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 formula (II), or a pharmaceutically acceptable salt thereof:
wherein
X is O;
R 2 and R 4 are each isobutyl;
R 5 is selected from the group consisting of:
(i) —NHC(═O)CH 2 OH;
(ii) —NHC(═O)CH 2 OP(O)(O − Na + ) 2 ;
(iii) —NHC(═O)CH 2 N(CH 3 ) 2 ;
(iv) —NHC(═O)CH 2 -(1-piperidyl);
(v) —NHC(═O)CH 2 -(cyclopropyl); and
(vi) —NHC(═O)CH 2 CH 2 CH 2 N(CH 3 ) 2 ;
the method comprising reacting a first compound, or a salt thereof, having a first formula, which is selected from the group consisting of:
with a second compound, or a salt thereof, having a second formula:
2. The method of claim 1 , wherein the first compound has the formula:
3. The method of claim 1 , wherein the first compound has the formula:
4. The method of claim 1 , wherein the first compound has the formula:
5. The method of claim 1 , wherein the first compound has the formula:
6. The method of claim 1 , wherein the first compound has the formula:
7. The method of claim 1 , wherein the first compound has the formula:
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 β-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:
wherein
X is O;
R 2 and R 4 are each isobutyl;
R 5 is selected from the group consisting of:
(i) —NHC(═O)CH 2 OH;
(ii) —NHC(═O)CH 2 OP(O)(O − Na + ) 2 );
(iii) —NHC(═O)CH 2 N(CH 3 ) 2 ;
(iv) —NHC(═O)CH 2 -(1-piperidyl);
(v) —NHC(═O)CH 2 -(cyclopropyl); and
(vi) —NHC(═O)CH 2 CH 2 CH 2 N(CH 3 ) 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:
X is O;
R 2 - and R 4 are each isobutyl;
R 5 is selected from the group consisting of:
(i)
(ii) —NHC(═O)NHPh; and
(iii) —NHC(═S)NHPh; and
the method comprising:
(a) reacting a first compound, or a salt thereof, having a first formula:
with a second compound, or a salt thereof, having a second formula:
in the presence of H 2 /Pd/C, to form a third compound, or a salt thereof, having a third formula:
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:
X is O;
R 2 - and R 4 are each isobutyl;
R 5 is selected from the group consisting of:
(i)
(ii) —NHC(═O)NHPh; and
(iii) —NHC(═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 β-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 .