Mitoquinone derivatives used as mitochondrially targeted antioxidants
AssigneeAntipodean Pharmaceuticals, Inc.
InventorsMichael Patrick Murphy, Robin Smith
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Abstract
This invention relates to methods to screen for, identify, select and synthesise amphiphilic mitochondrially targeted antioxidant compounds, and compositions, dosage forms and methods reliant on said compounds. The exemplified compounds are all mitoquinone derivatives, being methoxyphenyl alkyl triphenylphosphonium or methoxy dioxocyclohexadiene alkyl triphenylphosphonium derivatives. The compounds, compositions, dosage forms and methods are useful in, for example, the treatment of diseases or conditions associated with oxidative stress.
Claims40
A mitochondrially targeted antioxidant compound, comprising:
- a lipophilic cationic moiety linked by a linking moiety to an antioxidant moiety;
- and
- a salt forming anion that is not a bromide anion or a nitrate anion and does not exhibit reactivity against the lipophilic cationic moiety, the linking moiety or the antioxidant moiety, wherein the antioxidant compound accumulates within mitochondria of an intact cell, and wherein at least one of the linking moiety, the lipophilic cationic moiety and the antioxidant moiety is selected such that within mitochondria the antioxidant moiety resides at a desired location within said mitochondria.
A mitochondrially targeted antioxidant compound, comprising:
- a lipophilic cationic moiety linked by a linking moiety to an antioxidant moiety;
- and
- a salt forming anion that is not a bromide anion or a nitrate anion and does not exhibit reactivity against the lipophilic cationic moiety, the linking moiety or the antioxidant moiety, wherein the antioxidant compound accumulates within mitochondria of an intact cell, and wherein within said mitochondria the antioxidant moiety is at a distance from the lipophilic cationic moiety of between about 5 Angstroms and about 60 Angstroms.
A mitochondrially targeted antioxidant compound, comprising:
- a lipophilic cationic moiety linked by a linking moiety to an antioxidant moiety;
- and
- a salt forming anion that is not a bromide anion or a nitrate anion and does not exhibit reactivity against the lipophilic cationic moiety, the linking moiety or the antioxidant moiety, wherein the antioxidant compound has a partition coefficient of less than about 20 in octanol:water and accumulates within mitochondria of an intact cell.
A method of screening for a mitochondrially localizing amphiphilic antioxidant compound, comprising:
- (a) administering a candidate amphiphilic antioxidant compound to a mitochondrial preparation comprising deenergized mitochondria, to determine binding of the compound to mitochondria that substantially lack a mitochondrial membrane potential;
- (b) energizing the mitochondria of (a) to determine mitochondrial uptake of the candidate amphiphilic antioxidant compound in the presence of a mitochondrial membrane potential;
- (c) deenergizing the mitochondria to abolish the membrane potential;
- and
- (d) determining mitochondrial release of the candidate amphiphilic antioxidant compound in the absence of the mitochondrial membrane potential, wherein incomplete release of said compound indicates mitochondrial localization.
A method for synthesizing a compound of the formula I
- or its quinol form, wherein R1, R2, and R3, are the same or different and are selected from C1 to C5 alkyl, substituted C1 to C5 alkyl and H, and wherein n is an integer from 2 to 20, and wherein Z is a salt forming anion that is not a bromide anion or a nitrate anion and does not exhibit reactivity against the compound, the method comprising formation of the compound from triphenylphosphonium without a reaction solvent.
A method for synthesizing an antioxidant compound of the formula I
- or its quinol form, wherein R1, R2, and R3, are the same or different and are selected from C1 to C5 alkyl, substituted C1 to C5 alkyl and H, and wherein n is an integer from 2 to 20, and wherein Z is a salt forming anion that is not a bromide anion or a nitrate anion and does not exhibit reactivity against the compound, the method comprising a reaction of a reactant compound of the formula IV
- or its quinol form in the presence of Ph3PHX and Ph3P, where X is a halogen atom.
A method for synthesizing an antioxidant compound of the formula (2)
- or its quinol form, wherein Z is a salt forming anion that is not a bromide anion or a nitrate anion and does not exhibit reactivity against the compound, the method comprising a reaction of a reactant compound of the formula (3)
- in the presence of Ph3P and X, where X comprises a halogen atom.
Dependencies are inferred from the claim text.