Antidepressant arylpiperazine derivatives of heterocycle-fused benzodioxans

Abstract

Compounds of the formula I: are useful for the treatment of depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction and related illnesses.

1 . A method of treating a subject suffering from a condition selected from depression, anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders, vasomotor flushing, cocaine and alcohol addiction, and sexual dysfunction, comprising the step of: 
 providing to said subject a therapeutically effective amount of (2S)-2-{[4-(dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline, or a pharmaceutically acceptable salt thereof.    
   
   
       2 . The method according to  claim 1 , wherein said condition is depression.  
   
   
       3 . The method according to  claim 1 , wherein said condition is selected from the group consisting of obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, and social anxiety disorder.  
   
   
       4 . A method of treating a subject suffering from cocaine addiction, comprising the step of: 
 providing to said subject a therapeutically effective amount of a compound of formula I                          wherein    R 1  is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;    the group X—Y is —N═C(R 2 )—C(R 3 )═N—, —N═C(R 2 )—C(R 4 )═CH—, —N═C(R 2 )—N═CH—, —N═C(R 2 )—O—, or —NH—C(R 5 )═CH—;    R 2  and R 3  are, independently, hydrogen, halo, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms;    R 4  is hydrogen or alkyl of 1 to 6 carbon atoms;    R 5  is hydrogen, halo, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms;    Ar is phenyl, naphthyl, indolyl, indazolyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, benzofuranyl, benzothienyl, benzoisothiazolyl, or benzisoxazolyl, each optionally substituted with one to three substituents independently selected from hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; and,    n is 1 or 2;    or a pharmaceutically acceptable salt thereof.    
   
   
       5 . The method according to  claim 4 , wherein R 1  is hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.  
   
   
       6 . The method according to  claim 4 , wherein R 1  is hydrogen, halo or alkoxy of 1 to 6 carbon atoms.  
   
   
       7 . The method according to  claim 4 , wherein R 1  is hydrogen.  
   
   
       8 . The method according to  claim 4 , wherein Ar is phenyl, quinolinyl, benzofuranyl, benzothienyl, or indolyl, each optionally substituted.  
   
   
       9 . The method according to  claim 4 , wherein X—Y is —N═C(R 2 )—C(R 4 )═CH— and R 4  is hydrogen or alkyl of 1 to 3 carbon atoms.  
   
   
       10 . The method according to  claim 4 , wherein R 2  and R 3  when present are independently selected from the group consisting of hydrogen, amino, and alkyl of 1 to 6 carbon atoms.  
   
   
       11 . The method according to  claim 4 , wherein R 5  is hydrogen, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms.  
   
   
       12 . The method according to  claim 4 , wherein R 5  is hydrogen, trifluoromethyl or alkyl of 1 to 3 carbon atoms.  
   
   
       13 . The method according to  claim 4 , wherein said compound is selected from the group consisting: 
 (2S)-2-{[4-(3-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxine[2,3-f]quinoline;    (2S)-2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-8-methyl-2-[4-(3-trifluoromethyl-phenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-8-methyl-2-[4-(3-fluorophenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(3,4-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-8-methyl-2-[(4-quinolin-2-ylpiperazin-1-yl)methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    ((2S)-8-methyl-2-{4-(6-nitroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-8-methyl-2-{4-(6-chloroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    2-(4-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}piperazin-1-yl}quinoline-6-carbonitrile;    (2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    ((2S)-2-{[4-(7-methoxy-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-8-methyl-2-{[(2S)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    2-((3R)-3-methyl-4-{[(2S))-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}piperazin-1-yl]quinoline-6-carbonitrile;    (2S)-8-methyl-2-{[(2R)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-8-methyl-2-{[4-(2-naphthyl)piperazin-1-yl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-[4-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-piperazin-1-yl]-quinoline-6-carboxylic acid amide;    (2S)-2-[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile;    (2S)-2-[4-(8-Ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile;    (2S)-2-[4-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile;    (2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    2-[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}-1,4-diazepan-1-yl)quinoline-6-carbonitrile;    (2S)-2-{[4-(6-Trifluoromethoxy-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;    (2S)-2-{[4-(6-Bromo-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;    8-Methyl-2-(4-quinolin-2-yl-[1,4]diazepan-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; and,    8-Methyl-2-[4-(4-methyl-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline, and 
 pharmaceutically acceptable salts thereof.