Spiro[2.4]heptanes for treatment of flaviviridae infections

• US 8,921,384 B2
• Filed: 01/23/2014
• Issued: 12/30/2014
• Est. Priority Date: 02/14/2012
• Status: Active Grant

• Current Assignee: The University of Georgia Research Foundation, Inc.
• Original Assignee: The University of Georgia Research Foundation, Inc.
• Inventors: Chu, Chung K.
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Pagano, Alexander R
• Application Number:
  US14/162,618
• Publication Number:
  US 20140140957A1
• Time in Patent Office: 341 Days
• Field of Search: 514/263.1, 514/263.37, 514/274, 544/277, 544/265, 544/304, 544/317
• US Class Current: 514/263.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/42 viral
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07F 9/2458 of aliphatic amines
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65616 : containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07F 9/65744 : condensed with carbocyclic or heterocyclic rings or ring systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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.

Claims

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:

2. The method of claim 1, wherein R¹ 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 R⁵ is a phosphoramidate.

8. The method of claim 2, wherein R² is methyl, R³ is F, and R⁴ is OR⁷.

9. The method of claim 8, wherein R¹ is uracil.

10. The method of claim 9, wherein R⁵ 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:

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 R³ is F or R² is F.

26. The method of claim 1, wherein R⁴ and R⁵ 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 R¹ 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 R⁵ is a phosphoramidate.

33. The method of claim 27, wherein R² is methyl, R³ is F, and R⁴ is OR⁷.

34. The method of claim 33, wherein R¹ is uracil.

35. The method of claim 34, wherein R⁵ 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 R⁴ and R⁵ 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 R² is F and R³ 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: