Design,Synthesis And Polymorphism Of Potential 4-phenylaminonicotinic Acid Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs(NSAIDs),the world's largest prescription drugs,are clinically used for the treatment of chronic dull pain in various body parts.It's also possible to treat collagen tissue diseases such as rheumatoid arthritis,lupus erythematosus and ankylosing spondylitis.With the deepening of current research,some NSAIDs have been found to have the effect of preventing cardiovascular diseases and rectal cancer treatment.Due to the medicinal mechanism of these drugs,reducing toxic side effects and further improving bioavailability are the main directions of current research.Therefore,we have explored the design of some new potential compounds and also carried out crystallographic studies related to bioavailability.Based on previous experiments,we designed a series of 4-phenylaminonicotinic acid compounds after structural modification and studied their crystal forms.Before the synthesis work,molecular docking was performed to provide a preliminary understanding of its properties,so as to achieve the molecular design of the "symptomatic drug" type.Target compounds were synthesized by reacting4-chloronicotinic acid with phenylamine analogs with p-Ts OH as catalyst under a nucleophilic aromatic substitution(SNAr)mechanism according to literature.And twelve compounds were synthesized and characterized by NMR,IR and MS.Then,the obtained substance was subjected to polymorphs screening.The main method was to dissolve the target compound in different solvents and through slow evaporation to grow crystals,at the same time,the method of rapid cooling and mixed solvents were used for screening.After crystals were obtained,the crystal structures were determined by single-crystal X-ray diffraction,and the purity of the crystal form was determined by powder X-ray diffraction.The stability of the crystal forms was explored using differential scanning calorimetry(DSC).And calculation of the ?p Ka between –COOH and =NH and the investigation of the crystal synthon further provided understanding of the reasons for the new synthon formation in the crystal form.