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

Fish PV, Deur C, Gan X, Greene K, Hoople D, Mackenny M, Para KS, Reeves K, Ryckmans T, Stiff C, Stobie A, Wakenhut F, Whitlock GA

Department of Genitourinary Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. paul.fish@pfizer.com

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.

Published 15 April 2008 in Bioorg Med Chem Lett, 18(8): 2562-6.
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