Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators

Abstract

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       where 
 R 1  is selected from the group consisting of H, halogen, C 1-10 alkyl, C 2-10  alkenyl, C 2-10  alkynyl, perhaloalkyl, CN, N(R 6 ) 2 , SR 6 , CON(R 6 ) 2 , NR 6 COR 7 , NR 6 CO 2 R 7 , SO 2 N(R 6 ) 2 , NR 6 SO 2 R 7 , aryl, heteroaryl, C 1-10 alkylaryl, and C 1-10 alkylhetroaryl; and when m+n=1, R 1  may also be OR 6  or OCOR 7 ;  
 R 2 , R 3  and R 4  are independently selected from the group consisting of H, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-0 alkynyl, perhaloalkyl, CN, OR 6 , N(R 6 ) 2 , SR 6 , OCOR 7 , CON(R 6 ) 2 , NR 6 COR 7 , NR 6 CO 2 R 7 , SO 2 N(R 6 ) 2 , NR 6 SO 2 R 7 , aryl, heteroaryl, C 1-10  alkylaryl, and C 1-10 alkylhetroaryl or R 2  and R 3  together with the ring to which they are attached form a 5 to 7 membered carbocyclic or heterocyclic ring;  
 R 5  is selected from the group consisting of H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, perhaloalkyl, CN, OR 6 , N(R 6 ) 2 , SR 6 , OCOR 7 , CON(R 6 ) 2 , NR 6 COR 7 , NR 6 CO 2 R 7 , NR 6 SO 2 R 7 , aryl, heteroaryl, C 1-10 alkylaryl, and C 1-10  alkylhetroaryl, or R 4  and R 5  together with the ring to which they are attached form a 6 to 8 membered aryl or heteroaryl ring;  
 R 5 a is H; or R 5  and R 5 a taken together form a cyclopropane ring;  
 R 6  is selected from the group consisting of H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, perhaloalkyl, C 1-10  alkyl- 0 -C 1-10  alkyl, aryl, heteroaryl, C 1-10 alkyl-O-aryl, C 1-10  alkyl-O-heteroaryl, C 1-10  alkylaryl, and C 1-10  alkylhetroaryl; and R 7  is selected from the group consisting of C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, perhaloalkyl, C 1-10 alkyl-O-C 1-10  alkyl, aryl, heteroaryl, C 1-10 alkyl-O-aryl, C 1-10 alkyl-O-heteroaryl, C 1-10  alkylaryl, and C 1-10  alkylhetroaryl; provided that if R 1 , R 2 , R 5  and R 5 a are H, then R 3  and/or R 4  must be H and the pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound as in  claim 1  where R 1  is C 1-5  alkyl, halogen, CF 3 , aryl, heteroaryl or H; R 2 , R 3  and R 4  are independently C 1-5 alkyl, —OR 6 , halogen, CF 3 , aryl, heteroaryl or H or R 2  and R 3  together with the ring to which they are attached form a 5 to 7 membered aryl or heteroaryl ring; R 5  is C 1-5 -alkyl, —OR 6  or C 2-6 alkene; and R 6  is C 1-5 alkyl or H.  
     
     
         3 . A compound as in  claim 1  selected from the group consisting of 
 5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    5-Hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    6-Chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    5-(4-Flourobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrrole;    6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    4,5-Dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;    4,6-Dichloro-5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; and    6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.    
     
     
         4 . A pharmaceutical composition comprising at least one compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         5 . A method of treating a disease, disorder and/or condition in a patient wherein modulation of a 5-HT 2c  function is desired comprising administering an effective amount of at least one compound of  claim 1  to a patient in need of such treatment.