Design and synthesis of reboxetine analogs morpholine derivatives as selective norepinephrine reuptake inhibitors

As part of a discovery effort aimed at identifying novel norepinephrine reuptake inhibitors (NRIs), a number of substituted morpholines were designed and synthesized. The target compounds contain vicinal stereogenic centers, and the program was greatly facilitated by the adoption of efficient synthetic routes which allowed for the late stage incorporation of structural and physicochemical diversity into the targets. Structure–activity relationships were developed by optimizing individual ring components of the structure for NRI potency and for selectivity against other monoamine reuptake transporters. Several novel morpholine derivatives with a potent and selective NRI profile are described.

Graphical abstractThe design and synthesis of morpholine compounds with binding affinity for the norepinephrine reuptake transporter are reported. Effective chemical routes allowed access to compounds with varied physicochemical properties.Figure optionsDownload full-size imageDownload as PowerPoint slide