Cannabinoid derivatives, methods of making, and use thereof

A method of modifying the activity of a cannabinoid receptor comprising:

• providing a compound according to formula (I)
• wherein,
• X is selected from the group of C(CH3)2, C(—Y(CH2)nY—), CH2, C(O),
• Y is selected from the group of S and O;
• R1 is selected from the group of a C3 to C8 cycloalkyl, biphenyl, methyltetrazolyl,
• with the proviso that, when X is CH2, R1 is not cyclohexyl or phenyl;
• R2 and R3 are methyl for compounds containing a Δ8 or a Δ9 double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a Δ6a-10a double bond;
• R4 is selected from the group of methyl, methanol, —(CH2)mCOOH, and —(CH2)mCOH for compounds containing a Δ8 or a Δ9 double bond, or is methyl for compounds containing a Δ6a-10a double bond;
• R5 is selected from the group of H, OH, methoxy, and ethoxy;
• R6-R10 are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl;
• at least one of R11-R13 is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R11-R13 can optionally be H;
• n is an integer from 2 to 4;
• and
• m is an integer that is either 0 or 1;
• and
• contacting a cannabinoid receptor of a cell with the compound, whereby said contacting modifies the activity of the cannabinoid receptor in the cell.

A method of treating a cannabinoid receptor-mediated condition comprising:

• providing a compound that acts as an agonist on the cannabinoid receptor, wherein the compound is a compound according to formula (I)
• wherein,
• X is selected from the group of C(CH3)2, C(—Y(CH2)nY—), CH2, C(O),
• Y is selected from the group of S and O;
• R1 is selected from the group of a C3 to C8 cycloalkyl, biphenyl, methyltetrazolyl,
• with the proviso that, when X is CH2, R1 is not cyclohexyl or phenyl;
• R2 and R3 are methyl for compounds containing a Δ8 or a Δ9 double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a Δ6a-10a double bond;
• R4 is selected from the group of methyl, methanol, —(CH2)mCOOH, and —(CH2)mCOH for compounds containing a Δ8 or a Δ9 double bond, or is methyl for compounds containing a Δ6a-10a double bond;
• R5 is selected from the group of H, OH, methoxy, and ethoxy;
• R6-R10 are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl;
• at least one of R11-R13 is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R11-R13 can optionally be H;
• n is an integer from 2 to 4;
• and
• m is an integer that is either 0 or 1;
• and
• administering to a patient an amount of the compound that is effective to treat a cannabinoid receptor-mediated condition.

A method of making a Δ8-THC or Δ9-THC analog, said method comprising:

• reacting an intermediate compound having the structure of formula (II)
• with a reactant according to either formula (IIIa) or formula (IIIb)
• under conditions effective to form a compound according to formula (I)
• wherein,
• X is selected from the group of C(CH3)2, C(—Y(CH2)nY—), CH2, C(O),
• Y is selected from the group of S and O;
• R1 is selected from the group Of a C3 to C8 cycloalkyl, biphenyl, methyltetrazolyl,
• with the proviso that, when X is CH2, R1 is not cyclohexyl or phenyl;
• R2 and R3 are methyl for compounds containing a Δ8 or a Δ9 double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a Δ6a-10a double bond;
• R4 is selected from the group of methyl, methanol, —(CH2)mCOOH, and —(CH2)mCOH for compounds containing a Δ8 or a Δ9 double bond, or is methyl for compounds containing a Δ6a-10a double bond;
• R5 is selected from the group of H, OH, methoxy, and ethoxy;
• R6-R10 are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl;
• at least one of R11-R13 is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R11-R13 can optionally be H;
• n is an integer from 2 to 4;
• and
• m is an integer that is either 0 or 1;
• wherein the compound contains a double bond at the Δ8 or Δ9 position of the C ring.