Synthesis and antinociceptive activity of new 2-substituted 4-(trifluoromethyl)-5,6-dihydrobenzo[h]quinazolines

A useful synthetic route for an initial new series of 2-substituted 4-(trifluoromethyl)-5,6-dihydrobenzo [h] quinazolines (3), as well as an evaluation of their analgesic effect in a mice pain model, is reported. Five new quinazolines were formed from the cyclocondensation reactions of 2,2,2-trifluoro-1-(1-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) ethanone (1) with some well-known amidine salts [NH2CR (=NH)] (2), in which R = H, Me, Ph, NH2 and SMe, at a 40-70% yield. Subsequently, due to the importance of the pyrrole nucleus, a 2-(pyrrol-1-yl) quinazoline (4) was obtained through a Clauson-Kaas reaction from the respective 2-(amino) quinazoline, in a reaction with 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation demonstrated that four 5,6-dihydrobenzo[h] quinazolines (compounds of 3c (R = Ph), 3d (R = NH2), 3e (R = SMe), and 4 (R = pyrrol-1-yl); 100 mg/kg, p.o.) and ketoprofen (100 mg/kg, p.o.) significantly reduced the spontaneous nociception in a capsaicin-induced test. Moreover, in comparison with ketoprofen (100 and 300 mg/kg, p.o.), compound 3c (30-300 mg/kg, p.o.) showed an anti-hyperalgesic action in an arthritic pain model without locomotor alterations in the mice, suggesting that quinazoline 3c is a promising prototype scaffold for new analgesic drugs in the treatment of pathological pain such as that in arthritis. (C) 2016 Elsevier Ltd. All rights reserved.