Novel application of proton nuclear magnetic resonance spectroscopy in the identification of 2'-chloronordiazepam metabolites in the dog

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Abstract
The only metabolite of 2''-chloronordiazepam, [a potent, CNS active, benzodiazepine], 7-chloro-1,3-dihydro-5(2''-chlorophenyl)-2H-1,4-benzodiazepin-2-one (1), previously identified in the dog was lorazepam (2), which was a product of 3-hydroxylation. Two phenolic metabolites (3 and 4) in the dog corresponding to 4''-hydroxylation of the 5-phenyl ring and 9-hydroxylation of the fused benzene ring, respectively, have now been identified. The structure of the 9-hydroxy isomer 4 was deduced simply from the observed NMR spectral AB (Jmeta = 2.5 Hz) pattern of the protons of the fused benzene ring. Since a 2''-chloro substituent was present on the 5-phenyl ring of the parent drug, the usual method of recognizing 4''-hydroxylation of this ring by observation of AA''BB'' multiplets in the PMR spectra was inapplicable. A novel method was introduced to identify the r''-hydroxy isomer 3, based on attributing different sets of NMR substituent effect parameters to hydroxyl groups, depending on whether these groups are m or p to the benzodiazepinimine function. The urinary plus fecal excretion of 2-4 by 1 dog given a single oral 10 mg/kg dose of 14C-labeled 1 amounted to 20, 5 and 7% of the dose, respectively; the urinary metabolites were excreted predominantly as conjugates of glucuronic acid and/or sulfate.

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