4-(P-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases

Patent metadata

Field	Value
Publication number	US-10968166-B2
Application number	US-201816228657-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Nov 6, 2007
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

Methods of treating or suppressing mitochondrial diseases, such as Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Kearns-Sayre Syndrome (KSS), are disclosed, as well as compounds useful in the methods of the invention, such as 4-(p-quinoly)-2-hydroxybutanamide derivatives. Methods and compounds useful in treating other disorders such as amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, and pervasive developmental disorders such as autism are also disclosed. Energy biomarkers useful in assessing the metabolic state of a subject and the efficacy of treatment are also disclosed. Methods of modulating, normalizing, or enhancing energy biomarkers, as well as compounds useful for such methods, are also disclosed.

First claim

What is claimed is:

1. A compound of Formula A:

wherein:
R 5 is hydrogen, and R 6 is C 1 -C 6 -alkyl; where the alkyl group is optionally substituted with —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10 , C 3 -C 6 -cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—NR 11 R 11 , —C(O)—NH—C 0 -C 6 -alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl, and heterocyclyl ring substituents are optionally further substituted with halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl, or —C(O)—O—C 1 -C 6 -alkyl;
and where one of the carbons of the R 6 C 1 -C 6 -alkyl group is replaced with a heteroatom selected from the group consisting of —O—, —N—, and —S—;
and wherein the R 6 C 1 -C 6 -alkyl group is cyclic or a combination of cyclic and linear or branched;
R 10 and R 10′ are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, and —C(O)—C 1 -C 6 -alkyl-aryl; and
R 11 is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl;
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

2. The compound of claim 1 , where R 6 is unsubstituted; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

3. The compound of claim 1 , where the R 6 C 1 -C 6 -alkyl group is cyclic or a combination of cyclic and linear; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

4. The compound of claim 1 , where the R 6 C 1 -C 6 -alkyl group is cyclic; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

5. The compound of claim 1 , where one of the carbons of the R 6 C 1 -C 6 alkyl is replaced with —O— or —N—; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

6. The compound of claim 1 , where one of the carbons of the R 6 C 1 -C 6 -alkyl is replaced with an —O— or —N— and where the R 6 C 1 -C 6 -alkyl is cyclic or a combination of cyclic and linear; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

7. The compound of claim 1 , where one of the carbons of the R 6 C 1 -C 6 -alkyl is replaced with an —O— or —N— and where the R 6 C 1 -C 6 -alkyl is cyclic; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

8. The compound of claim 1 , where R 6 is cyclopentylmethyl, cyclopentyl, or cyclohexyl, and where one of the carbons of R 6 is replaced with —O— or —N—; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

9. The compound of claim 1 , which is 6-hydroxy-2,5,7,8-tetramethyl-N-((tetrahydrofuran-2-yl)methyl)chroman-2-carboxamide; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

Assignees

• Ptc Therapeutics Inc

Inventors

• Jankowski Orion D
• Wesson Kieron E
• Mollard Paul
• Shrader William D

Classifications

• C07D307/14

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07D295/24

  Oxygen atoms · CPC title

• C07D295/192

  from aromatic carboxylic acids · CPC title

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07D295/02

  containing only hydrogen and carbon atoms in addition to the ring hetero elements · CPC title