Boron-containing small molecules as anti-protozoal agents

• US 9,493,489 B2
• Filed: 10/15/2009
• Issued: 11/15/2016
• Est. Priority Date: 10/15/2008
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Yi, Long, Jacobs, Robert, Orr, Matthew, Wring, Stephen, Chen, Daitao, Zhou, Huchen, Ding, Dazhong, Feng, Yiqing, Hernandez, Vincent S., Zhang, Yong-Kang, Plattner, Jacob J.
• Primary Examiner(s): Oh, T. Victor
• Application Number:
  US13/062,450
• Publication Number:
  US 20110207702A1
• Time in Patent Office: 2,588 Days
• Field of Search: 544/69, 544/229, 549/213, 514/64, 546/13, 435/258.1, 558/384, 564/8, 548/110
• US Class Current: 1/1
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• 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

This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.

Claims

1. A compound, or a salt thereof, having a structure according to the following formula:

2. The compound of claim 1, or a salt thereof, wherein X is phenyl, substituted with at least one member selected from the group consisting of:

halogen, cyano, nitro, OR, SR, NRR, unsubstituted alkyl, substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl,

wherein each R is independently selected from the group consisting of unsubstituted alkyl, substituted alkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl.

3. The compound of claim 1, or a salt thereof, having a structure according to the following formula:

4. The compound of claim 3, or a salt thereof, wherein said Y¹ is a halogen, and said halogen is fluoro.

5. The compound of claim 3, or a salt thereof, wherein said Y is halo-substituted C₁-C₆ alkyl, and said halo-substituted C₁-C₆ alkyl is trifluoromethyl.

6. The compound of claim 3, or a salt thereof, having a structure according to the following formula:

7. The compound of claim 3, or a salt thereof, having a structure according to the following formula:

8. The compound of claim 3, or a salt thereof, having a structure according to the following formula:

9. A combination comprising the compound of claim 1, or a salt thereof, together with at least one other therapeutically active agent.

10. A pharmaceutical formulation comprising:

a) the compound of claim 1, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.

11. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation is a unit dosage form.

12. The compound of claim 1, wherein the salt of said compound is a pharmaceutically acceptable salt.

13. A method of killing and/or inhibiting the growth of a protozoa, comprising:

contacting the protozoa with an effective amount of the compound of claim 1, or a salt thereof, thereby killing and/or preventing the growth of the protozoa, wherein the protozoa is of a genus selected from the group consisting of Trypanosoma, Leishmania, and Plasmodium.

14. The method of claim 13, wherein the compound is according to claim 1, or a salt thereof.

15. The method of claim 13, wherein the protozoa is of the genus Trypanosoma.

16. The method of claim 13, wherein the protozoa is Trypanosoma brucei.

17. The method of claim 16, wherein the Trypanosoma brucei is selected from the group consisting of Trypanosoma brucei brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense.

18. A method of treating a disease in an animal, comprising:

administering to the animal a therapeutically effective amount of the compound of claim 1, or a salt thereof, thereby treating the disease, wherein the disease is associated with a protozoa of a genus selected from the group consisting of Trypanosoma, Leishmania, and Plasmodium.

19. The method of claim 18, wherein the compound is according to claim 1.

20. The method of claim 18, wherein the disease is sleeping sickness.

21. The method of claim 18, wherein the animal is a human.

22. The compound of claim 2, or a salt thereof, wherein X is phenyl, substituted with at least one member which is halosubstituted alkyl.

23. The compound of claim 2, or a salt thereof, wherein X is phenyl, substituted with at least one member which is trifluoromethyl.

24. The compound of claim 1, or a salt thereof, having a structure according to the following formula:

25. The compound of claim 24, or a salt thereof, wherein Y is C₁-C₆ alkyl, substituted with one, two, three, or four halogens.

26. The compound of claim 24, or a salt thereof, wherein Y is C₁-C₆ alkyl, substituted with one, two, three, or four fluorines.

27. The compound of claim 24, or a salt thereof, wherein Y is C₁-C₆ alkyl, substituted with one, two, three, or four chlorines.

28. The compound of claim 24, or a salt thereof, wherein Y is trifluoromethyl.

29. The compound of claim 24, or a salt thereof, which is N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethyl)benzamide.

30. The compound of claim 24, or a salt thereof, which is N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromethyl)benzamide.

31. The compound of claim 24, or a salt thereof, which is N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(trifluoromethyl)benzamide.

32. The compound of claim 1, or a salt thereof, having a structure according to the following formula:

33. The compound of claim 32, or a salt thereof, wherein Y⁵ is substituted with one or two or three halogens.

34. The compound of claim 32, or a salt thereof, wherein said Y⁵ is halosubstituted C₁-C₆ alkoxy, and said halosubstituted C₁-C₆ alkoxy is fluoro-substituted C₁-C₆ alkoxy.

35. The compound of claim 32, or a salt thereof, wherein said Y⁵ is halosubstituted C₁-C₆ alkoxy, and said halosubstituted C₁-C₆ alkoxy is trifluoro-substituted C₁-C₆ alkoxy.

36. The compound of claim 1, or a salt thereof, which is N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluoromethoxy)benzamide.

37. The compound of claim 1, or a salt thereof, having a structure according to the following formula:

38. The compound of claim 37, or a salt thereof, wherein one Y is fluoro-substituted C₁-C₆ alkyl.

39. The compound of claim 37, or a salt thereof, wherein one Y is trifluoro-substituted C₁-C₆ alkyl.

40. The compound of claim 37, or a salt thereof, wherein each Y is fluoro-substituted C₁-C₆ alkyl.

41. The compound of claim 37, or a salt thereof, wherein each Y is trifluoro-substituted C₁-C₆ alkyl.

42. The compound of claim 1, or a salt thereof, which is N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-bis-trifluoromethyl-benzamide.

43. The compound of claim 1, or a salt thereof, which is N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,5-bis-trifluoromethyl-benzamide.

44. The compound of claim 1, or a salt thereof, which is N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3,5-bis-trifluoromethyl-benzamide.

45. The compound of claim 1, or a salt thereof, having a structure according to the following formula:

46. The compound of claim 5, or a salt thereof, wherein Y is fluoro-substituted C₁-C₆ alkyl.

47. The compound of claim 45, or a salt thereof, wherein Y is trifluoro-substituted C₁-C₆ alkyl.

48. The compound of claim 45, or a salt thereof, wherein Y is fluoro-substituted C₁-C₆ alkyl, and each Y¹ is chloro.

49. The compound of claim 45, or a salt thereof, wherein Y is fluoro-substituted C₁-C₆ alkyl, and each Y¹ is fluoro.

50. The compound of claim 45, or a salt thereof, wherein Y is fluoro-substituted C₁-C₆ alkyl, a Y¹ is fluoro, and another Y¹ is chloro.

51. The compound of claim 45, or a salt thereof, wherein Y is trifluoro-substituted C₁-C₆ alkyl, and each Y¹ is chloro.

52. The compound of claim 45, or a salt thereof, wherein Y is trifluoro-substituted C₁-C₆ alkyl, and each Y¹ is fluoro.

53. The compound of claim 45, or a salt thereof, wherein Y is trifluoro-substituted C₁-C₆ alkyl, a Y¹ is fluoro, and another Y¹ is chloro.

54. The compound of claim 45, or a salt thereof, having a structure which is

55. The compound of claim 45, or a salt thereof, having a structure which is

56. The compound of claim 45, or a salt thereof, having a structure which is

57. The compound of claim 1, or a salt thereof, wherein said compound is 3-chloro-2-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-trifluoromethyl-benzamide.