Synthesis, Structural Characterization, and Antiangiogenic Activity of Polyfluorinated Benzamides

The introduction of fluorine into bioactive molecules is a matter of importance in medicinal chemistry. In this study, representatives of various chemical entities of fluoroaromatic compounds were synthesized. Depending on the reaction conditions, either tetrafluorophthalimides or ammonium tetrafluorophthalamates are accessible from tetrafluorophthalic anhydride and primary amines. Tetrafluorophthalamic acids undergo thermal decarboxylation to yield tetrafluorobenzamides. These could be successfully converted upon treatment with primary amines, in the course of an aromatic nucleophilic substitution, to 2,3,5‐trifluorobenzamides with respective amino substituents at the 4‐position. The five structure types were characterized by means of spectroscopic and crystallographic methods. The synthesized compounds were evaluated as inhibitors of angiogenesis by measuring microvessel outgrowth in a rat aortic ring assay. The biological activity was maintained throughout these different polyfluorinated chemotypes. Two or one ring, four or three fluorines: A path of stepwise structural modifications led from tetrafluorophthalimides via tetrafluorophthalamic acids and tetrafluorobenzamides to 4‐amino‐2,3,5‐trifluorobenzamides. The representatives of these chemotypes were investigated by means of spectroscopic and crystallographic methods and evaluated as inhibitors of angiogenesis.