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WO2010053127A1 - Modulateur du récepteur α1-gabaa ou du récepteur α5-gabaa - Google Patents

Modulateur du récepteur α1-gabaa ou du récepteur α5-gabaa Download PDF

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Publication number
WO2010053127A1
WO2010053127A1 PCT/JP2009/068914 JP2009068914W WO2010053127A1 WO 2010053127 A1 WO2010053127 A1 WO 2010053127A1 JP 2009068914 W JP2009068914 W JP 2009068914W WO 2010053127 A1 WO2010053127 A1 WO 2010053127A1
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substituent
optionally substituted
pharmaceutically acceptable
acceptable salt
optionally
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PCT/JP2009/068914
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English (en)
Japanese (ja)
Inventor
正森 菅原
友浩 檀上
高雄 中島
真一 内田
範明 上坂
崇子 堀田
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協和発酵キリン株式会社
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    • 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
    • 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
    • A61P25/20—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
    • A61P25/24—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
    • A61P25/32—Alcohol-abuse
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to an ⁇ 1GABA A receptor modulator or ⁇ 5GABA A receptor modulator having a pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • GABA ⁇ -aminobutyric acid
  • GABA A and GABA C receptors with built-in ion channels and GA protein B- coupled GABA B receptors, of which GABA A receptors are four-transmembrane subunits.
  • a heteropentameric structure consisting of The subunit types are: ⁇ : 6 species ( ⁇ 1-6), ⁇ : 3 species ( ⁇ 1-3), ⁇ : 3 species ( ⁇ 1-3), ⁇ : 3 species ( ⁇ 1-3) and ⁇ , ⁇ , ⁇ is one each, but most receptors are composed of three types, ⁇ , ⁇ , and ⁇ .
  • GABA A receptors, Cl contained in the receptor by binding of GABA - increasing the permeability of the ion channel, Cl - is possible to suppress the excitation of nerve cells are known by influx of ions.
  • an agonist binds to the benzodiazepine binding site contained in the GABA A receptor, and acts to enhance the action of GABA for GABA A receptor, Cl - increase the flux of ions.
  • benzodiazepine derivatives such as diazepam have anticonvulsant, anti-anxiety, muscle relaxation, hypnosis, and amnesia effects, so GABA A receptors are epilepsy, anxiety, muscle contraction, arousal, learning / memory, etc. [Journal of Pharmacology and Experimental Therapeutics, Vol. 300, p. 2 (2002)].
  • the pharmacological actions of these GABA and benzodiazepine derivatives are considered to be based on the diversity of ⁇ subunits constituting the GABA A receptor and the distribution of in vivo expression of each subtype.
  • GABA A receptors containing ⁇ 1 subunits ⁇ 1GABA A receptors
  • ⁇ 1GABA A receptors are known to be widely distributed in the brain.
  • benzodiazepine receptor inverse agonists have been reported to improve cognitive function and promote arousal [Nature (321), p.864 (1986), pharmacology, biochemistry, And Behavior (Pharmacology Biochemistry and Behavior), Volume 35, p. 889 (1990)].
  • Benzodiazepine receptor antagonists have been reported for use in overdose benzodiazepines to release sedation and improve respiratory depression [Emergency Medicine Journal, Vol. 23, p. 162. (2006)].
  • ligands for the ⁇ 1GABA A receptor include, for example, sleep disorders, depression, epilepsy, Alzheimer's disease, Down syndrome, cerebrovascular dementia, and cognitive impairment associated with psychiatric / neurological diseases ( Treatment and / or prevention of central nervous system diseases such as ataxia, bipolar disorder, depression, chronic fatigue syndrome, etc., or release of sedation with sedative hypnotics, anesthetics, muscle relaxants, benzodiazepines and Expected to improve respiratory depression.
  • GABA A receptor containing ⁇ 2 subunit exists mainly in the limbic system
  • GABA A receptor containing ⁇ 3 subunit ⁇ 3GABA A receptor
  • GABA A receptor containing ⁇ 5 subunit ( ⁇ 5GABA A receptor) is localized particularly in the hippocampus, and mice lacking this receptor reported higher spatial learning / memory ability than wild type. [The Journal of Neuroscience, Vol. 22, p. 5572 (2002)].
  • inverse agonists to ⁇ 5GABA A receptor show an effect of improving cognitive function, and ⁇ 5GABA A receptor is considered to be involved in learning and memory [Journal of Medicinal Chemistry (Journal of Medicinal Chemistry), 47, p. 5829 (2004)].
  • ligands for ⁇ 5GABA A receptor are cognitive dysfunctions associated with Alzheimer's disease, Down's syndrome, cerebrovascular dementia, neuropsychiatric disorders (e.g. attention deficit hyperactivity disorder, schizophrenia, Bipolar disorder, depression, chronic fatigue syndrome, etc.), and are expected as therapeutic and / or preventive drugs for central nervous system diseases such as drug dependence (such as alcoholism).
  • neuropsychiatric disorders e.g. attention deficit hyperactivity disorder, schizophrenia, Bipolar disorder, depression, chronic fatigue syndrome, etc.
  • drug dependence such as alcoholism
  • Examples of ⁇ 1GABA A receptor modulators include imidazopyridine derivatives (Patent Document 1), imidazopyrazine derivatives (Patent Document 2), pyrazolopyrimidine derivatives (Patent Document 3), quinolone derivatives (Patent Document 4), cinnoline derivatives ( A large number of compounds such as Patent Document 5) are known.
  • Examples of ⁇ 5GABA A receptor modulators include imidazotriazolobenzodiazepine derivatives (Patent Document 6), imidazopyridine derivatives (Patent Document 7), triazoloindane derivatives (Patent Document 8), and triazolopyridazine derivatives (Patent Document 9). Many compounds such as phenylpyridazine derivatives (Patent Document 10) are known.
  • a compound represented by the following formula (A) (Patent Document 11) is known as a compound having a lower alkyl substituted with an aryl group at the 2-position.
  • compounds represented by the following formulas (B) and (C) (Patent Document 12, Non-Patent Document 1) and the like are also known as compounds having an amino group substituted with a lower alkyl group at the 2-position.
  • a compound represented by the following (D) (Patent Document 13) is also known.
  • compounds having a lower alkyl group at the 1-position and a hydrogen atom at the 2-position compounds represented by the following formulas (E) and (F) (Non-patent Document 2) are also known.
  • An object of the present invention is to provide an ⁇ 1GABA A receptor modulator, an ⁇ 5GABA A receptor modulator or the like containing a pyridopyrimidone derivative as an active ingredient. Another object is to provide an ⁇ 1GABA A receptor modulator, a novel pyridopyrimidone derivative having an ⁇ 5GABA A receptor modulatory activity, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the following (1) to (30).
  • R 1 represents a hydrogen atom, optionally substituted lower alkyl or optionally substituted cycloalkyl
  • R 2 represents optionally substituted lower alkyl.
  • R 3 represents —NR 6 R 7 ( In the formula, R 6 and R 7 are the same or different, and may be a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted.
  • R 4 and R 5 are the same or different and represent a hydrogen atom, halogen, hydroxy, Nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, substituent Lower alkanoyl optionally substituted Lower alkoxy which may have a group, cycloalkyl which may have a substituent, lower alkylamino which may have a substituent, di-lower alkylamino which may have a substituent, Aryl which may have a substituent, aralkyl which may have a substituent, aroyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, substituent Represents an aromatic heterocyclic group which may have a substituent, an aliphatic heterocyclic alkyl which may have a substituent, substituent Represents an aromatic heterocyclic group which may have a substituent, an
  • R 1 represents a hydrogen atom, optionally substituted lower alkyl or optionally substituted cycloalkyl
  • R 2 represents optionally substituted lower alkyl.
  • R 3 represents —NR 6 R 7 ( In the formula, R 6 and R 7 are the same or different, and may be a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted.
  • R 4 and R 5 are the same or different and represent a hydrogen atom, halogen, hydroxy, Nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, substituent Lower alkanoyl optionally substituted Lower alkoxy which may have a group, cycloalkyl which may have a substituent, lower alkylamino which may have a substituent, di-lower alkylamino which may have a substituent, Aryl which may have a substituent, aralkyl which may have a substituent, aroyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, substituent An aromatic heterocyclic group which may have a substituent, an aliphatic heterocyclic alkyl which may have a substituent or an aromatic heterocyclic group which may have a substituent, an aliphatic heterocyclic alky
  • R 1A represents a hydrogen atom, optionally substituted lower alkyl, or optionally substituted cycloalkyl
  • R 2A represents optionally substituted lower alkyl.
  • R 3A represents —NR 6A R 7A ( In the formula, R 6A and R 7A are the same or different and each may have a hydrogen atom, a lower alkyl optionally having substituent (s), a lower alkenyl optionally having substituent (s), or a substituent (s).
  • R 3A is not unsubstituted aryl] or a pharmaceutically acceptable salt thereof (however, 2-butyl Except -5-methyl-7-methylamino-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one ).
  • R 1A is a hydrogen atom.
  • R 3A is tetrahydroisoquinolin-2-yl or tetrahydroisoquinolin-2-yl having 1 or 2 substituents, or a pyridopyrimidone derivative according to (3) or (4) or a pharmaceutically acceptable salt thereof salt.
  • R 3A is piperazin-1-yl substituted with an aromatic heterocyclic group at the 4-position or tetrahydropyridin-1-yl substituted with an aromatic heterocyclic group at the 4-position (3) or (4) The described pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof.
  • (10) The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (9), wherein R 2A is lower alkyl optionally having substituent (s).
  • (11) The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (9), wherein R 2A is cycloalkyl which may have a substituent.
  • a method for modulating an ⁇ 1GABA A receptor comprising administering an effective amount of the compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof.
  • Treatment of a disease associated with ⁇ 1GABA A receptor comprising administering an effective amount of the compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof.
  • And / or preventive methods comprising administering an effective amount of the compound according to any one of (2) or (3) to (14) or a pharmaceutically acceptable salt thereof.
  • the present invention provides an ⁇ 1GABA A receptor modulator or ⁇ 5GABA A receptor modulator containing a pyridopyrimidone derivative as an active ingredient.
  • various diseases involving ⁇ 1GABA A receptor that regulate ⁇ 1GABA A receptor eg sleep disorders, depression, epilepsy, Alzheimer's disease, Down's syndrome, cerebrovascular dementia, cognitive impairment associated with psychiatric / neurological disorders
  • central nervous disease such as attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome
  • treatment and / or prevention drugs or sedative hypnotics, anesthetics
  • Useful as a muscle relaxant, benzodiazepine release sedation and respiratory suppression or has ⁇ 5GABA A receptor modulation, such as Alzheimer's disease, schizophrenia, cerebrovascular dementia, drug dependence ( A novel pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof, which is useful for the treatment and / or prevention of alcohol dependence, etc. .
  • the compound represented by formula (I) is referred to as compound (I).
  • Examples of the lower alkyl portion of lower alkyl, lower alkanoyl, lower alkoxy, lower alkylamino and di-lower alkylamino include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically methyl, ethyl Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • the two lower alkyl moieties of the di-lower alkylamino may be the same or different.
  • lower alkenyl examples include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically, vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. Can be given.
  • lower alkynyl examples include linear or branched alkynyl having 2 to 10 carbon atoms, and more specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
  • cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, and more specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aryl and the aryl moiety of aralkyl and aroyl include aryl having 6 to 14 carbon atoms, and more specifically, phenyl, naphthyl, azulenyl, anthryl and the like.
  • aromatic heterocyclic group part of the aromatic heterocyclic group and the aromatic heterocyclic alkyl examples include, for example, a 5-membered or 6-membered monocyclic fragrance containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Examples of the aliphatic heterocyclic group and the aliphatic heterocyclic group part of the aliphatic heterocyclic alkyl include, for example, a 5-membered or 6-membered monocyclic fat containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • a heterocyclic heterocyclic group a bicyclic or tricyclic condensed 3- to 8-membered ring, and a condensed aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom More specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl 5,6-dihydro-2H-pyranyl, oxazolidinyl, mole Lino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl
  • Examples of the aralkyl and the alkylene moiety of the aromatic heterocyclic alkyl and the aliphatic heterocyclic alkyl include linear or branched alkylene having 1 to 10 carbon atoms, and more specifically methylene, ethylene, propylene, tetra Examples include methylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like.
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , Which may contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3- to 8-membered rings and containing at least one nitrogen atom ( The condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, Imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidin
  • the lower alkoxy which may have a substituent, the lower alkylamino which may have a substituent, and the di-lower alkylamino which may have a substituent may be the same or different.
  • R X and R Y are the same or different, a hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, an aromatic heterocyclic group, C 7-16 aralkyl, C 2 -11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl or C 7-16 aralkyloxycarbonyl), C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl, C 6- And a substituent selected
  • substituent in the aromatic heterocyclic alkyl optionally having the same or different, for example, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 1-10 alkyl, having 1 to 3 substituents, Trifluoromethyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C 1-10 alkoxy, C 3-8 cycloalkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, -NR X R Y (wherein , R X and R Y are the same meanings as defined above, respectively),
  • an optionally substituted cycloalkyl an optionally substituted aliphatic heterocyclic group, an optionally substituted aliphatic heterocyclic alkyl or an adjacent nitrogen atom
  • the substituents in the nitrogen-containing heterocyclic group which may have a substituent may be the same or different, for example, oxo, halogen, hydroxy, hydroxyethyl, sulfanyl, nitro, cyano having 1 to 3 substituents.
  • Examples of the C 1-10 alkyl moiety of diC 1-10 alkylcarbamoyl include the groups exemplified above for the lower alkyl.
  • the two C 1-10 alkyls in the diC 1-10 alkylcarbamoyl may be the same or different.
  • the C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy, e.g. groups mentioned for illustrative said cycloalkyl is exemplified.
  • Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples.
  • Examples of the aromatic heterocyclic moiety of the aromatic heterocyclic carbonyl include the groups exemplified above for the aromatic heterocyclic group.
  • Examples of the aryl moiety of C 7-16 aralkyloxy, C 7-16 aralkyl, and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above aryl, and examples of the alkyl moiety include, for example, the alkylene part of the aralkyl.
  • the groups mentioned in the above examples are exemplified.
  • Examples of the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen include the groups exemplified in the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen.
  • the aliphatic heterocyclic alkyl has the same meaning as described above.
  • R 1A is a hydrogen atom
  • R 2A is optionally substituted lower alkyl
  • R 3A is —NR 6A R 7A (wherein R 6A and R 7A are each As defined above, a compound in which R 4A is a hydrogen atom or R 5A is a hydrogen atom or an optionally substituted lower alkyl is preferable.
  • R 1A is a hydrogen atom
  • R 2A is an optionally substituted lower alkyl
  • R 3A is —NR 6AA R 7AA (wherein R 6AA and R 7AA Are as defined above)
  • R 4A is a hydrogen atom or R 5A is a hydrogen atom or a lower alkyl optionally having substituent (s) are preferred.
  • R 1A is a hydrogen atom
  • R 2A is a lower alkyl optionally having substituent (s)
  • R 3A is tetrahydroisoquinolin-2-yl or a tetrahydro having 1 or 2 substituents Isoquinolin-2-yl, isoindoline-2-yl or isoindoline-2-yl having 1 or 2 substituents, or piperazin-1-yl or 4-position substituted with an aromatic heterocyclic group at the 4-position
  • the compound is tetrahydropyridin-1-yl substituted with an aromatic heterocyclic group
  • R 4A is a hydrogen atom
  • R 5A is a hydrogen atom or a lower alkyl which may have a substituent.
  • the ⁇ 1GABA A receptor modulator means an ⁇ 1GABA A receptor agonist, an ⁇ 1GABA A receptor antagonist, or an ⁇ 1GABA A receptor inverse agonist.
  • the ⁇ 5GABA A receptor modulator means an ⁇ 5GABA A receptor agonist, an ⁇ 5GABA A receptor antagonist or an ⁇ 5GABA A receptor inverse agonist, and an ⁇ 5GABA A receptor inverse agonist is preferred.
  • Pharmaceutically acceptable salts of compounds (I) and (IA) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • Examples of pharmaceutically acceptable acid addition salts of compounds (I) and (IA) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, and citric acid.
  • Examples of the pharmaceutically acceptable metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and the like.
  • Examples of the pharmaceutically acceptable ammonium salt include salts such as ammonium and tetramethylammonium.
  • Examples of the pharmaceutically acceptable organic amine addition salt include morpholine and piperidine.
  • Examples of pharmaceutically acceptable amino acid addition salts include lysine, glycine, phenylalanine, aspartic acid, glutamine. Addition salts and the like.
  • the ⁇ 1GABA A receptor modulator of the present invention can be used for various diseases involving the ⁇ 1GABA A receptor (for example, sleep disorders, depression, epilepsy, Alzheimer's disease, Down's syndrome, cerebrovascular dementia, and cognitive impairment associated with psychiatric / neurological disorders.
  • diseases involving the ⁇ 1GABA A receptor for example, sleep disorders, depression, epilepsy, Alzheimer's disease, Down's syndrome, cerebrovascular dementia, and cognitive impairment associated with psychiatric / neurological disorders.
  • central nervous disease such as attention deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome
  • treatment and / or prevention drugs or sedative hypnotics, anesthetics
  • It is used as a muscle relaxant, a benzodiazepine-based sedation release agent, and an agent for improving respiratory depression.
  • Examples of the disease involving the ⁇ 5GABA A receptor to be treated and / or prevented by the ⁇ 5GABA A receptor modulator of the present invention include Alzheimer's disease, Down's syndrome, cerebrovascular dementia, and cognitive dysfunction associated with a psychiatric / neurological disorder ( For example, attention-deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.), central nervous system diseases such as drug dependence (such as alcoholism), and the like.
  • a psychiatric / neurological disorder For example, attention-deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.
  • central nervous system diseases such as drug dependence (such as alcoholism), and the like.
  • Compound (I) can be produced according to the following steps. Manufacturing method 1 Among compounds (I), compound (IA) in which R 3 is —NR 6 R 7 (wherein R 6 and R 7 are as defined above) can be produced by the following steps. .
  • Process 1 Compound (a-3) is preferably compound (a-1), preferably 1 to 20 equivalents of compound (a-2), in the absence of solvent or in a solvent, preferably 1 to 20 equivalents of a base.
  • the reaction can be carried out at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used or, if necessary, at a temperature higher than the boiling point using a microwave reactor for 5 minutes to 72 hours.
  • Compound (a-1) is obtained as a commercially available product, or by the method described in US5200522 or a method analogous thereto.
  • a known method from the corresponding carboxylic acid compound [for example, Experimental Chemistry Course 5th edition, Volume 16, p.119, edited by The Chemical Society of Japan, Maruzen (2005)] or a method according to them, or the corresponding nitrile It can also be obtained by subjecting the compound to hydrolysis [for example, Experimental Chemistry Course, 5th Edition, Volume 16, p.135, edited by The Chemical Society of Japan, Maruzen (2005)].
  • Compound (a-2) is obtained as a commercially available product or obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 14, p.351, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done.
  • the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N-dimethylaminopyridine.
  • DMAP potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate and the like.
  • the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, tetrahydrofuran (THF), ethyl acetate, diethyl ether, 1,2-dimethoxyethane (DME), 1,4- Examples include dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), pyridine, water, etc., either alone or in combination.
  • DMF N-dimethylformamide
  • DMA N-dimethylacetamide
  • NMP N-methylpyrrolidone
  • Process 2 Compound (a-5) is preferably compound (a-3) with 1 to 200 equivalents of compound (a-4a) in the absence of a solvent or in a solvent, preferably in the presence of 1 to 20 equivalents of an acid.
  • the reaction can be carried out at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
  • Compound (a-4a) is obtained as a commercially available product or obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 16, p.95, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done.
  • the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid, and the like.
  • solvent examples include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, THF, ethyl acetate, diethyl ether, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Acetic acid, acetic anhydride, water and the like, and these can be used alone or in combination.
  • compound (a-5) is preferably compound (a-3), preferably 1 to 20 equivalents of compound (a-4b), without solvent or in a solvent, preferably 1 to 20 equivalents of a base. It can also be obtained by reacting in the presence at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
  • Compound (a-4b) can be obtained as a commercially available product or by a known method [for example, Experimental Chemistry Course 5th edition, Volume 16, p.99, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done.
  • Examples of the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DMAP, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, Examples thereof include potassium hydroxide and potassium phosphate.
  • Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, THF, ethyl acetate, diethyl ether, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine.
  • Process 3 Compound (IA) is preferably compound (a-5) with 1 to 20 equivalents of compound (a-6) in the absence of a solvent or in a solvent, preferably in the presence of 1 to 20 equivalents of a base.
  • the reaction can be carried out at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used or, if necessary, at a temperature higher than the boiling point using a microwave reactor for 5 minutes to 72 hours.
  • Compound (a-6) is obtained as a commercially available product or obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 14, p.351, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done.
  • the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DMAP, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, Examples thereof include potassium hydroxide and potassium phosphate.
  • the solvent examples include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, THF, ethyl acetate, diethyl ether, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Acetic acid, acetic anhydride, water and the like, and these can be used alone or in combination.
  • Manufacturing method 2 Among the compounds (I), the compound (IB) in which R 3 is an optionally substituted aryl or an optionally substituted aromatic heterocyclic group is produced by the following steps. be able to.
  • R 1 , R 2 , R 4 , R 5 and Y 2 are the same as defined above, and A is an aryl which may have a substituent or an aromatic which may have a substituent.
  • M is B (OR ma ) (OR mb ) (wherein R ma and R mb are the same or different and represent a hydrogen atom, C 1-6 alkyl, or R ma and R mb are Together with C 1-6 alkylene which may be substituted by methyl) or SnR mc R md R me (wherein R mc , R md and R me are the same or different and are C 1-6 alkyl or phenyl Represents).
  • Compound (IB) is preferably compound (a-5), preferably 1 to 10 equivalents of compound (a-7), and preferably in the presence of 0.001 to 1 equivalents of a palladium catalyst, preferably 0.1 to 1 equivalents of palladium catalyst.
  • the reaction can be carried out in the presence of ⁇ 10 equivalents of base at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
  • Compound (a-7) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 18, p.95, 183, edited by The Chemical Society of Japan, Maruzen (2004)] or It can be obtained by a method according to them.
  • the palladium catalyst include compounds in which a phosphine ligand is coordinated to a palladium atom
  • examples of the palladium source include palladium acetate, palladium trifluoroacetate, tris (dibenzylideneacetone) dipalladium, and chloroform adducts thereof. can give.
  • phosphine ligand examples include triphenylphosphine, 1,1, -bis (diphenylphosphino) ferrocene, o-tolylphosphine, etc., and these are preferably used in an amount of 1 to 10 equivalents relative to the palladium source. .
  • a commercially available reagent such as tetrakis (triphenylphosphine) palladium can also be used.
  • Examples of the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DMAP, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, Examples thereof include potassium hydroxide and potassium phosphate.
  • Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.
  • the intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Some compounds (I) and (IA) may have stereoisomers such as positional isomers, geometric isomers, optical isomers, tautomers, etc., but all possible Isomers and mixtures thereof are used or included in the present invention.
  • a salt of compound (I) or (IA) When it is desired to obtain a salt of compound (I) or (IA), it can be purified as it is when compound (I) or (IA) is obtained in the form of a salt. Isolation and purification may be performed by dissolving or suspending (I) or (IA) in a suitable solvent and adding an acid or base to form a salt.
  • compounds (I) and (IA) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used in the present invention. Or included.
  • Test Example 1 GABA A receptor ( ⁇ 1 ⁇ 3 ⁇ 2s) binding action [ 3 H] Ro15-1788 binding inhibition test was performed by the method of Strakhova et al. [Molecular Pharmacology, Vol. 58, p.1434-1440 (2000) )].
  • ⁇ 1 subunit Accession No. NM_183326
  • ⁇ 3 subunit Accession No. NM_017065
  • ⁇ 2s subunit Accession No. NM_183327
  • Membrane specimens (final protein concentration 800 ⁇ g / mL) were combined with test compound and [ 3 H] Ro15-1788 (PerkinElmer, final concentration 1 nmol / L) with assay buffer [10 mmol / L Tris-HCl (pH 7 .4), 1 mmol / L EDTA] at 4 ° C. for 1 hour, and then filtered through a 0.3% polyethyleneimine-treated filter (UniFilter GF / B, Packard BioScience). After washing with assay buffer, the radioactivity on the filter was determined with a micro scintillation counter (TopCount NXT, Packard Instruments).
  • the inhibitory activity of the test compound on [ 3 H] Ro15-1788 binding to the rat GABA A receptor was calculated by the following formula.
  • the test compound concentration is 10 ⁇ mol / L.
  • the total binding amount in the formula is the radioactivity in the absence of the test compound, and the non-specific binding amount is the radiation in the presence of 10 ⁇ mol / L flunitrazepam (Sigma-Aldrich). Active.
  • ⁇ 5 subunit (Accession No. NM_017295), ⁇ 3 subunit (Accession No. NM_017065), and ⁇ 2s subunit (Accession No. NM_183327) of rat GABA receptor were expressed simultaneously and transiently.
  • a membrane fraction prepared from CHO-K1 cells was used. Membrane specimens (final protein concentration 150 ⁇ g / mL) were combined with test compound and [ 3 H] Ro15-1788 (PerkinElmer, final concentration 1 nmol / L) with assay buffer [10 mmol / L Tris-HCl (pH 7 .4), 1 mmol / L EDTA] at 4 ° C.
  • the inhibitory activity of the test compound on [ 3 H] Ro15-1788 binding to the rat GABA A receptor was calculated by the following formula.
  • the test compound concentration is 1 ⁇ mol / L, and the total binding amount in the formula is the radioactivity in the absence of the test compound, and the nonspecific binding amount is the radiation in the presence of 10 ⁇ mol / L flunitrazepam (Sigma-Aldrich). Active.
  • Compounds 1, 2, 4, 5, 10, 11, 14, 15, 16, 17, 19, 20, 22, 23, 24, 25, 26, 29, 30, 31, 32 are at a concentration of 1 ⁇ mol / L.
  • the binding inhibitory activity was 50% or more. From the above, it was confirmed that Compound (I) has a strong affinity for the ⁇ 5GABA A receptor.
  • Test Example 3 ⁇ 5GABA A receptor reverse agonist activity test was performed according to the method of Adkins et al. [The Journal of Biological Chemistry, 276, p.38934-38939 (2001)]. It was.
  • test compounds of the present invention inhibit changes in membrane potential when stimulated with 100 nM GABA. did. From these results, it was confirmed that these compounds have reverse agonist activity against rat ⁇ 5GABA A receptor. In other words, these compounds are associated with ⁇ 5GABA A receptor-related diseases (Alzheimer's disease, Down syndrome, cerebrovascular dementia, cognitive dysfunction associated with psychiatric / neurological disorders (eg attention deficit hyperactivity disorder, schizophrenia, bipolar) sexual disorders, depression, chronic fatigue syndrome, etc.), central nervous diseases such as drug dependence (such as alcoholism), etc.) and / or prevention. Test Example 4 The action test on scopolamine-induced spatial memory impairment was performed according to the method of Itoh et al. [European Journal of Pharmacology, Vol. 236, page 341 (1993)].
  • AF64A was prepared from Acetyl AF64A (Acetylethylcholine mustard hydrochloride, Sigma-Aldrich) and administered into the left ventricle of ddY mice (male, SLC Japan) (10 nmol / 5 ⁇ L / mouse). Mice were used for the study with a recovery period of one week or longer. Any of the radial water maze experimental device [6 arms made of black acrylic wall (33cm long, 20cm wide, 25cm deep) connected at an angle of 60 degrees each] A platform was placed at one end of the arm. The mouse was placed in one end of the arm other than the one with the platform and allowed to swim freely for 1 minute in the maze.
  • the state where all the limbs of the mouse were in one arm was defined as entry into the arm, and the number of times the mouse entered the arm without the platform before reaching the platform was recorded as the number of errors.
  • the above 1 minute work was set as 1 trial, and 15 trials were carried out by changing the starting point for each trial. After 15 trials, mice were grouped so that the average number of errors in the last 3 trials was equal.
  • the test compound or solvent was orally administered to the mice, and 15 trials were performed again 30 minutes after the treatment. Using the number of errors as an index, the effect on AF64A-induced spatial memory impairment was compared between the test compound administration group and the solvent group.
  • Ethanol was administered intraperitoneally (0.75 g / kg) to SD rats (male, Charles).
  • the rat was placed in the experimental box of the contextual learning experimental device (Ohara Seisakusho) and presented with foot shock (0.5 mA, 1 second) three times as an unconditional stimulus.
  • rats were placed in the same experimental box for 4 minutes to measure the onset time of freezing, an indicator of conditioned fear memory.
  • the behavior of animals in the test cage was recorded by a CCD camera installed on the ceiling of the experiment box and analyzed with a PC system. An immobile state that continued for 2 seconds or more was defined as freezing, and the freezing rate was calculated by the following formula.
  • Freezing rate (%) (Freezing time / measurement time) x 100 Test compounds or solvents were administered orally 30 minutes before ethanol treatment. Using freezing as an index, the effect on ethanol-induced fear-conditioned memory impairment was compared between the test compound-administered group and the solvent group.
  • test compound (I) or a pharmaceutically acceptable salt thereof was found to be associated with a disease involving ⁇ 5GABA A receptor (eg, Alzheimer's disease, cognitive dysfunction associated with psychiatric / neurological disorder (eg, attention deficit hyperactivity) Disability, Schizophrenia, Bipolar Disorder, Depression, Chronic Fatigue Syndrome, etc.), Drug Addiction (such as Alcoholism), etc.).
  • a disease involving ⁇ 5GABA A receptor eg, Alzheimer's disease, cognitive dysfunction associated with psychiatric / neurological disorder (eg, attention deficit hyperactivity) Disability, Schizophrenia, Bipolar Disorder, Depression, Chronic Fatigue Syndrome, etc.), Drug Addiction (such as Alcoholism), etc.
  • Test Example 7 The action test on the delayed non-sample matching task was performed according to the method of Roux et al. [Pharmacology Biochemistry and Behavior, 49, 683 (1994)].
  • test compound or solvent was orally administered to the rats subjected to the above training, and the test was performed 30 minutes after the treatment.
  • the effect on the positive selection rate of rats and the time until selection (selection reaction time) after 2 levers were presented was compared between the test compound administration group and the solvent group.
  • the selection reaction time was shortened without affecting the positive selectivity.
  • the test compound has an attention function and an information processing ability improvement effect.
  • compound (I) or a pharmaceutically acceptable salt thereof is a cognitive dysfunction associated with ⁇ 5GABA A receptor-related diseases (Alzheimer's disease, Down's syndrome, cerebrovascular dementia, psychiatric / neurological disorder) (Eg, attention deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.)) were considered useful for the treatment and / or prevention.
  • ⁇ 5GABA A receptor-related diseases Alzheimer's disease, Down's syndrome, cerebrovascular dementia, psychiatric / neurological disorder
  • Eg attention deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.
  • Test Example 8 Effects on pentylenetetrazole-induced convulsions
  • Non-selective benzodiazepine receptor inverse agonists are known to enhance pentylenetetrazole-induced convulsions [Progress in Neuropsychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry), 12, 951 (1988)]. Then, the effect
  • Pentylenetetrazole (40 or 60 mg / kg, Tokyo Chemical Industry) was intraperitoneally administered to ddY mice (male, Japan SLC), and the presence or absence of convulsions was recorded for 1 hour immediately after that. Test compounds or solvents were administered orally 60 minutes prior to pentylenetetrazole treatment. The effect on pentylenetetrazole-induced convulsions was compared between the test compound administration group and the solvent group. As a test compound, it was shown that pentylenetetrazole-induced convulsions were not enhanced in the group administered with the compound of the present invention.
  • Test compounds or solvents were orally administered to ddY mice (male, Japan SLC). After 60 minutes of treatment, the mouse was placed in the light room of a light / dark box device (Unicom) and allowed to freely explore the device for 5 minutes. At this time, the state where all the limbs of the animal were in the bright room was defined as entry into the bright room, and the staying time and the number of times of entry of the animal were measured. The presence or absence of anxiety-inducing action was compared between the test compound administration group and the solvent group using the staying time in the light room and the number of times of entry as indices.
  • a light / dark box device Unicom
  • Compound (I) or (IA) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide them as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
  • the pharmaceutical preparation according to the present invention contains the compound (I) or (IA) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. Can do.
  • these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers.
  • oral administration and parenteral administration such as intravenous administration.
  • examples of the dosage form include tablets and injections. Suitable for oral administration, such as tablets, excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and surface activity such as fatty acid esters And a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration preferably comprise a sterile aqueous solution containing the active compound that is isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of salt water and a glucose solution.
  • a carrier comprising a salt solution, a glucose solution, or a mixture of salt water and a glucose solution.
  • these parenteral agents one kind selected from excipients, disintegrating agents, lubricants, binders, surfactants, plasticizers and diluents, preservatives, flavors and the like exemplified for oral agents. Or more auxiliary components may be added.
  • Compound (I) or (IA) or a pharmaceutically acceptable salt thereof is usually administered systemically or locally in an oral or parenteral form when used for the above purpose.
  • the dose and frequency of administration vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc., but usually oral, 0.01 to 1000 mg per adult, preferably Administer once or several times daily in the range of 0.05 to 500 mg.
  • parenteral administration such as intravenous administration, usually 0.001 to 1000 mg, preferably 0.01 to 300 mg per adult is administered once to several times a day, or intravenously in the range of 1 to 24 hours per day. Administer continuously.
  • the dose and the number of doses vary depending on the various conditions described above.
  • Reference example 2 7-chloro-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound b)
  • Process 1 Compound a (382 mg, 2.00 mmol) obtained in Reference Example 1 is dissolved in 1,4-dioxane (2.5 mL), propylamine (0.820 mL, 10.0 mmol) is added, and 110 ° using a microwave reactor. Stir at C for 30 min. Saturated aqueous sodium hydrogen carbonate solution (1 mL) was added to the reaction mixture, the mixture was filtered through diatomaceous earth, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure.
  • Process 2 4- (Pyridin-3-yl) -1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (423 mg, 1.62 mmol) obtained in Step 1 was added to a 1% hydrogen chloride methanol solution (5.0 The reaction mixture was dissolved in mL) and stirred for 3 days under reflux. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound (200 mg, 77%).
  • an ⁇ 1GABA A receptor modulator or an ⁇ 5GABA A receptor modulator containing a pyridopyrimidone derivative as an active ingredient.
  • various diseases involving ⁇ 1GABA A receptor that regulate ⁇ 1GABA A receptor eg sleep disorders, depression, epilepsy, Alzheimer's disease, Down's syndrome, cerebrovascular dementia, cognitive impairment associated with psychiatric / neurological disorders
  • Treatment and / or prevention of central nervous disease eg attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.
  • sedative hypnotics, anesthetics muscles relaxants useful as such improve drug release and respiratory depression sedation by benzodiazepines, or having Arufa5GABA a receptor modulating effects, such as Alzheimer's disease, schizophrenia, vascular dementia, drug addiction (alcohol A novel pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof, which is useful for the treatment and / or prevention of

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Abstract

L'invention porte sur : un modulateur du récepteur α1-GABAA ou un modulateur du récepteur α5-GABAA comprenant, comme principe actif, un dérivé de pyridopyrimidone représenté par la formule générale (I) [dans laquelle R1 représente un atome d'hydrogène, un alkyle inférieur qui peut avoir un substituant, ou similaire; R2 représente un alkyle inférieur qui peut avoir un substituant, ou similaire; R3 représente –NR6R7 (où R6 représente un atome d'hydrogène, ou similaire; et R7 représente un atome d'hydrogène, un alkyle inférieur qui peut avoir un substituant, ou similaire), ou similaire; et R4 et R5 représentent indépendamment un halogène, un alkyle inférieur qui peut avoir un substituant, ou similaire] ou un sel pharmaceutiquement acceptable de celui-ci; et autres.
PCT/JP2009/068914 2008-11-05 2009-11-05 Modulateur du récepteur α1-gabaa ou du récepteur α5-gabaa WO2010053127A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2012059482A1 (fr) * 2010-11-05 2012-05-10 F. Hoffmann-La Roche Ag Utilisation de composés pharmaceutiques actifs pour le traitement d'états du système nerveux central
EP2457569A1 (fr) * 2010-11-05 2012-05-30 F. Hoffmann-La Roche AG Utilisation de composés pharmaceutiques actifs pour le traitement de conditions du système nerveux central
CN107298655A (zh) * 2017-08-24 2017-10-27 郑州轻工业学院 7,8‑二甲氧基‑2,3,4,5‑四氢‑1H‑苯并[c]氮杂卓盐酸盐及其制备方法
JP2022521968A (ja) * 2019-03-01 2022-04-13 エイシー イミューン ソシエテ アノニム タウ凝集体に関連する障害の治療、緩和、または予防のための新規化合物

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WO2008121257A1 (fr) * 2007-03-28 2008-10-09 Merck & Co., Inc. Dérivés de pyrido[2,3-d]pyrimidine substitués en tant que modulateurs de récepteur de cannabinoïde-1

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012059482A1 (fr) * 2010-11-05 2012-05-10 F. Hoffmann-La Roche Ag Utilisation de composés pharmaceutiques actifs pour le traitement d'états du système nerveux central
EP2457569A1 (fr) * 2010-11-05 2012-05-30 F. Hoffmann-La Roche AG Utilisation de composés pharmaceutiques actifs pour le traitement de conditions du système nerveux central
US8835425B2 (en) 2010-11-05 2014-09-16 Hoffmann-La Roche Inc. Use of selective GABA A α5 negative allosteric modulators for the treatment of central nervous system conditions
AU2011325190B2 (en) * 2010-11-05 2015-05-14 F. Hoffmann-La Roche Ag Use of active pharmaceutical compounds for the treatment of central nervous system conditions
CN107298655A (zh) * 2017-08-24 2017-10-27 郑州轻工业学院 7,8‑二甲氧基‑2,3,4,5‑四氢‑1H‑苯并[c]氮杂卓盐酸盐及其制备方法
JP2022521968A (ja) * 2019-03-01 2022-04-13 エイシー イミューン ソシエテ アノニム タウ凝集体に関連する障害の治療、緩和、または予防のための新規化合物
JP7232931B2 (ja) 2019-03-01 2023-03-03 エイシー イミューン ソシエテ アノニム タウ凝集体に関連する障害の治療、緩和、または予防のための新規化合物

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