.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 6,569,848

« Back to Dashboard

Details for Patent: 6,569,848

Title: Compounds for the treatment of alzheimer's disease
Abstract:The present invention is directed to analogs of galanthamine of the structure ##STR1## wherein the R terms are herein defined, for use in treating Alzheimer's disease.
Inventor(s): Davis; Bonnie M. (Syosset, NY), Joullie; Madeleine M. (Philadelphia, PA)
Assignee: Davis; Bonnie (Syosset, NY)
Filing Date:Nov 28, 2000
Application Number:09/723,700
Claims:1. A method of treating a patient with Alzheimer's disease 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.

2. A method of treating a patient with Alzheimer's disease which comprises administering to said patient a therapeutically effective amount of a compound of the formula ##STR51## 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, aryloxy, aralkoxy, R.sub.5 -substituted aryloxy, monoalkyl, dialkyl or aryl carbamate group, wherein the alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, R.sub.5 -substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, and R.sub.5 -substituted benzoyloxy; or R.sub.2 is an alkoxy of 1-6 carbon atoms; 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.

3. A method according to claim 2 wherein said compound is of the formula ##STR52##

wherein R.sub.1 is hydroxy, 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.

4. A method according to claim 3, 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.

5. A method according to claim 2 wherein R.sub.3 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.

6. A method according to claim 2, 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.

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

8. A method as claimed in claim 2 wherein R.sub.1 is alkanoyloxy or a monoalkyl, dialkyl or aryl carbamate.

9. A method of treating a patient with Alzheimer's disease in a patient which comprises administering to said patient a therapeutically effective amount of a compound of the formula ##STR53## wherein the broken line represents an optionally present double bond wherein R.sub.1 is selected from the group consisting of hydroxy, 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 aryloxymethyl, alkanoyloxy, 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.

10. A method of treating a patient with Alzheimer's disease 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.

11. A method of treating a patient with Alzheimer's disease which comprises administering to said patient a therapeutically effective amount of a compound of the formula: ##STR54##

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 alkyl 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.

12. A method according to claim 11, 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.

13. 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.

14. A method of treating a patient with Alzheimer's disease 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.

15. A method for treating a patient with Alzheimer's disease which comprises administering to said patient a therapeutically effective amount of a compound of the formula ##STR55##

wherein 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 alkyl 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.

16. A method according to claim 15 wherein R.sub.1 is hydroxy, 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.

17. A method according to claim 15, 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 of treating a patient with Alzheimer's disease 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.

19. A method of treating a patient with Alzheimer's disease which comprises administering to said patient a therapeutically effective amount of a compound of the formula ##STR56##

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 aryloxymethyl, 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.

20. A method of treating a patient with Alzheimer's disease 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.

21. A method of treating a patient with Alzheimer's disease which comprises administering to the patient a therapeutically effective amount of a compound of the formula ##STR57##

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, ##STR58##

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, ##STR59##

wherein n is 3, 4, or 5, or ##STR60##

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

22. A method as claimed in claim 21 wherein R.sub.1 is alkoxy of 1-6 carbon atoms.

23. A method of treating a patient with Alzheimer's disease as claimed in claim 21 wherein R.sub.1 is a carbonate group.

24. A method of treating a patient with Alzheimer's disease which comprises administering to said patient a therapeutically effective amount of a compound of the formula: ##STR61## 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 alkyl or aryl moiety may be R.sub.5 -substituted or unsubstituted, R.sub.5 -substituted aryloxmethyl, 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 ##STR62## 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 ##STR63## 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, ##STR64## wherein G is as defined above; ##STR65## 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.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc