Compositions and methods for preparing and using mitochondrial uncouplers

Patent metadata

Field	Value
Publication number	US-11896591-B2
Application number	US-201816615567-A
Country	US
Kind code	B2
Filing date	May 22, 2018
Priority date	May 22, 2017
Publication date	Feb 13, 2024
Grant date	Feb 13, 2024

Abstract

This disclosure provides compounds of Formula I, II, and III and pharmaceutically acceptable salts thereof for use as mitochondrial uncouplers, where the variables, e.g. R 1 -R 9 ,

X 1 , X 2 , and Y 1 are defined in the specification. The disclosure also provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formula I, II, or III, alone or in combination with another active compound. Compounds and compositions of Formula I, II, and III are useful for treating or preventing certain conditions such as obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH). Compounds of Formula I, II, and III are also useful for regulating glucose homeostatis and insulin action.

First claim

What is claimed is:

1. A compound or pharmaceutically acceptable salt thereof, wherein the compound is
N 5 -(2-fluorophenyl)-N 6 -(pyridin-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4b);
N 5 -(2-fluorophenyl)-N 6 -(3-fluorophenyl)-[1,2,]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4c);
N 5 -(2,3-difluorophenyl)-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4e);
N 5 -(2,4-difluorophenyl)-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4f);
N 5 -(2-fluorophenyl)-N 6 -(o-tolyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4g);
N 5 -(2-fluorophenyl)-N 6 -(m-tolyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4h);
N 5 -(2-fluorophenyl)-N 6 -(3-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4k);
N 5 -(2-fluorophenyl)-N 6 -(4-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4l);
N 5 -(2-ethoxyphenyl)-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4m);
N 5 -(3-ethoxyphenyl)-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4n);
N 5 -(4-ethoxyphenyl)-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4o);
3-((6-(2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenol (4p);
N 5 -(2-fluorophenyl)-N 6 -(2-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4q);
N 5 -(2-fluorophenyl)-N 6 -(3-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4r);
N 5 -(2-fluorophenyl)-N 6 -(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4s);
2,2,2-Trifluoro-N-(4-((6-(2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenyl)acetamide (4t);
N 5 -(2-fluorophenyl)-N 6 -(2-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4u);
N 5 -(2-fluorophenyl)-N 6 -(3-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4v);
N 5 -(2-fluorophenyl)-N 6 -(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4w);
Methyl 4-((6-((2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)benzoate (4y);
4-Fluoro-3-((6-((2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenol (4z);
N 5 -(3,5-bis(trifluoromethyl)phenyl)-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4aa);
N 5 -(2-fluoro-3-(trifluoromethyl)phenyl)-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4bb);
N 5 -(2-fluorophenyl)-N 6 -methyl[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7a);
N 5 -ethyl-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7b);
N 5 -(2-fluorophenyl)-N 6 -propyl[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7c);
N 5 -(2-fluorophenyl)-N 6 -(3,3,3-trifluoropropyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7d);
N 5 -(2-fluorophenyl)-N 6 -(1-methylpiperidin-4-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7e); or
N 5 -cyclohexyl-N 6 -(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7f).

2. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 as a first active agent, a pharmaceutically acceptable carrier, and optionally an additional active agent.

3. A method of therapeutically treating a condition responsive to mitochondrial uncoupling, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1 to a patient in need of such treatment.

4. The method of claim 3 , wherein the condition responsive to mitochondrial uncoupling is obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), or non-alcoholic steatohepatitis (NASH).

5. A method of regulating glucose homeostasis or insulin action in a patient comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1 to a patient in need thereof.

6. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound of claim 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A method of therapeutically treating a condition responsive to mitochondrial uncoupling, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 6 to a patient in need of such treatment.

9. The method of claim 8 , wherein the condition responsive to mitochondrial uncoupling is obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), or non-alcoholic steatohepatitis (NASH).

10. The method of claim 8 , wherein the condition responsive to mitochondrial uncoupling is non-alcoholic steatohepatitis (NASH).

11. A method of regulating glucose homeostasis or insulin action in a patient comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 6 to the patient.

Assignees

• Univ Virginia Patent Foundation
• Virginia Tech Intellectual Properties Inc
• Newsouth Innovations Pty Ltd

Inventors

• Hoehn Kyle
• Santos Webster L
• Childress Elizabeth S
• Dai Yumin
• Murray Jacob
• Santiago-Rivera Jose

Classifications

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title