Modified fluorinated nucleoside analogues

Abstract

The disclosed invention provides compositions and methods of treating a Flaviviridae infection, including hepatitis C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host, including animals, and especially humans, using a (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides, or a pharmaceutically acceptable salt or prodrug thereof.

1 - 129 . (canceled) 
     
     
         130 . A compound or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
       
       wherein the base is a purine base represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, a H-phosphonate, alkyl, an alkyl sulfonyl, or an arylalkyl sulfonyl, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1  is H or phosphate; 
         wherein R 4  is H, OH, NH 2 , NHR″, NR″, OR″, SR″, CL, Br, or I; 
         wherein R″ is linear or branched alkyl, alkenyl, alkynyl, cycloalkyl, or —NH 2 CF 3 ; and 
         wherein R 5  is H, NH 2 , or Cl. 
       
     
     
         131 . A method of synthesizing the compound of  claim 130 , which comprises glycosylating the purine with a compound having the following structure: 
       
         
           
           
               
               
           
         
         wherein R is lower alkyl, acyl, benzoyl, or mesyl; and 
         wherein Pg is selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 , CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg is may come together to form a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene). 
       
     
     
         132 . The method of  claim 131 , wherein the glycosylating step produces the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         133 . The method of  claim 130 , which comprises deprotecting a 3′-OPg and a 5′-OPg of a compound having the following structure: 
       
         
           
           
               
               
           
         
         wherein each Pg is independently a protecting group selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 , CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg is may come together to form a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene). 
       
     
     
         134 . The method of  claim 133 , which comprises selectively deprotecting a 3′-OPg or a 5′-OPg of a compound having the following structure: 
       
         
           
           
               
               
           
         
         wherein each Pg is independently a protecting group selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 , CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg is may come together to form a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene). 
       
     
     
         135 . A compound or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         wherein R 1  is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, a H-phosphonate, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1  is H or phosphate. 
       
     
     
         136 . A compound or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         wherein R is lower alkyl, acyl, benzoyl, or mesyl; and 
         wherein Pg is selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 , CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg is may come together to form a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene). 
       
     
     
         137 . A compound or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         wherein, each Pg is independently a protecting group selected from among C(O)-alkyl, C(O)Ph, C(O)aryl, CH 3 , CH 2 -alkyl, CH 2 -alkenyl, CH 2 Ph, CH 2 -aryl, CH 2 O-alkyl, CH 2 O-aryl, SO 2 -alkyl, SO 2 -aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or both Pg is may come together to form a 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).