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WO2013122107A1 - Novel fused-ring pyrrolidine derivative - Google Patents

Novel fused-ring pyrrolidine derivative Download PDF

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Publication number
WO2013122107A1
WO2013122107A1 PCT/JP2013/053413 JP2013053413W WO2013122107A1 WO 2013122107 A1 WO2013122107 A1 WO 2013122107A1 JP 2013053413 W JP2013053413 W JP 2013053413W WO 2013122107 A1 WO2013122107 A1 WO 2013122107A1
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Prior art keywords
group
methyl
dihydro
indol
carboxylate
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PCT/JP2013/053413
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French (fr)
Japanese (ja)
Inventor
孝明 住吉
洋子 ▲高▼橋
義治 宇留野
健太郎 ▲高▼井
篤志 諏訪
康子 村田
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大日本住友製薬株式会社
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Publication of WO2013122107A1 publication Critical patent/WO2013122107A1/en

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof

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 a therapeutic agent for central diseases related to these actions.
  • Non-Patent Document 1 Non-Patent Document 1
  • conventional muscarinic receptor agonists such as carbachol and pilocarpine have limited selectivity for muscarinic receptor subtypes and 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 pyrrolidine ring or the azetidine ring in that the 3-position carbon atom of the oxindole ring is bonded to the piperidine ring.
  • muscarinic M 1 and M 4 receptor agonists and muscarinic receptor selectivity are examples of the compound of the present invention.
  • Patent Document 2 discloses, for example, the following formula:
  • Patent Document 3 discloses, for example, the following formula:
  • An oxindole compound represented by the formula is disclosed.
  • these compounds are structurally different from the compounds of the present invention in which the 1-position nitrogen atom of the oxindole ring is bonded to the piperidine ring and the pyrrolidine ring or azetidine ring is bonded.
  • the agonist activity of the compound is selective for muscarinic M 1 receptor, and no specific disclosure or suggestion has been made regarding an oxindole compound that selectively activates both the muscarinic M 1 and M 4 receptors. .
  • the present invention selectively activates muscarinic M 1 and M 4 receptors to express central disease ameliorating effects and reduces side effects via other muscarinic receptors or other receptors. It is an object to provide a pyrrolidine compound.
  • 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 has been completed by finding that it has an excellent effect of improving central diseases including an improving action, and reduces side effects via other muscarinic receptors or other receptors.
  • 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, or an optionally substituted C 3-7 aliphatic A carbocyclic group or an optionally substituted 3- to 7-membered heterocyclic group, or R 1 and R 2 may be bonded to each other, and R 1 and R 2 may be substituted with adjacent carbon atoms Form a good C 3-7 aliphatic carbocyclic group or an optionally substituted 3-7 membered heterocyclic group, or R 1 and R 2 together form ⁇ CR 8 R 9 , R 8 and R 9 are the same or different and are each a hydrogen atom, a hydroxyl group, a sulfonylamino group or an optionally substituted C 1-6 alkyl group, or R 8 and R 9 are bonded to each other, R 8 and R 9 form an optionally substituted
  • n 0 or 1
  • Y and Z are the same or different and each represents an oxygen atom or a sulfur atom
  • a, b, c and d are the same or different and are each a nitrogen atom or CR 10
  • R 10 represents a hydrogen atom, a halogen atom, an optionally substituted C 3-7 aliphatic carbocyclic group, a C 6-14 aryl group, a 5- to 10-membered heteroaryl group, a C 6-14 arylalkyl group, Heteroarylalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkyloxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, substituted An amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group,
  • the cyclic group A is a piperidinyl group or the following formula (2); [Wherein X is —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 — or —CH 2 OCH 2 —, and p, q, r and s are the same or different, 0, 1 or 2 and the sum of p, q, r and s is 2, 3 or 4. Or a pharmaceutically acceptable salt thereof, which is a nitrogen-containing heterocyclic group represented by the formula:
  • the cyclic group A is represented by the following formula (3); Or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [7], which is a nitrogen-containing heterocyclic group represented by:
  • 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 fluorine atom or a hydroxyl 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 fluorine atom or a hydroxyl group.
  • R 10 is hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, trifluoromethyl group, difluoromethyl group, methoxy group, ethynyl group, ethenyl group, cyano group, hydroxyl group, substituted A compound or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [11], which may be an amino group or a nitro group;
  • a therapeutic agent for central diseases comprising the compound according to any one of [1] to [13] above or a pharmaceutically acceptable salt thereof;
  • a pharmaceutical composition comprising the compound according to any one of [1] to [13] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
  • 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.
  • 3 shows the evaluation results of the rat antimethamphetamine-induced momentum enhancing action of the compound of Example 3.
  • 3 is an evaluation result of rat catalepsy-inducing action of the compound of Example 3.
  • 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 methyl, ethyl, n-propyl, 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.
  • the “C 1-6 alkyl group” is preferably a C 1-3 alkyl group, more preferably a methyl group or an ethyl group.
  • optionally substituted C 1-6 alkyl group examples include trifluoromethyl group, difluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-methoxy group. Examples thereof include an ethyl group and a hydroxymethyl group.
  • C 2-6 alkenyl group means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms having one or more double bonds, such as 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 in the “C 2-6 alkenyl group” may be any position on the carbon chain.
  • the “C 2-6 alkenyl group” is preferably a C 2-3 alkenyl group.
  • C 2-6 alkynyl group means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms having one or more triple bonds, for example, Examples include ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group, and structural isomers thereof.
  • the position of the triple bond in the “C 2-6 alkynyl group” may be any position on the carbon chain.
  • the “C 2-6 alkynyl group” is preferably a C 2-3 alkynyl group.
  • the “C 3-7 aliphatic carbocyclic group” means a 3- to 7-membered saturated or unsaturated aliphatic hydrocarbon cyclic group that forms a ring only with carbon atoms.
  • Specific examples of the “C 3-7 aliphatic carbocyclic group” include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexyl group, cyclohexenyl group, 1,3-cyclohexyl group.
  • C 3-7 aliphatic carbocyclic group may optionally have one or more unsaturated bonds as long as an aromatic ⁇ -electron system does not occur, and a C 6-14 arene. And may be condensed.
  • the “C 3-7 aliphatic carbocyclic group” is preferably a C 3-6 saturated aliphatic carbocyclic group.
  • C 3-7 aliphatic carbocyclic group in “ optionally substituted C 3-7 aliphatic carbocyclic group”, a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, C 1-6 alkylcarbamoyl group, acyl group, C 1-6 alkyloxy group, optionally substituted C 1-6 alkyl group, mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl And one or more substituents selected from the group consisting of a group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, a sulfamoyl group, and a trifluoromethyl group.
  • Each of the above substituents can be substituted at any substitutable position on the C 3-7 aliphatic carbocyclic group.
  • C 6-14 arene means an aromatic hydrocarbon ring corresponding to a C 6-14 aryl group, and examples thereof include benzene, naphthalene, phenanthrene, and anthracene. Among these, benzene and naphthalene are preferable. Is particularly preferred.
  • the “heterocyclic group” is a 3- to 7-membered saturated or unsaturated aliphatic 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.
  • the “heterocyclic group” may optionally have one or more unsaturated bonds as long as an aromatic ⁇ -electron system does not occur, and may be a C 6-14 arene or a 5- to 10-membered heteroaryl. It may be condensed with a ring. Further, 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 the “heterocyclic group”.
  • the bonding position on the “heterocyclic group” may be on a heteroatom or a carbon atom, and in the case of a C 6-14 arene or a condensed product with a 5- to 10-membered heteroaryl ring, a C 6-14 arene Alternatively, it may be on a 5- to 10-membered heteroaryl ring.
  • 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,
  • a halogen atom a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkylcarbamoyl group, an acyl group, C 1 -6 alkyloxy group, optionally substituted C 1-6 alkyl group, mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-
  • substituents selected from the group consisting of a 6 alkylsulfonyl group, a sulfamoyl group, and a trifluoromethyl group are included.
  • Each of the above substituents can be substituted at any substitutable position on the heterocyclic group.
  • Heterocycle means a ring corresponding to the above-mentioned “heterocyclic group”, and includes 3 or more heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms.
  • 7-membered saturated or unsaturated aliphatic ring means, for example, pyrrolidine ring, piperidine ring, piperazine ring.
  • the “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 a 3- to 7-membered aliphatic carbocycle.
  • 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, hydroxyl group, amino group, cyano group, nitro group, C 1-6 alkylcarbamoyl group, acyl group, C 1-6 alkyloxy group, or optionally substituted.
  • 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 which is unsubstituted or the same or different and has one or two substituents.
  • C 6-14 aryl group examples include a phenyl group, a phenyl group substituted with a halogen atom (eg, 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 the C 1-6 alkyl group substituted with one or more C 6-14 aryl groups (ie, C 6-14 aryl-C 1-6 alkyl group).
  • C 6-14 aryl groups ie, C 6-14 aryl-C 1-6 alkyl group.
  • the C 6-14 arylalkyl group is preferably a C 6-10 aryl-C 1-4 alkyl group, more preferably a (C 6 or C 10 aryl) -C 1-4 alkyl group, particularly preferably A benzyl group is mentioned.
  • 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.
  • Specific examples of the “heteroaryl group” include a furyl group, a benzofuranyl group, a thienyl group, a benzothiophenyl group, a pyrrolyl group, a pyridyl group, an indolyl group, an oxazolyl group, a benzoxazolyl group, an isoxazolyl group, and a benzoyl group.
  • the “heteroaryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkylcarbamoyl group, an acyl group, a C 1-6 alkyloxy group, an optionally substituted C 1 1- 6 alkyl group, the group consisting of 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 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 alkyloxy group, and an optionally substituted C 1-6 alkyl group.
  • the “5- to 10-membered heteroaryl ring” means an aromatic heterocycle corresponding to a 5- to 10-membered heteroaryl group, and examples thereof include a furan ring, a benzofuran ring, and a thiophene ring.
  • Heteroarylalkyl group means the C 1-6 alkyl group substituted with one or more of the 5-10 membered heteroaryl group (ie, 5-10 membered heteroaryl-C 1-6 alkyl group).
  • the heteroarylalkyl group is preferably a 2-furylmethyl group, 2-furylethyl group, 3-furylmethyl group, 3-furylethyl group, 2-thienylmethyl group, 2-thienylethyl group, 3-thienylmethyl group.
  • the “C 1-6 alkyloxy group” means —O— to which a C 1-6 alkyl group is bonded, and specifically includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n- Examples include butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group and hexyloxy group.
  • a C 1-3 alkyloxy group is preferable, and a methoxy group and an ethoxy group are particularly preferable.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the “halogen atom” is preferably a fluorine atom, a chlorine atom or a bromine atom.
  • “Acyl group” means “C 1-6 alkyl-carbonyl group” (—CO— to which a C 1-6 alkyl group is bonded, for example, 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) and “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 group, propionyl group and benzoyl group Groups are preferred.
  • the benzene ring and naphthalene ring in the “acyl group” are 1 to 5 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 alkyloxy group. It may have a substituent, and the substitution position is not particularly limited.
  • the “optionally substituted amino group” means an amino group and a secondary or tertiary amino group substituted with a C 1-6 alkyl group, and examples thereof include an amino group and mono- or di-C 1 And -6 alkylamino groups (methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, butylamino group, dibutylamino group, etc.).
  • an amino group and a mono- or di-C 1-3 alkylamino group are preferable, and an amino group, a methylamino group and a dimethylamino group are particularly preferable.
  • C 1-6 alkylsulfanyl group means —S— to which a C 1-6 alkyl group is bonded.
  • a C 1-3 alkylsulfanyl group is preferable, and a
  • 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.
  • the “C 1-6 alkylsulfinyl group” is preferably a C 1-3 alkylsulfinyl group.
  • the “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 an isopropylsulfonyl group.
  • a C 1-3 alkylsulfonyl group is preferable, and a methylsulfonyl group and an ethylsulfonyl group are particularly preferable.
  • C 1-6 alkylcarbamoyl group is a carbamoyl group (mono or di-C 1-6 alkyl-carbamoyl group) in which one nitrogen atom or two identical or different C 1-6 alkyl groups are substituted. And N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group and the like.
  • Preferred alkylcarbamoyl groups include N-ethylcarbamoyl group and N, N-dimethylcarbamoyl group.
  • the “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.
  • a sulfamoyl group, and a mono- or di-C 1-6 alkylsulfamoyl group for example, a methylsulfamoyl group, a dimethylsulfamoyl group, an ethylsulfamoyl group, a diethylsulfamoyl group, a propylsulfamoyl group, Dipropylsulfamoyl group, butylsulfamoyl group and dibutylsulfamoyl group).
  • sulfamoyl group a sulfamoyl group and a mono- or di-C 1-3 alkylsulfamoyl group are preferable, and a sulfamoyl group, a methylsulfamoyl group and a dimethylsulfamoyl group are particularly preferable.
  • the "sulfonylamino group” means a secondary amino group substituted with an C 1-6 alkylsulfonylamino group substituted with a group or a C 1-6 alkylsulfonyl group and a C 1-6 alkyl group, Examples thereof include a methylsulfonylamino group, an ethylsulfonylamino group, and an isopropylsulfonylamino group.
  • the “nitrogen-containing heterocyclic group” means a 5- to 7-membered monocyclic saturated aliphatic heterocyclic group containing one nitrogen atom as a ring constituent atom, or represented by the following formula (2). This means a bicyclic saturated aliphatic nitrogen-containing heterocyclic group.
  • p, q, r and s are the same or different and are each 0, 1 or 2, and the sum of p, q, r and s is 4 or less, preferably 2, 3 or 4.
  • X is —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 —, —CH 2 OCH 2 —, preferably —CH 2 —, — (CH 2 ) 2 — or — (CH 2 ) 3 —.
  • nitrogen-containing heterocyclic group examples include a pyrrolidinyl group, a piperidinyl group, an azepanyl group, and a cyclic group represented by the following formula (4).
  • the pharmaceutically acceptable salt of the compound represented by the formula (1) refers to a base form of a functional group such as an amine contained in the compound represented by the formula (1). It means an acid addition salt obtained by treating with an acid.
  • the pharmaceutically acceptable acid include inorganic acids [eg, hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid), or sulfuric acid, nitric acid, phosphoric acid] Etc.] and 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,
  • the present invention includes solvates such as hydrates and ethanol solvates of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (1) obtained as a crystal and a pharmaceutically acceptable salt thereof may have a crystal polymorph, and the crystal polymorph is also included in the present invention.
  • the compound of the formula (1) of the present invention may have stereoisomers such as optical isomers, diastereoisomers, geometric isomers and the like depending on the mode of the substituent. ) Also includes all these stereoisomers and mixtures thereof.
  • a compound in which atoms constituting the compound are converted into isotopes (for example, a compound in which hydrogen is deuterated or a compound in which 12 C is converted into 14 C) is also encompassed in the present invention.
  • a, b, c and d are the same or different and are each a nitrogen atom or CR 10 , preferably a, b, c and d are each CR 10 . More preferably, a and d are CH.
  • R 10 represents a hydrogen atom, a halogen atom, a C 3-7 aliphatic carbocyclic group, a C 6-14 aryl group, a 5- to 10-membered heteroaryl group, or a C 6-14 arylalkyl group.
  • Heteroarylalkyl group C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkyloxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, substituted An optionally substituted amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group, preferably a hydrogen atom, a halogen atom, a C 1-6 alkyloxy group, A cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an optionally substituted amino group, a nitro group, or an optionally substituted C 1-6 alkyl group (preferably Preferably, it may be substituted with 1 to 4 substituents selected from the group consisting of a hydroxyl group, a C 1-6 alkylsulfanyl group, a
  • a good C 1-6 alkyl 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)
  • a hydrogen atom, a halogen atom, a methyl group, a cyano group, a hydroxyl group, a methoxy group or a trifluoromethyl group Preferably, the hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group or a trifluoromethyl
  • R 10 is independently selected.
  • 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, a hydroxyl group, a C 3-7 aliphatic carbocyclic 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 are a C 3-7 aliphatic carbocyclic group or a 3- to 7-membered heterocyclic group Form a cyclic group or R 1 and R 2 together form C ⁇ CR 8 R 9 .
  • R 8 and R 9 are the same or different and are each a hydrogen atom, a hydroxyl group, a sulfonylamino group or an optionally substituted C 1-6 alkyl group, or R 8 and R 9 are bonded to each other.
  • R 8 and R 9 together with the adjacent carbon atom form a C 3-7 aliphatic carbocyclic group or a 3- to 7-membered heterocyclic group.
  • 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, or a C 3-7 aliphatic carbocyclic group, Alternatively, R 1 and R 2 are bonded to each other, and R 1 and R 2 together with adjacent carbon atoms form a C 3-7 aliphatic carbocyclic group or a 3- to 7-membered heterocyclic group, and more preferably the same Or each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group or a C 3-7 aliphatic carbocyclic group, and more preferably the same or different, each a hydrogen atom , A fluorine atom, a hydroxyl group or an optionally substituted C 1-6 alkyl group. Note that hERG inhibition tends to be improved when both R 1 and R 2 are other than hydrogen atoms.
  • the cyclic group A is a monocyclic or bicyclic nitrogen-containing heterocyclic group.
  • the monocyclic nitrogen-containing heterocyclic group is preferably a pyrrolidinyl group or piperidinyl group, and more preferably a piperidinyl group.
  • the bicyclic saturated nitrogen-containing heterocyclic group is preferably a nitrogen-containing heterocyclic group represented by the formula (2), more preferably a nitrogen-containing heterocyclic ring represented by the formula (4). And particularly preferably a nitrogen-containing heterocyclic group represented by the formula (3).
  • the cyclic group A is preferably a piperidinyl group and a nitrogen-containing heterocyclic group represented by the above formula (3).
  • the nitrogen atom on the cyclic group A is substituted with —C ( ⁇ Y) —Z—R 7 (each symbol has the same meaning as described above).
  • the position of the other substituent on the cyclic group A is not particularly limited as long as it is chemically stable.
  • R 3 and R 4 are both hydrogen atoms, or R 3 and R 4 together form C ⁇ O or C ⁇ S with adjacent carbon atoms, preferably , R 3 and R 4 together form C ⁇ O with adjacent carbon atoms.
  • 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 5 and R 6 are the same or different and each represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group, a fluorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group.
  • Group or hydroxyl group preferably a hydrogen atom, methyl group, hydroxyl group, fluorine atom, difluoromethyl group, difluoromethoxy group or methoxy group, more preferably a hydrogen atom, methyl group, hydroxyl group, fluorine atom or methoxy group.
  • R 5 is two or more in the formula (1)
  • R 5 is selected independently. Even when two or more R 6 s of the formula (1) are present, R 6 is independently selected.
  • R 7 is an optionally substituted C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, preferably an optionally substituted C 1-6 alkyl group (preferably Or a C 2-6 alkenyl group, which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkyloxy group, more preferably a substituted group.
  • a linear C 1-3 alkyl group (which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkyloxy group). More preferably a methyl group, an ethyl group, or a 2-methoxyethyl group.
  • k and m are 1, 2 or 3, preferably k is 1 or 2, m is 1 or 2, and more preferably k and m are 1.
  • n is 0 or 1, preferably 1.
  • a preferable compound includes, for example, the following compound A, and a more preferable compound includes, for example, compound B.
  • Compound A a is CH, b is CR 10 (R 10 is as defined above); c is CR 10 (R 10 is as defined above); d is CH, R 1 and R 2 are the same or different and each is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group or a hydroxymethyl group; R 3 and R 4 together form C ⁇ O with adjacent carbon atoms, R 5 and R 6 are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a fluorine atom or a hydroxyl group; R 7 is a methyl group, an ethyl group or a 2-methoxyethyl group, k and m are the same or different and each is 1 or 2, n is 1, Y and Z are oxygen atoms; R 10 is is a CR 10 (R
  • a is CH
  • b is CR 10 (R 10 is as defined above);
  • c is CR 10 (R 10 is as defined above);
  • d is CH
  • R 1 and R 2 are the same or different and each is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group or a hydroxymethyl group;
  • R 3 and R 4 together form C ⁇ O with adjacent carbon atoms,
  • R 5 and R 6 are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a fluorine atom or a hydroxyl group;
  • R 7 is a methyl group, an ethyl group or a 2-methoxyethyl group,
  • k and m are the same or different and each is 1 or 2
  • n is 1, Y and Z are oxygen atoms;
  • R 10 is a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy
  • the compound of the present invention represented by the formula (1) can be produced by the following production method.
  • Manufacturing method 1 The compound of the formula (1) or a salt thereof is represented by the following formula (5); Or a salt thereof and the following formula (6): Or the following formula (7); Or the following formula (8); (In the formulas, each symbol has the same meaning as described above.
  • the compound of the formula (8) forms a spiro bond with an oxirane on the carbon atom of the cyclic group A. .)
  • the reaction of the compound of formula (5) or a salt thereof with the compound of formula (6) is a general purpose such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, pyridine borane, 2-picoline borane, etc.
  • the reductive amination reagent can be used.
  • the reaction of the compound of formula (5) or a salt thereof with the compound of formula (7) or the compound of formula (8) is carried out without a solvent or in a suitable solvent.
  • the solvent to be used include N, N-dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol and the like. These solvents are used alone or in combination of two or more.
  • This reaction is carried out in the presence of a base as necessary.
  • the base include potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like.
  • the reaction temperature is usually 0 ° C to 150 ° C.
  • 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 the 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, 1,4-dioxane, benzene, toluene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like. You can also.
  • the reaction temperature is usually ⁇ 78 ° C. to 140 ° C., preferably ⁇ 78 ° C. to 100 ° C.
  • Step 3 This step is performed in the same manner as in step 1 of this scheme.
  • the compound of formula (1-1) or a salt thereof can be synthesized according to the following scheme 2, scheme 3 or scheme 4. (Wherein X 1 represents a hydroxyl group or a halogen atom, X 2 represents a halogen atom, 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 available compound of formula (2-3). This reaction can be performed by a conventional method of amide bond forming reaction using a base or a condensing agent.
  • Step 2 The compound of formula (1-1) can be produced by reacting the compound of formula (2-2) 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
  • R represents a C 1-6 alkyl group, and other symbols are as defined above.
  • 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 N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane and the like, and these may be used alone or in combination of two or more.
  • the reaction is usually carried out 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 ethanol, methanol, acetic acid, ethyl acetate, tetrahydrofuran, dichloromethane and the like, and they are used alone or in combination of two or more.
  • a compound of formula (3-4) can be prepared by reacting a compound of formula (3-3) with an available compound of formula (3-5). This reaction can be performed according to the conditions of the above-mentioned reductive amination reaction.
  • the reagent include commonly used reagents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, pyridine borane and 2-picoline borane.
  • the solvent to be used include toluene, dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, diethyl ether, N, N-dimethylformamide, methanol, ethanol, ethyl acetate, and the like.
  • This reaction is carried out in the presence of an acid or a base as necessary.
  • the acid include acetic acid
  • examples of the base include triethylamine and N, N-diisopropylethylamine.
  • titanium tetraisopropoxide etc. can be used together as needed.
  • the reaction temperature is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • 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 N, N-dimethylformamide, tetrahydrofuran, dichloromethane, benzene, toluene, xylene and the like, and preferably benzene and toluene. Moreover, these can also be used in mixture of 2 or more types.
  • the reaction is usually carried out at 0 ° C to 200 ° C, preferably 70 ° C to 120 ° C.
  • X 3 represents a leaving group such as a halogen atom, —OSO 2 CH 3 or —OSO 2 C 6 H 4 CH 3 , and other symbols are as defined above.
  • Step 1 The compound of formula (4-2) is prepared by reacting an available compound of formula (4-1) with an available formula (4-3) 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 N, N-dimethylformamide, acetonitrile, tetrahydrofuran and the like, and these may be used alone or in combination of two or more.
  • the reaction is usually carried out at ⁇ 78 ° C. to 140 ° C., preferably 0 ° C. to 120 ° C.
  • Step 2 The compound of the formula (1-1) can be produced by reacting the compound of the formula (4-2) with N-bromosuccinimide and the like, and then oxidizing the compound in the presence of a metal catalyst such as palladium or manganese. . That is, it can be produced by the method described in Journal of Medicinal Chemistry, 27, 1379-88, (1984) or the like, or a method analogous thereto.
  • a metal catalyst such as palladium or manganese.
  • Step 1 The compound of formula (5-2) is obtained by reacting an available compound of formula (5-1) with a halogenating agent, oxidizing agent or alkylating agent corresponding to R 2 in the presence of a base in an inert solvent.
  • a base in an inert solvent.
  • the base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium hexamethyldisilazide.
  • potassium hexamethyldisilazide potassium hexamethyldisilazide.
  • the inert solvent examples include tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like. You can also.
  • the reaction temperature is usually ⁇ 78 ° C. to 140 ° C., preferably ⁇ 78 ° C. to 100 ° C.
  • Step 2 The compound of formula (5-3) can be produced by hydrolyzing the ester group of the compound of formula (5-2) according to a conventional method.
  • Step 3 This step is performed by a method according to Step 1 described in Scheme 2.
  • Step 4 This step is performed in the same manner as in step 2 described in Scheme 2.
  • Step 1 The compound of formula (6-1) is prepared from the compound of formula (3-4) synthesized according to Scheme 3 by the same method as in Step 1 described in Scheme 5.
  • Step 2 This step is performed in the same manner as in step 4 described in Scheme 3.
  • Step 3 This step is performed in the same manner as in Step 1 described in Scheme 5.
  • Step 1 The compound of formula (7-2) can be produced from an available compound of formula (7-1) by the same method as in Step 1 described in Scheme 4.
  • Step 2 This step is performed in the same manner as in Step 1 described in Scheme 1.
  • the compound of formula (6) is available from the following formula (9); Can be produced by oxidation by a known method, for example, the method described in New Experimental Chemistry Course Vol. 15 (Maruzen, 1978) or a method analogous thereto.
  • Step 1 The compound of formula (8) is prepared by mixing and stirring the available formula (8-1) with trimethylsulfonium iodide in a solvent such as dimethylsulfoxide in the presence of a base such as sodium hydride or potassium tert-butoxide. it can.
  • the reaction is usually carried out at -20 ° C to 60 ° C, preferably -10 ° C to 30 ° C.
  • Step 2 The compound of the formula (6) can be produced by allowing a Lewis acid such as boron trifluoride complex to act on the compound of the formula (8).
  • a Lewis acid such as boron trifluoride complex
  • the solvent to be used include tetrahydrofuran, 1,4-dioxane, methanol and the like, and two or more kinds thereof can be mixed and used.
  • the reaction temperature is usually ⁇ 20 ° C. to 60 ° C., preferably ⁇ 10 ° C. to 20 ° C.
  • Manufacturing method 2 A method for producing the compound of formula (1) according to the following scheme 9 (each symbol in the formula of scheme 9 has the same meaning as described above).
  • Step 1 The compound of the formula (9-2) is obtained by synthesizing the compound of the formula (9-1) synthesized according to the method described in Production Method 1, Scheme 2 to Scheme 7, in the same manner as in Step 1 of Production Method 1, Scheme 1. Can be manufactured by.
  • Step 2 The compound of the formula (9-3) can be produced by a method similar to the reaction of the formula (5) and the formula (6), (7) or (8) in the production method 1.
  • Step 3 The compound of Formula (1) can be manufactured by the method similar to the manufacturing method 1, the process 1 of the scheme 5 description.
  • 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 is performed using, for example, silica gel or alumina that has been subjected to acidic, basic, or various chemical treatments.
  • Examples of the developing solvent 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.
  • 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 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 the formula (1) can be obtained as a free base or an acid addition salt of the compound of the formula (1) depending on the type of functional group present in the structural formula, selection of the raw material compound, and reaction treatment conditions.
  • the acid addition salt of the compound of formula (1) can be converted to the compound of formula (1) which is a free base according to a conventional method.
  • the free base can be led to an acid addition salt of the compound of the formula (1) by treating with various acids according to a conventional method.
  • the compounds of the present 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 as a M 4 receptor agonist.
  • 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 an antipsychotic agent exhibiting excellent antipsychotic action It is. Furthermore, since the compound of the present invention has selectivity for muscarinic receptors and other receptors, it is expected to be used as a safe preventive and / or therapeutic agent for central diseases with fewer side effects than the prior agents. it can.
  • Disorders related to muscarinic M 1 receptors typically a mental disorder, for example, cognitive impairment, forgetfulness, confusion, memory loss, attention deficits, depression, pain, sleep disorders, such as psychosis and the like.
  • Disorders related to muscarinic M 4 receptor is typically a mental disorder, for example, confusion, attention deficit, pain, sleep disorders, such as schizophrenia.
  • the central diseases targeted by the compounds or pharmaceutical compositions 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, cognitive impairment, amnesia, confusion, memory loss, depression, sleep disorder, psychosis, etc.
  • 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.
  • 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 compound of the present invention 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, There are methods such as repeated administration.
  • repeated 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).
  • 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 pharmaceutical composition (pharmaceutical preparation) prepared by mixing with a pharmaceutically acceptable carrier, that is, a carrier for pharmaceutical preparation, when used for the above-mentioned pharmaceutical use.
  • a pharmaceutically acceptable carrier that is, a carrier for pharmaceutical preparation, when used for the above-mentioned pharmaceutical use.
  • a pharmaceutically acceptable carrier a nontoxic 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 composition 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 of dosage forms in the pharmaceutical composition of the present invention 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. Then, if necessary, taste masking, It can be produced by applying a coating for enteric or sustainable purposes. For example, in the case of 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.
  • (2) Injection The compound of the present invention is dissolved or suspended in an aqueous injection together with, for example, a dispersing agent, preservative, isotonic agent, etc., or in vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc. It can be produced by turbidity or emulsification to obtain 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 of the present invention and a pharmaceutically acceptable salt thereof can be used in combination with a therapeutic drug for schizophrenia such as risperidone, haloperidone and olanzapine for the purpose of enhancing the action.
  • a therapeutic drug for schizophrenia such as risperidone, haloperidone and olanzapine
  • drugs drugs such as mood disorders.
  • drugs such as antiemetics, sleep inducers, anticonvulsants and the like for the purpose of suppressing the side effects.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 1000 parts by weight per 1 part by weight of the compound of the present invention.
  • LC-MS For 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.
  • the mobile phase of LC-MS was 0.05% trifluoroacetic acid aqueous solution, 0.035% trifluoroacetic acid methanol solution or methanol.
  • LC-MS is measured under various conditions, which are described in detail in Table 1 below. In the experimental section of the specification, condition A was used unless otherwise specified.
  • the retention time (R.T.) represents the time when the mass spectrum peak appears in the LC-MS measurement.
  • Me methyl group
  • Et ethyl group
  • tBu tert-butyl group
  • Boc tert-butoxycarbonyl group
  • X-Phos 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl
  • min Minute
  • J coupling constant
  • s single line
  • d double line
  • dd double double line
  • t triple line
  • td triple double line
  • q quadruple line
  • m multiple line
  • Br wide
  • brd wide double line
  • brt wide triple line.
  • Reference example 2 (3S) -3- (2-Oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine-1-carboxylate tert-butyl
  • a tert-butyl alcohol solution 29 mL
  • palladium acetate 33 mg, 0.15 mmol
  • phenylboronic acid 36 mg, 0.3 mmol
  • X-Phos 141 mg, 0.3 mmol
  • potassium carbonate 1.0 g, 7.3 mmol
  • Reference Example 3 (3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine
  • the compound of Reference Example 2 (0.8 g) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3.0 mL) was added, and the mixture was stirred for 1 hour.
  • a 4 mol / L sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by amino silica gel column chromatography to obtain the target compound (0.5 g, 97%).
  • Reference example 5 (3S) -3- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine-1-carboxylate tert-butyl
  • a tert-butyl alcohol solution (4 mL) of the compound of Reference Example 4 (600 mg, 1.5 mmol), palladium acetate (16 mg, 0.07 mmol), phenylboronic acid (18 mg, 0.15 mmol), X-Phos (72 mg, 0.15 mmol) and potassium carbonate (501 mg, 3.6 mmol) were added, and the mixture was stirred for 20 minutes at 160 ° C. under microwave irradiation.
  • Reference Examples 7 to 14 The compounds shown in Table 2 below were obtained in the same manner as in Reference Examples 1 to 6 using the corresponding available raw materials. Some use azetidine derivatives instead of pyrrolidine derivatives.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to obtain the target compound (3.0 g, 75%).
  • Reference Example 16 2- (2-Bromophenyl) propionic acid To a mixed solution of the compound of Reference Example 15 (3.0 g) in tetrahydrofuran (12 mL) and methanol (12 mL) was added 2 mol / L sodium hydroxide aqueous solution and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the aqueous layer was washed with diethyl ether. To this aqueous layer was added 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target compound (2.7 g, 95%).
  • Reference Examples 20-22 The compounds shown in Table 3 below were obtained in the same manner as in Reference Examples 15 to 19 using the corresponding available raw materials.
  • Example 1 4- ⁇ [(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl ⁇ piperidine-1-carboxylate
  • the compound of Reference Example 3 (32 mg, 0.16 mmol) was dissolved in dichloromethane (1.5 mL), ethyl 4-formylpiperidine-1-carboxylate (36 mg) was added at room temperature, and the mixture was stirred for 10 minutes, and then triacetoxy hydrogenated.
  • Sodium boron 51 mg was added and stirred for 4 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with chloroform.
  • Examples 2-30 The compounds of Examples 2 to 30 shown in Tables 4 to 11 below were obtained in the same manner as in Example 1 using the compounds of Reference Example 3, 6 to 14, 19 to 22 or 24.
  • ethyl 4-formylpiperidine-1-carboxylate in Example 1 ethyl (3-exo) -3-formyl-8-azabicyclo [3.2.1] octane-8-carboxylate, (1R, 5S ) -3-formyl-8-azabicyclo [3.2.1] octane-8-carboxylate, (3-endo) -3-formyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid
  • Example 31 4-( ⁇ (3S) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl ⁇ Methyl) piperidine-1-carboxylate and 4-( ⁇ (3R) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indole- 1-yl] piperidin-1-yl ⁇ methyl) piperidine-1-carboxylate
  • Paraformaldehyde (18 mg, 0.20 mmol) and potassium carbonate (16 mg, 0.12 mmol) were added to a tetrahydrofuran solution (1 mL) of the compound of Example 23 (28 mg, 0.073 mmol), and the mixture was stirred for 24 hours.
  • Example 32 (3-exo) -3-( ⁇ (3S) -3-[(3S) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl ⁇ methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate and (3-exo) -3-( ⁇ (3S) -3-[(3R) -3-hydroxy-3 -Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl ⁇ methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate To a tetrahydrofuran solution (2 mL) of the compound of Example 24 (138 mg, 0.64 mmol) was added potassium carbonate (104 mg, 0.75 mmol), and the mixture was stirred for 24 hours while adding air to the solution.
  • Examples 33-35 Using the compound of Example 25, 27 or 28, according to the same method as in Example 31 or 32, the compounds of Examples 33 to 35 were obtained as shown in Table 12 below.
  • Table 12 In the structural formulas of Example 33a (higher polarity compound) and Example 33b (lower polarity compound) in Table 12 below, * means chiral.
  • 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, an in vivo test for confirming an antipsychotic effect and a cognitive impairment improving effect, and specific in vivo tests include an apomorphine-induced climbing test, methamphetamine-induced momentum.
  • 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. 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 operability test of human muscarinic M 1 -M 5 receptor The operability of each receptor was evaluated by measuring changes in intracellular calcium concentration in each receptor stably expressing cells using fluorescence intensity as an index. .
  • Human m1 receptor expression plasmid (pcDNA3.1_hM1) or human m3 receptor expression plasmid (pcDNA3.1_hM3) was introduced into CHO-K1 cells, and geneticin-resistant stable expression strains were obtained by the limiting dilution method.
  • 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) are respectively present in CHO-K1 cells together with cDNA encoding the G ⁇ 16 gene. 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 stably expressing cells becomes 100% confluent, it is temporarily increased by addition of a 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
  • Tables 13 to 15 show the results of in vitro pharmacological tests of human-type muscarinic receptors performed in accordance with Test Example 1 using Example compounds (in each table, “NT” indicates that the test was not performed. Means that there is.)
  • Test Example 2 Rat antimethamphetamine-induced momentum enhancement evaluation Methamphetamine-induced momentum enhancement in rats is considered to reflect the pathology of positive symptoms of schizophrenia.
  • the antipsychotic action was evaluated based on the degree of antagonizing the inhibitory action on methamphetamine-induced momentum increase when the compound of the present invention was administered alone or in combination with an antipsychotic drug to this model.
  • Seven-week-old male Sprague-Dawley rats are administered the compound of the present invention subcutaneously, intraperitoneally or orally alone or in combination with an antipsychotic drug, 30 minutes later (or 60 minutes in the case of oral administration) Methamphetamine (1 mg / kg) was administered intraperitoneally.
  • Test Example 3 Evaluation of rat anti-scopolamine-induced amnesia effect
  • a rat passive avoidance reaction test apparatus manufactured by Ohara Medical Industry Co., Ltd.
  • the compound of the present invention is subcutaneously, intraperitoneally or orally administered to 7-week-old male Wistar rats, and scopolamine (0.5 mg / kg) is intraperitoneally administered 15 minutes later (30 minutes after oral administration). did.
  • the rat was placed in a light box, and when the rat moved to a dark box, a foot shock of 0.3 mA was applied for 3 seconds.
  • the rat was placed in the light box again, and the latency until moving to the dark box was measured up to 300 seconds.
  • the latency of the solvent administration group was 100
  • the latency of the scopolamine alone group was 0, and the improvement rate (%) was expressed as a numerical value.
  • the compound of Example 4 improved scopolamine-induced amnesia.
  • Test Example 4 Rat Catalepsy Inducing Action Evaluation It is believed that extrapyramidal symptom catalepsy can be evaluated in this test. Catalepsy-inducing action when the compound of the present invention alone or in combination with a psychotic drug was evaluated. The compound of the present invention was administered to 8-week-old male Sprague-Dawley rats alone or in combination with the psychotic drug risperidone. The compound was administered subcutaneously, intraperitoneally or orally 60 minutes prior to catalepsy assessment. In catalepsy evaluation, the rat's forelimb was placed on a 1 cm diameter metal bar placed horizontally at a height of 9 cm, and the standing posture holding time was measured three times continuously up to 180 seconds.
  • the longest posture retention time among the three measurements was adopted as the value of each individual.
  • the subcutaneous administration (30 mg / kg) of the compound of Example 3 was 0 seconds.
  • a combination test with oral administration of risperitone was conducted.
  • the compound of Example 3 did not induce extrapyramidal symptoms, and even when used in combination with an antipsychotic drug, the possibility of exacerbating extrapyramidal symptoms was shown.
  • Test Example 5 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) The hERG potassium current at was recorded.
  • the hERG current is the amplitude of the tail current when the membrane potential is held at ⁇ 80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds after being changed to ⁇ 50 mV for 20 milliseconds, and then repolarized to ⁇ 50 mV for 5 seconds. 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 for each cell for 5 minutes, the inhibition rate of the inhibited current was calculated as compared to the current before the compound adaptation at each concentration, and the 50% inhibitory concentration was calculated by 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, 4 ATP
  • Table 18 shows the results of the hERG inhibition test conducted in accordance with Test Example 5 using the Example compounds.
  • Comparative example In addition, using the method of Test Example 1 above, using the known compounds disclosed in Patent Documents 1 to 4 as comparative examples, the operability against muscarinic M 1 -M 4 receptors was measured, and Example compounds of the present application were measured. And compared.
  • Comparative Example 1 Comparative Example 2: From Table 19, the compounds of Comparative Examples 1 and 2 have no muscarinic receptor selectivity, and the compounds of the present invention in which the nitrogen atom at the 1st position is bonded to pyrrolidine and the carbon atom at the 3rd position are in terms of muscarinic receptor selectivity. It is clear that it is excellent.
  • Comparative Example 3 From Table 20, 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 pyrrolidine and the carbon atom at position 3 is M 1 receptor activity. It is clear that it is superior.
  • Comparative Example 5 Comparative Example 6: Compound of Comparative Example 5 and Comparative Example 6 is disclosed it is very weak M 4 receptor agonist in Patent Document 4, the present compound is excellent in terms of M 4 receptor agonist is it is obvious.
  • the compound of the present invention selectively activates muscarinic M 1 and M 4 receptors, it has excellent central improvement 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

The present invention relates to: a compound represented by formula (1) or a pharmaceutically acceptable salt thereof; a pharmaceutical composition which contains, as an active ingredient, the compound or a pharmaceutically acceptable salt thereof; and a therapeutic agent for diseases mediated by muscarinic receptors, which contains the compound or a pharmaceutically acceptable salt thereof. (In the formula, each of a, b, c and d represents a nitrogen atom or CR10; each of Y and Z represents an oxygen atom or a sulfur atom; A represents a monocyclic or bicyclic nitrogen-containing heterocyclic group; each of R1, R2 and R5-R10 represents a hydrogen atom, an alkyl group or the like; each of R3 and R4 represents a hydrogen atom, or alternatively, R3 and R4 combine together to form C=O or C=S; each of k and m represents a number of 1-3; and n represents a number of 0-1.)

Description

新規縮環ピロリジン誘導体Novel fused pyrrolidine derivatives
　本発明は、ムスカリン受容体作動性を有する新規な縮環ピロリジン誘導体およびそれらを有効成分とする医薬組成物に関する。本発明はまた、それらを含有するムスカリン受容体仲介疾患の予防および／または治療剤も提供する。 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.
　神経伝達物質アセチルコリン受容体はニコチン受容体およびムスカリン受容体の２タイプのコリン作動性受容体が知られている。ムスカリン受容体は細胞膜結合Ｇタンパク質共役受容体（ＧＰＣＲ）であり、現在５個のサブタイプ(Ｍ１－Ｍ５)が知られている。これらＭ１－Ｍ５ムスカリン受容体は中枢および末梢組織に興奮性および抑制性制御を及ぼし、心拍、覚醒、認知、運動制御などを含む多くの生理的機能に関与する。 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.
　ムスカリン受容体作動薬は鎮痛作用、記憶改善作用、抗精神病作用、認知障害改善作用など種々の薬理作用を有しており、それら作用が関係する中枢性疾患の治療薬として使用できる可能性がある（非特許文献１）。しかしながら、カルバコールやピロカルピンのような従来のムスカリン受容体作動薬は、ムスカリン受容体サブタイプに対する選択性が低く副作用の発現が多く見られたことから、臨床への応用が限られている。 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 a therapeutic agent for central diseases related to these actions. (Non-Patent Document 1). However, conventional muscarinic receptor agonists such as carbachol and pilocarpine have limited selectivity for muscarinic receptor subtypes and many side effects have been observed, so their clinical application is limited.
　近年、ムスカリン受容体の分子クローニングおよびノックアウトマウスを使用する特定のサブタイプの生理学的役割の同定によって選択的ムスカリン受容体リガンドが新しい治療薬となりうる可能性が提示され、効果の増強および副作用の減少に必要な選択性プロファイルが研究されてきた。ザノメリン(xanomeline)は、ヒト統合失調症の陽性症状、陰性症状、認知障害のすべてに優れた臨床効果を示したことが報告されているが、Ｍ１およびＭ４ノックアウトマウスを用いた研究により、ザノメリンの抗精神病作用は主としてムスカリンＭ１およびＭ４受容体作動性を介していることが報告されている（非特許文献２））。 In recent years, molecular cloning of muscarinic receptors and identification of the physiological role of specific subtypes using knockout mice has shown the potential of selective muscarinic receptor ligands as new therapeutic agents, enhancing efficacy and reducing side effects The selectivity profile required for the study has been studied. Zanomerin (xanomeline) is of human schizophrenia positive symptoms, negative symptoms, but that all showed excellent clinical efficacy of cognitive impairment has been reported by studies with M 1 and M 4 knockout mice, It has been reported that the antipsychotic action of zanomeline is mainly mediated through muscarinic M 1 and M 4 receptor agonists (Non-patent Document 2)).
　以上の理由から、特に中枢性疾患治療剤としてムスカリンＭ１およびＭ４受容体に選択的に作動する薬剤の創出が、効果の増強および副作用の低減の観点から期待されている。 For these reasons, the creation of drugs that selectively act on muscarinic M 1 and M 4 receptors, particularly as therapeutic agents for central diseases, is expected from the viewpoint of enhancing effects and reducing side effects.
　特許文献１には、例えば、下記式で表されるオキシインドール化合物が開示されている。
Figure JPOXMLDOC01-appb-C000004
 　当該化合物は、オキシインドール環の３位炭素原子がピペリジン環と結合している点において、オキシインドール環の１位窒素原子がピロリジン環またはアゼチジン環と結合している本発明化合物と構造が異なる。また、ムスカリンＭ１およびＭ４受容体作動性およびムスカリン受容体選択性に関しては何ら具体的に開示も示唆もされていない。 Patent Document 1 discloses, for example, an oxindole compound represented by the following formula.
Figure JPOXMLDOC01-appb-C000004
 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 pyrrolidine ring or the azetidine 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.
　また、特許文献２には、例えば、下記式
Figure JPOXMLDOC01-appb-C000005
 で表されるオキシインドール化合物が開示されており、また特許文献３には、例えば、下記式
Figure JPOXMLDOC01-appb-C000006
 で表されるオキシインドール化合物が開示されている。しかしながら、これらの化合物は、オキシインドール環１位窒素原子がピペリジン環と結合しており、ピロリジン環またはアゼチジン環が結合している本発明化合物と構造的に異なる。また、当該化合物の作動性はムスカリンＭ１受容体選択的であり、ムスカリンＭ１およびＭ４の両受容体を選択的に作動するオキシインドール化合物に関しては何ら具体的に開示も示唆もされていない。 Patent Document 2 discloses, for example, the following formula:
Figure JPOXMLDOC01-appb-C000005
 In addition, Patent Document 3 discloses, for example, the following formula:
Figure JPOXMLDOC01-appb-C000006
 An oxindole compound represented by the formula is disclosed. However, these compounds are structurally different from the compounds of the present invention in which the 1-position nitrogen atom of the oxindole ring is bonded to the piperidine ring and the pyrrolidine ring or azetidine ring is bonded. In addition, the agonist activity of the compound is selective for muscarinic M 1 receptor, and no specific disclosure or suggestion has been made regarding an oxindole compound that selectively activates both the muscarinic M 1 and M 4 receptors. .
国際公開第99/32481号パンフレットWO99 / 32481 pamphlet 国際公開第2007/142585号パンフレットInternational Publication No. 2007/142585 Pamphlet 国際公開第2009/110844号パンフレットInternational Publication No. 2009/110844 Pamphlet
　本発明は、選択的にムスカリンＭ１およびＭ４受容体を作動して、中枢性疾患の改善効果を発現するとともに、その他のムスカリン受容体または他の受容体を介する副作用が低減された縮環ピロリジン化合物を提供することを課題とする。 The present invention selectively activates muscarinic M 1 and M 4 receptors to express central disease ameliorating effects and reduces side effects via other muscarinic receptors or other receptors. It is an object to provide a pyrrolidine compound.
　本発明者らは上記課題を解決するために鋭意検討した結果、特定の縮環ピロリジン構造を有する化合物が、選択的にムスカリンＭ１およびＭ４受容体を作動して、抗精神病作用、認知障害改善作用などを含む優れた中枢性疾患の改善効果を有するとともに、その他のムスカリン受容体または他の受容体を介する副作用を低減することを見出し、本発明を完成した。すなわち、本発明は、
［１］下記式（１）；
Figure JPOXMLDOC01-appb-C000007
 [式中、Ｒ１およびＲ２は、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、置換されていてもよいＣ３－７脂肪族炭素環基または置換されていてもよい３～７員の複素環基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに置換されていてもよいＣ３－７脂肪族炭素環基または置換されていてもよい３～７員の複素環基を形成するか、またはＲ１およびＲ２が一緒になって＝ＣＲ８Ｒ９を形成し、
　Ｒ８およびＲ９は、同一または異なって、それぞれ水素原子、水酸基、スルホニルアミノ基または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ８およびＲ９が互いに結合して、Ｒ８およびＲ９が隣接する炭素原子とともに置換されていてもよいＣ３－７脂肪族炭素環基または置換されていてもよい３～７員の複素環基を形成し、
　Ｒ３およびＲ４は、ともに水素原子であるか、またはＲ３およびＲ４が一緒になって、隣接する炭素原子とともにＣ＝ＯまたはＣ＝Ｓを形成してもよく、
　Ｒ５およびＲ６は、同一または異なって、それぞれ水素原子、メチル基、エチル基、メトキシ基、フッ素原子、ジフルオロメチル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基または水酸基であり、
　Ｒ７は、置換されていてもよいＣ１－６アルキル基、Ｃ２－６アルケニル基またはＣ２－６アルキニル基であり、
　ｋおよびｍは、同一または異なって、それぞれ１、２または３であり、
　ｎは、０または１であり、
　ＹおよびＺは、同一または異なって、それぞれ酸素原子または硫黄原子であり、
　ａ、ｂ、ｃおよびｄは、同一または異なって、それぞれ窒素原子またはＣＲ１０であり、
　Ｒ１０は、水素原子、ハロゲン原子、置換されていてもよいＣ３－７脂肪族炭素環基、Ｃ６－１４アリール基、５～１０員のヘテロアリール基、Ｃ６－１４アリールアルキル基、ヘテロアリールアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルキルオキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、アシル基、スルファモイル基、水酸基、置換されていてもよいアミノ基、ニトロ基、Ｃ１－６アルキルスルホニル基、または置換されていてもよいＣ１－６アルキル基であり、
　環状基Ａは、単環または二環の含窒素複素環基である。]で表される化合物またはその薬学的に許容される塩（以下、これらを「本発明の化合物」、「化合物（１）」、または「式（１）の化合物」と称することもある。）； As a result of intensive studies to solve the above problems, 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 has been completed by finding that it has an excellent effect of improving central diseases including an improving action, and reduces side effects via other muscarinic receptors or other receptors. That is, the present invention
[1] The following formula (1);
Figure JPOXMLDOC01-appb-C000007
 [Wherein, 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, or an optionally substituted C 3-7 aliphatic A carbocyclic group or an optionally substituted 3- to 7-membered heterocyclic group, or R 1 and R 2 may be bonded to each other, and R 1 and R 2 may be substituted with adjacent carbon atoms Form a good C 3-7 aliphatic carbocyclic group or an optionally substituted 3-7 membered heterocyclic group, or R 1 and R 2 together form ═CR 8 R 9 ,
R 8 and R 9 are the same or different and are each a hydrogen atom, a hydroxyl group, a sulfonylamino group or an optionally substituted C 1-6 alkyl group, or R 8 and R 9 are bonded to each other, R 8 and R 9 form an optionally substituted C 3-7 aliphatic carbocyclic group or an optionally substituted 3-7 membered heterocyclic group with adjacent carbon atoms;
R 3 and R 4 may both be hydrogen atoms, or R 3 and R 4 may be taken together to form C═O or C═S with adjacent carbon atoms;
R 5 and R 6 are the same or different and are each a hydrogen atom, methyl group, ethyl group, methoxy group, fluorine atom, difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group or hydroxyl group,
R 7 is an optionally substituted C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group,
k and m are the same or different and are 1, 2 or 3, respectively.
n is 0 or 1,
Y and Z are the same or different and each represents an oxygen atom or a sulfur atom,
a, b, c and d are the same or different and are each a nitrogen atom or CR 10 ;
R 10 represents a hydrogen atom, a halogen atom, an optionally substituted C 3-7 aliphatic carbocyclic group, a C 6-14 aryl group, a 5- to 10-membered heteroaryl group, a C 6-14 arylalkyl group, Heteroarylalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkyloxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, substituted An amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group,
The cyclic group A is a monocyclic or bicyclic nitrogen-containing heterocyclic group. Or a pharmaceutically acceptable salt thereof (hereinafter, these may be referred to as “compound of the present invention”, “compound (1)”, or “compound of formula (1)”). ;
［２］ＹおよびＺが、ともに酸素原子である上記［１］に記載の化合物またはその薬学的に許容される塩； [2] The compound according to the above [1], wherein Y and Z are both oxygen atoms, or a pharmaceutically acceptable salt thereof;
［３］ｎが１である上記［１］または［２］に記載の化合物またはその薬学的に許容される塩； [3] The compound according to the above [1] or [2], wherein n is 1, or a pharmaceutically acceptable salt thereof;
［４］ｋが１であり、Ｒ５が水素原子である上記［１］～［３］のいずれかに記載の化合物またはその薬学的に許容される塩； [4] The compound or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [3], wherein k is 1 and R 5 is a hydrogen atom;
［５］Ｒ３およびＲ４が、一緒になって、隣接する炭素原子とともにＣ＝Ｏを形成する、上記［１］～［４］のいずれかに記載の化合物またはその薬学的に許容される塩； [5] The compound according to any one of the above [1] to [4] or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together to form C═O together with an adjacent carbon atom. salt;
［６］Ｒ７が、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、メトキシエチル基、またはジフルオロメチル基である上記［１］～［５］のいずれかに記載の化合物またはその薬学的に許容される塩； [6] The compound according to any one of [1] to [5] above, wherein R 7 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxyethyl group, or a difluoromethyl group, or a pharmaceutical product thereof Acceptable salts;
［７］環状基Ａが、ピペリジニル基または下記式（２）；
Figure JPOXMLDOC01-appb-C000008
 [式中、Ｘは－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－または－ＣＨ２ＯＣＨ２－であり、ｐ、ｑ、ｒおよびｓは同一または異なって、それぞれ０、１または２であり、かつｐ、ｑ、ｒおよびｓの総和は２、３または４である。]で表される含窒素複素環基である上記［１］～［６］のいずれかに記載の化合物またはその薬学的に許容される塩； [7] The cyclic group A is a piperidinyl group or the following formula (2);
Figure JPOXMLDOC01-appb-C000008
 [Wherein X is —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 — or —CH 2 OCH 2 —, and p, q, r and s are the same or different, 0, 1 or 2 and the sum of p, q, r and s is 2, 3 or 4. Or a pharmaceutically acceptable salt thereof, which is a nitrogen-containing heterocyclic group represented by the formula:
［８］環状基Ａが、下記式（３）；
Figure JPOXMLDOC01-appb-C000009
 で表される含窒素複素環基である上記［１］～［７］のいずれかに記載の化合物またはその薬学的に許容される塩； [8] The cyclic group A is represented by the following formula (3);
Figure JPOXMLDOC01-appb-C000009
 Or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [7], which is a nitrogen-containing heterocyclic group represented by:
［９］Ｒ６が、メチル基、エチル基、メトキシ基または水酸基である上記［１］～［８］のいずれかに記載の化合物またはその薬学的に許容される塩； [9] The compound or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [8], wherein R 6 is a methyl group, an ethyl group, a methoxy group or a hydroxyl group;
［１０］Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、フッ素原子または水酸基である上記［１］～［９］のいずれかに記載の化合物またはその薬学的に許容される塩； [10] Any one of [1] to [9] above, wherein 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 fluorine atom or a hydroxyl group. The described compounds or pharmaceutically acceptable salts thereof;
［１１］ａ、ｂ、ｃおよびｄが、ＣＲ１０である上記［１］～［１０］のいずれかに記載の化合物またはその薬学的に許容される塩； [11] The compound according to any one of the above [1] to [10], wherein a, b, c and d are CR 10 , or a pharmaceutically acceptable salt thereof;
［１２］Ｒ１０が、水素原子、フッ素原子、塩素原子、臭素原子、メチル基、エチル基、トリフルオロメチル基、ジフルオロメチル基、メトキシ基、エチニル基、エテニル基、シアノ基、水酸基、置換されていてもよいアミノ基またはニトロ基である上記［１］～［１１］のいずれかに記載の化合物またはその薬学的に許容される塩； [12] R 10 is hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, trifluoromethyl group, difluoromethyl group, methoxy group, ethynyl group, ethenyl group, cyano group, hydroxyl group, substituted A compound or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [11], which may be an amino group or a nitro group;
［１３］４－{ [（３Ｒ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｒ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－endo)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(１Ｒ，５Ｓ)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸メチル；
 (３－exo)－３－{ [（３Ｓ）－３－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（４－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｒ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
 (３－exo)－３－{ [（３Ｓ）－３－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）アゼチジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－ヒドロキシ－４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－９－アザビシクロ[３．３．１]ノナン－９－カルボン酸メチル；
３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－９－アザビシクロ[３．３．１]ノナン－９－カルボン酸メチル；
４－メチル－４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [（３Ｓ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
 (３－exo)－３－{ [（３Ｓ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｒ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｒ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｒ）－３－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [（３Ｓ）－３－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－({(３Ｓ)－3－[(３Ｒ) －３－(ヒドロキシメチル)－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピペリジン－１－イル}メチル)ピペリジン－１－カルボン酸エチル；
４－({(３Ｒ)－３－[(３Ｒ) －３－(ヒドロキシメチル)－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピペリジン－１－イル}メチル)ピペリジン－１－カルボン酸エチル；
(３－exo)－３－({(３Ｓ)－３－[(３Ｓ) －３－ヒドロキシ－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル)－８－アザビシクロ[３.２.１]オクタン－８－カルボン酸エチル；
(３－exo)－３－({(３Ｓ)－３－[(３Ｒ) －３－ヒドロキシ－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル)－８－アザビシクロ[３.２.１]オクタン－８－カルボン酸エチル；
４－({ [（３Ｒ）－３－[３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；
４－({ [（３Ｒ）－３－[（３Ｒ）－５－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；および
４－({ [（３Ｓ）－３－[（３Ｓ）－５－フルオロ－３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；
からなる群から選択される、上記［１］に記載の化合物またはその薬学的に許容される塩； [13] 4-{[(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3-{[(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
(3-exo) -3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
(3-endo) -3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
(1R, 5S) -3- {[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] methyl octane-8-carboxylate;
(3-exo) -3- {[(3S) -3- (5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
(3-exo) -3- {[(3S) -3- (4-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
(3-exo) -3- {[(3S) -3- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3R) -3- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[3- (2-oxo-2,3-dihydro-1H-indol-1-yl) azetidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4-hydroxy-4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -9-azabicyclo [3.3.1] nonane Methyl 9-carboxylate;
3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -9-azabicyclo [3.3.1] nonane Methyl 9-carboxylate;
4-methyl-4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4-{[(3S) -3- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3R) -3- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3R) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3R) -3- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} piperidine-1-carvone Ethyl acid;
4-{[(3S) -3- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} piperidine-1-carvone Ethyl acid;
4-{[3- (2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3-{[3- (2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3.2.1] octane-8- Ethyl carboxylate;
4-({(3S) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} Methyl) piperidine-1-carboxylate;
4-({(3R) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} Methyl) piperidine-1-carboxylate;
(3-exo) -3-({(3S) -3-[(3S) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate;
(3-exo) -3-({(3S) -3-[(3R) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate;
4-({[(3R) -3- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl} methyl) piperidine 1-ethyl carboxylate;
4-({[(3R) -3-[(3R) -5-fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine 1-yl} methyl) piperidine-1-carboxylate; and 4-({[(3S) -3-[(3S) -5-fluoro-3-hydroxy-3-methyl-2-oxo-2, 3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl} methyl) ethyl piperidine-1-carboxylate;
The compound or pharmaceutically acceptable salt thereof according to the above [1], selected from the group consisting of:
［１４］上記［１］～［１３］のいずれかに記載の化合物またはその薬学的に許容される塩を含有する中枢性疾患の治療剤； [14] A therapeutic agent for central diseases comprising the compound according to any one of [1] to [13] above or a pharmaceutically acceptable salt thereof;
［１５］中枢性疾患がアルツハイマー病および／または統合失調症である、上記［１４］に記載の治療剤； [15] The therapeutic agent according to [14] above, wherein the central disease is Alzheimer's disease and / or schizophrenia;
［１６］上記［１］～［１３］のいずれかに記載の化合物またはその薬学的に許容される塩、および薬学的に許容される担体を含有する医薬組成物； [16] A pharmaceutical composition comprising the compound according to any one of [1] to [13] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
［１７］上記［１］～［１３］のいずれかに記載の化合物またはその薬学的に許容される塩を患者に投与して中枢性疾患を治療する方法； [17] A method for treating a central disease by administering to a patient the compound according to any one of [1] to [13] above or a pharmaceutically acceptable salt thereof;
［１８］中枢性疾患がアルツハイマー病および／または統合失調症である、上記［１７］に記載の方法； [18] The method described in [17] above, wherein the central disease is Alzheimer's disease and / or schizophrenia;
［１９］中枢性疾患治療薬としての使用のための上記［１］～［１３］のいずれかに記載の化合物またはその薬学的に許容される塩； [19] The compound according to any one of the above [1] to [13] or a pharmaceutically acceptable salt thereof for use as a therapeutic agent for central diseases;
［２０］中枢性疾患がアルツハイマー病および／または統合失調症である、上記［１９］に記載の化合物またはその薬学的に許容される塩；
を提供する。 [20] The compound of the above-mentioned [19] or a pharmaceutically acceptable salt thereof, wherein the central disease is Alzheimer's disease and / or schizophrenia;
I will provide a.
　本発明化合物は、抗精神病作用、認知障害改善作用などを含む優れた中枢性疾患の改善効果を示すため、新規な中枢性疾患の予防および／または治療剤として有用である。 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.
実施例３の化合物のラット抗メタンフェタミン誘発運動量亢進作用の評価結果である。3 shows the evaluation results of the rat antimethamphetamine-induced momentum enhancing action of the compound of Example 3. 実施例３の化合物のラットカタレプシー誘発作用の評価結果である。3 is an evaluation result of rat catalepsy-inducing action of the compound of Example 3.
　本明細書における用語を以下に説明する。 The terms used in this specification are explained below.
　本発明の目的に関して、化学元素は元素周期表、CAS version, Handbook of Chemistry and Physics, 75th Edに従って同定する。さらに、有機化学の一般的原理は、“Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999および“March's Advanced Organic Chemistry”, 5th Ed., : Smith, M.B. and March, J., John Wiley ＆ Sons, New York: 2001に記載されており、それらの全内容を参照することができる。 For the purposes of the present invention, chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physicals, 75th Ed. In addition, the general principles of organic chemistry are: “OrganicistChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th Ed.,: Smith, MB and March, J. & John Sons, New York: 2001, all of which can be referenced.
　受容体サブタイプを特定する接頭辞がない用語「ムスカリン受容体」は、５種の受容体サブタイプＭ１－Ｍ５の１種以上を意味する。 The term “muscarinic receptor” without a prefix identifying a receptor subtype means one or more of the five receptor subtypes M 1 -M 5 .
　ムスカリン受容体に結合してムスカリン活性を増強する化合物は作動薬またはアゴニストと称される。ムスカリン受容体の活性を減少させる化合物は拮抗薬またはアンタゴニストと称される。アゴニストはムスカリン受容体と相互作用して該受容体が内因性リガンド結合に応答して細胞内シグナルを伝達する能力を増加させる。アンタゴニストはムスカリン受容体と相互作用し、該受容体上の結合部位(複数可)を内因性リガンド(複数可)または基質(複数可)と競合して、該受容体が内因性リガンド結合に応答して細胞内シグナルを伝達する能力を低下させる。 Compounds that bind to muscarinic receptors and enhance muscarinic activity are called agonists or agonists. 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.
　「Ｃ１－６アルキル基」とは、炭素数が１～６個の直鎖状または分枝鎖状の飽和炭化水素基を意味し、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ネオペンチル基およびｎ－ヘキシル基、ならびにそれらの構造異性体が挙げられる。当該「Ｃ１－６アルキル基」としては、Ｃ１－３アルキル基が好ましく、メチル基およびエチル基がより好ましい。 “C 1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, 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. The “C 1-6 alkyl group” is preferably a C 1-3 alkyl group, more preferably a methyl group or an ethyl group.
　「置換されていてもよいＣ１－６アルキル基」におけるＣ１－６アルキル基の置換基としては、水酸基、ハロゲン原子、アミノ基、ホルミル基、カルバモイル基、シアノ基、ニトロ基およびＣ１－６アルキルオキシ基からなる群から選択される１～４個の原子または置換基が挙げられる。上記置換基はそれぞれＣ１－６アルキル基上の置換可能な任意の位置に置換することができる。当該「置換されていてもよいＣ１－６アルキル基」の具体例としては、トリフルオロメチル基、ジフルオロメチル基、２－フルオロエチル基、２、２、２－トリフルオロエチル基、２－メトキシエチル基およびヒドロキシメチル基などが挙げられる。 The substituent of the C 1-6 alkyl group in the "substituted optionally a C 1-6 alkyl group", a hydroxyl group, a halogen atom, an amino group, a formyl group, a carbamoyl group, a cyano group, a nitro group and a C 1- Examples include 1 to 4 atoms or substituents selected from the group consisting of 6 alkyloxy groups. Each of the above substituents can be substituted at any substitutable position on the C 1-6 alkyl group. Specific examples of the “ optionally substituted C 1-6 alkyl group” include trifluoromethyl group, difluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-methoxy group. Examples thereof include an ethyl group and a hydroxymethyl group.
　「Ｃ２－６アルケニル基」とは、１個以上の二重結合を有する炭素数が２～６個の直鎖状または分枝鎖状の不飽和の脂肪族炭化水素基を意味し、例えば、エテニル基、プロペニル基、クロチル基、ブテニル基、ペンテニル基およびヘキセニル基、ならびにそれらの構造異性体や幾何異性体が挙げられる。当該「Ｃ２－６アルケニル基」における二重結合の位置は炭素鎖上のどの位置であってもよい。「Ｃ２－６アルケニル基」としては、Ｃ２－３アルケニル基が好ましい。 “C 2-6 alkenyl group” means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms having one or more double bonds, such as 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 in the “C 2-6 alkenyl group” may be any position on the carbon chain. The “C 2-6 alkenyl group” is preferably a C 2-3 alkenyl group.
　「Ｃ２－６アルキニル基」とは、１個以上の三重結合を有する炭素数が２～６個の直鎖状または分枝鎖状の不飽和の脂肪族炭化水素基を意味し、例えば、エチニル基、プロピニル基、ブチニル基、ペンチニル基およびヘキシニル基、ならびにそれらの構造異性体が挙げられる。当該「Ｃ２－６アルキニル基」における三重結合の位置は炭素鎖上のどの位置であってもよい。当該「Ｃ２－６アルキニル基」としては、Ｃ２－３アルキニル基が好ましい。 “C 2-6 alkynyl group” means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms having one or more triple bonds, for example, Examples include ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group, and structural isomers thereof. The position of the triple bond in the “C 2-6 alkynyl group” may be any position on the carbon chain. The “C 2-6 alkynyl group” is preferably a C 2-3 alkynyl group.
　「Ｃ３－７脂肪族炭素環基」とは、炭素原子のみで環を構成している３～７員の飽和または不飽和の脂肪族炭化水素環基を意味する。当該「Ｃ３－７脂肪族炭素環基」の具体例としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロペンテニル基、シクロペンタジエニル基、シクロヘキシル基、シクロヘキセニル基、１，３－シクロヘキサジエニル基、１，４－シクロヘキサジエニル基、シクロヘプチル基、シクロヘプテニル基、１，２－シクロヘプタジエニル基、１，３－シクロヘプタジエニル基および１，４－シクロヘプタジエニル基が挙げられる。また、当該「Ｃ３－７脂肪族炭素環基」は、芳香族π電子系が生じない限り、任意に１個以上の不飽和結合を有していてもよく、また、Ｃ６－１４アレーンと縮合していてもよい。当該「Ｃ３－７脂肪族炭素環基」としては、Ｃ３－６の飽和の脂肪族炭素環基が好ましい。 The “C 3-7 aliphatic carbocyclic group” means a 3- to 7-membered saturated or unsaturated aliphatic hydrocarbon cyclic group that forms a ring only with carbon atoms. Specific examples of the “C 3-7 aliphatic carbocyclic group” include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexyl group, cyclohexenyl group, 1,3-cyclohexyl group. Sadienyl group, 1,4-cyclohexadienyl group, cycloheptyl group, cycloheptenyl group, 1,2-cycloheptadienyl group, 1,3-cycloheptadienyl group and 1,4-cycloheptadienyl group Can be mentioned. In addition, the “C 3-7 aliphatic carbocyclic group” may optionally have one or more unsaturated bonds as long as an aromatic π-electron system does not occur, and a C 6-14 arene. And may be condensed. The “C 3-7 aliphatic carbocyclic group” is preferably a C 3-6 saturated aliphatic carbocyclic group.
　「置換されていてもよいＣ３－７脂肪族炭素環基」における、「Ｃ３－７脂肪族炭素環基」の置換基としては、ハロゲン原子、水酸基、アミノ基、シアノ基、ニトロ基、Ｃ１－６アルキルカルバモイル基、アシル基、Ｃ１－６アルキルオキシ基、置換されていてもよいＣ１－６アルキル基、モノまたはジ－Ｃ１－６アルキルアミノ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、スルファモイル基およびトリフルオロメチル基からなる群より選択される１個以上の置換基が挙げられる。上記置換基はそれぞれＣ３－７脂肪族炭素環基上の置換可能な任意の位置に置換することができる。 As the substituent of “C 3-7 aliphatic carbocyclic group” in “ optionally substituted C 3-7 aliphatic carbocyclic group”, a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, C 1-6 alkylcarbamoyl group, acyl group, C 1-6 alkyloxy group, optionally substituted C 1-6 alkyl group, mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl And one or more substituents selected from the group consisting of a group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, a sulfamoyl group, and a trifluoromethyl group. Each of the above substituents can be substituted at any substitutable position on the C 3-7 aliphatic carbocyclic group.
　「Ｃ６－１４アレーン」とは、Ｃ６－１４アリール基に対応する芳香族炭化水素環を意味し、例えば、ベンゼン、ナフタレン、フェナントレン、アントラセンが挙げられ、中でも、ベンゼンおよびナフタレンが好ましく、ベンゼンが特に好ましい。 “C 6-14 arene” means an aromatic hydrocarbon ring corresponding to a C 6-14 aryl group, and examples thereof include benzene, naphthalene, phenanthrene, and anthracene. Among these, benzene and naphthalene are preferable. Is particularly preferred.
　「複素環基」とは、環構成原子として酸素原子、硫黄原子および窒素原子からなる群より選択される１個以上のヘテロ原子を含む３～７員の飽和または不飽和の脂肪族環基を意味する。当該「複素環基」は、芳香族π電子系が生じない限り、任意に１個以上の不飽和結合を有していてもよく、また、Ｃ６－１４アレーンまたは５～１０員のヘテロアリール環と縮合していてもよい。さらに、環構成メンバーとして、１個以上のカルボニルまたはチオカルボニルを含んでいてもよく、例えば、ラクタム、ラクトン、環式イミド、環式チオイミド、環式カルバメートなどの環状基も当該「複素環基」に含まれる。当該「複素環基」上の結合位置は、ヘテロ原子上でも炭素原子上でもよく、Ｃ６－１４アレーンまたは５～１０員のヘテロアリール環との縮合体の場合には、Ｃ６－１４アレーンまたは５～１０員のヘテロアリール環の環上であってもよい。 The “heterocyclic group” is a 3- to 7-membered saturated or unsaturated aliphatic 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. The “heterocyclic group” may optionally have one or more unsaturated bonds as long as an aromatic π-electron system does not occur, and may be a C 6-14 arene or a 5- to 10-membered heteroaryl. It may be condensed with a ring. Further, the ring-constituting member may contain one or more carbonyl or thiocarbonyl. For example, a cyclic group such as lactam, lactone, cyclic imide, cyclic thioimide, and cyclic carbamate is also the “heterocyclic group”. include. The bonding position on the “heterocyclic group” may be on a heteroatom or a carbon atom, and in the case of a C 6-14 arene or a condensed product with a 5- to 10-membered heteroaryl ring, a C 6-14 arene Alternatively, it may be on a 5- to 10-membered heteroaryl ring.
　当該「複素環基」の具体例としては、例えば、テトラヒドロチオピラニル基、４Ｈ－ピラニル基、テトラヒドロピラニル基、ピペリジル基、１－エトキシカルボニルピペリジル基、１－エトキシカルボニルピペリジニリデニル基、１，３－ジオキシニル基、１，３－ジオキサニル基、１，４－ジオキシニル基、１，４－ジオキサニル基、ピペラジニル基、１，３－オキサチアニル基、１，４－オキサチイニル基、１，４－オキサチアニル基、テトラヒドロ－１，４－チアジニル基、２Ｈ－１，２－オキサジニル基、マレイミド基、スクシンイミド基、ジオキソピペラジニル基、ヒダントイン基、ジヒドロウラシル基、モルホリノ基、ヘキサヒドロ－１，３，５－トリアジニル基、テトラヒドロチエニル基、テトラヒドロフラニル基、ジヒドロフラニル基、オキセタニル基、ピロリニル基、ピロリジニル基、ピロリドニル基、ピロリジオニル基、ピラゾリニル基、ピラゾリジニル基、イミダゾリニル基、イミダゾリジニル基、１，３－ジオキソリル基、１，３－ジオキソラニル基、１，３－ジチオリル基、１，３－ジチオラニル基、イソオキサゾリニル基、イソオキサゾリジニル基、オキサゾリニル基、オキサゾリジニル基、チアゾリニル基、チアゾリジニル基および１，３－オキサチオラニル基が挙げられる。 Specific examples of the “heterocyclic group” 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-1,3,5 -Triazinyl group, tetrahydrothienyl group, tetrahydrofuranyl group, dihydride Furanyl group, oxetanyl group, pyrrolinyl group, pyrrolidinyl group, pyrrolidonyl group, pyrrolidonyl group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, 1,3-dioxolyl group, 1,3-dioxolanyl group, 1,3-dithiolyl group 1,3-dithiolanyl group, isoxazolinyl group, isoxazolidinyl group, oxazolinyl group, oxazolidinyl group, thiazolinyl group, thiazolidinyl group and 1,3-oxathiolanyl group.
　「置換されていてもよい複素環基」における「複素環基」の置換基としては、ハロゲン原子、水酸基、アミノ基、シアノ基、ニトロ基、Ｃ１－６アルキルカルバモイル基、アシル基、Ｃ１－６アルキルオキシ基、置換されていてもよいＣ１－６アルキル基、モノまたはジ－Ｃ１－６アルキルアミノ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、スルファモイル基およびトリフルオロメチル基からなる群より選択される１個以上の置換基が挙げられる。上記置換基はそれぞれ複素環基上の置換可能な任意の位置に置換することができる。 As the substituent of the “heterocyclic group” in the “optionally substituted heterocyclic group”, a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkylcarbamoyl group, an acyl group, C 1 -6 alkyloxy group, optionally substituted C 1-6 alkyl group, mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1- One or more substituents selected from the group consisting of a 6 alkylsulfonyl group, a sulfamoyl group, and a trifluoromethyl group are included. Each of the above substituents can be substituted at any substitutable position on the heterocyclic group.
　「複素環」とは、上記「複素環基」に対応する環を意味し、環構成原子として酸素原子、硫黄原子および窒素原子からなる群より選択される１個以上のヘテロ原子を含む３～７員の飽和または不飽和の脂肪族環を意味し、例えば、ピロリジン環、ピペリジン環、ピペラジン環が挙げられる。 “Heterocycle” means a ring corresponding to the above-mentioned “heterocyclic group”, and includes 3 or more heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom as ring-constituting atoms. 7-membered saturated or unsaturated aliphatic ring means, for example, pyrrolidine ring, piperidine ring, piperazine ring.
　「Ｃ６－１４アリール基」とは、炭素数が６～１４の芳香族炭素環基を意味する。当該「Ｃ６－１４アリール基」は、少なくとも１つのＣ６－１４アレーンまたは３～７員の脂肪族炭素環と縮合していてもよい。当該「Ｃ６－１４アリール基」の具体例としては、フェニル基、ナフチル基、フェナントリル基、アントリル基、フルオレニル基、テトラヒドロナフチル基、インデニル基およびインダニル基が挙げられ、中でも、フェニル基およびナフチル基が好ましく、フェニル基が特に好ましい。 The “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 a 3- to 7-membered aliphatic carbocycle. 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. And a phenyl group is particularly preferable.
　当該「Ｃ６－１４アリール基」は、ハロゲン原子、水酸基、アミノ基、シアノ基、ニトロ基、Ｃ１－６アルキルカルバモイル基、アシル基、Ｃ１－６アルキルオキシ基、置換されていてもよいＣ１－６アルキル基、モノまたはジ－Ｃ１－６アルキルアミノ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、スルファモイル基およびトリフルオロメチル基からなる群から選択される１個以上の任意の置換基を有してもよく、好ましくは、無置換または同一もしくは異なって１個または２個の上記置換基を有するフェニル基である。Ｃ６－１４アリール基の代表例として、フェニル基、ハロゲン原子で置換されたフェニル基（例えば、３位または４位にハロゲン原子が置換されたフェニル基）、３－ヒドロキシフェニル基、４－ヒドロキシフェニル基、３－アミノフェニル基、４－アミノフェニル基、３－メチルフェニル基、４－メチルフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、３－シアノフェニル基、４－シアノフェニル基、３，４－ジメチルフェニル基、ナフチル基、１－ヒドロキシナフチル基、４－（ヒドロキシメチル）フェニル基および４－（トリフルオロメチル)フェニル基が挙げられるが、これらに限られるわけではない。 The “C 6-14 aryl group” is a halogen atom, hydroxyl group, amino group, cyano group, nitro group, C 1-6 alkylcarbamoyl group, acyl group, C 1-6 alkyloxy group, or optionally substituted. 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 which is unsubstituted or the same or different and has one or two substituents. Representative examples of the C 6-14 aryl group include a phenyl group, a phenyl group substituted with a halogen atom (eg, 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.
　「Ｃ６－１４アリールアルキル基」とは、１個以上の前記Ｃ６－１４アリール基で置換された前記Ｃ１－６アルキル基（すなわち、Ｃ６－１４アリール－Ｃ１－６アルキル基）を意味し、例えば、ベンジル基、１－フェニルエチル基、２－フェニルエチル基、１－ナフチルメチル基、１－（１－ナフチル）エチル基、２－（１－ナフチル）エチル基、２－ナフチルメチル基、１－（２－ナフチル）エチル基、２－（２－ナフチル）エチル基などが挙げられる。Ｃ６－１４アリールアルキル基としては、好ましくは、Ｃ６－１０アリール－Ｃ１－４アルキル基、より好ましくは、（Ｃ６またはＣ１０アリール）－Ｃ１－４アルキル基、特に好ましくは、ベンジル基が挙げられる。 “C 6-14 arylalkyl group” means the C 1-6 alkyl group substituted with one or more C 6-14 aryl groups (ie, C 6-14 aryl-C 1-6 alkyl group). For example, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-naphthylmethyl group, 1- (1-naphthyl) ethyl group, 2- (1-naphthyl) ethyl group, 2-naphthyl A methyl group, a 1- (2-naphthyl) ethyl group, a 2- (2-naphthyl) ethyl group and the like can be mentioned. The C 6-14 arylalkyl group is preferably a C 6-10 aryl-C 1-4 alkyl group, more preferably a (C 6 or C 10 aryl) -C 1-4 alkyl group, particularly preferably A benzyl group is mentioned.
　「ヘテロアリール基」とは、環構成原子として酸素原子、硫黄原子および窒素原子からなる群より選択される１個以上のヘテロ原子を含む５～１０員の芳香族環基を意味する。当該「ヘテロアリール基」の具体例としては、例えば、フリル基、ベンゾフラニル基、チエニル基、ベンゾチオフェニル基、ピロリル基、ピリジル基、インドリル基、オキサゾリル基、ベンゾオキサゾリル基、イソオキサゾリル基、ベンゾイソオキサゾリル基、チアゾリル基、ベンゾチアゾリル基、イソチアゾリル基、イミダゾリル基、ベンゾイミダゾリル基、ピラゾリル基、インダゾリル基、テトラゾリル基、フラザニル基、１，２，３－オキサジアゾリル基、１，２，３－チアジアゾリル基、１，２，４－チアジアゾリル基、１，２，３－トリアゾリル基、１，２，４－トリアゾリル基、ベンゾトリアゾリル基、キノリニル基、イソキノリニル基、ピリダジニル基、ピリミジニル基、プリニル基、ピラジニル基、プテリジニル基、フェノキサゾリル基、ベンゾピラゾリル基、キノリジニル基、シンノリニル基、フタラジニル基、キナゾリニル基およびキノキサリニル基が挙げられる。当該「ヘテロアリール基」は、少なくとも１つのＣ６－１４アレーンまたは複素環と縮合していてもよい。当該「ヘテロアリール基」としては、５員および６員のヘテロアリール基が好ましい。 “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. Specific examples of the “heteroaryl group” include a furyl group, a benzofuranyl group, a thienyl group, a benzothiophenyl group, a pyrrolyl group, a pyridyl group, an indolyl group, an oxazolyl group, a benzoxazolyl group, an isoxazolyl group, and a benzoyl group. Isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, tetrazolyl, furazanyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl 1,2,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, benzotriazolyl group, quinolinyl group, isoquinolinyl group, pyridazinyl group, pyrimidinyl group, purinyl group, pyrazinyl Group, pteridinyl group, pheno Sazoriru group, benzopyrazolyl group, quinolizinyl group, cinnolinyl group, phthalazinyl group, and quinazolinyl group and quinoxalinyl group. The “heteroaryl group” may be condensed with at least one C 6-14 arene or heterocycle. The “heteroaryl group” is preferably a 5-membered or 6-membered heteroaryl group.
　当該「ヘテロアリール基」は、ハロゲン原子、水酸基、アミノ基、シアノ基、ニトロ基、Ｃ１－６アルキルカルバモイル基、アシル基、Ｃ１－６アルキルオキシ基、置換されていてもよいＣ１－６アルキル基、モノまたはジ－Ｃ１－６アルキルアミノ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、スルファモイル基およびトリフルオロメチル基からなる群より選択される１個以上の置換基を有してもよく、好ましくは、同一または異なった１個または２個の上記置換基を有していてもよい。最も典型的な置換基は、ハロゲン原子、水酸基、シアノ基、Ｃ１－６アルキルオキシ基、および置換されていてもよいＣ１－６アルキル基である。 The “heteroaryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkylcarbamoyl group, an acyl group, a C 1-6 alkyloxy group, an optionally substituted C 1 1- 6 alkyl group, the group consisting of 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 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 alkyloxy group, and an optionally substituted C 1-6 alkyl group.
　「５～１０員のヘテロアリール環」とは、５～１０員のヘテロアリール基に対応する芳香族複素環を意味し、例えば、フラン環、ベンゾフラン環、チオフェン環が挙げられる。 The “5- to 10-membered heteroaryl ring” means an aromatic heterocycle corresponding to a 5- to 10-membered heteroaryl group, and examples thereof include a furan ring, a benzofuran ring, and a thiophene ring.
　「ヘテロアリールアルキル基」とは、１個以上の前記５～１０員のヘテロアリール基で置換された前記Ｃ１－６アルキル基（すなわち、５～１０員のヘテロアリール－Ｃ１－６アルキル基）を意味し、例えば、２－フリルメチル基、２－フリルエチル基、３－フリルメチル基、３－フリルエチル基、２－チエニルメチル基、２－チエニルエチル基、３－チエニルメチル基、３－チエニルエチル基、２－ピリジルメチル基、３－ピリジルメチル基、４－ピリジルメチル基、２－ピリジルエチル基、３－ピリジルエチル基、４－ピリジルエチル基、１－インドリルメチル基、２－インドリルメチル基、３－インドリルメチル基、１－インドリルエチル基、２－インドリルエチル基、３－インドリルエチル基などが挙げられる。ヘテロアリールアルキル基としては、好ましくは、２－フリルメチル基、２－フリルエチル基、３－フリルメチル基、３－フリルエチル基、２－チエニルメチル基、２－チエニルエチル基、３－チエニルメチル基、３－チエニルエチル基、２－ピリジルメチル基、３－ピリジルメチル基、４－ピリジルメチル基、２－ピリジルエチル基、３－ピリジルエチル基、４－ピリジルエチル基、より好ましくは、２－フリルメチル基、３－フリルメチル基、２－チエニルメチル基、３－チエニルメチル基、２－ピリジルメチル基、３－ピリジルメチル基、４－ピリジルメチル基が挙げられる。 “Heteroarylalkyl group” means the C 1-6 alkyl group substituted with one or more of the 5-10 membered heteroaryl group (ie, 5-10 membered heteroaryl-C 1-6 alkyl group). For example, 2-furylmethyl group, 2-furylethyl group, 3-furylmethyl group, 3-furylethyl group, 2-thienylmethyl group, 2-thienylethyl group, 3-thienylmethyl group, 3 -Thienylethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-pyridylethyl group, 3-pyridylethyl group, 4-pyridylethyl group, 1-indolylmethyl group, 2- Examples include indolylmethyl group, 3-indolylmethyl group, 1-indolylethyl group, 2-indolylethyl group, and 3-indolylethyl group. The heteroarylalkyl group is preferably a 2-furylmethyl group, 2-furylethyl group, 3-furylmethyl group, 3-furylethyl group, 2-thienylmethyl group, 2-thienylethyl group, 3-thienylmethyl group. Group, 3-thienylethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-pyridylethyl group, 3-pyridylethyl group, 4-pyridylethyl group, more preferably 2- Examples include furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, and 4-pyridylmethyl group.
　「Ｃ１－６アルキルオキシ基」とは、Ｃ１－６アルキル基が結合した－Ｏ－を意味し、具体的には、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、ネオペンチルオキシ基およびヘキシルオキシ基が挙げられる。当該「Ｃ１－６アルキルオキシ基」としては、Ｃ１－３アルキルオキシ基が好ましく、メトキシ基およびエトキシ基が特に好ましい。 The “C 1-6 alkyloxy group” means —O— to which a C 1-6 alkyl group is bonded, and specifically includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n- Examples include butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group and hexyloxy group. As the “C 1-6 alkyloxy group”, a C 1-3 alkyloxy group is preferable, and a methoxy group and an ethoxy group are particularly preferable.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。当該「ハロゲン原子」としては、フッ素原子、塩素原子および臭素原子が好ましい。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The “halogen atom” is preferably a fluorine atom, a chlorine atom or a bromine atom.
　「アシル基」とは、「Ｃ１－６アルキル－カルボニル基」（Ｃ１－６アルキル基が結合した－ＣＯ－、例えば、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、ピバロイル基、ヘキサノイル基およびヘプタノイル基）、「Ｃ６－１４アリール－カルボニル基」（Ｃ６－１４アリール基が結合した－ＣＯ－、例えば、ベンゾイル基およびナフトイル基）および「Ｃ６－１４アリールアルキル－カルボニル基」（Ｃ６－１４アリールアルキル基が結合した－ＣＯ－、例えば、ベンジルカルボニル基、２－フェニルエチルカルボニル基および３－フェニルプロピルカルボニル基）が挙げられ、中でも、アセチル基、プロピオニル基およびベンゾイル基が好ましい。当該「アシル基」中のベンゼン環およびナフタレン環はハロゲン原子、Ｃ１－６アルキル基、ニトロ基、シアノ基、水酸基およびＣ１－６アルキルオキシ基からなる群から選択される１～５個の置換基を有していてもよく、置換位置は特に限定されない。 “Acyl group” means “C 1-6 alkyl-carbonyl group” (—CO— to which a C 1-6 alkyl group is bonded, for example, 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) and “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 group, propionyl group and benzoyl group Groups are preferred. The benzene ring and naphthalene ring in the “acyl group” are 1 to 5 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 alkyloxy group. It may have a substituent, and the substitution position is not particularly limited.
　「置換されていてもよいアミノ基」とは、アミノ基、およびＣ１－６アルキル基で置換された２級または３級アミノ基であって、例えば、アミノ基、およびモノまたはジ－Ｃ１－６アルキルアミノ基（メチルアミノ基、ジメチルアミノ基、エチルアミノ基、ジエチルアミノ基、プロピルアミノ基、ジプロピルアミノ基、ブチルアミノ基、ジブチルアミノ基など）が挙げられる。当該「置換されていてもよいアミノ基」としては、アミノ基、およびモノまたはジ－Ｃ１－３アルキルアミノ基が好ましく、アミノ基、メチルアミノ基およびジメチルアミノ基が特に好ましい。 The “optionally substituted amino group” means an amino group and a secondary or tertiary amino group substituted with a C 1-6 alkyl group, and examples thereof include an amino group and mono- or di-C 1 And -6 alkylamino groups (methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, butylamino group, dibutylamino group, etc.). As the “optionally substituted amino group”, an amino group and a mono- or di-C 1-3 alkylamino group are preferable, and an amino group, a methylamino group and a dimethylamino group are particularly preferable.
　「Ｃ１－６アルキルスルファニル基」とは、Ｃ１－６アルキル基が結合した－Ｓ－を意味し、例えば、メチルスルファニル基、エチルスルファニル基、プロピルスルファニル基、ブチルスルファニル基、ペンチルスルファニル（すなわち、アミルスルファニル）基、ヘキシルスルファニル基、イソプロピルスルファニル基、イソブチルスルファニル基、ｓｅｃ－ブチルスルファニル基、ｔｅｒｔ－ブチルスルファニル基、イソペンチルスルファニル基、ネオペンチルスルファニル基および第３級ペンチルスルファニル基が挙げられる。当該「Ｃ１－６アルキルスルファニル基」としては、Ｃ１－３アルキルスルファニル基が好ましく、メチルスルファニル基およびエチルスルファニル基が特に好ましい。 “C 1-6 alkylsulfanyl group” means —S— to which a C 1-6 alkyl group is bonded. For example, a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, a butylsulfanyl group, a pentylsulfanyl group (ie, , Amylsulfanyl) group, hexylsulfanyl group, isopropylsulfanyl group, isobutylsulfanyl group, sec-butylsulfanyl group, tert-butylsulfanyl group, isopentylsulfanyl group, neopentylsulfanyl group and tertiary pentylsulfanyl group. As the “C 1-6 alkylsulfanyl group”, a C 1-3 alkylsulfanyl group is preferable, and a methylsulfanyl group and an ethylsulfanyl group are particularly preferable.
　「Ｃ１－６アルキルスルフィニル基」とは、Ｃ１－６アルキル基が結合した－ＳＯ－を意味し、例えば、メチルスルフィニル基、エチルスルフィニル基、プロピルスルフィニル基およびイソプロピルスルフィニル基が挙げられる。当該「Ｃ１－６アルキルスルフィニル基」としては、Ｃ１－３アルキルスルフィニル基が好ましい。 “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. The “C 1-6 alkylsulfinyl group” is preferably a C 1-3 alkylsulfinyl group.
　「Ｃ１－６アルキルスルホニル基」とは、Ｃ１－６アルキル基が結合した－ＳＯ２－を意味し、例えば、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基およびイソプロピルスルホニル基が挙げられる。当該「Ｃ１－６アルキルスルホニル基」としては、Ｃ１－３アルキルスルホニル基が好ましく、メチルスルホニル基およびエチルスルホニル基が特に好ましい。 The “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 an isopropylsulfonyl group. As the “C 1-6 alkylsulfonyl group”, a C 1-3 alkylsulfonyl group is preferable, and a methylsulfonyl group and an ethylsulfonyl group are particularly preferable.
　「Ｃ１－６アルキルカルバモイル基」とは、窒素原子が１個または同一もしくは異なる２個の前記Ｃ１－６アルキル基で置換されたカルバモイル基（モノもしくはジ－Ｃ１－６アルキル－カルバモイル基）を意味し、例えば、Ｎ－メチルカルバモイル基、Ｎ－エチルカルバモイル基、Ｎ－プロピルカルバモイル基、Ｎ，Ｎ－ジメチルカルバモイル基、Ｎ，Ｎ－ジエチルカルバモイル基などが挙げられる。好ましいアルキルカルバモイル基としては、Ｎ－エチルカルバモイル基、Ｎ，Ｎ－ジメチルカルバモイル基が挙げられる。 The “C 1-6 alkylcarbamoyl group” is a carbamoyl group (mono or di-C 1-6 alkyl-carbamoyl group) in which one nitrogen atom or two identical or different C 1-6 alkyl groups are substituted. And N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group and the like. Preferred alkylcarbamoyl groups include N-ethylcarbamoyl group and N, N-dimethylcarbamoyl group.
　「スルファモイル基」とは、スルファモイル基（－ＳＯ２ＮＨ２）、およびスルファモイル基の窒素原子上の１個または２個の水素原子がＣ１－６アルキル基と置換した基を意味し、例えば、スルファモイル基、およびモノまたはジ－Ｃ１－６アルキルスルファモイル基（例えば、メチルスルファモイル基、ジメチルスルファモイル基、エチルスルファモイル基、ジエチルスルファモイル基、プロピルスルファモイル基、ジプロピルスルファモイル基、ブチルスルファモイル基およびジブチルスルファモイル基）が挙げられる。当該「スルファモイル基」としては、スルファモイル基およびモノまたはジ－Ｃ１－３アルキルスルファモイル基が好ましく、スルファモイル基、メチルスルファモイル基およびジメチルスルファモイル基が特に好ましい。 The “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. A sulfamoyl group, and a mono- or di-C 1-6 alkylsulfamoyl group (for example, a methylsulfamoyl group, a dimethylsulfamoyl group, an ethylsulfamoyl group, a diethylsulfamoyl group, a propylsulfamoyl group, Dipropylsulfamoyl group, butylsulfamoyl group and dibutylsulfamoyl group). As the “sulfamoyl group”, a sulfamoyl group and a mono- or di-C 1-3 alkylsulfamoyl group are preferable, and a sulfamoyl group, a methylsulfamoyl group and a dimethylsulfamoyl group are particularly preferable.
　「スルホニルアミノ基」とは、前記Ｃ１－６アルキルスルホニル基で置換されたアミノ基または前記Ｃ１－６アルキルスルホニル基およびＣ１－６アルキル基で置換された２級アミノ基を意味し、例えば、メチルスルホニルアミノ基、エチルスルホニルアミノ基、イソプロピルスルホニルアミノ基などが挙げられる。 The "sulfonylamino group" means a secondary amino group substituted with an C 1-6 alkylsulfonylamino group substituted with a group or a C 1-6 alkylsulfonyl group and a C 1-6 alkyl group, Examples thereof include a methylsulfonylamino group, an ethylsulfonylamino group, and an isopropylsulfonylamino group.
　「含窒素複素環基」とは、環構成原子として１個の窒素原子を含む５ないし７員の単環の飽和脂肪族複素環基を意味するか、あるいは下記式（２）で表される二環の飽和脂肪族の含窒素複素環基を意味する。
Figure JPOXMLDOC01-appb-C000010
 　上記式（２）において、ｐ、ｑ、ｒおよびｓは同一または異なって、それぞれ０、１または２であり、ｐ、ｑ、ｒおよびｓの総和は４以下であり、好ましくは２、３または４である。また上記式（２）において、Ｘは－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－、－ＣＨ２ＯＣＨ２－であり、好ましくは－ＣＨ２－、－（ＣＨ２）２－または－（ＣＨ２）３－である。 The “nitrogen-containing heterocyclic group” means a 5- to 7-membered monocyclic saturated aliphatic heterocyclic group containing one nitrogen atom as a ring constituent atom, or represented by the following formula (2). This means a bicyclic saturated aliphatic nitrogen-containing heterocyclic group.
Figure JPOXMLDOC01-appb-C000010
 In the above formula (2), p, q, r and s are the same or different and are each 0, 1 or 2, and the sum of p, q, r and s is 4 or less, preferably 2, 3 or 4. In the above formula (2), X is —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 —, —CH 2 OCH 2 —, preferably —CH 2 —, — (CH 2 ) 2 — or — (CH 2 ) 3 —.
　当該「含窒素複素環基」の具体例としては、ピロリジニル基、ピペリジニル基、アゼパニル基、および下記式（４）で表される環状基が挙げられる。
Figure JPOXMLDOC01-appb-C000011
 Specific examples of the “nitrogen-containing heterocyclic group” include a pyrrolidinyl group, a piperidinyl group, an azepanyl group, and a cyclic group represented by the following formula (4).
Figure JPOXMLDOC01-appb-C000011
　式（１）で表される化合物の薬学的に許容される塩とは、式（１）で表される化合物に含まれるアミンなどの官能基の塩基型を、薬学的に許容される適当な酸で処理することによって得られる酸付加塩を意味する。上記の薬学的に許容される酸としては、例えば無機酸［例：ハロゲン化水素酸（例えば、塩酸、臭化水素酸、フッ化水素酸、ヨウ化水素酸）、または硫酸、硝酸、リン酸など］や、有機酸［例：酢酸、プロピオン酸、ヒドロ酢酸（hydroacetic acid）、２－ヒドロキシプロパン酸、２－オキソプロパン酸、エタン二酸、プロパン二酸、ブタン二酸、（Ｚ）－２－ブテン二酸、（Ｅ）－ブテン二酸、２－ヒドロキシブタン二酸、２，３－ジヒドロキシブタン二酸、２－ヒドロキシ－１，２，３－プロパントリカルボン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、４－メチルベンゼンスルホン酸、シクロヘキサンスルファミン酸、２－ヒドロキシ安息香酸、４－アミノ－２－ヒドロキシ安息香酸、および当業者に知られている他の有機酸］が挙げられる。 The pharmaceutically acceptable salt of the compound represented by the formula (1) refers to a base form of a functional group such as an amine contained in the compound represented by the formula (1). It means an acid addition salt obtained by treating with an acid. Examples of the pharmaceutically acceptable acid include inorganic acids [eg, hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid), or sulfuric acid, nitric acid, phosphoric acid] Etc.] and 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, methanesulfonic acid, ethanesulfonic acid Benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and others known to those skilled in the art Organic acid] and the like.
　本発明には、式（１）で表される化合物またはその薬学的に許容される塩の水和物およびエタノール溶媒和物等の溶媒和物も含まれる。 The present invention includes solvates such as hydrates and ethanol solvates of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
　結晶として得られる式（１）で表される化合物およびその薬学的に許容される塩には、結晶多形が存在する場合があり、その結晶多形も本発明に包含される。 The compound represented by the formula (1) obtained as a crystal and a pharmaceutically acceptable salt thereof may have a crystal polymorph, and the crystal polymorph is also included in the present invention.
　さらに本発明の式（１）の化合物は、その置換基の態様によって、光学異性体、ジアステレオ異性体、幾何異性体等の立体異性体が存在する場合があるが、本発明の式（１）の化合物はこれら全ての立体異性体及びそれらの混合物をも包含する。また、化合物を構成する原子を同位体に変換した化合物（例えば、水素を重水素化した化合物や１２Ｃを１４Ｃに変換した化合物）も本発明に包含される。 Furthermore, the compound of the formula (1) of the present invention may have stereoisomers such as optical isomers, diastereoisomers, geometric isomers and the like depending on the mode of the substituent. ) Also includes all these stereoisomers and mixtures thereof. In addition, a compound in which atoms constituting the compound are converted into isotopes (for example, a compound in which hydrogen is deuterated or a compound in which 12 C is converted into 14 C) is also encompassed in the present invention.
　前記式（１）で表される本発明の化合物を更に具体的に開示するため、式（１）において用いられる各種記号につき、その好適な具体例を挙げて更に詳細に説明する。 In order to more specifically disclose the compound of the present invention represented by the formula (1), the various symbols used in the formula (1) will be described in more detail with suitable specific examples.
　前記式（１）において、ａ、ｂ、ｃおよびｄは、同一または異なって、それぞれ窒素原子またはＣＲ１０であり、好ましくは、ａ、ｂ、ｃおよびｄがそれぞれＣＲ１０である。より好ましくは、ａおよびｄがＣＨである。 In the formula (1), a, b, c and d are the same or different and are each a nitrogen atom or CR 10 , preferably a, b, c and d are each CR 10 . More preferably, a and d are CH.
　前記式（１）において、Ｒ１０は、水素原子、ハロゲン原子、Ｃ３－７脂肪族炭素環基、Ｃ６－１４アリール基、５～１０員のヘテロアリール基、Ｃ６－１４アリールアルキル基、ヘテロアリールアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルキルオキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、アシル基、スルファモイル基、水酸基、置換されていてもよいアミノ基、ニトロ基、Ｃ１－６アルキルスルホニル基、または置換されていてもよいＣ１－６アルキル基であり、好ましくは、水素原子、ハロゲン原子、Ｃ１－６アルキルオキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、水酸基、置換されていてもよいアミノ基、ニトロ基、または置換されていてもよいＣ１－６アルキル基（好ましくは、水酸基、Ｃ１－６アルキルスルファニル基、ハロゲン原子、シアノ基、ニトロ基およびメトキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）であり、より好ましくは、水素原子、ハロゲン原子、Ｃ１－６アルキルオキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、水酸基、置換されていてもよいアミノ基、ニトロ基、または置換されていてもよいＣ１－６アルキル基（好ましくは、水酸基、Ｃ１－６アルキルスルファニル基、ハロゲン原子、シアノ基、ニトロ基およびメトキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）であり、さらに好ましくは、水素原子、ハロゲン原子、メチル基、シアノ基、水酸基、メトキシ基またはトリフルオロメチル基であり、特に好ましくは、水素原子、フッ素原子、塩素原子、臭素原子、メチル基、メトキシ基またはトリフルオロメチル基であり、最も好ましくは、フッ素原子、メチル基またはメトキシ基である。 In the formula (1), R 10 represents a hydrogen atom, a halogen atom, a C 3-7 aliphatic carbocyclic group, a C 6-14 aryl group, a 5- to 10-membered heteroaryl group, or a C 6-14 arylalkyl group. , Heteroarylalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkyloxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, substituted An optionally substituted amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group, preferably a hydrogen atom, a halogen atom, a C 1-6 alkyloxy group, A cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an optionally substituted amino group, a nitro group, or an optionally substituted C 1-6 alkyl group (preferably Preferably, it may be 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. More preferably, a hydrogen atom, a halogen atom, a C 1-6 alkyloxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an optionally substituted amino group, a nitro group, or an optionally substituted group A good C 1-6 alkyl 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) More preferably a hydrogen atom, a halogen atom, a methyl group, a cyano group, a hydroxyl group, a methoxy group or a trifluoromethyl group, Preferably, the hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group or a trifluoromethyl group, most preferably a fluorine atom, a methyl group or a methoxy group.
　前記式（１）のａ、ｂ、ｃおよびｄにおいて、２個以上のＣＲ１０が存在する場合には、Ｒ１０はそれぞれ独立して選択される。 In a, b, c and d in the formula (1), when two or more CRs 10 are present, R 10 is independently selected.
　前記式（１）において、Ｒ１およびＲ２は同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、Ｃ３－７脂肪族炭素環基または３～７員の複素環基であるか、あるいはＲ１およびＲ２が互いに結合してＲ１およびＲ２が隣接する炭素原子とともにＣ３－７脂肪族炭素環基または３～７員の複素環基を形成するか、またはＲ１およびＲ２が一緒になって、Ｃ＝ＣＲ８Ｒ９を形成する。ここで、Ｒ８およびＲ９は、同一または異なって、それぞれ水素原子、水酸基、スルホニルアミノ基または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ８およびＲ９が互いに結合して、Ｒ８およびＲ９が隣接する炭素原子とともにＣ３－７脂肪族炭素環基または３～７員の複素環基を形成する。 In the formula (1), 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, a hydroxyl group, a C 3-7 aliphatic carbocyclic 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 are a C 3-7 aliphatic carbocyclic group or a 3- to 7-membered heterocyclic group Form a cyclic group or R 1 and R 2 together form C═CR 8 R 9 . Here, R 8 and R 9 are the same or different and are each a hydrogen atom, a hydroxyl group, a sulfonylamino group or an optionally substituted C 1-6 alkyl group, or R 8 and R 9 are bonded to each other. Thus, R 8 and R 9 together with the adjacent carbon atom form a C 3-7 aliphatic carbocyclic group or a 3- to 7-membered heterocyclic group.
　Ｒ１およびＲ２は、好ましくは、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基またはＣ３－７脂肪族炭素環基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７脂肪族炭素環基または３～７員の複素環基を形成し、より好ましくは、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基またはＣ３－７脂肪族炭素環基であり、さらに好ましくは、同一または異なって、それぞれ水素原子、フッ素原子、水酸基または置換されていてもよいＣ１－６アルキル基である。なお、Ｒ１およびＲ２が、ともに水素原子以外の場合に、ｈＥＲＧ阻害が改善される傾向にある。 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, or a C 3-7 aliphatic carbocyclic group, Alternatively, R 1 and R 2 are bonded to each other, and R 1 and R 2 together with adjacent carbon atoms form a C 3-7 aliphatic carbocyclic group or a 3- to 7-membered heterocyclic group, and more preferably the same Or each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group or a C 3-7 aliphatic carbocyclic group, and more preferably the same or different, each a hydrogen atom , A fluorine atom, a hydroxyl group or an optionally substituted C 1-6 alkyl group. Note that hERG inhibition tends to be improved when both R 1 and R 2 are other than hydrogen atoms.
　前記式（１）において、環状基Ａは単環または二環の含窒素複素環基である。当該単環の含窒素複素環基としては、好ましくは、ピロリジニル基またはピペリジニル基であり、より好ましくは、ピペリジニル基である。当該二環の飽和含窒素複素環基としては、好ましくは、前記式（２）で表される含窒素複素環基であり、より好ましくは、前記式（４）で表される含窒素複素環基であり、特に好ましくは、前記式（３）で表される含窒素複素環基である。環状基Ａとして、好ましくは、ピペリジニル基および前記式（３）で表される含窒素複素環基である。当該環状基Ａ上の窒素原子には、－Ｃ（＝Ｙ）－Ｚ－Ｒ７が置換される（各記号は前述のものと同義である。）。当該環状基Ａ上のその他の置換基の位置は化学的に安定であれば特に制限されない。 In the formula (1), the cyclic group A is a monocyclic or bicyclic nitrogen-containing heterocyclic group. The monocyclic nitrogen-containing heterocyclic group is preferably a pyrrolidinyl group or piperidinyl group, and more preferably a piperidinyl group. The bicyclic saturated nitrogen-containing heterocyclic group is preferably a nitrogen-containing heterocyclic group represented by the formula (2), more preferably a nitrogen-containing heterocyclic ring represented by the formula (4). And particularly preferably a nitrogen-containing heterocyclic group represented by the formula (3). The cyclic group A is preferably a piperidinyl group and a nitrogen-containing heterocyclic group represented by the above formula (3). The nitrogen atom on the cyclic group A is substituted with —C (═Y) —Z—R 7 (each symbol has the same meaning as described above). The position of the other substituent on the cyclic group A is not particularly limited as long as it is chemically stable.
　前記式（１）において、Ｒ３およびＲ４は、ともに水素原子であるか、あるいはＲ３およびＲ４が一緒になって隣接する炭素原子とともにＣ＝ＯまたはＣ＝Ｓを形成し、好ましくは、Ｒ３およびＲ４が一緒になって隣接する炭素原子とともにＣ＝Ｏを形成する。 In the formula (1), R 3 and R 4 are both hydrogen atoms, or R 3 and R 4 together form C═O or C═S with adjacent carbon atoms, preferably , R 3 and R 4 together form C═O with adjacent carbon atoms.
　前記式（１）において、ＹおよびＺは、同一または異なって、それぞれ酸素原子または硫黄原子である。
　Ｙは、好ましくは、酸素原子である。
　Ｚは、好ましくは、酸素原子である。 In the formula (1), 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.
　前記式（１）において、Ｒ５およびＲ６は同一または異なって、それぞれ水素原子、メチル基、エチル基、メトキシ基、フッ素原子、ジフルオロメチル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基または水酸基であり、好ましくは水素原子、メチル基、水酸基、フッ素原子、ジフルオロメチル基、ジフルオロメトキシ基またはメトキシ基であり、より好ましくは水素原子、メチル基、水酸基、フッ素原子またはメトキシ基である。 In the formula (1), R 5 and R 6 are the same or different and each represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group, a fluorine atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group. Group or hydroxyl group, preferably a hydrogen atom, methyl group, hydroxyl group, fluorine atom, difluoromethyl group, difluoromethoxy group or methoxy group, more preferably a hydrogen atom, methyl group, hydroxyl group, fluorine atom or methoxy group. .
　前記式（１）のＲ５が２個以上存在する場合には、Ｒ５はそれぞれ独立して選択される。前記式（１）のＲ６が２個以上存在する場合においても、Ｒ６はそれぞれ独立して選択される。 When present R 5 is two or more in the formula (1), R 5 is selected independently. Even when two or more R 6 s of the formula (1) are present, R 6 is independently selected.
　Ｒ７は置換されていてもよいＣ１－６アルキル基、Ｃ２－６アルケニル基またはＣ２－６アルキニル基であり、好ましくは、置換されていてもよいＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルキルオキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）、またはＣ２－６アルケニル基であり、より好ましくは、置換されていてもよい直鎖のＣ１－３アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルキルオキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、さらに好ましくはメチル基、エチル基、または２－メトキシエチル基である。 R 7 is an optionally substituted C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group, preferably an optionally substituted C 1-6 alkyl group (preferably Or a C 2-6 alkenyl group, which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkyloxy group, more preferably a substituted group. A linear C 1-3 alkyl group (which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkyloxy group). More preferably a methyl group, an ethyl group, or a 2-methoxyethyl group.
　ｋおよびｍは、１、２または３であり、好ましくは、ｋが１または２であり、ｍが１または２であり、より好ましくは、ｋおよびｍが１である。
　ｎは、０または１であり、好ましくは、１である。 k and m are 1, 2 or 3, preferably k is 1 or 2, m is 1 or 2, and more preferably k and m are 1.
n is 0 or 1, preferably 1.
　本発明化合物において、好ましい化合物としては、例えば、以下の化合物Ａが挙げられ、さらに好ましい化合物としては、例えば、化合物Ｂが挙げられる。
［化合物Ａ］
ａが、ＣＨであり、
ｂが、ＣＲ１０（Ｒ１０は、前記と同義である。）であり、
ｃが、ＣＲ１０（Ｒ１０は、前記と同義である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、水酸基、フッ素原子、メチル基またはヒドロキシメチル基であり、
Ｒ３およびＲ４が、一緒になって、隣接する炭素原子とともにＣ＝Ｏを形成し、
Ｒ５およびＲ６が、同一または異なって、それぞれ水素原子、メチル基、メトキシ基、フッ素原子または水酸基であり、
Ｒ７が、メチル基、エチル基または２－メトキシエチル基であり、
ｋおよびｍが、同一または異なって、それぞれ１または２であり、
ｎが、１であり、
ＹおよびＺが、酸素原子であり、
Ｒ１０が、水素原子、フッ素原子、塩素原子、メトキシ基、シアノ基、水酸基または置換されていてもよいＣ１－６アルキル基であり、
環状基Ａが、前記式（３）で表される含窒素複素環基である、
化合物またはその薬学的に許容される塩。 In the compound of the present invention, a preferable compound includes, for example, the following compound A, and a more preferable compound includes, for example, compound B.
[Compound A]
a is CH,
b is CR 10 (R 10 is as defined above);
c is CR 10 (R 10 is as defined above);
d is CH,
R 1 and R 2 are the same or different and each is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group or a hydroxymethyl group;
R 3 and R 4 together form C═O with adjacent carbon atoms,
R 5 and R 6 are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a fluorine atom or a hydroxyl group;
R 7 is a methyl group, an ethyl group or a 2-methoxyethyl group,
k and m are the same or different and each is 1 or 2,
n is 1,
Y and Z are oxygen atoms;
R 10 is a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group, a cyano group, a hydroxyl group or an optionally substituted C 1-6 alkyl group,
The cyclic group A is a nitrogen-containing heterocyclic group represented by the formula (3).
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｂ］
ａが、ＣＨであり、
ｂが、ＣＲ１０（Ｒ１０は、前記と同義である。）であり、
ｃが、ＣＲ１０（Ｒ１０は、前記と同義である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、水酸基、フッ素原子、メチル基またはヒドロキシメチル基であり、
Ｒ３およびＲ４が、一緒になって、隣接する炭素原子とともにＣ＝Ｏを形成し、
Ｒ５およびＲ６が、同一または異なって、それぞれ水素原子、メチル基、メトキシ基、フッ素原子または水酸基であり、
Ｒ７が、メチル基、エチル基または２－メトキシエチル基であり、
ｋおよびｍが、同一または異なって、それぞれ１または２であり、
ｎが、１であり、
ＹおよびＺが、酸素原子であり、
Ｒ１０が、水素原子、フッ素原子、塩素原子、メトキシ基、シアノ基、水酸基または置換されていてもよいＣ１－６アルキル基であり、
環状基Ａが、ピペリジニル基である、
化合物またはその薬学的に許容される塩。 [Compound B]
a is CH,
b is CR 10 (R 10 is as defined above);
c is CR 10 (R 10 is as defined above);
d is CH,
R 1 and R 2 are the same or different and each is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group or a hydroxymethyl group;
R 3 and R 4 together form C═O with adjacent carbon atoms,
R 5 and R 6 are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a fluorine atom or a hydroxyl group;
R 7 is a methyl group, an ethyl group or a 2-methoxyethyl group,
k and m are the same or different and each is 1 or 2,
n is 1,
Y and Z are oxygen atoms;
R 10 is a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group, a cyano group, a hydroxyl group or an optionally substituted C 1-6 alkyl group,
The cyclic group A is a piperidinyl group,
A compound or a pharmaceutically acceptable salt thereof.
　本発明の化合物としては、
４－{ [（３Ｒ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｒ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－endo)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(１Ｒ，５Ｓ)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸メチル；
 (３－exo)－３－{ [（３Ｓ）－３－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（４－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｒ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
 (３－exo)－３－{ [（３Ｓ）－３－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｓ）－３－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｓ）－３－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）アゼチジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－ヒドロキシ－４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－９－アザビシクロ[３．３．１]ノナン－９－カルボン酸メチル；
３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－９－アザビシクロ[３．３．１]ノナン－９－カルボン酸メチル；
４－メチル－４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [（３Ｓ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
 (３－exo)－３－{ [（３Ｓ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｒ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [（３Ｒ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－{ [（３Ｒ）－３－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [（３Ｓ）－３－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
４－{ [３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
(３－exo)－３－{ [３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
４－({(３Ｓ)－3－[(３Ｒ) －３－(ヒドロキシメチル)－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピペリジン－１－イル}メチル)ピペリジン－１－カルボン酸エチル；
４－({(３Ｒ)－３－[(３Ｒ) －３－(ヒドロキシメチル)－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピペリジン－１－イル}メチル)ピペリジン－１－カルボン酸エチル；
(３－exo)－３－({(３Ｓ)－３－[(３Ｓ) －３－ヒドロキシ－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル)－８－アザビシクロ[３.２.１]オクタン－８－カルボン酸エチル；
(３－exo)－３－({(３Ｓ)－３－[(３Ｒ) －３－ヒドロキシ－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル)－８－アザビシクロ[３.２.１]オクタン－８－カルボン酸エチル；
４－({ [（３Ｒ）－３－[３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；
４－({ [（３Ｒ）－３－[（３Ｒ）－５－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；および
４－({ [（３Ｓ）－３－[（３Ｓ）－５－フルオロ－３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；
からなる群から選択される化合物またはその薬学的に許容される塩が特に好ましい。 As the compound of the present invention,
4-{[(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3-{[(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
(3-exo) -3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
(3-endo) -3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
(1R, 5S) -3- {[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] methyl octane-8-carboxylate;
(3-exo) -3- {[(3S) -3- (5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
(3-exo) -3- {[(3S) -3- (4-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
(3-exo) -3- {[(3S) -3- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3R) -3- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3S) -3- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[3- (2-oxo-2,3-dihydro-1H-indol-1-yl) azetidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4-hydroxy-4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -9-azabicyclo [3.3.1] nonane Methyl 9-carboxylate;
3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -9-azabicyclo [3.3.1] nonane Methyl 9-carboxylate;
4-methyl-4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4-{[(3S) -3- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3S) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3R) -3- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3- {[(3R) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
4-{[(3R) -3- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} piperidine-1-carvone Ethyl acid;
4-{[(3S) -3- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} piperidine-1-carvone Ethyl acid;
4-{[3- (2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
(3-exo) -3-{[3- (2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3.2.1] octane-8- Ethyl carboxylate;
4-({(3S) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} Methyl) piperidine-1-carboxylate;
4-({(3R) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} Methyl) piperidine-1-carboxylate;
(3-exo) -3-({(3S) -3-[(3S) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate;
(3-exo) -3-({(3S) -3-[(3R) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate;
4-({[(3R) -3- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl} methyl) piperidine 1-ethyl carboxylate;
4-({[(3R) -3-[(3R) -5-fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine 1-yl} methyl) piperidine-1-carboxylate; and 4-({[(3S) -3-[(3S) -5-fluoro-3-hydroxy-3-methyl-2-oxo-2, 3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl} methyl) ethyl piperidine-1-carboxylate;
A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof is particularly preferred.
化合物（１）の製造方法：
　次に本発明の化合物の製造方法について以下に説明する。式（１）で表される本発明の化合物は以下の製法により製造することができる。
製法１：
　前記式（1）の化合物またはその塩は、下記式（５）；
Figure JPOXMLDOC01-appb-C000012
 の化合物またはその塩と下記式（６）；
Figure JPOXMLDOC01-appb-C000013
 または下記式（７）；
Figure JPOXMLDOC01-appb-C000014
 または下記式（８）；
Figure JPOXMLDOC01-appb-C000015
 で表される化合物を反応させることにより製造できる（各式中の各記号は前記のものと同義である。式（８）の化合物は環状基Ａの炭素原子上でオキシランとスピロ結合を形成する。）。 Production method of compound (1):
Next, the manufacturing method of the compound of this invention is demonstrated below. The compound of the present invention represented by the formula (1) can be produced by the following production method.
Manufacturing method 1 :
The compound of the formula (1) or a salt thereof is represented by the following formula (5);
Figure JPOXMLDOC01-appb-C000012
 Or a salt thereof and the following formula (6):
Figure JPOXMLDOC01-appb-C000013
 Or the following formula (7);
Figure JPOXMLDOC01-appb-C000014
 Or the following formula (8);
Figure JPOXMLDOC01-appb-C000015
 (In the formulas, each symbol has the same meaning as described above. The compound of the formula (8) forms a spiro bond with an oxirane on the carbon atom of the cyclic group A. .)
　式（５）の化合物またはその塩と式（６）の化合物との反応は、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、ピリジンボラン、２－ピコリンボラン、などの汎用される還元的アミノ化試薬を用いて行うことができる。 The reaction of the compound of formula (5) or a salt thereof with the compound of formula (6) is a general purpose such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, pyridine borane, 2-picoline borane, etc. The reductive amination reagent can be used.
　式（５）の化合物またはその塩と式（７）の化合物または式（８）の化合物との反応は、無溶媒または適当な溶媒中で行われる。使用する溶媒はＮ，Ｎ－ジメチルホルムアミド、アセトニトリル、アセトン、ジメチルスルホキシド、テトラヒドロフラン、メタノール、エタノールなどが挙げられ、これらの溶媒は単独または２種以上を混合して用いられる。本反応は必要に応じて塩基の存在下で行われ、塩基としては例えば炭酸カリウム、炭酸セシウム、炭酸ナトリウム、トリエチルアミン、ジイソプロピルエチルアミンなどが挙げられる。また、反応温度は通常０℃から１５０℃である。 The reaction of the compound of formula (5) or a salt thereof with the compound of formula (7) or the compound of formula (8) is carried out without a solvent or in a suitable solvent. Examples of the solvent to be used include N, N-dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol and the like. These solvents are used alone or in combination of two or more. This reaction is carried out in the presence of a base as necessary. Examples of the base include potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and the like. The reaction temperature is usually 0 ° C to 150 ° C.
式（５）の化合物の製造方法：
　前記式（５）の化合物またはその塩のうち、Ｒ３およびＲ４が一緒になって、隣接する炭素原子とともにＣ＝Ｏを形成する式（１－２）または式（１－４）で表される化合物は、下記スキーム１に従って合成することができる。
Figure JPOXMLDOC01-appb-C000016
 （式中、Ｐｒｏｔはアミノ基の保護基を表し、その他の記号は前記と同義である。） Method for producing compound of formula (5):
Of the compounds of formula (5) or salts thereof, R 3 and R 4 are taken together to form C═O together with the adjacent carbon atom, represented by formula (1-2) or formula (1-4) The compound to be synthesized can be synthesized according to the following scheme 1.
Figure JPOXMLDOC01-appb-C000016
 (In the formula, Prot represents an amino-protecting group, and other symbols are as defined above.)
　アミノ基の保護基の具体例としては、例えばｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基などのアミノ基とカルバメート類を形成する基や、ベンジル基やトリチル基などのアミノ基とベンジルアミン類を形成する基などが挙げられる。 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.
工程１：
　式（１－２）の化合物は式（１－１）の化合物のアミノ基の保護基を常法に従って脱保護することで製造することができる。 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.
工程２：
　式（１－３）の化合物は式（１－１）の化合物とＲ１およびＲ２に対応するハロゲン化剤またはアルキル化剤等を塩基存在下、不活性溶媒中で反応させることで製造することができる。塩基としては、例えば水素化ナトリウム、水素化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、リチウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等が挙げられる。不活性溶媒としては、例えばテトラヒドロフラン、１，４－ジオキサン、ベンゼン、トルエン、キシレン、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジクロロエタン等が挙げられ、これらを２種以上混合して用いることもできる。反応温度は通常－７８℃から１４０℃で行われ、好ましくは－７８℃から１００℃である。 Step 2:
The compound of formula (1-3) is produced by reacting the compound of formula (1-1) with the halogenating agent or alkylating agent corresponding to R 1 and R 2 in the presence of a base in an inert solvent. be able to. Examples of the 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. Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like. You can also. The reaction temperature is usually −78 ° C. to 140 ° C., preferably −78 ° C. to 100 ° C.
工程３：
　本工程は本スキームの工程１と同様の方法によって行われる。 Step 3:
This step is performed in the same manner as in step 1 of this scheme.
　前記式（１－１）の化合物またはその塩は下記スキーム２、スキーム３またはスキーム４に従って合成することができる。
Figure JPOXMLDOC01-appb-C000017
 （式中、Ｘ１は水酸基またはハロゲン原子を表し、Ｘ２はハロゲン原子を表し、その他の記号は前記と同義である。） The compound of formula (1-1) or a salt thereof can be synthesized according to the following scheme 2, scheme 3 or scheme 4.
Figure JPOXMLDOC01-appb-C000017
 (Wherein X 1 represents a hydroxyl group or a halogen atom, X 2 represents a halogen atom, and other symbols are as defined above.)
工程１：
　式（２－２）の化合物は入手可能な式（２－１）の化合物と入手可能な式（２－３）の化合物とを反応させることで製造することができる。該反応は塩基や縮合剤を用いたアミド結合形成反応の常法により行うことができる。 Step 1:
The compound of formula (2-2) can be produced by reacting an available compound of formula (2-1) with an available compound of formula (2-3). This reaction can be performed by a conventional method of amide bond forming reaction using a base or a condensing agent.
工程２：
　式（１－１）の化合物は式（２－２）の化合物をパラジウムなどの金属触媒存在下反応させることで製造することができる。すなわちTetrahedron Lett., 45, 8535-8537 (2004)等に記載の方法あるいはそれに準じた方法によって製造することができる。 Step 2:
The compound of formula (1-1) can be produced by reacting the compound of formula (2-2) 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.
Figure JPOXMLDOC01-appb-C000018
 （式中、ＲはＣ１－６アルキル基を表し、その他の記号は前記と同義である。）
Figure JPOXMLDOC01-appb-C000018
 (Wherein R represents a C 1-6 alkyl group, and other symbols are as defined above.)
工程１：
　式（３－２）の化合物は入手可能な式（３－１）の２－ハロゲン化ニトロアリールを水素化ナトリウムや炭酸セシウムなどの塩基存在下でマロン酸ジエステルと反応させることで製造することができる。使用する溶媒としては、例えばＮ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、アセトニトリル、ジクロロメタンなどが挙げられ、単独または２種以上を混合して用いられる。反応は通常－２０℃から１５０℃で行われ、好ましくは０℃から１００℃である。 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. it can. Examples of the solvent to be used include N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane and the like, and these may be used alone or in combination of two or more. The reaction is usually carried out at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
工程２：
　式（３－３）の化合物は式（３－２）の化合物を水素雰囲気下パラジウムやロジウム等の金属触媒を用いて接触還元することで製造することができる。使用する溶媒としては、例えばエタノール、メタノール、酢酸、酢酸エチル、テトラヒドロフラン、ジクロロメタンなどが挙げられ、単独または２種以上を混合して用いられる。 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. Examples of the solvent to be used include ethanol, methanol, acetic acid, ethyl acetate, tetrahydrofuran, dichloromethane and the like, and they are used alone or in combination of two or more.
工程３：
　式（３－４）の化合物は式（３－３）の化合物を入手可能な式（３－５）の化合物と反応させることで製造することができる。該反応は上述の還元的アミノ化反応の条件に準じて行うことができる。試薬としては、例えば水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、ピリジンボラン、２－ピコリンボランなどの汎用される試薬が挙げられる。使用する溶媒としては、例えばトルエン、ジクロロメタン、ジクロロエタン、テトラヒドロフラン、ジメトキシエタン、ジエチルエーテル、Ｎ，Ｎ－ジメチルホルムアミド、メタノール、エタノール、酢酸エチルなどが挙げられ、単独または２種以上を混合して用いられる。本反応は必要に応じて酸または塩基の存在下で行われ、酸としては、例えば酢酸、塩基としては、例えばトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミンなどが挙げられる。また必要に応じてチタンテトライソプロポキシドなどを併用することができる。また、反応温度は通常－２０℃から１００℃で、好ましくは０℃から８０℃である。 Step 3:
A compound of formula (3-4) can be prepared by reacting a compound of formula (3-3) with an available compound of formula (3-5). This reaction can be performed according to the conditions of the above-mentioned reductive amination reaction. Examples of the reagent include commonly used reagents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, pyridine borane and 2-picoline borane. Examples of the solvent to be used include toluene, dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, diethyl ether, N, N-dimethylformamide, methanol, ethanol, ethyl acetate, and the like. . This reaction is carried out 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 N, N-diisopropylethylamine. Moreover, titanium tetraisopropoxide etc. can be used together as needed. The reaction temperature is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
工程４：
　式（１－１）の化合物は式（３－４）の化合物を酸存在下で加熱攪拌することで製造することができる。酸としては塩酸、硫酸、りん酸、ｐ－トルエンスルホン酸、４－エチルベンゼンスルホン酸などが挙げられ、好ましくはｐ－トルエンスルホン酸、４－エチルベンゼンスルホン酸などが挙げられる。溶媒としては、例えばＮ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、ジクロロメタン、ベンゼン、トルエン、キシレンなどが挙げられ、好ましくはベンゼン、トルエンが挙げられる。またこれらを２種以上混合して用いることもできる。反応は通常０℃から２００℃で行われ、好ましくは７０℃から１２０℃である。 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. Examples of 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. Examples of the solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane, benzene, toluene, xylene and the like, and preferably benzene and toluene. Moreover, these can also be used in mixture of 2 or more types. The reaction is usually carried out at 0 ° C to 200 ° C, preferably 70 ° C to 120 ° C.
Figure JPOXMLDOC01-appb-C000019
 （式中、Ｘ３はハロゲン原子、－ＯＳＯ２ＣＨ３または－ＯＳＯ２Ｃ６Ｈ４ＣＨ３などの脱離基を表し、その他の記号は前記と同義である。）
Figure JPOXMLDOC01-appb-C000019
 (Wherein X 3 represents a leaving group such as a halogen atom, —OSO 2 CH 3 or —OSO 2 C 6 H 4 CH 3 , and other symbols are as defined above.)
工程１：
　式（４－２）の化合物は、入手可能な式（４－１）の化合物を水素化ナトリウムや炭酸セシウムなどの塩基存在下で入手可能な式（４－３）と反応させることで製造することができる。使用する溶媒としては、例えばＮ，Ｎ－ジメチルホルムアミド、アセトニトリル、テトラヒドロフランなどが挙げられ、単独または２種以上を混合して用いられる。反応は通常－７８℃から１４０℃で行われ、好ましくは０℃から１２０℃である。 Step 1:
The compound of formula (4-2) is prepared by reacting an available compound of formula (4-1) with an available formula (4-3) in the presence of a base such as sodium hydride or cesium carbonate. be able to. Examples of the solvent to be used include N, N-dimethylformamide, acetonitrile, tetrahydrofuran and the like, and these may be used alone or in combination of two or more. The reaction is usually carried out at −78 ° C. to 140 ° C., preferably 0 ° C. to 120 ° C.
工程２：
　式（１－１）の化合物は式（４－２）の化合物を Ｎ－ブロモスクシンイミドなどと反応させハロゲン化した後に、パラジウムまたはマンガンなどの金属触媒存在下で酸化することで製造することができる。すなわち Journal of Medicinal Chemistry, 27, 1379-88,（1984）等記載の方法あるいはそれに準じた方法によって製造することができる。 Step 2:
The compound of the formula (1-1) can be produced by reacting the compound of the formula (4-2) with N-bromosuccinimide and the like, and then oxidizing the compound in the presence of a metal catalyst such as palladium or manganese. . That is, it can be produced by the method described in Journal of Medicinal Chemistry, 27, 1379-88, (1984) or the like, or a method analogous thereto.
　前記式（１－３）の化合物またはその塩は下記スキーム５またはスキーム６に従っても合成することができる。
Figure JPOXMLDOC01-appb-C000020
 （式中の各記号は前述したものと同義である。） The compound of formula (1-3) or a salt thereof can also be synthesized according to the following scheme 5 or scheme 6.
Figure JPOXMLDOC01-appb-C000020
 (Each symbol in the formula has the same meaning as described above.)
工程１：
　式（５－２）の化合物は入手可能な式（５－１）の化合物とＲ２に対応するハロゲン化剤、酸化剤またはアルキル化剤等を塩基存在下、不活性溶媒中で反応させることで製造することができる。塩基としては、例えば水素化ナトリウム、水素化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、リチウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等が挙げられる。不活性溶媒としては、例えばテトラヒドロフラン、１，４－ジオキサン、ベンゼン、トルエン、キシレン、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジクロロエタン等が挙げられ、これらを２種以上混合して用いることもできる。反応温度は通常－７８℃から１４０℃で行われ、好ましくは－７８℃から１００℃である。 Step 1:
The compound of formula (5-2) is obtained by reacting an available compound of formula (5-1) with a halogenating agent, oxidizing agent or alkylating agent corresponding to R 2 in the presence of a base in an inert solvent. Can be manufactured. Examples of the base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium hexamethyldisilazide. And potassium hexamethyldisilazide. Examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like. You can also. The reaction temperature is usually −78 ° C. to 140 ° C., preferably −78 ° C. to 100 ° C.
工程２：
　式（５－３）の化合物は式（５－２）の化合物のエステル基を常法に従って加水分解することで製造することができる。 Step 2:
The compound of formula (5-3) can be produced by hydrolyzing the ester group of the compound of formula (5-2) according to a conventional method.
工程３：
　本工程はスキーム２記載の工程１に準じた方法によって行われる。 Step 3:
This step is performed by a method according to Step 1 described in Scheme 2.
工程４：
　本工程はスキーム２記載の工程２と同様の方法によって行われる。 Step 4:
This step is performed in the same manner as in step 2 described in Scheme 2.
Figure JPOXMLDOC01-appb-C000021
 （式中の各記号は前述したものと同義である。）
Figure JPOXMLDOC01-appb-C000021
 (Each symbol in the formula has the same meaning as described above.)
工程１：
　式（６－１）の化合物はスキーム３に従って合成した式（３－４）の化合物から、スキーム５記載の工程１と同様の方法によって行われる。 Step 1:
The compound of formula (6-1) is prepared from the compound of formula (3-4) synthesized according to Scheme 3 by the same method as in Step 1 described in Scheme 5.
工程２：
　本工程はスキーム３記載の工程４と同様の方法によって行われる。 Step 2:
This step is performed in the same manner as in step 4 described in Scheme 3.
工程３：
　本工程はスキーム５記載の工程１と同様の方法によって行われる。 Step 3:
This step is performed in the same manner as in Step 1 described in Scheme 5.
　前記式（５）の化合物またはその塩は下記スキーム７に従っても合成することができる。
Figure JPOXMLDOC01-appb-C000022
 （式中の各記号は前述したものと同義である。） The compound of the formula (5) or a salt thereof can also be synthesized according to the following scheme 7.
Figure JPOXMLDOC01-appb-C000022
 (Each symbol in the formula has the same meaning as described above.)
工程１：
　式（７－２）の化合物は入手可能な式（７－１）の化合物から、スキーム４記載の工程１と同様の方法によって製造できる。 Step 1:
The compound of formula (7-2) can be produced from an available compound of formula (7-1) by the same method as in Step 1 described in Scheme 4.
工程２：
　本工程はスキーム１記載の工程１と同様の方法によって行われる。 Step 2:
This step is performed in the same manner as in Step 1 described in Scheme 1.
式（６）～（８）の化合物の製造方法：
　前記式（６）の化合物は入手可能な下記式（９）；
Figure JPOXMLDOC01-appb-C000023
 の化合物を公知の方法、例えば新実験化学講座１５巻（丸善、１９７８年）に記載されている方法あるいはそれに準じた方法で酸化することによって製造することができる。 Process for producing compounds of formulas (6) to (8):
The compound of formula (6) is available from the following formula (9);
Figure JPOXMLDOC01-appb-C000023
 Can be produced by oxidation by a known method, for example, the method described in New Experimental Chemistry Course Vol. 15 (Maruzen, 1978) or a method analogous thereto.
　前記式（６）または前記式（８）の化合物は下記スキーム８に従って合成することができる。
Figure JPOXMLDOC01-appb-C000024
 （式中の各記号は前述したものと同義である。） The compound of the formula (6) or the formula (8) can be synthesized according to the following scheme 8.
Figure JPOXMLDOC01-appb-C000024
 (Each symbol in the formula has the same meaning as described above.)
工程１：
　式（８）の化合物は入手可能な式（８－１）を水素化ナトリウム、カリウムｔｅｒｔ－ブトキシドなどの塩基の存在下、ジメチルスルホキシドなどの溶媒中でヨウ化トリメチルスルホニウムと混合攪拌することにより製造できる。反応は通常－２０℃から６０℃で行われ、好ましくは－１０℃から３０℃である。 Step 1:
The compound of formula (8) is prepared by mixing and stirring the available formula (8-1) with trimethylsulfonium iodide in a solvent such as dimethylsulfoxide in the presence of a base such as sodium hydride or potassium tert-butoxide. it can. The reaction is usually carried out at -20 ° C to 60 ° C, preferably -10 ° C to 30 ° C.
工程２：
　前記式（６）の化合物は式（８）の化合物に、三フッ化ホウ素錯体などのルイス酸を作用させることで製造することができる。使用する溶媒は、テトラヒドロフラン、１，４－ジオキサン、メタノール等が挙げられ、これらを２種以上混合して用いることもできる。反応温度は通常－２０℃から６０℃で行われ、好ましくは－１０℃から２０℃である。 Step 2:
The compound of the formula (6) can be produced by allowing a Lewis acid such as boron trifluoride complex to act on the compound of the formula (8). Examples of the solvent to be used include tetrahydrofuran, 1,4-dioxane, methanol and the like, and two or more kinds thereof can be mixed and used. The reaction temperature is usually −20 ° C. to 60 ° C., preferably −10 ° C. to 20 ° C.
製法２：
　下記スキーム９に従って、前記式（１）の化合物を製造する方法（スキーム９の式中の各記号は前述したものと同義である。）。
Figure JPOXMLDOC01-appb-C000025
 Manufacturing method 2:
A method for producing the compound of formula (1) according to the following scheme 9 (each symbol in the formula of scheme 9 has the same meaning as described above).
Figure JPOXMLDOC01-appb-C000025
工程１：
　式（９－２）の化合物は、製法１、スキーム２～スキーム７記載の方法に準じて合成される式（９－１）の化合物を、製法１、スキーム１記載の工程１と同様の方法によって製造することができる。 Step 1:
The compound of the formula (9-2) is obtained by synthesizing the compound of the formula (9-1) synthesized according to the method described in Production Method 1, Scheme 2 to Scheme 7, in the same manner as in Step 1 of Production Method 1, Scheme 1. Can be manufactured by.
工程２：
　式（９－３）の化合物は、製法１における、式（５）と式（６）、（７）または（８）の反応と同様の方法によって製造することができる。 Step 2:
The compound of the formula (9-3) can be produced by a method similar to the reaction of the formula (5) and the formula (6), (7) or (8) in the production method 1.
工程３：
　式（１）の化合物は、製法１、スキーム５記載の工程１と同様の方法によって製造することができる。 Step 3:
The compound of Formula (1) can be manufactured by the method similar to the manufacturing method 1, the process 1 of the scheme 5 description.
　上記で示す製造方法で得られた式（１）の化合物は、抽出、カラムクロマトグラフィー、再結晶、再沈殿のような常法に従って単離・精製される。抽出溶媒としては、例えばジエチルエーテル、酢酸エチル、クロロホルム、ジクロロメタン、トルエン等が挙げられる。カラムクロマトグラフィーによる精製は、例えば、酸性、塩基性もしくは各種化学処理をしたシリカゲルまたはアルミナ等を用いて行われる。展開溶媒としては、例えばヘキサン／酢酸エチル、ヘキサン／クロロホルム、酢酸エチル／メタノール、クロロホルム／メタノール、アセトニトリル／水、メタノール／水等が用いられる。 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. Examples of the extraction solvent include diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene and the like. Purification by column chromatography is performed using, for example, silica gel or alumina that has been subjected to acidic, basic, or various chemical treatments. Examples of the developing solvent include hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile / water, methanol / water, and the like.
　式（１）の化合物がラセミ体である場合は、光学活性カラムを用いるクロマトグラフィー、光学活性な酸並びに合成キラル分割剤などによる光学分割方法、優先晶出法、ジアステレオマー法等の常法に従って、それぞれのエナンチオマーへと分離・精製することができる。 When the compound of formula (1) is a racemate, conventional methods such as chromatography using an optically active column, an optically active method using an optically active acid and a synthetic chiral resolving agent, a preferential crystallization method, a diastereomeric method, etc. According to the above, each enantiomer can be separated and purified.
　式（１）の化合物の各エナンチオマーへの分離は、例えば光学活性酸を用い常法に従ってジアステレオマー塩を形成させた後、２種のジアステレオマー塩に分離し、次いでこれを遊離塩基に変換させることにより行われる。光学分割剤として用いられる光学活性酸としては、例えば（＋）－または（－）－ショウノウ酸、（１Ｓ）－（＋）－または（１Ｒ）－（－）－ショウノウ－１０－スルホン酸、Ｌ－（＋）－またはＤ－（－）－酒石酸、（＋）－または（－）－マンデル酸、（Ｓ）－（－）－または（Ｒ）－（＋）－リンゴ酸、Ｌ－ピログルタミン酸、（Ｓ）－（＋）－または（Ｒ）－（－）－１，１’－ビナフチル－２，２’－ジイル、（＋）－ジベンゾイル－Ｄ－酒石酸または（－）－ジベンゾイル－Ｌ－酒石酸等が挙げられる。 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. Examples of the optically active acid used as the optical resolution agent 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.
　水酸基を有する式（１）の化合物は、上記で示す製造方法において、常法に従った水酸基の保護工程と脱保護工程を適宜挿入することにより製造される。 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.
　式（１）の化合物は、構造式中に存在する官能基の種類、原料化合物の選定、反応処理条件により、遊離塩基または式（１）の化合物の酸付加塩で得られる。式（１）の化合物の酸付加塩は、常法に従って遊離塩基である式（１）の化合物に変換することができる。一方、遊離塩基は、常法に従って各種の酸と処理することにより式（１）の化合物の酸付加塩に導くことができる。 The compound of the formula (1) can be obtained as a free base or an acid addition salt of the compound of the formula (1) depending on the type of functional group present in the structural formula, selection of the raw material compound, and reaction treatment conditions. The acid addition salt of the compound of formula (1) can be converted to the compound of formula (1) which is a free base according to a conventional method. On the other hand, the free base can be led to an acid addition salt of the compound of the formula (1) by treating with various acids according to a conventional method.
　本発明の化合物は、ムスカリンＭ２、Ｍ３およびＭ５受容体サブタイプと比較して、ムスカリンＭ１およびＭ４受容体に対して高い選択性および親和性を持ち、選択的なムスカリンＭ１およびＭ４受容体作動薬として有用である。また本発明の化合物は少なくとも部分的にＭ１およびＭ４作動薬として作用する。 The compounds of the present 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 as a M 4 receptor agonist. The compounds of the invention also act at least in part as M 1 and M 4 agonists.
　本発明の化合物は、ムスカリンＭ１およびＭ４受容体が仲介する疾患に対して効果を示し、中枢性疾患の予防および／または治療薬、特に優れた抗精神病作用を発現する抗精神病剤として有用である。さらに本発明の化合物はムスカリン受容体選択性およびその他の受容体に対する選択性を有することから、先行剤と比べて副作用が少ない安全な中枢性疾患の予防および／または治療薬として使用することが期待できる。 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 an antipsychotic agent exhibiting excellent antipsychotic action It is. Furthermore, since the compound of the present invention has selectivity for muscarinic receptors and other receptors, it is expected to be used as a safe preventive and / or therapeutic agent for central diseases with fewer side effects than the prior agents. it can.
　ムスカリンＭ１受容体に関係する障害は、典型的には、精神障害であり、例えば、認知障害、健忘、錯乱、記憶喪失、注意欠陥、うつ、疼痛、睡眠障害、精神病などが挙げられる。 Disorders related to muscarinic M 1 receptors, typically a mental disorder, for example, cognitive impairment, forgetfulness, confusion, memory loss, attention deficits, depression, pain, sleep disorders, such as psychosis and the like.
　ムスカリンＭ４受容体に関係する障害は、典型的には精神障害であり、例えば、錯乱、注意欠陥、疼痛、睡眠障害、統合失調症などが挙げられる。 Disorders related to muscarinic M 4 receptor is typically a mental disorder, for example, confusion, attention deficit, pain, sleep disorders, such as schizophrenia.
　従って、本発明の化合物または医薬組成物が対象とする中枢性疾患としては、例えば、神経変性疾患、アルツハイマー病、パーキンソン病、統合失調症、ハンチントン病、フリードライヒ運動失調症、トゥレット症候群、ダウン症候群、疼痛、ピック病、痴呆、臨床的抑うつ、加齢性認知機能低下、注意欠陥障害、乳児突然死症候群、認知障害、健忘、錯乱、記憶喪失、うつ、睡眠障害、精神病などが挙げられ、好ましくは神経変性疾患、注意欠陥障害、疼痛、アルツハイマー病、統合失調症、認知障害であり、特に好ましくは統合失調症、アルツハイマー病、認知障害である。 Therefore, the central diseases targeted by the compounds or pharmaceutical compositions 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, cognitive impairment, amnesia, confusion, memory loss, depression, sleep disorder, psychosis, etc. Is neurodegenerative disease, attention deficit disorder, pain, Alzheimer's disease, schizophrenia, cognitive impairment, particularly preferably schizophrenia, Alzheimer's disease, cognitive impairment.
　また、ムスカリンＭ１受容体に関係する障害は精神障害であるとは限らず、例えば、眼内圧上昇もムスカリンＭ１受容体に関係している。したがって本発明の対象となる障害には非精神障害も含まれる。 Moreover, 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.
　本発明の化合物の投与経路としては、経口投与、非経口投与または直腸内投与のいずれでもよく、その一日投与量は、化合物の種類、投与方法、患者の症状・年齢等により異なるが、例えば、経口投与の場合は、通常、ヒトまたは哺乳動物１ｋｇ体重あたり約０．０１～１００ｍｇ、更に好ましくは、約０．１～１０ｍｇを１～数回に分けて投与することができる。静注などの非経口投与の場合は、通常、例えば、ヒトまたは哺乳動物１ｋｇ体重あたり約１μｇ～１０ｍｇ、更に好ましくは約１０μｇ～１ｍｇを投与することができる。ここでいう非経口投与には、静脈内、筋肉内、皮下、鼻腔内、皮内、点眼、脳内、直腸内、腟内および腹腔内などへの投与を含む。 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. In the case of 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. In the case of parenteral administration such as intravenous injection, usually, for example, about 1 μg to 10 mg, more preferably about 10 μg 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.
　本発明の化合物の投与期間および間隔は、種々の状況に応じて変更されるものであり、医師の判断により随時判断されるものであるが、分割投与、連日投与、間歇投与、短期大量投与、反復投与などの方法がある。例えば、経口投与の場合は、１日１ないし数回（特に１日２ないし３回）に分割して投与することが望ましい。また、徐放性の製剤として投与することや長時間かけて点滴静注することも可能である。 The administration period and interval of the compound of the present invention 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, There are methods such as repeated 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.
　本発明の化合物は、上記のごとき医薬用途に使用する場合、通常、薬学的に許容される担体、すなわち医薬製剤用担体と混合して調製された医薬組成物（医薬製剤）の形で投与される。薬学的に許容される担体としては、製剤分野において常用され、かつ本発明の化合物と反応しない無毒性の物質が用いられる。具体的には、クエン酸、グルタミン酸、グリシン、乳糖、イノシトール、ブドウ糖、マンニトール、デキストラン、ソルビトール、シクロデキストリン、デンプン、部分アルファー化マグネシウム、合成ケイ酸アルミニウム、結晶セルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルデンプン、カルボキシメチルセルロースカルシウム、イオン交換樹脂、メチルセルロース、ゼラチン、アラビアゴム、プルラン、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、アルギン酸、アルギン酸ナトリウム、軽質無水ケイ酸、ステアリン酸マグネシウム、タルク、トラガント、ベントナイト、ビーガム、カルボキシビニルポリマー、酸化チタン、ソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、グリセリン、脂肪酸グリセリンエステル、精製ラノリン、グリセロゼラチン、ポリソルベート、マクロゴール、植物油、ロウ、プロピレングルコール、エタノール、ベンジルアルコール、塩化ナトリウム、水酸化ナトリウム、塩酸、水等が挙げられる。 The compound of the present invention is usually administered in the form of a pharmaceutical composition (pharmaceutical preparation) prepared by mixing with a pharmaceutically acceptable carrier, that is, a carrier for pharmaceutical preparation, when used for the above-mentioned pharmaceutical use. The As the pharmaceutically acceptable carrier, a nontoxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, 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 glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide , Hydrochloric acid, water and the like.
　剤型としては、錠剤、カプセル剤、顆粒剤、散剤、液剤、シロップ剤、懸濁剤、注射剤、坐剤、点眼剤、軟膏剤、塗布剤、貼付剤、吸入剤等が挙げられる。これらの製剤は常法にしたがって調製することができる。液体製剤にあっては、用時、水または他の適当な媒体に溶解または懸濁する形であってもよい。また、錠剤および顆粒剤は周知の方法でコーティングしてもよい。非経口製剤、例えば、注射剤を製造する際には、水性溶剤（例：蒸留水、生理食塩水、リンゲル液等）、等張化剤（例：ブドウ糖、Ｄ－ソルビトール、Ｄ－マンニトール、塩化ナトリウム等）、安定化剤（例：ヒト血清アルブミン等）、防腐剤（例：ベンジルアルコール、クロロブタノール、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、フェノール等）、緩衝剤（例：リン酸塩緩衝液、酢酸ナトリウム緩衝液等）、無痛化剤（例：塩化ベンザルコニウム、塩酸プロカイン等）を適宜配合することができる。更に、これらの製剤は治療上価値のある他の成分を含有していてもよい。 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. When producing parenteral preparations such as injections, aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.), isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride) Etc.), stabilizers (eg human serum albumin etc.), preservatives (eg benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, phenol etc.), buffers (eg phosphate buffer) , Sodium acetate buffer, etc.) and soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.) can be appropriately blended. In addition, these formulations may contain other therapeutically valuable ingredients.
　本発明の医薬組成物は常法に従って製造することができ、製剤中の本発明の化合物の含有割合は通常０.０１～５０％（w／w）である。本発明の医薬組成物における剤型の具体例を以下に示す。 The pharmaceutical composition 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 of dosage forms in the pharmaceutical composition of the present invention are shown below.
（１）錠剤、散剤、顆粒剤、カプセル剤：本発明の化合物に、例えば賦形剤、崩壊剤、結合剤または滑沢剤などを添加して圧縮成型し、次いで必要により、味のマスキング、腸溶性あるいは持続性を目的とするコーティングを行うことにより製造することができる。
　例えば錠剤の場合、実施例１の化合物２０ｍｇ、乳糖１００ｍｇ、結晶セルロース２５ｍｇおよびステアリン酸マグネシウム１ｍｇを混合し、得られた混合物を打錠することにより製造できる。
（２）注射剤：本発明の化合物を、例えば分散剤、保存剤、等張化剤などとともに水性注射剤として、あるいはオリーブ油、ゴマ油、綿実油、コーン油等の植物油、プロピレングリコール等に溶解、懸濁あるいは乳化して油性注射剤とすることにより製造することができる。
（３）座剤：本発明の化合物を油性または水性の固状、半固状あるいは液状の組成物とすることにより製造される。このような組成物に用いる油性基剤としては、例えば、高級脂肪酸のグリセリド（例えば、カカオ脂、ウイテプゾル類など）、中級脂肪酸（例えば、ミグリオール類など）、あるいは植物油（例えば、ゴマ油、大豆油、綿実油など）などが挙げられる。水性ゲル基剤としては、例えば天然ガム類、セルロース誘導体、ビニール重合体、アクリル酸重合体などが挙げられる。 (1) Tablets, powders, granules, capsules: For example, excipients, disintegrants, binders or lubricants are added to the compounds of the present invention and compression molded. Then, if necessary, taste masking, It can be produced by applying a coating for enteric or sustainable purposes.
For example, in the case of 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.
(2) Injection: The compound of the present invention is dissolved or suspended in an aqueous injection together with, for example, a dispersing agent, preservative, isotonic agent, etc., or in vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc. It can be produced by turbidity or emulsification to obtain an oily injection.
(3) Suppository: produced by making the compound of the present invention into an oily or aqueous solid, semi-solid or liquid composition. Examples of the oily base used in such a composition 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.). Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
　本発明の化合物およびその薬学的に許容される塩は、その作用の増強を目的として、例えば、リスペリドン、ハロペリドン、オランザピンのような統合失調症治療薬と組み合わせて用いることができる。また、抗うつ薬、抗不安薬、ドーパミン受容体作動薬、パーキンソン病治療薬、抗癲癇薬、抗痙攣薬、鎮痛薬、ホルモン製剤、偏頭痛治療薬、アドレナリンβ受容体拮抗薬、認知症治療薬、気分障害治療薬などの薬剤とも組み合わせて用いることができる。また、その副作用抑制を目的として、制吐剤、睡眠導入剤、抗痙攣薬などの薬剤と組み合わせて用いることができる。本発明化合物及び併用薬剤の投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。また、本発明化合物と併用薬剤の合剤としても良い。併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物と併用薬剤との配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせなどにより適宜選択することができる。例えば投与対象がヒトである場合、本発明化合物１重量部に対し、併用薬剤を０．０１～１０００重量部用いればよい。 The compound of the present invention and a pharmaceutically acceptable salt thereof can be used in combination with a therapeutic drug for schizophrenia such as risperidone, haloperidone and olanzapine for the purpose of enhancing the action. In addition, antidepressants, anxiolytics, dopamine receptor agonists, Parkinson's disease treatments, antiepileptics, anticonvulsants, analgesics, hormone preparations, migraine treatments, adrenergic β receptor antagonists, dementia treatment It can also be used in combination with drugs, drugs such as mood disorders. Moreover, it can be used in combination with drugs such as antiemetics, sleep inducers, anticonvulsants and the like for the purpose of suppressing the side effects. The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 1000 parts by weight per 1 part by weight of the compound of the present invention.
　以下に参考例、実施例および試験例を挙げて本発明を更に具体的に説明するが、本願発明の技術的範囲はこれら実施例等に限定されるものではない。参考例および実施例におけるアミノシリカゲルクロマトグラフィーは、山善株式会社製のアミノシリカゲルカラムを用いた。化合物の同定はプロトン核磁気共鳴吸収スペクトル（１Ｈ－ＮＭＲ）、ＬＣ－ＭＳ等を用いて行った。プロトン核磁気共鳴吸収スペクトル（１Ｈ－ＮＭＲ）は、ＪＮＭ－ＬＡ３００（日本電子）またはＪＮＭ－ＡＬ４００（日本電子）を用いて測定した。プロトン核磁気共鳴吸収スペクトルには、テトラメチルシランを標準物質としてケミカルシフト値をδ値（ｐｐｍ）にて記載した。ＬＣ－ＭＳは２０１０ＥＶと２０１０ＨＴからなるシステム(島津製作所)またはＬＣ１０ＡＴＶＰ（島津製作所）とＡＰＩ１５０ＥＸ（Ｐｅｒｋｉｎ　Ｅｌｍｅｒ）からなるシステムを用いた。ＬＣ－ＭＳの移動相は０．０５％トリフルオロ酢酸水溶液、０．０３５％トリフルオロ酢酸メタノール溶液またはメタノールを用いた。 The present invention will be described more specifically with reference to the following reference examples, examples and test examples. However, the technical scope of the present invention is not limited to these examples. Amino silica gel chromatography manufactured by Yamazen Co., Ltd. was used for amino silica gel chromatography in Reference Examples and Examples. The compound was identified using proton nuclear magnetic resonance absorption spectrum ( 1 H-NMR), LC-MS and the like. The proton nuclear magnetic resonance absorption spectrum ( 1 H-NMR) was measured using JNM-LA300 (JEOL) or JNM-AL400 (JEOL). In the proton nuclear magnetic resonance absorption spectrum, the chemical shift value was described as a δ value (ppm) using tetramethylsilane as a standard substance. For 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. The mobile phase of LC-MS was 0.05% trifluoroacetic acid aqueous solution, 0.035% trifluoroacetic acid methanol solution or methanol.
　ＬＣ－ＭＳは種々の条件で測定しており、それらを下記表１に詳細に記す。明細書中の実験項において、特に記載が無い場合には、条件Ａを使用した。リテンションタイム（Ｒ.Ｔ.）はＬＣ－ＭＳ測定におけるマススペクトルピークが現れた時間を表す。 LC-MS is measured under various conditions, which are described in detail in Table 1 below. In the experimental section of the specification, condition A was used unless otherwise specified. The retention time (R.T.) represents the time when the mass spectrum peak appears in the LC-MS measurement.
　原料化合物、反応試薬および溶媒は、特に断りのない限り、市販のものを用いるか、または公知の方法に準じて製造したものを使用した。 The raw material compounds, reaction reagents, and solvents were either commercially available or manufactured according to known methods unless otherwise specified.
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
　以下において、本明細書の記載を簡略化するために次に示すような略号を用いることもある。Ｍｅ：メチル基、Ｅｔ：エチル基、ｔＢｕ：ｔｅｒｔ－ブチル基、Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル基、X-Phos：２－ジシクロヘキシルフォスフィノ－２’，４’，６’－トリイソプロピルビフェニル、ｍｉｎ:分、Ｊ：結合定数、ｓ：一重線、ｄ：二重線、ｄｄ：二重の二重線、ｔ：三重線、ｔｄ：三重の二重線、ｑ：四重線、ｍ：多重線、ｂｒ：幅広い、ｂｒｄ：幅広い二重線、ｂｒｔ：幅広い三重線。 In the following, the following abbreviations may be used to simplify the description of this specification. Me: methyl group, Et: ethyl group, tBu: tert-butyl group, Boc: tert-butoxycarbonyl group, X-Phos: 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, min: Minute, J: coupling constant, s: single line, d: double line, dd: double double line, t: triple line, td: triple double line, q: quadruple line, m: multiple line , Br: wide, brd: wide double line, brt: wide triple line.
参考例１：
（３Ｓ）－３－｛［（２－ブロモフェニル）アセチル］アミノ｝ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000027
 　２－ブロモフェニル酢酸（１．３ｇ）のジクロロメタン溶液（２２ｍＬ）に、（３Ｓ）－（－）－１－（ｔｅｒｔ－ブトキシカルボニル）－３－アミノピロリジン（８０１ｍｇ）、１－ヒドロキシベンゾトリアゾール（９１７ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（１．３ｇ）およびＮ，Ｎ－ジイソプロピルエチルアミン（２．７ｍＬ）を加え、室温で２４時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、目的化合物を得た（１．１ｇ，４８％）。 Reference example 1:
(3S) -3-{[(2-Bromophenyl) acetyl] amino} pyrrolidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000027
 To a dichloromethane solution (22 mL) of 2-bromophenylacetic acid (1.3 g) was added (3S)-(−)-1- (tert-butoxycarbonyl) -3-aminopyrrolidine (801 mg), 1-hydroxybenzotriazole (917 mg). ), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.3 g) and N, N-diisopropylethylamine (2.7 mL) were added, and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the target compound (1.1 g, 48%).
参考例２：
(３Ｓ)－３－(２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル)ピロリジン－1－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000028
 　参考例１の化合物（１．１ｇ，３．０ｍｍｏｌ）のｔｅｒｔ－ブチルアルコール溶液（２９ｍＬ）に、酢酸パラジウム（３３ｍｇ，０．１５ｍｍｏｌ）、フェニルボロン酸（３６ｍｇ，０．３ｍｍｍｏｌ）、Ｘ－Ｐｈｏｓ（１４１ｍｇ，０．３ｍｍｏｌ）および炭酸カリウム（１．０ｇ，７．３ｍｍｏｌ）を加え、窒素雰囲気下８５℃で３時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、目的化合物を得た（０．８ｇ，９２％）。 Reference example 2:
(3S) -3- (2-Oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000028
 To a tert-butyl alcohol solution (29 mL) of the compound of Reference Example 1 (1.1 g, 3.0 mmol), palladium acetate (33 mg, 0.15 mmol), phenylboronic acid (36 mg, 0.3 mmol), X-Phos ( 141 mg, 0.3 mmol) and potassium carbonate (1.0 g, 7.3 mmol) were added, and the mixture was stirred at 85 ° C. for 3 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 anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the target compound (0.8 g, 92%).
参考例３：
(３Ｓ)－３－(２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル)ピロリジン
Figure JPOXMLDOC01-appb-C000029
 　参考例２の化合物（０．８ｇ）をジクロロメタン（１０ｍＬ）に溶解し、トリフルオロ酢酸（３．０ｍＬ）を加え１時間攪拌した。反応液に４ｍｏｌ／Ｌ 水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して溶媒を減圧留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーで精製し、目的化合物を得た（０．５ｇ，９７％）。 Reference Example 3:
(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine
Figure JPOXMLDOC01-appb-C000029
 The compound of Reference Example 2 (0.8 g) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3.0 mL) was added, and the mixture was stirred for 1 hour. A 4 mol / L sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography to obtain the target compound (0.5 g, 97%).
参考例４：
（３Ｓ）－３－｛［（２－ブロモ－４－メトキシフェニル）アセチル］アミノ｝ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000030
 　２－ブロモフェニル酢酸の代わりに４－メトキシ－２－ブロモフェニル酢酸を用いて、参考例１と同様の方法に従って標記化合物を得た。 Reference example 4:
(3S) -3-{[(2-Bromo-4-methoxyphenyl) acetyl] amino} pyrrolidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000030
 The title compound was obtained in the same manner as in Reference Example 1 using 4-methoxy-2-bromophenylacetic acid instead of 2-bromophenylacetic acid.
参考例５：
（３Ｓ）－３－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000031
 　参考例４の化合物（６００ｍｇ，１．５ｍｍｏｌ）のｔｅｒｔ－ブチルアルコール溶液（４ｍＬ）に、酢酸パラジウム（１６ｍｇ，０．０７ｍｍｏｌ）、フェニルボロン酸（１８ｍｇ，０．１５ｍｍｏｌ）、Ｘ－Ｐｈｏｓ（７２ｍｇ，０．１５ｍｍｏｌ）および炭酸カリウム（５０１ｍｇ，３．６ｍｍｏｌ）を加え、マイクロウェーブ照射下、１６０℃の条件で２０分間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、目的化合物を得た（４０４ｍｇ，８４％）。 Reference example 5:
(3S) -3- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000031
 To a tert-butyl alcohol solution (4 mL) of the compound of Reference Example 4 (600 mg, 1.5 mmol), palladium acetate (16 mg, 0.07 mmol), phenylboronic acid (18 mg, 0.15 mmol), X-Phos (72 mg, 0.15 mmol) and potassium carbonate (501 mg, 3.6 mmol) were added, and the mixture was stirred for 20 minutes at 160 ° C. under microwave irradiation. 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 anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the target compound (404 mg, 84%).
参考例６：
(３Ｓ)－３－(６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル)ピロリジン
Figure JPOXMLDOC01-appb-C000032
 　参考例５の化合物を用いて、参考例３と同様の方法に従って標記化合物を得た。 Reference Example 6:
(3S) -3- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine
Figure JPOXMLDOC01-appb-C000032
 The title compound was obtained in the same manner as in Reference Example 3 using the compound of Reference Example 5.
参考例７～１４：
　対応する入手可能な原料を用いて、参考例１～６と同様の方法に従って、下記表２に示す化合物を得た。ピロリジン誘導体の代わりにアゼチジン誘導体を使用したものもある。
 Reference Examples 7 to 14:
The compounds shown in Table 2 below were obtained in the same manner as in Reference Examples 1 to 6 using the corresponding available raw materials. Some use azetidine derivatives instead of pyrrolidine derivatives.
参考例１５：
２－（２－ブロモフェニル）プロピオン酸メチル
Figure JPOXMLDOC01-appb-C000034
 　２－ブロモフェニル酢酸メチル（３．８ｇ）のテトラヒドロフラン溶液（５０ｍＬ）を、－７８°Ｃに冷却し、１．６ｍｏｌ／Ｌリチウムヘキサメチルジシラジド（１３．３ｍＬ，２１ｍｍｏｌ）を滴下して１時間攪拌した。続いてヨウ化メチルを加えて、室温に昇温し３時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥後、ろ過して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、目的化合物を得た（３．０ｇ，７５％）。 Reference Example 15:
2- (2-Bromophenyl) propionic acid methyl ester
Figure JPOXMLDOC01-appb-C000034
 A tetrahydrofuran solution (50 mL) of methyl 2-bromophenylacetate (3.8 g) was cooled to −78 ° C., and 1.6 mol / L lithium hexamethyldisilazide (13.3 mL, 21 mmol) was added dropwise. Stir for hours. Subsequently, methyl iodide was added, and the mixture was warmed to room temperature and stirred for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the target compound (3.0 g, 75%).
参考例１６：
２－（２－ブロモフェニル）プロピオン酸
Figure JPOXMLDOC01-appb-C000035
 　参考例１５の化合物（３．０ｇ）のテトラヒドロフラン（１２ｍＬ）とメタノール（１２ｍＬ）の混合溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加え２時間攪拌した。反応液を減圧下で濃縮し、水層をジエチルエーテルで洗浄した。この水層に５％硫酸水素カリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して溶媒を減圧留去し、目的化合物を得た（２．７ｇ，９５％）。 Reference Example 16:
2- (2-Bromophenyl) propionic acid
Figure JPOXMLDOC01-appb-C000035
 To a mixed solution of the compound of Reference Example 15 (3.0 g) in tetrahydrofuran (12 mL) and methanol (12 mL) was added 2 mol / L sodium hydroxide aqueous solution and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the aqueous layer was washed with diethyl ether. To this aqueous layer was added 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the target compound (2.7 g, 95%).
参考例１７：
（３Ｓ）－３－｛［２－（２－ブロモフェニル）プロピオニル］アミノ｝ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000036
 　参考例１６の化合物を用いて、参考例１と同様の方法に従って標記化合物を得た。 Reference Example 17:
(3S) -3-{[2- (2-Bromophenyl) propionyl] amino} pyrrolidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000036
 The title compound was obtained in the same manner as in Reference Example 1 using the compound of Reference Example 16.
参考例１８：
（３Ｓ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000037
 　参考例１７の化合物を用いて、参考例２と同様の方法に従って標記化合物を得た。 Reference Example 18:
(3S) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000037
 The title compound was obtained in the same manner as in Reference Example 2 using the compound of Reference Example 17.
参考例１９：
(３Ｓ)－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン
Figure JPOXMLDOC01-appb-C000038
 　参考例１８の化合物を用いて、参考例３と同様の方法に従って標記化合物を得た。 Reference Example 19:
(3S) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidine
Figure JPOXMLDOC01-appb-C000038
 The title compound was obtained in the same manner as in Reference Example 3 using the compound of Reference Example 18.
参考例２０～２２：
　対応する入手可能な原料を用いて、参考例１５～１９と同様の方法に従って、下記表３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000039
 Reference Examples 20-22:
The compounds shown in Table 3 below were obtained in the same manner as in Reference Examples 15 to 19 using the corresponding available raw materials.
Figure JPOXMLDOC01-appb-T000039
参考例２３：
３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－カルボン酸ｔｅｒｔ－ブチル
Figure JPOXMLDOC01-appb-C000040
 　２，３－ジヒドロ－１Ｈ－インドール（３２３ｍｇ，２．７ｍｍｏｌ）の塩化メチレン溶液（２０ｍＬ）にＮ－Ｂｏｃ－３－ピロリドン（５５２ｍｇ，３．０ｍｍｏｌ）、酢酸（０．３ｍＬ，５．４ｍｍｏｌ）およびトリアセトキシ水素化ホウ素ナトリウム（８６２ｍｇ，４．１ｍｍｏｌ）を加え２４時間攪拌した。続いて、４ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーに付し（ヘキサン／酢酸エチル＝５／１～酢酸エチル）、目的物を得た（０．７０ｇ，９０％）。 Reference Example 23:
Tert-Butyl 3- (2,3-dihydro-1H-indol-1-yl) pyrrolidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000040
 To a methylene chloride solution (20 mL) of 2,3-dihydro-1H-indole (323 mg, 2.7 mmol), N-Boc-3-pyrrolidone (552 mg, 3.0 mmol), acetic acid (0.3 mL, 5.4 mmol) and Sodium triacetoxyborohydride (862 mg, 4.1 mmol) was added and stirred for 24 hours. Subsequently, a 4 mol / L aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 5/1 to ethyl acetate) to obtain the desired product (0.70 g, 90%).
参考例２４：
３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン
Figure JPOXMLDOC01-appb-C000041
 　参考例２３の化合物を用いて、参考例３と同様の方法に従って標記化合物を得た。 Reference Example 24:
3- (2,3-Dihydro-1H-indol-1-yl) pyrrolidine
Figure JPOXMLDOC01-appb-C000041
 The title compound was obtained in the same manner as in Reference Example 3 using the compound of Reference Example 23.
実施例１：
４－｛［（３Ｒ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000042
 　参考例３の化合物（３２ｍｇ，０．１６ｍｍｏｌ）をジクロロメタン（１．５ｍＬ）に溶解し、４－ホルミルピペリジン－１－カルボン酸エチル（３６ｍｇ）を室温で加え１０分攪拌した後、トリアセトキシ水素化ホウ素ナトリウム（５１ｍｇ）を加え４時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウム水溶液で乾燥後、溶媒を減圧留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーに付し（ヘキサン／酢酸エチル＝９／１～酢酸エチル）、油状物質として目的物を得た（６７ｍｇ）。 Example 1:
4-{[(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000042
 The compound of Reference Example 3 (32 mg, 0.16 mmol) was dissolved in dichloromethane (1.5 mL), ethyl 4-formylpiperidine-1-carboxylate (36 mg) was added at room temperature, and the mixture was stirred for 10 minutes, and then triacetoxy hydrogenated. Sodium boron (51 mg) was added and stirred for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to amino silica gel column chromatography (hexane / ethyl acetate = 9/1 to ethyl acetate) to obtain the desired product as an oily substance (67 mg).
実施例２～３０：
　参考例３、６～１４、１９～２２または２４の化合物を用いて、実施例１と同様の方法に従って、下記表４～１１に示す実施例２～３０の化合物を得た。実施例１における４－ホルミルピペリジン－１－カルボン酸エチルの代わりに、（３－ｅｘｏ）－３－ホルミル－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル、（１Ｒ，５Ｓ）－３－ホルミル－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸メチル、（３－ｅｎｄｏ）－３－ホルミル－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル、３－ホルミル－９－アザビシクロ［３．３．１］ノナン－９－カルボン酸エチル、３－ホルミル－９－アザビシクロ［３．３．１］ノナン－９－カルボン酸メチル、１－オキサ－６－アザスピロ［２．５］オクタン－６－カルボン酸メチルまたは４－ホルミル－４－メチルピペリジン－９－カルボン酸エチルを使用したものもある。各表中、Ｎ．Ｄ．とあるのは、データがないこと（ｎｏ ｄａｔａ）を意味する。 Examples 2-30:
The compounds of Examples 2 to 30 shown in Tables 4 to 11 below were obtained in the same manner as in Example 1 using the compounds of Reference Example 3, 6 to 14, 19 to 22 or 24. Instead of ethyl 4-formylpiperidine-1-carboxylate in Example 1, ethyl (3-exo) -3-formyl-8-azabicyclo [3.2.1] octane-8-carboxylate, (1R, 5S ) -3-formyl-8-azabicyclo [3.2.1] octane-8-carboxylate, (3-endo) -3-formyl-8-azabicyclo [3.2.1] octane-8-carboxylic acid Ethyl, 3-formyl-9-azabicyclo [3.3.1] nonane-9-carboxylate, 3-formyl-9-azabicyclo [3.3.1] nonane-9-carboxylate methyl, 1-oxa- Some use methyl 6-azaspiro [2.5] octane-6-carboxylate or ethyl 4-formyl-4-methylpiperidine-9-carboxylate. In each table, N.I. D. This means that there is no data (no data).
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
実施例３１：
４－（｛（３Ｓ）－３－［（３Ｒ）－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝メチル）ピペリジン－１－カルボン酸エチルおよび４－（｛（３Ｒ）－３－［（３Ｒ）－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝メチル）ピペリジン－１－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000051
 　実施例２３の化合物（２８ｍｇ，０．０７３ｍｍｏｌ）のテトラヒドロフラン溶液（１ｍＬ）に、パラホルムアルデヒド（１８ｍｇ，０．２０ｍｍｏｌ）および炭酸カリウム（１６ｍｇ，０．１２ｍｍｏｌ）を加え２４時間攪拌した。反応液に、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウム水溶液で乾燥後、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーに付し（ヘキサン／酢酸エチル＝１／１～酢酸エチル）、ジアステレオマー混合物を得た（２６ｍｇ，８６％、ジアステレオ比 １：１）。このジアステレオマー混合物を高速液体クロマトグラフィーにより、より高極性の化合物（３１ａ）とより低極性の化合物（３１ｂ）に分割した。
化合物（３１ａ）：
ＭＳ（ｍ／ｚ）：４１６．２（Ｍ＋Ｈ）、Ｒ．Ｔ．：２．４５（条件Ａ）
化合物（３１ｂ）：
ＭＳ（ｍ／ｚ）：４１６．２（Ｍ＋Ｈ）、Ｒ．Ｔ．：３．１０（条件Ａ） Example 31:
4-({(3S) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} Methyl) piperidine-1-carboxylate and 4-({(3R) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indole- 1-yl] piperidin-1-yl} methyl) piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000051
 Paraformaldehyde (18 mg, 0.20 mmol) and potassium carbonate (16 mg, 0.12 mmol) were added to a tetrahydrofuran solution (1 mL) of the compound of Example 23 (28 mg, 0.073 mmol), and the mixture was stirred for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate aqueous solution, and concentrated under reduced pressure. The obtained residue was subjected to amino silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate) to obtain a diastereomeric mixture (26 mg, 86%, diastereo ratio 1: 1). This diastereomeric mixture was divided into a more polar compound (31a) and a less polar compound (31b) by high performance liquid chromatography.
Compound (31a):
MS (m / z): 416.2 (M + H), R.I. T.A. : 2.45 (Condition A)
Compound (31b):
MS (m / z): 416.2 (M + H), R.I. T.A. : 3.10 (Condition A)
実施例３２
　（３－ｅｘｏ）－３－（｛（３Ｓ）－３－［（３Ｓ）－３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピロリジン－１－イル｝メチル）－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチルおよび（３－ｅｘｏ）－３－（｛（３Ｓ）－３－［（３Ｒ）－３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピロリジン－１－イル｝メチル）－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル
Figure JPOXMLDOC01-appb-C000052
 　実施例２４の化合物（１３８ｍｇ，０．６４ｍｍｏｌ）のテトラヒドロフラン溶液（２ｍＬ）に、炭酸カリウム（１０４ｍｇ，０．７５ｍｍｏｌ）を加え、空気を溶液中に添加しながら２４時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウム水溶液で乾燥後、減圧濃縮して得られた残渣をアミノシリカゲルカラムクロマトグラフィーに付し（ヘキサン／酢酸エチル＝１／１～酢酸エチル）、ジアステレオマー混合物を得た（７６ｍｇ，７１％、ジアステレオ比 １：１）。このジアステレオマー混合物を高速液体クロマトグラフィーにより、より高極性の化合物（３２ａ）と、より低極性の化合物（３２ｂ）に分割した。
化合物（３２ａ）：
ＭＳ（ｍ／ｚ）：４２８．１（Ｍ＋Ｈ）、Ｒ．Ｔ．：３．１０（条件Ａ）
化合物（３２ｂ）：
ＭＳ（ｍ／ｚ）：４２８．１（Ｍ＋Ｈ）、Ｒ．Ｔ．：４．１５（条件Ａ） Example 32
(3-exo) -3-({(3S) -3-[(3S) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate and (3-exo) -3-({(3S) -3-[(3R) -3-hydroxy-3 -Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure JPOXMLDOC01-appb-C000052
 To a tetrahydrofuran solution (2 mL) of the compound of Example 24 (138 mg, 0.64 mmol) was added potassium carbonate (104 mg, 0.75 mmol), and the mixture was stirred for 24 hours while adding air to the solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate aqueous solution, and concentrated under reduced pressure. The residue obtained was subjected to amino silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate), and dia A stereomeric mixture was obtained (76 mg, 71%, diastereo ratio 1: 1). This diastereomeric mixture was separated into a more polar compound (32a) and a less polar compound (32b) by high performance liquid chromatography.
Compound (32a):
MS (m / z): 428.1 (M + H), R.I. T.A. : 3.10 (Condition A)
Compound (32b):
MS (m / z): 428.1 (M + H), R.I. T.A. : 4.15 (Condition A)
実施例３３～３５：
　実施例２５、２７または２８の化合物を用いて、実施例３１または３２と同様の方法に従って、下記表１２に示すとおり、実施例３３～３５の化合物を得た。下記表１２の実施例３３ａ（より高極性の化合物）および実施例３３ｂ（より低極性の化合物）の構造式において、＊はキラルであることを意味する。
Figure JPOXMLDOC01-appb-T000053
 Examples 33-35:
Using the compound of Example 25, 27 or 28, according to the same method as in Example 31 or 32, the compounds of Examples 33 to 35 were obtained as shown in Table 12 below. In the structural formulas of Example 33a (higher polarity compound) and Example 33b (lower polarity compound) in Table 12 below, * means chiral.
Figure JPOXMLDOC01-appb-T000053
　本発明の化合物の医薬としての有用性は、薬理作用を確認できる薬理試験、体内動態を確認できる薬物動態試験、安全性を確認できる安全性試験により証明される。これらの試験は、ムスカリンＭ１およびＭ４受容体作動性に基づく生理活性およびムスカリン受容体サブタイプ選択性を向上させることによる安全性向上を確認できるものであれば特に限定されないが、例えば以下の試験により証明される。薬理試験としては、ｉｎ ｖｉｔｒｏのムスカリン受容体作動性測定試験、抗精神病作用や認知障害改善作用を確認するｉｎ ｖｉｖｏ試験が挙げられ、具体的なｉｎ ｖｉｖｏ試験としてはアポモルフィン誘発クライミング試験、メタンフェタミン誘発運動量亢進試験、プレパルス抑制試験、マイクロダイアリシス試験、受動的回避反応試験、Ｙ迷路型試験などが挙げられる。薬物動態試験としては、例えば血中濃度評価試験、脳移行性評価試験、Ｐ－糖タンパク基質認識試験、薬物相互作用試験、薬物代謝経路同定試験、ダンシルグルタチオン付加試験などが挙げられる。安全性試験としては、ｈＥＲＧ阻害試験、細胞毒性試験、Ａｍｅｓ試験などのｉｎ ｖｉｔｒｏ試験に加えて、血圧や心拍数の測定試験、心電図測定試験、ラット味覚嫌悪条件付け試験、唾液分泌量測定試験、体温測定試験、消化器症状評価試験、共有結合試験、錐体外路症状評価試験、一般症状観察、一般毒性試験などが挙げられる。これらの試験は一般にマウス、ラット、イヌ、およびサルで行なうことができる。また、必要に応じて覚醒または麻酔下で実施することができる。下記試験例により、本発明の化合物の医薬としての有用性を説明する。 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, an in vivo test for confirming an antipsychotic effect and a cognitive impairment improving effect, and specific in vivo tests include an apomorphine-induced climbing test, methamphetamine-induced momentum. 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. In addition to in vitro tests such as hERG inhibition tests, cytotoxicity tests, and Ames tests, 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. 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.
試験例１：ヒト型ムスカリンＭ １ －Ｍ ５ 受容体のｉｎ ｖｉｔｒｏ作動性試験
　各受容体に対する作動性は、各受容体安定発現細胞における細胞内カルシウム濃度の変化を、蛍光強度を指標として評価した。ヒトｍ１受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ１）あるいはヒトｍ３受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ３）をＣＨＯ－Ｋ１細胞に導入し、限界希釈法にてＧｅｎｅｔｉｃｉｎ耐性の安定発現株を取得した。ヒトｍ２受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ２）、ヒトｍ４受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ４）およびヒトｍ５受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ５）は、それぞれＧα１６遺伝子をコードするｃＤＮＡとともにＣＨＯ－Ｋ１細胞に導入し、選択薬剤ＺｅｏｃｉｎおよびＨｙｇｒｏＧｏｌｄ耐性の安定発現株を取得した。ヒトｍ１およびヒトｍ３受容体安定発現細胞は４×１０４ｃｅｌｌｓ／１００μＬ／ｗｅｌｌの割合で、ヒトｍ２、ヒトｍ４およびヒトｍ５受容体安定発現細胞は２×１０４ｃｅｌｌｓ／１００μＬ／ｗｅｌｌの割合で９６－ｗｅｌｌ ｐｌａｔｅに播き込み、ＣＯ２インキュベーターにて一晩培養した。各受容体安定発現細胞が１００％コンフルエントになればＦＬＩＰＲ Ｃａｌｃｉｕｍ ４ ａｓｓａｙ ｋｉｔ（Ｍｏｌｅｃｕｌａｒ Ｄｅｖｉｃｅｓ社）を用い、ＦＬＩＰＲＴＥＴＲＡ（登録商標）（Ｍｏｌｅｃｕｌａｒ Ｄｅｖｉｃｅｓ社）にて、被検化合物添加により一過性に上昇した蛍光強度（ＲＦＵ（ｍａｘ－ｍｉｎ））を測定した。コントロール薬剤アセチルコリン（３μＭ）による蛍光強度を１００％としたとき、各被検化合物の蛍光強度の相対値を求め、これをアゴニスト活性（％）とした。 Test Example 1: In vitro operability test of human muscarinic M 1 -M 5 receptor The operability of each receptor was evaluated by measuring changes in intracellular calcium concentration in each receptor stably expressing cells using fluorescence intensity as an index. . Human m1 receptor expression plasmid (pcDNA3.1_hM1) or human m3 receptor expression plasmid (pcDNA3.1_hM3) was introduced into CHO-K1 cells, and geneticin-resistant stable expression strains were obtained by the limiting dilution method. 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) are respectively present in CHO-K1 cells together with cDNA encoding the Gα16 gene. 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 μL / well, human m2, human m4 and human m5 receptor stably expressing cells at a rate of 2 × 10 4 cells / 100 μL / well The cells were seeded in a 96-well plate and cultured overnight in a CO 2 incubator. When each receptor stably expressing cells becomes 100% confluent, it is temporarily increased by addition of a 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 μM) was 100%, the relative value of the fluorescence intensity of each test compound was determined, and this was defined as the agonist activity (%).
　実施例化合物を用いて、試験例１に従って行ったヒト型ムスカリン受容体のｉｎ ｖｉｔｒｏ薬理試験の結果を表１３～１５に示す（各表中、Ｎ．Ｔ．とあるのは、試験未実施であることを意味する。）。
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
 Tables 13 to 15 show the results of in vitro pharmacological tests of human-type muscarinic receptors performed in accordance with Test Example 1 using Example compounds (in each table, “NT” indicates that the test was not performed. Means that there is.)
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
試験例２：ラット抗メタンフェタミン誘発運動量亢進作用評価
　ラットにおけるメタンフェタミン誘発の運動量亢進は、統合失調症の陽性症状の病態を反映すると考えられている。本モデルに対して本発明化合物を単独で、もしくは抗精神病薬と併用投与した際の、メタンフェタミン誘発運動量亢進に対する抑制の作用を拮抗する程度によって抗精神病作用を評価した。７週齢の雄性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙラットに対して、本発明化合物を単独で、もしくは抗精神病薬と併用で皮下、腹腔内または経口投与し、３０分後（経口投与の場合は６０分後）にメタンフェタミン（１ｍｇ／ｋｇ）を腹腔内投与した。メタンフェタミン投与直後にラットをテストケージ（無色透明プラスチック製：３３５×３８５×１７３ｍｍ）に移し、１０分後から８０分間の運動量を測定した。測定にはＳｕｐｅｒＭｅｘ（室町機械株式会社）を用いた。８０分間の総運動量はメタンフェタミン単独投与群の運動量を基準とし、抑制率（％）を０～１００の数値で表すことによって統計学的に処理した。その結果を表１６に示す。
また、図１に示すとおり、実施例３の化合物の皮下投与（０．６ｍｇ／ｋｇ）と抗精神病薬リスペリドン（０．６ｍｇ／ｋｇ）の経口投与を併用した場合、メタンフェタミン誘発運動量亢進を相加的に抑制した。
Figure JPOXMLDOC01-appb-T000057
 Test Example 2: Rat antimethamphetamine-induced momentum enhancement evaluation Methamphetamine-induced momentum enhancement in rats is considered to reflect the pathology of positive symptoms of schizophrenia. The antipsychotic action was evaluated based on the degree of antagonizing the inhibitory action on methamphetamine-induced momentum increase when the compound of the present invention was administered alone or in combination with an antipsychotic drug to this model. Seven-week-old male Sprague-Dawley rats are administered the compound of the present invention subcutaneously, intraperitoneally or orally alone or in combination with an antipsychotic drug, 30 minutes later (or 60 minutes in the case of oral administration) Methamphetamine (1 mg / kg) was administered intraperitoneally. Immediately after methamphetamine administration, the rats were transferred to a test cage (made of colorless transparent plastic: 335 × 385 × 173 mm), and the momentum for 80 minutes was measured after 10 minutes. SuperMex (Muromachi Kikai Co., Ltd.) was used for the measurement. The total amount of exercise for 80 minutes was statistically processed by expressing the inhibition rate (%) as a numerical value of 0 to 100 based on the amount of exercise in the methamphetamine single administration group. The results are shown in Table 16.
In addition, as shown in FIG. 1, when the subcutaneous administration (0.6 mg / kg) of the compound of Example 3 and the oral administration of the antipsychotic drug risperidone (0.6 mg / kg) were combined, methamphetamine-induced increased momentum was added. Suppressed.
Figure JPOXMLDOC01-appb-T000057
試験例３：ラット抗スコポラミン誘発健忘作用評価
　本試験では認知障害改善作用を評価できると考えられている。実験には明箱（２００×２５０×２００ｍｍ）と暗箱（２００×１５０×２００ｍｍ）からなるラット受動回避反応試験装置（小原医科産業製）を用いた。７週齢の雄性Ｗｉｓｔａｒラットに対して、本発明化合物を皮下、腹腔内または経口投与し、１５分後（経口投与の場合は３０分後）にスコポラミン（０．５ｍｇ／ｋｇ）を腹腔内投与した。その３０分後に、訓練試行としてラットを明箱へ入れ、ラットが暗箱へ移動すると０．３ｍＡのフットショックを３秒間与えた。翌日にテスト試行として、ラットを再び明箱へ入れて、暗箱へ移動するまでの潜時を最長３００秒まで測定した。テスト試行における移動潜時を記憶の指標として、溶媒投与群の潜時を１００、スコポラミン単独群の潜時を０として改善率（％）を数値で表した。表１７に示すとおり、実施例４の化合物はスコポラミン誘発健忘を改善した。
Figure JPOXMLDOC01-appb-T000058
 Test Example 3: Evaluation of rat anti-scopolamine-induced amnesia effect In this test, it is considered that the cognitive impairment improving action can be evaluated. In the experiment, a rat passive avoidance reaction test apparatus (manufactured by Ohara Medical Industry Co., Ltd.) consisting of a light box (200 × 250 × 200 mm) and a dark box (200 × 150 × 200 mm) was used. The compound of the present invention is subcutaneously, intraperitoneally or orally administered to 7-week-old male Wistar rats, and scopolamine (0.5 mg / kg) is intraperitoneally administered 15 minutes later (30 minutes after oral administration). did. Thirty minutes later, as a training trial, the rat was placed in a light box, and when the rat moved to a dark box, a foot shock of 0.3 mA was applied for 3 seconds. On the next day, as a test trial, the rat was placed in the light box again, and the latency until moving to the dark box was measured up to 300 seconds. Using the movement latency in the test trial as an index of memory, the latency of the solvent administration group was 100, the latency of the scopolamine alone group was 0, and the improvement rate (%) was expressed as a numerical value. As shown in Table 17, the compound of Example 4 improved scopolamine-induced amnesia.
Figure JPOXMLDOC01-appb-T000058
試験例４：ラットカタレプシー誘発作用評価
　本試験では錐体外路症状カタレプシーを評価できると考えられている。本発明化合物単独もしくは精神病薬と併用した場合のカタレプシー誘発作用を評価した。８週齢の雄性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙラットに対して、本発明化合物を単独で、もしくは精神病薬リスペリドンと併用で投与した。化合物の皮下、腹腔内または経口投与は、カタレプシー評価の６０分前に行った。カタレプシー評価では、ラットの前肢を９ｃｍの高さに水平に設置した直径１ｃｍの金属製バー上に置き、立位の姿勢保持時間を最長１８０秒まで連続３回計測した。３回の測定の中で最長の姿勢保持時間を各個体の値として採用した。例えば、実施例３の化合物の皮下投与（３０ｍｇ／ｋｇ）では０秒であった。さらに、リスペリトンの経口投与との併用試験を行った。図２に示すとおり、実施例３の化合物は錐体外路症状を誘発せず、かつ抗精神病薬と併用しても錐体外路症状を悪化させない可能性が示された。 Test Example 4: Rat Catalepsy Inducing Action Evaluation It is believed that extrapyramidal symptom catalepsy can be evaluated in this test. Catalepsy-inducing action when the compound of the present invention alone or in combination with a psychotic drug was evaluated. The compound of the present invention was administered to 8-week-old male Sprague-Dawley rats alone or in combination with the psychotic drug risperidone. The compound was administered subcutaneously, intraperitoneally or orally 60 minutes prior to catalepsy assessment. In catalepsy evaluation, the rat's forelimb was placed on a 1 cm diameter metal bar placed horizontally at a height of 9 cm, and the standing posture holding time was measured three times continuously up to 180 seconds. The longest posture retention time among the three measurements was adopted as the value of each individual. For example, the subcutaneous administration (30 mg / kg) of the compound of Example 3 was 0 seconds. Furthermore, a combination test with oral administration of risperitone was conducted. As shown in FIG. 2, the compound of Example 3 did not induce extrapyramidal symptoms, and even when used in combination with an antipsychotic drug, the possibility of exacerbating extrapyramidal symptoms was shown.
試験例５：ｈＥＲＧ阻害試験
　自動パッチクランプ装置 ＱＰａｔｃｈ ＨＴ （Ｓｏｐｈｉｏｎ　Ｂｉｏｓｃｉｅｎｃｅ Ａ／Ｓ）を用いて、ホールセルパッチクランプ法により、ｈＥＲＧ（ｈｕｍａｎ ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ）遺伝子を安定発現させたＣＨＯ細胞におけるｈＥＲＧカリウム電流を記録した。ｈＥＲＧ電流は、ボルテージクランプモードで膜電位を－８０ｍＶに保持し、２０ミリ秒間－５０ｍＶにした後５秒間＋２０ｍＶに脱分極させ、続いて５秒間－５０ｍＶに再分極させた時のテール電流の振幅を評価した。刺激は１５秒おきに繰り返し行い、実験は室温（２２±２℃）で行った。化合物は１細胞あたり４濃度を各濃度５分間累積投与し、各濃度における化合物適応前の電流の大きさと較べて阻害された電流の阻害率を算出し、Ｈｉｌｌ式により５０％阻害濃度を計算した（ＩＣ５０［μＭ］）。試験溶液は以下のものを用いた：細胞外溶液（ｍＭ）：２ ＣａＣｌ２、１ ＭｇＣｌ２、１０ ＨＥＰＥＳ、４ ＫＣｌ、１４５ ＮａＣｌ、１０ グルコース、細胞内溶液（ｍＭ）：５．４ ＣａＣｌ２、１．８ ＭｇＣｌ２、１０ ＨＥＰＥＳ、３１ ＫＯＨ、１０ ＥＧＴＡ、１２０ ＫＣｌ、４ ＡＴＰ Test Example 5: 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) The hERG potassium current at was recorded. The hERG current is the amplitude of the tail current when the membrane potential is held at −80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds after being changed to −50 mV for 20 milliseconds, and then repolarized to −50 mV for 5 seconds. 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 for each cell for 5 minutes, the inhibition rate of the inhibited current was calculated as compared to the current before the compound adaptation at each concentration, and the 50% inhibitory concentration was calculated by the Hill equation. (IC 50 [μM]). 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, 4 ATP
　実施例化合物を用いて、試験例５に従って行ったｈＥＲＧ阻害試験の結果を表１８に示す。
Figure JPOXMLDOC01-appb-T000059
 Table 18 shows the results of the hERG inhibition test conducted in accordance with Test Example 5 using the Example compounds.
Figure JPOXMLDOC01-appb-T000059
比較例：
　また、上記試験例１の方法を用いて、特許文献１～４に開示されている公知の化合物を比較例として、ムスカリンＭ１－Ｍ４受容体に対する作動性を測定し、本願の実施例化合物との比較を行った。 Comparative example:
In addition, using the method of Test Example 1 above, using the known compounds disclosed in Patent Documents 1 to 4 as comparative examples, the operability against muscarinic M 1 -M 4 receptors was measured, and Example compounds of the present application were measured. And compared.
　比較例として、特許文献１に開示されている下記比較例１および比較例２の化合物を用いてムスカリンＭ１－Ｍ４受容体に対する作動性を測定し、表１９に示す結果を得た。
比較例１：
Figure JPOXMLDOC01-appb-C000060
 比較例２：
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-T000062
 表１９より比較例１および２の化合物はムスカリン受容体選択性が全く無く、１位窒素原子がピロリジンと結合し、かつ３位が炭素原子である本発明化合物がムスカリン受容体選択性の面で優れていることは明らかである。 As comparative examples, the operability against muscarinic M 1 -M 4 receptors was measured using the compounds of Comparative Examples 1 and 2 disclosed in Patent Document 1, and the results shown in Table 19 were obtained.
Comparative Example 1:
Figure JPOXMLDOC01-appb-C000060
 Comparative Example 2:
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-T000062
 From Table 19, the compounds of Comparative Examples 1 and 2 have no muscarinic receptor selectivity, and the compounds of the present invention in which the nitrogen atom at the 1st position is bonded to pyrrolidine and the carbon atom at the 3rd position are in terms of muscarinic receptor selectivity. It is clear that it is excellent.
　比較例として、特許文献２に開示されている下記比較例３の化合物を用いてムスカリンＭ１－Ｍ４受容体に対する作動性を測定し、表２０に示す結果を得た。
比較例３：
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-T000064
 　表２０より比較例３の化合物はＭ１受容体作動性が非常に弱く、１位窒素原子がピロリジンと結合し、かつ３位が炭素原子である本発明化合物がＭ１受容体作動性の面で優れていることは明らかである。 As a comparative example, the operability against muscarinic M 1 -M 4 receptor was measured using the compound of the following comparative example 3 disclosed in Patent Document 2, and the results shown in Table 20 were obtained.
Comparative Example 3:
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-T000064
 From Table 20, 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 pyrrolidine and the carbon atom at position 3 is M 1 receptor activity. It is clear that it is superior.
　比較例として、特許文献３に開示されている下記比較例４の化合物を用いてムスカリンＭ１－Ｍ４受容体に対する作動性を測定し、表２１に示す結果を得た。
比較例４：
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-T000066
 　表２１より比較例４の化合物はＭ４受容体作動性が非常に弱く、本発明化合物がＭ４受容体作動性の面で優れていることは明らかである。 As a comparative example, the activity of muscarinic M 1 -M 4 receptors was measured using the compound of comparative example 4 disclosed below in Patent Document 3, and the results shown in Table 21 were obtained.
Comparative Example 4:
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-T000066
 Compound of Comparative than Table 21 Example 4 M 4 receptor agonist is very weak, it is clear that the present invention compounds are superior in terms of M 4 receptor agonist.
　特許文献４に開示されている下記比較例５および比較例６の化合物を以下に示す。
比較例５：
Figure JPOXMLDOC01-appb-C000067
 比較例６：
Figure JPOXMLDOC01-appb-C000068
 　比較例５および比較例６の化合物は特許文献４にてＭ４受容体作動性が非常に弱いことが開示されており、本発明化合物がＭ４受容体作動性の面で優れていることは明らかである。 The compounds of Comparative Example 5 and Comparative Example 6 disclosed in Patent Document 4 are shown below.
Comparative Example 5:
Figure JPOXMLDOC01-appb-C000067
 Comparative Example 6:
Figure JPOXMLDOC01-appb-C000068
 Compound of Comparative Example 5 and Comparative Example 6 is disclosed it is very weak M 4 receptor agonist in Patent Document 4, the present compound is excellent in terms of M 4 receptor agonist is it is obvious.
　本発明の化合物は、選択的にムスカリンＭ１およびＭ４受容体を作動するので、抗精神病作用、認知障害改善作用などを含む優れた中枢改善効果を有するとともに、その他のムスカリン受容体または他の受容体を介する副作用を低減することができる。従って、本発明の化合物は、非常に有用な医薬となり得る。 Since the compound of the present invention selectively activates muscarinic M 1 and M 4 receptors, it has excellent central improvement 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.

Claims (20)

  1. 下記式（１）；
    Figure JPOXMLDOC01-appb-C000001
     [式中、Ｒ１およびＲ２は、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、置換されていてもよいＣ３－７脂肪族炭素環基または置換されていてもよい３～７員の複素環基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに置換されていてもよいＣ３－７脂肪族炭素環基または置換されていてもよい３～７員の複素環基を形成するか、またはＲ１およびＲ２が一緒になって＝ＣＲ８Ｒ９を形成し、
    　Ｒ８およびＲ９は、同一または異なって、それぞれ水素原子、水酸基、スルホニルアミノ基または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ８およびＲ９が互いに結合して、Ｒ８およびＲ９が隣接する炭素原子とともに置換されていてもよいＣ３－７脂肪族炭素環基または置換されていてもよい３～７員の複素環基を形成し、
    　Ｒ３およびＲ４は、ともに水素原子であるか、またはＲ３およびＲ４が一緒になって、隣接する炭素原子とともにＣ＝ＯまたはＣ＝Ｓを形成してもよく、
    　Ｒ５およびＲ６は、同一または異なって、それぞれ水素原子、メチル基、エチル基、メトキシ基、フッ素原子、ジフルオロメチル基、トリフルオロメチル基、ジフルオロメトキシ基、トリフルオロメトキシ基または水酸基であり、
    　Ｒ７は、置換されていてもよいＣ１－６アルキル基、Ｃ２－６アルケニル基またはＣ２－６アルキニル基であり、
    　ｋおよびｍは、同一または異なって、それぞれ１、２または３であり、
    　ｎは、０または１であり、
    　ＹおよびＺは、同一または異なって、それぞれ酸素原子または硫黄原子であり、
    　ａ、ｂ、ｃおよびｄは、同一または異なって、それぞれ窒素原子またはＣＲ１０であり、
    　Ｒ１０は、水素原子、ハロゲン原子、置換されていてもよいＣ３－７脂肪族炭素環基、Ｃ６－１４アリール基、５～１０員のヘテロアリール基、Ｃ６－１４アリールアルキル基、ヘテロアリールアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルキルオキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、アシル基、スルファモイル基、水酸基、置換されていてもよいアミノ基、ニトロ基、Ｃ１－６アルキルスルホニル基、または置換されていてもよいＣ１－６アルキル基であり、
    　環状基Ａは、単環または二環の含窒素複素環基である。]で表される化合物またはその薬学的に許容される塩。     Following formula (1);
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, 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, or an optionally substituted C 3-7 aliphatic A carbocyclic group or an optionally substituted 3- to 7-membered heterocyclic group, or R 1 and R 2 may be bonded to each other, and R 1 and R 2 may be substituted with adjacent carbon atoms Form a good C 3-7 aliphatic carbocyclic group or an optionally substituted 3-7 membered heterocyclic group, or R 1 and R 2 together form ═CR 8 R 9 ,
    R 8 and R 9 are the same or different and are each a hydrogen atom, a hydroxyl group, a sulfonylamino group or an optionally substituted C 1-6 alkyl group, or R 8 and R 9 are bonded to each other, R 8 and R 9 form an optionally substituted C 3-7 aliphatic carbocyclic group or an optionally substituted 3-7 membered heterocyclic group with adjacent carbon atoms;
    R 3 and R 4 may both be hydrogen atoms, or R 3 and R 4 may be taken together to form C═O or C═S with adjacent carbon atoms;
    R 5 and R 6 are the same or different and are each a hydrogen atom, methyl group, ethyl group, methoxy group, fluorine atom, difluoromethyl group, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group or hydroxyl group,
    R 7 is an optionally substituted C 1-6 alkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group,
    k and m are the same or different and are 1, 2 or 3, respectively.
    n is 0 or 1,
    Y and Z are the same or different and each represents an oxygen atom or a sulfur atom,
    a, b, c and d are the same or different and are each a nitrogen atom or CR 10 ;
    R 10 represents a hydrogen atom, a halogen atom, an optionally substituted C 3-7 aliphatic carbocyclic group, a C 6-14 aryl group, a 5- to 10-membered heteroaryl group, a C 6-14 arylalkyl group, Heteroarylalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkyloxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, substituted An amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group,
    The cyclic group A is a monocyclic or bicyclic nitrogen-containing heterocyclic group. Or a pharmaceutically acceptable salt thereof.
  2. 　ＹおよびＺが、ともに酸素原子である請求項１に記載の化合物またはその薬学的に許容される塩。 The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Y and Z are both oxygen atoms.
  3. 　ｎが１である請求項１または２に記載の化合物またはその薬学的に許容される塩。 N is 1, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  4. 　ｋが１であり、Ｒ５が水素原子である請求項１～３のいずれか一項に記載の化合物またはその薬学的に許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein k is 1 and R 5 is a hydrogen atom.
  5. 　Ｒ３およびＲ４が、一緒になって、隣接する炭素原子とともにＣ＝Ｏを形成する、請求項１～４のいずれか一項に記載の化合物またはその薬学的に許容される塩。 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together to form C═O with an adjacent carbon atom.
  6. 　Ｒ７が、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、メトキシエチル基、またはジフルオロメチル基である請求項１～５のいずれか一項に記載の化合物またはその薬学的に許容される塩。 R 7 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxyethyl group, or a difluoromethyl group, or a compound thereof or a pharmaceutically acceptable salt thereof. salt.
  7. 　環状基Ａが、ピペリジニル基または下記式（２）；
    Figure JPOXMLDOC01-appb-C000002
     [式中、Ｘは－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－または－ＣＨ２ＯＣＨ２－であり、ｐ、ｑ、ｒおよびｓは同一または異なって、それぞれ０、１または２であり、かつｐ、ｑ、ｒおよびｓの総和は２、３または４である。]で表される含窒素複素環基である請求項１～６のいずれか一項に記載の化合物またはその薬学的に許容される塩。     The cyclic group A is a piperidinyl group or the following formula (2);
    Figure JPOXMLDOC01-appb-C000002
     [Wherein X is —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 — or —CH 2 OCH 2 —, and p, q, r and s are the same or different, 0, 1 or 2 and the sum of p, q, r and s is 2, 3 or 4. 7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
  8. 　環状基Ａが、下記式（３）；
    Figure JPOXMLDOC01-appb-C000003
     で表される含窒素複素環基である請求項１～７のいずれか一項に記載の化合物またはその薬学的に許容される塩。     The cyclic group A is represented by the following formula (3);
    Figure JPOXMLDOC01-appb-C000003
     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is a nitrogen-containing heterocyclic group represented by the formula:
  9. 　Ｒ６が、メチル基、エチル基、メトキシ基または水酸基である請求項１～８のいずれか一項に記載の化合物またはその薬学的に許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 6 is a methyl group, an ethyl group, a methoxy group or a hydroxyl group.
  10. 　Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、フッ素原子または水酸基である請求項１～９のいずれか一項に記載の化合物またはその薬学的に許容される塩。 The compound according to any one of claims 1 to 9, wherein 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 fluorine atom, or a hydroxyl group. Its pharmaceutically acceptable salt.
  11. 　ａ、ｂ、ｃおよびｄが、ＣＲ１０である請求項１～１０のいずれか一項に記載の化合物またはその薬学的に許容される塩。 a, b, c and d, a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 it is CR 10.
  12. 　Ｒ１０が、水素原子、フッ素原子、塩素原子、臭素原子、メチル基、エチル基、トリフルオロメチル基、ジフルオロメチル基、メトキシ基、エチニル基、エテニル基、シアノ基、水酸基、置換されていてもよいアミノ基またはニトロ基である請求項１～１１のいずれか一項に記載の化合物またはその薬学的に許容される塩。 R 10 may be a hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, trifluoromethyl group, difluoromethyl group, methoxy group, ethynyl group, ethenyl group, cyano group, hydroxyl group, or substituted The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is a good amino group or nitro group.
  13. 　４－{ [（３Ｒ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    ４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｒ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    (３－endo)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    (１Ｒ，５Ｓ)－３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸メチル；
     (３－exo)－３－{ [（３Ｓ）－３－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｓ）－３－（４－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｓ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－{ [（３Ｓ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｒ）－３－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－{ [（３Ｓ）－３－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
     (３－exo)－３－{ [（３Ｓ）－３－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－{ [（３Ｓ）－３－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｓ）－３－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－{ [（３Ｓ）－３－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｓ）－３－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－{ [３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）アゼチジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    ４－ヒドロキシ－４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    ３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－９－アザビシクロ[３．３．１]ノナン－９－カルボン酸メチル；
    ３－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－９－アザビシクロ[３．３．１]ノナン－９－カルボン酸メチル；
    ４－メチル－４－{ [（３Ｓ）－３－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    ４－{ [（３Ｓ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
     (３－exo)－３－{ [（３Ｓ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－{ [（３Ｒ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    (３－exo)－３－{ [（３Ｒ）－３－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－{ [（３Ｒ）－３－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    ４－{ [（３Ｓ）－３－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    ４－{ [３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}ピペリジン－１－カルボン酸エチル；
    (３－exo)－３－{ [３－（２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピロリジン－１－イル]メチル}－８－アザビシクロ[３．２．１]オクタン－８－カルボン酸エチル；
    ４－({(３Ｓ)－3－[(３Ｒ) －３－(ヒドロキシメチル)－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピペリジン－１－イル}メチル)ピペリジン－１－カルボン酸エチル；
    ４－({(３Ｒ)－３－[(３Ｒ) －３－(ヒドロキシメチル)－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピペリジン－１－イル}メチル)ピペリジン－１－カルボン酸エチル；
    (３－exo)－３－({(３Ｓ)－３－[(３Ｓ) －３－ヒドロキシ－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル)－８－アザビシクロ[３.２.１]オクタン－８－カルボン酸エチル；
    (３－exo)－３－({(３Ｓ)－３－[(３Ｒ) －３－ヒドロキシ－３－メチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル)－８－アザビシクロ[３.２.１]オクタン－８－カルボン酸エチル；
    ４－({ [（３Ｒ）－３－[３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；
    ４－({ [（３Ｒ）－３－[（３Ｒ）－５－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；および
    ４－({ [（３Ｓ）－３－[（３Ｓ）－５－フルオロ－３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル]ピロリジン－１－イル}メチル）ピペリジン－１－カルボン酸エチル；
    からなる群から選択される、請求項１に記載の化合物またはその薬学的に許容される塩。     4-{[(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3-{[(3R) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
    (3-exo) -3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
    (3-endo) -3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] ethyl octane-8-carboxylate;
    (1R, 5S) -3- {[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3. 2.1] methyl octane-8-carboxylate;
    (3-exo) -3- {[(3S) -3- (5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    (3-exo) -3- {[(3S) -3- (4-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    (3-exo) -3- {[(3S) -3- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    4-{[(3S) -3- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3- {[(3R) -3- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    4-{[(3S) -3- (6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3- {[(3S) -3- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    4-{[(3S) -3- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3- {[(3S) -3- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    4-{[(3S) -3- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3- {[(3S) -3- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    4-{[3- (2-oxo-2,3-dihydro-1H-indol-1-yl) azetidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    4-hydroxy-4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -9-azabicyclo [3.3.1] nonane Methyl 9-carboxylate;
    3-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -9-azabicyclo [3.3.1] nonane Methyl 9-carboxylate;
    4-methyl-4-{[(3S) -3- (2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    4-{[(3S) -3- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3- {[(3S) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    4-{[(3R) -3- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3- {[(3R) -3- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8- Azabicyclo [3.2.1] octane-8-carboxylate;
    4-{[(3R) -3- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} piperidine-1-carvone Ethyl acid;
    4-{[(3S) -3- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} piperidine-1-carvone Ethyl acid;
    4-{[3- (2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    (3-exo) -3-{[3- (2,3-dihydro-1H-indol-1-yl) pyrrolidin-1-yl] methyl} -8-azabicyclo [3.2.1] octane-8- Ethyl carboxylate;
    4-({(3S) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} Methyl) piperidine-1-carboxylate;
    4-({(3R) -3-[(3R) -3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} Methyl) piperidine-1-carboxylate;
    (3-exo) -3-({(3S) -3-[(3S) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate;
    (3-exo) -3-({(3S) -3-[(3R) -3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine-1 -Yl} methyl) -8-azabicyclo [3.2.1] octane-8-carboxylate;
    4-({[(3R) -3- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl} methyl) piperidine 1-ethyl carboxylate;
    4-({[(3R) -3-[(3R) -5-fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] pyrrolidine 1-yl} methyl) piperidine-1-carboxylate; and 4-({[(3S) -3-[(3S) -5-fluoro-3-hydroxy-3-methyl-2-oxo-2, 3-dihydro-1H-indol-1-yl] pyrrolidin-1-yl} methyl) ethyl piperidine-1-carboxylate;
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:
  14. 　請求項１～１３のいずれか一項に記載の化合物またはその薬学的に許容される塩を含有する中枢性疾患の治療剤。 A therapeutic agent for central diseases comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
  15. 　中枢性疾患がアルツハイマー病および／または統合失調症である、請求項１４に記載の治療剤。 The therapeutic agent according to claim 14, wherein the central disease is Alzheimer's disease and / or schizophrenia.
  16. 　請求項１～１３のいずれか一項に記載の化合物またはその薬学的に許容される塩、および薬学的に許容される担体を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  17. 　請求項１～１３のいずれか一項に記載の化合物またはその薬学的に許容される塩を患者に投与して中枢性疾患を治療する方法。 A method for treating a central disease by administering to a patient the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
  18. 　中枢性疾患がアルツハイマー病および／または統合失調症である、請求項１７に記載の方法。 The method according to claim 17, wherein the central disease is Alzheimer's disease and / or schizophrenia.
  19. 　中枢性疾患治療薬としての使用のための請求項１～１３のいずれか一項に記載の化合物またはその薬学的に許容される塩。 The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use as a therapeutic agent for central diseases.
  20. 　中枢性疾患がアルツハイマー病および／または統合失調症である、請求項１９に記載の化合物またはその薬学的に許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to claim 19, wherein the central disease is Alzheimer's disease and / or schizophrenia.
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