Mitoquinone derivatives used as mitochondrially targeted antioxidants
AssigneeAntipodean Pharmaceuticals, Inc.
InventorsKenneth Martin Taylor, Robin A. J. Smith
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Abstract
This invention relates to pharmaceutically acceptable amphiphilic antioxidant compounds, compositions and dosage forms comprising said compounds, and methods and uses 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, uses and methods are useful in, for example, the treatment of diseases or conditions associated with oxidative stress.
Claims52
A chemically stable antioxidant compound, comprising:
- a lipophilic cationic moiety linked by a linking moiety to an antioxidant moiety;
- and
- an anionic complement for said cationic moiety,
- wherein the cationic moiety is capable of mitochondrially targeting the antioxidant moiety,
- wherein the anionic complement is a pharmaceutically acceptable anion that is not a halogen ion or a nitrate anion and is selected from the group consisting of an alkyl sulfonate, an aryl sulfonate, tetrafluoroborate, trifluoromethanesulfonate, hexafluoroantimonate, hexafluoroarsenate, hexafluorophosphate, tetraphenylborate, and tetra(perfluorophenyl)borate, and does not exhibit reactivity against the antioxidant moiety, the cationic moiety or the linking moiety, and wherein the antioxidant compound exhibits less than 10% decomposition after 60 days at 25° C., 50% relative humidity, the antioxidant compound having the general 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, wherein R4 and R5 are independently selected from the group consisting of H, hydroxyl, carboxyl, amide, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl and unsubstituted or substituted alkynyl, and wherein n is an integer from 2 to 20, and wherein Z is the anionic complement.
A pharmaceutical composition, comprising:
- (a) a chemically stable antioxidant compound that comprises a lipophilic cationic moiety linked by a linking moiety to an antioxidant moiety;
- an anionic complement for said cationic moiety, wherein the cationic moiety is capable of mitochondrially targeting the antioxidant moiety, wherein the anionic complement is a pharmaceutically acceptable anion that is not a halogen ion or a nitrate anion and is selected from the group consisting of an alkyl sulfonate, an aryl sulfonate, tetrafluoroborate, trifluoromethanesulfonate, hexafluoroantimonate, hexafluoroarsenate, hexafluorophosphate, tetraphenylborate, and tetra(perfluorophenyl)borate, and does not exhibit reactivity against the antioxidant moiety, the cationic moiety or the linking moiety, and wherein the antioxidant compound exhibits less than 10% decomposition after 60 days at 25° C., 50% relative humidity, the antioxidant compound having the general formula I:
- or its quinol form, wherein R1, R2, and R3 are the same or different and are selected from C1to C5 alkyl, substituted C1 to C5 alkyl and H, wherein R4 and R5 are independently selected from the group consisting of H, hydroxyl, carboxyl, amide, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl and unsubstituted or substituted alkynyl, and wherein n is an integer from 2 to 20, and wherein Z is the anionic complement;
- and
- (b) a carrier or excipient.
A method of reducing oxidative stress in a cell, comprising:
- contacting a cell that comprises mitochondria with a chemically stable antioxidant compound that comprises (i) a lipophilic cationic moiety linked by a linking moiety to an antioxidant moiety, and (ii) an anionic complement for said cationic moiety, wherein the cationic moiety is capable of mitochondrially targeting the antioxidant moiety, wherein the anionic complement is a pharmaceutically acceptable anion that is not a halogen ion or a nitrate anion and is selected from the group consisting of an alkyl sulfonate, an aryl sulfonate, tetrafluoroborate, trifluoromethanesulfonate, hexafluoroantimonate, hexafluoroarsenate, hexafluorophosphate, tetraphenylborate, and tetra(perfluorophenyl)borate, and does not exhibit reactivity against the antioxidant moiety, the cationic moiety or the linking moiety, and wherein the antioxidant compound exhibits less than 10% decomposition after 60 days at 25° C., 50% relative humidity, under conditions and for a time sufficient for accumulation of the antioxidant compound in the mitochondria, and thereby reducing oxidative stress in the cell, the antioxidant compound having the general 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, wherein R4 and R5 are independently selected from the group consisting of H, hydroxyl, carboxyl, amide, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl and unsubstituted or substituted and wherein n is an integer from 2 to 20, and wherein Z is the anionic complement.
A method of preparing an antioxidant compound that is capable of reducing oxidative stress in a cell, comprising admixing cyclodextrin or a cyclodextrin derivative that is selected from β-cyclodextrin, sulfobutylcyclodextrin, maltosylcyclodextrin, and hydroxypropylcyclodextrin, with 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, wherein R4 and R5 are independently selected from the group consisting of H, hydroxyl, carboxyl, amide, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl and unsubstituted or substituted alkynyl, wherein n is an integer from 2 to 20, wherein Z is a pharmaceutically acceptable anion that is not a bromide ion or a nitrate anion and does not exhibit reactivity against any moiety of the compound of formula I, and wherein the compound exhibits less than 10% decomposition after 60 days at 25° C., 50% relative humidity.
A method of preparing an antioxidant compound that is capable of reducing oxidative stress in a cell, comprising admixing cyclodextrin or a cyclodextrin derivative that is selected from β-cyclodextrin, sulfobutylcyclodextrin, maltosylcyclodextrin, and hydroxypropylcyclodextrin, with a compound having the formula:
- or its quinol form, wherein the compound exhibits less than 10% decomposition after 60 days at 25° C., 50% relative humidity.
A method of synthesis of a compound having the formula
- or its quinol form, said method comprising reacting idebenol mesylate with triphenylphosphine, wherein the compound exhibits less than 10% decomposition after 60 days at 25° C., 50% relative humidity.
Dependencies are inferred from the claim text.