Compounds for the treatment of alzheimer's disease

Abstract

The present invention is directed to analogs of galanthamine of the structure and their use in treating Alzehimer's diseases and related dementias.

1 . A method of treating Alzheimer's disease and related dementias which comprises administering to a patient suffering from such a disease a therapeutically effective amount of a compound of the Formula I  
       
         
           
           
               
               
           
         
       
       wherein the broken line represents an optionally present double bond in one or two of the positions shown, R 1  and R 2  are each selected independently from the group consisting of hydrogen, hydroxyl, amino, phenylamino or alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, alkylthio, aryloxy, aralkoxy, C 1-6  alkyl carbonate or R 5 -substituted phenyl or benzyl carbonate, R 5 -substituted aryloxy, R 5 -substituted arylthio, aralkoxy t an aliphatic or aryl carbamyl group wherein the aliphatic or aryl moiety may be R 5  substituted or unsubstituted, aralkylthio, R 5 -substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, aryloxy carbonyl, R 1  may also be alkyl of up to 14 carbon atoms, or hydroxy methyl, R 2  may also be carboxymethyl provided that at least one of R 1  and R 2  is hydroxy, amino or alkylamino unless R 7  or R 8  is hydroxymethyl, 
 R 3  is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkyl methyl, phenyl, R 5  substituted phenyl, alkylphenyl, R 5  alkylphenyl, heterocyclic selected from α- or β-furyl, α- or β-thienyl or thenyl, pyridyl, pyrazinyl and pyrimidyl, alkyl heterocyclic or R′-substituted heterocyclyl, where R′ is alkyl or alkoxy and heterocyclyl is selected from α- or  
 β-furyl, thienyl, thenyl, pyridyl, pyrazinyl, pyrimidyl or is methylpyrryl or  
 R 3  is alkanoyl of 1 to 8 carbon atoms or aroyl wherein the aryl group is of 6 to 10 carbon atoms, the alkyl and aryl portions of said groups optionally being substituted by R 5  groups as hereinafter defined or  
 R 3  is the residue of a compound having adrenergic or monoamino oxidase activity and said residue being selected from the group consisting of  
                     
 wherein Hal is a halogen, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1 and Z is selected from the group consisting of  
                     
 wherein Q is hydrogen or hydroxy, L is hydrogen or C 1-4  alkyl, G is hydrogen, C 1-4  alkyl, alkylphenyl wherein said phenyl group is optionally substituted by hydroxy or methylene deoxy, or is alkylamino  
                     
 wherein G is as defined above,  
                     
 c) CH 2 CH 2 NH—NH 2  and  
                     
 each R 4  is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkarloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo iodo and trifluoromethyl, R 5  is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl,  
 R 6  is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms,  
 R 7  is selected from the same groups as R 4  or may be hydroxy alkyl of 1-2 carbon atoms,  
 R 8  is hydrogen or hydroxymethyl,  
 R 9  is hydrogen or alkyl of 1 to 6 carbon atoms, or when R 2  is hydroxyl R 9  may be  
                     
 or  
 R 2  and R 9  may jointly form a keto group provided that R 1  is hydroxy or amino,  
 X is oxygen or NH  
 Y is nitrogen  
 with the proviso that when X is O, R 3  is not methyl when R 1  is methoxy, R 2  is hydroxy, all R 4 's are hydrogen or a pharmaceutically acceptable acid addition salt thereof.  
 
     
     
         2 . A method according to  claim 1  wherein the compounds used is on wherein R 1  and R 2  are each selected from 
 H, OR, SH, NH 2 , NHR,  
 CH 2 OH, CONHR  
                     
 wherein R is alkyl 1-6 carbon atoms or phenyl or naphthyl or R 5 -substituted naphthyl or R 5 -substituted phenyl or benzyl or R 5 -substituted benzyl, wherein R 5  is as defined in  claim 1  and R 10  is hydrogen, alkyl or alkoxy, R 3  is —H, or branched or linear alkyl or  
 —CH 2 —CH (CH 2 ) n    
 wherein n is 3, 4 or 5,  
                     
 wherein R 11  is as defined for R 10  above or is hydroxy or amino or R 3  is  
                     
 wherein Z is O, S, or NH or  
                     
 X is oxygen and Y is nitrogen.  
 
     
     
         3 . A method according to  claim 1  wherein said compound is of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydroxy, lower alkoxy, aryloxy, R 5  substituted aryloxy, benzyloxy or R 5  substituted benzyloxy, amino, alkylamino or an alkyl or aryl carbamyl group.  
     
     
         4 . A method according to  claim 3 , wherein R 1  is selected from the group consisting of hydroxy, methoxy, ethoxy, mono lower alkyl carbamate, phenyl carbamate, naphthyl carbamate, R 5 -substituted phenyl carbamate and R 5 -substituted naphthyl carbamate wherein R 5  is hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo or trifluoromethyl.  
     
     
         5 . A method according to  claim 3 , wherein said compound is selected from N-desmethyl galanthamine, O-desmethyl, N-desmethyl galanthamine; 13-O-ethyl, O-desmethyl, N-desmethyl galanthamine; 13-O-phenyl, O-desmethyl, N-desmethyl galanthamine; and 13-O-benzyl, O-desmethyl, N-desmethyl galanthamine; O-desmethyl, N-desmethyl, N-ethyl galanthamin; O-desmethyl, N-desmethyl, N-ethyl galanthamine, 13-O-methyl, 13-O-ethyl and 13-O-benzyl ethers; O-desmethyl, N-desmethyl, N-ethyl galanthamine, 13-phenyl, 13-α-naphthyl, 13-dimethyl and 13-diethyl carbamates; O-desmethyl, N-desmethyl, N-cyclopropyl methyl galanthamine; O-desmethyl, N-desmethyl, N-cyclopropyl methyl galanthamine, 13-O-methyl, 13-O-ethyl and 13-O-benzyl ethers; O-desmethyl, N-desmethyl, N-cyclopropylmethyl galanthamine, 13-phenyl, 13-d-α-naphthyl, 13-dimethyl and 13-diethyl carbamates; O-desmethyl, N-desmethyl, N-benzyl galanthamine; O-desmethyl, N-desmethyl, N-benzyl galanthamine, 13-O-methyl, 13-O-ethyl and 13-O-benzyl ethers and O-desmethyl, N-desmethyl, N-benzyl galanthamine.  
     
     
         6 . A method according to  claim 1  wherein said compound is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  is hydroxy, lower alkoxy, aryloxy, R 5 -substituted aryloxy, benzyloxy or R 5 -substituted benzyloxy or is an alkyl or aryl carbamyl group and R 3  is hydrogen or alkyl of 1-6 carbon atoms, methyl cyclopropyl or benzyl or R 5 -substituted benzyl wherein R 5  is hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo or trifluoromethyl.  
     
     
         7 . A method according to  claim 6  wherein R 2  is selected from the group consisting of hydroxy, methoxy, mono lower alkyl carbamate, phenyl carbamate, naphthyl carbamate, R 5 -substituted phenyl carbamate, R 5 -substituted naphthyl carbamate, lower alkanoyloxy benzoyloxy and R 5 -substituted benzoyloxy wherein R 5  is hydroxyl, sulfhydryl, alkyl, aryl, -alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryl, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo iodo or trifluoromethyl.  
     
     
         8 . A method according to  claim 7  wherein R 3  is selected from the group consisting of hydrogen, methyl and ethyl.  
     
     
         9 . A method according to  claim 6 , wherein said compound is selected from O-desmethyl galanthamine; O-demethyl galanthamine, O-methyl ether; O-desmethyl galanthamine, O-ethyl ether; O-desmethyl galanthamine, O-benzyl ether; O-desmethyl galanthamine, phenyl and O-desmethyl N-desmethyl galanthamine, α-naphthyl carbamates; O-desmethyl galanthamine dimethyl carbamate and O-desmethyl galanthamine diethyl carbamate wherein the carbamyl group is bonded to the oxygen of the cyclohexene ring, O-desmethyl N-desmethyl galanthamine; O-desmethyl N-desmethyl galanthamine, O-methyl, O-ethyl and O-benzyl ethers wherein etherification is at the 2-position; O-desmethyl N-desmethyl galanthamine phenyl, α-naphthyl, dimethyl and 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, α-naphthyl, dimethyl or diethyl carbamate wherein said carbamate substitution is in the 2-position; O-desmethyl-N-desmethyl-N-cyclopropyl methyl galanthamine, 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-cyclopropylmethyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position; O-desmethyl-N-desmethyl-N-cyclopropylmethyl galanthamine phenyl, α-naphthyl, dimethyl or diethyl carbamate wherein said carbamate substitution is in the 2-position; O-desmethyl-N-desmethyl-N-benzyl galanthamine; O-desmethyl-N-desmethyl-N-benzyl galanthamine, O-methyl, O-ethyl or O-benzyl ether wherein said etherification is in the 2-position, O-desmethyl-N-desmethyl-N-benzyl galanthamine phenyl, α-naphthyl, dimethyl or diethyl carbamate wherein the carbamate substitution is in the 2-position.  
     
     
         10 . A method according to  claim 1 , wherein said compound is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are as defined in  claim 1 .  
     
     
         11 . A method according to  claim 10 , wherein the compound employed is one wherein R 1  is hydroxy, lower alkoxy, benzyloxy or R 5  substituted benzyloxy, amino alkylamino or alkyl or aryl carbamyl, R 2  is hydroxy, lower alkoxy, aryloxy, benzyloxy or an alkyl or aryl carbamyl group and R 3  is hydrogen, methyl, ethyl, cyclopropyl methyl or benzyl.  
     
     
         12 . A method according to  claim 11 , wherein said compound is selected from O-desmethyl lycoramine; N-desmethyl, O-desmethyl lycoramine; N-desmethyl N-ethyl lycoramine; N-desmethyl N-cyclopropylmethyl lycoramine; N-desmethyl N-benzyl lycoramine; O-desmethyl lycoramine ethyl ether; 2-deoxy-13-O-desmethyl lycoramine; 2-O-deoxy-13-O-desmethyl lycoramine, benzyl ether O-desmethyl lycoramine-dimethyl carbamate, O-desmethyl lycoramine phenyl carbamate, -2-O-deoxy-13-desmethyl lycoramine dimethyl carbamate and 2-O-deoxy-13-desmethyl lycoramine dimethyl carbamate.  
     
     
         13 . A method according to  claim 1 , wherein said compound is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 3  is selected from hydrogen, lower alkyl, cycloalkyl methyl or benzyl.  
     
     
         14 . A method according to  claim 1  wherein said compound of formula I is one wherein R 1  is hydroxy, methoxy, ethoxy, acetyloxy or carbamoyl of the formula CONHR 11  wherein R 11  is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-valeryl, phenyl, naphthyl, and fluoro- or nitro-substituted phenyl or naphthyl, R 2  is hydroxy, methoxy, ethoxy, acetyloxy, propionyloxy, n-valeroyloxy, i-valeroyloxy or CONHR 11  wherein R 11  is as defined above and R 3  is hydrogen, methyl or ethyl.  
     
     
         15 . A method according to  claim 14 , wherein in the compound employed, the ring to which R 2  is bonded is a cyclohexane ring.  
     
     
         16 . A method according to  claim 1  wherein the compound employed is selected from the group consisting of galanthamine n-butyl carbamate, galanthamine acetate, O-demethyl galanthamine-13-methylcarbamate, N-demethyl galanthamine and childanthine.  
     
     
         17 . A method according to  claim 1 , wherein the administration is parenteral at a daily dosage of 0.5-1,000 mg of a compound of formula 1 as specified in  claim 1  or a pharmaceutically-acceptable acid addition salt thereof.  
     
     
         18 . 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.  
     
     
         19 . A method according to  claim 10 , wherein the administration is parenteral at a daily dosage of 0.5-1,000 mg of said compound.  
     
     
         20 . A method according to  claim 13 , wherein the administration is parenteral at a daily dosage of 0.5-1,000 mg of said compound.  
     
     
         21 . A method according to  claim 1 , wherein a compound of Formula I is administered at a dosage rate of 0.1-300 mg per day.  
     
     
         22 . A method according to claims  1 , wherein said compound is administered orally at a dosage in the range 0.1-2000 mg per day.  
     
     
         23 . A method according to  claim 3 , wherein said compound is administered orally at a dosage in the range 0.1-2000 mg per day.  
     
     
         24 . A method according to  claim 13 , wherein said compound is administered orally at a dosage in the range 0.1-200 per day.  
     
     
         25 . A method according to  claim 24 , wherein said dosage rate of 0.1-200 mg per day.  
     
     
         26 . A method according to  claim 1 , wherein said compound is administered at a dosage rate of 0.001 to 4 mg/kg body weight of a patient, parenterally.  
     
     
         27 . A method according to claims  1 , wherein a compound is administered intracerebroventricularly via an implanted reservoir at a dosage rate of 0.0001 to 5.0 mg/kg per day.  
     
     
         28 . A method according to any one of  claim 1 , wherein a compound is administered in a sustained release formulation.  
     
     
         29 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein the broken line represents an optionally present double bond in one of the two positions shown, R 1  and R 2  are each selected independently from the group consisting of hydrogen, hydroxyl, amino or alkylamino, cyano, sulfhydryl, alkoxy preferably of 1-6 carbon atoms, alkylthio, aryloxy, arylthio, R 5 -substituted aryloxy, R 5 -substituted arylthio, aralkoxy, an aliphatic or aryl carbamyl group wherein the aliphatic or aryl moiety may be R 5  substituted or unsubstituted, aralkylthio, R 5 -substituted aralkoxy, R 5 -substituted aralkylthio, aryloxymethyl, R 5  substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, R 5 -substituted benzoyloxy, aryloxy carbonyl and R 5 -substituted aryloxy carbonyl, R 1  may also by alkyl of up to 14 carbon atoms, or hydroxy methyl, R 2  may also be keto; R 2  may also be carboxymethyl provided that at least one of R 1  and R 2  is hydroxy amino or alkylamino unless R 7  or R 8  is hydroxymethyl, 
 R 3  is hydrogen, straight or branched chain alkyl, preferably of 1-6 carbon atoms, cycloalkyl methyl, alkylphenyl, R 5 -substituted alkylphenyl, heterocyclic selected from the group consisting of α- or β-furyl, α- or β-thienyl or thenyl, pyridyl, pyrazinyl or pyrimidyl groups or  
 R 3  is an alkyl or alkoxy substituted derivative of said heterocyclic groups or  
 R 3  is alkanoyl of 1 to 8 carbon atoms or aroyl wherein the aryl group is of 6 to 10 carbon atoms, the alkyl and aryl portions of said groups optionally being substituted by R 5  groups as hereinafter defined or  
 R 3  is the residue of a compound having adrenergic or monoamino oxidase activity and is selected from the group consisting of  
                     
 wherein Hal is a halogen, preferably chloro, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1 and Z is selected from the group consisting of  
                     
 wherein Q is hydrogen or hydroxy, L is hydrogen or C 1-4  alkyl, G is hydrogen, C 1-4  alkyl, alkylphenyl wherein said phenyl group is optionally substituted by hydroxy or methylene deoxy, or is alkyl alkanylamino  
                     
 wherein G is as defined above,  
                     
 c) —CH 2 —CH 2 NH—NH 2  and  
                     
 each R 4  is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkylaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo, and trifluoromethyl, and R 5  is selected from the groups consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo and trifluoromethyl,  
 R 6  is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms,  
 R 7  is selected from the same groups as R 4  or may be hydroxy or mercapto alkyl of 1-2 carbon atoms,  
 R 8  is hydrogen or hydroxymethyl,  
 R 9  is hydrogen or alkyl of 1 to 6 carbon atoms, or when R 2  is hydroxyl R 9  may be  
                     
 R 2  and R 9  may jointly form a semi carbazone, oxime, phenyl hydrazone or keto group,  
 and pharmaceutically-acceptable acid addition salts thereof with the provisoes that 1) is not methyl when R 1  is methoxy, R 2  is hydroxy, and all R 4 's are hydrogen, 2) that when the 3-4 bond is saturated that R 1  is not hydrogen when R 2  is methoxy or hydrogen, R 4  is hydrogen, R 3  is methyl and R 7  is hydrogen or ethoxy, 3) R 1  is not acetoxy when R 2  is hydroxy, R 3  is methyl, R 4  is hydrogen and R 7  is hydrogen, 4) when R 2  is hydroxy, R 3  is not hydrogen or benzyl when R 1  is methoxy and all of R 4  and R 7  are hydrogen, and 5) that the compound is not leucotamine, O-methyl leucotamine, O-methyl leucotamine acetate, sanguinine, lycoramine, O-demethyl lycoramine, childanthine, habranthine, N-formyl galanthamine, acetyl dihydrogalanthamine or N,O-diacetyl N-demethyl galanthamine, deoxydemethyl lycoramine, dihydrochildanthine, sanguinine, dihydrosanguinine lycoramine acetate, deoxylycoramine or deoxydemethyl, lycoramine carbamate.  
 
     
     
         30 . A compound according to  claim 29 , wherein R 1  is CONHR wherein R is alkyl of 1-6 carbon atoms, phenyl or R 5 -substituted phenyl or naphthyl or R 5 -substituted naphthyl or benzyl or R 5  substituted benzyl wherein R 5  is selected from hydroxy, sulfhydryl alkyl, aryl, aralkyl, alkoxy, thioalkyl, aryloxy, thioaryl, alkaryloxy, thioalkaryl, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl; R 2  is hydroxy, alkoxy of 1-6 carbon atoms, alkanoyloxy of 1-6 carbon atoms or CONHR wherein R is as defined above, R 3  is hydrogen, lower alkyl or cyclopropyl substituted lower alkyl and R 4 , R 6 , R 7 , R 8  and R 9  are all hydrogen.  
     
     
         31 . A compound according to  claim 29  wherein R 1  is hydroxy, alkoxy of 1-6 carbon atoms or alkanoyloxy of 1-6 carbon atoms, R 2  is CONHR wherein R is as defined in  claim 32 , R 3  is hydrogen, lower alkyl or cyclopropyl substituted lower alkyl and each of R 4 , R 6 , R 7 , R 8  and R 9  are hydrogen.  
     
     
         32 . A compound according to  claim 29:  galanthamine n-butyl carbamate.  
     
     
         33 . A compound according to  claim 29:  galanthamine n-propyl carbamate.  
     
     
         34 . A compound according to  claim 29:  galanthamine phenyl carbamate.  
     
     
         35 . A compound according to  claim 29:  galanthamine naphthyl carbamate.  
     
     
         36 . A compound according to  claim 29:  O-demethyl galanthamine-13-methyl carbamate.  
     
     
         37 . A compound according to  claim 29:  galanthamine acetate.  
     
     
         38 . A pharmaceutical composition for treatment of Alzheimer's disease and related dementias comprising a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein the broken line represents an optionally present double bond in one or two of the positions shown, R 1  and R 2  are each selected independently from the group consisting of hydrogen, hydroxyl, amino, phenylamino or alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, alkylthio, aryloxy, aralkoxy, C 1-6  alkyl carbonate or R 5 -substituted phenyl or benzyl carbonate, R 5 -substituted aryloxy, R 5 -substituted arylthio, aralkoxy, an aliphatic or aryl carbamyl group wherein the aliphatic or aryl moiety may be R 5  substituted or unsubstituted, aralkylthio, R 5 -substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, aryloxy carbonyl, R 1  may also be alkyl of up to 14 carbon atoms, or hydroxy methyl, R 2  may also be carboxymethyl provided that at least one of R 1  and R 2  is hydroxy, amino or alkylamino unless R 7  or R 8  is hydroxymethyl, 
 R 3  is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkyl methyl, phenyl, R 5  substituted phenyl, alkylphenyl, R 5  alkylphenyl, heterocyclic selected from α- or β-furyl, α- or β-thienyl or thenyl, pyridyl, pyrazinyl and pyrimidyl, alkyl heterocyclic or R′-substituted heterocyclyl, where R′ is alkyl or alkoxy and heterocyclyl is selected from α- or  
 β-furyl, thienyl, thenyl, pyridyl, pyrazinyl, pyrimidyl or is methylpyrryl or  
 R 3  is alkanoyl of 1 to 8 carbon atoms or aroyl wherein the aryl group is of 6 to 10 carbon atoms, the alkyl and aryl portions of said groups optionally being substituted by R 5  groups as hereinafter defined or  
 R 3  is the residue of a compound having adrenergic or monoamino oxidase activity and said residue being selected from the group consisting of  
                     
 wherein Hal is a halogen, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1 and Z is selected from the group consisting of  
                     
 wherein Q is hydrogen or hydroxy, L is hydrogen or C 1-4  alkyl, G is hydrogen, C 1-4  alkyl, alkylphenyl wherein said phenyl group is optionally substituted by hydroxy or methylene deoxy, or is alkylamino  
                     
 wherein G is as defined above,  
                     
 c) CH 2 CH 2 NH—NH 2  and  
                     
 each R 4  is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkarloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo iodo and trifluoromethyl, R 5  is selected from the group consisting of hydroxyl, sulfhydryl, alkyl, aryl, alkoxy, mercaptoalkyl, aryloxy, mercaptoaryl, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, fluoro, chloro, bromo, iodo and trifluoromethyl,  
 R 6  is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms,  
 R 7  is selected from the same groups as R 4  or may be hydroxy alkyl of 1-2 carbon atoms,  
 R 8  is hydrogen or hydroxymethyl,  
 R 9  is hydrogen or alkyl of 1 to 6 carbon atoms, or when R 2  is hydroxyl R 9  may be  
                     
 or  
 R 2  and R 9  may jointly form a keto group provided that R 1  is hydroxy or amino,  
 X is oxygen or NH  
 Y is nitrogen  
 with the proviso that when X is O, R 3  is not methyl when R 1  is methoxy, R 2  is hydroxy, all R 4 's are hydrogen and a pharmaceutically acceptable solvent diluent or carrier.  
 
     
     
         39 . A composition according to  claim 38  in the form of a Sustained release product.  
     
     
         40 . A method of treating Alzheimer's disease and related dementias comprising administering to a patient suffering from such a disease a therapeutically effective amount of lycoramine.