Synthesis, renal vasodilator and dopamine‐sensitive adenylate cyclase activities of O ‐Methyl derivatives of 6‐chloro‐2,3,4,5‐tetr ahydro‐1‐(4‐hydroxyphenyl)‐1 H ‐3‐benzazepin‐7,8‐diol (SK&F 82526)

The three possible mono‐ O ‐methyl derivatives of 6‐chloro‐2,3,4,5‐tetrahydro‐1‐(4‐hydroxyphenyl)‐1 H ‐3‐benzazepin‐7,8‐diol (SK&F 82526) ( 1 ) have been synthesized to facilitate the isolation and characterization of metabolites of this compound and for biological testing. The syntheses generally involved preparation of appropriately substituted benzaldehydes, conversion of these to phenylacetic acids and use of these to N ‐acylate arylethanolamines. The phenylacetamides thus formed were reduced to amines and these were deprotected and cyclized to the desired final products. In one case deprotection followed cyclization. These compounds were tested as activators of dopamine‐sensitive adenylate cyclase (a measure of DA‐1 agonist activity) and as renal vasodilators. All three O ‐methyl derivatives were much less potent than 1 in cyclase activation and as renal vasodilators. Weak inhibition of adenyl cyclase was also observed for all three compounds and one showed weak renal vasoconstrictor activity. Preliminary investigation of the metabolism of 1 disclosed that two of the three monomethoxy compounds were formed in trace amounts in the rat and the dog. In a related investigation, the trimethoxy derivative of 1 was subjected to acid‐catalyzed hydrolysis conditions. The relative ease of cleavage of methoxy groups was 7 > > 4′ > 8.