Synthesis, stereochemistry and anti-tetrabenazine activity of bicyclo analogues of 2-phenylmorpholines

A series of bicycle analogues of several 2-phenylmorpholines were synthesized and tested for anti-tetrabenazine activity in mice. Most of the target compounds were prepared by reaction of 2-bromopropiophenone (22) with the appropriate amino alcohol to form 2-phenylmorpholinols. Reduction of the 2-phenylmorpholinols with sodium borohydride gave amino diols, which were cyclized to morpholines with acid. Alternatively, oxazines 17 and 18 were synthesized by alkylation of phenyl-(2-pyrrolo)carbinol (32a) and phenyl-(2-piperidyl)carbinol (32b) with 2-bromoethanol, followed by cyclization of the resulting amino diols with acid. Only the spirocyclic compounds 8 and 9 had i.p. anti-tetrabenazine activity comparable to the non-cyclic compounds 2a-3b, but 8 and 9 were less active by the oral route of administration.