Development Of Doxazosin's Single Enantiomers And Its Pharmacokinetics Study

Chiral drugs, to which pharmacologists pay much attention, are always the important field in the medicinal study. They are both hot spot and nodus in the medicinal development and research. There are a lot of chiral biological macromolecules in the biosystem, so different drugs will interact with different macromolecules according to their stereochemical structure, which will bring about different biological responses and display different pharmacokinetics and pharmacodynamics. So the study based on the biological behavior differences of chiral drugs is of much scientific and realistic value. Cardiovascular disease is one of the principal diseases jeopardizing human's health with the aging and the living standards elevating. Hypertension is the most common one among cardiovascular diseases. So to develop safe and well therapeutic antihypertensive drugs is imminent. The project that will study a chiral antihypertensive drug, doxazosin is of much importance and extensive prospect. Doxazosin is a selective alpha1-adrenoceptor antagonist that can efficiently control the symptom of hypertension. Doxazosin has a high degree of selectivity for post-synaptic alpha1-adrenoceptor. It does not influence stimulant activity of noradrenaline either at pre-synaptic or at post-synaptic alpha2-adrenoceptors. The principal advantages of doxazosin are: 1. Ameliorate the microcirculation. The widespread vasodilatation induced by doxazosin relieves both cardiac preload and afterload, consequently, reduces left ventricular wall stress and myocardial oxygen consumption, that is, it can induce both resistance vessel and capacitance vessel vasodilatation , reflectively holdback or retard syncopexia; 2. Ameliorate plasma lipid metabolism. It can reduce the plasma concentrations of triglycerides and total cholesterol. So it can reduce the risk and liability of coronary artery disease. But in the recent ALLHAT reports, doxazosin in the alpha1-adrenoceptor antagonist group led higher probability of cardiovascular incidents, and then this group had to terminate the test in 2000. Such results severely prevent its clinical application and decrease its saleroom. However, why are there so many incidents in doxazosin group? Doxazosin is a chiral drug with two enantiomers because of one asymmetric carbon atom in its molecule. The racemic doxazosin is used in clinic. So this project is about to prepare (-)-doxazosin and (+)-doxazosin, compare their biological response differences, demonstrate their pharmacokinetics and pharmacodynamics, explain the reason leading toabove result. The principal purpose is to provide theoretical guide for its clinical application and industral production. The work developed in this dissertation is as follows, 1. Develop a chemical chiral separation method for the preparation of BCP single enantiomers. L-camphor sulphonic acid is selected as a chiral selector. The intermediate BCP is chirally separated in methanol-ketone to synthesize doxazosin single enantiomers. (+)-Doxazosin whose optical purity is nearly 100% and specific rotation is +119.3°has been prepared. While (-)-doxazosin whose optical purity is nearly 80% is still in the study. 2. Develop a method for the separation and the optical purity determination of BCP enantiomers. GITC is selected as a derivatization reagent. The diasteroisomers of BCP-GITC are separated by a reversed phase HPLC method. Diasteroisomers can be base line separated under the optimum chromatographic conditions, the resolution is above 1.4. 3. Develop a method for the determination of doxazosin in the biological samples. Doxazosin can be quantitatively determined under such chromatographic conditions: 4.6mm×250mm YMC C18 column, mobile phase: methanol-0.02mol·L-1KH2PO4 aqueous solution (pH3.0, 70:30, v/v) with a flow rate of 0.6mL·min-1,λ246nm, the column temperature is 30℃. In the biological analysis, methanol acts as a reagent to deproteinate the samples, and then all samples are processed by solid phase extraction and measured by reversed phase HPLC. Over the concentrati...