Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines

The synthesis and beta-adrenergic antagonist activities of (2R,2S)-, (2S)-, (2R)-1-(5-quinolyloxy)-3-alkylamino-2-propanols (10-21) and (2R,2S)-1-(5-isoquinolyloxy)-3-alkylamino-2-propanols (24-27) is described. beta 1-Adrenolytic (atria) structure-activity correlations indicated the N-alkyl substituent was a determinant of activity where the relative potency order was i-Pr and t-Bu > cyclohexyl. Compounds having the (2S)-configuration were more potent than the corresponding (2R)-analogs. The position of the heteroaryl nitrogen atom influences potency since the quinolyl analogs were ten-fold more active than the corresponding isoquinolyl isomers. All compounds in both the quinolyl and isoquinolyl series exhibited weak beta 2-adrenolytic activity (trachea), and high beta 1/beta 2 selectivity ratios when the N-alkyl substituent was i-Pr or t-Bu. The quinolyl ring system is an excellent bioisostere for the aryl moiety in aryloxypropanolamines since (2R,2S)- or (2S)-1-(5-quinolyloxy)-3-isopropyl (or t-Bu) amino-2-propanols exhibit very potent and highly cardioselective beta 1-adrenergic antagonist activities.