Boron-containing small molecules as antiprotozoal agents

• US 9,346,834 B2
• Filed: 10/19/2010
• Issued: 05/24/2016
• Est. Priority Date: 10/20/2009
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Ding, Dazhong, Zhou, Huchen, Sun, Daoan, Zhou, Yasheen, Zhang, Yong-Kang, Plattner, Jacob J.
• Primary Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US13/503,016
• Publication Number:
  US 20120295875A1
• Time in Patent Office: 2,044 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

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 having a structure according to the following formula:

2. The compound of claim 1, or a salt, hydrate, or solvate thereof, wherein R³ is —

C(O)R¹² and R² is unsubstituted linear alkylene and R¹² is unsubstituted alkyl.

3. The compound of claim 1, or a salt, hydrate, or solvate thereof, wherein R³ is —

C(O)R¹² and R² is methylene and R¹² is unsubstituted alkyl.

4. The compound of claim 1, or a salt, hydrate, or solvate thereof, wherein the compound has the following structure:

5. The compound of claim 4, or a salt, hydrate, or solvate thereof, wherein R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

6. The compound of claim 4, or a salt, hydrate, or solvate thereof, wherein R² is methylene or ethylene or propylene or butylene or pentylene or hexylene.

7. The compound of claim 4, or a salt, hydrate, or solvate thereof, wherein R² is methylene and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl.

8. The compound of claim 4, or a salt, hydrate, or solvate thereof, wherein R² is ethylene and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl.

9. The compound of claim 4, or a salt, hydrate, or solvate thereof, wherein R² is propylene and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl.

10. The compound of claim 1, or a salt, hydrate, or solvate thereof, wherein the compound has the following structure:

11. The compound of claim 10, or a salt, hydrate, or solvate thereof, wherein R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

12. The compound of claim 10, or a salt, hydrate, or solvate thereof, wherein R⁴ is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

13. The compound of claim 10, or a salt, hydrate, or solvate thereof, wherein R⁴ is methyl and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl.

14. The compound of claim 10, or a salt, hydrate, or solvate thereof, wherein R⁴ is methyl and R¹² is methyl.

15. The compound of claim 10, or a salt, hydrate, or solvate thereof, wherein R⁴ is ethyl and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl.

16. The compound of claim 10, or a salt, hydrate, or solvate thereof, wherein R⁴ is propyl and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl.

17. The compound of claim 10, or a salt, hydrate, or solvate thereof, wherein R⁴ is isopropyl and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl.

18. The compound of claim 1, or a salt, hydrate, or solvate thereof, wherein the compound has the following structure:

19. The compound of claim 18, or a salt, hydrate, or solvate thereof, wherein R¹² is methyl or ethyl or unsubstituted C₃ alkyl.

20. The compound of claim 18, or a salt, hydrate, or solvate thereof, wherein R⁴ is methyl, and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

21. The compound of claim 18, or a salt, hydrate, or solvate thereof, wherein R⁴ is ethyl, and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

22. The compound of claim 18, or a salt, hydrate, or solvate thereof, wherein R⁴ is unsubstituted C₃ alkyl, and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

23. The compound of claim 18, or a salt, hydrate, or solvate thereof, wherein R⁴ is methyl, R⁵ is methyl and R¹² is methyl or ethyl or unsubstituted C₃ alkyl of unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

24. The compound of claim 18, or a salt, hydrate, or solvate thereof, wherein R⁴ is methyl, R⁵ is methyl and R¹² is methyl or ethyl or unsubstituted C₃ alkyl.

25. The compound of claim 18, or a salt, hydrate, or solvate thereof, wherein R⁴ is ethyl, R⁵ is ethyl and R¹² is methyl or ethyl or unsubstituted C₃ alkyl or unsubstituted C₄ alkyl or unsubstituted C₅ alkyl or unsubstituted C₆ alkyl.

26. The compound of claim 1, or a salt, hydrate, or solvate thereof, which is methyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetamide, ethyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetamide, N-propyl-2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)acetamide, N-tert-butyl-2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)acetamide, or N-(2,6-dimethylphenyl)-[2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetamide.

27. The compound of claim 4, or a salt, hydrate, or solvate thereof, which is 1-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) butan-2-one, 1-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) pentan-2-one, 1-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)-4-methylpentan-2-one, 3-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) butan-2-one, 2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) pentan-3-one, 3-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) pentan-2-one, 3-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) hexan-2-one, 3-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) heptan-4-one, 3-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)-4-methyl-pentan-2-one, 3-(1,3-dihydro-1-hydroxyl-2,1-benzoxaborol-6-yloxy)-3-methylbutan-2-one, or 6-(2-hydroxy-1-methylbutoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole.

28. The compound of claim 1, or a salt, hydrate, or solvate thereof, which is 6-((2′

-chloro)thiazol-5-yl)methoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6-((3,5-dimethylisoxazol-4-yl)methoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6-((isoindoline-1,3-dione-2-yl)propoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, 6-(2-(1H-tetrazol-5-yl)oxymethyl)benzo[c][1,2]oxaborol-1(3H)-ol, 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N -(cyclopropylsulfonyl) acetamide, 5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)thiazolidine-2,4-dione, 5-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)methyl)thiazolidine-2,4-dione, or 5-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)ethyl)thiazolidine-2,4-dione.

29. The compound of claim 1, or a salt, hydrate, or solvate thereof, which is [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetic acid, methyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetate, ethyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetate, tert-butyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetate, [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]acetaldehyde, ethyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)] propanoate, ethyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]butanoate, ethyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]-2-methylpropanoate, ethyl [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]-2-phenylacetate, [3-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]propanoic acid, [4-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy]butanoic acid, [5-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy]pentanoic acid, [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) ]propanoic acid, [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy) ]butanoic acid, [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]-2-methylpropanoic acid, or [2-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-yloxy)]-2-phenylacetic acid.

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

31. A pharmaceutical formulation comprising:

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

b) a pharmaceutically acceptable excipient.

32. The pharmaceutical formulation of claim 31, wherein the pharmaceutical formulation is a unit dosage form.