Agents and crystals for improving excretory potency of urinary bladder

Abstract

Agents for improving potentcy of the urinary bladder which comprise an amine compound of non-carbamate-type having an acetylcholinesterase-inhibiting action. Particularly, crystals of a tricyclic, condensed, heterocyclic derivative are provided, which possess an excellent action to inhibit acetylcholinesterase and an action to improve the excretory potency of the urinary bladder. As an example, crystals of of 8-[3-[1-[(3-fluorophenyl)-methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one or a salt thereof and pharmaceutical compositions containing them are disclosed.

1 - 34 . (canceled)  
   
   
       35 . A pharmaceutical composition for improving excretory potency of the urinary bladder, said pharmaceutical composition comprising a combination of an α-blocker and a non-carbamate amine compound having an acetylcholinesterase-inhibiting action, 
 wherein the α-blocker is selected from the group consisting of prazosin, tamsulosin and a compound represented by the formula:                          the non-carbamate amine compound has the formula:                          wherein    Ar is a group of the formula:                          wherein    ring A is an optionally substituted benzene ring;    rings C′ and D′ are each a 5- to 9-membered nitrogen-containing heterocycle which may further be substituted by oxo;    n is an integer from I to 10;    R is hydrogen or an optionally substituted hydrocarbon group;    Y is an optionally substituted amino or an optionally substituted nitrogen-containing saturated heterocyclic group;    or a salt thereof.    
   
   
       36 . The pharmaceutical composition according to  claim 35 , wherein said ring A is a benzene ring which may be substituted by 1 or 2 substituents selected from (i) optionally halogenated lower alkyl, (ii) halogen, (iii) lower alkylenedioxy, (iv) nitro, (v) cyano, (vi) hydroxyl, (vii) optionally halogenated lower alkoxy, (viii) cycloalkyl, (ix) optionally halogenated lower alkylthio, (x) amino, (xi)mono-lower alkylamino, (xii) di-lower alkylamino, (xiii) 5- to 7-membered cyclic amino, (xiv) lower alkyl-carbonylamino, (xv) lower alkyl-sulfonylamino, (xvi) lower alkoxy-carbonyl, (xvii) carboxy, (xviii) lower alkyl-carbonyl, (xix) cycloalkyl-carbonyt, (xx) carbamoyl or thiocarbamoyl, (xxi) mono-lower alkyl-carbamoyl, (xxii) di-lower alkyl-carbamoyl, (xxiii) lower alkylsufonyl, (xxiv) cycloalkylsulfonyl, (xxv) phenyl, (xxvi) naphthyl, (xxvii) mono-phenyl-lower alkyl, (xxviii) di-phenyl-lower alkyl, (xxix) mono-phenyl-lower alkyl-carbonyloxy, (xxx) di-phenyl-lower alkyl-carbonyloxy, (xxxi) phenoxy, (xxxii) mono-phenyl-lower alkyl-carbonyl, (xxxiii) di-phenyl-lower alkyl-carbonyl, (xxxiv) benzoyl, (xxxv)phenoxycarbonyl, (xxxvi) phenyl-lower alkyl-carbamoyl, (xxxvii) phenylcarbamoyl, (xxxviii) phenyl-lower alkyl-carbonylamino, (xxxix) phenyl-lower alkylamino, (xxxx) phenyl-lower alkylsulfonyl, (xxxxi) phenylsulfonyl, (xxxxii) phenyl-lower alkylsulfinyl, (xxxxiii) phenyl-lower alkylsulfonylamino, and (xxxxiv) phenylsulfonylamino; 
 wherein the phenyl, naphthyl, mono-phenyl-lower alkyl, di-phenyl-lower alkyl, mono-phenyl-lower alkyl-carbonyloxy, di-phenyl-lower alkyl-carbonyloxy, phenoxy, mono-phenyl-lower alkyl-carbonyl, di-phenyl-lower alkyl-carbonyl, benzoyl, phenoxycarbonyl, phenyl-lower alkyl-carbamoyl, phenylcarbamoyl, pheny lower alkyl-carbonylamino, phenyl-lower alkylamino, phenyl-lower alkylsulfonyl, phenylsulfonyl, phenylower alkylsulfinyl, phenyl-lower alkylsulfonylamino and phenylsulfonylamino in (xxv) to (xxxxiv) may further be substituted by 1 to 4 substituents selected from lower alkyl, lower alkoxy, halogen, hydroxy, benzyloxy, amino, mono-lower alkylamino, di-lower alkylamino, nitro, lower alkyl-carbonyl and benzoyl; and    wherein rings C′ and D′ are each a 5- to 9-membered nitrogen containing heterocycle which may further be substituted by oxo and which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom.    
   
   
       37 . The pharmaceutical composition according to  claim 35 , wherein n is 2.  
   
   
       38 . The pharmaceutical composition according to  claim 35 , wherein R is: 
 (I) hydrogen or    (II) alkyl, alkenyl, alkynyl, cycloalkyl,bridged cyclic lower saturated hydrocarbon group, aryl, aralkyl, aryl-alkenyl, aryl-C 2-12  alkynyl, cycloalkyalkyl or aryl-aryl-C 1-10  alkyl which may be substituted by 1 to 5 substituents selected from (i) halogen, (ii) nitro, (iii) cyano, (iv) oxo, (v) hydroxy, (vi) optionally halogenated lower alkyl, (vii) optionally halogenated lower alkoxy, (viii) optionally halogenated lower alkylthio, (ix) amino, (x) mono-lower alkylamino, (xi) di-lower alkylamino, (xii) 5- to 7-membered cyclic amino and which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (xiii) lower alkyl-carbonylamino, (xiv) lower alkyl-sulfonylamino, (xv) lower alkoxy-carbonyl, (xvi) carboxy, (xvii) lower alkyl-carbonyl, (xviii) carbamoyl or thiocarbamoyl, (xix) mono-lower alkyl-carbamoyl, (xx) di-lower alkyl-carbamoyl, (xxi) lower alkylsulfonyl, (xxii) lower alkoxy-carbonyl-lower alkyl, (xxiii) carboxy-lower alkyl, (xxiv) 5- to 14-membered heterocyclic group which contains 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and which may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl, (xxv) C 6-14  aryl, (xxvi) C 7-16  aralkyl, (xxvii) ureido, 3-methylureido, 3-ethylureido, 3-phenylureid 3-(4-fluorophenyl)ureido, 3-(2-methylphenyl)ureido, 3-(4-methoxyphenyl)ureido, 3-(2,4-difluorophenyl)ureido, 3-[3,5-bis(trifluoromethyl)phenyl]ureido, 3-benzylureido, 3-(1-naphthyl)ureido, or 3-(2-biphenylyl)ureido, (xxviii) thioureido, 3-methylthioureido, 3-ethylthioureido, 3-phenylthioureido, 3-(4-fluorophenyl)thioureido, 3-(4-methylphenyl)thioureido, 3-(4-methoxyphenyl)thioureido, 3-(2,4-dichlorophenyl)thioureido, 3-benzylthioureido, or 3-(1-naphthyl)thioureido, (xxix) amidino, N 1 -methylamidino, N 1 -ethylamidino, N 1 -phenylamidino, N 1 ,N 1 -dimethylamidino, N 1 ,N 2 -dimethylamidino, N 1 -methyl-N 1 -ethylamidino, N 1 ,N 1 -diethylamidino, N 1 -methyl-N 1 -phenylamidino, or N 1 ,N 1 -di(4-nitrophenyl)amidino, (xxx) guanidino, 3-methyl-guanidino, 3,3-dimethylguanidino, or 3,3-diethylguanidino, (xxxi) pyrrolidinocarbonyl, piperidinocarbonyl, (4-methyl-piperidino)carbonyl, (4-phenylpiperidino)carbonyl, (4-benzylpiperidino)carbonyl, (4-benzoylpiperidino)carbonyl, [4-(4-fluorobenzoyl)piperidino]carbonyl, (4-methyl-piperazino)carbonyl, (4-phenylpiperazino)carbonyl, [4-(4-nitrophenyl)piperazino]carbonyl, (4-benzylpiperazino)-carbonyl, morpholinocarbonyl, or thiomorpholinocarbonyl, (xxxii) aminothiocarbonyl, methylaminothiocarbonyl, or dimethylaminothiocarbonyl, (xxxiii) aminosulfonyl, methyl-aminosulfonyl, or dimethylaminosulfonyl, (xxxiv) phenyl-sulfonylamino, (4-methylphenyl)sulfonylamino, (4-chloro-phenyl)sulfonylamino, (2,5-dichlorophenyl)sulfonylamino, (4-methoxyphenyl)sulfonylamino, (4-acetylaminophenylksulfonylamino, or (4-nitrophenyl)phenylsulfonylamino, (xxxv) sulfo, (xxxvi) sulfino, (xxxvii) sulfeno, (xxxviii) lower alkylsulfo, (xxxix) lower alkylsulfino, (xxxx) lower alkylsulfeno, (xxxxi) phosphono, and (xxxxii) di-lower alkoxyphosphoryl.    
   
   
       39 . The pharmaceutical composition according to  claim 35 , wherein R is hydrogen.  
   
   
       40 . The pharmaceutical composition according to  claim 35 , wherein Y is: 
 (A) a group of the formula:                          wherein R 4  and R 5  each is:    (I) hydrogen,    (II) alkyl, alkenyl, alkynyl, cycloalkyl, bridged cyclic lower saturated hydrocarbon group, aryl, aralkyl, aryl-alkenyl, aryl-C 2-12  alkynyl, cycloalkyalkyl or aryl-aryl-C 1-10  alkyl which may be substituted by 1 to 5 substituents selected from (i) halogen, (ii) nitro, (iii) cyano, (iv) oxo, (v) hydroxy, (vi) optionally halogenated lower alkyl, (vii) optionally halogenated lower alkoxy, (viii) optionally halogenated lower alkylthio, (ix) amino, (x) mono-lower alkylamino, (xi) di-lower alkylamino, (xii) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (xiii) lower alkyl-carbonylamino, (xiv) lower alkyl-sulfonylamino, (xv) lower alkoxy-carbonyl, (xvi) carboxy, (xvii) lower alkyl-carbonyl, (xviii) carbamoyl, thiocarbamoyl, (xix) mono-lower alkyl-carbamoyl, (xx) di-lower alkyl-carbamoyl, (xxi) lower alkylsulfonyl, (xxii) lower alkoxy-carbonyl-lower alkyl, (xxiii) carboxy-lower alkyl, (xxiv) 5- to 14-membered heterocyclic group which contains 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and which may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl, (xxv) C 6-14  aryl, (xxvi) C 7-16  aralkyl, (xxvii) ureido, 3-methylureido, 3-ethylureido, 3-phenylureido, 3-(4-fluorophenyl)ureido, 3-(2-methylphenyl)ureido, 3-(4-methoxyphenyl)ureido, 3-(2,4-difluorophenyl)ureido, 3-[3,5-bis(trifluoromethyl)phenyl]ureido, 3-benzylureido, 3-(1-naphthyl)ureido, or 3-(2-biphenylyl)ureido, (xxviii) thioureido, 3-methylthioureido, 3-ethylthioureido, 3-phenylthioureido, 3-(4-fluorophenyl)thioureido, 3-(4-methylphenyl)thioureido, 3-(4-methoxyphenyl)thioureido, 3-(2,4-dichlorophenyl)thioureido, 3-benzylthioureido, or 3-(1-naphthyl)thioureido, (xxix) amidino, N 1 -methylamidino, N 1 -ethylamidino, N 1 -phenylamidino, N 1 ,N 1 -dimethylamidino, N 1 ,N 2 -dimethylamidino, N 1 -methyl-N 1 -ethylamidino, N 1 ,N 1 -diethylamidino, N 1 -methyl-N 1 -phenylamidino, or N 1 ,N 1 -di(4-nitrophenyl)amidino, (xxx) guanidino, 3-methyl-guanidino, 3,3-dimethylguanidino, or 3,3-diethylguanidino, (xxxi) pyrrolidinocarbonyl, piperidinocarbonyl, (4-methyl-piperidino)carbonyl, (4-phenylpiperidino)carbonyl, (4-benzylpiperidino)carbonyl, (4-benzoylpiperidino)carbonyl, [4-(4-fluorobenzoyl)piperidino]carbonyl, (4-methylpiperazino)carbonyl, (4-phenylpiperazino)carbonyl, [4-(4-nitrophenyl)piperazino]carbonyl, (4-benzylpiperazino)carbonyl, morpholinocarbonyl, or thiomorpholinocarbonyl, (xxxii) aminothiocarbonyl, methylaminothiocarbonyl, or dimethylaminothiocarbonyl, (xxxiii) aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl, (xxxiv) phenylsulfonylamino, (4-methylphenyl)sulfonylamino, (4-chlorophenyl)sulfonylamino, (2,5-dichlorophenyl)sulfonylamino, (4-methoxyphenyl)sulfonylamino, (4-acetylaminophenyl)sulfonylamino, or (4-nitrophenyl)phenylsulfonylamino, (xxxv) sulfo, (xxxvi) sulfino, (xxxvii) sulfeno, (xxxviii) lower alkylsulfo, (xxxix) lower alkylsulfino, (xxxx) lower alkylsulfeno, (xxxxi) phosphono, and (xxxxii) di-lower alkoxyphosphoryl; (III) acyl of the formula: —(C═O)—R 2 , —(C═O)—NR 2 R 3 , —SO 2 —R 2 , —SO—R 2 , —(C═S)—OR 2  or —(C═S)NR 2 R 3  wherein R 2  and R 3  each is [1] hydrogen, [2] alkyl, alkenyl, alkynyl, cydoalkyl, bridged cyclic lower saturated hydrocarbon group, aryl, aralkyl, aryalkenyl, aryl-C 2-12  alkynyl, cycloalkyl-alkyl or aryl-aryl-C 1-10  alkyl which may be substituted by 1 to 5 substituents selected from (i) halogen, (ii) nitro, (iii) cyano, (iv) oxo, (v) hydroxy, (vi) optionally halogenated lower alkyl, (vii) optionally halogenated lower alkoxy, (viii) optionally halogenated lower alkylthio, (ix) amino, (x) mono-lower alkylamino, (xi) di-lower alkylamino, (xii) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (xiii) lower alkyl-carbonylamino, (xiv) lower alkyl-sulfonylamino, (xv) lower alkoxy-carbonyl, (xvi) carboxy, (xvii) lower alkyl-carbonyl, (xviii) carbamoyl or thiocarbamoyl, (xix) mono-lower alkyl-carbamoyl, (xx) di-lower alkyl-carbamoyl, (xxi) lower alkylsulfonyl, (xxii) lower alkoxy-carbonyl-lower alkyl, (xxiii) carboxy-lower alkyl, (xxiv) 5- to 14-membered heterocyclic group which contains 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and which may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl, (xxv) C 6-14  aryl, (xxvi) C 7-16  aralkyl, (xxvii) ureido, 3-methylureido, 3-ethylureido, 3-phenylureido, 3-(4-fluorophenyl)ureido, 3-(2-methylphenyl)ureido, 3-(4-methoxyphenyl)ureido, 3-(2,4-difluorophenyl)ureido, 3-[3,5-bis(trifluoromethyl)phenyl]ureido, 3-benzylureido, 3-(1-naphthyl)ureido, or 3-(2-biphenylyl)ureido, (xxviii) thioureido, 3-methylthioureido, 3-ethylthioureido, 3-phenylthioureido, 3-(4-fluorophenyl)thioureido, 3-(4-methylphenyl)thioureido, 3-(4-methoxyphenyl)thioureido, 3-(2,4-dichlorophenyl)thioureido, 3-benzylthioureido, or 3-(1-naphthyl)thioureido, (xxix) amidino, N 1 -methylamidino, N 1 -ethylamidino, N 1 -phenylamidino, N 1 ,N 1 -dimethylamidino, N 1 ,N 2 -dimethylamidino, N 1 -methyl-N 1 -ethylamidino, N 1 ,N 1 -diethylamidino, N 1 -methyl-N 1 -phenylamidino, or N 1 ,N 1 -di(4-nitrophenyl)amidino, (xxx) guanidino, 3-methylguanidino, 3,3-dimethylguanidino, or 3,3-diethylguanidino, (xxxi) pyrrolidinocarbonyl, piperidinocarbonyl, (4-methyl-piperidino)carbonyl, (4-phenylpiperidino)carbonyl, (4-benzylpiperidino)carbonyl, (4-benzoylpiperidino)carbonyl, [4-(4-fluorobenzoyl)piperidino]carbonyl, (4-methylpiperazino)carbonyl, (4-phenylpiperazino)carbonyl, [4-(4-nitrophenyl)piperazino]carbonyl, (4-benzylpiperazino)carbonyl, morpholinocarbonyl, or thiomorpholinocarbonyl, (xxxii) aminothiocarbonyl, methylaminothiocarbonyl, or dimethylaminothiocarbonyl, (xxxiii) aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl, (xxxiv) phenylsulfonylamino, (4-methylphenyl)sulfonylamino, (4chlorophenyl)sulfonylamino, (2,5-dichlorophenyl)sulfonylamino, (4-methoxyphenyl)sulfonylamino, (4-acetylaminophenyl)sulfonylamino, or (4-nitrophenyl)phenylsulfonylamino, (xxxv) sulfo, (xxxvi) sulfino, (xxxvii) sulfeno, (xxxviii) lower alkylsulfo, (xxxix) lower alkylsulfino, (xxxx) lower alkylsulfeno, (xxxxi) phosphono, and (xxxxii) di-lower alkoxyphosphoryl, [3] 5- to 14-membered heterocyclic group which contains 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and which may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl, [4] R 2  and R 3  are taken together with the adjacent nitrogen atom to form a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, wherein the heterocyclic group may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl; or    (B) a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom,    wherein said heterocyclic group may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl,    wherein the nitrogen atom in said nitrogen-containing saturated heterocyclic group may be substituted by (I) alkyl, alkenyl, alkynyl, cyclodkyl, bridged cyclic lower saturated hydrocarbon group, aryl, aralkyl, arylalkenyl, aryl-C 2-12  alkynyl, cycloalkyalkyl or aryl-aryl-C 1-10  alkyl which may be substituted by 1 to 5 substituents selected from (i) halogen, (ii) nitro, (iii) cyano, (iv) oxo, (v) hydroxy, (vi) optionally halogenated lower alkyl, (vii) optionally halogenated lower alkoxy, (viii) optionally halogenated lower alkylthio, (ix) amino, (x) mono-lower alkylamino, (xi) di-lower alkylamino, (xii) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (xiii) lower alkyl-carbonylamino, (xiv) lower alkylsulfonylamino, (xv) lower alkoxy-carbonyl, (xvi) carboxy, (xvii) lower alkyl-carbonyl, (xviii) carbamoyl or thiocarbamoyl, (xix) mono-lower alkyl-carbamoyl, (xx) di-lower alkyl-carbamoyl, (xxi) lower alkylsulfonyl, (xxii) lower alkoxy-carbonyl-lower alkyl, (xxiii) carboxy-lower alkyl, (xxiv) 5- to 14-membered heterocyclic group which contains 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and which may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl, (xxv) C 6-14  aryl, (xxvi) C 7-16  aralkyl, (xxvii) ureido, 3-methylureido, 3-ethylureido, 3-phenylureid 3-(4-fluorophenyl)ureido, 3-(2-methylphenyl)ureido, 3-(4-methoxyphenyl)ureido, 3-(2,4-difluorophenyl)ureido, 3-[3,5-bis(trifluoromethyl)phenyl]ureido, 3-benzylureido, 3-(1-naphthyl)ureido, or 3-(2-biphenylyl)ureido, (xxviii) thioureido, 3-methylthioureido, 3-ethylthioureido, 3-phenylthioureido, 3-(4-fluorophenyl)thioureido, 3-(4-methylphenyl)thioureido, 3-(4-methoxyphenyl)thioureido, 3-(2,4-dichlorophenyl)thioureido, 3-benzylthioureido, or 3-(1-naphthyl)thioureido, (xxix) amidino, N 1 -methylamidino, N 1 -ethylamidino, N 1 -phenylamidino, N 1 ,N 1 -dimethylamidino, N 1 ,N 2 -dimethylamidino, N 1 -methyl-N 1 -ethylamidino, N 1 ,N 1 -diethylamidino, N 1 -methyl-N 1 -phenylamidino, or N 1 ,N 1 -di(4-nitrophenyl)amidino, (xxx) guanidino, 3-methylguanidino, 3,3-dimethylguanidino, or 3,3-diethylguanidino, (xxxi) pyrrolidinocarbonyl, piperidinocarbonyl, (4-methyl-piperidino)carbonyl, (4-phenylpiperidino)carbonyl, (4-benzylpiperidino)carbonyl, (4-benzoylpiperidino)carbonyl, [4-(4-fluorobenzoyl)piperidino]carbonyl, (4-methylpiperazino)carbonyl, (4-phenylpiperazino)carbonyl, [4-(4-nitrophenyl)piperazino]carbonyl, (4-benzylpiperazino)carbonyl, morpholinocarbonyl, or thiomorpholinocarbonyl, (xxxii) aminothiocarbonyl, methylaminothiocarbonyl, or dimethylaminothiocarbonyl, (xxxiii) aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl, (xxxiv) phenylsulfonylamino, (4-methylphenyl)sulfonylamino, (4-chlorophenyl)sulfonylamino, (2,5-dichlorophenyl)sulfonylamino, (4-methoxyphenyl)sulfonylamino, (4-acetylaminophenylsulfonylamino, or (4-nitrophenyl)phenylsulfonylamino, (xxxv) sulfo, (xxxvi) sulfino, (xxxvii) sulfeno, (xxxviii) lower alkylsulfo, (xxxix) lower alkylsulfino, (xxxx) lower alkylsulfeno, (xxxxi) phosphono, and (xxxxii) di-lower alkoxyphosphoryl,    (II) acyl of the formula: —(C═O)—R 2 , —(C═O)—OR 2 , —(C═O)—NR 2 R 3 , —SO 2 —R 2 , —SO—R 2 , —(C═S)—OR 2  or —(C═S)NR 2 R 3  wherein R 2  and R 3  each is [1] hydrogen, or [2] alkyl, alkenyl, alkynyl, cycloalkyl, bridged cyclic lower saturated hydrocarbon group, aryl, aralkyl, aryl-alkenyl, aryl-C 2-12  alkynyl, cycloalkyl-alkyl or aryl-aryl-C 1-10  alkyl which may be substituted by 1 to 5 substituents selected from (i) halogen, (ii) nitro, (iii) cyano, (iv) oxo, (v) hydroxy, (vi) optionally halogenated lower alkyl, (vii) optionally halogenated lower alkoxy, (viii) optionally halogenated lower alkylthio, (ix) amino, (x) mono-lower alkylamino, (xi) di-lower alkylamino, (xii) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (xiii) lower alkyl-carbonylamino, (xiv) lower alkylsulfonylamino, (xv) lower alkoxy-carbonyl, (xvi) carboxy, (xvii) lower alkyl-carbonyl, (xviii) carbamoyl or thiocarbamoyl, (xix) mono-lower alkyl-carbamoyl, (xx) di-lower alkyl-carbamoyl, (xxi) lower alkylsulfonyl, (xxii) lower alkoxy-carbonyl-lower alkyl, (xxiii) carboxy-lower alkyl, (xxiv) 5- to 14-membered heterocyclic group which contains 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and which may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkylcarbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl, (xxv) C 6 -1 4  aryl, (xxvi) C 7-16  aralkyl, (xxvii) ureido, 3-methylureido, 3-ethylureido, 3-phenylureido, 3-(4-fluorophenyl)ureido, 3-(2-methylphenyl)ureido, 3-(4-methoxyphenyl)ureido, 3-(2,4-difluorophenyl)ureido, 3-[3,5-bis(trifluoromethyl)phenyl]ureido, 3-benzylureido, 3-(1-naphthyl)ureido, or 3-(2-biphenylyl)ureido, (xxviii) thioureido, 3-methylthioureido, 3-ethylthioureido, 3-phenylthioureido, 3-(4-fluorophenyl)thioureido, 3-(4-methylphenyl)thioureido, 3-(4-methoxyphenyl)thioureido, 3-(2,4-dichlorophenyl)thioureido, 3-benzylthioureido, or 3-(1-naphthyl)thioureido, (xxix) amidino, N 1 -methylamidino, N 1 -ethylamidino, N 1 -phenylamidino, N 1 ,N 1 -dimethylamidino, N 1 ,N 2 -dimethylamidino, N 1 -methyl-N 1 -ethylamidino, N 1 ,N 1 -diethylamidino, N 1 -methyl-N 1 -phenylamidino, or N′ ,N 1 -di(4-nitrophenyl)amidino, (xxx) guanidino, 3-methylguanidino, 3,3-dimethylguanidino, or 3,3-diethylguanidino, (xxxi) pyrrolidinocarbonyl, piperidinocarbonyl, (4-methylpiperidino)carbonyl, (4-phenylpiperidino)carbonyl, (4-benzylpiperidino)carbonyl, (4-benzoylpiperidino)carbonyl, [4-(4-fluorobenzoyl)piperidino]carbonyl, (4-methylpiperazino)carbonyl, (4-phenylpiperazino)carbonyl, [4-(4-nitrophenyl)piperazino]carbonyl, (4-benzylpiperazino)carbonyl, morpholinocarbonyl, or thiomorpholinocarbonyl, (xxxii) aminothiocarbonyl, methylaminothiocarbonyl, or dimethylaminothiocarbonyl, (xxxiii) aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl, (xxxiv) phenylsulfonylamino, (4-methylphenyl)sulfonylamino, (4-chlorophenyl)sulfonylamino, (2,5-dichlorophenyl)sulfonylamino, (4-methoxyphenyl)sulfonylamino, (4-acetylaminophenyl)sulfonylamino, or (4-nitrophenyl)phenylsulfonylamino, (xxxv) sulfo, (xxxvi) sulfino, (xxxvii) sulfeno, (xxxviii) lower alkylsulfo, (xxxix) lower alkylsulfino, (xxxx) lower alkylsulfeno, (xxxxi) phosphono, and (xxxxii) di-lower alkoxyphosphoryl, or (III) 5- to 14-membered heterocyclic group which contains 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur and which may be substituted by 1 to 5 substituents selected from (1) halogen, (2) nitro, (3) cyano, (4) oxo, (5) hydroxy, (6) lower alkyl, (7) lower alkoxy, (8) lower alkylthio, (9) amino, (10) mono-lower alkylamino, (11) di-lower alkylamino, (12) 5- to 7-membered cyclic amino which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms and one nitrogen atom, (13) lower alkyl-carbonylamino, (14) lower alkylsulfonylamino, (15) lower alkoxy-carbonyl, (16) carboxy, (17) lower alkyl-carbonyl, (18) carbamoyl or thiocarbamoyl, (19) mono-lower alkyl-carbamoyl, (20) di-lower alkyl-carbamoyl, and (21) lower alkylsulfonyl.    
   
   
       41 . The pharmaceutical composition according to  claim 35 , wherein Y is a group of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 6  is hydrogen, optionally substituted hydrocarbon group, acyl, or optionally substituted heterocyclic group.  
   
   
       42 . The pharmaceutical composition according to  claim 35 , wherein Ar is a group of the formula:  
     
       
         
         
             
             
         
       
     
     wherein the heterocyclic portion may be substituted by substituent(s) selected from (I) C 1-6  alkyl, (2) C 7-16  aralkyl which may be substituted by substituent(s) selected from halogen, C 1-6  alkyl, C 1-6  alkoxy and nitro, (3) C 1-6  alkyl-carbonyl, (4) C 7-16  aralkyl-carbonyl, (5) C 6-14  aryl-carbo alkyl-carbonyl-C 6-14  aryl, (7) C 1-6  alkoxy-carbonyl-C 6-14  aryl and (8) pyridyl; 
 n is 2;  
 R is hydrogen; and  
 Y is a group of the formula:  
                     
 wherein R 6  is (1) hydrogen, (2) C 1-6  alkyl which may have a substituent or substituents selected from cyano, hydroxy, mono- or di-C 1-6  alkylamino, pyridyl, and carboxy optionally esterified, (3) C 7-16  aralkyl which may be substituted by substituent(s) selected from halogen, C 1-6  alkyl, halogeno C 1-6  alkyl, hydroxy,  
 C 1-6  alkoxy, nitro, amino, cyano, carbamoyl, C 1-6  alkoxy optionally substituted by carboxy which may be esterified, carbamoyl optionally substituted by C 1-6  alkyl or amino optionally substituted by formyl, and C 1-3  alkylenedioxy, (4) C 1-6  alkyl which may be substituted by carboxy optionally esterified, or (5) C 1-6  alkyl-carbonyl optionally substituted by mono- or di-C 1-6  alkylamino.  
 
   
   
       43 . The pharmaceutical composition according to  claim 35 , wherein Ar is a group of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 2;  
 R is hydrogen; and  
 Y is a group of the formula:  
                     
 wherein R 6′  is a benzyl which may be substituted by 1 or 2 substituents selected from halogen, C 1-3  alkyl, C 1-3  alkoxy, cyano, nitro and hydroxy.  
 
   
   
       44 . The pharmaceutical composition according to  claim 35 , which comprises: 
 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one;    8-[3-[1-(phenylmethyl)-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one; and    8-[3-[1-[(2-hydroxyphenyl)methyl)-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3 ,2,1-ij]quinolin-4-one;    or a salt thereof, together with a pharmaceutically acceptable carrier.