Multifunctional radical quenchers for the treatment of mitochondrial dysfunction

1. A compound of formula:

wherein

X is halogen;

R 1 is hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, —OR 7 , —SR 7 , —NHR 7 , or —N(R 7 ) 2 , 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 heterocyclyl(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 2 is —OH, —O(C 1 -C 6 alkyl), —O(halo C 1 -C 6 alkyl), —NHR 11 , or —N(R 11 ) 2 ;

where each R u independently is C 4 -C 20 alkyl, C 4 -C 20 alkenyl, or C 4 -C 20 alkynyl;

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 ;

R 4 and R 5 are independently C 1 -C 20 alkyl, C 2 -C 20 alkenyl, or C 2 -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 heterocyclyl, 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, heterocyclyl, 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, 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 heterocyclyl(C 1 -C 6 alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R 9 .

2. The compound according to claim 1 , wherein X is Br or Cl.

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

4. The compound according to claim 1 , wherein R 2 is —OH.

5. The compound according to claim 1 , wherein R 2 is —NHR 11 or N(R 11 ) 2 .

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

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

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

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

10. The compound according to claim 1 , wherein R 6 is —OR 10 ,

where R 10 is 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 heterocyclyl (C 1 -C 6 alkyl), wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with R 9 .

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

12. 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, obesity, Alzheimer's disease and Parkinson's disease.

13. A method for treating or protecting mitochondria with respiratory chain lesions, comprising administering to a subject in need of such treatment an effective amount of one or more compounds according to claim 1 .

14. The compound according to claim 1 , wherein R 1 is hydrogen.

15. The compound according to claim 1 , wherein R 3 is hydrogen.

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

17. The compound according to claim 1 , wherein R 5 is C 1 -C 20 alkyl.

18. The compound according to claim 1 , wherein R 6 is hydrogen.

19. The compound according to claim 1 wherein R 1 is hydrogen, R 3 is hydrogen, R 6 is hydrogen, R 4 is optionally substituted C 1 -C 20 alkyl, and R 5 is optionally substituted C 1 -C 20 alkyl.