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WO2001096337A1 - Composes heterocycliques 4-oxoimidazolidine-2-spiro-azotes - Google Patents

Composes heterocycliques 4-oxoimidazolidine-2-spiro-azotes Download PDF

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Publication number
WO2001096337A1
WO2001096337A1 PCT/JP2001/004869 JP0104869W WO0196337A1 WO 2001096337 A1 WO2001096337 A1 WO 2001096337A1 JP 0104869 W JP0104869 W JP 0104869W WO 0196337 A1 WO0196337 A1 WO 0196337A1
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group
decane
triazaspiro
methyl
lower alkyl
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Japanese (ja)
Inventor
Atsushi Satoh
Tetsuya Kato
Naoko Ooi
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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • 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 clearly useful in the field of medicine. More specifically, the 4-oxoimidazolidin-12-spiro-nitrogen-containing heterocyclic compound of the present invention has an action of inhibiting the binding of nociceptin to nociceptin receptor ORL1, and is represented by analgesics and morphine.
  • Drugs for overcoming narcotic analgesic resistance Overcoming dependence on narcotic analgesics such as morphine, Analgesic enhancers, Antiobesity agents, Brain function improvers, Alzheimer's disease preventives, Alheimer's disease remedies, Dementia Prophylactic, anti-dementia, schizophrenia, Parkinson's disease and degenerative neurodegenerative diseases such as chorea, antidepressants, diabetes insipidus, polyuria or It is useful as a therapeutic agent for hypotension.
  • narcotic analgesics such as morphine, Analgesic enhancers, Antiobesity agents, Brain function improvers, Alzheimer's disease preventives, Alheimer's disease remedies, Dementia Prophylactic, anti-dementia, schizophrenia, Parkinson's disease and degenerative neurodegenerative diseases such as chorea, antidepressants, diabetes insipidus, polyuria or It is useful as a therapeutic agent for hypotension.
  • Background technology such as morphine,
  • Nociceptin (the same substance as orphan in FQ) is a 17-amino acid peptide with a structure similar to that of opioid peptides. Nociceptin enhances responsiveness to invasive stimuli, enhances appetite, reduces spatial learning ability, antagonizes the analgesic effect of classic opiate agonists, suppresses dopamine release, aquaretic effect, and vasodilatory effect It has a systemic blood pressure lowering effect, etc., and is thought to be involved in pain and appetite regulation, memory, learning, etc.
  • nociceptin receptor ORL 1 through the nociceptin receptor ORL 1 in the brain [Nature, 377, 532 (1995); Society for Neuroscience, 22, 455 (1996); Neurorepo rt, 8, 423 pages (1997); Pian Pang @ Journal 'ob' Neuroscience (Eur. J. Neurosci ence), Vol. 9, 194 (1997); Neuroscience (Neuro rosci ence), 75 Volume, pages 1 and 333 ( 1996); See Life Sciences, Vol. 60, PL pages 15 and PL 141 (1997)]. It is also known that knockout mice in which nociceptin receptor ORL 1 expression has been blocked have reduced morphine resistance or improved memory and learning abilities [Neuroscience et al. Neuroscience Letters), 237, 136 (1997); Nature, 394, 577 (1998), etc.].
  • substances that specifically inhibit the binding of nociceptin to the nociceptin receptor ORL1 are analgesic for painful diseases such as cancer pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain, and neuralgia.
  • Drugs Narcotic analgesics such as morphine Drugs for overcoming tolerance, Drugs for overcoming narcotic analgesics dependence such as morphine, Analgesic enhancers, Anti-obesity agents, Brain function improvers, Alzheimer's disease preventives, Alzheimer's disease Therapeutic agent, dementia preventive drug, anti-dementia drug, schizophrenia drug, degenerative neurodegenerative disease drug represented by Parkinson's disease and chorea, antidepressant drug, diabetes insipidus drug, polyuria drug Or, it can be expected to be useful as a therapeutic agent for hypotension.
  • Substances that specifically inhibit the binding of nociceptin to nociceptin receptor ⁇ RL 1 include, for example, International Publication Nos.WO 0Z27815, W099Z59997, W ⁇ 99Z48492, W ⁇ 99Z36421, EP 963987 A It is described in No. 2, etc. None of these are the 41-year-old xoimidazolidin-12-spiro nitrogen-containing heterocyclic compounds of the present invention.
  • the 41-year-old oxoimidazolidine-12-spiro nitrogen-containing heterocycle according to the compound of the present invention is characterized in that a piperidine is spiro-bonded to the 2-position of the 41-year-old xoimidazolidine ring. And a compound having such a skeleton is not known. Therefore, it is not known that this 4-oxoimidazolidin-12-spiro nitrogen-containing heterocyclic compound inhibits binding to the nociceptin receptor ORL1. Disclosure of the invention
  • An object of the present invention is to provide a novel analgesic having an action of inhibiting the binding of noseptin to noseptin receptor ⁇ RL1, a drug for overcoming narcotic analgesic resistance represented by morphine, Drugs for overcoming narcotic analgesic dependence such as morphine, analgesics, antiobesity drugs, brain function improvers, Alzheimer's disease preventives, Alzheimer's disease preventives, dementia preventives, anti-dementia, schizophrenia
  • the present invention provides a drug, a remedy for degenerative neurodegenerative disease represented by Parkinson's disease and chorea, an antidepressant, a drug for diabetes insipidus, a drug for polyuria, or a drug for hypotension.
  • the present inventors have conducted intensive studies on compounds that inhibit the binding of nociceptin to nociceptin receptor ORL1, and found that the 2-position of 4-oxoimidazolidin has a structure different from that of conventional nociceptin receptor antagonists. Further, the present inventors have found that a compound having a piperidine ring by a spiro bond is a novel substance not described in the literature and antagonizes the binding of nociceptin to the nociceptin receptor ORL1, thereby completing the present invention. That is, the present invention
  • A, D, C_, _ and D each independently represent a methine group or a nitrogen atom which may be substituted with a halogen atom;
  • R 1 represents a lower alkynyl group, a cyclo-lower alkyl group, a group represented by Ar 1 or a group represented by R 2 or a halogen atom, a cyclo-lower alkyl group, an amino group, Lower alkylamino group, di-lower alkylamino group, cyclo-lower alkylamino group, lower alkylsulfonylamino group, aminosulfonylamino group,
  • (Di-lower alkyl rubamoyl) amino group lower alkanoylamino group, hydroxyl group, lower alkoxy group which may be substituted by fluorine atom, carbamoyloxy group, Lower alkyl rubamoyloxy group, di-lower alkyl rubamoyloxy group, lipoxyl group, lower alkoxycarbonyl group, lower rubamoyl group, lower alkyl rubamoyl group, di-lower alkyl rubamoyl group, — a group represented by A r 1 And a lower alkyl group or a lower alkenyl group which may have a substituent selected from the group consisting of R 1 and R 2 ;
  • n 1 or 2;
  • Cy is substituted with a halogen atom, a cyclo-lower alkyl group, a lower alkylidene group, a lower alkenyl group, a lower alkynyl group, a lower alkylenedioxy group, a lower alkyl group which may be substituted with a fluorine atom, or a fluorine atom 5 to 15 carbon atoms which may have a substituent selected from the group consisting of a lower alkoxy group, a hydroxyl group, an amino group, a lower alkylamino group and a di-lower alkylamino group.
  • a r 1 is a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkylsulfonylamino group, a lower alkoxy group, a sulfonylamino group, an amino group, a hydroxyl group, a carbamoyl group, a lower alkanoylamino group, or fluorine.
  • An aromatic carbon or heterocycle optionally having a substituent selected from the group consisting of a lower alkoxy group which may be substituted, a lower alkyl group which may be substituted by fluorine, a hydroxymethyl group and an aminomethyl group Means a group;
  • R 2 is an aliphatic heterocyclic group containing a hetero atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and is substituted with an amino group, a lower alkylamino group, a di-lower alkylamino group, or a fluorine atom
  • R 2 is an aliphatic heterocyclic group containing a hetero atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and is substituted with an amino group, a lower alkylamino group, a di-lower alkylamino group, or a fluorine atom
  • Lower alkanoyl group which may be substituted
  • Ar 1 is a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkylsulfonylamino group, a lower alkoxycarbonylamino group, an amino group, a hydroxyl group, a carbamoyl group, a lower alkanoylamino group
  • a monocyclic ring optionally having a substituent selected from the group consisting of a lower alkoxy group optionally substituted with fluorine, a lower alkyl group optionally substituted with fluorine, a hydroxymethyl group and an aminomethyl group
  • Ar 1 is a phenyl group, a 3-fluorophenyl group, a 3-methylaminophenyl group, a 3-dimethylaminophenyl group, a 3-aminophenyl group, a 3-methylsulfonylaminophenyl group, or a 3-methoxycarbonylamino group Enyl, 3-acetylaminophenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 4-methylaminophenyl, 4-dimethylaminophenyl, 4-aminophenyl 2-, 4-methylsulfonylaminophenyl, 4-methoxycarbonylaminophenyl, 4-acetylaminophenyl, 4-trifluoromethylphenyl, 2-pyridyl , 3-pyridyl, 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazo
  • R 1 is a group represented by Ar 1 or a group represented by R 2 , or a halogen atom, a cyclo-lower alkyl group, an amino group, a lower alkylamino group, M alkylamino group, cyclo lower alkylamino group, lower alkylsulfonylamino group, aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, sulvamoylamino group, (lower Amino group, (di-lower alkyl group) amino group, lower alkanoylamino group, hydroxyl group, lower alkoxy group which may be substituted by fluorine atom, lower group, lower alkyl group, lower alkyl group Di-lower alkyl rubamoyloxy group, carboxyl group, lower alkoxycarbonyl group, lower
  • R 1 is a 3-piperidinyl group, a 2-oxopyrrolidine-15-yl group, a 2-morpholinyl group, a 3-morpholinyl group, a 2-piperazinyl group,
  • Cy is octogen, cyclo lower alkyl, lower alkenyl, lower alkynyl, lower alkylenedioxy, lower alkyleneoxy, lower alkyl optionally substituted with fluorine, fluorine A 1, 2 or tricyclic aliphatic carbocyclic group having 5 to 15 carbon atoms which may have a substituent selected from the group consisting of a lower alkoxy group optionally substituted with an atom and a hydroxyl group (1 ) Listed compounds,
  • Cy is cyclooctyl group, 1-methylcyclooctyl group, cycloheptyl group, cyclononyl group, cyclodecyl group, 1-hydroxycyclooctyl group, 2-methylcyclopentyl group, 2,2-dimethylcyclopentyl Group, 2,2,4-trimethylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group, 2,2-dimethylcyclohexyl group, 2,3-dimethylcyclohexyl group, 2,4-dimethylcyclo Hexyl, 2,6-dimethylcyclohexyl, 2,2,4-trimethylcyclohexyl, 2,2,6-trimethyl 2-cyclohexyl, 2-ethylcyclohexyl, 2-isopropylcyclohexyl, 2-trifluoromethylcyclohexyl, 2- (2,2-difluoroethyl) cyclohexyl,
  • Cy is cyclooctyl, 1-methylcyclooctyl, cycloheptyl, cyclononyl, cyclodecyl, 1-hydroxycyclooctyl, 2-methylcyclopentyl, 2,2-dimethyl Cyclopentyl group, 2,2,4-trimethylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group, 2,2-dimethylcyclohexyl group, 2,3-dimethylcyclohexyl group, 2,4 —Dimethylcyclohexyl group, 2,6-dimethylcyclohexyl group, 2,2,4-trimethylcyclohexyl group, 2,2,6-trimethylcyclohexyl group, 2-ethylcyclohexyl group, 2— Isopropylcyclohexyl group, 2-trifluoromethylcyclohexyl group, 2- (2,2-difluoroethyl) cyclohex
  • Analgesia overcoming narcotic analgesic resistance, overcoming narcotic analgesic dependence, analgesia Enhance action, anti-J Tomah, improve brain function, prevent Alzheimer's disease, treat Alzheimer's disease, prevent dementia, prevent dementia, prevent dementia, treat schizophrenia, treat Parkinson's disease, and regression represented by chorea
  • a pharmaceutical composition suitable for treatment of sexual neurodegenerative disease, antidepressant treatment, diabetes insipidus treatment, polyuria treatment or hypotension treatment,
  • Cy p represents a halogen atom, cyclo-lower alkyl group, a lower alkylidene group, a lower alkenyl group, lower alkynyl group, a fluorine atom in the optionally substituted lower alkyl group, it may be substituted with a fluorine atom It may have a substituent selected from the group consisting of a lower alkoxy group, a di-lower alkylamino group or a lower alkylenedioxy group or an optionally protected hydroxyl group, an amino group and a lower alkylamino group. It means a 12- or 3-cyclic aliphatic carbocyclic group having 5 to 15 carbon atoms; n has the meaning described above. And a compound represented by the general formula [III]
  • R lp is a lower alkynyl group, a cyclo lower alkyl group, a group represented by one Ar lp or a group represented by —R 2p , or a halogen atom, a cyclo lower alkyl group, a di lower alkyl amino group, (Di-lower alkyl rubamoyl) amino group, lower alkyl Kanoiruamino group, a lower alkoxy group optionally substituted by a fluorine atom, di-lower alkyl force Rubamoiruokishi group, a lower alkoxy Cal Poni group, a di-lower alkylcarbamoyl group, one A group represented by r lp and single R 2 p An amino group, a lower alkylamino group, a cyclo lower alkylamino group, a lower alkylsulfonylamino group, an aminosulfonylamino group, a (lower alkyl group
  • Ar lp is a halogen atom, a di-lower alkylamino group, a lower alkylsulfonylamino group, a lower alkoxyl-propionylamino group, a lower alkanoylamino group, a lower alkoxy group which may be substituted by fluorine, or a fluorine substitution Having a substituent selected from the group consisting of a lower alkyl group which may be protected and a lower alkylamino group, an amino group, a hydroxyl group, a carbamoyl group, a hydroxymethyl group and an aminomethyl group which may be protected. Also means an aromatic carbon or heterocyclic group;
  • R 2 p is an aliphatic heterocyclic group containing a hetero atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom which may be protected, and is substituted with a di-lower alkylamino group or a fluorine atom
  • A, Dan, C, and Dan have the above meaning.
  • 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 a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a sec-butyl group.
  • Tert-butyl group pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, hexyl group, iso- Hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 1,1,2 —Trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group, 1-ethyl-1-methylpropyl group, etc. And the like.
  • lower alkylamino group means an amino group monosubstituted with the lower alkyl group, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-amino. And a butylamino group.
  • the “di-lower alkylamino group” means an amino group di-substituted with the lower alkyl group. And an amino group.
  • “Lower alkylsulfonyl group” means an alkylsulfonyl group having a lower alkyl group, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, sec-butylsulfonyl And a tert-butylsulfonyl group.
  • the “lower alkylsulfonylamino group” means an amino group monosubstituted with the lower alkylsulfonyl group, such as a methylsulfonylamino group, an ethylsulfonylamino group, a propylsulfonylamino group, an isopropylsulfonylamino group, A butylsulfonylamino group, a sec-butylsulfonylamino group, a tert-butylsulfonylamino group and the like.
  • “Lower alkoxy group” means an alkoxy group having a lower alkyl group, that is, an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. , Isobutoxy group, tert-butoxy group, pentyloxy group and the like.
  • lower alkoxycarbonylamino group means an alkoxycarbonylamino group having a lower alkoxycarbonyl group, that is, an alkoxycarbonylamino group having 2 to 7 carbon atoms, for example, methoxycarbonylamino, ethoxy
  • Examples include a carbonylamino group, a propoxyl-ponylamino group, an isopropoxycarbonyl-amino group, a butoxycarbonylamino group, an isobutoxycarbonylamino group, a tert-butoxycarbonylamino group, and a pentyloxycarbonylamino group.
  • lower alkanol group means an alkanol group having a lower alkyl group, that is, an alkanol group having 2 to 7 carbon atoms, for example, an acetyl group, a portionyl group, a butyryl group, an isoptyryl group, a valeryl group, and an isopararyl. And piva groups.
  • “Lower alkanoylamino group” means an amino group monosubstituted with the above-mentioned lower alkanoyl group, such as acetylamino, propionylamino, isoptyrylamino, valerylamino, isopparylamino, piperoylamino. And the like.
  • “Lower alkoxy group optionally substituted by fluorine atom” refers to the lower alkyl An alkoxy group which may be substituted at one or more, preferably 1 to 3 fluorine atoms at any substitutable position of the oxy group, for example, in addition to the above-mentioned alkoxy group, fluoromethoxy Group, difluoromethoxy group, trifluoromethoxy group, 1,2-difluoroethoxy group and the like.
  • the ⁇ lower alkyl group optionally substituted with a fluorine atom '' means that any substitutable position of the lower alkyl group is substituted with one or more, preferably one to three, fluorine atoms.
  • a good alkyl group means, for example, in addition to the alkyl groups exemplified above, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 1,2-difluoroethyl group, a 2,2-difluoroethyl group, Examples include a 1,2,2-trifluoroethyl group, a 2,2,2-trifluoroethyl group, and a 3-fluoropropyl 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, for example, pyrrolyl, furyl, chenyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, triazolyl, tetrazolyl, oxaziazolyl, thiadiazolyl Group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyrid
  • “Lower alkenyl group” means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as a bier group, 1-propenyl group, 2-propenyl group, isopropyl group. Benzyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2 —Propenyl group, 2-methyl-1-propenyl group, 3-methyl-2-butenyl group, 4-pentenyl group and the like.
  • “Lower alkynyl group” means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, for example, ethenyl group, 2-propynyl group, 1-methyl-2-propynyl group, 2-butynyl group, Examples include a 1-methyl-2-butynyl group and a 2-pentynyl 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.
  • cyclo lower alkylamino group means an amino group monosubstituted with the cyclo lower alkyl group, that is, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, and a cyclohexylamino 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, Examples thereof include a butylaminosulfonyl group, a sec-butylaminosulfonyl group, a tert-butylaminosulfonyl 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. Amino group, (isopropylamino) sulfonylamino group, (butylamino) sulfonylamino group, (sec-butylamino) sulfonylamino group, (tert-butylamino) sulfonylamino group and the like.
  • the “(di-lower alkylamino) sulfonylamino group” means an amino group mono-substituted with the above-mentioned di-lower alkylaminosulfonyl group, such as a (dimethylamino) sulfonylamino group, a (getylamino) sulfonylamino group, (Ethylmethylamino) sulfonylamino group, (dipropylamino) sulfonylamino group, (Methylpropylamino) sulfonylamino group, (diisopropylamino) sulfonylamino group and the like.
  • lower alkyl group refers to a monosubstituted group of the lower alkyl group, for example, methylcarbamoyl, ethylcarbamoyl, propylrubumoyl, isopropylpropylumbamoyl, butylcarbamoyl, sec One butylcarbamoyl group, tert-butylcarbamoyl group and the like.
  • the “(lower alkyl carbamoyl) amino group” means an amino group monosubstituted with the lower alkylcarbamoyl group, for example, 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 alkyl group” refers to a di-substituted group of the lower alkyl group, for example, a dimethylcarbamoyl group, a getylcarbamoyl group, an ethylmethylcarbamoyl group, a dipropyl group.
  • Examples include a methylpropylcarbamoyl group and a diisopropylpropylcarbamoyl group.
  • 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, Butylmethylcarbamoyl) amino group, (dipropylcarbamoyl) amino group, (methylpropylcarbamoyl) amino group, (diisopropylcarbamoyl) amino group, and the like.
  • “Lower alkyl rubamoyloxy group” means an alkyl rubamoyloxy group having the lower alkyl rubamoyl group, for example, a methylcarbamoyloxy group, an ethylcarbamoyloxy group, a propylpower rubamoyloxy group, an isopropylcarbamoyloxy group.
  • “Di-lower alkyl rubamoyloxy group” means the dialkyl lower rubamoyloxy group having the di-lower alkyl carbamoyl group. Examples include a bamoyloxy group, a getylcarbamoyloxy group, an ethylmethylcarbamoyloxy group, a dipropyl-lubamoyloxy group, a methylpropyl-luvamoyloxy group, and a diisopropyl-luvamoyloxy group.
  • the “lower alkoxycarbonyl group” means an alkoxycarbonyl group having a lower alkoxy group, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxylpropanol group.
  • lower alkylidene group means a linear or branched alkylidene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylidene group, a propylidene group, an isopropylidene group and a butylidene group.
  • lower alkylenedioxy group means a linear or branched alkylenedioxy group having 1 to 6 carbon atoms, such as a methylenedioxy group, an ethylenedioxy group, a trimethylenedioxy group, a 1,2- Examples thereof include a dimethylethylenedioxy group, a 1,1,2,2-tetramethylethylenedioxy group, and a 2,2-dimethylpropylenedioxy group.
  • “Lower alkyleneoxy group” means a linear or branched alkyleneoxy group having 1 to 6 carbon atoms, for example, an ethyleneoxy group, a trimethyleneoxy group, a tetramethyleneoxy group, a pentamethyleneoxy group. And the like.
  • a 1, 2, or 3 cyclic aliphatic carbocyclic group is a saturated or unsaturated aliphatic carbocyclic group, and means a 1, 2 or 3 cyclic cyclic group, for example, a cyclopentyl group, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, 1-cyclohexenyl, 2-cyclohexenyl, 1,3-cyclohexyl Xaxenyl 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 — Cyclooctagenyl group, 1-cyclononenyl group, 2-cyclo
  • An "aliphatic heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen” is the same or different from the group consisting of oxygen, sulfur and nitrogen.
  • the ⁇ lower alkanoyl group optionally substituted with a fluorine atom '' means that any substitutable position of the lower alkanoyl group may be substituted with 1 or 2 or more, preferably 1 to 3 fluorine atoms.
  • An alkanol group means, for example, a fluoracetyl group, a difluoroacetyl group, a trifluoroacetyl group and the like in addition to the alkanol groups exemplified above.
  • Lower alkanoylamino group optionally substituted with a fluorine atom '' means that any substitutable position of the lower alkanoylamino group is substituted with one or more, preferably one to three, fluorine atoms.
  • An alkanoylamino group which may be substituted, for example, in addition to the alkanoylamino groups exemplified above, a fluoroacetylamino group, a difluoroacetylamino group, a trifluoroacetylamino group And the like.
  • “Lower alkoxycarbonylmethyl group” means a methyl group monosubstituted with the lower alkoxycarbonyl group, for example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, isopropoxycarbonyl group, Butoxycarbonylmethyl group, isobutoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, pentyloxycarbonylmethyl group And the like.
  • lower alkyl rubamoylmethyl group means a methyl group monosubstituted with the lower alkyl rubamoyl group, for example, methylcarbamoylmethyl, ethylcarbamoylmethyl, propylrubamoylmethyl, isopropylcarbamoylmethyl, butyric.
  • the “di-lower alkyl group rubamoylmethyl group” means a methyl group monosubstituted with the di-lower alkylcarbamoyl group, for example, dimethylcarbamoylmethyl group, getylcarbamoylmethyl group, ethylmethylcarbamoylmethyl group, And a dibutyl pyruvamoylmethyl group, a dipropyl pyruvamoylmethyl group, a diisopropyl pyruvamoylmethyl 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; for example, trimethylamine salt, triethylamine salt, dicyclohexane Organic amine salts such as hexylamine salt, ethanolamine salt, jetanolamine salt, triethanolamine salt, proforce salt, and N, N, -dibenzylethylenediamine salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt for example, trimethylamine salt, triethylamine salt, dicyclohexane Organic amine salts such as hexylamine salt, ethanolamine salt, jetanolamine salt, triethanolamine salt, proforce salt, and N, N, -dibenzylethylenediamine salt.
  • the acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate, etc .; for example, maleate, fumarate, tartrate, citrate, and ascorbate. And organic salts such as trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate, etc .
  • organic salts such as trifluoroacetate
  • sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
  • the “ester” of the compound represented by the general formula [I] includes, for example, a pharmaceutically acceptable conventional pharmaceutically acceptable group in the case of having a lipoxyl group.
  • Ester such as methyl, ethyl, propyl, isopyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl Group, lower alkyl ester such as cyclopentyl group, ester with aralkyl group such as benzyl group and phenethyl group, lower alkenyl ester such as aryl group, 2-butenyl group, methoxymethyl group, 2-methoxyethyl group, and 21-ethoxyethyl
  • Lower alkoxyalkyl esters such as lower alkoxyalkyl esters such as acetyloxymethyl group, bivaloyloxymethyl group, 1-pivaly
  • A, D, C, and D each independently represent a methine group or a nitrogen atom, which may be substituted with a halogen atom.
  • halogen atom for the substituent for example, a fluorine atom is preferable.
  • A, C, C, and D each represent a nitrogen atom, a compound in which only one of them is a nitrogen atom and the other is a methine group which may be substituted with a haegen atom. Is preferred.
  • A, D, C, D and E may be substituted with a halogen atom.
  • a methine group more preferably an unsubstituted methine group, is preferred.
  • R 1 represents a lower alkynyl group, a cyclo lower alkyl group, a group represented by —A r 1 or a group represented by R 2 , or 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, an aminosulfonylamino group, a (lower alkylamino) sulfonylamino group, a (di-lower alkylamino) sulfonylamino group, carpa Moylamino group, (lower alkyl group rubamoyl) amino group, (di-lower alkyl group rubamoyl) amino group, lower alkanoylamino group, hydroxyl group, lower alkoxy group optionally substituted by fluorine
  • R 1 represents a group represented by Ar 1 or a group represented by R 2 , or a halogen atom, a cyclo-lower alkyl group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a cyclo-lower group Alkylamino group, 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, lower alkanoylamino group, hydroxyl group, lower alkoxy group optionally substituted by fluorine atom, carbamoyloxy group, lower alkyl rubamoyloxy group, di-lower alkylcar
  • Preferable examples of the lower alkynyl group for R 1 include an ethynyl group and a 2-propynyl group.
  • Examples of the cyclo lower alkyl group for R 1 include a cyclopropyl group and a cyclobutyl group. And a cyclopentyl group are preferred.
  • a r 1 is a halogen atom, a lower alkylamino group, a di-lower alkylamino group, a lower alkylsulfonylamino group, a lower alkoxy group, a sulfonylamino group, an amino group, a hydroxyl group, a carbamoyl group, a lower alkanoylamino group, or fluorine.
  • Substituents selected from the group consisting of a lower alkoxy group which may be substituted, a lower alkyl group which may be substituted with fluorine, a hydroxymethyl group and an aminomethyl group are the same or different, and 1 or 2 or more, preferably 1 or 2 means an aromatic carbocyclic group or heterocyclic group which may be optionally selected.
  • aromatic carbocyclic group for Ar 1 for example, a phenyl group and the like are preferable, and as the aromatic heterocyclic group, for example, a pyridyl group, a triazolyl group, an imidazolyl group, a tetrazolyl group, a pyrazolyl group, a thiazolyl group Oxazolyl group, pyrazinyl group, pyrimigel group, pyridazinyl group and the like are preferred.
  • the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
  • 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 alkylsulfonylamino group for the substituent for example, a methylsulfonylamino group, an ethylsulfonylamino group and the like are preferable.
  • the lower alkoxy group of the substituent for example, a methoxycarponylamino group, an ethoxycarponylamino group and the like are preferable.
  • the lower alkanoylamino group for the substituent for example, an acetylamino group, a pionylamino group and the like are preferable.
  • the lower alkoxy group which may be substituted with fluorine for the substituent for example, a methoxy group, an ethoxy group, an isopropoxy group, a trifluoromethoxy group and the like are preferable.
  • a r 1 is preferably a monocyclic aromatic carbon or heterocyclic group which may have a substituent, specifically, a phenyl group, a 3-fluorophenyl group, and a 3-methylaminophenyl group.
  • R 2 is an aliphatic heterocyclic group containing a hetero atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, and is substituted with an amino group, a lower alkylamino group, a di-lower alkylamino group, or a fluorine atom Optionally substituted lower alkylamino group, halogen atom, oxo group, hydroxyl group, lower alkoxy group optionally substituted with fluorine atom, lower alkyl group optionally substituted with fluorine atom, substituted with fluorine atom Optionally substituted lower alkanoyl group, lower alkoxycarbonyl group, carbamoyl group, lower alkyl rubamoyl group, di-lower alkyl rubamoyl group, carboxyl group, lower alkylsulfonyl group, lower alkoxycarbonylmethyl group, A lower alkyl group having a substituent selected from the group consisting of a lower
  • the lower alkylamino group for the substituent is, for example, preferably a methylamino group, an ethylamino group.
  • the di-lower alkylamino group for the substituent is, for example, preferably a dimethylamino group, a methylamino group.
  • the lower alkylamino group which may be substituted by a fluorine atom of the substituent for example, an acetylamino group, a trifluoroacetylamino group and the like are preferable.
  • the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine 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.
  • Examples of the lower alkyl group which may be substituted with a fluorine atom of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group. Etc. are preferred.
  • the lower alkenyl group which may be substituted with a fluorine atom for the substituent is, for example, preferably an acetyl group, a trifluoroacetyl group or the like.
  • 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.
  • a methylsulfonyl group, an ethylsulfonyl group and the like are preferable.
  • a methylcarbamoylmethyl group, an ethylcarbamoylmethyl group and the like are preferable.
  • a rubamoylmethyl group is preferably a dimethylcarbamoylmethyl group, a getylcarbamoylmethyl group, or the like.
  • ⁇ aliphatic heterocyclic group '' includes an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group optionally substituted with a fluorine atom, a halogen atom, an oxo group, a hydroxyl group, A lower alkoxy group optionally substituted with a fluorine atom, a lower alkyl group optionally substituted with a fluorine atom, and the like are preferred.
  • Examples of the “aliphatic heterocyclic group containing a hetero atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom” include, for example, a 1-pyrrolidinyl group, a 2-pyrrolidinyl group,
  • an aliphatic heterocyclic group containing a hetero atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom of R 2 and which may have the substituent, for example, Pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 2-oxopyrrolidine-1-yl group, 2-oxopyrrolidine-13-yl group,
  • 3-yl group 2-oxo-1-3-pyrroline-1-4-yl group, 2-oxo-3-pyrroline-5-yl group, 2-oxooxozolidine-3-yl group, 2 —Sixoxoxazolidine-1-yl group, 2-oxoxazolidine-1-yl group, 2-oxo-5H—furan-1-yl group, 2-oxo-1H—furan-4— Yl, 2-oxo-5H-furan-5-yl, 4-oxo-1,3-dioxolan-1-yl, 4-oxo1-1,3-dioxolan-5-yl , 2-oxo-1,3-dioxoline-4-yl group, 3-oxoisoxazolidin-2-yl group, 3-oxoisoxazozolidine-1-yl group, 3-oxoisoxazozolidine-1-yl group, 3-oxoisoxoxa Zolidine-5-yl group,
  • 5-oxo-1 2-tetrazoline-1-yl group 5-oxo-1 2-pyrazolin-1 1 5-yl, 5-oxo-l-pyrazoline-l-yl, 5-oxo-l-pyrazoline-l 4-yl, 5-oxo-l-triazoline-l-yl, 5-oxo-l-triazoline-3 —Yl group, 5-oxo—2-triazoline—4-yl group, 5-oxo-13-pyrazolin-1-yl group, 5-oxo-1-3-pyrazolin-12-yl group, 5-oxo-13-pyrazolin 1-3-yl, 5-oxo-3-pyrazolin-4-yl, 4-oxo-12-yloxazoline-12-yl, 4-oxo1-2-2-oxazoline-1-5-yl, 2- Oxo 4-41-imidazoline-1-yl group, 2-oxo-41-imidazoline-4-yl group, 2-oxotetrahydrothiophen
  • R 1 Examples of the group represented by A r 1, phenyl group, 3-fluorophenyl group, 3-methyl ⁇ Minofu enyl, 3-dimethyl ⁇ Minofu enyl, 3-Aminofue group, 3-methylsulfonyl Aminophenyl group, 3-methoxycarbonylaminophenyl group, 3-acetylphenylaminophenyl group, 3-methoxyphenyl group, 3-trifluoromethylphenyl group, 4-fluorophenyl group, 4-methylaminophenyl group Phenyl, 4-dimethylaminophenyl, 4-aminophenyl, 4-methylsulfonylaminophenyl, 4-methoxycarbonylaminophenyl, 4-acetylaminophenyl, 4-methoxyphenyl Group, 4-trifluoromethyl Phenyl, 2-pyridyl, 3-pyridyl, 2-imidazolyl, 4-imidazolyl,
  • Examples of the group represented by one R 2 of R 1 include a 2-pyrrolidinyl group, a 3-pyrrolidinyl group, a 2-oxopyrrolidine-13-yl group, a 2-oxopyrrolidine-14-yl group, and a 2-oxopyrrolidine-15- 2-yl, 4-oxoimidazolidin-2-yl, 4-oxoimidazolidin-5-yl, 2-oxoimidazolidin-4-1-yl, 2-oxo-1-3-pyrroline 1-3-yl group, 2-oxo-3-pyrroline-1-yl group, 2-oxo-3-pyrroline-1-5-yl group, 2-oxooxazolidin-4-yl group, 2-o Xoxoxazolidine-1-yl, 2-oxo-5H-furan-3-yl, 2-oxo-5H-furan-4-yl, 2-oxo-1-5H-furan-5- 4-yl-1,4-diox
  • 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, carpamoylamino group, (Lower alkyl power rubamoyl) amino group, (di-lower alkyl power rubamoyl) amino group, lower alkanoylamino group, hydroxyl group, optionally substituted by fluorine atom, lower alkoxy group, power rubamoyloxy group, lower alkyl power rubamoyloxy Group, di-lower alkyl rubamoyloxy group, lipoxyl group, lower alkoxy propylonyl group, lipamoyl group, lower alkyl rubam
  • the substituent is a halogen atom, a cyclo-lower alkyl group, an amino group, a lower alkylamino group, Lower alkylamino group, cyclolower alkylamino group, lower alkylsulfonylamino group, aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, sulfamoylamino group, (lower alkylcarba) Moyl) amino group, (di-lower alkyl rubamoyl) amino group, 7jC acid group, lower alkoxy group optionally substituted by fluorine atom, carbamoyloxy group, lower alkyl rubamoyloxy group, di-lower alkyl rubamoyl oxy group From the group consisting of: a carboxyl group, a lower alkoxycarbonyl
  • 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.
  • the di-lower alkylamino group for the substituent is, for example, preferably a dimethylamino group, a acetylamino group.
  • cyclo lower alkylamino group for the substituent a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group and the like are preferable.
  • Examples of the lower alkylsulfonylamino group for the substituent include methylsulfonyl A lumino group and an ethylsulfonylamino group are preferred.
  • 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 of 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 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.
  • the lower alkyl group of the substituent preferred are, for example, a methylcarbamoyloxy group and an ethylcarbamoyloxy group.
  • the di-lower alkylcarbamoyloxy group for the substituent is, for example, preferably a dimethylcarbamoyloxy group, a getylcarbamoyloxy group.
  • 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.
  • the di-lower alkylcarbamoyl group for the substituent is, for example, preferably a dimethylcarbamoyl group, a getylcarbamoyl group.
  • Examples of the group represented by 1 R 2 as a substituent of the lower alkyl group of R 1 include 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3 _pyrrolidinyl group, 2-oxopyrrolidine 1-yl group, 2-oxopyrrolidine- 3-yl group, 2-oxopyrrolidine-1-4-yl group, 2-oxopyrrolidine-1-5-yl group, 4-oxoimidazolidine-1-yl group, 4-oxoimidazolidine-12-yl group, 4-oxoimidazolidin-1-3-yl group, 4-oxoimidazolidin-1-5-yl group, 2-oxoimidazolidin-1-1-yl group, 2-oxoimidazolidin-1-4-yl group, 2- Oxo-3-pyrroline-1-yl, 2-oxo-3-pyrroline-3-yl, 2-oxo-3-pyrroline-4-yl, 2-oxo-3-pyrroline-5-y
  • Examples of the lower alkyl group of the “lower alkyl group having the group” for R 1 include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group, and more preferably a methyl group, an ethyl group, and a propyl group. Etc. are preferred.
  • Examples of the substituent of the “lower alkyl group having the group” for R 1 include an 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, Aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, carbamoylamino group, 7K acid group, lower alkoxy group which may be substituted by fluorine atom, alkoxyl group, A group represented by one Ar 1 , a group represented by one R 2 and the like are preferable.
  • Examples of the “lower alkyl group having the group” for R 1 include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, an isopropyl group, an isopropyl group, a cyclopropylmethyl group, a 2-fluoroethyl group, a 2,2- Difluoroethyl, 1,2-hydroxyxethyl, 3,3-difluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, 2,3-dihydroxypropyl, 2-aminoethyl, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2-dimethylaminoethyl group, 2- (methylsulfonylamino) ethyl group, 2- (aminosulfonylamino) ethyl group, 2- [(dimethyl Aminosulfony
  • 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, (Di-lower alkylamino) sulfonylamino group, sulfamoylamino group, (Lower alkyl power rubamoyl) amino group, (di-lower alkyl power rubamoyl) amino group, lower alkanoylamino group, hydroxyl group, optionally substituted by fluorine atom, lower alkoxy group, power rubamoyloxy group, lower alkyl power rubamoyloxy group, a di-lower alkyl force Rubamoiruokishi group, a carboxyl group, a lower alkoxy
  • the substituent is a halogen atom, a cyclo-lower alkyl group, an amino group, a lower alkyl Group, di-lower alkylamino group, cyclo-lower alkylamino group, lower alkylsulfonylamino group, aminosulfonylamino group, (lower alkylamino) sulfonylamino group, (di-lower alkylamino) sulfonylamino group, dirubamoylamino group, ( Amino group, (di-lower alkyl group), amino group, hydroxyl group, lower alkoxy group optionally substituted with fluorine atom, lower group, lower alkyl group, lower alkyl group, lower dialkyl group force Rupokishiru group, a lower alkoxy Cal Poni group, Karubamo I group, a lower alkyl force Rubamoiru group, a di-lower alkyl force Rubamoiru
  • 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.
  • a propylamino group, a cyclobutylamino group, and a cyclobenzylamino group are preferred.
  • Examples of the lower alkylsulfonylamino group for the substituent include methylsulfonyl A lumino group and an ethylsulfonylamino group are preferred.
  • 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 of 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.
  • 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.
  • 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.
  • 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 aromatic carbocyclic group represented by 1 Ar 1 as a substituent of the lower alkenyl group of R 1 include a phenyl group, and examples of the aromatic heterocyclic group include a pyridyl group, a triazolyl group, and an imidazolyl group. , Tetrazolyl, pyrazolyl, thiazolyl, oxazolyl, birazinyl, pyrimigel, pyridazinyl, etc. It is.
  • the group represented by R 2 includes: 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, 2- Oxopyrrolidine-1-3-yl group, 2-oxopyrrolidine-14-yl group, 2-oxopyrrolidine-1-5-yl group, 4-oxoimidazolidin-1-1-yl group, 4-oxoimidazolidin-1-2-yl Group, 4-oxoimidazolidin-3-yl group, 4-oxoimidazolidin-5-yl group, 2-oxoimidazolidin-1-yl group, 2-oxoimidazolidin-1-yl group, 2-oxoimidazolidin-1-yl group, 2- Oxo-1-3-pyrroline-1-yl, 2-oxo-3-pyrroline-3-yl, 2-oxo-3-pyrroline-4f, 2-oxo-3-pyrroline-5-y 1-yl group, 2-
  • 2,4-Dioxothiazolidine-3-yl group 2,4-Dioxothiazolidine-1-yl group, 1,4-dihydropyridine-11-yl group, 1,4-dihydropyridin-2 —Yl group, 1,4-dihydropyridine-13-yl group, 1,4-dihydropyridine-14-yl group, 2-oxopyridine-1-yl group, 2-oxo-1H-pyridin-3 —Yl group, 2-oxo-1H-pyridine-1-4-yl group, 2-oxo-1H-pyridine-1-5-yl group, 2-oxo-1H-pyridine-16-yl group, 4-oxopyridine 1-yl group, 4-oxo-1H-pyridine-12-yl group, 4-oxo-1H-pyridine-3-yl group, 2-oxo-1,4,5-dihydropyrimidin-3-yl group, 2 _Oxo-1 3H—4,5-dihydropyrimidine
  • Examples of the lower alkenyl group of the “lower alkenyl group having the group” for R 1 include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 1-butenyl group, and a 3-butenyl group. Etc. are preferred.
  • Examples of the substituent of the “lower alkenyl group having the group” for R 1 include a halogen atom, a cyclo-lower alkyl group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkylsulfonylamino group, and an aminosulfonyl group.
  • Examples of the “lower alkenyl group having the group” for R 1 include vinyl group, 1-probenyl group, 2-propenyl group, 2-butenyl group, 1-butenyl group, 3-butenyl group, 3-butenyl group.
  • R 1 is bonded to the 5-position on the oxoimidazolidine ring, and the carbon atom at the 5-position is an asymmetric carbon.
  • the configuration of R 1 is (R) configuration, ) Any arrangement is acceptable.
  • Cy is substituted with a halogen atom, a cyclo-lower alkyl group, a lower alkylidene group, a lower alkenyl group, a lower alkynyl group, a lower alkylenedioxy group, a lower alkyl group which may be substituted with a fluorine atom, or a fluorine atom 5 to 15 carbon atoms which may have a substituent selected from the group consisting of a lower alkoxy group, a hydroxyl group, an amino group, a lower alkylamino group and a di-lower alkylamino group. It means a tricyclic aliphatic carbon ring group.
  • a halogen atom As Cy, a halogen atom, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylenedioxy group, a lower alkyleneoxy group, a lower alkyl group which may be substituted by a fluorine atom, a fluorine atom A 1, 2 or tricyclic aliphatic carbocyclic group having 5 to 15 carbon atoms which may have a substituent selected from the group consisting of a lower alkoxy group and a hydroxyl group which may be substituted It is suitable.
  • Halogen atom cyclo lower alkyl group, lower alkylidene group, lower alkenyl A lower alkynyl group, a lower alkylenedioxy group, a lower alkyl group optionally substituted with a fluorine atom, a lower alkoxy group optionally substituted with a fluorine atom, a hydroxyl group, an amino group, a lower alkylamino group,
  • An unsubstituted carbon atom having 5 to 15 carbon atoms which may have a substituent selected from the group consisting of a di-lower alkylamino group and having 5 to 15 carbon atoms
  • the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
  • the cyclo lower alkyl group for the substituent is, for example, preferably a cyclopropyl group, a cyclobutyl group.
  • 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 for example, an ethyl group, a 2-propyl group and the like are preferable.
  • the lower alkylenedioxy group for the substituent for example, an ethylenedioxy group, a trimethylenedioxy group and the like are preferable.
  • Examples of the lower alkyl group which may be substituted with a fluorine atom for the substituent include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group. Is preferred.
  • Examples of the lower alkoxy group which may be substituted with a fluorine atom for the substituent include a methoxy group, an ethoxy group, a propoxy group, a fluoromethoxy group and a difluoro group. A methoxy group, a trifluoromethoxy group and the like are preferred.
  • 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.
  • Examples of the substituent of Cy include a fluorine atom, a cyclopropyl group, a methylene group, a vinyl group, an ethynyl group, an ethylenedioxy group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a 2,2-difluoroethyl group, Examples include a trifluoromethoxy group, an amino group, a methylamino group, a dimethylamino group, a hydroxyl group, and the like. Among them, a fluorine atom, a cyclopropyl group, a methyl group, an ethyl group, a trifluoromethyl group, a hydroxyl group, and the like are preferable.
  • a C y having 5 to 13 carbon atoms and more preferably 5 to 11 carbon atoms is preferred.
  • a cyclopentyl group a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a bicyclo [2.2.1] hepter-2-yl group, a bicyclo [2.2] .2] Octa-2-yl group, Bisik mouth [3.2.1.1] Octa2-yl group, bicyclo [3.3.1.1] Nona9-11 group, bicyclo [3.3.2.
  • Dec-2-yl group bicyclo [4.4.0] Decal 2-yl group, tricyclo [3.3.1.I 3 ' 7 ] Dec-1-yl group, spiro [2.4] hepter 4-yl group, spiro [2.5] octyl 4-yl group, spiro [3.4] octyl 5-yl group, spiro [3.5] noner 5-yl group, spiro [4.4] Noner 6-yl group, spiro [4.5] decayl group, spiro [4.5] deca-6-yl group, spiro [bicyclo [2.2.1] heptane-1,2'-cyclopropa 1] 3-yl group, spin [Bicyclo [2.2.1] heptane-1,2,1-cyclobutane] -13-yl group, spiro [bicyclo [2.2.1] heptane-1,2,1'-cyclopentane] -13-yl Groups and the like
  • a 6-yl group, a spiro [bicyclo [2.2.1] heptane-1,2,1, -cyclopropane] -13-yl group and the like are preferable.
  • Cy for example, cyclooctyl, 1-methylcyclooctyl, cycloheptyl, cyclononyl, cyclodecyl, 1-hydroxycyclooctyl, 2-methylcyclopentyl, 2,2-dimethylcyclopentyl, 2, 2,4-trimethylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group, 2,2-dimethylcyclohexyl group, 2,3-dimethylcyclohexyl group, 2,4-dimethylcyclohexyl group, 2 2,6-dimethylcyclohexyl, 2,2,4-trimethylcyclohexyl, 2,2,6-trimethylcyclohexyl, 2-ethylcyclohexyl, 2-isopropylcyclohexyl, 2- Trifluoromethylcyclohexyl group, 2- (2,2-difluoroethyl) cyclohexyl group,
  • ⁇ means 1 or 2.
  • ⁇ is preferably 1.
  • the compound represented by the general formula [I] of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of the substituent.
  • the compound represented by the formula [I] also includes all these stereoisomers and a mixture thereof.
  • prodrugs of the compound represented by the general formula [I] of the present invention also belong to the scope of the present invention.
  • such prodrugs will be functional derivatives of the compounds of the present invention which are readily convertible in vivo into the required compound. Therefore, in the methods for prevention, treatment, etc. of various diseases according to the present invention, the term “administration” refers not only to the administration of a specific compound, but also to the specified compound in vivo after administration to a patient. And the administration of a compound that is converted to Conventional means for the selection and preparation of suitable prodrug derivatives are described, for example, in "DesignofProdrugs" ed.
  • Metabolites of these compounds include the active compounds produced by placing the compounds of the present invention in a biological environment and are within the scope of the present invention.
  • Specific examples of the compound represented by the general formula [I] of the present invention include, for example, 1-phenyl-2- (2-pyridyl) -18-cyclooctylmethyl-1,4,8-triazaspiro [4 .5] decane-3-one, 1-phenyl 2- (4-imidazolyl) -1-8-cyclooctylmethyl-1,4,8-triazaspiro [4.5] decane-3-one, 1-phenyl — 2— (2-Imidazolyl) -1-8-cyclooctylmethyl
  • decane-3-one 1-phenyl-1- (3-aminophenyl) -18- (2,2-dimethylcyclopentyl) methyl-1,4,8-triazaspiro [4.5] decane-3 —On, 1—Feniru 2—Pyrazirulu 8— (2,2-Dimethylcyclopentyl) methyl-1,4,8—Triazaspiro [4.5] decane—3—one, 1-Feniru 2— ( 2-pyrimidinyl) _8_ (2,2-dimethylcyclopentyl) methyl-1,4,8-triazaspiro [4.5] decane-1 3-o , 1-phenyl-1- (4-pyrimidinyl) -18- (2,2-dimethylcyclopentyl) methyl-1,4,8-triazaspiro [4.5] decane-3-one, 1_phenyl-2- ( 2-Oxazolyl) 18- (2,2-Dimethylcyclopentyl) methyl-1,4,8-tri
  • decane-3-one 1-phenyl-2- (2-pi-8- (2-methylcyclohexyl) methyl- 1,4,8-triazas Pyro [4.5] decane-1 3-one, 1-phenyl-2- (4-imidazolyl) -8- (2-methylcyclohexyl) methyl-1,4,8-triazaspiro [4.5] decane-1 3-one, 1-phenyl-2- (2-imidazolyl) -18- (2-methylcyclohexyl) methyl-1,4,8-triazaspiro [4.5] decane-3-one, 1-phenyl Lou 2- (2-thiazolyl) —8— (2-Methylcyclohexyl) methyl—1,4,8_triazaspiro [4.5] decane-3-one, 1-phenyl—2- (4-thiazolyl) — 8- (2-Methylcyclohexyl) methyl-1,4,8_triazaspiro [4.5] decane-3-one, 1-
  • decane-3-one 1- (3,5-difluorophenyl) -2- (2-pyridazinyl) -18- (spiro [4.4] nona 6-yl) methyl-1,4,8-triazaspiro [ 4.5]
  • Decane-3-one 1- (3,5-difluorophenyl) -1-2- [3- (1,2,4-triazolyl)]-1-8— (spiro [4.4] nona_6— Methyl-1,4,8-triazaspiro [4.5] decane-3-one, 1- (3,5-difluorophenyl) —2— [4— (1,2,3-triazolyl)] -8 — (Spiro [4.4] nona_6-yl) methyl — 1, 4, 8-triazaspiro [4.5] decane-3-one, 1— (3,5-difluorophenyl) 1-2— (2 —Morpholinyl) —8— (spi
  • decane-3-one 1- (3,5-difluorophenyl) -2- (4-thiazolyl) -18- (spiro [4.5] dec-6-yl) methyl-1,4,8 —Triazaspiro [4.5] decane-3-one, 11- (3,5-difluorophenyl) -2- (3-aminophenyl) -8— (spiro [4.5] deca6-yl) methyl 1,4,8-triazaspiro [4.5] decane-1-one, 1- (3,5-difluorophenyl) -1-2-pyrazinyl-8- (spiro [4.5] deca-6-yl) methyl — 1,4,8—triazaspiro [4.5] decane-3-one, 1- (3,5-difluorophenyl) 1-2- (2-pyrimidinyl) 18- (spiro [4.5] deca-1 6-yl) methyl-1,4,8-triazaspiro [4.5] de
  • the compound represented by the general formula [I] can be produced, for example, by the method shown in the following production method. Manufacturing method 1
  • R lp , A, Dan, C, _ and E have the above-mentioned meanings.
  • the compound represented by the general formula [I] can be obtained by reacting the compound represented by the formula [I] (condensation reaction) and removing the protecting group as necessary.
  • Examples of the protecting group for the amino group include benzyl, ⁇ -methoxybenzyl, 3,4-dimethoxybenzyl, ⁇ -nitrobenzyl, ⁇ -nitrobenzyl, benzylhydryl, and trityl.
  • Aralkyl groups such as formyl group, acetyl group, propionyl group, butyryl group, and piperyl group; lower alkanoyl groups such as benzoyl group; phenyl alkenyl groups such as phenyl acetyl group and phenoxy acetyl group; and methoxy carbonyl
  • a lower alkoxycarbonyl group such as an ethoxycarbonyl group or a propyloxycarbonyl group; for example, an aralkyloxy group such as a benzyloxycarbonyl group, a ⁇ -nitrobenzoyloxycarbonyl group, or a phenethyloxycarbonyl group.
  • Carbonyl group for example, phthaloyl group; for example, benzylidene , .Rho. black port base Njiriden group, o-mentioned such Araruki isopropylidene group and a nitro base Njiriden groups, especially downy Njiru group, benzyl O carboxymethyl Cal Poni group, Torichi Le group and the like.
  • acetal such as ethylene ketal and trimethylene ketone, ketal and the like are preferable.
  • hydroxyl-protecting group examples include:!: Substituted silyl groups such as ert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; A lower alkoxymethyl group such as -methoxyethoxymethyl group; for example, a tetrahydropyranyl group; for example, a trimethylsilylethoxymethyl group; for example, a benzyl group, a p-methoxybenzyl group, a 2,3-dimethoxybenzyl / group, an o-nitropent J And aralkyl groups such as p-nitrobenzyl group and trityl group; examples thereof include acetyl groups such as formyl group and acetyl group. Particularly, benzyl group, tert-butyldiphenylsilyl group and acetyl group. preferable.
  • Examples of the protective group for the carbonyl 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-trichloroethyl group; Lower alkenyl groups such as 2-propenyl group; for example, benzyl groups, p-methoxybenzyl groups, p-nitrobenzyl groups, aralkyl groups such as benzhydryl groups and trityl groups, and especially methyl groups; , An ethyl group, a tert-butyl group, a 2-propenyl group, a benzyl group, a p-methoxybenzyl group, a benzhydryl group and the like.
  • the introduction of the protecting group depends on the kind of the protecting group and the stability of the compound represented by the general formula [I], and the like.
  • the method described in the literature [Protective Drops 'In' Organic ⁇ Synthesis (Protectiv eGroup Organic Synthesis), written by TW Greene, John Wiley & Sons (1981) (hereinafter referred to as "Document P")]
  • Document P the method described in the literature [Protective Drops 'In' Organic ⁇ Synthesis (Protectiv ' Organic Synthesis), written by TW Greene, John Wiley & Sons (1981) (hereinafter referred to as "Document P”)]
  • Document P Alternatively, it can be performed according to a method equivalent thereto.
  • reaction between the compound represented by the general formula [II] and the compound represented by the general formula [III] is the same for both the compound represented by the general formula [II] and the compound represented by the general formula [III].
  • the reaction is carried out using an equimolar amount or a small molar amount of either one in the presence of an acid, usually in an inert solvent which does not adversely influence the reaction.
  • the inert solvent for example, benzene, toluene, xylene, chloroform, dichloroethane, cyclobenzene and the like are preferable.
  • the acid examples include sulfonic acids such as camphorsulfonic acid, P-toluenesulfonic acid, 2-naphthalenesulfonic acid, and methanesulfonic acid, or boron fluoride, Lewis acids such as titanium tetrachloride and zinc chloride, and preferably camphor. Sulfonic acid is mentioned.
  • the acid is used in an amount of 20 to 300 parts by weight, preferably 100 parts by weight, based on 100 parts by weight of the total of the compound represented by the general formula [II] and the compound represented by the general formula [III]. Use up to 200 parts by weight.
  • the reaction temperature is usually 60 ° C to 15 Ot, and the reaction time is usually 1 hour to 3 days, preferably 3 hours to 24 hours.
  • the method for removing the protecting group varies depending on the type of the protecting group and the stability of the compound represented by the general formula [I].
  • solvolysis using a base That is, for example, a method of reacting an equimolar to large excess of a base, preferably a hydroxide sphere, calcium hydroxide, or the like; chemical reduction using a metal hydride complex or a palladium carbon catalyst, palladium hydroxide carbon, water It is carried out by catalytic reduction using palladium oxide, Raney nickel catalyst or the like.
  • the compound represented by the general formula [II] or the general formula [III] can be, for example, a commercially available product, or a known method, or can be produced by the following method or the method described in Examples.
  • This production method is a method for producing a compound represented by the general formula [III].
  • a compound represented by the general formula hereinafter, referred to as “compound” is added to a compound represented by the general formula (hereinafter, referred to as “compound I”) in the presence of a cyanide.
  • compound a compound represented by the general formula [III] (hereinafter referred to as “compound”), and then hydrolyzing the cyano group of the compound A to produce a compound represented by the general formula [III] Can be.
  • step of producing compound _ from compound ⁇ for example, compound ⁇ ⁇ and compound _ and, for example, trimethylsilyl nitrile, potassium cyanide, cyanide in a solvent-free state or in acetic acid, water, methanol, ethanol, dioxane or the like or a mixed solvent thereof are used. It can be carried out by reacting cyanide such as sodium fluoride.
  • the amount of the compound and cyanide to be used is 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound I, respectively.
  • the reaction temperature is usually from 0 ° C to the boiling point of the solvent used in the reaction, preferably from 0 to room temperature.
  • the reaction time is generally 1 hour to 3 days, preferably 2 hours to 24 hours.
  • the above reaction can be carried out in the presence of a Lewis acid, if necessary.
  • a Lewis acid for example, ytterbium trifluoromethanesulfonate (111), boron trifluoride, zinc chloride and the like are preferable.
  • the amount of the Lewis acid used is 0.1 to 100 parts by weight, preferably 0.1 to 10 parts by weight, based on 100 parts by weight of the total amount of the compound II and the compound.
  • the step of producing the compound represented by the general formula [III] from _ can be carried out, for example, by reacting the compound A with an acid such as concentrated sulfuric acid, concentrated hydrochloric acid, phosphoric acid or the like to hydrolyze the compound. .
  • the acid is used in an amount of 100 to 1000 parts by weight, preferably 100 to 500 parts by weight, based on 100 parts by weight of the compound ⁇ J.
  • the reaction temperature is usually from 0 ° C to 100 ° C, preferably from o ° c to room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 1 hour to 8 hours.
  • an inorganic solvent such as sodium hydroxide, potassium hydroxide, potassium carbonate or the like in an alcoholic solvent such as methanol or ethanol.
  • the reaction temperature is usually from 0 ° C to the boiling point of the solvent used for the reaction, preferably from 0 to room temperature.
  • the reaction time is generally 1 hour to 24 hours, preferably 2 hours to 10 hours.
  • the amount of the base to be used is 2 mol to excess mol, preferably 2 to 3 mol, per 1 mol of compound_ ⁇ .
  • the amount of hydrogen peroxide used was 1.1 mol per 1 mol of compound _.
  • the molar excess is preferably 2 to 4 mol.
  • Compound I or compound can be produced by using commercially available product D, or by appropriately combining known methods, the methods described in the examples, or the methods analogous thereto. Manufacturing method B
  • R a is meaning taste such as a methyl group, Echiru group, a lower alkyl group such as propyl, R lp, A, Dan, C_, jR BiDan have the meanings. ]
  • This production method is a method for producing a compound represented by the general formula [III].
  • a compound represented by the general formula A (hereinafter, referred to as “compound”) is obtained by reacting a compound with the compound represented by the general formula A (hereinafter, referred to as “compound ⁇ ”). Then, the ester group of the compound is converted to an amide group by a functional group to obtain a compound of the general formula
  • the compound can also be produced by reacting a compound represented by the general formula (hereinafter, referred to as “compound”) with the compound to form an imine, and then reducing the imine.
  • compound a compound represented by the general formula
  • the step of producing compound __ ⁇ from compound 4 can be performed, for example, by reacting compound A with compound A in a solvent such as benzene, toluene, acetonitrile, dioxane, dimethylformamide or a mixed solvent thereof.
  • a solvent such as benzene, toluene, acetonitrile, dioxane, dimethylformamide or a mixed solvent thereof.
  • the amount of compound _ to be used is 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound J_.
  • the reaction temperature is usually 0 to the boiling point of the solvent used for the reaction, preferably room temperature or the boiling point of the solvent used for the reaction.
  • the reaction time is generally 1 hour to 24 hours, preferably 3 hours to 15 hours.
  • the above reaction can be carried out in the presence of a base, if necessary.
  • the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine, and sodium carbonate, for example.
  • inorganic bases such as carbon dioxide, sodium hydrogencarbonate and the like.
  • the amount of the base to be used is 2 mol to excess mol, preferably 2 to 3 mol, per 1 mol of compound A.
  • an excess ammonia water is allowed to act on the compound in water, methanol, ethanol, dioxane, toluene or the like or a mixed solvent thereof. Can be performed.
  • the reaction temperature is usually from 0 to the boiling point of the solvent used in the reaction, preferably from o ° C to room temperature.
  • the reaction time is generally 1 hour to 2 days, preferably 1 hour to 8 hours.
  • the compound _ ⁇ is allowed to act in a solvent such as toluene or benzene in the presence of a catalytic amount of an acid such as camphorsulfonic acid or toluenesulfonic acid. And then reducing it.
  • the amount of the compound to be used is 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the compound.
  • the reaction temperature at which the imine is produced is preferably the boiling point of the solvent used in the reaction, and the produced water is preferably removed using a Dean-Stark water separator or the like.
  • the reaction time is generally 1 hour to 3 days, preferably 5 hours to 15 hours.
  • a metal hydride complex such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, or the like is used. It can be carried out by catalytic reduction using a dime carbon, palladium carbon catalyst, Raney nickel catalyst or the like.
  • 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 used as appropriate, 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 methylene chloride, diglyme and the like; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aliphatic hydrocarbons such as pentane, hexane, heptane, cyclohexane and the like; benzene, toluene and the like And an inert solvent such as an aromatic hydrocarbon or a mixed solvent thereof.
  • the reaction temperature is usually from 120 to 100 ° (: preferably from 0 to room temperature.
  • the reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 6 hours.
  • the hydrogen pressure in the catalytic reduction reaction is usually preferably from normal pressure to 5 atm.
  • the amount of the catalyst used is usually from 1 to 100 parts by weight based on 100 parts by weight of compound 5. Preferably, it is 1 to 10 parts by weight.
  • the compound A or the compound can be produced by using a commercially available product, or by appropriately combining a known method, a method described in Examples, or a method analogous thereto as necessary. Manufacturing method C
  • This production method is a method for producing a compound represented by the general formula [II].
  • compound I 1,4-dioxa-18-azaspiro [4.5] decane is reacted with a compound represented by the general formula (hereinafter, referred to as “compound I”).
  • compound A compound represented by the general formula (hereinafter, referred to as “compound”) by reducing the compound, and then hydrolyzing the ketal.
  • the compound represented by the general formula [II] can be obtained.
  • 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 dichloroethane and the like; aromatic hydrocarbons such as benzene, toluene, benzene and xylene; aprotic polar solvents such as dimethylformamide, ethyl acetate, acetonitrile, hexamethylphosphate triamide; Or a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C to the boiling point of the solvent used in the reaction, preferably from room temperature to 10 ° C.
  • the reaction time is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours. After completion of the above reaction, either use the reaction solution as it is in the reduction reaction of the next step, or distill off the reaction solution, or isolate Compound A using ordinary separation means, and subject it to the subsequent reduction reaction. Can be.
  • a metal hydride complex such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, or the like is used. It can be carried out by catalytic reduction using a dime carbon, palladium carbon catalyst, Raney nickel catalyst or the like.
  • the compound ⁇ _ when a reducing agent that preferentially reduces imine, such as sodium cyanoborohydride or sodium triacetoxyborohydride, is used, the compound ⁇ _ can be subjected to a reduction reaction without isolation, without isolation.
  • a reducing agent that preferentially reduces imine such as sodium cyanoborohydride or sodium triacetoxyborohydride
  • 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 compound.
  • a solvent may be used, for example, alcohols such as methanol and ethanol; for example, dimethyl ether, ethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, dioxane, tetrahydrofuran, and diglyme.
  • Ethers such as methylene chloride, Halogenated hydrocarbons such as loroform and dichloroethane; aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane; inert solvents such as aromatic hydrocarbons such as benzene and toluene;
  • the mixed solvent can be used.
  • the reaction temperature is usually ⁇ 20 ° C. (: ⁇ 100 ° C., preferably 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, and the amount of the catalyst used is usually from 1 to 100 parts by weight based on 100 parts by weight of the starting compound. Parts, preferably 1 to 10 parts by weight.
  • the step of producing a compound represented by the general formula [II] from a compound is performed, for example, in a solvent such as tetrahydrofuran, acetone, water, or the like, using an excess amount of an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, oxalic acid, or the like.
  • a solvent such as tetrahydrofuran, acetone, water, or the like
  • an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, oxalic acid, or the like.
  • the reaction temperature is usually 0 to the boiling point of the solvent used for the reaction, preferably room temperature or the boiling point of the solvent used for the reaction.
  • the reaction temperature is generally 1 hour to 24 hours, preferably 1 hour to 8 hours.
  • Compound I can be produced by using a commercially available product, or by appropriately combining a known method or a method analogous thereto as necessary.
  • the compound represented by the general formula [I] obtained by the above method can be used in a conventional manner such as column chromatography using silica gel, alumina, an adsorption resin or the like, liquid chromatography, solvent extraction or recrystallization / reprecipitation. Isolation / purification can be performed by using a separation means alone or in an appropriate combination.
  • the compound represented by the general formula [I] can be converted into a pharmaceutically acceptable salt or ester by a conventional method. Conversely, the conversion of a salt or ester to a free compound can be easily performed according to a conventional method. It can be carried out.
  • CDNA encoding the human nociceptin receptor gene was incorporated into an expression vector pCR3 (manufactured by Invitrogen) to prepare pCR3ZORL1.
  • PCR3ZORL1 was introduced into CHO cells using transfectam (manufactured by Nippongene) to obtain a stable expression strain (CHOZORL1 cells) resistant to ImgZml G418.
  • a membrane fraction was prepared from this stable expression strain, and a receptor binding experiment was performed.
  • Membrane fraction 1 1 ⁇ g, 50 pM [ 125 I] Ty r 14 — No ciceptin (Amersh am Pharmamaciobiotech), 1 mg Wh eatge rm agg lutinin SPA beads (PVT-based Anamsh am Pharmacia Biotech) and a test compound were prepared using NC buffer (5 OmM Hepes, 10 mM sodium chloride, ImM magnesium chloride, 2.5 mM calcium chloride, 0.1% BSA, 0% The suspension was suspended in 25% bacitracin, pH 7.4), incubated at 37 ° C for 60 minutes, and the radioactivity was measured.
  • NC buffer 5 OmM Hepes, 10 mM sodium chloride, ImM magnesium chloride, 2.5 mM calcium chloride, 0.1% BSA, 0% The suspension was suspended in 25% bacitracin, pH 7.4), incubated at 37 ° C for 60 minutes, and the radioactivity was measured.
  • the binding activity to the nociceptin receptor was determined by the 50% inhibitory concentration (IC 5) calculated from the binding inhibitory activity of [ 125 I] Tyr 14 — No ciceptin to the ⁇ RL1 receptor by various concentrations of the compound of the present invention. Value). The results are shown in Table 1. This indicates that the compound of the present invention inhibits the action of nociceptin with high affinity for the nociceptin receptor.
  • CHOZORL 1 Membrane fraction prepared from the cells, 50 nM nociceptin, (manufactured by NEN Co.) 200 pM GTP ⁇ [35 S], 1.
  • Example 1 400 From the above, it was shown that the compound represented by the general formula [I] acts as a nociceptin receptor antagonist.
  • the compound represented by the general formula [I] is represented by morphine, an analgesic for painful diseases such as cancer pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia.
  • the compound represented by the general formula [I] is used for various diseases or symptoms involving nociceptin receptor (eg, obesity, Alzheimer's disease, dementia, schizophrenia, Parkinson's disease and chorea). Administration to patients with typical degenerative neurodegenerative diseases, depression, diabetes insipidus, polyuria or hypotension, etc. It can be used for the treatment of symptoms, and it can also prevent Alzheimer's disease and dementia.
  • nociceptin receptor eg, obesity, Alzheimer's disease, dementia, schizophrenia, Parkinson's disease and chorea.
  • a method for overcoming analgesia a method for overcoming narcotic analgesic resistance, a method for overcoming narcotic analgesic dependence, a method for enhancing analgesic action, and a method for improving brain function
  • a method for overcoming analgesia a method for overcoming narcotic analgesic resistance, a method for overcoming narcotic analgesic dependence, a method for enhancing analgesic action, and a method for improving brain function
  • a method for overcoming analgesia a method for overcoming narcotic analgesic resistance
  • a method for overcoming narcotic analgesic dependence a method for enhancing analgesic action
  • a method for improving brain function can be Pharmaceutical composition containing 4-oxoimidazolidin-2-spiro-nitrogen-containing heterocyclic compound represented by the general formula [I]
  • the compound represented by the general formula [I] of the present invention can be administered orally or parenterally, and is typified by an analgesic and morphine by being formulated into a form suitable for such administration.
  • Drugs for overcoming narcotic analgesic resistance drugs for overcoming narcotic analgesics dependence such as morphine, analgesic potentiators, antiobesity agents, brain function improvers, Alzheimer's disease preventives, Alzheimer's disease remedies, dementia prevention Drugs, anti-dementia drugs, schizophrenia drugs, degenerative neurodegenerative diseases such as Parkinson's disease and chorea, antidepressants, diabetes insipidus, polyuria or hypotension Can be offered.
  • a pharmaceutical composition is prepared by adding a pharmaceutically acceptable excipient according to the administration form, It is also possible to administer.
  • various additives commonly used in the field of pharmaceutical preparations can be used, such as gelatin, lactose, glucose, starch, corn starch, partially pregelatinized starch, crystalline cellulose, and methylcellulose.
  • Dosage forms formulated as pharmaceutical compositions include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs or injections. These can be prepared according to the usual methods in the pharmaceutical field.
  • a liquid preparation it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use.
  • a buffer or a preservative may be added.
  • compositions contain the compound represented by the general formula [I] of the present invention in a proportion of 0.1 to 99.5% by weight, preferably 1.0 to 60% by weight of the whole composition. And 0.5 to 99.9% by weight, preferably 40 to 99.0% by weight, of a pharmaceutically acceptable additive.
  • the composition may also include other therapeutically effective compounds.
  • the dosage and frequency of administration depend on the patient's sex, age, weight, degree of symptom and purpose.
  • nociceptin receptor antagonism In general, in the case of oral administration, 0.01 to 20 per adult per day mg Z kg 1 to several times Te, In the case of parenteral administration, 0. 0 0 2 ⁇ 1 O m gZ k g a preferably administered in one to several times.
  • the reaction solution was 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 dissolved in 6 ml of tetrahydrofuran, and triflic acid was added. 9 lmg of enylphosphine and 0.6 ml of water were added, and the mixture was stirred at 75 ° C for 2 hours.
  • the aqueous layer was made alkaline with a 1N aqueous sodium hydroxide solution saturated with sodium chloride, and then extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 97 mg of the title compound.
  • Example 8 Using 8-cyclooctylmethyl-2- (4-hydroxybutyryl) -1-1-phenyl-1,4,8-triazaspiro [4.5] decane-3-one obtained in Example 17 The title compound was obtained in the same manner as in 10.
  • reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • camphorsulfonic acid 97 mg was added to a solution of 38 mg of 2-anilino-2- (4-pyridyl) acetoamide and 41 mg of 1-cyclooctylmethyl-1-piperidone in 3 ml of 1,2-dichloroethane, and the mixture was refluxed for 12 hours.
  • the reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • the resulting residue was added with 2 ml of aqueous ammonia and 100 mg of ammonium chloride at 50 ° C. For 20 hours.
  • the reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, the obtained residue was suspended in hexane, and filtered to obtain 239 mg of the title compound. Obtained.
  • camphorsulfonic acid was added to a solution of 5 Omg of 2-anilino-2- (2-pyridyl) acetamide and 53 mg of 1-cyclooctylmethyl-4-piperidone in 3 ml of 1,2-dichlorobenzene, and the mixture was refluxed for 23 hours.
  • the solvent was concentrated, diluted with chloroform, washed with a 1N aqueous sodium hydroxide solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was subjected to preparative thin-layer chromatography.
  • K iese 1 ge 1 TM (Merck) 60 F 254, Ar t 5744 ; was separated and purified by click every mouth Holm Z methano Ichiru 19 Bruno 1) to give the title compound 42 mg.
  • the reaction solution was filtered have use celite, the solvent was evaporated and the obtained residue was purified by preparative thin layer chromatography (K iese 1 ge 1 TM 60 F 254, Ar t 5744 ( Merck); chloroform
  • the resulting compound was obtained as two kinds of stereoisomers by separation and purification with Lum Z methanolic ammonia (9Z1Z0.1%).
  • camphorsulfonic acid was added to a solution of 2 Omg of 2-anilino-2- (3-quinuclidinyl) acetamide and 2 Omg of 1-cyclooctylmethyl-4-piperidone in 2 mL of 1,2-dichloroethane and refluxed for 14 hours.
  • dilute it with chloroform for washing wash with 1N aqueous sodium hydroxide solution and saturated saline, dry over anhydrous sodium sulfate, evaporate the solvent, and remove the resulting residue by preparative thin-layer chromatography (A).
  • the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was added with 50 ml of formamide and 2 ml of water and stirred at 210 ° C for 6 hours.
  • the reaction solution was made alkaline with a 1N aqueous sodium hydroxide solution, and then extracted with toluene.
  • camphorsulfonic acid was added to a suspension of 92 mg of 2-anilinol 2- (2-thiazolyl) acetoamide and 139 mg of 1-cyclooctylmethyl-4-piperidone in 4 ml of 1,2-dichloroethane, and the mixture was refluxed for 13 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated saline, and dried over anhydrous sodium sulfate.
  • reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium hydroxide and saturated brine, dried over sodium sulfate, and the solvent was distilled off.
  • reaction solution was diluted with ethyl acetate, washed with 1N7K aqueous sodium oxide solution and saturated saline, and dried over sodium sulfate.
  • Triethylamine 201 and trifluoroacetic anhydride 18 ⁇ 1 were added at 0 ° C. to a solution of Omg in the form of closin form lm1, and the mixture was stirred at the same temperature for 20 minutes.
  • the reaction solution was diluted with Edel acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over sodium sulfate, and the solvent was distilled off.
  • Example 2 Compound 20.0 ⁇ of Example 1, lactose 417.0 g, microcrystalline cellulose 80.0 g, and partially alpha-starch starch 80.0 g were mixed using a V-type mixer, and then magnesium stearate 3. 0 g was added and mixed.
  • the mixed powder was tableted according to a conventional method to obtain 3000 tablets having a diameter of 7.0 mm and a tablet weight of 15 Omg.
  • the compound of the present invention inhibits the action of nociceptin by having a high affinity for the nociceptin receptor, and for example, reduces pain such as pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain, neuralgia, etc.
  • Analgesics for associated diseases drugs for overcoming narcotic analgesic resistance such as morphine, drugs for narcotic analgesic dependence such as morphine, analgesic potentiators, anti-obesity drugs, brain function improvers, Alzheimer's disease Prophylactic, anti-Alzheimer's disease, dementia prophylactic, anti-dementia, schizophrenia, degenerative neurodegenerative diseases such as Parkinson's disease and chorea, antidepressants, urine It is useful as a reversible drug, polyuria drug or hypotension drug.

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Abstract

L'invention concerne des composés de formule générale (I) inhibant la nociceptine étant donné leur affinité élevée pour le récepteur de la nociceptine. Ces composés présentent une efficacité élevée en termes d'atténuation de la douleur et de réaction contre la tolérance aux analgésiques narcotiques. Ils permettent également de réduire et de prévenir l'obésité, de stimuler les fonctions cérébrales, de prévenir la maladie d'Alzheimer, d'atténuer et de prévenir la démence, de traiter la schizophrénie, la maladie de Parkinson et la chorée, d'atténuer et de prévenir la dépression, de traiter le diabète insipide, la polyurie et l'hypotension, etc. Dans cette formule, ∫U⊃A∫/U⊃, ∫U⊃B∫/U⊃, ∫U⊃C∫/U⊃, et ∫U⊃E∫/U⊃ sont chacun un groupe méthine ou azote éventuellement substitué, R1 est alkyle inférieur éventuellement substitué, un groupe carbocyclique, un groupe hétérocyclique ou analogue, n vaut 1 ou 2, et Cy est un groupe carbocyclique aliphatique mono-, bi- ou tricyclique éventuellement substitué comprenant entre 5 et 15 atomes de carbone.
PCT/JP2001/004869 2000-06-14 2001-06-08 Composes heterocycliques 4-oxoimidazolidine-2-spiro-azotes Ceased WO2001096337A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003010168A1 (fr) * 2001-07-23 2003-02-06 Banyu Pharmaceutical Co., Ltd. Derive de 4-oxoimidazolidine-2-spiropiperidine
US7081463B2 (en) 2002-09-09 2006-07-25 Janssen Pharmaceutica N.V. Hydroxy alkyl substituted 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1receptor mediated disorders
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
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
US8703948B2 (en) 2006-11-28 2014-04-22 Janssen Pharmaceutica Nv Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one
US8741916B2 (en) 2007-04-09 2014-06-03 Janssen Pharmaceutica Nv 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor
CN115260195A (zh) * 2021-04-30 2022-11-01 上海齐鲁制药研究中心有限公司 Egfr降解剂

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US3725389A (en) * 1971-07-02 1973-04-03 American Home Prod Adducts of delta-aminobenzylpenicillin and n-substituted-4-piperidones
JPH01207291A (ja) * 1988-02-12 1989-08-21 Takeda Chem Ind Ltd トリアザスピロ化合物
EP0921125A1 (fr) * 1997-12-05 1999-06-09 F. Hoffmann-La Roche Ag Derives de la 1,3,8-triazaspiro[4,5]decan-4-one
WO2000034280A1 (fr) * 1998-12-09 2000-06-15 Banyu Pharmaceutical Co., Ltd. Composes heterocycliques de 4-oxo-imidazolidine-2-spiro-azote

Patent Citations (4)

* 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
JPH01207291A (ja) * 1988-02-12 1989-08-21 Takeda Chem Ind Ltd トリアザスピロ化合物
EP0921125A1 (fr) * 1997-12-05 1999-06-09 F. Hoffmann-La Roche Ag Derives de la 1,3,8-triazaspiro[4,5]decan-4-one
WO2000034280A1 (fr) * 1998-12-09 2000-06-15 Banyu Pharmaceutical Co., Ltd. Composes heterocycliques de 4-oxo-imidazolidine-2-spiro-azote

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7081463B2 (en) 2002-09-09 2006-07-25 Janssen Pharmaceutica N.V. Hydroxy alkyl substituted 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1receptor mediated disorders
US7582649B2 (en) 2002-09-09 2009-09-01 Janssen Pharmaceutica, Nv Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
US8778956B2 (en) 2002-09-09 2014-07-15 Janssen Pharmaceutica Nv Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
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
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
US8703948B2 (en) 2006-11-28 2014-04-22 Janssen Pharmaceutica Nv Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one
US8741916B2 (en) 2007-04-09 2014-06-03 Janssen Pharmaceutica Nv 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor
CN115260195A (zh) * 2021-04-30 2022-11-01 上海齐鲁制药研究中心有限公司 Egfr降解剂

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