Synthesis and Structure Investigations of Potential Sedative and Anticonvulsant Hydroxy- and Acetoxy-N-(3-oxobutyl)-pyrido[2,3-d]pyridazinones a

Abstract

Novel N-(3-oxobutyl)-hydroxy- and acetoxypyrido[2,3-d]pyridazinones were synthesized and tested in vivo for their sedative and anticonvulsant activity. The Michael-type reaction of quinolinic acid hydrazide and methyl vinyl ketone afforded a mixture of two isomers, 5-hydroxy-N7-(3-oxobutyl)-pyrido[2,3-d]pyridazin-8(7H)-one and 8-hydroxy-N6-(3-oxobutyl)-pyrido[2,3,-d]pyridazin-5-(6H)-one, in a ratio of 2:1 which were separated by crystallization. Subsequent acetylation of both isomers yielded the corresponding 5- and 8-acetoxy compounds. The structures of the compounds were proven and completely assigned on the basis of 1H, 13C, 15N NMR, and 1D NOE difference spectra as well as 2D C,H-correlation experiments. Preliminary pharmacological tests showed low acute toxicity with a LD50 > 1000 mg/kg in the mouse and sedative activity for the title compounds. 5-Acetoxy-N7- (3-oxobutyl)-pyrido[2,3-d]pyridazin-8(7H)-one displayed a borderline anticonvulsant activity in the metrazole test model.