论文总字数：15638字

摘 要

托匹司他（topiroxostat）是由日本富士制药公司研发，是新型黄嘌呤氧化酶抑制剂，同时具备高度选择性、可逆性。在2013年6月28日，托匹司他医药通过了日本医疗检测机构的审查，成功上市，用于治疗尿酸代谢紊乱病症，商品名为TOPILORIC®。别嘌呤醇类药物作为目前尿酸代谢紊乱的主要用药，有很大的缺点是会无特异性的影响涉及嘌呤及吡啶代谢其他酶活性。所以在别嘌呤醇的药物治疗中，大剂量的药物水平的不断重复会给临床带来困扰，由此带来由于药物蓄积所致地严重甚至致命地不良反应更加会严重影响患者的治疗。而托匹司他为非嘌呤类XOR抑制剂对XOR的氧化和还原作用均有显著地抑制作用，所以其降低尿酸地作用更强大、持续时间长。更加重要的是，其对于心血管系统没有药物性的副作用，具有更高的安全性，与如非布索坦和别嘌呤醇等以黄嘌呤氧化酶为原型而得出的酶抑制剂相比，表现出更为高效并且可逆的选择性抑制作用，使得治疗本身能形成一种动态平衡。特别是针对有肾损伤地患者有更好的安全性。临床疗效表现显著较别嘌呤醇好，可大幅度降低血尿酸水平,耐受性好且不良反应小,在治疗高尿酸血症及痛风上具有很大地应用前景。但托匹司他目前工业生产中仍面临很多问题，如合成工艺复杂，反应各个条件苛刻，使得无法大规模生产。本文探究了一种合成托比司他的新方法，一种起始原料是2-氰基异烟酸甲酯。这种方法能有效解决当前工业生产中对于反应条件苛刻，氰基化反应物昂贵且难以获得的问题。这种方法的实验步骤简单，无苛刻实验条件，产物产率较高，适合当今工业化生产的各项要求。

关键词：托匹司他；合成；黄嘌呤氧化酶抑制剂；高尿血酸症

Abstract

Topiroxostat , a Japan Fuji pharmaceutical company research and development, is a new type of highly selective and reversible inhibitor of Xanthine oxidase. Asked Division horses he (topiroxostat) on June 28, 2013 in Japan approved for patients with gout and high urine acids, brand name: TOPILORIC ®. Clinical medication for allopurinol therapy currently, allopurinol for purine analogues, inevitably causing metabolic activity of other enzymes involved in purine and pyridine. Allopurinol therapy, repeated large doses is needed to maintain a high level of drugs.

Resulting due to serious and even fatal adverse reactions due to drug accumulation. And supporting horse Division he for non-purine class XOR inhibitors on oxidation type and restore type of XOR are has significantly of inhibition, thus its reduced uric acid of role more powerful, and lasting, and on cardiovascular system no bad effect, has better of security, and to yellow purine oxidation enzyme for structure based design of inhibitors as non-busuotan and don't purine alcohol compared, performance out on yellow purine oxidation enzyme more effective and security of inhibition, especially for has kidney injury of patients.

Clinical performance significantly better than allopurinol, can significantly reduce serum uric acid levels, and is well tolerated and adverse reactions in the treatment of hyperuricemia and gout has very broad application prospects. But asked horse Division he still faces a lot of problems in the current industrial production, such as the synthesis of complex, demanding reaction conditions, making it impossible to mass production. With 2-cyano-acid methyl ester as raw materials, designing a new method for synthesis of Tobi Secretary he.

The solutions in the reference method at low temperature and using expensive toxic cyano-the shortage of reagents, easy, mild experimental conditions, high yield, suitable for the requirements of modern industrial production.

Keywords: topiroxostat ; synthesis ; XOR ; Hyperuricemia

目录

摘要 Ⅰ

Abstract Ⅱ

第一章文献综述 2

1.1黄嘌呤氧化酶抑制剂 2

1.2托匹司他地简介 2

1.2.1托匹司他地作用机制 4

1.2.2药理作用 5

1.2.2.1选择性抑制作用...................................................................................5

1.2.2.2可逆性抑制作用...................................................................................5

1.2.2.3其他作用...............................................................................................5

1.2.3临床研究..................................................................................................6

1.2.4安全性评价 7

1.3已报道托匹司他合成路线地介绍...................................................................8

1.3.1方法一 8

1.3.2方法二 8

1.3.1方法三 9

1.3.1方法四 9

1.4本课题地主要研究内容 10

1.4.1本课题地研究目标 10

1.4.2本课题地研究方法 10

第二章托匹司他地合成 11

2.1实验原料和器材 11

2.1.1实验仪器 11

2.1.2实验试剂 11

2.2托匹司他地合成步骤 11

第三章化合物确证...................................................................................13

第四章实验结论与展望.. 14

4.1实验结论 14

4.2展望 14

参考文献 15

附图...........................................................................................................17

致谢...........................................................................................................18

第一章 文献综述

1.1黄嘌呤氧化酶抑制剂

痛风通常被认为是尿酸代谢失常导致的疾病，对人体伤害巨大，近年来发病率随着人们物质生活的提高而提高。尿酸合成的减少或者合成的增加导致的高尿酸血症可以导致明显的痛风，而高尿酸又与几种人体病症密切相关。调节血尿酸的水平是治疗和预防痛风发生的重要方法。截止目前为止，治疗高尿酸血症的药物通常有分为3类，第一是尿酸氧化酶同类的类似物，第二种是尿酸盐阴离子转运蛋白1（URAT1）拮抗剂，第三是黄嘌呤氧化酶抑制剂。

请支付后下载全文，论文总字数：15638字