A new class of 4-ethoxyisophthalamides is reported, based on the novel approach of linking the 4-ethoxy to Picotamide. Picotamide, as a combined inhibitor of Thromboxane A2 synthase and receptor, is synthesized in 1985 and attracted the attention of researchers. To improve our knowledge of the structure-activity relationship (SAR) and to obtain new anti-platelet drugs, total 24 unreported compounds of 4-ethoxyisophthalamides were designed and synthesized and were devised taking example by structural features of Picotamide and 4-methoxy-N1,N3-diphenylisophthalamide. The structures of target compounds were identified by MS, 1H-NMR and IR and the in vitro anti-platelet aggregation activities were assessed by Born test. The in vitro results revealed that thirteen derivatives (2b, 2g, 2u, 2q, 2f, 2a, 2r, 2j, 2i, 2v, 2h, 2s, 2d) showed platelet aggregation inhibitory activities induced by 5.0 mM ADP with IC50 values ranging over 0.35 µM-1.12 µM and the pre-six compounds had superior anti-platelet aggregation activities than the reference drug Picotamide, while 2b was the best. These consequences suggested that this novel series may have potential as structural templates for the design and subsequent development of new platelet anti-aggregatory drugs.