Resolution of the potent α1-adrenoreceptor antagonist 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzoxathian (benoxathian)

The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzoxathian hydrochloride (1: benoxathian) were prepared from the chiral 1,4-benzoxathian-2-carboxylic acids [(+)- and (−)-3] which in turn were obtained through the resolution of the racemic acid with R- and S-α-methylbenzylamine. Their blocking activities and relative selectivities on α1- and α2-adrenoreceptors were evaluated on isolated rat vas deferens. For α1-adrenoreceptors the enantiomer (−)-1 was 10 times more potent than the enantiomer (+)-1, whereas no significant difference between the blocking activity of the enantiomers was observed for α2-adrenoreceptors. Furthermore, the enantiomer (−)-1 showed high activity and selectivity toward the α1-adrenoreceptor (pA2 = 9.36; selectivity ratio = 1230) which may have relevance in the characterization of α-adrenoreceptor subtypes.