Compositions and methods for inhibition of cathepsins
This invention is directed to compound of Formula I and methods of using these compounds in the treatment of conditions in which modulation of a cathepsin, particularly cathepsin K or cathepsin L, will be therapeutically useful.
1. A method of inhibiting an activity of a cathepsin, comprising contacting the cathepsin with a compound having a formula I, in an amount of effective to inhibit an activity of the cathepsin,
or a solvate or pharmaceutically acceptable salt thereof, wherein
X is selected from the group consisting of C(═O), CH(OR 6 ) and
n is 0, 1, 2 or 3;
m is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
R 1 is hydrogen, C 1 -C 3 alkyl, aryl and arylalkyl;
R 2 is hydrogen or C 1 -C 3 alkyl;
each R 3 and R 5 independently is selected from the group consisting of hydroxyl, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, fluoro, and chloro;
each R 4 independently is selected from the group consisting of hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, amino, nitro, nitroso and acyl; and
R 6 is selected from the group consisting of hydrogen and methyl.
2. The method of claim 1 , wherein the cathepsin is cathepsin K or cathepsin L.
3. The method of claim 1 , further comprising: contacting the cathepsin in vitro with the compound having formula I.
4. The method of claim 1 , further comprising contacting the cathepsin in a cell with the compound having formula I.
5. The method of claim 1 , wherein X is C(═O) or CH(OR 6 ).
6. The method of claim 5 , wherein X is C(═O).
7. The method of claim 1 , wherein m is zero.
8. The method of claim 7 , wherein n is zero and p is zero.
9. The method of claim 1 , wherein n is zero and p is zero.
10. The method of claim 1 , wherein m is 1.
11. The method of claim 10 , wherein R 4 is halo or acyl.
12. The method of claim 11 , wherein R 4 is substituted aryl-C(O)— or unsubstituted aryl-C(O)—.
13. The method of claim 11 , wherein R 4 is benzoyl.
14. The method of claim 1 , wherein
each of n and p, independently, is zero or one; and
each of R 3 and R 5 , independently, is selected from the group consisting of hydroxyl, methyl, methoxy and fluoro.
15. The method of claim 1 , wherein the compound having the formula I has a formula II, or a solvate or pharmaceutically acceptable salt thereof:
16. The method of claim 5 , wherein X is C(═O).
17. The method of claim 16 , wherein each of n, m and p, independently, is zero or one.
18. The method of claim 16 , wherein n is one and R 3 is selected from the group consisting of hydroxyl, methyl, methoxy, and fluoro.
19. The method of claim 16 , wherein p is one and R 5 is selected from the group consisting of hydroxyl, methyl, methoxy and fluoro.
20. The method of claim 16 , wherein m is one and R 4 is selected from the group consisting of halo and acyl.
21. The method of claim 15 , wherein X is
and m is zero or one.
22. A compound of claim 21 , wherein each of n and p, independently, is zero or one.
23. The method of claim 15 , wherein the compound is 3-benzoyl benzophenone thiosemicarbazone (3) having the formula:
24. The method of claim 15 , wherein n=1, m=0, and p=1.
25. The method of claim 24 , wherein R 3 and R 5 are fluoro.
26. The method of claim 25 , wherein the compound is 1,3-bis-(4-fluorobenzoyl) benzene thiosemicarbazone (13) having the formula:
27. The method of claim 15 , wherein n=0, m=1, and p=0.
28. The method of claim 27 , wherein R 4 is benzoyl.
29. The method of claim 28 , wherein the compound is 1,3,5-Tribenzoyl benzene thiosemicarbazone (25) having the formula: