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Synthesis and anti‐tetrabenazine activity of c‐3 analogues of dimethyl‐2‐phenylmorpholines
Author(s) -
Boswell G. Evan,
Musso David L.,
Kelley James L.,
Soroko Francis E.,
Cooper Barret R.
Publication year - 1996
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570330106
Subject(s) - chemistry , tetrabenazine , formylation , alkyl , aryl , hydrogenolysis , phosphonate , medicinal chemistry , stereochemistry , organic chemistry , catalysis , neuroscience , dopamine , biology
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 iso‐ butyl group of 16 were well tolerated; anti‐tetrabenazine ED 50′s were comparable to compounds 2–5 . The α‐branched, N ‐methylated, and side chain aryl derivatives were less active.