Nonsteroidal antiinflammatory agents - Part 1: Antiinflammatory, analgesic and antipyretic activity of some new 1-(pyrimidin-2-yl)-3- pyrazolin-5-ones and 2-(pyrimidin-2-yl)-1,2,4,5,6,7-hexahydro-3H-indazol-3- ones

Article abstract of DOI:10.1016/S0223-5234(98)80002-0

In our reinvestigation of the cyclocondensation reaction of aminoguanidine bicarbonate 1 with 2-acetylbutyrolactone 2 and ethyl cyclohexanone-2-carboxylate 6, we have obtained the respective 1-amidino-3- pyrazolin-5-one derivative 3 and the 2-amidino-1,2,4,5,6,7-hexahydro-3H- indazol-3-one 7. These intermediates were utilized for the synthesis of two novel series of 1-(pyrimidin-2-yl)-3-pyrazolin-5-ones and 2-(pyrimidin-2- yl)-l,2,4,5,6,7-hexahydro-3H-indazol-3-ones. Selected analogs from both series (15 compounds) were evaluated for their antiinflammatory activity in an acute and subacute model of inflammation. The analgesic and antipyretic activity of the target compounds were also evaluated. A structure-activity relationship (SAR) comparative study indicated that some compounds from both series exhibited excellent antiinflammatory activity, together with good analgesic and antipyretic activity and were found to be more potent than the reference drugs at a dose of 50 mg/kg, po. In consideration of the efficacy of the compounds in these assays, the 5-phenyl derivative 18 from the 1- (pyrimidin-2-yl)pyrazolinone series, the 5-butyl and 5-phenyl derivatives 26, 27 from the 2-(pyrimidin-2-yl)indazolone series were further studied at graded doses for their acute toxicity (ALD₅₀) and ulcerogenic activity and were shown to have a large safety margin (ALD₅₀ > 4.0 g/kg, po) and devoid of ulcerogenic potentialities when administered orally at a dose of 300 mg/kg.