Design, synthesis, and pharmacological evaluation of new neuroactive pyrazolo[3,4- b]pyrrolo[3,4- d]pyridine derivatives with in vivo hypnotic and analgesic profile

Abstract

The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4- b]pyrrolo[3,4- d]pyridine derivatives 2– 5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2– 5 was constructed in good yields, exploiting a regioselective hetero Diels–Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9– 12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4- b]pyrrolo[3,4- d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect.