ChemInform Abstract: CHIRAL 1,4‐BENZODIAZEPINE PART 7, CYCLIZATION RATES OF 2‐(N‐ALPHA‐AMMONIUMACYL)‐AMINO‐5‐CHLORO‐BENZOPHENONES IN THE CHIRAL 1,4‐BENZODIAZEPIN‐2‐ONES

Abstract

Die Cyclisierungsgeschwindigkeiten einiger α‐Aminosäurederivate (I) zu den chiralen 1,4‐Benzodiazepin‐2‐onen (II) wird unter physiologischähnlichen Bedingungen untersucht und die Werte mit den pKa‐Daten der entsprechenden Aminosäuren korreliert.

Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin.

“…Equally important, 5, unlike 1, was well-absorbed after oral administration and was found to be an orally effective antagonist of CCK (V. J. Lotti and R. S. L. Chang, personal communication). Consistent with our rationale, compound 5 was nearly 10-fold more potent than the known 3S enantiomer 6 (Table 2), which had been reported earlier (32) to be a weak anti-anxiety agent. This low anxiolytic activity is not unexpected in view of the known deleterious effect of most 3-alkyl substituents on anti-anxiety activity in the benzodiazepine series (33,34), and it is a desirable feature in our compounds, given our analog design objectives.…”

“…Thus, as shown by the data in Table 2, our 3-alkyl and 3-amido substituents greatly enhance CCK antagonist potency but greatly diminish the anti-anxiety-related benzodiazepine receptor binding activity: selectivity changes from >104 in favor of benzodiazepine vs. CCK receptors to >104 in favor of CCK (>108-fold reversal) in the conversion of 2 to 18. Furthermore, the stereochemical preference for anti-anxiety activity in the 3-alkyl enantiomers 5/6 is the same as that reported for 3-methylbenzodiazepines (3S) (32,40), and it is opposite to that preferred for CCK antagonist potency (3R) ( It should be noted that for all the CCK antagonists reported here, the preferred orientation of the 3-substituent in space is the same. The apparent change in preferred stereochemistry from R to S between the alkyl (e.g., 5/6) and amide (e.g., 18/19) series is an artifact of the convention used to assign the stereochemical designator (41).…”

“…3-Alkyl and 3-amido substituents are reported (23,(32)(33)(34)40) to be detrimental to anti-anxiety activity. Our results are consistent with these reports.…”

Biotransformations and plasma-level curves of chiral 1,4-benzodiazepine-2-ones

“…Special attention was paid to the relationships between the stereochemical properties of these drugs, their pharmacological effects and their metabolism. Differences in psychopharmacological activity have been reported for the enantiomers of 1 (6), as well as for the enantiomers of oxazepam hemisuccinate (7). Stereoselectivity in biotransformations was investigated in vitro using prochiral and C-3 chiral 1,4-benzodiazepine-2-ones.…”