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Synthesis and Antiplatelet‐Activity Evaluation of α ‐Methylidene‐ γ ‐butyrolactones Bearing 3,4‐Dihydroquinolin‐2(1 H )‐one Moieties
Author(s) -
Tzeng CherngChyi,
Chen I.Li,
Chen YehLong,
Wang TaiChi,
Chang YaLing,
Teng CheMing
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(20000216)83:2<349::aid-hlca349>3.0.co;2-b
Subject(s) - chemistry , alkylation , yield (engineering) , stereochemistry , tricyclic , arachidonic acid , ic50 , medicinal chemistry , in vitro , catalysis , organic chemistry , biochemistry , materials science , metallurgy , enzyme
In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several α ‐methylidene‐ γ ‐butyrolactones bearing 3,4‐dihydroquinolin‐2(1 H )‐one moieties. O ‐Alkylation of 3,4‐dihydro‐8‐hydroxyquinolin‐2(1 H )‐one ( 1 ) with chloroacetone under basic conditions afforded 3,4‐dihydro‐8‐(2‐oxopropoxy)quinolin‐2(1 H )‐one ( 2a ) and tricyclic 2,3,6,7‐tetrahydro‐3‐hydroxy‐3‐methyl‐5 H ‐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(1 H )‐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(1 H )‐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(1 H )‐one ( 10b ) was the most active against arachidonic acid (AA) induced platelet aggregation with an IC 50 of 0.23 μ M . 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(1 H )‐one ( 9c ) was the most potent with an IC 50 value of 1.83 μ M .