Details for Patent: 8,324,174

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:	Onyx Therapeutics, Inc. (South San Francisco, CA)
Filing Date:	Dec 22, 2011
Application Number:	13/334,372
Claims:	1. A method for preparing a compound having formula (II), or a pharmaceutically acceptable salt thereof: ##STR00029## wherein X is O; R.sup.2 and R.sup.4 are each isobutyl; R.sup.5 is selected from the group consisting of: (i) --NHC(.dbd.O)CH.sub.2OH; (ii) --NHC(.dbd.O)CH.sub.2OP(O)(O.sup.-Na.sup.+).sub.2; (iii) --NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2; (iv) --NHC(.dbd.O)CH.sub.2-(1-piperidyl); (v) --NHC(.dbd.O)CH.sub.2-(cyclopropyl); and (vi) --NHC(.dbd.O)CH.sub.2CH.sub.2CH.sub.2N(CH.sub.3).sub.2; the method comprising reacting a first compound, or a salt thereof, having a first formula, which is selected from the group consisting of: ##STR00030## with a second compound, or a salt thereof, having a second formula: ##STR00031## 2. The method of claim 1, wherein the first compound has the formula: ##STR00032## 3. The method of claim 1, wherein the first compound has the formula: ##STR00033## 4. The method of claim 1, wherein the first compound has the formula: ##STR00034## 5. The method of claim 1, wherein the first compound has the formula: ##STR00035## 6. The method of claim 1, wherein the first compound has the formula: ##STR00036## 7. The method of claim 1, wherein the first compound has the formula: ##STR00037## 8. The method of claim 1, wherein reacting the first compound with the second compound is carried out in the presence of BOP or PyBOP and HOBt. 9. The method of claim 8, wherein reacting the first compound with the second compound is carried out in the presence of DIEA. 10. The method of claim 1, wherein the method further comprises mixing the compound having formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers to form a composition. 11. The method of claim 10, wherein at least one of the one or more pharmaceutically acceptable carriers is a cyclodextrin. 12. The method of claim 10, wherein at least one of the one or more pharmaceutically acceptable carriers is a substituted or unsubstituted .beta.-cyclodextrin. 13. The method of claim 10, wherein the method further comprises adding an anti-oxidant. 14. The method of claim 13, wherein the anti-oxidant is citric acid. 15. A compound having formula (II), or a pharmaceutically acceptable salt thereof: ##STR00038## wherein X is O; R.sup.2 and R.sup.4 are each isobutyl; R.sup.5 is selected from the group consisting of: (i) --NHC(.dbd.O)CH.sub.2OH; (ii) --NHC(.dbd.O)CH.sub.2OP(O)(O.sup.-Na.sup.+).sub.2); (iii) --NHC(.dbd.O)CH.sub.2N(CH.sub.3).sub.2; (iv) --NHC(.dbd.O)CH.sub.2-(1-piperidyl); (v) --NHC(.dbd.O)CH.sub.2-(cyclopropyl); and (vi) --NHC(.dbd.O)CH.sub.2CH.sub.2CH.sub.2N(CH.sub.3).sub.2; prepared by a process as claimed in claim 1. 16. A composition prepared by a process as claimed in claim 10. 17. A method for preparing a compound having formula (II), or a pharmaceutically acceptable salt thereof: ##STR00039## X is O; R.sup.2- and R.sup.4 are each isobutyl; R.sup.5 is selected from the group consisting of: (i) ##STR00040## (ii) --NHC(.dbd.O)NHPh; and (iii) --NHC(.dbd.S)NHPh; and the method comprising: (a) reacting a first compound, or a salt thereof, having a first formula: ##STR00041## with a second compound, or a salt thereof, having a second formula: ##STR00042## in the presence of H.sub.2/Pd/C, to form a third compound, or a salt thereof, having a third formula: ##STR00043## and (b) reacting the third compound, or a salt thereof, with a fourth compound in the presence of trifluoroacetic acid, wherein the fourth compound is selected from the group consisting of: (i) 1,3,5-trimethyl-1-H-pyrazole-4-sulfonyl chloride; (ii) phenyl isocyanate; and (iii) phenyl isothiocyanate. 18. The method of claim 17, wherein the fourth compound is 1,3,5-trimethyl-1-H-pyrazole-4-sulfonyl chloride. 19. The method of claim 17, wherein the fourth compound is phenyl isocyanate. 20. The method of claim 17, wherein the fourth compound is phenyl isothiocyanate. 21. A compound having formula (II), or a pharmaceutically acceptable salt thereof: ##STR00044## X is O; R.sup.2- and R.sup.4 are each isobutyl; R.sup.5 is selected from the group consisting of: (i) ##STR00045## (ii) --NHC(.dbd.O)NHPh; and (iii) --NHC(.dbd.S)NHPh; prepared by a process as claimed in claim 17. 22. The method of claim 17, wherein the method further comprises mixing the compound having formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers to form a composition. 23. The method of claim 22, wherein at least one of the one or more pharmaceutically acceptable carriers is a cyclodextrin. 24. The method of claim 22, wherein at least one of the one or more pharmaceutically acceptable carriers is a substituted or unsubstituted .beta.-cyclodextrin. 25. The method of claim 22, wherein the method further comprises adding an anti-oxidant. 26. The method of claim 25, wherein the anti-oxidant is citric acid. 27. A composition prepared by a process as claimed in claim 22.