.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Claims for Patent: 7,232,818

« Back to Dashboard

Claims 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 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.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc