Synthesis and Bladder Smooth Muscle Relaxing Properties of Substituted 3-Amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.

Abstract We have reported on the design, synthesis, and biological characterization of ( R )-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile ( 1 ), 1 a novel, potent, and selective adenosine 5′-triphosphate-sensitive potassium (K ATP ) channel opener with potential utility for the treatment of urge urinary incontinence (UUI). Excising the aniline-derived nitrogen atom of 1 or replacing it with an aralkyl group, led to bladder smooth muscle relaxant chemotypes 3 and 4 , respectively. Prototype compounds in these series were found to produce significant increases in an iberiotoxin (IbTx)-sensitive hyperpolarizing current, thus suggesting that these relatively modest structural modifications resulted in a switch in the mechanism of action of these smooth muscle relaxants from K ATP channel openers to activators of the large-conductance Ca 2+ -activated potassium channel (BK Ca ). We report herein the syntheses and biological evaluation of a series of substituted 3-amino-4-aryl-(and aralkyl-)cyclobut-3-ene-1,2-diones.