Patent ID: 6015879
Filing Date: 2000-01-18
Classification: A61K,A61P,C07C,C07K

Abstract:
A compound of the formula: ##STR6## or a hydrate, isostere, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, with the proviso that: (1) at least one of R.sub.1, R.sub.3 and R.sub.5 is not a side chain of a naturally-occurring amino acid; (2) when X is an aldehyde, the side chain of the non-naturally occurring amino acid is other than the side chain of norleucine or norvaline; and (3) at least one of R.sub.1, R.sub.3 and R.sub.5 is C.sub.2-10 alkenyl or C.sub.2-6 alkynyl; wherein:R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, X, Q and n are selected from among (i), (ii), (iii), (iv), (v), (vi) or (vii) as follows:(i) R.sub.1, R.sub.3, and R.sub.5 are each independently selected from the group consisting of a side chain of a naturally occurring .alpha.-amino acid, H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, Y-substituted aryl, aralkyl, aralkenyl, aralkynyl, and Z-substituted heteroaryl, heteroaralkyl, heteroaralkenyl, in which Y is selected from the group consisting of halogen, lower alkyl, alkoxy, OH, haloalkyl, nitrile, S-alkyl, phenyl, and --NRR, R is H, alkyl, lower alkyl, OH or halo-lower alkyl, Z is lower alkyl or halo lower alkyl;R.sub.2, R.sub.4, R.sub.6, and R.sub.8 are each independently selected from H and lower alkyl;R.sub.7 is selected from the group consisting of C.sub.16 alkyl, aryl, alkenyl, 9-fluorenyl, aralkyl, aralkenyl and aralkynyl in which the aryl groups are unsubstituted or are substituted with Z;Q is selected from the group consisting of --C(O)--, --O--C(O), --S(O).sub.2 -- and HN--C(O)--;n is zero or one;X is selected from the group consisting of --(CH.sub.2).sub.r C(O)H, --(CH.sub.2).sub.r C(O)haloalkyl, --(CH.sub.2).sub.r C(O)(CH.sub.2),CHN.sub.2, --(CH.sub.2).sub.r C.tbd.N, --(CH.sub.2).sub.r C(O)(CH.sub.2).sub.r C(O)ORD, --(CH.sub.2).sub.r C(O)(CH.sub.2).sub.r C(O)NR.sub.D R.sub.D, --(CH.sub.2).sub.r C(O)W and --(CH.sub.2).sub.r C(O)CH.sub.2 W, in which: R.sub.D is selected from H, alkyl, phenyl, benzyl, and phenethyl; W is --OR.sub.D, --SR.sub.D, --NR.sub.D R.sub.D or a heterocyclic moiety, with the proviso that when X is --(CH.sub.2).sub.r C(O)W, then W is not --OR.sub.D ; and r is 0-5; or(ii) R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.8, Y and X are selected as in (i), (iv) or (v);n is zero; andR.sub.6 and R.sub.7 are each independently selected as follows:(a) from lower alkyl or lower alkyl bearing a heteroatom that is substituted with one of the following groups: lower alkyl, alkoxy, hydroxyl, haloalkyl, nitrile and phenyl, with the proviso that there is at least one carbon atom between the N to which R.sub.6 and R.sub.7 are each attached and the heteroatom, and(b) R.sub.6 and R.sub.7 are unsubstituted or substituted with one or more substituents selected from Y, and(c) together with the atoms to which each is attached form a heterocyclic moiety or a bicyclic or cyclic moiety containing from 3 to about 1 2 members; or(iii) R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.8, Y and X are selected as in (i);Q is C(O);n is one; andR.sub.6 and R.sub.7 are each independently selected from the group consisting of --C.dbd.O--Y, phenyl, phenyl substituted with Y, lower alkyl, lower alkyl substituted with Y, and lower alkyl bearing a heteroatom that is substituted with one of the following groups: lower alkyl, alkoxy, hydroxyl, haloalkyl, nitrile and phenyl: and R.sub.6 and R.sub.7, together with the atoms to which they are attached, form a 4-6 membered cyclic or 8-1 2 membered bicyclic moiety, with the proviso that if two or more heteroatoms are present, there is at least one carbon atom between the heteroatoms; or(iv) R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, Q, X, Y and n are as defined in any of (i)-(iii) or (v)-(vii),R.sub.8 is H; andR.sub.2 and R.sub.2 are each independently selected as follows:(a) from lower alkyl, lower alkyl bearing a heteroatom that is substituted with one of the following groups: lower alkyl, alkoxy, hydroxyl, haloalkyl, nitrile and phenyl, or a heteroatom, with the proviso when more than one heteroatom is present, there is at least one carbon atom between each heteroatom, and(b) R.sub.1 and R.sub.2 are unsubstituted or substituted with Y, and(c) together with the atoms to which they are attached form a 4-6 membered heterocyclic moiety; or(v) R.sub.1, R.sub.2, R.sub.5, R.sub.6, R.sub.7, R.sub.8, X, Q, Y and n are as defined in any of (i)-(iv) or (vi)-(vii);R.sub.3 and R.sub.4 are each independently selected as follows:(a) from lower alkyl, lower alkyl bearing a heteroatom that is substituted with one of the following groups: lower alkyl, alkoxy, hydroxyl, haloalkyl, nitrile and phenyl, or a heteroatom, with the proviso when more than one heteroatom is present, there is at least one carbon atom between each heteroatom, and(b) is unsubstituted or substituted with Y, and(c) together with the atoms to which they are attached form a 4-6 membered heterocyclic moiety; or(vi) R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8, Q, X, Y and n are as defined in any of (i), (iv) or (v);R.sub.5 and R.sub.6 are each independently selected as follows:(a) from lower alkyl, lower alkyl bearing a heteroatom that is substituted with one of the following groups: lower alkyl, alkoxy, hydroxyl, haloalkyl, nitrile and phenyl, or a heteroatom, with the proviso when more than one heteroatom is present, there is at least one carbon atom between each heteroatom, and(b) R.sub.5 and R.sub.6 are unsubstituted or substituted with Y, and(c) together with the atoms to which they are attached form a 4-6 membered heterocyclic moiety; or(vii) R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.8, Y and X are selected as in (i) (iv) or (v);n is zero; andR.sub.5 and R.sub.7 are each independently selected as follows:(a) from lower alkyl, lower alkyl bearing a heteroatom that is substituted with one of the following groups: lower alkyl, alkoxy, hydroxyl, haloalkyl, nitrile and phenyl, or a heteroatom, with the proviso when more than one heteroatom is present, there is at least one carbon atom between each heteroatom, and(b) R.sub.5 and R.sub.7 are unsubstituted or substituted with Y, and(c) together with the atoms to which they are attached form a 4-6 membered heterocyclic moiety; andthe compound modulates the processing of amyloid precursor protein (APP).