Ring-hydroxylated propranolol: synthesis and .beta.-receptor antagonist and vasodilating activities of the seven isomers

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Abstract
Propranolol (Inderal; 1) is extensively metabolized in man. Metabolites of pharmacological interest include ring-hydroxylated propranolols (1a-g). To identify these ring-oxidized products and to study the effect of hydroxyl position on biological activity, all 7 isomers were synthesized. With the exception of 1b and 1g, the desired compounds were prepared by alkylation of the respective methoxy-1-naphthols with epichlorohydrin and reaction of the resulting epoxide with isopropylamine. Cleavage of the methyl group in fused pyridine hydrochloride afforded 1a,c-f. The 1g was prepared by the direct alkylation of 1,8-naphthalenediol (17) with epichlorohydrin, followed by reaction with isopropylamine. The 1b was synthesized by treating 2-naphthol (9) with Cl gas and then treating the resulting 1,1-dichloronaphthalen-2(1H)-one (10) with sodium allyl oxide. Acetylation of the hydroxy function and epoxidation of the allyl group, followed by reaction with isopropylamine, gave 3''-hydroxy-4''-chloropropranolol (15). Dechlorination gave 1b. All of the racemic hydroxylated propranolols produced .beta.-blockade and direct vasodilation in anesthetized dogs. The potency is strongly dependent upon the position of the hydroxyl group, i.e., 1e is 4 times as potent as 1 as a .beta.-receptor antagonist, whereas 1a, 1b and 1g are all significantly less potent than 1. For direct vasodilation 1a and 1g are equipotent to 1, while 1b-f are less potent. The potencies of the compounds were compared with their 1-octanol/pH 7.4 buffer distribution coefficients; the direct vasodilating potency increased with increasing lipophilicity, while the .beta.-adrenergic antagonist potency decreased.