Design, Prins-cyclization reaction promoting diastereoselective synthesis of 10 new tetrahydropyran derivatives and in vivo antinociceptive evaluations

We described in this article the very efficient 2,6-cis ou 2,4,6-cis diastereoselective synthesis (2 or 3 steps, 62–65% global yields) from Prins-cyclization reaction as synthetic key-step to tetrahydropyran rings construction of 10 new congeners compounds (3–12) designed from Naproxen structure. These tetrahydropyran derivatives were in vivo bioevaluated on antinociceptive effect in the acetic acid-induced abdominal writhing test, the tail-flick test, the rota-rod performance and open field tests. All new compounds showed greater antinociceptive activity compared to compound 1a, an analgesic tetrahydropyran derivative previously described by us. We can detach the high activity of tetrahydropyran derivative 10 which presented 87.5% inhibition (14% inhibition was presented by 1a) in the acetic acid-induced abdominal writhing test. Besides that the tail-flick tests indicate compounds 7 and 10 as the most actives. All these new compounds showed no toxicity in mice in all biologically studied models.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Prins-cyclization as key-reaction on tetrahydropyranyl diastereoselective synthesis. ► Naproxen as inspiration to design of 10 new high in vivo selective analgesics. ► Acetic acid-induced writhing, tail-flick test, rota-rod performance and open field tests. ► Relative 2,4,6-cis determination by 2D-NOESY and M06-2X/6-311++g(d,p) calculations.