WO2012081665A1 - Substance apte à inhiber un transporteur de la glycine - Google Patents

Substance apte à inhiber un transporteur de la glycine Download PDF

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WO2012081665A1
WO2012081665A1 PCT/JP2011/079043 JP2011079043W WO2012081665A1 WO 2012081665 A1 WO2012081665 A1 WO 2012081665A1 JP 2011079043 W JP2011079043 W JP 2011079043W WO 2012081665 A1 WO2012081665 A1 WO 2012081665A1
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substituted
substituents selected
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修資 山本
裕之 太田
公美 阿部
裕子 荒木
実 守谷
相敏 孫
明登 安原
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大正製薬株式会社
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/08—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
    • A61P25/16—Anti-Parkinson drugs
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    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D401/14—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
    • 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
    • C07D405/14—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 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
    • C07D413/06—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 only aliphatic carbon atoms
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having a glycine transporter inhibitory action.
  • NMDA receptor which is one of glutamate receptors, exists on nerve cell membranes in the brain and is involved in various neurophysiological phenomena such as nerve plasticity, cognition, attention, and memory.
  • the NMDA receptor has a plurality of allosteric binding sites, one of which is the glycine binding site (NMDA receptor complex glycine binding site). It has been reported that the NMDA receptor complex glycine binding site is involved in the activation of the NMDA receptor (Non-patent Document 1).
  • Glycine transporter is a protein involved in the reuptake of extracellular glycine into cells, and the existence of two subtypes, GlyT1 and GlyT2, has been clarified so far.
  • GlyT1 is mainly expressed in cerebral cortex, hippocampus and thalamus, etc., and is schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, Post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, and sleep A relationship with a disease such as a disorder has been reported (Non-Patent Documents 2 to 4).
  • Patent Documents 1 and 2 Compounds having GlyT1 inhibitory activity and having an imidazolidin-2-one structure have been reported in the following documents (Patent Documents 1 and 2). These compounds described in Patent Documents 1 and 2 are compounds in which an aryl group is bonded to one ring nitrogen atom of imidazolidine via an amide or carbonyl.
  • the present invention relates to schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Prevention, depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders Alternatively, it is an object to provide a novel compound useful for treatment or a pharmaceutically acceptable salt thereof.
  • anxiety disorder general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Prevention, depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders
  • the present inventors have found that the compound is represented by the following formula, and is an amide or carbonyl group with respect to the nitrogen atom in the ring of imidazolidine.
  • the present inventors have found that a compound characterized in that an aryl group is bonded without intervening is an excellent GlyT1 inhibitor and completed the present invention.
  • R 1 represents a phenyl group, a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, or a pyridonyl group;
  • the phenyl group, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with 1 to 3 substituents selected from the substituent group 1.
  • Substituent group 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is selected from the group consisting of a hydroxy group, a C 1-6 alkanoyloxy group, and a group represented by the formula —NR 7 R 8.
  • R 7 and R 8 may be the same or different and each represents a hydrogen atom or a C 1-6 alkyl group), a halo C 1-6 alkyl group, C 1 -6 alkoxy group, halo C 1-6 alkoxy group, C 2-7 alkoxycarbonyl group, cyano group, halogen atom, 5-membered or 6-membered heteroaryl group (the 5-membered or 6-membered heteroaryl group is 1 And may be substituted with two C 1-6 alkyl groups), a C 1-6 alkanoyl group, and a formula —NR 9 R 10 (R 9 and R 10 may be the same or different and represent a hydrogen atom or C 1-6 represents an alkyl group, or a saturated double of R 9, and together with the nitrogen atom to which R 10 is attached 4-6 membered Forms a ring, saturated heterocyclic ring of the 4-6 membered are the group consisting of groups represented by oxo may be
  • the C 1-6 alkyl group is a C 1-6 alkoxy group, a phenyl group, a C 3-6 cycloalkyl group, a halo C 1-6 alkoxy group, a halo C 3-6 A cycloalkyl group, and 1 to 3 substituents selected from the group consisting of a 3-methyloxetane-3-yl group), a halo C 1-6 alkyl group, a C 1-6 alkoxy group (
  • the C 1-6 alkoxy group includes 1 to 3 substituents selected from the group consisting of a C 1-6 alkoxy group, a hydroxy group, a C 3-6 cycloalkyl group, and a 3-methyloxetane-3-yl group.
  • R 11 and R 12 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group, or R 11 , And a nitrogen atom to which R 12 is bonded to form a 4- to 6-membered saturated heterocyclic ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group, and formula -CONR 13 R 14 ( 13, and R 14 are the same or different, and represent a hydrogen atom or a C 1-6 alkyl group, or, R 13, and R 14 together with the nitrogen atom bonded 4-6 membered saturated heterocyclic Forming a ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group).
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, or a benzyl group, or R 3 and R 4 are Combined with the carbon atom to form a C 3-7 cycloalkane ring, tetrahydrofuran ring, or tetrahydropyran ring (except when R 3 and R 4 are both hydrogen atoms) R 5 and R 6 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group) or a pharmaceutically acceptable salt thereof (provided that R 1 is selected from substituent group 1)
  • R 2 is a monocyclic or bicyclic hetero ring which may be substituted with 1 to 3 substituents selected from Substituent Group 2; An aryl group).
  • R 5 and R 6 are both hydrogen atoms.
  • R 3 and R 4 together with the carbon atom to which R 4 is bonded form a C 3-7 cycloalkane ring.
  • R 2 may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 2 or with 1 to 3 substituents selected from Substituent Group 2
  • R 2 may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 3 or with 1 to 3 substituents selected from Substituent Group 4 A monocyclic heteroaryl group
  • Substituent group 3 is a group consisting of a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, and a 5-membered heteroaryl group
  • Substituent group 4 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom.
  • R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 3; an iso group which may be substituted with 1 to 2 substituents selected from Substituent Group 4; An oxazole group, an oxadiazole group which may be substituted with one substituent selected from substituent group 4, a triazole group which may be substituted with one or two substituents selected from substituent group 4, A pyrazole group which may be substituted with 1 to 3 substituents selected from group 4 or a pyridyl group which may be substituted with 1 to 3 substituents selected from substituent group 4 (1) A compound or a pharmaceutically acceptable salt thereof according to any one of (3) to (3).
  • R 2 is a phenyl group which may be substituted with one 5-membered heteroaryl group, an isoxazole group which may be substituted with 1 to 2 substituents selected from Substituent Group 4 and a substituent A pyrazole group which may be substituted with 1 to 3 substituents selected from group 4 or a pyridyl group which may be substituted with 1 to 3 substituents selected from substituent group 4 (1) to The compound according to any one of (3) or a pharmaceutically acceptable salt thereof.
  • R 1 is a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, or a pyridonyl group
  • the pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with any one of 1 to 3 substituents selected from Substituent Group 1 (1) to (7) Or a pharmaceutically acceptable salt thereof.
  • R 1 is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazyl group
  • the phenyl group, pyridyl group, pyrimidyl group, and pyrazyl group may be substituted with 1 to 3 substituents selected from the substituent group 5.
  • Substituent group 5 is a group consisting of a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, and a halogen atom (1).
  • the compound or a pharmaceutically acceptable salt thereof according to any one of (7) to (7).
  • R 1 is a pyridyl group substituted with 1 to 3 substituents selected from substituent group 5 or a pyrimidyl group substituted with 1 to 3 substituents selected from substituent group 5
  • a pharmaceutical composition comprising as an active ingredient the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof.
  • Schizophrenia Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, comprising as an active ingredient the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof,
  • the compound of the present invention has glycine transporter (GlyT1) inhibitory activity.
  • C xy (x and y are natural numbers) indicates that the number of carbon atoms is from x to y.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl Group, isobutyl group, tert-butyl group, pentyl group, isopentyl group and hexyl group.
  • C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • C 3-7 cycloalkane ring means a cycloalkane ring having 3 to 7 carbon atoms, and is a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
  • C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, A butoxy group, an isobutoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group can be exemplified.
  • C 3-6 cycloalkoxy group means a cycloalkoxy group having 3 to 6 carbon atoms, and is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, or a cyclohexyloxy group.
  • halogen is fluorine, chlorine, bromine or iodine.
  • C 1-6 alkanoyl group refers to a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propanoyl group, butanoyl group, pivaloyl group. The group can be mentioned.
  • C 1-6 alkanoyloxy group refers to a linear or branched alkanoyloxy group having 1 to 6 carbon atoms, such as formyloxy group, acetyloxy group, propanoyloxy group. Group, butanoyloxy group and pivaloyloxy group.
  • halo C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. There are 1 to 3, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a trichloromethyl group.
  • halo C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom. 1 to 3, for example, a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.
  • halo C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms substituted with a halogen atom, and the preferred number of substitution of halogen atoms is 1 to 3. Examples thereof include a fluorocyclopropyl group and a difluorocyclopropyl group.
  • R 9 , R 10 , R 11 , and R 12 , and R 13 and R 14 a “4- to 6-membered saturated heterocyclic ring together with the nitrogen atom to be bonded,” includes an azetidine ring. , A pyrrolidine ring and a piperidine ring. Furthermore, a ring structure containing a hetero atom in the ring such as a morpholine ring and a thiomorpholine ring is also included.
  • “monocyclic or bicyclic heteroaryl group” refers to a monocyclic or bicyclic heteroaryl having at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.
  • An aryl group is meant.
  • the nitrogen atom may be an N oxide.
  • the monocyclic heteroaryl group is preferably a 5- or 6-membered heteroaryl group, for example, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, pyrazolyl group, thiazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thienyl Group, triazolyl group and oxadiazolyl group.
  • examples of the “divalent monocyclic heteroaryl group” used in the present specification include groups in which any hydrogen atom of each of the above groups is removed.
  • the bicyclic heteroaryl group is preferably a 9- or 10-membered heteroaryl group, and examples thereof include an indolyl group, a benzofuranyl group, a benzimidazolyl group, an imidazolidyl group, a quinolyl group, and an isoquinolyl group.
  • C 2-7 alkoxycarbonyl group refers to a group in which a C 1-6 alkoxy group is substituted via a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group. Can do.
  • the “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid.
  • Inorganic 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 Mention may be made of organic acids. Conversion from the educt to the salt can be performed by conventional methods.
  • R 1 is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazyl group;
  • the phenyl group, pyridyl group, pyrimidyl group, and pyrazyl group are preferably compounds that may be substituted with 1 to 3 substituents selected from Substituent Group 5.
  • R 1 is selected from Substituent Group 5
  • a compound that is a pyridyl group substituted with 1 to 3 substituents or a pyrimidyl group substituted with 1 to 3 substituents selected from Substituent Group 5 is more preferable.
  • R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from substituent group 3, an isoxazole group which may be substituted with 1 to 2 substituents selected from substituent group 4, An oxadiazole group which may be substituted with one substituent selected from substituent group 4, a triazole group which may be substituted with one or two substituents selected from substituent group 4, substituent group 4 1-3 substituents optionally pyrazole group optionally substituted with, or compounds which may be substituted pyridyl group with 1 to 3 substituents selected from substituent group 4 is preferably selected from, R 2 Is selected from a phenyl group which may be substituted with one 5-membered heteroaryl group, an isoxazole group which may be substituted with 1 to 2 substituents selected from substituent group 4 and a substituent group 4 A pyrazole group optionally substituted by 1 to 3 substituents, Alternatively, a compound that is a pyridyl group that may be
  • a compound in which R 3 and R 4 together with the carbon atom to which R 4 is bonded forms a C 3-7 cycloalkane ring is preferred.
  • R 5 and R 6 are both hydrogen atoms are preferred.
  • the compound of the present invention can contain a plurality of asymmetric centers. Therefore, the compound can exist in an optically active form and also in a racemic form thereof, and a plurality of diastereomers can also exist. All of the above forms are included within the scope of the present invention.
  • the individual isomers are known methods, for example the use of optically active starting materials or intermediates, optically selective or diastereoselective reactions in the production of intermediates or final products, or intermediates or final products. It can be obtained by separation using chromatography in the production of Further, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
  • the compound according to the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (for example, Etc.) according to the 15th revision Japanese Pharmacopoeia. These dosage forms can be appropriately selected according to the patient's symptoms, age and purpose of treatment.
  • compositions containing the compounds of the invention are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
  • the compounds of the present invention can be combined with one or more other therapeutic agents, various antipsychotics, antidepressants such as 5HT3 antagonists, 5HT2 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake Inhibitor (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI), tricyclic antidepressant, dopaminergic antidepressant, H3 antagonist, 5HT1A antagonist, 5HT1B antagonist, 5HT1D antagonist, D1 agonist, M1 agonist, anti It may be used with anticonvulsants, cognitive enhancers, and other psychoactive drugs.
  • antidepressants such as 5HT3 antagonists, 5HT2 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake Inhibitor (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI), tricyclic antidepressant, dopaminergic antidepressant, H3 antagonist, 5HT
  • Particularly advantageous points related to the use and treatment methods of the combination of compounds of the present invention may include the same or improved effect of individual components at doses less than those normally used. Furthermore, further enhancement of the therapeutic effect on positive and / or negative symptoms of mental disorders and / or cognitive dysfunction is also expected.
  • the use and method of treatment according to the combination of the present invention may also provide benefits in the treatment of patients who do not fully respond to or are resistant to treatment with certain neuroleptic drugs.
  • the dose of the compound according to the present invention is 1 to 2000 mg per day when treating an adult, and this is administered once or divided into several times a day. This dosage can be appropriately increased or decreased depending on the age, weight and symptoms of the patient.
  • the compound of the formula [I] can be produced by various synthetic methods.
  • the following method is an illustration of the production method of the compound of the present invention, and is not limited thereto.
  • inert solvent means, for example, alcohols such as methanol, ethanol, isopropanol, n-butanol, ethylene glycol, diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane.
  • Ethers such as 1,2-dimethoxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene, xylene, esters such as ethyl acetate and ethyl formate, ketones such as acetone and methyl ethyl ketone, chloroform and dichloromethane
  • esters such as ethyl acetate and ethyl formate
  • ketones such as acetone and methyl ethyl ketone
  • amides such as dimethylformamide and N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, water or a mixed solvent thereof.
  • Base means, for example, hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or alkaline earth Lower alkoxides of similar metals; alkyllithiums such as butyllithium, sec-butyllithium, tert-butyllithium, methyllithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, water Alkali metal or alkaline earth metal hydroxides such as barium fluoride; Alkali metal or alkaline earth metal hydro
  • Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, oxalic acid, etc. Organic acid. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
  • X 1 and X 4 represent a halogen atom or a hydroxyl group
  • X 2 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group
  • X 3 represents a halogen atom or a trifluoromethanesulfonyloxy group
  • P 1 represents a protecting group for a nitrogen atom such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group (Theodora W.
  • P 2 is a methyl group, a protecting group of the ester such as a benzyl group (see ibid article)
  • P 3 is benzyl group, such as p- methoxybenzyl group
  • P 4 represents a 2- (trimethylsilyl) protecting group for the nitrogen atom of the pyrazole, such as ethoxymethyl group (see ibid article)
  • the R a substituent group 2 A phenyl group which may be substituted with 1 to 2 substituents selected, or a monocyclic or bicyclic heteroaryl group which may be substituted with 1 to 2 substituents selected from Substituent Group 2
  • R b is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting
  • R d and R e may be the same or different and represent a hydrogen atom or C 1- or it shows a 6 alkyl group, or, R d, and R e to bind Together with the nitrogen atom, forms a 4- to 6-membered saturated heterocyclic ring (the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group) or a 5-membered heteroaryl ring; It is synonymous.
  • Step 1 Compound [I] of the present invention can be obtained by reacting compound (1) with compound (2) wherein X 1 is a halogen atom in an inert solvent in the presence or absence of a base.
  • the compound (1) and the compound (2) in which X 1 is a hydroxyl group in an inert solvent in the presence or absence of a base are subjected to Mitsunobu reaction using an organic phosphorus compound and an azo compound or a phosphorus ylide reagent.
  • Invention compound [I] can be obtained.
  • Step 2 Compound (3) and Compound (4) are reacted in an inert solvent in the presence or absence of a base by using a palladium catalyst or a copper catalyst and optionally a metal catalyst ligand.
  • the compound [I] of the present invention can be obtained.
  • the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4
  • examples of the copper catalyst include CuI and CuBr.
  • Examples of the ligand for the palladium catalyst include triphenylphosphine, Xantphos, BINAP (registered trademark), and the like, and examples of the ligand for the copper catalyst include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, Examples include phenanthroline and proline.
  • Step 3 Compound (I) of the present invention can be obtained by cyclization of compound (5) in an inert solvent in the presence or absence of a base using a reagent such as triphosgene, phosgene, or carbonyldiimidazole.
  • a reagent such as triphosgene, phosgene, or carbonyldiimidazole.
  • the aforementioned compound (1) can be produced according to the following method.
  • General manufacturing method 4
  • Step 4 Compound (7) can be obtained by a general oxidation reaction from an alcohol to an aldehyde using an oxidizing agent in an inert solvent.
  • the oxidation reaction include a method using an oxidizing agent such as IBX, TEMPO, PCC, and PDC, and swallowing.
  • Step 5 Compound (9) can be obtained by subjecting compound (7) and compound (8) to a reductive amination reaction using an reducing agent in an inert solvent in the presence or absence of an acid.
  • the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • Step 6 Theodora W. Green, Peter G. et al. M.M.
  • Compound (10) can be obtained by the deprotection reaction described in Wuts, “Protecting Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
  • Step 7 Compound (10) can be converted to compound (1) by the same method as in Step 3 in General Production Method 3.
  • the aforementioned compound (1) can also be produced according to the following method.
  • General manufacturing method 5
  • Step 8 A urea structure is formed by reacting, for example, an isocyanate such as compound (12) with compound (11) in an inert solvent in the presence or absence of a base to obtain compound (13). it can.
  • Step 9 Compound (14) can be obtained by heating and stirring compound (13) in an inert solvent in the presence or absence of a base.
  • Step 10 Compound (1) can be obtained by reacting Compound (14) with a reducing agent in an inert solvent. Examples of the reducing agent include lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride, and heating and stirring and use of aluminum trichloride are preferable if necessary.
  • the aforementioned compound (1) can also be produced according to the following method. General manufacturing method 6
  • Step 11 Compound (15) can be converted to compound (16) by the same method as in Step 8 in General Production Method 5.
  • Step 12 Compound (1) can be obtained from compound (16) according to the method described in Journal of Organic Chemistry (1999, 64, 2941-2943). The aforementioned compound (1) can also be produced according to the following method.
  • General manufacturing method 7
  • Step 13 Compound by reacting compound (17) with a cyanating reagent such as ammonium carbonate, potassium cyanide or trimethylsilicon cyanide in an inert solvent in the presence or absence of a base, if necessary, by heating. (18) can be obtained.
  • Step 14 Compound (18) can be converted to compound (19) by the same method as in Step 10 in General Production Method 5.
  • Step 15 Compound (19) can be converted to compound (1) by the same method as in Step 2 in General Production Method 2.
  • the aforementioned compound (10) can also be produced according to the following method.
  • General manufacturing method 8 General manufacturing method 8
  • Step 16 Compound (21) can be obtained by subjecting Compound (20) to an amidation reaction using Compound (8) in an inert solvent in the presence or absence of a base.
  • the amidation reaction here can be carried out by a number of standard procedures known to those skilled in the art, for example amides via mixed acid anhydrides using ethyl chlorocarbonate, isobutyl chlorocarbonate, pivaloyl chloride, etc.
  • Step 17 Compound (21) can be converted to compound (22) by the same method as in Step 6 in General Production Method 4.
  • Step 18 Compound (10) can be obtained by reacting compound (22) with a reducing agent in an inert solvent.
  • the reducing agent is a reagent capable of reducing an amide to convert it to an amine, and examples thereof include lithium aluminum hydride, borane, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and the like. Can do.
  • the aforementioned compound (3) can be produced according to the following method.
  • Step 19 Compound (24) is reacted with an inorganic cyanide reagent or an organic cyanation reagent in the presence of compound (23) with compound (17) in the presence or absence of an acid in an inert solvent.
  • an inorganic cyanating reagent include potassium cyanide and sodium cyanide
  • examples of the organic cyanating reagent include trimethylsilyl cyanide.
  • a compound (25) can be obtained by performing a reductive reaction with respect to a compound (24) in an inert solvent.
  • the reduction reaction refers to a method of reducing a cyano group to a primary amine, for example, a method using a reducing agent such as lithium aluminum hydride in an inert solvent, or catalytic hydrogen using a catalyst such as palladium carbon in a hydrogen atmosphere. And the like.
  • Step 21 Theodora W. Green, Peter G. et al. M.M.
  • the compound (26) can be obtained from the compound (25) by the protection reaction of the amine described in Wuts, “Protecting Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
  • Step 22 Compound (26) can be converted to compound (27) by the same method as in Step 6 in General Production Method 4.
  • Step 23 Compound (30) can be obtained by reacting compound (27) with compound (27) in an inert solvent in the presence or absence of a base.
  • R 5 can be obtained by performing reductive amination reaction of Compound (27) and Compound (29) in the same manner as in Step 5 of General Production Method 4 in the presence or absence of an acid in an inert solvent.
  • Step 24 Compound (30) can be converted to compound (31) by the same method as in Step 6 in General Production Method 4.
  • Step 25 Compound (31) can be converted to compound (3) by the same method as in Step 3 in General Production Method 3.
  • the aforementioned compound (5) can be produced according to the following method.
  • General manufacturing method 10 General manufacturing method 10
  • Step 26 Compound (5) can be obtained by reacting compound (32) with compound (32) in the presence or absence of a base in an inert solvent.
  • X 3 is a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group
  • the compound (31) can be converted to the compound (5) by using a ligand as necessary.
  • Step 27 Compound (10) can be converted to compound (5) by the same method as in Step 23 in General Production Method 9. However, when the compound (29) is used, R 5 and R 6 are both hydrogen atoms.
  • Step 28 Compound (34) can be obtained from compound (1) and compound (33) by the same method as in Step 1 in General Production Method 1.
  • the present compound [I2] can be obtained by reacting.
  • the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4
  • examples of the ligand include triphenylphosphine, Xantphos, BINAP (registered trademark), and the like. It is done.
  • Compound (35) represents an organometallic reagent, for example, a Grignard reactant such as R b MgCl, a zinc reactant such as R b ZnCl, a boron reactant in which R b and boric acid or borate ester are bonded, or R b SnBu.
  • a Grignard reactant such as R b MgCl
  • a zinc reactant such as R b ZnCl
  • a boron reactant in which R b and boric acid or borate ester are bonded or R b SnBu.
  • the compound [I3] of the present invention can be obtained.
  • the palladium catalyst, the copper catalyst, and the respective ligands mentioned in Step 2 in General Production Method 2 may be used
  • Step 31 Compound of the present invention by reacting compound (37) wherein X 4 is a halogen atom with compound (37) wherein X 1 is a hydroxyl group in an inert solvent in the presence or absence of a base [I4] can be obtained.
  • the compound of the present invention can also be obtained by reacting the compound (34) in which X 4 is a hydroxyl group with a compound (37) in which X 1 is a halogen atom in an inert solvent in the presence or absence of a base. I4] can be obtained.
  • General manufacturing method 12
  • Step 32 Compound (39) can be obtained from compound (1) and compound (38) by the same method as in Step 1 in General Production Method 1.
  • Step 33 Compound (39) can be converted to compound (40) by the same method as in Step 6 in General Production Method 4.
  • Step 34 Compound (41) of the present invention can be obtained by reacting compound (41) with compound (40) in the presence or absence of a base in an inert solvent.
  • R b is a phenyl group which may be substituted or a heteroaryl group which may be substituted
  • the compound of the present invention can be obtained by reacting compound (41) with a copper catalyst and, if necessary, a ligand [ I5] can be obtained.
  • the copper catalyst include CuI and CuBr
  • examples of the ligand include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, phenanthroline, proline and the like.
  • microwave reactor used was Biotage Initiator.
  • Biotage (registered trademark) SNAP Cartridge KP-NH is used for the “NH silica gel cartridge” when purified using column chromatography
  • Biotage (registered trademark) SNAP Cartridge KP is used for the “silica gel cartridge”.
  • -Sil or HP-Sil was used.
  • MORITEX (registered trademark) Purif-Pack ODS was used for the “reverse phase silica gel cartridge”.
  • NH silica gel when purified using preparative thin layer chromatography (PTLC) is Wako, NH 2 silica gel 60F254 plate-Wako 20 cm ⁇ 20 cm, “silica gel” is Merck Silica gel 60F254, 20 cm ⁇ 20 cm was used.
  • PTLC preparative thin layer chromatography
  • N-bromosuccinimide (774 mg) and 2,2′-azobis (2-methylpropionitrile) (48 mg) were added to a carbon tetrachloride (15 mL) solution of 2-bromo-5-methylpyrazine (500 mg) at 80 ° C. Stir overnight. After filtration through celite, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (253 mg).
  • reaction solution was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give 3- [6- (trifluoromethyl) pyridin-3-yl] -1-[(1- ⁇ [2- (trimethylsilyl) ethoxy ] Methyl ⁇ -1H-pyrazol-4-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one (820 mg) was obtained.
  • Example 11 1- ⁇ [6- (propan-2-ylamino) pyridin-3-yl] methyl ⁇ -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4. 5] Decan-2-one
  • the filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (2 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (0.25 mL) was added under ice cooling. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate, and then washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give a yellow oil. This was dissolved in 1,4-dioxane (2 mL), 1M hydrochloric acid (2 mL) was added, and the mixture was stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate.
  • Example 16 3- [6- (Difluoromethoxy) pyridin-3-yl] -1- ⁇ [6- (propan-2-yloxy) pyridin-3-yl] methyl ⁇ -1,3-diazaspiro [4.5 ]
  • Example 19 1-[(1-Methyl-2-phenyl-1H-imidazol-4-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4 .5] Decan-2-one
  • Table 1-1, Table 1-2, and Tables 2-1 to 2-24 show the structural formulas of the compounds shown in Examples 1 to 26 and the compounds synthesized by the same method and their instrument data.
  • the numbers described in the column of the examples in the table indicate which of the above Examples 1 to 26 was synthesized by the same method as in the above Examples.
  • a compound in which the salt column is blank indicates a free form.
  • Compounds 14 to 302 are compounds having a structure represented by the following formula [II].
  • Test Example 1 Glycine uptake inhibition experiment. Glycine uptake experiments were performed according to the method described in Neuron, 8, 927-935, 1992. T98G cells that are gliomas expressing human type 1 glycine transporter (GlyT1) were used. T98G cells were seeded in a 96-well plate at 2.0 ⁇ 10 4 cells / well and cultured overnight in a carbon dioxide incubator. A test substance is dissolved in a 100% DMSO solution, and then dissolved in 10 mM HEPES buffer (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. Dissolved.
  • the test substance was pretreated for 10 minutes. Thereafter, a test substance and [ 3 H] glycine (final concentration 250 nM) were added to the cells and allowed to react at room temperature for 15 minutes. After completion of the reaction, the extracellular fluid was aspirated with a manifold, the excess labeled glycine present outside the cells was removed, and then the cells were lysed with a 0.5 M aqueous sodium hydroxide solution. The amount of glycine present in the cells was determined by measuring the radioactivity in the cell lysate with a liquid scintillation counter.
  • the glycine uptake in the presence of 10 ⁇ M ALX5407 was defined as nonspecific uptake, and the total uptake in the absence of 10 ⁇ M ALX5407 minus the nonspecific uptake was defined as the specific uptake. Further, the glycine uptake inhibitory activity (IC 50 value) was calculated from the suppression curve of the test substance at 10 ⁇ 9 to 10 ⁇ 5 M concentration.
  • ALX5407 is N-[(3R) -3-([1,1'-biphenyl] -4-yloxy) -3- (4-fluorophenyl) propyl] -N-methylglycine HCl salt.
  • the IC 50 values of the example compounds in the present invention were all less than 10 ⁇ M. Specific examples, an IC 50 value of Compound 3 0.23MyuM, an IC 50 value of Compound 18 2.3MyuM, an IC 50 value is 0.087 ⁇ M of compound 29, the IC 50 values for compounds 100 0.062MyuM, Compound 134 has an IC 50 value of 0.43 ⁇ M, Compound 194 has an IC 50 value of 1.8 ⁇ M, Compound 240 has an IC 50 value of 0.091 ⁇ M, Compound 248 has an IC 50 value of 0.13 ⁇ M, and Compound 253 has an IC 50 value of 0.065 ⁇ M, Compound 257 had an IC 50 value of 0.057 ⁇ M, and Compound 297 had an IC 50 value of 0.038 ⁇ M.
  • the compound of the present invention has glycine transporter (GlyT1) inhibitory activity, and therefore, diseases related to the glycine transporter, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generality) Anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / many It is effective for the prevention or treatment of dyskinesia, bipolar disorder, eating disorder, or sleep disorder.
  • GlyT1 glycine transporter

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Abstract

La présente invention concerne un nouveau composé représenté par la formule [I] ou un sel pharmaceutiquement acceptable de celui-ci. Ce composé est utile pour la prévention ou le traitement de maladies, telles que la schizophrénie, la maladie d'Alzheimer, un dysfonctionnement cognitif, une démence, des troubles de l'anxiété (trouble de l'anxiété généralisé, un trouble de la panique, un trouble obsessivo-compulsif, un trouble de l'anxiété sociale, un trouble du stress post-traumatique, une phobie spécifique, trouble du stress aigu et similaires), une dépression, une pharmacodépendance, des convulsions, des tremblements, une douleur, la maladie de Parkinson, un trouble du déficit de l'attention/d'hyperactivité, un trouble bipolaire, un trouble alimentaire, un trouble du sommeil et similaires, dans lesquels l'action repose sur une activité inhibitrice de l'entrée de glycine.
PCT/JP2011/079043 2010-12-15 2011-12-15 Substance apte à inhiber un transporteur de la glycine WO2012081665A1 (fr)

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WO2018009627A1 (fr) * 2016-07-07 2018-01-11 Bristol-Myers Squibb Company Urées cycliques spiro fusionnées en tant qu'inhibiteurs de rock

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WO2009034062A1 (fr) * 2007-09-11 2009-03-19 Glaxo Group Limited Composés qui inhibent le transporteur de glycine et ses utilisations en médecine
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JP2004107323A (ja) * 2002-07-26 2004-04-08 Nippon Nohyaku Co Ltd 新規なハロアルキルスルホンアニリド誘導体及び除草剤並びにその使用方法
JP2006509015A (ja) * 2002-12-04 2006-03-16 メルク　エンド　カムパニー　インコーポレーテッド スピロ環尿素、そのような化合物を含有する組成物、及び使用方法
JP2010517964A (ja) * 2007-02-01 2010-05-27 グラクソ グループ リミテッド ＧｌｙＴ１トランスポーター阻害薬および神経学的および神経精神病学的障害の治療におけるその使用
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WO2018009627A1 (fr) * 2016-07-07 2018-01-11 Bristol-Myers Squibb Company Urées cycliques spiro fusionnées en tant qu'inhibiteurs de rock
KR20190025683A (ko) * 2016-07-07 2019-03-11 브리스톨-마이어스 스큅 컴퍼니 Rock의 억제제로서의 스피로-융합 시클릭 우레아
CN109661396A (zh) * 2016-07-07 2019-04-19 百时美施贵宝公司 作为rock抑制剂的螺稠合环状脲
JP2019520396A (ja) * 2016-07-07 2019-07-18 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｒｏｃｋ阻害剤としてのスピロ縮合環尿素
US10787450B2 (en) 2016-07-07 2020-09-29 Bristol-Myers Squibb Company Spiro-fused cyclic ureas as inhibitors of rock
CN109661396B (zh) * 2016-07-07 2022-07-01 百时美施贵宝公司 作为rock抑制剂的螺稠合环状脲
KR102449652B1 (ko) * 2016-07-07 2022-09-29 브리스톨-마이어스 스큅 컴퍼니 Rock의 억제제로서의 스피로-융합 시클릭 우레아
JP7155102B2 (ja) 2016-07-07 2022-10-18 ブリストル－マイヤーズ スクイブ カンパニー Ｒｏｃｋ阻害剤としてのスピロ縮合環尿素

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