WO1998002432A1 - Composes bicycliques pour commander la miction - Google Patents

Composes bicycliques pour commander la miction Download PDF

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Publication number
WO1998002432A1
WO1998002432A1 PCT/JP1997/002447 JP9702447W WO9802432A1 WO 1998002432 A1 WO1998002432 A1 WO 1998002432A1 JP 9702447 W JP9702447 W JP 9702447W WO 9802432 A1 WO9802432 A1 WO 9802432A1
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Prior art keywords
optionally halogenated
alkoxy
mono
ring
substituted
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PCT/JP1997/002447
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English (en)
Inventor
Kaneyoshi Kato
Takayuki Doi
Yoshihiro Sugiura
Mitsuru Kawada
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Takeda Chemical Industries, Ltd.
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Priority to AU34607/97A priority Critical patent/AU3460797A/en
Publication of WO1998002432A1 publication Critical patent/WO1998002432A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/14—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 three or more hetero rings

Definitions

  • the present invention relates to bicyclic compounds, their production and use, especially a pharmaceutical composition for controlling micturition.
  • lower urinary tract dysfunctions generically refers to the subjective or objective abnormalities in the process from urine accumulation to excretion, including urine storage disorders (urinary incontinence, polla iuria etc.) and voiding dysfunctions (dysuria, micturition pain, urethral obstruction etc.).
  • urine storage disorders urinary incontinence, polla iuria etc.
  • voiding dysfunctions disuria, micturition pain, urethral obstruction etc.
  • lower urinary tract dysfunctions are found from young age, lower urinary tract dysfunctions, especially urine storage disorders, in the elderly, have recently posed a major social problem with the development of aging society.
  • the mechanism of micturition consists of contraction- relaxation of the urinary bladder, where urine is reserved for a given period of time, the urethral neck, which controls excretion, and the urethra.
  • Micturition is controlled by the peripheral nervous system, which comprises the parasympathetic nervous system, including the pelvic nerve, and the sympathetic nerves, including the hypogastric nerve, under the control of the micturition center, and has been suggested as mediated by various nerve transmitters (e.g., acetylcholine, adrenaline, ATP, substance P, neuropeptide Y).
  • various nerve transmitters e.g., acetylcholine, adrenaline, ATP, substance P, neuropeptide Y.
  • X represents hydrogen or a halogen
  • R represents a hydroxyl group, an alkoxy, or the like (JP-A-8-157452) .
  • R 1 represents a lower alkyl or the like (JP-A-8- 3045) .
  • isochroman-related compounds the following compounds are known.
  • EP-679642 and JP-A-8-12650 describe that a compound represented by the formula:
  • ring A is a benzene ring which may be substituted;
  • Ar represents an aromatic group which may be substituted;
  • each of R 1 and R 2 represents hydrogen or the like, or R 1 and R 2 may form, taken together, a nitrogen-containing heterocyclic group;
  • m represents an integer from 1 to 6;
  • n represents an integer from 1 to 3;
  • X represents 0, -NR 3 - or N; possesses gonadotropin-releasing hormone receptor- antagonizing activity, monoamine uptake-inhibiting activity and calcium ion uptake-inhibiting activity.
  • USP 3,880,885 describes that a compound represented by the formula:
  • Ri represents a C 1 - 3 alkyl or the like; a is 1 to 3; b is 0 or 1; each of R 2 through R 7 represents a C 1 - 3 alkyl or the like; Re represents a phenyl or the like; W represents O or S; A represents -(CH 2 ) n NR9R ⁇ o or the like; NR9R 1 0 represents -1 -z or the like; Z represents a pyridyl or the like; possesses antihypertensive activity and antipsychotic activity.
  • each of Ri and R 2 represents an alkyl having 3 or fewer carbon atoms, or they cooperate with each other to form 1-pyrrolidinyl, piperidino, hexahydro-lH-azepin-1-yl, 3-methylpiperidino or 2,6-dimethylpiperidino;
  • R 3 represents methyl, ethyl or allyl;
  • A represents ethylene, propylene or ethylidene;
  • Y represents methylene, ethylene or ethylidene;
  • Ar represents a phenyl or the like; is useful as a stegnotic.
  • ring A represents a benzene ring which may be substituted
  • ring B represents a 4- to 7-membered carbocyclic or heterocyclic ring which may be substituted
  • ring C represents a nitrogen-containing heterocyclic ring which may be substituted
  • X represents a carbon atom or a nitrogen atom
  • Y represents a bond or a lower alkylene group which may be substituted by an oxo
  • each of Ar 1 and Ar 2 represents an aromatic group which may be substituted
  • m represents an integer from 1 to 3; or a salt thereof [hereinafter also referred to as compound (I)], especially a new compound represented by the formula:
  • ring B' represents a 5- to 7-membered carbocyclic or heterocyclic ring which may be substituted;
  • W represents a divalent group represented by the formula: -CH 2 -CH 2 -,
  • R 6 and R 6a represents a hydrogen atom, a hydrocarbon group which may be substituted, an acyl or an amino which may be substituted; p represents an integer from 0 to 2); r represents an integer from 0 to 2; the other symbols have the same definitions as those shown above; or a salt thereof [hereinafter also referred to as compound (la)], which compound is characterized by a chemical structure wherein the carbon atoms constituting a ring condensed with a benzene ring is substituted for by both an aromatic
  • the present invention relates to:
  • ring A is a benzene ring which may be substituted by 1 to 4 substituents selected from the group consisting of halogen, C ⁇ _ 3 alkylenedioxy, nitro, cyano, optionally halogenated C ⁇ - 6 alkyl, optionally halogenated C 2 -6 alkenyl, optionally halogenated C 2 - 6 alkynyl, optionally halogenated 3- to 6- membered cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated C 1 - 6 alkoxy, optionally halogenated C 1 -6 alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Ci- ⁇ alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carb
  • composition of above (1) wherein m is 2
  • composition of above (1) which is for the prophylaxis or treatment of the lower urinary tract dysfunctions
  • a C ⁇ _6 alkyl, C 2 -6 alkenyl, C 2 - 6 alkynyl, C 3 _ 6 cycloalkyl, C ⁇ -14 aryl or C7- 1 6 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) C 1 - 3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C 1 - 6 alkyl, (6) optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, (7) optionally halogenated C 1 - 6 alkoxy, (8) optionally halogenated C 1 -6 alkylthio, (9) hydroxy, (10) amino, (11) mono-C ⁇ -6 alkylamino, (12) di-Ci- ⁇ alkylamin
  • optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated C ⁇ - 6 alkoxy, optionally halogenated C ⁇ _ 6 alkylthio, hydroxy, amino, mono-C ⁇ _ 6 alkylamino, di-C ⁇ -6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-C ⁇ -6 alkylsulfamoyl, di-C ⁇ - 6 alkylsulfamoyl, C ⁇ -io aryl, C ⁇ -io aryloxy, acyloxy, C ⁇ _ 6 alkoxy-C ⁇ -6 alkoxy, mono-C7_i6 aralkylamino and di-
  • Ci-e alkylthio hydroxy, amino, mono-Ci- ⁇ alkylamino, di-C ⁇ _ 6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-C ⁇ _ 6 alkylsulfamoyl, di-C ⁇ -6 alkylsulfamoyl, C ⁇ -io aryl, C ⁇ -io aryloxy, acyloxy, C ⁇ _6 alkoxy-C ⁇ -6 alkoxy, mono-C7_i6 aralkylamino and di-C7-i6 aralkylamino, (25) 5- to 10- membered aromatic heterocyclic group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C 1 - 3 alkylenedioxy,
  • ring C is a 6- membered nitrogen-containing heterocyclic ring containing 1 or 2 nitrogen atoms which may be oxidized, in addition to carbon atoms, which may be substituted by 1 to 3 0 substituents selected from the group consisting of halogen, cyano, optionally halogenated C ⁇ _ 6 alkyl, optionally halogenated C ⁇ _6 alkoxy, optionally halogenated C ⁇ - 6 alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino, di-C ⁇ -6 alkylamino, C ⁇ _ 6 alkyl-carbonyl, C ⁇ _ 6 alkoxy-carbonyl and 5 carboxy,
  • W is a divalent group of the formula: -NR6-CO- or -CH 2 -NR6-CO-, wherein R6 is a mono- or di-C ⁇ -6 alkylamino or a Ci- ⁇ alkyl which may be substituted by a 3- to 7-membered saturated cyclic amino, r is 0, ring C is a 6-membered nitrogen-containing heterocyclic ring containing 1 or 2 nitrogen atoms which may be oxidized, in addition to carbon atoms, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, optionally halogenated C 1 - 6 alkyl, optionally halogenated C ⁇ _ 6 alkoxy, optionally halogenated Ci- ⁇ alkylthio, hydroxy, amino, mono-C ⁇ - 6 alkylamino, di-Ci- ⁇ alkylamino, C 1 - 6 alkyl-carbonyl, Ci- ⁇ alkoxy-carbonyl and carboxy,
  • Ari is a phenyl or pyridyl which may be substituted by 1 to 3 halogen atoms
  • Ar2 is a phenyl or 5- or 6-membered aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, optionally halogenated C ⁇ _ 6 alkyl, optionally halogenated C ⁇ -6 alkoxy, amino, mono-Ci- ⁇ alkylamino, di- c ⁇ -6 alkylamino, C ⁇ -6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, mono-C ⁇ -6 alkyl-carbamoyl, di-Ci- ⁇ alkyl-carbamoyl, Ci- ⁇ alkylsulfonyl, C 1 -6 alkyl-carbonylamino, C ⁇ _ 6 alkoxy- carbonylamino, Ci-e alkylsulfonylamino and mono-C ⁇ _ 6 al
  • R 6 ' is (i) a hydrogen atom
  • Ci-e alkyl C 2 -6 alkenyl or C7- 1 6 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, cyano, 3- to 6-membered cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated C ⁇ _ 6 alkoxy, hydroxy, amino, mono- or di-Ci- ⁇ alkylamino, 3- to
  • ring C is a ring of the formula:
  • X' is (i) a nitrogen atom or (ii) a group of the formula: >C(R5')- wherein R5' is a hydrogen atom, cyano, hydroxy or Ci- ⁇ alkyl-carbonyl, and t is 0 or 1,
  • Ar2 is a phenyl or pyridyl which may be substituted by 1 to
  • (21) a process for producing the compound (la), which comprises (i) reacting a compound of the formula:
  • L represents a leaving group and the other symbols are as defined above, or a salt thereof with a compound of the formula
  • ring A represents an optionally substituted benzene ring
  • ring B represents an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring
  • W represents a divalent group of the formula: -CH 2 -CH 2 -,
  • -N N- f -NR 6 -S0 2 -, -SO 2 -NR 6 -, -NR 6 -NR 6a -, -CH 2 -0-, -CH 2 -NR 6 -,
  • R 6 and R 6a each represents a hydrogen atom, an optionally substituted hydrocarbon group, acyl or an optionally substituted amino, and p represents an integer of 0 to 2; r represents an integer of 0 to 2;
  • Ar 1 represents an optionally substituted aromatic group; and m represents an integer of 1 to 3, and or a salt thereof,
  • composition of above (24), which is for controlling micturition 0 (26) the composition of above (24), which is for the prophylaxis or treatment of the lower urinary tract dysfunctions,
  • the "substituent" for the "benzene ring which may be substituted” represented by ring A is exemplified by a halogen atom (e.g., fluorine, chlorine, bromine, iodine), C 1 - 3 alkylenedioxy (e.g.,
  • methylenedioxy, ethylenedioxy) , nitro, cyano, optionally halogenated C ⁇ -6 alkyl, optionally halogenated C 2 - 6 alkenyl, optionally halogenated C2-6 alkynyl, optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring- constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated C1- 6 alkoxy, optionally halogenated Ci- ⁇ alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino), di-Ci- ⁇ alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino) , 3- to 7- member
  • Ci- ⁇ alkyl includes, for example, Ci- ⁇ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl) which may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine).
  • Ci- ⁇ alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • such alkyl includes 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 and 6,6,6-trifluorohexyl.
  • C 2 - 6 alkenyl includes, for example, C 2 - 6 alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5- hexen-1-yl) which may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine).
  • C 2 - 6 alkenyl e.g., vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5- hexen-1-yl
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • C 2 - 6 alkynyl includes, for example, C 2 - 6 alkynyl (e.g., 2- butyn-1-yl, 4-pentyn-l-yl, 5-hexyn-l-yl) that may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine).
  • C 2 - 6 alkynyl e.g., 2- butyn-1-yl, 4-pentyn-l-yl, 5-hexyn-l-yl
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms
  • C 3 - 6 cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • such cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4- chlorocyclohexyl and epoxyethyl.
  • halogenated C 1 - 6 alkoxy includes, for example, Ci- ⁇ alkoxy which may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine).
  • alkoxy includes methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.
  • Ci- ⁇ alkylthio includes, for example, C ⁇ _ 6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio) which may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine).
  • alkylthio includes methylthio, difluoromethylthio.
  • the "substituent" for the above-described "4- substituted-piperazin-1-yl” includes, for example, C ⁇ _ 6 alkyl-carbonyl (e.g., acetyl, propionyl), C ⁇ _ 6 alkoxy- carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), C ⁇ -io aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) , mono-Ci- ⁇ alkyl- carbamoyl (e.g., methylcarbnamoyl, ethylcarbamoyl), di-C ⁇ - 6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl) and mono-C ⁇ -io aryl-carbamoyl (e
  • More preferable acyl includes, for example, Ci- ⁇ alkyl-carbonyl (e.g., acetyl, propionyl), Ce-io aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2- naphthoyl), Ci- ⁇ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), mono-C ⁇ - 6 alkylcarbamoyl (e.g., methylcarbamoyi, ethylcarbamoyl), di- c ⁇ -6 alkylcarbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl) , C ⁇ -io arylcarbamoyl which may be substituted, C 1 - 6 alkylsul
  • C ⁇ -io arylcarbamoyl which may be substituted includes, for example, phenylcarbamoyl and naphthylcarbamoyl.
  • the substituent which may be present in the "C ⁇ -io arylcarbamoyl” is exemplified by the same substituents as those mentioned to exemplify the substituent for the "benzene ring which may be substituted" represented by ring A above, the number of such substituents being 1 to 5, preferably 1 to 3.
  • acylamino includes, for example, amino substituted by 1 or 2 substituents selected from the “acyl” described in detail with respect to the “substituent” for the above-described "benzene ring which may be substituted", formyl, carboxy and carbamoyl, with preference given to the acylamino represented by the formula: -NR 3b COR 3 , -NR 3b COOR 3 or -NHS0 2 R 3a wherein R 3 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R 3a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R 3b represents a hydrogen atom or a C ⁇ - 6 alkyl.
  • Preferable acylamino includes C ⁇ _ 6 alkyl- carbonylamino (e.g., acetylamino, propionylamino) , C ⁇ _ 6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino) and C ⁇ - 6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino) .
  • C ⁇ _ 6 alkyl- carbonylamino e.g., acetylamino, propionylamino
  • C ⁇ _ 6 alkoxy-carbonylamino e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino
  • acyloxy includes, for example, an oxy substituted by one "acyl” described in detail with respect to the "substituent” for the above-described "benzene ring which may be substituted", with preference given to the acyloxy represented by the formula: -0-COR 3b , -0-COOR 3c or -0-CONHR 3c wherein R 3c has the same definition as that for R 3a above.
  • Preferable acyloxy includes C ⁇ - 6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy) , C ⁇ -io aryl-carbonyloxy (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy) , C ⁇ _ 6 alkoxy- carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) , mono-Ci- ⁇ alkyl- carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy) , di-C ⁇ -6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy) , C ⁇ -io aryl-carbamoyloxy (e.g.,
  • hydrocarbon group which may be substituted represented by R 1 , R 3 , R 3a or R 3c is a group resulting from removal of one hydrogen atom from a hydrocarbon compound, and is exemplified by chain or cyclic hydrocarbon group (e.g., alkyl, alkenyl, cycloalkyl, aryl, aralkyl). Of the hydrocarbon group, the following chain or cyclic hydrocarbon group having 1 to 16 carbon atoms, etc. is preferred.
  • C ⁇ - 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl
  • C 2 - 6 alkenyl e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl
  • C 2 - 6 alkynyl e.g., ethynyl, propargyl, butynyl, 1- hexynyl
  • C 3 - 6 cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • C ⁇ - 1 aryl e.g., phenyl, 1-naphthyl, 2-naph
  • hydrocarbon group C ⁇ _ 6 alkyl, C ⁇ - 1 aryl and C7-16 aralkyl are preferred.
  • the "substituent" for the "hydrocarbon group which may be substituted” is exemplified by a halogen atom (e.g., fluorine, chlorine, bromine, iodine), C 1 - 3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy) , nitro, cyano, optionally halogenated C ⁇ _ ⁇ alkyl, optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring- constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated C ⁇ _6 alkoxy, optionally halogenated C ⁇ _ 6 alkylthio, hydroxy, amino, mono-C ⁇ _ 6 alkylamino (e.g., methylamino, eth
  • C ⁇ -io aryl which may be substituted may have 1 to 5, preferably 1 to 3, "substituents” that may be present on the "benzene ring which may be substituted” represented by ring A above.
  • hydrocarbon group may have 1 to 5, preferably 1 to 3, substituents such as the above- mentioned substituents at any possible positions on the hydrocarbon group; provided that 2 or more substituents are present, they may be identical or not.
  • heterocyclic group which may be substituted represented by R 1 , R 3 , R 3a or R 3c is exemplified by a 5- to 10-membered (monocyclic or bicyclic) heterocyclic group containing 1 or 2 kinds of preferably 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, including a non-aromatic heterocyclic group such as 1-, 2- or 3-pyrrolidinyl, 2- or 4- imidazolynyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl and morpholino; and an aromatic heterocyclic group such as 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 3-, 4-, 5- or 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2- or 4-pyrimidinyl, 3-pyrrolyl, 2-imidazoly
  • heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, etc.
  • such heterocyclic group includes 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolynyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4- piperidyl, 1- or 2-piperazinyl, morpholino, thiomorpholino, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3- pyridazinyl, 3-isothiazolyl and 3-isoxazolyl.
  • substituted for the "heterocyclic group which may be substituted” is exemplified by the same substituents as those that may be present in the "benzene ring which may be substituted” represented by ring A above, the number of such substituents being 1 to 5, preferably 1 to 3. Provided that 2 or more substituents are present, they may be identical or not.
  • the "Ci- ⁇ alkyl" represented by R 2 or R 3b is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • nitrogen-containing heterocyclic ring formed by R 1 and R 2 , taken together with the adjacent nitrogen atom, is exemplified by a 5- to 7-membered nitrogen-containing heterocyclic ring which contains at least 1 nitrogen atom in addition to carbon atoms and which may contain 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur atoms, including piperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 2-oxoazetidine, 2- oxopyrrolidine and 2-oxopiperidine.
  • Ring A is preferably a benzene ring which may have 1 to 5, preferably 1 to 3, substituents selected from the group consisting of a halogen atom, C 1 - 3 alkylenedioxy, nitro, cyano, optionally halogenated Ci- ⁇ alkyl, optionally halogenated C ⁇ _e alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino, di-C ⁇ _ ⁇ alkylamino, carboxy, carbamoyl and C ⁇ _ ⁇ alkoxy-carbonyl.
  • substituents selected from the group consisting of a halogen atom, C 1 - 3 alkylenedioxy, nitro, cyano, optionally halogenated Ci- ⁇ alkyl, optionally halogenated C ⁇ _e alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino, di-C
  • ring A is a benzene ring which may have 1 to 3 substituents selected from the group consisting of a halogen atom and cyano. Also preferable is a benzene ring which may have 1 to 3 substituents selected from the group consisting of a halogen atom, optionally halogenated Ci- ⁇ alkyl and optionally halogenated C ⁇ _ ⁇ alkoxy.
  • the "4- to 7-membered carbocyclic or heterocyclic ring which may be substituted" represented by ring B is exemplified by (i) 4- to 7-membered carbocyclic ring consisting of carbon atoms only, and (ii) 4- to 7-membered (preferably 5- to 7-membered) heterocyclic ring containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms.
  • such heterocyclic ring includes a carbocyclic or heterocyclic ring represented by the formula:
  • the "hydrocarbon group" for the "hydrocarbon group which may be substituted” represented by R 4 is identical to the "hydrocarbon group” represented by R 1 , R3, R3» or R3C above and the C 3 - 6 cycloalkyl may contain as ring- constituting atoms 1 or 2 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms.
  • the "substituent" for the "hydrocarbon group which may be substituted” represented by R 4 is identical to the "substituent" of the "hydrocarbon group which may be substituted” represented by R 1 , R 3 , R 3a or R 3c above.
  • C ⁇ _ ⁇ alkyl or C 7 _i ⁇ aralkyl which may be substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, mono-Ci-e alkylamino, di-Ci- ⁇ alkylamino, carboxy, carbamoyl, Ci- ⁇ alkoxy-carbonyl, cyano, C 3 - 6 cycloalkyl, epoxyethyl, Ci-e alkoxy, 3- to 7-membered saturated cyclic amino, Cj,_ ⁇ alkyl-carbonyl and phthalimido.
  • substituents selected from a halogen atom, hydroxy, amino, mono-Ci-e alkylamino, di-Ci- ⁇ alkylamino, carboxy, carbamoyl, Ci- ⁇ alkoxy-carbonyl, cyano, C 3 - 6 cycloalkyl, epoxyethyl, Ci-e alkoxy, 3- to 7-membered saturated cycl
  • acyl represented by R 4 is identical to the "acyl” described in detail as the "substituent” for the "benzene ring which may be substituted” represented by ring A above.
  • preference is given to Ci- ⁇ alkyl- carbonyl, Ci- ⁇ alkylsulfonyl and C ⁇ _ ⁇ o arylsulfonyl, with greater preference given to Ci- ⁇ alkyl-carbonyl.
  • Z is a divalent group represented by the formula: -CH 2 -O-, -CO-O- or -CH 2 -S(0) P - wherein p is as defined above, n is preferably 1 or 2.
  • R 4 is preferably a C ⁇ _ ⁇ alkyl or a Ci- ⁇ alkyl-carbonyl.
  • substituted for the "4- to 7-membered carbocyclic or heterocyclic ring which may be substituted" represented by ring B is exemplified by the same substituents as those that may be present in the "benzene ring which may be substituted” represented by ring A above, the number of such substituents being 1 to 3. Provided that 2 or more substituents are present, they may be identical or not.
  • Preferable substituent that may be present in ring B includes mono-Ci- ⁇ alkylamino, di-Ci- ⁇ alkylamino and oxo.
  • Ring B is preferably a ring represented by the formula:
  • nitrogen-containing heterocyclic ring which may be substituted represented by ring C is exemplified by a 4- to 7-membered nitrogen-containing heterocyclic ring containing at least one nitrogen atom in addition to carbon atoms and may containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur atoms.
  • a 6-membered nitrogen-containing heterocyclic ring is preferred.
  • such nitrogen-containing heterocyclic ring includes the ring represented by the formula:
  • _ represents a single bond or a double bond
  • X is as defined above.
  • More preferable nitrogen-containing heterocyclic ring includes the ring represented by the formula:
  • nitrogen-containing heterocyclic ring includes the ring represented by the formula:
  • X is preferably (i) a nitrogen atom or (ii) a group represented by the formula: >C(R 5 )- wherein R 5 represents a hydrogen atom, cyano, optionally halogenated C ⁇ _ ⁇ alkyl, optionally halogenated C ⁇ _ ⁇ alkoxy, optionally halogenated Ci- ⁇ alkylthio, hydroxy, amino, a mono-Ci-e alkylamino, a di-Ci- ⁇ alkylamino, carboxy, a C ⁇ _e alkoxy-carbonyl, a C ⁇ _e alkyl-carbonylamino or a C ⁇ _e alkyl-carbonyl.
  • substituted for the "nitrogen-containing heterocyclic ring which may be substituted" represented by ring C is exemplified by the same substituents as those that may be present in the "benzene ring which may be substituted” represented by ring A above, the number of such substituents being 1 to 3. Provided that 2 or more substituents are present, they may be identical or not.
  • substituents that may be present in ring C are cyano, optionally halogenated Ci-e alkyl, optionally halogenated Ci- ⁇ alkoxy, optionally halogenated C ⁇ _e alkylthio, hydroxy, amino, mono-C ⁇ _e alkylamino, di-Ci- ⁇ alkylamino, carboxy, Ci-e alkyl-carbonyl, C ⁇ _e alkoxy- carbonyl and Ci- ⁇ alkyl-carbonylamino.
  • the nitrogen atoms on ring C may be N-oxidated. It is preferable that the nitrogen atom, bound directly to the group represented by the formula -(CH 2 )m ⁇ wherein the symbol has the same definition as that shown above, is N- oxidated.
  • the "lower alkylene group which may be substituted by an oxo" represented by Y is exemplified by a C 1 -. 4 alkylene such as methylene, ethylene, trimethylene, propylene and tetramethylene.
  • a C 1 -. 4 alkylene such as methylene, ethylene, trimethylene, propylene and tetramethylene.
  • Such C1-4 alkylenes may havs one oxo group at any possible position.
  • such alkylene includes methylene, carbonyl, ethylene, trimethylene, propylene and tetramethylene.
  • Y is preferably a bond or methylene. More preferred is a bond.
  • Xa represents (i) a nitrogen atom or (ii) a group represented by the formula: >C(R 5a )- wherein R 5a represents a hydrogen atom, cyano, an optionally halogenated C ⁇ _e alkyl, an optionally halogenated Ci-e alkoxy, an optionally halogenated Ci-e alkylthio, hydroxy, amino, a mono-Ci- ⁇ alkylamino, a di-Ci-e alkylamino, carboxy, a C ⁇ _ alkoxy- carbonyl, a Ci- ⁇ alkyl-carbonylamino or a Ci-e alkyl- carbonyl; Ya represents a bond or methylene; Ar 2 is as defined above.
  • aromatic hydrocarbon group which may be substituted represented by Ar 1 or Ar 2 is exemplified by an aromatic hydrocarbon group and an aromatic heterocyclic group.
  • aromatic hydrocarbon group includes, for example, a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • aromatic hydrocarbon group includes C ⁇ _ 14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, indenyl and anthryl.
  • phenyl, 1-naphthyl and 2-naphthyl are preferable.
  • aromatic heterocyclic group includes, for example, a 5- to 14-membered, preferably 5- to 10-membered, monocyclic or condensed aromatic heterocyclic group containing one or more (e.g., 1 to 4) hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.
  • aromatic heterocyclic group includes a monovalent group resulting from removal of an oaptionally chosen hydrogen atom from a ring such as aromatic heterocyclic ring such as thiophene, benzo[b] thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3- b]thiophene, thianthrene, furan, isoindolizine, xanthrene, phenoxathiine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H- indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthylidine, quinoxaline, quinazoline, cinnoline, carbazole,
  • aromatic heterocyclic group includes 5- or 6-membered aromatic heterocyclic group which may be condensed with one benzene ring.
  • aromatic heterocyclic groups includes 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.
  • substituted for the "aromatic heterocyclic group which may be substituted” is exemplified by the same substituents as those that may be present in the "benzene ring which may be substituted” represented by ring A above, the number of such substituents being 1 to 5, preferably 1 to 3. Provided that 2 or more substituents are present, they may be identical or not.
  • halogen C 1 - 3 alkylenedioxy, nitro, cyano, optionally halogenated Ci- ⁇ alkyl, optionally halogenated C 2 - ⁇ alkenyl, optionally halogenated C 2 - ⁇ alkynyl, optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring- constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated Ci_e alkoxy, optionally halogenated C ⁇ _ ⁇ alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Ci- ⁇ alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-e alkylsulfamoyl, di
  • halogen C 1 - 3 alkylenedioxy (preferably methylenedioxy) , an optionally halogenated Ci- ⁇ alkyl, an optionally halogenated Ci-e alkoxy, cyano, hydroxy etc.
  • Ar is preferably a phenyl or 5- or 6-membered aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, optionally halogeneated Ci-e alkyl and optionally halogenated C ⁇ _ alkoxy. More preferred is a phenyl or pyridyl group which may be substituted by 1 to 3 halogen atoms (e.g., chlorine, fluorine).
  • Ar 2 is preferably a phenyl or 5- or 6-membered aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1 - 3 alkylenedioxy, nitro, cyano, optionally halogenated C ⁇ _ ⁇ alkyl, optionally halogenated C 2 - 6 alkenyl, optionally halogenated C 2 - ⁇ alkynyl, optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring- constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated C ⁇ _ ⁇ alkoxy, optionally halogenated Ci- ⁇ alkylthio, hydroxy, amino, mono-C ⁇ _
  • a phenyl or 5- or 6-membered aromatic heterocyclic group (preferably, pyridyl) which may be substituted by 1 to 3 substituents selected from a halogen atom, an optionally halogenated C ⁇ _e alkyl and an optionally halogenated Ci-e alkoxy.
  • a phenyl which may be substituted by 1 to 3 halogen atoms or Ci_e alkoxy.
  • ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C 1 - 3 alkylenedioxy, nitro, cyano, an optionally halogenated Ci_e alkyl, an optionally halogenated Ci-e alkoxy, an optionally halogenated C ⁇ _e alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino, di-Ci-e alkylamino, carboxy, carbamoyl and Ci-e alkoxycarbonyl, ring B is a ring represented by the formula:
  • R 4a represents a Ci- ⁇ alkyl or a Ci-e alkyl- carbonyl
  • n represents an integer from 0 to 2
  • ring C is a 5- to 7-membered nitrogen-containing heterocyclic ring represented by the formula:
  • X represents a carbon atom or a nitrogen atom, which may be substituted by 1 to 3 substituents selected from the group consisting of cyano, an optionally halogenated Ci- ⁇ alkyl, an optionally halogenated C ⁇ _ ⁇ alkoxy, an optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino, di-Ci-e alkylamino, carboxy, C ⁇ _ ⁇ alkyl-carbonyl, Ci-e alkoxy-carbonyl and Ci_e alkyl- carbonylamino,
  • Y is a bond or a methylene
  • Ar 1 is a phenyl or pyridyl group which may be substituted by 1 to 3 halogen atoms,
  • Ar 2 is a phenyl or pyridyl group which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally halogenated Ci- 6 alkyl and an optionally halogenated C ⁇ _ ⁇ alkoxy, and m is 1 or 2.
  • ring A is a benzene ring
  • ring B is a ring represented by the formula:
  • n wherein Zb represents a divalent group represented by the formula: -CH 2 -CH 2 -, -CH2-O- or -CO-O-; n represents an integer of 1 or 2, 5 ring C is a 6-membered nitrogen-containing heterocyclic ring represented by the formula:
  • Xa represents (i) a nitrogen atom or (ii) a group represented by the formula: >C(R 5a )- wherein R 5a represents a hydrogen atom, cyano, an optionally halogenated Ci- ⁇ alkyl, an optionally halogenated C ⁇ _ ⁇ alkoxy, an optionally ,,- halogenated Ci-e alkylthio, hydroxy, amino, a mono-Ci- ⁇ alkylamino, a di-Ci-e alkylamino, carboxy, a C ⁇ _ ⁇ alkoxycarbonyl, a C ⁇ _ ⁇ alkyl-carbonylamino or a Ci- ⁇ alkyl- carbonyl,
  • Y is a bond
  • 2 _ Ar 1 is a phenyl which may be substituted by 1 to 3 halogen atoms
  • Ar 2 is a phenyl which may be substituted for by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally halogenated Ci- ⁇ alkyl and an , [ . optionally halogenated Ci-e alkoxy, and m is 2.
  • 35 ring C is a ring represented by the formula: which may be substituted by the substituents selected from the group consisting of a cyano, a hydroxy and a C ⁇ _ ⁇ alkyl-carbonyl ,
  • Y is a bond or a methylene
  • Ar 1 is a phenyl or pyridyl group which may be substituted by a halogen, preferably a phenyl,
  • Ar 2 is a phenyl which may be substituted by a halogen atom, an optionally halogenated C ⁇ _ ⁇ alkyl or a Ci- ⁇ alkoxy, and m is 2.
  • halogen atom an optionally halogenated C ⁇ _ ⁇ alkyl or a Ci- ⁇ alkoxy
  • m is 2.
  • compound (I) include
  • r is 0 or 1.
  • the "hydrocarbon group which may be substituted" represented by R 6 or R 6a is identical to the "hydrocarbon group which may be substituted” represented by R 4 above.
  • preferred is a Ci- ⁇ alkyl, C 2 - ⁇ alkenyl or C 7 -.
  • i ⁇ aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C 1 -.
  • Ci_e alkyl optionally halogenated 3- to 6- membered cycloalkyl which may contain 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms as ring-constituting atoms, optionally halogenated C ⁇ _ alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino, di-Ci- ⁇ alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci_e alkylsulfamoyl, di-Ci- ⁇ alkylsulfamoyl, C ⁇ _ ⁇ o aryl which may be substituted, Ce-io aryloxy which may be substituted, 5-
  • Ci-e alkyl or C 7 _i ⁇ aralkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, cyano, optionally halogenated C 3 _ ⁇ cycloalkyl, epoxyethyl, optionally halogenated Ci- ⁇ alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-C ⁇ _ ⁇ alkylamino, di-Ci- ⁇ alkylamino, 3- to 7-membered saturated cyclic amino, C ⁇ _ ⁇ alkyl-carbonyl, Ci-e alkoxy-carbonyl, carboxy, carbamoyl, Ci- ⁇ alkyl-carbonyloxy and phthalimido.
  • acyl represented by R 6 or R 6a is identical to the "acyl” described in detail as the "substituent" for the "benzene ring which may be substituted” represented by ring A above.
  • preferred is Ci-e alkyl-carbonyl, Ci-e alkoxy-carbonyl, Ci-e alkylsulfonyl and Ce-io arylsulfonyl. More preferred is Ci- ⁇ alkyl-carbonyl.
  • amino which may be substituted represented by R 6 or R 6a is exemplified by (i) an amino which may be substituted by 1 or 2 "hydrocarbon group which may be substituted” or “heterocyclic group which may be substituted, and (ii) a 3- to 7-membered saturated cyclic amino.
  • heterocyclic group which may be substituted and "3- to 7- membered saturated cyclic amino” described in detail with respect to the "substituent" for the "benzene ring which may be substituted” represented by ring A above.
  • the "amino which may be substituted” represented by R 6 or R 6a is preferably a mono-Ci- ⁇ alkylamino, a di-Ci- ⁇ alkylamino or a 3- to 7-membered saturated cyclic amino.
  • W is preferably a divalent group represented by the formula: -NR 6 -CO- or -CH 2 ⁇ NR 6 -CO- wherein R 6 is as defined above. Also preferred is the case wherein r is 0.
  • R 6 is preferably (i) a hydrogen atom, (ii) a C ⁇ _ ⁇ alkyl, C 2 - 6 alkenyl or C7_i aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C 1 - 3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-e alkyl, optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated Ci- ⁇ alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-C ⁇ _ ⁇ alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl (preferably, Ci-e alkyl-carbonyl
  • substituted for the "5- to 7-membered carbocyclic or heterocyclic ring which may be substituted" represented by ring B 1 is exemplified by the same substituents as those that may be present in the "benzene ring which may be substituted” represented by ring A above, the number of such substituents being 1 to 3. Provided that 2 or more substituents are present, they may be identical or not.
  • ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C 1 - 3 alkylenedioxy, nitro, cyano, an optionally halogenated C ⁇ _ ⁇ alkyl, an optionally halogenated Ci_e alkoxy, an optionally halogenated Ci_e alkylthio, hydroxy, amino, mono-Ci- ⁇ alkylamino, di-Ci- ⁇ alkylamino, carboxy, carbamoyl and Ci_e alkoxycarbonyl, ring B* is a ring represented by the formula:
  • R 6b represents (i) a hydrogen atom, (ii) a Ci-e alkyl or C7_i ⁇ aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C 1 - 3 alkylenedioxy, nitro, cyano, an optionally halogenated C ⁇ _ ⁇ alkyl, an optionally halogenated 3- to 6-membered cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, an optionally halogenated Ci-e alkoxy, an optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Ci- ⁇ alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl (preferably, Ci- ⁇ alkyl- carbonyl, Ci- ⁇ alk
  • a Ci-e alkyl-carbonyl a C ⁇ _ ⁇ alkoxy-carbonyl, a mono- C ⁇ - 6 alkyl-carbamoyl, a di-Ci-e alkyl-carbamoyl, a Ce-io aryl-carbamoyl, a Ci- ⁇ alkylsulfonyl or a C ⁇ _ ⁇ o arylsulfonyl, or (iv) a mono- or di-Ci-e alkylamino, a mono- or di-C7_ie aralkylamino or a 3- to 7-membered saturated cyclic amino, ring C is a 5- to 7-membered nitrogen-containing heterocyclic ring containing at least one nitrogen atom which may be oxidized, represented by the formula:
  • X represents a carbon atom or a nitrogen atom, which may be substituted by 1 to 3 substituents selected from the group consisting of cyano, an optionally halogenated C ⁇ _ ⁇ alkyl, an optionally halogenated C ⁇ _ ⁇ alkoxy, an optionally halogenated Ci_e alkylthio, hydroxy, amino, mono-C ⁇ _ ⁇ alkylamino, di-Ci-e alkylamino, carboxy, Ci- ⁇ alkyl-carbonyl, C ⁇ _ ⁇ alkoxy-carbonyl and C ⁇ _ ⁇ alkyl- carbonylamino,
  • Y is a bond or a methylene
  • Ar 1 is a phenyl or pyridyl group which may be substituted by 1 to 3 halogen atoms,
  • Ar 2 is a phenyl or pyridyl group which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, an optionally halogenated Ci- 6 alkyl and an optionally halogenated Ci_e alkoxy, and m is 1 or 2.
  • R 6b is (i) a hydrogen atom, (ii) a Ci_e alkyl or C 7 _ie aralkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of cyano, C 3 -6 cycloalkyl, epoxyethyl, an optionally halogenated Ci-e alkoxy, amino, di-Ci_e alkylamino, 3- to 7-membered saturated cyclic amino, C ⁇ _ ⁇ alkoxy-carbonyl, Ci_e alkyl- carbonyloxy and phthalimido, (iii) a C ⁇ _ ⁇ alkyl-carbonyl, or (iv) a di-Ci- ⁇ alkylamino, ring C is a 6-membered nitrogen-containing heterocyclic ring containing at least one nitrogen atom which may be oxidized, represented by the formula:
  • Xb represents (i) a nitrogen atom or (ii) a group represented by the formula: >C(R 5 )- wherein R 5b represents a hydrogen atom, an optionally halogenated Ci- ⁇ alkyl or a hydroxy,
  • Ar 1 is a phenyl
  • Ar 2 is a phenyl which may be substituted by an optionally halogenated Ci-e alkoxy, and m is 2.
  • Preferable compound of compound (la) include, for example, ring A is a benzene ring; W is a divalent group of the formula: -NR6-CO- or -CH 2 -NR6-CO-, wherein R6 is a mono- or di-Ci- ⁇ alkylamino or a Ci- ⁇ alkyl which may be substituted by a 3- to 7-membered saturated cyclic amino, r is 0, ring C is a 6-membered nitrogen-containing heterocyclic ring containing 1 or 2 nitrogen atoms which may be oxidized, in addition to carbon atoms, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, optionally halogenated Ci-e alkyl, optionally halogenated Ci-e alkoxy, optionally halogenated C ⁇ _ ⁇
  • Ari i s a phenyl or pyridyl which may be substituted by 1 to 3 halogen atoms,
  • Ar 2 is a phenyl or 5- or 6-membered aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, optionally halogenated C ⁇ _ ⁇ alkyl, optionally halogenated Ci_e alkoxy, amino, mono-Ci-e alkylamino, di- C ⁇ _ ⁇ alkylamino, Ci_e alkyl-carbonyl, Ci_e alkoxy-carbonyl, mono-Ci- ⁇ alkyl-carbamoyl, di-Ci-e alkyl-carbamoyl, Ci-e alkylsulfonyl, C ⁇ _ ⁇ alkyl-carbonylamino, C ⁇ _ ⁇ alkoxy- carbonylamino, Ci- ⁇ alkylsulfonylamino and mono-Ci- ⁇ alkylsulfamoyl, and m is 1 or 2.
  • ring A is an optionally halogenated benzene ring
  • ring B' is a ring of the formula: wherein R 6 ' is (i) a hydrogen atom
  • a C ⁇ _ ⁇ alkyl, C 2 - ⁇ alkenyl or C 7 - ⁇ aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, cyano, 3- to 6-membered cycloalkyl which may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen and sulfur atoms in addition to carbon atoms, optionally halogenated C ⁇ _ ⁇ alkoxy, hydroxy, amino, mono- or di-Ci- ⁇ alkylamino, 3- to
  • Ci-e alkyl-carbonyloxy phthalimido and C ⁇ _ ⁇ alkoxy-Ci-e alkoxy
  • ring C is a ring of the formula:
  • X' is (i) a nitrogen atom or (ii) a group of the formula: >C(R5')- wherein R5' is a hydrogen atom, cyano, hydroxy or Ci_e alkyl-carbonyl, and t is 0 or 1,
  • Ar is a phenyl or pyridyl which may be substituted by 1 to
  • Ci- ⁇ alkoxy, amino, mono- or di-Ci-e alkylamino, mono-Ci-e alkyl-carbonylamino, Ci-e alkyl-carbonyl, Ci-e alkoxy- carbonyl, and m is 2.
  • compound (la) include
  • the salts of compounds (I) and (la) include inorganic metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids.
  • Preferable inorganic metal salts include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; and aluminum salt.
  • Preferable salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine etc.
  • Preferable salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid etc.
  • Preferable salts with organic acids include, for example, 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, p-toluenesulfonic acid etc.
  • Preferable salts with basic amino acids include, for example, salts with arginine, lysine, ornithine etc.
  • Preferable salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid etc.
  • salts include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt), and ammonium salt when compound (I) or (la) has an acidic functional group therein; and inorganic salts such as hydrochloride, sulfate, phosphate and hydrobromide, or organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate and tartrate when compound (I) or (la) has a basic functional group therein.
  • alkali metal salts e.g., sodium salt, potassium salt
  • alkaline earth metal salts e.g., calcium salt, magnesium salt, barium salt
  • ammonium salt when compound (I) or (la) has an acidic functional group therein
  • inorganic salts such as hydrochloride, sulfate
  • a production method for compound (I), which includes compound (la) is described below.
  • Compound (I) can be obtained by commonly known methods, e.g., those described in JP-A-8-1154542, JP-A-8- 3045, EP-679642, JP-A-8-12650 , USP 3,880,885, USP 4,247,553, USP 2,759,936, USP 3,314,954, USP 3,595,866, USP 2,759,935, J. Am. Chem. Soc. Vol. 84, p. 4574 (1962), J. Am. Chem. Soc. Vol. 87, p. 3451 (1965) etc., or methods analogous thereto, and also by, for example, the methods shown by the following schemes.
  • L represents a leaving group
  • the "leaving group" represented by L is exemplified by a halogen atom (e.g., chlorine, bromine, iodine), C ⁇ _ ⁇ alkylsulfonyloxy which may be substituted by 1 to 3 halogen atoms (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy) , C ⁇ -io arylsulfonyloxy which may be substituted by 1 to 4 C ⁇ _ ⁇ alkyls or halogen atoms (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy, p- bromobenzenesulfonyloxy, mesitylenesulfonyloxy) .
  • a halogen atom e.g., chlorine, bromine, iodine
  • C ⁇ _ ⁇ alkylsulfonyloxy which may be substituted by
  • Compound (II) can be produced by commonly known methods, e.g., the method of the following scheme 3 or a method analogous thereto.
  • the converting reaction is carried out by a commonly known method, e.g., the method described in ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (published 1983).
  • the alkylation can be accomplished by reacting compound (III) with 1 to 5 equivalents (preferably 1 to 3 equivalents) of the compound represented by the formula:
  • each symbol has the same definition as those shown above, or its salt in an inert solvent at room temperature to 200°C, preferably room temperature to 50°C, for 0.5 hours to one day.
  • room temperature to 200°C preferably room temperature to 50°C
  • 1 to 3 equivalents of base is normally added, it is not always essential.
  • Useful inert solvents include alcohol solvents (e.g., methanol, ethanol, tert-butanol) , ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane), halogen solvents (e.g., dichloromethane), aromatic solvents (e.g., benzene, toluene, xylene), nitrile solvents (e.g., acetonitrile, propionitrile) , amide solvents (e.g., N,N-dimethylformamide (DMF)), ketone solvents (e.g., acetone, methyl ethyl ketone) and sulfoxide solvents (e.g., dimethyl sulfoxide); these solvents may be used singly or in combination of 2 or more kinds. Of these solvents, acetonitrile, DMF, acetone, ethanol etc. are preferred.
  • the base is exemplified by 1) strong bases such as alkali metal or alkaline earth metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride, calcium hydride), alkali metal or alkaline earth metal amides (e.g., lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide) , and alkali metal or alkaline earth metal lower alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide); 2) inorganic bases such as alkali metal or alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), alkali metal or alkaline earth metal carbonates (e.g., sodium carbonate, potassium carbonate
  • compound (I) can be also obtained by the following procedure:
  • L a represents a leaving group, and other symbols have the same definition as those shown above, or its salt.
  • amino protective group represented by T is as same as “amino protective group” described later.
  • the "leaving group" represented by L a is identical to “leaving group” of L above.
  • the deprotection reaction in above (1) can be accomplished by known methods.
  • hydrolysis can be utilized.
  • the alkali hydrolysis or the acid hydrolysis can be used for the hydrolysis and acid hydrolysis is preferable.
  • acid hydrolysis the ligand is stirred under heating with an excess mineral acid (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.) in an inert solvent at room temperature (0 to 30°C) to 120°C for 0.5 to 18 hours.
  • mineral acid e.g. hydrochloric acid, sulfuric acid, phosphoric acid, etc.
  • the inert solvent includes water and acetic acid. These solvents can be used singly or in combination of these two kinds.
  • the reaction can be done by reacting the ligand with excess hydrochloric acid in either water or acetic acid at a temperature of 80 to 120°C.
  • reaction (2) can be achieved by the similar manner as an alkylation referred to above. Where Y is a bond, the following reaction condition may be applicable.
  • Preferable solvents includes amide solvents (e.g., N,N-dimethylformamide (DMF)), ketone solvents (e.g., acetone, methylethylketone) and sulfoxide solvents (e.g., dimethylsulfoxide) . These solvents can be used singly or in combination of two or more kinds.
  • Preferred solvents are DMF, acetone and ethanol.
  • Preferred temperature is 50 to 200°C. Where the solvent is DMF, preferable temperature is 100 to 150 C C.
  • the reaction time is preferably 0.1 to 10 hours and more preferably 3 to 5 hours.
  • the catalytic to an excess amount (preferably 1 to 4 equivalents) of base may be utilized if nessary.
  • the preferable base includes carbonate salts such as potassium carbonate, sodium carbonate, etc., or an organic base such as triethylamine, diisopropylamine, N-methylmorpholine, dimethylaminopyridine, etc.
  • Compound (I) as obtained in process 2 may be subjected to a known hydrolysis, halogenation, oxidation, reduction, alkylation, acylation, and/or cyclization as necessary to yield the desired product; these reactions may be used singly or in combination of 2 or more kinds. These reactions may be carried out in accordance with, for example, the method described in "Shin Jikken Kagaku Koza, Vols. 14 and 15, edited by the Chemical Society of Japan, published 1977 and 1978.” Process 3
  • Compound (IV) can be produced by commonly known methods, e.g., the method of the following scheme 3 or a method analogous thereto.
  • the amide bond-forming reaction is carried out by a commonly known method, e.g., the above-mentioned method described in ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, ACADEMIC PRESS, INC. (published 1983).
  • ring B" represents an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring
  • optical isomer and a salt thereof can be produced by commonly methods, for example, the method which comprises forming a salt of a racemate of the formula:
  • optical active amine includes, for example, (+)- 1-phenethylamine, (-)-l-phenethylamine, cinchonine, (-)- cinchonidine, brucine, (lS,2S)-(+)-2-amino-l-phenyl-l,3- propanediol.
  • the reduction is carried out using a metal hydride.
  • a metal hydride e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutyl aluminum hydride
  • a metal e.g., zinc, iron, sodium, potassium
  • the metal hydride is preferably lithium aluminum hydride, for example .
  • Inert solvents include ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane), alcohol solvents (e.g., methanol, ethanol, tert-butanol) , aromatic solvents (e.g., benzene, toluene, xylene) and hydrocarbon solvents (e.g., hexane).
  • ether solvents e.g., ethyl ether, tetrahydrofuran, dioxane
  • alcohol solvents e.g., methanol, ethanol, tert-butanol
  • aromatic solvents e.g., benzene, toluene, xylene
  • hydrocarbon solvents e.g., hexane.
  • the metal hydride is exemplified by lithium aluminum hydride.
  • the amount of metal hydride used is normally about 2 to 20 equivalents, preferably 6
  • L' represents a leaving group stable to oxidization reaction; the other symbols have the same definitions as those shown above.
  • the "leaving group stable to oxidization reaction” represented by L' is exemplified by a halogen atom (preferably bromine, iodine), methanesulfonyloxy, p- toluenesulfonyloxy and benzenesulfonyloxy.
  • Compound (VI) can be produced by the method described in EP-679642 or a method analogous thereto.
  • the oxidation normally employs an oxidizing agent such as ruthenium oxide, chromic acid or a analog thereof, or a permanganate. It is preferable that ruthenium oxide be used stoichiometrically and catalytically .
  • the oxidation is carried out by the method described in the Journal of Organic Chemistry, Vol. 46, p. 3936 (1981), for example. Specifically, compound (VI), a catalytic amount of ruthenium trichloride hydrate, and excess sodium periodate are reacted at nearly room temperature in a mixed solvent system consisting of acetonitrile, carbon tetrachloride and water for 1 to 20 hours.
  • R represents a lower alkyl; the other symbols have the same definitions as those shown above.
  • the "lower alkyl” represented by R is exemplified by a Ci- ⁇ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl). 5 Process 6
  • a commercial product of compound (VIII) may be used as 0 the compound (VIII).
  • Process 7 _ Compound (IX) is subjected to a commonly known cyclization to yield compound (X). The cyclization is carried out in an acidic environment.
  • compound (IX) is reacted in an inert solvent (e.g., alcohol solvents, ether solvents, halogen solvents, aromatic solvents), in an organic acid (e.g., carboxylic acids such as acetic acid and formic acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and benzenesulfonic acid), or in a mixed system consisting of 2 or more thereof, in the presence of a catalytic to excess amount of acid catalyst added as necessary, at room temperature to 120°C
  • an inert solvent e.g., alcohol solvents, ether solvents, halogen solvents, aromatic solvents
  • organic acid e.g., carboxylic acids such as acetic acid and formic acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and benzenesulfonic acid
  • a mixed system consisting of 2 or more thereof
  • compound (IX) is reacted in a halogen solvent, such as dichloromethane, in the presence of a catalytic to excess amount of Lewis acid (preferably 1 to 2 equivalents of boron trifluoride-diethyl ether complex) at room temperature for 1 to 6 hours.
  • a halogen solvent such as dichloromethane
  • Compound (X) is subjected to reduction to yield compound (II) .
  • the reduction is carried out using a metal hydride.
  • compound (X) is reacted with a metal hydride (e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutyl aluminum hydride), a metal (e.g., zinc, iron, sodium, potassium), or the like, in an inert solvent.
  • a metal hydride e.g., lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutyl aluminum hydride
  • a metal e.g., zinc, iron, sodium, potassium
  • Inert solvents include ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane) , alcohol solvents (e.g., methanol, ethanol, tert-butanol) , aromatic solvents (e.g., benzene, toluene, xylene) and hydrocarbon solvents (e.g., hexane).
  • ether solvents e.g., ethyl ether, tetrahydrofuran, dioxane
  • alcohol solvents e.g., methanol, ethanol, tert-butanol
  • aromatic solvents e.g., benzene, toluene, xylene
  • hydrocarbon solvents e.g., hexane
  • metal hydrides preferably include lithium aluminum hydride.
  • the amount of metal hydride used is normally about 1 to 20 equivalents, preferably 2 to 6 equivalents
  • the hydrolysis is carried out by an alkali hydrolysis or an acid hydrolysis.
  • compound (X) is reacted with an alkali (e.g., inorganic base hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide) in a solvent.
  • the solvent is exemplified by water, ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane), alcohol solvents (e.g., methanol, ethanol, tert-butanol) and mixed solvents consisting of 2 or more thereof.
  • a water-methanol mixed solvent is preferred.
  • the alkali is preferably sodium hydroxide.
  • the amount of alkali used is normally about 2 to 100 equivalents, preferably about 5 to 10 equivalents, per mol of compound (X).
  • Reaction temperature is normally about 10°C to 120°C, preferably about 50°C to 120°C.
  • Reaction time is normally about 5 minutes to 100 hours, preferably about 10 hours to 50 hours.
  • the reaction is carried out in a water-methanol mixed solvent at about 50°C to 120 ⁇ C for about 10 to 50 hours.
  • An acid hydrolysis can be achieved by heating and stirring compound (X) and an excess amount of mineral acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid) in a solvent at room temperature to 120°C for 0.5 to 18 hours.
  • the solvent is exemplified by water, acetic acid and mixed solvents consisting thereof.
  • compound (X) is reacted with an excess amount of hydrochloric acid in water or acetic acid at room temperature to 100°C.
  • compound (II) or (IV) thus obtained is subjected to the same reaction process as the process in the above- described scheme 1 to yield compound (I).
  • compound (I) is an isoquinolone
  • the desired product may be produced from compound (XVII) as obtained by a commonly known method or the following scheme 4 via the same reaction process as the process in the above-described scheme 1.
  • each of R' and R" represents a lower alkyl; the other symbols have the same definitions as those shown above .
  • a commercial product of compound (XI) may be used as the compound (XI).
  • L" represents a leaving group, and 1 to 3 equivalents of base in an inert solvent at -20 to 50°C (preferably room temperature) for 0.5 to 8 hours.
  • the "leaving group" represented by L" is exemplified by a halogen atom (e.g., fluorine, chlorine, bromine, iodine), Ci- ⁇ alkylsulfonyloxy which may be substituted by 1 to 3 halogens (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy), C ⁇ -io arylsulfonyloxy which may be substituted by 1 to 4 substituents selected among C ⁇ _ ⁇ alkyl, nitro and halogen (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy, mesitylenesulfonyloxy) .
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • Ci- ⁇ alkylsulfonyloxy which may be substituted by 1 to 3 halogens (e.
  • the base is exemplified by the strong bases described in detail with respect to the above-described process 2.
  • sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, potassium tert-butoxide etc. are preferred.
  • the inert solvents include, for example, ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane), amide solvents (e.g., DMF) and sulfoxide solvents (e.g., dimethyl sulfoxide); these solvents may be used singly or in combination of 2 or more kinds. Of these solvents, tetrahydrofuran, DMF, dimethyl sulfoxide etc. are preferred. Process 11
  • the alkylation is carried out by stirring compound (XII), 1 to 3 equivalents of a compound represented by the formula: L-(CH 2 ) m - ⁇ -COOR" wherein the symbols have the same definitions as those shown above, and 1 to 3 equivalents of base in an inert solvent at -50 to 50°C (preferably 0°C) for 0.5 to 8 hours.
  • the base is exemplified by the strong bases, inorganic bases, organic bases etc. described in detail with respect to the above-described process 2.
  • sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, potassium tert-butoxide, potassium carbonate etc. are preferred.
  • the inert solvents include, for example, halogen solvents (e.g., dichloromethane), ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane), aromatic solvents (e.g., benzene, toluene, xylene), nitrile solvents (e.g., acetonitrile, propionitrile) , amide solvents (e.g., DMF) and sulfoxide solvents (e.g., dimethyl sulfoxide); these solvents may be used singly or in combination of 2 or more kinds. Of these solvents, tetrahydrofuran, DMF, dimethyl sulfoxide etc. are preferred.
  • halogen solvents e.g., dichloromethane
  • ether solvents e.g., ethyl ether, tetrahydrofuran, dioxane
  • aromatic solvents e.g
  • the reduction is carried out by reacting compound (XIII) with a catalytic amount of metal catalyst in an inert solvent at room temperature to 100°C (preferably 50 to 80°C) under a hydrogen pressure of 1 to 100 atm (preferably 3 to 10 atm) for 1 to 48 hours.
  • Metal catalysts include, for example, Raney nickel, Raney cobalt, platinum oxide, metallic palladium and palladium-carbon.
  • the inert solvents include, for example, alcohol solvents (e.g., methanol, ethanol, tert-butanol), ether solvents (e.g., tetrahydrofuran, dioxane) and aromatic solvents (e.g., benzene, toluene, xylene); these solvents may be used singly or in combination of 2 or more kinds. Of these solvents, ethanol etc. are preferred.
  • alcohol solvents e.g., methanol, ethanol, tert-butanol
  • ether solvents e.g., tetrahydrofuran, dioxane
  • aromatic solvents e.g., benzene, toluene, xylene
  • the alkylation or acylation is carried out by stirring compound (XIV), 1 to 3 equivalents of a compound represented by the formula: R 6 -L" ' ' wherein L' ' ' represents a leaving group; R 6 has the same definition as that shown above, and 1 to 3 equivalents of base in an inert solvent at -50 to 100°C (preferably 0°C) for 0.5 to 8 hours.
  • the "leaving group" represented by L" 1 is exemplified by a halogen atom (e.g., chlorine, bromine, iodine), Ci- ⁇ alkylsulfonyloxy which may be substituted by 1 to 3 Ci- ⁇ alkyl, nitro or halogen (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy) , C ⁇ _ ⁇ o arylsulfonyloxy which may be substituted by 1 to 4 halogen atoms (e.g., p- toluenesulfonyloxy, benzenesulfonyloxy, p- bromobenzenesulfonyloxy, mesitylenesulfonyloxy) , Ci-e alkyl-carbonyloxy which may be substituted by 1 to 3 Ci-e alkyl, nitro or halogen (e.g., acetyloxy, triflu
  • the base is exemplified by the strong bases, inorganic bases, organic bases etc. described in detail with respect to the above-described process 2.
  • sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, potassium tert-butoxide, potassium carbonate etc. are preferred.
  • the inert solvents include, for exampale, ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane), halogen solvents (e.g., dichloromethane), aromatic solvents (e.g., benzene, toluene, xylene), nitrile solvents (e.g., acetonitrile, propionitrile) , amide solvents (e.g., DMF) and sulfoxide solvents (e.g., dimethyl sulfoxide); these solvents may be used singly or in combination of 2 or more kinds. Of these solvents, tetrahydrofuran, DMF, dimethyl sulfoxide etc. are preferred.
  • ether solvents e.g., ethyl ether, tetrahydrofuran, dioxane
  • halogen solvents e.g., dichloromethane
  • aromatic solvents e
  • the reduction is carried out by reacting compound (XVI) and about 1 to 5 equivalents (preferably 1 to 2 equivalents) of metal hydride in an inert solvent at -70 to 100°C (preferably 20 to 60°C) for 1 to 24 hours.
  • the metal hydride is exemplified by lithium aluminum hydride, sodium borohydride, diborane and diisobutyl aluminum hydride.
  • diborane is preferred.
  • the inert solvents include, for example, ether solvents (e.g., ethyl ether, tetrahydrofuran, dioxane) and aromatic solvents (e.g., benzene, toluene, xylene); these solvents may be used singly or in combination of 2 or more kinds. Of these solvents, tetrahydrofuran etc. are preferred.
  • the amino-protecting group includes, for example, formyl, C ⁇ _ ⁇ alkyl-carbonyl (e.g., acetyl, propionyl), C ⁇ _ ⁇ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) , benzoyl, C 7 -- 10 aralkyl-carbonyl (e.g., benzylcarbonyl) , trityl, phthaloyl, N,N- dimethylaminomethylene, C7- 14 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl) , silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldi ethylsilyl, tert-butyldiethylsilyl)
  • the carboxy-protecting group includes, for example, Ci-e alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl), C 7 - 11 aralkyl (e.g., benzyl) and C 2 -e alkenyl (e.g., 1-allyl).
  • Ci-e alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl
  • silyl e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- buty
  • halogen e.g., fluorine, chlorine, bromine, iodine
  • formyl e.g., acetyl, propionyl, butyryl
  • Ci-e alkyl- carbonyl e.g., acetyl, propionyl, butyryl
  • the hydroxy-protecting group includes, for example, Ci-e alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, C7- 11 aralkyl (e.g., benzyl), formyl, Ci- ⁇ alkyl-carbonyl (e.g., acetyl, propionyl), benzoyl, C 7 - 11 aralkyl-carbonyl (e.g., benzylcarbonyl), 2- tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl), trityl and C 2 - e alkenyl (e.g., 1-allyl).
  • These groups may be substituted by 1 to 3 halogen (e.g., fluorine, chlorine, bromine, iodine), Ci- ⁇ alkyl (e.g., methyl, ethyl, propyl), phenyl, C7- 10 aralkyl (e.g., benzyl) or nitro.
  • halogen e.g., fluorine, chlorine, bromine, iodine
  • Ci- ⁇ alkyl e.g., methyl, ethyl, propyl
  • phenyl, C7- 10 aralkyl e.g., benzyl
  • These protecting groups can be removed by commonly known methods or methods analogous thereto, including those using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate etc., and reduction.
  • Compound (I) can be isolated and purified by known means such as solvent extraction, liquid nature conversion, re-dissolution, crystallization, recrystallization and chromatography. Also, the starting compounds and synthetic intermediates for compound (I) or a salt thereof can be isolated and purified by the same known means as those mentioned above, but may be used as the starting material for the next process as a reaction mixture as is without isolation.
  • compounds (I) and (la) may be hydrates or non- hydrates.
  • compound (I) or (la) contains an optical isomer, a stereoisomer , a position isomer or a rotational isomer
  • these isomers are also included in the scope of compound (I) or (la), and each can be obtained as a single product by commonly known means of synthesis and separation.
  • an optical isomer is present in compound (I) or (la)
  • the optical isomer separated from the compound is also included in the scope of compound (I) or (la).
  • An optical isomer can be produced by commonly known methods. Specifically, an optical isomer is obtained by using an optical active synthesis intermediate or by optically resolving the final racemate by a conventional method.
  • Useful methods of optical resolution include commonly known methods such as the fractional recrystallization method, the chiral column method and the diastereomer method.
  • a racemate is formed a salt thereof with an optically active compound [e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-malic acid, (-)-malic acid, (+)-camphor acid, (-)-camphor acid, (+)- camphor-10-sulfonic acid, (-)-camphor-lO-sulfonic acid, (+)-cis-2-benzamidocyclohexanecarboxylic acid, (-)-cis-2- benzamidocyclohexanecarboxylic acid, (+)-l,l '-binaphthyl- 2,2'-diyl hydrogen phosphate, (-)-l,l ' -binaphthyl-2, 2 ' -diyl hydrogen phosphate, (+)-0,0'-dibenzoyltartaric acid, (-)- O,0'-
  • a racemate or a salt thereof is applied to a column for optical isomer separation (chiral column) to separate it.
  • optical isomers are separated by adding a mixture thereof to a chiral column such as ENANTIO-OVM (produced by Tosoh Corporation) or the CHIRAL series, produced by Daicel Chemical Industries, and developing it in water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, acetonitrile) as a simple or mixed solution.
  • a chiral column such as CP-Chirasil-deX CB (produced by GL Science) is used to separate optical isomers.
  • Diastereomer method A diastereomer mixture, prepared from a racemate mixture using an optically active reagent and chemical reaction, is treated by ordinary means of separation (e.g., fractional recrystallization, chromatography etc.) to obtain a single substance, after which the optically active reagent moiety is cut off by a chemical treatment such as hydrolysis.
  • an ester or amide diastereomer is obtained by subjecting the compound, an optically active organic acid (e.g., MPTA [ ⁇ -methoxy- ⁇ -( trifluoromethyl)phenylacetic acid], (-)-methoxyacetic acid) etc. to a condensation.
  • an optically active organic acid e.g., MPTA [ ⁇ -methoxy- ⁇ -( trifluoromethyl)phenylacetic acid], (-)-methoxyacetic acid
  • Compounds (I) and (la) have a good activity of controlling 5 micturition and can be safely used at low doses as a pharmaceutical composition for controlling micturition in mammals such as humans to suppress micturition reflex and increase the bladder's volume. For example, it can be used to suppress the urge incontinence, or as a composition for o the prophylaxis or treatment of lower urinary tract dysfunctions such as pollakiuria and urinary incontinence (stress incontinence, urge incontinence, reflex incontinence, overflow incontinence, total incontinence, asymptomatic incontinence).
  • Compounds (I) and (la) are 5 preferably used as a composition for the prophylaxis or treatment of pollakiuria and/or urinary incontinence.
  • compounds (I) and (la) possess analgesic activity, and can also be used as a pharmaceutical composition for the prophylaxis or treatment of pain Q associated with bone diseases (e.g., arthritis, rheumatism, osteoporosis), chronic pain associated with cancer etc., lumbago, postoperative pain, neuralgia, pain associated with inflammatory diseases, tooth extraction pain, tooth pain, pain due to burns and traumas, and diseases such as 5 neuropathy (e.g., anxiety, depression, psychosis) and somnipathy, in mammals such as humans.
  • bone diseases e.g., arthritis, rheumatism, osteoporosis
  • chronic pain associated with cancer etc. lumbago, postoperative pain, neuralgia, pain associated with inflammatory diseases, tooth extraction pain, tooth pain, pain due to burns and traumas, and diseases such as 5 neuropathy (e.g., anxiety, depression, psychosis) and somnipathy, in mammals such as humans.
  • 5 neuropathy e.g., anxiety, depression
  • Compounds (I) and (la) can be prepared as pharmaceutical preparations by commonly known means, and can be safely administered orally or non-orally (e.g., topical, rectal, intravenous administration etc.), as such or as formulated with an appropriate amount of a pharmacologically acceptable carrier in the pharmaceutical preparation process, in the form of pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injectable preparations, suppositories and sustained-release preparations.
  • a pharmacologically acceptable carrier in the pharmaceutical preparation process, in the form of pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injectable preparations, suppositories and sustained-release preparations.
  • the content of compound (I) or (la) in the pharmaceutical composition for controlling micturition or the pharmaceutical composition of the present invention is 0.1 to 100% by weight relative to the entire composition or the composition. Dose varies depending on subject of administration, route of administration, target disease etc. As an oral therapeutic drug for urinary incontinence, for example, compound (I) or (la) can be administered at about 0.1 to 500 mg, preferably about 1 to 100 mg, and more preferably about 5 to 100 mg, based on the active ingredient (compound (I) or (la)), per dosing, for an adult (60 kg), in one to several portions daily.
  • Pharmacologically acceptable carriers used to produce the pharmaceutical composition for controlling micturition or the pharmaceutical composition of the present invention are various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders and disintegrants for solid preparations, and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations. Other additives such as preservatives, antioxidants, coloring agents, sweetening agents, absorbents and wetting agents may be used as necessary.
  • Excipients include, for example, lactose, saccharose, D-mannitol, starch, corn starch, crystalline cellulose and light silicic anhydride.
  • Lubricants include, for example, magnesium stearate, calcium stearate, talc and colloidal silica.
  • Binders include, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose and carboxymethyl cellulose sodium.
  • Disintegrants include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium and L-hydroxypropyl cellulose.
  • Solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil.
  • Dissolution aids include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
  • Suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniu chloride and monostearic glycerol; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniu chloride and monostearic glycerol
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose
  • Isotonizing agents include, for example, glucose, D- sorbitol, sodium chloride, glycerol and D-mannitol.
  • Buffers include, for example, buffer solutions of phosphates, acetates, carbonates and citrates.
  • Soothing agents include, for example, benzyl alcohol.
  • Preservatives include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • Antioxidants include, for example, sulfites and ascorbic acid.
  • room temperature means 0 to 30°C and anhydrous magnesium sulfate or anhydrous sodium sulfate was used to dry organic solvents. Unless otherwise stated, % values are by weight.
  • CDCI 3 deuterochloroform
  • Ethyl 4-cyano-4,4-diphenylbutyrate (24 g) was dissolved in THF (120 ml) and added dropwise to a suspension of lithium aluminum hydride (4.2 g) in THF (200 ml) under ice cooling conditions. After being stirred for 2 hours under ice cooling conditions, 2 N hydrochloric acid (200 ml) was added, followed by stirring under heating at 60 Q C for 2 hours. To the reaction mixture was added ethyl acetate (400 ml) and the organic layer was separated, dried, and concentrated under reduced pressure. The residue was dissolved in THF (200 ml) and lithium aluminum hydride (4 g) was added under ice cooling conditions.
  • 2,2-Diphenyl-l,4-butanediol (5 g) was dissolved in trifluoroacetic acid (50 ml). After the addition of paraformaldehyde (1.7 g), the reaction mixture was stirred under heating at 50°C for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) followed by additon of sodium hydroxide (4.0 g) and water (50 ml), followed by stirring at room temperature for 1 hour.
  • reaction mixture obtained was added to 1,2- dibromoethane (129 ml) at 60°C, followed by stirring at 60°C for 1 hour.
  • the solvent was concentrated under reduced pressure.
  • the residue was dissolved in ethyl acetate and washed with 1 N hydrochloric acid and brine.
  • the crystal obtained was removed and the mother liquor was treated with hydrochloric acid to yield a free compound, which was then reacted with (-)- cinchonidine (4.40 g) in ethanol to precipitate a salt, which was collected by filtration.
  • the crystal obtained was recrystallized from ethanol.
  • the crystals obtained were combined and recrystallized from ethanol, followed by treatment with hydrochloric acid to yield the title compound (5.22 g).
  • (+)-l-phenylethylamine (0.45 g) were mixed in ethanol and the mixture was concentrated under reduced pressure. The residue obtained was crystallized from ether/hexane. The crystal obtained was recrystallized from ethyl acetate 3 times to yield the title compound (0.13 g).
  • Reference Example 37-2 3-( 2-Bromoethyl )-l-ethyl-5- fluoro-1 , 3-dihydro-3-phenyl-2H-indol-2-one Melting point: 111 - 112 ⁇ C (crystallizing solvent: isopropyl ether/hexane)
  • Reference Example 22 Reference Example 38-1: l,3-Dihydro-3-phenyl-l- piperidino-2H-indol-2-one
  • Reference Example 39 The following Reference Example Compounds 39-1 through 39-3 were obtained in the same manner as in Reference Example 23.
  • the resulting precipitate was collected by filtration, washed with water, and dried to yield 4-(3-chlorophenyl)glutarimide (6.38 g).
  • the glutarimide derivative (6.38 g) obtained was added portionwise to a suspension of lithium aluminum hydride (3.25 g) in THF (90 ml) at 0°C and the mixtute was refluxed for 2 hours.
  • To the reaction mixture cooled at 0°C were added dropwise water (6.5 ml) and 3 N sodium hydroxide (5.2 ml), successively, and the resulting precipitate was removed by filtration.
  • the filtrate was concentrated under reduced pressure to yield the title compound (5.42 g).
  • Triphenylphosphine (2.45 g), imidazole (0.64 g) and iodine (2.37 g) were sequentially dissolved in THF (20.0 ml) followed by addition of a solution of 2-acetyl-l,2,3,4- tetrahydro-4-(2-hydroxyethyl)-4-phenylisoquinoline (1.42 g) in THF (5.0 ml). The mixture was stirred at room temperature under an argon stream for 14 hours. The reaction mixture was washed with an aqueous solution of sodium thiosulfate, dried over sodium sulfate, and evaporated to dryness.
  • Reference Example 47 Compounds in the following Reference Examples 47-1 and 47-2 were obtained in the same manner as in Reference Example 27-1.
  • Example 28-1 (2-Methoxymethyl-3-oxo-4- phenyl-1 ,2,3, 4-tetrahydroisoquinolin-4-yl )acetic acid IH-NMR (CDCI 3 ) ⁇ 3.17 (3H, s), 3.24 (IH, d), 3.83 (IH, d), 4.03 (IH, d), 4.31 (IH, d) , 4.96 (2H, q) , 6.95-7.05 (2H, m), 7.17-7.29 (4H, m) , 7.30-7.51 (3H, m)
  • Reference Example 48-2 ( 3-Oxo-4-phenyl-2-propyl- 1,2,3, 4-tetrahydroisoquinolin-4-yl )acetic acid IH-NMR (CDCI 3 ) ⁇ i 0.87 (3H, t), 1.50-1.70 (2H, m) , 3.23 (IH, d), 3.70 (IH, d), 3.30
  • Reference Examples 49-1 and 49-2 were obtained in the same manner as in Reference Example 29-1.
  • Reference Example 49-1 4-(2-Hydroxyethyl)-2- methoxymethyl-3-oxo-4-phenyl-l ,2,3, 4-tetrahydroisoquinoline IH-NMR (CDC1 3 ) ⁇ i 2.51-2.67 (IH, m) , 2.82-2.98 (IH, m) , 3.19 (3H, s), 3.59-3.78 (2H, m) , 4.04 (IH, d), 4.29 (IH, d), 4.95 (2H, q), 6.97-7.04 (2H, ) , 7.18-7.29 (4H, m), 7.30-7.48 (3H, m)
  • Reference Example 50 5 Compounds in the following Reference Examples 50-1 and
  • Reference Example 50-1 4-(2-Iodoethyl)-2- methoxymethyl-3-oxo-4-phenyl-l ,2,3, 4-tetrahydroisoquinoline o IH-NMR (CDCI 3 ) ⁇ i 2.69-2.85 (IH, m) , 3.01-3.39 (3H, m) ,
  • the above components (1) and (2) were mixed and filled in a soft capsule to yield a soft capsular preparation.
  • the oily residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (3/1 to 3/7) and crystallized from ethyl acetate/isopropyl ether to yield the title compound (7.69 g) as a crystal.
  • Example Compounds 4-2 and 4-3 below were obtained in the same manner as in Example 4-1.
  • Example Compound 4-2 l,3-Dihydro-3-(2-(4-hydroxy-4- phenylpiperidino)ethyl )-3-phenyl-2H-indol-2-one
  • Amorphous powder X H-NMR (CDCI 3 ) ⁇ : 1.58-1.80 (3H, m) , 1.88-2.18 (2H, m) , 2.19-2.54 (6H, m) , 2.68-2.88 (2H, m) , 6.93 (IH, d, J 7.7 Hz), 7.04-7.14 (IH, m) , 7.18-7.42 (10H, m) , 7.43-7.51 (2H, ), 8.03 (IH, br s)
  • Example Compound 4-3 l,3-Dihydro-3-(2-(4-(o- methoxypheny1 )piperazin-1-yl )ethyl )-3-phenyl-2H-indol-2-one
  • Example Compounds 5-2 and 5-3 below were obtained in the same manner as in Example 5-1.
  • Example Compound 5-2 l,3-Dihydro-l-methyl-3-phenyl-3- ( 2- ( 4-hydroxy-4-phenylpiperidino)ethyl )-2H-indol-2-one Melting point :127 - 129°C (recrystallizing solvent: isopropyl ether/diethyl ether)
  • Example Compound 5-3 1, 3-Dihydro-3-( 2-( 4-(o- methoxypheny1 )piperazin-1-yl ) ethyl )-l-methyl-3-phenyl-2H- indol-2-one dihydrochloride
  • Example 4-1 1, 3-Dihydro-3-pheny1-3-(2- (4-phenylpiperidino) ethyl )- 2H-indol-2-one (0.4 g) obtained in Example 4-1 was dissolved in THF (5 ml) and potassium tert-butoxide (0.14 g) was added, followed by stirring at room temperature for 15 minutes. To the solution obtained was added ethyl iodide (0.12 ml), followed by stirring at ambient temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure.
  • Example Compounds 5-5 through 5-12 below were obtained in the same manner as in Example 5-4.
  • Example Compound 5-5 Ethyl (2,3-dihydro-2-oxo-3- phenyl-3-( 2- ( 4-phenylpiperidino)ethyl )-lH-indol-1- yl)acetate Melting point: 72 - 74°C (recrystallizing solvent: isopropyl ether/diethyl ether)
  • Example Compound 5-6 ( 2,3-Dihydro-2-oxo-3-phenyl-3- ( 2-( 4-phenylpiperidino)ethyl)-lH-indol-l-yl)acetonitrile hydrochloride
  • Example Compound 5-7 l,3-Dihydro-3-phenyl-3-(2-(4- phenylpiperidino)ethyl )-l-propyl-2H-indol-2-one hydrochloride
  • Example Compound 5-10 l,3-Dihydro-l-(l-methylethyl)-
  • Example Compound 5-12 l-Cyclopropylmethyl-1,3- dihydro-3-phenyl-3-( 2- ( 4-phenylpiperidino) ethyl ) -2H-indol-
  • Example 5-14 1 3-Dihydro-3- ( 2- ( 4-hydroxy-4-phenylpiperidino)ethyl )-3- phenyl-l-propyl-2H-indol-2-one hydrochloride
  • the residue obtained was purified by silica gel column chromatography eluting with ethyl acetate/methanol (10/1).
  • the oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound (0.27 g) as an amorphous powder.
  • Example Compounds 5-18 through 5-20 below were obtained in the same manner as in Example 5-17.
  • Example Compound 5-18 l,3-Dihydro-l-(3- (dimethylamino) ropyl)-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl)-2H-indol-2-one dihydrochloride Melting point: 218 - 221°C (recrystallizing solvent: ethyl acetate/isopropyl ether)
  • Example Compound 5-19 l,3-Dihydro-l-(2- morpholinoethyl )-3-phenyl-3- ( 2-( 4-phenylpiperidino)ethyl ) - 2H-indol-2-one dihydrochloride
  • Example Compound 5-20 1, 3-Dihydro-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl )-l-(2-piperidinoethyl)-2H-indol-2- one dihydrochloride
  • the extract was washed with brine, dried with anhydrous sodium sulfate and concentrated.
  • the residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (7/3 to 1/1) to yield an oily substance (0.67 g).
  • the oily material obtained (0.20 g) was treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound (0.18 g) as an amorphous powder.
  • Example 4-1 3-Dihydro-3-phenyl-3- ( 2- ( 4-phenylpiperidino) ethyl )- 2H-indol-2-one (0.4 g) obtained in Example 4-1 was dissolved in acetic anhydride (10 ml) and 4-(N,N- dimethylamino)pyridine (6 mg) was added, followed by stirring at 50°C for 2 hours. After being diluted with ethyl acetate, the solution obtained was washed with 1 N sodium hydroxide, dried with anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example Compounds 6-2 and 6-3 below were obtained in the same manner as in Example 6-1.
  • Example Compounds 7-2 through 7-6 below were obtained in the same manner as in Example 7-1.
  • Example Compound 7-2 4-(2-(4-Hydroxy-4- phenylpiperidino) ethyl )-2-methyl-3-oxo-4-pheny1-1 ,2,3,4- tetrahydroisoquinoline hydrochloride
  • Example Compound 7-3 4-(2-(4-(o- Methoxyphenyl )piperazin-1-yl ) ethyl )-2-methyl-3-oxo-4- phenyl-1 ,2,3, 4-tetrahydroisoquinoline dihydrochloride Melting point: 141 - 144°C (crystallizing solvent: ethyl acetate)
  • Example Compound 7-6 2-Ethyl-4-(2-( 4-o- methoxyphenyl)piperazin-l-yl)ethyl) -3-oxo-4-phenyl-l ,2,3,4- tetrahydroisoquinoline dihydrochloride
  • Example 8-2 3- ( 2-( 4-Acetyl-4-phenylpiperidino)ethyl )-l , 3-dihydro-l- methyl-3-phenyl-2H-indol-2-one
  • Example 8-6 1-Ethyl-l, 3-dihydro-3-phenyl-3-( 2-( 4-( 4- pyridyl )piperazin-1-yl )ethyl ) -2H-indol-2-one dihydrochloride Amorphours powder
  • Example 8-8 l-Ethyl-l,3-dihydro-3-(2-(4-(4- methoxypheny1)piperazin-1-yl)ethyl )-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-10 l-Ethyl-l,3-dihydro-3-phenyl-3-(2-(4-(4- pyridyl)piperidino)ethyl)-2H-indol-2-one dihydrochloride
  • Example 8-11 3-(2-( 4-( 4-Chlorophenyl)piperazin-l- yl )ethyl )-1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-12 3-(2-(4-(2-Chlorophenyl)piperazin-l- yl)ethyl)-1-ethyl-l ,3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-13 1-Ethyl-l, 3-dihydro-3-( 2-( 4-(3- methylphenyl )piperazin-1-yl )ethyl)-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-14 l-Ethyl-l,3-dihydro-3-phenyl-3-(2-( 4-( 2- pyridyl )piperazin-l-yl)ethyl )-2H-indol-2-one dihydrochloride
  • Example 8-15 3-( 2-( 4-( 4-Acetylphenyl)piperazin-l- yl )ethyl )-1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-16 l-Ethyl-l,3-dihydro-3-(2-(4-( 3- nitropheny1 )piperazin-l-yl )ethyl ) -3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-17 3-( 2-( 4-( 3-Cyanophenyl)piperazin-l- yl ) ethyl ) -1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-18 l-Ethyl-3-( 2-(4-( 2- fluorophenyl )piperazin-l-yl )ethyl )-l,3-dihydro-3-phenyl-2H- indol-2-one dihydrochloride
  • Example 8-19 l-Ethyl-3-(2-( 4-( 3- fluorophenyl )piperazin-1-yl)ethyl )-l, 3-dihydro-3-phenyl-2H- indol-2-one dihydrochloride
  • Example 8-20 l-Ethyl-3-(2-( 4-(4- fluorophenyl )piperazin-1-yl)ethyl )-1 , 3-dihydro-3-phenyl-2H- indol-2-one dihydrochloride
  • Example 8-21 l-Ethyl-l,3-dihydro-3-( 2-( 4-( 3- methoxypheny1 )piperazin-1-yl )ethyl )-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-22 l-Ethyl-3-(2-(4-(3- fluorophenyl )piperidino) ethyl )-1 , 3-dihydro-3-phenyl-2H- indol-2-one hydrochloride
  • Example 8-23 3- (2- (4- (3- Chlorophenyl )piperidino) ethyl) -1-ethyl-l, 3-dihydro-3- phenyl-2H-indol-2-one hydrochloride
  • Example 8-26 1-( 5-Acetyloxypentyl )-1 , 3-dihydro-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl)-2H-indol-2-one hydrochloride
  • Example 8-28 l,3-Dihydro-3-phenyl-3-( 2-(4- phenylpiperidino)ethyl ) -1- ( 2-propeny1 )-2H-indol-2-one hydrochloride
  • Example 8-29 l,3-Dihydro-l-( 3-methoxypropyl)-3- phenyl-3- ( 2-( 4-phenylpiperidino)ethyl )-2H-indol-2-one hydrochloride
  • Example 8-28 (0.36 g)
  • Example 8-29 (0.06 g) as amorphous powder, o respectively.
  • Example 8-24 1-( 3-bromopropyl )-1 , 3-dihydro-3-phenyl-3-( 2-( 4- phenylpiperidino)-2H-indol-2-one (0.78 g) obtained in Example 8-24 and ethyl 1-piperazinecarboxylate (0.72 g) were reacted in the same manner as in Example 8-27 to yield the title compound (0.43 g).
  • Example 8-32 l-Ethyl-5-fluoro-l,3-dihydro-3-phenyl-3- (2-(4-phenylpiperidino)ethyl)-2H-indol-2-one hydrochloride Melting point: 201 - 204°C (crystallizing solvent: ethyl acetate/diethyl ether)
  • Example 8-33 l-Ethyl-5-fluoro-1, 3-dihydro-3-( 2-( 4-( 2- ethoxyphenyl )piperazin-l-yl )ethyl )-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 8-34 l-Ethyl-5-fluoro-1, 3-dihydro-3-phenyl-3- ( 2- ( 4-( 3-trifluoromethylphenyl)piperazin-l-yl ) ethyl) -2H- indol-2-one dihydrochloride
  • Example 9-1 Q 1- (Dimethylamino)-1 , 3-dihydro-3-phenyl-3-( 2-( 4- phenylpiperazin-1-yl )ethyl ) -2H-indol-2-one dihydrochloride The title compound was obtained in the same manner as in Example 6-1.
  • Example 9-3 l,3-Dihydro-3-(2-(4-(2- methoxyphenyl)piperazin-1-yl)ethyl )-3-phenyl-l-piperidino- 2H-indol-2-one dihydrochloride
  • Example 9-4 l,3-Dihydro-3- ⁇ 2-(4-(2- methylphenyl)piperazin-l-yl)ethyl)-3-phenyl-l-piperidino- 2H-indol-2-one dihydrochloride
  • Example 9-7 l-(Diethylamino)-l,3-dihydro-3-( 2-( 4- hydroxy-4-phenylpiperidino)ethyl )-3-phenyl-2H-indol-2-one hydrochloride
  • Example 9-10 3-Dihydro-l-bis (phenylmethyl)amino-3-phenyl-3-( 2-( - phenylpiperidino)ethyl)-2H-indol-2-one
  • Example 10 Compounds in Examples 10-1 through 10-7 below were obtained in the same manner as in Example 7-1.
  • Example 10-1 2-Methoxymethyl-3-oxo-4-phenyl-4-(2-(4- phenylpiperidino)ethyl ) -1 , 2 , 3, 4-tetrahydroisoquinoline Melting point: 113 - 114°C (crystallizing solvent: ethyl acetate/isopropyl ether)
  • Example 10-2 4-( 2-( 4-Hydroxy-4- phenylpiperidino)ethyl) -2-methoxymethyl-3-oxo-4-phenyl- 1,2,3, 4-tetrahydroisoquinoline Melting point: 164 - 165°C (crystallizing solvent: ethyl acetate/isopropyl ether)
  • Example 10-3 2-Methoxymethyl-4-( 2-( 4-( 2- methoxyphenyl)piperazin-1-yl )ethyl)-3-oxo-4-phenyl-l ,2,3,4- tetrahydroisoquinoline dihydrochloride Melting point: 172 - 176°C (crystallizing solvent: ethyl acetate/isopropyl ether)
  • Example 10-4 4-(2-(4- ⁇ 2-Methoxyphenyl)piperazin-l- yl )ethyl ) -3-oxo-4-phenyl-2-propyl-l ,2,3,4- tetrahydroisoquinoline dihydrochloride Melting point: 154 - 158 ⁇ C (crystallizing solvent: ethyl acetate/isopropyl ether)
  • Example 10-5 3-Oxo-4-phenyl-4-(2-(4- phenylpiperidino)ethyl )-2-propyl-l,2,3,4- tetrahydroisoquinoline Melting point: 112 - 114°C (crystallizing solvent: ethyl acetate/isopropyl ether)
  • Example 10-6 4-( 2-(4-Hydroxy-4- phenylpiperidino)ethyl)-3-oxo-4-phenyl-2-propyl-l ,2,3,4- tetrahydroisoquinoline Melting point: 174 - 175°C (crystallizing solvent: ethyl acetate/methanol)
  • Example 10-7 2-Ethyl-4-(2-(4-(3- fluorophenyl)piperidino) ethyl)-3-oxo-4-phenyl-l ,2,3,4- tetrahydroisoquinoline hydrochloride
  • Amorphous powder IH-NMR (CDCI 3 ) ⁇ i 1.15 (3H, t), 1.60-1.90 (3H, m) , 1.90- 2.15 (3H, m), 2.22-2.60 (4H, m) , 2.90-3.21 (3H, m) , 3.38- 3.57 (IH, m), 3.62-3.81 (IH, m) , 4.24 (2H, s), 6.81-7.42 (13H, m)
  • Example 11-2 3-(2-(4-(2-Cyanophenyl)piperazin-l- yl )ethyl ) -1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one hydrochloride Amorphous powder
  • Example 11-4 Methyl 2-(4-(2-(l-ethyl-2,3-dihydro-2- oxo-3-phenyl-lH-indol-3-yl )ethyl )piperazin-l-yl ) benzoate dihydrochloride
  • Example 11-5 Ethyl 4-( 4-( 2-( l-ethyl-2 , 3-dihydro-2- oxo-3-phenyl-lH-indol-3-yl )ethyl )piperazin-l-yl )benzoate dihydrochloride
  • Example 11-6 l-Ethyl-l,3-dihydro-3-(2-(4-(2- nitrophenyl)piperazin-l-yl)ethyl)-3-phenyl-2H-indol-2-one hydrochloride
  • Example 11-7 l-Ethyl-l,3-dihydro-3-( 2-( 4-( 4- nitropheny1)piperazin-l-yl)ethyl)-3-phenyl-2H-indol-2-one dihydrochloride
  • Example 11-8 l-Ethyl-l,3-dihydro-3-phenyl-3-(2-( 4-( 4- trifluoromethylphenyl)piperazin-l-yl)ethyl-2H-indol-2-one dihydrochloride
  • Example 15-1 Ethyl 3-(4-(2-(l-ethyl-2,3-dihydro-2- oxo-3-phenyl-lH-indol-3-yl)ethyl)piperazin-l-yl)benzoate dihydrochloride

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Abstract

L'invention concerne un composé de la formule (I) dans laquelle le composé cyclique A représente un noyau benzène pouvant être substitué; le composé cyclique B représente un noyau carbocyclique ou hétérocyclique de 4 à 7 chaînons pouvant être substitué; le composé cyclique C représente un noyau hétérocyclique azoté pouvant être substitué; X représente un atome de carbone ou un atome d'azote; Y représente une liaison ou un groupe alkylène inférieur pouvant être substitué par oxo; Ar?1 et Ar2¿ représentent chacun un groupe aromatique pouvant être substitué; m représente un entier de 1 à 3. Ce composé ou son sel est utile pour commander la miction.
PCT/JP1997/002447 1996-07-16 1997-07-15 Composes bicycliques pour commander la miction WO1998002432A1 (fr)

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AU34607/97A AU3460797A (en) 1996-07-16 1997-07-15 Bicyclic compounds for controlling micturition

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US6387926B1 (en) 1997-07-02 2002-05-14 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
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US8288431B2 (en) 2010-02-17 2012-10-16 Hoffmann-La Roche Inc. Substituted spiroindolinones
CN105705488A (zh) * 2013-06-05 2016-06-22 卡昂大学 具抗记忆错误效果的乙酰胆碱酯酶抑制剂和5-羟色胺受体4(5ht4)激动剂的化合物，其制备方法及其含有的药物组合物
CN108440378A (zh) * 2018-03-27 2018-08-24 宁波大学 一种室温下碘-双氧水促进的3-氨基-2-吲哚酮衍生物的制备方法

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US6262277B1 (en) 1994-09-13 2001-07-17 G.D. Searle And Company Intermediates and processes for the preparation of benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6784201B2 (en) 1994-09-13 2004-08-31 G.D. Searle & Company Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6387924B2 (en) 1994-09-13 2002-05-14 G.D. Searle & Co. Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6602883B1 (en) 1997-07-02 2003-08-05 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
US6387926B1 (en) 1997-07-02 2002-05-14 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
WO2000027815A3 (fr) * 1998-11-11 2000-10-26 Smithkline Beecham Spa Nouveaux composes
JP2002529451A (ja) * 1998-11-11 2002-09-10 スミスクライン・ビーチャム・ソシエタ・ペル・アチオニ Ｎ−置換アザ環、それらの製造方法およびｏｒｌ−１受容体リガンドとしてのそれらの使用
US6969724B2 (en) 1998-11-11 2005-11-29 Smithkline Beecham-Spa Compounds
WO2000027815A2 (fr) * 1998-11-11 2000-05-18 Smithkline Beecham Spa Nouveaux composes
US6462091B1 (en) 1998-12-23 2002-10-08 G.D. Searle & Co. Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications
WO2000047568A3 (fr) * 1999-02-12 2000-12-14 Searle & Co Nouvelles benzothiazepines-1,2 presentant une activite d'inhibition de transport d'acide biliaire ileal et d'absorption de taurocholate
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CN108440378A (zh) * 2018-03-27 2018-08-24 宁波大学 一种室温下碘-双氧水促进的3-氨基-2-吲哚酮衍生物的制备方法
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