The intramolecular radical cyclization of o-bromo a,P-unsaturated esters for the synthesis of carbocyclic compounds is described. The effect of carbon chain substituents, the bulk of the ester group, and the olefin geometry were examined. The highest level of stereoselectivity (translcis: 911) was achieved with the Z ester via an exo cyclization. The sequential radical cyclization of a dihalodienoate to give a cis-fused bicyclic structure is also described. STEPHEN HANESSIAN, DALJIT S. DHANOA et PIERRE L. BEAULIEU. Can. J . Chem. 65, 1859 (1987.Nous dCcrivons l'utilisation d'une reaction de cyclisation radicalaire intramolCculaire des esters w-bromo a,p-insatures pour la synthkse de composCs carbocycliques. Nous avons CtudiC les paramktres suivants : la substitution de la chaine, I'encombrement stCrique dfi 21 l'ester ainsi que la gComCtrie de la double liaison des prCcurseurs radicalaires. Le plus haut degrC de stCreosClection (translcis: 911) fut obtenu avec l'ester a,p-insaturC Z. exo. De plus, la cyclisation radicalaire en sCrie d'un dihalogkno dienoate donne un produit bicyclique.The utilization of radical reactions for carbon-carbon bond formation in synthetic organic chemistry has recently attracted considerable interest (1-10). The increasing popularity of radical-based synthetic methods in organic synthesis is attribu-

A series of N-acylated indoles (12-18), N-alkylated indoles (19-24), N-acylated dihydroindoles (26-30), and N-alkylated dihydroindoles (31-34) were synthesized and evaluated in the in vitro AT1 (rabbit aorta) and AT2 (rat midbrain) binding assay. The carboxylic acid 3-[[N-(2-carboxy-3,6-dichlorobenzoyl)-5-indolyl]methyl]-5,7-dimeth yl- 2-ethyl-3H-imidazo[4,5-b]pyridine (14b) was found to be the most potent AT1 (IC50 = 0.8 nM) antagonist in the N-acylated indole series and displayed a 25-fold higher potency than the parent unsubstituted derivative 14a (AT1 IC50 = 20 nM) and a 22-fold greater potency than the corresponding dihydroindole analog 27 (AT1 IC50 = 18 nM). Replacement of the terminal carboxyl (COOH) of 14a with the bioisostere tetrazole in 16 (AT1 IC50 = 5 nM, AT2 IC50 = 130 nM) not only improved the AT1 potency by 4-fold but also resulted in a 50-fold increase in AT2 activity. In the N-alkylated indole series, the tetrazole 3-[[N-(2-tetrazol-5-yl-6-chlorobenzyl)-5- indolyl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (24) exhibited the highest AT1 (IC50 = 1 nM) activity, revealing a 230-fold increase in AT1 activity as a result of the incorporation of the isosteric tetrazole for the carboxyl (COOH) of 20 and a nearly 9-fold increase over the corresponding deschloro analog 22 (AT1 IC50 = 8.7 nM). Tetrazole 34 was identified as the most potent (AT1 IC50 = 18 nM) AT1 receptor antagonist in a structurally distinct series of compounds derived from N-alkylation of dihydroindole 25. A new class of highly potent (14b, AT1 IC50 = 0.8 nM; 24, AT1 IC50 = 1 nM) AT1-selective non-peptide AII receptor antagonists derived from N-substituted indoles and dihydroindoles is disclosed. Tetrazole 24 of the N-alkylated indole series displayed good in vivo activity by blocking the AII-induced pressor response for 5.5 h after intravenous administration in conscious normotensive rats at a 1.0 mg/kg dose level.

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