Macrocycles with antioxidant and neuroprotective activities

A method for the treatment of diseases associated with oxidative stress, selected from neurodegenerative diseases, stroke and mitochondriopathies with neuromuscular affection, wherein the method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II):

• wherein
• the wavy bond ˜ is either a double bond or the epoxide,
• R1, R2, R3 and R4 are each independently selected from the group consisting of hydrogen and substituted or unsubstituted C1-C6 alkyl;
• R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, or halogen;
• X denotes a group represented by formulas (III) to (XII),
• wherein
• the dashed bond represents an optional double bond which, when present, is the double bond between X and (B) in the compound of formula (II);
• R6 is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, —CONH2, alkali metal, and sugar;
• and
• R7 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, nitrile, —CH2-nitrile and —CH2—CO—CH3;
• or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof.

A compound of formula (Ia) or (IIa):

• wherein
• the wavy bond ˜ is either a double bond or the epoxide,
• X denotes a group represented by formulas,
• wherein
• the dashed bond represents an optional double bond which, when present, is the double bond between X and (B) in the compound of formula (II);
• wherein R6 is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, —CONH2, alkali metal, and sugar;
• wherein R1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, nitrile, —CH2-nitrile and —CH2—CO—CH3;
• or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof,
• with the proviso that the following compounds, of formulae:
• are excluded.

A process for preparing a compound of formula (I) or (II)

• wherein
• the wavy bond ˜ is either a double bond or the epoxide,
• R1, R2, R3 and R4 are each independently selected from the group consisting of hydrogen and substituted or unsubstituted C1-C6 alkyl;
• R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, or halogen;
• X denotes a group represented by formulas (III) to (XII),
• wherein
• the dashed bond represents an optional double bond which, when present, is the double bond between X and (B) in the compound of formula (II);
• R6 is selected from the group consisting of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, —CONH2, alkali metal, and sugar;
• and
• R7 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, nitrile, —CH2-nitrile and —CH2—CO—CH3;
• or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof;
• wherein said process comprises cultivating the strain HT-09B-VENT-WQ002, available under accession number CECT 20769 from the Colección Española de Cultivos Tipo at Valencia University, Spain, in an aqueous nutrient medium, isolating and purifying the resulting compound from the cultured broth, and optionally modifying this compound, to obtain a compound of formula (I) or (II) as previously defined.