US 9,278,085 B2 · Side-chain variants of 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. 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.

A compound of the formula:

where n is an integer from 2-8 inclusive, and each unit is the same or different;
wherein the bonds indicated with dashed lines are single or double;
wherein R1, R2 and R3 are independently selected from the group consisting of —H, —C1-C5 alkyl, —C1-C5 haloalkyl, —C2-C5 alkenyl, —C2-C5 haloalkenyl, —C2-C5 alkynyl, and —C2-C5 haloalkynyl, and wherein at least one of R1, R2, and R3 is independently selected from the group consisting of —C1-C5 alkyl, —C1-C5 haloalkyl, —C2-C5 alkenyl, —C2-C5 haloalkenyl, —C2-C5 alkynyl, and —C2-C5 haloalkynyl;
with the proviso that when R2 is —C1-C5 alkyl and R1 is —H, then R3 is not —H;
where R4 is selected from the group consisting of —H, —OH, —S—R5, —F, —Cl, —I, and —NR5R6;
where X is selected from the group consisting of —H, —NR7R8, —OR9 and —(CH2)2C(CH3)2OH;
where R5 and R6 are independently selected from the group consisting of —H, —C1-C5 alkyl, —C3-C6 cycloalkyl, —C1-C5 haloalkyl, aryl, heteroaryl, —(C═O)—C1-C8 alkyl, —(C═O)—C1-C8 alkyl-C6-C10 aryl-C0-C8 alkyl, and —(C═O)—C0-C8 alkyl-C6-C10 aryl-C1-C8 alkyl, or where R5 and R6 selected from these groups are combined to form a ring;
where R7 and R8 are independently selected from the group consisting of —H, —C1-C8 alkyl, —C1-C8 haloalkyl, and —(C═O)—C1-C8 alkyl, or where either one of R7 and R8 is independently selected from the group consisting of —(C═O)—C1-C8 haloalkyl;
—(C═O)—NH2;
—(C═O)—NHC1-C8 alkyl;
—(C═O)—NHC1-C8 haloalkyl;
—(C═O)—NR20R21 where R20 is —(CH2)p—, R21 is —(CH2)q—, p and q are independently integers between 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R20 and R21 together with the nitrogen atom to which they are attached combine to form a 3- to 8-membered ring, and where another group selected from the group consisting of —NH—, —N(C1-C4 alkyl)-, —O—, and —S— is optionally incorporated in the ring formed by R20 and R21 and the nitrogen atom to which they are attached;
—(C═O)—OC1-C8 alkyl;
—(C═O)—OC1-C8 haloalkyl;
—S(O)2C1-C8 alkyl;
—S(O)2aryl;
and —S(O)2aralkyl;
and where the other of R7 and R8 is —H, —C1-C8 alkyl or —C1-C8 haloalkyl or where R7 and R8 selected from these groups are combined to form a ring, or where R7 is —(CH2)p—, R8 is —(CH2)q—, p and q are independently integers between 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R7 and R8 together with the nitrogen atom to which they are attached combine to form a 3- to 8-membered ring, and where another group selected from the group consisting of —NH—, —N(C1-C4 alkyl)-, —O—, and —S— is optionally incorporated in the ring formed by R7 and R8 and the nitrogen atom to which they are attached;
where R9 is independently selected from the group consisting of —H;
—C1-C8 alkyl;
—C1-C8 haloalkyl;
—(C═O)—C1-C8 alkyl;
—(C═O)—C1-C8 haloalkyl;
—(C═O)—NH2;
—(C═O)—NHC1-C8 alkyl;
—(C═O)—NHC1-C8 haloalkyl;
—(C═O)—NR20R21 where R20 is —(CH2)p—, R21 is —(CH2)q—, p and q are independently integers between 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R20 and R21 together with the nitrogen atom to which they are attached combine to form a 3- to 8-membered ring, and where another group selected from the group consisting of —NH—, —N(C1-C4 alkyl)-, —O—, and —S— is optionally incorporated in the ring formed by R20 and R21 and the nitrogen atom to which they are attached;
—(C═O)—OC1-C8 alkyl;
—(C═O)—OC1-C8 haloalkyl;
—S(O)2C1-C8 alkyl;
—S(O)2aryl;
and —S(O)2;
with the provisos that when n=3 and R4 is —H or —OH, then X is not —H, and that the compound is not
or any stereoisomer, mixture of stereoisomers, or salt thereof.

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Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers

Life of this patent

Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers

Life of this patent

Abstract

Claims14