A variety of agents are presently under development as potential treatments for migraine headaches. For example, MDL-72222 (tropine 3,5-dichlorobenzoate) is reported to block the M-receptors for 5-hydroxytryptamine (5-HT), now referred to as 5-HT.sub.3 receptors, thereby providing an antimigraine effect--see Bradley, et al., Neuropharmacology, 25(6), 563 (1986). Other 5-HT.sub.3 antagonists reported in the literature include Beecham compound 112-574, included in EPO Patent Application Publication 158,265, and Merrell-Toraude compound 105-834, (U.S. Pat. No. 4,486,441). All of these compounds are tropine or tropine-like esters or amides of a substituted benzoic acid.
Indole and related bicyclic derivatives are also reported to be anti-migraine agents. See, e.g., GB 2,125,398. Other bicyclic derivatives are reported in WO 84/03281 to have dopamine antagonist activity and to be useful for lowering blood pressure and treating emesis.
This invention provides potent specific 5-HT.sub.3 antagonists useful for treating migraine and emesis. The compounds are potent, orally active, and provide a long duration of effect.
USPTO Backgrounds
USPTO Backgrounds