Proteasome inhibitors and methods of using the same

• US 20050059636A1
• Filed: 08/12/2004
• Published: 03/17/2005
• Est. Priority Date: 08/14/2003
• Status: Active Grant

• Current Assignee: Sede Secondarla Della Cell Therapeitics, Inc., Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Chatteriee, Sankar, Oliva, Ambrogio, Menta, Ernesto, Iqbal, Mohamed
• Granted Patent: US 7,223,745 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.

Claims

1. A compound of Formula (I):

2. The compound of claim 1 wherein R¹ is ethyl, propyl, or butyl.

3. The compound of claim 1 wherein R¹ is 2-propyl.

4. The compound of claim 1 wherein Q is pinanediol boronic ester.

5. The compound of claim 1 wherein Q is bicyclohexyl-1,1′

-diol boronic ester.

6. The compound of claim 1 wherein Q is B(OH)₂.

7. The compound of claim 1 wherein Z is phthalimido, NRR⁴, or CN.

8. The compound of claim 1 wherein n is 8, 9, 10, or 11.

9. The compound of claim 1 wherein m is 3.

10. The compound of claim 1 wherein n is 8, 9, 1 0, or 11;

and m is 3.

11. A compound of claim 1 having Formula (I):

12. A compound of claim 1 of Formula (I-s):

13. A compound of claim 1 having the formula:

14. A composition comprising a compound of any one of claims 1-13 and a pharmaceutically acceptable carrier.

15. A method of inhibiting activity of proteasome comprising contacting a compound of any one of claims 1-13 with said proteasome.

16. A method of treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of any one of claims 1-13.

17. A method of treating cancer treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of any one of claims 1-13, and wherein said cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue.

18. A method of treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of any one of claims 1-13, and wherein said cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma.

19. A method of treating cancer comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of any one of claims 1-13 in combination with one or more antitumor or anticancer agent and/or radiotherapy.

20. A method of inhibiting activity of transcription factor NF-κ

B comprising contacting Iκ

B, the inhibitor of transcription factor NF-κ

B, with a compound of any one of claims 1-13.