Synthesis and evaluation of novel 2-aryl-2,5,6 7-tetrahydro-3H-thieno[2' ,3':6,7]cyclohepta[1,2-c]pyridazin-3-ones and 2-aryl-5,6-dihydrothieno[2,3-h ]cinnolin-3(2H)-ones as anxiolytics

Article abstract of DOI:10.1016/S0223-5234(97)83286-2

A series of 2-aryl-2,5,6,7-tetrahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-ones and 2-aryl-5,6-dihydrothieno[2,3-h]cinnolin-3(2H)-ones were synthesized and evaluated for their affinity to benzodiazepine receptors (BZRs) in the excised brain of rats and also for their intrinsic efficacy in augmentation of the γ-aminobutyric acid-induced chloride currents in the dissociated sensory neurons of frogs. The synthesized compounds showed a high affinity to BZRs. In these compounds, the substituents at the 2-position and at either the 8- or the 9-position and the ring size of the condensed ring affected the biological activity of the compounds. Thus, an introduction of 4-methyl- or 4-chloro-substituted phenyl ring into the 2-position, an introduction of methyl or ethyl into either the 8- or the g-position, and an expansion of the 6-membered condensed ring to a 7-membered ring brought about a continuous shift of compounds from inverse to full agonists. Among the synthesized compounds, 8-(1-hydroxyethyl)-2-(4-methylphenyl)-5,6- dihydrothieno[2,3-h]cinnolin-3(2H)-one, which can be classified as a BZR partial agonist, was found to exhibit an anxioselective feature.