Catechol derivatives for treatment of oxidative stress diseases
View Patent ↗Methods of treating or suppressing oxidative stress disorders affecting normal electron flow in the cells, including mitochondrial diseases, impaired energy processing disorders, neurodegenerative diseases, diseases of aging and diseases caused by reactive oxygen species are disclosed, as well as compounds useful in the methods of the invention, such as such as catechol or ortho-quinone derivatives of Formula (I).
1. A compound of Formula I:
where X is selected from the group consisting of:
where the * indicates the point of attachment of X to the rest of the molecule;
each bond indicated by a dashed line is independently double or single;
m is 0 or 1;
n is 1 to 10;
R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, and halogen;
R 4 is OH and R 5 is hydrogen; or R 4 and R 5 are both hydrogen; and
R 6 is hydrogen, C 1 -C 6 -alkyl, —C(O)C 1 -C 6 -alkyl or —C(O)aryl;
or a salt, a stereoisomer, a mixture of stereoisomers, a solvate or a hydrate thereof.
2. The compound of claim 1 , having the formula Ia:
where,
each bond indicated by a dashed line is independently double or single;
m is 0 or 1;
n is 1 to 4;
R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, and halogen;
R 4 is OH and R 5 is hydrogen; or R 4 and R 5 are both hydrogen;
or a salt, a stereoisomer, a mixture of stereoisomers, a solvate or a hydrate thereof.
3. The compound of claim 1 , having the Formula Ib:
where,
each bond indicated by a dashed line is independently double or single;
m is 0 or 1;
n is 1 to 4;
R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, and halogen;
R 4 is OH and R 5 is hydrogen; or R 4 and R 5 are both hydrogen;
or a salt, a stereoisomer, a mixture of stereoisomers, a solvate or a hydrate thereof.
4. The compound of claim 1 , where m is 1 and n is 1-4.
5. The compound of claim 1 , where m is 0 and n is 1-4.
6. The compound of claim 1 , where R 4 and R 5 are both hydrogen.
7. The compound of claim 1 , where R 4 is OH and R 5 is hydrogen.
8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
9. The compound of claim 1 , wherein the compound is selected from the group consisting of:
4-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)benzene-1,2-diol;
4-(3-hydroxy-3,7,11,15,19-pentamethylicosa-6,10,14,18-tetraen-1-yl)benzene-1,2-diol;
4-(3-hydroxy-3,7,11-trimethyldodeca-6,10-dien-1-yl)benzene-1,2-diol;
4-(3-hydroxy-3,7-dimethyloct-6-en-1-yl)benzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3,5,6-trimethylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3,5-dimethylbenzene-1,2-diol;
5-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3,4-dimethylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3,6-dimethylbenzene-1,2-diol;
5-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3-methylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-5-methylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3-methylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5,6-trimethylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,5-dimethylbenzene-1,2-diol;
5-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,4-dimethylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3,6-dimethylbenzene-1,2-diol;
5-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3-methylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-5-methylbenzene-1,2-diol;
4-(3-hydroxy-3,7,11,15-tetramethylhexadecyl)-3-methylbenzene-1,2-diol;
4-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
3,4,6-trimethyl-5-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
3,4-dimethyl-5-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
3,6-dimethyl-4-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
3,5-dimethyl-4-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
4-methyl-5-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
3-methyl-5-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
3-methyl-4-(3,7,11,15-tetramethylhexadecyl)benzene-1,2-diol;
3-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)benzene-1,2-diol;
3-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-4,5,6-trimethylbenzene-1,2-diol;
6-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-3,4-dimethylbenzene-1,2-diol;
3-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-4,5-dimethylbenzene-1,2-diol;
3-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-4,6-dimethylbenzene-1,2-diol;
3-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-4-methylbenzene-1,2-diol;
3-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-5-methylbenzene-1,2-diol;
3-(3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)-6-methylbenzene-1,2-diol;
3-(3-hydroxy-3,7,11,15,19-pentamethylicosa-6,10,14,18-tetraen-1-yl)benzene-1,2-diol;
3-(3-hydroxy-3,7,11-trimethyldodeca-6,10-dien-1-yl)benzene-1,2-diol; and
3-(3-hydroxy-3,7-dimethyloct-6-en-1-yl)benzene-1,2-diol;
or a stereoisomer, mixture of stereoisomers, solvate, or hydrate thereof.
10. The compound of claim 1 , wherein the compound is selected from the group consisting of: 4-(6E,10E)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)benzene-1,2-diol; and 3-((6E,10E)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trien-1-yl)benzene-1,2-diol.