Novel arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides as inhibitors of platelet aggregation. 1. Synthesis and pharmacological evaluation

A series of N-1-substituted derivatives of pyrazino[2,3-c][1,2,6]thiadiazin e 2,2-dioxides bearing aryl groups at the pyrazino moiety have been prepare d. The synthesis involves ring formation between the diaminothiadiazine and suitable dicarbonyl compounds and subsequent introduction of the substitue nt at N-1. The compounds have been tested in vitro, as inhibitors of rabbit and human platelet aggregation, and ex vivo against rat platelet aggregati on induced by arachidonic acid, ADP, collagen, U46619, and I-BOP. The resul ts obtained indicate that some pyrazino[2,3-c][1,2,6]thiadiazine derivative s show significant platelet aggregation inhibition similar to other antithr ombotic agents and that the antiplatelet properties may be mediated by inte rference with the arachidonic acid pathway.