Spiro[2.4]heptanes for treatment of flaviviridae infections

• US 8,946,242 B2
• Filed: 01/23/2014
• Issued: 02/03/2015
• 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): Pagano, Alexander R
• Application Number:
  US14/162,620
• Publication Number:
  US 20140140958A1
• Time in Patent Office: 376 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 spiro[2.4]heptane of the structure:

3. The spiro[2.4]heptane of claim 1, wherein R¹ is a purine or pyrimidine selected from the group consisting of cytosine, 5-halocytosine, uracil, 5-halouracil, 5-methylcytosine, thymine, adenine, guanine, xanthine, or hypoxanthine.

5. The spiro[2.4]heptane of claim 1, wherein R¹ is 5-fluorocytosine or 5-fluorouracil.

7. The spiro[2.4]heptane of claim 1, wherein R¹ is uracil.

9. The spiro[2.4]heptane of claim 1, wherein R¹ is cytosine.

11. The spiro[2.4]heptane of claim 1, wherein R⁵ is a phosphoramidate.

13. The spiro[2.4]heptane of claim 1, wherein R⁵ is a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R⁵ is H or mono, di, or tri-phosphate.

15. The spiro[2.4]heptane of claim 1, wherein R² is methyl, R³ is F or OR⁷, and R⁴ is OH.

16. The spiro[2.4]heptane of claim 15, wherein R¹ is uracil.

17. The spiro[2.4]heptane of claim 15, wherein R⁵ is phosphoramidate.

26. The spiro[2.4]heptane of claim 1, wherein R³ is F.

31. The spiro[2.4]heptane of claim 26, wherein R¹ is a purine or pyrimidine.

32. A pharmaceutical composition, comprising an effective amount of the spiro[2.4]heptane of claim 1, in a pharmaceutically acceptable carrier.

36. A pharmaceutical composition, comprising an effective amount of the spiro[2.4]heptane of claim 31, in a pharmaceutically acceptable carrier.

37. The pharmaceutical composition of claim 32, wherein the composition is suitable for oral delivery.

41. 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 claim 1, optionally in a pharmaceutically acceptable carrier.

46. The method of claim 41, further comprising administering the spiro[2.4]heptane in combination with another anti-HCV agent.

51. The method of claim 46, 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.

2. A spiro[2.4]heptane of the structure:

4. The spiro[2.4]heptane of claim 2, wherein B is a purine or pyrimidine selected from the group consisting of cytosine, 5-halocytosine, uracil, 5-halouracil, 5-methylcytosine, thymine, adenine, guanine, xanthine, or hypoxanthine.

6. The spiro[2.4]heptane of claim 2, wherein B is 5-fluorocytosine or 5-fluorouracil.

8. The spiro[2.4]heptane of claim 2, wherein B is uracil.

10. The spiro[2.4]heptane of claim 2, wherein B is cytosine.

12. The spiro[2.4]heptane of claim 2, wherein R⁵ is a phosphoramidate.

14. The spiro[2.4]heptane of claim 2, wherein R⁵ is a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R⁵ is H or mono, di, or tri-phosphate.

18. The spiro[2.4]heptane of claim 2, wherein B is a pyrimidine.

19. The spiro[2.4]heptane of claim 2, wherein R⁷ is H, and R⁵ is H or phosphoramidate.

20. The spiro[2.4]heptane of claim 19, wherein B is uracil.

21. The spiro[2.4]heptane of claim 20, wherein R⁵ is phosphoramidate.

33. A pharmaceutical composition, comprising an effective amount of the spiro[2.4]heptane of claim 2, in a pharmaceutically acceptable carrier.

38. The pharmaceutical composition of claim 33, wherein the composition is suitable for oral delivery.

42. 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 claim 2, optionally in a pharmaceutically acceptable carrier.

47. The method of claim 42, further comprising administering the spiro[2.4]heptane in combination with another anti-HCV agent.

52. The method of claim 47, 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.

22. A spiro[2.4]heptane of the formula:

23. The spiro[2.4]heptane of claim 22, wherein B is a pyrimidine.

24. The spiro[2.4]heptane of claim 23, wherein the pyrimidine is selected from the group consisting of cytosine, 5-halocytosine, uracil, 5-halouracil, 5-methylcytosine, or thymine.

25. The spiro[2.4]heptane of claim 22, wherein R⁷ is H.

27. The spiro[2.4]heptane of claim 22, wherein R⁵ is a phosphoramidate.

28. The spiro[2.4]heptane of claim 22, wherein R⁷ is H and R⁵ is a phosphoroamidate.

29. The spiro[2.4]heptane of claim 22, wherein R⁷ is H, B is uracil and R⁵ is a phosphoroamidate.

34. A pharmaceutical composition, comprising an effective amount of the spiro[2.4]heptane of claim 22, in a pharmaceutically acceptable carrier.

39. The pharmaceutical composition of claim 34, wherein the composition is suitable for oral delivery.

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 claim 22, optionally in a pharmaceutically acceptable carrier.

48. The method of claim 43, further comprising administering the spiro[2.4]heptane in combination with another anti-HCV agent.

49. The method of claim 48, 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.

30. A spiro[2.4]heptane of the formula:

35. A pharmaceutical composition, comprising an effective amount of the spiro[2.4]heptane of claim 30, in a pharmaceutically acceptable carrier.

40. The pharmaceutical composition of claim 35, wherein the composition is suitable for oral delivery.

44. 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 claim 30, optionally in a pharmaceutically acceptable carrier.

45. The method of claim 44, further comprising administering the spiro[2.4]heptane in combination with another anti-HCV agent.

50. The method of claim 45, 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.