Synthesis, Lipophilicity and Structure of 2,5-Disubstituted 1,3,5-Dithiazine Derivatives

A series of 2,5-disubstituted 1,3,5-dithiazine derivatives were synthesized as potential analogues of the potent dopamine uptake inhibitor GBR 12909. The lipophilic character of the 1,3,5-dithiazine derivatives were experimentally (log P) and computationally (clog P) determined. The in vitro binding affinities of the 2,5-disubstituted 1,3,5-dithiazine derivatives at the dopamine transporter were determined to be much less potent than the binding affinity of GBR 12909 due to steric and electronic effects inherent to the 1,3,5-dithiazine ring system. The X-ray crystal structure of 2-(2-[bis(4-fluorophenyl)methoxy]ethyl)-5-(3-phenylpropyl)-1,3,5-dithiazine (7) revealed that the 5-(3-phenylpropyl) group is in a pseudo-axial orientation and syn to the 2-ethoxybenzhydryl moiety.