Trisubstituted boron-containing molecules

• US 8,343,944 B2
• Filed: 07/27/2010
• Issued: 01/01/2013
• Est. Priority Date: 07/28/2009
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC), Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Xia, Yi, Alley, Michael Richard Kevin, Zhou, Yasheen, Singh, Rajeshwar, Ding, Charles, Cao, Kathy, Plattner, Jacob J., Ou, Ligong, Jia, Guofeng, Ramachandran, Sreekanth, Zhou, Ding, Saraswat, Neerja
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US12/844,748
• Publication Number:
  US 20110136763A1
• Time in Patent Office: 889 Days
• Field of Search: 558/288, 514/64
• US Class Current: 514/64
• 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 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

This invention largely relates to 3,4,6-trisubstituted benzoxaborole compounds, and their use for treating bacterial infections.

Claims

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

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

3. The compound of claim 1, wherein said R^3a is H.

4. The compound of claim 1, wherein said R⁴ is selected from unsubstituted C₁, C₂, C₃, C₄, C₅, or C₆ alkyl, or is selected from unsubstituted C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy.

5. The compound of claim 1, wherein said R⁴ is methyl.

6. The compound of claim 1, wherein said m is an integer selected from 1, 2, 3, or 4.

7. The compound of claim 1, wherein said R³ is —

CH₂C(O)OH.

8. The compound of claim 1 or 2, wherein said R⁴ is methyl and R³ is —

CH₂C(O)OH.

9. The compound of claim 8, wherein said R⁶ is H.

10. The compound of claim 8, wherein said R⁶ is selected from unsubstituted C₁, C₂, or C₃ alkyl.

11. The compound of claim 10, wherein said R⁶ is methyl.

12. The compound of claim 8, wherein said R⁶ is —

S(O)₂CH₃.

13. The compound of claim 8, wherein R⁶ is A and said A is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted thiazolyl, and substituted or unsubstituted thiadiazolyl.

14. The compound of claim 13, wherein said A is unsubstituted 1,3,4-thiadiazol-2-yl or amino substituted 1,3,4-thiadiazol-2-yl.

15. The compound of claim 13, wherein said A is thiazol-2-yl substituted with carbamoyl or carbamimidoyl.

16. The compound of claim 13, wherein said A is unsubstituted pyrazin-2-yl or pyrazin-2-yl substituted with aminomethyl or carbamimidoyl.

17. The compound of claim 13, wherein said A is pyridin-2-yl substituted with carbamimidoyl.

18. The compound of claim 13, wherein said A is 3-(3-aminopropoxy)phenyl.

19. The compound of claim 7, wherein said R⁶ is unsubstituted pyrazin-2-yl and R⁴ is OHor —

O(CH₂)₃NH₂.

20. A combination comprising:

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

b) at least one therapeutic agent.

21. The combination of claim 20, wherein said at least one therapeutic agent is an antibiotic which comprises a beta-lactam moiety.

22. The combination of claim 20, wherein said at least one therapeutic agent is selected from the group consisting of a penicillin, cephalosporin, cephamycin, monobactam, penem, and carbapenem.

23. A pharmaceutical formulation comprising:

a) a compound of claim 1 or a combination of claim 20, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.

24. The pharmaceutical formulation of claim 23, wherein said formulation is a unit dosage form.

25. The pharmaceutical formulation of claim 23, wherein said formulation is an oral unit dosage form or a topical unit dosage form.

26. A method of treating a bacterial infection comprising:

administering to an animal suffering from said infection an effective amount of a compound of claim 1, or a pharmaceutically-acceptable salt thereof, and an effective amount of an antibiotic, or a pharmaceutically acceptable salt thereof, wherein said antibiotic comprises a β

-lactam moiety, thereby treating the bacterial infection.

27. The method of claim 26, wherein a bacteria involved with said infection is resistant to said antibiotic.

28. The method of claim 26, wherein the antibiotic is selected from the group consisting of a penicillin, cephalosporin, cephamycin, monobactam, penem, and carbapenem.

29. The method of claim 26, wherein said animal is a human.

30. The use of a compound of claim 1 or a combination of claim 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of bacterial infection.

31. A method of killing or inhibiting the growth of a bacteria, said method comprising:

contacting said bacteria with an effective amount of the compound of claim 1 or the combination of claim 20, or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of the bacteria.

32. The method of claim 31, further comprises contacting said bacteria with an effective amount of an antibiotic, or a pharmaceutically acceptable salt thereof, wherein said antibiotic comprises a β

-lactam moiety.

33. The method of claim 31, wherein the bacteria is resistant to said antibiotic.

34. A method of inhibiting a β

-lactamase, comprising contacting the β

-lactamase with an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, thereby inhibiting the β

-lactamase.

35. The method of claim 34, wherein the β

-lactamase is selected from the group consisting of a Group 1 β

-lactamase, a Group 2 β

-lactamase, and a Group 4 β

-lactamase.

36. The method of claim 35, wherein said Group 1 β

-lactamase is a cephalosporinase.

37. The method of claim 35, wherein said Group 2 β

-lactamase is selected from the group consisting of penicillinase, a Group 2b β

-lactamase, Group 2be β

-lactamase, Group 2br β

-lactamase, carbenicillinase, cloxacilanase, cephalosporinase and carbapenamase.

38. The method of claim 35, wherein said Group 4 β

-lactamase is a penicillinase.

39. The method of claim 34, wherein the β

-lactamase is selected from the group consisting of a class A β

-lactamase, a class B β

-lactamase, a class C β

-lactamase, and a class D β

-lactamase.

40. The method of claim 39, wherein the class A β

-lactamase is selected from the group consisting of a TEM β

-lactamase, SHV β

-lactamase, CTX-M β

-lactamase and a KPC β

-lactamase.

41. The method of claim 39, wherein the class C β

-lactamase is a CMY β

-lactamase or a AmpC β

-lactamase.

42. The method of claim 39, wherein the class D β

-lactamase is an OXA β

-lactamase.

43. The compound of claim 1, wherein R⁶ is A and said A is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted thiazolyl, and substituted or unsubstituted thiadiazolyl.

44. The compound of claim 43, wherein said A is unsubstituted 1,3,4-thiadiazol-2-yl or amino substituted 1,3,4-thiadiazol-2-yl.

45. The compound of claim 43, wherein said A is thiazol-2-yl substituted with carbamoyl or carbamimidoyl.

46. The compound of claim 43, wherein said A is unsubstituted pyrazin-2-yl or pyrazin-2-yl substituted with aminomethyl or carbamimidoyl.

47. The compound of claim 43, wherein said A is pyridin-2-yl substituted with carbamimidoyl.

48. The compound of claim 43, wherein said A is 3-(3-aminopropoxy)phenyl.

49. The compound of claim 1, which is 2-(1-hydroxy-4-methyl-6-(methylsulfonyloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid, (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid, or (1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid.

50. The compound of claim 1, which is (3R)-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid or (3R)-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid.

51. The compound of claim 1, which is {6-[3-(3-amino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid or 2-(6-(4-carbamimidoylpyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid.

52. The compound of claim 1, which is [1-hydroxy-4-methyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid, [6-(6-aminomethyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid, [6-(5-aminomethyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid, [6-(5-carbamimidoyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihyhydro-benzo[c]oxaborol-3-yl)-acetic acid, 2-(1,4-dihydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid, or [4-(3-amino-propoxy)-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid.

53. The compound of claim 1, which is (3R)-[1-hydroxy-4-methyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid.

54. The compound of claim 1, which is 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoic acid, 2-(6-(5-carbamimidoythiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid or [6-(5-carbamoyl-thiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid.

55. The compound of claim 1, which is (R)-2-(6-(5-carbamoylthiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid.

56. The compound of claim 1, which is [6-(5-amino-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2oxaborol-3-yl]-acetic acid.

57. The compound of claim 1, which is (R)-2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid.

58. The compound of claim 1, which is [1-hydroxy-4-methyl-6-([1,3,4]thiadiazol-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid.

59. The compound of claim 1, which is (R)-2-(6-(1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid.