Spiro[2.4]heptanes for treatment of flaviviridae infections
Compounds, methods, and compositions for the treatment of infections in or exposure to humans and other host animals of Flaviviridae viruses, including HCV, that includes the administration of an effective amount of a spiro[2.4]heptane as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier, are provided. The spiro[2.4]heptane compounds either possess antiviral activity, or are metabolized to a compound that exhibits such activity.
1. A method for the treatment of a hepatitis C infection in a host in need thereof, comprising administering an effective amount of a spiro[2.4]heptane of the following structure:
wherein:
R 1 is a natural or non-natural heteroaryl or heterocyclic moiety;
R 2 is methyl or F;
R 3 is methyl, F, Cl, N 3 , or OR 7 ;
R 4 is OR 7 , H, methyl, F, Cl, or N 3 ;
R 5 is H, phosphate, a stabilized phosphate prodrug, phosphoramidate, acyl, alkyl, sulfonate ester, a lipid, a phospholipid, an amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 5 is H or mono, di, or tri-phosphate; and,
R 7 is H, acyl, phosphate, sulfate, amino acid, peptide, or an oxygen-protecting group;
or its pharmaceutically acceptable salt;
optionally in a pharmaceutically acceptable carrier.
2. The method of claim 1 , wherein R 1 is a pyrimidine or purine.
3. The method of claim 2 , wherein the purine or pyrimidine is selected from the group consisting of cytosine, 5-halocytosine, uracil, 5-halouracil, 5-methylcytosine, thymine, adenine, thymine, guanine, xanthine, or hypoxanthine.
4. The method of claim 2 , wherein the pyrimidine is 5-fluorocytosine or 5-fluorouracil.
5. The method of claim 2 , wherein the pyrimidine is uracil.
6. The method of claim 2 , wherein the pyrimidine is cytosine.
7. The method of claim 1 , wherein R 5 is a phosphoramidate.
8. The method of claim 2 , wherein R 2 is methyl, R 3 is F, and R 4 is OR 7 .
9. The method of claim 8 , wherein R 1 is uracil.
10. The method of claim 9 , wherein R 5 is phosphoramidate.
11. The method of claim 1 , wherein the spiro[2.4]heptane is administered orally.
12. The method of claim 1 , wherein the spiro[2.4]heptane is administered via controlled release.
13. The method of claim 1 , wherein the spiro[2.4]heptane is administered intravenously.
14. The method of claim 1 , further comprising administering the spiro[2.4]heptane in combination with another anti-HCV agent.
15. The method of claim 14 , wherein the additional anti-HCV agent is selected from the group consisting of a protease inhibitor; an NS5A inhibitor; another NS5B polymerase inhibitor; a non-substrate (allosteric) inhibitor; interferon alfa-2a, which may be pegylated; ribavirin; a helicase inhibitor; an antisense oligodeoxynucleotide (S-ODN); an aptamer; a nuclease-resistant ribozyme; iRNA; an antibody to HCV; a partial antibody to HCV; and a domain antibody to HCV.
16. A method for treating a hepatitis C infection in a host in need thereof, comprising administering an effective amount of spiro[2.4]heptane of the following formula:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are as defined in claim 1 ,
or a pharmaceutically acceptable salt thereof;
optionally in a pharmaceutically acceptable carrier.
17. The method of claim 16 , further comprising administering the spiro[2.4]heptane in combination with another anti-HCV agent.
18. The method of claim 17 , wherein the additional anti-HCV agent is selected from the group consisting of a protease inhibitor; an NS5A inhibitor; another NS5B polymerase inhibitor; a non-substrate (allosteric) inhibitor; interferon alfa-2a, which may be pegylated; ribavirin; a helicase inhibitor; an antisense oligodeoxynucleotide (S-ODN); an aptamer; a nuclease-resistant ribozyme; iRNA; an antibody to HCV; a partial antibody to HCV; and a domain antibody to HCV.
19. The method of claim 15 , wherein the protease inhibitor is selected from the group consisting of telaprevir and boceprevir.
20. The method of claim 18 , wherein the protease inhibitor is selected from the group consisting of telaprevir and boceprevir.
21. The method of claim 1 , further comprising administering the spiro[2.4]heptane in combination with an anti-hepatocellular carcinoma agent.
22. The method of claim 21 , wherein the anti-cancer agent is selected from the group consisting of an anti-angiogenic agents, sunitinib, brivanib, linifanib, ramcirumab, bavcizumab, cediranib, pazopanib, TSU-68, lenvatinib, antibodies against EGFR, mTor inhibitors, MEK inhibitors, and histone deacetylase inhibitors.
23. The method of claim 16 , further comprising administering the spiro[2.4]heptane in combination with an anti-hepatocellular carcinoma agent.
24. The method of claim 23 , wherein the anti-cancer agent is selected from the group consisting of an anti-angiogenic agents, sunitinib, brivanib, linifanib, ramcirumab, bavcizumab, cediranib, pazopanib, TSU-68, lenvatinib, antibodies against EGFR, mTor inhibitors, MEK inhibitors, and histone deacetylase inhibitors.
25. The method of claim 1 , wherein R 3 is F or R 2 is F.
26. The method of claim 1 , wherein R 4 and R 5 together form a bridge, wherein the bridge is selected from the group consisting of a phosphoester, carbodiester, and a phosphoramidate.
27. The method of claim 16 , wherein R 1 is a pyrimidine or purine.
28. The method of claim 27 , wherein the purine or pyrimidine is selected from the group consisting of cytosine, 5-halocytosine, uracil, 5-halouracil, 5-methylcytosine, thymine, adenine, thymine, guanine, xanthine, or hypoxanthine.
29. The method of claim 27 , wherein the pyrimidine is 5-fluorocytosine or 5-fluorouracil.
30. The method of claim 27 , wherein the pyrimidine is uracil.
31. The method of claim 27 , wherein the pyrimidine is cytosine.
32. The method of claim 16 , wherein R 5 is a phosphoramidate.
33. The method of claim 27 , wherein R 2 is methyl, R 3 is F, and R 4 is OR 7 .
34. The method of claim 33 , wherein R 1 is uracil.
35. The method of claim 34 , wherein R 5 is phosphoramidate.
36. The method of claim 16 , wherein the spiro[2.4]heptane is administered orally.
37. The method of claim 16 , wherein the spiro[2.4]heptane is administered via controlled release.
38. The method of claim 16 , wherein the spiro[2.4]heptane is administered intravenously.
39. The method of claim 16 , wherein R 4 and R 5 together form a bridge wherein the bridge is selected from the group consisting of a phosphoester, carbodiester, and a phosphoramidate.
40. The method of claim 15 , wherein the additional NS5B polymerase inhibitor is PSI-7977.
41. The method of claim 18 , wherein the additional NS5B polymerase inhibitor is PSI-7977.
42. The method of claim 16 , wherein R 2 is F and R 3 is F.
43. A method for the treatment of a hepatitis C infection in a host in need thereof, comprising administering an effective amount of a spiro[2.4]heptane of the following structure:
wherein:
R 1 is a natural or non-natural heteroaryl or heterocyclic moiety;
R 2 is H;
R 3 is F;
R 4 is OR 7 , H, methyl, F, Cl, or N 3 ;
R 5 is H, phosphate, a stabilized phosphate prodrug, phosphoramidate, acyl, alkyl, sulfonate ester, a lipid, a phospholipid, an amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 5 is H or mono, di, or tri-phosphate; and,
R 7 is H, acyl, phosphate, sulfate, amino acid, peptide, or an oxygen-protecting group;
or its pharmaceutically acceptable salt;
optionally in a pharmaceutically acceptable carrier.