Arylsulphonyl substituted-tetrahydro-and hexahydro-carbazoles

Abstract

The invention provides compounds of formula I for use in treating conditions in which 5-HT 6 receptors are involved such as in anxiety, depression, schizophrenia, Alzheimer's disease, stress-related disease, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, epilepsy, and other CNS disorders.

What is claimed:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 ---[b] is a single or double bond;  
 Each X, Y, and Z is independently selected from H, —OH, —O-alkyl, and —O-substituted alkyl;  
 R 1  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 R 2  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 R 3  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and -A-E-R 8 ;  
 A is selected from alkyl and substituted alkyl;  
 E is selected from —N(R 10 ) C(O)—, —C(O)N(R 10 )—, —N(R 10 ) C(S)—, —C(S)N(R 10 )—, —S(O)N(R 10 )—, —N(R 10 ) S(O)—, —S(O) 2 N(R 10 )—, and —N(R 10 )S(O) 2 —;  
 Each R 4 , R 5 , R 6 , and R 7  is independently selected from H, halogen, aryl, —CN, —NO 2 , alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, —OR 9 , —NH 2 , —C(O)NH 2 , —C(S)NH 2 , and —S(O) n aryl, provided that one of R 4 , R 5 , R 6 , and R 7  is —S(O) n aryl, and that at least one of R 4 , R 5 , R 6 , and R 7  is H;  
 n is 0, 1, or 2;  
 Each R 8 , R 9 , and R 10  is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 Each R 11  is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided that any of the alkyl, cycloalkyl, phenyl, naphthyl, or heteroaromatic is optionally substituted with up to 3 substituents independently selected from halogen, alkyl, —CF 3 , —OR 12 , —SR 12 , —CN, —NO 2 , —N 3 , —N(R 12 ) 2 , —C(O)N(R 12 ) 2 , and —C(S)N(R 12 ) 2 ;  
 Each R 12  is independently selected from H, alkyl, and cycloalkyl, provided that any of the alkyl or cycloalkyl is optionally substituted with up to 2 substituents independently selected from halogen, —CF 3 , —NO 2 , —NH 2 , —N 3 , —CN, —OH, —O-lower alkyl, and —O-lower substituted alkyl; and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound of  claim 1  having the Formula Ib  
       
         
           
           
               
               
           
         
       
       wherein 
 Each X, Y, and Z is independently selected from H, —OH, —O-alkyl, and —O-substituted alkyl;  
 R 1  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 R 2  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 R 3  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and -A-E-R 8 ;  
 A is selected from alkyl and substituted alkyl;  
 E is selected from —N(R 10 )C(O)—, —C(O)N(R 10 )—, —N(R 10 )C(S)—, —C(S)N(R 10 )—, —S(O)N(R 10 )—, —N(R 10 )S(O)—, —S(O) 2 N(R 10 )—, and —N(R 10 )S(O) 2 —;  
 Each R 4 , R 5 , R 6 , and R 7  is independently selected from H, halogen, aryl, —CN, —NO 2 , alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, —OR 9 , —NH 2 , —C(O)NH 2 , —C(S)NH 2 , and —S(O) n aryl, provided that one of R 4 , R 5 , R 6 , and R 7  is —S(O) n aryl, and that at least one of R 4 , R 5 , R 6 , and R 7  is H;  
 n is 0, 1, or 2;  
 Each R 8 , R 9 , and R 10  is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 Each R 11  is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided that any of the alkyl, cycloalkyl, phenyl, naphthyl, or heteroaromatic is optionally substituted with up to 3 substituents independently selected from halogen, alkyl, —CF 3 , —OR 12 , —SR 12 , —CN, —NO 2 , —N 3 , —N(R 12 ) 2 , —C(O)N(R 12 ) 2 , and —C(S)N(R 12 ) 2 ;  
 Each R 12  is independently selected from H, alkyl, and cycloalkyl, provided that any of the alkyl or cycloalkyl is optionally substituted with up to 2 substituents independently selected from halogen, —CF 3 , —NO 2 , —NH 2 , —N 3 , —CN, —OH, —O-lower alkyl, and —O-lower substituted alkyl; and pharmaceutically acceptable salts thereof.  
 
     
     
         3 . The compound of  claim 2 , wherein one of R 1  and R 2  is H, and the other is H, alkyl, or substituted alkyl.  
     
     
         4 . The compound of  claim 3 , wherein R 5  is arylS(O) n —, and wherein R 4 , R 6 , and R 7  are H.  
     
     
         5 . The compound of  claim 4 , wherein n is 2.  
     
     
         6 . The compound of  claim 5 , wherein R 3  is H or alkyl.  
     
     
         7 . The compound of  claim 6 , wherein the compound is 
 (rac)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3S)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3R)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine;    or a pharmaceutically acceptable salt thereof.    
     
     
         8 . The compound of  claim 7 , wherein the stereochemistry at the C-3 position is R.  
     
     
         9 . The compound of  claim 8 , wherein the compound is 
 (3R)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine;    or a pharmaceutically acceptable salt thereof.    
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 2 .  
     
     
         11 . A method for treating a disease or condition in a mammal in need thereof, wherein the 5-HT 6  receptor is implicated, comprising administering to the mammal a therapeutically effective amount of compound according to  claim 2 .  
     
     
         12 . The method according to  claim 11 , wherein the disease or condition is anxiety, depression, schizophrenia, Alzheimer's disease, stress-related disease, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, or epilepsy.  
     
     
         13 . The method according to  claim 11 , wherein said compound is administered rectally, topically, orally, sublingually, or parenterally.  
     
     
         14 . The method according to  claim 11 , wherein said compound is administered from about 0.001 to about 100 mg/kg of body weight of said mammal per day.  
     
     
         15 . The method according to  claim 11 , wherein said compound is administered from about 0.1 to about 50 mg/kg of body weight of said mammal per day.  
     
     
         16 . The compound of  claim 2 , wherein the compound includes at least one atom selected from Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18.  
     
     
         17 . A method of performing positron emission tomography comprising: 
 incorporating an isotopically labeled compound into tissue of a mammal, wherein the isotopically labeled compound is selected from a compound of Formula Ib as defined in  claim 1 .    
     
     
         18 . The method according to  claim 17 , wherein the compound is selected from 
 6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3S)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3R)-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine;    (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tertrahydro-1H-carbazol-3-amine; or    (3R)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine.    
     
     
         19 . A compound of  claim 1  having the Formula Ia  
       
         
           
           
               
               
           
         
       
       wherein 
 Each X, Y, and Z is independently selected from H, —OH, —O-alkyl, and —O-substituted alkyl;  
 R 1  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 R 2  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 R 3  is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and -A-E-R 8 ;  
 A is selected from alkyl and substituted alkyl;  
 E is selected from —N(R 10 )C(O)—, —C(O)N(R 10 )—, —N(R 10 )C(S)—, —C(S)N(R 10 )—, —S(O)N(R 10 )—, —N(R 10 )S(O)—, —S(O) 2 N(R 10 )—, and —N(R 10 )S(O) 2 —;  
 Each R 4 , R 5 , R 6 , and R 7  is independently selected from H, halogen, aryl, —CN, —NO 2 , alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, —OR 9 , —NH 2 , —C(O)NH 2 , —C(S)NH 2 , and —S(O) n aryl, provided that one of R 4 , R 5 , R 6 , and R 7  is —S(O) n aryl, and that at least one of R 4 , R 5 , R 6 , and R 7  is H;  
 n is 0, 1, or 2;  
 Each R 8 , R 9 , and R 10  is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl;  
 Each R 11  is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, phenyl, naphthyl, and heteroaromatic, provided that any of the alkyl, cycloalkyl, phenyl, naphthyl, or heteroaromatic is optionally substituted with up to 3 substituents independently selected from halogen, alkyl, —CF 3 , —OR 12 , —SR 12 , —CN, —NO 2 , —N 3 , —N(R 12 ) 2 , —C(O)N(R 12 ) 2 , and —C(S)N(R 12 ) 2 ;  
 Each R 12  is independently selected from H, alkyl, and cycloalkyl, provided that any of the alkyl or cycloalkyl is optionally substituted with up to 2 substituents independently selected from halogen, —CF 3 , —NO 2 , —NH 2 , —N 3 , —CN, —OH, —O-lower alkyl, and —O-lower substituted alkyl; and pharmaceutically acceptable salts thereof.  
 
     
     
         20 . The compound of  claim 19 , wherein one of R 1  and R 2  is H, and the other is H, alkyl, or substituted alkyl.  
     
     
         21 . The compound of  claim 20 , wherein R 5  is arylS(O) n —, and wherein R 4 , R 6 , and R 7  are H.  
     
     
         22 . The compound of  claim 21 , wherein n is 2.  
     
     
         23 . The compound of  claim 22 , wherein R 3  is H or alkyl.  
     
     
         24 . The compound of  claim 23 , wherein the compound is 
 (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;    (3S)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;    (3R)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;    (3S)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;    (rac)-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol;    (3S)-N,9-dimethyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;    (3R)-N, 9-dimethyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;    and pharmaceutically acceptable salts thereof.    
     
     
         25 . The compound of  claim 23 , wherein the stereochemistry at the C-3 position is R.  
     
     
         26 . The compound of  claim 25 , wherein the compound is 
 (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine;    or a pharmaceutically acceptable salt thereof.    
     
     
         27 . A pharmaceutical composition comprising a compound according to  claim 19 .  
     
     
         28 . A method for treating a disease or condition in a mammal in need thereof, wherein the 5-HT 6  receptor is implicated, comprising administering to the mammal a therapeutically effective amount of compound according to  claim 19 .  
     
     
         29 . The method according to  claim 28 , wherein the disease or condition is anxiety, depression, schizophrenia, Alzheimer's disease, stress-related disease, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, or epilepsy.  
     
     
         30 . The method according to  claim 28 , wherein said compound is administered rectally, topically, orally, sublingually, or parenterally.  
     
     
         31 . The method according to  claim 28 , wherein said compound is administered from about 0.001 to about 100 mg/kg of body weight of said mammal per day.  
     
     
         32 . The method according to  claim 28 , wherein said compound is administered from about 0.1 to about 50 mg/kg of body weight of said mammal per day.  
     
     
         33 . The compound of  claim 19 , wherein the compound includes at least one atom selected from Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18.  
     
     
         34 . A method of performing positron emission tomography comprising: 
 incorporating an isotopically labeled compound into tissue of a mammal, wherein the isotopically labeled compound is selected from  claim 19 .    
     
     
         35 . The method according to  claim 34 , wherein the compound is (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine.