â…  Synthesis Of Bisoprolol Fumarateâ…¡ Qsar Studies On Some Series Of Anti-inflammation Inhibitors

Bisoprolol fumarate,(1-4[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy)-3-[(l-methylethyl)amino]-2-propanol fumarate), is a novel and specific (3-adrenergic receptor blocking agent and has been used for the treatment of hypertension, angina pectoris,cardiac arrhythmias. In the first part, the synthesis and improvement of Bisoprolol fumarate have been studied based on the literatures.The product is synthesized from [4-(2-Isopropoxyethoxy)methyl]phenol, involved muti-step reactions:etherified with epichlorophydrin, amidation of epoxide with isopropylamine and salified with fumarate. The factors in reaction condition are also explored though orthoponal experiment. The solvent, temperature, materials ratio, catalyst, reaction time and separation method are all optimized, and yields in each step are improved.The second part is involved in some series of anti-inflammation inhibitors:1,5-diarylimidazoles COX-2inhibitors, a series of typical tricycle compound and diaryl-substituted-1,2,4-trizole derivatives COX-2inhibitors. Their quantitive structure activity relationshitp (QSAR) and molecular docking had been applied. There are four main subparts as follows:In the first subpart, the structures of a new series of inhibitors,1,5-diarylimidazoles cyclooxygenase-2were calculated by PM5semiempiri-cal quantum chemistry methods. These inhibitors docking with the active site in COX-2were evaluated with Dock into Active Site method. It was found that the structures of1,5-diarylimidazoles COX-2inhibitors are similar to the structures of typical tricyclic cycloxygenase-2selective inhibitors, and the inhibitory activities1g(IC50) are correlated with docking free energiesIn the second subpart, Self-organizing molecular field analysis (SOMFA), a simple three-dimensional quantitative structure-activity relationship (3D-QSAR) method is used to study the correlation between the molecular properties and the anti-inflammatory biological activities of a new series of1,5-diarylimidazoles that act as selective COX-2inhibitors. The statistical results, cross-validated rCv2(0.507) and non cross-validated r2(0.546), show a satisfied predictive ability.In the third subpart,30selective COX-2inhibitors of the tricycle series, initial geometric optimizations were carried out using the MMFF94force field. Further geometric optimizations were performed by PM5semiempirical quantum chemistry method and derived MOPAC charges, and all molecules were aligned by the common tricycle structure. The3D-QSAR models were developed using comparative molecular field analysis (CoMFA) and self-organizing molecular field analysis (SOMFA) respectively. Both the two3D-QSAR models can explain the dependence of COX-2inhibition upon the structures of the compounds and suggesting powerful predictive ability, especially the CoMFA model.In the fourth subpart, the structures of a new series of inhibitors, diaryl-substituted-1,2,4-trizole derivatives cyclooxygenase-2were calculated by PM5semiempirical quantum chemistry methods, and the2D-QSAR of inhibitors were studied by multiple regression method. These inhibitors docking with the active site in COX-2were evaluated with ICM-dock and Autodock method. It was found that the results of QSAR of1,5-Diarylimidazoles COX-2inhibitors are similar to that of typical tricyclic cycloxygenase-2selective inhibitors such as celecoxib, the structures of diaryl-substituted-1,2,4-trizole derivatives COX-2inhibitors are similar to the structures of typical tricyclic cycloxygenase-2selective inhibitors, and the inhibitory activities Log(IC50) are correlated with docking free energies.