Synthesis of 3-[4-acyl-2-(1-methoxy-1-methylethyl)morpholin-3-yl]- benzonitriles as novel potassium channel openers

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).