Boron-Containing Small Molecules as Anti-Inflammatory Agents

• US 20090291917A1
• Filed: 03/05/2009
• Published: 11/26/2009
• Est. Priority Date: 03/06/2008
• Status: Active Grant

• Current Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Anacor Pharmaceuticals, Inc. (Pfizer Inc.)
• Inventors: Jacobs, Robert T., Xia, Yi, Ding, Charles Z., Akama, Tsutomu, Plattner, Jacob J., Alley, Michael Richard Kevin, Singh, Rajeshwar, Baker, Stephen J., Maples, Kirk R., Zhang, Yong-Kang, Sharma, Rashmi, Chen, Daitao, Nieman, James A., Lu, Xiaosong, Sales, Marcelo, Freund, Yvonne, Sanders, Virginia
• Granted Patent: US 8,039,450 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• 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

Compounds and methods of treating anti-inflammatory conditions are disclosed.

Claims

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

2. The compound of claim 1, wherein R³ is a member selected from H and unsubstituted alkyl.

3. The compound of claim 1, the compound has a structure according to the formula:

4. The compound of claim 1, the compound has a formula which is a member selected from:

5. The compound of claim 1, the compound has a formula which is a member selected from:

6. The compound of claim 1, the compound has a formula which is a member selected from:

7. The compound of claim 1, the compound has a formula which is a member selected from:

8. The compound of claim 1, the compound has a structure according to the formula:

9. The compound of claim 1, the compound has a formula which is a member selected from:

10. The compound of claim 1, the compound has a formula which is a member selected from:

11. The compound of claim 1, the compound has a formula which is a member selected from:

12. The compound of claim 1, the compound has a formula which is a member selected from:

13. The compound of claim 1, the compound has a structure according to the formula:

14. The compound of claim 1, the compound has a formula which is a member selected from:

15. The compound of claim 1, the compound has a formula which is a member selected from:

16. The compound of claim 1, the compound has a formula which is a member selected from:

17. The compound of claim 1, the compound has a formula which is a member selected from:

18. The compound of claim 1, wherein R^b is a member selected from fluorine and chlorine.

19. The compound of claim 1, wherein R^b is a member selected from OR⁴ and NR⁴R⁵.

20. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is a member 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.

21. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and substituted or unsubstituted cycloalkyl.

22. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is unsubstituted C₁-C₆ alkyl.

23. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is unsubstituted cycloalkyl.

24. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is alkyl, substituted with a member selected from substituted or unsubstituted C₁-C₆ alkoxy.

25. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is alkyl, substituted with at least one halogen.

26. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is alkyl, substituted with at least one oxo moiety.

27. The compound of claim 1, wherein R^b is OR⁴, and R⁴ is a member selected from —

CH₃, —

CH₂CH₃, —

(CH₂)₂CH₃, —

CH(CH₃)₂, —

CH₂CF₃, —

CH₂CHF₂, —

CH₂CH₂(OH), —

CH₂CH₂(OCH₃), —

CH₂CH₂(OC(CH₃)₂), —

C(O)CH₃, —

CH₂CH₂OC(O)CH₃, —

CH₂C(O)OCH₂CH₃, —

CH₂C(O)OC(CH₃)₃, —

(CH₂)₃C(O)CH₃, —

CH₂C(O)OC(CH₃)₃, cyclopentyl, cyclohexyl

28. The compound of claim 1, wherein R^b is NR⁴R⁵,

wherein R⁴ and R⁵ are members 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.

29. The compound of claim 28, wherein R^b is NR⁴R⁵,

wherein R⁴ is H or unsubstituted alkyl;

and

R⁵ is unsubstituted alkyl or alkyl substituted with a member selected from hydroxyl, phenyl, unsubstituted alkoxy and alkoxy substituted with a phenyl.

30. The compound of claim 29, wherein R^b is NR⁴R⁵,

wherein R⁴ is a member selected from H or CH₃.

31. The compound of claim 28, wherein R^b is NR⁴R⁵,

wherein R⁴ and R⁵ are each members independently selected from substituted or unsubstituted alkyl.

32. The compound of claim 28, wherein R^b is NR⁴R⁵,

wherein R⁴ is unsubstituted alkyl;

and

R⁵ is substituted or unsubstituted alkyl.

33. The compound of claim 28, wherein R^b is NR⁴R⁵,

wherein R⁴ is unsubstituted alkyl;

and

R⁵ is alkyl, substituted with a member selected from substituted or unsubstituted alkoxy and hydroxyl.

34. The compound of claim 28, wherein R^b is NR⁴R⁵,

wherein R⁴ is unsubstituted alkyl;

and

R⁵ is alkyl, substituted with unsubstituted alkoxy.

35. The compound of claim 28, wherein R^b is NR⁴R⁵,

wherein R⁴ is unsubstituted alkyl;

and

R⁵ is alkyl, substituted with alkoxy, substituted with phenyl.

36. The compound of claim 28, wherein R^b is NR⁴R⁵,

wherein R⁴ is unsubstituted alkyl;

and

R⁵ is alkyl, substituted with unsubstituted alkoxy.

37. The compound of claim 28, wherein R^b is a member selected from N(CH₃)₂, N(CH₃)(CH₂CH₂(OCH₃)), N(CH₃)(CH₂CH₂OH), NH₂, NHCH₃, NH(CH₂CH₂(OCH₃)), NH(CH₂CH₂(OCH₂Ph), NH(CH₂Ph), NH(C(CH₃)₃) and NH(CH₂CH₂OH).

38. The compound of claim 1, wherein R^b is NR⁴R⁵,

wherein R⁴ and R⁵, together with the nitrogen to which they are attached, are combined to form a 4- to 8-membered substituted or unsubstituted heterocycloalkyl ring.

39. The compound of claim 38, wherein R^b is NR⁴R⁵,

wherein R⁴ and R⁵, together with the nitrogen to which they are attached, are combined to form a 5- or 6-membered substituted or unsubstituted heterocycloalkyl ring.

40. The compound of claim 1, wherein R^b is a member selected from:

41. A pharmaceutical formulation comprising:

(a) the compound of claim 1;

(b) a pharmaceutically acceptable excipient.

42. The formulation of claim 41, wherein the formulation is in a unit dosage form.

43. The formulation of claim 41, wherein the formulation is for oral or topical use.

44. A method of decreasing the release of a cytokine or a chemokine, the method comprising:

contacting a cell with the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the release of the cytokine or chemokine by the cell is decreased.

45. The method according to claim 44, wherein the cytokine is a member selected from IL-1α

, IL-1β

, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α

, LT, LIF, Oncostatin, IFNα

, IFNβ and

IFN-γ

.

46. The method according to claim 44, wherein the cytokine is a member selected from IL-1β

, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-23, TNF-α and

IFN-γ

.

47. The method according to claim 44, wherein the cytokine is a member selected from IL-2, IL-5, IL-10, IL-12, IL-23, TNF-α

and IFN-γ

.

48. The method according to claim 44, wherein the chemokine is a member selected from IL-8, Gro-α

, MIP-1, MCP-1, PGE2, ENA-78, and RANTES.

49. A method of treating a condition, in an animal, the method comprising administering to the animal a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, thereby treating the condition.

50. The method of claim 49, wherein the condition is a member selected from arthritis, rheumatoid arthritis, an inflammatory bowel disease, psoriasis, a pulmonary disease, multiple sclerosis, a neurodegenerative disorder, congestive heart failure, stroke, aortic valve stenosis, kidney failure, lupus, pancreatitis, allergy, fibrosis, anemia, atherosclerosis, a metabolic disease, a bone disease, a cardiovascular disease, a chemotherapy/radiation related complication, diabetes type I, diabetes type II, a liver disease, a gastrointestinal disorder, an ophthamological disease, allergic conjunctivitis, diabetic retinopathy, Sjogren'"'"'s syndrome, uvetitis, a pulmonary disorder, a renal disease, dermatitis, HIV-related cachexia, cerebral malaria, ankylosing spondolytis, leprosy, anemia and fibromyalgia.

51. The method of claim 50, wherein the condition is a member selected from psoriasis, atopic dermatitis, rheumatoid arthritis, an inflammatory bowel disease, asthma and chronic obstructive pulmonary disease.

52. The method of claim 50, wherein the condition is psoriasis, said psoriasis is a member selected from plaque psoriasis, flexural psoriasis, Guttate psoriasis, pustular psoriasis, nail psoriasis and erythrodermic psoriasis.

53. The method of claim 52, wherein the psoriasis is a member selected from plaque psoriasis and nail psoriasis.

54. A method of inhibiting a phosphodiesterase (PDE), the method comprising:

contacting the phosphodiesterase with a compound of claim 1 or a pharmaceutically acceptable salt thereof, thereby inhibiting the phosphodiesterase.

55. The method of claim 54, wherein said phosphodiesterase is a member selected from phosphodiesterase4 (PDE4) and phosphodiesterase7 (PDE7).