β-L-2′-deoxynucleosides for the treatment of resistant HBV strains and combination therapies
View Patent ↗It has been discovered that β-L-2′-deoxynucleosides are active against drug-resistant hepatitis B virus with mutations. A method for treating lamivudine resistant HBV (M552V) in a host is provided that includes administering a β-L-2′-deoxynucleoside or its pharmaceutically acceptable salt, ester or prodrug. In addition, a method for preventing lamivudine resistant HBV (M552V) mutation from occurring in a naïve host is provided that includes administering a β-L-2′-deoxynucleoside or its pharmaceutically acceptable salt, ester or prodrug. A method for preventing and/or suppressing the emergence of the HBV double mutant (L528M/M552V) in a host is also provided that includes administering a β-L-2′-deoxynucleoside or its pharmaceutically acceptable salt, ester or prodrug.
1. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula (I):
or a pharmaceutically acceptable salt, ester or prodrug thereof, to the host wherein:
R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, 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;
X is O; and
BASE is a thymine or cytosine.
2. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof to the host, wherein:
R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, 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
R 3 and R 4 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, acyl, acetyl, butyryl, 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.
3. The method of claims 2 , wherein R 3 and/or R 4 is H.
4. The method of claim 2 , wherein R 1 and/or R 2 is H.
5. The method of claim 2 , wherein at least one of R 1 , R 2 or R 4 is an amino acid residue of the formula:
C(O)C(R 8 )(R 9 )(NR 10 R 11 )
wherein:
R 8 is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R 10 form a ring structure;
R 9 is hydrogen, alkyl, or aryl; and
R 10 and R 11 are independently hydrogen, acyl, or alkyl.
6. The method of claim 5 , wherein the amino acid residue is L-valinyl.
7. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof to the host.
8. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof to the host.
9. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof to the host.
10. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof to the host.
11. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof, to the host wherein
R 1 and R 2 are independently hydrogen, straight chained, branched or cyclic alkyl, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkyl sulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and
R 3 is hydrogen, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, acyl, acetyl, butyryl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkyl sulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative.
12. The method of claim 11 , wherein R 3 is H.
13. The method of claim 11 , wherein R 1 and/or R 2 is H.
14. The method of claim 11 , wherein at least one of R 1 or R 2 is an amino acid residue of the formula:
C(O)C(R 8 )(R 9 )(NR 10 R 11 )
wherein:
R 8 is the side chain of an amino acid, alkyl, aryl, heteroaryl, heterocyclic, or can optionally attach to R 10 form a ring structure;
R 9 is hydrogen, alkyl, or aryl; and
R 10 and R 11 are independently hydrogen, acyl, or alkyl.
15. The method of claim 14 , wherein the amino acid residue is L-valinyl.
16. A method for the treatment of a host infected with a drug-resistant form of HBV that exhibits a mutation at the 552 codon from methionine to valine in the DNA polymerase region, comprising administering an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, ester or pro drug thereof to the host.
17. The method of claim 7 , wherein the compound is in the form of a pharmaceutically acceptable ester.
18. The method of claim 7 , wherein the compound is in the form of a pharmaceutically acceptable salt.
19. The method of claim 7 , wherein the compound is in the form of a pharmaceutically acceptable prodrug.
20. The method of claim 16 , wherein the compound is in the form of a pharmaceutically acceptable ester.
21. The method of claim 16 , wherein the compound is in the form of a pharmaceutically acceptable salt.
22. The method of claim 16 , wherein the compound is in the form of a pharmaceutically acceptable prodrug.
23. The method of any one of claims 1 , 2 , 7 – 11 or 16 wherein the host is a mammal.
24. The method of claim 16 , wherein the host is a human.