Nonsteroidal antiinflammatory agents—part 2 antiinflammatory, analgesic and antipyretic activity of some substituted 3-pyrazolin-5-ones and 1,2,4,5,6,7-3H-hexahydroindazol-3-ones

As a part of a research project on the synthesis of a number of substituted 1-(pyrimidin-2-yl)-3-pyrazolin-5-ones and 2-(pyrimidin-2-yl)hexahydroindazol-3-ones and as a result of the interesting antiinflammatory, analgesic and antipyretic activities recorded for some of these compounds, some new 3-pyrazolin-5-ones and hexahydroindazol-3-ones linked to substituted imidazolyl, pyrimidyl and tetrahydroquinazolinyl moieties were prepared and evaluated for such activity (Fig. 1). A structure–activity relationship (SAR) comparative study indicated that some compounds from 3-pyrazolin-5-one (2, 6–8, 10) and indazolone (18, 20, 24, 27, 29) series exhibited pronounced antiinflammatory, analgesic and antipyretic activities relative to indomethacin. Most of these compounds were found to be nearly equipotent in the antiinflammatory screen (ED50 = 16.8–19.9 mg/kg) whereas the lead compound, 2-indazolyl-4-pyrimidineacetic acid 24 (Fig. 1), was found to be the most potent among this series (ED50 = 9.9 mg/kg). Additionally, the most active compounds were shown to have a large safety margin (ALD50 = 3.0 g/kg, po) and devoid of ulcerogenic potentialities when administered orally at a dose of 300 mg/kg.

Some new 3-pyrazolin-5-ones and hexahydroindazol-3-ones linked to substituted imidazolyl, pyrimidyl and tetrahydroquinazolinyl moieties were prepared and evaluated for their antiinflammatory, analgesic and antipyretic activities. The results revealed that some 3-pyrazolin-5-ones (2, 6-8, 10) and indazolones (18, 20, 24, 27, 29) exhibited pronounced antiinflammatory, analgesic and antipyretic activities relative to indomethacin (ED50 = 9.9 - 19.9 mg/kg) with a large safety margin (ALD50 = 3.0g/kg, po) and devoid of ulcerogenic potentialities when administered orally at a dose of 300 mg/kg. Compound 24 was the most potent (ED50 = 9.9 mg/kg).Figure optionsDownload as PowerPoint slide