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Claims for Patent: 7,417,042

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Claims for Patent: 7,417,042

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 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)
Assignee: Proteolix, Inc. (South San Francisco, CA)
Application Number:11/199,899
Patent Claims: 1. A compound having a structure of formula I or a pharmaceutically acceptable salt thereof, ##STR00024## wherein X is O, NH, or N-alkyl; Y is NH, N-alkyl, O, or C(R.sup.9).sub.2; Z is O or C(R.sup.9).sub.2; R.sub.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; each R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from alkyl, amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; m is an integer from 0 to 2; and n is an integer from 0 to 2.

2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O.

3. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl; and R.sup.9 is hydrogen.

4. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.7 are independently C.sub.1-6aralkyl and R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl.

5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is selected from N-alkyl, O, and CH.sub.2.

6. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is CH.sub.2, and m and n are both 0.

7. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is CH.sub.2, m is 0, and n is 2.

8. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is O, m is 1, and n is 2.

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00025##

10. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00026##

11. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00027##

12. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00028##

13. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00029##

14. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure ##STR00030##

15. A compound of claim 1, having a structure of formula III or a pharmaceutically acceptable salt thereof, ##STR00031## wherein X is selected from O, NH, and N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; and R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether.

16. A compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein X is O.

17. A compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6 hydroxyalkyl, and C.sub.1-6aralkyl.

18. A compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.7 are independently C.sub.1-6aralkyl and R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl.

19. A compound of claim 1, having a structure of formula IV or a pharmaceutically acceptable salt thereof, ##STR00032## wherein X is O, NH, or N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; and R.sup.6 and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether.

20. A compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein X is O.

21. A compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl.

22. A compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl.

23. A compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are both isobutyl.

24. A compound of claim 19 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00033##

25. A compound of claim 1, having a structure of formula V or a pharmaceutically acceptable salt thereof, ##STR00034## where X is O, NH, or N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; and q is an integer from 0 to 3.

26. A compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein X is O.

27. A compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl.

28. A compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.7 are independently C.sub.1-6aralkyl and R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl.

29. A compound of claim 1, having a structure of formula VI or a pharmaceutically acceptable salt thereof, ##STR00035## wherein X is O, NH, or N-alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are all hydrogen; R.sup.6 and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; and q is an integer from 0 to 3.

30. A compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein X is O.

31. A compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, and C.sub.1-6aralkyl.

32. A compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are independently C.sub.1-6alkyl.

33. A compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R.sup.6 and R.sup.8 are both isobutyl.

34. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the structure ##STR00036##

35. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the structure ##STR00037##

36. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the following structure ##STR00038##

37. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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