Patent Evaluation: Thienopyrazine-2,3-diones as NMDA antagonists

Summary

Novelty: Novel thienopyrazine-2,3-diones are claimed along with their use for the treatment of CNS disorders. These compounds are described as potent, selective antagonists at the glycine binding site on the NMDA receptor complex.

Biology: Data are given for five compounds in both in vitro glycine binding and an in vivo convulsion induced by icv infusion of an NMDA model. The most potent compounds in vitro were the 6-chloro-7-propyl derivative (IC₅₀ = 0.18μM, ED₅₀ = 104μg/kg) and the 7-bromo derivative (IC₅₀ = 0.18μM, ED₅₀ = 70 μg/kg) but the most potent compound in vivo is the 7-methyl derivative (IC₅₀ = 1.0 μM, ED₅₀ = 46.4 μg/kg).

Chemistry: This series of compounds can be prepared from the methyl 3-aminothiophene-2-carboxylate via a Curtius rearragement on the N-Boc protected carboxylic acid using diphenylphosphoryl azide. Forty compounds are named with the claims, including 6-chloro-7-propylthieno[2,3-b]pyrazine-2,3-(1H,4H)dione.