This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent lipophilicity to allow increased central nervous system penetration and pharmacological activity (gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over those analogues that could not form an intramolecular hydrogen bond.

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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The synthesis and oral antihypertensive activity in conscious spontaneously hypertensive rats of two new series of compounds related to the prototype potassium channel activator cromakalim (1) are described. In the first series, replacement of the benzopyran oxygen atom by nitrogen or methylene led to the 1,2,3,4-tetrahydroquinoline 12 and 1,2,3,4-tetrahydronaphthalene 13, which were both less active than 1. However, in contrast to the equivalent activity found previously for 1 and its dehydrated analogue 28, the dihydronaphthalene 27 was found to be more active than 13. In the second series, replacement of the C(4) amide nitrogen atom in acyclic amides related to cromakalim by methylene gave ketone 16 that was less active than the corresponding amide 15. However, replacement of the 4-acetonyl substituent in 16 by N,N-dimethylacetamido as in compound 22 resulted in a marked enhancement in activity. The compounds described in this paper thus illustrate the importance of the benzopyran oxygen and C(4) substituent on antihypertensive activity in the cromakalim series of potassium channel activators.