Synthesis and cardiovascular activity of metoprolol analogues

The synthesis of four novel analogues of metoprolol, a well-known β1-blocker used to reduce arterial blood pressure, is described. The preparation of (2S,2′S)-7, (2R,2′S)-7, (2R,2′R)-8, and (2S,2′R)-8 was based on the reaction of racemic 2-[4-(2′-methoxyethyl)-phenoxymethyl]-oxirane (4) with (R)- or (S)-2-amino-1-butanol. Salient characteristics of analogues 7 and 8 relative to metoprolol are the incorporation of an additional stereogenic center, as well as a methyl group and a hydroxyl function on the nitrogen-containing chain. These novel derivatives present significant hypotensive and bradycardiac activity, although no blocking action toward β1 and β2 adrenergic receptor.