SYNTHESIS AND ANTI-TETRABENAZINE ACTIVITY OF C-3 ANALOGS OF DIMETHYL-2-PHENYLMORPHOLINES

A series of analogues of 2-phenylmorpholines with alkyl substituents a t 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 g ave aminodiols 23a-h which were cyclized to morpholines 6, 8, 10-12, 1 4-16, 18 and 19 by acid catalaysis. Compounds 7, 9, 13 and 17 were pre pared by reductive formylation. The smaller straight chain substituent s 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.