Mitochondrial uncouplers for treatment of metabolic diseases and cancer

Patent metadata

Field	Value
Publication number	US-10227315-B2
Application number	US-201715599177-A
Country	US
Kind code	B2
Filing date	May 18, 2017
Priority date	May 18, 2016
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

The present disclosure relates to benzamide compounds, prodrugs of the compounds, pharmaceutical compositions containing the compounds and/or the prodrugs and methods of using the compounds, prodrugs and pharmaceutical compositions in the treatment of diseases related to lipid metabolism including diabetes, Non-Alcholic Fatty Liver Disease (NAFLD), Non-Alcholic Steathohepatitis (NASH), diseases caused by abnormal cell proliferation including cancer, psoriasis, and infectious diseases.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,
wherein:
R 1a is selected from the group consisting of hydrogen; optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; optionally substituted C 3 -C 10 cycloalkyl; optionally substituted C 3 -C 10 heterocyclyl; optionally substituted C 3 -C 10 aryl; optionally substituted C 3 -C 10 heteroaryl; C 1 -C 6 perfluoroalkyl; halo; cyano; nitro; optionally substituted amino; —C(O)NHR 5 ; —C(O)NR 5 R 6 ; —C(O)H; —C(O)R 7 ; —C(O)OH; and —C(O)OR 5 ;
R 1b and R 1d at each instance are independently selected from the group consisting of: hydrogen; C 1 -C 6 perfluoroalkyl; and halo;
R 1c is chloro;
R 2 is selected from the group consisting of hydrogen; mono-saccharide; di-saccharide; C(O)NR 5 R 6 ; and C(O)R 7 ; wherein the mono-saccharides and di-saccharide are attached to the phenolic oxygen at the anomeric center to form a glycosidic bond;
R 3 is hydrogen, or alternatively, R 2 and R 3 taken together are a carbonyl group and together with the atoms to which they are attached, form a six-membered heterocyclic carbamate;
R 4a , R 4b , R 4c and R 4d at each instance are independently selected from the group consisting of hydrogen; C 1 -C 6 perfluoroalkyl; cyano; nitro; and halo;
R 5 and R 6 at each instance are independently selected from the group consisting of optionally substituted C 1 -C 6 alkyl; and C 1 -C 6 alkylsulfonyl; alternatively R 5 and R 6 taken together with the nitrogen to which they are attached form an optionally substituted C 3 -C 6 heterocyclyl; and
R 7 is an optionally substituted C 3 -C 6 heterocyclyl;
with the following proviso: when R 2 is hydrogen, R 1a is optionally substituted C 1-6 alkyl.

2. The compound of claim 1 , according to formula (II):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. The compound of claim 1 , wherein R 1a is selected from the group consisting of hydrogen; C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl, (N,N-dimethylamino)C 1 -C 6 alkyl; and ((C 1 -C 6 alkylsulfonyl)amino)C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein:
R 2 is selected from; C(O)NR 5 R 6 ; and C(O)R 7 ;
alternatively, R 2 and R 3 taken together are a carbonyl group and together with the atoms to which they are attached, form a six-membered heterocyclic carbamate,
R 5 and R 6 taken together with the nitrogen to which they are attached form an optionally substituted C 3 -C 6 heterocyclyl; and
R 7 is 2-pyrrolidine.

5. The compound of claim 1 , wherein R 4b and R 4d at each instance are independently selected from the group consisting of: hydrogen; trifluoromethyl; cyano; nitro; and fluoro.

6. A compound selected from the group consisting of

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

7. A compound selected from the group consisting of

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

8. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

9. A pharmaceutical composition comprising a compound according to claim 2 , or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition comprising a compound according to claim 7 , or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

11. A compound selected from the group consisting of

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

12. A compound selected from the group consisting of,

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

13. A pharmaceutical composition comprising a compound according to claim 11 , or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

14. A pharmaceutical composition comprising a compound according to claim 12 , or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

15. A pharmaceutical composition comprising a compound according to claim 7 , or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

Assignees

• Univ Rutgers

Inventors

• Jin Shengkan
• Augeri David J
• Cao Bin
• Tao Hanlin

Classifications

• A61K31/536

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• C07C235/64

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title