4,5,6, and 7-indole and indoline derivatives, their preparation and use

Abstract

A substituted 4-, 5-, 6-, and 7-indole derivative of Formula (I) wherein A is a group having formula (IIA), (IIB), (IIC) wherein X, U, Y, R 3 to R 12 , Z, W, n and m are as defined above. The compounds are potent serotonin reuptake inhibitors and have 5-HT 1A receptor antagonistic activity.

1 . A substituted 4-, 5-, 6-, or 7-indole or indoline derivative of Formula  
       
         
           
           
               
               
           
         
       
       wherein W is N, C, CH or COH and the dotted lines indicate optional bonds and 
 wherein A is a group having the formula  
                     
  wherein X is CR 1A , CHR 1A , N, NR 1B , O or S, where R 1A  is as defined for R 3  to R 9  below, and where R 1B  is as defined for R 10  below;  
 Y is CR 2A , CHR 2A , N, NR 2B , O, or S, where R 2A  is as defined for R 3  to R 9  below and where R 2B  is as defined for R 10  below, and  
 the dotted lines indicate optional bonds;  
 provided that X and Y are not both O or S;  
 A is a group having the formula  
                     
  wherein X is CR 1A , CHR 1A , N, NR 1B , O, or S, where R 1A  is as defined for R 3  to R 9  below, and where R 1B  is as defined for R 10  below;  
 U is C, CH, or N; and  
 the dotted lines indicate optional bonds; or  
 A is a group having the formula  
                     
  wherein U is C, CH, or N;  
 Y is CR 2A , CHR 2A , N, NR 2B , O, or S, where R 2A  is as defined for R 3  to R 9  below and where R 2B  is as defined for R 10  below; and  
 the dotted lines indicate optional bonds;  
 n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, 4, or 5;  
 Z is CH 2 , O, S, CO, SO, or SO 2 , provided that if n is 0 then Z is CH 2 ;  
 R 3 -R 9  and R 11  to R 12  are independently selected from hydrogen, halogen, cyano, nitro, C 1-6 -alk(en/yn)yl, C 1-6  alkoxy, C 1-6 -alkylthio, hydroxy, hydroxy-C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, C 1-6  alkylsulfonyl, aryl and heteroaryl, and/or two adjacent groups taken from R 3 -R 9  may together form a methylenedioxy group, and/or two adjacent groups R 7 -R 9  may together form a cyclopentyl or cyclohexyl ring which may be substituted with one or more methyl groups, and/or one of R 3 -R 9  may alternatively be a group —NR 13 R 14  wherein R 13  is as defined for R 10  below and R 14  is hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6  alk(en/yn)yl, aryl, heteroaryl, aryl-C 1-6  alkyl, or heteroaryl-C 1-6 -alkyl;  
 R 10  is 
 hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, acyl, thioacyl, C 1-6 -alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl, or heteroarylsulfonyl;  
 R 15 VCO— wherein V is O or S and R 15  is C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl, or heteroaryl; or  
 a group R 16 R 17 NCO— or R 16 R 17 NCS— wherein R 16  and R 17  are independently selected from hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, heteroaryl, or aryl, or R 16  and R 17  together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl, morpholinyl, or perhydroazepin group;  
 or an acid addition salt thereof.  
 
 
     
     
         2 . A compound according to  claim 1  wherein A is a group having the formula  
       
         
           
           
               
               
           
         
       
       wherein X, Y, the dotted lines and R 3 -R 6  are as defined in  claim 1 .  
     
     
         3 . A compound according to  claim 2  wherein A is a group having the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3  to R 6  and the dotted lines are as defined in  claim 2 .  
     
     
         4 . A compound according to  claim 3  wherein A is a group having the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3  to R 6  and the dotted lines are as defined in  claim 3 .  
     
     
         5 . A compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein R 7  to R 12 , W, A, Z, n, m and the dotted lines are as defined in  claim 1 .  
     
     
         6 . A compound according to  claims 1  to  5  wherein Z is CH 2  and n+m is 0, 1, 2, 3, 4, 5, or 6.  
     
     
         7 . A compound according to claim  1 - 6  wherein W is N.  
     
     
         8 . A compound according to  claim 1  having the formula  
       
         
           
           
               
               
           
         
       
       wherein R 7  to R 12 , W, Z, n, m and the dotted lines are as defined in  claim 1  and A is a group having the formula  
       
         
           
           
               
               
           
         
         wherein X, Y, the dotted lines and R 3 -R 6  is as defined in  claim 1 .  
       
     
     
         9 . A compound according to  claim 8  wherein A is a group having the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3  to R 6  and the dotted line is as defined in  claim 8 .  
     
     
         10 . A compound according to  claim 9  wherein A is a group having the formula  
       
         
           
           
               
               
           
         
       
       wherein R 3  to R 6  and the dotted line is as defined in  claim 9 .  
     
     
         11 . A compound of claims  1 - 10  wherein Z is CH 2  and n+m is 0, 1, 2, 3, 4, 5, or 6 and R 3 -R 9  and R 11 -R 12  is hydrogen, halogen, cyano, nitro, C 1-6 -alkyl, C 1-6 -alkoxy hydroxy, hydroxy-C 1-6 -alkyl, C 1-6 -alkoxycarbonyl and trifluoromethyl; and R 10  is hydrogen.  
     
     
         12 . A compound according to claims  8 - 11  wherein W is N.  
     
     
         13 . A compound according to  claim 1  which is 
 1-(2-(3-Benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(3-Benzofuranylmethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(5-Fluoro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(4-(5-Fluoro-3-benzofuranyl)-1-butyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(1H-Indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(3-(1H-Indol-3-yl)-1-propyl)-4-(1H-indol-4-yl)piperazine,  
 1-(4-(1H-Indol-3-yl)-1-butyl)-4-(1H-indol-4-yl)piperazine,  
 1-(3-(5-Fluoro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(2-Methyl-4,5,6,7-tetrafluoro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(3-Indazolyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-3-indazolyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(7-Cyano-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine,  
 1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine,  
 1-(2-(7-Bromo-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(1-Allyl-1H-indol-4-yl)-4-(2-(6-chloro-1H-indol-3-yl)ethyl)piperazine,  
 1-(1-Allyl-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperazine,  
 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(6-chloro-1H-indol-3-yl)ethyl)piperazine,  
 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperazine,  
 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(5-bromo-1H-indol-3-yl)ethyl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,  
 1-(2-(1H-Indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,  
 1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,  
 1-(2-(5-Bromo-1H-indol-3-yl)ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine,  
 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)ethyl)piperazine,  
 1-(2-(5-Bromo-1H-indol-3-yl)ethyl)-4-(1H-indol-5-yl)piperazine,  
 1-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-5-yl)piperazine,  
 1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine,  
 1-(2-(5-Bromo-1H-indol-3-yl)ethyl)-4-(1-hydroxymethyl-1H-indol-4-yl)piperazine,  
 1-(3-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-propyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(1H-Indol-3-yl)ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine,  
 1-(2-(5-Fluoro-3-benzofuranyl)ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine,  
 1-(5-Fluoro-3-benzofuranylmethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(3-Cyano-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)ethyl)piperazine,  
 1-(3-Cyano-1H-indol-4-yl)-4-(2-(5-fluoro-3-benzofuranyl)ethyl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine,  
 1-(2-(3-Benzofuranyl)ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine,  
 1-(1H-Indol-4-yl)-4-(2-(5-methyl-3-benzofuranyl)ethyl)piperazine,  
 1-(1H-Indol-4-yl)-4-(2-(4-methyl-3-benzofuranyl)ethyl)piperazine,  
 1-(3-(5-Fluoro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine,  
 1-(2-(5-Chloro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(1H-Indol-4-yl)-4-(2-(6-methyl-3-benzofuranyl)ethyl)piperazine,  
 1-(2-(7-Chloro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(7-Bromo-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(6-Trifluoromethyl-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(1H-Indol-4-yl)-4-(2-(5-methyl-1H-indol-3-yl)ethyl)piperazine,  
 1-(1H-Indol-4-yl)-4-(2-(6-methyl-1H-indol-3-yl)ethyl)piperazine,  
 1-(1H-Indol-4-yl)-4-(2-(7-methyl-1H-indol-3-yl)ethyl)piperazine,  
 1-(2-(4,5-Dichloro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(5-Bromo-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(4-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-4-yl)piperidine,  
 4-(1H-Indol-4-yl)-1-(2-(5-methyl-1H-indol-3-yl)ethyl)piperidine,  
 4-(1H-Indol-4-yl)-1-(2-(1H-indol-3-yl)ethyl)piperidine,  
 1-(1H-Indol-4-yl)-4-(3-(4-methyl-3-benzofuranyl)-1-propyl)piperazine,  
 4-(1H-Indol-4-yl)-1-(3-(4-methyl-3-benzofuranyl)-1-propyl)piperidine,  
 1-(3-(4-Chloro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-chloro-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-fluoro-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-cyano-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(7-chloro-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(7-cyano-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(2-cyano-1H-indol-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indolin-4-yl)piperazine,  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-6-yl)piperazine and  
 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-7-yl)piperazine or a pharmaceutically acceptable acid addition salt thereof.  
 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claims 1  to  13  or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.  
     
     
         15 . The use of a compound according to  claims 1  to  13  or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin reuptake and antagonism of 5-HT 1A  receptors.  
     
     
         16 . The use of a compound according to  claims 1  to  13  or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.  
     
     
         17 . A method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin reuptake and antagonism of 5-HT 1A  receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound according to  claims 1  to  13  or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         18 . A method for the treatment of an affective disorder, including depression psychosis, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound according to  claims 1  to  13  or a pharmaceutically acceptable acid addition salt thereof.