The Synthesis And QSAR Of The Nitrogen Heterocyclic Ring Class Medicine-Sulfinpyrazone

Sulfinpyrazone, Chemical called 1,2-diphenyl -4-[2 - (p-sulfonyl) ethyl] -3, 5-pyrazole - dione. It is an anti-gout drug, the action of promoting of uric acid excretion is stronger than probenecid. After clinical we found that it could prevent platelet coagulation and adhesion to the vessel wall, so it also used in treatment of certain cardiovascular diseases. It is mainly used as medicine now. Through careful analysis the formula, we protocoled a synthetic route reaction based on the principle of organic synthetic chemistry, and established feasible experimental scheme contraposing the reaction principles of every step. The phase transfer catalyst was used in the first step of the reaction, the yield reached 91.20%. In the second step of the reaction adding the phase transfer catalyst accelerate the rate and improved the response rate to 64.97%. In cyclization reaction we introduced microwave experiment, comparing with the method of ordinary Refluxing, the yield increased by 10%, reached at 46.90%,The final step of oxidation reaction we make it easier to react by changing the solvent used level, for a yield of 89.38%. The final product yield of sulfinpyrazone was 24.83%. In the synthesis of the key intermediate product-diphenylhydrazine, giving full consideration to the experimental conditions, we design of the three factors - level orthogonal L₉ (3⁴), Respectively inspected the ratio of the raw materials, solvents quantity, and reaction time, and choosed the optimum conditions, the yield reached 95.11%. Determinated the melting point and the refractive index of every products, it meet the standards of literature.QSAR is a method to investigate and analysis the quantitative relationships between the structures feature of molecules and their physical/chemical properties or biological activity. MEDV, based on the two-dimensional topological structure, is applicable to various simple molecular structures that contain drug, biologic, organic and inorganic molecules. Based on MEDV, H-MEDV was developed to describe the contribution of atom electronegativity in the molecules. In this thesis, both MEDV and H-MEDV are applied to express the molecular structures of 28 3, 5-pyrazole-dione derivates. The quantitative structure - activity relationship (QSAR) models are established to predict the anti-Streptococcus pneumoniae activity of Sulfinpyrazone. By using MEDV, the correlation coefficient Rx, cross-validation R_x(cv)² are 0.573 and -1.558, respectively. The standard deviations SD of modeling estimation, cross-validation are 1.497 and 2.921, respectively. The results are not very satisfactory. The main reason is the increasing of their structure complexity and their senior structures became apparent. The nature of the whole molecule is determined not only by the size of atomic electricity and the distances between the atoms, but also by the space distances and effort between the atoms and so on. The results show that MEDV is not able to accurately describe the molecules. By using H-MEDV, the satisfactory results are gained. By using zero-optimization, leave-one-out cross-validation, leave-group-out cross-validation and stepwise regression, their estimation performance and prediction capability of are improved. The quantitative linear models are established with the correlation coefficient Rv, leave-one-out cross-validation Rv(cv) are 0.858 and 0.428, respectively. The standard deviations SD of modeling estimation, cross-validation are 0.864 and 1.273, respectively. The results show that H-MEDV is an excellent topological index to well express the structures of 3, 5-pyrazole-dione derivates. As an important computational method and common technique in drug design, QSAR will be more and more used in drugs design, in order to reduce drug development costs and shorten the development cycle.