Design And Synthesis Of Potential 6-phenylaminonicotinic Acid Nonsteroidal Anti-inflammatory Drugs And Investigation Of Their Polymorphism

Nonsteroidal Anti-Inflammatory Drugs(NSAIDs)are a class of medicine with antipyretic,analgesic and anti-inflammatory effects.They also have anti-rheumatic and anti-coagulant effects and can treat some neurological diseases.In vivo,NSAIDs are involved in the metabolism of arachidonic acid and exert pharmacological effect by inhibiting the synthesis of prostaglandin through inhibition of cyclooxygenase.However,most of the current NSAIDs have side effects such as gastrointestinal and cardiovascular,which make the improvement of bioavailability and the reduction of side effects the research hotspot for obtaining efficient and high safety NSAIDs.According to the drug consistency evaluation,the research on polymorphism of drugs is an indispensable step.Research on polymorphs can also help improve the physical and chemical properties of drugs,such as solubility,stability,dissolution rate,etc.,to improve the bioavailability of the drug and help develop suitable dosage forms based on characteristics.Therefore,for the newly synthesized anthranilic acid NSAIDs,their crystallographic characteristics and drug activity can be explored in order to improve druggability.6-ANAs,target compounds obtained by structural modification of 2-anilinonicotinic acid by isomerization,are synthesized by using 6-chloronicotinic acid and various aniline compounds in water with p-toluenesulfonic acid as catalysts and pyridine as acid neutralizer.It is produced by nucleophilic substitution of an aromatic ring.In this thesis,we synthesized 15 target compounds and characterized them by NMR,IR and mass spectrometry.The crystal forms were then screened by different crystal growth methods and evaluated for activity by molecular docking and activity testing against the COX-2 enzyme.The crystals were subjected to structural analysis by single crystal X-ray diffraction method,and the crystal form and purity were determined by powder X-ray diffraction.Thermal testing was then performed using differential scanning calorimetry to study the relative stability and phase transition of the crystals.And through theoretical calculations,such as conformational scanning,energy calculation,etc.,it is known that some newly synthesized 6-ANAs produce a new synthon acid-aminopyridine,and no acid-acid dimer or acid-pyridine synthon in 2-ANAs is observed.