ENANTIOMERIC SEPARATION OF A SERIES OF 1,4-BENZODIAZEPIN-2-ONE CCK_B RECEPTOR ANTAGONISTS BEARING ACIDIC SUBSTITUENTS BY CHIRAL HPLC

Abstract

A series of 1,4-benzodiazepin-2-one CCK_B receptor antagonists are reported in which substitution at C3 of the benzodiazepine by a phenyl-urea group bearing acidic moieties has generated a chiral centre. As one of these enantiomers is substantially more selective for the CCK_B over the CCK_A receptor, an analytical separation of the enantiomers was developed to monitor the resolution of compounds by chemical means. It was shown that such compounds may be resolved using a Pirkle-type 3,5-dinitrobenzoyl-leucine chiral stationary phase to give high α and R_S values. However, traditional mobile phase methodologies proved unsuccessful with these compounds which were found not to elute without the addition of acetic acid. An investigation is described in which the effect of the acidic substituent, mobile phase composition, including addition of acid, and temperature is discussed for such compounds.

ACKNOWLEDGMENTS

The authors wish to thank Victor Matassa and Ray Baker for their discussions and support and Desmond O'Connor, Steve Matheson, and Steve Feeley for their expert technical contributions.