Imidazo[1,2-b]pyridazines. XXIV Syntheses of Some 3-(Variously Substituted) Imidazo[1,2-b] pyridazines, 6-Substituted 2-Benzoyl- imidazo[1,2-b]pyridazines and Pyrimido[1,2-b]pyridazin- 5-ium-3-olates and their Interaction with Central and Mitochondrial Benzodiazepine Receptors

Abstract

The syntheses of some ethyl 2-{2′-aryl-6′-(chloro, iodo and methoxy)imidazo[1,2-b]pyridazin-3′-yl}-2-(acetoxy, acylamino, hydroxy and methoxy)acetates, 6-methyl-2-(p-tolyl)- and 6-chloro-2-(4′-chlorophenyl)-3-trimethylammoniomethylimidazo[1,2-b]pyridazine iodides (and reactions thereof), 2-benzoyl 6-substituted imidazo[1,2-b]pyridazines and 7-(methoxy, chloro and phenylthio)-2-phenylpyrimido-[1,2-b]pyridazin-5-ium-3-olates are reported. The ability of these compounds to displace [³H]diazepam from rat forebrain membrane [central benzodiazepine receptor (BZR)] and rat kidney membrane [mitochondrial (peripheral-type) benzodiazepine receptor (PBR)] has been examined. The most active compound was ethyl 2-{6′-chloro-2′-(p-tolyl)imidazo[1,2-b]pyridazin-3′-yl}-2-hydroxyacetate with IC₅₀ 24 nM for displacement from the BZR and 91% displacement at 1000 nM from the PBR; the most selective for the PBR was 6-methyl-3-methylsulfonylmethyl-2-(p-tolyl)imidazo[1,2-b]pyridazine (PBR, IC₅₀ 92 nM; BZR, 15% inhibition of binding by [³H]diazepam at 1000 nM).