Phosphonates with reduced toxicity for treatment of viral infections

Abstract

There are provided, inter alia, acyclic nucleoside phosphonate compounds having reduced toxicity and enhanced antiviral activity, and pharmaceutically accepted salts and solvates thereof. There are also provided methods of using the disclosed compounds for inhibiting viral RNA-dependent RNA polymerase, inhibiting viral reverse transcriptase, inhibiting replication of virus, including hepatitis C virus or a human retrovirus, and treating a subject infected with a virus, including hepatitis C virus or a human retrovirus.

What is claimed is: 
     
         1 . A compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         wherein
 B N  is a substituted or unsubstituted nucleobase; 
 L 1  is a bond or —O—; 
 R 1  is halogen, —CF 3 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; 
 provided that, if L 1  is a bond, then R 1  is halogen, and
 if L 1  is —O—, then R 1  is —CF 3 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; and 
 
 R 2  is a permeability enhancing moiety, a phosphate, or a diphosphate; 
 
       
       or pharmaceutically accepted salt or solvate thereof. 
     
     
         2 . The compound of  claim 1 , wherein B N  is unsubstituted adenine, substituted adenine, unsubstituted thymine, substituted thymine, unsubstituted guanine, substituted guanine, unsubstituted cytosine, substituted cytosine, unsubstituted uracil, substituted uracil, 2,6-diaminopurine, 6-methoxypurine, or 6-O-methylguanine. 
     
     
         3 . The compound of  claim 1 , with structure of Formula (Ia): 
       
         
           
           
               
               
           
         
         wherein
 L 1  is —O—, and R 1  is —CF 3 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. 
 
       
     
     
         4 . The compound of  claim 1 , wherein R 1  is unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is unsubstituted C 1 -C 10  alkyl. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is methyl, ethyl or isopropyl. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is unsubstituted cycloalkyl. 
     
     
         8 . The compound of  claim 1 , wherein R 1  is unsubstituted aryl. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is phenyl. 
     
     
         10 . The compound of  claim 1 , wherein R 1  is substituted alkyl, substituted cycloalkyl, or substituted aryl. 
     
     
         11 . The compound of  claim 1 , with structure of Formula (Ib): 
       
         
           
           
               
               
           
         
         wherein L 1  is a bond, and R 1  is halogen. 
       
     
     
         12 . The compound of  claim 11 , wherein R 1  is fluoro. 
     
     
         13 . The compound of  claim 1 , wherein R 2  has the structure of Formula (II):
   -L 2 -O—R 3   (II)
   wherein
 L 2  is a substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted arylene; and 
 R 3  is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. 
   
     
     
         14 . The compound of  claim 13 , with the structure of Formulae (Ia1S) to (Ia7S): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein R 2  is octadecyloxyethyl, hexadecyloxyethyl, hexadecyloxypropyl, 15-methyl-hexadecyloxypropyl, 15-methyl-hexadecyloxyethyl, 13-methyl-tetradecyloxypropyl, 13-methyl-tetradecyloxyethyl, 14-cyclopropyl-tetradecyloxypropyl, 14-cyclopropyl-tetradecyloxyethyl, or 1-O-octadecyl-2-O-benzyl-sn-glyceryl. 
     
     
         16 . The compound of  claim 1  with structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         18 . A method of inhibiting a viral reverse transcriptase comprising contacting a cell comprising a viral reverse transcriptase with an effective amount of a compound of  claim 1 , thereby inhibiting said viral reverse transcriptase. 
     
     
         19 . The method according to  claim 18 , wherein said viral reverse transcriptase is from hepatitis C virus or a human retrovirus. 
     
     
         20 . The method according to  claim 19  wherein said human retrovirus is HIV.