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

(1S, 1'S)- and (1R, 1'R)-1-aryl-N-2'-hydroxy-1'-isopropylethyl-2-(4-substituted phenyl) ethylamines (7-13 and 18-23) 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, Ar=2-thienyl, R=H), 13 (1S : 1'S, Ar=2-thienyl, R=MeO), 19 (1R : 1'R, Ar=4-methoxyphenyl, R=H), 20 (1R : 1'R, Ar=2-thienyl, R=H), and 23 (1S : 1'S, Ar=2-thienyl, R=OH) showed inhibition of the writhing ; they were about equipotent with (-)-pentazocine hydrochloride. Moreover, the hydrochlorides of 8 (1S : 1'S, Ar=4-methoxyphenyl, R=H), 13 (1S : 1'S, Ar=2-thienyl, R=MeO), 18 (1R : 1'R, Ar=phenyl, R=H), 19 (1R : 1'R, Ar=4-methoxyphenyl, R=H), 20 (1R : 1'R, Ar=2-thienyl, R=H), and 21 (1R : 1'R, Ar=2-thienyl, R=MeO) were not antagonized by (-)-naloxone hydrochloride.