Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.

Abstract Single enantiomer ( SS ) and ( RR ) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5 , 8 – 23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n -butyl 4-benzylmorpholine-2-carboxylate ( 26 ) as the key step. Structure–activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, ( SS )- 5a was selected as a candidate for further pre-clinical evaluation.