Synthesis and Antiplatelet-Activity Evaluation ofα-Methylidene-γ-butyrolactones Bearing 3,4-Dihydroquinolin-2(1H)-one Moieties

Abstract

In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several α-methylidene-γ-butyrolactones bearing 3,4-dihydroquinolin-2(1H)-one moieties. O-Alkylation of 3,4-dihydro-8-hydroxyquinolin-2(1H)-one (1) with chloroacetone under basic conditions afforded 3,4-dihydro-8-(2-oxopropoxy)quinolin-2(1H)-one (2a) and tricyclic 2,3,6,7-tetrahydro-3-hydroxy-3-methyl-5H-pyrido[1,2,3-de][1,4]benzoxazin-5-one (3a) in a ratio of 1 : 2.84. Their Reformatsky-type condensation with ethyl 2-(bromomethyl)prop-2-enoate furnished 3,4-dihydro-8-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)methoxy]quinolin-2(1H)-one (4a), which shows antiplatelet activity, in 70% yield. Its 2′-Ph derivatives, and 6- and 7-substituted analogs were also obtained from the corresponding 3,4-dihydroquinolin-2(1H)-ones via alkylation and the Reformatsky-type condensation. Of these compounds, 3,4-dihydro-7-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]quinolin-2(1H)-one (10b) was the most active against arachidonic acid (AA) induced platelet aggregation with an IC50 of 0.23 μM. For the inhibition of platelet-activating factor (PAF) induced aggregation, 6-{[2-(4-fluorophenyl)-2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl]methoxy}-3,4-dihydroquinolin-2(1H)-one (9c) was the most potent with an IC50 value of 1.83 μM.