Modified nucleosides for the treatment of viral infections and abnormal cellullar proliferation

Abstract

The disclosed invention is a composition for and a method of treating a Flaviviridae (including BVDV and HCV), Orthomyxoviridae (including Influenza A and B) or Paramyxoviridae (including RSV) infection, or conditions related to abnormal cellular proliferation, in a host, including animals, and especially humans, using a nucleoside of general formula (I)-(XXIII) or its pharmaceutically acceptable salt or prodrug. This invention also provides an effective process to quantify the viral load, and in particular BVDV, HCV or West Nile Virus load, in a host, using real-time polymerase chain reaction (“RT-PCR”). Additionally, the invention discloses probe molecules that can fluoresce proportionally to the amount of virus present in a sample.

1 . A method for the treatment of a host having a Flaviviridae, Orthomyxoviridae or Paramyxoviridae viral infection or abnormal cellular proliferation comprising administering to the host an effective amount of a compound of formula I-b: 
       
         
           
           
               
               
           
         
         or its β-L enantiomer or a pharmaceutically acceptable salt thereof, wherein:
 each D is hydrogen, alkyl, acyl, monophosphate, diphosphate, triphosphate, monophosphate ester, diphosphate ester, triphosphate ester, phospholipid or amino acid; 
 each W 1  and W 2  is independently CH or N; 
 each X 1  and X 2  is independently hydrogen, F, Cl, Br, I, NH 2 , NHR 4 , NR 4 R 4′ , NHOR 4 , NR 4 NR 4′ R 4″ , OH, OR 4 , SH or SR 4 ; 
 each R 2  and R 2′  independently is hydrogen, F, Cl, Br, I, OH, SH, OCH 3 , SCH 3 , NH 2 , NHCH 3 , CH═CH 2 , CN, CH 2 NH 2 , CH 2 OH or CO 2 H; 
 each R 3  and R 3′  independently is hydrogen, F, Cl, Br, I, OH, SH, OCH 3 , SCH 3 , NH 2 , NHCH 3 , CH 3 , C 2 H 5 , CH═CH 2 , CN, CH 2 NH 2 , CH 2 OH or CO 2 H; and 
 each R 4 , R 4′ , and R 4″  independently is hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl; 
 such that for the nucleoside of formula I-b at least one of R 2  and R 2′  is hydrogen and at least one of R 3  and R 3′  is hydrogen; 
 
       
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the β-D nucleoside of formula (I-b) has variables X 1 , X 2 , W 1 , R 2 , R 2′ , R 3 , and R 3′  selected from one of the following rows: 
       
         
           
                 
                 
                 
                 
                 
                 
                 
                 
               
                     
                     
                 
                     
                   X 1   
                   X 2   
                   W 1   
                   R 2   
                   R 2′   
                   R 3   
                   R 3′   
                 
                     
                     
                 
                     
                   OH 
                   NH 2   
                   N 
                   H 
                   OH 
                   H 
                   OH 
                 
                     
                   OH 
                   NH 2   
                   CH 
                   F 
                   H 
                   H 
                   OH 
                 
                     
                   NH 2   
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   F 
                 
                     
                   NH 2   
                   H 
                   CH 
                   H 
                   H 
                   H 
                   H 
                 
                     
                   NH 2   
                   NH 2   
                   N 
                   H 
                   OH 
                   H 
                   OH 
                 
                     
                   NH 2   
                   NH 2   
                   CH 
                   H 
                   OH 
                   H 
                   OH 
                 
                     
                   Cl 
                   H 
                   CH 
                   F 
                   H 
                   H 
                   H 
                 
                     
                   Cl 
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   OH 
                 
                     
                   NH 2   
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   H 
                 
                     
                   Cl 
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   H 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or its β-L-enantiomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 - 41 . (canceled) 
     
     
         42 . A method for the treatment of a host having a Flaviviridae, Orthomyxoviridae or Paramyxoviridae viral infection or abnormal cellular proliferation comprising administering to the host an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 - 56 . (canceled) 
     
     
         57 . A method for the treatment of a hepatitis C virus infection in a host comprising administering to the host an effective amount of a nucleoside of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; optionally in a pharmaceutically acceptable carrier. 
       
     
     
         58 . (canceled) 
     
     
         59 . The method of  claim 1 , wherein the β-D nucleoside of formula (I-b) is selected from one of the following: 
       
         
           
                 
                 
                 
                 
                 
                 
                 
                 
                 
               
                     
                 
                   D 
                   W 2   
                   X 1   
                   X 2   
                   W 1   
                   R 2   
                   R 2′   
                   R 3   
                   R 3′   
                 
                     
                 
                   H 
                   N 
                   OH 
                   NH 2   
                   N 
                   H 
                   OH 
                   H 
                   OH 
                 
                   H 
                   N 
                   OH 
                   NH 2   
                   CH 
                   F 
                   H 
                   H 
                   OH 
                 
                   H 
                   N 
                   NH 2   
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   F 
                 
                   H 
                   N 
                   NH 2   
                   H 
                   CH 
                   H 
                   H 
                   H 
                   H 
                 
                   H 
                   N 
                   NH 2   
                   NH 2   
                   N 
                   H 
                   OH 
                   H 
                   OH 
                 
                   H 
                   N 
                   NH 2   
                   NH 2   
                   CH 
                   H 
                   OH 
                   H 
                   OH 
                 
                   H 
                   N 
                   Cl 
                   H 
                   CH 
                   F 
                   H 
                   H 
                   H 
                 
                   H 
                   N 
                   Cl 
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   OH 
                 
                   H 
                   N 
                   NH 2   
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   H 
                 
                   H 
                   N 
                   Cl 
                   H 
                   CH 
                   H 
                   OH 
                   H 
                   H 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or its β-L-enantiomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         60 . A method for the treatment of a host having a Flaviviridae, Orthomyxoviridae or Paramyxoviridae viral infection or abnormal cellular proliferation comprising administering to the host an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         or its β-L-enantiomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         61 . A method for the treatment of a host having a Flaviviridae, Orthomyxoviridae or Paramyxoviridae viral infection or abnormal cellular proliferation comprising administering to the host an effective amount of a compound of formula: 
       
         
           
           
               
               
           
         
         or its β-L-enantiomer or a pharmaceutically acceptable salt thereof. 
       
     
     
         62 . The method according to  claim 1 , wherein each R 4 , R 4′ , and R 4″  independently is unsubstituted or substituted phenyl or benzyl. 
     
     
         63 . A method for the treatment of a hepatitis C virus infection in a host comprising administering to the host an effective amount of a compound according to any one of  claims 1 ,  3 ,  59 ,  60 , and  61 .