A new nonsteroidal analgesic-antiinflammatory agent. Synthesis and activity of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone and related compounds

Abstract

In order to examine analgesic and antinflammatory activities, various 2-alkyl- or 2-alkenyl-4-alkoxy-5-(substituted amino)-3(2H)-pyridazinones were prepared. Among the compounds prepared, 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (8) was evaluated to be the most attractive compound as an analgesic-antiinflammatory agent. Compound 8 was shown to be more potent in analgesic and antiinflammatory activities and less potent in toxicity than aminopyrine and phenylbutazone. Some pyridazinone derivatives in which possible active sites of 8 are eliminated and altered were prepared, and their activities were evaluated by means of analogous assays. On the basis of available data, the structure-activity relationship in a series of 4-alkoxy-2-substituted-5-(substituted amino)-3(2H)-pyridazinones was also discussed.

Analgesic and anti-inflammatory activities of several 4-substituted-6-(3'-nitrophenyl)pyridazin-(2H)-3-one derivatives

“…Therefore, there is an increasing need for identification of lead structures that may be of use in designing new, potent drugs with less toxic effects (Takaya et al, 1979;Heinisch et al, 1990). In addition, some pyridazinone derivatives have been found to exhibit potent NSAIDs activity through the selective COX-2 inhibitory mechanism (Chintakunta et al, 2002) and some pyridazinone compounds were also found to be more potent than reference drugs.…”

Synthesis of ortho-Functionalized 4-Aminomethylpyridazines as Substrate-Like Semicarbazide-Sensitive Amine Oxidase Inhibitors

“…Attempts to directly replace the 4-chloro substituent in compounds of type 5 with a cyano function by palladium-catalyzed cyanation 15) failed, so we decided to introduce the requisite carbon side chain at position C-4 by an electrophilic substitution reaction, after reductive removal of the halogen. Thus, catalytic transfer hydrogenation of 5a, b with ammonium formate/palladium gave the known 5-cycloaminopyridazinones 6a 16) and 6b, 13) respectively. Vilsmeier-Haack formylation of these electronrich pyridazinones then afforded the aldehydes 7a, b.…”

“…Starting from 4,5-dichloro-2-methylpyridazin-3(2H)-one 12) (4), we made use of the well-known regioselective nucleophilic displacement of the 5-chloro function by secondary amines in aqueous medium (apolar solvents would favor substitution at position C-4). 13) Reaction of 4 with pyrrolidine or morpho-line gave the known 4-chloro-5-cycloaminopyridazinones 5a 14) and 5b, 13) respectively. Attempts to directly replace the 4-chloro substituent in compounds of type 5 with a cyano function by palladium-catalyzed cyanation 15) failed, so we decided to introduce the requisite carbon side chain at position C-4 by an electrophilic substitution reaction, after reductive removal of the halogen.…”

Utilization of Cyanoacetohydrazide and Oxadiazolyl Acetonitrile in the Synthesis of Some New Cytotoxic Heterocyclic Compounds

“…Pyridazinone derivatives, a class of compounds containing the N-N bond, exhibit a wide range of pharmacological activity [1], including analgesic, antidepressant, anti-inflammatory [2][3][4][5][6], antimicrobial [7,8] as well as herbicidal activities [9]. There are numerous reports available in the literature, which indicate the potential anticancer effects of pyridazinones.…”