.beta.1-Selective adrenoceptor antagonists. 1. Synthesis and .beta.-adrenergic blocking activity of a series of binary (aryloxy)propanolamines

Abstract

A series of binary (aryloxy)propanolamines was prepared and examined in vitro and in vivo [guinea pig] for .beta.-adrenoreceptor blocking activity. These symmetrical compounds consist of 2 (S)-(phenyloxy)propanolamine pharmacophores coupled through alkylenedioxy or poly(oxyethylenedioxy) linking units of varying lengths. Examples of such binary compounds linked through the 2,2'', 3,3'' and 4,4'' positions in the aromatic rings of the pharmacophores were prepared. In vitro and in vivo test data indicate that the 2,2'' compounds tend to be selective .beta.2-adrenergic blocking agents, the 4,4'' binaries tend to be selective .beta.1-blocking agents, and those compounds with 3,3'' linkages exhibit intermediate selectivities. One of the 4,4''-linked binary compounds, 4s [(S,S)-1,1''-[oxybis(2,1-ethanediyloxy)bis(1,4-phenylenoxy)]bis[3-[(1-methylethyl)amino]-2-propanol]], exhibited potent, cardioselective .beta.-blockade in vivo, which was of short duration and was accompanied by a prolonged tachycardia.