SYNTHESIS AND EVALUATION OF ALPHA-METHYLIDENE-GAMMA-BUTYROLACTONE BEARING FLAVONE AND XANTHONE MOIETIES

In a search for inhibitors of platelet aggregation, a number of alpha- methylidene-gamma-butyrolactones 5 and 6 bearing flavone or xanthone m oieties, respectively, were synthesized and evaluated for their antipl atelet activity against thrombin(Thr)-, arachidonic-acid(AA)-, collage n(Col)-, and platelet-activating-factor(PAF)-induced aggregation in wa shed rabbit platelets. These compounds were synthesized from 7-hydroxy flavone (1) or 3-hydroxyxanthone (2) via O-alkylation (--> 3 and 4, re sp.) and Reformatsky-type condensation (Scheme). Most of the flavone-c ontaining alpha-methylidene-gamma-butyrolactones 5a-d showed potent an tiplatelet effects on AA- and Col-induced aggregation, while xanthone derivatives 6c-e were found to have the same pharmacological profile t han aspirin in which only AA-induced aggregation was inhibited (Table 1). However, 6c-e were approximately three to ten times more potent th an aspirin (Table 2). For the vasorelaxing effects, 5a was the only co mpound which exhibited significant inhibitory activity on the high-K+- medium, Ca2+-induced vasoconstriction (Table 3). Both 5a and 6a, with an aliphatic Me substituent at C(gamma) of the lactone, were active ag ainst norepinephrine-induced phasic and tonic constrictions while thei r gamma-aryl-substituted counterparts 5b-f and 6b-f were inactive.