N,n-substituted 3-aminopyrrolidine compounds useful as monoamines reuptake inhibitors

Abstract

or a salt thereof, wherein R101 and R102 are each independently a phenyl group or a pyridyl group, the phenyl group or the pyridyl group may have one or more substituents selected from halogen atoms and lower alkyl groups optionally substituted with one or more halogen atoms, etc. The pyrrolidine compound or a salt thereof of the present invention is usable to produce a pharmaceutical preparation having a wider therapeutic spectrum and being capable of exhibiting sufficient therapeutic effects after short-term administration.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a pyrrolidine compound of General Formula (1) or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein R 101  and R 102  are each independently one of the following groups (1) to (32) and (40) to (50): 
         (1) a phenyl group, 
         (2) a pyridyl group, 
         (3) a benzothienyl group, 
         (4) an indolyl group, 
         (5) a 2,3-dihydro-1H-indenyl group, 
         (6) a naphthyl group, 
         (7) a benzofuryl group, 
         (8) a quinolyl group, 
         (9) a thiazolyl group, 
         (10) a pyrimidinyl group, 
         (11) a pyrazinyl group, 
         (12) a benzothiazolyl group, 
         (13) a thieno[3,2-b]pyridyl group, 
         (14) a thienyl group, 
         (15) a cycloalkyl group, 
         (16) a tetrahydropyranyl group, 
         (17) a pyrrolyl group, 
         (18) a 2,4-dihydro-1,3-benzodioxinyl group, 
         (19) a 2,3-dihydrobenzofuryl group, 
         (20) a 9H-fluorenyl group, 
         (21) a pyrazolyl group, 
         (22) a pyridazinyl group, 
         (23) an indolinyl group, 
         (24) a thieno[2,3-b]pyridyl group, 
         (25) a thieno[3,2-d]pyrimidinyl group, 
         (26) a thieno[3,2-e]pyrimidinyl group, 
         (27) a 1H-pyrazolo[3,4-b]pyridyl group, 
         (28) an isoquinolyl group, 
         (29) a 2,3-dihydro-1,4-benzoxadinyl group, 
         (30) a quinoxalinyl group, 
         (31) a quinazolinyl group, 
         (32) a 1,2,3,4-tetrahydroquinolyl group, 
         (40) a 1,3-benzodioxolyl group, 
         (41) a 2,3-dihydro-1,4-benzodioxinyl group, 
         (42) a 3,4-dihydro-1,5-benzodioxepinyl group, 
         (43) a dihydropyridyl group, 
         (44) a 1,2-dihydroquinolyl group, 
         (45) a 1,2,3,4-tetrahydroisoquinolyl group, 
         (46) a benzoxazolyl group, 
         (47) a benzoisothiazolyl group, 
         (48) an indazolyl group, 
         (49) a benzoimidazolyl group, and 
         (50) an imidazolyl group, and 
         each of the groups (1) to (32) and (40) to (50) may have one or more substituents selected from the following (1-1) to (1-37) on the cycloalkyl, aromatic or heterocyclic ring: 
         (1-1) halogen atoms, 
         (1-2) lower alkylthio groups optionally substituted with one or more halogen atoms, 
         (1-3) lower alkyl groups optionally substituted with one or more halogen atoms, 
         (1-4) lower alkoxy groups optionally substituted with one or more halogen atoms, 
         (1-5) nitro group, 
         (1-6) lower alkoxycarbonyl groups, 
         (1-7) amino groups optionally substituted with one or two lower alkyl groups, 
         (1-8) lower alkylsulfonyl groups, 
         (1-9) cyano group, 
         (1-10) carboxy group, 
         (1-11) hydroxy group, 
         (1-12) thienyl groups, 
         (1-13) oxazolyl groups, 
         (1-14) naphthyl groups, 
         (1-15) benzoyl group, 
         (1-16) phenoxy groups optionally substituted with one to three halogen atoms on the phenyl ring, 
         (1-17) phenyl lower alkoxy groups, 
         (1-18) lower alkanoyl groups, 
         (1-19) phenyl groups optionally substituted on the phenyl ring with one to five substituents selected from the group consisting of halogen atoms, lower alkoxy groups, cyano group, lower alkanoyl groups and lower alkyl groups, 
         (1-20) phenyl lower alkyl groups, 
         (1-21) cyano lower alkyl groups, 
         (1-22) 5 to 7-membered saturated heterocyclic group-substituted sulfonyl groups, the heterocyclic group containing on the heterocyclic ring one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, 
         (1-23) thiazolyl groups optionally substituted with one or two lower alkyl groups on the thiazole ring, 
         (1-24) imidazolyl groups, 
         (1-25) amino lower alkyl groups optionally substituted with one or two lower alkyl groups on the amino group, 
         (1-26) pyrrolidinyl lower alkoxy groups, 
         (1-27) isoxazolyl groups, 
         (1-28) cycloalkylcarbonyl groups, 
         (1-29) naphthyloxy groups, 
         (1-30) pyridyl groups, 
         (1-31) furyl groups, 
         (1-32) phenylthio group, 
         (1-33) oxo group, 
         (1-34) carbamoyl group, 
         (1-35) 5 to 7-membered saturated heterocyclic groups containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic group optionally being substituted with one to three substituents selected from the group consisting of oxo group; lower alkyl groups; lower alkanoyl groups; phenyl lower alkyl groups; phenyl groups optionally substituted on the phenyl ring with one to three members selected from the group consisting of halogen atoms and lower alkoxy groups; and pyridyl groups, 
         (1-36) oxido group and 
         (1-37) lower alkoxido groups, 
         with the proviso that R 101  and R 102  are not simultaneously unsubstituted phenyl, 
         as an active ingredient, and pharmaceutically acceptable carrier or excipient. 
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , comprising a pyrrolidine compound of General Formula (1) or a salt thereof,
 wherein R 101  is selected from the group consisting of:   (1) a phenyl group,   (3) a benzothienyl group,   (4) an indolyl group,   (5) a 2,3-dihydro-1H-indenyl group,   (6) a naphthyl group,   (7) a benzofuryl group,   (8) a quinolyl group,   (12) a benzothiazolyl group,   (18) a 2,4-dihydro-1,3-benzodioxinyl group,   (19) a 2,3-dihydrobenzofuryl group,   (20) a 9H-fluorenyl group,   (23) an indolinyl group,   (28) an isoquinolyl group,   (29) a 2,3-dihydro-1,4-benzoxadinyl group,   (30) a quinoxalinyl group,   (32) a 1,2,3,4-tetrahydroquinolyl group,   (40) a 1,3-benzodioxolyl group,   (41) a 2,3-dihydro-1,4-benzodioxinyl group,   (42) a 3,4-dihydro-1,5-benzodioxepinyl group,   (43) a dihydropyridyl group,   (44) a 1,2-dihydroquinolyl group,   (45) a 1,2,3,4-tetrahydroisoquinolyl group,   (46) a benzoxazolyl group,   (47) a benzoisothiazolyl group,   (48) an indazolyl group,   (49) a benzoimidazolyl group, and   each of the groups may have on the aromatic or heterocyclic ring one to three substituents selected from the group (1-1) to (1-37) defined in the  claim 1 ,   as an active ingredient, and pharmaceutically acceptable carrier or excipient.   
     
     
         3 . The pharmaceutical composition according to  claim 1 , comprising a pyrrolidine compound of General Formula (1) or a salt thereof,
 wherein R 101  is selected from the group consisting of:   (1) a phenyl group, and   (3) a benzothienyl group, and   each of the groups may have on the aromatic or heterocyclic ring one to three substituents selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms,   as an active ingredient, and pharmaceutically acceptable carrier or excipient.   
     
     
         4 . The pharmaceutical composition according to  claim 1 , comprising a pyrrolidine compound of General Formula (1) or a salt thereof,
 wherein R 102  is selected from the group consisting of:   (1) a phenyl group,   (2) a pyridyl group,   (9) a thiazolyl group,   (10) a pyrimidinyl group,   (11) a pyrazinyl group,   (14) a thienyl group, and   (48) an indazolyl group, and   each of the groups may have on the aromatic or heterocyclic ring one to three substituents selected from the group (1-1) to (1-37) defined in the  claim 1 ,   as an active ingredient, and pharmaceutically acceptable carrier or excipient.   
     
     
         5 . The pharmaceutical composition according to  claim 1 , comprising a pyrrolidine compound of General Formula (1) or a salt thereof,
 wherein R 101  is   a monohalophenyl group, a dihalophenyl group or a phenyl group substituted with one halogen atom and one lower alkyl group,   R102 is selected from the group consisting of:   (1) a phenyl group,   (2) a pyridyl group,   (9) a thiazolyl group,   (10) a pyrimidinyl group,   (11) a pyrazinyl group,   (14) a thienyl group, and   (48) an indazolyl group, and   each of the groups may have on the aromatic or heterocyclic ring one to three substituents selected from the group consisting of (1-1) halogen atoms, (1-3) lower alkyl groups optionally substituted with one or more halogen atoms, and   (1-9) cyano group,   as an active ingredient, and pharmaceutically acceptable carrier or excipient.   
     
     
         6 . A pharmaceutical composition selected from the group consisting of:
 (3-chloro-4-fluorophenyl)-3-thienyl-(S)-pyrrolidin-3-ylamine, (4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine, (4-fluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine, (3,4-difluorophenyl)phenyl-(S)-pyrrolidin-3-ylamine, bis-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine, (3,4-difluorophenyl)-(4-fluorophenyl)-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-yl-p-tolylamine, 4-[(S)-(4-fluoro-3-methylphenyl)pyrrolidin-3-ylamino]-benzonitrile, bis-(3-fluorophenyl)-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine, (4-fluorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine, (3,4-dichlorophenyl)-(S)-pyrrolidin-3-ylthiazol-2-ylamine, (3,4-dichlorophenyl)pyrimidin-5-yl-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)pyridin-2-yl-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine, (3,4-dichlorophenyl)pyridin-3-yl-(S)-pyrrolidin-3-ylamine, (3-chloro-4-fluorophenyl)-(S)-pyrrolidin-3-ylthiophen-3-ylamine, (3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine, (4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)-pyrrolidin-3-ylamine,   (3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine   benzo[b]thiophen-6-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine, and   benzo[b]thiophen-5-yl-(S)-pyrrolidin-3-ylthiophen-3-ylamine, and   the salts thereof,   as an active ingredient, and pharmaceutically acceptable carrier or excipient.   
     
     
         7 . A method of treating disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, comprising administering a therapeutically effective amount of a pharmaceutical composition according to  claim 1  to a human or an animal in need thereof,
 wherein the disorder is selected from depression, attention deficit hyperactivity disorder (ADHD), fibromyalgia syndrome and posttraumatic stress syndrome (PTSD).