Amide compounds

Abstract

This invention relates to new amide compounds having the potentiation of the cholinergic activity, etc., and represented by general formula [I]. wherein R 1 is acyl, R 2 is lower alkyl, etc., A is a single bond,  or —SO 2 —, E is lower alkylene, etc, X is CH or N, Y is a single bond, etc., Q is —CH 2 —, etc., and R 3 and R 4 are taken together to form lower alkylene, etc., and pharmaceutically acceptable salts thereof, to processes for preparation thereof and a pharmaceutical composition comprising the same.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is acyl,  
 R 2  is lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower alkenyloxy, lower alkenylamino, lower alkynyl, lower alkynyloxy, lower alkynylamino, cyclo(lower)alkyl, cyclo(lower)alkyloxy, cyclo(lower)alkylamino, aryl, aryloxy, arylamino, a heterocyclic group or amino substituted with a heterocyclic group, each of which may be substituted with suitable substituent(s); or acyl;  
 A is a single bond,  
                     
  or —SO 2 —,  
 E is lower alkylene optionally substituted with suitable substituent(s),  
 X is CH or N,  
 Y is a single bond, lower alkylene or  
                     
  (wherein R 5  is hydrogen, lower alkyl, substituted-lower alkyl, an N-protective group, aryl, acyl or a heterocyclic group),  
 Q is —CH 2 —,  
                     
  —SO 2 — or —N═CH—, and  
 R 3  and R 4  are each hydrogen or lower alkyl, or are taken together to form lower alkylene optionally condensed with a cyclic hydrocarbon or a heterocyclic ring,  
 provided that when X is N,  
 then 1) Y is a single bond, and Q is —CH 2 —,  
                     
  or —SO 2 —, or  
 2) Y is lower alkylene,  
 and pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound according to  claim 1 , wherein 
 R 2  is aryl, aryloxy or arylamino, each aryl of which may be substituted with halogen; pyridyl; or pyridylamino;    A is a single bond,    E is ethylene,    X is CH or N, R 5      Y is a single bond, lower alkylene or                           (wherein R 5  is hydrogen, lower alkyl or an N-protective group),    Q is —CH 2 —,                           or —SO 2 —, and    R 3  and R 4  are taken together to form ethylene.    
     
     
         3 . A compound according to  claim 2 , wherein 
 R 1  is lower alkanoyl, esterified carboxy, substituted or unsubstituted aroyl, lower alkylsulfonyl, substituted or unsubstituted arylsulfonyl, or cyclo(lower)alkylcarbonyl, and    R 2  is aryl or arylamino, each aryl of which may be substituted with halogen.    
     
     
         4 . A compound according to  claim 3 , wherein 
 R 1  is lower alkanoyl, lower alkoxycarbonyl, aroyl, aroyl substituted with halo(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl substituted with halogen, or cyclo(lower)alkylcarbonyl,    X is CH, H    Y is a single bond or                          and    Q is                           or —SO 2 —.    
     
     
         5 . A compound according to  claim 3 , wherein 
 R 1  is lower alkanoyl, lower alkoxycarbonyl, aroyl, aroyl substituted with halo(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl substituted with halogen, or cyclo(lower)alkylcarbonyl,    X is N,    Y is a single bond or lower alkylene, and    Q is                           or —SO 2 —.    
     
     
         6 . A compound according to  claim 4 , wherein 
 Y is                          and    Q is                          
     
     
         7 . A compound according to  claim 5 , wherein 
 Y is a single bond, and    Q is                          
     
     
         8 . A process for preparing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is acyl,  
 R 2  is lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower alkenyloxy, lower alkenylamino, lower alkynyl, lower alkynyloxy, lower alkynylamino, cyclo(lower)alkyl, cyclo(lower)alkyloxy, cyclo(lower)alkylamino, aryl, aryloxy, arylamino, a heterocyclic group or amino substituted with a heterocyclic group, each of which may be substituted with suitable substituent(s); or acyl;  
 A is a single bond,  
                     
  or —SO 2 —,  
 E is lower alkylene optionally substituted with suitable substituent(s),  
 X is CH or N  
 Y is a single bond, lower alkylene or  
                     
  (wherein R 5  is hydrogen, lower alkyl, substituted-lower alkyl, an N-protective group, aryl, acyl or a heterocyclic group),  
 Q is —CH 2 —,  
                     
  —SO 2 — or —N═CH—, and  
 R 3  and R 4  are each hydrogen or lower alkyl, or are taken together to form lower alkylene optionally condensed with a cyclic hydrocarbon or a heterocyclic ring,  
 provided that when X is N,  
 then 1) Y is a single bond, and  
 Q is —CH 2 —,  
                     
  or —SO 2 —, or  
 2) Y is lower alkylene,  
 or pharmaceutically acceptable salt thereof, which comprises,  
 1) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    HO-Q a -R 2   [III]   or its reactive derivative at the carboxy or sulfo group, or a salt thereof to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 2 , R 3 , R 4 , A and E are each as defined above, and Q a  is                           or —SO 2 —, or    
 2) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    R 6 —NCO  [IV]   to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 3 , R 4 , A and E are each as defined above, and    R 6  is aryl which may be substituted with suitable substituent(s); or pyridyl, or    
 3) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    HO-Q a -R 2   [III]   or its reactive derivative at the carboxy or sulfo group, or a salt thereof to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 2 , R 3 , R 4 , A, E and Q a  are each as defined above, or    
 4) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    R 6 —NCO  [IV]   to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 3 , R 4 , R 6 , A and E are each as defined above, or    
 5) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    R 1 -A-OH  [VII]   or its reactive derivative at the carboxy or sulfo group, or a salt thereof to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 2 , R 3 , R 4 , A, E, X, Y and Q are each as defined above, or    
 6) reacting a compound of the formula:  
                     or its reactive derivative at the carboxy or sulfo group, or a salt thereof with a compound of the formula:    H 2 N—R 7   [IX]   or its salt to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 3 , R 4 , A, E, X and Q a  are each as defined above, and    R 7  is lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, aryl or a heterocyclic group, each of which may be substituted with suitable substituent(s), or    
 7) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    R a   2 -Q b -Z a   [XI]   to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 3 , R 4 , A and E are each as defined above,    R a   5  is an N-protective group,    R a   2  is lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, aryl or a heterocyclic group, each of which may be substituted with suitable substituent(s),    Q b  is —CH 2 —,                           —SO 2 —, and    Z a  is an acid residue, or    
 8) subjecting a compound of the formula:  
                     or its salt to elimination reaction of the N-protective group to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R a   2 , R 3 , R 4 , A, E and Q b , are each as defined above, or    
 9) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    R b   5 -Z b   [XII]   to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R a   2 , R 3 , R 4 , A and E are each as defined above,    Z b  is an acid residue,    Q c  is                           and    R b   5  is lower alkyl, or    
 10) reacting a compound of the formula:  
                     or its salt with a compound of the formula:    Z c -Y a —Q a -R 2   [XIII]   to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 2 , R 3 , R 4 , A, E and Q a  are each as defined above,    Z c  is an acid residue, and    Y a  is lower alkylene.    
 
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1 , as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.  
     
     
         10 . A compound of  claim 1  for use as a medicament.  
     
     
         11 . A method for therapeutic treatment and/or prevention of amnesia or dementia which comprises administering an effective amount of a compound of  claim 1  to mammals.  
     
     
         12 . Use of a compound of  claim 1  for manufacture of a medicament for treating and/or preventing amnesia or dementia in mammals.