Synthesis of 3‐[4‐Acyl‐2‐(1‐methoxy‐1‐methylethyl)morpholin‐3‐yl]‐benzonitriles as Novel Potassium Channel Openers

Abstract

Potassium channel openers (KCO's) have been demonstrated to possess potent relaxant‐activity on smooth muscle. Tissue‐selective KCO's may find use in the treatment of a variety of diseases, such as hypertension, asthma, and urinary incontinence. We have previously reported a series of 1,9‐dioxa‐4‐aza‐phenanthrene‐6‐carbonitriles, including compounds 2 & 3, as bladder‐selective KCO's. As a continuation of our efforts, we have designed 3‐[4‐acyl‐2‐(1‐methoxy‐1‐methylethyl)morpholin‐3‐yl]‐benzonitriles as ring‐opened analogs of compounds 2 & 3. In this report, we describe the efficient construction of the novel 2,3‐disubstituted morpholine structure, as represented by the synthesis of compounds 4‐7. Compounds 4‐7 showed potent and selective relaxant‐activity on rat bladder detrusor strip preparation. In this series, the most potent derivatives are Boc‐substituted analogs 4 & 6 (IC50 = 3.9 and 2.9 μM, respectively).