Boronic acid derivatives of resveratrol for activating deacetylase enzymes

Patent metadata

Field	Value
Publication number	US-2016166592-A1
Application number	US-201414902783-A
Country	US
Kind code	A1
Filing date	Jul 3, 2014
Priority date	Jul 3, 2013
Publication date	Jun 16, 2016
Grant date	—

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.

First claim

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:

wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 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;
R 8 and R 9 are optionally cyclized to form cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally substituted with —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;
L is

or L is absent when R 8 and R 9 are cyclized;
wherein at least one position in the compound is substituted with —B(OH) 2 , and at least one position in the compound is substituted with alkoxy, alkoxydialkylamino or hydroxyl, wherein the composition activates deacetylase enzymes.

2 . The method of claim 1 , wherein:
R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 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 R 8 and R 9 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 R 2 is —B(OH) 2 , hydroxyl or C 1 -C 3 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

wherein:
R 12 , R 13 , R 14 and R 15 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.

7 . The method of claim 6 wherein, R 13 and R 15 are hydrogen and R 12 and R 14 are independently —B(OH) 2 , hydroxyl, C 1 -C 3 alkoxy or C 1 -C 3 alkoxydialkylamino.

8 . The method of claim 1 , having the structure:

9 . The method of claim 1 , wherein the subject is in need of treatment of a disease or condition.

10 . The method of claim 9 , wherein the disease or condition is associated with expression of a deacetylase enzyme.

11 . The method of claim 10 , wherein the deacetylase enzyme is SIRT1.

12 . The method of claim 9 , wherein cells of the subject express mutant p53, under-express SIRT1, have low SIRT1 activity, or a combination.

13 . The method of claim 9 further comprising, prior to administering the composition to the subject, assaying a sample from the subject to determine if cells of the subject express mutant p53, under-express SIRT1, have low SIRT1 activity, or a combination.

14 . The method of claim 9 , 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 a combination.

15 . The method of claim 9 , 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.

16 . The method of claim 15 , wherein the subject is diagnosed with colon cancer or prostate cancer.

17 . The method of claim 9 , wherein the subject has been determined to have an increased risk of colon cancer or prostate cancer.

18 . The method of claim 9 , wherein the disease is prostate cancer.

19 . 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.

Assignees

• Univ Georgetown

Inventors

• Bae Insoo
• Yi Yong Weon
• Kang Hyo Jin
• Kim Hee Jeong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/69 Primary

  Boron compounds · CPC title