Positive allosteric AMPA receptor modulators (PAARM), processes for preparing them, and their use as pharmaceutical compositions

Abstract

Compounds of formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, and m, are as defined herein, or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof; processes for preparing these compounds, and their use in pharmaceutical compositions.

We claim:  
     
         1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, —SO 2 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —CO—C 1 -C 6 -alkyl, —O, phenyl-C 1 -C 4 -alkyl, —C 1 -C 4 -alkyl-NR 6 R 7 , and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl, and C 3 -C 6 -cycloalkyl,  
 R 2  and R 3 , which are identical or different, are each a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —NO 2 , —SO 2 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —CO—C 1 -C 6 -alkyl, —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —C 1 -C 4 -alkyl-NR 6 R 7 , and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl, and C 3 -C 6 -cycloalkyl, or  
 R 1  and R 2  together are a C 4 -C 6 -alkylene bridge;  
 R 6  and R 7 , which are identical or different, are each hydrogen, C 1 -C 4 -alkyl, or —CO—C 1 -C 4 -alkyl;  
 R 4 , each of which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, —CN, —NO 2 , —SO 2 H, —SO 3 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —SO 2 —NR 6 R 7 , —COOH, —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —NR 6 R 7  and an aryl group optionally mono or polysubstituted by halogen atoms, —NO 2 , —SO 2 H, or C 1 -C 4 -alkyl;  
 R 5 , each of which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, —CN, —NO 2 , —SO 2 H, —SO 3 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —SO 2 —NR 6 R 7 , —COOH, —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —NR 6 R 7 , and an aryl group optionally mono or polysubstituted by halogen atoms, —NO 2 , —SO 2 H, or C 1 -C 4 -alkyl; and  
 n and m, which are identical or different, are each 0, 1, 2, or 3,  
 with the proviso that naphtho[1,8-de]-2,3-dihydro-1,1-dioxide-1,2-thiazine is excluded,  
 or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof.  
 
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein: 
 R 1  is a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, —SO 2 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —CO—C 1 -C 6 -alkyl, —O—C 1 -C 4 -alkyl-NR 7 R 8 , and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl, benzyl,    R 2  and R 3 , which are identical or different, are each a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —NO 2 , —SO 2 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —CO—C 1 -C 6 -alkyl, —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —C 1 -C 4 -alkyl-NR 6 R 7 , and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl, or    R 1  and R 2  together are a C 4 -C 6 -alkylene bridge;    R 6  and R 7 , which are identical or different, are each hydrogen, C 1 -C 4 -alkyl, or —CO—C 1 -C 2 -alkyl, and    R 4 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —CN, —NO 2 , —SO 2 H, —SO 3 H, —COOH, —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, and —NR 6 R 7 ;    R 5 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —CN, —NO 2 , —SO 2 H, —SO 3 H, —COOH, —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, and —NR 6 R 7 ; and    n and m, which are identical or different, are each 0, 1, or 2,    or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof.    
     
     
         3 . The compound of formula (I) according to  claim 1 , wherein: 
 R 1  is hydrogen, C 1 -C 4 -alkyl, or benzyl,    R 2  and R 3 , which are identical or different, are each hydrogen or C 1 -C 4 -alkyl, or    R 1  and R 2  together are a butylene bridge;    R 4 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —CN, —NO 2 , —COOH, —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, -CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, and —NR 6 R 7 ;    R 5 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —CN, —NO 2 , —COOH, —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, and —NR 6 R 7 ; and    n and m, which are identical or different, are each 0, 1, or 2,    or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof.    
     
     
         4 . The compound of formula (I) according to  claim 1 , wherein: 
 R 1 , R 2 , R 3 , which are identical or different, are each hydrogen or C 1 -C 4 -alkyl;    R 4 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —NO 2 , —O—CO—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —O—C 1 -C 6 -alkyl, and —NR 6 R 7 ;    R 5 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —NO 2 , —O—CO—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —O—C 1 -C 6 -alkyl, and —NR 6 R 7 ; and    n and m, which are identical or different, are each 0, 1, or 2,    or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof.    
     
     
         5 . The compound of formula (I) according to  claim 1 , wherein: 
 R 1  is methyl, ethyl, isopropyl, n-butyl, or benzyl,    or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof.    
     
     
         6 . The compound of formula (I) according to  claim 1 , wherein: 
 R 1  is methyl,    or a pharmacologically acceptable salt thereof.    
     
     
         7 . The compound of formula (I) according to  claim 1 , wherein: 
 R 1  is methyl;    R 2  and R 3  are each hydrogen;    R 4  and R 5 , which are identical or different, are each halogen; and    n and m, which are identical or different, are each 0, 1, or 2,    or a pharmacologically acceptable salt thereof.    
     
     
         8 . A compound of general formula (I)  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, —SO 2 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —CO—C 1 -C 6 -alkyl, —O, phenyl-C 1 -C 4 -alkyl, —C 1 -C 4 -alkyl-NR 6 R 7 , and —C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl, and C 3 -C 6 -cycloalkyl,  
 R 2  and R 3 , which are identical or different, are each a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, —NO 2 , —SO 2 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —CO—C 1 -C 6 -alkyl, —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —C 1 -C 4 -alkyl-NR 6 R 7 , —C 1 -C 4 -alkyl-O—, C 1 -C 4 -alkyl, and C 3 -C 6 -cycloalkyl, or  
 R 1  and R 2  together are a C 4 -C 6 -alkylene bridge;  
 R 6  and R 7 , which are identical or different, are each hydrogen, C 1 -C 4 -alkyl, or —CO—C 1 -C 4 -alkyl;  
 R 4 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, —CN, —NO 2 , —SO 2 H, —SO 3 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —SO 2 —NR 6 R 7 , —COOH, —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —NR 6 R 7 , and an aryl group optionally mono or polysubstituted by halogen atoms, —NO 2 , —SO 2 H, or C 1 -C 4 -alkyl;  
 R 5 , which are identical or different, are each a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, —CN, —NO 2 , —SO 2 H, —SO 3 H, —SO 2 —C 1 -C 6 -alkyl, —SO—C 1 -C 6 -alkyl, —SO 2 —NR 6 R 7 , —COOH —CO—C 1 -C 6 -alkyl, —O—CO—C 1 -C 4 -alkyl, —CO—O—C 1 -C 4 -alkyl, —O—CO—O—C 1 -C 4 -alkyl, —CO—NR 6 R 7 , —OH, —O—C 1 -C 6 -alkyl, —S—C 1 -C 6 -alkyl, —NR 6 R 7 , and an aryl group optionally mono or polysubstituted by halogen atoms, —NO 2 , —SO 2 H, or C 1 -C 4 -alkyl; and  
 n and m, which are identical or different, are each 0, 1, 2, or 3,  
 or an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof.  
 
     
     
         9 . A pharmaceutical composition comprising: 
 (a) a compound of general formula (I) according to  claim 1;  and    (b) a pharmaceutically acceptable excipient or carrier.    
     
     
         10 . A pharmaceutical composition comprising: 
 (a) a compound of general formula (I) according to  claim 8;  and    (b) a pharmaceutically acceptable excipient or carrier.    
     
     
         11 . A method of treating neurodegenerative diseases and/or cerebral ischaemia of various origins in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of formula (I) according to one of  claims 1  to  8 .  
     
     
         12 . A method of treating schizophrenia in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of formula (I) according to one of  claims 1  to  8 .  
     
     
         13 . A method of treating memory disorders in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of formula (I) according to one of  claims 1  to  8 .  
     
     
         14 . A method of treating dementias in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of formula (I) according to one of  claims 1  to  8 .