US20050148650A1 - Antidepressant - Google Patents

Antidepressant Download PDF

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Publication number
US20050148650A1
US20050148650A1 US10/506,269 US50626904A US2005148650A1 US 20050148650 A1 US20050148650 A1 US 20050148650A1 US 50626904 A US50626904 A US 50626904A US 2005148650 A1 US2005148650 A1 US 2005148650A1
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benzofuran
dihydro
pentamethyl
optionally substituted
group
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Inventor
Shigenori Ohkawa
Masaomi Miyamoto
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Takeda Pharmaceutical Co Ltd
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Individual
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Assigned to TAKEDA CHEMICAL INDUSTRIES LTD. reassignment TAKEDA CHEMICAL INDUSTRIES LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MIYAMOTO, MASAOMI, OHKAWA, SHIGENORI
Assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED reassignment TAKEDA PHARMACEUTICAL COMPANY LIMITED CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: TAKEDA CHEMICAL INDUSTRIES, LTD.
Publication of US20050148650A1 publication Critical patent/US20050148650A1/en
Priority to US11/475,539 priority Critical patent/US7750037B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to protein kinase B (hereinafter, referred to as PKB in some cases) activating agents and use of these PKB activating agents for preventing or treating depression, PTSD, Parkinson's disease, Alzheimer's diseases, and the like.
  • PKB protein kinase B
  • Protein kinase B is also referred to as Akt, is one of protein phosphorylases, transmits stimuli from the extracellular to the inside of a cell, and is known to be involved in response of a cell to these stimuli.
  • a signal transduction from phosphatidylinositol-3 (hereinafter, referred to as PI-3) is involved in nerve cell survival, nerve regeneration or nerve differentiation.
  • GSK glycogen synthase kinase-3 ⁇
  • PKB activation and effects of treating neurodegenerative diseases such as Parkinson's disease are not necessarily confirmed in vitro.
  • a relationship between PKB activation and effects of preventing or treating depression, anxiety, manic-depressive psychosis or PTSD (posttraumatic stress disorder; hereinafter, abbreviated as PTSD in some cases) is not confirmed.
  • Alzheimer's diseases that is, selective nerve cell death occurs progressively
  • Parkinson's disease amyotrophic lateral sclerosis (ALS) and Huntington's disease are known.
  • a dopamine agonist such as L-dopa which is a precursor of dopamine is used as a replacement therapeutic agent or a symptomatic therapeutic agent.
  • those replacement therapeutic agent and symptomatic therapeutic agent do not suppress progression of neurodegeneration, and effects are gradually lost with disease progression. For this reason, exploitation of drugs which suppress progression of neurodegeneration and promote regeneration of remaining nerve ending is desired, but drugs having such the activity have not been found out.
  • neurodegenerative diseases it is considered that a majority of nerve cells are degenerated at sideration, and it is thought that only degeneration suppression or promotion of regeneration of nerve ending can not regenerate sufficient function.
  • Benzofuran derivatives which have nerve regeneration promoting activity and are useful as a medicine for preventing or treating nerve degeneration diseases are reported in WO98/55454 and WO 00/34262.
  • One object of the present invention is to provide a medicine for preventing or treating Parkinson's diseases and the like by promoting nerve regeneration and maintaining survival of a nerve cell including fundamental nerve neogenesis, not by mere replacement therapy or symptomatic therapy.
  • Another object of the present invention is to provide a PKB activating agent which is suitable for achieving such the object.
  • PTSD posttraumatic stress disorder
  • drugs which have fewer side effect, and have higher preventing or treating efficacy are demanded.
  • Another object of the present invention is to provide an agent for preventing or treating depression, anxiety, manic-depressive psychosis and PTSD (posttraumatic stress disorder) which has low side effect, and has new different action of mechanism from the previously known monoamine inhibitory activity, selective serotonin re-uptake inhibitory activity, and cortisol synthesis inhibitory activity.
  • the present inventors intensively studied drugs which exert actions or effects of nerve regeneration, nerve neogenesis, and nerve survival maintenance together with clarification of action of mechanism and, as the result, found that the compound represented by the following formula (I) has excellent PKB activating activity, and further found out that compounds having the PKB activating activity can be a useful drug for preventing or treating Parkinson's diseases, by promoting nerve regeneration, and maintaining/protecting survival of a nerve cell, including nerve neogenesis.
  • PTSD posttraumatic stress disorder
  • a PKB activating agent in particular, a nerve regeneration promoting agent and/or a nerve stem cell or nerve precursor cell differentiation promoting agent due to PKB activation are unexpectedly effective in treating or preventing these diseases, inter alia, the following benzofuran derivative is effective in treating or preventing them as such the nerve regeneration promoting agent, and further continued to study, which resulted in completion of the present invention.
  • the present invention relates to:
  • FIG. 1 is a graph showing Akt phosphorylation promoting activity of Compound A and IGF-I in a rat hippocampus glia mixed culturing system.
  • R 1 and R 2 are the same or different, and represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R 1 and R 2 may be taken together with an adjacent carbon to form an optionally substituted 3- to 8-membered homocycle or heterocycle.
  • R 2 when represents a double bond, R 2 is not present. That is, in the above formula,
  • hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R 1 or R 2 examples include linear or cyclic hydrocarbon groups (e.g. alkyl, alkenyl, alkynyl, cycloalkyl, aryl, etc.). Among them, linear or cyclic hydrocarbon groups having 1 to 16 carbon atoms are preferable.
  • alkyl for example, C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) is preferable.
  • C 1-6 alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • alkenyl for example, C 2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) is preferable.
  • alkynyl for example, C 2-6 alkynyl (e.g. ethynyl, propargyl, butynyl, 1-hexynyl, etc.) is preferable.
  • cycloalkyl for example, C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is preferable.
  • aryl for example, C 6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.) is preferable.
  • Examples of the “substituent” in the “optionally substituted hydrocarbon group” represented by R 1 or R 2 include (1) a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), (2). C 1-3 alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, etc.), (3) nitro, (4) cyano, (5) optionally halogenated C 1-6 alkyl, (6) optionally halogenated C 2-6 alkenyl, (7) optionally halogenated C 2-6 alkynyl, (8) optionally halogenated C 3-6 cycloalkyl (9) C 6-14 aryl (e.g.
  • dimethylamino, diethylamino, etc. 17.
  • di-C 6-14 arylamino e.g. diphenylamino, etc.
  • (18) acyl (19) acylamino, (20) acyloxy, (21) optionally substituted 5- to 7-membered saturated cyclic amino, (22) 5- to 10-membered aromatic heterocyclic group (e.g.
  • 2- or 3-thienyl 2-, 3- or 4-pyridiyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, etc.), (23) sulfo, (24) C 6-14 aryloxy (e.g. phenyloxy, naphthyloxy, etc.), and the like.
  • hydrocarbon group may be substituted with 1 to 5, preferably 1 to 3 the above substituents at replaceable positions and, when the number of substituents is 2 or more, respective substituents may be the same or different.
  • C 1-6 alkyl examples include C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl. sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having 1 to 5 preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, and the like.
  • C 2-6 alkenyl examples include C 2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
  • halogen atoms e.g. fluorine, chlorine, bromine, iodine, etc.
  • Specific examples include vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 3,3,3-trifluoro-1-propenyl, 4,4,4-trifluoro-1-butenyl, and the like.
  • C 2-6 alkynyl examples include C 2-6 alkynyl (e.g. ethynyl, propargyl, butynyl, 1-hexynyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodide, etc.).
  • halogen atoms e.g. fluorine, chlorine, bromine, iodide, etc.
  • Specific examples include ethynyl, propargyl, butynyl, 1-hexynyl, 3,3,3-trifluoro-1-propynyl, 4,4,4-trifluoro-1-butynyl, and the like.
  • C 3-6 cycloalkyl examples include C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodide, etc.).
  • halogen atoms e.g. fluorine, chlorine, bromine, iodide, etc.
  • Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, and the like.
  • C 1-6 alkoxy examples include C 1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
  • Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, and the like.
  • C 1-6 alkylthio examples include C 1-6 alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
  • Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, and the like.
  • acyl examples include formyl, carboxy, carbamoyl, C 1-6 alkyl-carbonyl (e.g. acetyl, propionyl, etc.), C 3-6 cycloalkyl-carbonyl (e.g. cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C 1-6 alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C 6-14 aryl-carbonyl (e.g.
  • nicotinoyl isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl, etc.), mono-C 1-6 alkyl-carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), di-C 1-6 alkyl-carbamoyl (e.g.
  • methylsulfinyl, ethylsulfinyl, etc. C 6-14 arylsulfinyl (e.g. phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), and the like.
  • acylamino examples include formylamino, C 1-6 alkyl-carbonylamino (e.g. acetylamino, etc.), C 6-14 aryl-carbonylamino (e.g. phenylcarbonylamino, naphthylcarbonylamino, etc.), C 1-6 alkoxy-carbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino. etc.), C 1-6 alkylsulfonylamino (e.g.
  • methylsulfonylamino, ethylsulfonylamino, etc. C 6-14 arylsulfonylamino (e.g. phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), and the like.
  • acyloxy examples include C 1-6 alkyl-carbonyloxy (e.g. acetoxy, propionyloxy, etc.), C 6-14 arylcarbonyloxy (e.g. benzoyloxy, naphthylcarbonyloxy, etc.), C 1-6 alkoxy-carbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C 1-6 alkyl-carbamoyloxy (e.g. methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C 1-6 alkyl-carbamoyloxy (e.g.
  • Examples of the above “5- to 7-membered saturated cyclic amino” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, and the like.
  • Examples of the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include 1 to 3 of C 1-6 alkyl (e.g.
  • 2- or 3-thienyl 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoqiunolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, etc.), and the like.
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R 1 or R 2 examples include 5- to 14-membered heterocyclic groups (aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group) containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms.
  • aromatic heterocyclic group examples include 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic groups containing 1 or more (e.g. 1 to 4) hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms.
  • aromatic heterocycles such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolidine, xanthrene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pirimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ⁇ -carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole
  • aromatic heterocyclic group examples include 5- or 6-membered aromatic heterocyclic groups which may be fused with one benzene ring, and the like.
  • Specific examples include 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, 2- or 3-thienyl, and the like. More preferred are 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2-benzothiazolyl, and the like.
  • non-aromatic heterocyclic group examples include 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (aliphatic heterocyclic groups) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like.
  • aliphatic heterocyclic groups such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like.
  • Examples of the “3- to 8-membered homocycle” of the “optionally substituted 3- to 8-membered homocycle” formed by R 1 and R 2 include C 3-8 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclehexane, and the like.
  • Examples of the “3- to 8-membered heterocycle” of the “optionally substituted 3- to 8-membered heterocycle” formed by R 1 and R 2 include 3- to 8-membered heterocycles containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, such as aziridine, azetidine, morpholine, thiomorpholine, piperazine, piperidine, pyrrolidine, hexamethyleneimine, heptamethyleneimine, hexahydropyrimidine, and the like.
  • W represents:
  • R 3 is preferably a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group (hereinafter, referred to as R 3a in some cases).
  • the A ring represents an optionally substituted benzene ring.
  • the benzene ring may have the same 1 to 4 (preferably 1 or 2) substituents as those of the above “optionally substituted hydrocarbon group” represented by R 1 or R 2 at replaceable positions.
  • substituents may be the same or different.
  • the B ring represents an optionally substituted 5- to 7-membered nitrogen-containing heterocycle.
  • Examples of the “5- to 7-membered nitrogen-containing heterocycle” represented by the B ring include 5- to 7-membered nitrogen-containing heterocycles such as pyrrole (e.g. 1H-pyrrole, etc.), dihydropyrrole (e.g. 2,5-dihydro-1H-pyrrole, etc.), dihydropyridine (e.g. 1,2-dihydropyrridine, etc.), tetrahydropyridine (e.g. 1,2,3,4-tetrahydropyrridine, etc.), azepine (e.g. 1H-azepine, etc.), dihydroazepine (e.g.
  • pyrrole e.g. 1H-pyrrole, etc.
  • dihydropyrrole e.g. 2,5-dihydro-1H-pyrrole, etc.
  • dihydropyridine e.g. 1,2-dihydropyrridine, etc.
  • 2,3-dihydro-1H-azepine 2,5-dihydro-1H-azepine, 2,7-dihydro-1H-azepine, etc.
  • tetrahydroazepine e.g. 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine, etc.
  • the C ring represents a benzene ring optionally further substituted in addition to a group represented by the formula W.
  • the C ring may have 1 to 3 (preferably 1) groups represented by the formula W at replaceable positions and, when the number of substituents is 2 or more, respective substituents may be the same or different.
  • Examples of the “substituent” which may be further possessed by the C ring include the same substituents as those of the above “optionally substituted hydrocarbon group” represented by R 1 or R 2 .
  • the “C 1-6 alkyl” as the “substituent” of the C ring may be substituted with “4- to 8-membered lactone optionally substituted with hydroxy (e.g. 3-hydroxy- ⁇ -valerolactone, etc.)”, or the like.
  • the C ring may have 1 to 3 (preferably 3) of these substituents at replaceable positions and, when the number of substituents is 2 or more, respective substituents may be the same or different.
  • a benzene ring substituted with 3 C 1-6 alkyls such as methyl is preferable.
  • a benzene ring optionally further substituted with substituent(s) selected from halogen, optionally halogenated lower alkyl, optionally halogenated lower alkoxy and optionally halogenated lower alkylthio in addition to the group represented by the formula: wherein respective symbols are as defined above (hereinafter, referred to as C 1 ring in some cases), is preferable.
  • the C 1 ring may have 1 to 3 (preferably 1) of substituents represented by the formula: at replaceable positions and, when the number of substituents is 2 or more, respective substituents may be the same or different.
  • halogen as the “substituent” which may be further possessed by the C 1 ring include fluorine, chlorine, bromine, iodine, and the like.
  • optionally halogenated lower alkyl include C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g.
  • fluorine, chlorine, bromine, iodine, etc. include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, and the like.
  • halogenated lower alkoxy examples include C 1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.).
  • halogen atoms e.g. fluorine, chlorine, bromine, iodine, etc.
  • Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, and the like.
  • the C 1 ring may have 1 to 3 (preferably 3) of these substituents at replaceable positions and, when the number of substituents is 2 or more, respective substituents may be the same or different.
  • R 3 is preferably an optionally substituted C 6-14 aryl group (hereinafter, referred to as R 3b in some cases).
  • R 3b an optionally substituted C 6-14 aryl group
  • Examples of the “C 6-14 aryl” of the “optionally substituted C 6-14 aryl” represented by R 3b include C 6-14 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, and the like.
  • R 4 represents (1) an aliphatic hydrocarbon group substituted with an optionally substituted aromatic group, and optionally further substituted, or (2) an acyl group containing an optionally substituted aromatic group.
  • Examples of the “aromatic group” of the “optionally substituted aromatic group” as the substituent of the “aliphatic hydrocarbon group substituted with an optionally substituted aromatic group, and optionally further substituted” represented by R 4 include an aromatic hydrocarbon group, and an aromatic heterocyclic group.
  • aromatic hydrocarbon group examples include monocyclic or fused polycyclic (di- or tri-cyclic) aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specific examples include C 6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, and the like, preferably C 6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, and the like.
  • aromatic heterocyclic group examples include 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic groups containing 1 or more (e.g. 1 to 4) hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms.
  • aromatic heterocycles such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolidine, xanthrene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ⁇ -carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole
  • aromatic heterocyclic group examples include 5- or 6-membered aromatic heterocyclic groups which may be fused with one benzene ring.
  • Specific examples include 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, 2- or 3-thienyl, and the like.
  • Examples of the “aliphatic hydrocarbon group” of the “aliphatic hydrocarbon group substituted with an optionally substituted aromatic group, and optionally further substituted” represented by R 4 include alkyl, alkenyl, alkynyl, and cycloalkyl. Inter alia, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl and C 3-10 cycloalkyl are preferable.
  • alkyl for example, C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) is preferable.
  • C 1-6 alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.
  • alkenyl for example, C 2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl etc.) is preferable.
  • alkynyl for example, C 2-6 alkynyl (e.g. ethynyl, propargyl, butynyl, 1-hexynyl etc.) is preferable.
  • cycloalkyl for example, C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) is preferable.
  • C 1-6 alkyl is preferable.
  • the “aliphatic hydrocarbon group” may be optionally substituted with 1 to 3 “optionally substituted aromatic groups” at replaceable positions, and when the number of the substituents is 2 or more, respective substituents may be the same or different.
  • acyl group of the “acyl group containing an optionally substituted aromatic group” represented by R 4 the same acyl group as that of the “substituent” of the “optionally substituted hydrocarbon group” represented by R 1 or R 2 is used.
  • acyl group containing an optionally substituted aromatic group represented by R 4
  • R 4 preferably, include C 6-14 aryl-carbonyl (e.g. benzoyl, 1-naphthoyl, 2-naphthoyl etc.), C 7-16 aralkyl-carbonyl (e.g. phenylacetyl, phenylpropionyl etc.), C 6-14 aryloxy-carbonyl (e.g. phenoxycarbonyl etc.), C 7-16 aralkyloxy-carbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl etc.), 5- or 6-membered heterocyclic carbonyl (e.g.
  • nicotinoyl isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl etc.), C 6-14 aryl-carbamoyl (e.g. phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), 5- or 6-membered heterocyclic carbamoyl (e.g.
  • C 6-14 arylsulfonyl e.g. phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.
  • R 5 represents a hydrogen atom, a C 1-6 alkyl group or an acyl group.
  • Examples of a C 1-6 alkyl group represented by R 5 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • acyl group represented by R 5
  • the same acyl group as that of the “substituent” of the “optionally substituted hydrocarbon group” represented by R 1 or R 2 is used.
  • the C ring represents a benzene ring which may be further substituted in addition to a group represented by the formula —NR 4 (R 5 ) (hereinafter, referred as the C 2 ring in some cases).
  • the C 2 ring may be substituted with 1 to 3 groups represented by the formula —NR 4 (R 5 ) at replaceable positions and, when the number of the substituents is 2 or more, respective substituents may be the same or different.
  • substituents include a halogen atom (e.g. fluorine, chlorine, bromine, iodine etc.), C 1-3 alkylenedioxy (e.g.
  • phenylamino 1-naphthylamino, 2-naphthylamino etc.
  • di-C 1-6 alkylamino e.g. dimethylamino, diethylamino etc.
  • di-C 6-14 arylamino e.g. diphenylamino etc.
  • acyl acylamino, optionally substituted 5- to 7-membered saturated cyclic amino, 5- to 10-membered aromatic heterocyclic groups (e.g.
  • 2- or 3-thienyl 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl etc.) and sulfo.
  • Examples of the “optionally halogenated C 1-6 alkyl”, the “optionally halogenated C 2-6 alkenyl”, the “optionally halogenated C 2-6 alkynyl”, the “optionally halogenated C 3-6 cycloalkyl”, the “optionally halogenated C 1-6 alkoxy”, the “acyl”, the “acylamino” and the “optionally substituted 5-to 7-membered saturated cyclic amino” include the same groups as those of the “substituent” of the “optionally substituted hydrocarbon group” represented by R 1 or R 2 .
  • R 4c represents an optionally substituted aromatic group, an optionally substituted aliphatic hydrocarbon group or an acyl group.
  • Examples of the “aromatic group” of the “optionally substituted aromatic group” represented by R 4c include an aromatic hydrocarbon group and an aromatic heterocyclic group.
  • aromatic hydrocarbon group examples include monocyclic or fused polycyclic (bi- or tri-cyclic) aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specific examples thereof include C 6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl and anthryl.
  • aromatic heterocyclic group examples include 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic groups containing 1 or more (e.g. 1 to 4) hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms.
  • aromatic heterocycles such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xanthrene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ⁇ -carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazo
  • aromatic heterocyclic group examples include 5- or 6-membered aromatic heterocyclic groups which may be fused with one benzene ring.
  • aromatic heterocyclic groups include 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, and 2- or 3-thienyl.
  • Further preferable examples include 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, 1- or 2-indolyl, and 2-benzothiazolyl.
  • substituted aromatic group examples include a halogen atom (e.g. fluorine, chlorine, bromine, iodine etc.), C 1-3 alkylenedioxy (e.g. methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionally halogenated C 1-6 alkyl, optionally halogenated C 2-6 alkenyl, optionally halogenated C 2-6 alkynyl, optionally halogenated C 3-6 cycloalkyl, optionally halogenated C 1-6 alkoxy, optionally halogenated C 1-6 alkylthio, hydroxy, amino, mono-C 1-6 alkylamino (e.g.
  • a halogen atom e.g. fluorine, chlorine, bromine, iodine etc.
  • C 1-3 alkylenedioxy e.g. methylenedioxy, ethylenedioxy etc.
  • nitro, cyano optionally halogenated C 1-6 alky
  • di-C 1-6 alkylamino e.g. dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino etc.
  • Examples of the “optionally halogenated C 1-6 alkyl”, the “optionally halogenated C 2-6 alkenyl”, the “optionally halogenated C 2-6 alkynyl”, the “optionally halogenated C 3-6 cycloalkyl”, the “optionally halogenated C 1-6 alkoxy”, the “optionally halogenated C 1-6 alkylthio”, the “optionally substituted 5- to 7-membered saturated cyclic amino”, the “acyl”, the “acylamino” and the “acyloxy” include the same groups as those of the “substituent” of the “optionally substituted hydrocarbon group” represented by R 1 or R 2 .
  • the “aromatic group” may be optionally substituted with 1 to 3 above-mentioned substituents at replaceable positions and, when the number of the substituents is 2 or more, respective substituents may be the same or different.
  • optionally substituted aromatic group examples include phenyl, 2-, 3- or 4-pyridyl, 2- or 3-quinolyl, and 1-isoquinolyl, each of which may be optionally substituted with 1 to 3 substituents selected from halogen, C 1-3 alkylenedioxy, nitro, cyano, optionally halogenated C 1-6 alkyl, optionally halogenated C 2-6 alkenyl, optionally halogenated C 2-6 alkynyl, optionally halogenated C 3-6 cycloalkyl, optionally halogenated C 1-6 alkoxy, optionally halogenated C 1-6 alkylthio, hydroxy, amino, mono-C 1 -6 alkylamino, di-C 1-6 alkylamino, optionally substituted 5- to 7-membered saturated cyclic amino, acyl, acylamino, acyloxy, sulfo, C 6-14 aryl and C 6-14 aryloxy.
  • substituents selected from hal
  • Examples of the “aliphatic hydrocarbon group” of the “optionally substituted aliphatic hydrocarbon group” represented by R 4c include alkyl, alkenyl, alkynyl, and cycloalkyl. Among them, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, and C 3-10 cycloalkyl are preferable.
  • alkyl for example, C 1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) is preferable.
  • C 1-6 alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.
  • alkenyl for example, C 2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl etc.) is preferable.
  • alkynyl for example, C 2-6 alkynyl (e.g. ethynyl, propargyl, butynyl, 1-hexynyl etc.) is preferable.
  • cycloalkyl for example, C 3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.) is preferable.
  • C 1-6 alkyl is preferable.
  • acyl e.g. carboxy, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryl-carbonyl etc.
  • acyl group represented by R 4c
  • the same acyl group as that of the “substituent” of the “optionally substituted hydrocarbon group” represented by R 1 or R 2 is used.
  • Examples of the “optionally oxidized sulfur atom” represented by X or Y include S, SO and SO 2 .
  • Examples of the “substituent” of the “optionally substituted imino” represented by Y include an optionally substituted hydrocarbon group and acyl.
  • acyl are the same as those of the “acyl” mentioned above as the “substituent” of the “optionally substituted hydrocarbon group” represented by R 1 or R 2 .
  • Preferable examples of the “optionally substituted imino” represented by Y include imino, C 1-6 alkylimino (e.g. methylimino, ethylimino etc.), C 6-14 arylimino (e.g. phenylimino, 1-naphthylimino, 2-naphthylimino etc.), and C 7-16 aralkylimino (e.g. benzylimino).
  • C 1-6 alkylimino e.g. methylimino, ethylimino etc.
  • C 6-14 arylimino e.g. phenylimino, 1-naphthylimino, 2-naphthylimino etc.
  • C 7-16 aralkylimino e.g. benzylimino
  • X and Y are preferably an oxygen atom.
  • the compound (I) of the present invention includes a compound (Ia) represented by the formula: wherein respective symbols are as defined above, a compound (Ib) represented by the formula: wherein respective symbols are as defined above, and a compound (Ic) represented by the formula: wherein respective symbols are as defined above.
  • R 1 and R 2 are the same or different and are preferably a hydrogen atom or an optionally substituted C 1-6 alkyl group (particularly, C 1-3 alkyl group such as methyl) or taken together with the adjacent carbon atom to form an optionally substituted 3-to 8-membered homocycle or heterocycle, more preferably R 1 and R 2 are each a C 1-6 alkyl group.
  • R 1 is preferably an optionally substituted C 1-6 alkyl group, more preferably a C 1-3 alkyl group such as methyl.
  • R 3a for example, an optionally substituted C 6-14 aryl group is preferable.
  • a ring for example, a benzene ring optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylenedioxy is preferable.
  • B ring for example, a 5- to 7 membered nitrogen-containing heterocycle optionally substituted with 1 to 2 C 1-6 alkyl is preferable.
  • a benzene ring optionally further substituted with 1 to 3 substituents selected from C 1-6 alkyl and C 1-6 alkoxy is preferable.
  • R 6 and R 7 are preferably a hydrogen atom
  • the A ring is preferably a benzene ring optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkoxy and C 1-6 alkylenedioxy.
  • the position at which the C 1 ring is substituted with a group represented by the formula: wherein respective symbols are as defined in claim 1 is preferably the 5-position of the benzofuran ring or the dihydrobenzofuran ring.
  • the compound (Ia) is preferably a compound in which R 1 and R 2 are each a hydrogen atom or a C 1-6 alkyl group (in particular C 1-3 alkyl group such as methyl), R 3a is a hydrogen atom or a phenyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl (in particular C 1-3 alkyl such as methyl, ethyl, propyl or isopropyl) and halogen (in particular, fluorine), the A ring is a benzene ring optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkyl (in particular, C 1-3 alkyl such as methyl), C 1-6 alkoxy (in particular, C 1-3 alkoxy such as methoxy) and C 1-6 alkylenedioxy (in particular, C 1-3 alkylenedioxy such as methylenedioxy), the B ring is a 5- to 7-membered nitrogen-containing heterocycle
  • R 2 is not present and R 1 is preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group such as methyl.
  • R 3a is a phenyl group optionally substituted with 1 to 3 C 1-6 alkyl (in particular, C 1-3 alkyl such as methyl, ethyl, propyl or isopropyl)
  • the A ring is a benzene ring optionally substituted with 1 to 3 C 1-6 alkoxy (in particular, methoxy)
  • the B ring is a 5- to 7-membered nitrogen-containing heterocycle
  • the C 1 ring is a benzene ring optionally further substituted with 1 to 3 C 1-6 alkyl (in particular, C 1-3 alkyl such as methyl) (in particular, a benzene ring substituted with three C 1-6 alkyl such as methyl) and Y
  • Specific examples of the compound (Ia) include, preferably, the following compound 1a to 22a or salts thereof.
  • R 1 and R 2 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group (particularly, C 1-3 alkyl group such as methyl), or R 1 and R 2 are taken together with the adjacent carbon atom to form an optionally substituted 3- to 8-membered homocycle (e.g.
  • R 1 and R 2 are the same or different and are each a hydrogen atom or a C 1-6 alkyl group (particularly, C 1-3 alkyl group such as methyl), or R 1 and R 2 are taken together with the adjacent carbon atom to form a 3- to 8-membered homocycle.
  • R 1 and R 2 are more preferably each a C 1-6 alkyl group, and R 1 and R 2 are especially preferably each a methyl group.
  • R 3b is preferably, for example, a phenyl group optionally substituted with 1 to 3 substituents selected from halogen (in particularly, fluorine)and C 1-6 alkyl (in particular, C 1-3 alkyl such as methyl, ethyl, propyl or isopropyl), and more preferably a phenyl group optionally substituted with fluorine, methyl or isopropyl.
  • R 4 is preferably, for example, (1) a C 1-6 alkyl group substituted with an aromatic group (in particular, a C 6-14 aryl group such as phenyl or a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms, such as thienyl and pyridyl) optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkoxy and C 1-3 alkylenedioxy, or (2) an acyl group containing an aromatic group (in particular, C 6-14 aryl group such as phenyl) optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkoxy and C 1-3 alkylenedioxy, and more preferably (1) a C 1-6 alkyl group (in particular, C 1-3 alkyl group such as methyl) substituted with C 6-14 aryl (in particular, phenyl),
  • R 5 is preferably, for example, a hydrogen atom, a C 1-6 alkyl group (in particular, C 1-3 alkyl group such as methyl) or a C 1-6 alkyl-carbonyl group (in particular, C 1-3 alkyl-carbonyl group such as acetyl), and more preferably a hydrogen atom or a methyl group.
  • the C 2 ring is preferably a benzene ring optionally further substituted with 1 to 3 C 1-6 alkyl (in particular, C 1-3 alkyl such as methyl) and more preferably a benzene ring further substituted with three methyl.
  • the compound (Ib) is preferably a compound in which R 1 and R 2 are the same or different and are each a hydrogen atom or a C 1-6 alkyl group (in particular, C 1-3 alkyl group such as methyl), or R 1 and R 2 are taken together with the adjacent carbon atom to form a 3- to 8-membered homocycle;
  • R 2 is not present and R 1 is preferably a C 1-6 alkyl group and more preferably a C 1-3 alkyl group such as methyl.
  • R 3b is a phenyl group optionally substituted with 1 to 3 substituens selected from halogen (in particular fluorine) and C 1-6 alkyl (in particular, C 1-3 alkyl such as methyl, ethyl, propyl or isopropyl);
  • R 4 is (1) a C 1-6 alkyl group (in particular, C 1-3 alkyl group such as methyl) which is substituted with C 6-14 aryl (in particular, phenyl) optionally substituted with 1 to 3 substituents selected from halogen (in particular, fluorine) and C 1-6 alkoxy (in particular, C 1-3 alkoxy group such as methoxy), or (2) a C 6-14 aryl-carbonyl group
  • Specific examples of the compound (Ib) include preferably the following Compounds 1b to 67b.
  • the group represented by the formula —X—R 4c is preferably at the 5-position of the basic skeleton as follows:
  • the compound (Ic) is preferably a compound in which R 1 and R 2 are each C 1-6 alkyl which may be optionally substituted with 1 to 3 substituents selected from (1) C 6-14 aryl, (2) C 1-6 alkoxy, (3) C 1-6 alkylthio, (4) hydroxy, (5) amino, (6) mono-C 1-6 alkylamino, (7) mono-C 6-14 arylamino, (8) di-C 1-6 alkylamino, (9) di-C 6-14 arylamino, (10) carboxy, (11) C 1-6 alkylsulfonyl, (12) C 6-14 arylsulfonyl, (13) C 1-6 alkylsulfinyl, (14) C 6-14 arylsulfinyl and (15) 5- to 7-membered saturated cyclic amino optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl, C 6-14 aryl and 5- to 10-membered aromatic groups, or
  • R 1 and R 2 are each C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from C 6-14 aryl, C 1-6 alkoxy, C 1-6 alkylthio, hydroxy, amino, mono-C 1-6 alkylamino, mono-C 6-14 arylamino, di-C 1-6 alkylamino, di-C 6-14 arylamino, carboxy, C 1-6 alkylsulfonyl, C 6-14 arylsulfonyl, C 1-6 alkylsulfinyl and C 6-14 arylsulfinyl, or
  • R 1 and R 2 are each C 1-6 alkyl optionally substituted with phenyl-substituted 6-membered saturated cyclic amino, or
  • Specific examples of the compound (Ic) include preferably the following Compound 1c to 33c.
  • preferable Compound (Ic) includes:
  • a salt of such a compound may be, for example, a metal salt, an ammonium salt or a salt with an organic base when the compound has an acidic group such as —COOH, or an inner salt such as a salt with an inorganic acid, an organic acid, or a basic or acidic amino acid when the compound has a basic group such as —NH 2 .
  • a metal salt include alkali metal salts such as a sodium salt or a potassium salt; alkaline earth metal salts such as a calcium salt, a magnesium salt or a barium salt; and an aluminum salt.
  • a salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N-dibenzylethylenediamine.
  • a salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phospholic acid.
  • a salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • a salt with basic amino acid include salts with arginine, lysine and ornithine.
  • a salt with an acidic amino acid include salts with aspartic acid and glutamic acid.
  • pharmaceutically acceptable salts are preferable.
  • examples thereof include inorganic salts such as alkali metal salts (e.g. sodium salt, potassium salt etc.) or alkaline earth metal salts (e.g. calcium salt, magnesium salt, barium salt etc.) and an ammonium salt when the compound has an acidic functional group, and inorganic salts such as hydrochloride, sulfate, phosphate or hydrobromide and organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate or tartrate when the compound has a basic functional group.
  • inorganic salts such as alkali metal salts (e.g. sodium salt, potassium salt etc.) or alkaline earth metal salts (e.g. calcium salt, magnesium salt, barium salt etc.) and an ammonium salt when the compound has an acidic functional group
  • inorganic salts such as hydrochloride, sulfate,
  • the compound (I) (including the compounds (Ia), (Ib) and (Ic)) can be prepared by a method known per se, for example, a method described in WO 98/55454, WO 00/34262, WO 95/29907, JP-A 5-194466, U.S. Pat. No. 4,881,967, U.S. Pat. No. 4,212,865 or Tetrahedron Letters, vol. 37, No. 51, p. 9183-9186, 1996, or the similar method.
  • a prodrug of the compound (I) may be a compound which is converted into the compound (I) by a reaction with an enzyme or gastric acid under the physiological condition in vivo, that is, a compound which is changed into the compound (I) by enzymatic oxidation, reduction or hydrolysis or a compound which is changed into the compound (I) by hydrolysis with gastric acid or the like.
  • Examples of a prodrug of the compound (I) include a compound obtained by acylation, alkylation or phosphorylation of an amino group of the compound (I) (e.g. a compound obtained by eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation of an amino group of the compound (I)); a compound obtained by acylation, alkylation, phosphorylation or boration of a hydroxy group of the compound (I) (e.g.
  • the prodrug of the compound (I) may be a compound which is changed into the compound (I) under the physiological condition as described in “Development of medicines”, vol. 7, Molecular Design, p. 163-198 published by Hirokawashoten in 1990.
  • the PKB activating agent of the present invention leads to nerve degeneration inhibiting effect, nerve regeneration promoting effect, neural stem cell self-replication promoting effect, stem cell (e.g. embryonic stem cell, neural stem cell etc.) proliferation promoting effect, or neural precursor cell differentiation promoting effect by activating PKB, or leads to medical effect such as neural stem cell self-replication promoting effect, stem cell (e.g.
  • PBK activating agent of the present invention inter alia, Compound (I) has excellent nature as a medicine such as low toxicity and little side effect, it is useful as an agent for preventing or treating Parkinson's disease and Alzheimer's disease.
  • the PKB activating agent of the present invention is also useful as an agent for preventing or treating depression (particularly preferably, depression accompanied with atrophy or deficiency of nerve), anxiety, manic-depressive psychosis or PTSD.
  • depression particularly preferably, depression accompanied with atrophy or deficiency of nerve
  • anxiety manic-depressive psychosis or PTSD.
  • PTSD manic-depressive psychosis
  • it is particularly useful for depression accompanied with atrophy or deficiency of nerve.
  • it is also effective against cognition impairment accompanied with depression.
  • Compound (I) is useful for treating or preventing these disorders.
  • a medicine containing the PKB activating agent including Compound (I) is also effective against other diseases such as neurodegenerative disease (e.g. mild cognition impairment (MCI), amyotrophic lateral sclerosis (ALS), Huntington's disease, spinocerebellar degenerative disease, multiple sclerosis (MS), Pick's disease etc.), other mental disease (e.g.
  • MCI mild cognition impairment
  • ALS amyotrophic lateral sclerosis
  • MS spinocerebellar degenerative disease
  • MS multiple sclerosis
  • Pick's disease etc. other mental disease (e.g.
  • a medicine containing the PKB activating agent including Compound (I) also has differentiation-promoting effect on various stem cell systems and thereby can activate endogenous self-regenerating ability and promote regeneration of the tissue or function of pancreatic ⁇ -cells, hepatic cells, osteoblasts or the like; and thus it can be used as, for example, an agent for preventing or treating diabetic retinopathy, diabetic nephropathy, liver cirrhosis, alcoholic hepatitis, or various senile diseases accompanied with decrease in self-regenerating ability; an osteogenesis promoting agent, a bone disease preventing or treating agent, a fracture preventing or treating agent, a chondrogenesis promoting agent or a chondropathy preventing or treating agent (e.g.
  • non-metabolic bone disease e.g. fracture, re-fracture, bone deformation-spondylosis deformans, osteosarcoma, myeloma, osteogenesis imperfecta, scoliosis etc. in the orthopedic field
  • metabolic bone disease e.g. bone defect, osteoporosis, osteomalacia, rickets, osteitis fibrosa, renal osteodystrophy, bone Paget's disease, rigid myelitis etc.
  • joint disease e.g.
  • a medicine containing the PKB activating agent including Compound (I) can be also used for treating periodontal disease, repairing periodontal tissue defect caused by periodontal disease, stabilizing a dental implant, forming alveolar ridge or repairing cleft palate.
  • the PKB activating agent such as Compound (I) can be safely administered orally or parenterally (e.g. locally, rectally, venously etc.), as it is or as a pharmaceutical composition, for example, a tablet (including a sugar-coated tablet, a film coated tablet, an orally disintegrating tablet etc.), powder, a granule, a capsule (including a soft capsule), liquid, injection, a suppository, a sustained-release preparation and a patch, produced by mixing with a pharmacologically acceptable carrier according to a per se known means.
  • a tablet including a sugar-coated tablet, a film coated tablet, an orally disintegrating tablet etc.
  • powder a granule
  • a capsule including a soft capsule
  • liquid injection, a suppository, a sustained-release preparation and a patch, produced by mixing with a pharmacologically acceptable carrier according to a per se known means.
  • the content of Compound (I) in the preparation of the present invention is, for example, about 0.01 to about 100% by weight of the whole preparation.
  • the dose varies depending on an administration subject, an administration route, disease and the like.
  • the compound of the present invention as an active ingredient may be administered in an amount of about 0.1 to about 20 mg/kg body weight, preferably about 0.2 to about 10 mg/kg body weight, further preferably about 0.5 to about 10 mg/kg body weight, preferably about 0.5 to about 5 mg/kg body weight.
  • the dose may be administered in one or several divided portions per day.
  • the PKB activating agent such as Compound (I) is used for treating or preventing Parkinson's disease, Alzheimer's disease, depression, anxiety, manic-depressive psychosis or PTSD, or applied to treatment or prevention of the above-mentioned disease such as neurodegenerative disease (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, spinocerebellar degenerative disease, multiple sclerosis (MS), etc.), psychoneurotic disease (e.g.
  • neurodegenerative disease e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, spinocerebellar degenerative disease, multiple sclerosis (MS), etc.
  • psychoneurotic disease e.g.
  • schizophrenia, etc. head trauma, spinal cord injury, cerebrovascular disorder, cerebrovascular dementia, spinal cord injury, polyglutamine disease (dentatorubral-pallidoluysian atrophy, bulbospinal muscular atrophy, Machado-Jacob disease, spinocerebellar ataxia type 6), prion disease (Creutzfeldt-Jacob disease, Gerstmann-straussler-Scheinker disease), corticobasal ganglionic degeneration, progressive supranuclear palsy, AIDS encephalopathy, muscular dystrophy, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, liver cirrhosis, alcoholic hepatitis or osteoporosis, together with or independent of the treatment of Parkinson's disease, Alzheimer's disease, depression, anxiety, manic-depressive psychosis or PTSD; the PKB activating agent such as Compound (I) may be used in combination with another active ingredient.
  • the PKB activating agent such as
  • a concomitant drug examples include an acetylcholinesterase inhibitor (e.g. donepezil, rivastigmine, galantamine, zanapezil (TAK-147) etc.), a ⁇ -amyloid protein production, secretion, accumulation, aggregation and/or deposition inhibitor [a ⁇ -secretase inhibitor (e.g.
  • dopamine receptor agonist L-dopa, Bromocriptine, pergolide, talipexole, pramipexole, cabergoline, adamantadine etc.
  • MAO monoamine oxidase
  • an anti-choline agent e.g. trihexyphenidyl, biperidene etc.
  • COMT inhibitor e.g. entacapone etc.
  • amyotrophic lateral sclerosis treating drug e.g.
  • a hyperlipemia treating drug such as a cholesterol lowering drug [statin series (e.g. sodium pravastatin, atorvastatin, simvastatin, rosuvastatin etc.), fibrate (e.g. clofibrate etc.), a squalene synthase inhibitor], a drug for treating abnormal behavior or dromomania accompanied with progression of dementia (e.g. sedative, anti-anxiety drug etc.), an apoptosis inhibitor (e.g.
  • a nerve differentiation/regeneration promoting agent eprinim, xaliproden (SR-57746-A), SB-216763 etc.
  • a hypotensive drug e.g. meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin etc.
  • DMARD disease modifying anti-rheumatoid drug
  • an anti-cytokine drug e.g.
  • TNF inhibitor TNF inhibitor, MAP kinase inhibitor etc.
  • a steroid drug e.g. dexamethasone, hexestrol, cortisone acetate etc.
  • sex hormone or a derivative thereof e.g. progesterone, estradiol, estradiol benzoate etc.
  • parathyroid hormone PTH
  • a calcium receptor antagonist e.g. a ⁇ -secretase inhibitor such as 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin hydrochloride monohydrate.
  • Such another active ingredient and the PKB activating agent, the agent for preventing or treating Parkinson's disease, Arzheimer's disease, depression or the like, including Compound (I) of the present invention may be mixed according to a known per se method to be formulated into one pharmaceutical composition (e.g. a tablet, powder, a granule, a capsule (including a soft capsule), liquid, a injection, a suppository, a sustained-release preparation etc.), or they may be formulated into separate compositions and then administered to the same subject simultaneously or at a certain interval.
  • one pharmaceutical composition e.g. a tablet, powder, a granule, a capsule (including a soft capsule), liquid, a injection, a suppository, a sustained-release preparation etc.
  • a pharmacologically acceptable carrier which may be used for preparing the preparation of the present invention includes various organic or inorganic carrier substances which are conventional as a drug formulation material, for example, excipients, lubricants, binders and disintegrants for a solid preparation; and solvents, solubilizers, suspending agents, isotonizing agents, buffering agents and soothing agents for a liquid preparation. If necessary, conventional additives such as preservatives, anti-oxidants, coloring agents, sweeteners, adsorbents and wetting agents may be used.
  • excipients examples include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose and light anhydrous silicic acid.
  • lubricants examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • binders include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and carboxymethylcellulose sodium.
  • disintegrants examples include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and L-hydroxypropylcellulose.
  • solvents examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and olive oil.
  • solubilizers examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
  • suspending agents examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.
  • isotonizing agents examples include glucose, D-sorbitol, sodium chloride, glycerin and D-mannitol.
  • buffering agents include buffer solutions of phosphate, acetate, carbonate, citrate, and the like.
  • Examples of soothing agents include benzyl alcohol.
  • preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • antioxidants examples include sulfite, ascorbic acid and ⁇ -tocopherol.
  • the above (1) to (6) are mixed and compressed into a tablet with a tableting machine.
  • the above (1) to (6) are mixed and compressed into a tablet with a tableting machine.
  • the above (1) to (6) were mixed and compressed into a tablet with a tableting machine.
  • the hippocampus was removed from a 3 day-old rat and the cells were dispersed in a nerve dispersing solution. After the number of the cells was counted, the cells were suspended in a DMEM/F-12 medium containing 10% FCS (Embryo Max) and was then seeded on a 6-well plate coated with type I collagen at a density of 3 ⁇ 10 5 cells/cm 2 . After cultured for 4 days, the medium was replaced with a N2 supplement-containing medium.
  • Compound (I) Compound 17a was used; hereinafter referred to Compound A) was added to a well at 300 nM or 100 nM, and IGF-1 was added to a well at 100 ng/mL.
  • the cells were collected using Lysis Buffer containing protease inhibitor cocktail. Each cell suspension was centrifuged at 20000 rpm for 30 minutes and the supernatant was collected. An anti-5G3 Akt antibody was added to the supernatant to immunoprecipitate intracellular Akt. The resulting precipitate was subjected to SDS-PAGE using a 5-20% polyacrylamide gel and then to Western blotting. An anti-Phospho Akt antibody as a primary antibody and an HRP-linked anti-Rabbit antibody as a secondary antibody were used to detect the bands of phosphorylated Akt (Ser473 and Thr308).
  • the PVDF membrane was immersed in a reprobe buffer and permeated at 55° C. for 20 minutes to peel the antibodies. After that, an anti-Akt antibody (Cell signaling technology) as a primary antibody and an HRP-linked anti-Rabbit antibody (Cell signaling technology) as a secondary antibody were used to detect the band of total Akt.
  • an anti-Akt antibody Cell signaling technology
  • an HRP-linked anti-Rabbit antibody Cell signaling technology
  • FIG. 1 Effects of Compound A and insulin-like growth factor-1 (IGF-1) are shown in FIG. 1 .
  • the addition of Compound A promoted phosphorylation at both Thr308 and Ser473 sites after one day and three days ( FIG. 1 ).
  • the addition of 100 ng/mL of IGF-1 also promoted phosphorylation of Thr308 and Ser473. From these results, it was revealed that Compound A has Akt activating effect.
  • the PKB activating agent of the present invention is useful for preventing or treating Parkinson's disease by more fundamentally promoting endogenous proliferation or differentiation of nerve stem cells or by promoting engraftment or differentiation in a nerve stem cell or nerve cell transplantation.
  • the PKB activating agent of the present invention inter alia, the PKB activating agent containing Compound (I) or a salt or a prodrug thereof, and a nerve regeneration promoting agent based on the PKB activation have medical effects such as neural stem cell self-replication promoting effect, neural precursor cell differentiation promoting effect, neurotrophic factor-like effect, neurotrophic factor activity enhancing effect, nerve degeneration inhibiting effect, nerve regeneration promoting effect, and neural cell death inhibiting effect by antioxidative effect or ⁇ amyloid, which lead to inhibiting atrophy of pyramidal cells in the CA3 region of hippocampus, preventing suppression of nerve neogenesis in hippocampus caused by stress, or promoting nerve neogenesis or differentiation in hippocampus; and therefore are useful as an agent for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD. From these findings, the agent of the present invention is also effective as a treating drug of cognition impairment accompanied with depression.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060225143A1 (en) * 2003-03-19 2006-10-05 Gal Yadid Animal exhibiting ptsd-like behavior, per pct rule 4.3
US20100291069A1 (en) * 2009-05-14 2010-11-18 University Of Maryland, Baltimore Methods of treating a diabetic embryopathy
WO2018172527A1 (en) * 2017-03-24 2018-09-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of neurodegenerative disease

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2668864A1 (en) * 2006-11-09 2008-05-15 Takeda Pharmaceutical Company Limited Pharmaceutical composition comprising a dihydrobenzofuranyl isoindoline and a lipophilic component
EP2250176B1 (de) * 2008-01-30 2012-08-01 Cephalon, Inc. Substituierte spirocyclische piperidinderivate als histamin-3-(h3)rezeptorliganden
EP2406243B1 (de) 2009-03-10 2014-05-07 Takeda Pharmaceutical Company Limited Benzofuranderivate
WO2013035826A1 (ja) * 2011-09-08 2013-03-14 武田薬品工業株式会社 縮合複素環化合物
SI3186241T1 (sl) * 2014-08-29 2021-03-31 Chdi Foundation, Inc. Sonde za slikanje Huntingtonovega proteina
US12479816B2 (en) 2019-02-08 2025-11-25 University of Pittsburgh—of the Commonwealth System of Higher Education 20-HETE formation inhibitors
CA3226162A1 (en) 2021-07-09 2023-01-12 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate ikzf2

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5266707A (en) * 1991-09-18 1993-11-30 Fujirebio Inc. 3,5-dihydroxyheptanoic acid derivatives
US20010026796A1 (en) * 2000-03-14 2001-10-04 Croce Carlo M. TCL1 enhances Akt kinase activity and mediates its nuclear translocation
US20020160996A1 (en) * 1998-12-04 2002-10-31 Shigenori Ohkawa Benzofuran derivatives, their production and use
US20040034049A1 (en) * 2000-10-05 2004-02-19 Shigenori Okawa Promoters for the proliferation and differentiation of stem cells and/or neuron precursor cells
US20040167171A1 (en) * 2001-07-05 2004-08-26 Shigenori Ohkawa Benzo-fused 5-membered hetrocycle compounds, process for preparation of the same, and use thereof
US6878831B2 (en) * 2000-12-28 2005-04-12 Takeda Chemical Industries, Ltd. Process for preparing optically active 2,3-dihydrobenzofuran compounds

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4799934A (en) 1987-10-30 1989-01-24 Clairol Incorporated Sulfur-containing nitroaminobenzene dyes, process and hair dye compositions
US5854204A (en) 1995-03-14 1998-12-29 Praecis Pharmaceuticals, Inc. Aβ peptides that modulate β-amyloid aggregation
JP2001500852A (ja) 1996-08-27 2001-01-23 プレーシス ファーマスーティカルズ インコーポレイテッド Ｄ―アミノ酸を含むβ―アミロイドペプチド凝集のモジュレーター
EP0988289A2 (de) 1997-06-05 2000-03-29 Takeda Pharmaceutical Company Limited Benzofurane und benzothiophene als unterdrücker der neurodegeneration
JPH1149765A (ja) * 1997-06-05 1999-02-23 Takeda Chem Ind Ltd 複素環化合物、その製造法および剤
AU6111699A (en) 1998-10-08 2000-05-01 Smithkline Beecham Plc Novel method and compounds
CA2374610A1 (en) 1999-06-28 2001-01-04 Jordan J. N. Tang Catalytically active recombinant memapsin and methods of use thereof
JP2002201172A (ja) * 2000-02-25 2002-07-16 Japan Tobacco Inc ベンズアミド誘導体及びその用途
GB0022333D0 (en) 2000-09-12 2000-10-25 Glaxo Group Ltd Methods for identifying modulators of protein interactions
JP2002348239A (ja) 2000-10-05 2002-12-04 Takeda Chem Ind Ltd 幹細胞・神経前駆細胞の増殖・分化促進剤
US7153871B2 (en) * 2001-01-22 2006-12-26 Memory Pharmaceuticals Corporation Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs
US6566550B2 (en) * 2001-06-21 2003-05-20 Pfizer Inc Substituted aromatic ethers as inhibitors of glycine transport

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5266707A (en) * 1991-09-18 1993-11-30 Fujirebio Inc. 3,5-dihydroxyheptanoic acid derivatives
US20020160996A1 (en) * 1998-12-04 2002-10-31 Shigenori Ohkawa Benzofuran derivatives, their production and use
US6479536B1 (en) * 1998-12-04 2002-11-12 Takeda Chemical Industries, Ltd. Benzofuran derivatives, process for the preparation of the same and uses thereof
US20050187238A1 (en) * 1998-12-04 2005-08-25 Shigenori Ohkawa Benzofuran derivatives, their production and use
US20010026796A1 (en) * 2000-03-14 2001-10-04 Croce Carlo M. TCL1 enhances Akt kinase activity and mediates its nuclear translocation
US20040034049A1 (en) * 2000-10-05 2004-02-19 Shigenori Okawa Promoters for the proliferation and differentiation of stem cells and/or neuron precursor cells
US6878831B2 (en) * 2000-12-28 2005-04-12 Takeda Chemical Industries, Ltd. Process for preparing optically active 2,3-dihydrobenzofuran compounds
US20040167171A1 (en) * 2001-07-05 2004-08-26 Shigenori Ohkawa Benzo-fused 5-membered hetrocycle compounds, process for preparation of the same, and use thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060225143A1 (en) * 2003-03-19 2006-10-05 Gal Yadid Animal exhibiting ptsd-like behavior, per pct rule 4.3
US7652191B2 (en) 2003-03-19 2010-01-26 Bar Ilan University Nonhuman mammals exhibiting PTSD-like behavior
US20100291069A1 (en) * 2009-05-14 2010-11-18 University Of Maryland, Baltimore Methods of treating a diabetic embryopathy
US8828924B2 (en) 2009-05-14 2014-09-09 University Of Maryland, Baltimore Methods of treating a diabetic embryopathy
WO2018172527A1 (en) * 2017-03-24 2018-09-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical composition for the treatment of neurodegenerative disease
US11510936B2 (en) 2017-03-24 2022-11-29 Inserm Methods and pharmaceutical composition for the treatment of neurodegenerative disease

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