Binding of E-selectin or P-selectin to sialyl Lewis.sup.x or sialyl-Lewis. sup.a

摘要

This invention relates to compounds that inhibit the binding of E- selectin and/or P-selectin to sialyl-Lewis.sup.x or sialyl-Lewis. sup.a presented on a cell surface having the general structure ##STR1## wherein X is selected from the group consisting of --(CH.sub.2).sub.n CO. sub.2 H, --O(CH.sub.2).sub.m CO.sub.2 H, --(CH.sub.2).sub.n O(CH.sub.2). sub.m CO. sub.2 H, --CONH(CH.sub.2).sub.m CO.sub.2 H, --CH(OZ)(CO.sub.2 H) , --CH(Z) (CO.sub.2 H), --(CH.sub.2).sub.n SO.sub.3 H, --(CH.sub.2).sub.n PO.sub.3 D.sub.1 D.sub.2, --NH(CH.sub.2).sub.m CO.sub.2 H, --CONH(CHR.sub. 6)CO.sub. 2 H, (1-H-tetrazolyl-5-alkyl-), and --OH;PPR. sub.1 and R. sub.2 are independently selected from the group consisting of hydrogen, alkyl, halogen, --OZ, --NO.sub.2, --NH.sub.2 and --NHZ; PP R.sub.3 is selected from the group consisting of hydrogen, halogen, alkyl, --OZ and --NHZ;PPR.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, hydroxyl, hydroxyl-O- sulfate and - -OZ;PPR.sub.5 is selected from the group consisting of hydroxyl, --CN, --N.sub.3, --NH.sub.2, --NHNH.sub.2, --NE. sub.1 E.sub.2, - -NHE.sub.1, --NHCO(CH.sub.2).sub.n CO.sub.2 H, --S(CH. sub.2).sub.m CO.sub. 2 H and --NHCHNHNH.sub.2 ;PPR.sub.6 is selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkyl carboxylic acid and alkyl carboxamide; PPwherein n is 0 to 6, m is 1 to 6, p is 0 to 6, b is 0 to 2, Z is alkyl, aryl or aralkyl, D.sub.1 and D.sub.2 are independantly hydrogen or alkyl, E.sub.1 is alkyl or --(CH.sub.2).sub.8 CO.sub.2 H, and E.sub.2 is alkyl, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. This invention also relates to methods of inhibiting the binding of E- selectin and/or P-selectin to sialyl-Lewis. sup.x or sialyl-Lewis.sup.a presented on a cell surface using said compounds and to pharmaceutically active compositions comprising compounds that inhibit the binding of E- selectin to sialyl-Lewis.sup.x and to methods of treatment of septic shock, ARDS, Crohn's disease, chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis, and reperfusion injuries that occur following heart attacks, strokes and organ transplants.