Polymorphism Of 2-Phenylamino-Chlorinated Benzoic Acids

As an important branch of NSAIDs,diaryl compounds are dominated by diarylamines,which mainly can be divided into two types;fenamic acids and nicotinic acids.Many available NSAIDs,especially fenamic acids,are reported to be cardiotoxic.Diphenylamines are found to produce reactive oxygen species by the inhibition of the mitochondria in plants cells,similar to the mechanism of the adverse effects of fenamic acids in NSAIDs.Fenamates are proven to induce mitochondrial permeability transition?MPT?as well as inhibit AKR₁Cs,which are relevant to several kinds of cancer.We conclude that the synergistic action between MPT and AKR₁Cs inhibition can enhance the anticancer effect,and make fenamates potential anticancer drugs.In this thesis,we investigated one series of fenamates—the derivatives of2-phenylamino-chlorinated benzoic acids?chloro-phenylanthranilic acids?.We synthesized the target compounds and observed their polymorphic behaviors.The contents are the following:First,four compounds,4-chloro-phenylanthranilic acid,5-chloro-phenylanthranilic acid,6-chloro-phenylanthranilic acid,and 3-chloro-phenylanthranilic acid were synthesized by the Ullmann reaction.After purification,the compounds were characterized by NMR,MS,and IR.The pure compounds were subjected to crystal growth in a variety of solvents by slow evaporation and slow cooling methods to generate polymorphs for each compound.Second,the polymorphs of the target compounds were characterized by differential scanning calorimetry?DSC?,single crystal X-ray diffraction?SCXRD?,and theoretical studies such as Hirschfeld analysis and lattice energy calculations,and so on.The experimental and theoretical results were discussed in the context of polymorphism.With the above studies,the ROS-based anti-cancer mechanism of fenamate drug was clarified and the polymorphic behavior of four derivatives of 2-phenylamino-chlorinated benzoic acids was explored.The results are as follows:1.Four derivatives of2-phenylamino-chlorinated benzoic acid and five kinds of crystals were obtained;2.The three polymorphs with five conformations of 4-chloro-phenylanthranilic acid were analyzed,and the stability of polymorphs was compared through a combination of both experimental and theoretical approaches.