Synthesis and structure of novel 4,5-dihydro-1H-pyrazoles: salicylic acid based analgesic agents

Abstract

An efficient method to obtain 4-alkoxy-2-oxo-but-3-enoic acid ethyl esters [EtO 2 CC(O)C(R 2)=C(R 1)OR, where R = Me, Et; R 1 = Me, Ph, 4-MeC 6 H 4 , 4-BrC 6 H 4 , 4-FC 6 H 4 ; R 2 = H, Me] from the acylation of enol ethers or acetals with ethyl oxalyl chloride is reported. The cyclocondensation reaction of these substrates and their trifluoromethylated analogues [CF 3 C(O)C(R 2)=C(OR)R 1 ] with salicylic hydrazide furnished a series of ethyl 5-hydroxy-1-(2-hydroxybenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylates and 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(2-hydroxybenzoyl) pyrazoles, respectively. The structure of the compounds was supported by crystallographic data. Orally administrated, one of each of the series of pyrazoles (R 2 = H, R 1 = Me) showed significant analgesic effects in the writhing test in mice. The decrease in pain-related behavior obtained was close to that achieved with aspirin activity.