Asymmetric .ALPHA.-substituted phenethylamines. III. The synthesis and analgesic activity of optically pure (S)- and (R)-1-aryl-2-phenylethylamines.

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Abstract
(1S, 1''S)- and (1R, 1''R)-1-aryl-N-2''-hydroxy-1''-isopropylethyl-2-(4-substituted phenyl)ethylamines were synthesized by the asymmetric reaction of (E)-(S)- and (E)-(R)-N-(2-hydroxy-1-isopropylethyl)arylmethylideneamines with Grignard reagents. The products showed 100% optical purities; their absolute configurations were determined by means of circular dichroism. These optically pure chiral amines were converted into hydrochlorides and then evaluated for analgesic activity in the acetic acid-induced mouse-writhing assay. Among these compounds, the hydrochlorides of 9 [(1S, 1''S)-1-aryl-N-2''-hydroxy-1''-isopropylethyl-2-phenylethylamine hydrochloride], 13 [(1S, 1''S)-1-aryl-N-2''-hydroxy-1''-isopropylethyl-2-(4-methoxyphenyl)ethylamine hydrochloride], 19 [(1R, 1''R)-1-aryl-N-2''-hydroxy-1''-isopropylethyl-2-phenylethylamine hydrochloride], 20 [(1R, 1''R)-1-aryl-N-2''-hydroxy-1-isopropylethyl-2-phenylethylamine hydrochloride], and 23 [(1S, 1''S)-1aryl-N-2''-hydroxy-1''-isopropylethyl-2-(4-hydroxyphenyl)ethylamine hydrochloride], showed inhibition of the writhing; they were about equipotent with (-)-pentazocine hydrochloride. The hydrochlorides of 13, 18 [(1R, 1''R)-1-aryl-N-2''-hydroxy-1''-isopropylethyl-2-phenylethylamine hydrochloride], 19, 20 and 21 [1R, 1''R)-N-2''-hydroxy-1''-isopropylethyl-2-(4-methoxyphenyl)-1-(2-thienyl)ethylamine hydrochloride] were not antagonized by (-)-naloxone hydrochloride.

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