Abstract
The synthesis and antihypertensive activity of a series of novel 4-(cyclic amido)-2H-1-benzopyran-3-ols, administered orally to conscious spontaneously hypertensive rats, are described. The effects of lactam ring size, the presence of heteroatoms in the lactam ring, substitution at C(2) and C(3), relative stereochemistry at C(3) and C(4), and aromatic substitution pattern on the blood pressure lowering activity of this series have been determined. The key compound 2 from this work [BRL 34915; (+/-)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxopyrrolidin-1- yl)-2H-1-benzopyran-3-ol] has been resolved, and antihypertensive activity was found to reside primarily in the (-) enantiomer. The key step in the preparation of this class of compounds is the action of a cyclo amidic anion on an appropriate epoxide. Another approach, involving a cyclization step to the lactam was found to be more convenient in certain cases, particularly in forming the cis analogue of compound 2. Compound 2 has been shown to possess a novel mechanism of action, and it has been selected for progression to the clinic.
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