BORON-CONTAINING SMALL MOLECULES

• US 20100256092A1
• Filed: 05/12/2009
• Published: 10/07/2010
• Est. Priority Date: 05/12/2008
• Status: Abandoned Application

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC), Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: GlaxoSmithKline PLC, Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Benowitz, Andrew, Mohammed, Rahim, Banda, Goverdhan Reddy, Keramane, Mehdi, Subedi, Rajendra, Diaper, Chris, Xia, Yi, Ding, Charles Z., Liang, Hong, Akama, Tsutomu, Cao, Kathy, Saraswat, Neerja, Plattner, Jacob J., Zhou, Yasheen, Ou, Ligong, Alley, Michael Richard Kevin, Singh, Rajeshwar, Jia, Guofeng, Ramachandran, Sreekanth, Zhang, Yong-Kang, Zhang, Yanchen, Hernandez, Vincent S., Nieman, James A., Sligar, Jessica
• Application Number:
  US12/464,829
• Publication Number:
  US 20100256092A1
• Time in Patent Office: Days
• 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 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• 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: 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 relates to, among other items, 6-substituted 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 2, having a structure which is a member selected from:

4. The compound of claim 3, wherein R^a is a member selected from H, F, Cl, —

OR^10a and —

C(O)OR^10b,

wherein R^10a is alkyl, optionally substituted with a member selected from NH₂ and phenyl

wherein R^10b is unsubstituted alkyl.

5. The compound of claim 3, wherein R^a is —

O(CH₂)_nNH₂, wherein n is an integer selected from 1 to 6.

6. The compound of claim 5, wherein n is 2 or 3 or 4.

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

8. The compound of claim 7, wherein m is 1 or 2 or 3.

9. The compound of claim 7, having a structure according to the formula:

10. The compound of claim 9, wherein R²⁰ is H.

11. The compound of claim 9, wherein R²⁰ is C₁ or C₂ or C₃ unsubstituted alkyl.

12. The compound of claim 2, wherein R³ is —

CH₂COOH or —

CH₂COOCH₃ or —

CH₂COOCH₂CH₃.

13. The compound of claim 9, having a structure according to the formula:

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

15. The compound of claim 14, wherein C* is a stereocenter which has a (R) configuration.

16. The compound of claim 14, having a structure according to the formula:

17. The compound of claim 16, wherein R²⁰ is H.

18. The compound of claim 16, having a structure according to the formula:

19. The compound of claim 18, which is:

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

21. The compound of claim 20, wherein A is a member selected from phenyl, pyridinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, and piperidinyl.

22. The compound of claim 20, wherein R^a is a member selected from cyano, nitro, aminoalkyl, hydroxyalkyl, —

C(O)(CH₂)_m1CH₃, —

COOH, —

C(O)O(CH₂)_m1CH₃, —

O(CH₂)_m1CH₃, —

O(CH₂)_m1CF₃, —

O(CH₂)_m1CHF₂, —

OH, —

NH₂, —

NHCH₃, —

NHC(O)H, —

NHC(O)(CH₂)_m1CH₃, —

NHOH, —

NHS(O)₂NH₂, —

NH₂S(O)₂CH₃, —

S(O)₂CH₃,

wherein m1 is an integer which is a member selected from 0 to 3.

23. The compound of claim 21, having a structure according to the formula:

24. The compound of claim 23, having a structure according to the formula:

25. The compound of claim 24, wherein R^a is a member selected from OH and NH₂.

26. A combination comprising:

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

b) a therapeutically active agent.

27. The combination of claim 26, wherein said therapeutically active agent is an antibiotic which comprises a β

-lactam moiety.

28. A pharmaceutical formulation comprising:

a) a compound of claim 1 or a combination of claim 26, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically acceptable excipient.

29. The pharmaceutical formulation of claim 28, wherein said formulation is a unit dosage form.

30. The pharmaceutical formulation of claim 29, wherein said formulation is a member selected from an oral unit dosage form and a topical unit dosage form.

31. 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.

32. The method of claim 31, wherein a bacteria involved with said infection is resistant to said antibiotic.

33. The method of claim 31, wherein the antibiotic is a member selected from a penicillin, cephalosporin, monobactam, carbapenem and derivatives thereof.

34. The method of claim 33, wherein the antibiotic is a penicillin or derivatives thereof.

35. The method of claim 34, wherein said penicillin is a member selected from narrow spectrum penicillins, narrow spectrum penicillinase-resistant penicillins, narrow spectrum β

-lactamase-resistant penicillins, moderate spectrum penicillins, broad spectrum penicillins and extended spectrum penicillins.

36. The method of claim 35, wherein said penicillin is a narrow spectrum penicillin which is a member selected from benzathine penicillin, benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V) and procaine penicillin.

37. The method of claim 35, wherein said penicillin is a narrow spectrum penicillinase-resistant penicillins which is a member selected from methicillin, dicloxacillin and flucloxacillin.

38. The method of claim 35, wherein said penicillin is a narrow spectrum β

-lactamase-resistant penicillin which is temocillin.

39. The method of claim 35, wherein said penicillin is a moderate spectrum penicillin which is a member selected from amoxicillin and ampicillin.

40. The method of claim 35, wherein said penicillin is a broad spectrum penicillin which is a member selected from co-amoxiclav (amoxicillin and clavulanic acid).

41. The method of claim 35, wherein said penicillin is an extended spectrum penicillin, which is a member selected from azlocillin, carbenicillin, ticarcillin, mezlocillin and piperacillin.

42. The method of claim 31, wherein the antibiotic is a cephalosporin or a derivative thereof.

43. The method of claim 42, wherein the cephalosporin is a member selected from a first-generation cephalosporin, second-generation cephalosporin, second-generation cephamycin, third-generation cephalosporin and fourth-generation cephalosporin.

44. The method of claim 42, wherein the cephalosporin is a member selected from cefalexin, cephalothin and cefazolin.

45. The method of claim 42, wherein the cephalosporin is a member selected from cefaclor, cefuroxime and cefamandole.

46. The method of claim 42, wherein the cephalosporin is a member selected from cefotetan and cefoxitin.

47. The method of claim 42, wherein the cephalosporin is a member selected from ceftriaxone, cefotaxime, cefpodoxime and ceftazidime.

48. The method of claim 42, wherein the cephalosporin is a member selected from cefepime and cefpirome.

49. The method of claim 31, wherein the antibiotic is a monobactam.

50. The method of claim 49, wherein the monobactam is aztreonam.

51. The method of claim 31, wherein the antibiotic is a carbapenem.

52. The method of claim 51, wherein the carbapenem is a member selected from imipenem, cilastatin, meropenem, ertapenem and faropenem.

53. The method of claim 31, wherein said animal is a human.

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

contacting said bacteria with an effective amount of a compound of claim 1 or a combination of claim 26, or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of the bacteria.

55. The method of claim 54, further comprising contacting said bacteria with an effective amount of an antibiotic, or a pharmaceutically acceptable salt thereof, wherein said antibiotic comprises a β

-lactam moiety.

56. The method of claim 55, wherein the bacteria is resistant to said antibiotic.

57. A method of inhibiting a β

-lactamase, comprising contacting the β

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

-lactamase.

58. The method of claim 57, wherein the β

-lactamase is a member selected from a Group 1 β

-lactamase, a Group 2 β

-lactamase, a Group 3 β

-lactamase, and a Group 4 β

-lactamase.

59. The method of claim 58, wherein said Group 1 β

-lactamase is a cephalosporinase.

60. The method of claim 58, wherein said Group 2 β

-lactamase is a member selected from penicillinase, a Group 2b, Group 2be, Group 2br, carbenicillinase, cloxacilanase, cephalosporinase and carbapenamase.

61. The method of claim 58, wherein said Group 3 β

-lactamase is a metallo-β

-lactamase.

62. The method of claim 58, wherein said Group 4 β

-lactamase is a penicillinase.

63. The method of claim 57, wherein the β

-lactamase is a member selected from a class A β

-lactamase, a class B β

-lactamase, a class C β

-lactamase, and a class D β

-lactamase.

64. The method of claim 63, wherein the class A β

-lactamase is a member selected from a TEM β

-lactamase, SHV β

-lactamase, CTX-M β

-lactamase and a KPC β

-lactamase.

65. The method of claim 63, wherein the class C β

-lactamase is a member selected from a CMY β

-lactamase and a AmpC β

-lactamase.

66. The method of claim 63, wherein the class D β

-lactamase is an OXA β

-lactamase.

67. The method of claim 63, wherein the β

-lactamase is a metallo β

-lactamase.

68. The method of claim 63, wherein the metallo β

-lactamase is a member selected from an IMP carbapenemase and a VIM β

-lactamase.

69. The method of claim 57, wherein the contacting takes place in vitro.

70. 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, thereby treating the bacterial infection.

71. A method of inhibiting the editing domain of a t-RNA synthetase, comprising:

contacting the synthetase with an effective amount of a compound of claim 1, or a pharmaceutically-acceptable salt thereof, thereby inhibiting the synthetase.

72. The method of claim 71, wherein the synthetase is a leucyl t-RNA synthetase.

73. The use of a compound of claim 1 or a combination of claim 26, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of bacterial infection.