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WO2000034280A1 - Composes heterocycliques de 4-oxo-imidazolidine-2-spiro-azote - Google Patents

Composes heterocycliques de 4-oxo-imidazolidine-2-spiro-azote Download PDF

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Publication number
WO2000034280A1
WO2000034280A1 PCT/JP1999/006921 JP9906921W WO0034280A1 WO 2000034280 A1 WO2000034280 A1 WO 2000034280A1 JP 9906921 W JP9906921 W JP 9906921W WO 0034280 A1 WO0034280 A1 WO 0034280A1
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group
lower alkyl
amino
atom
alkylamino
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Japanese (ja)
Inventor
Atsushi Satoh
Hiroshi Kawamoto
Satoshi Ozaki
Yoshiki Ito
Yoshikazu Iwasawa
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MSD KK
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Banyu Phamaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary 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
    • A61P25/24—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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention is useful in the field of medicine. More specifically, the 4-oxoimidazolidin-2-spiro-nitrogen-containing heterocyclic compound of the present invention has an inhibitory action on the binding of nociceptin to nociceptin receptor ⁇ RL1, and is useful for analgesics and morphine.
  • Drugs for overcoming narcotic analgesic tolerance such as morphine
  • drugs for overcoming dependence on narcotic analgesics such as morphine
  • analgesic potentiators anti-obesity agents
  • brain function improvers Alzheimer's disease drugs, anti-dementia drugs, psychiatric It is useful as a schizophrenia drug, Parkinson's disease drug, chorea drug, antidepressant drug, diabetes insipidus drug, polyuria drug or hypotension drug.
  • Nociceptin (the same substance as orphan in FQ) is a peptide consisting of 17 amino acids with a similar structure to the opioid peptide. Nociceptin enhances responsiveness to noxious stimuli, increases appetite, reduces spatial learning ability, antagonizes the analgesic effect of classical obiate agonists, inhibits dopamine release, aquaretic effect, and vasodilator effect It has a systemic blood pressure lowering effect and is thought to be involved in the regulation of pain and appetite or in memory and learning via the nociceptin receptor ORL1 in the brain [Naichiya (Na ture), 377, 532 (1995); Society for Neurology (S 0 ciety for Neuroscience), 22, 455 (1996); New mouth report (Ne) ur oR eport), 8 volumes, 423 pages (1997); Neuron 'Journal of Ob' neuroscience (Eur.
  • a substance that specifically inhibits the binding of nociceptin to nociceptin receptor ⁇ RL 1 is an analgesic for painful diseases such as cancer pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain, and neuralgia.
  • Drugs Narcotic analgesics represented by morphine Overcoming drugs for overcoming resistance, Drugs for overcoming narcotic analgesics dependence represented by morphine, Analgesic potentiators, Antiobesity agents, Brain function improvers, Alzheimer's disease therapeutics, Anti-dementia It is expected to be useful as a drug, a drug for schizophrenia, a drug for Parkinson's disease, a drug for chorea, an antidepressant, a drug for diabetes insipidus, a drug for polyuria, or a drug for hypotension. Disclosure of the invention
  • An object of the present invention is to provide a novel analgesic having an action of inhibiting the binding of nociceptin to nociceptin receptor ⁇ RL1, a drug for overcoming a narcotic analgesic resistance represented by morphine, a narcotic analgesic represented by morphine Drugs for overcoming dependence, analgesics, anti-obesity drugs, brain function improvers, Alzheimer's disease drugs, anti-dementia drugs, schizophrenia drugs, Parkinson's disease drugs, chorea drugs, antidepressants, urine It is an object of the present invention to provide a remedies for diabetes, polyuria or hypotension.
  • Cy is a halogen atom, a cyclo-lower alkyl group, a lower alkylidene group, a lower alkenyl group, a lower alkynyl group, an amino group, a lower alkylamino group, a di-lower group
  • ⁇ represents an integer of 0 to 3
  • R 1 represents a hydrogen atom, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group which may be substituted with a fluorine atom, a lower alkoxycarbonyl group, Rubamoyl group, lower alkyl rubamoyl group, di-lower alkyl rubamoyl group, lower alkylsulfonyl group, aminosulfonyl group, lower alkylaminosulfonyl group Di lower alkylaminosulfonyl group, or halogen atom, cyclo lower alkyl group, amino group, lower alkyl amino group, di lower alkyl amino group, cyclo lower alkyl amino group, lower alkyl sulfonyl amino group, amino Sulfonylamino group, (lower alkylamino) sulfonylamino group, (
  • Analgesics for accompanying diseases drugs for overcoming narcotic analgesic resistance such as morphine
  • drugs for overcoming narcotic analgesics dependence such as morphine
  • analgesic potentiators anti-obesity agents
  • brain function improvers Alzheimer's disease It is found to be useful as a therapeutic drug, anti-dementia drug, schizophrenia drug, Parkinson's disease drug, chorea drug, antidepressant drug, diabetes insipidus drug, polyuria drug or hypotension drug
  • the present invention has been completed.
  • the present invention relates to a compound represented by the general formula [I], a salt or ester thereof, and a production method and use thereof.
  • the symbols and terms described in this specification will be described.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group.
  • Cyclo lower alkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • lower alkylidene group means a linear or branched alkylidene group having 1 to 6 carbon atoms, such as a methylene group, an ethylidene group, a propylidene group, an isopropylidene group and a butylidene group.
  • “Lower alkenyl group” means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, for example, vinyl group, 1-propenyl group, 2-propenyl group, isopropyl group, 3 -Butenyl group, 2-butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl group, 2-methyl-2-pro Examples thereof include a benzyl group, a 2-methyl-1-propenyl group, a 3-methyl-2-butenyl group, and a 4-pentenyl group.
  • “Lower alkynyl group” means a straight or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, 2-propynyl group, 1-methyl-2-propynyl group, 2-butynyl group. Group, 1-methyl-2-butynyl group, 2-pentynyl group and the like.
  • the term "lower alkylamino group” means an amino group monosubstituted with the lower alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, sec-butylamino group, tert- And a butylamino group.
  • the “di-lower alkylamino group” means an amino group di-substituted with the lower alkyl group, for example, dimethylamino, getylamino, ethylmethylamino, dipropylamino, methylpropylamino, diisopropyl And an amino group.
  • “Lower alkoxy group” means an alkoxy group having a lower alkyl group, that is, an alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group, a propyloxy group, an isopropoxy group, a butoxy group, an isobutoxy group. Tert-butoxy group, pentyloxy group and the like.
  • the ⁇ lower alkoxy group optionally substituted with a fluorine atom '' means that any substitutable position of the lower alkoxy group is substituted with one or more, preferably one to three, fluorine atoms. It means a good alkoxy group, and examples thereof include, in addition to the above-mentioned alkoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1, .. 2-difluoroethoxy group and the like.
  • a mono-, bi- or tricyclic aliphatic carbocyclic group is a saturated or unsaturated aliphatic carbocyclic group, and means a mono-, bi- or tricyclic cyclic group, for example, cyclohexyl Group, cyclohexyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, cycloundecyl group, cyclododecyl group, 1-cyclohexenyl group, 2-cyclohexenyl group, 1,3-cyclohexenyl group, 1 -Cycloheptenyl group, 2-cycloheptenyl group, 1,3-cycloheptenyl group, 1-cyclooctenyl group, 2-cyclooctenyl group, 3-cyclooctenyl group, 4-cyclooctenyl group, 1,3- Cyclooctenyl, 1-cyclononenyl, 2-cyclon
  • the “lower alkoxycarbonyl group” means an alkoxycarbonyl group having the lower alkoxy group, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, Examples include an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, and a pentyloxycarbonyl group.
  • “Monocyclic aliphatic nitrogen-containing heterocyclic group” means a saturated monocyclic aliphatic heterocyclic group containing at least one nitrogen atom as a ring atom.
  • lower alkyl group refers to a monosubstituted group of the lower alkyl group, such as a methylcarbamoyl group, an ethylcarbamoyl group, a propyllumbamoyl group, an isopropyllrubamoyl group, a butylcarbamoyl group, sec-butylcarbamoyl group, tert-butylcarbamoyl group and the like.
  • di-lower alkyl group refers to a di-substituted group of the lower alkyl group, such as a dimethylcarbamoyl group, a getylcarbamoyl group, an ethylmethylcarbamoyl group, a dipropyl group.
  • examples include a methylpropylcarbamoyl group and a diisopropylcaproluvyl group.
  • “Lower alkylsulfonyl group” means an alkylsulfonyl group having a lower alkyl group, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl And a tert-butylsulfonyl group.
  • “Lower alkylaminosulfonyl group” means an alkylaminosulfonyl group having a lower alkylamino group, such as a methylaminosulfonyl group, an ethylaminosulfonyl group, a propylaminosulfonyl group, an isopropylaminosulfonyl group, Butylaminosulfonyl group, sec-butylaminosulfonyl group, tert-butylaminosulfonyl group and the like.
  • the “di-lower alkylaminosulfonyl group” means a dialkylaminosulfonyl group having the above-mentioned di-lower alkylamino group, for example, dimethylaminosulfonyl group, getylaminosulfonyl group, ethylmethylaminosulfonyl group, dipropyl
  • dimethylaminosulfonyl group getylaminosulfonyl group
  • ethylmethylaminosulfonyl group dipropyl
  • Examples include an aminosulfonyl group, a methylpropylaminosulfonyl group, and a diisopropylaminosulfonyl group.
  • Cyclo lower alkylamino group means an amino group monosubstituted with the cyclo lower alkyl group, and includes a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, and a cyclohexylamino group.
  • “Lower alkylsulfonylamino group” means an amino group monosubstituted with the lower alkylsulfonyl group, for example, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, isopropylsulfonylamino group, A butylsulfonylamino group, a sec-butylsulfonylamino group, a tert-butylsulfonylamino group and the like.
  • the “(lower alkylamino) sulfonylamino group” means an amino group monosubstituted with the lower alkylaminosulfonyl group, for example, (methylamino) sulfonylamino group, (ethylamino) sulfonylamino group, (propylamino) sulfonyl group.
  • An amino group (isopropylamino) sulfonylamino group, (butylamino) sulfonylamino group, (sec-butylamino) sulfonylamino group, (tert-butylamino) sulfonylamino group and the like.
  • (Di-lower alkylamino) sulfonylamino group refers to the di-lower alkyl It means an amino group mono-substituted with an aminosulfonyl group. If it is clear, (dimethylamino) sulfonylamino group, (getylamino) sulfonylamino group, (ethylmethylamino) sulfonylamino group, (dipropylamino) sulfonylamino Group, (methylpropylamino) sulfonylamino group, (diisopropylamino) sulfonylamino group and the like.
  • the “(lower alkyl carbamoyl) amino group” means an amino group mono-substituted with the lower alkylcarbamoyl group, and a (methylcarbamoyl) amino group, a (ethylcarbamoyl) amino group, (Propyl rubamoyl) amino group, (isopropyl rubamoyl) amino group, (butyl carbamoyl) amino group, (sec-butyl carbamoyl) amino group, (tert-butyl carbamoyl) amino group, and the like.
  • the “(di-lower alkylcarbamoyl) amino group” means an amino group monosubstituted with the di-lower alkylcarbamoyl group, for example, a (dimethylcarbamoyl) amino group, a (getylcarbamoyl) amino group, Tylmethylcarbamoyl) amino group, (dipropyl-capable rubamoyl) amino group, (methylpropyl-capable rubamoyl) amino group, (diisopropyl-capable rubamoyl) amino group, and the like.
  • lower alkyl rubamoyloxy group means an alkyl rubamoyloxy group having the lower alkyl rubamoyl group, such as methylcarbamoyloxy, ethylcarbamoyloxy, propyl rubamoyloxy, isopropyl rubamoyloxy, Butyl carbamoyloxy group, sec-butyl carbamoyloxy group, tert-butyl carbamoyloxy group and the like.
  • the “di-lower alkyl rubamoyloxy group” means the dialkyl lower rubamoyloxy group having the di-lower alkyl carbamoyl group, for example, dimethylcarbamoyloxy, getylcarbamoyloxy, ethylmethylcarbamoyloxy, Examples thereof include a dipropyl rubamoyloxy group, a methyl propyl rubamoyloxy group, and a diisopropyl rubamoyloxy group.
  • cycloalkyl group having 3 to 10 carbon atoms examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.
  • “Aromatic carbocyclic group” means a phenyl group, a naphthyl group or an anthryl group.
  • Aromatic heterocyclic group means one or more members selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, which are the same or different, and preferably a 5- or 6-membered member containing 1 to 3 heteroatoms
  • a condensed ring in which the monocyclic aromatic heterocyclic group or the monocyclic aromatic heterocyclic group and the aromatic carbocyclic group are condensed, or in which the same or different monocyclic aromatic heterocyclic groups are condensed with each other Means an aromatic heterocyclic group of the formula, e.g., a piperyl group, a furyl group, a cyenyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isooxazolyl group, a triazolyl group, a tetrazolyl group, an oxazodazolyl group , Thiadia
  • nitrogen-containing heterocyclic group optionally containing an oxygen atom or a sulfur atom refers to a group containing at least one nitrogen atom and, if necessary, the same or more than the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • a nitrogen-containing heterocyclic group which may contain an oxygen atom or a sulfur atom together with an adjacent nitrogen atom means, in addition to an adjacent nitrogen atom, an oxygen atom, a nitrogen atom and a sulfur atom, if necessary.
  • a 5- or 6-membered saturated or unsaturated monocyclic nitrogen-containing heterocyclic group which may contain a heteroatom selected from the same or different groups, for example, 1-pyrrolidinyl group, 2-pyrroline-1-yl Group, 1-pyrrolyl group, 1-imidazolidinyl group, 2-imidazoline-1-yl group, 1 imidazolyl group, 1-villazolidinyl group, 3-pyrazolin-2-yl group, 1-pyrazolyl group, 1 A 2,2,3-triazol-1-yl group, a 1-tetrazolyl group, a 1-piperidyl group, a 1-piperagel group, a 4-morpholinyl group, a 4-thiomorpholinyl group and the like.
  • the “salt” of the compound represented by the general formula [I] means a pharmaceutically acceptable and conventional one, for example, when the compound has a carboxyl group, a base addition salt or an amino group at the carboxyl group. Salts of acid addition salts of the amino group or the basic heterocyclic ring in the case of having the compound.
  • the base addition salt examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; such as trimethylamine salt, triethylamine salt, dicycloalkyl salt Organic amine salts such as hexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, proforce salt, and N, N'-dibenzylethylenediamine salt.
  • the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate, etc .; for example, maleate, fumarate, tartrate, citrate, ascorbate.
  • Organic acid salts such as trifluoroacetate; methanesulfonate; Sulfonates such as isethionate, benzenesulfonate, p-toluenesulfonate and the like can be mentioned.
  • the “ester” of the compound represented by the general formula [I] means, for example, a pharmaceutically acceptable conventional compound having a carboxyl group when the carboxyl group has a carboxyl group, such as a methyl group, an ethyl group, and a propyl group.
  • Ester with lower alkyl groups such as isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, benzyl group, phenethyl Ester with an aralkyl group such as an ester, an ester with a lower alkenyl group such as an aryl group or a 2-butenyl group, an ester with a lower alkoxyalkyl group such as a methoxymethyl group, a 2-methoxyethyl group, or a 2-ethoxyethyl group, and acetoxymethyl Group, bivaloyloxymethyl group, 1 Esters with lower alkanoyloxyalkyl groups such as roxityl group, esters with lower alkoxycarbonylalkyl groups such as methoxycarbonylmethyl group
  • the compound of the general formula [ ⁇ ] of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of the substituent, but the compound of the general formula [I ] Also encompasses all these stereoisomers and their mixtures.
  • Cy is a halogen atom, cyclo lower alkyl group, lower alkylidene group, lower alkyl
  • R 1 may have a substituent selected from the group consisting of groups represented by R 3 and may have 6 to 15 1, 2 or 3 cyclic aliphatic carbocyclic group '' 6 to 15 said 1, 2 or 3 cyclic aliphatic carbocyclic groups or 6 to 15 carbon atoms having a substituent at any substitutable position of said 1, 2 or 3 cyclic aliphatic carbocyclic group
  • the substituent is a halogen atom, a cyclo-lower alkyl group, a lower alkylidene group, a lower alkenyl group, a lower alkynyl group, an amino group, a lower alkylamino group, a di-
  • the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
  • cyclo lower alkyl group for the substituent for example, a cyclopentyl group, a cyclohexyl group and the like are preferable.
  • the lower alkylidene group for the substituent for example, a methylene group, an ethylidene group and the like are suitable.
  • the lower alkenyl group for the substituent is, for example, preferably a vinyl group, a 1-propenyl group, a 2-propenyl group.
  • the lower alkynyl group for the substituent is, for example, preferably an ethynyl group, a 2-propynyl group.
  • the lower alkylamino group for the substituent for example, a methylamino group, an ethylamino group and the like are preferable.
  • di-lower alkylamino group for the substituent examples include a dimethylamino group, A thiamino group and the like are preferred.
  • the lower alkoxy group which may be substituted with a fluorine atom for the substituent, for example, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and the like are preferable.
  • R 3 represents a lower alkyl group which may have a substituent selected from the group consisting of a cycloalkyl group having 3 to 10 carbon atoms and an aromatic carbon or heterocyclic group.
  • a lower alkyl group which may have a substituent selected from the group consisting of a cycloalkyl group having 3 to 10 carbon atoms and an aromatic carbon or heterocyclic group is an unsubstituted lower alkyl group or A lower alkyl group having a substituent at any substitutable position, wherein the substituent is the same or different from the group consisting of a cycloalkyl group having 3 to 10 carbon atoms and an aromatic carbon or heterocyclic group; Alternatively, two or more, preferably one can be selected.
  • cycloalkyl group having 3 to 10 carbon atoms for the substituent include a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group.
  • aromatic carbocyclic group for the substituent for example, a phenyl group is preferable.
  • aromatic heterocyclic group for the substituent for example, a furyl group, a phenyl group, a phenyl group, and the like are preferable.
  • a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group and the like are preferable.
  • R 3 for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a cyclohexylmethyl group, a benzyl group, a pyridylmethyl group Among them, a methyl group, an ethyl group, a propyl group and the like are preferable.
  • a halogen atom As the substituent for Cy, a halogen atom, a cyclo-lower alkyl group, a lower alkylidene group, a group represented by R 3 , and the like are preferable.
  • Examples of the 1, 2, or 3 cyclic aliphatic carbocyclic group having 6 to 15 carbon atoms of Cy include 6 to 15 carbon atoms, more preferably 8 to 12 carbon atoms of 1, 2, or 3 cyclic aliphatic groups. carbon Ring groups are preferred.
  • dec - 2 I group 1 one indanyl group, 2-indanyl group, 1, 2, 3, 4 Tetorahidoro one 1-naphthyl group, 1 , 2,3,4-Tetrahydro-1-naphthyl group, 5,6,7,8,9,10-Hexahydrobenzocyclooctene-16Tl group, 2,3-dihydrophenalene-1- And a 9,10-dihydroanthracene-91-yl group are preferred, and a cyclooctyl group and the like are particularly preferred.
  • Cy for example, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, 1-cyclohexenyl, 2-cyclohexenyl, 1,3-cyclohexenyl group, 1-cycloheptenyl group, 2-cycloheptenyl group, 1,3-cycloheptenyl group, 1-cyclooctenyl group, 2-cyclooctenyl group, 3-cyclooctenyl group , 4-cyclooctenyl, 1,3-cyclooctenyl, 1-cyclononenyl, 2-cyclononenyl, 3-cyclononenyl, 4-cyclononenyl, 1,3-cyclononagenyl, 1-cyclodecenyl Nyl group, 2-cyclodecenyl group, 3-cyclodecenyl group,
  • dec - 2 I group 1 one indanyl group, 2- ⁇ f Ndaniru group, 1, 2, 3, 4 —Tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 5,6,7,8,9,10-hexahydrobenzozocyclooctene-1-yl Group, 2.3-dihydrophenalene-1-yl group, 2,2-difluorocycloheptyl group, 3,3-difluorocycloheptyl group, 4,4-difluorocycloheptyl group, 2,2-difluorocyclooctyl group , 3,3-difluorocycloctyl, 4,4 difluorocyclooctyl, 5,5-difluorocyclooctyl, 4,4,7,7-tetrafluorocyclooctyl, 1 —Meth
  • n CON (R 5 ) means a monocyclic aliphatic nitrogen-containing heterocyclic group having 3 to 9 carbon atoms which may have a substituent selected from the group consisting of groups represented by R 6. , Adjacent
  • a heterocyclic group wherein the substituent is lower alkenyl Group, lower alkynyl group, amino group, lower alkylamino group, di-lower alkylamino group, hydroxyl group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, a group represented by R 4 and — (CH 2 ) n CON (R 5 )
  • R 4 a group represented by R 4 and — (CH 2 ) n CON (R 5 )
  • One or more, preferably one or two, identical or different groups can be selected from the group consisting of the group represented by R 0 .
  • the lower alkenyl group for the substituent is, for example, preferably a vinyl group, a 1-propenyl group, a 2-propenyl group.
  • the lower alkynyl group for the substituent is, for example, preferably an ethynyl group, a 2-propynyl group.
  • the lower alkylamino group for the substituent for example, a methylamino group, an ethylamino group and the like are preferable.
  • the di-lower alkylamino group for the substituent is, for example, preferably a dimethylamino group, a acetylamino group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group, a propoxy group.
  • the lower alkoxycarbonyl group for the substituent is, for example, preferably a methoxycarbonyl group, an ethoxycarbonyl group.
  • R 4 is an amino group, a lower alkylsulfonylamino group, an aminosulfonylamino group, a (lower alkylamino) sulfonylamino group, a (di-lower alkylamino) sulfonylamino group, a carbamoylamino group, a (lower alkyl rubamoyl) amino group are tables (di-lower alkyl force Rubamoiru) amino group, a hydroxyl group, a force Rubamoiruokishi group, a lower alkyl force Rubamoiruokishi group, a di-lower alkyl force Rubamoiruokishi group, carboxyl group, lower alkoxycarbonyl group, an aromatic heterocyclic group and one R 7 A lower alkyl group which may have a substituent selected from the group consisting of
  • Amino group lower alkylsulfonylamino group, aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, carbamoylamino group, (lower alkyl rubamoyl) amino group, Lower alkyl group (lvamoyl) amino group, hydroxyl group, l-bamoyloxy group, low
  • the term "good lower alkyl group” means the unsubstituted lower alkyl group or the lower alkyl group having a substituent at any substitutable position, wherein the substituent is an amino group, a lower alkylsulfonylamino group, Aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, carbamoylamino group, (lower alkyl rubamoyl) amino group, (di-lower alkyl rubamoyl) amino group, water Acid group, rubamoyloxy group, lower alkyl rubamoyloxy group, di-lower alkyl Carbamoyl O alkoxy group, carboxyl group, lower alkoxycarbonyl group, from the group consisting of groups represented by aromatic heterocyclic group and one R 7, same or different one or more, preferably 1 or 2 to select it
  • the lower alkylsulfonylamino group for the substituent for example, a methylsulfonylamino group, an ethylsulfonylamino group and the like are preferable.
  • the (lower alkylamino) sulfonylamino group for the substituent for example, a (methylamino) sulfonylamino group, a (ethylamino) sulfonylamino group and the like are preferable.
  • the (di-lower alkylamino) sulfonylamino group for the substituent for example, a (dimethylamino) sulfonylamino group, a (getylamino) sulfonylamino group and the like are preferable.
  • the (lower alkyl rubamoyl) amino group for the substituent for example, a (methyl rubamoyl) amino group, a (ethylcarbamoyl) amino group and the like are preferable.
  • a (di-lower alkyl group rubamoyl) amino group for the substituent for example, a (dimethylmethylcarbamoyl) amino group, a (getylcarbamoyl) amino group and the like are preferable.
  • the lower alkyl group of the substituent preferred are, for example, a methylcarbamoyloxy group and an ethylcarbamoyloxy group.
  • di-lower alkyl group of the substituent for example, a dimethylcarbamoyloxy group, a dimethylcarbamoyloxy group, and the like are preferable.
  • the lower alkoxycarbonyl group for the substituent is, for example, preferably a methoxycarbonyl group, an ethoxycarbonyl group.
  • aromatic heterocyclic group for the substituent for example, a triazolyl group, a tetrazolyl group and the like are preferable.
  • R 7 represents a lower alkylamino group which may have an aromatic carbon or a heterocyclic group, a lower alkylamino group, a di-lower alkylamino group, a cyclo-lower alkylamino group or a lower alkoxy group which may be substituted with a fluorine atom .
  • the unsubstituted lower alkylamino group, di-lower alkylamino group, lower alkylamino group, lower alkoxy group which may be substituted by a fluorine atom, or aromatic carbon or aromatic carbon at any substitutable position; It means the lower alkylamino group, di-lower alkylamino group, cyclo-lower alkylamino group or lower alkoxy group which may be substituted by a fluorine atom, having a heterocyclic group as a substituent.
  • aromatic carbocyclic group for the substituent a phenyl group or the like is preferable, and as the aromatic heterocyclic group, a pyridyl group or the like is preferable.
  • the lower alkylamino group for R 7 for example, a methylamino group, an ethylamino group and the like are preferable.
  • di-lower alkylamino group for R 7 for example, a dimethylamino group, a getylamino group, and the like are preferable.
  • cyclo lower alkylamino group for R 7 for example, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, and the like are preferable.
  • the lower alkoxy group optionally substituted with a fluorine atom for R 7 for example, a methoxy group, an ethoxy group, a propoxy group and the like are suitable.
  • R 7 a lower alkoxy group which may be substituted with the above-mentioned fluorine atom having an aromatic carbon or a heterocyclic group as a substituent at any substitutable position is preferable.
  • R 7 is, for example, methylamino, dimethylamino, benzylamino, benzyl (methyl) amino, cyclopropylamino, cyclohexylamino, methoxy, benzyloxy, 2-pyridylmethylamino, 3 —Pyridylmethylamino group, 4-pyridylmethylamino group, 2-pyridylmethyloxy group, 3-pyridylmethyloxy group, 4-pyridylmethyloxy group and the like, among which methylamino group, methoxy group and benzyloxy group , 3- Pyridylmethyloxy group and the like are preferred.
  • Examples of the substituent for R 4 include an amino group, a lower alkylsulfonylamino group, an aminosulfonylamino group, a (lower alkylamino) sulfonylamino group, a (di-loweralkylamino) sulfonylamino group, a carbamoylamino group, and a alkyl force Rubamoiru) amino group, (di-lower alkyl force Rubamoiru) amino group, a hydroxyl group, low class alkoxycarbonyl group, such as a group represented by one R 7, more preferably amino group, a lower alkylsulfonyl ⁇ amino group, aminosulfonyl amino groups, force Rubamoirua amino group, a hydroxyl group, and a group represented by one R 7 is preferred.
  • the lower alkyl group for R 4 for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group and the like are preferable.
  • R 4 is, for example, a methyl group, an ethyl group, an aminomethyl group, a 1-aminoethyl group, a 2-aminoethyl group, a 3-aminobutyryl group, a methylaminomethyl group, a 1-methylaminoethyl group, Methylaminoethyl, dimethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, cyclopropylaminomethyl, (methylsulfonylamino ) Methyl group, 2- (methylsulfonylamino) ethyl group, (aminosulfonylamino) methyl group, 2- (aminosulfonylamino) ethyl group, [(dimethylaminosulfonyl) amino] methyl group, 2- [(dimethylaminos
  • n represents an integer of 0 to 3;
  • R 5 represents a hydrogen atom or a lower alkyl group, or an oxygen atom or Or a nitrogen-containing heterocyclic group which may contain a sulfur atom, comprising a group represented by N (R 8 ) R 9 , a hydroxyl group and a lower alkoxy group which may be substituted by a fluorine atom
  • a nitrogen-containing heterocyclic group which may be a substituent selected from the group consisting of a group represented by 1 N (R 8 ) R 9 , a hydroxyl group and a lower alkoxy group which may be substituted with a fluorine atom.
  • R 6 represents a hydrogen atom or a lower alkyl group, or Together
  • R 5 for example, a methyl group, an ethyl group and the like are suitable.
  • a group optionally having a substituent selected from the group consisting of lower alkoxy groups '' The unsubstituted nitrogen-containing heterocyclic group optionally containing an oxygen atom or a sulfur atom, or the unsubstituted nitrogen-containing heterocyclic group optionally having a substituent at any substitutable position, which may contain an oxygen atom or a sulfur atom;
  • the lower alkoxy group which may be substituted with a fluorine atom for the substituent, for example, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and the like are suitable.
  • R 8 and R 9 are the same or different and each represent a hydrogen atom or a lower alkyl group.
  • R 8 and R 9 are the same or different and are preferably a hydrogen atom, a methyl group, an ethyl group, or the like.
  • the group represented by —N (R 8 ) R 9 includes, for example, an amino group, a methylamino group, a dimethylamino group, a dimethylamino group and the like, and among them, an amino group, a methylamino group, a dimethylamino group and the like are preferable. .
  • nitrogen-containing heterocyclic group optionally containing an oxygen atom or a sulfur atom for example, 3-pyrrolidinyl group, 1-piperidyl group, 3-piperidyl group, 4-piperidyl group, 3-pyridyl group and the like are preferable. It is.
  • the nitrogen-containing heterocyclic group which may contain an oxygen atom or a sulfur atom represented by R 5 and which may have the substituent is, for example, a monopyrrolidinyl group or a 2-pyrrolidinyl group , 3-pyrrolidinyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, etc.
  • 3-pyrrolidinyl group, 11-piridyl group, 3-piridyl group, 4-piperidyl group, 3-pyridyl group and the like are preferable.
  • lower alkyl group of the “lower alkyl group having the group” for R 5 for example, a methyl group, an ethyl group and the like are suitable.
  • the “lower alkyl group having the group” for R 5 includes, for example, 3-pyrrolidinylmethyl group, 1-piperidylmethyl group, 3-piperidylmethyl group, 4- Examples thereof include a piperidylmethyl group and a 3-pyridylmethyl group, and among them, a 4-piberidylmethyl group and the like are preferable.
  • R 5 and R s together form a ⁇ nitrogen-containing heterocyclic group which may contain an oxygen atom or a sulfur atom together with an adjacent nitrogen atom, and which is represented by N (R) R 9 A group which may have a substituent selected from the group consisting of a group to be substituted, a hydroxyl group and a lower alkoxy group which may be substituted by a fluorine atom.
  • N (R) R 9 A group which may have a substituent selected from the group consisting of a group to be substituted, a hydroxyl group and a lower alkoxy group which may be substituted by a fluorine atom.
  • '' A nitrogen-containing heterocyclic group which may contain an atom or a sulfur atom, or a nitrogen-containing heterocyclic group which may contain an oxygen atom or a sulfur atom together with the adjacent nitrogen atom having a substituent at any substitutable position.
  • a substituent represented by 1 or 2 (R 8 ) R 9 a hydroxyl group and
  • N (R 8 ) R 9 is the substituent represented by —N (R 3 ) of the above-mentioned “nitrogen-containing heterocyclic group optionally containing an oxygen atom or a sulfur atom”.
  • R 9 can be exemplified, and among them, an amino group, a methylamino group, a dimethylamino group and the like are preferable.
  • the lower alkoxy group which may be substituted with a fluorine atom for the substituent, for example, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and the like are suitable.
  • Examples of the ⁇ nitrogen-containing heterocyclic group which may contain an oxygen atom or a sulfur atom together with an adjacent nitrogen atom '' include, for example, 1-pyrrolidinyl group, 1-piperidyl group, 1-piperazinyl group, and 4-morpholinyl group. It is.
  • a nitrogen-containing heterocyclic group which may contain an oxygen atom or a sulfur atom together with an adjacent nitrogen atom and is formed by R 5 and R 6 together, and may have the substituent
  • the group include 1-pyrrolidinyl group, 1-piperidyl group, 1-piperazinyl group, 41-morpholinyl group, 3-dimethylaminopyrrolidine-1-yl group, 3-hydroxypyrrolidine-1-yl group, and 3-hydroxypiberyl.
  • Examples thereof include a di-nitro group, a 4-hydroxypiperidine-1-yl group, and among them, a 1-pyrrolidinyl group, a 1-piperidyl group, a 1-piperazinyl group, and a 4-morpholini group.
  • R * 3 for example, a methyl group, an ethyl group and the like are preferable.
  • R 5 is a nitrogen-containing heterocyclic group which may contain an oxygen atom or a sulfur atom and means a group which may have the substituent
  • R 13 may be, for example, a hydrogen atom or the like. Is preferred.
  • the group represented by 1 (CH 2 ) n CON (R 5 ) R 6 includes, for example, rubamoyl, methylcarbamoyl, dimethylcarbamoyl, getylcarbamoyl, ethylmethylcarbamoyl, and 1-pyrrolidinyl.
  • Rucarbamoyl group 2-pyrrolidinylcarbamoyl group, 3-pyrrolidinylcarbamoyl group, 1-pyridylcarbamoyl group, 2-piberidylcarbamoyl group, 3-piberidylcarbamoyl group, 4-piberidylcarbamoyl group, 2-pyridyl Carbamoyl group, 3-pyridylcarbamoyl group, 4-pyridylcarbamoyl group, 2-thiazolylcarbamoyl group, carbamoylmethyl group, methylcarbamoylmethyl group, dimethylcarbamoylmethyl group, (3-pyrrolidinylcarbamoyl) methyl group, (1-piperidylcarbamoyl) ) Group, (3-piberidylcarbamoyl) methyl group, (4-piberidylcarbamoyl) methyl
  • a lower alkenyl group, a lower alkoxycarbonyl group, a group represented by R 4 , and a group represented by 1 (CHJ n CON (R 5 ) R 6 ) are preferable.
  • the monocyclic aliphatic nitrogen-containing heterocyclic group having 3 to 9 carbon atoms a group formed from a piperidyl ring or the like is preferable, in which case, the adjacent 4-position carbon atom of 4-imidazolidinone skeleton Compounds in which an atom is shared as a ring carbon atom at the 4-position of the piperidine ring to form a spiro ring group are preferred.
  • Examples thereof include a 1-pyrrolidinyl-3-ylidene group, a 1-piperidyl-13-ylidene group, a 1-pyberylidene 4-ylidene group, a 1-perhydroazepinyl-4-ylidene group, and a 3-vinyl-1-piberidylyl 4-ylidene group , 3-Amino-1-pibelidyl-4f-ylidene group, 3-Carboxy-1-piperidyl-4-ylidene group, 2-Ethoxycarbonyl_1-Piberidylou 4--1-ylidene group, 3-Ethoxycarbonylone 1-Piberidylou 4-ylidene group, 2,3-bis (ethoxycarbonyl) -1-piperidyl 4-ylidene group, 3-capillumyl-1-piperidyl—4-ylidene group, 2-methyl_1-piveridyl 4-1-ylidene group, 3-methyl-1-piperid
  • R 1 is a hydrogen atom, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group which may be substituted with a fluorine atom, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkyl rubamoyl group, a di-lower group Alkylcarbamoyl group, lower alkylsulfonyl group, aminosulfonyl group, lower alkylaminosulfonyl group or di-lower alkylaminosulfonyl group, or halogen atom, cyclo-lower alkyl group, amino group, lower alkylamino group, A lower alkylamino group, a cyclo lower alkylamino group, a lower alkylsulfonylamino group, an aminosulfonylamino group, a (lower alkylamino)
  • cyclo lower alkyl group for R 1 for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and the like are preferable.
  • lower alkenyl group for R 1 for example, a vinyl group, a 1-propenyl group, a 2-propenyl group and the like are preferable.
  • Preferable examples of the lower alkynyl group for R 1 include an ethynyl group and a 2-propynyl group.
  • Examples of the lower alkoxy group optionally substituted with a fluorine atom for R 1 include a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, and a difluorometho group.
  • Xyl groups, trifluoromethoxy groups and the like are preferred.
  • R 1 for example, a methoxycarbonyl group, an ethoxycarbonyl group and the like are suitable.
  • the lower alkyl group rubamoyl group for R 1 for example, a methylcarbamoyl group, an ethylcarbamoyl group and the like are preferable.
  • di-lower alkyl rubamoyl group for R 1 for example, a dimethylcarbamoyl group, a getylcarbamoyl group and the like are preferable.
  • the lower alkylsulfonyl group for R 1 for example, a methylsulfonyl group, an ethylsulfonyl group and the like are preferable.
  • the lower alkylaminosulfonyl groups of R 1, for example, methylaminosulfonyl group, E chill aminosulfonyl group and the like.
  • di-lower alkylaminosulfonyl group for R 1 for example, a dimethylaminosulfonyl group, a getylaminosulfonyl group and the like are preferable.
  • Halogen atom cyclo lower alkyl group, amino group, lower alkyl amino group, di lower alkyl amino group, cyclo lower alkyl amino group, lower alkyl sulfonyl amino group, amino sulfonylamino group, (lower alkyl amino) sulfonylamino group, (Di-lower alkylamino) sulfonylamino group, rubamoylamino group, (lower alkyl rubamoyl) amino group, (di-lower alkyl rubamoyl) amino group, hydroxyl group, lower alkoxy group optionally substituted by fluorine atom, carbamo From the group consisting of yloxy, lower alkyl rubamoyloxy, di-lower alkyl rubamoyloxy, carboxyl, lower alkoxycarbonyl, sorbamoyl, lower alkyl rubamoyl and di-lower alkyl rubamoyl
  • lower alkyl group optionally having substituent (s) selected means the unsubstituted lower alkyl group or the lower alkyl group having a substituent at any substitutable position, wherein the substituent is Halogen atom, cyclo lower alkyl group, amino group, lower alkyl amino group, di lower alkyl amino group, cyclo lower alkyl amino group, lower alkylsulfonylamino group, aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (Di-lower alkylamino) sulfonylamino, rubamoyl lumino, (lower alkyl rubamoyl) amino, (di-lower alkyl) Moyl) amino group, hydroxyl group, lower alkoxy group optionally substituted by fluorine atom, carbamoyloxy group, lower alkyl rubamoyloxy group, di-lower alkylcarb
  • the halogen atom for the substituent is, for example, preferably a fluorine atom.
  • the cyclo lower alkyl group for the substituent is, for example, preferably a cyclopropyl group, a cyclobutyl group.
  • the lower alkylamino group for the substituent for example, a methylamino group, an ethylamino group and the like are preferable.
  • di-lower alkylamino group for the substituent for example, a dimethylamino group, a methylamino group and the like are preferable.
  • cyclo lower alkylamino group for the substituent for example, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group and the like are preferable.
  • the lower alkylsulfonylamino group for the substituent is, for example, preferably a methylsulfonylamino group, an ethylsulfonylamino group.
  • the (lower alkylamino) sulfonylamino group for the substituent for example, a (methylamino) sulfonylamino group, a (ethylamino) sulfonylamino group and the like are preferable.
  • the (di-lower alkylamino) sulfonylamino group for the substituent for example, a (dimethylamino) sulfonylamino group, a (getylamino) sulfonylamino group and the like are preferable.
  • the (lower alkyl rubamoyl) amino group for the substituent for example, a (methyl rubamoyl) amino group, a (ethylcarbamoyl) amino group and the like are preferable.
  • a (di-lower alkyl rubamoyl) amino group for the substituent for example, a (dimethylmethylcarbamoyl) amino group, a (dielpylcarbamoyl) amino group and the like are preferable.
  • Examples of the lower alkoxy group which may be substituted with a fluorine atom of the substituent include: For example, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and the like are preferable.
  • the lower alkyl group of the substituent preferred are, for example, a methylcarbamoyloxy group and an ethylcarbamoyloxy group.
  • di-lower alkyl group of the substituent a dimethylcarbamoyloxy group, a getylcarbamoyloxy group, and the like are preferable as long as it is clear.
  • the lower alkoxycarbonyl group for the substituent is, for example, preferably a methoxycarbonyl group, an ethoxycarbonyl group.
  • the lower alkyl group rubamoyl group for the substituent for example, a methylcarbamoyl group, an ethylcarbamoyl group and the like are preferable.
  • di-lower alkyl group of the substituent for example, a dimethylcarbamoyl group, a getylcarbamoyl group and the like are preferable.
  • Examples of the substituent for the lower alkyl group represented by R 1 include a halogen atom, a cyclo lower alkyl group, an amino group, a lower alkyl amino group, a di-lower alkyl amino group, a lower alkyl sulfonyl amino group, an amino sulfonyl amino group, (Lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, carbamoylamino group, hydroxyl group, lower alkoxy group which may be substituted by a fluorine atom, carboxyl group and the like are preferable.
  • the lower alkyl group for R 1 for example, a methyl group, an ethyl group, a propyl group and the like are suitable.
  • the lower alkyl group which may have the substituent of R 1 includes, for example, methyl group, ethyl group, propyl group, isopropyl group, isobutyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2 , 2,2-Trifluoroethyl group, cyclopropylmethyl group, 2-aminoethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2-getylaminoethyl group, 2- (cyclopropylamino) Ethyl group, 2- (methylsulfonylamino) ethyl group, 2- (aminosulfonylamino) ethyl group, 2-[(dimethylaminosulfonyl) amino] ethyl group, 2- (pothamamoylamino) ethyl group, 2- Hydroxyethyl, 3-hydroxypropyl, 2-flu
  • R 1 is, for example, a hydrogen atom, a lower alkylsulfonyl group, a halogen atom, a cyclo-lower alkyl group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a cyclo-lower alkylamino group, a lower alkylsulfonylamino group , Aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, carbamoylamino group, (lower alkylcarbamoyl) amino group, (di-lower alkyl rubamoyl) amino group, Hydroxyl group, lower alkoxy group optionally substituted by fluorine atom, carbamoyloxy group, lower alkyl rubamoyloxy group, di-lower alkyl rub
  • R 1 is, for example, a hydrogen atom, a 2-propenyl group, a 2-propynyl group, a cyclobutyl group, a cyclopentyl group, a dimethylamino group, a hydroxyl group, a methoxy group, a trifluoromethoxy group, an ethoxycarbonyl group, Methylsulfonyl, ethylsulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, methyl, ethyl, propyl, isopropyl, isobutyl, 2-fluoroethyl, 2,2-difluoroethyl Group, 2,2,2-trifluoroethyl group, cyclopropylmethyl group, 2-aminoethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2-di
  • hydrogen atom hydrogen atom, methylsulfonyl group, ethylsulfonyl group, methyl group, ethyl group, propyl group, 2-fluoroethyl group, 2,2 —Difluoroethyl group, cyclopropylmethyl group, 2-aminoethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2- (potamoylamino) ethyl group, 2-hydroxyethyl group and the like are preferable.
  • R 2 represents a hydrogen atom or a lower alkyl group.
  • R 2 for example, a hydrogen atom, a methyl group, an ethyl group, a propyl group, etc., more preferably a hydrogen atom, a methyl group, etc. are preferred.
  • X represents a hydrogen atom, a halogen atom, a lower alkyl, a trifluoromethyl group or a lower alkoxy group which may be substituted by a fluorine atom, and is the same or different on the phenyl group, one or more, preferably one or more, Or there can be two.
  • halogen atom for X for example, a fluorine atom, a chlorine atom and the like are preferable.
  • lower alkyl for X for example, a methyl group, an ethyl group, a propyl group and the like are preferable.
  • the lower alkoxy group which may be substituted with a fluorine atom for X for example, a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and the like are preferable.
  • X is preferably, for example, a hydrogen atom, a halogen atom or the like.
  • the compound of the present invention represented by the general formula [I] can be produced, for example, by the method shown in the following Production Method 1, 2 or 3.
  • R lp is a protecting group for an amino group, a hydrogen atom, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group which may be substituted with a fluorine atom, a lower alkoxy group Carbonyl group, di-lower alkyl group rubamoyl group, lower alkylsulfonyl group or di-lower alkylaminosulfonyl group, or optionally protected Lower alkyl group means a rubamoyl group, an aminosulfonyl group or a lower alkylaminosulfonyl group, or a lower alkoxy group which may be substituted by a halogen atom, a cyclo-lower alkyl group, a di-lower alkylamino group, or a fluorine atom Di-lower alkyl rubamoyloxy group, lower alkoxycarbonyl group and di-
  • Cy p represents a halogen atom, cyclo-lower alkyl group, a lower alkylidene group, a lower alkenyl group, lower alkynyl group, a di-lower alkylamino group, a lower alkoxy group which may be substituted by fluorine atoms and - in R 3 Represented groups as well as protected A 1, 2 or tricyclic aliphatic carbocyclic group having 6 to 15 carbon atoms which may have a substituent selected from the group consisting of an amino group and a lower alkylamino group; L 1 represents a leaving group, and R 2 and R 3 have the above-mentioned meanings], and a compound represented by the general formula [IV]
  • R lp , R 2 and X have the same meaning as described above], and the compound represented by the general formula [I] can be obtained by removing a protecting group as necessary.
  • Examples of the leaving group represented by L 1 include a chlorine atom, a halogen atom such as a bromine atom or an iodine atom, an organic sulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group, and a benzenesulfonyl group, or a methanesulfonyloxy group.
  • Examples thereof include organic sulfonyloxy groups such as trifluoromethansulfonyloxy group and p-toluenesulfonyloxy group.
  • the amino group, the hydroxyl group, and the carboxyl group may be appropriately substituted with an amino-protecting group, a hydroxyl-protecting group, or It is preferable to carry out the reaction after protecting the group with a protecting group, and to remove the protecting group after the reaction.
  • amino-protecting group examples include benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzylhydryl, and trityl groups.
  • a lower alkanol group such as a formyl group, an acetyl group, a propionyl group, a butyryl group or a bivaloyl group; an alkenyl group such as a benzoyl group; an aryl group such as a phenylacetyl group or a phenoxyacetyl group; Lucanyl group; for example, lower alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, tert-butoxycarbonyl group; for example, benzyloxycarbonyl group, p-ditrobenzyloxycarbonyl group, phenylene
  • An aralkyloxycarbonyl group such as a carbonyl group; a lower alkylsilyl group such as a trimethylsilyl group and a tert-butyldimethylsilyl group; a phthaloyl group; a benz
  • hydroxyl-protecting group examples include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; lower alkoxymethyl groups such as methoxymethyl group and 2-methoxymethoxylmethyl group; tetrahydroviranyl group such as trimethylsilyl Ethoxymethyl group; for example, benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, aralkyl group such as trityl group; for example, formyl group, acetyl And methoxymethyl group, tetrahydroviranyl group, trityl group, trimethylsilylethoxymethyl group, tert-butyldimethylsilyl group, and acetyl group.
  • lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethyl
  • Examples of the carboxyl-protecting group include: lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group; lower haloalkyl groups such as 2,2,2-trichloromethyl group; —Lower alkenyl groups such as propenyl group; and aralkyl groups such as benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group and trityl group, and especially methyl group, Preferred are an ethyl group, a tert-butyl group, a 2-propenyl group, a benzyl group, a p-methoxybenzyl group, a benzhydryl group and the like.
  • lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group
  • the reaction between the compound represented by the general formula [II] and the compound represented by the general formula [III] is carried out by using an equimolar amount of both the compound [II] and the compound [III] or a slight excess of either one.
  • the reaction is usually performed in an inert solvent that does not adversely influence the reaction.
  • the inert solvent include solvents such as tetrahydrofuran and dioxane.
  • Preferred are halogenated hydrocarbons such as methylene chloride and chloroform, and non-porous polar solvents such as dimethylformamide, N, N-dimethylacetamide and acetonitrile.
  • the above reaction is preferably carried out in the presence of a base.
  • a base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminoviridine, and lithium diisopropylamide, and, for example, sodium hydride.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminoviridine, and lithium diisopropylamide
  • sodium hydride inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate are preferred.
  • the amount of the base to be used is 1 mol to excess mol, preferably 1 to 2 mol, per 1 mol of the compound represented by the general formula [II].
  • the reaction temperature is usually from -78: to 150, preferably from room temperature to 120 ° C.
  • the reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.
  • a usual treatment is performed to obtain a crude product of the compound represented by the general formula [IV].
  • the thus-obtained compound represented by the general formula [IV] is purified according to a conventional method, or without purification, where necessary, removal of protecting groups for amino group, hydroxyl group and carboxyl group.
  • the compound of the general formula [I] can be produced by appropriately combining the reactions.
  • the method for removing the protecting group varies depending on the type of the protecting group and the stability of the target compound [I].
  • the method described in the literature [Protective Grooves in Organic Synthesis (Protective Group O) rg anic Synthesis), TW Greene (John Wiley & Sons, Inc. (1981)) or a method analogous thereto, for example, solvolysis using an acid or a base.
  • R lp and X have the above-mentioned meaning] and a compound represented by the general formula [V]
  • R 1 p and X have the above-mentioned meanings], and after reducing the compound [VI] and removing the protecting group as necessary, the compound represented by the general formula [I-11] [1-1]
  • R 1 and X have the above-mentioned meanings].
  • Production method 2 is a method for producing a compound of the present invention represented by the general formula [I], wherein R 2 in the formula is a hydrogen atom, that is, a compound represented by the general formula [1-1]. is there.
  • the reaction of the compound represented by the general formula [II] with the compound represented by the general formula [V] is usually carried out using equimolar amounts of both or a slight excess of either one.
  • the reaction is usually carried out in an inert solvent.
  • the inert solvent include alcohols such as methanol, ethanol and propanol; ethers such as ethyl ether, tetrahydrofuran and dioxane; methylene chloride, chloroform and the like.
  • Halogenated hydrocarbons such as benzene, dichloroethane, etc .
  • Aromatic hydrocarbons such as benzene, toluene, chloroform, xylene, etc .
  • Non-protons such as dimethylformamide, ethyl acetate, acetonitrile, hexamethylphosphate triamide
  • a polar solvent, a mixed solvent thereof and the like can be mentioned.
  • the reaction temperature is usually from 0 to the boiling point of the solvent used in the reaction, preferably from room temperature to 100.
  • the reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the reaction solution is used as it is in the reduction reaction of the next step, or the reaction solution is distilled off, or the compound represented by the general formula [VI] is isolated using a usual separation means. And can be subjected to the subsequent reduction reaction.
  • the reduction reaction includes, for example, lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, hydride
  • the reaction can be carried out by using a metal hydride complex such as lithium aluminum or the like, or by catalytic reduction using, for example, a palladium carbon catalyst or a Raney nickel catalyst.
  • a metal hydride complex such as lithium aluminum or the like
  • a palladium carbon catalyst or a Raney nickel catalyst a reducing agent that preferentially reduces imine, such as sodium cyanoborohydride or sodium triacetoxyborohydride
  • the compound represented by the general formula [VI] should be subjected to the reduction reaction without isolation. Can be.
  • the amount of the reducing agent to be used is generally 1 mol to excess mol, preferably 1 to 5 mol, per 1 mol of the imine.
  • a solvent may be appropriately used, for example, alcohols such as methanol and ethanol; for example, dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, and tetrahydrofuran.
  • Ethers such as diglyme; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; An inert solvent such as aromatic hydrocarbons such as toluene or a mixed solvent thereof can be used.
  • halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane
  • An inert solvent such as aromatic hydrocarbons such as toluene or a mixed solvent thereof can be used.
  • the reaction temperature is usually from 20 ° C to 100 t, preferably from 0 ° C to room temperature.
  • the reaction time is generally 5 minutes to 7 days, preferably 1 hour to 6 hours.
  • the hydrogen pressure in the catalytic reduction reaction is preferably from normal pressure to 5 atm.
  • the amount of the catalyst used is usually 1/100 to 1 times the weight 1 of the raw material compound [VI]. Preferably 1Z100 or more: LZ10 times the amount.
  • the product After the reaction, if the product has a protecting group, if the protecting group is removed, or if the product does not have a protecting group, the product is subjected to a usual treatment to obtain a compound of the general formula [I-11]. Can be manufactured.
  • R 2 and X have the above-mentioned meanings] and a compound represented by the general formula [VII]:
  • R lap is a cyclo lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxycarbonyl group, a di-lower alkyl group, a lower alkyl sulfonyl group, a lower alkyl sulfonyl group or a di-lower alkylamino sulfonyl group, or may be protected.
  • R lap , R 2 and X have the above-mentioned meanings], and a protecting group is removed as necessary to obtain a compound of the general formula [I 1]
  • R 1 a is a lower cycloalkyl group, a lower alkenyl group, lower alkynyl group, a lower alkoxycarbonyl group, a force Rubamoiru group, a lower alkyl force Rubamoiru group, a di-lower alkyl force Rubamoiru group, lower alkylsulfonyl group, aminosulfonyl Group, lower alkylaminosulfonyl group or di-lower alkylaminosulfonyl group, or halogen atom, cyclo-lower alkyl group, amino group, lower alkylamino group, di-lower alkylamino group, cyclo-lower alkylamino group, lower alkyl Sulfonylamino group, aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group
  • R 1 is a cyclic lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxycarbonyl group, a carbamoyl group
  • Lower alkyl group means rubamoyl group, di-lower alkylcarbamoyl group, lower alkylsulfonyl group, aminosulfonyl group, lower alkylaminosulfonyl group or di-lower alkylaminosulfonyl group, or halogen atom, cyclo-lower alkyl group, amino Group, lower alkylamino group, di lower alkylamino group, cyclo lower alkylamino group, lower alkylsulfonylamino group, aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (dilower alkylamin
  • the leaving group represented by L 2 the same leaving group and the L 1.
  • the reaction between the compound represented by the general formula [IV-1] and the compound represented by the general formula [VII] is performed by reacting the compound represented by the general formula [II] and the compound represented by the general formula [III] in the above-mentioned production method 1.
  • the reaction can be carried out according to the reaction with the represented compound.
  • the product After completion of the reaction, if the product has a protecting group, after removing the protecting group, or if the product does not have a protecting group, the product is subjected to a usual treatment, and the compound of general formula [I-12] Can be manufactured. ⁇
  • the compound of general formula [I] or [1-2] obtained by the above method is isolated and purified by, for example, column chromatography using silica gel, an adsorption resin, etc., liquid chromatography, solvent extraction or recrystallization. ⁇ It can be achieved by using conventional separation means such as reprecipitation alone or in an appropriate combination.
  • the compound of the general formula [I] or [1-2] can be converted into a pharmaceutically acceptable salt or ester by a conventional method, and conversely, the conversion of a salt or ester into a free compound is also performed by a conventional method. Can be.
  • P 1 represents a protecting group for an amino group
  • R lbp represents a protecting group for an amino group, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxycarbonyl group, a di-lower alkyl group.
  • Lower alkyl group means a rubamoyl group, an aminosulfonyl group or a lower alkylaminosulfonyl group, or a halogen atom, a cyclo-lower alkyl group, a di-lower alkylamino group, a lower alkoxy group which may be substituted by a fluorine atom, A lower alkyl group such as a rubamoyloxy group, a lower alkoxycarbonyl group and a di-lower alkylcarbamoyl group, and an optionally protected amino group, lower alkylamino group, cyclo lower alkylamino group, lower alkylsulfonylamino group, aminosulfonylamino group, (Lower alkylamino) sulfonylamino
  • This production method is a method for producing a compound represented by the general formula [II-11] or [II-12].
  • the compound represented by the general formula _ is allowed to act on the compound represented by the general formula ⁇ ⁇ to produce the compound represented by the general formula __.
  • the compound! _ The amino Formula protecting group P 1 is removed the group [II one 1] or to produce a compound represented, or (2) the formula to the compound!
  • the protective group P 1 of Amino group protecting groups Amino groups described in the above Production Process 1 can be mentioned up.
  • the process for producing a compound from compound I is usually performed using benzene, toluene, xylene, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethylformamide, N, N-dimethylacetamide, methanol, ethanol, acetonitrile, etc.
  • the reaction can be carried out by reacting the compound with the compound in an inert solvent.
  • the amount of the compound to be used is 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound I.
  • the reaction temperature is usually preferably from 0 to 150, and the reaction time is usually preferably from 10 minutes to 24 hours.
  • the above reaction can be carried out in the presence of an acid, if necessary.
  • the acid include hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, 2-naphthylenesulfonic acid, pyridinium paratoluenesulfonic acid, acetic acid and the like. Is preferred.
  • the step of producing a compound from compound A can be carried out in the same manner as the step of reacting the compound represented by the general formula [IV-1] with the compound represented by the general formula [VII] in the above-mentioned production method 3. Therefore, similar conditions can be applied to the reaction conditions and the like.
  • the a method described in Production Process 1 can be adapted as it is, there are protecting groups ⁇ Mi amino group other than P 1 is especially in the compound case, it is preferable to selectively remove protecting groups Amino groups represented by P 1. Selective removal of the protecting group of Amino groups is carried out take advantage of the difference in stability to acid, base or reduction or the like and the protective group of the protected groups and other amino group represented by P 1.
  • the compound represented by the general formula (1) or (2) can be produced by using a commercially available product, or by appropriately combining a known method or a method described in Reference Examples or a method analogous thereto as needed.
  • the cDNA encoding the human nociceptin receptor gene was incorporated into an expression vector pCR3 (InV itrogen) to prepare pCR3 protein RL1.
  • pCR3ZORL1 was introduced into CH0 cells using transfectam (Nippon gene) to obtain a stable expression strain (CHOZORL1 cells) resistant to lmg / ml G418.
  • a membrane fraction was prepared from this stable expression strain, and a receptor binding experiment was performed.
  • the antagonism of nociceptin-induced G protein activation was expressed as the 50% inhibitory concentration (IC 5 value) of GT Pr C 35 S] binding by various concentrations of the compounds of the present invention. The results are shown in Table 2. This indicates that the compound of the present invention has an antagonistic effect on G protein activation by nociceptin. Table 2 Antagonism of nociceptin-induced G protein activation
  • Example-127 Based on the above results, it was found that the compound of the present invention is nociceptin receptor OR L 1
  • morphine an analgesic for painful diseases such as cancer pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain, and neuralgia.
  • Drugs for overcoming narcotic analgesic resistance drugs for overcoming dependence on narcotic analgesics such as morphine, analgesics, anti-obesity drugs, brain function improvers, Alzheimer's disease drugs, anti-dementia drugs, schizophrenia It is useful as a remedy for Parkinson's disease, a drug for the treatment of chorea, an antidepressant, a drug for diabetes insipidus, a drug for polyuria, or a drug for hypotension.
  • the compound represented by the general formula [I] can be administered orally or parenterally, and when formulated into a form suitable for such administration, a narcotic analgesic represented by an analgesic, morphine Overcoming drug resistance, Overcoming drugs such as morphine, Overcoming drugs of analgesic dependence, Analgesic enhancer, Antiobesity, Brain function improver, Alzheimer's disease, Antidementia, Schizophrenia, Parkinson's disease It can be used as a remedy, chorea drug, antidepressant, diabetes insipidus, polyuria or hypotension.
  • the compound of the present invention can be administered after formulating various preparations by adding pharmaceutically acceptable excipients according to the dosage form.
  • additives for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch.
  • Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders and suppositories; or liquids such as syrups, elixirs and injections Preparations and the like can be mentioned, and these can be prepared according to a usual method in the field of preparations.
  • liquid preparations they may be in the form of being dissolved or suspended in water or another appropriate medium before use.
  • it can be dissolved or suspended in physiological saline or glucose solution as necessary.
  • a buffer or a preservative may be added.
  • formulations may contain the compounds of the present invention in a proportion of 1.0 to 100%, preferably 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.
  • An analgesic a drug for overcoming narcotic analgesic resistance represented by morphine, a drug for overcoming narcotic analgesic dependence, represented by morphine, an analgesic potentiator, an antiobesity agent, a brain function improving agent, Used as Alzheimer's disease drug, anti-dementia drug, schizophrenia drug, Parkinson's disease drug, chorea drug, antidepressant drug, diabetes insipidus drug, polyuria drug or hypotension drug In such cases, the dose and frequency of administration vary depending on the patient's sex, age, weight, degree of symptoms, and the type and range of the intended therapeutic effect.
  • a catalyst amount of p-toluenesulfonic acid was added to a suspension of 16 mg of anilinoacetamide and 215 mg of 1-benzyl-1-piperidone in 2 Om1 of toluene, and refluxed for 5 hours. After concentrating the solvent, dilute the residue with a chloroform solution, wash with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dry over anhydrous sodium sulfate.
  • C-200 manufactured by Wako Pure Chemical Industries
  • Hexane Z: ethyl acetate 1Z1) I got
  • Example 2 was repeated using 1-phenyl-1,4,8-triazaspiro [4.5] decane-3-one obtained in Example 1 and bicyclo [3.2.1] octane-12-carbaldehyde. The title compound was obtained in a similar manner.
  • Example 2 To a suspension of 16 mg of sodium hydride in 3 ml of dimethylformamide was added, under ice-cooling, the 8-cyclooctylmethyl-1-phenyl-1,4,8-triazaspiro obtained in Example 1 [4.5. A solution of 7 lmg of decane-3-one in 1 ml of dimethylformamide lm1 was added. After stirring at room temperature for 30 minutes, 0.125 ml of methyl iodide was added, and the mixture was stirred at room temperature for 2 hours.
  • camphorsulfonic acid 12 mg was added to a suspension of 59 mg of anilinoacetamide and 72 mg of 1-benzyloxycarbonyl 3-pyrrolidinone in 30 ml of toluene, and the mixture was refluxed for 13 hours.
  • the solvent was concentrated, diluted with ethyl acetate, washed with a 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was separated by preparative thin-layer chromatography ( Kieselgel TM 60 F 2 54.
  • the reaction mixture was diluted with ethyl acetate, washed with a 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the reaction solution was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated saline, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off, and the obtained residue was dissolved in 20 ml of dimethylformamide. 0.80 g of sodium azide was added, and the mixture was stirred at 10 Ot: for 21 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate.
  • reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Kieselgel TM 60 F 254 , Art 5 744 (Merck); Hexane / ethyl acetate 1/1), and purified by purification. 8-benzyloxycarbone 2-1-1-fluoro-6-trifluoro There was obtained 18 mg of roacetylaminomethyl-1,4,8-triazaspiro [4.5] decane-3-one.
  • decane-1-one 18 mg was dissolved in 2 ml of methanol and 2 5 mg of 0% palladium hydroxide carbon was added, and the mixture was stirred under a hydrogen atmosphere at normal pressure and room temperature for 1 hour. After the reaction solution was filtered using celite, the solvent was distilled off. The obtained residue was dissolved in tetrahydrofuran lm1, and 1 mg of carbaldehyde and 12 mg of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour.
  • reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the reaction mixture was diluted with ethyl acetate, washed with a 1N aqueous sodium hydroxide solution and saturated saline, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane Z). Separation and purification were performed using ethyl acetate (9Z1) to obtain 15-mg of 3- (3-tert-butyldimethylsilyloxypropyl) -11-cyclooctylmethyl-1-piperidone.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • decane-3-one 118 mg dissolved in methanol 3m1, 20% palladium hydroxide 1 Omg of carbon was added, and the mixture was stirred under a hydrogen atmosphere at normal pressure and room temperature for 19 hours. After the reaction solution was filtered using celite, the solvent was distilled off. The obtained residue was dissolved in 3 ml of tetrahydrofuran, 34 mg of cyclooctanecarbaldehyde and 74 mg of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 7 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated saline, and dried over anhydrous magnesium sulfate.
  • 6-azidomethyl-8-benzyloxycarbonyl-1,4-dioxa-18-azaspiro [4.5] decane obtained in Example 20 1.03 g of tetrahydrofuran in 50 ml of a 50 ml solution of water and 5 ml of triphenylphosphine were added. 90 g was added and the mixture was refluxed for 2 hours. The reaction solution was concentrated, and the obtained residue was dissolved in chloroform (2Om1) .Triethylamine (0.6 lm1) and methanesulfonyl chloride (0.27 ml) were added under ice-cooling, followed by stirring at room temperature for 20 minutes. .
  • reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated saline, and dried over anhydrous magnesium sulfate.
  • the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was separated by preparative thin-layer chromatography (Kiese). 1 ge 1 ⁇ 1 Separation and purification using 60 F 2S , Art 5744 (manufactured by Merck); ethyl acetate) gave 8 mg of the title compound.
  • Example 2 The same procedure as in Example 2 was carried out using 1.1-fluoro-1,4-triazaspiro [4.5] decane-3-one and 3-methylcyclohexanecarbaldehyde obtained in Example 1. The title compound was obtained.
  • Example 3 The same as in Example 3 using 1-phenyl-1,4,8-triazaspiro [4.5] decane-3-one obtained in Example 1 and (4-methylcyclohexyl) methylmethanesulfonate The title compound was obtained by the method.
  • the compound of the present invention specifically inhibits the binding of nociceptin to nocicebutin receptor ⁇ RL1, painful diseases such as cancer pain, postoperative pain, headache, gout, chronic rheumatism, chronic pain, and neuralgia
  • painful diseases such as cancer pain, postoperative pain, headache, gout, chronic rheumatism, chronic pain, and neuralgia
  • drugs for overcoming narcotic analgesic resistance such as morphine
  • drugs for overcoming narcotic analgesic dependence such as morphine
  • analgesic potentiators anti-obesity agents, brain function improvers
  • treatment for Alzheimer's disease It is useful as a drug, a drug for dementia, a drug for schizophrenia, a drug for Parkinson's disease, a drug for chorea, an antidepressant, a drug for diabetes insipidus, a drug for polyuria, or a drug for hypotension.

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Abstract

Cette invention se rapporte à des composés représentés par la formule générale (I), et à des sels et esters de ceux-ci; à des procédés pour leur préparation; et à des analgésiques, des antagonistes contre la tolérance aux analgésiques narcotiques y compris la morphine, des antagonistes contre la dépendance aux analgésiques narcotiques y compris la morphine, des agents de potentialisation de l'action analgésique, des agents contre l'obésité, des améliorants de la fonction cérébrale, des remèdes contre la maladie d'Alzheimer, des nootropes, des remèdes contre la schizophrénie, des remèdes contre la maladie de Parkinson, des remèdes contre la chorée, des antidépresseurs, des remèdes contre le diabète insipide, des remèdes contre la polyurie et des remèdes contre l'hypotension, qui contiennent ces composés, sels ou esters comme principe actif. Dans cette formule, Cy représente un groupe carbalicyclique éventuellement substitué; (a) représente un groupe hétéroalicyclique azoté éventuellement substitué; R1 représente hydrogène, alkyle inférieur éventuellement substitué, ou similaire; R2 représente hydrogène ou alkyle inférieur; et X représente hydrogène, halogéno, ou similaire.
PCT/JP1999/006921 1998-12-09 1999-12-09 Composes heterocycliques de 4-oxo-imidazolidine-2-spiro-azote Ceased WO2000034280A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096337A1 (fr) * 2000-06-14 2001-12-20 Banyu Pharmaceutical Co.,Ltd Composes heterocycliques 4-oxoimidazolidine-2-spiro-azotes
WO2003010168A1 (fr) * 2001-07-23 2003-02-06 Banyu Pharmaceutical Co., Ltd. Derive de 4-oxoimidazolidine-2-spiropiperidine
WO2003095427A1 (fr) * 2002-05-10 2003-11-20 Taisho Pharmaceutical Co.,Ltd. Compose a noyau spiranique
JP2007529568A (ja) * 2004-03-22 2007-10-25 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 置換１，４，８−トリアザスピロ［４．５］デカン−２−オン化合物
JP2007529565A (ja) * 2004-03-22 2007-10-25 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 置換１，４，８−トリアザスピロ［４．５］デカン−２−オン化合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725389A (en) * 1971-07-02 1973-04-03 American Home Prod Adducts of delta-aminobenzylpenicillin and n-substituted-4-piperidones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725389A (en) * 1971-07-02 1973-04-03 American Home Prod Adducts of delta-aminobenzylpenicillin and n-substituted-4-piperidones

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096337A1 (fr) * 2000-06-14 2001-12-20 Banyu Pharmaceutical Co.,Ltd Composes heterocycliques 4-oxoimidazolidine-2-spiro-azotes
WO2003010168A1 (fr) * 2001-07-23 2003-02-06 Banyu Pharmaceutical Co., Ltd. Derive de 4-oxoimidazolidine-2-spiropiperidine
US7192964B2 (en) 2001-07-23 2007-03-20 Banyu Pharmaceutical Co., Ltd. 4-oxoimidazolidine-2-spiropiperidine derivatives
US7557117B2 (en) 2001-07-23 2009-07-07 Banyu Pharmaceutical Co., Ltd. 4-oxoimidazolidine-2-spiropiperidine derivatives
WO2003095427A1 (fr) * 2002-05-10 2003-11-20 Taisho Pharmaceutical Co.,Ltd. Compose a noyau spiranique
JP2007529568A (ja) * 2004-03-22 2007-10-25 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 置換１，４，８−トリアザスピロ［４．５］デカン−２−オン化合物
JP2007529565A (ja) * 2004-03-22 2007-10-25 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 置換１，４，８−トリアザスピロ［４．５］デカン−２−オン化合物

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