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US20090048325A1 - Prophylactic or Therapeutic Agent for Irritable Bowel Syndrome - Google Patents

Prophylactic or Therapeutic Agent for Irritable Bowel Syndrome Download PDF

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Publication number
US20090048325A1
US20090048325A1 US12/225,269 US22526907A US2009048325A1 US 20090048325 A1 US20090048325 A1 US 20090048325A1 US 22526907 A US22526907 A US 22526907A US 2009048325 A1 US2009048325 A1 US 2009048325A1
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group
optionally substituted
ring
hydrocarbon group
hydrogen atom
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Jun Terauchi
Fumihiko Sato
Nobuhiro Inatomi
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • 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
    • C07D307/93—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 condensed with a ring other than six-membered
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a prophylactic or therapeutic agent for irritable bowel syndrome.
  • IBS Irritable bowel syndrome
  • melatonin known as a hormone regulating sleep-wake cycle, improves significantly the abdominal symptoms such as abdominal pain, abdominal bloating and sense of urgency for defecation in female patients suffering from irritable bowel syndrome (see non-patent document 3).
  • melatonin shows an inhibitory action on partial restraint stress-induced defecation which is an experimental model based on defecation abnormality for irritable bowel syndrome (see non-patent document 4).
  • patent document 1 discloses that (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (general name: Ramelteon) has a melatonin receptor MT1/MT2 agonistic action.
  • the object of the present invention is to provide a prophylactic or therapeutic agent for irritable bowel syndrome.
  • the present inventors found out that certain melatonin agonists are effective for a prevention or treatment of irritable bowel syndrome, and resulted in the completion of the present invention.
  • the present invention provides:
  • a pharmaceutical composition for a prevention or treatment of irritable bowel syndrome which comprises a compound represented by formula (I):
  • R 1 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • X represents CHR 4 , NR 4 , CO, O or S (wherein, R 4 represents a hydrogen atom, an optionally substituted hydrocarbon group or hydroxyl group)
  • Y represents C, CH or N, represents a single bond or double bond
  • ring A represents an optionally substituted 5- to 7-membered heterocyclic ring containing an oxygen atom
  • ring B represents an optionally substituted benzene ring
  • m represents an integer of 1 to 4, or a salt thereof
  • R 1 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • X represents CHR 4 , NR 4 , CO, O or S (wherein, R 4 represents a hydrogen atom, an optionally substituted hydrocarbon group or hydroxyl group)
  • Y represents C, CH or N, represents a single bond or double bond
  • ring A represents an optionally substituted 5- to 7-membered heterocyclic ring containing an oxygen atom
  • ring B represents an optionally substituted benzene ring
  • m represents an integer of 1 to 4, or a salt thereof
  • R 1 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • X represents CHR 4 , NR 4 , CO, O or S (wherein, R 4 represents a hydrogen atom, an optionally substituted hydrocarbon group or hydroxyl group)
  • Y represents C, CH or N, represents a single bond or double bond
  • ring A represents an optionally substituted 5- to 7-membered heterocyclic ring containing an oxygen atom
  • ring B represents an optionally substituted benzene ring
  • m represents an integer of 1 to 4, or a salt thereof, for the manufacture of a pharmaceutical composition for a prevention or treatment of irritable bowel syndrome
  • FIG. 1 is a graph showing viscerosensory response test for compound A.
  • FIG. 2 is a graph showing restraint stress-induced defecation test for compound A.
  • FIG. 3 is a graph showing normal defecation test for compound A.
  • FIG. 4 is a graph showing a restraint stress-induced defecation test for melatonin.
  • Examples of melatonin agonists to be used for a preventive or therapeutic agent for irritable bowel syndrome in the present invention include a compound represented by the above formula (I) or a salt thereof, VEC-162 (Vanda), LY-156735 (Lilly), Agomelatine (Servier) and the like. Among them, the compound represented by the above formula (I) or a salt thereof is preferred.
  • R 1 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • X represents CHR 4 , NR 4 , CO, O or S (wherein, R 4 represents a hydrogen atom, an optionally substituted hydrocarbon group or hydroxyl group)
  • Y represents C, CH or N, represents a single bond or double bond
  • ring A represents an optionally substituted 5- to 7-membered heterocyclic ring containing an oxygen atom
  • ring B represents an optionally substituted benzene ring
  • m represents an integer of 1 to 4.
  • Y is C or CH.
  • examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” include an aliphatic hydrocarbon group, a monocyclic saturated hydrocarbon group and an aromatic hydrocarbon group, and preferred is a group having 1 to 16 carbons. Specifically, for example, an alkyl group, an alkenyl group, and an alkynyl group, a cycloalkyl group and aryl group are used.
  • alkyl group for example, a lower alkyl group and the like are preferred, and a C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl is used generally.
  • alkenyl group for example, a lower alkenyl group and the like are preferred, and a C 2-6 alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl and isobutenyl is used generally.
  • alkynyl group for example, a lower alkynyl group and the like are preferred, and a C 2-6 alkynyl group such as ethynyl, propargyl and 1-propynyl is used generally.
  • cycloalkyl group for example, a lower cycloalkyl group and the like are preferred, and a C 3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is used generally.
  • aryl group for example, a C 6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like are preferred, and for example, phenyl group is used generally.
  • hydrocarbon group of the “optionally substituted hydrocarbon group” may have 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the hydrocarbon group, and when the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • heterocyclic group of the “optionally substituted heterocyclic group” include a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic to tricyclic, preferably monocyclic or bicyclic) heterocyclic group containing one or two kinds of 1 to 4 (preferably 1 to 3) heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms.
  • 5-membered ring group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms such as 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyrazolidinyl, 2-, 4- or 5-imidazolyl, 1-, 2- or 3-triazolyl, 1-, 2- or 4-triazolyl, 1H- or 2H-tetrazolyl, and the like, 6-membered ring group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms, such as 2-, 3- or 4-pyridyl
  • C 1-6 alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.
  • an arylsulfinyl group e.g., C 6-10 arylsulfinyl group such as phenylsulfinyl, naphthylsulfinyl, etc.
  • a lower alkylsulfonyl group e.g.
  • C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.
  • an arylsulfonyl group e.g., C 6-10 arylsulfonyl group such as phenylsulfonyl, naphthylsulfonyl, etc.
  • heterocyclic group of the “optionally substituted heterocyclic group” may have 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions of the heterocyclic group, and when the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • the “optionally substituted amino group” includes an amino group that may have one or two of the above-mentioned “optionally substituted hydrocarbon group” and the like as a substituent.
  • the “amino group” may have, for example, an optionally substituted C 1-6 alkyl group and an optionally substituted C 6-10 aryl group are exemplified.
  • substituents similar to those that may be possessed by the above-mentioned “hydrocarbon group” are used.
  • the “lower alkyl group” of the “optionally substituted lower alkyl group” indicates C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, and may have 1 to 3 of the substituents that may be possessed by the above-mentioned “hydrocarbon group”, as a substituent.
  • the “lower alkoxy group” of the “optionally substituted lower alkoxy group” indicates a C 1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, and may have 1 to 3 of the substituents that may be possessed by the above-mentioned “hydrocarbon group”, as a substituent.
  • the “optionally substituted benzene ring” indicates a benzene ring that may have one or two substituents selected from a halogen atom (e.g., fluorine, chlorine, bromine, iodine), an optionally substituted hydrocarbon group, an optionally substituted amino group, an amido group (e.g., C 1-3 acylamino group such as formamide, acetamide, etc.), hydroxy group, an optionally substituted lower alkoxy group and lower alkylene dioxy group (e.g., C 1-3 alkylene dioxy group such as methylene dioxy, ethylene dioxy, etc.), at substitutable positions.
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • an optionally substituted hydrocarbon group e.g., an optionally substituted amino group, an amido group (e.g., C 1-3 acylamino group such as formamide, acetamide, etc.),
  • Preferred examples of the “optionally substituted benzene ring” include a benzene ring that may be substituted with one or two substituents selected from a halogen atom (e.g., fluorine, chlorine), a C 1-6 alkyl (e.g., methyl, ethyl, etc.), hydroxy group and mono-C 1-6 alkylamino group.
  • a halogen atom e.g., fluorine, chlorine
  • a C 1-6 alkyl e.g., methyl, ethyl, etc.
  • hydroxy group e.g., methyl, ethyl, etc.
  • R 1 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or optionally substituted heterocyclic group.
  • alkyl group may have 1 to 5, preferably, 1 to 3, substituents such as those that the above-mentioned “hydrocarbon group” may have, preferably, halogen atom such as fluorine, etc.
  • the preferred substituent of the “optionally substituted amino group” represented by R 1 for example, one or two of an optionally substituted lower alkyl group, an optionally substituted aryl group and the like are used, in particular, one of the optionally substituted lower alkyl group and the like is used.
  • the “lower alkyl group” for example, C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl is used.
  • the “lower alkyl group” may have 1 to 3 substituents that may be possessed by, for example, the above-mentioned “hydrocarbon group”.
  • aryl group for example, C 6-10 aryl group such as phenyl group and the like is used.
  • the “aryl group” may have 1 to 5, preferably 1 to 3, substituents such as those that the above-mentioned “hydrocarbon group” may have, preferably, halogen atom such as fluorine, chlorine, etc., C 1-6 alkoxy group such as methoxy, ethoxy, etc.
  • phenyl amino group substituted with 1 to 3 lower alkoxys e.g., C 1-4 alkoxy group such as methoxy, etc.
  • mono-alkylamino group substituted with lower alkyl group e.g., C 1-4 alkyl group such as methyl, ethyl, propyl, butyl and tert-butyl
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R 1 for example, 5- or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms is used.
  • 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholinyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-furyl or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, and the like are exemplified.
  • a 6-membered nitrogen containing-heterocyclic group e.g., pyridyl, etc.
  • the like are particularly preferably used.
  • a halogen atom e.g., chlorine, fluorine, etc.
  • a C 1-6 alkyl group e.g., methyl, ethyl, etc.
  • C 1-6 alkoxy group e.g., methoxy, ethoxy, etc.
  • aralkyloxycarbonyl group e.g., C 7-12 aralkyloxy-carbonyl such as benzyloxycarbonyl
  • R 1 is preferably, for example, (i) an optionally substituted lower alkyl group, (ii) an optionally substituted lower cycloalkyl group, (iii) an optionally substituted lower alkenyl group, (iv) an optionally substituted aryl group, (v) an optionally substituted mono- or di-lower alkylamino group, (vi) an optionally substituted arylamino group or (vii) an optionally substituted 5- or 6-membered nitrogen containing-heterocyclic group.
  • lower alkyl group are C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl, and the like.
  • Preferred examples of the “lower cycloalkyl group” are C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the like.
  • lower alkenyl group are C 2-6 alkenyl group such as vinyl, 1-propenyl, butenyl, and the like.
  • aryl group are C 6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, and the like.
  • Preferred examples of the “lower alkylamino group” are mono- or di-C 1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, dimethylamino, diethylamino, methylethylamino, and the like.
  • Preferred examples of the “arylamino group” are C 6-10 arylamino group such as phenylamino, and the like.
  • Preferred examples of the “5- or 6-membered nitrogen containing-heterocyclic group” are a 5- or 6-membered nitrogen containing-heterocyclic group such as 2-, 3- or 4-pyridyl, and the like. These groups may each have 1 to 5 substituents such as those the above-mentioned “hydrocarbon group” may have.
  • R 1 include i) C 1-6 alkyl group which may be substituted with 1 to 4 of halogen, hydroxy group or C 1-6 alkoxy group, ii) C 3-6 cycloalkyl group, iii) C 2-6 alkenyl group, iv) C 6-10 aryl group which may be substituted with 1 to 4 of C 1-6 alkoxy, nitro, halogenoC 1-6 alkyl-carbonylamino or halogen atom, v) mono- or di-C 1-6 alkylamino group, yl) C 6-10 arylamino group which may be substituted with 1 to 3 of C 1-6 alkoxy or vii) 6-membered nitrogen containing-heterocyclic group which may be substituted with 1 or 2 of C 7-11 aralkyloxycarbonyl group.
  • an optionally halogenated C 1-6 alkyl group e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.), C 3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) or mono-C 1-6 alkyla
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group.
  • a hydrogen atom or an optionally substituted lower (C 1-6 ) alkyl group is preferably used, and more preferably a hydrogen atom or a lower (C 1-6 ) alkyl group, in particular, a hydrogen atom is used widely.
  • R 3 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • alkyl group e.g., C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, etc.
  • alkenyl group e.g., C 2-6 alkenyl group such as vinyl, etc.
  • alkynyl group e.g., C 2-6 alkynyl group such as ethynyl, etc.
  • cycloalkyl group e.g., C 3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • aryl group e.g., C 6-14 aryl group such as phenyl, etc.
  • alkyl group e.g., C 1-6 alkyl group such as methyl, etc.
  • aryl group e.g., C aryl group
  • alkyl group may have 1 to 5, preferably, 1 to 3, substituents such as those that the above-mentioned “hydrocarbon group” may have, preferably, halogen atom such as fluorine atom, etc.
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R 3 , a 5- or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms is used.
  • 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholinyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, and the like are exemplified.
  • a 6-membered nitrogen containing heterocyclic group e.g., pyridyl, etc.
  • a halogen atom e.g., chlorine, fluorine, etc.
  • a C 1-6 alkyl e.g., methyl, ethyl, etc.
  • a C 1-6 alkoxy group e.g., methoxy, ethoxy, etc.
  • an aralkyloxycarbonyl group e.g., C 7-12 aralkyloxy-carbonyl such as benzyloxycarbonyl, etc.
  • amino group, mono-C 1-6 alkylamino group e.g., methylamino, ethylamino, etc.
  • di-C 1-6 alkylamino group e.g., dimethylamino, diethylamino, etc.
  • R 3 is preferably, for example, (i) a hydrogen atom, (ii) an optionally substituted lower alkyl group, (iii) an optionally substituted aryl group, (iv) an optionally substituted 5- or 6-membered heterocyclic group or the like, furthermore for example, (i) a hydrogen atom, (ii) a lower alkyl group, (iii) an optionally substituted C 6-10 aryl group, (iv) an optionally substituted 6-membered nitrogen containing heterocyclic group or the like is preferred.
  • substituents examples include a halogen atom, a C 1-6 alkyl, a C 1-6 alkoxy group, amino group, mono-C 1-6 alkylamino group, di-C 1-6 alkylamino group, and the like.
  • R 3 a hydrogen atom, phenyl group and 2-, 3- or 4-pyridyl group are more preferred. Particularly preferred is a hydrogen atom for R 3 .
  • X represents CHR 4 , NR 4 , CO, or S (wherein, R 4 represents a hydrogen atom, a hydroxyl group or an optionally substituted hydrocarbon group).
  • R 4 examples include a hydrogen atom, a hydroxyl group and an optionally substituted lower (C 1-6 ) alkyl group, and a hydrogen atom is used widely.
  • X is preferably CHR 4 (R 4 has the same meaning as the above-mentioned), CO, O or S. Or X is preferably CHR 4 or NR 4 (R 4 has the same meaning as the above-mentioned).
  • ring A represents an optionally substituted 5- to 7-membered heterocyclic ring containing an oxygen atom.
  • Examples of the “5- to 7-membered heterocyclic ring containing an oxygen atom” include a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic ring optionally containing 1 to 3 (preferably 1 or 2) of one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and an oxygen atom, and the like.
  • a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic ring optionally containing 1 to 3 (preferably 1 or 2) of one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to carbon atoms and an oxygen atom, and the like.
  • the ring represented by formula:
  • E represents (i) CH 2 CH 2 , (ii) CH ⁇ CH, (iii) CH 2 O, (iv) OCH 2 , (v) CH 2 S(O) q′ (q′ is an integer of 0 to 2), (vi) S(O) q′ CH 2 (q′ is as defined above), (vii) CH 2 NH, (viii) NHCH 2 , (ix) N ⁇ N, (x) CH ⁇ N, (xi) N ⁇ CH or (xii) CONH, and n′ represents an integer of 0 to 2, is preferred.
  • a 5-membered heterocyclic ring containing an oxygen atom such as 2,3-dihydrofuran, furan, 1,3-dioxole, oxazoline, isoxazole, 1,2,3-oxadiazole and oxazole
  • a 6-membered heterocyclic ring containing an oxygen atom such as 2H-3,4-dihydropyran, 2H-pyran, 2,3-dehydro-1,4-dioxane and 2,3-dehydromorpholine are preferred.
  • n represents an integer of 0 to 2, and represents a single bond or double bond.
  • 2,3-dihydrofuran, furan, 2H-3,4-dihydropyran and 2H-pyran are used widely.
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • an optionally substituted lower alkyl group an optionally substituted cycloalkyl group, an optionally substituted lower alkynyl group, an optionally substituted lower alkenyl group, an optionally substituted aryl group, a lower alkoxy group (e.g., C 1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), an aryloxy group (e.g., C 6-10 aryloxy group such as phenoxy, etc.), a lower alkanoyl group (e.g., formyl, C 1-6 alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, etc.), an arylcarbonyl group (
  • C 1-6 alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.
  • an arylsulfinyl group e.g., C 6-10 arylsulfinyl group such as phenylsulfinyl, naphthylsulfinyl, etc.
  • a lower alkylsulfonyl group e.g.
  • C 1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.
  • an arylsulfonyl group e.g., C 6-10 arylsulfonyl group such as phenylsulfonyl, naphthylsulfonyl, etc.
  • lower alkyl group “lower alkenyl group”, “lower alkynyl group”, “lower cycloalkyl group” and “aryl group” may have 1 to 5, preferably 1 to 3, of the substituents that may be possessed by the above-mentioned “hydrocarbon group”.
  • substituent for ring A examples include a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, hydroxyl group, nitro group, cyano group, an optionally substituted amino group, oxo group, and the like.
  • the substituent of the “optionally substituted C 1-6 alkyl group”, “optionally substituted C 1-6 alkoxy group” and “optionally substituted amino group” may be the substituents that may be possessed by the above-mentioned “hydrocarbon group”.
  • the ring A may have 1 to 4, preferably 1 to 2 of the above-mentioned substituents at substitutable positions depending on the ring size, and when the number of the substituents is 2 or more, the respective substituents may be the same or different.
  • ring A examples include
  • R 5 represents a hydrogen atom or 1 or 2 of the substituents represented by the above-mentioned “preferable substituent for ring A”, and the other symbols are as defined above, and the like.
  • a ring wherein R 5 is a hydrogen atom, hydroxyl group or an optionally substituted C 1-6 alkyl group, in particular, R 5 is a hydrogen atom (unsubstituted ring A), is used widely.
  • n represents an integer of 0 to 2, and n is preferably an integer of 0 or 1. Particularly, preferred is the case when n is 0.
  • ring B represents an optionally substituted benzene ring.
  • substituent for ring B examples include the “substituent” of the above-mentioned “optionally substituted benzene ring”.
  • a halogen atom, hydroxyl group or an optionally substituted lower (C 1-6 ) alkyl group is preferred, in particular, a halogen atom, hydroxyl group or a lower (C 1-6 ) alkyl group (preferably methyl) is used widely.
  • the “substituent” of the “optionally substituted lower (C 1-6 ) alkyl group” may be the substituents that may be possessed by the above-mentioned “hydrocarbon group”.
  • the ring B may have 1 or 2, preferably 1 of the above-mentioned substituents at substitutable positions, and when the number of the substituents is 2, the respective substituents may be the same or different.
  • Preferred examples of ring B include
  • R 6 represents a hydrogen atom, hydroxyl group, a halogen atom, an optionally substituted lower (C 1-6 ) alkyl group or an optionally substituted lower (C 1-6 ) alkoxy group.
  • R 6 is preferably a hydrogen atom, hydroxyl group, a halogen atom or lower (C 1-6 ) alkyl group (preferably methyl).
  • R 5 is more preferably a hydrogen atom.
  • m represents an integer of 1 to 4.
  • m is an integer of 1 to 3. More preferably, m is 2 or 3, and in particular, preferred is the case when m is 2.
  • R 4′ represents an optionally substituted hydrocarbon group or hydroxyl group, and the other respective symbol is as defined above.
  • R 4′ is preferably an optionally substituted lower (C 1-3 ) alkyl.
  • R 1 is (i) an optionally substituted lower alkyl group, (ii) an optionally substituted lower cycloalkyl group, (iii) an optionally substituted lower alkenyl group, (iv) an optionally substituted aryl group, (v) an optionally substituted mono- or di-lower alkylamino group, (vi) an optionally substituted arylamino group or (vii) an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group, R 2 is a hydrogen atom or an optionally substituted lower (C 1-6 ) alkyl group, R 3 is (i) a hydrogen atom, (ii) an optionally substituted lower alkyl group or (iii) an optionally substituted aryl group, X is CHR 4 or NR 4 (R 4 represents a hydrogen atom or lower (C 1-6 ) alkyl group optionally substituted with oxo group), Y is C, CH or N (provided that, when X represents CH 2
  • R 1 is i) C 1-6 alkyl group optionally substituted with 1 to 4 of halogen, hydroxyl group or C 1-6 alkoxy group, ii) C 3-6 cycloalkyl group, iii) C 2-6 alkenyl group, iv) C 6-10 aryl group optionally substituted with 1 to 4 of C 1-6 alkoxy group, nitro, halogenoC 1-6 alkyl-carbonylamino or halogen atom, v) mono- or di-C 1-6 alkylamino group, (vi) C 6-10 arylamino group optionally substituted with 1 to 3 of C 1-6 alkoxy group or vii) 6-membered nitrogen-containing heterocyclic group optionally substituted with 1 to 2 of C 7-11 aralkyloxy-carbonyl group, R 2 is a hydrogen atom or a lower (C 1-6 ) alkyl group, R 3 is (i) a hydrogen atom, (ii) a lower (C 1-6
  • R 6a represents a hydrogen atom, a halogen atom or a lower (C 1-6 ) alkyl group, and m is 1 or 2, and the like.
  • R 1b represents a C 1-6 alkyl group optionally having a hydroxyl group
  • R 6b represents a hydrogen atom or a halogen atom
  • n represents 0 or 1
  • X b represents CH 2
  • X b represents NH
  • a salt thereof is preferred.
  • R 1b represents a C 1-6 alkyl group optionally having a hydroxyl group
  • X′ represents CH 2 , NH or NCHO
  • R 3a represents a hydrogen atom or phenyl group, represents a single bond or double bond
  • E a represents CH 2 CH 2 , CH ⁇ CH, CH 2 O, CH ⁇ N, CONH or CH 2 NH
  • n a represents 0 or 1
  • ring A′′ represents an oxygen-containing 5- or 6-membered heterocyclic ring which may have 1 or 2 of C 1-6 alkyl group optionally substituted with a hydroxyl group
  • ring B′ represents a benzene ring optionally substituted with a halogen atom, or a salt thereof is also preferred.
  • a compound wherein, when X′ is CH 2 or NCHO, is a single bond or double bond and when X′ is NH, is a single bond, or a salt thereof is also preferred.
  • compound (I) include N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide, N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butylamide, N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(3,7,8,9-tetrahydropyrano[3,2-e]indol-1-yl)ethyl]propionamide, N-[2-(5-fluoro-3,7,8,9-tetrahydrocycopenta[f][l]benzopyran-9-yl)ethyl]propionamide, N-[2-(3,7,8,9-tetrahydropyrano
  • compound (I) is N-[2-[(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide, N-[2-[(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(5-fluoro-3,7,8,9-tetrahydrocycopenta[f][l]benzopyran-9-yl)ethyl]propionamide, N-[2-(5-fluoro-1,2,3,7,8,9-hexahydrocycopenta[f][l]benzopyran-9-yl)ethyl]propionamide, (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, (R)—N-[
  • compound (I) is (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]butylamide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butylamide, (2S)-2-hydroxy-N-[2-[(8S)
  • a salt of compound represented by formula (I) of the present invention for example, a pharmacologically acceptable salt is used.
  • the salt include salts with inorganic base, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like.
  • Preferred examples of the salts with inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt, ammonium salt, and the like.
  • Preferred examples of the salts with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, and the like.
  • Preferred examples of the salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of the salts with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • Preferred examples of the salts with basic amino acid include salts with arginine, lysine, ornithine, and the like, and preferred examples of a salt with acidic amino acid include salts with asparaginic acid, glutamic acid, and the like.
  • a pharmaceutically acceptable salt is preferred, and as examples thereof, in case that the compound represented by formula (I) has a basic functional group within the molecule, a salt with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like and a salt with organic acid such as acetic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like are exemplified, furthermore in case that the compound represented by formula (I) has a acidic functional group, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, and the like are exemplified.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, and the
  • the compound represented by formula (I) of the present invention may be a hydrate or non-hydrate.
  • the compound represented by formula (I) or a salt thereof is a known therapeutic agent for sleep disorder disclosed in U.S. Pat. No. 6,034,239 and the like, and can be produced by a known method such as the method described in said reference.
  • the compound represented by formula (I) of the present invention can be synthesized according to the production method described in JP 10-287665A or an analogous method thereto, and if desired, a combination of the method and a conventional oxidation method.
  • the compound represented by formula (I) or a salt thereof can be used for a prevention or treatment of irritable bowel syndrome, and for a prevention or treatment of abdominal pain associated with irritable bowel syndrome and bowel movement disorder associated with irritable bowel syndrome.
  • the compound represented by formula (I) or a salt thereof since the compound represented by formula (I) or a salt thereof has an antianxiety action, it can be used as a prophylactic or therapeutic agent for irritable bowel syndrome known for involvement of mental stress.
  • the compound represented by formula (I) or a salt thereof can also be used for a prevention or treatment of inflammatory bowel disease (IBD), functional dyspepsia and gastroesophageal reflux disease (GERD).
  • IBD inflammatory bowel disease
  • GFD gastroesophageal reflux disease
  • the compound represented by formula (I) or a salt thereof is extremely low toxic, it can be used for a prevention or treatment of irritable bowel syndrome, and for a prevention or treatment of abdominal pain associated with irritable bowel syndrome and bowel movement disorder associated with irritable bowel syndrome by combining with one or more of other prophylactic or therapeutic agents for irritable bowel syndrome, and thus the side effects caused by the other prophylactic or therapeutic agents for irritable bowel syndrome can be reduced by lowering the dose of such drugs.
  • prophylactic or therapeutic agents for irritable bowel syndrome examples include alosetron, tegaserod, polycarbophil calcium and trimebutine.
  • the compound represented by formula (I) or a salt thereof is extremely low toxic, it may be used in combination with one or more of other gastrointestinal motilitystimulant, sedative drug, antidepressant, and/or antianxiety drug.
  • gastrointestinal motility stimulant examples include domperidone, metoclopramide, mosapride, itopride, tegaserod, and the like.
  • antidepressant examples include tricyclic antidepressants [e.g., Doxepin, Imipramine hydrochloride, Amitriptyline, Clomipramine], tetracyclic antidepressants [e.g., Mianserine, Setiptiline, Maprotiline], SSRI [e.g., Fluoxetine, Sertraline, Paroxetine, Citalopram, Escitalopram, Fluvoxamine], SNRI [e.g., Milnacipran, Duloxetine, Venlafaxine, Trazodone, Nefazodone, Minaprine, Mirtazapine], triple uptake inhibitors [e.g., DOV-216303, NS-2359], NK1 receptor antagonist, and drugs having both melatonin receptor agonistic action and serotonin 2 receptor antagonistic action [e.g., Agomelatine], and the like.
  • tricyclic antidepressants e.g., Doxepin, Imipra
  • antianxiety drug examples include GABA-A agonistic antianxieties [e.g., Diazepam, Flutazolam, Lorazepam, Ethyl loflazepate, Flutoprazepam, Mexazolam, Clotiazepam, Etizolam, Hydroxyzine, Alprazolam, Fludiazepam, Chlordiazepoxide, Cloxazolam, Clorazepate, Oxazolam], serotonin antianxieties [e.g., Buspirone, Tandospirone], and the like.
  • GABA-A agonistic antianxieties e.g., Diazepam, Flutazolam, Lorazepam, Ethyl loflazepate, Flutoprazepam, Mexazolam, Clotiazepam, Etizolam, Hydroxyzine, Alprazolam, Fludiazepam, Chlordia
  • the compound represented by formula (I) or a salt thereof may be used in combination with the following drugs.
  • 5-HT 3 receptor antagonist for example, dolasetron, palonosetron, alosetron, azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620, ondansetron and indisetron
  • 5-HT 4 receptor agonist for example, tegaserod, mosapride, cinitapride and oxtriptane
  • laxative agent for example, Trifyba (trade name), Fybogel (trade name), Konsyl (trade name), Isogel (trade name), Regulan (trade name), Celevac (trade name) and Normacol (trade name); Amitiza (trade name)
  • dopamine receptor antagonist for example, metoclopramide, domperidone and levosulpiride
  • tachykinin (NK) receptor antagonist for example, nepad
  • drugs to be used in combination may be a free form or a pharmaceutically acceptable salt.
  • timing of administration of the prophylactic or therapeutic agent for irritable bowel syndrome of the present invention and the concomitant drugs is not limited, and these can be administered to the subjects simultaneously or at different times.
  • administration forms include
  • Dosage of concomitant drug can be appropriately selected on the basis of the clinically used dosage.
  • the combination ratio of the compound of the present invention and concomitant drug can be appropriately selected depending on a subject to be administered, an administration route, targeted diseases, symptoms, combinations thereof or the like.
  • the concomitant drug may be used with an amount of 0.01 to 100 parts by weight based on 1 part by weight of compound A.
  • dosage of the concomitant drug can be decided according to compound A.
  • the melatonin agonist to be used in the present invention can be safely administered orally or parenterally (e.g. topically, rectally, intravenously etc.) as it is or as a pharmaceutical composition mixed with pharmacologically acceptable carriers according to a conventional method (e.g., method described in Japanese Pharmacopoeia, etc.), such as tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules, solutions, emulsions, suspensions, injectables, suppositories, sustained-release agents (controlled-release preparation), adhesive preparations, and the like.
  • a conventional method e.g., method described in Japanese Pharmacopoeia, etc.
  • the content of compound A in the pharmaceutical composition is usually about 0.01 to 100% by weight based on a total weight of the composition.
  • the content of other melatonin agonist can be decided according to compound A.
  • the dose of the melatonin agonist to be used in the present invention differs depending on melatonin agonist to be used, administration subject, administration route, and the like.
  • the dose is about 0.0005 to 2 mg/kg body weight, preferably about 0.001 to 1 mg/kg body weight, more preferably about 0.01 to 1 mg/kg body weight as an active ingredient.
  • the pharmaceutical composition may be administered once to several times in divided doses per day.
  • the dose of other melatonin agonist can be decided according to compound A.
  • Compound A 160 g
  • lactose 4064 g
  • corn starch 640 g
  • Compound A 160 g
  • lactose 4064 g
  • corn starch 640 g
  • the mixture is granulated with spraying a solution of hydroxypropyl cellulose (160 g) in water in the dryer, followed by drying in said drier.
  • the resulting granulated material is crushed by 1.5 mm ⁇ punching screen using a power mill apparatus to obtain uniform granules.
  • To the uniform granules 3894 g
  • corn starch 124 g
  • magnesium stearate (12.4 g
  • These granules are tableted in a weight of 130 mg per tablet with a 7.0 mm ⁇ die using a tableting machine to prepare bare tablets.
  • the obtained bare tablets are sprayed with a solution of hydroxypropylmethylcellulose 2910 and copolividone wherein titanium oxide and yellow ferric oxide are dispersed, in a film coating machine, to give about 25000 tablets which are film-coated tablets each containing 4 mg of compound A per tablet and having a prescription shown in Table 1.
  • acetic acid was instilled into the colon to produce a hypersensitive condition.
  • a balloon was inserted into the colon, fixed, and colonic distension stimulus was loaded for 10 minutes by inflating the balloon.
  • the colonic distension stimulus was loaded two times before and after administration of compound A, and the observed contraction number of the abdominal oblique muscle was counted. The result was expressed as inhibition percent. Determination of the abdominal muscle contraction was conducted with the naked eye and waveform of force transducer.
  • Compound A was suspended in a 0.5% methylcellulose, and administered orally with a volume of 4 mL/kg 30 minutes before the second colonic distension stimulus (0.3, 3 and 30 mg/kg).
  • a prophylactic or therapeutic agent for irritable bowel syndrome is provided.

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US5633276A (en) * 1993-12-22 1997-05-27 Glaxo Group Limited Indoline derivatives, method of preparation and use
US6034239A (en) * 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
US6218429B1 (en) * 1996-03-08 2001-04-17 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
US20070088079A1 (en) * 2005-09-20 2007-04-19 Takeda Pharmaceutical Company Limited Prophylactic or therapeutic agent for sleep disorder
US20080214559A1 (en) * 2007-01-10 2008-09-04 Solvay Pharmaceuticals B.V. Compounds with a combination of cannabinoid cb1 antagonism and serotonin reuptake inhibition

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JP2884153B2 (ja) * 1996-03-08 1999-04-19 武田薬品工業株式会社 三環性化合物、その製造法および剤
AU4060599A (en) * 1998-06-09 1999-12-30 Takeda Chemical Industries Ltd. Pharmaceutical composition for treating or preventing sleep disorders
FR2795323B1 (fr) * 1999-06-23 2001-11-16 Adir Utilisation de ligands melatoninergiques pour l'obtention de compositions pharmaceutiques destinees a la prevention ou au traitement des pathologies du systeme gastrointestinal
JP2002226367A (ja) 2001-02-02 2002-08-14 Fuji Chem Ind Co Ltd 薬物障害の予防または治療剤
US20050203130A1 (en) * 2003-12-02 2005-09-15 Erik Buntinx Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
AR056076A1 (es) * 2005-09-20 2007-09-19 Takeda Pharmaceutical Agente profilactico o terapeutico para el desorden de sueno

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
US5633276A (en) * 1993-12-22 1997-05-27 Glaxo Group Limited Indoline derivatives, method of preparation and use
US6034239A (en) * 1996-03-08 2000-03-07 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
US6218429B1 (en) * 1996-03-08 2001-04-17 Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use
US20070088079A1 (en) * 2005-09-20 2007-04-19 Takeda Pharmaceutical Company Limited Prophylactic or therapeutic agent for sleep disorder
US20080214559A1 (en) * 2007-01-10 2008-09-04 Solvay Pharmaceuticals B.V. Compounds with a combination of cannabinoid cb1 antagonism and serotonin reuptake inhibition

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