ISSN:
0899-0042
Keywords:
antipsoriatic agent
;
10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one
;
stereogenic axis
;
interconversion half-lives
;
dynamic HPLCs
;
SIMUL
;
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
The antipsoriatic 10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8] naphthyridin-5(7H)-one, Sch 40120, is chiral only because it lacks planarity and possesses a stereogenic axis. It comprises short-lived, interconverting atropisomeric enantiomers distinguished by the chlorine substitutent. The atropisomers form diastereomeric complexes with the shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol, which were detected by 1H NMR spectroscopy. Liquid chromatography on an ovomucoid chiral column isolated each enantiomer from the racemic mixture. Re-injections of the separated enantiomers onto the same column held constant at 10°C established that each enantiomer formed the other. Under identical chromatographic conditions, both stereoisomers independently recreated the racemic mixture. The calculated enantiomer half-life lasted 1.6 min at the physiological temperature of 37°C. Simulations of dynamic liquid chromatograms acquired with a chiral stationary phase indirectly yielded values of the half-lives. The chromatograms were modeled with the computer program SIMUL. Also determined were the rate constants for enantiomerization and the corresponding Gibbs free energies of activation, all at varying temperatures. At 37°C, the rate constant and activation energy respectively equaled 0.213 min-1 and 21.6 kcal mole-1. An Arrhenius plot was linear. The intractably brief life spans necessitated development of the racemic drug, rather than advancement of one enantiomer only. The pharmacological, biological, and chemical consequences of molecular asymmetry inherent to the drug were therefore nil. © 1996 Wiley-Liss, Inc.
Additional Material:
7 Ill.
Type of Medium:
Electronic Resource
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