Synthesis, anticonvulsant, sedative and anxiolytic activities of novel annulated pyrrolo[1,4]benzodiazepines

Abstract

Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

Figure 1

Members of the fused hetero-cyclic benzodiazepine family.

Scheme 1

Synthesis of annulated benzodiazepines. Reagents and conditions: (a) chlorocarbonylsulfenyl chloride, Na₂CO₃, CH₂Cl₂–H₂O, 0 °C, 30 min, 65% yield; (b) ethyl propiolate, EtOH, 150 °C, 20 min, MW, 66% yield; (c) ethyl acetoacetate, AcOH, 150 °C, 20 min, MW, 72% yield; (d) diethyl ethoxymethylenemalonate, EtOH, 150 °C, 20 min, MW, 61% yield.

Figure 2

The effects of PBDTs 13–16 (1 mg/kg, ip) or diazepam (1 mg/kg, ip) on the (A) the latency to the loss of righting reflex and (B) total duration of sleeping time induced by sodium pentobarbital (30 mg/kg, ip). Values are the mean ± SEM, n = 4 mice; * p < 0.05, ** p < 0.01, compared with the vehicle group.

Figure 3

The effects of PBDTs 13–16 (1 mg/kg, ip) or diazepam (1 mg/kg, ip) on the (A) the percentage of open arm entries; (B) the percentage of time spent in open arm entries; (C) the percentage of closed arm entries and (D) the percentage of time spent in the closed arm entries of the elevated pus maze during a 5-min test in male mice. Values are the mean ± SEM, n = 4 mice; * p < 0.05, *** p < 0.001, compared with the vehicle group.