Claims for Patent: 7,232,818

Summary for Patent: 7,232,818

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. (Foster City, 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:	Proteolix, Inc. (South San Francisco, CA)
Application Number:	11/106,879
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,232,818
Patent Claims:	1. A compound having a amacuire of formula (I) or a pharmaceutically acceptable salt thereof, ##STR00031## wherein each A is independantly 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 in 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 O, 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 O, 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, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, caiboxylic 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.1-6alkyl-, 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, or R.sup.8 and R.sup.9 together are C.sub.1-6alkyl, thereby forming a ring; 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), beozoyl (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. A compound of claim 1, wherein R.sup.1, R.sup.2 R.sup.3, and R.sup.4 are independently selected from C.sub.1-6alkyl and C.sub.1-6aralkyl. 3. A compound of claim 2, 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. 4. A compound of claim 3, 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. 5. A compound of claim 4, wherein L and Q are absent and R.sup.6 is C.sub.1-6alkyl. 6. A compound of claim 5, wherin 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. 7. A compound of claim 6, wherein R.sup.7 is C.sub.1-6alkyl. 8. A compound of claim 7, wherein R.sup.7 is butyl. 9. A compound of claim 6, wherein R.sup.7 is C.sub.1-6alkenyl. 10. A compound of claim 9, wherein R.sup.7 is allyl. 11. A compound of claim 6, wherein R.sup.7 is C.sub.1-6alkynyl. 12. A compound of claim 11, wherein R.sup.7 is propargyl. 13. A compound of claim 6, wherein R.sup.7 is C.sub.1-6aralkyl. 14. A compound of claim 13, wherein R.sup.7 is phenylmethyl. 15. A compound of claim 6, wherein R.sup.7 is C.sub.1-6heteroaralkyl. 16. A compound of claim 15, wherein R.sup.7 is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl. 17. A compound of claim 4, wherein Q is absent and L is SO.sub.2. 18. A compound of claim 17, wherein R.sup.7 is selected from C.sub.1-6alkyl and C.sub.1-6aralkyl. 19. A compound of claim 18, wherein R.sup.7 is C.sub.1-6alkyl. 20. A compound of claim 19, wherein R.sup.7 is methyl. 21. A compound of claim 18, wherein R.sup.7 is C.sub.1-6aralkyl. 22. A compound of claim 21, wherein R.sup.7 is phenyl. 23. A compound of claim 4, wherein L is C.dbd.O. 24. A compound of claim 23, 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.1-6hetcroaralkyl, 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.1-6alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-6alkyl-Z-C.sub.1-8alkyl-, R.sup.8ZA-C.sub.1-8 alkyl-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.1-6alky-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 fomiing 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 R.sup.6 and R.sup.7 are C.sub.1-6alkyl. 27. A compound of claim 26, wherein R.sup.7 is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, and 2-(methylsulfonyl)ethyl. 28. A compound of claim 25, wherein R.sup.7 is C.sub.1-6aralkyl. 29. A compound of claim 28, wherein R.sup.7 is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, and (4-fluorophenyl)methyl. 30. A compound of claim 25, wherein R.sup.6 is C.sub.1-6alkyl and R.sup.7 is aryl. 31. A compound of claim 30, wherein R.sup.7 is substituted or unsubstituted phenyl. 32. A compound of claim 24, wherein Q is absent or O and R.sup.7 is carbocyclylM-. 33. A compound of claim 32, wherein carbocyclyl is cyclopropyl or cyclohexyl. 34. A compound of claim 25, wherein R.sup.7 is selected from R.sup.8ZA-C.sub.1-6alkyl-, 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-, heteroeyclylMZAZ-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. 35. A compound of claim 34, wherein Z is O. 36. A compound of claim 35, 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 arc C.sub.1-6alkyl-Y--C.sub.1-6alkyl, thereby forming a ring. 37. A compound of claim 36, 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. 38. A compound of claim 25, wherein R.sup.7 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 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. 41. A compound of claim 40, wherein R.sup.7 is selected from methyl, ethyl, isopropyl, phenylmethyl, and (4-pyridyl)methyl. 42. A compound of claim 24, 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. 43. A compound of claim 42, 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. 44. A compound of claim 1, 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. 45. A compound of claim 42, 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. 46. A compound of claim 42, wherein L is C.dbd.O, Y is absent and R.sup.6 and R.sup.7 together are C.sub.1-2alkyl-Y--C.sub.1-3alkyl. 47. A compound of claim 42, 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. 48. A compound 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. 49. A compound having a structure of formula II or a pharmaceutically acceptable salt thereof, ##STR00032## 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 occulTence 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 O, 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 O, S, NH, and N--C.sub.1-6alkyl; or Z is optionally a covalent bond when adjacent to an occunence of A; R.sup.2 and R.sup.4 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, any of which is 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.11ZAZ-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.1-6alkyl-, R.sup.8ZAZ-C.sub.1-8alkyl-ZAZ-C.sub.1-8alkyl-, heteroeyelylMZAZ-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--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, or R.sup.8 and R.sup.9 together are C.sub.1-6alkyl, thereby forming a ring; 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, hoterocyclyl, 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), benayloxycarbonyl (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. 50. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.