Patent Evaluation: Indolalkylamine derivatives as 5-HT₂ antagonists

Summary

Patent Evaluation: Indolalkylamine derivatives as 5-HT₂ antagonists

Novelty: Novel 3-arylindole and 3-arylindazole derivatives are disclosed. They are reported to be 5HT antagonists with minimal side-effects. The compounds may be suitable for the treatment of various CNS disorders.

Biology: In vitro inhibition of [³H]-ketanserin binding to serotonin S₂ (5HT) receptors in rat cerebral cortex is illustrated in male Wistar rats. In vitro inhibition of [³H]-spiperone binding to dopamine D₂ receptors in rat corpus striatum is also mentioned. The most active compound has IC₅₀ values of 1.4 and 320 nM, respectively. Tests to demonstrate quipazine inhibition in rats (Amt) and antagonism of pergolide-induced circling in rats (Arnt and Hyttel) are discussed. However, no data are presented on these tests. The compounds are strong, selective 5-HT antagonists and are without dopamine D₂ activity.

Chemistry: Twenty-seven examples of syntheses, by conventional methods, are given and a large number of compounds are claimed in view of the many substituents possible. The preferred compound is 3-(4-fiuorophenyl)-1-[1[2-(imidazolidin-2-one-1-yl)ethyl]-1,2,3,6-tetrahydropyridin-4-yl]-5-methyl-1H-indole.

Structure: