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WO2008018639A2 - Inhibiteur de transporteurs de glycine - Google Patents

Inhibiteur de transporteurs de glycine Download PDF

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Publication number
WO2008018639A2
WO2008018639A2 PCT/JP2007/065988 JP2007065988W WO2008018639A2 WO 2008018639 A2 WO2008018639 A2 WO 2008018639A2 JP 2007065988 W JP2007065988 W JP 2007065988W WO 2008018639 A2 WO2008018639 A2 WO 2008018639A2
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Prior art keywords
phenyl
methyl
chloro
hydrate
trifluoromethyl
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WO2008018639A3 (fr
Inventor
Yoshinori Sekiguchi
Taketoshi Okubo
Tsuyoshi Shibata
Kumi Abe
Shuji Yamamoto
Shuhei Kashiwa
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
    • A47J27/00—Cooking-vessels
    • A47J27/002—Construction of cooking-vessels; Methods or processes of manufacturing specially adapted for cooking-vessels
    • A—HUMAN NECESSITIES
    • A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
    • A47J36/00—Parts, details or accessories of cooking-vessels
    • A47J36/02—Selection of specific materials, e.g. heavy bottoms with copper inlay or with insulating inlay
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a compound having a glycine transporter inhibitory effect .
  • An NMDA receptor one of glutamate receptors, exists in neural cell membranes in the brain and participates in various neurophysiological phenomena such as neural plasticity, cognition, attention, and memory.
  • the NMDA receptor has several allosteri ⁇ binding sites, one of which is a glycine- binding site (glycine-binding site of an NMDA receptor complex) .
  • the glycine-binding site of an NMDA receptor complex has been reported to participate in the activation of the NMDA receptor (Molecular Psychiatry (2004) 9, 984-997).
  • An action potential reaches the presynaptic terminal of the glycinergic nerve, starting glycine release into synaptic clefts.
  • the released glycine binds to postsynaptic receptors and so on and is then removed from the synaptic clefts by transporters .
  • glycine transporters presumably regulate the amount of glycine in extracellular fluids and thereby regulate NMDA receptor function.
  • the glycine transporter (GIyT) is a protein that participates in reuptake of extracellular glycine into the cells .
  • the presence of two subtypes , GIyTl and GlyT2 has been elucidated so far.
  • GIyTl is expressed mainly in the cerebral cortex, hippocampus, and thalamus, and has been reported to be associated with diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post- traumatic stress disorder, particular phobias, acute stress disorder, etc.) * depression, drug abuse, convulsion, tremor, and sleep disorders (Current Medicinal Chemistry, 2006, 13, 1017-1044, Neuropsychopharmacology (2005), 1-23, Expert Opinion on Therapeutic Patents (2004) 14 (2) 201-214).
  • diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post- traumatic stress disorder, particular phobias, acute stress disorder, etc.) * depression, drug abuse, convulsion, tremor, and sleep disorders (Current Medicinal Chemistry, 2006, 13, 1017-1044, Neuropsychopharmac
  • Piperidine derivatives and pyrrolidine derivatives have been reported as compounds having a GIyTl inhibitory effect (WO 03/089411, WO 2004/013100, WO 2004/013101, WO 2005/037781, WO 2005/037782, WO 2005/037783, WO 2005/037785, WO 2005/037792) .
  • GIyTl inhibitory effect WO 03/089411, WO 2004/013100, WO 2004/013101, WO 2005/037781, WO 2005/037782, WO 2005/037783, WO 2005/037785, WO 2005/037792
  • An object of the present invention is to provide a novel compound, a salt thereof or a hydrate of the compound or the salt, which is useful for the prevention or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders, based on glycine uptake inhibitory effect.
  • diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders, based on glycine uptake inhibitory effect.
  • the present inventors have conducted diligent studies for a compound with a novel skeleton having an inhibitory effect on GIyTl and have consequently completed the present invention by finding out that compounds represented by the formulas described below are an excellent GIyTl inhibitor.
  • An embodiment of the present invention relates to a compound of the following formula [I], or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt:
  • ring A is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci. 6 alkyl, Ci-e haloalkyl, cyano, Ci_ 6 alkoxy, halogen, Ci.
  • Ar 1 is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, cyano, Ci- ⁇ alkoxy, Ci_ 6 acyl, Ci. 6 haloacyl, Ci- 6 haloalkoxy, C 3 _ 8 cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy;
  • R 1 is hydrogen, Ci_ 6 alkyl, C 3 - 6 alkenyl, or C 3 _ 8 cycloalkyl, wherein the Ci_ 6 alkyl is unsubstituted or substituted with cyano ;
  • R 3 is hydrogen, C ⁇ . 6 alkyl, or halogen; and n is 1 or 2.
  • ring A is a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur as endocyclic atoms, wherein the aromatic ring is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci_ 6 alkyl, Ci- 6 alkoxy and halogen;
  • Ar 1 is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, Ci. 6 alkyl, C 3.
  • - 6 haloalkyl ⁇ yano, Ci_ 6 alkoxy, Ci- 6 acyl, C 3 ._ 6 haloacyl, Ci_ 6 haloalkoxy, C 3 _ 8 cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy (preferably, phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci.6 alkyl and Ci-6 haloalkyl) ;
  • R 1 is hydrogen, C 1 . 6 alkyl, C 3 . 6 alkenyl, or C 3 -B cycloalkyl, wherein the Ci- ⁇ alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.
  • R 4 is hydrogen, C ⁇ - 6 haloalkyl, cyano or Ci_ 6 acyl (preferably, cyano or C ⁇ - 6 acyl) ;
  • Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C ⁇ _ 6 alkyl, Ci_ 6 haloalkyl, cyano, Ci_ 6 alkoxy, Ci_ 6 acyl, Ci- 6 haloacyl and Ci_ 6 haloalkoxy or with methylenedioxy;
  • R 1 is hydrogen, Ci_ 6 alkyl, C 3 -6 alkenyl, or C 3 _ 8 cycloalkyl, wherein the C ⁇ . 6 alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.
  • ring A is a monocyclic or bicyclic aromatic ring (particularly, a five- or six-membered aromatic ring) having 1 or 2 nitrogen atoms as endocyclic atoms, wherein the aromatic ring is unsubstituted or substituted with one substituent selected from the group consisting of C 1 . 6 alkyl, halogen and Ci. 6 alkoxy (particularly, one C ⁇ . 6 alkyl);
  • Ar 1 is phenyl, pyridyl, or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci- ⁇ alkyl, Ci. ⁇ haloalkyl, Ci_ 6 alkoxy and Ci_ 6 haloalkoxy; and n is 1 or 2.
  • Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci- 6 alkyl and Ci- 6 haloalkyl;
  • R 2 is hydrogen or Ci. 6 alkyl; and n is 1 or 2, wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.
  • Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_6 alkyl and Ci-6 haloalkyl; R 2 is hydrogen or Ci_ ⁇ alkyl; and n is 1 or 2 , wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.
  • R 5 is hydrogen, halogen or Ci- 6 alkoxy
  • Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci- ⁇ alkyl and Ci- 6 haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4. 11.
  • R 5 is hydrogen, halogen or Ci_ 6 alkoxy
  • Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_ 6 alkyl and Ci_ 6 haloalkyl; and n is 1 or 2, wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4.
  • Ar 1 is phenyl, pyridyl or isoquinolin-1- ⁇ l, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, C 1 . 6 alkyl and C 1 - S haloalkyl; and n is 1 or 2, wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.
  • Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci- 6 alkyl and Ci- 6 haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.
  • Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, C x . 6 alkyl and Ci- 6 haloalkyl; and n is 1 or 2, wherein the substitution position of the pyrazinyl in the benzene ring is position 3 or 4.
  • a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient .
  • the pharmaceutical composition according to embodiment 33 which is a glycine transporter inhibitor.
  • a pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders, depression, drug abuse, convulsion, tremor, and sleep disorders, comprising a compound according to any one of embodiments 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient .
  • monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms refers to a monocyclic (e.g. 5- or 6- membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring the same or different 1 or 2 atoms selected from nitrogen, oxygen and sulfur.
  • Examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, furyl, isoxazolyl, thienyl, thiazolyl, indolyl, quinolyl and isoquinolyl.
  • the phrase "monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur as endocyclic atoms" refers to a monocyclic (e.g. 5- or 6- membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring the same or different 1 or 2 atoms selected from nitrogen and sulfur.
  • Examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, indolyl, quinolyl and isoquinolyl.
  • monocyclic or bicycli ⁇ aromatic ring having 1 or 2 nitrogen atoms as endocyclic atoms refers to a monocyclic (e.g. 5- or 6-membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring 1 or 2 nitrogen atoms.
  • examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, indolyl, quinolyl and isoquinolyl.
  • Ci_ 6 alkyl used herein means a linear or branched alkyl group having 1 to 6 carbon atoms , and examples may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl.
  • halogen halo-
  • halogen means fluorine, chlorine , bromine , and iodine atoms .
  • Ci_6 haloalkyl used herein means a halogen atom-substituted linear or branched alkyl group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples of the C 3. _ 6 haloalkyl may include fluoromethyl, difluoromethyl, trifluoromethyl and trichloromethyl .
  • Ci_ 6 alkoxy used herein means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy and hexyloxy.
  • C 3 - 8 cycloalkyl used herein means a saturated carbocyclic group having 3 to 8 carbon atoms, and examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Ci- 6 acyl used herein means a carbonyl group bound with a hydrogen atom or linear or branched Ci_ 5 alkyl or cyclic C 3 - 5 alkyl, and examples may include formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopropylcarbonyl and cyclobutylcarbonyl .
  • Ci_6 haloacyl used herein means a halogen atom-substituted linear or branched acyl group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples of the C 1 - 6 haloacyl may include fluoroacetyl, difluoroacetyl, trifluoroacetyl and trichloroacetyl .
  • Ci. 6 haloalkoxy used herein means a halogen atom-substituted linear or branched alkoxy group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples may include fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • C3- 6 alkenyl used herein means a linear or branched C 3 . 6 alkyl incorporating one double bond therein, and examples may include allyl and but-2-enyl.
  • C2-7 alkoxycarbonyl refers to a group composed of the above-defined Ci_ 6 alkoxy and carbonyl attached to each other. Examples may include methoxycarbonyl and tert- butoxycarbonyl .
  • pharmaceutically acceptable salt means an acid-addition salt that can be pharmaceutically accepted.
  • the acid used may include: inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid; and organic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • the conversion of the free form to the salt can be conducted in a conventional way.
  • ring A is preferably, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl, indolyl, imidazolyl, thienyl, thiazolyl (wherein the pyrazolyl and imidazolyl is unsubstituted or substituted with one Ci_ 6 alkyl group, the thiazolyl is unsubstituted or substituted with one or two Ci_ 6 alkyl groups , and the pyridyl is unsubstituted or substituted with halogen or Ci_ 6 alkoxy) , further preferably, unsubstituted or C 1 .
  • pyrazolyl e.g., lH-pyrazol-4-yl, 1- methyl-lH-pyrazol-4-yl, l-ethyl-lH-pyrazol-4-yl, 1-isopropyl- lH-pyrazol-4-yl, l-propyl-lH-pyrazol-4-yl
  • pyridyl which is unsubstituted or substituted with halogen or d_ 6 alkoxy
  • pyrimidinyl e.g., pyrimidin-5-yl
  • pyrazinyl e.g., pyrazin- 2-yl
  • Ci_ 6 alkyl-substituted imidazolyl e.g., 3-methyl-3H- imidazol-4-yl
  • a substitution position of ring A in the benzene ring is preferably, position 3 or 4 , more preferably, position 3.
  • R 1 is preferably, hydrogen or Ci_ 6 alkyl, more preferably, hydrogen or methyl.
  • R 1 is hydrogen in light of the hepatic metabolic stability of the compound of the present invention.
  • the hepatic metabolic stability was confirmed by a hepatic metabolic stability test , wherein a human liver microsome (obtained from XENOTECH LLC (Kansas City, KS, USA)) (1 mg of protein/mL) and the compound (5 ⁇ M) were added to 0.25 M phosphate buffer solution at pH 7.4 and preincubated at 37°C for 5 minutes, and reaction was then started by the addition of an NADPH production system and terminated 15 minutes later by the addition of a reaction stop solution, followed by measurement of the remaining compound by LC-MS.
  • Ar 1 is preferably, (i) phenyl which has chloro, fluoro, or methyl at position 2 and has trifluoromethyl at position 3, 5 or 6 and/or chloro at position 3 or 6 (more preferably, phenyl which has chloro or methyl at position 2 and trifluoromethyl at position 3 or 5 , and may further have chloro at position 6); (ii) pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2 or (iii) isoquinolin-1-yl.
  • Ar 1 is 2-chloro-3- trifluoromethylphenyl , 3-chloro-2-methylphenyl, 2,3- dichlorophenyl , 2-methyl-3-trifluoromethylphenyl, 2-chloro-3- methylphenyl , 2-chloro-5-trifluoromethylphenyl, 2-methyl-5- trifluoromethylphenyl, 2 , 5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dichloro-3-trifluoromethylphenyl , 3-chloro-2-fluoro-6- trifluoromethylphenyl , 2 , 6-dimethylphenyl , 2,4,6- trichlorophenyl , 2-chloro-6-methylphenyl, 3-chloro-4- trifluoromethyl-pyridin-2-yl, 3-chloro-2-trifluoromethyl- pyridin-4-yl, and isoquinolin-1-yl, more preferably
  • Ar 1 is, in particular, preferably, pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2.
  • Preferable compounds in the present invention are the compounds of formula [IA], [II], [III], [IIIA], [IV], [IVA], [V], [VA] and [VI] shown above.
  • Examples of preferable specific compounds may include: 2-chloro-N-( (S) -( ( 2S) -l-methylpiperidin-2-yl) ( 4-pyridin-3- ylphenyl)methyl) -3- (trifluoromethyl)benzamide,
  • Examples of more preferable specific compounds may include :
  • Examples of further preferable specific compounds may include : 3-chloro-N- ( (S) -( 2S) -piperidin-2-yl(3-pyridin-3- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide , 2-chloro-N-( (S) - (3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl ) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S) - ( 2S) -piperidin-2-yl( 3-pyrimidin-5- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide,
  • Examples of most preferable specific compounds may include :
  • the compound represented by formula [I] can be produced by a variety of synthesis methods .
  • the methods described below are just a few examples of production processes for the compound of the present invention, and the present invention is not intended to be limited to them.
  • each step is optionally interchangeable, and in each step, a nitrogen atom and a hydroxyl group can be protected with a protective group, if necessary and then, the protective group can be removed when the protection is unnecessary.
  • P 1 is a nitrogen protecting group by forming carbamate, such as a methoxycarbonyl , ethoxycarbonyl , tert- butoxycarbonyl or benzyloxycarbonyl group (see Theodora W. Greene and Peter G. M.
  • P 2 is a protecting group for a phenolic hydroxyl group, such as a methyl, benzyl or tert-butyldimethylsilyl group (supra.);
  • P 3 is an amino protecting group by forming an tertiary amino group, such as a methyl group or a benzyl or allyl group (supra.);
  • P 4 is a protecting group for a hydroxyl group, such as a pivaloyl group (supra.);
  • X 1 is a chlorine, bromine or iodine atom;
  • R a is Ci_ 6 alkyl (wherein the Ci.
  • X 6 alkyl is unsubstituted or substituted with a cyano group) ; and X 2 is a chlorine, bromine, or iodine atom or a methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group . All of other symbols are as already defined.
  • an “inactive solvent” examples include: alcohols such as methanol, ethanol, isopropanol, n- butanol and ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbons such as pentane, hexane, toluene, benzene and xylene; esters such as ethyl acetate and ethyl formate; ketones such as acetone and methyl ethyl ketone; halogenated carbon solvents such as chloroform and dichloromethane; amides such as dimethylformamide and N-methylpyrrolidone; acetonitrile, dimethyl sulfoxide and water; and mixed solvents thereof.
  • alcohols such as methanol, ethanol, isopropanol, n- butanol and ethylene glycol
  • ethers such as die
  • Examples of a “base” include: amines such as triethylamine , N,N-diisopropylethylamine, pyridine, 1,8- diazabicyclo[ 5.4.0]undec-7-ene, N,N-dimethylaniline, N,N- diethylaniline and 4-dimethylaminopyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide and sodium hydride; metal alcoholates such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; metal amides such as sodium amide, lithium diisopropylamide , lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide; alkyllithium such as n-butyllithium, sec-butyllithium, tert- buty
  • an “acid” examples include: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.
  • a compound (2) can be obtained by amidation reaction of a compound (1) with N,0-dimethylhydroxyamine in the presence or absence of a base in an inactive solvent .
  • the amidation reaction can be practiced by many standard procedures generally known by those skilled in the art, and examples may include: amidation via a mixed anhydride using ethyl chlorocarbonate, isobutyl chlorocarbonate , or pivaloyl chloride; and amidation using a condensing agent such as l-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,3- dicyclohexylcarbodiimide , diphenylphosphorylazide, diethyl cyanophosphate , carbonyldiimidazole, or benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) .
  • Step 2 A compound (3) can be converted into a metal reagent with a metal or alkyllithium reagent and then reacted with the compound (2) in an inactive solvent to thereby obtain a compound ( 4 ) .
  • the metal may include magnesium and zinc
  • examples of the alkyllithium reagent may include n-butyllithium, sec-butyllithium, tert- butyllithium and phenyllithium reagents .
  • Step 3 The compound ( 4 ) can be reacted with a reducing agent in an inactive solvent to thereby obtain a compound ( 5 ) .
  • the reducing agent is a reagent that can convert carbonyl groups into hydroxyl groups through reduction, and examples may include lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, lithium tri- sec-butylborohydride, potassium tri-sec-butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride , tetramethylammonium borohydride , lithium aluminum hydride, sodium aluminum hydride, sodium bis ( 2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and trichlorosilane.
  • Step 4 A compound (6) can be obtained by hydrolysis of the compound (5) with an acid or base or deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" in an inactive solvent.
  • Step 5 The compound ( 6 ) can be reacted with an allylating agent such as allyl chloride or allyl bromide or a benzylating agent such as benzyl chloride or benzyl bromide in the presence or absence of a base in an inactive solvent to thereby obtain a compound (7).
  • an allylating agent such as allyl chloride or allyl bromide
  • a benzylating agent such as benzyl chloride or benzyl bromide
  • Step 6 When P 3 is a methyl group , the compound ( 5 ) can be reacted with a reducing agent in an inactive solvent to thereby obtain a compound (7).
  • the reducing agent is a reagent that can convert carbamate into methyl groups through reduction, and examples may include borane, lithium aluminum hydride, sodium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and diisobutylaluminum hydride .
  • Step 7 The compound ( 7 ) can be reacted with a sulfonylating agent in the presence or absence of a base in an inactive solvent and then reacted with ammonia to thereby obtain a compound (8).
  • the sulfonylating agent is a reagent that can sulfonylate hydroxyl groups, and examples may include p- toluenesulfonyl chloride, methanesulfonyl chloride, p- toluenesulfonic acid anhydrides , methanesulfonic acid anhydrides , trifluoromethanesulfonic acid anhydrides and N- phenylbis ( trifluoromethanesulfonimide) .
  • Step 8 The compound (10) can be obtained by amidation reaction of the compounds ( 8 ) with a compound ( 9 ) in the presence or absence of a base in an inactive solvent .
  • Step 9 The compound (10) can be (1) reacted with, for example, boron tribromide, aluminum (III) bromide, or aluminum (III) chloride in an inactive solvent (when P 2 is a methyl group); or (2) reacted with, for example, boron tribromide, aluminum (III) bromide, or aluminum (III) chloride in an inactive solvent or hydrogenated with a palladium or platinum catalyst (when P 2 is a benzyl group) to thereby obtain a compound (11).
  • the palladium catalyst may include palladium black, palladium carbon and palladium hydroxide
  • examples of the platinum catalyst may include platinum oxide.
  • the compound (11) can be obtained by removing P 2 through deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition".
  • Step 10 The compound (11) can be reacted with a triflating agent in the presence or absence of a base in an inactive solvent to thereby obtain a compound (12).
  • the triflating agent may include trifluoromethanesulfonic acid anhydrides and N- phenylbis (trifluoromethanesulfonimide) .
  • Step 11 The compound (12) can be reacted with a boric acid- or boric acid ester-substituted ring A by use of a palladium catalyst and, if necessary, a ligand for a palladium catalyst, in the presence or absence of a base in an inactive solvent to thereby obtain a compound (13) of the present invention.
  • examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 J 4 , PEPPSI-Ipr( trade mark) , and Pd(dppf)Cl 2
  • examples of the ligand may include triphenylphosphine, 2 , 2-bis(diphenylphosphino) -1, 1-binaphthyl (BINAP), 2-(di-tert-butylphosphino)biphenyl and 9 , 9-dimethyl- 4,5-bis(diphenylphosphino)xanthene (Xantphos) .
  • the compound (13) can be (1) subjected to deprotection reaction with N,N-dimethylbarbituric acid and a palladium catalyst (in this context, examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , and Pd(PPh 3 J 4 ) (when P 3 is an allyl group); or (2) subjected to deprotection reaction through hydrogenation with a palladium or platinum catalyst (in this context, examples of the palladium catalyst may include palladium black, palladium carbon, and palladium hydroxide, and examples of the platinum catalyst may include platinum oxide) (when P 3 is a benzyl group) to thereby obtain a compound (14) of the present invention.
  • a palladium catalyst in this context, examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , and Pd(PPh 3 J 4 ) (when P 3 is an allyl group); or (2) subjected to
  • the compound (14) of the present invention can be obtained by removing P 3 through deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition"
  • Step 13 The compound (4) can be converted into a compound (15) by the same procedure as in Step 9 in the general production process 1.
  • Step 14 The compound (15) can be converted into a compound (16) by the same procedure as in Step 10 in the general production process 1.
  • Step 15 The compound (16) can be converted into a compound
  • Step 16 The compound (17) can be converted into a compound
  • Step 17 The compound (18) can be converted into a compound
  • Step 18 The compound (19) can be converted into a compound
  • Step 19 When P 3 is a methyl group, the compound (18) can be converted into the compound (20) by the same procedure as in Step 6 in the general production process 1.
  • Step 20 The compound (20) can be converted into a compound
  • Step 23 The compound (14) of the present invention can be reacted with a compound (22) in the presence or absence of a base in an inactive solvent to thereby obtain a compound (23)
  • the intermediate (18) can also be produced according to a general production process 4 below.
  • Step: 24 The compound (17) can be reacted with bispinacolborane using a palladium catalyst and, if necessary, a ligand for a palladium catalyst, in the presence or absence of a base in an inactive solvent to thereby obtain a compound (24).
  • examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , PEPPSI-Ipr( trade mark) and Pd(dppf)C1 2
  • examples of the ligand may include triphenylphosphine, 2,2-bis (diphenylphosphino) - 1 , 1-binaphthyl (BINAP), 2-(di-tert-butylphosphino)biphenyl, 9 , 9-dimethyl-4, 5- bis (diphenylphosphino)xanthene (Xantphos), and 1,1'- bisdiphenylphosphinoferrocene (dppf ) .
  • Step 25 The compound (24) can be reacted with a halogen- substituted ring A in the same way as in Step 11 in the general production process 1 to thereby obtain the compound (18).
  • Step 26 The compound (24) can be converted into a compound (30) through reaction with a halogenating reagent such as copper (II) bromide, bromine, iodine, N-bromosuccinimide, or N-iodosuc ⁇ inimide, reaction with iodine or iodine monochloride in the presence of a base such as sodium hydroxide or sodium methoxide, reaction with chloramine-T and sodium iodide, or reaction with 1 , 3-dibromo-5 , 5-dimethylhydantoin, in an inactive solvent .
  • a halogenating reagent such as copper (II) bromide, bromine, iodine, N-bromosuccinimide, or N-iodosuc ⁇ inimide
  • reaction with iodine or iodine monochloride in the presence of a base such as sodium hydroxide or sodium methoxide
  • the intermediate (7) can also be produced according to a general production process 5 below. [General production process 5]
  • Step 27 When P 4 is a pivaloyl group, the compound (5) can be reacted with pivaloyl chloride in the presence or absence of a base in an inactive solvent to thereby obtain a compound (25).
  • the compound (25) can be obtained by the procedure described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" .
  • Step 28 The compound (25) can be converted into a compound
  • Step 29 The compound (26) can be converted into a compound
  • Step 30 When P 4 is a pivaloyl group, the compound (7) can be obtained by carrying out deprotection with a reducing agent such as lithium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, or diisobutylaluminum hydride in an inactive solvent or carrying out deprotection by the procedure described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" . When P 4 is any of other protecting groups, the compound (7) can be obtained by the deprotection procedure described in this literature .
  • a reducing agent such as lithium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, or diisobutylaluminum hydride in an inactive solvent
  • the intermediate (18) can also be produced according to a general production process 6 below.
  • General production process 6 [General production process 6]
  • Step 31 A compound (28) can be converted into a metal reagent by the procedure shown in Step 2 in the general production process 1 and then reacted with the compound (2) to thereby obtain a compound (29).
  • Step 32 The compound (18) can be obtained by the same procedure as in Step 3 in the general production process 1. [General production process 7]
  • Step 33 The compound (2) can be reacted with a compound (31) by the same procedure as in Step 2 in the general production process 1 to thereby convert into a compound (32).
  • Step 34 The compound (32) can be reacted with hydroxylamine hydrochloride in an inactive solvent to thereby convert into a compound (33) .
  • Step 35 The compound (33) can be converted into a compound
  • Step 36 The compound (34) can be converted into a compound
  • examples of the metal catalyst may include: palladium catalysts such as palladium hydroxide, palladium carbon and palladium black; nickel catalysts such as Raney nickel; and platinum catalysts such as platinum oxide.
  • Examples of the reducing agent may include: boron reagents such as boron hydride (BH 3 ) , sodium borohydride (NaBH 4 ) and sodium cyanoborohydride (NaBH 3 CN) ; aluminum reagents such as lithium aluminum hydride (LiAlH 4 ); metals such as zinc, magnesium and sodium; samarium iodide; and lithium naphthalenide .
  • boron reagents such as boron hydride (BH 3 ) , sodium borohydride (NaBH 4 ) and sodium cyanoborohydride (NaBH 3 CN)
  • aluminum reagents such as lithium aluminum hydride (LiAlH 4 )
  • metals such as zinc, magnesium and sodium
  • samarium iodide samarium iodide
  • lithium naphthalenide .
  • Step 38 The compound (36) can be converted into the compound (14) of the present invention by the same procedure as in Step 4 in the general production process 1.
  • Step 39 The compound (30) can be converted into a compound
  • Step 40 The compound (37) can be converted into a compound
  • Step 41 The compound (38) can be converted into a compound
  • Step 42 The compound (39) can be converted into a compound
  • Step 43 The compound (40) can be converted into a compound (41) by the same procedure as in Step 12 in the general production process 1.
  • Step 44 The compound (41) can be converted into a compound
  • Step 45 The compound (42) can be converted into a compound
  • Step 46 The compound (43) can be converted into the compound (14) of the present invention by the same procedure as in Step 4 in the general production process 1.
  • the compound of the present invention may have plural asymmetric centers.
  • the compound can exist in any of the forms of an optically active substance and a racemic body thereof and may further include plural diastereoisomers . All of these forms are encompassed within the scope of the present invention.
  • Individual isomers may be obtained by a method known in the art, for example, the use of optically active starting materials or intermediates, optically selective or diasteroselective reaction in the production of intermediates or final products, or chromatographic separation in the production of intermediates or final products.
  • the compound of the present invention forms a hydrate or solvate, these compounds are also encompassed within the scope of the present invention.
  • the compound of the present invention can be administered orally or parenterally .
  • Examples of the dosage form thereof include tablets, capsules, granules, powdered medicines, powders, troches, ointments, creams, emulsions, suspensions, suppositories, and injections. Any of these preparations can be produced by a routine pharmaceutical technique (e.g., methods specified by Japanese Pharmacopoeia, 14th ed. ) . These dosage forms can be selected appropriately according to the conditions and age of a patient and the purpose of treatment .
  • compositions can be produced by incorporating pharmacologically acceptable carriers , that is , excipients (e.g., crystalline cellulose, starch, lactose, and mannitol), binders (e.g., hydroxypropylcellulose and polyvinyl pyrrolidone) , lubricants (e.g., magnesium stearate and talc), disintegrants (e.g., carboxymethylcellulose calcium), and various other pharmacologically acceptable additives, into a composition comprising the compound of the present invention.
  • excipients e.g., crystalline cellulose, starch, lactose, and mannitol
  • binders e.g., hydroxypropylcellulose and polyvinyl pyrrolidone
  • lubricants e.g., magnesium stearate and talc
  • disintegrants e.g., carboxymethylcellulose calcium
  • the dosage of the compound of the present invention is 1 to 2000 mg/day in the treatment of an adult, which is administered at a single or divided daily dose. This dosage can be increased or decreased appropriately according to the age, body weight, and conditions of a patient.
  • “Silica gel” and “NH-silica gel” used for purification using column chromatography were silica gel 6ON (Kanto Chemical Co., Inc.) and Chromatorex NH (Fuji Silysia) , respectively.
  • TLC (silica gel) and TLC (NH-silica gel) used for purification using TLC were Silica gel 60F254 (Merck Ltd. ) and TLC Plate NH (Fuji Silysia) .
  • MS spectrum Shimadzu LCMS-20IOEV or micromass Platform LC
  • BOP reagent benzotriazol-1- yloxytris (dimethylamino)phosphonium hexafluorophosphate
  • TBS tert-butyldimethylsilyl
  • Tf trifluoromethanesulfonyl
  • Triethylamine (218 g) and N, O-dimethylhydroxyamine hydrochloride (84 g) were added to a chloroform solution (1200 ml) of (S) -l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (165 g) .
  • a BOP reagent (334 g) was gradually added thereto .
  • the mixture was stirred overnight at room temperature.
  • the reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with ethyl acetate and sequentially washed with 0.5 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water, and saturated brine .
  • the organic layer was dried over anhydrous magnesium sulfate.
  • L-Selectride (trade mark) (I M tetrahydrofuran solution, 200 ml) was added dropwise thereto over 40 minutes. The mixture was stirred at the same temperature for 3 hours. Then, 15% aqueous hydrogen peroxide solution (200 ml) was added dropwise thereto over 15 minutes , and the mixture was stirred at room temperature for 30 minutes . The organic solvent was evapolated under reduced pressure. Ethyl acetate and water were added to the resulting solution, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
  • Triethylamine (0.7 ml) was added to a chloroform solution (15 ml) of (S) -((2S) -l-allylpiperidin-2-yl) ( 4-pyridin-3-yl phenyl)methanol (1.1 g) .
  • methanesulfonyl chloride (0.31 ml) was added dropwise thereto.
  • the mixture was stirred under ice cooling for 30 minutes .
  • the reaction solution was concentrated under reduced pressure. The residue was dissolved in 8 M ammonia/methanol solution (8 ml).
  • Reaction was carried out in a microwave reactor at 120 0 C for 20 minutes.
  • the reaction solution was concentrated under reduced pressure.
  • Lithium aluminum hydride (3.3 g) was suspended in dry tetrahydrofuran (100 ml). A tetrahydrofuran solution (30 ml) of (S)-( (2S) -l-allylpyrrolidin-2-yl) ( 3-methoxyphenyl)methyl pivalate (26 g) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water and 10% aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was filtered off with a funnel firmly covered with anhydrous magnesium sulfate.
  • the chloroform layer was dried over anhydrous sodium sulfate, and passed through an NH-silica gel for removing the drying agent and preliminary purification.
  • the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in chloroform (8 ml).
  • tert-Butyl Dicarbonate (1.2 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours .
  • 1,3-Dibromobenzene (148.3 g) was dissolved in tetrahydrofuran (680 ml) under a nitrogen atmosphere. 2.64 M Hexane solution (175 ml) of n-butyllithium was added dropwise to this solution at -70 0 C or lower. The mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (230 ml) of tert-butyl (2S) -2- ( (methoxy(methyl) amino) carbony1)piperidine- 1- carboxylate (114 g) was added dropwise thereto at -70 0 C or lower. The mixture was stirred at the same temperature for 2 hours.
  • Triethylamine (5.8 ml) was added thereto, and di-tert-butyl dicarbonate (9.5 ml) was added dropwise to this mixture. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue. This ethyl acetate layer was washed with 5% aqueous potassium bisulfate solution and a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
  • 3-ylphenyl) methanamine (0.30 g) was added thereto, and the mixture was stirred at room temperature for 4 hours .
  • Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
  • 3-ylphenyl) methanamine (0.30 g) was added thereto, and the mixture was stirred overnight at room temperature.
  • Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate .
  • the drying agent was filtered off , and the filtrate was concentrated under reduced pressure.
  • the obtained purified product was dissolved in ethyl acetate (8 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the acetate solution under ice cooling. The resulting solution was stirred at room temperature for 1 hour. The precipitate was collected by filtration to obtain the title compound (0.24 g) as a colorless solid.
  • the obtained purified product was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.15 ml) was added to the ethyl acetate solution under ice cooling. The solvent was distilled off under reduced pressure to obtain the colorless, amorphous title compound (0.11 g) .
  • the aqueous layer was extracted with ethyl acetate , and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
  • the obtained purified product was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.2 ml) was added to the ethyl acetate solution under ice cooling. The resulting solution was stirred at room temperature for 30 minutes . The precipitate was collected by filtration to obtain the title compound (0.12 g) .
  • the obtained purified product was dissolved in ethyl acetate (2 ml) and methanol (1 ml) and 4 M HCl/ethyl acetate solution (2 ml) was added to the ethyl acetate solution under ice cooling. The solvent was distilled off under reduced pressure to obtain the title compound (0.14 g) .
  • the obtained purified product was dissolved in ethyl acetate (4 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the mixture. The resulting solution was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was solidified with a mixed solvent of chloroform (1 ml) and diisopropyl ether (3 ml). The obtained solid was collected by filtration to obtain the title compound (0.14 g) .
  • the obtained compound was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.2 ml) was added to the ethyl acetate solution.
  • the solvent was distilled off under reduced pressure.
  • the glycine uptake experiment was conducted according to the method described in Neuron, 8, 927-935, 1992.
  • Glioma T98G cells which expressed human glycine transporter-1 (GIyTl) were used.
  • the T98G cells were seeded at a density of 2.0 x 10 4 cells/well onto a 96-well plate and cultured overnight in a carbon dioxide incubator.
  • the test compound was dissolved in 100% DMSO and then dissolved in 10 mM HEPES buffer solution (pH 7.4) containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin.
  • test compound and [ 3 H] glycine were added to the cells and reacted at room temperature for 15 minutes.
  • the labeled glycine solution was aspirated with a manifold.
  • the cells were then lysed with 0.5 M sodium hydroxide solution.
  • An intracellular glycine amount was determined by measuring radio activity in the cell lysate with a liquid scintillation counter.
  • a glycine uptake amount in the presence of 10 ⁇ M ALX5407 is defined as nonspecific uptake, and a specific uptake amount was determined by subtracting the nonspecific uptake amount from a total uptake amount in the absence of 10 ⁇ M ALX5407.
  • Glycine uptake inhibitory activity (IC 50 value) was calculated from an inhibition curve at test compound concentrations of 10 '10 to 10 "6 .
  • the compound of the present invention has glycine transporter-1 (GIyTl) inhibitory activity and is thus effective for the prevention or treatment of glycine transporter-related diseases, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, posttraumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders.
  • GIPl glycine transporter-1

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Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de ce composé, ou un hydrate de ce composé ou de son sel, servant à la prévention ou au traitement de maladies telles que la schizophrénie, la maladie d'Alzheimer, le dysfonctionnement cognitif, la démence, les troubles de l'anxiété (état d'anxiété généralisé, état de panique, trouble obsessionnel compulsif, état d'anxiété social, état de stress post-traumatique, phobies particulières, état de stress grave etc.), la dépression, l'abus de drogues, les convulsions, les tremblements et les troubles du sommeil, sur la base de l'effet d'inhibition de l'absorption de glycine.
PCT/JP2007/065988 2006-08-11 2007-08-10 Inhibiteur de transporteurs de glycine Ceased WO2008018639A2 (fr)

Applications Claiming Priority (2)

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JP2006-220267 2006-08-11
JP2006220267A JP2009179562A (ja) 2006-08-11 2006-08-11 グリシントランスポーター阻害剤

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Cited By (5)

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WO2010087761A1 (fr) * 2009-01-28 2010-08-05 Astrazeneca Ab Composés 2-aza-bicyclo[2.2.2]octane et leurs utilisations
WO2010087762A1 (fr) * 2009-01-28 2010-08-05 Astrazeneca Ab Composés 2-aza-bicyclo[2.2.1]heptane et leurs utilisations
FR2943056A1 (fr) * 2009-03-16 2010-09-17 Sanofi Aventis Derives de n-°2-aza-bicyclo°2.1.1!hex-1-yl)-aryl-methyl!- heterobenzamide, leur preparation et leur application en therapeutique
WO2010106269A3 (fr) * 2009-03-16 2010-12-02 Sanofi-Aventis Derives de n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, leur preparation et leur application en therapeutique
EP2679585A4 (fr) * 2011-02-21 2014-08-06 Taisho Pharmaceutical Co Ltd Inhibiteur de transport de glycine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2838739B1 (fr) * 2002-04-19 2004-05-28 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl)benzamide, leur preparation et leur application en therapeutique
WO2006134341A1 (fr) * 2005-06-13 2006-12-21 Merck Sharp & Dohme Limited Agents therapeutiques

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010087761A1 (fr) * 2009-01-28 2010-08-05 Astrazeneca Ab Composés 2-aza-bicyclo[2.2.2]octane et leurs utilisations
WO2010087762A1 (fr) * 2009-01-28 2010-08-05 Astrazeneca Ab Composés 2-aza-bicyclo[2.2.1]heptane et leurs utilisations
CN102405222A (zh) * 2009-01-28 2012-04-04 阿斯利康(瑞典)有限公司 2-氮杂-二环[2.2.1]庚烷化合物及其用途
FR2943056A1 (fr) * 2009-03-16 2010-09-17 Sanofi Aventis Derives de n-°2-aza-bicyclo°2.1.1!hex-1-yl)-aryl-methyl!- heterobenzamide, leur preparation et leur application en therapeutique
WO2010106269A3 (fr) * 2009-03-16 2010-12-02 Sanofi-Aventis Derives de n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, leur preparation et leur application en therapeutique
EP2679585A4 (fr) * 2011-02-21 2014-08-06 Taisho Pharmaceutical Co Ltd Inhibiteur de transport de glycine

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WO2008018639A3 (fr) 2008-04-03
JP2009179562A (ja) 2009-08-13

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