antidepressantigemsine( 191 ) acts by some other as yet undefined mecha-
mism. The compound is described as a ligand for sigma receptors, a sub-
class of opiate receptors not associated with pain pathways. Alkylation of
the anion from 2-phenylbutyric acid with the allylic halide ( 185 ) yields the
acid ( 186 ). The carboxylic acid is then converted to the corresponding
azide by reaction in turn with thionyl chloride and sodium azide.
Heating this compound in an aprotic solvent then affords the isocyanate
rearrangement product. Reduction with LiAlH 4 gives theN-methylamine
189. This compound is then acylated with the acid chloride from cyclopro-
pyl carboxylic acid ( 190 ). Reduction of the amide, again with hydride,
gives the antidepressant 191.^30
Virtually all estrogen antagonists that have been in the clinic incorporate
a basic side chain in the form of an tertiary-aminoethoxy aromatic ether.
An exception, published in the 1960s, reported that the amine could be
replaced by a glycol.^31 The estrogen antagonistospemifene( 195 ) takes
this one step further. Antiestrogenic activity is retained when the basic
HOOH192Cl ONaOHHOO O193ClO O194CCl 4 ,(C 6 H 5 ) 3 PC 6 H 5C 6 H 5C 6 H 5ClO OHClO N(CH^3 )^2195196H 2- MISCELLANEOUS MONOCYCLIC AROMATIC COMPOUNDS 65