Diclofensine

Diclofensine was developed by Hoffmann-La Roche in the 1970s in the search for a new antidepressant. It was found that the -isomer was responsible for activity. Diclofensine is a stimulant drug which acts as a triple monoamine reuptake inhibitor, primarily inhibiting the reuptake of dopamine and norepinephrine, with affinities of 16.8 nM, 15.7 nM, and 51 nM for DAT, NET, and SERT, respectively. It was found to be an effective antidepressant in human trials, with relatively few side effects, but was ultimately dropped from clinical development, possibly due to concerns about its abuse potential.
Diclofensine is chemically a tetrahydroisoquinoline derivative, as is nomifensine.

Synthesis

The condensation of m-anisaldehyde with methylamine gives N-methyl-3-methoxybenzenemethanimine . Reduction of this Schiff-base intermediate with sodium borohydride gives methylamine . Alkylation of this with 3,4-dichlorophenacylbromide would give . Reduction of the benzoyl ketone with sodium borohydride gives the alcohol . Acid catalyzed intramolecular cyclization then completes the synthesis of the 4-aryl-THIQ derivative, diclofensine.