Benzoquinone derivatives for treating oxidative stress disorders

Abstract

Disclosed herein are compounds and methods of using such compounds for treating or suppressing oxidative stress disorders, including mitochondrial disorders, impaired energy processing disorders, neurodegenerative diseases and diseases of aging, or for modulating one or more energy biomarkers, normalizing one or more energy biomarkers, or enhancing one or more energy biomarkers, wherein the compound is a compound of Formula I or Formula II: wherein: R 1 and R 2 are independently hydrogen, (C 1 -C 6 )alkyl or —O(C 1 -C 6 )alkyl; or R 1 and R 2 together represent —CH═CH—CH═CH—; R 3 is (C1-C6)alkyl; X is —CH═CH— or —C≡C—; m is 1-10; n is 1-5; k is 1-3, with the proviso that when k is an integer of 2 or 3, n is independently 1-5 in each occurrence of the —X—(CH 2 ) n — group; Y is —OR 4 , —CN, —C(═O)OR 5 , —C(═O)R 5 , or —C(═O)N(R 6 ) 2 ; R 4 and R 5 are independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 1 -C 6 )haloalkyl, —C(═O)—NH(C 1 -C 6 )alkyl, —C(═O)—N((C 1 -C 6 )alkyl) 2 , —C(═O)—NH 2 , and phenyl, wherein the phenyl group may optionally be substituted with a substituent selected from the group consisting of —(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, and halo; each R 6 is independently hydrogen or —(C 1 -C 6 )alkyl; and M is —H, —C(O)—R 7 or —C(O)O—R 7 , wherein R 7 is —(C 1 -C 6 )alkyl or phenyl; or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, crystalline form, non-crystalline form, hydrate or solvate thereof.

1 . A method of treating or suppressing 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 in need of such treatment a therapeutically effective amount or effective amount of a compound of Formula I or Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently hydrogen, (C 1 -C 6 )alkyl or —O(C 1 -C 6 )alkyl; or R 1  and R 2  together represent —CH═CH—CH═CH—; 
         R 3  is (C 1 -C 6 )alkyl; 
         X is —CH═CH— or —C═C—; 
         m is 1-10; 
         n is 1-5; 
         k is 1-3, with the proviso that when k is an integer of 2 or 3, n is independently 1-5 in each occurrence of the —X—(CH 2 ) n — group; 
         Y is —OR 4 , —CN, —C(═O)OR 5 , —C(═O)R 5 , or —C(═O)N(R 6 ) 2 ; 
         R 4  and R 5  are independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 1 -C 6 )haloalkyl, —C(═O)—NH(C 1 -C 6 )alkyl, —C(═O)—N((C 1 -C 6 )alkyl) 2 , —C(═O)—NH 2 , and phenyl, wherein the phenyl group is may optionally substituted with a substituent independently selected from the group consisting of —(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, and halo; 
         each R 6  is independently hydrogen or —(C 1 -C 6 )alkyl; and 
         M is —H, —C(O)—R 7  or —C(O)O—R 7 , wherein R 7  is —(C 1 -C 6 )alkyl or phenyl; 
         or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, crystalline form, non-crystalline form, hydrate or solvate thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the compound is a compound of Formula I. 
     
     
         4 . The method of  claim 1 , wherein X is —CH═CH—. 
     
     
         5 . The method of  claim 1 , wherein X is —C≡C—. 
     
     
         6 . The method of  claim 1 , wherein m is 1-5. 
     
     
         7 . The method of  claim 1 , wherein m is 4. 
     
     
         8 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein Y is —OR 4 . 
     
     
         14 . The method of  claim 13 , wherein R 4  is H. 
     
     
         15 . The method of  claim 1 , wherein Y is —CN. 
     
     
         16 . The method of  claim 1 , wherein Y is —C(═O)OR 5 . 
     
     
         17 . The method of  claim 16 , wherein R 5  is H. 
     
     
         18 . The method of  claim 1 , wherein Y is —C(═O)N(R 6 ) 2 . 
     
     
         19 . The method of  claim 18 , wherein R 6  is independently H or CH 3 . 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein R 1 , R 2  and R 3  are independently —(C 1 -C 4 )alkyl. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein R 1  and R 2  together represent —CH═CH—CH═CH—. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the compound is selected from the group consisting of:
 2-(12-hydroxydodeca-5,8-dien-1-yl)-3, 5,6-trimethylcyclohexa-2,5-diene-1,4-dione;   2-(10-hydroxydeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;   2-(12-hydroxydodeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;   2-(10-hydroxydeca-5,8-dien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;   2-(9-hydroxynon-5-yn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;   2-(11-hydroxyundeca-5, 8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;   13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynenitrile;   13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynoic acid;   13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienenitrile;   13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienoic acid;   N,N-dimethyl-13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide;   13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide;   2-(12-hydroxydodeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione;   2-(11-hydroxyundeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione;   2-(10-hydroxydeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione; and   2-(10-hydroxydeca-5,8-dien-1-yl)-3-methylnaphthalene-1,4-dione;   or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, crystalline form, non-crystalline form, hydrate or solvate thereof.   
     
     
         26 . The method of  claim 1 , wherein the compound is 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, crystalline form, non-crystalline form, hydrate or solvate thereof. 
     
     
         27 - 30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein the compound is administered as a pharmaceutical formulation comprising the compound and a pharmaceutically acceptable excipient. 
     
     
         32 . The method of  claim 1 , wherein the method is a method of treating or suppressing an oxidative stress disorder selected from the group consisting of: Alpers Disease; Barth syndrome; a Beta-oxidation Defect; Carnitine-Acyl-Carnitine Deficiency; Carnitine Deficiency; a Creatine Deficiency Syndrome; Complex I Deficiency; Complex II Deficiency; Complex III Deficiency; Complex IV Deficiency; Complex V Deficiency; COX Deficiency; chronic progressive external ophthalmoplegia (CPEO); CPT I Deficiency; CPT II Deficiency; Glutaric Aciduria Type II; Kearns-Sayre Syndrome (KSS); Lactic Acidosis; Long-Chain Acyl-CoA Dehydrogenase Deficiency (LCAD); LCHAD; Leigh Syndrome; Leigh-like Syndrome; Lethal Infantile Cardiomyopathy (LIC); Luft Disease; Multiple Acyl-CoA Dehydrogenase Deficiency (MAD); Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS);
 Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Recessive Ataxia Syndrome (MIRAS); Mitochondrial Cytopathy, Mitochondrial DNA Depletion; Mitochondrial Encephalopathy; Mitochondrial Myopathy; Myoneurogastrointestinal Disorder and Encephalopathy (MNGIE); Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP);   Pearson Syndrome; Pyruvate Carboxylase Deficiency; Pyruvate Dehydrogenase Deficiency; a POLG Mutation; a Respiratory Chain Disorder; Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCAD); SCHAD; Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD); a myopathy; cardiomyopathy; encephalomyopathy; a neurodegenerative disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); a motor neuron disease; a neurological disease; epilepsy; an age-associated disease; macular degeneration; diabetes; metabolic syndrome; cancer; brain cancer; a genetic disease; a mood disorder; schizophrenia; bipolar disorder; a pervasive developmental disorder; autistic disorder; Asperger's syndrome; childhood disintegrative disorder (CDD); Rett's disorder; PDD-not otherwise specified (PDD-NOS); a cerebrovascular accident; stroke; a vision impairment; optic neuropathy; dominant inherited juvenile optic atrophy; optic neuropathy caused by a toxic agent; glaucoma; Stargardt's macular dystrophy; diabetic retinopathy; diabetic maculopathy; retinopathy of prematurity; ischemic reperfusion-related retinal injury; oxygen poisoning; a haemoglobinopathy; thalassemia; sickle cell anemia; seizures; ischemia; renal tubular acidosis; attention deficit/hyperactivity disorder (ADHD); a neurodegenerative disorder resulting in hearing or balance impairment; Dominant Optic Atrophy (DOA); Maternally inherited diabetes and deafness (MIDD); chronic fatigue; contrast-induced kidney damage; contrast-induced retinopathy damage; Abetalipoproteinemia; retinitis pigmentosum; Wolfram's disease; Tourette syndrome; cobalamin c defect; methylmalonic aciduria; glioblastoma; Down's syndrome; acute tubular necrosis; a muscular dystrophy; a leukodystrophy; Progressive Supranuclear Palsy; spinal muscle atrophy; hearing loss; noise induced hearing loss; and traumatic brain injury.   
     
     
         33 - 88 . (canceled) 
     
     
         89 . The method of  claim 1 , wherein the mitochondrial disorder is an inherited mitochondrial disease.