Heterocyclic compounds for treating or preventing disorers caused by reduced neurotransmission of serotonin, norephnephrine or dopamine

Abstract

A heterocyclic compound represented by the general formula (1) or a salt thereof: wherein m, I, and n respectively represent an integer of 1 or 2; X represents —O— or —CH 2 —; R 1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group; R 2 and R 3 , which are the same or different, each independently represent hydrogen or a lower alkyl group; or R 2 and R 3 are bonded to form a cyclo-C3-C8 alkyl group; and R 4 represents an aromatic group or a heterocyclic group, wherein the aromatic or heterocyclic group may have one or more arbitrary substituent(s).

1 . A method for treating depression and/or depression status caused by adjustment disorder, comprising administering to a subject in need a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein m=2, I=1 and n=1; X represents CH 2 —; 
       R 1  represents hydrogen, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a protecting group selected from unsubstituted C1-C6 alkanoyl, phthaloyl, C1-C6 alkoxycarbonyl, unsubstituted aralkyloxycarbonyl, 9-fluorenylmethoxycarbonyl, nitrophenylsulfenyl, aralkyl and C1-C6 alkylsilyl groups, or a tri C1-C6 alkylsilyloxy C1-C6 alkyl group; 
       R 2  and R 3 , which are the same or different, each independently represent hydrogen or a C1-C6 alkyl group; or R 2  and R 3  are bonded to form a cyclo-C3-C8 alkyl group; and 
       R 4  represents any of 
       (1) a phenyl group, 
       (2) an indolyl group, 
       (3) a benzothienyl group, 
       (4) a naphthyl group, 
       (5) a benzofuryl group, 
       (6) a quinolyl group, 
       (7) an isoquinolyl group, 
       (8) a pyridyl group, 
       (9) a thienyl group, 
       (10) a dihydrobenzoxazinyl group, 
       (11) a dihydrobenzodioxinyl group, 
       (12) a dihydroquinolyl group, 
       (13) a chromanyl group, 
       (14) a quinoxalinyl group, 
       (15) a dihydroindenyl group, 
       (16) a dihydrobenzofuryl group, 
       (17) a benzodioxolyl group, 
       (18) an indazolyl group, 
       (19) a benzothiazolyl group, 
       (20) an indolinyl group, 
       (21) a thienopyridyl group, 
       (22) a tetrahydrobenzazepinyl group, 
       (23) a tetrahydrobenzodiazepinyl group, 
       (24) a dihydrobenzodioxepinyl group, 
       (25) a fluorenyl group, 
       (26) a pyridazinyl group, 
       (27) a tetrahydroquinolyl group, 
       (28) a carbazolyl group, 
       (29) a phenanthryl group, 
       (30) a dihydroacenaphthylenyl group, 
       (31) a pyrrolopyridyl group, 
       (32) an anthryl group, 
       (33) a benzodioxinyl group, 
       (34) a pyrrolidinyl group, 
       (35) a pyrazolyl group, 
       (36) an oxadiazolyl group, 
       (38) a tetrahydronaphthyl group, 
       (39) a dihydroquinazolinyl group, 
       (40) a benzoxazolyl group, 
       (41) a thiazolyl group, 
       (42) a quinazolinyl group, 
       (43) a phthalazinyl group, 
       (44) a pyrazinyl group, and 
       (45) a chromenyl group, wherein 
       these aromatic or heterocyclic groups may have one or more substituent(s) selected from 
       (1-1) a halogen atom, 
       (1-2) a C1-C6 alkyl group, 
       (1-3) a C1-C6 alkanoyl group, 
       (1-4) a halogen-substituted C1-C6 alkyl group, 
       (1-5) a halogen-substituted C1-C6 alkoxy group, 
       (1-6) a cyano group, 
       (1-7) a C1-C6 alkoxy group, 
       (1-8) a C1-C6 alkylthio group, 
       (1-9) an imidazolyl group, 
       (1-10) a tri C1-C6 alkylsilyl group, 
       (1-11) an oxadiazolyl group which may have one or more C1-C6 alkyl group(s), 
       (1-12) a pyrrolidinyl group which may have one or more oxo group(s), 
       (1-13) a phenyl group which may have one or more C1-C6 alkoxy group(s), 
       (1-14) a C1-C6 alkylamino C1-C6 alkyl group, 
       (1-15) an oxo group, 
       (1-16) a pyrazolyl group which may have one or more C1-C6 alkyl group(s), 
       (1-17) a thienyl group, 
       (1-18) a furyl group, 
       (1-19) a thiazolyl group which may have one or more C1-C6 alkyl group(s), 
       (1-20) a C1-C6 alkylamino group, 
       (1-21) a pyrimidyl group which may have one or more C1-C6 alkyl group(s), 
       (1-22) a phenyl C2-C6 alkenyl group, 
       (1-23) a phenoxy group which may have one or more halogen atom(s), 
       (1-24) a phenoxy C1-C6 alkyl group, 
       (1-25) a pyrrolidinyl C1-C6 alkoxy group, 
       (1-26) a C1-C6 alkylsulfamoyl group, 
       (1-27) a pyridazinyloxy group which may have one or more C1-C6 alkyl group(s), 
       (1-28) a phenyl C1-C6 alkyl group, 
       (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, 
       (1-30) an imidazolyl C1-C6 alkyl group, 
       (1-31) a phenyl C1-C6 alkoxy group, 
       (1-32) a hydroxy group, 
       (1-33) a C1-C6 alkoxycarbonyl group, 
       (1-34) a hydroxyl C1-C6 alkyl group, 
       (1-35) an oxazolyl group, 
       (1-36) a piperidyl group, 
       (1-37) a pyrrolyl group, 
       (1-38) a morpholinyl C1-C6 alkyl group, 
       (1-39) a piperazinyl C1-C6 alkyl group which may have one or more C1-C6 alkyl group(s), 
       (1-40) a piperidyl C1-C6 alkyl group, 
       (1-41) a pyrrolidinyl C1-C6 alkyl group, 
       (1-42) a morpholinyl group, and 
       (1-43) a piperazinyl group which may have one or more C1-C6 alkyl group(s). 
     
     
         2 . (canceled) 
     
     
         3 . The method according to  claim 1 , wherein in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof 
       R 4  represents any of 
       (1) a phenyl group, 
       (2) an indolyl group, 
       (3) a benzothienyl group, 
       (4) a naphthyl group, 
       (5) a benzofuryl group, 
       (6) a quinolyl group, 
       (7) an isoquinolyl group, 
       (8) a pyridyl group, 
       (9) a thienyl group, 
       (10) a dihydrobenzoxazinyl group, 
       (11) a dihydrobenzodioxinyl group, 
       (12) a dihydroquinolyl group, 
       (13) a chromanyl group, 
       (14) a quinoxalinyl group, 
       (15) a dihydroindenyl group, 
       (16) a dihydrobenzofuryl group, 
       (17) a benzodioxolyl group, 
       (18) an indazolyl group, 
       (19) a benzothiazolyl group, 
       (20) an indolinyl group, 
       (21) a thienopyridyl group, 
       (22) a tetrahydrobenzazepinyl group, 
       (23) a tetrahydrobenzodiazepinyl group, 
       (24) a dihydrobenzodioxepinyl group, 
       (25) a fluorenyl group, 
       (26) a pyridazinyl group, 
       (27) a tetrahydroquinolyl group, 
       (28) a carbazolyl group, 
       (29) a phenanthryl group, 
       (30) a dihydroacenaphthylenyl group, 
       (31) a pyrrolopyridyl group, 
       (32) an anthryl group, 
       (33) a benzodioxinyl group, 
       (34) a pyrrolidinyl group, 
       (35) a pyrazolyl group, 
       (36) an oxadiazolyl group, 
       (38) a tetrahydronaphthyl group, 
       (39) a dihydroquinazolinyl group, 
       (40) a benzoxazolyl group, 
       (41) a thiazolyl group, 
       (42) a quinazolinyl group, 
       (43) a phthalazinyl group, 
       (44) a pyrazinyl group, and 
       (45) a chromenyl group, wherein 
       these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from 
       (1-1) a halogen atom, 
       (1-2) a C1-C6 alkyl group, 
       (1-3) a C1-C6 alkanoyl group, 
       (1-4) a halogen-substituted C1-C6 alkyl group, 
       (1-5) a halogen-substituted C1-C6 alkoxy group, 
       (1-6) a cyano group, 
       (1-7) a C1-C6 alkoxy group, 
       (1-8) a C1-C6 alkylthio group, 
       (1-9) an imidazolyl group, 
       (1-10) a tri C1-C6 alkylsilyl group, 
       (1-11) an oxadiazolyl group which may have 1 C1-C6 alkyl group, 
       (1-12) a pyrrolidinyl group which may have 1 oxo group, 
       (1-13) a phenyl group which may have 1 C1-C6 alkoxy group, 
       (1-14) a C1-C6 alkylamino C1-C6 alkyl group, 
       (1-15) an oxo group, 
       (1-16) a pyrazolyl group which may have 1 C1-C6 alkyl group, 
       (1-17) a thienyl group, 
       (1-18) a furyl group, 
       (1-19) a thiazolyl group which may have 1 C1-C6 alkyl group, 
       (1-20) a C1-C6 alkylamino group, 
       (1-21) a pyrimidyl group which may have 1 C1-C6 alkyl group, 
       (1-22) a phenyl C1-C6 alkenyl group, 
       (1-23) a phenoxy group which may have 1 halogen atom, 
       (1-24) a phenoxy C1-C6 alkyl group, 
       (1-25) a pyrrolidinyl C1-C6 alkoxy group, 
       (1-26) a C1-C6 alkylsulfamoyl group, 
       (1-27) a pyridazinyloxy group which may have 1 C1-C6 alkyl group, 
       (1-28) a phenyl C1-C6 alkyl group, 
       (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, 
       (1-30) an imidazolyl C1-C6 alkyl group, 
       (1-31) a phenyl C1-C6 alkoxy group, 
       (1-32) a hydroxy group, 
       (1-33) a C1-C6 alkoxycarbonyl group, 
       (1-34) a hydroxy C1-C6 alkyl group, 
       (1-35) an oxazolyl group, 
       (1-36) a piperidyl group, 
       (1-37) a pyrrolyl group, 
       (1-38) a morpholinyl C1-C6 alkyl group, 
       (1-39) a piperazinyl C1-C6 alkyl group which may have 1 C1-C6 alkyl group, 
       (1-40) a piperidyl C1-C6 alkyl group, 
       (1-41) a pyrrolidinyl C1-C6 alkyl group, 
       (1-42) a morpholinyl group, and 
       (1-43) a piperazinyl group which may have 1 C1-C6 alkyl group. 
     
     
         4 . The method according to  claim 3 , wherein in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof 
       m represents 2; I and n respectively represent 1; X represents —CH 2 —; 
       R 1  represents hydrogen, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a benzyl group, or a tri C1-C6 alkylsilyloxy C1-C6 alkyl group; and 
       R 4  represents any of 
       (1) a phenyl group, 
       (2) an indolyl group, 
       (4) a naphthyl group, 
       (5) a benzofuryl group, and 
       (31) a pyrrolopyridyl group, wherein 
       these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from 
       (1-1) a halogen atom, 
       (1-2) a C1-C6 alkyl group, 
       (1-3) a C1-C6 alkanoyl group, 
       (1-4) a halogen-substituted C1-C6 alkyl group, 
       (1-5) a halogen-substituted C1-C6 alkoxy group, 
       (1-6) a cyano group, 
       (1-7) a C1-C6 alkoxy group, 
       (1-8) a C1-C6 alkylthio group, 
       (1-9) an imidazolyl group, 
       (1-10) a tri C1-C6 alkylsilyl group, 
       (1-11) an oxadiazolyl group which may have 1 C1-C6 alkyl group, 
       (1-12) a pyrrolidinyl group which may have 1 oxo group, 
       (1-13) a phenyl group which may have 1 C1-C6 alkoxy group, 
       (1-14) a C1-C6 alkylamino C1-C6 alkyl group, 
       (1-15) an oxo group, 
       (1-16) a pyrazolyl group which may have 1 C1-C6 alkyl group, 
       (1-17) a thienyl group, 
       (1-18) a furyl group, 
       (1-19) a thiazolyl group which may have 1 C1-C6 alkyl group, 
       (1-20) a C1-C6 alkylamino group, 
       (1-21) a pyrimidyl group which may have 1 C1-C6 alkyl group, 
       (1-22) a phenyl C1-C6 alkenyl group, 
       (1-23) a phenoxy group which may have 1 halogen atom, 
       (1-24) a phenoxy C1-C6 alkyl group, 
       (1-25) a pyrrolidinyl C1-C6 alkoxy group, 
       (1-26) a C1-C6 alkylsulfamoyl group, 
       (1-27) a pyridazinyloxy group which may have 1 C1-C6 alkyl group, 
       (1-28) a phenyl C1-C6 alkyl group, 
       (1-29) a C1-C0 alkylamino C1-C6 alkoxy group, 
       (1-30) an imidazolyl C1-6 alkyl group, 
       (1-31) a phenyl C1-C6 alkoxy group, 
       (1-32) a hydroxy group, 
       (1-34) a hydroxy C1-C6 alkyl group, 
       (1-35) an oxazolyl group, 
       (1-36) a piperidyl group, 
       (1-37) a pyrrolyl group, 
       (1-38) a morpholinyl C1-C6 alkyl group, 
       (1-39) a piperazinyl C1-6 alkyl group which may have 1 C1-C6 alkyl group(s), 
       (1-40) a piperidyl C1-C6 alkyl group, 
       (1-41) a pyrrolidinyl C1-C6 alkyl group, 
       (1-42) a morpholinyl group, and 
       (1-43) a piperazinyl group which may have 1 C1-C6 alkyl group. 
     
     
         5 . The method according to  claim 4 , wherein in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof 
       R 1  represents hydrogen; 
       R 2  and R 3 , which are the same or different, each independently represent a C1-C6 alkyl group; or R 2  and R 3  are bonded to form a cyclo-C3-C8 alkyl group; and 
       R 4  represents any of 
       (1) a phenyl group, 
       (2) an indolyl group, 
       (4) a naphthyl group, 
       (5) a benzofuryl group, and 
       (31) a pyrrolopyridyl group, wherein 
       these aromatic or heterocyclic groups may have 1 to 2 substituent(s) selected from 
       (1-1) a halogen atom, 
       (1-2) a C1-C6 alkyl group, 
       (1-5) a halogen-substituted C1-C6 alkoxy group, 
       (1-6) a cyano group, and 
       (1-7) a C1-C6 alkoxy group. 
     
     
         6 . The method according to  claim 5 , wherein in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is selected from (4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline, 2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)benzonitrile, (4aS,8aR)-1-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxaline, (4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline, 5-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-1-methyl-1H-indole-2-carbonitrile, (4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline], (4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline, 5-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-1H-indole-2-carbonitrile, 6-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-2-naphthonitrile, (4aS,8aS)-3,3-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline, (4aS,8aS)-1-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline, (4aS,8aS)-1-(4-(difluoromethoxy)phenyl-3,3-dimethyldecahydroquinoxaline, and (4aR,8aR)-1-(4-difluoromethyoxy)-3-fluorophenyl-3,3-dimethyldecahydroquinoxaline. 
     
     
         7 - 16 . (canceled) 
     
     
         17 . The method according to any one of  claims 1 , and  3  to  5 , wherein in the depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state bipolar disorder; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression; chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by physical diseases, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct, brain hemorrhage, subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer; presenile depression; senile depression; depression in children and adolescents; and depression induced by drugs. 
     
     
         18 . The method according to  claim 17 , wherein the depression is caused by physical disease caused by physical disease selected from hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct, brain hemorrhage, subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer.