Therapeutic DNP derivatives and methods using same

Patent metadata

Field	Value
Publication number	US-11597697-B2
Application number	US-202217713759-A
Country	US
Kind code	B2
Filing date	Apr 5, 2022
Priority date	Aug 30, 2013
Publication date	Mar 7, 2023
Grant date	Mar 7, 2023

Abstract

The present invention includes DNP derivatives 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.

First claim

What is claimed is:

1. A method of ameliorating a disease or disorder in a subject in need thereof,
wherein the disease or disorder is at least one selected from the group consisting of hypertriglyceridemia, fatty liver, and insulin resistance,
the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
R 1 , R 2 , and R 3 are H;
X 1 is OR 4 ;
R 4 is independently selected from the group consisting of —C 1 -C 3 alkyl-(C 6 -C 10 aryl), —C 1 -C 3 alkyl-(C 3 -C 6 cycloalkyl), and —C 1 -C 3 alkyl-(C 5 -C 10 heteroaryl); and
wherein the aryl, cycloalkyl, or heteroaryl is independently optionally substituted by at least one substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, acetamido, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —OCF 3 , —OCH 2 CF 3 , and nitro.

2. The method of claim 1 , wherein R 4 is selected from the group consisting of —C 1 alkyl-(C 6 -C 10 aryl), —C 1 alkyl-(C 3 -C 6 cycloalkyl), and —C 1 alkyl-(C 5 -C 10 heteroaryl).

3. The method of claim 1 , wherein:
R 4 is —C 1 alkyl-(C 5 -C 10 heteroaryl), and
the C 5 -C 10 heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

4. The method of claim 1 , wherein:
R 4 is —C 1 alkyl-(C 5 -C 10 heteroaryl), and
the C 5 -C 10 heteroaryl is imidazolyl.

5. The method of claim 1 , wherein:
R 4 is -C 1 alkyl-(C 5 -C 10 heteroaryl),
the C 5 -C 10 heteroaryl is imidazolyl, and
the imidazolyl is substituted by at least one substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, acetamido, and nitro.

6. The method of claim 1 , wherein:
R 4 is —C 1 alkyl-(C 5 -C 10 heteroaryl),
the C 5 -C 10 heteroaryl is imidazolyl, and
the imidazolyl is substituted by at least one substituent selected from CH 3 and nitro.

7. The method of claim 1 , wherein the compound is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient.

8. The method of claim 7 , wherein the pharmaceutical composition is in the form of a tablet, dragee, liquid, drop, suppository, capsule, caplet, or gelcap.

9. The method of claim 8 , wherein the tablet comprises a multi-layered delayed release tablet.

10. The method of claim 1 , wherein the administering provides a non-toxic peak plasma 2,4-dinitrophenol (DNP) level of less than 380 μM in the subject.

Assignees

• Univ Yale

Inventors

• Shulman Gerald I
• Spiegel David A

Classifications

• C07C205/37 Primary

  the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom · CPC title

• A61K31/085

  having an ether linkage to aromatic ring nuclear carbon · CPC title

• C07J41/0055 Primary

  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 · CPC title