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Synthesis, stereochemistry and anti‐tetrabenazine activity of bicyclo analogues of 2‐phenylmorpholines
Author(s) -
Boswell G. Evan,
Musso David L.,
Davis Ann O.,
Kelley James L.,
Soroko Francis E.,
Cooper Barret R.
Publication year - 1997
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.5570340629
Subject(s) - chemistry , tetrabenazine , sodium borohydride , alkylation , bicyclic molecule , alcohol , stereochemistry , organic chemistry , medicinal chemistry , catalysis , neuroscience , dopamine , biology
A series of bicyclo 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‐bromopropio‐phenone ( 22 ) with the appropriate amino alcohol to form 2‐phenylmorpholinols. Reduction of the 2‐phenyl‐morpholinols 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.