WO2006137465A1 - Dérivé hétérocyclique azoté - Google Patents

Dérivé hétérocyclique azoté Download PDF

Info

Publication number
WO2006137465A1
WO2006137465A1 PCT/JP2006/312466 JP2006312466W WO2006137465A1 WO 2006137465 A1 WO2006137465 A1 WO 2006137465A1 JP 2006312466 W JP2006312466 W JP 2006312466W WO 2006137465 A1 WO2006137465 A1 WO 2006137465A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
hydroxy
group
pharmaceutically acceptable
Prior art date
Application number
PCT/JP2006/312466
Other languages
English (en)
Japanese (ja)
Inventor
Moriyasu Masui
Akira Matsumura
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to JP2007522349A priority Critical patent/JPWO2006137465A1/ja
Publication of WO2006137465A1 publication Critical patent/WO2006137465A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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 nitrogen-containing heterocyclic derivative which has few side effects on symptoms (eg, schizophrenia) and is useful as a medicine such as an analgesic.
  • 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 (NR2A, 2B, 2C, 2D) subfamilies 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. 2004Z11430 Pamphlet
  • Patent Document 2 International Publication No. 2003Z084948 Pamphlet
  • Patent Document 3 JP-A-8-22569
  • Patent Document 4 Pamphlet of International Publication No.98Z18793
  • Patent Document 5 Pamphlet of International Publication No. 2003Z010159
  • Patent Document 6 International Publication No. 2004Z054579 Pamphlet
  • Patent Document 7 Japanese Patent Laid-Open No. 11 71350
  • Patent Document 8 Pamphlet of International Publication No. 99Z45925
  • Patent Document 9 Japanese Patent Laid-Open No. 3-206086
  • Patent Document 10 Pamphlet of International Publication No. 03Z035641
  • Patent Document 11 Pamphlet of International Publication No. 2005Z030720
  • Patent Document 12 International Publication No. 2002Z50070 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:
  • R 1 is hydrogen, hydroxy, acyloxy, lower alkoxy or lower alkyl
  • R 2 is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2 may be joined together to form a single bond
  • n 0 or 1
  • X may be a lower alkylene which may be substituted with hydroxy n and r are each independently an integer of 0 to 4, n + r is 4 or less,
  • a 1 may be protected, hydroxy, and / or protected, may have at least one amino group, and may be further substituted with another group.
  • X— (CO) m— is — S (CR 3 R 4 ) n— —Y—A 2 is not substituted with unsubstituted benzyl
  • R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , 1 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently hydrogen or substituent Or a pharmaceutically acceptable salt thereof, which is lower alkyl, and may be different when there are a plurality of R 3 and R 4 , respectively. Or a solvate thereof.
  • the ring contains —NH—, and other ring-constituting atoms may be protected by hydroxy and protected, or may be substituted by substituents other than amino.
  • R 1 is hydrogen or hydroxy
  • R 2 is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2 may be joined together to form a single bond
  • n 0 or 1
  • X may be a lower alkylene which may be substituted with hydroxy n and r are each independently an integer of 0 to 4, n + r is 4 or less,
  • a 1 may be protected, hydroxy, and / or protected, may have at least one amino group, and may be further substituted with another group.
  • a 2 is not substituted with unsubstituted benzyl
  • 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, and may be lower alkyl, and a plurality of R 3 and R 4 are present respectively. Each is different! /, But! /,)
  • ring—containing NH and other ring-constituting atoms may be protected by hydroxy and protected, or may be substituted with substituents other than amino, or nitrogen-containing An aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group,
  • It may have a substituent, and may have an aromatic hydrocarbon cyclic group or a substituent.
  • An aromatic heterocyclic group is an aromatic heterocyclic group
  • R 1 is hydrogen or hydroxy
  • R 2 is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2 may be joined together to form a single bond
  • n 0 or 1
  • a 1 may be protected, hydroxy and / or protected, may be less amino
  • At least one nitrogen-containing aromatic monocyclic group which may be substituted with another group or —NH— in the ring, and other ring-constituting nuclear power, protected Good hydroxy and protected, substituted with substituents other than amino, may be aromatic monocyclic groups
  • 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, and may be lower alkyl, and a plurality of R 3 and R 4 are present respectively. Each is different! /, But! /,)
  • 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
  • a substituted pyridyl an imidazolyl ring which may be substituted with a ring atom other than —NH, a ring atom other than NH may be substituted, or a ring atom other than pyrrolyl or NH may be substituted; Ring atoms other than virazolyl and NH may be substituted !, or benzopyrazolyl, benzimidazolyl, which may be substituted with a ring atom other than NH—, or other than NH
  • a pharmaceutically acceptable compound thereof which is an indolyl which may be substituted on a ring-constituting atom of (1), (1 ′)
  • 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 To (4 ′), a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • composition according to (13) above which is a therapeutic agent for tinnitus, epilepsy, Huntington's disease, movement disorder or alcoholism.
  • a method for alleviating pain or single-headed pain comprising administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof, Treatment of stroke, head injury, Arno, Imah's disease, Parkinson's disease, tinnitus, epilepsy, Huntington's disease, movement disorders or alcoholism.
  • Tinnitus Tinnitus, epilepsy, Huntington's disease, dyskinesia or alcohol dependence, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof
  • Use of solvates Tinnitus, epilepsy, Huntington's disease, dyskinesia or alcohol dependence, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (10) above, which is an analgesic, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a disease caused by an NMDA receptor characterized by administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof. How to prevent or treat a patient.
  • a method for alleviating pain comprising administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the compound of the present invention is useful as an analgesic (eg, cancer pain analgesic) having few side effects with force, and used for neurodegeneration treatment such as stroke and brain trauma.
  • analgesic eg, cancer pain analgesic
  • neurodegeneration treatment such as stroke and brain trauma.
  • protected or hydroxy means, for example, lower alkyl (methyl, tert-butyl, etc.), aryl lower alkyl (trifluoromethyl, benzyl, etc.), tri-lower alkylsilyl, etc.
  • 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), diazo,
  • 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. For example
  • “Protected ! may be hydroxy and Z or protected, may have at least one amino and may be further substituted with another group, nitrogen-containing aromatic
  • the term “cyclic group or nitrogen-containing aromatic condensed cyclic group” means a hydroxy group in which the above “nitrogen-containing aromatic monocyclic group” or “nitrogen-containing aromatic condensed cyclic group” may be protected on the ring. And Z or at least one optionally protected amino group, and further substituted with one or more groups selected by the substituent group ⁇ force, including a cyclic group.
  • the substituent group a is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, acyl, acyloxy, lower alkylamino-substituted carbon. Boxy, lower alkoxy carbo, nitro-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.
  • nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic condensed cyclic group refers to the above-mentioned “nitrogen-containing aromatic monocyclic group” and “nitrogen-containing aromatic condensed cyclic group”. Including a group containing an NH group. For example
  • 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.
  • Ring atoms other than 1st— may be substituted with imidazolyl
  • ring atoms other than 1st— may be substituted with pyrrolyl
  • ring atoms other than “benzopyrazolyl” and “one--” are substituted.
  • the ring atoms other than - ⁇ - may be substituted with a ring atom other than - ⁇ -! May be substituted with a ring atom other than - ⁇ -, respectively.
  • 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 alkoxy, lower alkyl sulfo-loxy. , Halogeno lower alkyl sulfo-loxy, acyl, acyloxy, ami-substituted lower alkyl ami-sil acylamino, nitro, sialin-ruboxy, lower alkoxy carbo-yl, rubamoyl, lower alkyl rubamoyl, substituent group 1
  • the aryl group which may be substituted with the above groups, the substituent group y force is also selected.
  • 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” Lower alkoxy lower alkyl ",” low
  • the aryl moiety of the “secondary alkyl aryl sulfone” and “aryl aryl lower alkoxy carbo” is the same as the above “aromatic hydrocarbon cyclic group”. Preferred is phenyl.
  • An "aromatic heterocyclic group” is a heteroatom that also has a group force consisting of N 2 O and S 1
  • aromatic monocyclic groups e.g., pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, triazolyl, triazyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, Thiazolyl, thiadiazolyl, furyl and chale, etc.) and aromatic fused cyclic groups (eg indolyl, isoindolyl, indolizyl, benzimidazolyl, benzpyrazolyl, indazolyl, cinnolinyl, phthalajur, benzoxazolyl, benz) Isoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, is
  • the substituent of the “aromatic heterocyclic group which may have a substituent” is the same as the substituent of the above “having a substituent! Or may be an aromatic hydrocarbon cyclic group”. It is.
  • Halogen includes F 2 Cl Br and the like.
  • halogeno lower alkyl halogeno lower alkyl
  • halogeno lower alkoxy halogeno lower alkoxy group
  • halogenoacyl halogeno lower alkyl sulfol
  • “Lower alkyl” includes linear or branched alkyl having 1 to LO, preferably 16 carbon atoms, more preferably 13 carbon atoms, and includes methyl, ethyl, and n-propyl. , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-butyl, isoheptyl, n-octyl, isooctyl, n-nor and Examples include n-decyl and the like. Particularly preferred is methyl or ethyl.
  • the 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, amide-containing lower alkyl amide-containing carboxy, lower alkoxy carbo, cyano-nitro, and the like.
  • Preferred examples of the substituted lower 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 any position. Includes branched alkenyl. Specifically, bur, aryl, probe, isoprobe, butur, isobutenyl, prennore, butagenyl, pentenyl, isopentenyl, pentageninore, hexeninore, isohexenore, hexageninore, hepteninore, otatenore, none Including dill and desalin.
  • the lower alkenyl portion of the “lower alkyloxyball” is the same as the above “lower alkell”.
  • “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. Examples of the 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.
  • “Asil” 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.
  • acyl moiety of “acyloxy”, “acylamino” and “halogenoacyl” is the same as the above “acyl”.
  • the compound (I) of the present invention includes all possible isomers and racemates, not limited to specific isomers.
  • it contains a ketoeenol tautomer as follows.
  • a general method for synthesizing the compound of the present invention is shown below, but is not limited to this synthesis method.
  • the amine compound represented by the formula ( ⁇ ) (hereinafter referred to as the compound ()) and the carboxylic acid compound represented by the formula ( ⁇ ) (hereinafter referred to as the compound ( ⁇ )) are condensed.
  • the amido compound represented by (la) (hereinafter referred to as compound (la)) can be synthesized.
  • the compound ( ⁇ ) is described in T. Kumagai et al. Bioorg. Med. Chem., 9, 1357 (2001), S. Imamura et al. Bio org. Med. Chem., 13, 397 (2005), S. Sakamuri et al. Bioorg. Med. Chem. Lett., 11, 495 (2001), Z.-L.Zhou et al. J. Org. Chem., 64, 3763 (1999), SMN Efange et al. J. Med. Chem., 33, 3133 (1990), the method described in Reference Examples 1 to 3, and a method analogous thereto.
  • Compound (III) can be synthesized by the methods described in Reference Examples 4 and 5 and methods analogous thereto.
  • Compound (III) can be used at 0.5 to 2 molar equivalents relative to compound ().
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
  • condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbonyldiimidazole, etc., and for the compound represented by the formula (V), 0.5 to 2 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, and these can be used alone or in combination. It is possible to use 0.05 to 2 molar equivalents of compound ( ⁇ ), respectively.
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (la) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • compound ( ⁇ ) and the compound represented by formula (IV) are condensed to form an amine compound represented by formula (lb) (hereinafter referred to as compound (lb)). Can be synthesized.
  • L 1 is halogen or CI 4 alkyl sulfo-loxy; AA 2 , R ⁇ R 2 , X and Y are as defined above)
  • the compound (IV) can be used at 0.5 to 3 molar equivalents relative to the compound ( ⁇ ).
  • reaction solvent examples include acetonitrile, acetone, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide and the like.
  • Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound ( ⁇ ). Potassium iodide and sodium iodide should be used at 0.05-1. 5 molar equivalents relative to the compound ( ⁇ ).
  • reaction temperature examples include 20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound (lb) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Compound (II) and a compound represented by formula (V) are condensed in the presence of a reducing agent to synthesize an amine compound represented by formula (Ic) (hereinafter referred to as compound (Ic)). can do.
  • p is an integer from 0 to 3
  • q is an integer from 1 to 3
  • a ⁇ A 2 , R ⁇ R 2 , R 3 and Y are as defined above
  • the compound (V) can be used at 0.5 to 2 molar equivalents relative to the compound ( ⁇ ).
  • the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.
  • Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanohydrohydroboron and the like, and 0.5 to 6 molar equivalents can be used with respect to the compound ( ⁇ ).
  • reaction temperature examples include 0 to 80 ° C.
  • acetic acid or the like as an acid can be used in an amount of 0.5 to 2 molar equivalents relative to the compound ( ⁇ ).
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (Ic) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Z 1 is a CI 3 alkyl carbo yl or tert butoxy carbo ol, t is an integer from 2 to 4; R 4 , R 5 and Y are as defined above)
  • the compound ( ⁇ ) and the compound represented by the formula (VI) are condensed to form an amine compound represented by the formula (VII) (hereinafter referred to as the compound (VII)).
  • Compound (VI) can be used at 0.5 to 3 molar equivalents relative to compound ().
  • the reaction solvent include acetonitrile, acetone, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide, and the like.
  • Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound ( ⁇ ). Potassium iodide and sodium iodide should be used at 0.05-1. 5 molar equivalents relative to the compound ( ⁇ ).
  • reaction temperature examples include 20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (VII) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • Compound (VII) can be acid-treated to synthesize a compound represented by the formula (VIII) (hereinafter referred to as Compound (VIII)).
  • reaction solvent examples include 1,2-dichloroethane, tetrahydrofuran, dioxane, and no solvent.
  • Examples of the acid include hydrochloric acid, trifluoroacetic acid and the like, and 2 to: LOO molar equivalent can be used with respect to compound (VII).
  • reaction temperature examples include 0 to 80 ° C.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (VIII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • compound (VIII) and a carboxylic acid compound represented by formula (IX) are condensed to form an amide compound represented by formula (Id) (hereinafter referred to as compound (Id)).
  • compound (Id) amide compound represented by formula (Id)
  • Compound (IX) can be used at 0.5 to 2 molar equivalents relative to Compound (VIII).
  • Reaction solvents include methylene chloride, tetrahydrofuran, N, N-dimethylformamide Etc.
  • condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N, carbodiimidazole and the like. 5 to 2 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, and these can be used alone or in combination.
  • the compound (VIII) can be used in an amount of 0.05 to 2 mole equivalents, respectively.
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound (Id) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • compound (II) and a compound represented by formula (X) are condensed to form an amine compound represented by formula (XI) (hereinafter referred to as compound (XI)).
  • compound (XI) can be synthesized.
  • Compound (X) can be used at 0.5 to 2 molar equivalents relative to compound ( ⁇ ).
  • the reaction solvent include 1,2-dichloroethane, tetrahydrofuran and the like.
  • Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanohydrohydroboron and the like, and 0.5 to 6 molar equivalents can be used with respect to the compound ( ⁇ ).
  • reaction temperature examples include 0 to 80 ° C.
  • acetic acid or the like as an acid can be used in an amount of 0.5 to 2 molar equivalents relative to the compound ( ⁇ ).
  • reaction time is 0.5 to 72 hours.
  • the resulting compound (XI) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Compound (XI) can be acid-treated to synthesize a compound represented by the formula ( ⁇ ) (hereinafter referred to as compound ()).
  • reaction solvent examples include 1,2-dichloroethane, tetrahydrofuran, dioxane, and no solvent.
  • Examples of the acid include hydrochloric acid, trifluoroacetic acid and the like, and 2 to LOO molar equivalents can be used with respect to compound (XI).
  • reaction temperature examples include 0 to 80 ° C.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound ( ⁇ ) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Compound (XII) and compound (IX) can be condensed in the presence of a condensing agent to synthesize an amido compound represented by formula (Ie) (hereinafter referred to as compound (Ie)).
  • Compound (IX) can be used at 0.5 to 2 mole equivalent based on Compound (XII).
  • Reaction solvents include methylene chloride, tetrahydrofuran, N, N-dimethylformamide Etc.
  • condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbonyldiimidazole, etc., and for the compound represented by the formula ( ⁇ ), 0.5 to 2 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.
  • the compound (XII) that can be used alone or in combination, 0.05 to 2 molar equivalents! /, Respectively. it can.
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (Ie) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • the compound ( ⁇ ) can be used at 0.5 to 3 molar equivalents relative to the compound ( ⁇ ).
  • the reaction solvent include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.
  • Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound ( ⁇ ). Potassium iodide and sodium iodide should be used at 0.05-1. 5 molar equivalents relative to the compound ( ⁇ ).
  • reaction temperature examples include 20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (XIV) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • compound (XV) By treating compound (XIV) with hydrazine hydrate, an amine compound represented by formula (XV) (hereinafter, compound (XV)) can be synthesized.
  • Hydrazine hydrate can be used at 1.0 to 5 molar equivalents relative to compound (XV).
  • reaction solvent 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 obtained compound (XV) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Compound (XV) and compound (IX) can be condensed in the presence of a condensing agent to synthesize an amido compound represented by formula (If) (hereinafter referred to as compound (If)).
  • reaction solvent examples include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
  • condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N'-carbodiimidazole, and the like. 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, and these can be used alone or in combination.
  • the compound (XV) can be used in an amount of 0.05 to 2 mole equivalents, respectively.
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (If) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • compound (II) and a compound represented by formula (XVI) are condensed to form an amine compound represented by formula (XVII) (hereinafter referred to as compound (XVII)).
  • XVII a compound represented by formula (XVI)
  • XVII an amine compound represented by formula (XVII)
  • the compound (XVI) can be used at 0.5 to 2 mole equivalent based on the compound ( ⁇ ).
  • reaction solvent examples include 1,2-dichloroethane, tetrahydrofuran and the like.
  • Examples of the reducing agent include sodium triacetoxyborohydride and cyanohydrohydroboron sodium. And 0.5 to 6 molar equivalents can be used with respect to the compound ( ⁇ ).
  • reaction temperature examples include 0 to 80 ° C.
  • acetic acid or the like as an acid can be used in an amount of 0.5 to 2 molar equivalents relative to the compound ( ⁇ ).
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (XVII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • compound ( ⁇ ) By treating compound (XVII) with hydrazine hydrate, an amine compound represented by formula (XVIII) (hereinafter referred to as compound ( ⁇ )) can be synthesized.
  • Hydrazine hydrate can be used in an amount of 1.0 to 5 molar equivalents relative to compound (XVII).
  • reaction solvent 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 obtained compound (XVIII) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Compound (XVIII) and compound (IX) can be condensed in the presence of a condensing agent to synthesize an amide compound represented by formula (Ig) (hereinafter referred to as compound (Ig)).
  • Compound (IX) can be used at 0.5 to 2 molar equivalents relative to Compound (XVIII).
  • the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
  • condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbodiimidazole, etc., and 0.5% relative to compound (XVIII). ⁇ 2 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.
  • the compound (XVIII) can be used in an amount of 0.05 to 2 mole equivalents, respectively.
  • reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the resulting compound (Ig) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • Z 2 is CI—4 alkyl, u is an integer from 1 to 4; R 5 and ⁇ are as defined above)
  • compound ( ⁇ ) and a compound represented by formula (XIX) are condensed to produce an ester compound represented by formula (XX) (hereinafter referred to as compound (XX)).
  • compound (XX) is condensed to produce an ester compound represented by formula (XX) (hereinafter referred to as compound (XX)).
  • Compound (XIX) can be used at 0.5 to 3 molar equivalents relative to compound ( ⁇ ).
  • reaction solvent examples include acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like.
  • Examples of the base include potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like, and 0.5 to 2 molar equivalents can be used with respect to the compound ( ⁇ ). Potassium iodide and sodium iodide should be used at 0.05-1. 5 molar equivalents relative to the compound ( ⁇ ).
  • Examples of the reaction temperature include 20 ° C to the reflux temperature of the solvent.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (XX) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • compound (XXI) By hydrolyzing the compound (XX), a carboxylic acid represented by the formula (XXI) (hereinafter, compound (XXI)) can be synthesized.
  • reaction solvent examples include methanol, ethanol, water and the like.
  • reaction temperature examples include 0 to 80 ° C.
  • reaction time examples include 0.5 to 24 hours.
  • the obtained compound (XXI) can be isolated and purified by known means (eg, chromatography, recrystallization, etc.).
  • compound (XXI) and an amine compound represented by formula (XXII) are condensed to form an amide compound represented by formula (Ih) (hereinafter referred to as compound (Ih)).
  • compound (Ih) an amide compound represented by formula (Ih) (hereinafter referred to as compound (Ih)).
  • Compound (XXII) can be used at 0.5 to 2 molar equivalents relative to compound (XXI).
  • the reaction solvent include methylene chloride, tetrahydrofuran, N, N-dimethylformamide and the like.
  • condensing agent examples include 1- (3-dimethylaminopropyl) -3-ethyl carpositimide hydrochloride, N, N′-carbonyldiimidazole, etc., and 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, and these can be used alone or in combination.
  • the compound (XXI) can be used in an amount of 0.05 to 2 mole equivalents, respectively.
  • An example of a reaction temperature is 0 to 100 ° C.
  • reaction time is 0.5 to 72 hours.
  • the obtained compound (Ih) can be isolated and purified by a known means (eg, chromatography, recrystallization, etc.).
  • a 1 is protected, hydroxy and / or protected! A nitrogen-containing aromatic monocyclic group or a nitrogen-containing aromatic condensed cyclic group or —NH 2 in the ring, which is substituted with another group. Substituted with a substituent other than protected hydroxy and protected amino !, may! /, Nitrogen-containing aromatic monocyclic group or nitrogen-containing aromatic group In the case of a fused cyclic group, the protecting group is removed under commonly used reaction conditions (for example, the method described in TW Green et al., Protective Groups in Organic Chemistry, Second Edition, John Wiley & Sons (1991)). Can be protected.
  • 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.
  • 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 eg (+) mandelic acid, (1) mandelic acid, (+)-tartaric acid, (1) -tartaric acid, (+)-1-1-phenethylamine, (1) -1-phenethylamine, cinchonine, (1) -cinchon-zine, brucine, etc.
  • optically active compounds eg (+) mandelic acid, (1) mandelic acid, (+)-tartaric acid, (1) -tartaric acid, (+)-1-1-phenethylamine, (1) -1-phenethylamine, cinchonine, (1) -cinchon-zine, brucine, etc.
  • optical isomer separation column Separation of racemates or their salts through an optical isomer separation column (chiral column) Law.
  • a mixture of optical isomers is added to a chiral column such as ENANTIO- OVM (manufactured by Toso Corporation) or CHIRAL series manufactured by Daicel Corporation, 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.
  • an organic solvent for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, jetylamine, etc.
  • 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.), and then a hydrolysis reaction, etc.
  • normal separation means for example, fractional recrystallization, chromatography, etc.
  • hydrolysis reaction etc.
  • the compound of the present invention when 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, MTPA [a-methoxy-ex (trifluoromethyl) phenolacetic acid], ( 1) -menthoxyacetic acid or the like) can be subjected to a condensation reaction to obtain diastereomers of ester or amide, respectively.
  • an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted to the optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis.
  • a pharmaceutically acceptable salt can be used.
  • the basic carbonate include alkali metal salts such as sodium salt and potassium salt; alkaline earth such as calcium salt and magnesium salt.
  • Metal salts for example, ammonium salts; for example, trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, jetanolamine salts, triethanolamine salts, brocaine salts; —Aralkylamine salts such as dibenzylethylenediamine; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyl Trimethylammonium salt, benzyltri Ethylammo-um salt, benzyltributylammo-um salt, methyltrioct
  • Examples include quaternary ammonium salts such as humic salts and tetraptyl ammonium humic salts; arginine salts; basic amino acid salts such as lysine salts.
  • 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 Ring atoms other than imidazolyl and NH may be substituted, and pyrrolyl and -NH- may be substituted.
  • a benzimidazolyl hereinafter referred to as A 1 is al
  • a 1 is al
  • a 1 optionally substituted by a ring member atom other than NH—
  • 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 Compound),
  • a 1 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
  • 7) is one. 0 (z11) 11 CONH (CHR 3 ) n—NHCO (CHR 3 ) n— or one A 3 —CHR 3 —, n is 1 to 3, and R 3 is hydrogen or methyl (each R 3 may be different) (hereinafter, X is assumed to be x3),
  • X is one CO (CHR 3 ) CONH (CHR 3 ) NHCO (CHR 3 ) —or one
  • R 1 is hydrogen
  • R 2 is hydrogen, hydroxy or lower alkyl
  • R 1DR 1 and R 2 are joined together to form a single bond (hereinafter R 1 and R 2 are assumed to be r3),
  • m is 0 and Y is a single bond, CH 2 O— or NH, or R
  • m is 0 and Y is a single bond or CH— (hereinafter m and Y are y2
  • m is 1, Y is a single bond, CH—, —O—, —S or —NH, or R
  • m is 1 and Y is a single bond or CH— (hereinafter m and Y are y5
  • a 2 is phenyl optionally substituted with one or more groups selected from halogen, halogenated lower alkyl and halogeno lower alkoxy (hereinafter A 2 is a5),
  • a 2 is substituted with one or more groups which are also selected from halogen, trifluoromethyl and trifluoromethoxy, and may be a phenol (hereinafter A 2 is a6) )Compound,
  • a 2 is a phenyl substituted with one or more groups in which para-position is also selected from halogen, trifluoromethyl and trifluoromethoxyca (hereinafter, A 2 is a7),
  • n is an integer from 0 to 4,
  • R 1 is hydrogen
  • R 2 is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2 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 — or — A 3 — CR 3 R 4 —, and n is an integer from 0 to 4,
  • R 1 and R 2 are both hydrogen together may form a single bond
  • R 3 , 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;
  • Q 1 is 0, NH or CR B R e (wherein R B and R e are each independently hydrogen or a group selected by the substituent group a force),
  • Q 2 is N or CH
  • 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 or A 3 — CHR 3
  • n 2 or 3
  • R 1 is hydrogen
  • R 2 is hydrogen, hydroxy or methyl
  • R 1 and R 2 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 or halogeno lower alkyl
  • R A is hydroxy or amino
  • Q 1 is O or NH
  • X is one CONR 5 (CHR 3 ) n NR 5 CO (CHR 3 ) — or one A 3 — CHR 3 —
  • R 1 is hydrogen
  • R 2 is hydrogen or hydroxy
  • R 1 and R 2 may be joined together to form a single bond
  • R 3 is hydrogen or lower alkyl It ’s a quinole (each R 3 is different! /, But! /),
  • 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) — or — A 3
  • R 1 is hydrogen
  • R 2 is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2 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 or halogeno lower alkyl
  • Q 3 is N or CH
  • X is — CONR 5 (CHR 3 ) —, — NR 5 CO (CHR 3 ) — or — A 3 — CHR 3 ;
  • R 1 is hydrogen
  • R 2 is hydrogen or hydroxy
  • R 1 and R 2 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 a compound which is hydrogen, halogen, halogeno lower alkyl or lower alkoxy, [0061] 27) In the formula (In):
  • R A is hydroxy or amino But
  • Substituted by hydroxy may be lower alkylene, may have a substituent! /, May be lower alkylene, optionally substituted lower alkylene, CO (CHR 3 ) n — C
  • n 0 3
  • a 3 is phenylene
  • R 1 is hydrogen
  • R 2 is hydrogen or hydroxy
  • R 1 and R 2 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 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
  • n 1 or 2
  • R 1 is hydrogen
  • R 2 is hydrogen or hydroxy
  • R 1 and R 2 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
  • Y is a single bond or lower alkylene, A compound wherein R is hydrogen, halogen or halogeno lower alkyl,
  • Q 2 is N or CH
  • X is one CO (CHR 3 ) n—, one CONR 5 (CHR 3 ) n—, one NR 5 CO (CHR 3 ) n—, or one A 3 —CHR 3 —,
  • n 0-2
  • R 1 is hydrogen
  • R 2 is hydrogen, hydroxy or lower alkyl
  • R 1 and R 2 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
  • 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-, one CONR 5 (CHR 3 ) n-, one NR 5 CO (CHR 3 ) n, one or one
  • n 1 or 2
  • R 1 is hydrogen
  • R 2 is hydrogen or hydroxy
  • R 1 and R 2 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
  • Y is a single bond or lower alkylene
  • R is hydrogen, halogen, halogeno lower alkyl or lower alkoxy.
  • a compound in which the following formula (Ir), (Is), (It) or (Iu) has the following combination of AX, Y and R is also a preferred embodiment of the present invention. It is.
  • tetramethylsilane was measured as an internal standard.
  • the ⁇ value was expressed in ppm, and the binding constant 0) was expressed in Hz.
  • s is single line
  • d is double line
  • t is triple line
  • q quadruple line
  • quint is quintet line
  • m is multiple line
  • br is wide line
  • brs is wide single line
  • brt is wide Means a triple line.
  • DIBAL Diisobutylaluminum hydride
  • ester 1 (5.15 g, 20.0 mmol) prepared by the method described in PJ Gilligan et al., J. Med. Chem., 37, 364 (1994) was dissolved in THF (80 ml) and dried ice-acetate. The solution was cooled to -78 ° C with a water bath. LDA (2.0 M heptane / THF / benzene solution, 11 ml, 22.0 mmol) was added dropwise, and the mixture was stirred at -70 ° C or lower for 1 hour.
  • LDA 2.0 M heptane / THF / benzene solution, 11 ml, 22.0 mmol
  • the animals were male, Sl C : Wistar rats, and the brains after decapitation were removed and the cerebral cortex was fractionated.
  • the cerebral cortex was homogenized with 20 times the amount of ice-cold 50 mM Tris'HCl buffer (pH 7.4) and centrifuged at 4 ° C. and 27,500 ⁇ g for 10 minutes.
  • the resulting precipitate was suspended in the same buffer and then centrifuged again. This operation was repeated three times, and the resulting precipitate was suspended in a buffer and stored at ⁇ 80 ° C.
  • the mixture was centrifuged at 27 ° C. for 10 minutes at 4 ° C., and the resulting precipitate was suspended in a buffer solution. Furthermore, it was diluted 10-fold with a buffer solution, and this was used for experiments as a membrane preparation.
  • the bound and free bodies were separated using Whatman GF / C filter paper (Whatman), and the filter paper was washed 4 times with 2.5 ml of ice-cold buffer.
  • the filter paper was immersed in a liquid scintillation (Clearsol I, manufactured by Nacalai Tester) in a vial, and the radioactivity (dpm) was measured with a liquid scintillation counter. Based on the measured value, the binding inhibition rate (%) was determined by the following formula, and the dose (IC) that suppressed binding by 50% was calculated. Table 11 shows the IC values of the test substances.
  • GBR-12909 (vanoxerin) is shown below.
  • the complementary DNA (cDNA) of the mouse NMDA receptor subunit was transiently introduced into HEK293 cells, and one day after the introduction, changes in intracellular Ca content induced by glutamate Z-glycine were measured using a Ca ion-reactive fluorescent dye.
  • HEK293 cells were cultured and passaged using modified Dulbecco's Eagle medium (DMEM, low glucose).
  • DMEM modified Dulbecco's Eagle medium
  • 20,000 HEK293 Z-wells are seeded in a 96-well plate, and the NR1 and NR2B subunits of the NMDA receptor incorporated into the pcDAN3.1 plasmid are transiently introduced into the cell to co-express the subunits.
  • the amount of DNA introduced is NR1 0.025 g and NR2B subunit 0.075 g. After the introduction, the cell death was suppressed by using 50 ⁇ of NMDA receptor antagonist MK-801.
  • a Krepes 'Ringer' Hepes buffer (KRH, Ca: 5 mM) was used for the preparation of test compounds and cell washing.
  • the NMDA receptor antagonist MK-801 was washed away with KRH buffer, and the Ca ion-directed fluorescent dye Fluo-3 / -3 was taken up into the cells.
  • Ca ion influx was induced by glutamate 20 ⁇ ⁇ glycine 2 ⁇ . Changes in the amount of fluorescence due to Ca ion inflow into the cells were measured using a fluorescence imaging system FDSS3000 at an excitation of 480 nm.
  • test compound shows NMDA receptor antagonism, the influx of Ca ions into the cell decreases, and the amount of fluorescence decreases.
  • the inhibition rate (%) of Ca ion influx was determined from the measured value of the test compound by the following formula, and the dose (IC) that inhibits inflow by 50% was calculated.
  • Table 12 shows the IC values of the test substances.
  • Ca ion inflow inhibition rate (%) 100 [(fluorescence amount in the presence of test compound-background fluorescence amount) I (total fluorescence amount background fluorescence amount)] X 100
  • the present invention shows specific antagonism to glutamate receptors of central nerve cells, particularly NR1ZNR2B receptor, which is one of NMDA receptors, such as motor function (sensory abnormalities), psychiatric symptoms (schizophrenia), etc. It is useful as an analgesic and Z or neuroprotective agent with few side effects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Addiction (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Il a été découvert qu'un dérivé hétérocyclique azoté représenté par la formule (I) peut lier spécifiquement un récepteur NR1/NR2B et peut être utilisé comme agent analgésique. L'invention concerne un composé représenté par la formule (I) ou un sel acceptable du point de vue pharmaceutique de celui-ci ou similaire : (I) où A1 représente un groupe monocyclique aromatique azoté ou un groupe aromatique fusionné azoté qui a au moins un hydroxyle et/ou un amino et qui peut être substitué par un autre groupe ou un cycle monocyclique aromatique azoté ou un groupe aromatique fusionné azoté qui a -NH- dans le noyau et dans lequel un autre atome constituant le noyau peut être substitué ; A2 représente un groupe cyclique hydrocarboné aromatique qui peut avoir un substituant ou similaire ; R1 et R2 représentent indépendamment un hydrogène, un hydroxyle ou similaire ; m est 0 ou 1 ; X représente un alkylène inférieur, -CO(CR3R4)n- ou -A3-(CR3R4)n- lesquels peuvent avoir un substituant ou similaire ; Y représente une simple liaison, un alkylène inférieur ou similaire ; et R3 à R15 représentent indépendamment un hydrogène, un alkyle inférieur ou similaire.
PCT/JP2006/312466 2005-06-24 2006-06-22 Dérivé hétérocyclique azoté WO2006137465A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2007522349A JPWO2006137465A1 (ja) 2005-06-24 2006-06-22 含窒素複素環誘導体

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2005185100 2005-06-24
JP2005-185100 2005-06-24
JP2005309760 2005-10-25
JP2005-309760 2005-10-25

Publications (1)

Publication Number Publication Date
WO2006137465A1 true WO2006137465A1 (fr) 2006-12-28

Family

ID=37570492

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/312466 WO2006137465A1 (fr) 2005-06-24 2006-06-22 Dérivé hétérocyclique azoté

Country Status (2)

Country Link
JP (1) JPWO2006137465A1 (fr)
WO (1) WO2006137465A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US20100204274A1 (en) * 2007-07-24 2010-08-12 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
EP2345328A1 (fr) * 2008-09-19 2011-07-20 Sumitomo Chemical Company, Limited Composition utilisée en milieu agricole
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
WO2013147160A1 (fr) * 2012-03-29 2013-10-03 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson
US8648079B2 (en) 2011-10-07 2014-02-11 Takeda Pharmaceutical Company Limited Heterocyclic compounds
WO2016152955A1 (fr) * 2015-03-24 2016-09-29 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
WO2016152952A1 (fr) * 2015-03-24 2016-09-29 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
US10011601B2 (en) 2014-04-04 2018-07-03 X-Rx, Inc. Substituted spirocyclic inhibitors of autotaxin
JP2018530582A (ja) * 2015-10-14 2018-10-18 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 選択的ｎｒ２ｂアンタゴニスト
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
JP2020516672A (ja) * 2017-04-18 2020-06-11 セルジーン クオンティセル リサーチ，インク． 治療用化合物
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6124323A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
JP2001525321A (ja) * 1997-12-02 2001-12-11 フアルマシア・エ・アツプジヨン・エツセ・ピー・アー アミノベンゾチアゾール誘導体
WO2002085352A1 (fr) * 2001-04-25 2002-10-31 Merck Patent Gmbh Antagonistes des nmda et agonistes des nmda utilises pour traiter des toxicomanies
JP2003513069A (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 １，４置換ピペリジニルｎｍｄａｎｒ２ｂアンタゴニスト
JP2004515544A (ja) * 2000-12-11 2004-05-27 藤沢薬品工業株式会社 キナゾリノン誘導体
JP2004516295A (ja) * 2000-12-21 2004-06-03 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー サブタイプ選択的なｎ−メチル−ｄ−アスパラギン酸拮抗薬としてのピペリジン誘導体
WO2004048364A1 (fr) * 2002-11-22 2004-06-10 Merck & Co., Inc. Utilisation de derives de 2-[(4-benzyl)-1-piperidinyl)methyl]benzimidazole-5-ol comme antagonistes des recepteurs du nr2b

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6124323A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
JP2001525321A (ja) * 1997-12-02 2001-12-11 フアルマシア・エ・アツプジヨン・エツセ・ピー・アー アミノベンゾチアゾール誘導体
JP2003513069A (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 １，４置換ピペリジニルｎｍｄａｎｒ２ｂアンタゴニスト
JP2004515544A (ja) * 2000-12-11 2004-05-27 藤沢薬品工業株式会社 キナゾリノン誘導体
JP2004516295A (ja) * 2000-12-21 2004-06-03 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー サブタイプ選択的なｎ−メチル−ｄ−アスパラギン酸拮抗薬としてのピペリジン誘導体
WO2002085352A1 (fr) * 2001-04-25 2002-10-31 Merck Patent Gmbh Antagonistes des nmda et agonistes des nmda utilises pour traiter des toxicomanies
WO2004048364A1 (fr) * 2002-11-22 2004-06-10 Merck & Co., Inc. Utilisation de derives de 2-[(4-benzyl)-1-piperidinyl)methyl]benzimidazole-5-ol comme antagonistes des recepteurs du nr2b

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
US20100204274A1 (en) * 2007-07-24 2010-08-12 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US8501782B2 (en) * 2007-07-24 2013-08-06 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
EP2345328A4 (fr) * 2008-09-19 2014-06-25 Sumitomo Chemical Co Composition utilisée en milieu agricole
EP2345328A1 (fr) * 2008-09-19 2011-07-20 Sumitomo Chemical Company, Limited Composition utilisée en milieu agricole
US9440990B2 (en) 2011-10-07 2016-09-13 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
US9586930B2 (en) 2011-10-07 2017-03-07 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
US10144743B2 (en) 2011-10-07 2018-12-04 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
US8865717B2 (en) 2011-10-07 2014-10-21 Takeda Pharmaceutical Company Limited Heterocyclic compounds
US8871766B2 (en) 2011-10-07 2014-10-28 Takeda Pharmaceutical Co., Ltd. Heterocyclic compounds
US9193709B2 (en) 2011-10-07 2015-11-24 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
US10273245B2 (en) 2011-10-07 2019-04-30 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
US10550129B2 (en) 2011-10-07 2020-02-04 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
US11174272B2 (en) 2011-10-07 2021-11-16 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
US8648079B2 (en) 2011-10-07 2014-02-11 Takeda Pharmaceutical Company Limited Heterocyclic compounds
US10717748B2 (en) 2011-10-07 2020-07-21 Takeda Pharmaceutical Company Limited 1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases
WO2013147160A1 (fr) * 2012-03-29 2013-10-03 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson
US10011601B2 (en) 2014-04-04 2018-07-03 X-Rx, Inc. Substituted spirocyclic inhibitors of autotaxin
US10233182B2 (en) 2014-04-04 2019-03-19 X-Rx, Inc. Substituted spirocyclic inhibitors of autotaxin
US10752588B2 (en) 2014-12-19 2020-08-25 The Broad Institute, Inc. Dopamine D2 receptor ligands
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
US11498896B2 (en) 2014-12-19 2022-11-15 The Broad Institute, Inc. Dopamine D2 receptor ligands
JPWO2016152955A1 (ja) * 2015-03-24 2018-01-11 東レ株式会社 環状アミン誘導体及びその医薬用途
US10253014B2 (en) 2015-03-24 2019-04-09 Toray Industries, Inc. Cyclic amine derivative and pharmaceutical use thereof
US10117853B2 (en) 2015-03-24 2018-11-06 Toray Industries, Inc. Cyclic amine derivative and pharmaceutical use thereof
CN107207462B (zh) * 2015-03-24 2020-03-06 东丽株式会社 环状胺衍生物和其医药用途
JPWO2016152952A1 (ja) * 2015-03-24 2018-01-11 東レ株式会社 環状アミン誘導体及びその医薬用途
CN107207462A (zh) * 2015-03-24 2017-09-26 东丽株式会社 环状胺衍生物和其医药用途
WO2016152952A1 (fr) * 2015-03-24 2016-09-29 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
CN115124512A (zh) * 2015-03-24 2022-09-30 东丽株式会社 环状胺衍生物和其医药用途
WO2016152955A1 (fr) * 2015-03-24 2016-09-29 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
JP2018530582A (ja) * 2015-10-14 2018-10-18 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 選択的ｎｒ２ｂアンタゴニスト
US10954225B2 (en) 2015-10-14 2021-03-23 Bristol-Myers Squibb Company Selective NR2B antagonists
JP2020516672A (ja) * 2017-04-18 2020-06-11 セルジーン クオンティセル リサーチ，インク． 治療用化合物
US11890275B2 (en) 2017-04-18 2024-02-06 Celgene Quanticel Research, Inc. Therapeutic compounds

Also Published As

Publication number Publication date
JPWO2006137465A1 (ja) 2009-01-22

Similar Documents

Publication Publication Date Title
WO2006137465A1 (fr) Dérivé hétérocyclique azoté
US11639353B2 (en) Cyclobutanes- and azetidine-containing mono and spirocyclic compounds as αV integrin inhibitors
CN107567438B (zh) 利鲁唑前药及其用途
CN114173803A (zh) 氨基酸化合物的剂型和方案
CN112135612A (zh) 氨基酸化合物和使用方法
CN111094233A (zh) 化合物、组合物及方法
CN103201260B (zh) 药物衍生物
JP6453231B2 (ja) ウレア誘導体、またはその薬理学的に許容される塩
JP5813223B2 (ja) Ｅｐ４レセプターアンタゴニストとしての環状アミン誘導体
WO2007099828A1 (fr) Derives heterocycliques azotes substitues par des groupes cycliques
JP4324221B2 (ja) Ｐｐａｒアゴニスト活性を有する誘導体
EP1716135B1 (fr) Piperidinyl-carbonyl-pyrrolidines et leur utilisation en tant que agonistes de la melanocortine
WO2000044726A1 (fr) Derives 2h-phthalazine-1-one et medicaments renfermant ces derives comme principe actif
CN107848962B (zh) 脲衍生物或其药理学上可接受的盐
CN115989235A (zh) 使用氨基酸化合物治疗呼吸系统疾病的方法
WO2006073167A1 (fr) Derives de la pyrrolidine
CN114105950B (zh) 吡唑类化合物及其应用
WO2013064467A1 (fr) Composés d'azétidine, compositions et leur utilisation comme inhibiteurs de l'époxyde hydrolase soluble
JP2021519266A (ja) ３−ヒドロキシ−Ｎ−（３−（７Ｈ−ピロロ［２，３−ｄ］ピリミジン−４−イル）フェニル）ピロリジン−１−カルボキサミド誘導体
WO2018234775A1 (fr) Cyanopyrrolidines substituées présentant une activité en tant qu'inhibiteurs de dub
MX2011010396A (es) Compuesto de pirimidina.
CN112638376A (zh) 取代的四氢环戊二烯并[c]吡咯、取代的二氢吡咯嗪、其类似物和其使用方法
WO2004096775A1 (fr) Derive de 4,4-difluoro-1,2,3,4-tetrahydro-5h-1-benzazepine ou sel de celui-ci
KR20240024060A (ko) 인테그린 억제제에 대한 확장된 투여량 요법
CN1694870A (zh) 乙酰基2－羟基－1,3－二氨基烷烃

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2007522349

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06767124

Country of ref document: EP

Kind code of ref document: A1