Benzo-cycloheptene-based drugs with planar chirality: experimental and theoretical evaluation of their stereochemical lability and possible chemical modifications useful for modulating it

It is well known that stereoisomerism may play exceptional effects in the case of drugs with regard to the expression of pharmacodynamic and/or pharmacokinetic properties 1. As an example, drugs containing a stereocenter or a stereogenic axis or plane exist in two enantiomeric forms, and it is strongly probable that one of them would manifest pharmacologic and/or toxic effects significantly different with respect to the other one 2. This is the reason why, in recent years, drug stereochemistry has become a significant issue for both pharmaceutical industry and regulatory authorities1. Relevant to such a subject is also the unfavourable effect that the possible lability of a stereogenic element possessed by drugs administrated as single enantiomers can have on the pharmaceutical activity, since, in the biological environment, the manifestation of stereochemical fragility could give rise to racemization. Here we present a both experimental and theoretical study, addressed to analyse the configurational lability possessed by the enantiomers of some popular second-generation antihistaminic drugs, endowed with a central seven-membered benzo-cycloheptadiene non-planar ring, responsible for the manifested chirality (Figure 1). The energy barrier that opposes the inversion of the tricyclic scaffold in the presence of some different R1, R2 and R3 substituents has been investigated by resorting to Dynamic–HPLC, Dynamic–HNMR and off‑column racemization (monitored by decay of the CD signal) techniques, as well as through assessments based on molecular modelling approaches.