Proteasome inhibitors

• US 8,871,745 B2
• Filed: 08/12/2013
• Issued: 10/28/2014
• Est. Priority Date: 08/06/2007
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Olhava, Edward J., Danca, Mihaela Diana
• Primary Examiner(s): WITHERSPOON, SIKARL A
• Application Number:
  US13/964,708
• Publication Number:
  US 20130331356A1
• Time in Patent Office: 442 Days
• Field of Search: 568/450, 564/169, 514/64, 562/7
• US Class Current: 514/64
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 233/83 of an acyclic saturated carbon skeleton
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/05 Cyclic compounds having at least one ring containing boron but no carbon in the ring

Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Claims

1. A method of treating cancer, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a boronic acid anhydride thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a boronic acid anhydride thereof, and a pharmaceutically acceptable carrier:

2. The method of claim 1, wherein Ring A is

3. The method of claim 2, wherein Z¹ and Z² are each hydroxyl.

4. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of:

[(1R)-1-({[(2,3-difluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(5-chloro-2-fluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(3,5-difluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2,5-difluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2-bromobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2-fluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2-chloro-5-fluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(4-fluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(3,4-difluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(3-chlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(3,4-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(3-fluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2-chloro-4-fluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2,3-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2-chlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2,4-difluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(4-chloro-2-fluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(4-chlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid;

[(1R)-1-({[(2,4-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid; and

[(1R)-1-({[(3,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid.

5. The method as in any one of claims 1-3, wherein the cancer is multiple myeloma.

6. The method as in any one of claims 1-3, wherein the cancer is lymphoma.

7. The method as in any one of claims 1-3, wherein the patient in need of the treatment is a patient having or at risk of developing or experiencing a recurrence in a cancer selected from the group consisting of multiple myeloma and lymphoma.

8. The method as in any one of claims 1-3, wherein the second therapeutic agent is melphalan.

9. The method as in any one of claims 1-3, wherein the second therapeutic agent is lenalidomide.

10. The method as in any one of claims 1-3, wherein the compound or pharmaceutical composition is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.

11. The method of claim 10, wherein the compound or composition is administered orally, intravenously, or subcutaneously.

12. The method of claim 10, wherein the compound or composition is administered systemically.

13. The method of claim 10, wherein the compound or composition is administered locally.

14. A method of treating cancer, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I),

15. The method of claim 14, wherein Z¹ and Z² are each hydroxyl.

16. The method of claim 15, wherein Z¹ and Z² together form a moiety derived from a boronic acid complexing agent.

17. The method as in any one of claims 14-16, wherein the cancer is multiple myeloma.

18. The method as in any one of claims 14-16, wherein the cancer is lymphoma.

19. The method as in any one of claims 14-16, wherein the patient in need of the treatment is a patient having or at risk of developing or experiencing a recurrence in a cancer selected from the group consisting of multiple myeloma and lymphoma.

20. A method of treating cancer, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I),

21. The method of claim 20, wherein Z¹ and Z² are each hydroxyl.

22. The method of claim 20, wherein Z¹ and Z² together form a moiety derived from a boronic acid complexing agent.

23. The method as in any one of claims 20-22, wherein the cancer is multiple myeloma.

24. The method as in any one of claims 20-22, wherein the cancer is lymphoma.

25. The method as in any one of claims 20-22, wherein the patient in need of the treatment is a patient having or at risk of developing or experiencing a recurrence in a cancer selected from the group consisting of multiple myeloma and lymphoma.