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Claims for Patent: 8,207,297

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Claims for Patent: 8,207,297

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 Therapeutics, Inc. (South San Francisco, CA)
Application Number:13/334,469
Patent Claims: 1. A method for preparing a compound having the formula: ##STR00030## or a pharmaceutically acceptable salt thereof, the method comprising reacting a first compound of formula: ##STR00031## with a second compound of formula: ##STR00032##

2. The method of claim 1, wherein reacting the first compound with the second compound is carried out in the presence of PyBOP and HOBt.

3. The method of claim 2, wherein reacting the first compound with the second compound is carried out in the presence of 10 equivalents of DIEA.

4. The method of claim 1, wherein the method further comprises mixing the compound, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers to form a composition.

5. The method of claim 4, 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.

6. The method of claim 4, 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.

7. The method of claim 4, wherein at least one of the one or more pharmaceutically acceptable carriers is a cyclodextrin.

8. The method of claim 4, wherein at least one of the one or more pharmaceutically acceptable carriers is a substituted or unsubstituted .beta.-cyclodextrin.

9. The method of claim 4, wherein at least one of the one or more pharmaceutically acceptable carriers is a buffer.

10. The method of claim 4, wherein the method further comprises adding an anti-oxidant.

11. The method of claim 10, wherein the anti-oxidant is citric acid.

12. A method of making compound 6 ##STR00033## comprising the steps of: 1) mixing a compound of formula (V) ##STR00034## with TFA/DCM to give the TFA salt of the compound of formula (V); 2) dissolving the TFA salt of the compound of formula (V) in DMF and 2-morpholino acetic acid, adding DIEA, cooling the mixture to 0 C, and adding PyBOP to give an intermediate ester; 3) reacting the intermediate ester with Pd/C under an atmosphere of hydrogen to give a compound of formula (W) ##STR00035## 4) reacting formula (W) with a compound of formula (F) ##STR00036## to yield compound 6.

13. The method of claim 12, wherein the method further comprises mixing compound 6, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers to form a composition.

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 method further comprises adding an anti-oxidant.

20. The method of claim 10, wherein the anti-oxidant is citric acid.

21. A compound having the formula: ##STR00037## or a pharmaceutically acceptable salt thereof; prepared by a process as claimed in claim 1.

22. A composition prepared by a process as claimed in claim 4.

23. A composition prepared by a process as claimed in claim 8.

24. A compound having the formula: ##STR00038## or a pharmaceutically acceptable salt thereof; prepared by a process as claimed in claim 12.
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