Boronic acid derivatives of resveratrol for activating deacetylase enzymes

• US 10,478,445 B2
• Filed: 07/03/2014
• Issued: 11/19/2019
• Est. Priority Date: 07/03/2013
• Status: Active Grant

• Current Assignee: Georgetown University
• Original Assignee: Georgetown University
• Inventors: Bae, Insoo, Yi, Yong Weon, Kang, Hyo Jin, Kim, Hee Jeong
• Primary Examiner(s): Davis, Brian J
• Application Number:
  US14/902,783
• Publication Number:
  US 20160166592A1
• Time in Patent Office: 1,965 Days
• Field of Search: None
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Disclosed herein are compounds, compositions and methods for the treatment of a disease or disorder related to activation of deacetylase enzymes. The compounds and methods are related to boronic acid derivatives of resveratrol. In some forms, the compound, compositions and methods relate to treatment of prostate cancer, colon cancer, or breast cancer, a cardiovascular disease, inflammation, obesity, diabetes, or a neurodegenerative disease.

Claims

1. A method comprising administering a composition to a subject, wherein the composition comprises a compound, or a pharmaceutically acceptable salt, prodrug, clathrate, tautomer or solvate thereof, wherein the compound has the structure:

2. The method of claim 1, wherein:

R¹, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, —

B(OH)₂, alkyl, alkenyl, alkynyl, halo, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, alkoxydialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylamino carbonyl, haloalkyl, haloalkloxy, haloalkylamino, or di(haloalkyl)amino; and

R⁸ and R⁹ are optionally cyclized to form cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally substituted with —

B(OH)₂, mild Lewis acid, strong acid, weak acid, alkyl, alkenyl, alkynyl, halo, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, alkoxydialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylamino carbonyl, haloalkyl, haloalkloxy, haloalkylamino, di(haloalkyl)amino or sugars.

3. The method of claim 1, wherein R² is —

B(OH)₂, hydroxyl or C₁-C₃ alkoxy.

4. The method of claim 1, wherein L is present and is:

5. The method of claim 1, wherein L is absent.

6. The method of claim 1, having the structure

7. The method of claim 6 wherein, R¹³ and R¹⁵ are hydrogen and R¹² and R¹⁴ are independently —

B(OH)₂, hydroxyl, C₁-C₃ alkoxy or C₁-C₃ alkoxydialkylamino.

8. The method of claim 1, wherein the compound has the structure:

9. The method of claim 1, wherein the deacetylase enzyme is SIRT1.

10. The method of claim 1, wherein cells of the subject under-express SIRT1.

11. The method of claim 1, wherein the subject has been diagnosed with cancer, wherein cancer cells of the subject express mutant p53, under-express SIRT1, have low SIRT1 activity, or combinations thereof.

12. The method of claim 1, wherein the subject has been diagnosed with prostate cancer, colon cancer, leukemia, non-small cell lung cancer, melanoma, CNS cancer, ovarian cancer, renal cancer, or breast cancer.

13. The method of claim 12, wherein the subject is diagnosed with colon cancer or prostate cancer.

14. The method of claim 1, wherein the subject has been determined to have an increased risk of colon cancer or prostate cancer.

15. The method of claim 1, wherein the disease is prostate cancer.

16. The method of claim 1, wherein the disease or condition is cardiovascular disease, obesity, diabetes, neurodegenerative disease, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, or inflammation.

17. The method of claim 1, wherein the disease or condition is other than cancer.

18. The method of claim 1, wherein cells of the subject have low SIRT1 activity.

19. The method of claim 1, wherein the compound has the structure:

20. The method of claim 1, wherein when R₂ or R₄ is —

B(OH)₂, R₃ is not alkoxy, and wherein when R₇ or R₉ is —

B(OH)₂, R₈ is not alkoxy.

21. The method of claim 20, wherein the compound has the structure: