Synthesis and pharmacological evaluation of some novel 5-aryl-6-arylamino-1-phenylpyrazolo[3,4-d]pyrimidin-4(5H)-ones as analgesic and anti-inflammatory agents

A series of novel title compounds 4a-o has been synthesized through two different synthetic routes. While the first involves the condensation of pyrazole o-aminoester 1 with aryl isothiocyanates 2, the second involves cyclocondensation of alkyl isothiourea ethers of sym-diarylthioureas 5 with 1. The compounds have been evaluated for analgesic, as well as, anti-inflammatory activities in rodents. The lead compound, 4c (LM-22835), exhibits analgesic activity comparable to morphine and aspirin at the dose levels of 10 mg/kg p.o. and 100 mg/kg p.o. In the acetic acid induced writhing test, in mice, it has been found to be superior to aspirin in the rat caudal immersion test. Efforts towards optimization of lend compound 4c have resulted in identifying more active compounds. Compounds 4b, 4c, 4e, 4h, 4i and 4o exhibit antiinflammatory activity superior to aspirin at 100 mg/kg, p.o. in the cotton pellet induced granuloma test(rats); compound 4o, is also found to be superior to aspirin when evaluated by the carageenan induced rat paw edema test. Acute toxicity studies reveal that these compounds are non-toxic upto 4.0 g/kg, p.o. in mice. The lead compound, 4c, has been found to be safe and without any untoward effects in the 30, as well as, 60 days chronic toxicity studies in mice.