Modifications of 4‐Amino‐substituted 5‐Phenyl‐3‐(trifluoromethyl)pyrazoles for the Development of New Analgesics

Abstract

To develop the new analgesics, different approaches to the modification of 4‐amino‐5‐phenyl‐3‐(trifluoromethyl)pyrazoles were proposed. A series of 4‐(het)arylimino‐3‐(trifluoromethyl)‐5‐phenylpyrazoles, existing as the E‐isomer, was synthesized by condensation of the 4‐aminopyrazoles with various aldehydes. Methylation of the initial substrates occurred at the NH2 group, while alkylation with bromobutyl was successfully carried out only for NH‐pyrazole to yield 3‐ and 5‐CF3‐isomeric N‐butyl‐substituted pyrazoles. The addition of phenylisothiocyanate to 4‐aminopyrazoles allowed us to introduce a thiourea fragment into their structure. According to computer calculations, all derivatives of aminopyrazoles have an acceptable ADME profile. Using the “hot plate” test in vivo, the analgesic activity of a number of the synthesized compounds was evaluated. Introducing the phenylmethanimine fragment allows us to obtain 1‐phenyl‐N‐(5‐phenyl‐3‐(trifluoromethyl)pyrazol‐4‐yl)methan‐imine as the lead compound with the analgesic activity in 1.4–2.2 times more than effect of the initial 4‐aminopyrazole, diclofenac and metamizole. In addition, the lead compound had low acute toxicity.