Synthesis and pharmacological evaluation of 2,3-dihydro-3-oxo-4H-thieno[3,4-e][1,2,4]thiadiazine 1,1-dioxides as voltage-dependent calcium channel blockers

The synthesis of a novel series of 2,3-dihydro-3-oxo-4H-thieno [3,4-e][1,2, 4]thiadiazine 1,1-dioxides and their pharmacological evaluation as drugs wi th effects on the rat cardiovascular system are described. The compounds un der study were synthesized via Curtius rearrangement of appropriate sulfamo ylacylazides which, in turn, were prepared from known starting materials. I n isolated rat portal vein, these thienothiadiazines, like verapamil and di azoxide, inhibited the spontaneous motility produced by KCl (20 mM). In add ition, the new compounds, like verapamil and unlike diazoxide, also exhibit ed inhibitory effects in the same preparation when the cell membrane was de polarized by an increased extracellular KCl concentration (80 mM) and, cons equently, the membrane potential approached a level close to the K+ equilib rium potential. Further characterization of this inhibitory activity led to the identification of a selective inhibitory effect of the new compounds o n KCl (80 mM)-induced Ca-45(2+) uptake in the same vascular tissue. When te sted in vivo (anaesthetized normotensive rats), acute administration of ver apamil, diazoxide and some of the most in vitro potent compounds in Ca-45(2 +) uptake experiments produced a gradual, dose-dependent and sustained decr ease in diastolic arterial blood pressure, devoid of cardiac effects. These results suggest that, like verapamil, the cardiovascular effects produced by the new thienothiadiazines seem to be due, at least in part, to a blocka de of transmembrane voltage-dependent calcium channels present in vascular smooth muscle cells and not to an activation of ATP-sensitive K+ channels. Compounds 5b, 5e and 5i have been selected for further studies as antihyper tensive agents. (C) 2000 Editions scientifiques et medicales Elsevier SAS.