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WO1998002432A1 - Bicyclic compounds for controlling micturition - Google Patents

Bicyclic compounds for controlling micturition 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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WIPO (PCT)
Prior art keywords
optionally halogenated
alkoxy
mono
ring
substituted
Prior art date
Application number
PCT/JP1997/002447
Other languages
French (fr)
Inventor
Kaneyoshi Kato
Takayuki Doi
Yoshihiro Sugiura
Mitsuru Kawada
Original Assignee
Takeda Chemical Industries, Ltd.
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Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU34607/97A priority Critical patent/AU3460797A/en
Publication of WO1998002432A1 publication Critical patent/WO1998002432A1/en

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Classifications

    • 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

A compound of formula (I), wherein 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 Ar2¿ represents an aromatic group which may be substituted; m represents an integer of 1 to 3; or a salt thereof is useful for controlling micturition.

Description

DESCRIPTION BICYCLIC COMPOUNDS FOR CONTROLLING MICTURITION
TECHNICAL FIELD The present invention relates to bicyclic compounds, their production and use, especially a pharmaceutical composition for controlling micturition.
BACKGROUND ART Tne term, 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.). Although 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).
On the other hand, for the treatment of urinary incontinence or pollakiuria, there has been reported an indole-2-carboxyanilide derivative represented by the formula:
Figure imgf000004_0001
wherein X represents hydrogen or a halogen; R represents a hydroxyl group, an alkoxy, or the like (JP-A-8-157452) .
As a micturition disturbance-improving agent, there has been reported an agent containing a compound represented by the formula:
Figure imgf000004_0002
wherein R1 represents a lower alkyl or the like (JP-A-8- 3045) .
Also, as isochroman-related compounds, the following compounds are known.
1) EP-679642 and JP-A-8-12650 describe that a compound represented by the formula:
Figure imgf000004_0003
wherein ring A is a benzene ring which may be substituted; Ar represents an aromatic group which may be substituted; each of R1 and R2 represents hydrogen or the like, or R1 and R2 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, -NR3- or N; possesses gonadotropin-releasing hormone receptor- antagonizing activity, monoamine uptake-inhibiting activity and calcium ion uptake-inhibiting activity. 2) USP 3,880,885 describes that a compound represented by the formula:
Figure imgf000005_0001
wherein R represents hydrogen or the like; Ri represents hydrogen or the like; R2 represents hydrogen or the like; each of R3 and R4 represents a lower alkyl or the like, or they cooperate with each other to form -(CH2)n~ (π is 4 to
7) or z ; Z represents 0, S or -Rβ; R5 represents hy drogen or the like; Rε represents a lower alkyl; X represents -CH2- or -CO-; possesses diuretic activity. 3) USP 4,247,553 describes that a compound represented by the formula:
Figure imgf000005_0002
wherein Ri represents a C1-3 alkyl or the like; a is 1 to 3; b is 0 or 1; each of R2 through R7 represents a C1-3 alkyl or the like; Re represents a phenyl or the like; W represents O or S; A represents -(CH2)nNR9Rιo or the like; NR9R10 represents -1 -z or the like; Z represents a pyridyl or the like; possesses antihypertensive activity and antipsychotic activity.
As for oxindol-related compounds, USP 3,595,866 describes that a compound represented by the formula:
Figure imgf000006_0001
wherein each of Ri and R2 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; R3 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.
As therapeutic drugs for lower urinary tract dysfunctions (especially urinary incontinence and pollakiuria), drugs that act on the bladder and/or the urethra to control their urinary relaxation and contraction are mainly used. For example, anticholinergic agents or a receptor modulating agents etc. are commonly used as therapeutic drugs for urinary incontinence but no satisfactory drug has been found. Thus, there are strong demands for the development of excellent micturition- controlling therapeutic drugs for lower urinary tract dysfunctions, especially improving, prophylactic and therapeutic agents for urine storage disorders such as urinary incontinence and pollakiuria. The present inventors conducted various investigations of compounds that potentially control micturition, and for the first time found that a compound represented by the formula:
Figure imgf000007_0001
wherein 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 Ar1 and Ar2 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:
Figure imgf000007_0002
wherein 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: -CH2-CH2-,
-CH=CH-, -CO-O-, -CO-NR6-, -NR6-C0-, -N=CH-, -CH2-S(0)p-, -N=N-, -NR6-S02-, -SO2-NR6-, -NR6-NR6a-, -CH2-NR6-C0- or - CO-NR6-CO- (each of R6 and R6a 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 group and a substituent (including cyclic amino groups) represented by the formula:
Figure imgf000008_0001
wherein the symbols have the same definitions as those shown above, unexpectedly possesses excellent urination- controlling activity and serves well as a pharmaceutical. The inventors made further investigations based on these findings, and developed the present invention.
DISCLOSURE OF INVENTION
The present invention relates to:
(1) a pharmaceutical composition for controlling micturition which comprises compound (I),
(2) the composition of above (1), wherein ring A is a benzene ring which may be substituted by 1 to 4 substituents selected from the group consisting of halogen, Cι_3 alkylenedioxy, nitro, cyano, optionally halogenated Cι-6 alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Ci-β alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, C6-10 aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7_i6 aralkylamino and di-C7-i6 aralkylamino; ring B is a 4- to 7-membered carbocyclic or heterocyclic ring optionally containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, Cι-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι-6 alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι_6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, C6-10 aryloxy, acyloxy, Cι_6 alkoxy-Cι-6 alkoxy, 1r.ono-C7-.i6 aralkylamino, di-C7-i6 aralkylamino and oxo; ring C is a 4- to 7-membered nitrogen-containing heterocyclic ring containing at least one nitrogen atom which may be oxidized, in addition to carbon atoms, and optionally containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, C6-ιo aryloxy, acyloxy, Cι-6 alkoxy-Ci-e alkoxy, mono-C7-i6 aralkylamino and di-C7_ιβ aralkylamino; Y is a bond or a C1-4 alkylene which may be substituted by an oxo; and Ari and Ar2 each is an aromatic group selected from the group consisting of a Cβ-n aryl and a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which group may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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-β alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Ci-β alkoxy, mono-C7_i6 aralkylamino and di-C7_i6 aralkylamino, (3) the composition of above (1), wherein ring B is a ring of the formula:
Figure imgf000010_0001
(4) the composition of Claim 1, wherein ring C is an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic ring,
(5) the composition of above (1), wherein m is 2, (6) the composition of above (1), which is for the prophylaxis or treatment of the lower urinary tract dysfunctions,
(7) the composition of above (6), wherein the lower urinary tract dysfunctions is urinary incontinence or pollakiuria,
(8) compound (la),
(9) the compound of above (8), wherein R6 and R6a each is (i) a hydrogen atom,
(ii) a Cι_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_6 cycloalkyl, Cε-14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 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 C1-6 alkoxy, (8) optionally halogenated C1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-Cι-6 alkylamino, (12) di-Ci-β alkylamino, (13) 3- to 7-membererd saturated cyclic amino, (14) formyl, (15) acyl, (16) acylamino, (17) carboxy, (18) carbamoyl, (19) sulfo, (20) sulfamoyl, (21) mono-Cι_6 alkylsulfamoyl, (22) di-Cι-6 alkylsulfamoyl, (23) Cβ-io aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, C6-10 aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι_6 alkoxy, mono-C7-ιe aralkylamino and i-C7-ιe aralkylamino, (24) Cβ-io aryloxy which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, Cι_3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 Cχ-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-e alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι_6 alkoxy-Cι_6 alkoxy, mono-C7-i6 aralkylamino and di-C7-ιe 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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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 Cι_6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, i-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cχ_6 alkylsulfamoyl, Cβ-io aryl, Ce-io aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7-ιβ aralkylamino, (26) acyloxy, (27) phthalimido which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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 Cι-6 alkoxy, optionally halogenated Cι_6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι_6 alkoxy-Cι-6 alkoxy, mono-C7_i6 aralkylamino and di-C7-i6 aralkylamino, (28) Cι_6 alkoxy-Ci-β alkoxy, (29) mono-C7-i6 aralkylamino and (30) di-C7_i6 aralkylamino; the C3-6 cycloalkyl may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms,
(iii) an acyl represented by the formula: -(C=0)-Ri, -(C=0)-NR1R2, -(C=S)-NHR1, -(C=0)-ORl, -SO2-R1 or -SO-Rl wherein Ri is (iii-1) a Ci-β alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, Cβ-i aryl or C7-.16 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) C1-.3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 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 C1-6 alkoxy, (8) optionally halogenated C1-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-Ci-β alkylamino, (12) di-Cι-6 alkylamino, (13) 3- to 7-membererd saturated cyclic amino, (14) formyl, (15) acyl, (16) acylamino, (17) carboxy, (18) carbamoyl, (19) sulfo, (20) sulfamoyl, (21) mono-Cι-6 alkylsulfamoyl, (22) di-Cι-6 alkylsulfamoyl, (23) Cβ-io aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β alkyl, optionally halogenated C2-6 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 Cι-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, C6-10 aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι_6 alkoxy, mono-C7-i6 aralkylamino and di-C7_i6 aralkylamino, (24) Cβ-io aryloxy which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β alkyl, optionally halogenated C2-6 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 cι-6 alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cχ-6 alkylsulfamoyl, Ce-io aryl, Ce-io aryloxy, acyloxy, Cj._6 alkoxy-Cι-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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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 Cι_6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι_6 alkoxy-Cι_6 alkoxy, mono-C7_i6 aralkylamino and di-C7_i6 aralkylamino, (26) acyloxy, (27) phthalimido which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 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 - alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, C -β alkoxy-Cι-6 alkoxy, mono-C7_i6 aralkylamino and di-C7-ιβ aralkylamino, (28) Ci-β alkoxy-Cι-6 alkoxy, (29) mono-C7-i6 aralkylamino and (30) di-C7_i6 aralkylamino, or (iii-2) a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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 C -e alkoxy, optionally halogenated Cι_β alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7_i6 aralkylamino; R2 is a hydrogen atom or a Ci-β alkyl; or Ri and R2 form, taken together with the adjacent nitrogen atom, a 5- to 7-membered nitrogen-containing heterocyclic ring,
(iv) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of (iv-1) a cι-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C&- 14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated Ci-β 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 Cι_6 alkoxy, (8) optionally halogenated Cι_e alkylthio, (9) hydroxy, (10) amino, (11) mono-Cι-6 alkylamino, (12) di-Ci-β alkylamino, (13) 3- to 7- membererd saturated cyclic amino, (14) formyl, (15) acyl, (16) acylamino, (17) carboxy, (18) carbamoyl, (19) sulfo, (20) sulfamoyl, (21) mono-Cι-6 alkylsulfamoyl, (22) di-Cι-6 alkylsulfamoyl, (23) Cβ-io aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, Cι_3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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 Ci-β alkoxy, optionally halogenated Ci-β alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl. Cβ-io aryl, Cβ-io aryloxy, acyloxy, Ci-β alkoxy-Cι-6 alkoxy, mono-C7_i6 aralkylamino and di-C7_i6 aralkylamino, (24) Cβ-io aryloxy which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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-e alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Cι_6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι_6 alkoxy-Cι-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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated C2-6 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 Ci-β alkoxy, optionally halogenated Cχ-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7_i6 aralkylamino, (26) acyloxy, (27) phthalimido which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cj._6 alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-e alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7_iβ aralkylamino and di-C7_i6 aralkylamino, (28) C1-6 alkoxy-Cι_6 alkoxy, (29) mono-C7_i6 aralkylamino and (30) di-C7_i6 aralkylamino, and (iv-2) a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cis alkyl, optionally halogenated C2-6 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 Cι_6 alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-e alkylsulfamoyl, di-Ci-e alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7-i6 aralkylamino or (v) a 3- to 7-membered saturated cyclic amino, (10) the compound of above (8), wherein W is a divalent group of the formula: -NR6-C0- or -CH2-NR6-CO- wherein R6 is as defined above (8), (11) the compound of above (8), wherein r is 0, (12) the compound of above (8), wherein ring A is a benzene ring which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, optionally halogenated Ci-β alkyl and optionally halogenated Cι_6 alkoxy,
(13) the compound of above (8), wherein 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 Cι_6 alkyl, optionally halogenated Cι_6 alkoxy, optionally halogenated Cι-6 alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Cι-6 alkylamino, Cι_6 alkyl-carbonyl, Cι_6 alkoxy-carbonyl and 5 carboxy,
(14) the compound of above (8), wherein Y is a bond or a methylene,
(15) the compound of above (8), wherein Ar* is a phenyl or 5- or 6-membered aromatic heterocyclic group which may be o substituted by 1 to 3 substituents selected from the group consisting of halogen, optionally halogeneated Cχ-6 alkyl and optionally halogenated Cι_6 alkoxy,
(16) the compound of above (8), wherein Ar 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, Cι_3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 alkenyl, optionally halogenated C2-6 alkynyl, optionally halogenated 3- to 6-membered cycloalkyl which 0 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 Cι_6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated g cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7-i6 aralkylamino,
(17) the compound of above (8), wherein m is 1 or 2, (18) the compound of above (8), wherein ring A is a benzene ring;
W is a divalent group of the formula: -NR6-CO- or -CH2-NR6-CO-, wherein R6 is a mono- or di-Cι-6 alkylamino or a Ci-β 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 C1-6 alkyl, optionally halogenated Cι_6 alkoxy, optionally halogenated Ci-β alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Ci-β alkylamino, C1-6 alkyl-carbonyl, Ci-β alkoxy-carbonyl and carboxy, Y is a bond,
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 Cι_6 alkyl, optionally halogenated Cι-6 alkoxy, amino, mono-Ci-β alkylamino, di- cι-6 alkylamino, Cχ-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, mono-Cι-6 alkyl-carbamoyl, di-Ci-β alkyl-carbamoyl, Ci-β alkylsulfonyl, C1-6 alkyl-carbonylamino, Cι_6 alkoxy- carbonylamino, Ci-e alkylsulfonylamino and mono-Cι_6 alkylsulfamoyl, and m is 1 or 2, (19) the compound of above (8), wherein ring A is an optionally halogenated benzene ring; ring B' is a ring of the formula:
Figure imgf000021_0001
wherein R6' is (i) a hydrogen atom,
(ii) a Ci-e alkyl, C2-6 alkenyl or C7-16 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 Cι_6 alkoxy, hydroxy, amino, mono- or di-Ci-β alkylamino, 3- to
7-membered saturated cyclic amino, Cι-6 alkoxy-carbonyl,
Cι_6 alkyl-carbonyloxy, phthalimido and Cι_β alkoxy-Cι_6 alkoxy,
(iii) a C1-6 alkyl-carbonyl, or
(iv) a mono- or di-Cι_6 alkylamino, a mono- or i-C7-i6 aralkylamino or a 3- to 7-membered saturated cyclic amino, ring C is a ring of the formula:
Figure imgf000021_0002
wherein 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-β alkyl-carbonyl, and t is 0 or 1,
Y is a bond,
Ari is a phenyl,
Ar2 is a phenyl or pyridyl which may be substituted by 1 to
3 substituents selected from the group consisting of halogen, nitro, cyano, optionally halogenated Ci-β alkyl, Ci-e alkoxy, amino, mono- or di-Cι_6 alkylamino, mono-Cι-6 alkyl-carbonylamino, Ci-β alkyl-carbonyl, Cι_6 alkoxy- carbonyl, and m is 2, (20) the compound of above (8), which is
1 , 3-dihydro-l-ethyl-3-phenyl-3- ( 2-( 4- phenylpiperidino)ethyl ) -2H-indol-2-one,
1 , 3-dihydro-l-ethyl-3- ( 2- ( 4-hydroxy-4- phenylpiperidino) ethyl )-3-phenyl-2H-indol-2-one, 2-methyl-3-oxo-4-phenyl-4- (2- (4-phenylpiperidino) ethyl )-
1,2,3,4-tetrahydroisoquinoline, l-ethyl-l,3-dihydro-3-phenyl-3-(2-(4-(3- trifluoromethylphenyl)piperidino) ethyl )-2H-indol-2-one,
3- ( 2-( 4- ( 3-chlorophenyl )piperazin-1-yl)ethyl ) -1-ethyl-l , 3- dihydro-3-phenyl-2H-indol-2-one,
3-( 2- ( 4-cyano-4-phenylpiperidino) ethyl )-1-ethyl-l, 3- dihydro-3-phenyl-2H-indol-2-one,
2-ethyl-4-(2-(4-(o-methoxyphenyl)piperazin-l-yl)ethyl)-3- oxo-4-phenyl-l ,2,3, 4-tetrahydroisoquinoline, 1, 3-dihydro-l-(dimethylamino)-3-(2-(4-(o- methoxyphenyl )piperazin-l-yl )ethyl ) -3-phenyl-2H-indol-2- one,
1 , 3-dihydro-l-( 2-(morpholino)ethyl )-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl)-2H-indol-2-one, 1-ethyl-l , 3-dihydro-3-phenyl-3-( 2- ( 4-( 3- trifluoromethylphenyl )piperazin-l-yl)ethyl)-2H-indol-2-one, or a salt thereof,
(21) a process for producing the compound (la), which comprises (i) reacting a compound of the formula:
Figure imgf000022_0001
wherein L represents a leaving group and the other symbols are as defined above, or a salt thereof with a compound of the formula;
Figure imgf000023_0001
wherein all symbols are as defined above, or a salt thereof or (ii) subjecting a compound of the formula:
Figure imgf000023_0002
wherein all symbols are as defined above, or a salt thereof to reduction,
(22) an optical isomer of the formula:
Figure imgf000023_0003
wherein 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: -CH2-CH2-,
-CH=CH-, -C0-0-, -CO-NR6-, -NR6-C0-, -N=CH-, -CH2-S(0)p-,
-N=N-f -NR6-S02-, -SO2-NR6-, -NR6-NR6a-, -CH2-0-, -CH2-NR6-,
-NR6-CH2-, -CH=N-, -CH2-NR6-CO- or -CO-NR6-CO- wherein R6 and R6a 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;
Ar1 represents an optionally substituted aromatic group; and m represents an integer of 1 to 3, and or a salt thereof,
(23) a process for producing the optical isomer of above
(22) or a salt thereof, which comprises forming a salt of a racemate of the formula:
Figure imgf000024_0001
wherein all symbols are as defined above, with an optical active amine, and then subjecting the resultant salt to 5 fractional recrystallization,
(24) a pharmaceutical composition which comprises compound (la),
(25) the 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,
(27) the composition of above (26), wherein the lower urinary tract dysfunctions is urinary incontinence or
J pollakiuria,
(28) a method for controlling micturition in a mammal which comprises administering to such mammal an effective amount of compound ( I ) , and
(29) use of compound (I) for the manufacture of a 0 pharmaceutical composition for controlling micturition.
With respect to formula (I) above, 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), C1-3 alkylenedioxy (e.g.,
" methylenedioxy, ethylenedioxy) , nitro, cyano, optionally halogenated Cι-6 alkyl, optionally halogenated C2-6 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-β alkylthio, hydroxy, amino, mono-Ci-β alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino), di-Ci-β alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, dibutylamino) , 3- to 7- membered saturated cyclic amino (e.g., morpholino, thiomorpholino, piperazin-1-yl, 4-substituted-piperazin-l- yl, piperidino, pyrrolidin-1-yl) , formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl (e.g., methylsulfamoyl, ethylsulfamoyl) , di- C1-6 alkylsulfamoyl (e.g., dimethylsulfamoyl, diethylsulfamoyl) , Cβ-io aryl (e.g., phenyl, naphthyl), Cβ- 10 aryloxy (e.g., phenyloxy, naphthyloxy) , acyloxy, Cχ-6 alkoxy-Cι-6 alkoxy (e.g., methoxymethoxy, 2-methoxyethoxy, 3-methoxypropoxy) , mono-C7-i6 aralkylamino (e.g., benzylamino, phenethylamino, 1-naphthylamino, 2- naphthylamino, 3-phenylpropylamino) , di-C7_i6 aralkylamino (e.g., dibenzylamino, diphenethylamino) .
The above-described "optionally halogenated Ci-β alkyl" includes, for example, Ci-β 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). Specifically, 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. The above-described "optionally halogenated C2-6 alkenyl" includes, for example, C2-6 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). The above-described "optionally halogenated C2-6 alkynyl" includes, for example, C2-6 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).
The above-described "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" includes, for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) that may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine) or epoxyethyl. Specifically, such cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4- chlorocyclohexyl and epoxyethyl.
The above-described "optionally halogenated C1-6 alkoxy" includes, for example, Ci-β alkoxy which may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine). Specifically, such alkoxy includes methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy. The above-described "optionally halogenated Ci-β alkylthio" includes, for example, Cι_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). Specifically, such alkylthio includes methylthio, difluoromethylthio. trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4, 4, 4-trifluorobutylthio, pentylthio and hexylthio.
The "substituent" for the above-described "4- substituted-piperazin-1-yl" includes, for example, Cι_6 alkyl-carbonyl (e.g., acetyl, propionyl), Cι_6 alkoxy- carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), Cβ-io aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) , mono-Ci-β alkyl- carbamoyl (e.g., methylcarbnamoyl, ethylcarbamoyl), di-Cι-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl) and mono-Cβ-io aryl-carbamoyl (e.g., phenylcarbamoyl) .
The above-described "acyl" includes, for example, an acyl represented by the formula: -(C=0)-R1, -(C=0)-NR1R2, -(C^J-OR1, -(C=S)-NHR1, -SO2-R1 or -SO-R1 wherein R1 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R2 represents a hydrogen atom or a Cι_6 alkyl; or R1 and R2 may form, taken together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring. Among others, the acyl represented by the formula:
-(C^J-R1, -(COJ- R^2, -(COJ-OR1, -SO2-R1, -SO-R1, or the like wherein the symbols have the same definitions as those shown above, is preferred. More preferable acyl includes, for example, Ci-β alkyl-carbonyl (e.g., acetyl, propionyl), Ce-io aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2- naphthoyl), Ci-β alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), mono-Cι-6 alkylcarbamoyl (e.g., methylcarbamoyi, ethylcarbamoyl), di- cι-6 alkylcarbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl) , Cβ-io arylcarbamoyl which may be substituted, C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl) and Cβ-io arylsulfonyl (e.g., phenylsulfonyl, naphthylsulfonyl) . The above-described "Cβ-io arylcarbamoyl which may be substituted" includes, for example, phenylcarbamoyl and naphthylcarbamoyl. The substituent which may be present in the "Cβ-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.
The above-described "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: -NR3bCOR3, -NR3bCOOR3 or -NHS02R3a wherein R3 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R3a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R3b represents a hydrogen atom or a Cι-6 alkyl. Preferable acylamino includes Cι_6 alkyl- carbonylamino (e.g., acetylamino, propionylamino) , Cι_6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino) and Cι-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino) . The above-described "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-COR3b, -0-COOR3c or -0-CONHR3c wherein R3c has the same definition as that for R3a above. Preferable acyloxy includes Cχ-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy) , Cβ-io aryl-carbonyloxy (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy) , Cι_6 alkoxy- carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) , mono-Ci-β alkyl- carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy) , di-Cι-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy) , Cβ-io aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) and nicotinoyloxy.
The "hydrocarbon group which may be substituted" represented by R1, R3, R3a or R3c 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. a) Cι-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl), b) C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl) , c) C2-6 alkynyl (e.g., ethynyl, propargyl, butynyl, 1- hexynyl) , d) C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), e) Cβ-1 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-indenyl, 2-anthryl), preferably phenyl, f) C7-16 aralkyl (e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2, 2-diphenylethyl, 3- phenylpropyl, 4-phenylbutyl, 5-phenylpentyl) , preferably benzyl.
Of the hydrocarbon group, Cχ_6 alkyl, Cβ-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), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy) , nitro, cyano, optionally halogenated Cι_β 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 Cι_6 alkoxy, optionally halogenated Cι_6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino (e.g., methylamino, ethylamino), di-Cι_e alkylamino (e.g., dimethylamino, diethylamino) , 3- to 7-membered saturated cyclic amino (e.g., morpholino, thio orpholino, piperazin- 1-yl, 4-substituted-piperazin-l-yl, piperidino, pyrrolidin- 1-yl), formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl (e.g., methylsulfa oyl, ethylsulfamoyl) , di-Ci-β alkylsulfamoyl (e.g., dimethylsulfamoyl, diethylsulfamoyl) , Cβ-io aryl which may be substituted (e.g., phenyl, naphthyl), Cβ-io aryloxy which may be substituted (e.g., phenyloxy, naphthyloxy) , 5- to 10-membered aromatic heterocyclic group which may be substituted, acyloxy, phthalimido which may be substituted, Ci-e alkoxy-Cι-6 alkoxy (e.g., methoxymethoxy, methoxyethoxy, methoxypropoxy) , mono-C7-i6 aralkylamino (e.g., benzylamino, phenethylamino, 1-naphthylamino, 2- naphthylamino, 3-phenylpropylamino) and di-C7-iβ aralkylamino (e.g., dibenzylamino, diphenethylamino) . The above-described "Cβ-io aryl which may be substituted", "Cβ- ιo aryloxy which may be substituted", "5- to 10-membered aromatic heterocyclic group which may be substituted" and "phthalimido 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.
The above-described "optionally halogenated Ci-β 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 Cι_β alkoxy", "optionally halogenated Cι_e alkylthio", "3- to 7-membered saturated cyclic amino", "acyl", "acylamino" and "acyloxy" are identical to those described in detail as substituents that may be present in ring A above. With respect to the "acyl" in the "acyl", "acylamino" and "acyloxy", it is preferable that R1 in the above-described formulas: -(C=0)-R1, -(C=0)-NR1R2, -(CsOJ-OR1, -(C=S)-NHR1, -(C=0)-OR1, -SO2-R1 and -SO-R1 be (i) a hydrocarbon group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β 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 Cι_β alkoxy, optionally halogenated Ci-β alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-e alkylsulfamoyl, di-Cχ-6 alkylsulfamoyl, Cβ-10 aryl, Cβ-10 aryloxy, 5- to 10-membered aromatic heterocyclic group, phthalimido, Ci-e alkoxy-Cι_β alkoxy, mono-C7-i6 aralkylamino and di-C7_ιe aralkylamino, or (ii) a heterocyclic group which may be substituted 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated C2-e 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 Cι_β alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci-β alkylamino, optionally halogenated di-Cχ_β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, Cβ_ιo aryloxy, Ci-β alkoxy-Ci_e alkoxy, mono-C7_i6 aralkylamino and di-C7-iβ aralkylamino.
The above-described "5- to 10-membered aromatic heterocyclic group which may be substituted" is exemplified by 5- to 10-membered aromatic heterocyclic group selected from the "aromatic heterocyclic group" represented by Ar1 or Ar2 below.
The above-described "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.
The "heterocyclic group which may be substituted" represented by R1, R3, R3a or R3c 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-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl and 2-isoindolyl.
Among others, a 5- to 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, etc. is preferred. Specifically, 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.
The "substituent" 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.
With respect to the "acyl" in the "acyl", "acylamino" and "acyloxy" as a "substituent" for the above-described "heterocyclic group which may be substituted", it is preferable that R1 in the above-described formulas: -(COJ-R1, - ( C=0) - lR2 , - ( C=0) -OR1 t -(C=S)-NHR1, -SO2-R1 and -SO-R1 is (i) a hydrocarbon group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β 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 Cι_e alkoxy, optionally halogenated Ci-β alkylthio, hydroxy, amino, mono-Ci_e alkylamino, di-Cι_ 6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, Cβ_ιo aryloxy, 5- to 10-membered aromatic heterocyclic group, phthalimido, Cι_β alkoxy-Ci-β alkoxy, mono-C7_iβ aralkylamino and di-C7_iβ aralkylamino, or (ii) a heterocyclic group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β alkyl, optionally halogenated C2-β 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 Ci-e alkoxy, optionally halogenated Ci-β alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci_e alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, Cβ_ιo aryloxy, Cι_β alkoxy-Cι_β alkoxy, mono-C7_iβ aralkylamino and di-C7_iβ aralkylamino.
The "Ci-β alkyl" represented by R2 or R3b is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.
The "nitrogen-containing heterocyclic ring" formed by R1 and R2, 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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated Cι_e alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Cχ_β alkylamino, carboxy, carbamoyl and Cι_β alkoxy-carbonyl. More preferably, 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-β alkyl and optionally halogenated Cι_β 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. Specifically, such heterocyclic ring includes a carbocyclic or heterocyclic ring represented by the formula:
Figure imgf000035_0001
wherein Ar1 has the same definition as that shown above; n represents an integer from 0 to 2; Z represents the formula: -CH2-CH2-, -CH=CH-, -CH2-0-, -CO-0-, -CH2-NR4-, -NR -CH2~, -CO-NR4-, -NR4-CO-, -CH=N-, -N=CH- or -CH2-S(0)p- wherein R4 represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl; p represents an integer from 0 to 2.
The "hydrocarbon group" for the "hydrocarbon group which may be substituted" represented by R4 is identical to the "hydrocarbon group" represented by R1, R3, R3» or R3C above and the C3-6 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 R4 is identical to the "substituent" of the "hydrocarbon group which may be substituted" represented by R1, R3, R3a or R3c above. Of the "hydrocarbon group which may be substituted", preference is given to Cι_β alkyl or C7_iβ aralkyl (preferably Cι_β alkyl) which may be substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, mono-Ci-e alkylamino, di-Ci-β alkylamino, carboxy, carbamoyl, Ci-β alkoxy-carbonyl, cyano, C3-6 cycloalkyl, epoxyethyl, Ci-e alkoxy, 3- to 7-membered saturated cyclic amino, Cj,_β alkyl-carbonyl and phthalimido.
The "acyl" represented by R4 is identical to the "acyl" described in detail as the "substituent" for the "benzene ring which may be substituted" represented by ring A above. Among others, preference is given to Ci-β alkyl- carbonyl, Ci-β alkylsulfonyl and Cβ_ιo arylsulfonyl, with greater preference given to Ci-β alkyl-carbonyl.
When Z is a divalent group represented by the formula: -CH2-O-, -CO-O- or -CH2-S(0)P- wherein p is as defined above, n is preferably 1 or 2.
Z is preferably a divalent group represented by the formula: -CH2-CH2-, -CH2-0-, -CO-O-, -CH2-NR4-, -CH=N- or -N=CH- wherein R4 is as defined above. R4 is preferably a Cι_β alkyl or a Ci-β alkyl-carbonyl.
The "substituent" 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-β alkylamino, di-Ci-β alkylamino and oxo.
Ring B is preferably a ring represented by the formula:
Figure imgf000036_0001
0 more preferred is a ring represented by the formula:
Figure imgf000036_0002
The "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. Among others, preferred is a 6-membered nitrogen-containing heterocyclic ring. Specifically, such nitrogen-containing heterocyclic ring includes the ring represented by the formula:
Figure imgf000037_0001
wherein _ 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:
Figure imgf000037_0002
wherein, X is as defined above. Still more preferable nitrogen-containing heterocyclic ring includes the ring represented by the formula:
-N X-
wherein X is as defined above.
X is preferably (i) a nitrogen atom or (ii) a group represented by the formula: >C(R5)- wherein R5 represents a hydrogen atom, cyano, optionally halogenated Cι_β alkyl, optionally halogenated Cι_β alkoxy, optionally halogenated Ci-β alkylthio, hydroxy, amino, a mono-Ci-e alkylamino, a di-Ci-β alkylamino, carboxy, a Cι_e alkoxy-carbonyl, a Cι_e alkyl-carbonylamino or a Cι_e alkyl-carbonyl.
The "optionally halogenated Ci-e alkyl", "optionally halogenated Ci-β alkoxy" and "optionally halogenated Cι_β alkylthio" represented by R5 are identical to those described in detail as substituents that may be present in ring A above.
The "substituent" 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.
Preferable substituents that may be present in ring C are cyano, optionally halogenated Ci-e alkyl, optionally halogenated Ci-β alkoxy, optionally halogenated Cι_e alkylthio, hydroxy, amino, mono-Cι_e alkylamino, di-Ci-β alkylamino, carboxy, Ci-e alkyl-carbonyl, Cι_e alkoxy- carbonyl and Ci-β alkyl-carbonylamino. The substituents selected from the group consisting of a halogen atom, cyano, optionally halogenated Ci-e alkyl, optionally halogenated Ci-e alkoxy, optionally halogenated Cι_e alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Ci-β alkylamino, carboxy, Ci-e alkyl-carbonyl and Ci-β alkoxy- carbonyl are also preferable.
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 -(CH2)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 C1-.4 alkylene such as methylene, ethylene, trimethylene, propylene and tetramethylene. Such C1-4 alkylenes may havs one oxo group at any possible position. Specifically, such alkylene includes methylene, carbonyl, ethylene, trimethylene, propylene and tetramethylene.
Y is preferably a bond or methylene. More preferred is a bond.
The group represented by the formula:
Figure imgf000039_0001
wherein the symbols have the same definitions as those shown above, is preferably a group represented by the formula:
Figure imgf000039_0002
wherein Xa represents (i) a nitrogen atom or (ii) a group represented by the formula: >C(R5a)- wherein R5a represents a hydrogen atom, cyano, an optionally halogenated Cι_e alkyl, an optionally halogenated Ci-e alkoxy, an optionally halogenated Ci-e alkylthio, hydroxy, amino, a mono-Ci-β alkylamino, a di-Ci-e alkylamino, carboxy, a Cι_ alkoxy- carbonyl, a Ci-β alkyl-carbonylamino or a Ci-e alkyl- carbonyl; Ya represents a bond or methylene; Ar2 is as defined above.
The "aromatic group which may be substituted" represented by Ar1 or Ar2 is exemplified by an aromatic hydrocarbon group and an aromatic heterocyclic group. Such "aromatic hydrocarbon group" includes, for example, a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Specifically, such aromatic hydrocarbon group includes Cβ_ 14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, indenyl and anthryl. Among others, phenyl, 1-naphthyl and 2-naphthyl are preferable. Such "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. Specifically, such 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, /?-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazane and phenoxazine; and a monovalent group resulting from removal of an optionally chosen hydrogen atom from a ring formed by condensation of the above-described ring with one or more (preferably 1 or 2) aromatic rings (e.g., benzene rings) . Preferable examples of "aromatic heterocyclic group" includes 5- or 6-membered aromatic heterocyclic group which may be condensed with one benzene ring. Specifically, such aromatic heterocyclic groupsincludes 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. Among others, preferred is 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-quinolyl, 1-isoquinolyl, 1- or 2- indolyl, 2-benzothiazolyl etc.
The "substituent" 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. Among others, preferred is halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated C2-β alkenyl, optionally halogenated C2-β 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 Cι_β alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-e alkylsulfamoyl, di-Cι_e alkylsulfamoyl, Cβ-10 aryl, Cβ_ιo aryloxy, acyloxy, Ci-β alkoxy-Ci-β alkoxy, mono-C7_ie aralkylamino, di-C7_iβ aralkylamino, etc. More preferred is halogen, C1-3 alkylenedioxy (preferably methylenedioxy) , an optionally halogenated Ci-β 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 Cι_ alkoxy. More preferred is a phenyl or pyridyl group which may be substituted by 1 to 3 halogen atoms (e.g., chlorine, fluorine). Specifically, phenyl, 4- chlorophenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl or 4- pyridyl is exemplified. Ar2 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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β alkyl, optionally halogenated C2-6 alkenyl, optionally halogenated C2-β 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 Cι_β alkoxy, optionally halogenated Ci-β alkylthio, hydroxy, amino, mono-Cι_e alkylamino, di-Cι_β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Cχ_β alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Ci-β alkoxy-Ci-β alkoxy, mono-C7_ιe aralkylamino and di-C7-ιe aralkylamino. More preferred is 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 Cι_e alkyl and an optionally halogenated Ci-e alkoxy. Specifically, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2- fluorophenyl, 3-fluorophenyl , 4-fluorophenyl , 3,5- dichlorophenyl, 3, 5-difluorophenyl, 3- trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl is exemplified. Especially preferred is a phenyl which may be substituted by 1 to 3 halogen atoms or Ci_e alkoxy.
Of the compounds represented by formula (I) above, preference is given to those compounds wherein ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 alkylenedioxy, nitro, cyano, an optionally halogenated Ci_e alkyl, an optionally halogenated Ci-e alkoxy, an optionally halogenated Cι_e alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-e alkylamino, carboxy, carbamoyl and Ci-e alkoxycarbonyl, ring B is a ring represented by the formula:
Figure imgf000042_0001
wherein Za represents a divalent group represented by the formula: -CH2-CH2-, -CH2-0-, -CO-O-, -CH2-NR4a-, -CH=N- or N=CH- wherein R4a represents a Ci-β 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:
Figure imgf000043_0001
wherein 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-β alkyl, an optionally halogenated Cι_β alkoxy, an optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-e alkylamino, carboxy, Cχ_β alkyl-carbonyl, Ci-e alkoxy-carbonyl and Ci_e alkyl- carbonylamino,
Y is a bond or a methylene,
Ar1 is a phenyl or pyridyl group which may be substituted by 1 to 3 halogen atoms,
Ar2 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 Cι_β alkoxy, and m is 1 or 2.
More preference is given to those compounds wherein ring A is a benzene ring, ring B is a ring represented by the formula:
n
Figure imgf000043_0002
wherein Zb represents a divalent group represented by the formula: -CH2-CH2-, -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:
-N Xa"
10 wherein Xa represents (i) a nitrogen atom or (ii) a group represented by the formula: >C(R5a)- wherein R5a represents a hydrogen atom, cyano, an optionally halogenated Ci-β alkyl, an optionally halogenated Cι_β alkoxy, an optionally ,,- halogenated Ci-e alkylthio, hydroxy, amino, a mono-Ci-β alkylamino, a di-Ci-e alkylamino, carboxy, a Cι_β alkoxycarbonyl, a Cι_β alkyl-carbonylamino or a Ci-β alkyl- carbonyl,
Y is a bond, 2_ Ar1 is a phenyl which may be substituted by 1 to 3 halogen atoms,
Ar2 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-β alkyl and an ,[. optionally halogenated Ci-e alkoxy, and m is 2.
Also preferred are those compounds wherein the condensed ring formed by ring A and ring B is a ring represented by the formula:
Figure imgf000044_0001
35 ring C is a ring represented by the formula:
Figure imgf000045_0001
which may be substituted by the substituents selected from the group consisting of a cyano, a hydroxy and a Cι_β alkyl-carbonyl ,
Y is a bond or a methylene,
Ar1 is a phenyl or pyridyl group which may be substituted by a halogen, preferably a phenyl,
Ar2 is a phenyl which may be substituted by a halogen atom, an optionally halogenated Cι_β alkyl or a Ci-β alkoxy, and m is 2. Preferable examples of compound (I) include
4-phenyl-4-[ 2-( 4-phenylpiperidino)ethyl ] isochroman,
4-phenyl-4- [ 2-( 4-hydroxy-4- phenylpiperidino]ethyl) isochroman,
4-{2-[ 4- (m-fluorophenyl)piperidino]ethyl}-4- phenylisochroman,
4-{2-[ 4-(o-methoxyphenyl)piperazin-l-yl]ethyl}-4- phenylisochroman,
1 , 3-dihydro-l-ethyl-3-phenyl-3-( 2-( 4- phenylpiperidino) ethyl )-2H-indol-2-one, 1 , 3-dihydro-l-ethyl-3- ( 2-( 4-hydroxy-4- phenylpiperidino)ethyl)-3-phenyl-2H-indol-2-one,
2-methyl-3-oxo-4-pheny1-4- (2-( 4-phenylpiperidino)ethyl )-
1,2,3, 4-tetrahydroisoquinoline and salts thereof. Of the compounds represented by formula (I), compound
(la) is a new compound.
"Ring A", "ring C", "X", "Y", "Ar1", "Ar2" and "m" in formula (la) above are defined as the same as "ring A",
"ring C", "X", "Y" , "Ar1", "Ar2" and "m" described in detail with respect to formula (I) above. The "5- to 7-membered carbocyclic or heterocyclic ring which may be substituted" represented by ring B' is exemplified by the 5- to 7-membered carbocyclic or heterocyclic ring represented by the formula:
)r
Figure imgf000046_0001
wherein Ar1 is as defined above; r represents an integer from 0 to 2; W represents a divalent group represented by the formula: -CH-CH2-, -CH=CH-, -CO-O-, -CO-NR6-, -NR6- CO-, -N=CH-, -CH2-S(0)p-, -N=N-, -NR6-S02-, -S02-NR6-, -NR6- NR6a-, -CH2-NR6-CO- or -CO-NR6-CO- wherein each of R6 and R6a 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. When W is -CH2-NR6-CO- or -CO-NR6-CO-, r is 0 or 1. The "hydrocarbon group which may be substituted" represented by R6 or R6a is identical to the "hydrocarbon group which may be substituted" represented by R4 above. Among others, preferred is a Ci-β alkyl, C2-β alkenyl or C7-. iβ aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-.3 alkylenedioxy, nitro, cyano, optionally halogenated 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 Cι_ alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-β alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci_e alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ_ιo aryl which may be substituted, Ce-io aryloxy which may be substituted, 5- to 10-membered aromatic heterocyclic group which may be substituted, acyloxy, phthalimido which may be substituted, Ci-e alkoxy-Ci-e alkoxy, mono-C7-iβ aralkylamino and di-C7_ie aralkyl. More preferred is a Ci-e alkyl or C7_iβ aralkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, cyano, optionally halogenated C3_β cycloalkyl, epoxyethyl, optionally halogenated Ci-β alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Cι_β alkylamino, di-Ci- β alkylamino, 3- to 7-membered saturated cyclic amino, Cι_β alkyl-carbonyl, Ci-e alkoxy-carbonyl, carboxy, carbamoyl, Ci-β alkyl-carbonyloxy and phthalimido. The "acyl" represented by R6 or R6a is identical to the "acyl" described in detail as the "substituent" for the "benzene ring which may be substituted" represented by ring A above. Among others, preferred is Ci-e alkyl-carbonyl, Ci-e alkoxy-carbonyl, Ci-e alkylsulfonyl and Ce-io arylsulfonyl. More preferred is Ci-β alkyl-carbonyl.
The "amino which may be substituted" represented by R6 or R6a 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.
The above "hydrocarbon group which may be substituted", "heterocyclic group which may be substituted" and "3- to 7-membered saturated cyclic amino" are identical to the "hydrocarbon group which may be substituted",
"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 R6 or R6a is preferably a mono-Ci-β alkylamino, a di-Ci-β alkylamino or a 3- to 7-membered saturated cyclic amino. W is preferably a divalent group represented by the formula: -NR6-CO- or -CH2~NR6-CO- wherein R6 is as defined above. Also preferred is the case wherein r is 0.
R6 is preferably (i) a hydrogen atom, (ii) a Cι_β alkyl, C2-6 alkenyl or C7_i aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 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-β alkoxy, optionally halogenated Ci-e alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Cι_ β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl (preferably, Ci-e alkyl-carbonyl, Cι_β alkoxycarbonyl, mono-Ci_e alkylcarbamoyl, di-Ci_e alkylcarbamoyl, c6-ιo arylcarbamoyl, Ci-e alkylsulfonyl, Ce_io arylsulfonyls) , acylamino (preferably, Ci-e alkyl- carbonylamino, Ci_e alkoxy-carbonylamino, Cι_β alkylsulfonylamino) , carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_β alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-10 aryl which may be substituted, Cβ-10 aryloxy which may be substituted, 5- to 10-membered aromatic heterocyclic group which may be substituted, acyloxy (preferably, Ci-β alkyl- carbonyloxy, Cβ_ιo aryl-carbonyloxy, Ci-e alkoxy- carbonyloxy, mono-Ci-β alkyl-carbamoyloxy, di-Ci-e alkyl- carba oyloxy, Cg-io aryl-carbamoyloxy, nicotinoyloxy) , phthalimido which may be substituted, Ci-e alkoxy-Ci-e alkoxy, mono-C7-iβ aralkylamino and di-C7_ie aralkylamino, (iii) a Ci-e alkyl-carbonyl, a Ci-β alkoxy-carbonyl, a mono- Ci-e alkyl-carbamoyl, a di-Ci-β alkyl-carbamoyl, a Ce_io aryl-carbamoyl, a Ci_e alkylsulfonyl or a Ce-io arylsulfonyl, or (iv) a mono- or di-Ci-β alkylamino, a mono- or di-C7-iβ aralkylamino or a 3- to 7-membered saturated cyclic amino.
The "substituent" for the "5- to 7-membered carbocyclic or heterocyclic ring which may be substituted" represented by ring B1 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.
Of the compounds represented by formula (la) above, preference is given to those compounds wherein ring A is a benzene ring which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 alkylenedioxy, nitro, cyano, an optionally halogenated Cι_β alkyl, an optionally halogenated Ci_e alkoxy, an optionally halogenated Ci_e alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-β alkylamino, carboxy, carbamoyl and Ci_e alkoxycarbonyl, ring B* is a ring represented by the formula:
Figure imgf000049_0001
wherein R6b represents (i) a hydrogen atom, (ii) a Ci-e alkyl or C7_iβ aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of a halogen atom, C1-3 alkylenedioxy, nitro, cyano, an optionally halogenated Cι_β 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-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl (preferably, Ci-β alkyl- carbonyl, Ci-β alkoxy-carbonyl, mono-Ci-β alkylcarbamoyl, di-Cι_β alkylcarbamoyl, Ce-io arylcarbamoyl, Cι_β alkylsulfonyl, Cβ-io arylsulfonyl) , acylamino (preferably, Ci_e alkyl-carbonylamino, Ci-e alkoxy-carbonylamino, Cι_β alkylsulfonylamino) , carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-e alkylsulfamoyl, di-Ci-e alkylsulfamoyl, Ce-io aryl which may be substituted, Ce-io aryloxy which may be substituted, 5- to 10-membered aromatic heterocyclic group which may be substituted, acyloxy (preferably, Ci-e alkyl- carbonyloxy, Cβ-io aryl-carbonyloxy, Ci-e alkoxy- carbonyloxy, mono-Ci-β alkyl-carbamoyloxy, di-Ci-e alkyl- carbamoyloxy, Ce-io aryl-carbamoyloxy, nicotinoyloxy) and phthalimido which may be substituted,
(iii) a Ci-e alkyl-carbonyl, a Cι_β alkoxy-carbonyl, a mono- Cι-6 alkyl-carbamoyl, a di-Ci-e alkyl-carbamoyl, a Ce-io aryl-carbamoyl, a Ci-β alkylsulfonyl or a Cβ_ιo 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:
Figure imgf000050_0001
wherein 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 Cι_β alkyl, an optionally halogenated Cι_β alkoxy, an optionally halogenated Ci_e alkylthio, hydroxy, amino, mono-Cι_β alkylamino, di-Ci-e alkylamino, carboxy, Ci-β alkyl-carbonyl, Cι_β alkoxy-carbonyl and Cι_β alkyl- carbonylamino,
Y is a bond or a methylene,
Ar1 is a phenyl or pyridyl group which may be substituted by 1 to 3 halogen atoms,
Ar2 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.
Of these compounds, more preference is given to those compounds wherein ring A is a benzene ring,
R6b is (i) a hydrogen atom, (ii) a Ci_e alkyl or C7_ie aralkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of cyano, C3-6 cycloalkyl, epoxyethyl, an optionally halogenated Ci-e alkoxy, amino, di-Ci_e alkylamino, 3- to 7-membered saturated cyclic amino, Cι_β alkoxy-carbonyl, Ci_e alkyl- carbonyloxy and phthalimido, (iii) a Cι_β alkyl-carbonyl, or (iv) a di-Ci-β 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:
-N Xb"
wherein Xb represents (i) a nitrogen atom or (ii) a group represented by the formula: >C(R5 )- wherein R5b represents a hydrogen atom, an optionally halogenated Ci-β alkyl or a hydroxy,
Y is a bond,
Ar1 is a phenyl,
Ar2 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 -CH2-NR6-CO-, wherein R6 is a mono- or di-Ci-β alkylamino or a Ci-β 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 Cι_β alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-e alkylamino, Ci-β alkyl-carbonyl, Ci_e alkoxy-carbonyl and carboxy,
Y is a bond,
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 Cι_β alkyl, optionally halogenated Ci_e alkoxy, amino, mono-Ci-e alkylamino, di- Cι_β alkylamino, Ci_e alkyl-carbonyl, Ci_e alkoxy-carbonyl, mono-Ci-β alkyl-carbamoyl, di-Ci-e alkyl-carbamoyl, Ci-e alkylsulfonyl, Cι_β alkyl-carbonylamino, Cι_β alkoxy- carbonylamino, Ci-β alkylsulfonylamino and mono-Ci-β alkylsulfamoyl, and m is 1 or 2.
Also preferred is a compound wherein ring A is an optionally halogenated benzene ring; ring B' is a ring of the formula:
Figure imgf000053_0001
wherein R6' is (i) a hydrogen atom,
(ii) a Cι_β alkyl, C2-β alkenyl or C7-ιβ 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 Cι_β alkoxy, hydroxy, amino, mono- or di-Ci-β alkylamino, 3- to
7-membered saturated cyclic amino, Ci-β alkoxy-carbonyl,
Ci-e alkyl-carbonyloxy, phthalimido and Cι_β alkoxy-Ci-e alkoxy,
(iii) a Ci-β alkyl-carbonyl, or
(iv) a mono- or di-Ci_e alkylamino, a mono- or di-C7_iβ aralkylamino or a 3- to 7-membered saturated cyclic amino, ring C is a ring of the formula:
(0)t
-N X'-
wherein 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,
Y is a bond,
Ari is a phenyl, Ar is a phenyl or pyridyl which may be substituted by 1 to
3 substituents selected from the group consisting of halogen, nitro, cyano, optionally halogenated Cι_β alkyl,
Ci-β 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. Preferable examples of compound (la) include
1 , 3-dihydro-l-ethyl-3-phenyl-3- ( 2- ( 4- phenylpiperidino)ethyl )-2H-indol-2-one,
1, 3-dihydro-l-ethyl-3- ( 2-( 4-hydroxy-4- phenylpiperidino)ethyl)-3-phenyl-2H-indol-2-one,
2-methyl-3-oxo-4-pheny1-4-( 2-( 4-phenylpiperidino)ethyl )-
1, 2, 3, 4-tetrahydroisoquinoline,
1-ethyl-l , 3-dihydro-3-phenyl-3-{ 2-( 4-( 3- trifluoromethylphenyl)piperidino) ethyl )-2H-indol-2-one, 3- ( 2- ( 4- ( 3-chlorophenyl ) iperazin-1-yl ) ethyl )-1-ethyl-l , 3- dihydro-3-phenyl-2H-indol-2-one,
3-(2-( -cyano-4-phenylpiperidino)ethyl) -1-ethyl-l, 3- dihydro-3-phenyl-2H-indol-2-one,
2-ethyl-4-( 2- ( 4- ( o-methoxyphenyl )piperazin-1-yl )ethyl )-3- oxo-4-phenyl-l,2,3,4-tetrahydroisoquinoline, l,3-dihydro-l-(dimethylamino)-3-(2-(4-(o- methoxyphenyl)piperazin-l-yl)ethyl)-3-phenyl-2H-indol-2- one,
1 , 3-dihydro-l-( 2-(morpholino)ethyl )-3-phenyl-3- ( 2-( 4- phenylpiperidino)ethyl )-2H-indol-2-one, l-ethyl-l,3-dihydro-3-phenyl-3-(2-(4-(3- trifluoromethylphenyl )piperazin-l-yl )ethyl )-2H-indol-2-one, and salts thereof.
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.
Of these salts, pharmaceutically acceptable salts are preferred. Examples of such 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.
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.
The compounds shown in the following schemes include their salts, exemplified by the same salts as those of compound (I) . Scheme 1
Figure imgf000056_0001
(IV) (V)
wherein L represents a leaving group; the other symbols have the same definitions as those shown above.
The "leaving group" represented by L is exemplified by a halogen atom (e.g., chlorine, bromine, iodine), Cι_β alkylsulfonyloxy which may be substituted by 1 to 3 halogen atoms (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy) , Cβ-io arylsulfonyloxy which may be substituted by 1 to 4 Cι_β alkyls or halogen atoms (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy, p- bromobenzenesulfonyloxy, mesitylenesulfonyloxy) . Process 1
The hydroxy of compound (II) is converted to a leaving group to yield compound (III).
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). Process 2
Compound (III) is subjected to a conventional alkylation to yield compound (I).
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:
Figure imgf000057_0001
wherein 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. Although 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, cesium carbonate), and alkali metal or alkaline earth metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate); and 3) organic bases such as amines such as triethylamine, diisopropylethylamine, N- methylmorpholine, dimethylaminopyridine, DBU (1,8- diazabicyclo[5.4.0]-7-undecene) , DBN (1,5- diazabicyclo[4.3.0]non-5-ene, and basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine.
Where X in compound (I) is a nitrogen atom, compound (I) can be also obtained by the following procedure:
(1) compound (III) is subjecting to alkylation with the compound represented by the formula:
HN c X-T
wherein X represents a nitrogen atom, T represents a hydrogen atom or an amino protective group, and other symbols have the same definition as those shown above, or its salt, by the similar manner as the alkylation shown above, followed by a deprotection reaction, if necessary, to synthesize the following compound represented by the formula:
Figure imgf000058_0001
wherein each symbol has the same definition as those shown above; and then (2) the above compound or its salt is reacted with 1 to 2 equivalents of the compound represented by the formula:
La-Y-Ar2 wherein La represents a leaving group, and other symbols have the same definition as those shown above, or its salt.
The "amino protective group" represented by T is as same as "amino protective group" described later.
The "leaving group" represented by La is identical to "leaving group" of L above.
The deprotection reaction in above (1) can be accomplished by known methods. For example, where T is formyl, hydrolysis can be utilized. The alkali hydrolysis or the acid hydrolysis can be used for the hydrolysis and acid hydrolysis is preferable. As a typical procedure of the 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.
The inert solvent includes water and acetic acid. These solvents can be used singly or in combination of these two kinds. Typically, 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.
The above-described 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 150CC. 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) is subjected to a commonly known amide bond-forming reaction to yield compound (V) .
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).
In compound (IV), an optical isomer of the formula:
—COOH
Figure imgf000060_0001
wherein ring B" represents an optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring; W' represents a divalent group of the formula: -CH2-CH2-, -CH=CH-, -C0-0-, -CO-NR6-, -NR6-CO-, -N=CH-, -CH2-S(0)p-, -N=N-, -NR6-S02~, -SO2-NR6-, -NR6-NR6a-, -CH2-0-, -CH2-NR6-, -NR6-CH2-, -CH=N-, -CH2-NR6-CO- or -CO-NR6-CO- wherein R6 and R6a 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; and the other symbols have the same definitions as those shown above, and or a salt thereof is a new compound. The "optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring" for B" ring is identical to the "optionally substituted 5- to 7-membered carbocyclic or heterocyclic ring" for B' ring above.
The above 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:
Figure imgf000061_0001
wherein all symbols are as defined above, with an optical active amine, and then subjecting the resultant salt to fractional recrystallization.
The "optical active amine" includes, for example, (+)- 1-phenethylamine, (-)-l-phenethylamine, cinchonine, (-)- cinchonidine, brucine, (lS,2S)-(+)-2-amino-l-phenyl-l,3- propanediol. Process 4
The amide bond in compound (V) is reduced to yield compound ( I ) .
The reduction is carried out using a metal hydride. Specifically, compound (V) and 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. 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). The metal hydride is exemplified by lithium aluminum hydride. The amount of metal hydride used is normally about 2 to 20 equivalents, preferably 6 to 12 equivalents, per equivalent of compound (V). Reaction temperature is -70°C to 100°C. Although reaction temperature varies depending on the reducing agent used, it is preferably 30°C to 70°C when lithium aluminum hydride is used.
When compound (I) is an isochroman analog, the desired product may be produced from compound (VII) as obtained by the following scheme 2 via the same reaction process as process 2 in the above-described scheme 1. Scheme 2
Figure imgf000062_0001
(VI) (VII)
wherein 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. Process 5
Compound (VI) is subjected to a commonly known oxidation to yield compound (VII).
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.
Compound (VII) as obtained by the above-described oxidation is converted to compound (I) by the same method as process 2 in the above-described scheme 1. When compound (I) is a tetrahydronaphthalene, the desired product may, for example, be produced from compound (II) or (IV) as obtained by the following scheme 3 via the same reaction process as the process in the above-described scheme 1.
Scheme 3
Figure imgf000064_0001
(VIII) (IX) (X)
Figure imgf000064_0002
0 wherein 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-β alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl). 5 Process 6
Compound (VIII) is subjected to a commonly known Reformatsky reaction to condense the ester and yield compound (IX) .
A commercial product of compound (VIII) may be used as 0 the compound (VIII).
Regarding the conditions for the reaction, the method described in Organic Reaction, Vol. 22, p. 426, for example, can be used. Process 7 _ Compound (IX) is subjected to a commonly known cyclization to yield compound (X). The cyclization is carried out in an acidic environment. For example, 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
(preferably room temperature to 50°C) for 1 to 24 hours. Preferably, 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. Process 8
Compound (X) is subjected to reduction to yield compound (II) . The reduction is carried out using a metal hydride. For example, 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.
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). Such 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, per mol of compound (X). Reaction temperature is -70 to 100°C. Although reaction temperature varies depending on the reducing agent used, it is preferably 0 to 50°C when lithium aluminum hydride is used. Process 9
Compound (X) is subjected to a hydrolysis to yield compound (IV) .
The hydrolysis is carried out by an alkali hydrolysis or an acid hydrolysis. In the case of alkali 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. In a preferred mode of reaction, the reaction is carried out in a water-methanol mixed solvent at about 50°C to 120βC 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. In a preferred mode of reaction, 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). When compound (I) is an isoquinolone, for example, 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.
Scheme 4
Figure imgf000067_0001
Process 12
Figure imgf000067_0002
( XIV) ( XV)
Process 14 Process 15
Figure imgf000067_0003
Figure imgf000067_0004
(XVI ) ( XVII )
Figure imgf000067_0005
wherein each of R' and R" represents a lower alkyl; the other symbols have the same definitions as those shown above .
The "lower alkyl" represented by R' or R" is identical to the "lower alkyl" represented by R above. Process 10
Compound (XI) is subjected to a commonly known aromatic substitution to yield compound (XII).
A commercial product of compound (XI) may be used as the compound (XI).
The reaction is carried out by stirring compound (XI), 0.5 to 2 equivalents of a compound represented by the formula:
Figure imgf000068_0001
wherein 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-β alkylsulfonyloxy which may be substituted by 1 to 3 halogens (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy), Cβ-io arylsulfonyloxy which may be substituted by 1 to 4 substituents selected among Cι_β alkyl, nitro and halogen (e.g., p-toluenesulfonyloxy, benzenesulfonyloxy, mesitylenesulfonyloxy) .
The base is exemplified by the strong bases described in detail with respect to the above-described process 2. Among others, 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
Compound (XII) is subjected to a commonly known alkylation to yield compound (XIII).
The alkylation is carried out by stirring compound (XII), 1 to 3 equivalents of a compound represented by the formula: L-(CH2)m-ι-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. Among others, 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. Process 12
Compound (XIII) is subjected to a commonly known catalytic reduction to yield compound (XIV) .
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. Process 13
Compound (XIV) is subjected to a commonly known alkylation or acylation to yield compound (XV).
The alkylation or acylation is carried out by stirring compound (XIV), 1 to 3 equivalents of a compound represented by the formula: R6-L" ' ' wherein L' ' ' represents a leaving group; R6 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-β alkylsulfonyloxy which may be substituted by 1 to 3 Ci-β alkyl, nitro or halogen (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy) , Cβ_ιo 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, trifluoroacetyloxy , propionyloxy) and Ce-io aryl- carbonyloxy which may be substituted by 1 to 4 halogen atoms (e.g., benzoyloxy).
The base is exemplified by the strong bases, inorganic bases, organic bases etc. described in detail with respect to the above-described process 2. Among others, 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. Process 14
Compound (XV) is subjected to a hydrolysis to yield compound (XVI ) .
The hydrolysis may be carried out in the same manner as in the above-described process 9. Process 15
Compound (XVI) is subjected to a commonly known reduction to yield compound (XVII).
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. Among others 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.
Compound (XVII) thus obtained is subjected to the same reaction process as the process for preparing compound (I) from compound (II) in the above-described scheme 1 to yield compound (I) or (la), which has an isoquinolone structure. When the starting compound involved in each reaction described above has amino, carboxy or hydroxy as a substituent, the group may be protected by a protecting group commonly used in peptide chemistry and other fields; the desired compound can be obtained by removing the protecting group if necessary after reaction. The amino-protecting group includes, for example, formyl, Cχ_β alkyl-carbonyl (e.g., acetyl, propionyl), Cι_β alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl) , benzoyl, C7--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) and C2-e alkenyl (e.g., 1-allyl). These groups may be substituted by 1 to 3 halogen (e.g., fluorine, chlorine, bromine, iodine), Ci-β alkoxy (e.g., methoxy, ethoxy, propoxy) or nitro.
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), C7-11 aralkyl (e.g., benzyl) and C2-e alkenyl (e.g., 1-allyl). These groups may be substituted by 1 to 3 halogen (e.g., fluorine, chlorine, bromine, iodine), formyl, Ci-e alkyl- carbonyl (e.g., acetyl, propionyl, butyryl) or nitro.
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-β alkyl-carbonyl (e.g., acetyl, propionyl), benzoyl, C7- 11 aralkyl-carbonyl (e.g., benzylcarbonyl), 2- tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl), trityl and C2- e alkenyl (e.g., 1-allyl). These groups may be substituted by 1 to 3 halogen (e.g., fluorine, chlorine, bromine, iodine), Ci-β alkyl (e.g., methyl, ethyl, propyl), phenyl, C7-10 aralkyl (e.g., benzyl) or nitro. 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.
Also, compounds (I) and (la) may be hydrates or non- hydrates.
When 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. For example, when 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. 1) Fractional recrystallization 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'-dibenzoyltartaric acid, (+)-l-phenethylamine, (-)-l- phenethylamine, cinchonine, (-)-cinchonidine, brucine, (lS,2S)-(+)-2-amino-l-phenyl-l,3-propanediol] and then subjected to fractional recrystallization to yield a free optical isomer via a neutralization process as desired.
2) Chiral column method
A racemate or a salt thereof is applied to a column for optical isomer separation (chiral column) to separate it. In the case of liquid chromatography, for example, 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. Also, in the case of gas chromatography, for example, a chiral column such as CP-Chirasil-deX CB (produced by GL Science) is used to separate optical isomers.
3) 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. When compound (I) has hydroxy or primary or secondary amino in the molecular structure thereof, an ester or amide diastereomer, respectively, is obtained by subjecting the compound, an optically active organic acid (e.g., MPTA [α-methoxy-α-( trifluoromethyl)phenylacetic acid], (-)-methoxyacetic acid) etc. to a condensation. On the other hand, when compound (I) or (la) has a carboxylic acid group, an ester or amide diastereomer, respectively, is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation. The diastereomer thus separated is converted to an optical isomer of the original compound by an acid hydrolysis or basic hydrolysis. 0 Compounds (I) and (la) are low in toxicity. For example, in an acute toxicity study using rats, no death was observed when the compound obtained in Reference Example 4-1 below was orally administered at 100 mg/kg. 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.
Also, 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. 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.
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.
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.
BEST MODE FOR CARRYING OUT OF THE INVENTION The present invention is hereinafter described in more detail by means of the following reference examples, examples and a test example, which may be varied, as long as they remain within the scope of the invention.
In the reference examples and examples below, "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.
The other abbreviations used herein are defined as follows: s : singlet d : doublet t : triplet q : quartet
ABq : AB quartet dd : double doublet dt : double triplet ddd : double double doublet m : multiplet br : broad
J : coupling constant
Hz : Hertz
CDCI3 : deuterochloroform
THF : tetrahydrofuran
DMF : N,N-dimethylformamide DMSO : dimethyl sulfoxide
1H-NMR: proton nuclear magnetic resonance (measured in CDCI3 normally as a free form) Examples
Reference Example 1-1
2 , 2-Diphenyl-l, 4-butanediol a,o-Diphenyl-7~butyrolactone (7 g) was dissolved in anhydrous THF (80 ml) and lithium aluminum hydride (1 g) was added under ice cooling conditions, followed by stirring for 3 hours. To the reaction mixture was added dropwise a saturated aqueous solution of Rochelle salt under ice cooling conditions to precipitate inorganic material such as aluminum hydroxide. The supernatant was separated by decantation, dried, and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to yield the title compound (7 g). 1H-NMR (CDC13) δ i 2.54 (2H, t), 3.61 (2H, t), 4.21 (2H, s), 7.16-7.45 (10H, m)
Reference Example 1-2
2 , 2-Diphenyl-l , 5-pentanediol
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 60QC 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. After being stirred for 2 hours, a saturated aqueous solution of Rochelle salt was added dropwise to the reaction mixture under ice cooling conditions to precipitate inorganic material such as aluminum hydroxide. The supernatant was separated by decantation, dried, and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether/ethyl acetate to yield the title compound (20.5 g).
XH-NMR (CDC13) δi 1.28-1.42 (2H, m) , 2.19-2.30 (2H, m) , 3.59 (2H, t), 4.17 (2H, s), 7.15-7.37 (10H, m)
Reference Example 2-1
4- ( 2-Hydroxyethyl )-4-phenylisochroman
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. After being concentrated under reduced pressure, the mixture was dissolved in ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with isopropyl ether/ethyl acetate to yield the title compound (4.5 g). 1H-NMR (CDCI3) δ: 2.26-2.39 (1H, m) , 2.68 (1H, m) , 3.38 (1H, m), 3.52-3.67 (1H, m) , 3.85 (1H, dd) , 4.08 (1H, d), 4.91 (2H, s), 6.86 (1H, dd) , 7.04-7.38 (8H, m)
Reference Example 2-2
4-( 3-Hydroxypropyl) -4-phenylisochroman
The title compound was obtained in the same manner as in Reference Example 2-1.
XH-NMR (CDCI3) δ: 1.4-1.8 (2H, m) , 2.1-2. (2H, m) , 3.64 (2H, t), 3.93 (2H, s), 4.88 (2H, s), 6.80-7.40 (9H, m)
Reference Example 3-1 4-(2-Iodoethyl)-4-phenylisochroman 4-(2-Hydroxyethyl)-4-phenylisochroman (1 g) was dissolved in methylene chloride (20 ml) followed by addition of tosyl chloride (0.85 g) and triethylamine (1.5 ml) under ice cooling conditions. After being stirred at room temperature for 2 hours. The mixture was acidified by the addition of 2 N hydrochloric acid and extracted with isopropyl ether. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in acetone (50 ml) followed by addition of sodium iodide (2 g) was added, followed by stirring under heating at 50°C for 24 hours. After the mixture was cooled, water was added, followed by extraction with isopropyl ether. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with isopropyl ether to yield the title compound. 1H-NMR (CDC13) δ : 2.76-3.08 (3H, m) , 3.20-3.39 (IH, m) , 3.89 (2H, q), 4.87 (2H, s), 6.90 (IH, d), 7.01-7.38 (8H, m)
Reference Example 3-2
4-( 3-Iodopropyl)-4-phenylisochroman
The title compound was obtained in the same manner as in Reference Example 3-1.
Melting point: 39 - 40°C XH-NMR (CDCI3) δ i 1.50-2.00 (2H, m) , 2.29 (2H, m) , 3.16
(2H, dt), 3.90 (2H, s), 4.88 (2H, s), 6.90-7.30 (9H, m)
Reference Example 4-1
4-Phenyl-4- [ 2-( 4-phenylpiperidino) ethyl ] isochroman hydrochloride
To a solution of 4-phenyl-4-(2-iodoethyl) isochroman
(2.6 g) in acetonitrile (50 ml) were added 4- phenylpiperidine (1.39 g) and potassium carbonate (1.56 g).
The mixture was stirred under heating at 60°C overnight. The insoluble material in the reaction mixture was filtered off and the filtrate was concentrated to dryness. The residue obtained was purified by silica gel column chromatography and treated with a 4N solution of hydrogen chloride/ethyl acetate to yield the title compound (2.56 g). Melting point : 222 - 226°C
Elemental analysis: (for C 8H3iNO-HCl-l/5H20) Calculated : C, 76.85; H, 7.46; N, 3.20 Found : C, 76.82; H, 7.37; N, 3.25
Reference Example 4-2
4-Phenyl-4- [ 2- ( 4-hydroxy-4- phenylpiperidino) ethyl ] isochroman hydrochloride
To a solution of 4-phenyl-4-( 2-iodoethyl ) isochroman (500 mg) in acetonitrile (5 ml) were added 4-hydroxy-4- phenylpiperidine (266 mg) and potassium carbonate (420 mg), followed by stirring under heating at 60°C for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in ethyl acetate-water. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with ethyl acetate, treated with a 4N solution of hydrogen chloride/ethyl acetate, and the formed salt was recrystallized from methanol/isopropyl ether to yield the title compound (520 mg). Melting point : 231 - 233°C Elemental analysis: (for C2βH3iNθ2*HCl-3/10H2θ) Calculated : C, 73.84; H, 7.21; N, 3.08 Found : C, 73.99; H, 7.18; N, 3.04
The following Reference Example Compounds 4-3 through
4-14 were obtained in the same manner as in Reference
Example 4-1.
Reference Example Compound 4-3: 4-Phenyl-4-[ 2-(4- cyano-4-phenylpiperidino)ethyl] isochroman hydrochloride 1H-NMR ( CDCI3 ) δ: 1 .90-2 . 22 ( 4H, m) , 2. 25-2 .66 ( 6H, m) , 2.96-3.11 ( 2H, m) , 3 . 94 ( 2H, s ) , 4 .88 ( 2H, s ) , 6 . 94-7 . 53 ( 14H , m)
Reference Example Compound 4-4: 4-{2-[4-(o- Fluorophenyl )piperidino]ethyl}-4-phenylisochroman hydrochloride Melting point: 174 - 176°C
Reference Example Compound 4-5: 4-{2-[4-(m- Fluorophenyl )piperidino]ethyl}-4-phenylisochroman hydrochloride
Melting point: 232 - 236°C
Reference Example Compound 4-6: 4-{2-[4-(p- Fluoropheny1 )piperidino]ethyl}-4-phenylisochroman hydrochloride Melting point: 245-250°C
Reference Example Compound 4-7: 4-Phenyl-4-[ 2-( 4- phenylpiperazin-1-yl )ethyl ] isochroman dihydrochloride Melting point : 238 - 240°C Elemental analysis: (for C27H3oN2θ*2HCl) Calculated : C, 68.78; H, 6.84; N, 5.94 Found : C, 68.53; H, 6.98; N, 5.81
Reference Example Compound 4-8: 4-{2-[4-(o- Methoxyphenyl )piperazin-l-yl )ethyl}-4-phenylisochroman dihydrochloride Melting point: 158 - 161°C
Reference Example Compound 4-9: 4-{2-[4-(p- Chlorophenyl)-4-hydroxypiperidino]ethyl}-4-phenylisochroman hydrochloride
1H-NMR (CDCI3) δι 1.16-1.85 (3H, m) , 2.00-2.20 (2H, m) , 2.22-2.62 (6H, m) , 2.73-2.90 (2H, m) , 3.94 (2H, s), 4.87 (2H, s), 6.95-7.35 (11H, m) , 7.43 (2H, d)
Reference Example Compound 4-10: 4-{2-[4-(p- Chlorophenyl)piperidino]ethyl}-4-phenylisochroman hydrochloride 1H-NMR (CDCI3) δi 1.60-1.86 (4H, m) , 1.87 (2H, m) , 2.20-
2.59 (5H, m), 3.04 (2H, br d), 3.95 (2H, s), 4.87 (2H, s),
6.95-7.30 (13H, m)
Reference Example Compound 4-11: 4-[2- (4- Phenylhexamethyleneimino)ethyl ]-4-phenylisochroman hydrochloride
^- MR (CDCI3) δ: 1.50-1.94 (6H, m) , 2.28-2.52 (3H, m) ,
2.53-2.83 (6H, m) , 3.94 (2H, s), 4.87 (2H, s), 6.96-7.30
(14H, m) Reference Example Compound 4-12: 4- [2-(4-
Phen lmethy1 )piperidino]ethyl]-4-phenylisochroman hydrochloride
1H-NMR (CDCI3) δi 1.18-1.54 (3H, m) , 1.57-1.63 (2H, m) ,
1.72-1.87 (2H, m) , 2.15-2.28 (IH, m) , 2.35-2.43 (3H, m) , 2.51 (2H, d), 2.84-2.93 (2H, m) , 3.92 (2H, s), 4.85 (2H, s), 6.93-7.32 (14H, m)
Reference Example Compound 4-13: 4-[2- (3-
Phenylpyrrolidin-1-yl )ethyl ]-4-phenylisochroman hydrochloride ^-NMR (CDCI3) δi 1.77-1.95 (IH, m) , 2.16-2.72 (6H, m) ,
2.85-3.01 (IH, m), 3.07-3.20 (IH, m) , 3.22-3.48 (2H, m) ,
3.94 (2H, dd), 4.86 (2H, s), 6.96-7.07 (2H, m) , 7.10-7.36
(12H, m)
Reference Example Compound 4-14: 4-[2-(4-Acetyl-4- phenylpiperidino) ethyl ]-4-phenylisochroman hydrochloride
1H-NMR (CDCI3) δ: 1.87 (3H, s), 1.93-2.53 (10H, m) , 2.64-
2.80 (2H, m), 3.91 (2H, s), 4.85 (2H, s), 6.90-7.20 (14H, m)
Reference Example 5
Ethyl 2-benzoyl-4-phenylbutyrate
To a solution of ethyl benzoylacetate (1 g) and phenethyl iodide (1.32 g) in DMF (8 ml) was added potassium carbonate (0.79 g). The mixture was stirred at room temperature overnight. The reaction mixture was added to ice/water and neutralized with 1 N hydrochloric acid. The oily residue separated was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (1.1 g). 1H-NMR (CDC13) δ i 1.18 (3H, t), 2.21-2.45 (2H, m) , 2.70 (2H, t), 4.15 (2H, q), 4.29 (IH, t), 7.14-7.50 (7H, m) , 7.51-7.61 (IH, m), 7.88 (2H, dd)
Reference Example 6 1,4-Diphenyl-l-butanone
To a solution of ethyl 2-benzoyl-4-phenylbutyrate (7 g) in ethanol (120 ml) was added a 1 N solution of sodium hydroxide (60 ml). The mixture was heated under reflux for 8 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in water. The aqueous solution obtained was acidified with hydrochloric acid and the oily substance separated was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (4.6 g) .
1H-NMR (CDCI3) δ: 2.01-2.16 (2H, m) , 2.73, 2.98 ( 2H each, t), 7.15-7.34 (5H, m) , 7.40-7.60 (3H, m) , 7.92 (2H, dt)
Reference Example 7
Ethyl 3 ,6-diphenyl-3-hydroxyhexanoate
1,4-Diphenyl-l-butanone (0.5 g), ethyl bromoacetate (0.38 g) and zinc powder (0.15 g) in benzene (15 ml) were heated under reflux for 2 hours. 1 N Hydrochloric acid was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.5 g). XH-NMR ( CDC13 ) δ i 1. 07 ( 3H , t ) , 1 . 30-1 . 50 ( IH , m) , 1 . 58- 1.87 ( 3H, m) , 2. 47-2. 58 ( 2H, m) , 2.85 ( 2H, q) , 4. 00 ( 2H, q) , 4 . 37 ( IH, s ) , 7 .04-7 . 40 ( 10H, m)
Reference Example 8
Ethyl ( 1-phenyl-l ,2,3, 4-tetrahydronaphthalen-1-yl )acetate
To a solution of ethyl 3,6-diphenyl-3-hydroxyhexanoate (0.5 g) in methylene chloride (10 ml) was added boron trifluoride-diethyl ether complex (0.3 ml). The mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.38 g). ^-NMR (CDCI3) δ : 1.01 (3H, t), 1.41-1.80 (2H, m) , 2.00- 2.12 (IH, m), 2.62 (IH, m) , 2.76-2.87 (2H, m) , 3.19 (2H, s), 3.92 (2H, q), 6.99-7.28 (9H, m)
Reference Example 9
1- ( 2-Hydroxyethyl)-1-phenyl-l ,2,3, 4-tetrahydronaphthalene To a solution of ethyl (l-phenyl-1,2,3,4- tetrahydronaphthalen-1-yl)acetate (1.2 g) in THF (20 ml) was added lithium aluminum hydride (0.23 g) gradually under ice cooling conditions. After completion of the addition, the mixture was further stirred for 1.5 hours. To the reaction mixture being cooled with ice, water (0.6 ml), a 15% solution of sodium hydroxide (1.8 ml) and water (0.6 ml) were sequentially added. The resulting precipitate was filtered off and the filtrate was extracted with ethyl acetate and brine. The organic layer was concentrated to dryness and the residue obtained was purified by silica gel column chromatography to yield the title compound (0.7 g). ^-NMR (CDCI3) δ: 1.22 (IH, br s), 1.47-1.80 (2H, m) , 1.98- 2.10 (2H, m), 2.49 (2H, t), 2.74-2.83 (2H, m) , 3.49-3.76 (2H, m), 7.00-7.30 (9H, m)
Reference Example 10 1- ( 2-Iodoethyl )-1-phenyl-l ,2,3, 4-tetrahydronaphthalene
To a solution of triphenylphosphine (0.95 g) in methylene chloride (15 ml) were added imidazole (0.25 g) and iodine (0.92 g) sequentially. A solution of l-(2- hydroxyethyl )-l-phenyl-l, 2, 3, 4-tetrahydronaphthalene (0.7 g) in methylene chloride (5 ml) was added and the mixture was stirred at room temperature in an argon stream for 3 hours. The reaction mixture was washed with a solution of sodium thiosulfate and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.70 g). Melting point: 82 - 83°C
Reference Example 11 1-[ 2-( 4-Phenylpiperidino)ethyl ]-1-phenyl-l ,2,3,4- tetrahydronaphthalene hydrochloride (Reference Example
Compound 11)
To a solution of l-( 2-iodoethyl)-l-phenyl-l, 2, 3, 4- tetrahydronaphthalene (0.14 g) and 4-phenylpiperidine (75 mg) in DMF (3 ml) was added potassium carbonate (80 mg) and the mixture was stirred under heating at 65°C for 1 day.
After the reaction mixture was concentrated to dryness, the residue was dissolved in ethyl acetate. The insoluble material was filtered off and the filtrate was concentrated to dryness. The residue obtained was purified by silica gel column chromatography and treated with a 4N solution of hydrogen chloride/ethyl acetate to yield the title compound
(0.14 g) .
XH-NMR (CDC13) δ : 1.44-2.30 (11H, m) , 2.30-2.56 (4H, m) , 2.73-2.86 (2H, m) , 3.00-3.15 (2H, m) , 7.02-7.35 (14H, m)
Reference Example 12 l-Oxo-4-phenyl-4-[ 2- ( 4-phenylpiperidino)ethyl ] isochroman hydrochloride (Reference Example Compound 12) 4-( 2-Iodoethyl)-4-phenylisochroman (1.8 g) was dissolved in a solvent mixture of acetonitrile (15 ml), carbon tetrachloride (15 ml) and water (25 ml). Sodium periodate (1.5 g) and ruthenium trichloride trihydrate (0.1 g) were added at room temperature. After the mixture was stirred for 3 hours, ethyl acetate was added and the aqueous layer was separated. The organic layer was washed with water, dried, and concentrated under reduced pressure to yield 4-(2-iodoethyl)-l-oxo-4-phenylisochroman (1.8 g) as a crude product.
To the solution of the 4-(2-iodoethyl)-l-oxo-4- phenylisochroman obtained in DMF (20 ml) was added potassium carbonate (3 g), followed by stirring at 50°C in the presence of 4-phenylpiperidine (2 g) for 16 hours. To the reaction mixture was added water (50 ml) followed by extraction with ether. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/isopropyl ether = 1/1) and treated with a solution of 4 N hydrogen chloride/ethyl acetate to yield l-oxo-4-phenyl-4-[2-(4- phenylpiperidino)ethyl] isochroman hydrochloride (amorphous, 1.5 g).
Elemental analysis: (for C28H30NO2CIΗ2O) Calculated : C, 72.17; H, 6.92; N, 3.01 Found : C, 72.54; H, 6.88; N, 2.82
Reference Example 13
The following Reference Example Compounds 13-1 through 13-9 were obtained in the same manner as in Reference Example 4-1.
Reference Example Compound 13-1: 4-(2-(4-(o- Chlorophenyl )piperazin-1-yl)ethyl)-4-phenylisochroman hydrochloride
Melting point : 215 - 219°C Elemental analysis: (for C27H2gClN2θ*HCl -1/5^0) Calculated : C, 68.55; H, 6.48; N, 5.92 Found : C, 68.52; H, 6.50; N, 5.81 Reference Example Compound 13-2: 6,7-Dimethoxy-4-(2- ( 4-hydroxy-4-phenylpiperidino)ethyl )-4-phenylisochroman hydrochloride
Melting point: 238 - 241°C Reference Example Compound 13-3: 4-(p-Fluorophenyl)-4- ( 2- ( 4-phenylpiperidino)ethyl ) isochroman hydrochloride Melting point: 134 - 137°C
Reference Example Compound 13-4: 4-(p-Fluorophenyl)-4- ( 2- ( 4-( o-methoxyphenyl )piperazin-1-yl )ethyl ) isochroman dihydrochloride
Melting point: 152 - 157°C
Reference Example Compound 13-5: 4-( 2-( 4-Hydroxy-4-(m- trifluoromethylphenyl )piperidino)ethyl )-4-phenylisochroman hydrochloride Melting point: 201 - 204°C
Reference Example Compound 13-6: 4-Phenyl-4-(2-(4-m- trifluoromethylphenyl)piperidino)ethyl) isochroman hydrochloride
Melting point: 199 - 203°C Reference Example Compound 13-7: 4-(2-(4- Phenylpiperidino) ethyl )-4- ( 2-pyridyl ) isochroman dihydrochloride Melting point: 113 - 118°C
Reference Example Compound 13-8: 4-(2-(4-Hydroxy-4-(m- methoxypheny1 )piperidino)ethyl )-4-phenylisochroman hydrochloride Melting point: 188 - 191°C
Reference Example Compound 13-9: 4-(2-(4-Methyl-4- phenylpiperidino)ethyl)-4-phenylisochroman hydrochloride Melting point: 227 - 230°C
Reference Example 14
Reference Example Compound 14-1: (R)-(+)-4-Phenyl-4- ( 2-( 4-phenylpiperidino)ethyl ) isochroman ( S) -mandelate Reference Example Compound 14-2: (S)-(-)-4-Phenyl-4- (2-( 4-phenylpiperidino)ethyl) isochroman (R)-mandelate ( 1 ) 4-Phenyl-4-( 2- ( 4-phenylpiperidino)ethyl ) isochroman (1.00 g) was treated with (S)-mandelic acid (0.38 g) in ethanol (10 ml) to precipitate a diastereomer salt as a crystal, which was collected by filtration and recrystallized form ethanol 4 times to yield Reference Example Compound 14-1 (0.23 g). Melting point: 176 - 177°C [ a ] D 20 = +67.9° (c = 0.560, methanol)
(2) The mother liquor of paragraph (1) above was concentrated to dryness and the residue was treated with aqueous sodium bicarbonate to yield a free base. To a solution of this base in ethanol (4 ml) was added (R)- mandelic acid (0.17 g) to precipitate a diastereomer salt as a crystal, which was collected by filtration and recrystallized form ethanol 2 times to yield Reference Example Compound 14-2 (0.23 g). Melting point: 176 - 177°C [α]D 20 = -68.2° (c = 0.618, methanol)
Reference Example 15
Reference Example Compound 15-1: (R)-(+)-4-Phenyl-4-
( 2- ( 4-phenylpiperidino)ethyl) isochroman hydrochloride
Reference Example Compound 15-2: (S)-(-)-4-Phenyl-4-
( 2- ( 4-phenylpiperidino)ethyl ) isochroman hydrochloride 4-Phenyl-4-(2-(4-phenylpiperidino)ethyl) isochroman was separated by high performance liquid chromatography (HPLC) using an optical isomer separation column under the conditions shown below and treated with hydrochloric acid to yield each title compound. Column: Chiralcel OD, 4.6 dia. x 250 mm (produced by
Daicel Chemical Industries)
Mobile phase : Hexane/isopropanol = 7/3, 0.5 ml/min
Column temperature : Room temperature
Detector : UV 254 nm Reference Example Compound 15-1:
Melting point: 222 - 226°C [ ]D 20 = +47.2° (c = 0.490, methanol) HPLC retention time: 11.68 minutes
Reference Example Compound 15-2: Melting point: 222 - 226°C [ a ] D 20 = -45.8° (c = 0.507, methanol) HPLC retention time: 21.93 minutes
Reference Example 16 N-Methyl-2-bromo-2-phenylacetanilide ff-Bromophenylacetic acid (43.0 g) was added to thionyl chloride (43.6 ml), followed by refluxing for 3 hours. The excess thionyl chloride was distilled off under reduced pressure and toluene (100 ml) was added to the residue and the mixture was again concentrated under reduced pressure. The residue was added to a solution of N-methylaniline
(43.5 ml) in toluene (100 ml) at room temperature, followed by stirring for 2 hours. The insoluble material was filtered off and the filtrate was washed with 1 N hydrochloric acid, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (4/1) to yield a light-yellow oily substance, which was then crystallized from hexane- isopropyl ether to yield the title compound (47.5 g). Melting point: 58 - 60°C
Reference Example 17
1 , 3-Dihydro-l-methyl-3-phenyl-2H-indol-2-one
A mixture of N-methyl-2-bromo-2-phenylacetanilide (45.6 g) obtained in Reference Example 16 and anhydrous aluminum chloride (40.0 g) was stirred at 100°C for 30 minutes. The reaction mixture was poured into ice water (1,000 ml) and the resulting crystal was collected by filtration. The crystal obtained was dissolved in ethyl acetate and washed with 1 N hydrochloric acid, brine, and dried with anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was suspended in isopropyl ether, followed by collection by filtration to yield the title compound (24.9 g). Melting point: 117 - 118°C
Reference Example 18
3-( 2-Bromoethyl ) -1 , 3-dihydro-l-methyl-3-phenyl-2H-indol-2- one l,3-Dihydro-l-methyl-3-phenyl-2H-indol-2-one (22.3 g) obtained in Reference Example 17 was dissolved in degassed
THF (225 ml). Potassium tert-butoxide (14.6 g) was added, followed by stirring at room temperature for 30 minutes.
The 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 solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (5/1) to yield the title compound (22.8 g).
Melting point: 117 - 118°C (recrystallizing solvent: isopropyl ether/hexane)
Reference Example 19
Ethyl 2-( 2-nitrophenyl)-2-ρhenylacetate
To a suspension of 60% sodium hydride (42 g), washed with hexane in advance, in DMF (250 ml) was added ethyl phenylacetate (164 g) over a period of 1 hour, while the internal temperature was kept at 40°C, followed by stirring at room temperature for 1 hour. The solution obtained was added dropwise to a solution of 2-fluoronitrobenzene (141 g) in DMF (250 ml), followed by stirring at room temperature for 30 minutes. The reaction mixture was added to 1 N hydrochloric acid and extracted with toluene. The extract was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. The solvent and the excess starting materials were distilled off and the residue obtained was purified by silica gel column chromatography (hexane/ethyl acetate = 5/1) to yield the title compound (176.6 g) as an oily substance.
XH-NMR (CDC13) <5: 1.16 (3H, t, J=7.1 Hz), 4.07 (2H, q, J=7.1 Hz), 5.57 (IH, s), 6.99-7.06 (IH, m) , 7.13-7.42 (7H, m), 7.89-7.97 (IH, m)
Reference Example 20
1 , 3-Dihydro-3-phenyl-2H-indol-2-one
Iron powder (138.3 g) was added to a solution of ethyl 2-( 2-nitrophenyl)-2-phenylacetate (176.6 g) obtained in Reference Example 19 in acetic acid (1.5 L) . After the reaction mixture was stirred under heating at 100°C for 1 hour, the acetic acid was distilled off under reduced pressure. To the residue, ethyl acetate was added and the insoluble material was filtered off. The insoluble material was washed with ethyl acetate and the filtrate and washings were combined and washed with 1 N hydrochloric acid. The organic layer was dried with anhydrous sodium sulfate; the solvent was distilled off. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1) to yield the title compound (84.0 g) as a crystal.
Melting point: 182-184°C ( recrystallizing solvent: isopropyl ether/diethyl ether)
Reference Example 21
3- ( 2-Bromoethyl )-1 , 3-dihydro-3-phenyl-2H-indol-2-one
To a solution of l,3-dihydro-3-phenyl-2H-indol-2-one (24.9 g) obtained in Reference Example 20 in degassed THF (200 ml) was added 90% potassium tert-butoxide (14.8 g) under an argon atmosphere, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled to -20°C, 1,2-dibromoethane (103 ml) was added at one time. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 38 hours. The excess 1,2-dibromoethane and THF were distilled off under reduced pressure; the residue was dissolved in ethyl acetate and washed with 1 N hydrochloric acid. The organic layer was dried with anhydrous sodium sulfate and concentrated. The oily substance obtained was purified by silica gel column chromatography (hexane/ethyl acetate = 5/1 to 3/1) and crystallized from isopropyl ether to yield the title compound (20.0 g) as a crystal. Melting point: 142 - 143°C
Reference Example 22 1 , 3-Dihydro-l-dimethylamino-3-phenyl-2H-indol-2-one
To a solution of 1-chlorodiphenylacetyl chloride (10.0 g) in THF (38 ml) was added a solution of 1,1- dimethylhydrazine (2.27 g) in THF (3.8 ml), followed by heating under reflux for 1 hour. The reaction mixture was cooled to room temperature under a nitrogen atmosphere and 4-ethylmorpholine (7.63 g) was added, followed by heating under reflux for 1.5 hours. The reaction mixture was cooled to 0°C under nitrogen atmosphere and the precipitated hydrochloride salt was filtered off. The filtrate was concentrated and crystallized from isopropyl alcohol to yield the title compound (6.09 g) as a crystal. Melting point: 90 - 91°C
Reference Example 23 3-( 2-Bromoethyl)-1, 3-dihydro-l-dimethylamino-3-phenyl-2H- indol-2-one
To a solution of l,3-dihydro-l-dimethylamino-3-phenyl-
2H-indol-2-one (5.00 g) obtained in Reference Example 22 and 1,2-dibromoethane (7.45 g) in toluene (30 ml) and THF (5 ml) was added 60% sodium hydride (0.79 g), washed in advance with hexane, gradually at room temperature under an argon atmosphere, followed by heating under reflux for 14 hours. After the reaction mixture was cooled to room temperature, water was added to stop the reaction. The mixture was extracted with ethyl acetate and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried with anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1). The oily residue obtained was crystallized from hexane to yield the title compound (4.37 g) as a crystal. Melting point: 88 - 90°C
Reference Example 24
Ethyl 2- ( 2-cyanophenyl )-α-phenylacetate To a suspension of 60% sodium hydride (1.58 g), previously washed with hexane, in DMF (30 ml) was added ethyl phenylacetate (5.43 g) dropwise under ice cooling conditions. After being stirred at room temperature for 30 minutes, the mixture was again cooled with ice. Subsequently, o-fluorobenzonitrile (2.00 g) was added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was added to ice water and made weakly acidic with concentrated hydrochloric acid. The organic layer separated was extracted with ethyl acetate and the extract was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (4 g). 1H-NMR (CDC13) δi 1.27 (3H, t), 4.27 (2H, q) , 5.46 (IH, s), 7.28-7.40 (6H, m) , 7.56 (2H, d) , 7.66 (IH, d)
Reference Example 25
Diethyl 2- ( 2-cyanophenyl ) -2-phenylsuccinate
To a suspension of 60% sodium hydride (0.54 g), previously washed with hexane, in DMF (20 ml) was added dropwise a solution of ethyl 2-(2-cyanophenyl)-α— phenylacetate (3.00 g) in DMF (10 ml) under ice cooling conditions. After the mixture was stirred for 30 minutes, ethyl bromoacetate (1.63 ml) was added dropwise, followed by stirring for 1 hour. The reaction mixture was added to ice water and the organic layer separated was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (2.40 g).
XH-NMR (CDC13) δ : 1.10, 1.22 ( 3H each, t), 3.74 (2H, q) , 3.97 (2H, q), 4.03-4.38 (2H, m) , 7.29-7.41 (6H, m) , 7.45- 7.65 (3H, )
Reference Example 26
Ethyl ( 3-oxo-4-phenyl-l ,2,3, 4-tetrahydroisoquinolin-4- yl)acetate
To a solution of diethyl 2-( 2-cyanophenyl)-2- phenylsuccinate (2.40 g) in ethanol (40 ml) was added Raney nickel (2.40 g). The mixture was hydrogenated at 80°C under 5 atm for 8 hours. The catalyst in the reaction mixture was filtered off and the filtrate was concentrated to dryness. The residue obtained was washed with ether to yield the title compound (1.57 g) .
1H-NMR (CDCI3) δ: 1.09 (3H, t), 3.24, 3.95 ( IH each, d), 3.88-4.12 (2H, m) , 4.26 (IH, d) , 4.38 (IH, dd) , 6.34 (IH, br), 7.03-7.38 (9H, m)
Reference Example 27-1
Ethyl ( 2-methyl-3-oxo-4-phenyl-l, 2,3,4- tetrahydroisoquinolin-4-yl)acetate To a solution of ethyl { 3-oxo-4-phenyl-l, 2,3,4- tetrahydroisoquinolin-4-yl)acetate (0.40 g) in DMF (4 ml) was added 60% sodium hydride (62 mg) gradually under ice cooling conditions. After the mixture was stirred for 30 minutes, methyl iodide (0.12 ml) was added dropwise, followed by stirring for 1 hour. The reaction mixture was added to ice water and the precipitated crystal was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue obtained was washed with isopropyl ether to yield the title compound (0.38 g) . ^- MR (CDC13) δ : 1.10 (3H, t), 3.13 (3H, s), 3.21, 4.00 (IH each, d), 3.91-4.06 (2H, m) , 4.33 (2H, s), 7.00-7.10 (2H, m), 7.15-7.38 (7H, m)
Reference Example 27-2 Ethyl (2-ethyl-3-oxo-4-phenyl-l,2,3,4- tetrahydroisoquinolin-4-yl)acetate
The title compound was obtained in the same manner as in Reference Example 27-1.
XH-NMR (CDCI3) δ: 1.09, 1.14 ( 3H each, t), 3.20, 3.95 (IH each, d), 3.40-3.80 (2H, m) , 3.89-4.09 (2H, m) , 4.24 (2H, s), 7.00-7.10 (2H, m), 7.15-7.38 (7H, m)
Reference Example 28-1
( 2-Methyl-3-oxo-4-phenyl-l ,2,3, 4-tetrahydroisoquinolin-4- yl)acetic acid
To a solution of ethyl (2-methyl-3-oxo-4-phenyl- l,2,3,4-tetrahydroisoquinolin-4-yl)acetate (1.38 g) in ethanol (15 ml) was added a 1 N aqueous solution of sodium hydroxide (7 ml). The mixture was stirred under heating at 60°C for 4 hours. After the ethanol was distilled off from the reaction mixture, the residue obtained was diluted with water. The dilution was acidified with 1 N hydrochloric acid and the precipitated crystal was collected by filtration, sequentially washed with water and ether to yield the title compound (1.20 g). 1H-NMR (CDCI3) δ : 3.00 (3H, s), 3.33, 3.56 ( IH each, d), 4.33 (2H, q), 6.90-7.05 (2H, m) , 7.05-7.40 (7H, m)
Reference Example 28-2 ( 2-Ethy1-3-oxo-4-pheny1-1, 2, 3, 4-tetrahydroisoquinolin-4- yl)acetic acid The title compound was obtained in the same manner as in Reference Example 28-1.
^-NMR (CDC13) δ: 1.16 (3H, t), 3.23, 3.70 ( IH each, d) , 3.40-3.59 (IH, m) , 3.70-3.91 (IH, m) , 4.04 (2H, q), 6.96 (2H, dd), 7.17-7.50 (6H, m) , 7.66 (IH, d)
Reference Example 29-1
4- ( 2-Hydroxyethyl )-2-methyl-3-oxo-4-phenyl-l ,2,3,4- tetrahydroisoquinoline 0 To a solution of (2-methyl-3-oxo-4-phenyl-l, 2,3,4- tetrahydroisoquinolin-4-yl)acetic acid (0.45 g) in THF (15 ml) was added a 1 M solution of borane-THF complex in THF (2.5 ml) dropwise under ice cooling conditions. The mixture was then warmed to room temperature and stirred 5 overnight. Water was added to the reaction mixture and the organic layer was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.23 g). o ^-NMR (CDCI3) δ: 2.45-2.60 (IH, m) , 2.76-3.00 (IH, m) ,
3.11 (3H, s), 3.46-3.77 (2H, m) , 4.19 (2H, s), 6.97-7.04 (2H, m), 7.15-7.42 (7H, m)
Reference Example 29-2 5 2-Ethyl-4- ( 2-hydroxyethyl)-3-oxo-4-phenyl-l ,2,3,4- tetrahydroisoquinoline
The title compound was obtained in the same manner as in Reference Example 29-1.
^-NMR (CDCI3) δ: 1.14 (3H, t), 2.50-2.60 (IH, m) , 2.76- 0 2.91 (IH, m), 3.35-3.55 (IH, m) , 3.60-3.84 (3H, m) , 4.08
(2H, s), 6.95-7.05 (2H, m) , 7.16-7.42 (7H, m)
Reference Example 30-1
4-( 2-Iodoethyl ) -2-methyl-3-oxo-4-phenyl-l, 2,3,4- 5 tetrahydroisoquinoline Triphenylphosphine (0.28 g), imidazole (73 mg) and iodine (0.27 g) were sequentially dissolved in THF (4 ml). To the solution was added a solution of 4-(2-hydroxyethyl)- 2-methyl-3-oxo-4-phenyl-l,2,3,4-tetrahydroisoquinoline (0.23 g) in THF (2 ml). The mixture was stirred at room temperature in an argon stream for 3 hours. To the reaction mixture, a saturated aqueous solution of sodium thiosulfate was added and the organic layer was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue obtained was purified by silica gel column chromatography to yield the title compound (70 mg).
^-NMR (CDC13) δ : 2.66-2.83 (IH, m) , 2.95-3.12 (IH, m) , 3.11 (3H, s), 3.18-3.43 (2H, m) , 4.20 (2H, q), 6.96-7.05 (2H, m), 7.16-7.49 (7H, )
Reference Example 30-2
2-Ethyl-4- ( 2-iodoethyl ) -3-oxo-4-phenyl-l ,2,3,4- tetrahydroisoquinoline The title compound was obtained in the same manner as in Reference Example 30-1.
1H-NMR (CDCI3) δ i 1.12 (3H, t), 2.64-2.82 (IH, m) , 2.99-
3.17 (IH, m), 3.20-3.54 (3H, m) , 3.61-3.80 (IH, m) , 4.10
(2H, s), 6.95-7.03 (2H, m) , 7.15-7.28 (4H, m) , 7.29-7.50 (3H, m)
Reference Example 31 (R)-(-)-(4-Phenylisochroman-4-yl)acetic acid
(4-Phenylisochroman-4-yl)acetic acid (21.85 g) and (-)-cinchonidine (23.98 g) were mixed in ethanol, and the separated salt was collected by filtration and recrystallized from ethanol. The mother liquor obtained was concentrated, after which it was again recrystallized to yield crystals. The mother liquor obtained initially was treated with hydrochloric acid to yield a free compound. The free compound obtained and (IS, 2S)-(+)-2- amino-l-phenyl-l,3-propanediol (8.53 g) were mixed in ethanol to form a salt. 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).
Melting point: 133 - 135°C
[ a ] D 20 = - 10.3° (c = 1.000, methanol)
Reference Example 32 (S)-(4-Phenylisochroman-4-yl)acetic acid (R)-l- phenylethylamine salt
(4-Phenylisochroman-4-yl)acetic acid (1.0 g) and (R)-
(+)-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).
Melting point: 131 - 134°C
Reference Example 33
( S)-4-Phenyl-l- ( ( 4-phenylisochroman-4-yl )acetyl)piperidine
(S)-(4-Phenylisochroman-4-yl)acetic acid and (R)-l- phenylethylamine salt (0.05 g) was treated with hydrochloric acid to yield a free compound, which was then dissolved in DMF (1 ml). This solution was cooled to 0°C and 4-phenylpiperidine (0.03 g), diethyl cyanophosphonate (0.03 g) and triethylamine (0.04 g) were sequentially added dropwise. After the reaction mixture was stirred at 0°C for 30 minutes, it was warmed to room temperature and stirred for 30 minutes. After dilution with water, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with brine and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (3/1) to yield the title compound (0.08 g) as an oily substance.
XH-NMR (CDC13) δ i 1.35-1.80 (4H, m) , 2.22-2.66 (2H, m) , 2.90-3.08 (IH, m), 3.19 (IH, dd) , 3.49 (IH, dd), 3.68-3.96 (IH, m), 3.97-4.32 (2H, m) , 4.63-4.81 (IH, m) , 4.93 (2H, s) , 6.96-7.45 (14H, m)
Reference Example 34
( S ) - ( - )-4-Phenyl-4- ( 2- ( 4-phenylpiperidino)ethyl ) isochroman To a solution of (S)-4-phenyl-l-( (4-phenylisochroman- 4-yl)acetyl)piperidine (0.08 g) in THF (1 ml), lithium aluminum hydride (0.01 g) was added, followed by heating under reflux for 2 hours. To the reaction mixture, water was added and the insoluble material was filtered off; the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (2/1) to yield the title compound (0.03 g). When the title compound was subjected to HPLC under the same conditions as those in Reference Example 15 above, the retention time was the same as that of Reference Example Compound 15-2.
Reference Example 35-1
N-Ethyl-2-bromo-2-phenylacetanilide
The title compound was obtained in the same manner as in Reference Example 16
Melting point: 65 - 66°C (crystallizing solvent: isopropyl ether/hexane)
Reference Example 35-2
N-Ethyl-N- ( 4-fluorophenyl )-2-bromo-2-phenylacetamide To a solution of 4-fluoroaniline (19.1 ml) and triethylamine (41.8 ml) in THF (200 ml) was added dropwise acetyl chloride (15.6 ml) under ice cooling conditions and the mixture was stirred at room temperature for an hour. The reaction mixture was poured into ice water (400 ml) and the organic layer separated was extracted with ethyl acetate (400 ml). The extract was washed with 1 N hydrochloric acid and brine, successively, dried with sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with ethyl acetate. The eluate was evaporated to dryness and the resulting residue was crystallized from isopropyl ether to yield N-(4- fluorophenyl )acetamide (26.0 g). N-(4-
Fluorophenyl)acetamide (23.0 g) was dissolved in THF (30 ml) and the solution was then added dropwise to a suspension of lithium aluminum hydride (5.7 g) in THF (200 ml) at ambient temperature. After being stirring at 60°C for additional 2 hours, the reaction mixture was cooled to 0°C. Water (6 ml) was added to the reaction mixture and the resulting precipitate was removed by filtration. The filtrate was dried with sodium sulfate, concentrated to dryness and chromatographed by silica gel column eluting with hexane-ethyl acetate (3/1) to give N-ethyl -4- fluoroaniline (18.1 g). The title (40.0 g) compound was synthesized in the same manner as in Reference Example 16 5 from N-ethyl-4-fluoroaniline (18.1 g) obtained.
1H-NMR (CDC13) δ: 1.11 (3H, t, J=7.2Hz), 3.74 (2H, q, J=7.2Hz), 5.23 (IH, s), 7.02-7.23 (3H, m) , 7.27-7.40 (6H, m)
Q Reference Example 36
Compounds in Reference Examples 36-1 and 36-2 below were obtained in the same manner as in Reference Example 17.
Reference Example 36-1: l-Ethyl-l,3-dihydro-3-phenyl- 5 2H-indol-2-one Melting point: 95 - 96°C (crystallizing solvent: isopropyl ether/hexane)
Reference Example 36-2: l-Ethyl-5-fluoro-l,3-dihydro- 3-phenyl-2H-indol-2-one Melting point: 108 - 110°C (crystallizing solvent: ethyl acetate/hexane)
Reference Example 37
Compounds in Reference Examples 37-1 and 37-2 below were obtained in the same manner as in Reference Example 18.
Reference Example 37-1: 3- (2-Bromoethyl) -1-ethyl-l, 3- dihydro-3-phenyl-2H-indol-2-one
Melting point: 55 - 56°C (crystallizing solvent: isopropyl ether/hexane)
Reference Example 37-2: 3-( 2-Bromoethyl )-l-ethyl-5- fluoro-1 , 3-dihydro-3-phenyl-2H-indol-2-one Melting point: 111 - 112βC (crystallizing solvent: isopropyl ether/hexane)
Reference Example 38
Compounds in the following Reference Examples 38-1 through 38-3 were obtained in the same manner as in
Reference Example 22. Reference Example 38-1: l,3-Dihydro-3-phenyl-l- piperidino-2H-indol-2-one
Melting point: 123 - 125°C (crystallizing solvent: isopropyl alcohol)
Reference Example 38-2: l-(Diethylamino)-l,3-dihydro- 3-phenyl-2H-indol-2-one
Melting point: 71 - 74°C (crystallizing solvent: ethyl acetate/hexane)
Reference Example 38-3: 1,3-Dihydro-l- bis (phenylmethy1 )amino-3-phenyl-2H-indol-2-one IH-NMR (CDC13) δ: 4.21 (IH, d, J=12.5 Hz), 4.37 (IH, s),
4.43 (IH, d, J=12.5 Hz), 4.56 (IH, d, J=12.5Hz), 4.58 (IH, d, J=12.5 Hz), 6.81-6.89 (4H, m) , 6.98 (IH, d, J=7.7 Hz), 7.06-7.38 (12H, m) , 7.44-7.52 (2H, m)
Reference Example 39 The following Reference Example Compounds 39-1 through 39-3 were obtained in the same manner as in Reference Example 23.
Reference Example 39-1: 3-(2-Bromoethyl)-l,3-dihydro- 3-phenyl-l-piperidino-2H-indol-2-one Melting point: 86 - 88°C (crystallizing solvent: hexane/ethyl acetate)
Reference Example 39-2: 3-{2-Bromoethyl)-l- (diethylamino)-l,3-dihydro-3-phenyl-2H-indol-2-one Melting point: 117 - 119°C (crystallizing solvent: ethyl acetate/hexane)
Reference Example 39-3: 3-( 2-Bromoethyl)-l ,3-dihydro- 1-bis (phenyl ethyl )amino-3-phenyl-2H-indol-2-one Melting point: 113 - 114°C (crystallizing solvent: hexane)
Reference Example 40 l-Ethyl-3- ( 2- ( 4-formylpiperazin-1-yl )ethyl )-1 , 3-dihydro-3- phenyl-2H-indol-2-one
To a solution of 3- (2-bromoethyl) -1-ethyl-l, 3-dihydro- 3-phenyl-2H-indol-2-one (25.8 g) obtained in Reference Example 37-1 and 1-piperazinecarboxyaldehyde (38.7 ml) in DMF (260 ml) was added potassium iodide (1.3 g), and the mixture was heated at 60°C for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with IN sodium hydroxide (100 ml) and brine (500 ml). The organic layer was wahed with brine 3 times, dried with sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate/methanol (9/1), to yield the title compound (18.9 g). IH-NMR (CDC13) δ i 1.26 (3H, t, J=7.3 Hz), 2.02-2.44 (7H, m), 2.67-2.84 (IH, m) , 3.22 (2H, t, J=5.2 Hz), 3.24-3.52 (2H, m) , 3.55-3.73 (IH, m) , 3.78-3.96 (IH, m) , 6.92 (IH, d, J=7.7 Hz), 7.10 (IH, t, J=7.4 Hz), 7.20-7.38 (7H, m) , 7.96 (IH, s)
Reference Example 41
1-Ethyl-l , 3-dihydro-3-phenyl-3-( 2-(piperazin-1-yl ) ethyl ) - 2H-indol-2-one
A mixture of l-ethyl-3-(2-( 4-formylpiperazin-l- yl)ethyl )-l, 3-dihydro-3-phenyl-2H-indol-2-one (17.9 g) obtained in Reference Example 40 and 3 N hydrochloric acid (270 ml) was refluxed with stirring for 2 hours. The reaction mixture was cooled to 0C, adjusted to over pH 8 with 12 N sodium hydroxide, and extracted with ethyl acetate (500 ml). The organic layer was washed with brine, dried over sodium sulfate, and cocentrated under reduced pressure to yield the title compound (14.8 g). IH-NMR (CDC13) δ: 1.26 (3H, t, J=7.1 Hz), 1.96-2.22 (4H, m), 2.26-2.41 (3H, m) , 2.63-2.85 (5H, m) , 3.61-3.96 (2H, m), 6.91 (IH, d, J=7.7 Hz), 7.08 (IH, dt, J=l.l, 7.3 Hz), 7.18-7.37 (7H, m)
Reference Example 42
Reference Example 42-1
N- ( 3-Cyanopheny1 )piperazine 3-Aminobenzonitrile (5.9 g) was dissolved in butanol (60 ml), followed by addition of bis(2-chloroethyl)amine hydrochloride (8.9 g). The mixture was refluxed with stirring for 24 hours and then sodium carbonate (5.3 g) was added. The mixture was refluxed for additional 48 hours. The reaction mixture was cooled to room temperature and the insoluble material was collected by filtration, followed by partition between ethyl acetate and 1 N sodium hydroxide. The organic layer separated was washed with brine 3 times, dried over sodium sulfate, and purified by silica gel column chromatography eluting with ethyl acetate/methanol (7/3) to yield the title compound (3.1 g) . IH-NMR (CDCI3 ) δ: 3. 01-3.07 ( 4H, m) , 3 .14-3. 21 ( 4H, m) , 7 . 07-7 . 14 ( 3H, m) , 7 . 28-7. 37 ( IH, m)
Compounds in the following Reference Examples 42-2 through 42-5 were obtained in the same manner as in Reference Example 42-1.
Reference Example 42-2: N-(3-Nitrophenyl)piperazine IH-NMR (CDCI3) δi 1.65 (IH, br ) , 3.02-3.09 (4H, m) , 3.22- 3.29 (4H, m), 7.19 (IH, dd, J=2.6, 8.4Hz), 7.37 (IH, dd, J=8.1, 8.4 Hz), 7.66 (IH, dd, J=2.2, 8.1 Hz), 7.72 (IH, dd, J=2.2, 2.6 Hz)
Reference Example 42-3: N-( 3-Fluorophenyl)piperazine IH-NMR (CDCI3) δ: 1.65 (IH, br ) , 2.98-3.06 (4H, m) , 3.12- 3.19 (4H, m), 6.47-6.72 (3H, m) , 7.19 (IH, dd, J=8.1, 15.0 Hz) Reference Example 42-4: N-(3- Ethoxycarbonylphenyl)piperazine
IH-NMR (CDCI3) δ: 1.39 (3H, t, J=7.1 Hz), 2.13 (IH, s), 3.03-3.09 (4H, m) , 3.17-3.23 (4H, m) , 4.37 (2H, q, J=7.1 Hz), 7.07-7.13 (IH, m) , 7.32 (IH, t, J=7.8 Hz), 7.50-7.56 (IH, m), 7.59-7.62 (IH, m)
Reference Example 42-5: N-(3-Acetylphenyl)piperazine IH-NMR (CDCI3) δ: 2.59 (3H, s), 3.02-3.07 (4H, m) , 3.18- 3.23 (4H, m), 7.10-7.16 (IH, m) , 7.28-7.43 (2H, m) , 7.44- 7.54 (IH, m)
Reference Example 43
4-(3-Chlorophenyl)piperidine
A mixture of 4-(3-chlorophenyl)glutaric anhydride
(8.78 g), 25% ammonium hydroxide (11.8 ml), and water (8.4 ml) was heated at 110°C for an hour. The reaction mixture was cooled and acidified with hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and hexane, successively, and dried to yield 4- (3-chlorophenyl)glutaramic acid (10.58 g). The glutaramic acid derivative (10.58 g) obtained was dissolved in acetic anhydride (18.5 ml), followed by addition of sodium acetate (3.85 g). The mixture was refluxed with stirring for 1 hour and then poured into ice-water. 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). IH-NMR (CDC13) δ i 1.49-1.93 (5H, m) , 2.50-2.63 (IH, m) , 2.64-2.83 (2H, m) , 3.12-3.27 (2H, m) , 7.04-7.32 (4H, m)
Reference Example 44
1,2,3, 4-Tetrahydro-4-( 2-hydroxyethyl )-4-phenylisoquinoline
To a stirred solution of ethyl ( 3-oxo-4-phenyl- l,2,3,4-tetrahydroisoquinolin-4-yl) acetate (2.00 g) obtained in Reference Example 26 in THF (20 ml) was added portionwise lithium aluminum hydride (0.49 g) under ice cooling condition.
After completion of the addition, the mixture was heated under reflux for 6 hours. The reaction mixture was cooled to 0°C and water (1.0 ml) and 15% sodium hydroxide (0.8 ml) were added. The resulting precipitate was filtered and the filtrate was dried and concentrated to dryness. The residue obtained was purified by silica gel column chromatography eluting with ethyl acetate/methanol (10/1) to yield the title compound (1.18 g).
Melting point: 116 - 117°C (crystallizing solvent: ethyl acetate/isopropyl ether)
Reference Example 45 2-Acetyl-l,2,3,4-tetrahydro-4-(2-hydroxyethyl)-4- phenylisoquinoline To a solution of l,2,3,4-tetrahydro-4-(2- hydroxyethyl)-4-phenylisoquinoline (0.97 g) in THF (5.0 ml) was added 1 N sodium hydroxide (3.8 ml), followed by a solution of acetic anhydride (0.39 g) in THF (2.0 ml) under ice cooling condition. After stirring for additional 30 minutes, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and evaporated to yield the title compound (1.12 g). IH-NMR (CDC13) δ: 1.74 and 2.14 (3H, s and s), 2.33-2.60 (2H, m), 3.56-3.96 and 4.08-4.19 (4H, m and m) , 4.43 and 4.61 (IH, d, J=15.7 Hz and d, J=17.4 Hz), 4.66 and 4.90 (IH, d, J=15.7 Hz and d, J=17.4 Hz), 7.02-7.34 (9H, m)
Reference Example 46
2-Acetyl-l ,2,3, 4-tetrahydro-4-( 2-iodoethyl )-4- phenylisoquinoline
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. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (7/3~l/l) to yield the title compound (1.12 g). J-H-NMR (CDCI3) δ i 1.80 and 2.15 (3H, s and s), 2.63-3.28 (4H, m), 3.70 and 3.72 (IH, s and s), 3.84-4.08 (IH, m) , 4.38-4.92 (2H, m) , 6.97-7.36 (9H, m)
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.
Reference Example 47-1: Ethyl ( 2-methoxymethyl-3-oxo- 4-phenyl-l,2,3,4-tetrahydroisoquinolin-4-yl)acetate
IH-NMR (CDC13) δi 1.10 (3H, t), 3.23 (IH, d), 3.21 (3H, s), 3.97 (IH, d), 3.95-4.11 (2H, m) , 4.28 (2H, q) , 4.98 (2H, q), 7.00-7.09 (2H, m) , 7.18-7.40 (7H, m)
Reference Example 47-2: Ethyl (3-oxo-4-phenyl-2- propyl-l,2,3,4-tetrahydroisoquinolin-4-yl)acetate
IH-NMR (CDCI3) δ: 0.85 (3H, t), 1.08 (3H, t), 1.49-1.70 (2H, m), 3.20 (IH, d) , 3.94 (IH, d) , 3.30-3.46 (IH, m) , 3.54-3.70 (IH, m) , 3.90-4.08 (2H, m) , 4.22 (2H, s), 7.00- 7.09 (2H, m), 7.15-7.40 (7H, m)
Reference Example 48
Compounds in the following Reference Examples 48-1 and
48-2 were obtained in the same manner as in Reference
Example 28-1. Reference Example 48-1: (2-Methoxymethyl-3-oxo-4- phenyl-1 ,2,3, 4-tetrahydroisoquinolin-4-yl )acetic acid IH-NMR (CDCI3) δ 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 (CDCI3) δ i 0.87 (3H, t), 1.50-1.70 (2H, m) , 3.23 (IH, d), 3.70 (IH, d), 3.30-3.47 (IH, m) , 3.65-3.80 (IH, ), 4.02 (2H, q), 6.92-7.01 (2H, m) , 7.17-7.51 (6H, m) , 7.70 (IH, d)
Reference Example 49
Compounds in the following 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 (CDC13) δi 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 49-2: 4-(2-Hydroxyethyl)-3-oxo-4- phenyl-2-propyl-l,2,3,4-tetrahydroisoquinoline IH-NMR (CDCI3) δ : 0.86 (3H, t), 1.45-1.64 (2H, m) , 2.49- 0 2.64 (IH, m), 2.78-2.92 (IH, m) , 3.24-3.41 (IH, m) , 3.60- 3.83 (3H, m), 4.07 (2H, s), 6.94-7.08 (2H, m) , 7.13-7.45 (7H, m)
Reference Example 50 5 Compounds in the following Reference Examples 50-1 and
50-2 were obtained in the same manner as in Reference
Example 30-1.
Reference Example 50-1: 4-(2-Iodoethyl)-2- methoxymethyl-3-oxo-4-phenyl-l ,2,3, 4-tetrahydroisoquinoline o IH-NMR (CDCI3) δi 2.69-2.85 (IH, m) , 3.01-3.39 (3H, m) ,
3.18 (3H, s), 4.04 (IH, d), 4.25 (IH, d), 4.94 (2H, q) ,
6.95-7.04 (2H, ) , 7.17-7.30 (4H, m) , 7.32-7.53 (3H, m) Reference Example 50-2: 4-(2-Iodoethyl)-3-oxo-4- phenyl-2-propyl-l ,2,3, 4-tetrahydroisoquinoline 5 IH-NMR (CDCI3) δi 0.84 (3H, t), 1.45-1.65 (2H, m) , 2.65-
2.82 (IH, m), 2.99-3.41 (4H, m) , 3.52-3.71 (IH, m) , 4.09
(2H, s), 6.94-7.02 (2H, m) , 7.12-7.48 (7H, m)
The chemical structural formulas of Reference Example 0 Compounds 4-1 through 4-14, 11, 12, 13-1 through 13-9, 14-1 through 14-2 and 15-1 through 15-2 obtained are shown below.
5
Figure imgf000111_0001
Reference Example 4-1 Reference Example 4-6
Figure imgf000111_0002
Reference Example 4-2 Reference Example 4-7
Figure imgf000111_0003
Reference Example 4-3 Reference Example 4-8
Figure imgf000111_0004
Reference Example 4-4 Reference Example 4-9
Figure imgf000111_0005
Reference Example 4-5 Reference Example 4-10
Figure imgf000112_0001
Reference Example 4-11 Reference Example 11
Figure imgf000112_0002
Reference Example 4-12 Reference Example 12
Figure imgf000112_0003
Reference Example 4-13
Figure imgf000112_0004
Reference Example 4-14
Figure imgf000113_0001
Reference Example 13-1 Reference Example 13-6
Figure imgf000113_0002
Reference Example 13-2 Reference Example 13-7
Figure imgf000113_0003
Reference Example 13-3 Reference Example 13-8
Figure imgf000113_0004
Reference Example 13-4 Reference Example 13-9
Figure imgf000113_0005
Reference Example 13-5
Figure imgf000114_0001
Reference Example 14-1 Reference Example 15-1
Figure imgf000114_0002
Reference Example 14-2 Reference Example 15-2
Example 1
(1) Reference Example Compound 4-1 50 mg
(2) Lactose 34 mg
(3) Corn starch 10.6 mg
(4) Corn starch (pasty) 5 mg (5) Magnesium stearate 0.4 mg
(6) Carboxymethyl cellulose calcium 20 mg
Total 120 mg In accordance with a conventional method, the above components (1) through (6) were mixed and tableted using a tableting machine to yield a tablet.
Example 2
(1) Reference Example Compound 4-1 50 mg
(2) Finely powdered cellulose 30 mg
(3) Lactose 37 mg (4) Magnesium stearate 3 mg
Total 120 mg In accordance with a conventional method, the above components (1) through (4) were mixed and filled in a gelatin capsule to yield a capsular preparation.
Example 3
(1) Reference Example Compound 4-1 50 mg
(2) Corn oil 100 mg Total 150 mg
In accordance with a conventional method, the above components (1) and (2) were mixed and filled in a soft capsule to yield a soft capsular preparation.
Example 4
Example 4-1
1, 3-Dihydro-3-phenyl-3-( 2-( 4-phenylpiperidino)ethyl)-2H- indol-2-one
A solution of 3-(2-bromoethyl)-l,3-dihydro-3-phenyl- 2H-indol-2-one (10.0 g) obtained in Reference Example 21 and 4-phenylpiperidine (10.7 g) in acetonitrile (100 ml) was stirred under heating at 60βC for 14 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried with anhydrous sodium sulfate and concentrated. 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.
Melting point: 156 - 157°C
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 XH-NMR (CDCI3) δ: 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 Melting point :181 - 184°C ( recrystallizing solvent: ethyl acetate/isopropyl ether)
Example 5
Example 5-1
1 , 3-Dihydro-l-methyl-3-phenyl-3- (2-( 4- phenylpiperidino)ethyl )-2H-indol-2-one
3-( 2-Bromoethyl)-1 , 3-dihydro-l-methyl-3-phenyl-2H- indol-2-one (3.3 g) obtained in Reference Example 18 was dissolved in DMF (33 ml) and 4-phenylpiperidine (2.4 g), potassium carbonate (2.8 g) and a catalytic amount of potassium iodide (0.17 g) were added, followed by stirring at 60°C for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (1/1) to yield a light-yellow oily substance, which was then crystallized from isopropyl ether to yield the title compound (2.6 g) . Melting point: 104 - 105°C
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 Amorphous powder 1H-NMR (CDCI3) δ : 2.13-2.38 (5H, m) , 2.52-2.68 (2H, ) , 2.77-3.05 (5H, m) , 3.21 (3H, s), 3.82 (3H, s), 6.80-7.03 (5H, m), 7.08-7.16 (IH, m) , 7.23-7.43 (7H, m)
Example 5-4 l,3-Dihydro-l-ethyl-3-phenyl-3-(2-(4- phenylpiperidino)ethyl )-2H-indol-2-one hydrochloride
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. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (2/1) to yield a light-yellow oily substance, which was then treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound (0.2 g). Amorphous powder
1H-NMR (CDCI3) δi 1.28 (3H, t, J=7.1 Hz), 1.49-2.27 (8H, m), 2.32-2.47 (2H, m) , 2.66-2.84 (2H, m) , 2.87-2.99 (IH, br d), 3.62-3.94 (2H, m) , 6.92 (IH, d, J=7.6 Hz), 7.05-7.40 (13H, m)
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
Amorphous powder
XH-NMR (CDC13) δi 1.38-1.99 (6H, m) , 2.05-2.23 (2H, m) , 2.25-2.57 (3H, m) , 2.81-3.02 (2H, m) , 4.64 (2H, ABq, J=17.6, 36.2 Hz), 7.07 (IH, d, J=7.6 Hz), 7.10-7.43 (13H, )
Example Compound 5-7: l,3-Dihydro-3-phenyl-3-(2-(4- phenylpiperidino)ethyl )-l-propyl-2H-indol-2-one hydrochloride
Amorphous powder Η-NMR (CDCI3) δs 0.94 (3H, t, J=7.3 Hz), 1.48-2.28 (10H, m), 2.32-2.49 (2H, m) , 2.68-2.83 (2H, m) , 2.93 (IH, br d,
J=10.6 Hz), 3.62-3.84 (2H, m) , 6.91 (IH, d, J=7.6 Hz),
7.03-7.39 (13H, m)
Example Compound 5-8: 2-(2,3-Dihydro-2-oxo-3-phenyl-3- (2-(4-phenylpiperidino)ethyl)-lH-indol-l-yl)ethyl acetate
Amorphous powder -NMR (CDCI3) δ: 1.50-2.28 (12H, m) , 2.31-2.47 (2H, m) ,
2.63-3.01 (3H, m) , 3.81-3.95 (IH, m) , 4.06-4.43 (3H, m) ,
6.97 (IH, d, J=7.8 Hz), 7.03-7.41 (13H, m) Example Compound 5-9: l,3-Dihydro-l-(2,3-epoxypropyl)-
3-phenyl-3-( 2-( 4-phenylpiperidino)ethyl)-2H-indol-2-one
Amorphous powder
XH-NMR (CDCI3) δi 1.42-2.87 (14H, m) , 2.96 (IH, br d),
3.12-3.25 (IH, m) , 3.45 (0.5H, dd, J=6.1, 14.8 Hz), 3.80 (0.5H, dd, J=5.1, 15.0 Hz), 4.05-4.18 (0.5H, m) , 4.41
(0.5H, dd, J=2.9, 15.0 Hz), 7.06-7.29 (14H, m)
Example Compound 5-10: l,3-Dihydro-l-(l-methylethyl)-
3-phenyl-3-(2-(4-phenylpiperidino)ethyl)-2H-indol-2-one hydrochloride Amorphous powder 1H-NMR (CDCI3) δi 1.50 (3H, d, J=7.0 Hz), 1.51 (3H, d,
J=7.0 Hz), 1.67-1.84 (4H, m) , 1.88-2.26 (4H, m) , 2.33-2.53
(2H, m), 2.63-2.80 (IH, m) , 2.86-3.05 (2H, m) , 4.59-4.73
(IH, m), 7.04-7.13 (2H, m) , 7.16-7.38 (12H, m) Example Compound 5-11: l,3-Dihydro-3-phenyl-l- phenylmethyl-3- ( 2-( 4-phenylpiperidino)ethyl ) -2H-indol-2-one hydrochloride
Amorphous powder
Η-NMR (CDCI3) δi 1.58-1.84 (4H, m) , 1.88-1.99 (2H, m) , 2.00-2.32 (2H, m) , 2.35-2.54 (2H, m) , 2.72-2.89 (2H, m) ,
2.90-3.03 (IH, m), 4.82 (IH, d, J=15.4 Hz), 5.06 (IH, d,
J=15.4 Hz), 6.79 (IH, d, J=7.7 Hz), 7.03-7.13 (IH, m) ,
7.17-7.43 (17H, m)
Example Compound 5-12: l-Cyclopropylmethyl-1,3- dihydro-3-phenyl-3-( 2- ( 4-phenylpiperidino) ethyl ) -2H-indol-
2-one hydrochloride
Amorphous powder
1H-NMR (CDCI3) δ: 0.36-0.58 (4H, m), 1.56-1.82 (4H, m) ,
1.84-2.03 (2H, m) , 2.07-2.32 (2H, m) , 2.34-2.52 (2H, m) , 2.67-3.00 (4H, m) , 3.59 (IH, dd, J=7.0, 14.3 Hz), 3.70 (IH, dd, J=7.0, 14.3 Hz), 6.96-7.40 (14H, m)
Example 5-13
1 , 3-Dihydro-l-ethyl-3- ( 2- ( 4-hydroxy-4- phenylpiperidino)ethyl )-3-phenyl-2H-indol-2-one hydrochloride
1 , 3-Dihydro-3- ( 2- ( 4-hydroxy-4-phenylpiperidino) ethyl)- 3-phenyl-2H-indol-2-one (0.43 g) obtained in Example 4-2 was dissolved in THF (5 ml) and potassium tert-butoxide (0.10 g) was added, followed by stirring at room temperature for 15 minutes. To the solution obtained was added ethyl iodide (0.34 g), 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 to yield an amorphous powder, which was then treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound (0.29 g) . Amorphous powder
Η-NMR (CDC13) δ: 1.26 (3H, t, J=7.1 Hz), 1.57-1.74 (3H, m), 1.84-2.62 (8H, m), 2.66-2.86 (2H, m), 3.64-3.94 (2H, m), 6.92 (IH, d, J=7.7 Hz), 7.05-7.14 (IH, m) , 7.18-7.40 (10H, m), 7.43-7.50 (2H, m)
Example 5-14 1 , 3-Dihydro-3- ( 2- ( 4-hydroxy-4-phenylpiperidino)ethyl )-3- phenyl-l-propyl-2H-indol-2-one hydrochloride
The title compound was obtained in the same manner as in Example 5-13.
Amorphous powder 1H-NMR (CDCI3) δ: 0.93 (3H, t, J=7.3 Hz), 1.56-1.81 (5H, m), 1.86-2.58 (8H, m) , 2.67-2.85 (2H, m) , 3.54-3.84 (2H, m), 6.91 (IH, d, J=7.7 Hz), 7.04-7.15 (IH, m), 7.18-7.40
(10H, m), 7.42-7.52 (2H, m)
Example 5-15
1 , 3-Dihydro-l-ethyl-3-( 2-( 4-(o-methoxypheny1 )piperazin-1- yl)ethyl )-3-phenyl-2H-indol-2-one dihydrochloride
1 , 3-Dihydro-3-( 2-( 4-(o-methoxypheny1)piperazin-1- yl) ethyl )-3-phenyl-2H-indol-2-one (0.30 g) obtained in Example 4-3 was dissolved in THF (5 ml) and potassium tert- butoxide (0.10 g) was added, followed by stirring at room temperature for 15 minutes. To the solution obtained was added ethyl iodide (0.13 g), followed by stirring at ambient temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure to yield an amorphous powder, which was then treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was recrystallized from ethanol to yield the title compound (0.19 g). Melting point: 169 - 172°C Example 5-16
1 , 3-Dihydro-3- ( 2-( 4- (o-methoxyphenyl )piperazin-l-yl ) ethyl ) - 3-phenyl-l-propyl-2H-indol-2-one dihydrochloride The title compound was obtained in the same manner as in Example 5-15.
Melting point: 149 - 152°C (recrystallizing solvent: ethanol)
Example 5-17
1 , 3-Dihydro-l- ( 2- (dimethylamino) ethyl ) -3-phenyl-3- ( 2-( 4- phenylpiperidino)ethyl )-2H-indol-2-one dihydrochloride
To a suspension of l,3-dihydro-3-phenyl-3-(2-(4- phenylpiperidino)ethyl)-2H-indol-2-one (0.30 g) obtained in Example 4-1 and N,N-dimethyl-2-chloroethylamine hydrochloride (0.16 g) in 4-methyl-2-pentanone (3.2 ml) was added an 18% aqueous solution of sodium hydroxide (0.7 ml), followed by heating under reflux for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The extract was dried with anhydrous sodium sulfate and concentrated. 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. 1H-NMR (CDC13) δ i 1.48-1.83 (4H, m) , 1.84-2.27 (4H, m) , 2.30 (6H, s), 2.32-2.66 (4H, m) , 2.67-2.85 (2H, m) , 2.88- 3.02 (IH, m), 3.71-4.02 (2H, m) , 6.94 (IH, d, J=7.7 Hz), 7.04-7.41 (13H, m)
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
Melting point: 218 - 221°C (recrystallizing solvent: ethyl acetate/isopropyl ether)
Example Compound 5-20: 1, 3-Dihydro-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl )-l-(2-piperidinoethyl)-2H-indol-2- one dihydrochloride
Melting point (decomposed) : 229 - 232°C (recrystallizing solvent: ethyl acetate/isopropyl ether)
Example 5-21 1, 3-Dihydro-3-phenyl-3-( 2-( 4-phenylpiperidino)ethyl )-1- ( 2- phthalimidoethyl )-2H-indol-2-one hydrochloride
To a suspension of l,3-dihydro-3-phenyl-3-(2-(4- phenylpiperidino)ethyl)-2H-indol-2-one (0.50 g) obtained in Example 4-1 in DMF (5 ml) was added 90% potassium tert- butoxide (0.17 g), followed by stirring at room temperature for 30 minutes. Potassium iodide (0.05 g) and N-(2- bromoethyl)phthalimide (1.01 g) were sequentially added, followed by stirring at room temperature for 4 days. A saturated aqueous solution of sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. 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. 1H-NMR (CDCI3) δt 1.48-2.00 (6H, m) , 2.01-2.48 (4H, m) , 2.60-2.84 (2H, m) , 2.86-3.04 (IH, m) , 3.80-4.51 (4H, m) , 6.91-7.42 (14H, m) , 7.62-7.92 (4H, m) Example 5-22
1 , 3-Dihydro-3-phenyl-3- ( 2- ( 4-phenylpiperidino)ethyl )-1-( 3- phthalimidopropyl)-2H-indol-2-one hydrochloride The title compound was obtained in the same manner as in Example 5-21. Amorphous powder -NMR (CDC13) δ: 1.53-1.80 (4H, m) , 1.84-1.99 (2H, m) , 2.00-2.29 (4H, m) , 2.31-2.49 (2H, m) , 2.68-2.86 (2H, m) , 2.88-2.99 (IH, m) , 3.68-3.99 (4H, m) , 6.90 (IH, d, J=7.7
Hz), 7.05-7.41 (13H, m) , 7.68-7.76 (2H, m), 7.79-7.88 (2H, m)
Example 5-23 1-Acetyl-l , 3-dihydro-3-phenyl-3- ( 2- ( 4- phenylpiperidino)ethyl )-2H-indol-2-one
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. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (3/2) to yield a colorless oily residue, which was then crystallized from isopropyl ether to yield the title compound (0.2 g). Melting point: 109 - 111°C
Example 5-24
1-( 2-Aminoethyl )-1 , 3-dihydro-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl)-2H-indol-2-one dihydrochloride
To a solution of l,3-dihydro-3-phenyl-3-(2-( 4- phenylpiperidino)ethyl )-l- ( 2-phthalimidoethyl )-2H-indol-2- one (0.47 g) obtained in Example 5-21 in methanol (2 ml) was added hydrazine hydrate (0.40 g), followed by stirring at 70°C for 6 hours. The solvent was distilled off and a 3 N aqueous solution of sodium hydroxide was added to the residue, followed by extraction with ethyl acetate. The extract was dried with anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography eluting with ethyl acetate/methanol (3/1). The oily residue obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate to yield the title compound (0.18 g). Melting point: 221 - 223°C
Example 5-25 1-( 3-Aminopropyl )-1 , 3-dihydro-3-phenyl-3-( 2- ( 4- phenylpiperidino)ethyl )-2H-indol-2-one dihydrochloride
The title compound was obtained in the same manner as in Example 5-24.
Melting point: 164 - 166°C (recrystallizing solvent: ethyl acetate)
Example 6
Example 6-1
1 , 3-Dihydro-l- (dimethylamino)-3-phenyl-( 3-( 2-( 4- phenylpiperidino)ethyl)-2H-indol-2-one hydrochloride A suspension of 3-(2-bromoethyl)-l,3-dihydro-l- dimethylamino-3-phenyl-2H-indol-2-one (0.50 g) obtained in Reference Example 23, 4-phenylpiperidine (0.22 g) and potassium carbonate (0.38 g) in DMF (5 ml) was stirred under heating at 85°C for 36 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. 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 (3/1). The oily substance obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound
(4.37 g) as an amorphous powder.
Η-NMR (CDC13) δi 1.69-1.84 (4H, m) , 1.88-2.03 (2H, m) ,
2.04-2.32 (2H, m) , 2.34-2.51 (2H, m) , 2.59-2.76 (IH, m) , 2.86-3.06 (8H, m) , 7.03-7.39 (14H, m)
Example Compounds 6-2 and 6-3 below were obtained in the same manner as in Example 6-1.
Example Compound 6-2: 1,3-Dihydro-l- (dimethylamino)-3-
( 2- ( 4-hydroxy-4-phenylpiperidino) ethyl ) -3-phenyl-2H-indol- 2-one hydrochloride
Amorphous powder
1H-NMR (CDCI3) δ i 1.53-1.68 (2H, m) , 1.71 (IH, br s), 1.95-
2.23 (3H, m), 2.24-2.52 (4H, m) , 2.60-2.78 (3H, m) , 2.98
(6H, m), 7.03-7.23 (2H, m) , 7.24-7.40 (10H, m) , 7.43-7.52 (2H, m)
Example Compound 6-3: 1, 3-Dihydro-l-(dimethylamino)-3-
( 2- ( 4- (o-methoxypheny1 )piperazin-1-yl )ethyl )-3-phenyl-2H- indol-2-one dihydrochloride
Melting point: 114 - 116°C (recrystallizing solvent: ethyl acetate)
Example 7
Example 7-1
2-Methyl-3-oxo-4-phenyl-4-( 2-(4-phenylpiperidino) ethyl )- 1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 4-(2-iodoethyl)-2-methyl-3-oxo-4-phenyl- 1,2,3,4-tetrahydroisoquinoline (70 mg) (Reference Example 30-1), 4-phenylpiperidine (44 mg) and potassium carbonate (38 mg) was stirred in acetonitrile (5 ml) under heating at 60°C overnight. The insoluble material in the reaction mixture was filtered off and the filtrate was concentrated to dryness. The residue obtained was purified by silica gel column chromatography and treated with a 4N solution of hydrogen chloride/ethyl acetate to afford the title compound (50 mg) after crystallizing the salt from isopropyl ether. Melting point: 147 - 152°C
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
Melting point: 233 - 236°C (crystallizing solvent: ethyl acetate)
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 7-4: 2-Ethyl-3-oxo-4-phenyl-4-( 2-( 4- phenylpiperidino)ethyl )-1, 2, 3 , 4-tetrahydroisoquinoline hydrochloride
Melting point: 129 - 134°C (crystallizing solvent: isopropyl ether)
Example Compound 7-5: 2-Ethyl-4-(2-(4-hydroxy-4- phenylpiperidino)ethyl)-3-oxo-4-phenyl-l,2,3,4- tetrahydroisoquinoline
Melting point: 164 - 165°C (recrystallizing solvent: ethyl acetate/isopropyl ether)
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
Melting point: 165 - 170°C (crystallizing solvent ethyl acetate/isopropyl ether)
Example 8
Example 8-1
1 , 3-Dihydro-l- ( 2-hydroxyethyl ) -3-phenyl-3- ( 2- ( 4- phenylpiperidino)ethyl )-2H-indol-2-one
2- ( 2 , 3-Dihydro-2-oxo-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl)-lH-indol-l-yl)ethyl acetate (742 mg) obtained in Reference Example 5-8 was dissolved in methanol (10 ml) and IN sodium hydroxide (3 ml) was added, followed by stirring at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (1/9) to yield the title compound (390 mg) as an amorphous powder. -NMR (CDC13) δ i 1.65-2.48 (11H, m) , 2.68 (IH, br d, 11.4 Hz), 2.76-2.81 (IH, m) , 3.02 (IH, br d, J=10.4 Hz), 3.92 (4H, s), 6.98 (IH, d, J=8.0 Hz), 7.18 -7.40 (13H, m)
Example 8-2 3- ( 2-( 4-Acetyl-4-phenylpiperidino)ethyl )-l , 3-dihydro-l- methyl-3-phenyl-2H-indol-2-one
The title compound was obtained in the same manner as in Example 5-1.
IH-NMR (CDCI3) δ i 1.65-2.38 (10H, m) , 1.84 (3H, s), 2.57- 2.83 (2H, m), 3.14 (3H, s), 6.88 (IH, t, J=7.5 Hz), 7.06-
7.38 (13H, m)
Example 8-3
1-Ethyl-l , 3-dihydro-3-phenyl-3- ( 2- ( 4- ( 3- trifluoromethylphenyl)piperidino)ethyl)-2H-indol-2-one hydrochloride
3-( 2-(Bromoethyl ) -1-ethyl-l , 3, -dihydro-3-phenyl-2H- indol-2-one (1.0 g) obtained in Reference Example 37-1 was dissolved in DMF (10 ml) and 4-(3- trifluoromethylphenyl)piperidine (0.7 g), potassium carbonate (0.6 g), and potassium iodide (0.05 g) were added, followed by stirring at 60°C for 48 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed three times with brine (50 ml). The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (2/1) to yield an oil. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate/diethyl ether to yield the title compound (0.57 g). Melting point: 126 - 128°C
Example 8-4 l-Ethyl-l,3-dihydro-3-phenyl-3-(2-(4-(3- trifluoromethylphenyl )piperazin-1-yl )ethyl )-2H-indol-2-one dihydrochloride
3- ( 2- (Bromoethyl ) -1-ethyl-l , 3-dihydro-3-phenyl-2H- indol-2-one (1.0 g) obtained in Reference Example 37-1 was dissolved in DMF (15 ml) and N-(3- trifluoromethylphenyl)piperazine (1.1 g), potassium carbonate (0.4 g), and potassium iodide (0.05 g) were added, followed by stirring at 60°C for 48 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed three times with brine (50 ml). The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (3/2) to yield an oil. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate to yield the title compound (0.25 g). Melting point: 114 - 116°C
Example 8-5
3-( 2-( 4-( 3-Chlorophenyl)piperazin-l-yl)ethyl) -1-ethyl-l, 3- dihydro-3-phenyl-2H-indol-2-one dihydrochloride
3- ( 2-(Bromoethyl)-1-ethyl-l, 3 ,-dihydro-3-phenyl-2H- indol-2-one (1.0 g) obtained in Reference Example 37-1 was dissolved in DMF (15 ml) and N-(3-chlorophenyl)piperazine hydrochloride (1.4 g), potassium carbonate (0.8 g), and potassium iodide (0.05 g) were added, followed by stirring at 60°C for 48 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed three times with brine (50 ml). The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (2/1) to yield an oil. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate/diethyl ether to yield the title compound (0.37 g). Melting point: 122 - 124°C Compounds in Examples 8-6 through 8-23 below were obtained in the same manner as in Example 8-5.
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
IH-NMR (CDC13) δ: 1.25 (3H, t, J=7.1 Hz), 2.12-2.90 (5H, m), 3.02-4.02 (9H, m) , 6.63 (2H, t, J=6.2 Hz), 6.95 (IH, dd, J=3.3, 7.7 Hz), 7.10 (IH, t, J=7.5 Hz), 7.22-7.39 (5H, m), 8.27 (2H, br) Example 8-7: l-Ethyl-l,3-dihydro-3-phenyl-3-( 2-( 4- phenylpiperazin-1-yl )ethyl )-2H-indol-2-one dihydrochloride Amorphours powder
IH-NMR (CDCI3) δ i 1.24 (3H, t, J=7.1 Hz), 2.25-2.63 (6H, m), 2.68-2.90 (2H, m) , 2.94-3.21 (4H, m) , 3.56-3.93 (2H, m), 6.79-6.98 (4H, m) , 7.04-7.45 (10H, m)
Example 8-8: l-Ethyl-l,3-dihydro-3-(2-(4-(4- methoxypheny1)piperazin-1-yl)ethyl )-3-phenyl-2H-indol-2-one dihydrochloride Amorphours powder IH-NMR (CDCI3) δi 1.25 (3H, dt , J=2.1, 7.1 Hz), 2.07-2.41 (4H, m), 2.45-2.59 (2H, m) , 2.63-3.04 (6H, m) , 3.58-3.98 ( 2H, m) , 3.75 ( 3H, s ) , 6.75-6 . 94 ( 5H, m ) , 7 . 09 ( IH, t ,
J=7 . 3 Hz ) , 7 .18-7 . 39 ( 7H , m)
Example 8-9: 3- (2- ( 4-Cyano-4-phenylpiperidino) ethyl )-
1-ethyl-l, 3-dihydro-3-phenyl-2H-indol-2-one hydrochloride Melting point: 200 - 203°C (crystallizing solvent: ethyl acetate/diethyl ether)
Example 8-10: l-Ethyl-l,3-dihydro-3-phenyl-3-(2-(4-(4- pyridyl)piperidino)ethyl)-2H-indol-2-one dihydrochloride
Amorphours powder -NMR (CDCI3) δi 1.28 (3H, t, J=7.3 Hz), 1.42-1.78 (4H, m), 1.82-2.29 (4H, m) , 2.31-2.47 (2H, m) , 2.68-2.79 (2H, m), 2.83-2.99 (IH, m), 3.63-3.95 (2H, m) , 6.92 (IH, d,
J=7.7 Hz), 7.06-7.13 (3H, m) , 7.18-7.38 (7H, m) , 8.49 (2H, dd, J=1.4, 14.4 Hz) Example 8-11: 3-(2-( 4-( 4-Chlorophenyl)piperazin-l- yl )ethyl )-1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 147 - 149°C (crystallizing solvent: ethyl acetate) Example 8-12: 3-(2-(4-(2-Chlorophenyl)piperazin-l- yl)ethyl)-1-ethyl-l ,3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 112 - 115°C (crystallizing solvent: ethyl acetate) Example 8-13: 1-Ethyl-l, 3-dihydro-3-( 2-( 4-(3- methylphenyl )piperazin-1-yl )ethyl)-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 227 - 229°C (crystallizing solvent: ethyl acetate/diethyl ether) Example 8-14: l-Ethyl-l,3-dihydro-3-phenyl-3-(2-( 4-( 2- pyridyl )piperazin-l-yl)ethyl )-2H-indol-2-one dihydrochloride
Melting point: 173 - 175°C (crystallizing solvent: ethyl acetate) Example 8-15: 3-( 2-( 4-( 4-Acetylphenyl)piperazin-l- yl )ethyl )-1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 134 - 136°C (crystallizing solvent: ethyl acetate)
Example 8-16: l-Ethyl-l,3-dihydro-3-(2-(4-( 3- nitropheny1 )piperazin-l-yl )ethyl ) -3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 149 - 152°C (crystallizing solvent: ethyl acetate)
Example 8-17: 3-( 2-( 4-( 3-Cyanophenyl)piperazin-l- yl ) ethyl ) -1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 128 - 131°C (crystallizing solvent: ethyl acetate)
Example 8-18: l-Ethyl-3-( 2-(4-( 2- fluorophenyl )piperazin-l-yl )ethyl )-l,3-dihydro-3-phenyl-2H- indol-2-one dihydrochloride
Melting point: 116 - 118°C (crystallizing solvent: ethyl acetate)
Example 8-19: l-Ethyl-3-(2-( 4-( 3- fluorophenyl )piperazin-1-yl)ethyl )-l, 3-dihydro-3-phenyl-2H- indol-2-one dihydrochloride
Melting point: 158 - 161°C (crystallizing solvent: ethyl acetate)
Example 8-20: l-Ethyl-3-(2-( 4-(4- fluorophenyl )piperazin-1-yl)ethyl )-1 , 3-dihydro-3-phenyl-2H- indol-2-one dihydrochloride
Melting point: 169 - 172°C (crystallizing solvent: ethyl acetate)
Example 8-21: l-Ethyl-l,3-dihydro-3-( 2-( 4-( 3- methoxypheny1 )piperazin-1-yl )ethyl )-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 138 - 140°C (crystallizing solvent: ethyl acetate) Example 8-22: l-Ethyl-3-(2-(4-(3- fluorophenyl )piperidino) ethyl )-1 , 3-dihydro-3-phenyl-2H- indol-2-one hydrochloride
Amorphous powder IH-NMR (CDC13) δ i 1.28 (3H, t, J=7.3 Hz), 1.44-1.82 (4H, m), 1.82-2.28 (4H, m) , 2.30-2.50 (2H, m) , 2.65-2.83 (2H, m), 2.85-3.00 (IH, m) , 3.63-3.97 (2H, m), 6.80-6.98 (4H, m), 7.04-7.39 (9H, m)
Example 8-23: 3- (2- (4- (3- Chlorophenyl )piperidino) ethyl) -1-ethyl-l, 3-dihydro-3- phenyl-2H-indol-2-one hydrochloride
Amorphous powder
IH-NMR (CDCI3) δ : 1.28 (3H, t, J=7.3 Hz), 1.48-1.81 (4H, m), 1.82-2.02 (2H, m) , 2.04-2.27 (2H, m) , 2.28-2.48 (2H, m), 2.66-2.84 (2H, m) , 2.86-2.99 (IH, m) , 3.68-3.92 (2H, m), 6.93 (IH, d, J=8.1 Hz), 7.02-7.40 (12H, m)
Example 8-24
1-( 3-Bromopropyl ) -1 , 3-dihydro-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl ) -2H-indol-2-one
The title compound was obtained in the same manner as in Example 5-4.
Amorphous powder
IH-NMR (CDCI3) δi 1.52-1.81 (4H, m) , 1.82-2.03 (2H, m) , 2.04-2.50 (6H, m) , 2.61-2.87 (2H, m) , 2.90-3.02 (IH, m) ,
3.34-3.47 (2H, m) , 3.72-4.07 (2H, m) , 6.98-7.42 (14H, m)
Example 8-25
1 , 3-Dihydro-l-( 2- ( 2-methoxyethoxy)ethyl )-3-phenyl-3- ( 2-( 4- phenylpiperidino)ethyl)-2H-indol-2-one hydrochloride
The title compound was obtained in the same manner as in Example 5-4.
Amorphous powder
IH-NMR (CDCI3) δ : 1.54-1.81 (4H, m) , 1.83-2.04 (2H, m) , 2.06-2.28 (2H, m) , 2.30-2.49 (2H, m) , 2.68-2.87 (2H, m) ,
2.88-3.01 (IH, m), 3.32 (3H, s), 3.39-3.47 (2H, m) , 3.53- 3 . 61 ( 2H , m) , 3 . 67-3 . 93 ( 3H , m) , 3 . 99-4 . 11 ( IH, m) , 7 . 02- 7 . 41 ( 14H , m)
Example 8-26 1-( 5-Acetyloxypentyl )-1 , 3-dihydro-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl)-2H-indol-2-one hydrochloride
The title compound was obtained in the same manner as in Example 5-4. Amorphous powder Η-NMR (CDCI3) δ i 1.32-1.48 (2H, m) , 1.50-1.82 (8H, m) ,
1.83-2.00 (2H, m), 2.01 (3H, s), 2.04-2.28 (2H, m) , 2.31- 2.48 (2H, m), 2.66-2.84 (2H, m) , 2.88-3.01 (IH, m) , 3.56- 3.72 (IH, m) , 3.76-3.93 (IH, m) , 4.00 (2H, t, J=6.7 Hz), 6.91 (IH, d, J=7.7 Hz), 7.05-7.39 (13H, m)
Example 8-27
1 , 3-Dihydro-l- ( 3-morpholinopropyl )-3-phenyl-3- ( 2- ( 4- phenylpiperidino)ethyl )-2H-indol-2-one dihydrochloride
A solution of l-(3-bromopropyl)-l,3-dihydro-3-phenyl- 3-(2-( 4-phenylpiperidino)ethyl)-2H-indol-2-one (0.5 g) obtained in Example 8-24 and morpholine (0.25 g) in acetonitrile (5 ml) was stirred at 80°C for 24 hours. To the reaction mixture was added a saturated sodium bicarbonate (5 ml) and extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue 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, and the formed salt was crystallized by ethyl acetate to yield the title compound (0.38 g) . Melting point: 205 - 209°C
Examples 8-28 and 8-29 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
A solution of l-(3-bromopropyl)-l,3-dihydro-3-phenyl- 3-(2-{4-phenylpiperidino)ethyl)-2H-indol-2-one (0.5 g) obtained in Example 8-24 and sodium methoxide (0.10 g) in 0 THF (5 ml) was stirred at room temperature for 4 days. To the reaction mixture was added a saturated sodium bicarbonate (5 ml) and extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The 5 residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane (1/2) to yield two products. Each oil was treated with a 4N solution of hydrogen chloride/ethyl acetate to yield Example 8-28 (0.36 g) and Example 8-29 (0.06 g) as amorphous powder, o respectively.
Example 8-28: IH-NMR (CDCI3) δ i 1.46-1.82 (4H, m) , 1.83-2.04 (2H, m) , 2.07-2.30 (2H, m) , 2.31-2.48 (2H, m) , 2.67-2.88 (2H, m) , 5 2.89-3.02 (IH, m) , 4.27 (IH, ddd, J=1.8, 5.1, 16.3 Hz), 4.47 (IH, ddd, J=1.8, 4.8, 16.3 Hz), 5.17 (IH, s), 5.23 (IH, dd, J=1.8, 4.0 Hz), 5.84 (IH, ddd, J=4.0, 4.8, 5.1 Hz), 6.90 (IH, d, J=7.7 Hz), 7.06-7.42 (13H, m)
0 Example 8-29:
IH-NMR (CDCI3) δ: 1.53-1.81 (6H, m) , 1.83-2.04 (4H, m) , 2.05-2.28 (2H, m) , 2.29-2.49 (2H, m) , 2.67-2.85 (2H, m) , 2.89-3.02 (IH, ) , 3.23 (3H, s), 3.73 (IH, dt, J=20.9, 6.6 Hz), 3.94 (IH, dt, J=20.9, 7.0 Hz), 6.99 (IH, d, J=7.7 Hz), 5 7.05-7.40 (13H, m) Example 8-30
1- ( 3-( 4-Ethoxycarbonylpiperazin-1-yl )propyl ) -1 , 3-dihydro-3- phenyl-3- ( 2- ( 4-phenylpiperidino)ethyl ) -2H-indol-2-one dihydrochloride
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).
Melting point: 127 - 129°C (crystallizing solvent: ethyl acetate)
Example 8-31
1, 3-Dihydro-3-pheny1-3-( 2-( 4-phenylpiperidino)ethyl )-l- ( 3- (piperazin-l-yl)propyl)-2H-indol-2-one trihydrochloride A mixture of l-( 3-(4-ethoxycarbonylpiperazin-l- yl)propyl)-l,3-dihydro-3-phenyl-3-(2-(4- phenylpiperidino)ethyl)-2H-indol-2-one (0.30 g) (free form of the compound obtained in Example 8-30) and cone. hydrochloric acid (3.0 ml) in ethanol (3.0 ml) was stirred at 80°C for 24 hours. Then, hydrochloric acid (3.0 ml) was added to the resulting mixture and stirring was continued at 80°C for 38 hours. The reaction mixture was made basic by a solution of sodium hydroxide and extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethanol/ethyl acetate to yield the title compound (0.14 g). Melting point: 181 - 184°C
Compounds in Examples 8-32 through 8-34 below were obtained in the same manner as in Example 5-1.
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
Melting point: 120 - 122°C (crystallizing solvent: ethyl acetate)
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
Melting point: 124 - 126°C (crystallizing solvent: ethyl acetate)
Example 8-35 3-(2-(4-(3-Aminophenyl)piperazin-l-yl)ethyl)-l-ethyl-l,3- dihydro-3-phenyl-2H-indol-2-one trihydrochloride
To a solution of 1-ethyl-l,3-dihydro-3-( 2-(4-(3- nitrophenyl)piperazin-l-yl)ethyl-3-phenyl-2H-indol-2-one (3.21 g) (free form of the compound obtained in Example 8- 16) in ethanol (100 ml) was added 10% palladium on carbon (0.32 g). The mixture was hydrogenated under atmospheric pressure at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (2/1) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate to yield the title compound (3.15 g). Melting point: 171 - 174 °C
Example 8-36
3-(2-(4-(3-(Acetylamino)phenyl)piperazin-l-yl)ethyl)-l- ethyl-l,3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride To a solution of 3-(2-(4-(3-aminophenyl)piperazin-l- yl ) ethyl)-1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one (0.30 g) (free form of the compound obtained in Example 8-35) in acetonitrile (5.0 ml) were added acetic anhydride (0.13 g) and triethylamine (0.17 ml) sequentially. The resulting mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The extracts were dried with anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate 0 (1/3) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate and crystallized from ethyl acetate to yield the title compound (0.58 g). Melting point: 163 - 165°C 5
Example 8-37
1 , 3-Dihydro-l- ( 5-hydroxypentyl )-3-phenyl-3- ( 2- ( 4- phenylpiperidino) ethyl )-2H-indol-2-one hydrochloride
The title compound was obtained in the same manner as 0 in Example 8-1. Amorphous powder
IH-NMR (CDC13) δ i 1.33-1.48 (2H, m) , 1.51-1.84 (9H, m) , 1.85-2.03 (2H, m) , 2.04-2.29 (2H, m) , 2.31-2.48 (2H, m) , 2.68-2.87 (2H, m) , 2.89-3.02 (IH, m) , 3.57 (2H, t, J=6.2 5 Hz), 3.61-3.74 (IH, m) , 3.75-3.92 (IH, m) , 6.92 (IH, d, J=8.1 Hz), 7.05-7.40 (13H, m)
Example 9
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.
Melting point: 177 - 179°C (crystallizing solvent: ethyl 5 acetate) Example 9-2
1 , 3-Dihydro-3-phenyl-3-( 2-( 4-phenylpiperidino)ethyl) -1- piperidino-2H-indol-2-one hydrochloride
To a solution of 3-(2-bromoethyl)-l,3-dihydro-3- phenyl-l-piperidino-2H-indol-2-one (1.0 g) obtained in Reference Example 39-1 in DMF (15 ml) were added 4- phenylpiperidine (0.8 g), potassium carbonate (0.35 g), and potassium iodide (0.04 g). The mixture was stirred at 60°C for 48 hours. The reaction mixture was diluted with ethyl 0 acetate (50 ml) and the organic layer was washed with brine three times. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl 5 acetate (2/1) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound (0.25 g). Amorphous powder o Η-NMR (CDC13) δi 1.18-1.42 (2H, m) , 1.46-2.48 (13H, m) , 2.57-2.82 (2H, m) , 2.84-3.13 (4H, m) , 3.49-3.80 (2H, m) , 7.03-7.38 (14H, m)
Compounds in Examples 9-3 through 9-5 below were obtained in the same manner as in Example 9-2. 5 Example 9-3: l,3-Dihydro-3-(2-(4-(2- methoxyphenyl)piperazin-1-yl)ethyl )-3-phenyl-l-piperidino- 2H-indol-2-one dihydrochloride
Melting point: 221 - 224°C (crystallizing solvent: ethyl acetate/diethyl ether) 0 Example 9-4: l,3-Dihydro-3-{2-(4-(2- methylphenyl)piperazin-l-yl)ethyl)-3-phenyl-l-piperidino- 2H-indol-2-one dihydrochloride
Melting point: 178 - 181°C (crystallizing solvent: ethyl acetate/diethyl ether) 5 Example 9-5: l,3-Dihydro-3-phenyl-l-piperidino-3-(2- (4-(3-trifluoromethylphenyl)piperazin-l-yl)ethyl)-2H-indol- 2-one dihydrochloride Amorphous powder IH-NMR (CDC13) δ : 1.16-1.42 (IH, m) , 1.48-1.82 (5H, m) , 2.04-2.56 (7H, m) , 2.62-2.79 (IH, m) , 2.89-3.23 (6H, m) , 3.49-3.78 (2H, m) , 6.97-7.38 (13H, m)
Example 9-6 l-(Diethylamino)-l,3-dihydro-3-phenyl-3-(2-(4- phenylpiperidino)ethyl )-2H-indol-2-one hydrochloride
To a solution of 3-( 2-bromoethyl)-l-(diethylamino)- l,3-dihydro-3-phenyl-2H-indol-2-one (0.50 g) obtained in Reference Example 39-2 in DMF (5.0 ml) were added 4- phenylpiperidine (0.25 g), potassium carbonate (0.21 g), and potassium iodide (0.05 g). The mixture was stirred at 80°C for 48 hours. A saturated aqueous sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (4/1) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound (0.46 g). Amorphous powder
IH-NMR (CDCI3) δ i 0.87 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.4 Hz), 1.66-1.86 (4H, m) , 1.90-2.09 (2H, m) , 2.10-2.20 (IH, m), 2.22-2.33 (IH, ) , 2.34-2.54 (2H, m) , 2.59-2.77 (IH, m), 2.87-3.15 <4H, m) , 3.38-3.68 (2H, m) , 6.99-7.38 (14H, m)
Compounds in Examples 9-7 through 9-9 below were obtained in the same manner as in Example 9-6.
Example 9-7: l-(Diethylamino)-l,3-dihydro-3-( 2-( 4- hydroxy-4-phenylpiperidino)ethyl )-3-phenyl-2H-indol-2-one hydrochloride
Amorphous powder IH-NMR (CDC13) δi 0.87 (3H, t, J=7.1 Hz), 1.10 (3H, t,
J=7.1 Hz), 1.47-1.78 (5H, m) , 2.02-2.24 (2H, m) , 2.28-2.56
(4H, m), 2.60-2.84 (2H, m) , 2.85-3.15 (2H, m) , 3.37-3.69
(2H, m), 7.03-7.39 (12H, m), 7.44-7.53 (2H, m) Example 9-8: l-(Diethylamino)-l,3-dihydro-3-phenyl-3-
( 2- ( 4-phenylpiperazin-l-yl )ethyl )-2H-indol-2-one dihydrochloride
Melting point: 177 - 180°C (crystallizing solvent: ethyl acetate) Example 9-9: l-(Diethylamino)-l,3-dihydro-3-( 2-( 4-( 2- methoxylphenyl )piperazin-1-yl ) ethyl ) -3-phenyl-2H-indol-2- one dihydrochloride
Amorphous powder
IH-NMR (CDCI3) δi 0.87 (3H, t, J=7.1 Hz), 1.09 (3H, t, J=7.1 Hz), 2.16-2.79 (8H, m) , 2.86-3.16 (6H, m) , 3.38-3.69
(2H, m), 3.84 (3H, s), 6.81-7.00 (3H, m) , 7.01-7.38 (10H, m)
Example 9-10 1 3-Dihydro-l-bis (phenylmethyl)amino-3-phenyl-3-( 2-( - phenylpiperidino)ethyl)-2H-indol-2-one
To a solution of 3-(2-bromoethyl)-l,3-dihydro-l- bis(phenylmethyl)amino-3-phenyl-2H-indol-2-one (4.0 g) obtained in Reference Example 39-3 in DMF (40 ml) were added 4-phenylpiperidine (1.5 g) and potassium carbonate
(1.3 g). The mixture was stirred at 80°C for 24 hours. A saturated aqueous sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The extracts were washed with brine, dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (3/1) and recrystallized from isopropyl ether/hexane to yield the title compound (2.1 g). Melting point: 80 - 83°C
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 - 158βC (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 (CDCI3) δi 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
Example 11-1
3-(2-(4-(4-Cyanophenyl)piperazin-l-yl)ethyl)-l-ethyl-l,3- dihydro-3-phenyl-2H-indol-2-one dihydrochloride To a solution of 1-ethyl-l, 3-dihydro-3-phenyl-3-( 2- (piperazin-l-yl)ethyl)-2H-indol-2-one (1.0 g) obtained in Reference Example 41 in DMF (10 ml) were added 4- fluorobenzonitrile (0.55 g) and potassium carbonate (0.41 g). The mixture was stirred at 150°C for 4 hours. After the mixture was cooled, ethyl acetate (50 ml) was added and the organic layer was washed with brine (50 ml) three times. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (1/1) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate/methanol to yield the title compound (0.95 g).
Melting point: 130 - 132°C
Compounds in Examples 11-2 through 11-8 below were obtained in the same manner as in Example 11-1.
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
IH-NMR (CDCI3) δi 1.26 (3H, t, J=7.1 Hz), 2.05-2.43 (5H, m), 2.56-2.62 (2H, m) , 2.64-2.83 (IH, m) , 3.02-3.22 (4H, m), 3.60-3.97 (2H, m) , 6.89-7.01 (3H, m) , 7.04-7.15 (IH, m) , 7.20-7.57 (9H, m) Example 11-3: 3-( 2-( 4-( 2-Acetylphenyl)piperazin-l- yl)ethyl ) -1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 108 - 110°C (crystallizing solvent: ethyl acetate/diethyl ether)
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
Melting point: 146 - 151°C (crystallizing solvent: ethyl acetate/isopropyl ether)
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
Melting point: 119 - 124°C (crystallizing solvent: ethyl acetate/isopropyl ether)
Example 11-6: l-Ethyl-l,3-dihydro-3-(2-(4-(2- nitrophenyl)piperazin-l-yl)ethyl)-3-phenyl-2H-indol-2-one hydrochloride
Melting point: 160 - 161°C (crystallizing solvent: ethyl acetate/methanol)
Example 11-7: l-Ethyl-l,3-dihydro-3-( 2-( 4-( 4- nitropheny1)piperazin-l-yl)ethyl)-3-phenyl-2H-indol-2-one dihydrochloride
Melting point: 142 - 144°C (crystallizing solvent: ethyl acetate/methanol)
Example 11-8: l-Ethyl-l,3-dihydro-3-phenyl-3-(2-( 4-( 4- trifluoromethylphenyl)piperazin-l-yl)ethyl-2H-indol-2-one dihydrochloride
Melting point: 131 - 134°C (crystallizing solvent: ethyl acetate)
Example 12 Example 12-1
1-( 2- ( 1-(Dimethylamino)-2 , 3-dihydro-2-oxo-3-phenyl-lH- indol-3-yl)ethyl )-4-phenylpiperidine 1-oxide To a solution of 1,3-dihydro-l- (dimethylamino)-3- phenyl-3-( 2-( 4-phenylpiperidino)ethyl )-2H-indol-2-one (0.29 g) obtained in Example 6-1 in acetonitrile (5.0 ml) was added m-chloroperbenzoic acid (0.17 g) under ice cooling condition. The resulting mixture was stirred at 0°C for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The extracts were dried with anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography eluting with ethyl acetate/methanol (10/1) to yield the title compound (0.20 g) . Amorphous powder IH-NMR (CDC13) δ i 1.66-1.82 (2H, m) , 2.56-2.84 (3H, m) , 2.85-3.24 (12H, m) , 3.26-3.51 (2H, m) , 7.02-7.16 (2H, m) , 7.18-7.45 (12H, m)
Example 12-2
1-( 2-(1-(Dimethylamino)-2 , 3-dihydro-2-oxo-3-phenyl-lH- indol-3-yl)ethyl)-4-(2-methoxyphenyl)piperazine 1-oxide
The title compound was obtained in the same manner as in Example 12-1.
Amorphous powder
IH-NMR (CDCI3) δi 2.90-3.05 (8H, m) , 3.05-3.22 (4H, m) , 3.23-3.35 (2H, m) , 3.36-3.53 (2H, m) , 3.55-3.77 (2H, m) ,
3.86 (3H, s), 6.84-7.17 (6H, m) , 7.22-7.45 (7H, m)
Example 13
2-Acetyl-l,2,3, 4-tetrahydro-4-phenyl-4-( 2-( 4- phenylpiperidino)ethyl)isoquinoline hydrochloride
To a solution of 2-acetyl-l,2,3,4-tetrahydro-4-(2- iodoethyl)-4-phenylisoquinoline (1.38 g) obtained in Reference Example 46 in DMF (7.0 ml) were added 4- phenylpiperidine (0.60 g) and potassium carbonate (0.52 g) . The mixture was stirred at 50βC for 8 hours and the mixture was cooled to room temperature. After stirring for additional 48 hours, a saturated aqueous sodium hydrogen carbonate was added, followed by extraction with ethyl acetate. The extracts were washed with brine, dried with anhydrous sodium sulfate, and concentrated. The residue was disolved in THF (10 ml) and 1 N aqueous sodium hydroxide (4.0 ml) and acetic anhydride (0.35 g) was added dropwise to the solution under ice cooling condition. The mixture was stirred at room temperature for 38 hours. Water was added, followed by extraction with ethyl acetate. The extracts were dried with anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography eluting with ethyl acetate/methanol (10/1) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate to yield the title compound (0.42 g) . Amorphous powder
IH-NMR (CDC13) δ i 1.73 and 2.15 (3H, s and s), 1.81-1.94 (4H, m), 2.36-2.94 (8H, m) , 3.10-3.33 (2H, m) , 3.68-3.88 (IH, m), 4.20-5.01 (2H, m) , 7.04-7.38 (14H, m)
Example 14
3-0xo-4-phenyl-4-( 2-( 4-phenylpiperidino)ethyl)-1, 2, 3, 4- tetrahydroisoquinoline To a solution of 2-methoxymethyl-3-oxo-4-phenyl-4-(2- ( 4-phenylpiperidino) ethyl)-1 ,2 ,3 , 4-tetrahydroisoquinoline (0.12 g) obtained in Example 10-1 in methanol (5.0 ml) was added hydrochloric acid (0.5 ml). The resulting mixture was refluxed for 3 days. Methanol was removed in vacuo and the residue was diluted with water. The solution was basified with aqueous ammonia and the precipitate was collected by filtration. The crude crystalline was recrystallized from DMF/water to yield the title compound (90 mg) . Melting point: 250 - 252°C Example 15
Compounds in the following Examples 15-1 and 15-2 were obtained in the same manner as in Example 5-1.
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
Melting point: 170 - 173°C (recrystallizing solvent: ethanol/isopropyl ether)
Example 15-2: 3-( 2-(4-( 3-Acetylphenyl)piperazin-l- yl ) ethyl ) -1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one dihydrochloride Amorphous powder
IH-NMR (CDC13) δ 1.25 (3H, t, J=7.1 Hz), 2.06-2.44 (5H, m), 2.45-2.56 (2H, m) , 2.57 (3H, s), 2.66-2.90 (IH, m) , 3.02-3.22 (4H, m) , 3.55-3.95 (2H, m) , 6.91 (IH, d, J=7.6 Hz), 7.04-7.16 (2H, ) , 7.18-7.48 (10H, m) Example 15-3
1-Ethyl-l , 3-dihydro-3- ( 2- ( 4-(3- (methylamino)phenyl )piperazin-l-yl )ethyl ) -3-phenyl-2H- indol-2-one trihydrochloride
To a solution of 3-(2-(4-(3-aminophenyl)piperazin-l- yl)ethyl)-l-ethyl-l,3-dihydro-3-phenyl-2H-indol-2-one (free form of the compound obtained in Example 8-35) (1.38 g) in acetonitrile (5.0 ml) were added methyl chlorocarbonate (0.15 g) and triethylamine (0.22 ml) sequentially and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate was added to the resulting mixture, followed by extraction with ethyl acetate. The extracts were dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (5.0 ml) and lithium aluminum hydride (0.12 g) was added to the solution. The mixture was stirred at 60°C for 2 hours. Water was added, followed by filtration to remove the precipitate and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (1/1) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate/diethyl ether to yield the title compound (0.17 g). Melting point: 174 - 177°C Example 15-4
1-Ethyl-l , 3-dihydro-3- ( 2- ( 4- ( 3- ( dimethylamino)phenyl )piperazin-l-yl ) ethyl ) -3-phenyl-2H- indol-2-one trihydrochloride
To a solution of 3-(2-(4-(3-aminophenyl)piperazin-l- yl ) ethyl )-1-ethyl-l , 3-dihydro-3-phenyl-2H-indol-2-one (free form of the compound obtained in Example 8-35) (0.64 g) in acetonitrile (5.0 ml) were added formalin (0.90 ml) and sodium cyanoborohydride (0.21 g) sequentially. Acetic acid (0.11 ml) was added dropwise to the mixture and the resulting mixture was stirred at room temperature for 4 hours. Sodium cyanoborohydride (0.21 g) was added and the mixture was stirred at room temperature for additional 14 hours. A saturated aqueous sodium hydrogen carbonate was added to the resulting mixture, followed by extraction with ethyl acetate. The extracts were dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexane/ethyl acetate (1/1) to yield an oily substance. The oily material obtained was treated with a 4 N solution of hydrogen chloride/ethyl acetate, and the formed salt was crystallized from ethyl acetate/diethyl ether to yield the title compound (0.43 g). Melting point: 123 - 126°C
The chemical structural formulas of the compounds obtained in Examples 4 through 15 are shown below.
Figure imgf000148_0001
Example 4-1 Example 5-3
Figure imgf000148_0002
Example 4-2 Example 5-4
Figure imgf000148_0003
Figure imgf000149_0001
Example 5-10 Example 5-15
Figure imgf000149_0002
Example 5-11 Example 5-16
Figure imgf000149_0003
Figure imgf000150_0001
Example 5-18 Example 5-23
Figure imgf000150_0002
Figure imgf000150_0003
Figure imgf000151_0001
Example 6-3 Example 7-4
Figure imgf000151_0002
Example 7-5
Figure imgf000151_0003
Figure imgf000151_0004
Example 7-2 Example 7-6
Figure imgf000151_0005
Example 7-3
Figure imgf000152_0001
Example 8-5 Example 8-10
Figure imgf000153_0001
Example 8-12 Example 8-17
Figure imgf000153_0002
Figure imgf000154_0001
Figure imgf000154_0003
Figure imgf000154_0007
Figure imgf000154_0004
Figure imgf000154_0005
Figure imgf000154_0002
Figure imgf000154_0006
Figure imgf000155_0001
Figure imgf000155_0002
Example 8-35
Figure imgf000155_0003
Figure imgf000156_0001
Figure imgf000156_0003
Figure imgf000156_0002
Figure imgf000156_0004
Figure imgf000157_0001
Figure imgf000157_0002
Example 10-5
Figure imgf000157_0004
Example 10-6
Figure imgf000157_0005
Figure imgf000157_0003
Figure imgf000158_0001
Example 13 Example 15-4 Example 16
(1) Example Compound 7-1 50 mg
(2) Lactose 34 mg
(3) Corn starch 10.6 mg (4) Corn starch (pasty) 5 mg
(5) Magnesium stearate 0.4 mg
(6) Carboxymethyl cellulose calcium 20 mg
Total 120 mg In accordance with a conventional method, the above components (1) through (6) were mixed and tableted using a tableting machine to yield a tablet.
Example 17
(1) Example Compound 5-4 50 mg (2) Finely powdered cellulose 30 mg
(3) Lactose 37 mg
(4) Magnesium stearate 3 mg
Total 120 mg In accordance with a conventional method, the above components (1) through (4) were mixed and filled in a gelatin capsule to yield a capsular preparation.
Text Example 1
Action on distension-induced rhythmic bladder contractions in urethane-anesthetized guinea pigs
Five to ten male guinea pigs (weighing 250 to 300 g) per group were anesthetized with urethane (1.2 g/kg, i.p.); a median incision was made in the lower abdomen and the urethra was ligated. A polyethylene cannula (PE-90) was inserted into the urinary bladder to allow injection of physiological saline and measurement of the bladder's inner pressure. The cannula was fixed in place with a quick adhesive (Aron Alpha (trade name)). The bladder's inner pressure was recorded on a polygraph via a pressure transducer. A given amount (about 3 ml) of physiological saline, warmed to 38°C, was injected into the bladder; after stable rhythmic bladder contractions were noted at least 3 times, the compound was intravenously administered.
After the compound administration, relatively stable rhythmic bladder contractions were noted for at least 1 hour. In determining the time for disappearance of rhythmic bladder contractions by the compound, the maximum observation time (cutoff time) was set at 30 minutes.
Because the rhythmic bladder contraction cycle was slightly extended after the solvent DMSO was intravenously administered in some animals, the data obtained were statistically analyzed by Student's t-test in two groups: animals receiving DMSO alone and those receiving the compound in DMSO.
Minimum effective doses of the compound on rhythmic bladder contractions (p < 0.05) are shown in Table 1.
Table 1
Compound Minimum Effective Dose (mg/kg, i.v. )
Reference Example Compound 4-1 0.3
Reference Example Compound 4-2 0.03
Reference Example Compound 4-5 0.1 Reference Example Compound 4-8 0.1
Example Compound 5-4 0.003
Example Compound 5-13 0.001
Example Compound 5-16 0.003 Example Compound 5-19 0.003
Example Compound 7-1 0.03
These results demonstrate that compound (I), especially compound (la), possesses excellent micturition __ . .. .. reflex-suppressing activity. INDUSTRIAL APPLICABILITY
Compounds (I) and (la) are useful as a pharmaceutical composition for controlling micturition because they possess excellent micturition reflex-suppressing activity and are low in toxicity. They are also effective as prophylactic and therapeutic agents for lower urinary tract dysfunctions such as pollakiuria and urinary incontinence.

Claims

1. A pharmaceutical composition for controlling micturition which comprises a compound of the formula:
Figure imgf000162_0001
wherein ring A represents an optionally substituted benzene ring; ring B represents an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring; ring C represents an optionally substituted nitrogen- containing heterocyclic ring;
X represents a carbon atom or a nitrogen atom; Y represents a bond or a lower alkylene which may be substituted by an oxo;
Ar1 and Ar2 each represents an optionally substituted aromatic group; and m represents an integer of 1 to 3, or a salt thereof.
2. A composition of Claim 1, wherein ring A is a benzene ring which may be substituted by 1 to 4 substituents selected from the group consisting of halogen, Cι-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι-6 alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι_6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Ci-β alkoxy-Cι-6 alkoxy, mono-C7_i6 aralkylamino and di-C7_i6 aralkylamino; ring B is a 4- to 7-membered carbocyclic or heterocyclic ring optionally containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, Cι-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 Cι-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino, di-C7-i6 aralkylamino and oxo; ring C is a 4- to 7-membered nitrogen-containing heterocyclic ring containing at least one nitrogen atom which may be oxidized, in addition to carbon atoms, and optionally containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 Cι_β alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-Ci-β alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino. formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, Cβ-io aryl, C6-10 aryloxy, acyloxy, Cι_6 alkoxy-Cι_6 alkoxy, mono-C7_i6 aralkylamino and di-C7_i6 aralkylamino; Y is a bond or a C1-4 alkylene which may be substituted by an oxo; and
Ari and Ar2 each is an aromatic group selected from the group consisting of a Cβ-i4 aryl and a 5- to 14-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which group may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cχ-6 alkyl, optionally halogenated C2-6 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 Ci-β alkoxy, optionally halogenated Cι-6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι_6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, Cβ-io aryl, C6-10 aryloxy, acyloxy, C1-6 alkoxy-Cι_6 alkoxy, mono-C7-i6 aralkylamino and di-C7-i6 aralkylamino.
3. A composition of Claim 1, wherein ring B is a ring of the formula:
Figure imgf000164_0001
4. A composition of Claim 1, wherein ring C is an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic ring.
5. A composition of Claim 1, wherein m is 2.
6. A composition of Claim 1, which is for the prophylaxis or treatment of the lower urinary tract dysfunctions.
7. A composition of Claim 6, wherein the lower urinary tract dysfunctions is urinary incontinence or pollakiuria.
8. A compound of the formula:
Figure imgf000165_0001
wherein 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: -CH2-CH2-, -CH=CH-, -CO-O-, -CO-NR6-, -NR6-CO-, -N=CH-, -CH2-S(0)p-, -N=N-, -NR6-S02", -SO2-NR6-, -NR6-NR6a-, -CH2-NR6-CO- or -CO-NR6-CO- wherein R6 and R6a 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; ring C represents an optionally substituted nitrogen- containing heterocyclic ring; 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;
Ar1 and Ar2 each represents an optionally substituted aromatic group; and m represents an integer of 1 to 3, or a salt thereof.
9. A compound of Claim 8, wherein R6 and Rβa each is (i) a hydrogen atom,
(ii) a Cι-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_6 cycloalkyl, Cβ-i4 aryl or C7-.16 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 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 Cι_6 alkoxy, (8) optionally halogenated Cι_6 alkylthio, (9) hydroxy, (10) amino, (11) mono-Ci-β alkylamino, (12) di-Cχ-6 alkylamino, (13) 3- to 7-membererd saturated cyclic amino, (14) formyl, (15) acyl, (16) acylamino, (17) carboxy, (18) carbamoyl, (19) sulfo, (20) sulfamoyl, (21) mono-Cι-6 alkylsulfamoyl, (22) di-Cι-6 alkylsulfamoyl, (23) Cβ-io aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Ci-e alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, Ce-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7-i6 aralkylamino, (24) Cβ-io aryloxy which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β alkyl, optionally halogenated C2-6 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 Ci-β alkoxy, optionally halogenated C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, Ce-io aryl, Cβ-io aryloxy, acyloxy, Cι_6 alkoxy-Cι-6 alkoxy, ono-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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Ce-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7-i6 aralkylamino, (26) acyloxy, (27) phthalimido which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι-6 alkyl, optionally halogenated C2-6 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 Cι-6 alkoxy, optionally halogenated Cι_6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι-6 alkoxy-Cι-6 alkoxy, mono-C7_i6 aralkylamino and di-C7_i6 aralkylamino, (28) Cι_6 alkoxy-Cι-6 alkoxy, (29) mono-C7_i6 aralkylamino and (30) di-C _i6 aralkylamino; the C3-6 cycloalkyl may contain as ring-constituting atoms 1 or 2 hetero atoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms,
(iii) an acyl represented by the formula: -(C=0)-Ri, -(C=0)-NR1R2, -(C=S)-NHR1, -(C=0)-ORl, -SO2-R1 or -SO-Rl wherein R1 is (iii-1) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, Cβ-1 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated Ci-β 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 C1-6 alkoxy, (8) optionally halogenated Cχ-6 alkylthio, (9) hydroxy, (10) amino, (11) mono-Cι-6 alkylamino, (12) di-Cχ-6 alkylamino, (13) 3- to 7-membererd saturated cyclic amino, (14) formyl, (15) acyl, (16) acylamino, (17) carboxy, (18) carbamoyl, (19) sulfo, (20) sulfamoyl, (21) mono-Ci-β alkylsulfamoyl, (22) di-Cι_6 alkylsulfamoyl, (23) Cβ-io aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated C2-6 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 Cι-6 alkoxy, optionally halogenated Cι_6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, C6-ιo aryl, C6-ιo aryloxy, acyloxy, Cι_6 alkoxy-Cχ-6 alkoxy, mono-C7-i6 aralkylamino and di-C7-i6 aralkylamino, (24) Cβ-io aryloxy which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, Cχ-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 Cι-6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι-6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Cι_6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι_6 alkoxy-Cι-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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated C2-6 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 C1-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι_β alkoxy-Cι_6 alkoxy, mono-C7-i6 aralkylamino and di-C7_i6 aralkylamino, (26) acyloxy, (27) phthalimido which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_β alkyl, optionally halogenated C2-6 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 Ci-e alkoxy, optionally halogenated Cχ-6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι_6 alkylsulfamoyl, di-Cι_β alkylsulfamoyl, Cβ-io aryl, C6_ιo aryloxy, acyloxy, Cι_6 alkoxy-Cι-6 alkoxy, mono-C7-i6 aralkylamino and di-C7-i6 aralkylamino, (28) Cι-6 alkoxy-Cι-6 alkoxy, (29) mono-C7_i6 aralkylamino and (30) di-C7_i6 aralkylamino, or (iii-2) a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cj-β alkyl, optionally halogenated C2-6 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 Cι-6 alkoxy, optionally halogenated Cχ-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cι-6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Ci-β alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Ci-β alkoxy-Ci-e alkoxy, mono-C7_i6 aralkylamino and di-C7_i6 aralkylamino; R2 is a hydrogen atom or a Cι-6 alkyl; or Ri and R2 form, taken together with the adjacent nitrogen atom, a 5- to 7-membered nitrogen-containing heterocyclic ring,
(iv) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of (iv-l) a Cι-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6_ 14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of (1) halogen, (2) C1-.3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated Cι_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 Ci-β alkoxy, (8) optionally halogenated Cι_6 alkylthio, (9) hydroxy, (10) amino, (11) mono-Cι-6 alkylamino, (12) di-Cι-6 alkylamino, (13) 3- to 7- membererd saturated cyclic amino, (14) formyl, (15) acyl, (16) acylamino, (17) carboxy, (18) carbamoyl, (19) sulfo, (20) sulfamoyl, (21) mono-Cι-6 alkylsulfamoyl, (22) di-Cι_6 alkylsulfamoyl, (23) Cβ-io aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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 Cι_6 alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι_6 alkoxy, mono-C7_i6 aralkylamino and di-C7-i6 aralkylamino, (24) Cβ-io aryloxy which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, Cι_3 alkylenedioxy, nitro, cyano, optionally halogenated Cι_6 alkyl, optionally halogenated C2-6 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-e alkylthio, hydroxy, amino, mono-Cι_6 alkylamino, di-Cι-6 alkylamino, 3- to 7- membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Ce-io aryloxy, acyloxy, Cι_6 alkoxy-Cχ-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, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated Ci-β alkyl, optionally halogenated C2-6 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-β alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Ci-β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Ci-β alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, C1-6 alkoxy-Cι-6 alkoxy, mono-C7_i6 aralkylamino and di-C7_j.6 aralkylamino, (26) acyloxy, (27) phthalimido which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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 Cι_6 alkoxy, optionally halogenated Cι-6 alkylthio, hydroxy, amino, mono-Cι-6 alkylamino, di-Cχ_β alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cι-6 alkylsulfamoyl, di-Cι-6 alkylsulfamoyl, Cβ-io aryl, Cβ-io aryloxy, acyloxy, Cι_6 alkoxy-Cι_6 alkoxy, mono-C7_i6 aralkylamino and di-C7-ι6 aralkylamino, (28) Cχ_6 alkoxy-Cχ-6 alkoxy, (29) mono-C7_i6 aralkylamino and (30) di-C7-i6 aralkylamino, and (iv-2) a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-3 alkylenedioxy, nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 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 Cχ-6 alkoxy, optionally halogenated Cχ_6 alkylthio, hydroxy, amino, mono-Cχ_6 alkylamino, di-Cχ_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cχ-6 alkylsulfamoyl, di-Cχ-6 alkylsulfamoyl, Cβ-xo aryl, Cε-io aryloxy, acyloxy, Cχ_6 alkoxy-Cχ-6 alkoxy, mono-C7-χ6 aralkylamino and di-C7_χ6 aralkylamino or (v) a 3- to 7-membered saturated cyclic amino.
10. A compound of Claim 8, wherein W is a divalent group of the formula: -NR6-CO- or -CH2-NR6-CO- wherein Rβ is as defined in Claim 8.
11. A compound of Claim 8, wherein r is 0.
12. A compound of Claim 8, wherein ring A is a benzene ring which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, optionally halogenated Cχ_6 alkyl and optionally halogenated Cχ_6 alkoxy.
13. A compound of Claim 8, wherein 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 Cχ-6 alkyl, optionally halogenated Cχ-6 alkoxy, optionally halogenated Cχ_6 alkylthio, hydroxy, amino, mono-Cχ-6 alkylamino, di-Cχ-β alkylamino, Cχ_6 alkyl-carbonyl, C _6 alkoxy-carbonyl and carboxy.
14. A compound of Claim 8, wherein Y is a bond or a methylene.
15. A compound of Claim 8, wherein Ari 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, optionally halogeneated Cχ_6 alkyl and optionally halogenated Cχ_6 alkoxy.
16. A compound of Claim 8, wherein 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, Cχ-3 alkylenedioxy, nitro, cyano, optionally halogenated Cχ-6 alkyl, optionally halogenated C2-6 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 Cχ-6 alkoxy, optionally halogenated Cχ-6 alkylthio, hydroxy, amino, mono-Cχ-6 alkylamino, di-Cχ_6 alkylamino, 3- to 7-membered saturated cyclic amino, formyl, acyl, acylamino, carboxy, carbamoyl, sulfo, sulfamoyl, mono-Cχ-6 alkylsulfamoyl, di-Cχ-6 alkylsulfamoyl, Cβ-xo aryl, Cβ-xo aryloxy, acyloxy, C _6 alkoxy-Cχ-6 alkoxy, mono-C7_χ6 aralkylamino and di-C7_χβ aralkylamino.
17. A compound of Claim 8, wherein m is 1 or 2.
18. A compound of Claim 8, wherein ring A is a benzene ring;
W is a divalent group of the formula: -NR&-C0- or
-CH2-NR6-CO-, wherein R6 is a mono- or di-Cχ_β alkylamino or a C _6 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 Cχ_6 alkyl, optionally halogenated Cχ-e alkoxy, optionally halogenated Cχ-6 alkylthio, hydroxy, amino, mono-Cχ_6 alkylamino, di-Cχ-6 alkylamino, Cχ_6 alkyl-carbonyl, Cχ_6 alkoxy-carbonyl and carboxy,
Y is a bond,
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 Cχ-6 alkyl, optionally halogenated Cχ-6 alkoxy, amino, mono-Cχ-6 alkylamino, di-
Cχ_6 alkylamino, Cχ-β alkyl-carbonyl, Cχ-6 alkoxy-carbonyl, mono-Cχ-6 alkyl-carbamoyl, di-Cχ_e alkyl-carbamoyl, Cχ-6 alkylsulfonyl, Cχ_6 alkyl-carbonylamino, Cχ_6 alkoxy- carbonylamino, Cχ_6 alkylsulfonylamino and mono-Cχ_6 alkylsulfamoyl, and m is 1 or 2.
19. A compound of Claim 8, wherein ring A is an optionally halogenated benzene ring; ring B' is a ring of the formula:
Figure imgf000176_0001
wherein R6' is (i) a hydrogen atom,
(ii) a Cχ_6 alkyl, C2-6 alkenyl or C7-X6 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-Cχ-e alkylamino, 3- to
7-membered saturated cyclic amino, Cχ-β alkoxy-carbonyl,
Ci-e alkyl-carbonyloxy, phthalimido and Cχ-e alkoxy-Cχ_6 alkoxy,
(iii) a Cχ_6 alkyl-carbonyl, or
(iv) a mono- or di-Cχ_6 alkylamino, a mono- or di-C7-χβ aralkylamino or a 3- to 7-membered saturated cyclic amino, ring C is a ring of the formula:
(O)t
-N X'-
wherein X' is (i) a nitrogen atom or (ii) a group of the formula: >C(R5')- wherein R5' is a hydrogen atom, cyano, hydroxy or Cχ-6 alkyl-carbonyl, and t is 0 or 1, Y is a bond, Ari is a phenyl,
Ar2 is a phenyl or pyridyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, optionally halogenated Cχ_6 alkyl, C _6 alkoxy, amino, mono- or di-Cχ-6 alkylamino, mono-Cχ-6 alkyl-carbonylamino, Cχ-6 alkyl-carbonyl, Cχ_6 alkoxycarbonyl, and m is 2.
20. A compound of Claim 8, which is 1 , 3-dihydro-l-ethyl-3-phenyl-3-( 2-( 4- phenylpiperidino)ethyl )-2H-indol-2-one, 1 , 3-dihydro-l-ethyl-3- ( 2- ( 4-hydroxy-4- phenylpiperidino) ethyl ) -3-phenyl-2H-indol-2-one, 2-methyl-3-oxo-4-phenyl-4-( 2-( 4-phenylpiperidino)ethyl )- 1,2,3 , 4-tetrahydroisoquinoline, 1-ethyl-l , 3-dihydro-3-phenyl-3- ( 2-( 4- ( 3- trifluoromethylphenyl)piperidino)ethyl )-2H-indol-2-one, 3- ( 2- ( 4-( 3-chlorophenyl )piperazin-1-yl )ethyl )-1-ethyl-l , 3- dihydro-3-phenyl-2H-indol-2-one,
3- ( 2-( 4-cyano-4-phenylpiperidino) ethyl ) -1-ethyl-l , 3- dihydro-3-phenyl-2H-indol-2-one,
2-ethyl-4- ( 2- ( 4- (o-methoxyphenyl )piperazin-l-yl )ethyl )-3- oxo-4-phenyl-l ,2,3, 4-tetrahydroisoquinoline, 1 , 3-dihydro-l- (dimethylamino)-3-( 2-( 4- (o- methoxyphenyl )piperazin-l-yl )ethyl )-3-phenyl-2H-indol-2- one,
1, 3-dihydro-l-( 2-(morpholino)ethyl)-3-phenyl-3-( 2-( 4- phenylpiperidino) ethyl )-2H-indol-2-one, 1-ethyl-l , 3-dihydro-3-phenyl-3-( 2-{ 4-( 3- trifluoromethylphenyl )piperazin-1-yl ) ethyl )-2H-indol-2-one , or a salt thereof.
21. A process for producing the compound of Claim 8, which comprises (i) reacting a compound of the formula:
Figure imgf000178_0001
wherein L represents a leaving group and the other symbols are as defined in Claim 8, or a salt thereof with a compound of the formula;
Figure imgf000178_0002
wherein all symbols are as defined in Claim 8, or a salt thereof or
(ii) subjecting a compound of the formula:
Figure imgf000178_0003
wherein all symbols are as defined in Claim 8, or a salt thereof to reduction.
22. An optical isomer of the formula:
Figure imgf000178_0004
wherein 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: -CH2-CH2-,
-CH=CH-, -CO-O-, -CO-NR6-, -NR6-CO-, -N=CH- , -CH2-S(0)p-,
-N=N-, -NR6-S02-, -SO2-NR6-, -NR6-NR6a-, -CH2-0- , -CH2-NR6-,
-NR6-CH2-, -CH=N-, -CH2-NR6-C0- or -CO-NR6-C0- wherein R6 and R6a 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;
Ar1 represents an optionally substituted aromatic group; and m represents an integer of 1 to 3, and or a salt thereof.
23. A process for producing the optical isomer of Claim 22 or a salt thereof, which comprises forming a salt of a racemate of the formula:
Figure imgf000179_0001
wherein all symbols are as defined in Claim 22, with an optical active amine, and then subjecting the resultant salt to fractional recrystallization.
24. A pharmaceutical composition which comprises a compound of Claim 8.
25. A composition of Claim 24, which is for controlling micturition.
26. A composition of Claim 24, which is for the prophylaxis or treatment of the lower urinary tract dysfunctions.
27. A composition of Claim 26, wherein the lower urinary tract dysfunctions is urinary incontinence or pollakiuria.
28. A method for controlling micturition in a mammal which comprises administering to such mammal an effective amount of a compound of the formula:
Figure imgf000180_0001
wherein ring A represents an optionally substituted benzene ring; ring B represents an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring; ring C represents an optionally substituted nitrogen- containing heterocyclic ring; X represents carbon atom or nitrogen atom; Y represents a bond or a lower alkylene which may be substituted by an oxo;
Ar and Ar2 each represents an optionally substituted aromatic group; and m represents an integer of 1 to 3, or a pharmaceutically acceptable salt thereof wi^th a pharmaceutically acceptable excipient, carrier or diluent.
29. Use of a compound of the formula:
Figure imgf000181_0001
wherein ring A represents an optionally substituted benzene ring; ring B represents an optionally substituted 4- to 7- membered carbocyclic or heterocyclic ring; ring C represents an optionally substituted nitrogen- containing heterocyclic ring; X represents carbon atom or nitrogen atom; Y represents a bond or a lower alkylene which may be substituted by an oxo;
Ari and Ar2 each represents an optionally substituted aromatic group; and m represents an integer of 1 to 3, or a salt thereof for the manufacture of a pharmaceutical composition for controlling micturition.
PCT/JP1997/002447 1996-07-16 1997-07-15 Bicyclic compounds for controlling micturition WO1998002432A1 (en)

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US6943189B2 (en) 1994-09-13 2005-09-13 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG CO-A reductase inhibitors
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
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
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
US6387926B1 (en) 1997-07-02 2002-05-14 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
US6602883B1 (en) 1997-07-02 2003-08-05 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
US6969724B2 (en) 1998-11-11 2005-11-29 Smithkline Beecham-Spa Compounds
JP2002529451A (en) * 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-substituted aza rings, methods for their preparation and their use as ORL-1 receptor ligands
WO2000027815A3 (en) * 1998-11-11 2000-10-26 Smithkline Beecham Spa N-substituted azacycles, their preparation and their use as orl-1 receptor ligands
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
US6890958B2 (en) 1998-12-23 2005-05-10 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
WO2000047568A3 (en) * 1999-02-12 2000-12-14 Searle & Co 1,2-benzothiazepines for the treatment of hyperlipidemic diseases
US7279468B2 (en) 2000-06-14 2007-10-09 Abbott Gmbh & Co. Kg Integrin ligands
US6852753B2 (en) 2002-01-17 2005-02-08 Pharmacia Corporation Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
WO2006136606A3 (en) * 2005-06-24 2007-04-26 Hoffmann La Roche Oxindole derivatives
US7576082B2 (en) 2005-06-24 2009-08-18 Hoffman-La Roche Inc. Oxindole derivatives
US7956050B2 (en) 2005-07-15 2011-06-07 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8791101B2 (en) 2005-07-15 2014-07-29 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9403776B2 (en) 2005-07-15 2016-08-02 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8288431B2 (en) 2010-02-17 2012-10-16 Hoffmann-La Roche Inc. Substituted spiroindolinones
US8217044B2 (en) 2010-04-28 2012-07-10 Hoffmann-La Roche Inc. Spiroindolinone pyrrolidines
CN105705488A (en) * 2013-06-05 2016-06-22 卡昂大学 Acetylcholinesterase inhibitor compounds and 5HT4 serotonergic receptor agonisis, with promnesia effect, methods for the preparation thereof and pharmaceutical compositions containing same
CN108440378A (en) * 2018-03-27 2018-08-24 宁波大学 A kind of preparation method for the 3- amino -2- indolone derivatives that hydrogen peroxide iodo- at room temperature promotes
CN108440378B (en) * 2018-03-27 2021-03-12 宁波大学 Preparation method of iodine-hydrogen peroxide promoted 3-amino-2-indolone derivative at room temperature

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