N,N‐dimethylcarbamyl derivatives of oxazepam

Abstract

Three N,N-dimethylcarbamyl derivatives of oxazepam (1-(N,N-dimethylcarbamyl)oxazepam, 3-O-(N,N-dimethylcarbamyl)oxazepam, and 1,3-O-bis(N,N-dimethylcarbamyl) oxazepam) and a 3-O-acyl-1-(N,N-dimethylcarbamyl)-oxazepam were synthesized from either oxazepam or demoxepam. Enantiomeric pairs of these derivatives and of camazepam were resolved by high-performance liquid chromatography on at least two of three commercially available chiral stationary phase columns employed. Absolute configurations of resolved enantiomers were established by comparing their circular dichroism spectra to those of enantiomeric oxazepams with known absolute stereochemistry. Similar to those of oxazepam, enantiomers of 1-(N,N-dimethylcarbamyl)oxazepam undergo rapid racemization (t1/2 1.9 min at 23 degrees C and 0.9 min at 37 degrees C) in an aqueous solution at pH 7.5. The (R)-enantiomer of rac-3-O-acyl-1-(N,N-dimethylcarbamyl)oxazepam was hydrolyzed approximately 4.6-fold faster than the (S)-enantiomer by esterases in rat liver microsomes, whereas the (S)-enantiomer was hydrolyzed approximately 43-fold faster than the (R)-enantiomer by esterases in rat brain S9 fraction.

Resolution and stability of oxazepam enantiomers

“…Immediately afterward, changes of ellipticity (A@, in millidegrees) were recorded at a wavelength (255,310,320, or 330 nm) as a function of time at ambient temperature on a JASCO Model 500A spectropolarimeter uapan Scientific Co., Easton, MD). [7][8][9][10] The monitoring wavelength was chosen to avoid strong absorption by the solvent. The tlh was determined by plotting log (A@) versus time.…”

Cannabinoid-Induced Stereoselective Inhibition of R-S-Oxazepam Glucuronidation: Cannabinoid–Oxazepam Drug Interactions

“…The potential limitations of the present study also include the fact that the spontaneous racemization of oxazepam has been reported in an aqueous solution at 37 °C with a half-life of less than 4 min [ 2 , 69 ], which is much shorter than the incubation times used in the present study (30–120 min). Therefore, purified stereoisomers of oxazepam (R- and S-) cannot be used for the studies outlined here (i.e., all oxazepam preparations will become racemic after a few minutes at 37 °C).…”