Methods and compositions for treating flaviviruses and pestiviruses
View Patent ↗A method and composition for treating a host infected with flavivirus or pestivirus comprising administering an effective flavivirus or pestivirus treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.
1. A method for the treatment of a flavivirus or pestivirus infection in a host, comprising administering to said host an anti-virally effective amount of a compound of Formula XVII:
or a pharmaceutically acceptable salt or ester thereof, wherein:
Base is a purine;
R 1 and R 2 are independently H; phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate, either unprotected or protected as necessary; a lipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 1 and R 2 are independently H or phosphate;
R 6 is alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —O(acyl), —O(alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , or —N(acyl) 2 ;
R 7 and R 9 are independently OR 2 , hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —O(acyl), —O(alkyl), —O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , or —N(acyl) 2 ;
R 10 is H, alkyl, chlorine, bromine or iodine;
X is O, S, SO 2 or CH 2 .
2. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, wherein the base is selected from the group consisting of N 6 -alkylpurine, N 6 -acylpurine, N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, C 5 -hydroxyalkyl purine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, adenine, guanine, hypoxanthine, 2,6-diaminopunne and 6-chloropurine.
3. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an anti-virally effective amount of a compound of Formula X or XI:
or a pharmaceutically acceptable salt or ester thereof, wherein:
Base is a purine;
R 1 , R 2 and R 3 are independently H; phosphate or a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; or benzyl, wherein the phenyl group is optionally substituted; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 1 , R 2 and R 3 are independently H or phosphate;
R 6 is alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), O(acyl), —O(alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO 2, NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , or —N(acyl) 2 ;
R 7 is, OR 3 , hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —O(acyl), —O(alkyl), —O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , or —N(acyl) 2 ; and
X is O, S, SO 2 or CH 2 .
4. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, wherein, in the compound of Formula XVII:
R 10 is H, alkyl, chlorine, bromine or iodine;
R 7 and R 9 are independently OR 2 , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , or —N(acyl) 2 ;
R 6 is alkyl, chlorine, bromine or iodine;
X is O, S, SO 2 or CH 2 .
5. The method of claim 1 wherein R 1 hydrogen or phosphate.
6. The method of claim 1 wherein R 2 is hydrogen, acyl or alkyl.
7. The method of claim 1 wherein R 6 is alkyl.
8. The method of claim 1 wherein R 7 and R 9 are independently selected from OR 2 or hydroxy.
9. The method of claim 1 wherein R 7 is hydroxy.
10. The method of claim 1 wherein R 9 is hydroxy.
11. The method of claim 1 wherein R 7 and R 9 are hydroxy.
12. The method of claim 1 wherein R 10 is hydrogen.
13. The method of claim 1 wherein X is O.
14. The method of claim 1 wherein
R 1 is hydrogen or phosphate;
R 2 is hydrogen, acyl or alkyl;
R 6 is alkyl;
R 7 and R 9 are independently OR 2 , or hydroxy;
R 10 is hydrogen; and
X is O.
15. The method of claim 1 , wherein the base is a purine selected from the group consisting of N 6 -alkylpurines, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.
16. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:
or a pharmaceutically acceptable salt or ester thereof.
17. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:
or a pharmaceutically acceptable salt or ester thereof, wherein R is hydrogen or alkyl.
18. The method of claim 17 , wherein R is methyl, ethyl, propyl, isopropyl, or cyclopropyl.
19. The method of claim 18 wherein R is butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, or neopentyl.
20. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:
or a pharmaceutically acceptable salt or ester thereof.
21. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:
or a pharmaceutically acceptable salt or ester thereof.
22. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:
or a pharmaceutically acceptable salt or ester thereof.
23. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:
or a pharmaceutically acceptable salt or ester thereof.
24. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, comprising administering an antivirally effective amount of a compound of the structure:
or a pharmaceutically acceptable salt or ester thereof.
25. The method of claim 1 for the treatment of a flavivirus or pestivirus infection in a host, wherein the purine base is selected from the group consisting of
wherein R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, or neopentyl.
26. The method of claim 1 , wherein the method comprises administering the compound or a pharmaceutically acceptable salt or ester thereof in combination or alternation with a second anti-flavivirus or anti-pestivirus agent.
27. The method of claim 26 , wherein the second anti-flavivirus or anti-pestivirus agent is selected from the group consisting of consisting of interferon, ribavirin, a protease inhibitor, a thiazolidine derivative, a polymerase inhibitor, and a helicase inhibitor.
28. The method of claim 27 , wherein the second anti-flavivirus or anti-pestivirus agent is interferon.
29. The method of claim 27 , wherein the second anti-flavivirus or anti-pestivirus agent is a protease inhibitor.
30. The method of claim 27 , wherein the second anti-flavivirus or anti-pestivirus agent is ribavirin.
31. The method of claim 1 , wherein the compound is in the form of a dosage unit.
32. The method of claim 31 , wherein the dosage unit contains 50 to 1000 mg of said compound.
33. The method of claim 31 , wherein said dosage unit is a tablet or capsule.
34. The method of claim 1 , wherein the host is a human.
35. The method of claim 1 , wherein the compound is in substantially pure form.
36. The method of claim 1 , wherein the compound is at least 90% by weight of the β-D-isomer.
37. The method of claims 1 , wherein the compound is at least 95% by weight of the β-D-isomer.
38. The method of claim 1 , wherein the flavivirus or pestivirus is a Dengue virus.
39. The method of claim 1 , wherein the flavivirus or pestivirus is a West Nile virus.
40. The method of claim 1 , wherein the flavivirus or pestivirus is a yellow fever virus.
41. The method of claim 1 , wherein the flavivirus or pestivirus is a bovine viral diarrhea virus (BVDV).
42. The method of claim 1 , wherein the flavivirus or pestivirus is not a hepatitis C virus.