Cubane derivatives as metabotropic glutamate receptor antagonists and process for their preparation

Abstract

Thee present invention relates to therapeutically active cubane compounds, a method of preparing the same, and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in creating diseases of the central nervous system related to the metabotropic glutamate receptor system.

We claim:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R1 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, —CH 2 -carboxyl, —CH 2 -phosphono, —CH 2 -phosphino, —CH 2 -sulfono, —CH 2 -sulfino, —CH 2 -borono, —CH 2 -tetrazol, and —CH 2 -isoxazol;  
 R2 can be a basic group selected from the group consisting of 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea, thiourea,  
 R3 can be H, aliphatic, aromatic or heterocyclic;  
 R4 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol; and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound as claimed in  claim 1 , wherein R1 is COOH  
     
     
         3 . A compound as claimed in  claim 1 , wherein R2 is COOH  
     
     
         4 . A compound as claimed in  claim 1 , wherein R3 can be —H, or -Me; or xanthyl or thioxanthyl and R4 is NH 2    
     
     
         5 . A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable metabolically-labile ester or amide thereof, or a pharmaceutically acceptable salt thereof, which comprises:  
       (a) hydrolyzing a compound of formula:  
       
         
           
           
               
               
           
         
       
       in which R1 is defined as above, R5 represents a hydrogen atom or an acyl group and R4 has the meaning defined above. Preferred values for R5 are hydrogen and (2-6C), alkanoyl groups, such as acetyl;  
       (b) hydrolyzing a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein R6 and R7 each independently represent a hydrogen atom, a (2-6C) alkanoyl group, a (1-4C) alkyl group, a (3-4C) alkenyl group or a phenyl (1-4C) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (1-4C) alkyl or (1-4C) alkoxy, or a salt thereof; or  
       (c) deprotecting a compound of formula:  
       
         
           
           
               
               
           
         
       
       in which R8 represents a hydrogen atom or a carboxyl protecting group, or a salt thereof, and R9 represents a hydrogen atom or a nitrogen protecting group;  
       whereafter, if necessary and/or desired.  
       (i) resolving the compound of Formula I;  
       (ii) converting the compound of Formula I into a non-toxic metabolically-labile ester or amide thereof; and/or;  
       (iii) converting the compound of Formula I or a non-toxic metabolically-labile ester or amide thereof into a pharmaceutically acceptable salt thereof.  
     
     
         6 . A pharmaceutical formulation, which comprises a compound as claimed in  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient.  
     
     
         7 . A method of modulating one or more metabotropic glutamate receptor functions in a warm blooded mammal requiring such treatment, which comprises administering an effective amount of a compound as claimed in  claim 1 .  
     
     
         8 . A compound of formula:  
       
         
           
           
               
               
           
         
         in which R1, R4 and R5 have the meanings as defined above.  
       
     
     
         9 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein R6 and R7 have meanings as defined above.  
     
     
         10 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       in which R8 and R9 have meanings as defined above.