BORON-CONTAINING SMALL MOLECULES

• US 20090227541A1
• Filed: 06/19/2008
• Published: 09/10/2009
• Est. Priority Date: 06/20/2007
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Akama, Tsutomu, Plattner, Jacob J., Alley, Michael Richard Kevin, Singh, Rajeshwar, Baker, Stephen J., Zhang, Yong-Kang, Sharma, Rashmi, Hernandez, Vincent S., Nieman, James A., Rock, Fernando
• Granted Patent: US 7,816,344 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/02 Local antiseptics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• 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 bacterial 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 formula:

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

3. The compound of claim 1, wherein R³ is —

(CR²⁰R²¹)NR²²R²³ in which

n is an integer selected from 1 to 10;

each R²⁰ and each R²¹ is a member independently selected from H, R²⁶, OR²⁶, NR²⁶R²⁷, SR²⁶, S(O)R²⁶, —

S(O)₂R²⁶, —

S(O)₂NR²⁶R²⁷, —

C(O)R²⁷, C(O)OR²⁷, —

C(O)NR²⁶R²⁷

R²² and R²³ are members independently selected from H, —

S(O)R²⁸, —

S(O)₂R²⁸, —

S(O)₂NR²⁸R²⁹, —

C(O)R²⁸, —

C(O)OR²⁸, —

C(O)NR²⁸R²⁹, nitro, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl

wherein

each R²⁶, each R²⁷, each R²⁸ and each R²⁹ is a member independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

4. The compound of claim 3, wherein n is an integer selected from 1 to 5.

5. The compound of claim 4, wherein n is 1.

6. The compound of claim 3, wherein R²⁰ is substituted or unsubstituted alkyl.

7. The compound of claim 6, wherein R²⁰ is unsubstituted alkyl.

8. The compound of claim 7, wherein R²⁰ is C₁-C₄ unsubstituted alkyl.

9. The compound of claim 8, wherein R²⁰ is methyl.

10. The compound of claim 3, wherein R²¹ is H.

11. The compound of claim 3, wherein R²³ is H.

12. The compound of claim 3, wherein R³ is a member selected from cyano and —

CH₂NO₂.

13. The compound of claim 3, wherein R²² is a member selected from —

C(O)R²⁸ and —

C(O)OR²⁸.

14. The compound of claim 3, wherein R²⁸ is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl.

15. The compound of claim 3, wherein

R²⁸ is a member selected from —

(CR³⁰R³¹)_mR³², wherein R³² is a member selected from substituted or unsubstituted aryl, —

NR³³R³⁴ and OR³³

wherein

m is an integer selected from 0 to 10;

each R³³ and each R³⁴ is a member independently selected from H, nitro, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

16. The compound of claim 3, wherein R²⁸ is a member selected from

17. The compound of claim 1, wherein R⁵ is:

18. The compound of claim 17, wherein a is an integer selected from 1 to 5.

19. The compound of claim 17, wherein a is an integer selected from 2 to 4.

20. The compound of claim 17, wherein each R¹⁰ and each R¹¹ is a member selected from H, substituted or unsubstituted alkyl, OH and NH₂.

21. The compound of claim 20, wherein each R¹⁰ and each R¹¹ is a member selected from H, hydroxyalkyl and NH₂.

22. The compound of claim 17, wherein at least one R¹⁰ or R¹¹ is a member selected from hydroxyalkyl and NH₂.

23. The compound of claim 17, wherein each R¹⁰ and each R¹¹ is H.

24. The compound of claim 17, wherein R¹² is a member selected from H, cyano, amidino, —

N(R⁷)S(O)₂R⁸, OR⁷, NR⁷R⁸, —

C(O)OR⁷, —

C(O)NR⁷R⁸

each R⁷ and each R⁸ is a member independently selected from H substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

25. The compound of claim 24, wherein each R⁷ and each R⁸ is a member independently selected from H, —

C(O)R⁹, —

C(O)NHR⁹, substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl

wherein R⁹ is substituted or unsubstituted C₁-C₄ alkyl.

26. The compound of claim 24, wherein at least one member selected from R⁷ and R⁸ is a member independently selected from —

C(O)R⁹ and —

C(O)NHR⁹

wherein R⁹ is substituted or unsubstituted C₁-C₄ alkyl.

27. The compound of claim 17, wherein R¹² is a member selected from OH, NH₂, methyl, ethyl, —

NHS(O)₂CH₃, cyano, —

NHC(O)CH₃, —

NHC(O)NHCH₂CH₃, —

C(O)NH₂, —

C(O)OH, 4-(methoxy)phenyl, benzyl, —

NHC(O)OCH₂Ph, —

C(O)NHCH₂CH₂OH and —

C(NH₂)(NH).

28. The compound of claim 17, wherein

when R¹² comprises OR⁷, said R⁷ comprises a hydroxy-protecting group;

and

when R¹² comprises NR⁷R⁸, at least one of said R⁷ or R⁸ comprises an amino-protecting group.

29. The compound of claim 17, wherein

R³ is a member selected from H, —

CH₂NH₂ and —

CH₂NO₂; and

R¹² is a member selected from OH, NH₂, methyl, ethyl, —

NHS(O)₂CH₃, cyano, —

NHC(O)CH₃, —

NHC(O)NHCH₂CH₃, —

C(O)NH₂, —

C(O)OH, 4-(methoxy)phenyl, benzyl, —

NHC(O)OCH₂Ph, —

C(O)NHCH₂CH₂OH and —

C(NH₂)(NH).

30. The compound of claim 1, wherein

R³ is a member selected from H, —

CH₂NH₂ and —

CH₂NO₂; and

R^a is a member selected from H, —

O(CH₂)₃NH₂, —

O(CH₂)₃OH, —

OCH₂CH₃, —

O(CH₂)₃NHS(O)₂CH₃, —

O(CH₂)₃CN, —

O(CH₂)₃NHC(O)CH₃, —

O(CH₂)₃NHCH₃, —

O(CH₂)₃OCH₃, —

O(CH₂)₄OH, —

OCH₃, —

O(CH₂)₃NHC(O)NHCH₂CH₃, —

O(CH₂)₃C(O)NH₂, —

O(CH₂)₃C(O)OH, —

O(CH₂)₄NH₂, —

O(CH₂)₂NH₂, —

OCH₂CH₂CH(NH₂)CH₂OH, —

OCH₂Ph(4-methoxy), —

O(CH₂)₄OCH₂Ph, —

O(CH₂)₃NHC(O)OCH₂Ph, —

OCH₂C(O)NH(CH₂)₂OH, —

O(CH₂)₃NHC(O)CH₃, —

O(CH₂)₃C(NH₂)(NH), —

C(O)OCH₃, —

OCH₂C(O)OH and —

OCH₂CH(CH₂OH)(CH₂)OH.

31. The compound of claim 30, wherein

when R³ is H, R^a is a member selected from —

O(CH₂)₃NH₂, —

O(CH₂)₃NHS(O)₂CH₃, —

O(CH₂)₃CN, —

O(CH₂)₃NHC(O)CH₃, —

O(CH₂)₃NHCH₃, —

O(CH₂)₄OH, —

O(CH₂)₃NHC(O)NHCH₂CH₃, —

O(CH₂)₃C(O)NH₂, —

O(CH₂)₃C(O)OH, —

O(CH₂)₄NH₂, —

O(CH₂)₂NH₂, —

OCH₂CH₂CH(NH₂)CH₂OH, —

OCH₂Ph(4-methoxy), —

O(CH₂)₄OCH₂Ph, —

OCH₂C(O)NH(CH₂)₂OH and —

OCH₂CH(CH₂OH)(CH₂)OH;

when R³ is —

CH₂NH₂, R^a is a member selected from H, —

O(CH₂)₃OH, —

OCH₂CH₃, —

O(CH₂)₃OCH₃, —

OCH₃, —

O(CH₂)₄NH₂, —

O(CH₂)₃NHS(O)₂CH₃, —

O(CH₂)₃NHC(O)OCH₂Ph, —

O(CH₂)₃NHC(O)CH₃, —

O(CH₂)₃NH₂; and

when R³ is —

CH₂NO₂, R^a is a member selected from —

O(CH₂)₃CN and —

OCH₂CH₃.

32. The compound of claim 30, wherein

when R³ is H, R^a is a member selected from —

O(CH₂)₃NH₂, —

O(CH₂)₃NHS(O)₂CH₃, —

O(CH₂)₃CN, —

O(CH₂)₃NHC(O)CH₃, —

O(CH₂)₃NHCH₃, —

O(CH₂)₄OH, —

O(CH₂)₃NHC(O)NHCH₂CH₃, —

O(CH₂)₃C(O)NH₂, —

O(CH₂)₃C(O)OH, —

O(CH₂)₄NH₂, —

O(CH₂)₂NH₂, —

OCH₂CH₂CH(NH₂)CH₂OH,

when R³ is —

CH₂NH₂, R^a is a member selected from H, —

O(CH₂)₃OH, —

OCH₂CH₃, —

O(CH₂)₃OCH₃, —

OCH₃.

33. The compound of claim 30, wherein

when R³ is H, R^a is a member selected from —

O(CH₂)₃NH₂, —

O(CH₂)₃CN, —

O(CH₂)₃NHC(O)CH₃, —

O(CH₂)₃NHCH₃; and

when R³ is —

CH₂NH₂, R^a is a member selected from H, —

O(CH₂)₃OH, and —

OCH₂CH₃.

34. The compound of claim 1, having a structure which is a member selected from

37. The compound of claim 1 or claim 35, wherein R³ is a member selected from H, —

CH₂NH₂ and —

CH₂NO₂.

38. The compound of claim 1 or claim 35, wherein R* is H.

39. The compound of claim 2 or claim 36, wherein R³ is not H, and the C* stereocenter is in a (S) configuration.

40. The compound of claim 39, wherein R³ is —

CH₂NH₂.

41. The compound of claim 1 or claim 35, wherein said alkyl is a member selected from linear alkyl and branched alkyl, and wherein said heteroalkyl is a member selected from linear heteroalkyl and branched heteroalkyl.

42. A composition comprising:

a) a first stereoisomer of the compound of claim 2 or claim 36, wherein R³ is not H;

b) at least one additional stereoisomer of the first stereoisomer;

wherein the first stereoisomer is present in an enantiomeric excess of at least 80% relative to said at least one additional stereoisomer.

43. The composition of claim 42, wherein said enantiomeric excess is at least 92%.

44. The composition of claim 42, wherein the C* stereocenter of the first stereoisomer is in a (S) configuration.

45. The composition of claim 44, wherein R³ is —

CH₂NH₂.

46. A composition comprising the compound of claim 2 or claim 36, wherein R is not H and the C* stereocenter is in a (S) configuration, and said composition is substantially free of the enantiomer of the compound.

47. A composition comprising the compound of claim 40, wherein the composition is substantially free of the enantiomer of the compound.

48. A combination comprising the compound of claim 1 or claim 35, or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.

49. A pharmaceutical formulation comprising:

a) the compound of claim 1 or claim 35, or a pharmaceutically acceptable salt thereof, and

b) a pharmaceutically acceptable excipient.

50. The pharmaceutical formulation of claim 49 wherein the pharmaceutical formulation is a unit dosage form.

51. A method of inhibiting an enzyme, comprising:

contacting the enzyme with the compound of claim 1 or claim 35, thereby inhibiting the enzyme.

52. The method of claim 51, wherein the enzyme is a t-RNA synthetase which comprises an editing domain.

53. The method of claim 52, wherein the enzyme is a leucyl t-RNA synthetase.

54. A method of killing and/or preventing the growth of a microorganism, comprising:

contacting the microorganism with an effective amount of the compound of claim 1 or claim 35, thereby killing and/or preventing the growth of the microorganism.

55. The method of claim 54, wherein the microorganism is a bacterium.

56. A method of treating and/or preventing a disease in an animal, comprising:

administering to the animal a therapeutically effective amount of the compound of claim 1 or claim 35, or a pharmaceutically-acceptable salt thereof, thereby treating and/or preventing the disease.

57. The method of claim 56, wherein the disease is pneumonia.

58. The method of claim 56, wherein the animal is a human.

59. The compound of claim 1 or claim 35, wherein the salt is a pharmaceutically acceptable salt.

35. A compound having a structure according to a formula which is a member selected from:

36. The compound of claim 35, having a structure according to a formula which is a member selected from: