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 (5 a ) 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 method of inhibiting replication of an HIV virion, comprising contacting a cell comprising an HIV virion with a nucleotide analog compound according structure (Ia):  
       
         
           
           
               
               
           
         
       
       and/or a salt and/or solvate thereof, wherein: 
 R 6a  is selected from hydrogen and phenyl;  
 R 6b  is selected from hydrogen, methyl, ethyl and isopropyl; and  
 R 7  is selected from methyl, ethyl and benzyl, and which comprises at least about 60% by weight a diastereomer according to structure (Ib):  
                     
 
     
     
         2 . The method of  claim 1  in which the nucleotide analog compound, salt and/or solvate comprises at least about 80% by weight the diastereomer of structure (Ib).  
     
     
         3 . The method of  claim 1  in which the nucleotide analog compound, salt and/or solvate comprises at least about 95% by weight the diastereomer of structure (Ib).  
     
     
         4 . The method of  claim 1  in which the nucleotide analog compound, salt and/or solvate is substantially free of the diastereomer of structure (Ic):  
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1  in which in which the nucleotide analog compound, salt and/or solvate is selected from Metabolite Y, Metabolite X, GS-6957a, GS-7003a, GS-7119, GS-7114, GS-7340, and GS-7342.  
     
     
         6 . The method of  claim 1  in which the nucleotide analog compound is in the form of a salt.  
     
     
         7 . The method of  claim 6  in which the salt is a 1:1 fumarate salt.  
     
     
         8 . A method of treating an HIV infection, comprising administering to a subject having an HIV infection a therapeutically effective amount of a nucleotide analog compound according structure (Ia):  
       
         
           
           
               
               
           
         
       
       and/or a salt and/or solvate thereof, wherein: 
 R 6a  is selected from hydrogen and phenyl;  
 R 6b  is selected from hydrogen, methyl, ethyl and isopropyl; and  
 R 7  is selected from methyl, ethyl and benzyl, and which comprises at least about 60% by weight a diastereomer according to structure (Ib):  
                     
 
     
     
         9 . The method of  claim 8  in which the nucleotide analog compound, salt and/or solvate comprises at least about 80% by weight the diastereomer of structure (Ib).  
     
     
         10 . The method of  claim 8  in which the nucleotide analog compound, salt and/or solvate comprises at least about 95% by weight the diastereomer of structure (Ib).  
     
     
         11 . The method of  claim 8  in which the nucleotide analog compound, salt and/or solvate is substantially free of the diastereomer of structure (Ic):  
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 8  in which in which the nucleotide analog compound, salt and/or solvate is selected from Metabolite Y, Metabolite X, GS-6957a, GS-7003a, GS-7119, GS-7114, GS-7340, and GS-7342.  
     
     
         13 . The method of  claim 8  in which the nucleotide analog compound is in the form of a salt.  
     
     
         14 . The method of  claim 13  in which the salt is a 1:1 fumarate salt.  
     
     
         15 . The method of  claim 8  in which the nucleotide analog compound is administered in the form of a pharmaceutical composition comprising the nucleotide analog compound and a pharmaceutically acceptable excipient.  
     
     
         16 . The method of any one of  claim 8  in which the nucleotide analog compound is administered orally.  
     
     
         17 . A method of preventing an HIV infection in a subject, comprising administering to the subject a prophylactically effective amount of a nucleotide analog compound according structure (Ia):  
       
         
           
           
               
               
           
         
       
       and/or a salt and/or solvate thereof, wherein: 
 R 6a  is selected from hydrogen and phenyl;  
 R 6b  is selected from hydrogen, methyl, ethyl and isopropyl; and  
 R 7  is selected from methyl, ethyl and benzyl, and which comprises at least about 60% by weight a diastereomer according to structure (Ib):  
                     
 
     
     
         18 . The method of  claim 17  in which the nucleotide analog compound, salt and/or solvate comprises at least about 80% by weight the diastereomer of structure (Ib).  
     
     
         19 . The method of  claim 17  in which the nucleotide analog compound, salt and/or solvate comprises at least about 95% by weight the diastereomer of structure (Ib).  
     
     
         20 . The method of  claim 17  in which the nucleotide analog compound, salt and/or solvate is substantially free of the diastereomer of structure (Ic):  
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 17  in which in which the nucleotide analog compound, salt and/or solvate is selected from Metabolite Y, Metabolite X, GS-6957a, GS-7003a, GS-7119, GS-7114, GS-7340, and GS-7342.  
     
     
         22 . The method of  claim 17  in which the nucleotide analog compound is in the form of a salt.  
     
     
         23 . The method of  claim 22  in which the salt is a 1:1 fumarate salt.  
     
     
         24 . The method of  claim 17  in which the nucleotide analog compound is administered in the form of a pharmaceutical composition comprising the nucleotide analog compound and a pharmaceutically acceptable excipient.  
     
     
         25 . The method of  claim 17  in which the nucleotide analog compound is administered orally.  
     
     
         26 . A method of selectively delivering (R)-9-[2-(phosphonomethoxy)propyl]adenine to lymphoid tissue and/or non-lymphoid tissue enriched in lymphoid cells, comprising administering to a subject comprising such lymphoid and/or non-lymphoid tissue a prodrug compound according to structural formula (Ia):  
       
         
           
           
               
               
           
         
       
       and/or a salt and/or solvate thereof, wherein: 
 R 6a  is selected from hydrogen and phenyl;  
 R 6b  is selected from hydrogen, methyl, ethyl and isopropyl; and  
 R 7  is selected from methyl, ethyl and benzyl, and which comprises at least about 60% by weight a diastereomer according to structure (Ib):