Synthesis and anti-tetrabenazine activity of C-3 analogues of dimethyl-2-phenylmorpholines

A series of analogues of 2-phenylmorpholines with alkyl substituents at the C-3 position were synthesized for anti-tetrabenazine (anti-TBZ) testing in mice. The target compounds were prepared by reaction of (2-bromoalkyl) phenyl ketones 21a-h with the appropriate aminoalcohol 20a-b to form morpholinols 22a-h. Hydride reduction of the morpholinols gave aminodiols 23a-h which were cyclized to morpholines 6, 8, 10-12, 14-16, 18 and 19 by acid catalaysis. Compounds 7, 9, 13 and 17 were prepared by reductive formylation. The smaller straight chain substituents of 6, 8, 12 and 15, and the beta branching of the isobutyl group of 16 were well tolerated; anti-tetrabenazine ED(50's) were comparable to compounds 2-5. The alpha-branched, N-methylated, and side chain aryl derivatives were less active.