Compositions and methods for inhibition of cathepsins

• US 9,873,668 B2
• Filed: 08/31/2016
• Issued: 01/23/2018
• Est. Priority Date: 03/23/2012
• Status: Active Grant

• Current Assignee: Baylor University, Mateon Therapeutics, Inc.
• Original Assignee: Baylor University, Mateon Therapeutics, Inc.
• Inventors: Chaplin, David J., Gaddale Devanna, Kishore Kumar, Parker, Erica, Pinney, Kevin G., Song, Jiangli, Trawick, Mary Lynn
• Primary Examiner(s): Bakshi, Pancham
• Assistant Examiner(s): LUDERER, MARK R
• Application Number:
  US15/253,504
• Publication Number:
  US 20160368869A1
• Time in Patent Office: 510 Days
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 337/08 the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
• CPC Class Codes: C07C 49/786 Benzophenone

Abstract

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.

Claims

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,

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(OR⁶).

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 R⁴ is halo or acyl.

12. The method of claim 11, wherein R⁴ is substituted aryl-C(O)—

or unsubstituted aryl-C(O)—

.

13. The method of claim 11, wherein R⁴ is benzoyl.

14. The method of claim 1, wherein

each of n and p, independently, is zero or one;

and

each of R³ and R⁵, 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 R³ is selected from the group consisting of hydroxyl, methyl, methoxy, and fluoro.

19. The method of claim 16, wherein p is one and R⁵ is selected from the group consisting of hydroxyl, methyl, methoxy and fluoro.

20. The method of claim 16, wherein m is one and R⁴ is selected from the group consisting of halo and acyl.

21. The method of claim 15, wherein X is

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 R³ and R⁵ 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 R⁴ is benzoyl.

29. The method of claim 28, wherein the compound is 1,3,5-Tribenzoyl benzene thiosemicarbazone (25) having the formula: