Patent Evaluation: Pyranyl Cyanoguanidine K⁺ Channel Activators

Summary

Novelty: Novel pyranyl cyanoguanidine compounds with a substituted phenyl attached to nitrogen are claimed as anti-ischaemic agents. They are said to have little or no vasodilatory activity but are potassium channel activators in ischaemic tissue. They are potentially useful in transplant surgery.

Biology: Selectivity was assayed in male Wistar Kyoto rat aorta studies; the lack of vasodilator activity in normal tissue was compared to cromakalin. Preferred compounds have IC₅₀ values fifty times greater than cromakalim. The anti-ischaemic efficacy was assayed in a globally ischaemic rat heart model (male SD) by measurement of % decrease in LDH release or EC₂₅ (increase in time to contracture at 10 μM). The 4-chloro and 4-fluoro derivatives, which are said to be most preferred, have IC₅₀ = 1.1 μM and 1.4 μM, respectively, and EC₂₅ = 18.3 μM and 16 μM, respectively.

Chemistry: A process for preparing the novel derivatives is claimed which comprizes reacting a thiourea with an amine in the presence of a coupling agent. Trans-N-(4-chlorophenyl)-N″-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H1-benzopyran-4-yl)guanidine is one of nineteen specifically claimed compounds.

Structure: