Adrenergic agents. 6. Synthesis and potential .beta.-adrenergic agonist activity of some meta-substituted p-hydroxyphenylethanolamines related to salbutamol

Salbutamol, an adrenergic receptor agonist with selectivity for tracheobronchial vs. cardiac muscle, differs from the catecholamine N-tert-butylnorepinephrine in that it bears a hydroxymethyl, rather than a phenolic, group in the meta position. In a search for new bronchodilating agents with minimal cardiovascular side effects, a series of derivatives, in which this m-hydroxymethyl group is modified, was prepared. These compounds were examined for potential bronchodilator activity in an in vitro test that measures relaxation of guinea pig tracheal smooth muscle. Potential cardiac stimulant activity was evaluated in vitro by monitoring changes in the rate of contraction of spontaneously beating guinea pig right atria. Although many of these compounds retained a high degree of potency, all were less effective than salbutamol in the tracheal test. Several of the derivatives, notably ones bearing 1-hydroxyethyl (1d), 1,2-dihydroxyethyl (1f), 1-hydroxy-2-methoxyethyl (1g), and 2-hydroxy-1-methoxyethyl (1h) substituents in place of the parent's m-hydroxymethyl group, however, were considerably more selective for tracheobronchial vs. cardiac muscle in the in vitro tests utilizing guinea pig tracheal and right atrial muscle.