Synthesis and renal vasodilator activity of some dopamine agonist 1-aryl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diols: halogen and methyl analogues of fenoldopam.

Certain 6-halo-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were found to be potent D-1 dopamine agonists. The 1-(4-hydroxyphenyl) analogues did not have central nervous system activity because their high polarity inhibited entry into the brain. However, these compounds were potent renal vasodilators. Fenoldopam, the 6-chloro analogue, is an especially significant member of the series, and its synthesis, pharmacology, and clinical properties have been studied extensively. The 6-methyl and 6-iodo congeners were potent renal vasodilators, but nonpotent partial D-1 agonists as measured by stimulation of rat caudate adenylate cyclase. A possible rationalization suggests different receptor reserves for these activities. The 9-substituted benzazepines were either inactive or of low potency as dopamine agonists, while the N-methyl analogues had significant antagonist potency as measured by inhibition of dopamine stimulation of rat caudate adenylate cyclase.

A facile synthesis of beta-(S-benzylmercapto)-beta, beta-cyclopentamethylene-propionic acid.

The title compound is a key intermediate for the preparation of oxytocin and vasopressin antagonists. Using sodium benzylmercaptide instead of boron trifluoride etherate as catalyst gives a better than four fold overall improvement in yield of the title compound from ethyl cyclohexylideneacetate and benzylmercaptan. The preparation of the corresponding acid labile S-p-methylbenzylmercapto and S-p-methoxybenzylmercapto analogs is also described.