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Details for Patent: 6,150,354

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Details for Patent: 6,150,354

Title: Compounds for the treatment of Alzheimer's disease
Abstract:A method of treating Alzheimer's disease and related dementias by treatment with analogs of galanthamine, particularly those wherein the methoxy and hydroxy substituents are replaced by, for example carbamate groups, the methoxy is replaced by hydroxy and esters of galanthamine and O-desmethyl galanthamine. Many of the useful compounds are novel.
Inventor(s): Davis; Bonnie (Huntington, NY), Joullie; Madeleine M. (Philadelphia, PA)
Assignee: Davis; Bonnie (Syosset, NY)
Filing Date:Oct 19, 1993
Application Number:08/139,338
Claims:1. A method of inhibiting acetyl, cholinesterase activity in a patient which comprises administering to said patient a compound selected from the group consisting of galanthamine 13-acetate, a galanthamine alkyl or aryl carbamate and lycoramine.

2. 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 I ##STR45## 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, a monoalkyl, dialkyl or aryl carbamate group wherein the alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, alkanoyloxy, hydroxy-substituted alkanoyloxy, and benzoyloxy,

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, phenyl, or alkylphenyl or R.sub.3 is heterocyclic selected from .alpha.- or .beta.- furyl, .alpha.- or .beta.-thienyl, pyridyl, pyrazinyl, and pyrimidyl, each R.sub.4 is independently selected from hydrogen, hydroxy, 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.6 is selected from the group consisting of hydrogen, halo, trifluoromethyl and alkyl of 1 to 4 carbon atoms;

R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms, with the proviso that R.sub.3 is not methyl when R.sub.1 is methoxy, R.sub.2 is hydroxyl and all R.sub.4 's are hydrogen; 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 of the formula ##STR46## wherein R.sub.1 is hydroxyl, alkoxy of 1-6 carbon atoms, aryloxy, R.sub.5 -substituted aryloxy, benzoyloxy or 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, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo, and trifluoromethyl.

4. A method according to claim 2, where R.sub.1 is selected from the group consisting of hydroxyl, methoxy, ethoxy, mono alkyl 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 or trifluoromethyl, R.sub.2 is hydroxyl and all of R.sub.3, R.sub.4, R.sub.6 and R.sub.9 are hydrogen.

5. A method according to claim 2, wherein said compound is of the formula: ##STR47## wherein R.sub.2 is hydroxyl, alkoxy of 1-6 carbon atoms, aryloxy, R.sub.5 -substituted aryloxy, benzyloxy, benzoyloxy or is a monoalkyl, dialkyl or aryl carbamate group wherein the alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted wherein R.sub.5 is alkyl or alkoxy and R.sub.3 is hydrogen or alkyl of 1-6 carbon atoms, cyclopropylmethyl or benzyl.

6. A method according to claim 5, wherein R.sub.2 is selected from the group consisting of hydroxyl, methoxy, monoalkyl carbamate, phenyl carbamate, naphthyl carbamate, R.sub.5 -substituted phenyl carbamate, and R.sub.5 -substituted naphthyl carbamate wherein R.sub.5 is alkyl or alkoxy.

7. A method according to claim 5, herein R.sub.3 is selected from the group consisting of hydrogen, methyl and ethyl.

8. A method of inhibiting acetycholinesterase 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-desmethylgalanthamine O-benzyl ether; wherein the etherification is in the 2-position; the carbamates: O-desmethyl galanthamine phenyl carbamate; O-desmethyl galanthamine-N-desmethyl-.alpha.-naphthyl carbamate, O-desmethyl galanthamine 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-desmethyl galanthamine phenyl, .alpha.-naphthyl, dimethyl or diethyl carbamates wherein the carbamate substitution is at the 2-position; O-desmethyl-N-desmethyl-N-ethyl galanthamine; O-desmethyl-N-desmethyl-N-ethyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position, O-desmethyl-N-desmethyl-N-ethyl galanthamine 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-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position; O-desmethyl-N-cyclopropylmethylgalanthamine phenyl, a-naphthyl, dimethyl or diethyl carbamate wherein said carbamate substitution is in the 2-position; O-desmethyl-N-desmethyl-N-benzylgalanthamine O-methyl, O-ethyl or benzyl ether wherein said etherification is in the 2-position, and O-desmethyl-N-desmethyl-N-benzyl galanthamine phenyl, .alpha.-naphthyl, dimethyl or diethyl carbamate wherein the carbamate substitution is in the 2-position.

9. A method according to claim 2, wherein said compound is of the formula: ##STR48## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 2.

10. A method according to claim 9, wherein the compound employed is one wherein R.sub.1 is hydroxyl, benzoyloxy, amino, alkylamino or a monoalkyl, dialkyl or aryl carbamate, R.sub.2 is hydroxyl, alkoxy of 1-6 carbon atoms, aryloxy, benzoyloxy or a monoalkyl, dialkyl or aryl carbamate group and R.sub.3 is hydrogen, methyl, ethyl, cyclopropyl methyl or phenyl.

11. A method of inhibiting acetyl cholinesterase activity in a patient which comprises administering to the patient a pharmaceutically acceptable amount of a compound selected from O-desmethyl lycoramine; N-desmethyl-O-desmethyl lycoramine; N-desmethyl N-ethyl lycoramine; O-desmethyllycoramine-13-ethyl ether; 2-deoxy-13-O-desmethyl-lycoramine; 13-O-desmethyllycoramine-2-benzyl ether; O-desmethyllycoramine-2-dimethyl carbamate, and O-desmethyllycoramine-2-phenyl carbamate.

12. A method according to claim 2, wherein the administration is parenteral at a daily dosage of 0.5-1,000 mg of a compound of Formula I as specified in claim 2 or pharmaceutically-acceptable acid addition salt thereof.

13. A method according to claim 3, wherein the administration is parenteral at a daily dosage of 0.5-1,000 mg of a compound of as specified in claim 3 or a pharmaceutically-acceptable acid addition salt thereof.

14. A method according to claim 9, wherein the administration is parenteral at a daily dosage of 0.5-1,000 mg of said compound or a pharmaceutically acceptable acid addition salt thereof.

15. A method according to claim 2, wherein a compound of Formula I is administered at a dosage rate of 0.1-300 mg per day or a pharmaceutically acceptable acid addition salt thereof.

16. A method according to claim 2, wherein said compound is administered orally in the form of tablets or capsules containing 5, 10 or 25 mg of hydrobromide of said compound.

17. A method according to claim 3, wherein said compound is administered orally in the form of tablets or capsules containing 5, 10 or 25 mg of hydro-bromide of said compound.

18. A method according to claim herein said compound is administered at a dosage rate of 0.001 to 4 mg/kg body weight of a patient, parenterally.

19. A method according to claim 2, wherein a compound is administered intracerebroventricularly via an implanted reservoir at a dosage rate of 0.0001 to 5.0 mg/kg per day.

20. A method according to claim 2, wherein a compound is administered in a sustained release formulation.

21. A compound of the formula: ##STR49## wherein R.sub.1 and R.sub.2 are each selected independently from the group consisting of hydrogen, hydroxyl, amino, alkylamino, cyano, sulfhydryl, aralkoxy, monoalkyl, dialkyl or aryl carbamate group wherein the alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, and benzoyloxy wherein R.sub.5 is alkyl or alkoxy; or R.sub.2 may be alkanoyloxy,

R.sub.3 is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, or cycloalkylmethyl, with the proviso that the compound is not leucotamine, sanguinine, or N,O-diacetyl-N-desmethylgalanthamine.

22. A compound of the formula: ##STR50## wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxyl, 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 alkyl 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.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 alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, 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 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 or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not leucotamine, O-methylleucotamine, O-methylleucotamine acetate, sanguinine, chlidanthine or N,O-diacetyl-N-desmethylgalanthamine.

23. A compound of the formula: ##STR51## wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino, cyano, sulfhydryl, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, alkanoyloxy, hydroxyl-substituted alkanoyloxy, and benzoyloxy wherein R.sub.5 is alkyl or alkoxy;

R.sub.2 is selected from the group consisting of hydrogen, hydroxyl, 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 alkyl or aryl moiety may be R.sub.5 -substituted, or unsubstituted, 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 alkylphenyl;

each R.sub.4 is independently selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy of 1-6 carbon atoms aryloxy, alkaryloxy, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo and trifluoromethyl, or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not leucotamine, sanguinine, chlidanthine, or N,O-diacetyl-N-desmethyl-galanthamine.

24. A compound of the formula ##STR52## wherein R.sub.1 is hydroxyl, alkoxy of 1-6 carbon atoms or alkanoyloxy, R.sub.2 is OCONHR wherein R is alkyl of 1 to 6 carbon atoms, phenyl or R.sub.5 -substituted phenyl wherein R.sub.5 is selected from alkyl and alkoxy; R.sub.3 is hydrogen, lower alkyl or cyclopropylmethyl and R.sub.4 are all hydrogen.

25. A compound of the formula ##STR53## wherein R.sub.1 is OCONHR wherein R is alkyl of 1 to 6 carbon atoms, phenyl or R.sub.5 -substituted phenyl wherein R.sub.5 is selected from alkyl and alkoxy; R.sub.2 is hydroxyl, alkoxy of 1-6 carbon atoms, alkanoyloxy or OCONHR wherein R is alkyl of 1-6 carbon atoms, phenyl or R.sub.5 -substituted phenyl, wherein R.sub.5 is selected from alkyl and alkoxy, R.sub.3 is hydrogen, lower alkyl or cyclopropyl methyl and R.sub.4 are all hydrogen.

26. A method of inhibiting acetyl cholinesterase activity in a patient which comprises administering to the patient a therapeutically effective amount of a compound of the formula: ##STR54## wherein the broken line represents an optionally present double bond and R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, OR, amino, NHR, CH.sub.2 OH, OC(O)R.sub.5 or OC(O)OR wherein R is alkyl of 1-6 carbon atoms, phenyl, R.sub.5 -substituted phenyl or benzyl and R.sub.5 is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, aryloxy, nitro, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl; and

R.sub.3 is selected from hydrogen, branched or linear alkyl of 1 to 6 carbon atoms, ##STR55## wherein n is 3, 4 or 5, ##STR56## wherein R.sub.11 is hydrogen, alkyl or alkoxy of 1-6 carbon atoms.

27. A method of inhibiting acetycholinesterase activity in a patient which comprises administering to said patient a compound selected from the group consisting of N-desmethyl galanthamine; O-desmethyl, N-desmethyl galanthamine-13-O-ethyl ether; O-desmethyl, N-desmethyl galanthamine-13-O-phenyl ether; O-desmethyl, N-desmethyl galanthamine- 13-O-benzyl ether; O-desmethyl, N-desmethyl galanthamine-13-phenyl carbamate; O-desmethyl, N-desmethyl galanthamine-13-.alpha.-naphthyl carbamate; O-desmethyl, N-desmethyl galanthamine-13-dimethyl carbamate; and O-desmethyl, N-desmethyl N-ethyl galanthamine.

28. A method as claimed in claim 2, wherein the compound is one wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

29. A compound as claimed in claim 22, wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

30. A method as claimed in claim 2, wherein the compound is one wherein R.sub.1 is alkanoyloxy or a mono alkyl, dialkyl or aryl carbamate wherein the alkyl or aryl moiety may be R.sub.5 -substituted wherein R, 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.

31. A compound as claimed in claim 2, wherein R.sub.1 is a monoalkyl, dialkyl or aryl carbamate wherein the alkyl or aryl moiety may be R.sub.5 -substituted and R.sub.5 is alkyl or alkoxy.

32. A compound as claimed in claim 21, wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate wherein the alkyl or aryl group may be R.sub.5 -substituted and R.sub.5 is alkyl or alkoxy.

33. A compound as claimed in claim 23, wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate wherein the alkyl or aryl group may be R.sub.5 -substituted and R.sub.5 is alkyl or alkoxy.

34. A pharmaceutical composition comprising a compound of the formula:

wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxyl, amino, alkylamino, ##STR57## 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 alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, alkanoyloxy, hydroxyl-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 from 1 to 6 carbon atoms, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the allyl 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 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, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

35. The method as claimed in claim 5, wherein the compound employed is a galanthamine-2-(C.sub.1-6 alkyl carbamate).

36. The method as claimed in claim 35, wherein the compound employed is galanthamine-2-n-butyl carbamate.

37. Galanthamine-2-(C.sub.1-6 alkyl carbamate).

38. Galanthamine-2-n-butyl carbamate.

39. A method of inhibiting acetyl cholinesterase activity in a patient which comprises administering to said patient a compound of the formula ##STR58## 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, alkoxy of 1-6 carbon atoms, alkanoyloxy, a monoalkyl, dialkyl or aryl carbamate group wherein the alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, R.sub.5 is alkyl or alkoxy;

R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl or a pharmaceutically acceptable acid addition salt thereof with the proviso that R.sub.3 is not methyl when R.sub.1 is methoxy, and R.sub.2 is hydroxy.
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