论文总字数：20081字

摘 要

帕拉米韦是一个独特的环戊烷类神经氨酸酶抑制剂，前一代NA抑制剂扎那米韦和奥司他韦研制成功并上市已是10多年以前，它成为这以后的又一代新型流感病毒NA抑制药物，它以流感病毒表面糖蛋白神经氨酸酶为作用靶点，是第一种以静脉注射剂剂型开发的NA抑制药物。临床实验发现，帕拉米韦对于患有急性流感且无其他并发症的成年患者具有很好的疗效，帕拉米韦三水合物对于抑制病毒神经氨酸酶具有选择性，其中包括H1N1、H2N3在内的四种甲型流感病毒和两种人源禽流感(H5N1)病毒的复制传播都有较好的抑制效果，与上一代NA抑制剂磷酸奥塞米韦、扎那米韦相比较，表现出同等级以上的药用效果。它能够有效对抗各种流感病毒的增殖过程，杀死并消灭病毒，同时具有良好的耐受性、毒性较弱等许多优点^[1]。帕拉米韦（peramivir)由BioCryst制药公司研发并批准上市，它被做成了静脉注射液剂型。目前，已在亚洲，欧洲等诸多国家上市。本文以1,2,4-三氮唑、50%氨基氰溶液和盐酸为原料，1,4-二氧六环为溶剂制备合成帕拉米韦的关键中间体1-脒基-1,2,4-三唑甲脒盐酸盐。本文欲探究在不同的反应条件下，如不同反应温度、不同反应物投料比、不同反应时长等，产物产率何时能够达到最优的课题实验。

关键词：合成帕拉米韦的关键中间体；合成；神经氨酸酶抑制剂；抗流感病毒

Abstract

Peramivir is a cyclopentane novel class neuraminidase inhibitor, zanamivir is the second (Zanamivir) and oseltamivir (Oseltamivir) successfully developed and listed in 1999, another new flu virus NA inhibitors,t influenza virus surface glycoproteins neuraminidase targets, it is the first approved as a single intravenous neuraminidase inhibitor for injectable use.Preclinical experiments showed peramivir applies aged 18 and older with acute uncomplicated influenza and flu symptoms just two days,Peramivir trihydrate selectively inhibiting viral neuraminidase, including H1N1, H2N3, including four influenza virus replication and two humanized bird flu (H5N1) virus are very good inhibition, and oseltamivir phosphate, zanamivir compared to exhibit equal or inhibition.The drug can inhibit the replication and propagation of various influenza strains, with good tolerance, toxicity, etc.Peramivir (peramivir) developed by the pharmaceutical company BioCryst in December 2014 by 19 US FDA clearance to market its dosage form is intravenous injection, under the trade name Rapivab,in June 2008 the State Food and Drug Administration (CFDA) approval of peramivir trihydrate Sodium Chloride Injection clinical trials.Currently, listed in many Asian and European countries.In this paper, 1,2,4-triazole, cyanamide and hydrochloric acid as raw materials, the synthesis of dioxane as a solvent for preparing a key intermediate 1-peramivir amidino-1,2,4-triazole hydrochloride.To explore the article at different reaction conditions, such as reaction temperature, reactant feed ratio of different, have a different order of addition of reactants, etc., can be achieved when optimal yield of the product subject experiments.

Keywords: Peramivir key intermediate; synthesis; Neuraminidase inhibitors; Anti-influenza virus

目录

摘要 Ⅰ

ABSTRACT Ⅱ

1.1神经氨酸酶抑制剂 1

1.2帕拉米韦及其关键中间体的简介 3

1.2.1帕拉米韦的作用机制 6

1.2.2药理作用 7

1.2.2.1在具有生命特征体外，对流感病毒NA的作用效果.........................7

1. 2.2.2对感染流感病毒小鼠的效果...............................................................7

1.2.2.2.1对染有A型流感的动物实验疗效......................................................... 7

1.2.2.2.2对患有B型流感的动物实验疗效................................................. .........7

1.2.2.2.3在动物体外帕拉米韦与NA的相互结合及分离速度的快慢.........7

1.2.2.3在动物体外对病毒增殖的作用效果..........................................................7

1.2.2.4本品对已产生耐药性病毒的作用效果...............................................7

1.2.2.5通过对本品进行抑制活性的处理，来检测它的药效实验............. 8

1.2.2.6对严重流感病毒的疗效............................................................................... 8

1.2.2.7对新变异的流感病毒的药效作用..................................................... 8

1.2.2.8耐药性............................................................................................................... 8

1.2.3药动学.................................................................................................... 8

1.2.4临床研究................................................................................................ 9

1.2.5安全性评价........................................................................................... 10

1.3已报道的帕拉米韦关键中间体合成路线的介绍.........................................10

1.4本课题的主要研究内容.................................................................................11

1.4.2本课题的研究目标................................................................................11

1.4.2本课题的研究方法.............................................................................. 12

第二章帕拉米韦关键中间体的合成 13

2.1实验原料和器材 13

2.1.1实验仪器 13

2.1.2实验试剂 13

2.2帕拉米韦关键中间体的合成及最优反应条件的筛选 14

第三章化合物确证...................................................................................16

3.11H-1,2,4-三氮唑-1-甲脒单盐酸盐结构确证.......................................... 16

第四章实验结论与展望 17

4.1实验结论 17

4.2展望 17

参考文献 18

附图..........................................................................................................20

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