ALPHA-METHYLIDENE-GAMMA-BUTYROLACTONES - SYNTHESIS AND EVALUATION OF QUINOLIN-2(1H)-ONE DERIVATIVES

As a continuation of our previous studies on the synthesis and antipla telet activity of qninolin-2(1H)-ones with an alpha-methyilidene-gamma -butyrolactone substituted at O(8), the O(6)- and N(1)-substituted iso mers were synthesized and evaluated for antiplatelet activity against thrombin (Thr)-, arachidonic acid (AA)-, collagen (Col)-, and platelet -activating-factor (PAF)-induced aggregation in washed rabbit platelet s. These compounds were synthesized from 6-hydroxyquinolin-2(1H)-one v ia alkylation and Reformatsky-type condensation (Schemes 1 and 2). All of them were found to inhibit the platelet aggregation perfectly whic h was induced by AA and Col. 6-Substituted isomers 5b-g exhibited very strong inhibitory activities against AA- and PAF-induced aggregation and are approximately ten times more potent than their 8-substituted c ounterparts. However, the 1-substituted (11a and 11b) and the 1,6-disu bstituted (6) counterparts were relatively inactive. Their effects on the Ca2+-dependent vasoconstriction induced by high K+, and the phasic and tonic vasoconstrictions induced by norepinephrine (NE) in rat aor ta were also evaluated. Except 5g, all of them were found to have sign ificant inhibitory activity on the NE-induced phasic and tonic vasocon strictions. Compounds 6 and 11b also exhibited strong inhibitory activ ity on high-K+ medium, Ca2+-induced vasoconstriction.