Beta-L-2'-Deoxy-Nucleosides for the Treatment of Hepatitis B

Abstract

This invention is directed to a method for treating a host infected with hepatitis B comprising administering an effective amount of an anti-HBV biologically active 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof, wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside has the formula: wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. The 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof may be administered either alone or in combination with another 2′-deoxy-β-L-erythro-pentofuranonucleoside or in combination with another anti-hepatitis B agent.

1 . A method for treating a host infected with hepatitis B comprising administering an effective amount of an anti-HBV biologically active 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof, wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. 
     
     
         2 . The method of  claim 1 , wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside is β-L-2′-deoxyadenosine or a pharmaceutically acceptable salt or prodrug thereof, of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 
     
     
         3 . The method of  claim 1 , wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside is β-L-2′-deoxycytidine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 
     
     
         4 . The method of  claim 1 , wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside is β-L-2′-deoxyuridine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 
     
     
         5 . The method of  claim 1 , wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside is β-L-2′-deoxyguanosine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 
     
     
         6 . The method of  claim 1 , wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside is β-L-2′-deoxyinosine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 
     
     
         7 . The method of  claim 1 , wherein the 2′-deoxy-β-L-erythro-pentofuranonucleoside is β-L-thymidine or a pharmaceutically acceptable salt or prodrug thereof of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 
     
     
         8 . A method for treating a host infected with hepatitis B comprising administering an effective amount of two or more anti-HBV biologically active 2′-deoxy-β-L-erythro-pentofuranonucleosides or a pharmaceutically acceptable salt or prodrug thereof in combination of alternation, wherein the 2′-deoxy-β-L-erythro-pentofuranonucleosides have the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. 
     
     
         9 . A method for treating a host infected with hepatitis B comprising administering an effective amount of an anti-HBV biologically active 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof in combination or alternation with an additional anti-hepatitis B agent, wherein the 2′-deoxy-β-L-erythro-pentofuranonucleosidehas the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and BASE is a purine or pyrimidine base which may be optionally substituted. 
     
     
         10 . The method of  claim 9 , wherein the additional anti-hepatitis B agent is selected from the group consisting of 3TC, FTC, L-FMAU, DAPD, famciclovir, penciclovir, BMS-200475, bis pom PMEA (adefovir, dipivoxil), lobucavir, ganciclovir, or ribavarin. 
     
     
         11 . A compound or pharmaceutically acceptable salt or prodrug thereof of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is H, mono, di or tri phosphate, amino acid residue, acyl, or alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug). 
     
     
         12 . A compound or pharmaceutically acceptable salt or prodrug of  claim 11  wherein R is L-valinyl. 
     
     
         13 . A pharmaceutical composition comprising an effective amount of a compound of  claim 11  in combination with a pharmaceutically acceptable carrier. 
     
     
         14 . The method of  claim 1 , wherein the amino acid is L-valinyl. 
     
     
         15 . The method of  claim 3 , wherein the amino acid is L-valinyl. 
     
     
         16 . The method of  claim 4 , wherein the amino acid is L-valinyl. 
     
     
         17 . The method of  claim 5 , wherein the amino acid is L-valinyl. 
     
     
         18 . The method of  claim 6 , wherein the amino acid is L-valinyl. 
     
     
         19 . The method of  claim 7 , wherein the amino acid is L-valinyl. 
     
     
         20 . The method of  claim 8 , wherein the amino acid is L-valinyl. 
     
     
         21 . The method of  claim 9 , wherein the amino acid is L-valinyl.