Acylaminothiazole derivatives, their preparation and their therapeutic use

Abstract

The invention relates to a compound corresponding to the general formula (I): wherein, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ and R 6 are as defined herein. More specifically, this invention relates to intermediates to prepare a compound of formula (I) as well as its utility in treating a variety of diseases including Alzheimer's disease and Parkinson's disease.

1 . A compound of formula (VI):  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents an oxygen atom;  
 R 2  represents a C 1-4  alkyl group optionally substituted with a C 4-7  cycloalkyl or phenyl group; 
 a C 4-7  cycloalkyl, piperidinyl or phenyl group;  
 the C 4-7  cycloalkyl, piperidinyl and phenyl groups being optionally substituted with 1 or 2 C 1-3  alkyl or C 1-3  alkoxy groups;  
 
 R 4  represents a hydrogen atom or a methyl;  
 R 6  represents a hydrogen atom or a methoxy; and  
 Pg represents a diphenyl ketone imine.  
 
     
     
         2 . A compound of formula (VII):  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents an oxygen atom;  
 R 2  represents a C 1-4  alkyl group optionally substituted with a C 4-7  cycloalkyl or phenyl group; 
 a C 4-7  cycloalkyl, piperidinyl or phenyl group;  
 the C 4-7  cycloalkyl, piperidinyl and phenyl groups being optionally substituted with 1 or 2 C 1-3  alkyl or C 1-3  alkoxy groups;  
 
 R 4  represents a hydrogen atom or a methyl; and  
 R 6  represents a hydrogen atom or a methoxy.  
 
     
     
         3 . A compound of formula (XIII)  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents an oxygen atom;  
 R 2  represents a C 1-4  alkyl group optionally substituted with a C 4 A7 cycloalkyl or phenyl group; 
 a C 4-7  cycloalkyl, piperidinyl or phenyl group;  
 the C 4-7  cycloalkyl, piperidinyl and phenyl groups being optionally substituted with 1 or 2 C 1-3  alkyl or C 1-3  alkoxy groups;  
 
 R 3  represents a methyl, ethyl or propyl;  
 R 4  represents a hydrogen atom or a methyl; and  
 R 6  represents a hydrogen atom or a methoxy.  
 
     
     
         4 . A method for treating a disease selected from the group consisting of senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyloid angiopathy and cerebrovascular disorders, which comprises administering to a patient in need of said treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein,  
         n is equal to 0, 1, 2 or 3;  
         X represents an oxygen or sulfur atom;  
         R 1  represents, independently of each other when 
 n=2 or 3, a halogen atom, a hydroxyl, a C 1-3  alkyl, a C 1-3  alkoxy, a trifluoromethyl, a trifluoromethyloxy or a methylenedioxy;  
 
         R 2  represents a C 1-6  alkyl group optionally substituted with a C 3-7  cycloalkyl group, a phenyl, a C 1-3  alkoxy group, a hydroxyl or a halogen atom; 
 a C 3-7  cycloalkyl, piperidinyl or phenyl group;  
 the C 3-7  cycloalkyl, piperidinyl and phenyl groups being optionally substituted with one or more C 1-3  alkyl groups, C 1-3  alkoxy groups, a hydroxyl or a halogen atom;  
 
         R 3  represents a hydrogen atom or a C 1-6  alkyl group optionally substituted with a C 3-7  cycloalkyl group;  
         R 4  represents a hydrogen atom or a C 1-4  alkyl group;  
         R 5  and R 5′  represent, independently of each other, a hydrogen atom, a hydroxyl, a halogen atom, a C 1-3  alkyl group; or R 5  and R 5 ′ form together an oxo group; and  
         R 6  represents a hydrogen atom, a halogen atom, a C 1-3  alkyl, a C 1-3  alkoxy, a trifluoromethyl or a trifluoromethoxy.  
       
     
     
         5 . The method according to  claim 4 , wherein 
 X represents an oxygen or sulfur atom;    R 1  represents, independently of each other when n=2 or 3, a halogen atom, a methylenedioxy, a C 1-3  alkyl group, a C 1-3  alkoxy group or a trifluoromethyloxy;    R 2  represents a C 1-4  alkyl group optionally substituted with a C 4-7  cycloalkyl or phenyl group; 
 a C 4-7  cycloalkyl, piperidinyl or phenyl group;  
 the C 4-7  cycloalkyl, piperidinyl and phenyl groups being optionally substituted with one or more C 1-3  alkyl or C 1-3  alkoxy groups;  
   R 3  represents a hydrogen atom or a C 1-4  alkyl group, optionally substituted with a C 4-7  cycloalkyl group;    R 4  represents a hydrogen atom or a C 1-3  alkyl group;    R 5  and R 5′  represent, independently of each other, a hydrogen or halogen atom, a hydroxyl or a C 1-3  alkyl group; or R 5  and R 5′  form together an oxo group; and    R 6  represents a hydrogen atom or a C 1-3  alkoxy.    
     
     
         6 . The method according to  claim 4 , wherein 
 X represents an oxygen atom;    R 1  represents, independently of each other when n=2 or 3, a halogen atom;    R 2  represents a C 1-4  alkyl group optionally substituted with a C 4-7  cycloalkyl or phenyl group; 
 a C 4-7  cycloalkyl, piperidinyl or phenyl group;  
 the C 4-7  cycloalkyl, piperidinyl and phenyl groups being optionally substituted with 1 or 2 C 1-3  alkyl or C 1-3  alkoxy groups;  
   R 3  represents a methyl, ethyl or propyl;    R 4  represents a hydrogen atom or a methyl;    R 5  and R 5′  represent, independently of each other, a hydrogen or fluorine atom, a hydroxyl or a methyl; or R 5  and R 5′  form together an oxo group; and    R 6  represents a hydrogen atom or a methoxy.    
     
     
         7 . The method according to  claim 4 , wherein the disease is senile dementia.  
     
     
         8 . The method according to  claim 4 , wherein the disease is Alzheimer's disease.  
     
     
         9 . The method according to  claim 4 , wherein the disease is Down's syndrome.  
     
     
         10 . The method according to  claim 4 , wherein the disease is Parkinson's disease.  
     
     
         11 . The method according to  claim 4 , wherein the disease is amyloid angiopathy.  
     
     
         12 . The method according to  claim 4 , wherein the disease is cerebrovascular disorders.