The Synthesis And Quantitative Structure-Activity Relationship Studies On Drug Metyrapone

Hypertension is a kind of commonly and frequently encountered disease which severely threatens people's health and life. With the development of science and technology, the occurence of hypertension is still in an upward trend. Nowadays, developing anti-hypertension drugs has been paid much more attention by governments of different countries. Diuretic drugs, as the most important anti-hypertension drug, not only cure light and moderate degree hypertension as single drug, but also could cure deep degree hypertension through working with other anti-hypertension drugs. Furthermore, it could make some control impact on complications which are caused by hypertension. Cushing's syndrome is one kind of hydrocortisone acetate increased disease, as one of complications which are caused by hypertension, which also can make sufferers depressed, and it is more and more paid attention by human.Metyrapone, named 2-methyl-1,2-dipyridin-3-yl-propan-1-one by IUPAC, belonged to light diuretic drugs, is used to be cure hypertension working with other drugs, and it is also used to diagnose and cure cushing syndrome. In this thesis, based on the actual condition of our laboratory, we make the exploratory synthesis study on metyrapone because there is no synthesis reference or patent about it. There are two main parts in this thesis: one is synthesis of metyrapone, the other is QSAR study on metyrapone similar structure compounds.The clinical studies show that metyrapone has the weak therapeutic effect on hypertension as the single curing drug; and it is often used with other anti-hypertension drugs as light diuretic drugs. Metyrapone not only is the main diagnose reagent and drug of cushing syndrome, but also it can be used to the anti-depressant drug which is caused by cushing syndrome. In this thesis, we make the exploratory synthesis study based on similar structure synthesis and organic theory. 3-acetylpyridine is as the primal material, through esterified reaction, claissen retractation, and pinacol synthesis and rearrangement, and the target compound is got by 6 steps reactions. The total collection rate is about 20%, and this route has some using reference value.As an important computational method and common technique in drug design, quantitative structure-activity relationship (QSAR) plays an important role in drug design and development. In recent half century, great impetus has been made by QSAR to the development of synthetic chemistry, pharmaceutical chemistry and drug design, it is proved to be a powerful tool for correlating molecular structure with their physical/chemical property or biological activity. In this thesis, 3D holographic vector of atomic interaction field (3D-HoVAIF) was used to describe the chemical structures of 52 metyrapone similar structure compounds. In the modeling process, stepwise multiple linear regression (SMR), multiple linear regression (MLR), partial least squares (PLS) regression, are used to correlate the 3D vector of molecules with their dissolved data, most obtained models have superior quality compared with literatures. The QSAR study main contents are as follows:3D-HoVAIF is used to characterize the metyrapone silimar structures compounds and correlate with their dissolved data. It is showed from the result that electrostatic, steric and hydrophobic interaction all contribute to biological activity, and aromatic ring structure and carbonyl structure have the important impact on their dissolved data. The result of PLS model is superior to the value of reference, and correlation coefficient (R2) is 0.810, which the value of reference is 0.735. And the value is 0.661, which shows this QSAR model has favorable estimation stability capability. The cumulative multiple correlation coefficients of MLR and CV are 0.918 and 0.751, respectively, which are also acceptable.