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DIBENZOPYRAN AMPK ACTIVATOR COMPOUNDS, COMPOSITIONS, METHODS AND USES THEREOF

20230026772 · 2023-01-26

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to a compound having general formula I for use in the activation of AMPK. A composition comprising said compound for use in the activation of AMPK is also provided.

    Claims

    1. A method for the activation of AMPK comprising administering a compound having the general formula I, said compound having the general formula (I), ##STR00013## wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, or substituted and/or branched C4 to C20 polyalkynyl; and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    2. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R2, R3, R4, R5, R6, R7, and R8, are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, or substituted and/or branched C4 to C20 polyalkynyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    3. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, or substituted and/or branched C4 to C20 polyalkynyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    4. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    5. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R3, R5, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R2 and R4 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    6. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R3, R5, and R8 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R2, R4, R6, and R7 are each independently selected from the group consisting of OH; OCH3; 0-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    7. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R3, R5, R6, and R8 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R2, R4, and R7 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    8. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1 and R3 are selected from the group consisting of H; R2 and R4 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R5, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    9. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R3, R5, and R8 are H; R2, R4, R6, and R7 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    10. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R3, R5, R6, and R8 are H; R2, R4, and R7 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated 0-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    11. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1 and R3 are H; R2 and R4 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R5, R6, R7, and R8 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    12. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R3, R5, and R8 are H; R2, R4, R6, and R7 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    13. A method according to claim 1 wherein said compound is a compound of Formula I wherein R1, R3, R5, R6, and R8 are H; R2, R4, and R7 are each independently selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; R9 and R10 are each independently selected from the group consisting of H; a C1 to C20 alkyl chain; a CH2-R chain where R is a C5 isoprenoid unit of the type 3-methylbutyl (1a), 3,3-dimethylallyl (1b), 1,1-dimethylallyl (1c), 3-methyl-but-1-enyl (1d), 3-methyl-but-1,3-dienyl (1e), 3-hydroxymethylbutyl (1f), 3-hydroxy-3-methylbutyl (1g), 3-hydroxymethyl-3-methyl-but-2-enyl (1h), 3-hydroxymethyl-3-methyl-but-1-enyl (1i), 1-hydroxy-3-methyl-but-2-enyl (1j), 3-hydroxy-3-methyl-but-1-enyl (1k), 2-hydroxy-3-methyl-but-3-enyl (1l), epoxyprenyl (1m), 2,3-dihydroxy-3-methylbutyl (1n), 3-methyl-2-butanone (1o), 2-hydroxy-3-methylbutyl (1p); a CH2-R chain where R is a C10 isoprenoid unit of the type tetrahydrogeranyl (2a), citonellyl (2b), geranyl (2c), neryl (2d), lavandulyl (2e), 5-hydroxy-3,7-dimethyl-octa-2,6-dienyl (2f), 6-hydroxy-3,7-dimethyl-octa-2,7-dienyl (2g), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2h), 3-methyl-7-hydroxymethyl-octanyl (2i), 5-methyl-2-(1-methylethenyl)-5-hydroxyhexanyl (2j); a CH2-R chain where R is a C15 isoprenoid unit of the type hexahydrofarnesyl (3a), farnesyl (3b); a CH2-R chain where R is a C20 isoprenoid unit of the type phytanyl (4a), geranylgeranyl (4b); or a derivative or analogue thereof.

    14. A method according to claim 1 wherein said compound is 3-methoxy-6H-benzo[c]chromene-1,8-diol.

    15. A method according to claim 1 wherein said compound is 8-methoxy-6H-benzo[c]chromene-3,10-diol.

    16. A method according to claim 1 for the activation of AMPK to treat or prevent a condition, disorder, or disease related to cardiometabolic health, obesity, type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease, and/or cancer.

    17. A method according to claim 16, wherein the subject is a human.

    18. A compound for use method according to claim 1 wherein the activation of AMPK is through a direct activation mechanism.

    19-28. (canceled)

    29. An in vitro method of activating AMPK, comprising contacting a compound of general formula I, said compound having the general formula (I), ##STR00014## wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, or substituted and/or branched C4 to C20 polyalkynyl; and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof, with AMPK.

    30. A method of treatment or prevention of a condition, disorder, or disease related to cardiometabolic health, obesity, type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease, and/or cancer comprising administration of a composition having the general formula I, said compound having the general formula (I), ##STR00015## wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; a carboxylic acid; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, or substituted and/or branched C4 to C20 polyalkynyl; and a OCH3 group can cyclize with a neighboring OH group to form a methylene dioxy bridge; or a derivative or analogue thereof.

    Description

    BRIEF DESCRIPTION OF FIGURES

    [0705] FIG. 1. Compound 1 and compound 2 activation of bacterially-expressed AMPKα2β1γ1 complexes.

    [0706] compound 1: 3-methoxy-6H-benzo[c]chromene-1,8-diol

    [0707] compound 2: 8-methoxy-6H-benzo[c]chromene-3,10-diol

    [0708] Varying concentrations of compound 1 and compound 2 were incubated with phosphorylated purified AMPK α2β1γ1 for 30 mins. AMPK activity was determined using the HTRF KinEASE assay kit and results are presented as the ratio of 665/620 nm (STK1 phosphorylation).

    [0709] FIG. 2. Compound 1 and compound 2 increase the phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC), in U-2 OS Flp-In T-REx mammalian cells.

    [0710] compound 1: 3-methoxy-6H-benzo[c]chromene-1,8-diol

    [0711] compound 2: 8-methoxy-6H-benzo[c]chromene-3,10-diol

    [0712] U-2 OS cells were treated with varying concentrations of compound 1 or compound 2 for 30 mins at 37 C. Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the average fold increase in activation relative to untreated cells.

    [0713] FIG. 3. Compound 1 and compound 2 do not activate AMPK in cells stably expressing an ADaM-binding site AMPK mutant (β1 S108A).

    [0714] compound 1: 3-methoxy-6H-benzo[c]chromene-1,8-diol

    [0715] compound 2: 8-methoxy-6H-benzo[c]chromene-3,10-diol

    [0716] The β1 WT or β1 S108A mutant were stably expressed in AMPKβ1β2 double knockout cells and treated with varying concentrations of compound 1 or compound 2 for 30 mins at 37 C. Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the average fold increase in activation relative to untreated cells.

    [0717] FIG. 4. Compound 1 and compound 2 do not activate AMPK in cells stably expressing the β2 isoform.

    [0718] compound 1: 3-methoxy-6H-benzo[c]chromene-1,8-diol

    [0719] compound 2: 8-methoxy-6H-benzo[c]chromene-3,10-diol

    [0720] U-2 OS cells AMPKβ1β2 double knockout cells stably expressing AMPK β1 or β2 were treated with varying concentrations of Compound 1 or compound 2 for 30 mins at 37 C.

    [0721] Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the average fold increase in activation relative to untreated cells.

    EXAMPLES

    Example 1

    [0722] Compound 1 and Compound 2 Activated Bacterially-Expressed AMPKα2β1γ1 Complexes in a Dose-Dependent Manner.

    [0723] The AMPKα2β1γ1 complex was expressed in bacteria and purified through the His-α subunit by nickel purification, purified through gel filtration and phosphorylated by incubation with CaMKKβ, and then further purified through a final gel filtration purification step. Phosphorylated purified AMPK was incubated with varying concentrations of ligand for 30 mins along with substrate and reagents from the HTRF-KinEASE Cisbio assay kit (STK S1 Kit). Phosphorylation of the substrate was measured by incubating with donor and acceptor antibodies for 2 h at room temperature as per the manufacturer's protocol (Coulerie et al., (2016), J Nat Prod. 2016 Nov. 23; 79(11):2856-2864. Epub 2016 Oct. 28.) and phosphorylated peptide detected by performing HTRF. AMPK activity is displayed as the 665 nm/620 nm ratio. FIG. 1 shows that compound 1 and compound 2 allosterically activate AMPKα2β1γ1 in a dose-dependent manner. Compound 1 is 3-methoxy-6H-benzo[c]chromene-1,8-diol and Compound 2 is 8-methoxy-6H-benzo[c]chromene-3,10-diol. These data show that these two compounds directly activate AMPK in vitro.

    Example 2

    [0724] Compound 1 and Compound 2 Increased the Phosphorylation of the AMPK Substrate, Acetyl-CoA Carboxylase (ACC), in U-2 OS Flp-In T-REx Mammalian Cells.

    [0725] U-2 OS Flp-In T-REx cells were seeded at 50 K in a 96-well plate and left overnight at 37 C in DMEM GlutaMAX (Thermo Fisher Scientific) supplemented with 10% (vol/vol) FBS and 100 U/ml penicillin G, and 100 μg/ml streptomycin. Cells were treated for 30 mins with varying concentrations of Compound 1 in media lacking FBS and then cells were lysed in 50 μl of Cisbio lysis buffer #1 supplemented with blocking solution as per the manufacturer's protocol (Cisbio). Cells were lysed for 30 mins at room temperature before 16 μl of lysate was incubated with 4 μl of the HTRF antibodies (1:40 dilution of the acceptor and donor (p) ACC antibodies, as per the manufacturers protocol). Lysates were incubated overnight with the antibodies before 665 nm/620 nm ratio was determined using a MolecularDevices i3 plate reader (with a HTRF cartridge add-on). The results are plotted as fold activation compared to the respective AMPK complex without any compound.

    [0726] FIG. 2 shows that using the pACC HTRF assay kit (Cisbio), Compound 1 and 2 increase the phosphorylation of the AMPK substrate, ACC, in a dose-dependent manner in U-2 OS Flp-In T-REx mammalian cells. Compound 1 is 3-methoxy-6H-benzo[c]chromene-1,8-diol and Compound 2 is 8-methoxy-6H-benzo[c]chromene-3,10-diol. Phosphorylation of ACC is widely used as a cellular indicator of AMPK activity. These data show that compound 1 and 2 are AMPK activators in cells.

    Example 3

    [0727] In Cells Compound 1 and 2 Did not Activate AMPK Complexes Containing a Mutation (S108A) at the Allosteric Drug and Metabolite (ADaM) Site in Cells.

    [0728] AMPKβ1/β2 double knockout U-2 OS Flp-In™ T-Rex™ cell lines were generated and cells were genotyped and analysed by Western blotting to confirm that there was a complete knockout of AMPKβ1/β2. We took these AMPKβ1/β2 double knockout cells, and re-introduced the expression of human β1 wild-type (WT) or a β1 Serine 108 to alanine mutation (S108A). This was achieved using the Flp-In™ system (Invitrogen) present in this cell line and stable cells expressing β1 WT or a β1 S108A mutant were generated according to the manufacturers' protocols. Re-expression of the β1 subunit was confirmed by western blot analysis, and was comparable between the β1 WT and β1 S108A mutant. Mutation of β1 S108A has previously been shown to interfere with regulation of AMPK by compounds binding to the allosteric drug and metabolite (ADaM) binding site formed at the interface between the (3 subunit carbohydrate binding module (CBM) and the a subunit kinase domain. In contrast, activators through the nucleotide binding site on the AMPK γ subunit can still regulate the β1 S108A mutant similar to β1 WT activation.

    [0729] Cells stably expressing β1 WT or a β1 S108A mutant were treated with varying concentrations of compound 1 and compound 2 and subjected to the pACC HTRF (Cisbio) assay to determine the level of phosphorylation of the AMPK substrate, ACC, in cell lysates, as in Example 2. As shown in FIG. 3, Compound 1 is 3-methoxy-6H-benzo[c]chromene-1,8-diol and Compound 2 is 8-methoxy-6H-benzo[c]chromene-3,10-diol. Compound 1 and 2 was able to dose-dependently increase pACC in cells stably expressing the β1 WT subunit. In contrast, Compound 1 and 2 were not able to increase pACC in cells expressing the β1 S108A mutant. This suggests that Compound 1 and 2 activate AMPK by binding to the ADaM pocket of AMPK.

    Example 4

    [0730] In Cells Compound 1 and 2 Did not Activate AMPK Complexes Containing the β2 Isoform Subunit.

    [0731] We took AMPKβ1/β2 double knockout cells, and re-introduced the expression of human β1 WT or β2 WT isoforms. Re-expression of the β1 and β2 subunit was confirmed by Western blot analysis and were shown to be expressed to a similar extent. Cells stably expressing β1 WT or β2 WT were treated with varying concentrations of compound 1 and compound 2, and subjected to the pACC HTRF (Cisbio) assay to determine the level of phosphorylation of the AMPK substrate, ACC, in cell lysates, as in example 2. As shown in FIG. 4, Compound 1 is 3-methoxy-6H-benzo[c]chromene-1,8-diol and Compound 2 is 8-methoxy-6H-benzo[c]chromene-3,10-diol. Compound 1 and compound 2 were able to dose-dependently increase pACC in cells stably expressing β1 WT. In contrast, compound 1 and 2 were not able to increase pACC in cells expressing the β2 WT isoform. This activation profile is characteristic of activators that bind to the ADaM site and consistent with previous studies showing that ADaM-site activators have poorer activation of β2-containing complexes in vitro and in cells. Taken together, we showed that in cells, compound 1 and compound 2 activate AMPK by binding to the ADaM pocket of AMPK separate from the nucleotide-binding site in the AMPKγ subunit.