Claims for Patent: 8,129,346

Summary 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):	Mark S. Smyth, Guy J. Laidig, Ronald T. Borchardt, Barry A. Bunin, Craig M. Crews, John H. Musser
Assignee:	Onyx Therapeutics Inc
Application Number:	US11/578,626
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,129,346
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, wherein each A is independently selected from C═O, C═S, and SO2; or A is optionally a covalent bond when adjacent to an occurrence of Z; L is absent or is selected from C═O, C═S, and SO2; M is absent or is C1-12alkyl; Q is absent or is selected from O, NH, and N—C1-6alkyl; X is selected from O, NH, and N—C1-6alkyl; Y is absent or is selected from 0, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from 0, S, NH, and N—C1-6alkyl; or Z is optionally a covalent bond when adjacent to an occurrence of A; R1 and R3 are each independently C1-6aralkyl, optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R2 and R4 are each independently C1-6alkyl, optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZAZ—C1-8alkyl-, R11Z—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, R8ZAZ—C1-8alkyl-ZAZ—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-12alkyl-, (R10)3N+-C1-12alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZAZ—C1-6alkyl, ZAZ—C1-6alkyl-ZAZ—C1-6alkyl, ZAZ—C1-6alkyl-ZAZ, or C1-6alkyl-A, thereby forming a ring; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl; each R10 is independently selected from hydrogen and C1-6alkyl, preferably C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, provided that when R6 is H or CH3 and Q is absent, LR7 is not hydrogen, unsubstituted C1-6alkylC═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 R1 and R3 are both C1-6aralkyl and both R2 and R4 are C1-6alkyl. 3. The method of claim 2, wherein X is O, R1 is 2-phenylethyl, R2 is isobutyl, R3 is phenylmethyl, and R4 is isobutyl. 4. The method of claim 3, wherein L and Q are absent and R6 is C1-6alkyl. 5. The method of claim 4, wherein R7 is selected from C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6aralkyl, and C1-6heteroaralkyl. 6. The method of claim 5, wherein R7 is C1-6alkyl. 7. The method of claim 6, wherein R7 is butyl. 8. The method of claim 5, wherein R7 is C1-6alkenyl. 9. The method of claim 8, wherein R7 is allyl. 10. The method of claim 5, wherein R7 is C1-6alkynyl. 11. The method of claim 10, wherein R7 is propargyl. 12. The method of claim 5, wherein R7 is C1-6aralkyl. 13. The method of claim 12, wherein R7 is phenylmethyl. 14. The method of claim 5, wherein R7 is C1-6heteroaralkyl. 15. The method of claim 14, wherein R7 is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl. 16. The method of claim 3, wherein Q is absent and L is SO2. 17. The method of claim 16, wherein R7 is selected from C1-6alkyl and C1-6aralkyl. 18. The method of claim 17, wherein R7 is C1-6alkyl. 19. The method of claim 18, wherein R7 is methyl. 20. The method of claim 17, wherein R7 is C1-6aralkyl. 21. The method of claim 20, wherein R7 is phenyl. 22. The method of claim 3, wherein L is C═O. 23. The method of claim 22, wherein R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZA-C1-8alkyl-, R11Z—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-Z—C1-8alkyl-, R8ZA-C1-8alkyl-ZAZ—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-8alkyl-, (R10)3N+-C1-8alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-A or C1-6alkyl-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 R6 and R7 are C1-6alkyl. 26. The method of claim 25, wherein R7 is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, and 2-(methylsulfonyl)ethyl. 27. The method of claim 24, wherein R7 is C1-6aralkyl. 28. The method of claim 27, wherein R7 is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, and (4-fluorophenyl)methyl. 29. The method of claim 24, wherein R6 is C1-6alkyl and R7 is aryl. 30. The method of claim 29, wherein R7 is substituted or unsubstituted phenyl. 31. The method of claim 23, wherein Q is absent or O and R7 is carbocyclylM-. 32. The method of claim 31, wherein carbocyclyl is cyclopropyl or cyclohexyl. 33. The method of claim 24, wherein R7 is selected from (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-Z—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, A is C═O, and Z is O or NH. 34. The method of claim 33, wherein Z is O. 35. The method of claim 34, wherein R7 is heterocyclylMZAZ—C1-8alkyl- and heterocyclyl is oxodioxolenyl or N(R12)(R13), wherein R12 and R13 together are C1-6alkyl-Y—C1-6alkyl, thereby forming a ring. 36. The method of claim 35, wherein R7 is selected from (R10)2N—C1-8alkyl- and (R10)3N+(CH2)n—, and R10 is C1-6alkyl. 37. The method of claim 24, wherein R7 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 R6 is C1-6alkyl and R7 is selected from C1-6alkyl, C1-6aralkyl, and C1-6heteroaralkyl. 40. The method of claim 39, wherein R7 is selected from methyl, ethyl, isopropyl, phenylmethyl, and (4-pyridyl)methyl. 41. The method of claim 23, wherein R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, or C1-6alkyl-A, thereby forming a ring. 42. The method of claim 41, wherein L is C═O, Q and Y are absent, and R6 and R7 together are C1-3alkyl-Y—C1-3alkyl. 43. The method of claim 41, wherein L and Q are absent, and R6 and R7 together are C1-3alkyl-Y—C1-3alkyl. 44. The method of claim 41, wherein L is C═O, Q is absent, Y is selected from NH and N—C1-6alkyl, and R6 and R7 together are C1-3alkyl-Y—C1-3alkyl. 45. The method of claim 41, wherein L is C═O, Y is absent and R6 and R7 together are C1-3alkyl-Y—C1-3alkyl. 46. The method of claim 41, wherein L and A are C═O and R6 and R7 together are C1-2alkyl-ZA-C1-2alkyl. 47. The method of claim 42, wherein L and A are C═O and R6 and R7 together are C2-3alkyl-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, wherein each A is independently selected from C═O, C═S, and SO2; or A is optionally a covalent bond when adjacent to an occurrence of Z; L is absent or is selected from C═O, C═S, and SO2; M is absent or is C1-12alkyl; Q is absent or is selected from 0, NH, and N—C1-6alkyl; X is selected from 0, NH, and N—C1-6alkyl; Y is absent or is selected from 0, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from 0, S, NH, and N—C1-6alkyl; or Z is optionally a covalent bond when adjacent to an occurrence of A; R2 and R4 are each independently C1-6alkyl optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZAZ—C1-8alkyl-, R11Z—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, R8ZAZ—C1-8alkyl-ZAZ—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-12alkyl-, (R10)3N+-C1-12alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZAZ—C1-6alkyl, ZAZ—C1-6alkyl-ZAZ-C1-6alkyl, ZAZ—C1-6alkyl-ZAZ, or C1-6alkyl-A; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl; each R10 is independently selected from hydrogen and C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, provided that when R6 is H or CH3 and Q is absent, LR7 is not hydrogen, unsubstituted C1-6alkylC═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; R5 is N(R6)LQR7, wherein Q is absent; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZAZ-C1-8alkyl-, R11Z-C1-8alkyl-, (R8O)(R9O)P(=O)O-C1-8alkyl-ZAZC1-8alkyl-, R8ZAZ-C1-8alkyl-ZAZ-C1-8alkyl-, heterocyclylMZAZ-C1-8alkyl-, (R8O)(R9O)P(=O)O-C1-8alkyl-, (R10)2N-C1-12alkyl-, (R10)3N+-C1-12 alkyl-, heterocyclyIM, carbocyclyIM-, R11SOzC1-8alkyl-, and R11SOzNH; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl; each R10 is independently selected from hydrogen and C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, provided that when R6 is H or CH, and Q is absent, LR7 is not hydrogen, unsubstituted C1-6alkyIC=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 R7 is heterocyclylM- and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino. 56. The method of claim 55, wherein R6 is H and R7 is heterocyclylM-, wherein heterocyclyl is morpholino and M is CH2-. 57. The method of claim 56, wherein R2 and R4 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, wherein L is C=O, M is CH2-; Q is absent; X is O; R2 and R4 are both isobutyl; R5 is N(R6)LQR7; R6 is hydrogen; and R7 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.