Patent ID: 6153652
Filing Date: 2000-11-28
Classification: A61K

Abstract:
A method for inhibiting .beta.-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of .beta.-amyloid peptide wherein said compounds are represented by formula I: ##STR10## wherein R.sup.1 is selected from the group consisting of(a) alkyl, alkenyl, alkaryl, alkcycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy;(b) a substituted phenyl group of formula II: ##STR11## wherein R is alkylene of from 1 to 8 carbon atoms, m is an integer equal to 0 or 1,R.sup.a and R.sup.a' are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl;R.sup.b and R.sup.b' are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halo, heteroaryl, heteroaryloxy, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and --C(O)R.sup.4 where R.sup.4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy; andR.sup.c is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and where R.sup.b and R.sup.c are fused to form a methylenedioxy ring with the phenyl ring; andwhen R.sup.b and/or R.sup.b' and/or R.sup.c is fluoro, chloro, bromo and/or nitro, then R.sup.a and/or R.sup.a' can also be chloro; and(c) 1- or 2-naphthyl substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy;R.sup.2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms; andR.sup.3 and R.sup.3' are independently selected from the group consisting of:(a) hydrogen with the proviso that both R.sup.3 and R.sup.3' cannot be hydrogen;(b) alkyl with the proviso that when R.sup.3 is hydrogen, then the R.sup.3' alkyl group has a linear carbon chain length of at least 5 carbon atoms from the nitrogen atom which chain can be optionally substituted with one or more alkyl groups and with the further proviso that when both R.sup.3 and R.sup.3' are alkyl then at least one of the alkyl group has a carbon chain length of at least 5 carbon atoms which chain can be optionally substituted with one or more alkyl groups;(c) --(R.sup.7).sub.n (W).sub.p wherein R.sup.7 is an alkylene group, W is selected from the group consisting of: ##STR12## where R.sup.5, R.sup.5', R.sup.9 and R.sup.9' are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, an alkyl group having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acyloxy, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxyl, esters, thio, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- heterocyclic amino, mono -and di-heteroaryl amino and unsymmetric, di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroayl, and heterocyclic provided that when the substituent is monoheteroarylamino or unsymmetric di- substituted amines having different substituents selected from alkyl and heteroaryl then the heteroaryl ring is monocyclic, alkoxy, substituted alkoxy, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters, heteroaryl and heterocyclic; andR.sup.6 is selected from the group consisting of hydrogen, hydroxyl, alkyl, an alkyl group having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acyloxy, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxyl esters, thio, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heterocyclic amino, mono- and di-heteroaryl amino and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroayl, and heterocyclic provided that when the substituent is monoheteroarylamino or unsymmetric di-substituted amines having different substituents selected from alkyl and heteroaryl then the heteroaryl ring is monocyclic, amin, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters, heteroaryl, heterocyclic and where R.sup.6 and one of R.sup.5 or R.sup.5' are fused to from a heterocyclic ring of from 4 to 10 atoms having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;with the proviso that when n is zero, R.sup.9 and R.sup.9' are hydrogen;(ii) heteroaryl; and(iii) N-heterocyclic with the proviso that when W is N-heterocyclic then n is not zero; andn is an integer equal to 0 or 1, andp is an integer equal to 1 to 3 with the proviso that when n is zero then p is equal to 1, and(d) --CH(.phi.)CH.sub.2 C(O)O--Q where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclicX' is hydrogen, hydroxy or fluoro;X"" is hydrogen, hydroxy or fluoro, or X' and X"" together form an oxo group,Z is selected from the group consisting of a bond covalently linking R.sup.1 to --CX'X""--, oxygen and sulfur; andwith the proviso that when R.sup.1 is phenyl, R.sup.2 is methyl, X' and X"" are hydrogen, Z is a group covalently linking R.sup.1 to --CX'X""--, m is zero, R.sup.3 is hydrogen, R.sup.3' is --(R.sup.7).sub.n (W).sub.p where n is zero and p is one and W is ##STR13## then (i) R.sup.5, R.sup.5', R.sup.9, R.sup.9' and R.sup.6 are not all hydrogen and (ii) R.sup.5, R.sup.5', R.sup.9, R.sup.9' are hydrogen and R.sup.6 is methoxy;with the further proviso that when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, X' and X"" are hydrogen, Z is a group covalently linking R.sup.1 to --CX'X""--, m is zero, R.sup.3 is hydrogen, R.sup.3' is --(R.sup.7).sub.n (W).sub.p where n is one and p is one, R.sup.7 is ethylene and W is ##STR14## then R.sup.5, R.sup.5', R.sup.9, R.sup.9' and R.sup.6 are not all hydrogen; andwith still the further proviso that when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, X' and X"" are hydrogen, Z is a group covalently linking R.sup.1 to --CX'X""--, and m is zero, R.sup.3 is hydrogen, R.sup.3' is --(R.sup.7).sub.n (W).sub.p where n is zero and p is one, W is ##STR15## and R.sup.5', R.sup.9, R.sup.9' are hydrogen, then R.sup.5 and R.sup.6 are not fused to form, with the phenyl ring to which they are attached, a phthalimido group.