2-Benzazepines. 6. Synthesis and pharmacological properties of the metabolites of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine

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Abstract
The 2-benzazepine, 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazapine (1) was selected for development as an anxiolytic agent. The structures of 3 in vitro (rat liver homogenate) metabolites of 1 and the structure of the major in vivo (dog and man) metabolite of 1, compound 2 [9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-5-ol], were confirmed by chemical synthesis. Two of the metabolites, arising from hydroxylation of the pyrimidobenzazapine ring at the 5-position (2) and N-oxide formation at the 3-position of the pyrimidobenzazapine ring (3) [9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d]benzazepine 3-oxide], were as active as 1 in a series of pharmacological tests. The 3rd metabolite, formed by hydroxylation of the 7-phenyl group in the 4-position (4) [3-chloro-4-(9-chloro-5H-pyrimido[5,4-d][2]benzazepin-7-yl)phenol hydrochloride hydrate], was inactive in the same pharmacological screens.