BETA-L-2'-DEOXY-NUCLEOSIDES FOR THE TREATMENT OF HEPATITIS B
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 faun a stabilized nucleotide prodrug).
7 . The method of claim 1 , wherein the 2′-deoxy-j3-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-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.
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.