Inhibitors of the Tissue Factor/Factor VIIa-induced coagulation: Synthesisand in vitro evaluation of novel specific 2-aryl substituted 4H-3,1-benzoxazin-4-ones

The synthesis of a series of novel 2-aryl substituted 4H-3,1-benzoxazin-4-o nes and their evaluation as specific inhibitors of the Tissue Factor (TF)/F actor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory a ctivities (IC50 values) in the range 0.17 to > 40 mu M on the activation of Factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F, Cl and NO2 in the 2-aryl sub stituent. Different substitutions both electron-attracting and donating gro ups were allowed in the 5, 6, 7 and 8 positions. Several of the compounds s howed a selectivity ratio towards FX and thrombin of > 50, thus being the f irst small molecules described as potential drugs for oral antithrombotic t reatment without side effects such as bleeding which is observed especially with thrombin inhibitors. The best substituent pattern being the 2-aryl gr oup substituted with: 2-F; 2,6-F-2; or 2-FX; 6-Cl; together with electroneg ative substitution in the 5, 6, 7, or 8 positions. 7-Heteroaryl substituent s like thienyl and furanyl were of low activity while some 2-(2-chloro-3-py ridyl) derivatives had inhibitory activity < 10 mu M and a good selectivity . (C) 2000 Elsevier Science Ltd. All rights reserved.