Multifunctional radical quenchers for the treatment of mitochondrial dysfunction

Patent metadata

Field	Value
Publication number	US-9388163-B2
Application number	US-201514731950-A
Country	US
Kind code	B2
Filing date	Jun 5, 2015
Priority date	Apr 4, 2011
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

The present disclosure provides methods for identifying therapeutic agents that are multifunctional radical quenchers. It also provides compounds of formula:

and pharmaceutically acceptable salts thereof, compositions comprising these compounds, and methods of using these compounds in a variety of applications, such as treatment or suppression of diseases associated with decreased mitochondrial function resulting in diminished ATP production and/or oxidative stress and/or lipid peroxidation.

First claim

We claim:

1. A compound of formula:

wherein
R 3 is hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, or —OR 7 , each optionally substituted with one to four substituents selected from halogen, —CN, —NO 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), —OR 8 , —NR 8 2 , —CO 2 R 8 , —CONR 8 2 , C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, and heterocyclyl, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R 9 ;
where each R 7 independently is hydrogen, C 1 -C 6 alkyl, or halo(C 1 -C 6 alkyl);
where each R 8 independently is hydrogen, C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl(C 1 -C 6 alkyl), aryl(C 1 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), or heterocycle(C 1 -C 6 alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R 9 ;
where each R 9 independently is halogen, —CN, —NO 2 , —N 3 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, or diC 1 -C 6 alkylamino;

R 4 and R 5 are independently C 4 -C 20 alkyl, C 4 -C 20 alkenyl, or C 4 -C 20 alkynyl, each optionally substituted with one to four substituents selected from halogen, —CN, —NO 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), —OR 8 , —NR 8 2 , —CO 2 R 8 , —CONR 8 2 , C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, and heterocycle, wherein each cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R 9 ;
each R 6 is hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, heterocycle, or —OR 10 , wherein each alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from halogen, —CN, —NO 2 , C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), —OR 8 , —NR 8 2 , —CO 2 R 8 , —CONR 8 2 , C 3 -C 8 cycloalkyl optionally substituted with R 9 , C 3 -C 8 cycloalkenyl optionally substituted with R 9 , aryl optionally substituted with R 9 , heteroaryl optionally substituted with R 9 , and heterocyclyl optionally substituted with R 9 ;
where R 10 is C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, aryl, heteroaryl, heterocycle, aryl(C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl(C 1 -C 6 alkyl), aryl(C 1 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), or heterocycle(C 1 -C 6 alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocycles are optionally substituted with R 9 .

2. The compound according to claim 1 , wherein R 3 is hydrogen, optionally substituted C 1 -C 20 alkyl, or —OR 7 .

3. The compound according to claim 2 , wherein R 3 is hydrogen.

4. The compound according to claim 2 , wherein R 3 is optionally substituted C 1 -C 20 alkyl.

5. The compound according to claim 1 , wherein R 3 is C 1 -C 20 alkyl optionally substituted with —OR 8 , C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, or aryl, wherein each cycloalkyl, cycloalkenyl, and aryl are optionally substituted with R 9 .

6. The compound according to claim 5 , wherein R 3 is C 1 -C 20 alkyl optionally substituted with C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, or aryl, wherein each cycloalkyl, cycloalkenyl, and aryl are optionally substituted with R 9 .

7. The compound according to claim 1 , wherein R 3 is —OR 7 and R 7 is C 1 -C 6 alkyl.

8. The compound according to claim 1 , wherein R 4 is optionally substituted C 4 -C 20 alkyl.

9. The compound according to claim 8 , wherein R 4 is C 4 -C 20 alkyl.

10. The compound according to claim 1 , wherein R 5 is optionally substituted C 4 -C 20 alkyl.

11. The compound according to claim 10 , wherein R 5 is C 4 -C 20 alkyl.

12. The compound according to claim 1 , wherein R 6 is hydrogen or optionally substituted C 1 -C 20 alkyl.

13. The compound according to claim 12 , wherein R 6 is hydrogen.

14. The compound according to claim 12 , wherein R 6 is C 1 -C 20 alkyl optionally substituted with —OR 8 , C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, or aryl, wherein each cycloalkyl, cycloalkenyl, and aryl are optionally substituted with R 9 .

15. The compound according to claim 14 , wherein R 6 is C 1 -C 20 alkyl optionally substituted with C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, or aryl, wherein each cycloalkyl, cycloalkenyl, and aryl are optionally substituted with R 9 .

16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt according to claim 1 and an acceptable carrier, excipient and/or diluent.

17. A method of treating or suppressing diseases associated with decreased mitochondrial function resulting in diminished ATP production and/or oxidative stress and/or lipid peroxidation, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt according to claim 1 , wherein the disease is selected from the group consisting of Friedreich's ataxia, Leber's Hereditary Optic Neuropathy, Kearns-Sayre Syndrome, Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes, Leigh syndrome, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease and Parkinson's disease.

18. A method according to claim 17 , wherein the disease is Friedreich's ataxia.

19. The compound of claim 1 , which is:

7-(didecylamino)-3H-phenothiazine-3-one; or

7-(dipentylamino)-3H-phenothiazin-3-one.

Assignees

• Hecht Sidney
• Khdour Omar
• Chowdhury Sandipan Roy
• Talukder Poulami
• Univ Arizona

Inventors

• Hecht Sidney
• Khdour Omar
• Chowdhury Sandipan Roy
• Talukder Poulami

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61P3/00

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

• A61P27/02

  Ophthalmic agents · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title