【作者】 刘少静；

【导师】 马政生；

【作者基本信息】 西北大学 ， 应用化学， 2009， 硕士

【摘要】 心脑血管疾病（CDV）是“威胁人类健康的第一杀手”,研究和开发高效创新药物是治疗这一疾病的主要手段,也是医药领域研究的热点问题。丹参素冰片酯（简写:DBZ）,是由作者所在研究中心应用代谢组学研究技术,在对复方丹参滴丸、丹参饮和冠心丹参片等复方丹参方的深入研究过程中提出,并结合有机合成、现代药理学等技术合成的一个全新化合物,该化合物具有明显的抗大鼠急性心肌缺血、降低血压等作用。本论文以丹参素冰片酯为研究对象,围绕其结构表征、质量控制和体内代谢方法的建立展开研究,对进一步将其开发为1类化学新药具有重要意义。主要研究内容如下:1、采用MS、IR、NMR等手段对丹参素冰片酯（DBZ）进行了结构表征。结果表明:DBZ分子量为334.2,化学名称为3-（3,4-二羟基苯基）-2-羟基丙酸-1,7,7-三甲基双环[2.2.1]-2-庚醇酯。拟定合成路线,所得产物为旋光异构体,在反相液相色谱图中出峰特征为双峰。2、围绕样品的性状、理化常数、鉴别、检查及含量测定等初步建立了丹参素冰片酯的质量标准。有机溶剂残留检查结果表明,三批样品均未检测出乙醚、丙酮、四氢呋喃、乙酸乙酯和甲醇,乙醇残留量小于0.5%;有关物质和含量测定的方法学考察表明丹参素冰片酯在5 mg·L^-1～1000 mg·L^-1范围内线性关系良好,检测限为10 ng,证明所建方法专属性强、灵敏度高,可用于丹参素冰片酯的质量控制研究。稳定性研究表明:丹参素冰片酯在高温、强光照射下不够稳定,应当低温、避光保存。3、建立了兔含药血浆中丹参素冰片酯的高效液相色谱分析新方法,并采用该方法研究了丹参素冰片酯在正常家兔体内的药代动力学过程。结果显示:丹参素冰片酯在0.08～19.92 mg·L^-1范围内具有良好的线性关系,检测限为14.4 ng,回收率、精密度和稳定性等指标均符合美国FDA生物样品分析要求;家兔以30 mg·kg^-1的剂量静脉注射丹参素冰片酯后,血浆药-时曲线符合三室开放模型,证明所建方法能用于丹参素冰片酯的非临床药代动力学和生物等效性研究。更多还原

【Abstract】 Cardiovascular and cerebrovascular diseases（CDV） is the "first killer which threat to human health",the research and development of highly effective new drugs is the main means to remedy the disease,and also the hot topic in the field of medicine research.Bomylβ-（3,4-dihydroxyphenyl）-α-hydroxypropionate（Abbreviation:DBZ） is a new compound which was advanced from in-depth study of Compound Danshen Dripping Pills,Decoction of Radix Salviae Miltiorrrhizae and Fufang Danshen Tablets,and was synthesized with technologies of organic synthesis and modern pharmacology by the research center where the auther works.The compound also presented a strong efficiency for againsting acute myocardial ischemia and lowering blood pressure in rats.In this thesis,DBZ was selected as a target for the investigation on its structrual identification,quality control and establishment of the analyzing method of pharmacokinetic study in vivo.The above investigation could play an important role in developing DBZ as one grade innovative medicine.The main contents of this thesis are showed as following:1.Mass spectroscopy,infrared spectroscopy and nuclear magnetic resonance spectroscopy method were used for the identification of DBZ.The results showed that the molecular weight of DBZ is 334.2,and its chemical name is 1,7,7-trimethylbicyclo[2.2.1]heptan-2- y1 3-（3,4-dihydroxyphenyl）-2-hydroxy-propanoate. With the proposed synthetic method,the reacting product has the properties of optical isomers and bimodal peak in reverse liquid chroamtogram.2.A new quality controling method was established for the research on characteristics, physico-chemical constants,identification,examination and determination of DBZ.The results of residual solvents showed that there are no ether,acetone,tetrahydrofuran,ethyl acetate and methanol by investigating three parallel DBZ samples.In addition,the residual quantity of alcohol is lower than 0.5%.Methodology of related substances and determination showed that the linear range of DBZ is 5～1000 mg·L^-1,and the detection limit is 10.0 ng, demonstrating that the method is specific,sensitive and could be used for quality control of DBZ.The results of stability experment indicated that DBZ is lack of stability under high temperature and strong light,demonstating that it should be stocked without high temperature and strong light. 3.A new high performance liquid chromatography（HPLC） method for analysis of the DBZ in plasma was established.Moreover,the pharmacokinetics of DBZ was studied by the method in healthy rabbit.The results showed that the linear range of DBZ is 0.08¹9.92 mg·L^-1,the detection limit is 14.4 ng.The recovery,relative standard deviations（RSD） of precision and stability were accorded in the requirements of biological sample analysis in Food and drug administration.The time - concentration curve of DBZ with the intravenous dosage of 30 mg·kg^-1 confirmed to the model of three compartment,indicating that the method could be used to pre-clinical pharmacokinetic and bioequivalence study.更多还原