Azaindoles having serotonin receptor affnity

Abstract

Described herein are compounds with affinity for the 5-HT 6 receptor, which have the general formula I: wherein: R represents a group of Formula II or Formula III; one of A, B D or E is a N atom, the remainder being CH groups; R 1 is selected from the group consisting of SO 2 Ar, C(O)Ar, CH 2 Ar and Ar; R 2 , R 3 and R 4 are independently selected from the group consisting of H and alkyl; ----- represents a single or double bond, with the proviso that there is only one double bond in the ring at a time; n is an integer of from 1-3; Z is selected from the group consisting of C, CH and N, provided that when ----- is a double bond, Z is C and when ----- is a single bond, Z is selected from CH and N; Ar is an optionally substituted aryl group; with the proviso that when R is a group of Formula II, R 1 is SO 2 Ar. Also described is the use of these compounds as pharmaceuticals to treat indications where inhibition of the 5-HT 6 receptor is implicated, such as schizophrenia.

We claim:  
     
         1 . A compound according to Formula I and a salt, solvate or hydrate thereof, wherein:  
       
         
           
           
               
               
           
         
         wherein:  
         R represents a group of Formula II or Formula III;  
         one of A, B D or E is a N atom, the remainder being CH groups;  
         R 1  is selected from the group consisting of SO 2 Ar, C(O)Ar, CH 2 Ar and Ar;  
         R 2 , R 3  and R 4  are independently selected from the group consisting of H and alkyl;  
         ----- represents a single or double bond, with the proviso that there is only one double bond in the ring at a time;  
         n is an integer of from 1-3;  
         Z is selected from the group consisting of C, CH and N, provided that when ----- is a double bond, Z is C and when ----- is a single bond, Z is selected from CH and N;  
         Ar is an optionally substituted aryl group;  
         with the proviso that when R is a group of Formula II, R 1  is SO 2 Ar.  
       
     
     
         2 . A compound according to    claim 1    wherein R is a group of Formula III.  
     
     
         3 . A compound according to    claim 2    wherein R 1  is selected from the group consisting of SO 2 Ar and C(O)Ar.  
     
     
         4 . A compound according to    claim 3    wherein R 1  is SO 2 Ar.  
     
     
         5 . A compound according to    claim 4    wherein Ar is selected from the group consisting of substituted phenyl and naphthyl.  
     
     
         6 . A compound according to    claim 5    wherein Ar is naphthyl.  
     
     
         7 . A compound according to    claim 1    wherein R is a group of Formula II.  
     
     
         8 . A compound according to    claim 7    wherein Ar is selected from the group consisting of substituted phenyl and naphthyl.  
     
     
         9 . A compound according to    claim 8    wherein Ar is naphthyl.  
     
     
         10 . A compound selected from the group consisting of: 
 3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-4-azaindole;    3-(Octahydro-7-indolizinyl)-1H-4-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-4-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-4-azaindole;    3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-4-azaindole;    1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;    1-(2,6-Dichlorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole;    1-(2,6-Dichlorobenzoyl)-3-(1-methyl-4-piperidinyl)-5-azaindole;    1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;    1-(2-Chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;    1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-5-azaindole;    1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;    1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;    1-(1-Naphthalenesulfonyl)-3-(octahydro-8-quinolizinyl)-5-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-5-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;    3-(1,2,4,6,7,9a-Hexahydro-2H-quinolizine-2-yl)-5-azaindole;    3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-5-azaindole;    3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole;    3-(1-Methyl-4-piperidinyl)-5-azaindole;    3-(1-Methyl-4-piperidinyl)-1-benzenesulfonyl-5-azaindole;    3-(Octahydro-7-indolizinyl)-1H-5-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;    3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;    3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;    3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole;    3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole;    3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;    3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;    3-(Octahydro-quinolizine)-1H-5-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-6-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;    3-(Octahydro-7-indolizinyl)-1H-6-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;    1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;    1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;    1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-7-azaindole;    1-(4-Fluorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;    1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;    1-(4-Fluorobenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;    1-(4-Methoxybenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;    1-(4-Methoxybenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;    1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;    1-Benzoyl-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-7-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-7-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl)-7-azaindole;    3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole;    3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-7-azaindole;    3-(Octahydro-7-indolizinyl)-1H-7-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1- naphthalenesulfonyl)-7-azaindole;    3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;    3-(Octahydro-7-indolizinyl)-4-(1-benzenesulfonyl-7-azaindole;    3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole; and    3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole.    
     
     
         11 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and, in an amount effective to antagonize the 5-HT 6  receptor, a compound of Formula I, or a salt, solvate or hydrate thereof.  
     
     
         12 . A method for treating a patient having a medical condition for which a 5-HT 6  antagonist is indicated, comprising the step of administering to the patient a pharmaceutical composition comprising a compound of    claim 1   , or a salt or solvate thereof.