Compounds for the treatment of Alzheimer's disease
AssigneeBonnie Davis
InventorsBonnie Davis, Madeleine M. Joullie
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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.
Claims39
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Galanthamine-2-(C.sub.1-6 alkyl carbamate).
Galanthamine-2-n-butyl carbamate.
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.
Dependencies are inferred from the claim text.