Benzodiazepines are controlled substances and are in clinical use as antianxiety agents. Prolonged use may be habit forming. Benzodiazepine abuse is a widespread social problem. There is a practical need to screen for the presence of benzodiazepines and their metabolites in body fluids. Oxazepam glucuronide is the final metabolite of oxazepam and related benzodiazepines in humans. We propose its use in drug screening to establish protocol which will be simpler, faster and more reliable than methods in current use, which require a hydrolysis step. This project proposes: (a) to improve the synthesis of oxazepam glucuronide based on the research in our Phase I program; (b) to apply the methodology to the synthesis of N-ethyl oxazepam, a new calibration standard for benzodiazepine determinations, (c) to develop a commercial laboratory scale preparation of oxazepam glucuronide to meet the projected demand in drug screening; (d) to apply the synthetic methodology to synthesize lorazepam glucuronide, temazepam glucuronide, alpha- hydroxyalprazolam glucuronide and N-ethyl oxazepam glucuronide. The proposed project will provide optimized synthetic procedures for the preparation of diverse benzodiazepine glucuronides for which there is a present need for use as internal and external standards for analysis.
The industrial scale production of the benzodiazepine glucuronides outlined above will provide our commercial partner, Bio-Rad Corporation, with the internal and external standards necessary to develop and promote it's instrumental line of clinical, analytical hardware for the therapeutic and forensic detection of glucuronides in urine.
