Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections

Abstract

2′ and/or 3′ prodrugs of 1′, 2′, 3′ or 4′-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

1 - 13 . (canceled) 
     
     
         14 . A method for the treatment of a host infected with a Flaviviridae virus, comprising administering to the host an effective treatment amount of a compound of Formula (IX): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2  are independently H; monophosphate; diphosphate; triphosphate; a stabilized phosphate, straight chained, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; or a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1  and/or R 2  is independently H or phosphate; 
 X is O, S, SO 2  or CH 2 ; 
 Base* is a purine or pyrimidine base; 
 R 12  is C(Y 3 ) 3 ; 
 Y 3  is independently H, F, Cl, Br or I; and 
 R 13  is fluoro; 
 
         in combination or alternation with a second anti-viral agent. 
       
     
     
         15 . The method of  claim 14 , wherein X is O, and each Y 3  is H. 
     
     
         16 . The method of  claim 14 , wherein the Flaviviridae virus is hepatitis C virus. 
     
     
         17 . The method of  claim 16 , wherein the second anti-viral agent is an interferon, a ribavirin, or a combination thereof. 
     
     
         18 . The method of  claim 14 , wherein the second antiviral agent is ribavirin. 
     
     
         19 . The method of  claim 17 , wherein the second antiviral agent is pegylated interferon alpha 2a. 
     
     
         20 . The method of  claim 19 , further comprising administering ribavirin to the host. 
     
     
         21 . The method of  claim 15 , wherein R 1  is monophosphate, diphosphate, triphosphate, a stabilized phosphate; and R 2  is H. 
     
     
         22 . The method of  claim 21 , wherein Base* is uracil. 
     
     
         23 . The method of  claim 21 , wherein the second antiviral agent is an interferon, a ribavirin, or a combination thereof. 
     
     
         24 . The method of  claim 23 , wherein the second antiviral agent is ribavirin. 
     
     
         25 . The method of  claim 23 , further comprising administering pegylated interferon alpha 2a to the host. 
     
     
         26 . The method of  claim 14 , wherein X is O, each Y 3  is H; R 2  is H and R 1  is monophosphate, diphosphate, triphosphate, or a stabilized phosphate. 
     
     
         27 . The method of  claim 26 , wherein R 1  is monophosphate, diphosphate, or triphosphate. 
     
     
         28 . A method for the treatment of a host infected with a Flaviviridae virus, comprising administering to the host an effective treatment amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Base is selected from the group consisting of adenine, N 6 -alkylpurine, N 6 -acylpurine, N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -nitropyrimidine, C 5 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine,  2 ,6-diaminopurine, and 6-chloropurine; 
         R 7  is F; 
         R 1  is H; monophosphate; diphosphate; triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 1  is H or phosphate; 
         R 2  is monophosphate; diphosphate; triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl or arylalkyl sulfonyl; methanesulfonyl; benzylsulfonyl; a lipid; a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 2  is H or phosphate; and 
         Y 3  is independently H, F, Cl, Br or I. 
       
     
     
         29 . The method of  claim 28 , wherein R 1  is H, monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug. 
     
     
         30 . The method of  claim 28 , wherein each Y 3  is H. 
     
     
         31 . The method of  claim 28 , wherein Base is uracil. 
     
     
         32 . A method for the treatment of a host infected with a Flaviviridae virus, comprising administering to the host an effective treatment amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 2  are independently H; monophosphate; diphosphate; triphosphate; a stabilized phosphate prodrug; straight chained, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; or a cholesterol; 
         X is O; 
         Base* is a purine or pyrimidine base; 
         R 12  is C(Y 3 ) 3 ; 
         each Y 3  is H; and 
         R 13  is fluoro. 
       
     
     
         33 . The method of  claim 32 , wherein Base* is uracil. 
     
     
         34 . The method of  claim 28 , wherein the Flaviviridae virus is hepatitis C virus. 
     
     
         35 . The method of  claim 32 , wherein the Flaviviridae virus is hepatitis C virus.