Compounds for enzyme inhibition
View Patent ↗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.
1. A method for preparing a compound having the formula:
or a pharmaceutically acceptable salt thereof,
the method comprising reacting a first compound of formula:
with a second compound of formula:
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 β-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 β-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
comprising the steps of:
1) mixing a compound of formula (V)
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)
4) reacting formula (W) with a compound of formula (F)
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 β-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 β-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:
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:
or a pharmaceutically acceptable salt thereof; prepared by a process as claimed in claim 12 .