Methods of treating disorders associated with castor

Patent metadata

Field	Value
Publication number	US-11547709-B2
Application number	US-201816957996-A
Country	US
Kind code	B2
Filing date	Dec 26, 2018
Priority date	Dec 27, 2017
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The present disclosure relates to methods of treating a coenzyme A reduction, elevation, sequestration, toxicity, or redistribution (CASTOR) disease such as, for example, defects in fatty acid oxidation enzymes, methylmalonic acidemia, glutaric acidemia, propionic academia, and HMG-CoA lyase, via small molecule modulators of CoA levels. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A method of treating propionic acidemia (PA) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure represented by a formula:

or a pharmaceutically acceptable salt thereof,
wherein:
A is CH 2 ;
Q 1 is CH; and R 2 is selected from —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy; or
Q 1 is N; and R 2 is selected from halogen, —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy;
Q 2 is a structure selected from:

each of R 3a and R 3b is independently selected from hydrogen, halogen, —OH, C1-C4 alkoxy, and C1-C4 alkyl; and
R 23 is selected from halogen and —CN.

2. The method of claim 1 , wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the subject is a mammal.

5. The method of claim 1 , wherein the mammal is a human.

6. The method of claim 1 , further comprising the step of administering to the subject a therapeutically effective amount of carnitine, pantothenate, and/or pantothenic acid.

7. The method of claim 1 , wherein the PA is hereditary.

8. The method of claim 1 , wherein the PA is acquired.

9. A kit for treating propionic acidemia (PA) in a subject in need thereof, comprising:
(a) an effective amount of a compound of claim 1 ; and
(b) at least one agent known to treat the PA,
together with instructions for effective administration.

10. The kit of claim 9 , wherein the at least one agent is carnitine, pantothenate, or pantothenic acid.

11. The kit of claim 9 , wherein the compound is represented by the formula:

or a pharmaceutically acceptable salt thereof.

12. The kit of claim 9 , wherein the compound is represented by the formula:

or a pharmaceutically acceptable salt thereof.

13. The kit of claim 9 , wherein the compound is represented by the formula:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein Q 1 is CH.

15. The method of claim 1 , wherein R 2 is cyclopropyl.

16. The method of claim 1 , wherein Q 2 is a structure:

17. The method of claim 1 , wherein the compound is represented by the formula:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is represented by the formula:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound is represented by the formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• St Jude Childrens Res Hospital Inc
• Coa Therapeutics Inc

Inventors

• Jackowski Suzanne
• Rock Charles O
• Lee Richard E
• Sharma Lalit Kumar
• Yun Mi Kyung
• Subramanian Chitra
• Tangallapally Rajendra P
• Edwards Anne V
• Zamboni Robert
• Reddy T Jagadeeswar
• Liu Jiuyu

Classifications

• A61K31/501 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/205

  Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine · CPC title

• A61K31/197

  the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) · CPC title

• A61P3/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title