Stereoselective Synthesis and Thromboxane A_2 (TXA_2) Receptor Antagonistic Activity of Optically Active Phenol Derivatives

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Enantiomers of four potent nonprostanoid thromboxane A_2 (TXA_2) receptor antagonists, (±)-7-(4-fluoro-phenyl)-7-(2-hydroxyphenyl)heptanoic acids (1-4), were synthesized stereoselectively by direct ortho-alkylation of phenols under modified Mitsunobu conditions. The reaction of 5 eq of phenols (6a-c) with 1 eq of (S)- or (R)-methyl 7-(4-fluorophenyl)-7-hydroxyheptanoate ((S)-or (R)-y) afforded ortho-alkylated phenol derivatives (6a-c) enantioselectively in 33 to 42% chemical yield and 90 to 93% ee. In these compounds, the (R)-enantiiomers (1-4) exhibited potent TXA_2 receptor antagonistic activity and the (S)-isomer (3) was much less active. In particular, compound (R)-3 strongly inhibited U-46619-induced human platelet aggregation (IC_<50>=48 nM), and also showed a very potent inhibitory effect with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) on U-46619-induced bronchoconstriction in guinea pigs.
公益社団法人日本薬学会の論文
1996-04-15