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Claims for Patent: 8,129,346

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Claims for Patent: 8,129,346

Title:Compounds for enzyme inhibition
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.
Inventor(s): Smyth; Mark S. (San Mateo, CA), Laidig; Guy J. (Menlo Park, CA), Borchardt; Ronald T. (Lawrence, KS), Bunin; Barry A. (San Mateo, CA), Crews; Craig M. (New Haven, CT), Musser; John H. (San Carlos, CA)
Assignee: Onyx Therapeutics, Inc. (South San Francisco, CA)
Application Number:11/578,626
Patent Claims: 1. A method of inhibiting an N-terminal nucleophile hydrolase or of treating inflammation or fever, comprising administering to a subject a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, ##STR00030## wherein each A is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; or A is optionally a covalent bond when adjacent to an occurrence of Z; L is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; M is absent or is C.sub.1-12alkyl; Q is absent or is selected from O, NH, and N--C.sub.1-6alkyl; X is selected from O, NH, and N--C.sub.1-6alkyl; Y is absent or is selected from 0, NH, N--C.sub.1-6alkyl, S, SO, SO.sub.2, CHOR.sup.10, and CHCO.sub.2R.sup.10; each Z is independently selected from 0, S, NH, and N--C.sub.1-6alkyl; or Z is optionally a covalent bond when adjacent to an occurrence of A; R.sup.1 and R.sup.3 are each independently C.sub.1-6aralkyl, optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R.sup.2 and R.sup.4 are each independently C.sub.1-6alkyl, optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R.sup.5 is N(R.sup.6)LQR.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; R.sup.7 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, R.sup.8ZAZ--C.sub.1-8alkyl-, R.sup.11Z--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, R.sup.8ZAZ--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, (R.sup.10).sub.2N--C.sub.1-12alkyl-, (R.sup.10).sub.3N.sup.+-C.sub.1-12alkyl-, heterocyclylM-, carbocyclylM-, R.sup.11SO.sub.2C.sub.1-8alkyl-, and R.sup.11SO.sub.2NH; or R.sup.6 and R.sup.7 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZAZ--C.sub.1-6alkyl, ZAZ--C.sub.1-6alkyl-ZAZ--C.sub.1-6alkyl, ZAZ--C.sub.1-6alkyl-ZAZ, or C.sub.1-6alkyl-A, thereby forming a ring; R.sup.8 and R.sup.9 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl; each R.sup.10 is independently selected from hydrogen and C.sub.1-6alkyl, preferably C.sub.1-6alkyl; and R.sup.11 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, provided that when R.sup.6 is H or CH.sub.3 and Q is absent, LR.sup.7 is not hydrogen, unsubstituted C.sub.1-6alkylC.dbd.O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

2. The method of claim 1, wherein R.sup.1 and R.sup.3 are both C.sub.1-6aralkyl and both R.sup.2 and R.sup.4 are C.sub.1-6alkyl.

3. The method of claim 2, wherein X is O, R.sup.1 is 2-phenylethyl, R.sup.2 is isobutyl, R.sup.3 is phenylmethyl, and R.sup.4 is isobutyl.

4. The method of claim 3, wherein L and Q are absent and R.sup.6 is C.sub.1-6alkyl.

5. The method of claim 4, wherein R.sup.7 is selected from C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl.

6. The method of claim 5, wherein R.sup.7 is C.sub.1-6alkyl.

7. The method of claim 6, wherein R.sup.7 is butyl.

8. The method of claim 5, wherein R.sup.7 is C.sub.1-6alkenyl.

9. The method of claim 8, wherein R.sup.7 is allyl.

10. The method of claim 5, wherein R.sup.7 is C.sub.1-6alkynyl.

11. The method of claim 10, wherein R.sup.7 is propargyl.

12. The method of claim 5, wherein R.sup.7 is C.sub.1-6aralkyl.

13. The method of claim 12, wherein R.sup.7 is phenylmethyl.

14. The method of claim 5, wherein R.sup.7 is C.sub.1-6heteroaralkyl.

15. The method of claim 14, wherein R.sup.7 is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl.

16. The method of claim 3, wherein Q is absent and L is SO.sub.2.

17. The method of claim 16, wherein R.sup.7 is selected from C.sub.1-6alkyl and C.sub.1-6aralkyl.

18. The method of claim 17, wherein R.sup.7 is C.sub.1-6alkyl.

19. The method of claim 18, wherein R.sup.7 is methyl.

20. The method of claim 17, wherein R.sup.7 is C.sub.1-6aralkyl.

21. The method of claim 20, wherein R.sup.7 is phenyl.

22. The method of claim 3, wherein L is C.dbd.O.

23. The method of claim 22, wherein R.sup.7 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, R.sup.8ZA-C.sub.1-8alkyl-, R.sup.11Z--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-Z--C.sub.1-8alkyl-, R.sup.8ZA-C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, (R.sup.10).sub.2N--C.sub.1-8alkyl-, (R.sup.10).sub.3N.sup.+-C.sub.1-8alkyl-, heterocyclylM-, carbocyclylM-, R.sup.11SO.sub.2C.sub.1-8alkyl-, and R.sup.11SO.sub.2NH; or R.sup.6 and R.sup.7 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-A or C.sub.1-6alkyl-A, thereby forming a ring; and each occurrence of Z and A is independently other than a covalent bond.

24. The method of claim 23, wherein Q is absent.

25. The method of claim 24, wherein R.sup.6 and R.sup.7 are C.sub.1-6alkyl.

26. The method of claim 25, wherein R.sup.7 is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, and 2-(methylsulfonyl)ethyl.

27. The method of claim 24, wherein R.sup.7 is C.sub.1-6aralkyl.

28. The method of claim 27, wherein R.sup.7 is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, and (4-fluorophenyl)methyl.

29. The method of claim 24, wherein R.sup.6 is C.sub.1-6alkyl and R.sup.7 is aryl.

30. The method of claim 29, wherein R.sup.7 is substituted or unsubstituted phenyl.

31. The method of claim 23, wherein Q is absent or O and R.sup.7 is carbocyclylM-.

32. The method of claim 31, wherein carbocyclyl is cyclopropyl or cyclohexyl.

33. The method of claim 24, wherein R.sup.7 is selected from (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-Z--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, A is C.dbd.O, and Z is O or NH.

34. The method of claim 33, wherein Z is O.

35. The method of claim 34, wherein R.sup.7 is heterocyclylMZAZ--C.sub.1-8alkyl- and heterocyclyl is oxodioxolenyl or N(R.sup.12)(R.sup.13), wherein R.sup.12 and R.sup.13 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, thereby forming a ring.

36. The method of claim 35, wherein R.sup.7 is selected from (R.sup.10).sub.2N--C.sub.1-8alkyl- and (R.sup.10).sub.3N.sup.+(CH.sub.2).sub.n--, and R.sup.10 is C.sub.1-6alkyl.

37. The method of claim 24, wherein R.sup.7 is heterocyclylM- and heterocyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.

38. The method of claim 23, wherein Q is O or NH.

39. The method of claim 38, wherein R.sup.6 is C.sub.1-6alkyl and R.sup.7 is selected from C.sub.1-6alkyl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl.

40. The method of claim 39, wherein R.sup.7 is selected from methyl, ethyl, isopropyl, phenylmethyl, and (4-pyridyl)methyl.

41. The method of claim 23, wherein R.sup.6 and R.sup.7 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, or C.sub.1-6alkyl-A, thereby forming a ring.

42. The method of claim 41, wherein L is C.dbd.O, Q and Y are absent, and R.sup.6 and R.sup.7 together are C.sub.1-3alkyl-Y--C.sub.1-3alkyl.

43. The method of claim 41, wherein L and Q are absent, and R.sup.6 and R.sup.7 together are C.sub.1-3alkyl-Y--C.sub.1-3alkyl.

44. The method of claim 41, wherein L is C.dbd.O, Q is absent, Y is selected from NH and N--C.sub.1-6alkyl, and R.sup.6 and R.sup.7 together are C.sub.1-3alkyl-Y--C.sub.1-3alkyl.

45. The method of claim 41, wherein L is C.dbd.O, Y is absent and R.sup.6 and R.sup.7 together are C.sub.1-3alkyl-Y--C.sub.1-3alkyl.

46. The method of claim 41, wherein L and A are C.dbd.O and R.sup.6 and R.sup.7 together are C.sub.1-2alkyl-ZA-C.sub.1-2alkyl.

47. The method of claim 42, wherein L and A are C.dbd.O and R.sup.6 and R.sup.7 together are C.sub.2-3alkyl-A.

48. A method of inhibiting an N-terminal nucleophile hydrolase or of treating inflammation or fever, comprising administering to a subject a compound having a structure of formula II or a pharmaceutically acceptable salt thereof, ##STR00031## wherein each A is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; or A is optionally a covalent bond when adjacent to an occurrence of Z; L is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; M is absent or is C.sub.1-12alkyl; Q is absent or is selected from 0, NH, and N--C.sub.1-6alkyl; X is selected from 0, NH, and N--C.sub.1-6alkyl; Y is absent or is selected from 0, NH, N--C.sub.1-6alkyl, S, SO, SO.sub.2, CHOR.sup.10, and CHCO.sub.2R.sup.10; each Z is independently selected from 0, S, NH, and N--C.sub.1-6alkyl; or Z is optionally a covalent bond when adjacent to an occurrence of A; R.sup.2 and R.sup.4 are each independently C.sub.1-6alkyl optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R.sup.5 is N(R.sup.6)LQR.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; R.sup.7 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, R.sup.8ZAZ--C.sub.1-8alkyl-, R.sup.11Z--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, R.sup.8ZAZ--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, (R.sup.10).sub.2N--C.sub.1-12alkyl-, (R.sup.10).sub.3N.sup.+-C.sub.1-12alkyl-, heterocyclylM-, carbocyclylM-, R.sup.11SO.sub.2C.sub.1-8alkyl-, and R.sup.11SO.sub.2NH; or R.sup.6 and R.sup.7 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZAZ--C.sub.1-6alkyl, ZAZ--C.sub.1-6alkyl-ZAZ-C.sub.1-6alkyl, ZAZ--C.sub.1-6alkyl-ZAZ, or C.sub.1-6alkyl-A; R.sup.8 and R.sup.9 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl; each R.sup.10 is independently selected from hydrogen and C.sub.1-6alkyl; and R.sup.11 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, provided that when R.sup.6 is H or CH.sub.3 and Q is absent, LR.sup.7 is not hydrogen, unsubstituted C.sub.1-6alkylC.dbd.O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

49. A method of inhibiting an N-terminal nucleophile hydrolase, comprising administering a therapeutically effective amount of a compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof or of formula II of claim 48 or a pharmaceutically acceptable salt thereof.

50. A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof or of formula II of claim 48 or a pharmaceutically acceptable salt thereof.

51. A method for the treatment of fever, comprising administering a therapeutically effective amount of a compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof or of formula II of claim 48 or a pharmaceutically acceptable salt thereof.

52. The method of claim 48, wherein X is O.

53. The method of claim 48, wherein: X is O; R.sup.5 is N(R.sup.6)LQR.sup.7, wherein Q is absent; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; R.sup.7 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, R.sup.8ZAZ-C.sub.1-8alkyl-, R.sup.11Z-C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(=O)O-C.sub.1-8alkyl-ZAZC.sub.1-8alkyl-, R8ZAZ-C.sub.1-8alkyl-ZAZ-C.sub.1-8alkyl-, heterocyclylMZAZ-C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(=O)O-C.sub.1-8alkyl-, (R.sup.10).sub.2N-C.sub.1-12alkyl-, (R.sup.10).sub.3N.sup.+-C.sub.1-12 alkyl-, heterocyclyIM, carbocyclyIM-, R.sup.11SOzC.sub.1-8alkyl-, and R.sup.11SOzNH; R.sup.8 and R.sup.9 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl; each R.sup.10 is independently selected from hydrogen and C.sub.1-6alkyl; and R.sup.11 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, provided that when R.sup.6 is H or CH, and Q is absent, LR.sup.7 is not hydrogen, unsubstituted C.sub.1-6alkyIC=O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

54. The method of claim 53, wherein L is C=O.

55. The method of claim 54, wherein R.sup.7 is heterocyclylM- and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.

56. The method of claim 55, wherein R.sup.6 is H and R.sup.7 is heterocyclylM-, wherein heterocyclyl is morpholino and M is CH.sub.2-.

57. The method of claim 56, wherein R.sup.2 and R.sup.4 are isobutyl.

58. A method of inhibiting an N-terminal nucleophile hydrolase or of treating inflammation or fever, comprising administering to a subject a compound having a structure of formula II or a pharmaceutically acceptable salt thereof, ##STR00032## wherein L is C=O, M is CH.sub.2-; Q is absent; X is O; R.sup.2 and R.sup.4 are both isobutyl; R.sup.5 is N(R.sup.6)LQR.sup.7; R.sup.6 is hydrogen; and R.sup.7 is heterocyclylM-, and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.

59. The method of claim 58, wherein heterocyclyl is morpholino, or a pharmaceutically acceptable salt of said compound of Formula II.

60. A method of inhibiting an N-terminal nucleophile hydrolase, comprising administering a therapeutically effective amount of a compound of formula II of claim 58 or 59, or a pharmaceutically acceptable salt thereof.

61. A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a compound of formula II of claim 58 or 59, or a pharmaceutically acceptable salt thereof.

62. A method for the treatment of fever, comprising administering a therapeutically effective amount of a compound of formula II of claim 58 or 59, or a pharmaceutically acceptable salt thereof.
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