Proteasome inhibitors and methods of using the same

• US 7,915,236 B2
• Filed: 07/01/2009
• Issued: 03/29/2011
• Est. Priority Date: 08/14/2003
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Messina McLaughlin, Patricia A., Ferretti, Edmondo, Oliva, Ambrogio, Bernareggi, Alberto, D'Arasmo, Germano, Cassara, Paolo G., Bernardini, Raffaella, Menta, Ernesto, Iqbal, Mohamed, De Munari, Sergio, Chatterjee, Sankar
• Primary Examiner(s): Zucker; Paul A
• Application Number:
  US12/496,359
• Publication Number:
  US 20090291918A1
• Time in Patent Office: 636 Days
• Field of Search: None
• US Class Current: 514/64
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds

Abstract

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.

Claims

1. A compound of Formula (I)

2. The compound of claim 1 wherein R¹ is C₁-C₄ alkyl.

3. The compound of claim 1 wherein R¹ is 2-propyl.

4. The compound of claim 1 wherein R² is —

(CH₂)_aCH₂NHC(═

NR⁴)NH—

Y, —

(CH₂)_bCH₂CONR⁵R⁶, —

(CH₂)_cCH₂N(R⁴)CONH₂, —

(CH₂)_dCH(R⁷)NR⁹R¹⁰, or —

(CH₂)_eCH(R⁷)ZR⁸.

5. The compound of claim 1 wherein R² is —

(CH₂)_aCH₂NHC(═

NR⁴)NH—

Y.

6. The compound of claim 5 wherein a is 1, 2, 3, or 4.

7. The compound of claim 5 wherein a is 2.

8. The compound of claim 1 wherein R² is —

(CH₂)_dCH(R⁷)NR⁹R¹⁰.

9. The compound of claim 8 wherein d is 0, 1, or 2.

10. The compound of claim 8 wherein d is 0.

11. The compound of claim 8 wherein R⁹ is H.

12. The compound of claim 1 wherein R² is —

(CH₂)_eCH(R⁷)ZR⁸.

13. The compound of claim 12 wherein Z is O.

14. The compound of claim 13 wherein e is 0, 1, or 2.

15. The compound of claim 13 wherein e is 0.

16. The compound of claim 1 wherein Q is B(OH)₂ or a cyclic boronic ester wherein said cyclic boronic ester contains from 6 to 10 carbon atoms and contains at least one cycloalkyl moiety.

17. The compound of claim 16 wherein Q is pinanediol boronic ester.

18. The compound of claim 16 wherein Q is bicyclohexyl-1,1′

-diol boronic ester.

19. The compound of claim 16 wherein Q is 1,2-dicyclohexyl-ethane-1,2-diol boronic ester.

20. The compound of claim 1 wherein X is R^AC(═

O)—

.

21. The compound of claim 1 wherein X is R^ANHC(═

O)—

.

22. The compound of claim 1 wherein X is R^AS(═

O)₂—

.

23. The compound of claim 1 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

24. A compound of claim 1 of Formula (I):

25. The compound of claim 24 wherein R¹ is 2-propyl.

26. The compound of claim 24 wherein Q is —

B(OH)₂.

27. The compound of claim 24 wherein Q is pinanediol boronic ester.

28. The compound of claim 24 wherein X is R^AC(═

O)—

.

29. The compound of claim 24 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

30. A compound of claim 1 having Formula (I):

31. A compound of claim 1 having Formula (I):

32. The compound of claim 31 wherein R¹ is 2-propyl.

33. The compound of claim 31 wherein Q is —

B(OH)₂.

34. The compound of claim 31 wherein Q is pinanediol boronic ester.

35. The compound of claim 31 wherein X is R^AC(═

O)—

.

36. The compound of claim 31 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

37. A compound of claim 1 having Formula (I):

38. The compound of claim 37 wherein R¹ is 2-propyl.

39. The compound of claim 37 wherein Q is —

B(OH)₂.

40. The compound of claim 37 wherein Q is pinanediol boronic ester.

41. The compound of claim 37 wherein X is R^AC(═

O)—

.

42. The compound of claim 37 wherein R² is —

CH₂NH—

C(═

O)OCH₂(C₆H₅).

43. A compound of claim 1 of Formula (I):

46. The compound of claim 1, wherein the compound is boronic acid, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenyl-pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl], or a pharmaceutically acceptable salt or boronic ester thereof.

47. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

48. A pharmaceutical composition comprising a compound according to claim 24 and a pharmaceutically acceptable carrier.

49. A pharmaceutical composition comprising a compound according to claim 30 and a pharmaceutically acceptable carrier.

50. A pharmaceutical composition comprising a compound according to claim 31 and a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising a compound according to claim 37 and a pharmaceutically acceptable carrier.

52. A pharmaceutical composition comprising a compound according to claim 43 and a pharmaceutically acceptable carrier.

55. A pharmaceutical composition comprising a compound according to claim 46 and a pharmaceutically acceptable carrier.

44. A compound selected from:

53. A pharmaceutical composition comprising a compound according to claim 44 and a pharmaceutically acceptable carrier.

45. A compound selected from:

54. A pharmaceutical composition comprising a compound according to claim 45 and a pharmaceutically acceptable carrier.