Purine nucleoside analogues for treating
View Patent ↗This invention is directed to a method for treating a host, especially a human, infected with hepatitis C, flavivirus and/or pestivirus, comprising administering to that host an effective amount of an anti-HCV biologically active pentofuranonucleoside where the pentofuranonucleoside base is an optionally substituted 2-azapurine. The optionally substituted pentofuranonucleoside, or a salt or prodrug thereof, may be administered alone or in combination with one or more optionally substituted pentofuranonucleosides or other anti-viral agents.
1. A method of treating a host infected with HCV, comprising administering an effective amount of a ribofuranonucleoside of Formula (III):
or a pharmacologically acceptable salt thereof, wherein:
R, R 2 *, and R 3 * are each independently H, mono-, di-, or triphosphate; phosphonate; or optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)(lower alkyl), —C(O)-(alkenyl), or —C(O)-(alkynyl);
X is O;
R 2′ is H; optionally substituted alkyl, alkenyl, or alkynyl; and
Base is selected from the group consisting of:
wherein:
each R′ and R″ independently is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;
each W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —OC(O)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and
each R 4 is independently H, acyl, or C 1-6 alkyl.
2. The method of claim 1 , wherein R 2′ is CH 3 or CF 3 .
3. The method of claim 1 , wherein R, R 2 *, and R 3 * are each independently H, mono-, di-, or triphosphate, or phosphonate.
4. The method of claim 1 , wherein each R, R 2 *, and R 3 * is H.
5. The method of claim 1 , wherein each R, R 2 *, and R 3 * is independently H, acyl, or an amino acid acyl residue.
6. The method of claim 1 , wherein the host is a mammal.
7. The method of claim 6 , wherein the mammal is a human.
8. The method of claim 1 , further comprising administering an antivirally effective amount of the compound, or a pharmaceutically acceptable salt thereof, in combination or alternation with one or more additional antivirally effective agents.
9. The method of claim 8 , wherein the additional antivirally effective agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, phenanthrenequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.
10. The method of claim 9 , wherein the additional antivirally effective agent is an interferon.
11. The method of claim 10 , wherein the additional antivirally effective agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.
12. The method of claim 1 , wherein the compound is in the form of a dosage unit.
13. The method of claim 12 , wherein the dosage unit contains 50 to 1000 mg of the compound.
14. The method of claim 13 , wherein the said dosage unit is a tablet or capsule.
15. The method of claim 1 , wherein the compound is in substantially pure form.
16. The method of claim 15 , wherein the compound is at least 90% by weight of the β-D-isomer.
17. The method of claim 15 , wherein the compound is at least 95% by weight of the β-D-isomer.
18. The method of claim 15 , wherein the compound is at least 90% by weight of the β-L-isomer.
19. The method of claim 15 , wherein the compound is at least 95% by weight of the β-L-isomer.
20. A pharmaceutical composition comprising an anti-virally effective amount of a compound of Formula (III) or a pharmacologically acceptable salt thereof:
wherein:
R, R 2 *, and R 3 * are each independently H, mono-, di-, or triphosphate; phosphonate; or optionally substituted alkyl, lower alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)-(lower alkyl), —C(O)-(alkenyl), or —C(O)-(alkynyl);
X is O;
R 2′ is optionally substituted alkyl, alkenyl, or alkynyl; and
Base is
wherein
R′ and R″ are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, halogenated alkyl, OH, CN, N 3 , carboxy, C 1-4 alkoxycarbonyl, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-6 alkoxy, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;
W is Cl, Br, I, F, halogenated alkyl, alkoxy, OH, SH, O-alkyl, S-alkyl, O-alkenyl, O-alkynyl, S-alkenyl, S-alkynyl, —OC(O)NR 4 R 4 , O-acyl, S-acyl, CN, SCN, OCN, NO 2 , N 3 , NH 2 , NH(alkyl), N(alkyl) 2 , NH-cycloalkyl, NH-acyl, CONH 2 , CONH(alkyl), or CON(alkyl) 2 ; and
each R 4 is independently H, acyl, or C 1-6 alkyl;
and a pharmaceutically acceptable carrier, diluent or excipient.
21. The pharmaceutical composition of claim 20 , wherein R 2′ is CH 3 or CF 3 .
22. The pharmaceutical composition of claim 20 , wherein R, R 2 *, and R 3 * are each independently H, mono-, di-, or triphosphate, or phosphonate.
23. The pharmaceutical composition of claim 20 , wherein R, R 2 *, and R 3 * are H.
24. The pharmaceutical composition of claim 20 , wherein R, R 2 *, and R 3 * are each independently H, acyl, or an amino acid acyl residue.
25. The pharmaceutical composition of claim 20 , wherein the compound or salt thereof is in the form of a dosage unit.
26. The pharmaceutical composition of claim 25 , wherein the dosage unit contains from about 50 to about 1000 mg of the compound.
27. The pharmaceutical composition of claim 26 , wherein said dosage unit is a tablet or capsule.
28. The pharmaceutical composition of claim 20 , further comprising one or more additional anti-virally effective agents.
29. The pharmaceutical composition of claim 28 , wherein the additional anti-virally agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a thiazolidine derivative, a thiazolidine, a benzanilide, phenanthrenequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, gliotoxin, cerulenin, an antisense oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.
30. The pharmaceutical composition of claim 29 , wherein the additional anti-virally effective agent is an interferon.
31. The pharmaceutical composition of claim 30 , wherein the additional anti-virally effective agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.
32. The pharmaceutical composition of claim 20 , wherein the compound is in substantially pure form.
33. The pharmaceutical composition of claim 32 , wherein the compound is at least 90% by weight of the β-D-isomer.
34. The pharmaceutical composition of claim 32 , wherein the compound is at least 95% by weight of the β-D-isomer.
35. The pharmaceutical composition of claim 32 , wherein the compound is at least 90% by weight of the β-L-isomer.
36. The pharmaceutical composition of claim 32 , wherein the compound is at least 95% by weight of the β-L-isomer.
37. The pharmaceutical composition of claim 20 , wherein the compound is
38. The method of claim 1 , wherein the compound is