4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
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-quinolyl)-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.
1. A method of treating a mitochondrial disorder, the method comprising contacting mitochondria in a cell of a subject with a therapeutically effective amount or effective amount of one or more compounds selected from Formula I:
where R is selected from the group consisting of
where the * indicates the point of attachment of R to the remainder of the molecule;
R 1 , R 2 , and R 3 are independently selected from hydrogen and C 1 -C 6 -alkyl;
R 4 is C 1 -C 6 -alkyl;
R 5 is hydrogen;
R 6 is selected from hydroxy, alkoxy, C 1 -C 40 -alkyl, C 2 -C 40 -alkenyl, C 2 -C 40 -alkynyl, and aryl;
where the alkyl, alkenyl, alkynyl, and aryl groups are optionally substituted with —OR 10 , —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , oxo, C 3 -C 6 -cycloalkyl, aryl, aryl-C 1 -C 6 -alkyl, 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 , —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents may be further substituted with C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl and —C(O)—O—C 1 -C 6 -alkyl; and where one of the carbons of the alkyl, alkenyl, or alkynyl groups may be substituted with a heteroatom selected from —O—, —N— or —S—; or
R 5 and R 6 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating 1, 2, or 3 additional N, O, or S atoms, optionally substituted with oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl; hydroxy-C 1 -C 6 -alkyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, —C(O)—OH, or —C(O)—O—C 1 -C 6 -alkyl; or
R 5 and R 6 together with the nitrogen atom to which they are attached form a N,N′-disubstituted piperazine where the nitrogen substitution at the 4-position is a group identical to the substitution at the 1-position forming a compound of formula Iaa or Ibb, where R 1 , R 2 , R 3 , and R 4 are as defined above:
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;
R 11 and R 11′ are selected from hydrogen and C 1 -C 6 -alkyl; and
M and M′ are independently selected from hydrogen, —C(O)—R 12 , —C(O)—C 1 -C 6 -alkenyl, —C(O)—C 1 -C 6 -alkynyl, —C(O)-aryl; —C(O)-heteroaryl, —C(O)O—R 12 , —C(O)NR 12 R 12 , —SO 2 OR 12 , —SO 2 —C 1 -C 6 -alkyl, —SO 2 -haloC 1 -C 6 -alkyl; —SO 2 -aryl, —SO 2 —NR 12 R 12 , —P(O)(OR 12 )(OR 12 ), and C-linked mono or di-peptide, where R 12 is hydrogen or C 1 -C 6 -alkyl optionally substituted with —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C(O)—OH, —C(O)—O—C 1 -C 4 -alkyl or halogen;
and a salt, a stereoisomer, and a mixture of stereoisomers thereof;
wherein the mitochondrial disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA) Parkinson's disease, and Huntington's Disease.
2. The method of claim 1 , where the one or more compounds are selected from compounds where R 5 is hydrogen and R 6 is C 1 -C 6 alkyl; and a salt, a stereoisomer, and a mixture of stereoisomers thereof.
3. The method of claim 1 , where the one or more compounds of Formula I are selected from Formula Ia:
and a salt, a stereoisomer, and a mixture of stereoisomers thereof.
4. The method of claim 3 , where the mitochondrial disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Leigh Disease; Friedreich's Ataxia (FA); encephalomyopathy; Parkinson's disease; amyotrophic lateral sclerosis (ALS); and Huntington's Disease.
5. The method of claim 3 , where the mitochondrial disease is selected from group consisting of Leber's Hereditary Optic Neuropathy (LHON); Leigh Disease; and Friedreich's Ataxia (FA).
6. The method of claim 1 , where in the one or more compounds of Formula I are selected from Formula Ib
R 1 , R 2 , and R 3 are each methyl;
R 4 is methyl;
and a salt, a stereoisomer, and a mixture of stereoisomers.
7. The method of claim 6 , where the one or more compounds is selected from compounds where R 5 is hydrogen and R 6 is C 1 -C 6 alkyl and a salt, a stereoisomer, and a mixture of stereoisomers.
8. The method of claim 3 , where the one or more compounds are selected from compounds 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 where the R 6 C 1 -C 6 -alkyl group is cyclic or a combination of cyclic and linear or branched; and a salt, a stereoisomer, and a mixture of stereoisomers thereof.
9. The method of claim 7 , where the one or more compounds are selected from compounds 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 where the R 6 C 1 -C 6 -alkyl group is cyclic or a combination of cyclic and linear or branched; and a salt, a stereoisomer, and a mixture of stereoisomers thereof.
10. The method of claim 1 , where the one or more compounds are selected from
N-(cyclopropylmethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-cyclopropyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-((tetrahydrofuran-2-yl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-(3-hydroxy-3-methyl-4-oxo-4-(piperidin-1-yl)butyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione; and
2-hydroxy-2-methyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide; and
a salt, a stereoisomer, and a mixture of stereoisomers thereof.
11. The method of claim 1 , wherein mitochondria in the cell in the subject are defective.
12. The method of claim 11 , wherein the contacting occurs in a tissue in the subject.
13. The method of claim 11 , wherein the contacting occurs in an organ in the subject.