Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
AssigneePTC Therapeutics, Inc.
InventorsGuy M. Miller, Sidney M. HECHT
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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.
Claims31
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 R11, R12, and R13 are independently selected from H, —C1-C4 alkyl, —C1-C4 haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R11, R12, and R13 is H, then at least one of the other two substituents is neither H nor methyl;
- and all stereoisomers, mixtures of stereoisomers thereof.
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A compound of the formula:
- where Rh is selected from the group consisting of:
- where the * indicates the point of attachment of Rh to the remainder of the molecule;
- where R1, R2, and R3 are independently selected from —C1-C4 alkyl, —C1-C4 haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that at least one of R1, R2, and R3 is not methyl;
- and all stereoisomers, and mixtures of stereoisomers, prodrugs thereof.
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 R11, R12, and R13 are independently selected from H, —C1-C4 alkyl, —C1-C4 haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R11, R12, and R13 is H, then at least one of the other two substituents is neither H nor methyl;
- and all stereoisomers, and mixtures of stereoisomers thereof.
A compound of the formula:
- where R1, R2, and R3 are independently selected from —C1-C4 alkyl, —C1-C4
- haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that at least one of R1, R2, and R3 is not methyl;
- R8 is independently selected from H and —C1-C6 alkyl optionally substituted with —OR9, where R9 is independently selected from H and —C1-C6 alkyl;
- and all salts, stereoisomers, and mixtures of stereoisomers thereof.
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 R11, R12, and R13 are independently selected from H, —C1-C4 alkyl, —C1-C4
- haloalkyl, —CN, —F, —Cl, —Br, and —I;
- R8 is independently selected from H and —C1-C6 alkyl optionally substituted with —OR9, where R9 is independently selected from H and —C1-C6 alkyl;
- and all salts, stereoisomers, and mixtures of stereoisomers thereof.
A compound selected from the group of compounds of the formulas:
- where R1, R2, and R3 are independently selected from —C1-C4 alkyl, with the proviso that at least one of R1, R2, and R3 is not methyl;
- and all salts, stereoisomers, and mixtures of stereoisomers.
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 R11, R12, and R13 are independently selected from H, —C1-C4 alkyl, —C1-C4
- haloalkyl, —CN, —F, —Cl, —Br, and —I, with the proviso that if any of R11, R12, and R13 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.
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Dependencies are inferred from the claim text.