Methods and compositions for treating flaviviruses and pestiviruses

Abstract

A method and composition for treating a host infected with flavivirus or pestivirus comprising administering an effective flavivirus or pestivirus treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

1 - 129 . (canceled) 
     
     
         130 . A method for the treatment of a flavivirus or pestivirus infection in a host, comprising administering to a host infected with a flavivirus or a pestivirus an anti-virally effective amount of a compound of Formula X: 
       
         
           
           
               
               
           
         
         or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, wherein: 
         Base is a purine or pyrimidine base; 
         R 1 , R 2 , and R 3  are independently H; phosphate; mono phosphate; diphosphate; 
         triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl sulfonyl; arylalkyl sulfonyl; methanesulfonyl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate. phosphonic acid, phosphate or phosphonate; 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 , R 2 , or R 3  is independently H or phosphate; 
         R 6  is alkyl; and 
         X is O, S, SO 2  or CH 2 . 
       
     
     
         131 . The method of  claim 130 , wherein R 1  and R 2  are independently H;
 phosphate; monophosphate; diphosphate; triphosphate; or a stabilized phosphate prodrug.   
     
     
         132 . The method of  claim 130 , wherein R 1  and R 2  are each hydrogen. 
     
     
         133 . The method of  claim 130 , wherein X is O. 
     
     
         134 . The method of  claim 130 , wherein R 6  is methyl. 
     
     
         135 . The method of  claim 130 , wherein Base is a purine or pyrimidine base selected from adenine, N6-alkyl purine, N6-acyl purine, N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkyl purine, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C5-alkylpyrimidine, C5-benzyl pyrimidine, C5-halopyrimidine, C5-vinyl pyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkyl purine, N2-alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, or 6-chloropurine. 
     
     
         136 . The method of  claim 130 , wherein Base is a purine or pyrimidine base selected from adenine, thymine, cytosine, uracil or guanine. 
     
     
         137 . The method of  claim 130 , wherein Base is cytosine or uracil. 
     
     
         138 . The method of  claim 130 , wherein the flavivirus or pestivirus is selected from dengue hemorrhagic fever virus, yellow fever virus, shock syndrome or Japanese encephalitis virus. 
     
     
         139 . A method for the treatment of a flavivirus or pestivirus infection in a host, comprising contacting a cell infected with a flavivirus or a pestivirus with an anti-virally effective amount of a compound of Formula X: 
       
         
           
           
               
               
           
         
         or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, wherein: 
         Base is a purine or pyrimidine base; 
         R 1 , R 2 , and R 3  are independently H; phosphate; mono phosphate; diphosphate; 
         triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl sulfonyl; arylalkyl sulfonyl; methanesulfonyl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate. phosphonic acid, phosphate or phosphonate; 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 , R 2 , or R 3  is independently H or phosphate; 
         R 6  is alkyl; and 
         X is O, S, SO 2  or CH 2 . 
       
     
     
         140 . The method of  claim 139 , wherein R 1  and R 2  are independently H; phosphate; monophosphate; diphosphate; triphosphate; or a stabilized phosphate prodrug. 
     
     
         141 . The method of  claim 139 , wherein R 1  and R 2  are each hydrogen. 
     
     
         142 . The method of  claim 139 , wherein X is O. 
     
     
         143 . The method of  claim 139 , wherein R 6  is methyl. 
     
     
         144 . The method of  claim 139 , wherein Base is a purine or pyrimidine base selected from adenine, N6-alkyl purine, N6-acyl purine, N6-benzyl purine, N6-halopurine, N6-vinyl purine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkyl purine, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C5-alkylpyrimidine, C5-benzyl pyrimidine, C5-halopyrimidine, C5-vinyl pyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkylpurine, N2-alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, or 6-chloropurine. 
     
     
         145 . The method of  claim 139 , wherein Base is a purine or pyrimidine base selected from adenine, thymine, cytosine, uracil or guanine. 
     
     
         146 . The method of  claim 139 , wherein Base is cytosine or uracil. 
     
     
         147 . The method of  claim 139 , wherein the flavivirus or pestivirus is selected from dengue hemorrhagic fever virus, yellow fever virus, shock syndrome or Japanese encephalitis virus. 
     
     
         148 . A method for the treatment of a flavivirus or pestivirus infection in a host, comprising contacting a flavivirus or pestivirus polymerase with an anti-virally effective amount of a compound of Formula X: 
       
         
           
           
               
               
           
         
         or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, wherein: 
         Base is a purine or pyrimidine base; 
         R 1 , R 2 , and R 3  are independently H; phosphate; mono phosphate; diphosphate; 
         triphosphate; a stabilized phosphate prodrug; acyl; lower acyl; alkyl; lower alkyl; sulfonate ester; alkyl sulfonyl; arylalkyl sulfonyl; methanesulfonyl; benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate. phosphonic acid, phosphate or phosphonate; 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 , R 2 , or R 3  is independently H or phosphate; 
         R 6  is alkyl; and 
         X is O, S, SO 2  or CH 2 . 
       
     
     
         149 . The method of  claim 148 , wherein R 1  and R 2  are independently H; phosphate; monophosphate; diphosphate; triphosphate; or a stabilized phosphate prodrug. 
     
     
         150 . The method of  claim 148 , wherein R 1  is triphosphate and R 2  is hydrogen. 
     
     
         151 . The method of  claim 148 , wherein X is O. 
     
     
         152 . The method of  claim 148 , wherein R 6  is methyl. 
     
     
         153 . The method of  claim 148 , wherein Base is a purine or pyrimidine base selected from adenine, N6-alkyl purine, N6-acyl purine, N6-benzyl purine, N6-halopurine, N6-vinyl purine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkyl purine, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil 5-halouracil, 5-fluorouracil C5-alkyl pyrimidine, C5-benzylpyrimidine, C5-halopyrimidine, C5-vinyl pyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkylpurine, N2-alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, or 6-chloropurine. 
     
     
         154 . The method of  claim 148 , wherein Base is a purine or pyrimidine base selected from adenine, thymine, cytosine, uracil or guanine. 
     
     
         155 . The method of  claim 148 , wherein Base is cytosine or uracil. 
     
     
         156 . The method of  claim 148 , wherein the flavivirus or pestivirus is selected from dengue hemorrhagic fever virus, yellow fever virus, shock syndrome or Japanese encephalitis virus.