Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders

A method of treating or suppressing an oxidative stress disorder selected from the group consisting of:

• a mitochondrial disorder;
• an inherited mitochondrial disease;
• Alpers Disease;
• Barth syndrome;
• a Beta-oxidation Defect;
• Carnitine-Acyl-Carnitine Deficiency;
• Carnitine Deficiency;
• a Creatine Deficiency Syndrome;
• Co-Enzyme Q10 Deficiency;
• 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;
• Friedreich's Ataxia (FA);
• Glutaric Aciduria Type II;
• Kearns-Sayre Syndrome (KSS);
• Lactic Acidosis;
• Long-Chain Acyl-CoA Dehydrogenase Deficiency (LCAD);
• LCHAD;
• Leigh Syndrome;
• Leigh-like Syndrome;
• Leber's Hereditary Optic Neuropathy (LHON);
• 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;
• Parkinson's disease;
• amyotrophic lateral sclerosis (ALS);
• a motor neuron disease;
• epilepsy;
• macular degeneration;
• metabolic syndrome;
• brain cancer;
• Huntington's 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 muscular atrophy;
• hearing loss;
• noise induced hearing loss;
• traumatic brain injury;
• Juvenile Huntington's Disease;
• Multiple Sclerosis;
• NGLY1;
• Multisystem atrophy;
• Adrenoleukodystrophy;
• and Adrenomyeloneuropathy;
• comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):
• wherein:
• R1 and R2 are independently selected from the group consisting of:
• —C1-C4 alkyl, —O—C1-C4 alkyl, —H, and —C1-C4 haloalkyl, and R3 is selected from the group consisting of:
• —C1-C12 alkyl, —H, —O—C1-C12 alkyl, and —C1-C12 haloalkyl;
• or
• R1 and R2 are both —CH3 or R1 and R2 are both —OCH3, and R3 is selected from the group consisting of:
• wherein two or three of R1, R2, and R3 are not —H;
• n is 0, 1, 2, 3, or 4;
• R4, R5, R6, and R7 are independently selected from the group consisting of:
• —C1-C12 haloalkyl, —C(O)—N(R13)(R14), —C1-C12 alkyl, —H, —OH, —C2-C12 alkenyl, —O—C1-C12 alkyl, —O—C(O)—C1-C12 alkyl, —O—C1-C12 haloalkyl, —C6-C10 aryl, —O—C6-C10 aryl, —C1-C6 alkyl-C6-C10 aryl, —O—C1-C6 alkyl-C6-C10 aryl, —N—(R8)(R9), —C(O)—O—C1-C12 alkyl, —S(O)2—C1-C12 alkyl,
• with the proviso that at least two of R4, R5, R6, and R7 are independently selected from the group consisting of:
• —H and —CH3;
• R8 and R9 are independently —H or —C1-C12 alkyl;
• R13 is —H or —C1-C4 alkyl;
• R14 is —C1-C12 alkyl optionally substituted with hydroxy, —O—C1-C4, heterocyclyl, aryl, or heteroaryl, or wherein R14 is —C1-C15 alkyl wherein two or more of the carbons in the alkyl group have been replaced by oxygen;
• m is 0, 1, 2, or 3;
• and
• R11 is S;
• or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

A compound of formula (I):

• wherein:
• R1 and R2 are both —CH3 or R1 and R2 are both —OCH3, and R3 is selected from the group consisting of:
• n is 0, 1, 2, 3, or 4;
• R4, R5, R6, and R7 are independently selected from the group consisting of:
• —C1-C12 haloalkyl, —C(O)—N(R13)(R14), —C1-C12 alkyl, —H, —OH, —C2-C12 alkenyl, —O—C1-C12 alkyl, —O—C(O)—C1-C12 alkyl, —O—C1-C12 haloalkyl, —C6-C10 aryl, —O—C6-C10 aryl, —C1-C6 alkyl-C6-C10 aryl, —O—C1-C6 alkyl-C6-C10 aryl, —N—(R8)(R9), —C(O)—O—C1-C12 alkyl, —S(O)2—C1-C12 alkyl,
• with the proviso that at least two of R4, R5, R6, and R7 are independently selected from the group consisting of:
• —H and —CH3;
• R8 and R9 are independently —H or —C1-C12 alkyl;
• R13 is —H or —C1-C4 alkyl;
• R14 is —C1-C12 alkyl optionally substituted with hydroxy, —O—C1-C4, heterocyclyl, aryl, or heteroaryl, or wherein R14 is —C1-C15 alkyl wherein two or more of the carbons in the alkyl group have been replaced by oxygen;
• m is 0, 1, 2, or 3;
• and
• R11 is S;
• or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.