Adrenergic agents. 3. Synthesis and adrenergic activity of some catecholamine analogs bearing a substituted sulfonyl or sulfonylalkyl group in the meta position

Abstract

The m-phenolic group of catecholamine beta-adrenergic agonists may be replaced by various functionalities capable of undergoing H bonding. Considerable latitude in the nature of the OH simulating group is permissible with retention of activity; however, the most extensively studied analogs are ones in which a mobile proton is attached to an O or N atom. In a search for new selective bronchodilators a series of catecholamine analogs bearing a substituted sulfonyl or sulfonylalkyl group in the meta position (i.e., groups in which the mobile H is attached to a C atom) was examined. These compounds were studied for beta-adrenergic agonist activity in vitro by measuring their ability to relax tracheal smooth muscle and to increase the rate of spontaneously beating right atria of guinea pigs. Adrenergic activity was influenced by the nature of the alkylene bridge between the sulfonyl and aromatic groups, branching of the ethanolamine side chain, stereochemistry, and substitution of the sulfonyl and amino groups. Beta-adrenergic blockage was noted for some compounds having the sulfonyl attached directly to the ring. Greatest beta-adrenergic agonist potency and tissue selectivity was observed with a m-MeSO2CH2 substituent. One of these compounds, alpha-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-3-[(methylsulfonyl)methyl]benzenemethanol hydrochloride (sulfonterol hydrochloride, USAN), was studied more extensively in animals and is presently being examined for bronchodilator activity in man.