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 - 18 . (canceled) 
     
     
         19 . 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. 
 
     
     
         20 . The method of  claim 19 , wherein R 1  is H, monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug. 
     
     
         21 . The method of  claim 19 , wherein R 2  is 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. 
     
     
         22 . The method of  claim 19 , wherein each Y 3  is H. 
     
     
         23 . The method of  claim 19 , wherein Base is selected from the group consisting of cytosine, thymine, uracil, pyrrolopyrimidine and pyrazolopyrimidine. 
     
     
         24 . The method of  claim 19 , wherein Base is cytosine. 
     
     
         25 . The method of  claim 19 , wherein Base is uracil. 
     
     
         26 . The method of  claim 19 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 
     
     
         27 . The method of  claim 26 , wherein the pharmaceutical composition is in the form of an oral dosage. 
     
     
         28 . The method of  claim 27 , wherein the oral dosage comprises from 50 to 1000 mg of the compound or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method of  claim 28 , wherein the dosage is in the form of a tablet or capsule. 
     
     
         30 . The method of  claim 19 , wherein R 1  is monophosphate, which has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         31 . 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. 
 
     
     
         32 . The method of  claim 31 , wherein R 1  and R 2  are each H. 
     
     
         33 . The method of  claim 31 , wherein Base* is a pyrimidine base. 
     
     
         34 . The method of  claim 31 , wherein Base* is uracil. 
     
     
         35 . The method of  claim 19 , wherein the Flaviviridae virus is hepatitis C virus. 
     
     
         36 . The method of  claim 31 , wherein the Flaviviridae virus is hepatitis C virus.