Sialyl le^x analogues as inhibitors of cellular adhesion

摘要

The present invention relates to analogues of sialyl (Le) that inhibit cellular adhesion between a selectin and cells that express sialyl Le on their surfaces, as well as methods and compositions using the same, intermediates and methods for the preparation of the cellular adhesion inhibitor compounds and their intermediates. A contemplated intermediate or inhibitor compound has a structure that corresponds to that of formula (A), wherein Z is selected from the group consisting of hydrogen, C1-C6 acyl and formula (B); Y is selected from the group consisting of C(O), SO2, HNC(O), OC(O) and SC(O); R<1> is selected from the group consisting of a linking group for a lipid, a lipid, a linking group with attached lipid, an aryl, a substituted aryl and a phenyl C1-C3 alkylen group, wherein an aryl group has one five- or six-membered aromatic ring, a fused five/six-membered aromatic ring, or two fused six-membered aromatic rings, which rings are selected from the group consisting of hydrocarbyl, monooxahydrocarbyl, monothiahydrocarbyl, monoazahydrocarbyl and diazahydrocarbyl rings, and a substituted aryl group is said aryl group having a substituent selected from the group consisting of a halo, trifluoromethyl, nitro, C1-C18 alkyl, C1-C18 alkoxy, amino, mono-C1-C18 alkylamino, di-C1-C18 alkylamino, benzylamino, C1-C18 alkylbenzylamino, C1-C18 thioalkyl and C1-C18 alkyl carboxamido groups, or R<1>Y is allyloxycarbonyl or chloroacetyl; R<2> is selected from the group consisting of hydrogen, a linking group for a lipid, a lipid, a linking group with attached lipid, C1-C18 straight chain, branched chain or cyclic hydrocarbyl, C1-C6 alkyl C1-C5 alkylene omega -carboxylate, omega -tri (C1-C4 alkyl/phenyl)silyl C2-C4 alkylene, monosaccharide and disaccharide, or OR<2> together form a C 1-C18 straight chain, branched chain or cyclic hydrocarbyl carbamate; R<3> is hydrogen or C1-C6 acyl; R<4> is hydrogen, C 1-C6 alkyl or benzyl; R<5> is selected from the group consisting of hydrogen, benzyl, methoxybenzyl; dimethoxybenzyl and C1-C6 acyl; R<7> is methyl or hydroxymethyl; and X is selected from the group consisting of C1-C6 acyloxy, C2-C6 hydroxylacyloxy, hydroxy, halo and azido.