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WO2012020813A1 - Dérivé de pyrrolidine cyclique condensée - Google Patents

Dérivé de pyrrolidine cyclique condensée Download PDF

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Publication number
WO2012020813A1
WO2012020813A1 PCT/JP2011/068316 JP2011068316W WO2012020813A1 WO 2012020813 A1 WO2012020813 A1 WO 2012020813A1 JP 2011068316 W JP2011068316 W JP 2011068316W WO 2012020813 A1 WO2012020813 A1 WO 2012020813A1
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group
oxo
piperidin
carboxylate
dihydro
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Japanese (ja)
Inventor
健太郎 ▲高▼井
孝明 住吉
篤志 諏訪
洋子 ▲高▼橋
義治 宇留野
康子 村田
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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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
    • C07D401/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P25/18—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
    • A61P25/28—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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
    • 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
    • C07D413/14—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
    • 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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to novel fused pyrrolidine derivatives having muscarinic receptor activity and pharmaceutical compositions containing them as active ingredients.
  • the present invention also provides a preventive and / or therapeutic agent for muscarinic receptor-mediated diseases containing them.
  • the neurotransmitter acetylcholine receptor is known to have two types of cholinergic receptors, nicotine receptor and muscarinic receptor.
  • Muscarinic receptors are cell membrane-bound G protein-coupled receptors (GPCRs), and five subtypes (M 1 -M 5 ) are currently known. These M 1 -M 5 muscarinic receptors exert excitatory and inhibitory control on central and peripheral tissues and are involved in many physiological functions including heart rate, arousal, cognition, motor control and the like.
  • Muscarinic receptor agonists have various pharmacological actions such as analgesic action, memory improving action, antipsychotic action, and cognitive impairment improving action, and may be used as therapeutic agents for these (Non-Patent Document 1).
  • conventional muscarinic receptor agonists such as carbachol and pilocarpine have low selectivity for muscarinic receptor subtypes, and as a result, many side effects have been observed, so their clinical application is limited.
  • Patent Document 1 discloses, for example, an oxindole compound represented by the following formula.
  • the compound differs in structure from the compound of the present invention in which the 1-position nitrogen atom of the oxindole ring is bonded to the piperidine ring in that the 3-position carbon atom of the oxindole ring is bonded to the piperidine ring. Also, there is no specific disclosure or suggestion regarding muscarinic M 1 and M 4 receptor agonists and muscarinic receptor selectivity.
  • Patent Document 2 discloses a compound having muscarinic M 4 receptor activity as, for example, the following formula:
  • Patent Document 4 discloses, for example, the following formula:
  • An oxindole compound is disclosed. However, these compounds are structurally different from the compounds of the present invention in that the pyrrolidine ring is bonded to the nitrogen atom of the piperidine ring.
  • the agonist activity of the compound is selective for muscarinic M 1 receptor, and no specific disclosure or suggestion is made regarding an oxindole compound that selectively activates both muscarinic M 1 and M 4 receptors. .
  • the present invention provides a fused-ring pyrrolidine compound that selectively activates muscarinic M 1 and M 4 receptors to express effects and has reduced side effects via other muscarinic receptors or other receptors. This is the issue.
  • the present inventors have found that a compound having a specific condensed pyrrolidine structure selectively activates muscarinic M 1 and M 4 receptors, thereby causing antipsychotic action and cognitive impairment.
  • the present invention was completed by finding that it has an excellent effect of improving central diseases including an improving action and the like and reduces side effects via other muscarinic receptors or other receptors. That is, the present invention [1] The following formula (I)
  • R 5 represents a halogen atom, a C 3-7 cycloalkyl group, a C 6-14 aryl group, a heteroaryl group, a C 6-14 arylalkyl group, a heteroarylalkyl group, a C 2-6 alkenyl group, a C 2-6 Alkynyl group, C 1-6 alkoxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, amino group, nitro group, C 1-6 alkylsulfonyl group, or optionally substituted
  • a C 1-6 alkyl group, R 1 and R 2 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl
  • R 1 and R 2 are bonded to each other so that R 1 and R 2 together with the adjacent carbon atom form a C 3-7 cycloalkane or a 3-7 membered heterocyclic ring, or together
  • Form CR 6 R 7
  • R 6 and R 7 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 6 and R 7 are bonded to each other to form R 6 and R 7.
  • R 3 and R 4 together form ⁇ O or ⁇ S;
  • X is a single bond or methylene,
  • Y and Z are the same or different and each represents an oxygen atom or a sulfur atom,
  • R is an optionally substituted C 1-6 alkyl group, a C 2-6 alkynyl group or a C 2-6 alkenyl group,
  • Ring A is a 6- to 7-membered nitrogen-containing group optionally substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group Heterocycle.
  • Ring A is represented by the following formula (2a)
  • Ring A is represented by the following formula (2)
  • R 8 represents a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group.
  • the compound according to [7] The above [1], [2a], [2], [3], [4a], [4], [5]
  • the compound of the present invention exhibits an excellent effect of improving central diseases including an antipsychotic effect, a cognitive impairment improving effect, and the like, and thus is useful as a novel preventive and / or therapeutic agent for central diseases.
  • muscle receptor without a prefix identifying a receptor subtype means one or more of the five receptor subtypes M 1 -M 5 .
  • agonists or agonists Compounds that bind to muscarinic receptors and enhance muscarinic activity are called agonists or agonists.
  • antagonists or antagonists Compounds that reduce the activity of muscarinic receptors are called antagonists or antagonists.
  • Agonists interact with muscarinic receptors to increase their ability to transduce intracellular signals in response to endogenous ligand binding.
  • Antagonists interact with the muscarinic receptor and compete for binding site (s) on the receptor with endogenous ligand (s) or substrate (s) and the receptor responds to endogenous ligand binding Reducing the ability to transmit intracellular signals.
  • C 1-6 alkyl group means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group and n-hexyl group, and structural isomers thereof, Among these, a C 1-4 alkyl group is preferable, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are more preferable, and a methyl group and an ethyl group are particularly preferable.
  • C 2-6 alkenyl group means a linear or branched unsaturated aliphatic hydrocarbon having 2 to 6 carbon atoms having one or more double bonds.
  • Group includes, for example, ethenyl group, propenyl group, crotyl group, butenyl group, pentenyl group and hexenyl group, and structural isomers and geometric isomers thereof.
  • the position of the double bond may be any position on the carbon chain. Of these, a C2-4 alkenyl group is preferable.
  • C 2-6 alkynyl group means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and having one or more triple bonds. And includes, for example, ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group, and structural isomers thereof.
  • the position of the triple bond may be any position on the carbon chain. Of these, a C 2-4 alkynyl group is preferable.
  • C 3-7 cycloalkyl group means a 3- to 7-membered saturated or unsaturated aliphatic carbocyclic group constituting a ring only with carbon atoms.
  • Specific examples of the “C 3-7 cycloalkyl group” include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexyl group, cyclohexenyl group, 1,3-cyclohexadienyl.
  • C 3-6 cycloalkyl group is preferable.
  • the “C 3-7 cycloalkyl group” may optionally have one or more unsaturated bonds as long as an aromatic ⁇ -electron system does not occur, and is condensed with a C 6-14 arene. You may do it.
  • heterocyclic group means 3 to 7-membered saturated or unsaturated containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms as ring-constituting atoms.
  • the “heterocyclic group” may optionally have one or more unsaturated bonds as long as an aromatic ⁇ -electron system does not occur, and C 6-14 It may be condensed with an arene or a heterocyclic ring.
  • the ring-constituting member may contain one or more carbonyl or thiocarbonyl.
  • a cyclic group such as lactam, lactone, cyclic imide, cyclic thioimide, and cyclic carbamate is also included in the heterocyclic group. It is. Binding position of the "heterocyclic group” may even on the carbon atoms also on hetero atoms, in the case of condensate of C 6-14 arene or heterocyclic ring, on a ring of C 6-14 arene or heterocyclic There may be.
  • heterocyclic group examples include, for example, a tetrahydrothiopyranyl group, 4H-pyranyl group, tetrahydropyranyl group, piperidyl group, 1-ethoxycarbonylpiperidyl group, 1-ethoxycarbonylpiperidinylidenyl group, 1,3-dioxinyl group, 1,3-dioxanyl group, 1,4-dioxinyl group, 1,4-dioxanyl group, piperazinyl group, 1,3-oxathianyl group, 1,4-oxathiinyl group, 1,4-oxathianyl group Group, tetrahydro-1,4-thiazinyl group, 2H-1,2-oxazinyl group, maleimide group, succinimide group, dioxopiperazinyl group, hydantoin group, dihydrouracil group, morpholino group, hexahydro-1,3,
  • C 6-14 aryl group means an aromatic carbocyclic group having 6 to 14 carbon atoms.
  • the “C 6-14 aryl group” may be condensed with at least one C 6-14 arene or C 3-7 cycloalkane.
  • Specific examples of the “C 6-14 aryl group” include a phenyl group, a naphthyl group, a phenanthryl group, an anthryl group, a fluorenyl group, a tetrahydronaphthyl group, an indenyl group and an indanyl group, and among them, a phenyl group and a naphthyl group.
  • a phenyl group is particularly preferable.
  • the “C 6-14 aryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkyl-carbamoyl group, an acyl group, a C 1-6 alkoxy group or an optionally substituted group.
  • C 1-6 alkyl group a mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, a sulfamoyl group and a trifluoromethyl group It may have one or more arbitrary substituents selected from the group consisting of, preferably a phenyl group having the same or different one or two substituents.
  • C 6-14 aryl group examples include a phenyl group, a phenyl group substituted with a halogen atom (for example, a phenyl group substituted with a halogen atom at the 3-position or 4-position), a 3-hydroxyphenyl group, 4-hydroxy Phenyl group, 3-aminophenyl group, 4-aminophenyl group, 3-methylphenyl group, 4-methylphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group 3,4-dimethylphenyl group, naphthyl group, 1-hydroxynaphthyl group, 4- (hydroxymethyl) phenyl group and 4- (trifluoromethyl) phenyl group, but are not limited thereto.
  • C 6-14 arylalkyl group means a C 1-6 alkyl group substituted with a C 6-14 aryl group.
  • heteroaryl group means a 5- to 10-membered aromatic ring group containing one or more heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms. Means.
  • heteroaryl group examples include, for example, furyl group, benzofuranyl group, thienyl group, benzothiophenyl group, pyrrolyl group, pyridyl group, indolyl group, oxazolyl group, benzoxazolyl group, isoxazolyl group, benzoiso Oxazolyl group, thiazolyl group, benzothiazolyl group, isothiazolyl group, imidazolyl group, benzoimidazolyl group, pyrazolyl group, indazolyl group, tetrazolyl group, furazanyl group, 1,2,3-oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, benzotriazolyl group, quinolinyl group, isoquinolinyl group, pyridazinyl group, pyrroly
  • the “heteroaryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkyl-carbamoyl group, an acyl group, a C 1-6 alkoxy group, an optionally substituted C 1 1- 6 alkyl group, a mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, from a sulfamoyl group and a group consisting of a trifluoromethyl group It may have one or more selected substituents, and may preferably have one or two of the same or different substituents. The most typical substituents are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkoxy group, and an optionally substituted C 1-6 alkyl group
  • heteroarylalkyl group means a C 1-6 alkyl group substituted with a heteroaryl group.
  • C 1-6 alkoxy group means —O— to which a C 1-6 alkyl group is bonded, specifically, a methoxy group, an ethoxy group, an n-propoxy group, an iso Examples include propoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, and hexyloxy group, and among them, C 1-3 alkoxy group Are preferred, and methoxy and ethoxy groups are particularly preferred.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among these, a fluorine atom, a bromine atom and a chlorine atom are preferable.
  • C 1-6 alkylsulfanyl group means —S— to which a C 1-6 alkyl group is bonded.
  • Groups pentylsulfanyl (ie, amylsulfanyl), hexylsulfanyl, isopropylsulfanyl, isobutylsulfanyl, secondary butylsulfanyl, tertiary butylsulfanyl, isopentylsulfanyl, neopentylsulfanyl and tertiary
  • a primary pentylsulfanyl group is exemplified, among which a C 1-3 alkylsulfanyl group is preferable, and a methylsulfanyl group and an ethylsulfanyl group are particularly preferable.
  • acyl group means “C 1-6 alkyl-carbonyl group” (—CO— to which a C 1-6 alkyl group is bonded, such as acetyl group, propionyl group, butyryl group, isobutyryl group).
  • Valeryl group pivaloyl group, hexanoyl group and heptanoyl group
  • C 6-14 aryl-carbonyl group (—CO— to which a C 6-14 aryl group is bonded, such as benzoyl group and naphthoyl group)
  • C 6 -14 arylalkyl-carbonyl group (-CO- to which a C 6-14 arylalkyl group is bonded, such as benzylcarbonyl group, 2-phenylethylcarbonyl group and 3-phenylpropylcarbonyl group), among which acetyl Groups, propionyl groups and benzoyl groups are preferred.
  • the benzene ring and naphthalene ring in the “acyl group” are 1 to 5 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a nitro group, a cyano group, a hydroxyl group, and a C 1-6 alkoxy group. It may have a group, and the substitution position is not particularly limited.
  • amino group refers to a secondary or tertiary amino group having an amino group and a C 1-6 alkyl group, such as an amino group and mono- or di-C 1-6.
  • alkylamino groups methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, butylamino group, dibutylamino group, etc.
  • a —C 1-3 alkylamino group is preferred, and an amino group, a methylamino group and a dimethylamino group are particularly preferred.
  • C 1-6 alkylsulfonyl group means —SO 2 — to which a C 1-6 alkyl group is bonded, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and And a isopropylsulfonyl group.
  • a C 1-3 alkylsulfonyl group is preferable, and a methylsulfonyl group and an ethylsulfonyl group are particularly preferable.
  • C 1-6 alkylsulfinyl group means —SO— to which a C 1-6 alkyl group is bonded, and examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, and an isopropylsulfinyl group. Among them, a C 1-3 alkylsulfinyl group is preferable.
  • sulfamoyl group means a sulfamoyl group (—SO 2 NH 2 ) and a group in which one or two hydrogen atoms on the nitrogen atom of the sulfamoyl group are substituted with a C 1-6 alkyl group.
  • sulfamoyl group means, for example, a sulfamoyl group, and mono- or di -C 1-6 alkylsulfamoyl group (e.g., methylsulfamoyl group, dimethylsulfamoyl group, ethylsulfamoyl group, diethylsulfamoyl group, Propylsulfamoyl group, dipropylsulfamoyl group, butylsulfamoyl group and dibutylsulfamoyl group), among which sulfamoyl group and mono- or di-C 1-3 alkylsulfamoyl group are preferred, amino Particularly preferred are groups, methylsulfamoyl and dimethylsulfamoyl groups.
  • nitrogen-containing heterocycle means a 6- to 7-membered saturated aliphatic ring containing at least one nitrogen atom as a ring-constituting atom, and further oxygen atom and It may contain one or more heteroatoms selected from sulfur atoms and may be fused with at least one C 6-14 arene, C 3-7 cycloalkane or 3-7 membered heterocycle .
  • Specific examples of the “nitrogen-containing heterocycle” include piperidine, piperazine, azepan, diazepan, oxazepan, thiazepan, morpholine and thiomorpholine.
  • C 1-6 alkyl group means a hydroxyl group, C 1-6 alkylsulfanyl group, halogen atom, amino group, formyl group, carbamoyl group at a substitutable position.
  • cyano group, nitro group, C 1-6 alkoxy, C 3-7 cycloalkyl and heterocycle may be substituted with 1 to 4 atoms or substituents selected from the group consisting of group C 1 -6 means an alkyl group.
  • substituted C 1-6 alkyl group examples include a trifluoromethyl group, a fluoromethyl group, a 2-fluoroethyl group, a methoxyethyl group, a hydroxymethyl group, a cyclopropylmethyl group, a furylmethyl group, an oxa group.
  • substituted C 1-6 alkyl group examples include a trifluoromethyl group, a fluoromethyl group, a 2-fluoroethyl group, a methoxyethyl group, a hydroxymethyl group, a cyclopropylmethyl group, a furylmethyl group, an oxa group.
  • C 6-14 arene means a ring corresponding to “C 6-14 aryl group”.
  • heterocycle means a ring corresponding to “heterocyclic group”.
  • C 3-7 cycloalkane means a ring corresponding to the "C 3-7 cycloalkyl group”.
  • salt refers to the basic form of a functional group such as an amine and a suitable acid, such as an inorganic acid [eg, hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid).
  • a suitable acid such as an inorganic acid [eg, hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid).
  • organic acids eg acetic acid, propionic acid, hydroacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, Butanedioic acid, (Z) -2-butenedioic acid, (E) -butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid Acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, It can be obtained by treatment with another organic acid] known to beauty those skilled in the art, to mean a pharmaceutically acceptable acid addition
  • the compound of the general formula (1) of the present invention may have stereoisomers such as optical isomers, diastereoisomers and geometric isomers depending on the mode of the substituent.
  • the compound of 1) also includes all these stereoisomers and mixtures thereof.
  • a, b, c and d are the same or different and are each CH or CR 5 , preferably a and d are both CH, and b and c are same or different, CH or CR 5.
  • c is CR 5
  • the selectivity of muscarinic M 1 and M 4 receptors is improved and the pharmacokinetics tends to be improved.
  • a and d are both CH, and either of b and c is CH, the other is CR 5.
  • R 5 represents a halogen atom, a C 3-7 cycloalkyl group, a C 6-14 aryl group, a heteroaryl group, a C 6-14 arylalkyl group, a heteroarylalkyl group, a C 2- 6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, amino group, nitro group, C 1-6 alkylsulfonyl group Or an optionally substituted C 1-6 alkyl group.
  • R 5 is preferably a halogen atom, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, an acyl group, a sulfamoyl group, a hydroxyl group, An amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group (preferably a hydroxyl group, a C 1-6 alkylsulfanyl group, a halogen atom, a cyano group, a nitro group, and And optionally substituted with 1 to 4 substituents selected from the group consisting of methoxy groups), More preferably, a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an
  • a halogen atom, a methyl group, an ethyl group, a propyl group, a cyano group, a hydroxyl group, a methoxy group or a trifluoromethyl group Particularly preferably, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or a trifluoromethyl group, Most preferably, they are a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, or a methoxy group.
  • R 1 and R 2 are the same or different and each is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group or A 3- to 7-membered heterocyclic group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with an adjacent carbon atom form a C 3-7 cycloalkane or a 3- to 7-membered heterocyclic ring. Or together form ⁇ CR 6 R 7 .
  • R 6 and R 7 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 6 and R 7 are bonded to each other, and R 6 And R 7 together with the adjacent carbon atom form a C 3-7 cycloalkane or a 3-7 membered heterocycle.
  • R 1 and R 2 are preferably the same or different and each is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group, or a 3-7 member.
  • R 1 and R 2 are bonded to each other, or R 1 and R 2 form a heterocyclic ring of C 3-7 cycloalkane or 3-7 membered together with the carbon atom adjacent, Or R 1 and R 2 together form ⁇ CR 6 R 7 , More preferably, they are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, or a C 3-7 cycloalkyl group, or R 1 and R 2 are Bonded to each other, R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocyclic ring; More preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group, or R 1 and R 2
  • R 1 and R 2 are bonded together to form a 3- to 7-membered heterocycle with R 1 and R 2 together with adjacent carbon atoms; Particularly preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; Most preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or a C 1-3 alkyl group (particularly hydroxymethyl) optionally substituted with a hydroxyl group, or R 1 and R 2 are Together, R 1 and R 2 together with the adjacent carbon atoms form a tetrahydropyran ring.
  • R 1 and R 2 are the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (4) hydroxyl group, (5) a C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopentyl group
  • R 1 and R 2 are preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (4) hydroxyl group, (5) a C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopenty
  • R 1 and R 2 are more preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (4) hydroxyl group, or (5) C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopenty
  • R 1 and R 2 are more preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) fluorine atom, chlorine atom or bromine atom, or (4) is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with adjacent carbon atoms (1) C 3-7 cyclo
  • R 1 and R 2 are particularly preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl
  • substituents selected from the group consisting of butyl, preferably a C 1-3 alkyl group
  • fluorine atom or chlorine atom or (4) It is a hydroxyl group, or R
  • R 1 and R 2 are particularly preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl
  • substituents selected from the group consisting of butyl, preferably a C 1-3 alkyl group
  • fluorine atom or (4) It is a hydroxyl group, or R 1 and R 2
  • R 1 and R 2 are most preferably the same or different, (1) hydrogen atom, (2) a C 1-3 alkyl group optionally substituted with a hydroxyl group (eg, methyl, ethyl, propyl, isopropyl, preferably methyl) (particularly preferably hydroxymethyl), (3) fluorine atom, or (4) It is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with the adjacent carbon atom form a tetrahydropyran ring.
  • a hydroxyl group eg, methyl, ethyl, propyl, isopropyl, preferably methyl
  • fluorine atom or (4) It is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with the adjacent carbon atom form a tetrahydropyran ring.
  • ring A may be substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group.
  • Ring A is preferably a 6- to 7-membered nitrogen-containing heterocyclic ring optionally substituted with 1 to 2 C 1-6 alkyl groups (the two C 1-6 alkyl groups are bonded to form a bicyclo A ring may be formed) More preferably, the following formula (2)
  • R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group.
  • R 8 is preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or an ethoxy group, more preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, A methoxy group, more preferably a hydrogen atom or a methyl group.
  • Ring A is particularly preferably
  • R 3 and R 4 together form ⁇ O or ⁇ S.
  • R 3 and R 4 are preferably taken together to form ⁇ O.
  • X is a single bond or methylene.
  • Y and Z are the same or different and each represents an oxygen atom or a sulfur atom.
  • Y is preferably an oxygen atom.
  • Z is preferably an oxygen atom.
  • R represents an optionally substituted C 1-6 alkyl group, a C 2-6 alkynyl group, or a C 2-6 alkenyl group.
  • R is preferably an optionally substituted C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • a C 2-6 alkynyl group or a C 2-6 alkenyl group More preferably, it may be substituted with an optionally substituted C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • it may be a linear C 1-6 alkyl group which may be substituted (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). May be) Even more preferably, an optionally substituted straight chain C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). May be) Even more preferably, it is a straight chain C 1-3 alkyl group, Particularly preferred is a methyl group or an ethyl group.
  • examples of preferable compounds include the following compounds.
  • X is a single bond, Y is an oxygen atom or a sulfur atom, Z is an oxygen atom or a sulfur atom, R is an optionally substituted C 1-6 alkyl group (preferably optionally substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and
  • a is CH, b is CH or CR 5 (R 5 is as defined above); c is CR 5 (R 5 is a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an amino group, a nitro group, or an optionally substituted C 1-6 alkyl A group (preferably substituted with 1 to 4 substituents selected from the group consisting of a hydroxyl group, a C 1-6 alkylsulfanyl group, a halogen atom, a cyano group, a nitro group and a methoxy group).
  • Is) d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (2a):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • [Compound C] a is CH, b is CH, c is CR 5 (R 5 is a fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group or trifluoromethyl group, preferably a fluorine atom, chlorine atom, bromine atom, methyl group or methoxy group; Yes.)
  • d is CH, R 1 and R 2 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group (preferably a C 1-3 alkyl group); R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group) and ring A is represented by the following formula (2a):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • Compound D a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom or a C 3-7 cycloalkyl group, or R 1 and R 2 are Bonded together, R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocycle; R 3 and R 4 together form ⁇ O or ⁇ S; X is a single bond or methylene, Y is an oxygen atom or a sulfur atom, Z is an oxygen atom or a sulfur atom, R is an optionally substituted C 1-6 alkyl group (preferably optionally substituted with 1 to 4 substitu
  • Compound E a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound F a is CH, b is CH, c is CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group), and ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, or a methoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound G a is CH, b is CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group, or trifluoromethyl group); c is CH, d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group), and ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, or a methoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound H a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is methylene, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound I a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (3):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • Compound J] a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (4):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention represented by the general formula (1) can be produced by the following production method. Manufacturing method 1: following formula (5)
  • a method for producing a compound of the above formula (1) which comprises reacting a compound represented by the formula:
  • Reaction of a compound of formula (5) or a salt thereof with an available compound of formula (6) or a compound of formula (7) comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborate, pyridine borane , 2-picoline borane and other commonly used reductive amination reagents can be used.
  • the reaction of the compound of formula (5) or a salt thereof with the compound of formula (6) or the compound of formula (7) is carried out without solvent or in a suitable solvent.
  • the solvent to be used include dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, methanol, ethanol, ethyl acetate and the like, and these reactions are used alone or in combination of two or more.
  • This reaction is performed in the presence of an acid or a base, if necessary.
  • the acid include acetic acid
  • examples of the base include triethylamine, and diisopropylethylamine.
  • condensing agents such as titanium tetraisopropoxide, can be used together as needed.
  • the reaction temperature is usually -78 ° C to 100 ° C.
  • the compound of the formula (5) or a salt thereof can be synthesized according to the following scheme 1 (the compound of the formula (1-4) in which R 3 and R 4 are combined to form ⁇ O).
  • Prot represents an amino-protecting group, and other symbols are as defined above.
  • Specific examples of amino-protecting groups include groups that form carbamates with amino groups such as tert-butoxycarbonyl and benzyloxycarbonyl groups, and amino groups and benzylamines such as benzyl and trityl groups. And the like.
  • Step 1 The compound of formula (1-2) can be produced by deprotecting the amino-protecting group of the compound of formula (1-1) according to a conventional method.
  • Step 2 The compound of formula (1-3) is produced by reacting the compound of formula (1-1) with a halogenating agent or alkylating agent corresponding to R 1 and R 2 in the presence of a base in an inert solvent.
  • a base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium hexamethyldisilazide, potassium hexamethyl. And disilazide.
  • the inert solvent examples include tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like, and these can be used in combination.
  • the reaction temperature is usually ⁇ 78 ° C. to 140 ° C., preferably ⁇ 78 ° C. to 100 ° C.
  • Step 3 This step is carried out by the same method as in step 1 of this scheme.
  • the compound of the formula (1-1) or a salt thereof can be synthesized according to the following scheme 2, 3, 4 or 5.
  • R ′ represents a C 1-6 alkyl group, and other symbols are as defined above.
  • Step 1 The compound of formula (2-2) can be produced by reacting an available compound of formula (2-1) with an alkyl halide in the presence of a base such as sodium hydride or cesium carbonate.
  • a base such as sodium hydride or cesium carbonate.
  • the solvent to be used include dimethylformamide, tetrahydrofuran, dichloromethane and the like, and they are used alone or in combination of two or more.
  • the reaction is usually carried out at -40 ° C to 40 ° C, preferably -10 ° C to 10 ° C.
  • Step 2 The compound of formula (2-3) can be produced by catalytic reduction of the compound of formula (2-2) using a metal catalyst such as palladium in a hydrogen atmosphere.
  • a metal catalyst such as palladium in a hydrogen atmosphere.
  • the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, dichloromethane, and the like.
  • a compound of formula (1-1) can be prepared by reacting a compound of formula (2-3) with an available compound of formula (2-4). This reaction can be performed according to the reductive amination conditions described above.
  • the reagent include commonly used reagents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborate, pyridine borane, 2-picoline borane.
  • the solvent to be used include toluene, dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, methanol, ethanol, ethyl acetate, and the like. This reaction is performed in the presence of an acid or a base as necessary.
  • Examples of the acid include acetic acid, and examples of the base include triethylamine and diisopropylethylamine. Moreover, condensing agents, such as titanium tetraisopropoxide, can be used together as needed.
  • the reaction temperature is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 1 The compound of formula (3-2) can be produced by reacting the available 2-halogenated nitroaryl of formula (3-1) with a malonic acid diester in the presence of a base such as sodium hydride or cesium carbonate.
  • a base such as sodium hydride or cesium carbonate.
  • the solvent to be used include dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane and the like, and they are used alone or in combination of two or more.
  • the reaction is usually performed at ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • Step 2 The compound of formula (3-3) can be produced by catalytic reduction of the compound of formula (3-2) using a metal catalyst such as palladium or rhodium in a hydrogen atmosphere.
  • a metal catalyst such as palladium or rhodium in a hydrogen atmosphere.
  • the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, dichloromethane, and the like.
  • Step 3 This step is performed in the same manner as in Step 3 described in Scheme 2.
  • Step 4 The compound of formula (1-1) can be produced by heating and stirring the compound of formula (3-4) in the presence of an acid.
  • the acid include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid and the like, preferably p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, dichloromethane, benzene, toluene, xylene and the like, preferably benzene and toluene. Two or more of these may be mixed and used.
  • the reaction is usually carried out at 0 ° C. to 200 ° C., preferably 70 ° C. to 140 ° C.
  • the compound of the formula (4-1) can be produced by reacting an available 2-halogenated acetic acid with a chlorinating agent such as thionyl chloride or oxalyl dichloride.
  • a chlorinating agent such as thionyl chloride or oxalyl dichloride.
  • the solvent to be used include dimethylformamide, tetrahydrofuran, chloroform, dichloromethane and the like, and these may be used alone or in combination of two or more.
  • Step 1 The compound of formula (4-3) can be produced by reacting the compound of formula (4-1) with an available compound of formula (4-2) in the presence of a base.
  • a base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like, and preferably dimethylformamide, acetonitrile, dichloromethane and the like. Two or more of these may be mixed and used.
  • the reaction is usually carried out at ⁇ 20 ° C. to 120 ° C., preferably 0 ° C. to 70 ° C.
  • Step 2 The compound of formula (1-1) can be produced by reacting the compound of formula (4-3) in the presence of a metal catalyst such as palladium. That is, it can be produced by the method described in Tetrahedron Lett., 45, 8535-8537 (2004) or the like or a method analogous thereto.
  • a metal catalyst such as palladium
  • Step 1 The compound of formula (5-2) can be produced by reacting an available aniline derivative of formula (5-1) with a compound of formula (2-4) in the same manner as in Step 3 described in Scheme 2. it can.
  • Step 2 The compound of formula (5-3) can be produced by reacting the compound of formula (5-2) with chloroacetyl chloride in the presence of a base.
  • a base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, pyridine and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, benzene, toluene, xylene, chloroform, dichloromethane, and the like, and two or more of these can be used in combination.
  • the reaction is usually carried out at ⁇ 20 ° C. to 140 ° C., preferably 20 ° C. to 100 ° C.
  • Step 3 The compound of formula (1-1) can be produced by reacting the compound of formula (5-3) in the presence of a Lewis acid in an inert solvent or in the absence of a solvent.
  • Lewis acids include zinc chloride and aluminum chloride.
  • the inert solvent include benzene, toluene, xylene, chlorobenzene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, and the like, and two or more of these can be used in combination.
  • the reaction is usually carried out at -20 ° C to 220 ° C, preferably 20 ° C to 200 ° C.
  • the compound of the formula (3) or a salt thereof can be synthesized according to the following scheme 6 (the compound of the formula (6-1) in which R 3 and R 4 together form ⁇ S).
  • Step 1 The compound of formula (6-1) can be produced by thioamidation of the compound of formula (1-4).
  • the thioamidation reagent to be used include Lawesson's reagent and phosphorus pentasulfide. This reaction is carried out without solvent or in a suitable solvent.
  • the solvent to be used include chloroform, dichloromethane, toluene, benzene, xylene, and the like, and two or more of these can be mixed and used.
  • a method for producing a compound of the above formula (1) which comprises reacting a compound of the above and an alkylating agent corresponding to R 1 and R 2 in the presence of a base in an inert solvent.
  • Examples of the base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, tert-butoxypotassium and the like.
  • Examples of the inert solvent include tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like, and these can be used in combination.
  • the reaction is usually carried out at ⁇ 20 ° C. to 140 ° C., preferably 20 ° C. to 100 ° C.
  • Step 1 The compound of formula (7-3) is obtained by reacting the compound of formula (7-1) synthesized by the method of step 1 and step 2 described in production method 1, scheme 3 with the compound of formula (7-2). Can be manufactured. The reaction is carried out in the same manner as in Production method 1, step 3 described in scheme 2.
  • Step 2 A compound of formula (7-4) can be produced by reacting a compound of formula (7-3) with an alkylating agent corresponding to R 1 in the presence of a base in an inert solvent.
  • Examples of the base include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and the like.
  • Examples of the inert solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like. You may use these in mixture of 2 or more types.
  • the reaction is usually carried out at ⁇ 20 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C.
  • Step 3 This step is performed in the same manner as in step 4 described in Scheme 3.
  • Step 4 The compound of formula (1) can be produced by reacting the compound of formula (7-5) with an alkylating agent corresponding to R 2 in the same manner as in Step 1 described in this scheme.
  • Step 1 The compound of formula (8-2) is obtained by reacting N-ethyl-4-piperidone which is an available compound of formula (8-1) with an alkyl halide in the absence of a solvent or in a suitable solvent.
  • the alkyl halide include methyl iodide, ethyl iodide, methyl bromide, and ethyl bromide, and preferably methyl iodide.
  • the solvent to be used include acetone, toluene, chloroform, dichloromethane, ethyl acetate, hexane, and the like, and two or more of these can be mixed and used.
  • the reaction temperature is usually from ⁇ 20 ° C. to 140 ° C., preferably 0 ° C. to 50 ° C.
  • the compound of the formula (7-2) can be produced by reacting the compound of the formula (8-2) with an available amine of the formula (8-3) in a suitable solvent in the presence of a base.
  • a suitable solvent include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the solvent to be used include water, ethanol, methanol, 2-propanol and the like, and two or more kinds thereof can be mixed and used.
  • the reaction temperature is usually 0 to 140 ° C, preferably 20 to 100 ° C.
  • Step 1 The compound of formula (9-3) can be produced by reacting an available compound of formula (9-1) with a compound of formula (9-2) with a nucleophile having an elimination ability.
  • the nucleophilic agent include sodium cyanide, potassium cyanide, triazole, tetrazole, dimethylaluminum cyanide and the like.
  • the solvent to be used include toluene, xylene, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethoxyethane, and the like, and two or more kinds thereof can be mixed and used.
  • the reaction temperature is usually from 0 ° C to 200 ° C, preferably from 20 ° C to 160 ° C.
  • Step 2 The compound of the formula (9-4) can be produced by reacting the compound of the formula (9-3) with an alkylating agent corresponding to R 8 .
  • the alkylating agent include alkyl lithium, alkyl magnesium chloride, alkyl magnesium bromide and the like corresponding to R 8 .
  • the solvent used include dimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like. You may use these in mixture of 2 or more types.
  • the reaction is usually carried out at ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 3 The compound of formula (9-5) can be produced by deprotecting the Boc group of the compound of formula (9-4) in the presence of an acid.
  • the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like.
  • the reaction is usually carried out at ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 4 The compound of the formula (9-6) can be produced by reacting the compound of the formula (9-5) with carbonyl chloride or thiocarbonyl chloride corresponding to Y, Z and R in the presence of a base.
  • a base include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like. You may use these in mixture of 2 or more types.
  • the reaction is usually carried out at ⁇ 20 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C.
  • Step 5 The compound of formula (9-7) can be produced by deprotecting the acetal part of the compound of formula (9-6) in the presence of an acid.
  • the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like.
  • the reaction is usually carried out at -20 ° C to 160 ° C, preferably 0 ° C to 120 ° C.
  • Step 1 The compound of the formula (10-2) can be produced by dehydrating and condensing the compound of the formula (10-1) that is available to the compound of the formula (1-1) that can be synthesized according to the production method 1. .
  • This step is performed in the presence of an acid as necessary.
  • the acid include acetic acid, sulfuric acid, hydrochloric acid, zinc chloride, aluminum chloride, titanium chloride, titanium tetraisopropoxide and the like.
  • the solvent is used in the absence of a solvent or in a suitable solvent. Examples of the solvent used include benzene, toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, 1,4-dioxane, and the like. You may mix and use seeds or more.
  • the reaction temperature is usually ⁇ 20 ° C. to 200 ° C., preferably 20 ° C. to 140 ° C.
  • Step 2 The compound of the formula (10-3) can be produced by deprotecting the amino-protecting group from the compound of the formula (10-2) according to the same method as in Step 1 of Production Method 1 and Scheme 1. it can.
  • Step 3 The compound of the formula (10-4) can be produced by subjecting the compound of the formula (10-3) to a reductive amination reaction according to the same method as in Step 3 of Production Method 1 and Scheme 2. .
  • Step 4 The compound of the formula (1) can be produced by catalytic reduction of the compound of the formula (10-4) using a metal catalyst such as palladium or rhodium in the presence of a hydrogen atmosphere.
  • a metal catalyst such as palladium or rhodium
  • the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, chloroform, dichloromethane, and the like. These may be used alone or in combination of two or more.
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.
  • Step 1 The compound of the formula (11-2) is obtained by converting an aniline derivative, which is a compound of the formula (11-1), and a compound of the formula (7-2), in the same manner as in Step 3 of Production Method 1 and Scheme 2.
  • an aniline derivative which is a compound of the formula (11-1)
  • a compound of the formula (7-2) in the same manner as in Step 3 of Production Method 1 and Scheme 2.
  • Step 2 The compound of the formula (11-3) can be produced by reacting the compound of the formula (11-2) with oxalyl dichloride in an appropriate solvent in the presence of an acid.
  • the acid include aluminum trichloride, zinc trichloride, titanium trichloride and the like.
  • the solvent include benzene, toluene, chloroform, dichloromethane, dichloroethane, and the like. These may be used alone or in combination of two or more.
  • the reaction temperature is usually ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C.
  • Step 3 The compound of formula (1) can be produced by reducing the carbonyl group of the compound of formula (11-3) with a suitable reducing agent in a solvent.
  • a suitable reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like.
  • the solvent include methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, and the like. These may be used alone or in combination of two or more.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 1 The compound of the formula (12-2) can be produced by reducing an indole derivative which is a compound of the formula (12-1) which is commercially available or can be synthesized by a method known to those skilled in the art to indoline.
  • the reducing agent is not particularly limited as long as it can reduce indole to indoline.
  • sodium cyanoborohydride can be used.
  • the solvent that can be used is not particularly limited as long as it can be used in this reaction, and examples thereof include dichloromethane and dichloroethane.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 2 The compound of the formula (12-3) can be produced by performing a reductive amination reaction between the compound of the formula (12-2) and the compound of the formula (12). This reaction can be carried out according to the conditions described in Production Method 1.
  • Step 3 The compound of the formula (12-4) can be produced by oxidizing the compound of the formula (12-3) with a suitable oxidizing agent in a solvent.
  • a suitable oxidizing agent include manganese dioxide.
  • the solvent include chloroform and dichloromethane. These may be used alone or in combination of two or more.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • the compound of formula (1) can be produced by oxidizing the compound of formula (12-4) in a solvent with a suitable oxidizing agent.
  • the oxidizing agent is not particularly limited as long as it is a general oxidizing agent capable of oxidizing alkenes, and examples thereof include 2-iodoxybenzoic acid (IBX).
  • the solvent include acetonitrile and water, and these may be used alone or in combination of two or more.
  • cerium chloride or the like may be used.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • a compound of formula (13-2) can be produced by reacting a compound of formula (13-1), which can be synthesized according to Scheme 7, with an alkyl halide formate in the presence of a base.
  • the base is not particularly limited as long as it can be used in this reaction, and examples thereof include diisopropylamine lithium amide (LDA).
  • Examples of the solvent that can be used include diethyl ether and tetrahydrofuran.
  • the reaction temperature is usually -80 ° C to 100 ° C, preferably -80 ° C to 50 ° C.
  • Step 2 The compound of formula (13-3) can be produced according to the method of Reference Example 93 by reacting the compound of formula (13-2) with a general fluorinating agent in the presence of a base.
  • the reaction conditions are preferably those for reacting with N-fluorobenzenesulfonimide at 0 to 50 ° C. in the presence of potassium carbonate in THF.
  • Step 3 The compound of the formula (1) can be produced by reducing the compound of the formula (13-3).
  • the reducing agent is not particularly limited as long as it can reduce only the ester, and examples thereof include lithium borohydride.
  • the solvent include tetrahydrofuran, diethyl ether, ethanol, methanol and the like, and these may be used alone or in combination of two or more.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • the compound of formula (1) obtained by the production method shown above is isolated and purified according to conventional methods such as extraction, column chromatography, recrystallization, and reprecipitation.
  • the extraction solvent include diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene and the like.
  • Purification by column chromatography uses silica gel or alumina treated with acidic, basic or various chemical treatments, and examples of developing solvents include hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile. / Water, methanol / water and the like.
  • each enantiomer can be separated and purified.
  • the compound of formula (1) having a hydroxyl group is produced by appropriately inserting a hydroxyl protecting step and a deprotecting step according to a conventional method in the production method described above.
  • the compound of formula (1) can be obtained in the form of a free base or an acid addition salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds. On the other hand, the compound of formula (1) can be converted into an acid addition salt by treating with various acids according to a conventional method.
  • Separation of the compound of the formula (1) into each enantiomer is performed by, for example, forming a diastereomeric salt according to a conventional method using an optically active acid, and then separating the diastereomeric salt into two free diastereomeric salts. This is done by converting.
  • optically active acid used as the optical resolution agent examples include (+)-or ( ⁇ )-camphoric acid, (1S)-(+)-or (1R)-( ⁇ )-camphor-10-sulfonic acid, L -(+)-Or D-(-)-tartaric acid, (+)-or (-)-mandelic acid, (S)-(-)-or (R)-(+)-malic acid, L-pyroglutamic acid , (S)-(+)-or (R)-( ⁇ )-1,1′-binaphthyl-2,2′-diyl, (+)-dibenzoyl-D-tartaric acid or ( ⁇ )-dibenzoyl-L- Examples include tartaric acid.
  • the compounds of the invention have a high selectivity and affinity for the muscarinic M 1 and M 4 receptors compared to the muscarinic M 2 , M 3 and M 5 receptor subtypes, and the selective muscarinic M 1 and M 4 is useful as receptor agonists.
  • the compounds of the invention also act at least in part as M 1 and M 4 agonists.
  • the compound of the present invention has an effect on diseases mediated by muscarinic M 1 and M 4 receptors, and is useful as a preventive and / or therapeutic agent for central diseases, particularly as an antipsychotic agent exhibiting excellent antipsychotic action. is there. Furthermore, since the compound of the present invention has selectivity for muscarinic receptors and other receptors, it can be expected to be used as a safe preventive and / or therapeutic agent for central diseases with fewer side effects than the prior agents. .
  • Disorders related to muscarinic M 1 receptors typically include cognitive impairment, forgetfulness, confusion, memory loss, attention deficit, visual defects, depression, pain, sleep disorders, psychosis, etc. It is done.
  • disorders related to muscarinic M 1 receptor is not limited to a mental disorder, for example, increased intraocular pressure is also related to the muscarinic M 1 receptor. Accordingly, non-psychiatric disorders are also included in the disorders targeted by the present invention.
  • Disorders related to muscarinic M 4 receptor is typically a mental disorder, for example, confusion, attention deficit, pain, sleep disorders, such as schizophrenia.
  • the disorders targeted by the compound or pharmaceutical composition of the present invention include, for example, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, Friedreich's ataxia, Tourette's syndrome, Down's syndrome, pain Pick disease, dementia, clinical depression, age-related cognitive decline, attention deficit disorder, sudden infant death syndrome, glaucoma, cognitive impairment, amnesia, confusion, memory loss, visual deficit, depression, sleep disorder, psychosis Preferred are neurodegenerative diseases, attention deficit disorders, pain, Alzheimer's disease, schizophrenia and cognitive impairment, and particularly preferred are schizophrenia, Alzheimer's disease and cognitive impairment.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and its daily dose varies depending on the type of compound, administration method, patient symptom / age, etc.
  • oral administration usually about 0.01 to 100 mg, more preferably about 0.1 to 10 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 1 ⁇ g to 10 mg, more preferably about 10 ⁇ g to 1 mg per kg body weight of a human or mammal can be administered.
  • the parenteral administration herein includes intravenous, intramuscular, subcutaneous, intranasal, intradermal, eye drop, intracerebral, intrarectal, intravaginal, intraperitoneal, and the like.
  • the administration period and interval of the pharmaceutical preparation are changed according to various situations, and are determined at any time according to the judgment of a doctor, but divided administration, daily administration, intermittent administration, short-term large-scale administration, repeated administration There are methods such as administration. For example, in the case of oral administration, it is desirable to divide and administer 1 to several times a day (particularly 2 to 3 times a day). Moreover, it can be administered as a sustained-release preparation or can be administered by intravenous infusion over a long period of time.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above.
  • a pharmaceutical carrier a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • citric acid glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized magnesium, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, Carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, stearic acid Magnesium, talc, tragacanth, bentonite, veegum, karuboki Vinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid
  • Examples of the dosage form include tablets, capsules, granules, powders, solutions, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. Liquid preparations may be dissolved or suspended in water or other suitable medium when used. Tablets and granules may be coated by a known method.
  • aqueous solvents eg, distilled water, physiological saline, Ringer's solution, etc.
  • isotonic agents eg, glucose, D-sorbitol, D-mannitol, sodium chloride
  • stabilizers eg human serum albumin etc.
  • preservatives eg benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, phenol etc.
  • buffers eg phosphate buffer
  • soothing agents eg, benzalkonium chloride, procaine hydrochloride, etc.
  • these formulations may contain other therapeutically valuable ingredients.
  • the pharmaceutical preparation of the present invention can be produced according to a conventional method, and the content ratio of the compound of the present invention in the preparation is usually 0.01 to 50% (w / w). Specific examples are shown below.
  • Tablets, powders, granules, capsules For example, excipients, disintegrants, binders or lubricants are added to the compounds of the present invention and compression molded, and if necessary, taste masking, It can be produced by applying a coating for enteric or sustainable purposes.
  • a tablet it can be produced by mixing 20 mg of the compound of Example 1, 100 mg of lactose, 25 mg of crystalline cellulose and 1 mg of magnesium stearate, and tableting the resulting mixture.
  • the compound of the present invention is dissolved or suspended in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol or the like as an aqueous injection together with a dispersing agent, preservative, tonicity agent and the like. It can be produced by turbidity or emulsification and molding as an oily injection.
  • a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol or the like
  • a dispersing agent preservative, tonicity agent and the like. It can be produced by turbidity or emulsification and molding as an oily injection.
  • Suppository produced by making the compound of the present invention into an oily or aqueous solid, semi-solid or liquid composition.
  • oily base used in such a composition examples include glycerides of higher fatty acids (for example, cacao butter, witepsols), intermediate fatty acids (for example, miglyols), or vegetable oils (for example, sesame oil, soybean oil, Cottonseed oil, etc.).
  • aqueous gel base examples include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
  • the compound was identified using proton nuclear magnetic resonance absorption spectrum ( 1 H-NMR), LC-MS, and the like.
  • the amino silica gel column made from Yamazen Co., Ltd. was used for the amino silica gel chromatography in a reference example and an Example.
  • LC-MS a system consisting of 2010EV and 2010HT (Shimadzu Corporation) or a system consisting of LC10ATVP (Shimadzu Corporation) and API150EX (Perkin Elmer) was used.
  • acetonitrile (1-99%) and 0.05% aqueous trifluoroacetic acid solution or methanol (10-99%) and 0.05% aqueous trifluoroacetic acid solution were used.
  • the retention time represents the time when the mass spectrum peak appears in the LC-MS measurement.
  • LC-MS is measured under various conditions, which are described in detail below.
  • Me represents a methyl group
  • Et represents an ethyl group
  • tBu represents a tert-butyl group
  • Boc represents a tert-butoxycarbonyl group.
  • Abbreviations used in NMR include s for single line, d for double line, dd for double double line, t for triple line, td for triple double line, q for quadruple line, and m for multiple line.
  • Line, br means broad
  • brd means broad double line
  • brt means broad triple line
  • J means coupling constant.
  • the compound of Reference Example 23 (1.0 g, 2.41 mmol) was dissolved in tert-butyl alcohol (24 ml), and palladium acetate (27 mg, 0.12 mmol), phenylboronic acid (29 mg, 0.24 mmol), X- Phos (114 mg, 0.24 mmol) and potassium carbonate (833 mg, 6.03 mmol) were added, and the mixture was stirred at 85 ° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (237 mg, 35%).
  • the compound of Reference Example 22 (69 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL), acetic acid (36 mg), 1-ethoxycarbonylpiperidin-4-one (57 mg), titanium tetraisopropoxide (427 mg). Was added at room temperature. After stirring for 10 minutes, sodium triacetoxyborohydride (127 mg) was added, and the mixture was stirred overnight with heating under reflux. After cooling to room temperature, a 25% aqueous ammonia solution was added to adjust the pH to 10. The filtrate filtered through Celite was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine.
  • Process 1 Using the compound of Reference Example 4 (436 mg, 2.02 mmol), an oily substance (547 mg, 85%) was obtained in the same manner as in Example 1.
  • Process 2 The compound (547 mg, 1.47 mmol) obtained in Step 1 was dissolved in dimethylformamide (8 ml), cesium carbonate (1.19 g, 3.68 mmol) was added, and the mixture was stirred at room temperature for 3 minutes. 1,3-dibromopropane (164 ⁇ l, 1.62 mmol) was added thereto, and the mixture was stirred at 70 ° C. for 3 hours.
  • the compound of Reference Example 16 (108 mg) was dissolved in dichloromethane (2 mL) and dimethoxyethane (2 mL), and 1-ethoxycarbonylpiperidin-4-one (86 mg) and titanium tetraisopropoxide (568 mg) were added at room temperature. Added in. After stirring at room temperature for 3 days, the mixture was cooled to ⁇ 78 ° C., methanol (0.5 mL) and sodium borohydride (39 mg) were added, and the temperature was slowly raised to room temperature. A 10% aqueous hydrochloric acid solution was added and stirred for 15 minutes, and then a 25% aqueous ammonia solution was added to adjust the pH to 10.
  • Process 2 The compound obtained in step 1 (210 mg) was dissolved in 4 mol / L hydrochloric acid-dioxane solution (5 mL) under ice cooling and stirred for 1 hour.
  • Example 11 4-( ⁇ 3- [1- (ethoxycarbonyl) piperidin-4-ylidene] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl ⁇ piperidin-1-yl) piperidine- 1-ethyl carboxylate
  • Example 12 4-( ⁇ 3- [1- (ethoxycarbonyl) piperidin-4-yl] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl ⁇ piperidin-1-yl) piperidine- 1-ethyl carboxylate
  • Example 11 The compound of Example 11 (18 mg) was dissolved in ethanol (1.5 ml), 10% Pd / C (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through Celite, and the residue concentrated under reduced pressure was subjected to amino silica gel chromatography to obtain the title compound as an oily substance (2 mg).
  • LC-MS RT 7.1 min., M / z 567.2 (M + Na).
  • the compound of Reference Example 3 (200 mg) was dissolved in dichloromethane (9 ml), and 1-ethoxycarbonylazepan-4-one (154 mg), titanium tetraisopropoxide (392 mg), and acetic acid (66 mg) were added at room temperature. Added in. After stirring for 10 minutes, sodium triacetoxyborohydride (234 mg) was added and stirred with heating for 2 hours. After cooling to room temperature, a 25% aqueous ammonia solution was added to adjust the pH to 10. The filtrate filtered through Celite was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine.
  • Step 2 The compound obtained in Step 1 (3.4 g, 8.6 mmol) was dissolved in 4 mol / L hydrochloric acid-dioxane solution (11 ml) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the desired product, which was used in Step 3 as a crude product.
  • 3-Oxonortropane-8-carboxylic acid (3.3 g) was dissolved in methanol (50 ml) and water (5 ml), and ammonium formate (9.5 g) and 10% Pd / C (3.0 g) were added. For 24 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound (3.9 g, 74%).
  • Example 104 (3-endo) -3- [4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] Ethyl octane-8-carboxylate
  • Titanium tetraisopropoxide (425 mg) and acetone (87 mg) were added to a dichloromethane (2 mg) solution of the compound (100 mg) of Reference Example 33 and stirred at 50 ° C. overnight.
  • Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was filtered through celite, washed with chloroform, and extracted. The obtained organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (122 mg, quantitative).
  • Example 107 The compound of Example 107 (20 mg) was dissolved in methanol (1 ml), 10% palladium / carbon (10 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (13 mg, 65%).
  • Example 107 or Example 108 The following compounds were synthesized in the same manner as in Example 107 or Example 108 using the compounds of Reference Example 3, 31, 33 or 40 and the corresponding reagents.
  • Example 148 Using the compound of Example 1, 66-71, 75, 76, 104, 105, or 136, the following compound was obtained in the same manner as in Example 148.
  • Example 161 4- ⁇ 4- [3-Ethyl-3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl ⁇ piperidine-1-carboxylate
  • Example 162 4- ⁇ 4- [6-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro (indole-3,4′-pyran) -1 (2H) -yl] piperidine-1- Yl ⁇ -4-methylpiperidine-1-carboxylate
  • Example 96 Using the compound of Example 96, 98 or 101, the following compound was obtained in the same manner as in Example 162.
  • Example 94 The following compound was obtained in the same manner as in Example 94 using the compound of Reference Example 73 or the compound of Reference Example 94.
  • the usefulness of the compound of the present invention as a medicine is proved by a pharmacological test capable of confirming pharmacological action, a pharmacokinetic test capable of confirming pharmacokinetics, and a safety test capable of confirming safety. These tests are not particularly limited as long as they can confirm physiological activity based on muscarinic M 1 and M 4 receptor operability and safety improvement by improving muscarinic receptor subtype selectivity. Proven by testing.
  • Examples of the pharmacological test include an in vitro muscarinic receptor agonist measurement test and an in vivo test for confirming an antipsychotic action and a cognitive impairment improving action.
  • Specific in vivo tests include an apomorphine-induced climbing test, methamphetamine-induced exercise amount.
  • Examples include an enhancement test, a prepulse inhibition test, a microdialysis test, a passive avoidance reaction test, and a Y maze type test.
  • Examples of the pharmacokinetic test include a blood concentration evaluation test, a brain migration evaluation test, a P-glycoprotein substrate recognition test, a drug interaction test, a drug metabolic pathway identification test, and a dansyl glutathione addition test.
  • safety tests include blood pressure and heart rate measurement tests, electrocardiogram measurement tests, rat taste aversion conditioning tests, salivary secretion measurement tests, body temperature Measurement tests, gastrointestinal symptom evaluation tests, covalent bonding tests, extrapyramidal symptom evaluation tests, general symptom observations, general toxicity tests and the like can be mentioned. These tests can generally be performed on mice, rats, dogs, and monkeys. Moreover, it can implement under awakening or anesthesia as needed.
  • the following test examples illustrate the usefulness of the compounds of the present invention as pharmaceuticals.
  • Test Example 1 In Vitro Efficacy Test of Human-type Muscarin M 1 -M 5 Receptor
  • Human m1 receptor expression plasmid pcDNA3.1_hM1
  • human m3 receptor expression plasmid pcDNA3.1_hM3
  • the human m2 receptor expression plasmid (pcDNA3.1_hM2), the human m4 receptor expression plasmid (pcDNA3.1_hM4) and the human m5 receptor expression plasmid (pcDNA3.1_hM5), together with the cDNA encoding the G ⁇ 16 gene, were introduced into CHO-K1 cells. After introduction, stable expression strains resistant to the selection drugs Zeocin and HygroGold were obtained.
  • Human m1 and human m3 receptor stably expressing cells at a rate of 4 ⁇ 10 4 cells / 100 ⁇ L / well, human m2, human m4 and human m5 receptor stably expressing cells at a rate of 2 ⁇ 10 4 cells / 100 ⁇ L / well The cells were seeded in a 96-well plate and cultured overnight in a CO 2 incubator. When each receptor stable expression cell becomes 100% confluent, it is increased transiently by addition of test compound at FLIPR TETRA (registered trademark) (Molecular Devices) using FLIPR Calcium 4 assay kit (Molecular Devices). The measured fluorescence intensity (RFU (max-min)) was measured. When the fluorescence intensity by the control agent acetylcholine (3 ⁇ M) was 100%, the relative value of the fluorescence intensity of each test compound was determined, and this was defined as the agonist activity (%).
  • FLIPR TETRA registered trademark
  • FLIPR Calcium 4 assay kit FLIPR Calcium 4 as
  • the compound of the present invention is administered subcutaneously, intraperitoneally or orally, and apomorphine is administered 20 minutes later (50 minutes in the case of oral administration). .
  • the behavior from 10 minutes to 30 minutes after apomorphine administration is observed, and the degree of climbing is scored and evaluated.
  • the inhibition rate (%) can be treated statistically by expressing it with a numerical value of 0-100.
  • Test Example 3 Rat Antimethamphetamine-Induced Momentum Activity Enhancement Evaluation: When methamphetamine (1 mg / kg) is administered intraperitoneally to rats, the amount of exercise increases for about 1 hour immediately after the administration. Such behavior is a pathological condition of positive symptoms of schizophrenia. It is thought to reflect a part.
  • the antipsychotic action can be evaluated by the degree to which the action of methamphetamine is antagonized when the compound of the present invention is administered to this model.
  • the compound of the present invention is administered subcutaneously, intraperitoneally or orally to male male Sprague-Dawley rats at 7 weeks of age, and methamphetamine is administered 30 minutes later (or 60 minutes in the case of oral administration).
  • the rat is transferred to a test cage (made of colorless transparent plastic), and the momentum is measured for 80 minutes after 10 minutes.
  • SuperMex Moromachi Machine Co., Ltd.
  • the total exercise amount for 80 minutes can be statistically processed by expressing the inhibition rate (%) as a numerical value of 0 to 100, based on the exercise amount of the methamphetamine single administration group.
  • Test Example 4 Rat Taste Aversion Conditioning Test After giving a solution having an inexperienced taste (conditioned stimulus, CS) and then injecting a drug that induces gastrointestinal disorders / nausea (unconditional stimulated muscles, US), the animal becomes CS and US Even if you give CS next time, you will refuse to take it because of its taste.
  • CS conditioned stimulus
  • US unconditional stimulated muscles
  • the experiment uses 9-week-old male Sprague-Dawley rats.
  • Training After 15 hours of water outage, training is performed to ensure water supply by presenting a water bottle with water to the rat for 1 hour. Thereafter, water is freely supplied for 8 hours, and water is stopped for 15 hours over the next day.
  • a water bottle containing 0.5% saccharin water (CS) was presented to rats under water-absorptive conditions for 1 hour, and immediately after removing the bottle, the compound (US) of the present invention was added. Subcutaneous, intraperitoneal or oral administration. Thereafter, water is freely supplied for 8 hours, and water is stopped for 15 hours over the next day.
  • CS saccharin water
  • the value obtained by dividing the saccharin intake at the time of the test by the saccharin intake at the time of conditioning is calculated, and the rate of decrease compared to that of the solvent-administered group is evaluated as the aversion reaction formation rate.
  • hERG Inhibition Test In CHO cells in which hERG (human ether-a-go-go) gene is stably expressed by whole cell patch clamp method using QPatch HT (Sophion Bioscience A / S) automatic patch clamp device hERG potassium current was recorded.
  • the hERG current is the tail current when the membrane potential is held at ⁇ 80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds, then depolarized to +20 mV for 20 seconds, and then repolarized to ⁇ 50 mV for 5 seconds. Amplitude was evaluated. Stimulation was repeated every 15 seconds, and the experiment was performed at room temperature (22 ⁇ 2 ° C.).
  • the compound was cumulatively administered at a concentration of 4 per cell for 5 minutes, and the inhibition rate of the inhibited current was calculated as compared to the magnitude of the current before compound adaptation at each concentration, and the 50% inhibitory concentration was calculated using the Hill equation. (IC 50 [ ⁇ M]).
  • the following test solutions were used: extracellular solution (mM): 2 CaCl 2 , 1 MgCl 2 , 10 HEPES, 4 KCl, 145 NaCl, 10 glucose, intracellular solution (mM): 5.4 CaCl 2 , 1.8 MgCl 2 , 10 HEPES, 31 KOH, 10 EGTA, 120 KCl, 4ATP
  • the compounds of Comparative Examples 1 and 2 have no muscarinic receptor selectivity, and the compounds of the present invention in which the 1st nitrogen atom is bonded to piperidine and the 3rd position is a carbon atom are in terms of muscarinic receptor selectivity. It is clear that it is excellent.
  • the compound of Comparative Example 3 has very weak M 1 receptor activity, and the compound of the present invention in which the nitrogen atom at position 1 is bonded to piperidine and the carbon atom at position 3 is M 1 receptor activity. It is clear that it is superior.
  • the compound of the present invention selectively activates muscarinic M 1 and M 4 receptors, it has excellent central improving effects including antipsychotic effects, cognitive impairment improving effects, etc., and other muscarinic receptors or other Side effects through the receptor can be reduced. Therefore, the compound of the present invention can be a very useful medicament.

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Abstract

La présente invention concerne un dérivé de pyrrolidine cyclique condensée qui conduit sélectivement les récepteurs muscariniques M1 et M4 à agir et produire ainsi un effet et qui est réduit en termes d'effets secondaires médiés par d'autres récepteurs muscariniques ou d'autres récepteurs. La présente invention concerne un composé représenté par la formule (1) (les symboles dans la formule (1) sont comme décrit dans la description) ou un sel pharmaceutiquement acceptable de celui-ci, une composition médicinale contenant le composé ou un sel de celui-ci en tant que substance active, et un agent prophylactique et/ou thérapeutique pour des maladies médiées par des récepteurs muscariniques qui contient le composé ou un sel de celui-ci.
PCT/JP2011/068316 2010-08-10 2011-08-10 Dérivé de pyrrolidine cyclique condensée Ceased WO2012020813A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013122107A1 (fr) * 2012-02-14 2013-08-22 大日本住友製薬株式会社 Nouveau dérivé de pyrrolidine cyclique fusionné
JP2017505323A (ja) * 2014-02-06 2017-02-16 ヘプタレス セラピューティクス リミテッドＨｅｐｔａｒｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ ムスカリンｍ１受容体アゴニストとしての二環式アザ化合物
WO2017112719A1 (fr) * 2015-12-23 2017-06-29 Merck Sharp & Dohme Corp. Modulateurs allostériques 6,7-dihydro-5h-pyrrolo[3,4-b] pyridine-5-one du récepteur de l'acétylcholine muscarinique m4
JP2017522366A (ja) * 2014-05-30 2017-08-10 スプハエラ ファーマ ピーヴィーティー リミテッド 抗結核薬としての新規な化合物
US10512638B2 (en) 2015-12-23 2019-12-24 Merck Sharp & Dohme Corp. 3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor
US10836775B2 (en) 2016-12-22 2020-11-17 Merck Sharp & Dohme Corp. 6,6-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor
US10981902B2 (en) 2017-06-27 2021-04-20 Merck Sharp & Dohme Corp. 5-(pyridin-3-yl)oxazole allosteric modulators of the M4 muscarinic acetylcholine receptor
US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11149036B2 (en) 2017-06-27 2021-10-19 Msd R&D (China) Co., Ltd. 3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11319298B2 (en) 2016-12-22 2022-05-03 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor
US11339156B2 (en) 2017-06-27 2022-05-24 Merck Sharp & Dohme Corp. 3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
JP2024003167A (ja) * 2015-12-02 2024-01-11 アストライア セラピューティクス， エルエルシー ピペリジニルノシセプチン受容体化合物

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JP2009539833A (ja) * 2006-06-09 2009-11-19 アストラゼネカ・アクチエボラーグ 疼痛、アルツハイマー病および統合失調症の治療に有効なムスカリン受容体アゴニスト
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013122107A1 (fr) * 2012-02-14 2013-08-22 大日本住友製薬株式会社 Nouveau dérivé de pyrrolidine cyclique fusionné
CN109851610B (zh) * 2014-02-06 2021-09-21 赫普泰雅治疗有限公司 作为毒蕈碱m1和/或m4受体激动剂的双环氮杂化合物
JP2017505323A (ja) * 2014-02-06 2017-02-16 ヘプタレス セラピューティクス リミテッドＨｅｐｔａｒｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ ムスカリンｍ１受容体アゴニストとしての二環式アザ化合物
CN109851610A (zh) * 2014-02-06 2019-06-07 赫普泰雅治疗有限公司 作为毒蕈碱m1和/或m4受体激动剂的双环氮杂化合物
JP2017522366A (ja) * 2014-05-30 2017-08-10 スプハエラ ファーマ ピーヴィーティー リミテッド 抗結核薬としての新規な化合物
JP2024003167A (ja) * 2015-12-02 2024-01-11 アストライア セラピューティクス， エルエルシー ピペリジニルノシセプチン受容体化合物
WO2017112719A1 (fr) * 2015-12-23 2017-06-29 Merck Sharp & Dohme Corp. Modulateurs allostériques 6,7-dihydro-5h-pyrrolo[3,4-b] pyridine-5-one du récepteur de l'acétylcholine muscarinique m4
US10329289B2 (en) 2015-12-23 2019-06-25 Merck Sharp & Dohme Corp. 6,7-dihydro-5H-pyrrolo[3,4-B]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor
US10351564B2 (en) 2015-12-23 2019-07-16 Merck Sharop & Dohme, Corp. 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor
US10512638B2 (en) 2015-12-23 2019-12-24 Merck Sharp & Dohme Corp. 3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor
US10933056B2 (en) 2015-12-23 2021-03-02 Merck Sharp & Dohme Corp. 3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor
US11319298B2 (en) 2016-12-22 2022-05-03 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor
US10836775B2 (en) 2016-12-22 2020-11-17 Merck Sharp & Dohme Corp. 6,6-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor
US11149036B2 (en) 2017-06-27 2021-10-19 Msd R&D (China) Co., Ltd. 3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor
US10981902B2 (en) 2017-06-27 2021-04-20 Merck Sharp & Dohme Corp. 5-(pyridin-3-yl)oxazole allosteric modulators of the M4 muscarinic acetylcholine receptor
US11339156B2 (en) 2017-06-27 2022-05-24 Merck Sharp & Dohme Corp. 3-(1H-pyrazol-4-yl)pyridine allosteric modulators of the M4 muscarinic acetylcholine receptor
US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US12258346B2 (en) 2018-10-31 2025-03-25 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
US12037342B2 (en) 2019-05-23 2024-07-16 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof

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