Synthetic Study On Non-Benzodiazepine Compounds

Modern physiological and pharmacological studies testifiedγ—aminobutyric acid plays a important role in the course of aged learning and memory decline. GABA_A receptors are the major inhibitory neurotransmitter receptors in the brain. Current evidence also indicates that most anxiolytics and hypnotic-sedative drugs such as benzodiazepines and barbiturates exert their pharmacological actions via interactions with a discrete and neuronal site on the GABAa receptor-benzodiazepine receptor-chloride ion channel complex.Comparative quantitative structure-activity relationship studies (QSAR) have revealed that non-benzodiazepine compounds, such as imidazo[1,2-b]pyridazine derivatives, is a class of new benzodiazepine receptor ligands. Barlin reported imidazo[1,2-b]pyridazines with substituents in the 2-, 3- and 6- positions have interacted with the receptors in the central nervous system. These compounds have very high potential clinical application for mediating the anxiolytic, anticonvulsant, muscle-relaxant, hypnotic and other activities of the benzodiazepine class of drugs. This work focused on development of imidazo[1,2-b]pyridazine derivatives. The coupling of the core structure with substituents under palladium-catalyzed was investigated. About fifty-two new compounds have been synthesized, which are included in the following three aspects:1. Under the catalyst of Pd₂(dba)₃, the ligand of (+)-BINAP and the base of t-BuONa, 6-chloroimidazo[1,2-b]pyridazine was converted to the corresponding amino-containing seventeen compounds (NRR'= benzylamine, pyrroline, morpholine, etc.). All compounds were confirmed by NMR and HRMS.2. An optimized catalyst system was found for Palladium-catalyzed regioselective arylation of imidazo[1,2-b]pyridazine or 6-cloroimidazo[1,2-b]pyridazine with variant aryl bromides to afford twenty-four target compounds. It is efficient for preparation of 3-arylimidazo [1,2-b]pyridazines by using Pd(PPh₃)₄ catalyst in the presence of CsCO₃ and acetate ions as base. They all were confirmed by NMR, HRMS, E.A. The compound 3-p-tolylimidazo[1,2-b]pyridazine (51) was identified regioselective arylation by X-ray crystallography.3. The same optimized catalyst system was applied in the coupling reaction of 6-chloro-2-(4-fluorophenyl) imidazo[1,2-b]pyridazine and various aryl bromides. And eleven target compounds were prepared. They all were confirmed by NMR, HRMS, E.A.