THERAPEUTIC DNP DERIVATIVES AND METHODS USING SAME

• US 20160207873A1
• Filed: 08/28/2014
• Published: 07/21/2016
• Est. Priority Date: 08/30/2013
• Status: Active Grant

• Current Assignee: Yale University
• Original Assignee: Yale University
• Inventors: Shulman, Gerald I., Spiegel, David A.
• Granted Patent: US 10,457,629 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/085 having an ether linkage to aromatic ring nuclear carbon
• CPC Class Codes: C07C 205/37 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07J 41/0055 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives

Abstract

The present invention includes DNP derivatives of formula (I) that are useful for preventing or treating a metabolic disease or disorder in a subject in need thereof. In certain embodiments, the subject is further administered at least one additional therapeutic agent.

Claims

1. A compound of formula (I), or a salt, solvate, N-oxide thereof:

2. The compound of claim 1, which is selected from the group consisting of N-(2-hydroxy-3,5-dinitrobenzyl)-4-mercaptobutanamide, 2-(1-hydroxypropyl)-4,6-dinitrophenol, 4-(2,4-dinitrophenoxy)pentan-2-ol, 3-(2,4-dinitrophenoxy)cyclohexanol, 2,4-dinitrophenyl dihydrogen phosphate, 3-((4-((2,4-dinitrophenoxy)methyl)phenyl)disulfanyl)propanoic acid, 3-((4-((((4-((2,4-dinitrophenoxy)methyl)phenyl)carbamoyl)oxy)methyl)phenyl) disulfanyl)propanoic acid, (R)-4-((3R,5R,7R,8R,9S,10S,12S,13R,14S,17S)-3-(2-(3-((4-((2,4- dinitrophenoxy)methyl)phenyl)disulfanyl)propanamido)ethoxy)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)pentanoic acid, a salt, solvate, N-oxide thereof, and any combinations thereof.

3. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable carrier.

4. The composition of claim 3, further comprising at least one additional therapeutic agent.

5. A method of preventing or treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

6. The method of claim 5, wherein the compound is at least one selected from the group consisting of:

2,4-dinitrophenyl methyl ether, 2,4-dinitrophenyl boronic acid, 2,4-dinitrophenyl vinyl ether, 2,4-dinitrophenyl allyl ether, 2,4-dinitrophenyl isopropyl ether, 2,4-dinitrophenyl ethyl ether, 1-((4-methoxybenzyl)oxy)-2,4-dinitrobenzene, N-(2-hydroxy-3,5-dinitrobenzyl)-4-mercaptobutanamide, 2-(1-hydroxypropyl)-4,6-dinitrophenol, 4-(2,4-dinitrophenoxy)pentan-2-ol, 3-(2,4-dinitrophenoxy)cyclohexanol, (2,4-dinitrophenoxy)methyl dihydrogen phosphate, 2,4-dinitrophenyl dihydrogen phosphate, 3-((4-((2,4-dinitrophenoxy) methyl)phenyl)disulfanyl)propanoic acid, 3-((4-((((4-((2,4-dinitrophenoxy)methyl)phenyl)carbamoyl)oxy)methyl)phenyl)disulfanyl)propanoic acid, (R)-4-((3R,5R,7R,8R,9S,10S,12S, 13R,14S,17S)-3-(2-(3-((4-((2,4-dinitrophenoxy)methyl)phenyl)disulfanyl)propanamido)ethoxy)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid, a salt, solvate, or N-oxide thereof, and any combinations thereof.

7. The method of claim 5, wherein the disease or disorder is at least one selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes (T2D), acquired lipodystrophy, lipodystrophy (inherited), partial lipodystrophy, hypertriglyceridemia, obesity, metabolic syndrome, Rett'"'"'s syndrome, metabolic syndrome associated with aging, metabolic diseases associated with increased reactive oxygen species (ROS), Friedreich'"'"'s ataxia, and insulin resistance.

8. The method of claim 5, wherein the therapeutically effective amount of the compound of formula (I) is about 25 μ

moles/kg.

9. The method of claim 5, wherein the method further comprises administering to the subject at least one additional therapeutic agent.

10. The method of claim 9, wherein the pharmaceutical composition and the at least one additional therapeutic agent are co-administered to the subject.

11. The method of claim 10, wherein the pharmaceutical composition and the at least one additional therapeutic agent are co-formulated.

12. The method of claim 5, wherein the subject is a mammal.

13. The method of claim 12, wherein the mammal is human.

14. A method of increasing energy expenditure in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a salt, solvate, N-oxide thereof:

15. The method of claim 14, wherein the compound is at least one selected from the group consisting of:

2,4-dinitrophenyl methyl ether, 2,4-dinitrophenyl boronic acid, 2,4-dinitrophenyl vinyl ether, 2,4-dinitrophenyl allyl ether, 2,4-dinitrophenyl isopropyl ether, 2,4-dinitrophenyl ethyl ether, 1-((4-methoxybenzyl)oxy)-2,4-dinitrobenzene, N-(2-hydroxy-3,5-dinitrobenzyl)-4-mercaptobutanamide, 2-(1-hydroxypropyl)-4,6-dinitrophenol, 4-(2,4-dinitrophenoxy)pentan-2-ol, 3-(2,4-dinitrophenoxy)cyclohexanol, (2,4-dinitrophenoxy)methyl dihydrogen phosphate, 2,4-dinitrophenyl dihydrogen phosphate, 3-((4-((2,4-dinitrophenoxy)methyl)phenyl)disulfanyl)propanoic acid, 3-((4-((((4-((2,4-dinitrophenoxy)methyl)phenyl)carbamoyl)oxy)methyl)phenyl)disulfanyl)propanoic acid, (R)-4-((3R,5R,7R,8R,9S,10S,12S, 13R,14S,17S)-3-(2-(3-((4-((2,4-dinitrophenoxy)methyl)phenyl)disulfanyl)propanamido)ethoxy)-7,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid, a salt, solvate, or N-oxide thereof, and any combinations thereof.

16. The method of claim 14, wherein the therapeutically effective amount of the compound of formula (I) is about 25 μ

moles/kg.

17. The method of claim 14, wherein the subject is afflicted with at least one disease or disorder selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic steatosis, type 2 diabetes (T2D), acquired lipodystrophy, lipodystrophy (inherited), partial lipodystrophy, hypertriglyceridemia, obesity, metabolic syndrome, Rett'"'"'s syndrome, metabolic syndrome associated with aging, metabolic diseases associated with increased reactive oxygen species (ROS), Friedreich'"'"'s ataxia, and insulin resistance.

18. The method of claim 14, wherein the subject is a mammal.

19. The method of claim 18, wherein the mammal is human.