Synthesis and Analgesic and Anti-inflammatory Activity of Ethyl (6-Substituted-3(2H)-pyridazinone-2-yl)acetate Derivatives

Abstract

A number of 6-substituted-3(2H)-pyridazinones and the corresponding methyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives carrying the arylpiperazinyl structure present in potent antinociceptive agents reported in the literature were synthesized. As part of a programme a series of diverse arylpiperazine derivatives of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate were prepared and tested for their in vivo analgesic and anti-inflammatory activity by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference non-steroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure-activity relationship in the series of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives was also discussed. When compared to parent 6-substituted-3(2H)-pyridazinones, the new ester derivatives, for example ethyl (6-4-[(2-fluoro)phenyl]piperazine-3(2H)-pyridazinone-2-yl)acetate exhibited better analgesic and anti-inflammatory activity and a lower ulcerogenic effect.

Synthesis and Biological Evaluation of 2‐substituted‐6‐(morpholinyl/piperidinyl)pyridazin‐3(2H)‐ones as Potent and Safer Anti‐inflammatory and Analgesic Agents

“…3‐Chloro‐6‐substituted pyridazine derivatives 1a, 1b were synthesized in accordance with the literature reports by nucleophilic displacement of 3,6‐dichloropyridazine with morpholine and piperidine, respectively . Synthesis of 6‐substituted 3‐oxo‐pyridazinones derivatives 2a, 2b is reported previously by simply refluxing 3‐chloro‐6‐substituted pyridazines 1a, 1b in glacial acetic acid for 6 h , but because of the noncompletion of the reaction even after 3 days, an alternative time saving synthetic route using microwave irradiation was adopted. In this method, pyridazines 1a and 1b were hydrolyzed at 140°C using glacial acetic acid in a microwave oven (Biotage, Sweden), which resulted in formation of 3‐oxo products 2a , 2b in high yields in only 15 min.…”

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

“…The SAR in the series of ethyl (6-substituted-3(2H)pyridazinone-2-yl)acetates was also discussed. When compared to parent 6-substituted-3(2H)-pyridazinones, the ester derivatives, ethyl (6-4-[(2-fluoro)phenyl]piperazine-3(2H)-pyridazinone-2-yl)acetate exhibited better analgesic and anti-inflammatory activity and a lower ulcerogenic effect (Dündar at al., 2007).…”

Synthesis of 1,3-benzothiazol-2(3H)-one and some its derivatives

“…These include cyclization of 2-aminobenzenethiols by the action of phosgene, chloroformates, and urea [3,11]; reductive carbonylation of substituted nitrobenzenes with sulfur, carbon(II) oxide, and water in the presence of vases [3]; cyclization of carbamothioates with subsequent cleavage of 2-alkoxybenzothiazoles thus formed [12]; oxidation of 2-sulfanyl-or 2-alkylsulfanylbenzothiazoles to the corresponding sulfones and hydrolysis of the latter; reaction of o-chloronitrobenzenes with 2-sulfanylacetic acid followed by cyclocondensation of 2-(o-nitrophenylsulfanyl)acetic acid with acetic anhydride and deacylation [3]; reaction of 1,3-benzothiazol-2-amines with alkali metal hydroxides in anhydrous medium and subsequent cyclization of o-sulfanylphenylureas [3,13]; and reaction of 2-sulfanylbenzoic acid with ammonium azide and 3 equiv of the DMF-POCl 3 complex [14]. Various 2-and 3-substituted 1,3-benzothiazol-2(3H)-one derivatives exhibit a broad spectrum of biological activity, in particular herbicidal, antimicrobial, analgesic, antioxidant, anticonvulsant, antifungal, etc.…”