A new orally potent /¡-adrenergic blocking agent has been prepared which can be considered to be a classical antagonist since it had no /¡-sympathomimetic activity. Bunolol (1) (ó-[3-(í-butylamino)-2-hydroxypropoxy]-.'¡,4-dihydro-l (2//)-naphthaIenone) was 3 times more potent titan propranolol (30) intravenously and 20-30 times more active orally. Bunolol possessed relatively weak activity against ouabain-induced ventricular arrhythmias. The synthesis of bunolol and its analogs was accomplished by treating the appropriate hydroxytetralone with epichlorohydrin followed by reaction of the epoxide intermediate so obtained with the desired amine. A systematic study of the positional isomers in the tetralone series possessing identical side chain structures showed that the 5 isomer (bunolol) had the greatest activity as a /3-adrenergic blocking agent. The subsequent comparison of amino group substitutions was devoted mainly to the most active -isomeric series. It was shown that the classical structure requirements prevailed. Alteration in the side chain in other ways led to less active compounds. Resolution of bunolol revealed that the l isomer possessed the major activity. The keto group of bunolol was shown to be responsible for the greatly enhanced oral potency and for the relative lack of activity against ouabain-induced ventricular arrhythmias. Due to a favorable therapeutic index and greater oral activity, bunolol may have clinical advantage when compared to existing /¡-adrenergic blocking agents.
may 1961 ß-[3-IODO-4-(4 '-hydroxyphenoxy) phenyl ]propionic acid 1413 (20%), m.p. 158-159°. When mixed with the quinaldoin N,N '-dioxide obtained in the benzoin condensation, no depression in melting point was obtained.A mixture of 0.1 g. of the quinaldoin, 20 ml. of pyridine and 5 ml. of water was allowed to stand for 10 days under an atmosphere of nitrogen. At the end of the period the dark solid which had formed was separated and washed with methanol and ether. The dry product, 0.015 g. (15%), when crystallized from pyridine under an atmosphere of nitrogen gave red needles of the enediol, m.p. 192-193°dec. Potassium, salt of 1,2-di-2-quinolyl-l ,2-ethsnediol N,N'dioxide. To a mixture of 1.0 g. of quinaldehyde JV-oxide in 10 ml. of pyridine was added, with stirring, 0.08 g. of potassium cyanide in 2 ml. of water. A white, glistening precipitate, which formed immediately, went into solution after the mixture was stirred for 30 min. at room temperature and refluxed for an equal length of time. Cooling in an ice bath gave a white solid which was crystallized twice from 95% ethanol by adding absolute ether and cooling to give 0.3 g.
33% ethylamine was added rapidly at below 5°, 10.4 ml. of IN iodine in potassium iodide solution. The resulting solution was then acidified by the dropwise addition of acetic acid to a pH of 8.3. The crystalline precipitate was filtered off and recrystallized from aqueous alcohol. The product weighed 1 g. (co. 38%) and melted at about 90°when dried under vacuum at room temperature. The product contained nitrogen. To remove traces of the 3,3'5'-triiodo compound, additional recrystallizations from absolute ethanol were required. Recrystallization from ethanol without water was possible only after the compound was at most only slightly contaminated with triiodo compound. Drying under 1 mm. pressure at 100°for several hours resulted in a loss of iodine.Drying under 1 mm. pressure at 56°for 8 hr. resulted in an oil free of nitrogen and which had a proper analysis. This oil solidified on standing to a product with á poor melting point. The same product, free of nitrogen, could be obtained by precipitation of the oil from a hot acetic acid solution, by addition of water and cooling.
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