Salicylamide derivatives related to medroxalol with .alpha.- and .beta.-adrenergic antagonist and antihypertensive activity

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Abstract
Analogs of medroxalol (1) were prepared in which the carboxamide function, the phenolic hydroxy group and the aralkylamine side chain were modified. N-Alkyl-substituted amide analogs of 1 showed diminishing .beta.-blocking activity with increasing steric bulk of the alky group. Deactivation of the phenolic hydroxy group of 1 by the carbonyl group of the amide function is responsible for the .beta.-adrenergic antagonistic properties of 1. The phenolic O-methyl analog-5-[2-[[3-(1,3-benzodioxol-5-yl)-1-methylpropyl]amino]-1-hydroxyethyl]-2-methoxybenzamide (13) had enhanced .beta.-adrenergic blocking activity. The 13 had decreased .alpha.-blocking activity compared to 1; the phenolic hydroxy group of 1 apparently enhances .alpha.-adrenergic antagonism. The 1 and 13 showed a large difference in relative .alpha.- to .beta.-blocking potency while exhibiting approximately equal antihypertensive activity in spontaneously hypertensive rats. Pharmacologic properties other than .alpha.- and .beta.-adrenergic blockade may contribute to the antihypertensive activity of medroxalol. One of the analogs in which the aralkylamine side chain of 1 was replaced by a fragment of a known .alpha.-adrenergic receptor blocker, 2-hydroxy-5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]benzamide (22), showed an interesting pharmacologic profile of potential therapeutic usefulness.