Potential antidepressants and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain: Synthesis of several potential metabolites of moxifetin and of two A-ring fluorinated analogues

Abstract

A series of potential metabolites of the potent inhibitor of 5-hydroxytryptamine re-uptake in the brain structures – moxifetin (I) – i.e. the O-methylated and hydroxylated, further methoxylated, and N-monodemethylated analogues (III – VII, IX, and X) was synthesized from the acids XV, XIX, XXIIIa, XXIIIb, XXVIIa, and XXVIIb. The synthesis of III and V proceeded with protection of one hydroxyl group by benzyl and by the final debenzylation by short heating with hydrobromic acid. Compound IV was obtained by partial demethylation of N,N-dimethyl-(3-,4-dimethoxyphenylthio)benzylamine with sodium 4-toluenethiolate. Synthesis of VI, VII, IX, and X proceeded without protection of the hydroxyl group via the mixed anhydrides of the mentioned acids and methanesulfonic acid which were coupled with dimethylamine and the dimethylamides obtained were directly reduced to the final products. Two A-ring fluorinated analogues of I, i.e. VIII and XI were prepared from the acids XXIIIc and XXVIIc via acid chlorides, dimethylamides, and amines XXVIc and XXXc. The final step was demethylation by heating with hydrobromic acid. The N-oxide XII was obtained by oxidation of I with hydrogen peroxide in ethanol. Compounds III (VUFB-18285) and especially XI (VUFB-17724) were found to be selective inhibitors of the 5-hydroxytryptamine re-uptake in the brain. Some compounds (IV, VI, VII, X) indicate a similar type of activity. In addition to II (described previously), compounds IV and V were found to be moxifetin metabolites in the animals.