Compounds for enzyme inhibition

• US 20050245435A1
• Filed: 04/14/2005
• Published: 11/03/2005
• Est. Priority Date: 04/15/2004
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Proteolix, Inc. (Amgen Inc.)
• Inventors: Schneekloth, John S. Jr., Musser, John H., Chabala, John Clifford, Laidig, Guy J., Smyth, Mark S., Crews, Craig M., Bunin, Barry A., Borchardt, Ronald T.
• Granted Patent: US 7,232,818 B2
• Time in Patent Office: Days
• US Class Current: 514/231.500
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1016 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/1024 with the first amino acid being heterocyclic

Abstract

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

Claims

1. A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

2. A compound of claim 1, wherein R¹, R², R³, and R⁴ are independently selected from C_1-6alkyl and C_1-6aralkyl.

3. A compound of claim 2, wherein R¹ and R³ are both C_1-6aralkyl and both R² and R⁴ are C_1-6alkyl.

4. A compound of claim 3, wherein X is O, R¹ is 2-phenylethyl, R² is isobutyl, R³ is phenylmethyl, and R⁴ is isobutyl.

5. A compound of claim 4, wherein L and Q are absent and R⁶ is C_1-6alkyl.

6. A compound of claim 5, wherein R⁷ is selected from C_1-6alkyl, C_1-6alkenyl, C_1-6alkynyl, C_1-6aralkyl, and C_1-6heteroaralkyl.

7. A compound of claim 6, wherein R⁷ is C_1-6alkyl.

8. A compound of claim 7, wherein R⁷ is butyl.

9. A compound of claim 6, wherein R⁷ is C_1-6alkenyl.

10. A compound of claim 9, wherein R⁷ is allyl.

11. A compound of claim 6, wherein R⁷ is C_1-6alkynyl.

12. A compound of claim 11, wherein R⁷is propargyl.

13. A compound of claim 6, wherein R⁷ is C_1-6aralkyl.

14. A compound of claim 13, wherein R⁷ is phenylmethyl.

15. A compound of claim 6, wherein R⁷ is C_1-6heteroaralkyl.

16. A compound of claim 15, wherein R⁷ is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl.

17. A compound of claim 4, wherein Q is absent and L is SO₂.

18. A compound of claim 17, wherein R⁷ is selected from C_1-6alkyl and C_1-6aralkyl.

19. A compound of claim 18, wherein R⁷ is C_1-6alkyl.

20. A compound of claim 19, wherein R⁷ is methyl.

21. A compound of claim 18, wherein R⁷ is C_1-6aralkyl.

22. A compound of claim 21, wherein R⁷ is phenyl.

23. A compound of claim 4, wherein L is C═

O.

24. A compound of claim 23, wherein R⁷ is selected from hydrogen, C_1-6alkyl, C_1-6alkenyl, C_1-6alkynyl, aryl, C_1-6aralkyl, heteroaryl, C_1-6heteroaralkyl, R⁸ZA-C_1-8alkyl-, R¹¹Z- C_1-8alkyl-, (R⁸O)(R⁹O)P(═

O)O—

C_1-8alkyl-ZAZ-C_1-8alkyl-, (R⁸O)(R⁹O)P(═

O)O—

C_1-8alkyl-Z-C_1-8alkyl-, R⁸ZA-C_1-8alkyl-ZAZ-C_1-8alkyl-, heterocyclylMZAZ-C_1-8alkyl-, (R⁸O)(R⁹O)P(═

O)O—

C_1-8alkyl-, (R¹⁰)₂N—

C_1-8alkyl-, (R¹⁰)₃N⁺-C_1-8alkyl-, heterocylyl-M, carbocyclylM-, R¹¹SO₂C_1-8alkyl-, and R¹¹SO₂NH;

or

R⁶ and R⁷ together are C_1-6alkyl-Y—

C_1-6alkyl, C_1-6alkyl-ZA-C_1-6alkyl, A-C_1-6alkyl-ZA-C_1-6alkyl, A-C_1-6alkyl-A or C_1-6alkyl-A, thereby forming a ring;

and each occurrence of Z and A is independently other than a covalent bond.

25. A compound of claim 24, wherein Q is absent.

26. A compound of claim 25, wherein R⁶ and R⁷ are C_1-6alkyl.

27. A compound of claim 26, wherein R⁷ is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, and 2-(methylsulfonyl)ethyl.

28. A compound of claim 25, wherein R⁷ is C_1-6aralkyl.

29. A compound of claim 28, wherein R⁷ is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, and (4-fluorophenyl)methyl.

30. A compound of claim 25, wherein R⁶ is C_1-6alkyl and R⁷ is aryl.

31. A compound of claim 30, wherein R⁷ is substituted or unsubstituted phenyl.

32. A compound of claim 24, wherein Q is absent or O and R⁷ is carbocyclylM-.

33. A compound of claim 32, wherein carbocyclyl is cyclopropyl or cyclohexyl.

34. A compound of claim 25, wherein R⁷ is selected from R⁸ZA-C_1-8alkyl-, R¹¹Z-C_1-8alkyl-, (R⁸O)(R⁹O)P(═

O)O—

C_1-8alkyl-ZAZ-C_1-8alkyl-, (R⁸O)(R⁹O)P(═

O)O—

C_1-8alkyl-Z-C_1-8alkyl-, R⁸ZA-C_1-8alkyl-ZAZ-C_1-8alkyl-, heterocyclylMZAZ-C_1-8alkyl-, (R⁸O)(R⁹O)P(═

O)O—

C_1-8alkyl-, A is C═

O, and Z is O or NH.

35. A compound of claim 34, wherein Z is O.

36. A compound of claim 35, wherein R⁷ is heterocyclylMZAZ-C_1-8alkyl- and heterocyclyl is oxodioxolenyl or N(R¹²)(R¹³), wherein R¹² and R¹³ together are C_1-6alkyl-Y—

C_1-6alkyl, thereby forming a ring.

37. A compound of claim 36, wherein R⁷ is selected from (R¹⁰)₂N—

C_1-8alkyl- and (R¹⁰)₃N⁺(CH₂)_n—

, and R¹⁰ is C_1-6alkyl.

38. A compound of claim 25, wherein R⁷ is heterocyclylM- and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.

39. A compound of claim 24, wherein Q is O or NH.

40. A compound of claim 39, wherein R⁶ is C_1-6alkyl and R⁷ is selected from C_1-6alkyl, C_1-6aralkyl, and C_1-6heteroaralkyl.

41. A compound of claim 40, wherein R⁷ is selected from methyl, ethyl, isopropyl, phenylmethyl, and (4-pyridyl)methyl.

42. A compound of claim 24, wherein R⁶ and R⁷ together are C_1-6alkyl-Y—

C_1-6alkyl, C_1-6alkyl-ZA-C_1-6alkyl, or C_1-6alkyl-A, thereby forming a ring.

43. A compound of claim 42, wherein L is C═

O, Q and Y are absent, and R⁶ and R⁷ together are C_1-3alkyl-Y—

C_1-3alkyl.

44. A compound of claim 42, wherein L and Q are absent, and R⁶ and R⁷ together are C_1-3alkyl-Y—

C_1-3alkyl.

45. A compound of claim 42, wherein L is C═

O, Q is absent, Y is selected from NH and N—

C_1-6alkyl, and R⁶ and R⁷ together are C_1-3alkyl-Y—

C_1-3alkyl.

46. A compound of claim 42, wherein L is C═

O, Y is absent and R⁶ and R⁷ together are C_1-3alkyl-Y—

C_1-3alkyl.

47. A compound of claim 42, wherein L and A are C═

O and R⁶ and R⁷ together are C_1-2alkyl-ZA-C_1-2alkyl.

48. A compound of claim 42, wherein L and A are C═

O and R⁶ and R⁷ together are C_2-3alkyl-A.

51. A pharmaceutical composition comprising a compound of claim 1 or 50 and a pharmaceutically acceptable carrier.

52. A method of inhibiting an N-terminal nucleophile hydrolase, comprising administering a therapeutically effective amount of a compound of claim 1.

53. A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a compound of claim 1.

54. A method for inhibiting or reducing HIV infection, comprising administering a therapeutically effective amount of a compound of claim 1.

55. A method for the treatment of neurodegenerative diseases, comprising administering a therapeutically effective amount of a compound of claim 1.

56. A method for the treatment of muscle-wasting diseases, comprising administering a therapeutically effective amount of a compound of claim 1.

57. A method for the treatment of cancer, comprising administering a therapeutically effective amount of a compound of claim 1.

58. A method for the treatment of chronic infectious diseases, comprising administering a therapeutically effective amount of a compound of claim 1.

59. A method for the treatment of fever, comprising administering a therapeutically effective amount of a compound of claim 1.

60. A method for the treatment of immune-related conditions, comprising administering a therapeutically effective amount of a compound of claim 1.

61. A method for the treatment of denervation or nerve injury, comprising administering a therapeutically effective amount of a compound of claim 1.

62. A method for affecting the level of viral gene expression in a subject, comprising administering a therapeutically effective amount of a compound of claim 1.

63. A method for altering the variety of antigenic peptides produced by the proteasome in an organism, comprising administering therapeutically effective amount of a compound of claim 1.

49. A compound having a structure of formula II or a pharmaceutically acceptable salt thereof,

50. A compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof,