Synthesis of Novel Succinamide Derivatives Having the 5, 11-Dihydro-6H-pyrido[2, 3-b][1, 4]benzodiazepin-6-one Skeleton as Potent and Selective M₂ Muscarinic Receptor Antagonists. I

Abstract

A series of 5, 11-dihydro-6H-pyrido[2, 3-b][1, 4]benzodiazepin-6-one derivatives containing the succinamide skeleton has been synthesized and evaluated for M₁, M₂ and M₃ muscarinic receptor binding affinities (in vitro) and M₂ and M₃ muscarinic receptor antagonistic activities (in vivo). Some of them showed higher and more selective binding affinities for M₂ muscarinic receptors than that of AF_DX 116. Among them, 11-[3-[N-[2-(N-benzyl-N-methylamino)ethyl]-N-ethylcarbamoyl]propiony]-5, 11-dihydro-6H-pyrido[2, 3-b][1, 4]benzodiazepin-6-one (68) was found to be the most potent and selective M₂ muscarinic receptor antagonist in vitro. This compound also strongly inhibited the oxotremorine-induced bradycardia after intravenous administration and showed 130-fold selectivity for M₂ muscarinic receptors over M₃ muscarinic receptors in vivo.