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Claims for Patent: 8,207,127

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Claims for Patent: 8,207,127

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)
Assignee: Onyx Technologies, Inc. (South San Francisco, CA)
Application Number:13/334,544
Patent Claims: 1. A method for treating a hematopoietic cancer, which comprises administering to a subject in need thereof an effective amount of a compound having the formula: ##STR00031## or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the hematopoietic cancer is leukemia.

3. The method of claim 2, wherein the leukemia is acute lymphocytic leukemia.

4. The method of claim 2, wherein the leukemia is acute myelocytic leukemia.

5. The method of claim 4, wherein the acute myelocytic leukemia is acute promyelocytic leukemia.

6. The method of claim 2, wherein the leukemia is adult T-cell leukemia.

7. The method of claim 2, wherein the leukemia is chronic lymphocytic leukemia.

8. The method of claim 2, wherein the leukemia is chronic myelocytic leukemia.

9. The method of claim 1, wherein the hematopoietic cancer is lymphoma.

10. The method of claim 9, wherein the lymphoma is Burkitt's lymphoma.

11. The method of claim 9, wherein the lymphoma is histiocytic lymphoma.

12. The method of claim 1, wherein compound or pharmaceutically acceptable salt thereof is administered by intravenous administration.

13. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is in the form of a composition comprising the compound or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

14. The method of claim 13, wherein each of the one or more pharmaceutically acceptable carriers is independently selected from a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and a buffer.

15. The method of claim 13, wherein each of the one or more pharmaceutically acceptable carriers is independently selected from: (1) a sugar selected from lactose, glucose, and sucrose; (2) a starch selected from corn starch, potato starch, and substituted or unsubstituted .beta.-cyclodextrin; (3) cellulose or a derivative selected from sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) an excipient selected from cocoa butter and suppository waxes; (9) an oil selected from peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) propylene glycol; (11) a polyol selected from glycerin, sorbitol, mannitol, and polyethylene glycol; (12) an ester selected from ethyl oleate and ethyl laurate; (13) agar; (14) a buffering agent selected from magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

16. The method of claim 13, wherein at least one of the one or more pharmaceutically acceptable carriers is a cyclodextrin.

17. The method of claim 13, wherein at least one of the one or more pharmaceutically acceptable carriers is a substituted or unsubstituted .beta.-cyclodextrin.

18. The method of claim 13, wherein at least one of the one or more pharmaceutically acceptable carriers is a buffer.

19. The method of claim 13, wherein the composition further comprises an anti-oxidant.

20. The method of claim 19, wherein the anti-oxidant is citric acid.

21. The method of claim 13, wherein the composition further comprises one or more other therapeutic agents.

22. The method of claim 21, wherein at least one of the one or more other therapeutic agents is a chemotherapeutic agent.

23. The method of claim 13, wherein the composition is in a solid form that is suitable for reconstitution in a sterile injectable medium.

24. The method of claim 13, wherein the composition further comprises water.

25. The method of claim 24, wherein the water is sterile water.

26. The method of claim 25, wherein the composition is in the form of an aqueous solution, dispersion, suspension or emulsion.

27. The method of claim 13, wherein the composition is administered by intravenous administration.
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