Prodrugs of phosphonate nucleotide analogues

Abstract

A novel method has led to the identification of novel mixed ester-amidates of PMPA for retroviral or hepadnaviral therapy, including compounds of structure (5a) having substituent groups as defined herein. Compositions of these novel compounds in pharmaceutically acceptable excipients and their use in therapy and prophylaxis are provided.

1 . A composition comprising a pharmaceutically acceptable excipient and a nucleotide analog compound and/or a salt and/or a solvate thereof, wherein the nucleotide analog compound has the structure (Ia):  
       
         
           
           
               
               
           
         
         and comprises at least about 80% by weight a diastereomer according to structure (Ib):  
         
           
             
             
                 
                 
             
           
         
       
     
     
         2 . The composition of  claim 1  in which the nucleotide analog compound is in the form of a salt.  
     
     
         3 . The composition of  claim 2  in which the salt is a fumarate salt.  
     
     
         4 . The composition of  claim 1  in which the nucleotide analog compound comprises at least about 95% by weight the diastereomer according to structure (Ib).  
     
     
         5 . The composition of  claim 4  in which the nucleotide analog compound is in the form of a salt.  
     
     
         6 . The composition of  claim 5  in which the salt is a fumarate salt.  
     
     
         7 . The composition of  claim 1  in which the nucleotide analog compound comprises at least about 99% by weight the diastereomer according to structure (Ib).  
     
     
         8 . The composition of  claim 7  in which the nucleotide analog compound is in the form of a salt.  
     
     
         9 . The composition of  claim 8  in which the salt is a fumarate salt.  
     
     
         10 . The composition of  claim 1  in which the nucleotide analog compound comprises at least about 95% by weight a fumarate salt according to structure (Ic):  
       
         
           
           
               
               
           
         
       
     
     
         11 . A composition comprising substantially pure 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine, and/or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable excipient.  
     
     
         12 . A composition comprising substantially pure 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate (1:1) and a pharmaceutically acceptable excipient.