Water-soluble prodrugs of azole compounds

Abstract

Water soluble prodrugs of azole antifungal agents are provided by quaternizing a nitrogen atom of the azole ring with a phosphonooxymethyl group.

What is claimed is:  
     
         1 . A compound of the formula  
                   
       wherein R and R 1  are each independently hydrogen or (C 1 -C 6 )alkyl, Z is nitrogen or CH, Q is the residue of an azole compound of the formula  
                 
 
       possessing antifungal activity, X {circle over (-)}  is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.  
     
     
         2 . A compound of    claim 1    wherein R and R 1  are both hydrogen.  
     
     
         3 . A compound of the formula  
                   
       wherein Z is N, R and R 1  are each independently hydrogen or (C 1 -C 6 )alkyl, Q is  
                 
 
       X {circle over (-)}  is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.  
     
     
         4 . A compound of the formula  
                   
       wherein Z is CH, R and R 1  are each independently hydrogen or (C 1 -C 6 )alkyl, Q is  
                 
 
       X {circle over (-)}  is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.  
     
     
         5 . A compound of    claim 3    or    claim 4    wherein R and R 1  are both hydrogen.  
     
     
         6 . A compound of the formula  
                   
        and its racemate wherein R and R 1  are each independently hydrogen or (C 1 -C 6 )alkyl and X{circle over (-)} is a pharmaceutically acceptable anion.  
     
     
         7 . A compound of    claim 6    wherein R and R 1  are both hydrogen.  
     
     
         8 . A compound of the formula  
                   
       wherein R and R 1  are each independently hydrogen or (C 1 -C 6 )alkyl, X {circle over (-)}  is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.  
     
     
         9 . The compound, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H, 4-phosphonooxymethyl-1,2,4-triazol-1-yl) butan-2-ol, or a pharmaceutically acceptable salt thereof.  
     
     
         10 . A method for the treatment of fungal infections, which comprises administering an effective antifungal amount of a compound of    claim 1    to a mammalian host in need thereof.  
     
     
         11 . A pharmaceutical composition comprising a compound of    claim 1    in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.