Galanthamine derivatives for treatment of alzheimer's disease

A method of inhibiting acetylcholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound of the formula:

• wherein the broken line represents an optionally present double bond;
• R1 and R2 are each selected independently from the group consisting of hydrogen, hydroxyl, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy;
• R1 may also be alkyl of up to 14 carbon atoms or hydroxymethyl;
• R3 is a residue of a compound having adrenergic or monoamine oxidase activity and said residue being selected from the group consisting of
• wherein Hal is a halogen, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1 and Z is selected from the group consisting of
• wherein Q is hydrogen or hydroxy, L is hydrogen or C1-4 alkyl, G is hydrogen, C1-4 alkyl, alkylphenyl wherein said phenyl group is optionally substituted by hydroxy, methylenedioxy or is alkylamino,
• each R4 group is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms and R9 is hydrogen or alkyl of 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.

A method of inhibiting acetylcholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound of the formula

• wherein R1 is selected from the group consisting of hydroxy, methoxy, ethoxy, monoalkyl carbamate, dialkyl carbamate, phenyl carbamate, naphthyl carbamate, R5-substituted phenyl carbamate and R5-substituted naphthyl carbamate wherein R5 is hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl,
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, and R5-substituted benzoyloxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl or R3 is a heterocyclic selected from α- or β-thienyl, thenyl, pyridyl, pyrazinyl or pyrimidyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R6 is selected from the group consisting of hydrogen, halo, trifluoromethyl or alkyl of from 1 to 4 carbon atoms;
• R9 is hydrogen or alkyl of 1 to 6 carbon atoms;
• or a pharmaceutically acceptable acid addition salt thereof with the proviso that R3 is not methyl when R1 is methoxy, R2 is hydroxy and all R4's are hydrogen.

A method of inhibiting acetylcholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound selected from O-desmethyl-N-desmethylgalanthamine;

• 13-O-ethyl-O-desmethyl-N-desmethylgalanthamine;
• 13-O-phenyl-O-desmethyl-N-desmethylgalanthamine;
• O-desmethyl-N-desmethyl-N-ethylgalanthamine;
• O-desmethyl-N-desmethyl-N-ethylgalanthamine 13-O-ethyl and 13-O-benzyl ethers;
• O-desmethyl-N-desmethyl-N-ethylgalanthamine 13-phenyl, 13-α-naphthyl, 13-dimethyl and 13-diethyl carbamates;
• O-desmethyl-N-desmethyl-N-cyclopropylmethylgalanthamine;
• N-desmethyl-N-cyclopropylmethylgalanthamine;
• O-desmethyl-N-desmethyl-N-cyclopropylmethylgalanthamine 13-O-ethyl and 13-O-benzyl ethers;
• O-desmethyl-N-desmethyl-cyclopropylmethylgalanthamine 13-phenyl, 13-α-naphthyl, 13-dimethyl and 13-diethyl carbamates;
• O-desmethyl-N-desmethyl-N-benzylgalanthamine;
• and O-desmethyl-N-desmethyl-N-benzylgalanthamine 13-O-methyl, 13-O-ethyl and 13-O-benzyl ethers.

A method of inhibiting acetylcholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound selected from the group consisting of O-desmethylgalanthamine;

• O-desmethylgalanthamine, O-methyl ether;
• O-desmethylgalanthamine, O-ethyl ether;
• O-desmethyl galanthamine, O-benzyl ether, wherein the etherification is at the 2-position;
• O-desmethylgalanthamine phenyl carbamate;
• O-desmethyl-N-desmethylgalanthamine α-naphthyl carbamate;
• O-desmethylgalanthamine dimethyl carbamate and O-desmethylgalanthamine diethyl carbamate wherein the carbamate group is bonded to the cyclohexene ring;
• O-desmethyl-N-desmethylgalanthamine;
• O-desmethyl-N-desmethylgalanthamine, O-methyl, O-ethyl and O-benzyl ethers wherein etherification is at the 2-position;
• O-desmethyl-N-desmethylgalanthamine, phenyl, α-naphthyl, dimethyl and diethyl carbamates wherein the carbamate substitution is at the 2-position;
• O-desmethyl-N-desmethyl-N-ethylgalanthamine;
• O-desmethyl-N-desmethyl-N-ethylgalanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position;
• O-desmethyl-N-desmethyl-N-ethylgalanthamine phenyl, α-naphthyl, dimethyl or diethyl carbamate wherein said carbamate substitution is in the 2-position;
• O-desmethyl-N-desmethyl-N-cyclopropylmethylgalanthamine O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position;
• O-desmethyl-N-desmethyl-N-cyclopropylmethyl galanthamine;
• O-desmethyl-N-desmethyl-N-cyclopropylmethylgalanthamine phenyl, α-naphthyl, dimethyl or diethyl carbamate wherein said carbamate substitution is in the 2-position;
• O-desmethyl-N-desmethyl-N-benzyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position;
• and O-desmethyl-N-desmethyl-N-benzylgalanthamine phenyl, α-naphthyl, dimethyl or diethyl carbamate wherein the carbamate substitution is at the 2-position.

A method of inhibiting acetylcholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound selected from O-desmethyllycoramine;

• N-desmethyl-O-desmethyllycoramine;
• N-desmethyl-N-ethyllycoramine;
• N-desmethyl-N-benzyllycoramine;
• O-desmethyllycoramine ethyl ether;
• 2-deoxy-13-O-desmethyllycoramine;
• 2-O-deoxy-13-O-desmethyllycoramine benzyl ether;
• O-desmethyllycoramine dimethyl carbamate;
• O-desmethyllycoramine phenyl carbamate and 2-O-deoxy-13-desmethyllycoramine dimethyl carbamate.

A pharmaceutical composition comprising a compound of the formula:

• wherein the broken line represents an optionally present double bond, R1 and R2 are each selected independently from the group consisting of hydrogen, hydroxy, alkoxy of 1-6 carbon atoms, amino, alkylamino, cyano, sulfhydryl, or R1 may be alkoxy of 1-6 carbon atoms provided that R2 is not hydroxy, aryloxy, aralkoxy, R5-substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, R1 may also be alkyl of up to 14 carbon atoms, or hydroxymethyl;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R9 is hydrogen, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solvent, diluent or carrier with the provisos that
• 1) R1 is not alkoxy of 1-6 carbon atoms, when R2 is hydroxy, R3 is methyl and all R4's are hydrogen;
• 2) R1 is not acetoxy, when R2 is hydroxy, R3 is methyl and all R4's are hydrogen;
• or
• 3) the compound is not leucotamine, sanguinine or chlidanthine.

A compound of the formula:

• wherein R1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl or a pharmaceutically acceptable salt thereof provided that R2 is not hydroxy when R1 is hydrogen and R3 is methyl and R4 is hydrogen.

A method of inhibiting acetylcholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound selected from the group consisting of N-desmethyl-O-desmethyllycoramine;

• N-desmethyl-N-ethyllycoramine;
• N-benzyllycoramine;
• 2-O-deoxy-13-O-desmethyllycoramine benzyl ether;
• O-desmethyllycoramine dimethyl carbamate;
• O-desmethyllycoramine phenyl carbamate;
• and 2-O-deoxy-13-desmethyllycoramine dimethyl carbamate.

A compound of the formula

• wherein R1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-alkarylamino, fluoro, chloro, bromo, iodo, and trifluoromethyl or a pharmaceutically acceptable salt thereof with the proviso that the compound is not leucotamine, O-methylleucotamine, O-methylleucotamine acetate, chlidanthine, habranthine or N,O-diacetyl-N-desmethylgalanthamine.

A compound of the formula

• wherein R1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl or a pharmaceutically acceptable salt thereof with the proviso that the compound is not leucotamine, sanguinine, or chlidanthine.

A method of inhibiting acetylcholinesterase activity in a patient which comprises administering to the patient a therapeutically effective amount of a compound of the formula

• wherein the broken line represents an optionally present double bond and wherein R1 and R2 are each selected from the group consisting of hydrogen, sulfhydryl, amino, alkylamino, OR,
• wherein R is alkyl of from 1-6 carbon atoms, phenyl, benzyl, R5-substituted phenyl, or R5-substituted benzyl wherein R5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl, R3 is selected from hydrogen, branched or linear alkyl of 1 to 6 carbon atoms,
• wherein n is 3, 4, or 5, or
• wherein R11 is hydrogen, alkyl or alkoxy;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula

• wherein R1 and R2 are each selected from the group consisting of hydrogen, sulfhydryl, amino, alkylamino, OR,
• wherein R is alkyl of from 1-6 carbon atoms, phenyl, benzyl, R5-substituted phenyl or R5-substituted benzyl wherein R5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl, R3 selected from hydrogen, branched or linear alkyl of 1 to 6 atoms,
• wherein n is 3, 4, or 5, or
• wherein R11 is hydrogen, alkyl or alkoxy;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula

• wherein R1 and R2 are each selected from the group consisting of hydrogen, sulfhydryl, amino, alkylamino, OR,
• wherein R is alkyl of from 1-6 carbon atoms, phenyl, benzyl, R5-substituted phenyl, or R5-substituted benzyl wherein R5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R3 is selected from hydrogen, straight or branched alkyl of 1 to 6 carbon atoms,
• wherein n is 3, 4, or 5 or
• wherein R11 is hydrogen, alkyl or alkoxy;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a compound of the formula

• wherein R1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl group is R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, benzoyloxy, R5-substituted benzoyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, -cycloalkylmethyl or alkylphenyl;
• or a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent, solvent or carrier with the proviso that the compound is not chlidanthine, or leucotamine.

A compound of the formula:

• wherein the broken line represents an optionally present double bond;
• R1 and R2 are each selected independently from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, aryloxy, aralkoxy, C1-6 alkyl carbonate, R5-substituted phenyl carbonate, R5-substituted benzyl carbonate, R5-substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety be R5-substituted or unsubstituted, (R5-substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy;
• R1 may also be alkyl of up to 14 carbon atoms or hydroxymethyl;
• R2 may also be carboxymethyl provided that at least one of R1 and R2 is hydroxy;
• amino or alkylamino;
• R3 is a residue of a compound having adrenergic or monoamine oxidase activity and said residue is selected from the group consisting of
• wherein Hal is halogen, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1 and Z is selected from the group consisting of
• wherein Q is hydrogen or hydroxy, L is hydrogen or C1-4 alkyl, G is hydrogen, C1-4 alkyl, or alkylphenyl wherein said phenyl group is optionally substituted by hydroxy or methylene dioxy, or is alkylamino;
• each R4 group is independently selected from hydrogen, hydroxy, alkyl, alkoxy, fluoro, chloro, bromo, iodo, and trifluoromethyl;
• R5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl;
• R6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms;
• R9 is hydrogen or alkyl of 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.

A pharmaceutical composition comprising a compound of the formula:

• wherein R1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl provided that R2 is not hydroxy or methoxy when R1 is hydrogen and R3 is methyl and R4 is hydrogen, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, solvent or carrier.

A pharmaceutical composition comprising a compound of the formula:

• wherein R1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, solvent or carrier with the proviso that the compound is not leucotamine, sanguine or chlidanthine.

A pharmaceutical composition comprising a compound of the formula:

• wherein R1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl group may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the monoalkyl, dialkyl or aryl group may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, or R5-substituted benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl provided that R2 is not hydroxy or methoxy when R1 is hydrogen and R3 is methyl and R4 is hydrogen, and a pharmaceutically acceptable diluent, solvent or carrier.

A pharmaceutical composition comprising a compound of the formula

• wherein R1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, alkoxy of 1 to 6 carbon atoms, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl group may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R5-substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the monoalkyl, dialkyl or aryl moiety may be R5-substituted or unsubstituted, (R5-substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R5 is alkyl or alkoxy;
• R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl;
• each R4 is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl or a pharmaceutically acceptable salt thereof with the proviso that the compound is not leucotamine, chlidanthine and R1 is not alkoxy of 1-6 carbon atoms when R2 is hydroxy, R3 is methyl and all R4's are hydrogen.