, N, N, monodisuccimidyloxalate, 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride, black mouth formate
  • Examples thereof include chill, isobutyl chloroformate or benzotriazo-1-yloxy-tris (dimethylamino) phospho-hexafluorophosphate, and examples thereof include thiol chloride, 1-ethyl 3- (3 dimethyla).
  • Minopropyl carbodiimide hydrochloride N, N dicyclohexylcarbodiimide or ben Zotriazo 1-yloxy tris (dimethylamino) phospho-hexafluorophosphate, 1-chlorodiethyl N, N, 2-trimethyl-1-probelamin and the like are suitable.
  • a base and a condensation aid may be used together with the above ester bond forming reagent.
  • Examples of the base to be used include trimethylamine, triethylamine, N, N disopyl pyrethylamine, N methylmorpholine, N methylpyrrolidine, N-methylbiveridi.
  • N N Dimethyl-line, 1,8 Diazabicyclo [5. 4. 0] Wunde force 7 (D BU), 1, 5 Azabicyclo [4. 3. 0] Nona 5 (DBN)
  • tertiary aliphatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline, and the like. Among them, tertiary aliphatic amines are preferred. In particular, for example, triethylamine or N, N diisopropylethylamine is preferable.
  • condensation aid used examples include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-1,5-norbornene-1,2,3-dicarboximide, or 3-hydroxy3,4-dihydro-4oxo1,2,3.
  • Benzotriazole and the like can be mentioned, among which N-hydroxybenzotriazole and the like are preferable.
  • the amount of benzyl alcohol used is usually 0.1 to 50 equivalents, preferably 0.5 to 5 equivalents, relative to 1 equivalent of the compound (2) or a reactive derivative thereof.
  • the amount of ester bond forming reagent used varies depending on the type of compound and solvent used and other reaction conditions, but is usually 0.1 to 50 per 1 equivalent of compound (2) or its reactive derivative. Equivalent, preferably 1 to 5 equivalents.
  • the amount of the condensation aid to be used varies depending on the type of compound and solvent used and other reaction conditions, but is usually 0.1 to 50 equivalents, preferably 1 to 50 equivalents, preferably 1 equivalent of compound (2) or its reactive derivative. 1 to 5 equivalents.
  • the amount of the base used varies depending on the compound used, the type of solvent, and other reaction conditions, and is usually 0.01 to 50 equivalents, preferably 0.02 to 5 equivalents.
  • the reaction solvent used in this step includes, for example, an inert solvent, and is not particularly limited as long as the reaction is not hindered.
  • an inert solvent for example, methylene chloride, chloroform, 1,2-dichloroethane, N, N Dimethylformamide, ethyl acetate, acetic acid methyl ester, acetonitrile, benzene, xylene, toluene, 1,4 dioxane, tetrahydrofuran, dimethoxyethane, or a mixed solvent thereof may be mentioned, from the viewpoint of securing a suitable reaction temperature.
  • methylene chloride, black mouth form, 1,2-dichloroethane, acetonitrile, N, N dimethylformamide and the like are preferable.
  • the reaction temperature in this step is usually 78 ° C to the boiling point of the solvent, preferably 30 ° C to the boiling point of the solvent.
  • the reaction time in this step is usually 0.1 to 96 hours, preferably 0.5 to 24 hours.
  • the base, ester bond forming reagent, and condensation aid used throughout this step can be used alone or in combination.
  • the compound (3) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like. Can be attached to the next process
  • This step is a method for producing compound (4) by deprotecting the Boc group of compound (3).
  • the reaction in this step is performed according to the method described in the literature (Protective Groups in Organic Synthesis, TW Green, 3rd edition, John Wiley & Sons, 1999, etc.) It can be performed by combining with conventional methods.
  • the compound (4) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc. It can be subjected to the next step without separation and purification.
  • This step is a method for producing compound (6) by reacting compound (4) with compound (5).
  • Examples of the base to be used include trimethylamine, triethylamine, N, N disopyl pyrethylamine, N methylmorpholine, N methylpyrrolidine, N-methylbiveridine, N, N dimethylamine, 1,8 diazabicyclo [5. 4. 0] Wunde 7 1 (D BU), 1, 5 Azabicyclo [4. 3.
  • Nona 5 Nen (DBN) and other tertiary aliphatic amines for example, pyridine, 4-dimethyla Aromatic amines such as minopyridine, picoline, lutidine, quinoline or isoquinoline are mentioned, among which tertiary aliphatic amines are preferred, for example, triethylamine or N, N diisopropylethylamine is preferred. It is.
  • condensation auxiliary used examples include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-1,3-dicarboximide, or 3-hydroxy3,4-dihydro-4oxo1,2,3.
  • Benzotriazole and the like can be mentioned, among which N-hydroxybenzotriazole and the like are preferable.
  • the amount of compound (4) used varies depending on the type of compound and solvent used and other reaction conditions, but is usually 0.1 to 1 equivalent of carboxylic acid derivative (5) or its reactive derivative. To 50 equivalents, preferably 0.5 to 10 equivalents.
  • the amount of the amide-forming reagent used varies depending on the type of compound and solvent used and other reaction conditions, but is usually based on 1 equivalent of the carboxylic acid compound (5) or its reactive derivative. Usually 1 to 50 equivalents, preferably 1 to 10 equivalents.
  • the amount of the condensation aid used varies depending on the type of compound used, the type of solvent, and other reaction conditions, but usually 1 to 1 equivalent to 1 equivalent of the carboxylic acid compound (7) or its reactive derivative. 50 equivalents, preferably 1 to 10 equivalents.
  • the amount of the base used varies depending on the compound used, the type of solvent and other reaction conditions, and is usually 1 to 50 equivalents, preferably 1 to 10 equivalents.
  • Examples of the compound (5) to be used include 6 fluoronicotinic acid, 6-methoxynicotinic acid, 6 cyanonicotinic acid, 2, 4 difluorobenzoic acid, nicotinic acid, 4 fluoro oral benzoic acid, 3 fluorobenzoic acid, 2 Fluorobenzoic acid, benzoic acid, 4-cianobenzoic acid, 3-cyanobenzoic acid, 2-cyanobenzoic acid, 4-methoxybenzoic acid, 3-methoxybenzoic acid, 2-methoxybenzoic acid, 4-trifluoromethylbenzoic acid, 3 trifluoromethylbenzoic acid, 2 trifluoromethylbenzoic acid, 4-difluoromethoxybenzoic acid, 3 difluoromethoxybenzoic acid or 2 difluoromethoxybenzoic acid.
  • the acid chloride may be a force using a commercially available compound or a product prepared by a method commonly used by those skilled in the art using a carboxylic acid compound (5) or a method analogous thereto. it can.
  • the reaction solvent used in this step includes, for example, an inert solvent, and is not particularly limited as long as the reaction is not hindered.
  • an inert solvent for example, methylene chloride, chloroform, 1, 2 —Dichloroethane, N, N dimethylformamide, acetic acid ethyl ester, acetic acid methyl ester, acetonitrile, benzene, xylene, toluene, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, or a mixture thereof.
  • methylene chloride, black mouth form, 1,2-dichloroethane, acetonitrile, N, N dimethylformamide and the like are preferable.
  • the reaction temperature in this step is usually 78 ° C to the boiling point of the solvent, preferably 0 to the boiling point of the solvent.
  • reaction time in this step is usually 0.5 to 96 hours, preferably 3 to 24 hours.
  • the base, amide-forming reagent, and condensation aid used in this step are one or more kinds. Can be used by combining the upper thread.
  • the compound (6) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • This step is a method for producing the compound (7) by removing the benzyl group of the compound (6).
  • This process is based on literature (Protective Groups murganic Syntnesis, TW Green, 3rd edition, John Wiley & Sons, 1999, etc.) Can be performed in combination.
  • the removal of the benzyl group can be performed, for example, by catalytic hydrogenation using a palladium hydroxide carbon catalyst or the like.
  • the amount of the catalyst to be used is usually 1 to 1000% by weight, preferably 10 to 100% by weight, relative to 1 equivalent of the compound (7).
  • the reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, dioxane, tetrahydrated furan, and ethyl acetate.
  • the reaction temperature is usually 0 ° C to the boiling point of the solvent, preferably 5 ° C to 80 ° C.
  • the reaction time is usually 0.5 to 96 hours, preferably 0.5 to 24 hours.
  • the compound (7) thus obtained can be obtained by known separation and purification means such as concentration and reduced pressure. It can be isolated and purified by concentration, crystallization, solvent extraction, reprecipitation, chromatography or the like, or subjected to the next step without isolation and purification.
  • This step is a method for producing the compound (8) by reacting the compound (7) with tert butyl alcohol, which is a so-called Curtius rearrangement reaction.
  • This reaction is carried out in the presence of a base using a phosphoric acid azide compound and tert-butyl alcohol (for example, Tetrahedron, 31st, 1974, P2151-2157, etc.), a method according to it, or a combination thereof with a conventional method.
  • a base using a phosphoric acid azide compound and tert-butyl alcohol (for example, Tetrahedron, 31st, 1974, P2151-2157, etc.), a method according to it, or a combination thereof with a conventional method.
  • the amount of tert-butyl alcohol used varies depending on the type of compound and solvent used and other reaction conditions, but is generally 0.1 to 100 equivalents, preferably 0. 5 to 50 equivalents.
  • the amount of the base used varies depending on the compound used, the type of solvent, and other reaction conditions, but is usually 0.1 to 20 equivalents, preferably 0.5 to 5 equivalents.
  • Any phosphoric acid azide compound may be used as long as it can produce compound (8) in the reaction of compound (7) and tert-butyl alcohol in this step.
  • Examples thereof include jetyl phosphate azide, diphenyl phosphate azide and the like.
  • Any base can be used as long as it can produce compound (8) in the reaction of compound (7) with tert-butyl alcohol in this step.
  • triethylamine, hydrogenated Sodium, cesium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, potassium acetate, potassium t-butoxide and the like can be mentioned.
  • the reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction, and examples thereof include toluene, tetrahydrofuran, methylene chloride, chloroform, 1,4-dioxane, benzene and the like.
  • the reaction temperature in this step is usually 0 ° C to the reflux temperature of the reaction solvent, preferably room temperature to 150 ° C.
  • the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • the compound (8) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without purification.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. It can be subjected to the next step without purification.
  • This step is a method for producing compound (9) by removing the Boc group of compound (8).
  • the reaction in this step is the same method as in Step 3 above, a method analogous thereto or Can be carried out by a combination of these and conventional methods.
  • the compound (9) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like. It can be attached to the next process without doing.
  • This step is a method for producing compound (11) by reacting compound (9) with compound (10).
  • This step can be carried out by the same method as in step 4 above, a method analogous thereto, or a combination of these with conventional methods.
  • the compound (11) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • This step is a method for producing compound (12) by hydrolyzing compound (11) in the presence of a base.
  • the amount of the base used is generally 0.1 equivalent to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of the compound (11).
  • the base used examples include sodium hydroxide and potassium hydroxide.
  • the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include water, methanol, ethanol, dioxane, and tetrahydrate-furan.
  • the reaction temperature is usually -30 ° C to the boiling point of the solvent, preferably 0 ° C to 50 ° C.
  • the reaction time is usually 0.1 hour to 96 hours, preferably 0.5 hour to 24 hours.
  • the compound (12) thus obtained is isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or without isolation and purification. It can be attached to the next process.
  • This step is a method for producing the compound (13) by introducing a Boc group into the amino group of the compound (12), and this reaction is carried out according to the method described in the literature (for example, protective dull). Protective Groups in Organic Synth hesis)), TW Green, 3rd edition, John Wiley & Sons, 1999, etc.), a method according to them, or a combination of these with conventional methods .
  • the compound (13) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • This step is a method for producing the compound (15) by reacting the compound (13) with the compound (14) in the presence of a base.
  • the amount of the base to be used is generally 0.1 to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (13).
  • the amount of the compound (14) to be used is usually 0.1 to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of the compound (13).
  • Examples of the compound (14) to be used include methyl iodide, iodoacetyl and the like.
  • the reaction temperature is usually 30 ° C to the boiling point of the solvent, preferably 0 ° C to 80 ° C.
  • the reaction time is usually 0.1 to 96 hours, preferably 1 to 24 hours.
  • Examples of the base to be used include sodium hydride, potassium tert-butoxide and the like.
  • the compound (15) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • This step is a method for producing the compound (16) by removing the Boc group of the compound (15), and this reaction is carried out in the same manner as in the above step 3 and the like as described in the literature (for example, protective Protective Groups in Organic Synthesis), TW Green, 3rd edition, John Wiley & Sons, 1999, etc.), a method based on them, or a combination of these with conventional methods.
  • Monkey for example, protective Protective Groups in Organic Synthesis
  • the compound (16) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or is isolated and purified. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.
  • This step is a method for producing the compound (I2) according to the present invention by reacting the compound (16) with the compound (5).
  • reaction in this step can be carried out in the same manner as in Step 4, a method analogous thereto, or a combination of these with conventional methods.
  • the compound (I2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • (I 2-1) contained in the compound (1-2) can also be produced, for example, by the following method.
  • This step is a method for producing compound (15) by reacting N alkylthiourea (14) with chloroacetonitrile.
  • N-alkylthiourea (14) to be used examples include N-methylthiourea, Nethylthiourea, N- (n-propyl) thiourea and the like.
  • the amount of chloroacetonitrile used is usually from 0.1 to 0.1 per 1 equivalent of the compound (14). 5 equivalents, preferably 0.3 to 1.5 equivalents.
  • the compound (15) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or is isolated and purified. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc.
  • This step is a method for producing compound (16) by reacting compound (15) with compound (10) or acid anhydride (10-1) in the presence of a base.
  • Examples of the base used in this step include triethylamine, N, N diisopropylethylamine, N methylmorpholine, N methylpyrrolidine, N-methylpiperidine, N, N dimethylamine, 1,8 diazabicyclo. [5. 4. 0] tertiary aliphatic amines such as Wunde 7 (DBU), 1, 5 Azabicyclo [4. 3.
  • Nona 5 eg pyridine, 4 -Aromatic amines such as dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc., among which, for example, tertiary aliphatic amines and the like are preferable, and particularly, for example, triethylamine or N, N diisopropylethylamine etc. Preferred.
  • the amount of the base used is generally 0.1 to 5 equivalents, preferably 0.3 to 3 equivalents, relative to 1 equivalent of the compound (15).
  • the compound (10) or its acid anhydride (10-1) to be used includes, for example, pivaloyl chloride, 2-methylpropanoyl chloride, isopropyl chloride carbonate, di-tert-butyl carbonate (Boc O) and the like.
  • the amount of compound (10) used is usually 0.1 to 3 equivalents relative to 1 equivalent of compound (15).
  • it is 0.1 to 1.5 equivalents.
  • the compound (16) thus obtained is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolated and purified. It can be attached to the next process.
  • This step is a method for producing the compound (I2-1) according to the present invention by reacting the compound (16) with the compound (5). [0140] This step can be carried out by the same method as in step 13, a method analogous thereto, or a combination of these and conventional methods.
  • the compound (I2-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. .
  • This step is a method for producing the compound (I 3) according to the present invention by reacting the compound (7) with the compound (17).
  • the compound (7) used in this step may be a reactive derivative thereof.
  • Examples of the reactive derivative include acid chloride.
  • the reactive derivative can be produced by a conventional method using the carboxylic acid of compound (7) as a raw material.
  • the amount of the compound (7) or its reactive derivative used is 1 equivalent of the compound (17).
  • the amount is usually 0.1 to 100 equivalents, preferably 0.1 to 20 equivalents, more preferably 0.1 to 3 equivalents.
  • the carboxylic acid represented by the compound (7) for example, carbodiimidazole, N, N, -dicyclohexylcarbodiimide, 1-ethyl 3 (3-dimethyla
  • a condensing agent such as minopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide triphenylphosphine, and preferably carbodiimidazole.
  • the amount of the condensing agent is not strictly limited, but is usually 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents, relative to 1 equivalent of the compound (7).
  • the reaction is usually carried out in an inert solvent, and examples of the inert solvent include tetrahydrofuran, N, N dimethylformamide, 1,4 dioxane, benzene, toluene, chloromethylene, and chloroform. , Carbon tetrachloride, 1,2-dichloroethane, pyridine and the like, or a mixture of these solvents.
  • the reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent, preferably from room temperature to the reflux temperature of the reaction solvent.
  • the reaction time is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
  • the above reaction can be carried out in the presence of a base and a condensation aid in order to facilitate the reaction.
  • Examples of the base include 4-dimethylaminopyridine, triethylamine and the like.
  • the amount of the base to be used is generally 0.1 to 100 equivalents, preferably 0.1 to 1 equivalent, relative to 1 equivalent of the carboxylic acid represented by compound (7) or a reactive derivative thereof.
  • condensation aid examples include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide and the like.
  • the amount of the condensation aid used is usually 1 to 100 equivalents, preferably 1 to 5 equivalents, per 1 mol of the carboxylic acid represented by compound (7) or its reactive derivative.
  • It can be manufactured by a method according to this, or by combining these with conventional methods. wear.
  • the compound (I3) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • the arylamide derivative according to the present invention can exist as a pharmaceutically acceptable salt, and the salt is represented by the above (I) and (I 1), (I 2) or (I 3) included therein. It can be produced according to a conventional method using the compound represented.
  • the acid addition salt examples include hydrohalates such as hydrochloride, hydrofluoride, hydrobromide, and hydroiodide; nitrate, perchlorate, sulfate, phosphate, Inorganic acid salts such as carbonates; Lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, and ethane sulfonate; Aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; Organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate and maleate; and acid addition salts which are organic acids such as amino acid such as glutamate and aspartate Can be mentioned.
  • hydrohalates such as hydrochloride, hydrofluoride, hydrobromide, and hydroiodide
  • nitrate, perchlorate, sulfate, phosphate Inorganic acid
  • the compound of the present invention when it has an acidic group in the group, for example, when it has a carboxyl group or the like, it can be obtained by treating the compound with a base.
  • a base To an acceptable salt.
  • the base addition salt include organic metal salts such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, guanidine, triethylamine, and dicyclohexylamine. Examples include salts with bases.
  • the compounds of the present invention may exist as any hydrate or solvate of the free compound or salt thereof.
  • salt or ester strength and conversion to free compounds can be carried out according to conventional methods.
  • the compound according to the present invention may have a stereoisomer or a tautomer such as an optical isomer, a diastereoisomer, or a geometric isomer depending on the mode of the substituent. Needless to say, all of these isomers are included in the compounds of the present invention. Furthermore, it goes without saying that any mixture of these isomers is also encompassed by the compounds according to the invention.
  • the aromatic hydrogen in the compound is tritium
  • the methyl group is 3H C, 14 CH, CH
  • the fluorine is 18 F
  • the carbon of the carbo group is isotope such as 14 C.
  • radiolabel can also be used as a radio label body by converting it into a group.
  • the radiolabel can be synthesized by a method commonly used by those skilled in the art, a method according to this, or a combination of these with a conventional method.
  • the compound according to the present invention has a mGluRl inhibitory action.
  • mGluRl inhibitory action is not limited as long as it inhibits the function of mGluRl.
  • a compound having an mGluRl antagonistic action Those that are non-competitive and have mGluRl receptor antagonistic activity are included.
  • the compound represented by the general formula (I) can be administered orally or parenterally, and by formulating it into a form suitable for such administration, convulsions and acute pain using the same Treatment of inflammatory pain, chronic pain, cerebral infarction or transient cerebral ischemic attack, mental dysfunction such as schizophrenia, anxiety, drug dependence, Parkinson's disease or gastrointestinal disorder and Z or preventive agent provide.
  • the compound of the present invention When the compound of the present invention is used clinically, it can be administered after various preparations by adding pharmaceutically acceptable additives according to the administration form.
  • various additives commonly used in the pharmaceutical field can be used as the additive, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropenoremethinoresenorelose, cano Levoxy methino resenololose, corn starch, microtalister wax, white petrolatum, magnesium aluminate metasilicate, calcium phosphate anhydrous, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, Polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polybulur pyrrolidone, magnesium stearate, light anhydrous key acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, They are real down.
  • Examples of the dosage form formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders, or suppositories; or syrups, elixirs, etc.
  • Liquid preparations such as pharmaceuticals and injections, and the like, and these can be prepared according to a usual method in the pharmaceutical field. Liquid preparations may be dissolved or suspended in water or other appropriate medium at the time of use. In particular, in the case of injections, buffering agents or preservatives may be added as necessary, which may be dissolved or suspended in physiological saline or glucose solution.
  • the compounds of the present invention all the drug 1. 0 to: LOO weight 0/0, preferably be in a proportion of 1.0 to 6 0% by weight. These formulations may also contain other therapeutically effective compounds.
  • the compounds of the present invention can be used in combination with other agents useful for the treatment of metabolic disorders and Z or eating disorders.
  • the individual components of such a combination can be administered in divided or single formulations at different times or simultaneously during the treatment period.
  • the present invention should be construed to include all simultaneous or timed administrations, and administration in the present invention should be construed as such.
  • the compounds of the present invention can be used for convulsions, acute pain, inflammatory pain, chronic pain, cerebral infarction or transient cerebral ischemic attack, mental disorders such as schizophrenia, anxiety, drug dependence, Parkinson's disease or It can be used in combination with a drug effective for gastrointestinal disorders (hereinafter referred to as “drug for combination use”).
  • drug for combination use a drug effective for gastrointestinal disorders
  • Such agents can be administered simultaneously, separately or sequentially in the prevention or treatment of the disease.
  • the compound of the present invention is used at the same time as one or more concomitant drugs, it can be a pharmaceutical composition in a single dosage form.
  • the composition containing the compound of the present invention and the concomitant drug may be administered to the administration target in different packages at the same time, separately or sequentially. Good. They may be administered at a time lag.
  • the dose of the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease, combination, etc., in accordance with the clinically used dose.
  • the administration mode of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include: 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) separate administration of the compound of the present invention and the concomitant drug.
  • Simultaneous administration of two different preparations obtained by formulation into the same administration route 3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same route of administration by the same route of administration, 4) The compound of the present invention and the concomitant drug 5) Simultaneous administration of two types of preparations obtained by separate formulation, 5) Different administration routes of the two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug (For example, the compound of the present invention; administration in the order of the concomitant drugs, or administration in the reverse order).
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the dose and frequency of administration vary depending on the sex, age, weight, degree of symptom of the patient, and the type and range of the desired treatment effect.
  • adults per day 0.01 to: LOOmgZkg, preferably 0.03 to lmgZkg divided into 1 to several times, and in the case of parenteral administration, 0.001 to 10 mgZkg, preferably It is preferable to administer 0.001 to 0.1 mgZkg in 1 to several divided doses.
  • Formulation Example 4 To 90 parts of the granule obtained by the method of Formulation Example 2, 10 parts of crystalline cellulose and 3 parts of calcium stearate are compressed and formed into tablets with a diameter of 8 mm. Dragee mixture is added to make dragees.
  • Chroma torex (registered trademark) NH 100-250mesh or 200-350mesh
  • Fuji Silysia Chemical Ltd. was used for basic silica gel column chromatography.
  • Doublet dd Double doublet
  • Benzyl 2 [(4 Fluorobenzoyl) (methyl) amino] 1, 3 Thiazole 4—Carboxylate 5. 54 g is dissolved in 30 ml of 1,4 dioxane, a catalytic amount of palladium hydroxide— The mixture was stirred at 50 ° C for 6 hours. The reaction was filtered through celite. The residue obtained by distilling off the solvent was suspended in ethyl acetate and collected by filtration to obtain 1.20 g of the title compound.
  • reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • the residue obtained by distilling off the solvent was dissolved in 3 ml of toluene, and 0.07 ml of triethylamine and 0.04 ml of 4 fluorobenzoyl chloride were added and stirred at 80 ° C. for 30 minutes.
  • reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 1 1) Benzyl 2 (tert-butoxycarbol) (methyl) amino] -1, 3 thiazole 4-carboxylate lOOmg dissolved in chloroform 2 Oml, trifluoroacetic acid 1.Oml The mixture was further stirred at room temperature for 2 hours. After the solvent was distilled off, saturated sodium bicarbonate was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 2 ml of toluene, 0.2 ml of benzoyl chloride and 0.1 ml of triethylamine were added, and the mixture was stirred at 120 ° C.
  • reaction mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 31 [(1,1, Dimethyl) ethylcarbolumino] 2— [N— (4 fluorobenzoyl) —N-methylamino] — 1,3
  • thiazole 4 (1 — Methylethyl) carboluminamino 2— [N— (4 Fluorobenzoyl) N-methylamino] — 1, 3
  • the title compound was prepared in the same manner as in Example 36 1) and 2).
  • the title compound was obtained as a white solid by the same method as 3).
  • 6-Methoxynicotinic acid was used instead of 6-fluoronicotinic acid, and the title compound was obtained as a white solid by the same method as in Example 24.
  • tertbutyl ⁇ 4 [(2,2 dimethylpropanoyl) amino] 1,3 thiazole-2-yl ⁇ methylcarbamate obtained in Example 36 was dissolved in 1 ml of trifluoroacetic acid, and 1 ml at room temperature. Stir for hours. Excess trifluoroacetic acid was distilled off, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with black mouth form. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the residue obtained by distilling off the solvent was dissolved in 1 ml of toluene, triethylamine 100 1 and 4-methoxybenzoyl chloride 80 1 were added, and the mixture was stirred at 120 ° C. for 6 hours.
  • the reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated Japanese brine, and dried over anhydrous sodium sulfate.

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Abstract

L'invention concerne un composé représenté par la formule (I) : (I) (où E représente un cycle aromatique à 5 ou 6 membres qui peut comporter un substituant ou similaire, W représente –NR-CO- (R représente un groupe alkyle inférieur) ou similaire, X représente –NR2-COR1 (R1 représente un groupe alkyle inférieur ou similaire et R2 représente un atome d'hydrogène ou similaire), et Y représente un atome d'hydrogène ou similaire) ou l'un de ses sels pharmaceutiquement acceptables, qui est utile pour traiter des troubles tels que convulsion, douleur aiguë, douleur inflammatoire, douleur chronique, trouble gastrointestinal, trouble cérébral de type infarctus cérébral ou accident ischémique transitoire, trouble mental de type schizophrénie, anxiété ou toxicomanie, car il agit en inhibant le récepteur métabotropique 1 du glutamate.
PCT/JP2007/057537 2006-04-05 2007-04-04 Nouveau derive d'arylamide WO2007116901A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01110683A (ja) * 1986-09-27 1989-04-27 Sawai Seiyaku Kk Ｎ−テトラゾリルチアゾールカルボキシアミド誘導体およびその用途
WO1996036619A1 (fr) * 1995-05-18 1996-11-21 Zeria Pharmaceutical Co., Ltd. Derives d'aminothiazole, medicament contenant ces derives et produit intermediaire obtenu durant la production des composes
JP2003510323A (ja) * 1999-09-28 2003-03-18 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ 医薬として活性なスルホニル・ヒドラジド誘導体
US20050159469A1 (en) * 2003-12-11 2005-07-21 Randolph John T. HIV protease inhibiting compounds
JP2005538086A (ja) * 2002-07-17 2005-12-15 サノフィ−アベンティス アシルアミノチアゾール誘導体、その製造法および治療用途
WO2006020767A2 (fr) * 2004-08-13 2006-02-23 Genentech, Inc. Composes a base de 2-amido-thiazole presentant une activite inhibitrice enzymatique utilisant de l'adenosine triphosphate (atp), et compositions, et leurs utilisations

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01110683A (ja) * 1986-09-27 1989-04-27 Sawai Seiyaku Kk Ｎ−テトラゾリルチアゾールカルボキシアミド誘導体およびその用途
WO1996036619A1 (fr) * 1995-05-18 1996-11-21 Zeria Pharmaceutical Co., Ltd. Derives d'aminothiazole, medicament contenant ces derives et produit intermediaire obtenu durant la production des composes
JP2003510323A (ja) * 1999-09-28 2003-03-18 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ 医薬として活性なスルホニル・ヒドラジド誘導体
JP2005538086A (ja) * 2002-07-17 2005-12-15 サノフィ−アベンティス アシルアミノチアゾール誘導体、その製造法および治療用途
US20050159469A1 (en) * 2003-12-11 2005-07-21 Randolph John T. HIV protease inhibiting compounds
WO2006020767A2 (fr) * 2004-08-13 2006-02-23 Genentech, Inc. Composes a base de 2-amido-thiazole presentant une activite inhibitrice enzymatique utilisant de l'adenosine triphosphate (atp), et compositions, et leurs utilisations

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