Sustituted 2,3,4,5-tetrahydro-1h-pyrido[4,3-b]indoles, methods for use thereof

Abstract

The present invention relates to a method of antagonizing a 5-HT 6 serotonin receptor and simultaneously regulating Ca +2 ion homeostasis in a cell, comprising administering to the cell a compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a C 1 -C 5 alkyl; R 2 i is independently hydrogen, halogen, a C 1 -C 3 alkyl, CF 3 , OCF 3 or OCH 3 ; i is 1, 2, 3 or 4; Ar is an unsubstituted phenyl or a substituted phenyl substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted amino group or trifluoromethyl; or Ar is a substituted or unsubstituted 6-membered aromatic heterocycle with one or two nitrogen atoms in the heterocycle; and W is an ethylene group —CH 2 —CH 2 —, ethenyl group —CH═CH—, or ethynyl group —C≡C—. The invention also relates to new compounds selected from the group of compounds of the general formula 1, method for their preparation, pharmaceutical compositions and method for treating a cognitive disorder or neurodegenerative disease, or obesity in a subject in need thereof comprising administering an effective dose to the subject of a compound of formula 1 according to claim 1 , or a pharmaceutically acceptable salt thereof.

1 . A method of antagonizing a 5-HT 6  serotonin receptor and simultaneously regulating Ca +2  ion homeostasis in a cell, comprising administering to the cell a compound of formula 1, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is a C 1 -C 5  alkyl; 
         R 2   i  is independently hydrogen, halogen, a C 1 -C 3  alkyl, CF 3 , OCF 3  or OCH 3 ; 
         i is 1, 2, 3 or 4; 
         Ar is an unsubstituted phenyl or a substituted phenyl substituted with halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted amino group or trifluoromethyl; or Ar is a substituted or unsubstituted 6-membered aromatic heterocycle with one or two nitrogen atoms in the heterocycle; and 
         W is an ethylene group —CH 2 —CH 2 —. 
       
     
     
         2 . The method of  claim 1 , wherein the compound is a compound of formula 1.2, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 2 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A method for treating a cognitive disorder or neurodegenerative disease, or obesity in a subject in need thereof comprising administering an effective dose to the subject of a compound of formula 1, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is a C 1 -C 5  alkyl; 
         R 2   i  is independently hydrogen, halogen, a C 1 -C 3  alkyl, CF 3 , OCF 3  or OCH 3 ; 
         i is 1, 2, 3 or 4; 
         Ar is an unsubstituted phenyl or a substituted phenyl substituted with halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted amino group or trifluoromethyl; or Ar is a substituted or unsubstituted 6-membered aromatic heterocycle with one or two nitrogen atoms in the heterocycle; and 
         W is an ethylene group —CH 2 —CH 2 —, ethenyl group —CH═CH—, or ethynyl group —C≡C—. 
       
     
     
         5 . The method of  claim 4  of treating Alzheimer's disease, Huntington's disease, a psychotic disorder, schizophrenia, depression, an anxiety disorder, hypoxia-ischemia, a convulsive state, cerebral damage, lathyrism, amyotrophic lateral sclerosis, or premature senility. 
     
     
         6 . The method of  claim 4  of treating obesity. 
     
     
         7 . The method of  claim 4 , wherein the compound is a compound of formula 1.1, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein R 3  is —CH═CH—Ar group. 
       
     
     
         8 . The method of  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The method of  claim 4 , wherein the compound is a compound of formula 1.2, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 9 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 4 , wherein the compound is a compound of formula 1.3, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.