Tail variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
View Patent ↗Methods of treating or suppressing mitochondrial diseases, such as Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), or Kearns-Sayre Syndrome (KSS) are disclosed, as well as compounds useful in the methods of the invention. Energy biomarkers useful in assessing the metabolic state of a subject and the efficacy of treatment are also disclosed.
1. A method of treating a mitochondrial disorder, modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers, comprising administering to a subject a therapeutically effective amount or effective amount of one or more compounds of the formulas:
where R 1 and R 2 are independently selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —CN, —F, —Cl, —Br, and —I;
R 3 is selected from —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —CN, —F, —Cl, and —I;
R 20 is independently selected from —C 1 -C 20 alkyl, —C 1 -C 20 alkenyl, —C 1 -C 20 alkynyl, and —C 1 -C 20 containing at least one double bond and at least one triple bond;
and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
2. The method of claim 1 , with the proviso that R 20 excludes C 6 n-alkyl, C 7 n-alkyl, and C 11 n-alkyl.
3. The method of claim 1 , where R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, and methyl-cyclopropane, where the point of attachment of R 1 to the remainder of the molecule can be at any location on the alkyl fragment;
where R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, and methyl-cyclopropane, where the point of attachment of R 2 to the remainder of the molecule can be at any location on the alkyl fragment;
where R 3 is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, and methyl-cyclopropane, where the point of attachment of R 3 to the remainder of the molecule can be at any location on the alkyl fragment;
where R 20 is independently selected from —C 1 -C 20 alkyl, —C 1 -C 20 alkenyl, —C 1 -C 20 alkynyl, and —C 1 -C 20 containing at least one double bond and at least one triple bond
and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
4. The method of claim 3 , with the proviso that R 20 excludes C 6 n-alkyl, C 7 n-alkyl, and C 11 n-alkyl.
5. The method of claim 1 , wherein at least one of R 1 , R 2 , and R 3 is not methyl.
6. The method of claim 2 , wherein at least one of R 1 , R 2 , and R 3 is not methyl.
7. The method of claim 3 , wherein at least one of R 1 , R 2 , and R 3 is not methyl.
8. The method of claim 4 , wherein at least one of R 1 , R 2 , and R 3 is not methyl.
9. The method of claim 1 , wherein the mitochondrial disorder is selected from the group consisting of inherited mitochondrial diseases; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); Leigh Disease; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA); other myopathies; cardiomyopathy; encephalomyopathy; renal tubular acidosis; neurodegenerative diseases; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); motor neuron diseases; epilepsy; Huntington's Disease; mood disorders; schizophrenia; bipolar disorder; macular degeneration; diabetes; and lung cancer.
10. The method of claim 1 , wherein the mitochondrial disorder is selected from the group consisting of inherited mitochondrial diseases; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); Leigh Disease; Kearns-Sayre Syndrome (KSS); and Friedreich's Ataxia (FA).
11. The method of claim 1 , wherein the energy biomarker is selected from the group consisting of: lactic acid (lactate) levels, either in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; pyruvic acid (pyruvate) levels, either in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; lactate/pyruvate ratios, either in whole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid; phosphocreatine levels, NADH (NADH+H + ) levels; NADPH (NADPH+H + ) levels; NAD levels; NADP levels; ATP levels; reduced coenzyme Q (CoQ red ) levels; oxidized coenzyme Q (CoQ ox ) levels; total coenzyme Q (CoQ tot ) levels; oxidized cytochrome C levels; reduced cytochrome C levels; oxidized cytochrome C/reduced cytochrome C ratio; acetoacetate levels, β-hydroxy butyrate levels, acetoacetate/β-hydroxy butyrate ratio, 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels; levels of reactive oxygen species; levels of oxygen consumption (VO2); levels of carbon dioxide output (VCO2); respiratory quotient (VCO2/VO2); exercise tolerance; and anaerobic threshold.
12. The method of claim 1 , wherein the subject is selected from the group consisting of: a subject with a mitochondrial disease; a subject undergoing strenuous or prolonged physical activity; a subject with chronic energy problems; a subject with chronic respiratory problems; a pregnant female; a pregnant female in labor; a neonate; a premature neonate; a subject exposed to an extreme environment; a subject exposed to a hot environment; a subject exposed to a cold environment; a subject exposed to an environment with lower-than-average oxygen content; a subject exposed to an environment with higher-than-average carbon dioxide content; a subject exposed to an environment with higher-than-average levels of air pollution; a subject with lung disease; a subject with lower-than-average lung capacity; a tubercular patient; a lung cancer patient; an emphysema patient; a cystic fibrosis patient; a subject undergoing acute trauma; a subject in shock; a subject requiring acute oxygen administration; a subject requiring chronic oxygen administration; an elderly subject; an elderly subject experiencing decreased energy; and a subject suffering from chronic fatigue.
13. A compound of the formula:
where R 1 is selected from —C 1 -C 4 alkyl, —C 1 -C 4 perhaloalkyl, —CN, —F, -and —Br;
R 2 is selected from —C 1 -C 4 alkyl, —C 1 -C 4 perhaloalkyl, —CN, —F, —Cl,—Br, and —I;
R 3 is selected from —C 1 -C 4 alkyl, —C 1 -C 4 perhaloalkyl, —CN, —F, —Cl, and —I;
R 20 is independently selected from —C 1 -C 20 alkyl, —C 1 -C 20 alkenyl, —C 1 -C 20 alkynyl, and —C 1 -C 20 containing at least one double bond and at least one triple bond;
with the proviso that R 20 excludes C 6 n-alkyl, C 7 n-alkyl, and C 11 n-alkyl when R 1 , R 2 , and R 3 are all methyl; and all salts, stereoisomers, mixtures, of stereosoisomers, and prodrugs thereof.
14. A compound of claim 13 , where R 20 excludes C 6 n-alkyl, C 7 n-alkyl, and C 11 n-alkyl for any selections of R 1 , R 2 , and R 3 .
15. A compound of claim 13 , where R 1 is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, and methyl-cyclopropane, where the point of attachment of R 1 to the remainder of the molecule can be at any location on the alkyl fragment;
where R 2 is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, and methyl-cyclopropane, where the point of attachment of R 2 to the remainder of the molecule can be at any location on the alkyl fragment;
and where R 3 is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl, and methyl-cyclopropane, where the point of attachment of R 3 to the remainder of the molecule can be at any location on the alkyl fragment;
and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
16. A compound of claim 13 , wherein at least one of R 1 , R 2 , and R 3 is not methyl, and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
17. A compound of claim 16 , wherein R 1 , R 2 , and R 3 are independently selected from C 2 -C 4 alkyl, and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
18. A compound of claim 13 , wherein one and only one of R 1 , R 2 , and R 3 is methyl, and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
19. A compound of claim 13 , wherein two and only two of R 1 , R 2 , and R 3 are methyl, and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
20. A compound of claim 13 , wherein all of R 1 , R 2 , and R 3 are methyl, and all salts, stereoisomers, mixtures of stereoisomers, and prodrugs thereof.
21. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier.