Access to Fluorazones by Intramolecular Dehydrative Cyclization of Aromatic Tertiary Amides: A Synthetic and Mechanistic Study.

An efficient synthesis has been developed for the preparation of 9H-pyrrolo[1,2-a]indol-9-ones (fluorazones) from readily available anthranilic acid derivatives via a one-pot amide- and pyrrole-formation step, followed by an intramolecular cyclodehydration. The cyclodehydration process is mediated by the activation of aromatic tertiary amides by triflic anhydride (Tf2O). Comparison of various benzo-substituents is shown to demonstrate the high functional group tolerance of this transformation. In addition, study of the reaction mechanism is also presented to unfold the exact role of the applied base additive. Herein, as a first example, we report our findings that Tf2O-mediated amide activation is obstructed by the easy protonation of amides by the formed triflic acid during the activation step. Additionally, it has been also proven that the base additive is not involved in the transformation of O-triflyliminium triflates into reactive species (e.g., nitrilium triflates) and is only responsible to neutralize the superacid to avoid the protonation of both the secondary or tertiary amides.

New P2X3 receptor antagonists. Part 2: Identification and SAR of quinazolinones.

Numerous potent P2X3 antagonists have been discovered and the therapeutic potential of P2X3 antagonism already comprises proof-of-concept data obtained in clinical trials with the most advanced compound. We have lately reported the discovery and optimization of thia-triaza-tricycle compounds with potent P2X3 antagonistic properties. This Letter describes the SAR of a back-up series containing a 4-oxo-quinazoline central ring. The discovery of the highly potent compounds 51 is presented.

Effect of Binding Linkers on the Efficiency and Metabolite Profile of Biomimetic Reactions Catalyzed by Immobilized Metalloporphyrin.

The investigation of liver-related metabolic stability of a drug candidate is a widely used key strategy in early-stage drug discovery. Metalloporphyrin-based biomimetic catalysts are good and well-described models of the function of CyP450 in hepatocytes. In this research, the immobilization of an iron porphyrin was performed on nanoporous silica particles via ionic interactions. The effect of the metalloporphyrin binding linkers was investigated on the catalytic efficiency and the metabolic profile of chloroquine as a model drug. The length of the amino-substituted linkers affects the chloroquine conversion as well as the ratio of human major and minor metabolites. While testing the immobilized catalysts in the continuous-flow reactor, results showed that the presented biomimetic system could be a promising alternative for the early-stage investigation of drug metabolites regarding analytical or synthetic goals as well.