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Details for Patent: 6,319,919

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Details for Patent: 6,319,919

Title: Galanthamine derivatives for treatment of alzheimer's disease
Abstract:Compounds of the formula ##STR1## wherein the broken line represents an optionally present double bond, and R.sub.1 -R.sub.3, R.sub.4, R.sub.6 and R.sub.9 are as defined herein, and compositions containing these compounds can be used to inhibit acetylcholinesterase activity and treat Alzheimer's Disease.
Inventor(s): Davis; Bonnie (Huntington, NY), Joullie; Madeleine M. (Philadelphia, PA)
Assignee: Davis; Bonnie (Syosset, NY)
Filing Date:Jun 07, 1995
Application Number:08/476,383
Claims:1. A method of inhibiting acetyl cholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound of the formula ##STR48##

wherein the broken line represents an optionally present double bond, R.sub.1 and R.sub.2 are each selected independently from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, and R.sub.5 -substituted benzoyloxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl or R.sub.3 is a heterocyclic selected from .alpha.- or .beta.-furyl, or .alpha.- or .beta.-thienyl, thenyl, pyridyl, pyrazinyl or pyrimidyl;

each R.sub.4 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;

R.sub.5 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;

R.sub.6 is selected from the group consisting of hydrogen, halo, trifluoromethyl or alkyl of from 1 to 4 carbon atoms; R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof with the proviso that R.sub.3 is not methyl when R.sub.1 is methoxy, R.sub.2 is hydroxy and all R.sub.4 's are hydrogen.

2. 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: ##STR49##

wherein the broken line represents an optionally present double bond; R.sub.1 and R.sub.2 are each selected independently from the group consisting of hydrogen, hydroxyl, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy; R.sub.1 may also be alkyl of up to 14 carbon atoms or hydroxymethyl;

R.sub.3 is a residue of a compound having adrenergic or monoamine oxidase activity and said residue being selected from the group consisting of ##STR50##

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 ##STR51##

wherein Q is hydrogen or hydroxy, L is hydrogen or C.sub.1-4 alkyl, G is hydrogen, C.sub.1-4 alkyl, alkylphenyl wherein said phenyl group is optionally substituted by hydroxy, methylenedioxy or is alkylamino, ##STR52##

each R.sub.4 group is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl;

R.sub.5 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;

R.sub.6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms and R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.

3. A method of inhibiting acetyl cholinesterase activity in a patient which comprises administering to said patient a therapeutically effective amount of a compound selected from the group consisting of galanthamine-13-acetate and galanthamine monoalkyl, dialkyl or aryl carbamates.

4. A method according to claim 1 wherein said compound is of the formula ##STR53##

wherein R.sub.1 is hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, R.sub.5 -substituted aryloxy, benzoyloxy, R.sub.5 -substituted benzoyloxy, amino, alkylamino, or a monoalkyl, dialkyl or aryl carbamate group, wherein R.sub.5 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; R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or methylphenyl, and each R.sub.4 is hydrogen.

5. 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 ##STR54##

wherein R.sub.1 is selected from the group consisting of hydroxy, methoxy, ethoxy, monoalkyl carbamate, dialkyl carbamate, phenyl carbamate, naphthyl carbamate, R.sub.5 -substituted phenyl carbamate and R.sub.5 -substituted naphthyl carbamate wherein R.sub.5 is hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl,

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, and R.sub.5 -substituted benzoyloxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl or R.sub.3 is a heterocyclic selected from .alpha.- or .beta.-thienyl, thenyl, pyridyl, pyrazinyl or pyrimidyl;

each R.sub.4 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;

R.sub.5 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;

R.sub.6 is selected from the group consisting of hydrogen, halo, trifluoromethyl or alkyl of from 1 to 4 carbon atoms;

R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof with the proviso that R.sub.3 is not methyl when R.sub.1 is methoxy, R.sub.2 is hydroxy and all R.sub.4 's are hydrogen.

6. 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-.alpha.-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-.alpha.-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.

7. 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: ##STR55##

wherein R.sub.2 is hydroxy, alkoxy of 1 to 6 atoms, aryloxy, R.sub.5 -substituted aryloxy, benzoyloxy or is a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted wherein R.sub.5 is alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo or trifluoromethyl; and

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or methylphenyl.

8. A method according to claim 7, wherein R.sub.2 is selected from the group consisting of hydroxy, alkoxy of 1 to 6 carbon atoms, benzyloxy, monoalkyl carbamate, phenyl carbamate, naphthyl carbamate, R.sub.5 -substituted phenyl carbamate and R.sub.5 -substituted naphthyl carbamate.

9. A method according to claim 1 wherein R.sub.3 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.

10. 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 .alpha.-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, .alpha.-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, .alpha.-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, .alpha.-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, .alpha.-naphthyl, dimethyl or diethyl carbamate wherein the carbamate substitution is at the 2-position.

11. A method according to claim 1 wherein said compound is of the formula: ##STR56##

wherein R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1.

12. A method according to claim 11 wherein R.sub.1 is hydroxy, alkoxy of 1 to 6 carbon atoms, benzoyloxy, amino, alkylamino or monoalkyl, dialkyl, or aryl carbamate; R.sub.2 is hydroxy, alkoxy of 1 to 6 carbon atoms, aryloxy, benzoyloxy or monoalkyl, dialkyl or aryl carbamate group and R.sub.3 is hydrogen, methyl, ethyl, cyclopropylmethyl or alkylphenyl.

13. 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.

14. A method according to claim 1, wherein said compound is administered orally in the form of a tablet or a capsule containing from 5, 10 or 25 mg of hydrobromide of said compound.

15. A method according to claim 4, wherein said compound is administered orally in the form of a tablet or a capsule containing from 5, 10 or 25 mg of hydrobromide of said compound.

16. A method according to claim 7, wherein said compound is administered orally in the form of a tablet or capsule containing from 5, 10 or 25 mg of hydrobromide of said compound.

17. A method according to claim 11, wherein said compound is administered orally in the form of a tablet or capsule containing from 5, 10 or 25 mg of hydrobromide of said compound.

18. A method according to claim 1, wherein a compound is administered in a sustained release formulation.

19. A method as claimed in claim 1 wherein the compound is one wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate.

20. Galanthamine phenyl carbamate.

21. Galanthamine naphthyl carbamate.

22. A pharmaceutical composition comprising a compound of the formula: ##STR57##

wherein the broken line represents an optionally present double bond, R.sub.1 and R.sub.2 are each selected independently from the group consisting of hydrogen, hydroxy, alkoxy of 1-6 carbon atoms, amino, alkylamino, cyano, sulfhydryl, or R.sub.1 may be alkoxy of 1-6 carbon atoms provided that R.sub.2 is not hydroxy, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, R.sub.1 may also be alkyl of up to 14 carbon atoms, or hydroxymethyl;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, alkylphenyl;

each R.sub.4 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;

R.sub.5 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;

R.sub.9 is hydrogen, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solvent, diluent or carrier with the provisos that

1) R.sub.1 is not alkoxy of 1-6 carbon atoms, when R.sub.2 is hydroxy, R.sub.3 is methyl and all R.sub.4 's are hydrogen;

2) R.sub.1 is not acetoxy, when R.sub.2 is hydroxy, R.sub.3 is methyl and all R.sub.4 's are hydrogen; or

3) the compound is not leucotamine, sanguinine or chlidanthine.

23. A composition according to claim 22 in the form of a sustained release product.

24. A composition according to claim 22 in the form of a tablet or capsule containing from 5, 10 or 25 mg of the hydrobromide of said compound.

25. A composition according to claim 22 wherein in said compound, R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, alkanoyloxy, monoalkyl, dialkyl or aryl carbamates, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted, wherein R.sub.5 is selected from the group consisting of hydrogen, hydroxyl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, fluoro, chloro, bromo, iodo and trifluoromethyl; R.sub.3 is selected from the group consisting of alkyl, cycloalkylmethyl, and each R.sub.4 is independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylmino, fluoro, chloro, bromo, iodo and trifluoromethyl.

26. A composition as claimed in claim 25 wherein each R.sub.4 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo and trifluoromethyl.

27. A composition as claimed in claim 25 wherein said compound is one wherein one of R.sub.1 and R.sub.2 is an alkanoyloxy.

28. A composition comprising a compound selected from the group consisting of galanthamine n-butyl carbamate, galanthamine phenyl carbamate, galanthamine naphthyl carbamate and galanthamine acetate or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable solvent, diluent or carrier.

29. A composition according to claim 22 wherein said compound is of the formula: ##STR58##

wherein R.sub.1 and R.sub.2 are each selected independently from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, alkanoyloxy, hydroxy-substituted alkanoyloxy, and benzoyloxy, wherein R.sub.5 is alkyl or alkoxy; R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkphenyl; with the provisos that 1) R.sub.1 is not acetoxy when R.sub.2 is hydroxy and R.sub.3 is methyl and 2) that the compound is not leucotamine or sanguinine.

30. A composition according to claim 22 wherein said compound is of the formula: ##STR59##

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, or R.sub.5 -substituted phenyl or benzyl carbamate, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 atoms, cycloalkylmethyl, or alkylphenyl; each R.sub.4 is independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-alkarylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solvent, diluent or carrier with the proviso that the compound is not leucotamine, O-methylleucotamine, O-methylleucotamine acetic acid ester, sanguinine or chlidanthine.

31. A composition according to claim 22 wherein said compound is of the formula ##STR60##

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl, or aryl carbamate group wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted; (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, or R.sub.5 -substituted phenyl or benzyl carbamate, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl; each R.sub.4 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 carrier, diluent or solvent with the proviso that the compound is not leucotamine, sanguinine, or chlidanthine.

32. 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 ##STR61##

wherein R.sub.1 and R.sub.2 are each selected independently from the group consisting of hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, and R.sub.5 -substituted benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl and all of R.sub.4 are independently hydrogen, alkyl, alkoxy, fluoro, chloro, bromo, iodo, or trifluoromethyl or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier diluent or solvent with the proviso that the compound is not leucotamine, or sanguinine.

33. A composition according to claim 22 wherein said compound is one wherein said broken line represents either no double bond or a single double bond in the 3,4 position, R.sub.1 and R.sub.2 are each selected from hydroxy, alkanoyloxy and monoalkyl, dialkyl or aryl carbamate; R.sub.3 is selected from hydrogen, alkyl, cycloalkylmethyl and alkylphenyl and each of R.sub.4 and R.sub.9 is hydrogen.

34. A compound of the formula: ##STR62##

wherein R.sub.1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl; each R.sub.4 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 R.sub.2 is not hydroxy when R.sub.1 is hydrogen and R.sub.3 is methyl and R.sub.4 is hydrogen.

35. A compound of the formula ##STR63##

wherein R.sub.1 is OCONHR wherein R is alkyl of 1-6 carbon atoms, phenyl, or R.sub.5 -substituted phenyl, or R.sub.5 -substituted benzyl wherein R.sub.5 is selected from alkyl or alkoxy;

R.sub.2 is hydroxy, alkoxy of 1-6 carbon atoms, alkanoyloxy, or OCONHR wherein R alkyl of 1-6 carbon atoms, phenyl, or R.sub.5 -substituted phenyl, wherein R.sub.5 is selected from alkyl or alkoxy; R.sub.3 is hydrogen, lower alkyl or cyclopropylmethyl and R.sub.4 is hydrogen or a pharmaceutically acceptable salt thereof.

36. 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.

37. A compound of the formula ##STR64##

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, and benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy wherein R.sub.5 is alkyl or alkoxy,

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl or a pharmaceutically acceptable salt thereof with the proviso that the compound is not chlidanthine, leucotamine or sanguinine.

38. A compound of the formula ##STR65##

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl;

each R.sub.4 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.

39. A compound of the formula ##STR66##

wherein R.sub.1 is hydroxy, alkoxy of 1-6 carbon atoms or alkanoyloxy of 1-6 carbon atoms, R.sub.2 is OCONHR wherein R is alkyl of 1-6 carbon atoms, phenyl, R.sub.5 -substituted phenyl, or R.sub.5 -substituted benzyl wherein R.sub.5 is selected from alkyl or alkoxy; R.sub.3 is hydrogen, lower alkyl or cyclopropylmethyl and each of R.sub.4 is hydrogen or a pharmaceutically acceptable salt thereof.

40. A compound of the formula ##STR67##

wherein R.sub.1 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 R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl;

each R.sub.4 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.

41. 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 ##STR68##

wherein the broken line represents an optionally present double bond and wherein R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, sulfhydryl, amino, alkylamino, OR, ##STR69##

wherein R is alkyl of from 1-6 carbon atoms, phenyl, benzyl, R.sub.5 -substituted phenyl, or R.sub.5 -substituted benzyl wherein R.sub.5 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, R.sub.3 is selected from hydrogen, branched or linear alkyl of 1 to 6 carbon atoms, ##STR70##

wherein n is 3, 4, or 5, or ##STR71##

wherein R.sub.11 is hydrogen, alkyl or alkoxy; or a pharmaceutically acceptable salt thereof.

42. A compound of the formula ##STR72##

wherein R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, sulfhydryl, amino, alkylamino, OR, ##STR73##

wherein R is alkyl of from 1-6 carbon atoms, phenyl, benzyl, R.sub.5 -substituted phenyl or R.sub.5 -substituted benzyl wherein R.sub.5 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, R.sub.3 selected from hydrogen, branched or linear alkyl of 1 to 6 atoms, ##STR74##

wherein n is 3, 4, or 5, or ##STR75##

wherein R.sub.11 is hydrogen, alkyl or alkoxy; or a pharmaceutically acceptable salt thereof.

43. A compound of the formula ##STR76##

wherein R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, sulfhydryl, amino, alkylamino, OR, ##STR77##

wherein R is alkyl of from 1-6 carbon atoms, phenyl, benzyl, R.sub.5 -substituted phenyl, or R.sub.5 -substituted benzyl wherein R.sub.5 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;

R.sub.3 is selected from hydrogen, straight or branched alkyl of 1 to 6 carbon atoms, ##STR78##

wherein n is 3, 4, or 5 or ##STR79##

wherein R.sub.11 is hydrogen, alkyl or alkoxy; or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound of the formula ##STR80##

wherein R.sub.1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl group is R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, benzoyloxy, R.sub.5 -substituted benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 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.

45. A compound of the formula: ##STR81##

wherein the broken line represents an optionally present double bond;

R.sub.1 and R.sub.2 are each selected independently from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, aryloxy, aralkoxy, C.sub.1-6 alkyl carbonate, R.sub.5 -substituted phenyl carbonate, R.sub.5 -substituted benzyl carbonate, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy;

R.sub.1 may also be alkyl of up to 14 carbon atoms or hydroxymethyl; R.sub.2 may also be carboxymethyl provided that at least one of R.sub.1 and R.sub.2 is hydroxy; amino or alkylamino; R.sub.3 is a residue of a compound having adrenergic or monoamine oxidase activity and said residue is selected from the group consisting of ##STR82##

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 ##STR83##

wherein Q is hydrogen or hydroxy, L is hydrogen or C.sub.1-4 alkyl, G is hydrogen, C.sub.1-4 alkyl, or alkylphenyl wherein said phenyl group is optionally substituted by hydroxy or methylene dioxy, or is alkylamino; ##STR84##

each R.sub.4 group is independently selected from hydrogen, hydroxy, alkyl, alkoxy, fluoro, chloro, bromo, iodo, and trifluoromethyl; R.sub.5 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;

R.sub.6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms; R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.

46. A pharmaceutical composition comprising a compound of the formula: ##STR85##

wherein R.sub.1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl;

each R.sub.4 is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl provided that R.sub.2 is not hydroxy or methoxy when R.sub.1 is hydrogen and R.sub.3 is methyl and R.sub.4 is hydrogen, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, solvent or carrier.

47. A pharmaceutical composition comprising a compound of the formula: ##STR86##

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy or aryloxycarboxyl, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate, wherein the monoalkyl dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, or alkylphenyl or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, solvent or carrier with the proviso that the compound is not chlidanthine, leucotamine or sanguinine.

48. A pharmaceutical composition comprising a compound of the formula: ##STR87##

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxmethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl; each R.sub.4 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.

49. A method as claimed in claim 1 wherein the compound is one wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

50. A compound as claimed in claim 37 wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

51. A compound as claimed in claim 38 wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

52. A method of as claimed in claim 41 wherein the compound is one wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

53. A compound as claimed in claim 42 wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

54. A compound as claimed in claim 43 wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

55. A pharmaceutical composition comprising a compound of the formula: ##STR88##

wherein R.sub.1 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl group may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the monoalkyl, dialkyl or aryl group may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, or R.sub.5 -substituted benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl;

each R.sub.4 is independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, fluoro, chloro, bromo, iodo and trifluoromethyl provided that R.sub.2 is not hydroxy or methoxy when R.sub.1 is hydrogen and R.sub.3 is methyl and R.sub.4 is hydrogen, and a pharmaceutically acceptable diluent, solvent or carrier.

56. A composition according to claim 55 wherein R.sub.2 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, or hydroxy-substituted alkanoyloxy, benzoyloxy, wherein R.sub.5 is alkyl or alkoxy.

57. A pharmaceutical composition as claimed in claim 47 wherein the compound is one wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

58. A pharmaceutical composition comprising a compound of the formula ##STR89##

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, aryloxy, alkoxy of 1 to 6 carbon atoms, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group, wherein the monoalkyl, dialkyl or aryl group may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the monoalkyl, dialkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzoyloxy, wherein R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or alkylphenyl;

each R.sub.4 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 R.sub.1 is not alkoxy of 1-6 carbon atoms when R.sub.2 is hydroxy, R.sub.3 is methyl and all R.sub.4 's are hydrogen.

59. A pharmaceutical composition according to claim 58 wherein R.sub.2 is selected from the group consisting of hydrogen, amino, alkylamino, cyano, sulfhydryl, alkoxy of from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, aryl or benzyl carbamate group, (R.sub.5 -substituted aryl)oxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, or benzyloxy, wherein R.sub.5 is alkyl or alkoxy.

60. A method according to claim 4 wherein said compound is one wherein R.sub.3 and R.sub.4 are all hydrogen and R.sub.1 is alkoxy of 1 to 6 carbon atoms.

61. A compound as claimed in claim 43 wherein R.sub.1 is a carbonate group.

62. A compound as claimed in claim 37 wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate, wherein the aryl group may be R.sub.5 -substituted.

63. A pharmaceutical composition as claimed in claim 22 wherein the compound is one wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate wherein the aryl group may be R.sub.5 -substituted.

64. A compound as claimed in claim 42 wherein R.sub.1 is a carbonate group.

65. A pharmaceutical composition as claimed in claim 47 wherein the compound is one wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate, wherein the aryl group may be R.sub.5 -substituted.

66. A pharmaceutical composition as claimed in claim 48 wherein the active compound is one wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate, wherein the aryl group may be R.sub.5 -substituted.

67. A method of inhibiting acetylcholinesterase activity as claimed in claim 41 wherein the compound used is one wherein R.sub.1 is a carbonate group.
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