Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers

Abstract

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, such as alpha-tocopherol quinone. Methods and compounds useful in treating other disorders 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, 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 selected from the formula: 
       
         
           
           
               
               
           
         
       
       where R 11 , R 12 , and R 13  are independently selected from H, —C 1 -C 4  alkyl, —C 1 -C 4  haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R 11 , R 12 , and R 13  is H, then at least one of the other two substituents is neither H nor methyl; and all stereoisomers, mixtures of stereoisomers thereof. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       where R h  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       where the * indicates the point of attachment of R h  to the remainder of the molecule; 
       where R 1 , R 2 , and R 3  are independently selected from —C 1 -C 4  alkyl, —C 1 -C 4  haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that at least one of R 1 , R 2 , and R 3  is not methyl; and all stereoisomers, and mixtures of stereoisomers, prodrugs thereof. 
     
     
         6 . 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  claim 5 . 
     
     
         7 . The compound of  claim 5 , according to the formula: 
       
         
           
           
               
               
           
         
       
       and all stereoisomers, and mixtures of stereoisomers thereof. 
     
     
         8 . The method of  claim 6 , wherein the one or more compounds is selected from the formula: 
       
         
           
           
               
               
           
         
       
       and all stereoisomers, and mixtures of stereoisomers thereof. 
     
     
         9 . The compound of  claim 5 , according to the formula: 
       
         
           
           
               
               
           
         
       
       and all stereoisomers, and mixtures of stereoisomers. 
     
     
         10 . The method of  claim 6 , wherein the one or more compounds is selected from the formula: 
       
         
           
           
               
               
           
         
       
       and all stereoisomers, and mixtures of stereoisomers thereof. 
     
     
         11 . 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 formula IV: 
       
         
           
           
               
               
           
         
       
       where R 11 , R 12 , and R 13  are independently selected from H, —C 1 -C 4  alkyl, —C 1 -C 4  haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R 11 , R 12 , and R 13  is H, then at least one of the other two substituents is neither H nor methyl; and all stereoisomers, and mixtures of stereoisomers thereof. 
     
     
         12 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       where R 1 , R 2 , and R 3  are independently selected from —C 1 -C 4  alkyl, —C 1 -C 4    
       haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that at least one of R 1 , R 2 , and R 3  is not methyl; R 8  is independently selected from H and —C 1 -C 6  alkyl optionally substituted with —OR 9 , where R 9  is independently selected from H and —C 1 -C 6  alkyl; and all salts, stereoisomers, and mixtures of stereoisomers thereof. 
     
     
         13 . 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, by administering to a subject a therapeutically effective amount or effective amount of one or more compounds of  claim 12 . 
     
     
         14 . 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, by administering to a subject a therapeutically effective amount or effective amount of one or more compounds of formula VI: 
       
         
           
           
               
               
           
         
       
       where R 11 , R 12 , and R 13  are independently selected from H, —C 1 -C 4  alkyl, —C 1 -C 4    
       haloalkyl, —CN, —F, —Cl, —Br, and —I; R 8  is independently selected from H and —C 1 -C 6  alkyl optionally substituted with —OR 9 , where R 9  is independently selected from H and —C 1 -C 6  alkyl; 
       and all salts, stereoisomers, and mixtures of stereoisomers thereof. 
     
     
         15 . A compound selected from the group of compounds of the formulas: 
       
         
           
           
               
               
           
         
       
       where R 1 , R 2 , and R 3  are independently selected from —C 1 -C 4  alkyl, with the proviso that at least one of R 1 , R 2 , and R 3  is not methyl; and all salts, stereoisomers, and mixtures of stereoisomers. 
     
     
         16 . 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, by administering to a subject a therapeutically effective amount or effective amount of one or more compounds of  claim 15 . 
     
     
         17 . 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 formula X-O, formula X-R, formula XI-O, formula XI-R, formula XII-O, or formula XII-R: 
       
         
           
           
               
               
           
         
       
       where R 11 , R 12 , and R 13  are independently selected from H, —C 1 -C 4  alkyl, —C 1 -C 4    
       haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R 11 , R 12 , and R 13  is H, then at least one of the other two substituents is neither H nor methyl; and all salts, stereoisomers, and mixtures of stereoisomers thereof. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 6 , 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; other neurological diseases; epilepsy; genetic diseases; Huntington's Disease; mood disorders; schizophrenia; bipolar disorder; age-associated diseases; macular degeneration; diabetes; and cancer. 
     
     
         20 . The method of  claim 19 , 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). 
     
     
         21 . The method of  claim 6 , 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. 
     
     
         22 . A pharmaceutical composition comprising the compound of  claim 5 , and additionally comprising a pharmaceutically acceptable excipient. 
     
     
         23 . The method of  claim 6 , 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 recovering from surgery; a subject recovering from illness; 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. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 8 , 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; other neurological diseases; epilepsy; genetic diseases; Huntington's Disease; mood disorders; schizophrenia; bipolar disorder; age-associated diseases; macular degeneration; diabetes; and cancer. 
     
     
         26 . The method of  claim 10 , 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; other neurological diseases; epilepsy; genetic diseases; Huntington's Disease; mood disorders; schizophrenia; bipolar disorder; age-associated diseases; macular degeneration; diabetes; and cancer. 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled)