Boron containing small molecules as antiprotozoal agents

• US 9,440,994 B2
• Filed: 08/06/2010
• Issued: 09/13/2016
• Est. Priority Date: 08/14/2009
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Chen, Daitao, Orr, Matthew, Sligar, Jessica, Jacobs, Robert, Plattner, Jacob J.
• Primary Examiner(s): DRAPER, LESLIE A ROYDS
• Application Number:
  US12/852,351
• Publication Number:
  US 20110190235A1
• Time in Patent Office: 2,230 Days
• US Class Current: 1/1
• CPC Class Codes: A01N 55/08 containing boron
• 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. The exemplary compounds have the following formula:

wherein X is selected from the group consisting of substituted phenyl, substituted or unsubstituted heteroaryl and unsubstituted cycloalkyl; R^3a is selected from the group consisting of H, unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl and unsubstituted C₃ or C₄ or C₅ or C₆ cycloalkyl; R^3b is selected from the group consisting of H, unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl and unsubstituted C₃ or C₄ or C₅ or C₆ cycloalkyl;
with the proviso that R^3a and R^3b, along with the atom to which they are attached, are optionally joined to form a 3 or 4 or 5 or 6 membered ring, with the proviso that R^3a and R^3b cannot both be H, or a salt thereof.

Claims

1. A compound having a structure according to the following formula:

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

3. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

4. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

5. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

6. The compound of claim 2, or a salt thereof,

wherein

one member selected from R², R³, R⁴, R⁵ and R⁶ is halogen or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl or halosubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

7. The compound of claim 6, or a salt thereof,

wherein

one member selected from R², R³, R⁴, R⁵ and R⁶ is a member selected from F, Cl, Br, I, CH₃, CF₃ and OCH₃;

and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

8. The compound of claim 7, or a salt thereof,

wherein

one member selected from R², R³, R⁴, R⁵ and R⁶ is F or Cl or CH₃ or CF₃;

and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

9. The compound of claim 2, or a salt thereof,

wherein

two members selected from R², R³, R⁴, R⁵ and R⁶ are the same or different and are each selected from halogen;

and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

10. The compound of claim 2, or a salt thereof,

wherein

one member selected from R², R³, R⁴, R⁵ and R⁶ is halogen;

one member selected from R², R³, R⁴, R⁵ and R⁶ is halogen or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl or halosubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl; and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

11. The compound of claim 10, or a salt thereof,

wherein

one member selected from R², R³, R⁴, R⁵ and R⁶ is halogen;

one member selected from R², R³, R⁴, R⁵ and R⁶ is F or Cl or Br or I or CH₃ or CF₃ or OCH₃; and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

12. The compound of claim 2, or a salt thereof,

wherein

one member selected from R², R³, R⁴, R⁵ and R⁶ is F;

one member selected from R², R³, R⁴, R⁵ and R⁶ is halogen or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl or halosubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl; and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

13. The compound of claim 12, or a salt thereof,

wherein

one member selected from R², R³, R⁴, R⁵ and R⁶ is F;

and

one member selected from R², R³, R⁴, R⁵ and R⁶ is Cl or CH₃ or CF₃; and

the remaining members of R², R³, R⁴, R⁵ and R⁶ are H.

14. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

15. The compound of claim 14, or a salt thereof, having a structure according to the following formula:

16. The compound of claim 15, or a salt thereof, wherein R² is a member selected from F, Cl, CH₃ and CF₃.

17. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

18. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

19. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

20. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

21. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

22. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

23. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

24. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

25. The compound of claim 2, or a salt thereof, having a structure according to the following formula:

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

27. A pharmaceutical formulation comprising:

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

b) a pharmaceutically acceptable excipient.

28. The pharmaceutical formulation of claim 27, wherein the pharmaceutical formulation is a unit dosage form.

41. The compound of claim 1, which is 4-fluoro-N-(1-hydroxy-3,3-spirocyclopropyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl benzamide, 4-fluoro-N-(1-hydroxy-3,3-spirocyclobutyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl benzamide, 2-chloro-4-fluoro-N-(1-hydroxy-3,3-spirocyclobutyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide, 4-fluoro-N-(1-hydroxy-3,3-spirocyclopentyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl benzamide, or 2-chloro-N-(1-hydroxy-3,3-spirocyclopentyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide;

or a salt thereof.

29. 4-Fluoro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl benzamide, or a salt thereof.

30. A combination comprising the compound of claim 29, or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.

31. A pharmaceutical formulation comprising:

a) the compound of claim 29, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.

32. A compound, which is N-(1-hydroxy-3-isobutyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide, 4-fluoro-N-(1-hydroxy-3-isobutyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide, 4-fluoro-N-(1-hydroxy-3-isobutyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide, or 2-chloro-N-(1-hydroxy-3-isobutyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide;

or a salt thereof.

33. A combination comprising the compound of claim 32, or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.

34. A pharmaceutical formulation comprising:

a) the compound of claim 32, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.

35. A compound, which is N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide, 2-chloro-N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide, N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-fluoro-2-trifluoromethyl-benzamide, N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-fluoro-benzamide, or N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-acetamide;

or a salt thereof.

36. A combination comprising the compound of claim 35, or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.

37. A pharmaceutical formulation comprising:

a) the compound of claim 35, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.

38. A compound, which is N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-thiophen-2-yl-benzamide, N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-morpholin-4-yl-benzamide, or biphenyl-4-carboxylic acid (1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide;

or a salt thereof.

39. A combination comprising the compound of claim 38, or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.

40. A pharmaceutical formulation comprising:

a) the compound of claim 38, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.