Stereospecificity of myofibrillar calcium sensitivity and PDE inhibition in cardiotonic thiadiazinones

In pyridazinone or thiadiazinone cardiotonic agents with one chiral centre, the PDE inhibitory action resides mainly in one enantiomer and the myofibrillar calcium sensitization mainly in the other. This phenomenon is observed when the chiral centre is located on the pyridazinone or thiadiazinone heterocycle, but cannot be extended to structures where the chiral centre is elsewhere on the molecule. For the first time a stereoselective synthesis of a 5-substituted 3,6-dihydro-6-methyl-2H-1,3,4-thiadiazine-2-one has been achieved and an absolute configuration is proposed.