WO2013122107A1 - Nouveau dérivé de pyrrolidine cyclique fusionné - Google Patents

Nouveau dérivé de pyrrolidine cyclique fusionné Download PDF

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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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group
methyl
dihydro
indol
carboxylate
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PCT/JP2013/053413
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Japanese (ja)
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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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    • 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.

Abstract

La présente invention concerne : un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable lui correspondant; une composition pharmaceutique qui contient, comme ingrédient actif, le composé ou un sel pharmaceutiquement acceptable de celui-ci ; et un agent thérapeutique pour traiter les maladies dont la médiation est assurée par des récepteurs muscariniques, et qui contient le composé ou son sel pharmaceutiquement acceptable correspondant. (Dans la formule, a, b, c et d sont chacun un atome d'azote ou CR10 ; Y et Z sont chacun un atome d'oxygène ou un atome de soufre ; A représente un groupe hétérocyclique contenant de l'azote monocyclique ou bicyclique; R1, R2 et R5-R10 représentent chacun un atome d'hydrogène, un groupe alkyle ou similaire ; R3 et R4 représentent chacun un atome d'hydrogène, ou selon un autre mode de réalisation, R3 et R4 se combinent ensemble pour former C = O ou C = S ; k et m représentent chacun un nombre de 1 -3 ; et n représente un nombre de 0 -1.)
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