Unit 1 Production of Drugs.doc

Unit 1 Production of Drugs1单元 药物制造1 Depending on their production or origin 根据其生产或来源pharmaceutical agent代理，制剂s can be split into three groups:1.Totally synthetic materials (synthetics)2.Natural products, and 3.Products from partial synthesesSynthesis的复数，合成法 (semi-synthetic products)2 The emphasis of the present book is on the most important compounds of groups 1 and 3-thus Drug synthesis. This does not mean, however, that natural products or other agents are less important. They can serve as valuable lead structures引导结构 ,and they are frequently needed as starting materials or as intermediates for important synthetic products.3Table 1 gives an overview总的看法 of the different methods for obtaining pharmaceutical agents. 根据生产制造或者来源，药物制剂可以分为三种类型：1.完全合成物质合成物2.天然产品3.用部分合成的方法生产的产品（半合成产品） 本书的重点是第一种和第三种类型中最重要的一些化合物，例如药物合成方法。然而，这也不是说天然产品或其他类型的制剂不重要。他们可以作为重要的先导结构，并且他们经常的被用作重要合成产品的起始物质或中间体。图表1给出了不同的获得药物制剂的方法的总括Table 1 Possibilities for the preparation制备，准备：做准备的行为或过程；制剂，制品：已制成的备用药；标本：已制成并保存起来供研究用的解剖或病理标本 of drugsMethodsExamples1. Total synthesisover 75% of all pharmaceutical agents (synthetics).2. Isolation from natural sources ( natural products)2.1 Plants alkaloids; enzymes; heart glycosides; polysaccharides; tocopherol生育酚,维生素E; steroid甾类，甾族化合物；类固醇：一组含氢化环戊烷多氢菲环系脂化物的类名。包括孕酮、肾上腺皮质激素、性激素、强心甙配基、胆汁酸、固醇(如胆固醇)、蟾毒、皂甙和某些致癌碳氢化合物 precursors (diosgenin, sitosterin)谷氨酸甘油酯 ; citral柠檬醛一种流动的淡黄色液体，CHCOH，从柠檬草油中制得，作为香料用于香水制造业 (intermediate product for vitamins A, E, and K)2.2 Animal organsEnzymes; peptide hormones; cholic acid from gall ; insulin from the pancreas; sera and vaccines2.3 Other sourcesCholesterol from wool oils; L-amino acids from keratin and gelatine hydrolysates3.Fermentation Antibiotics; L-amino acids; dextran; targeted modifications on steroids, e.g.例如 (exempli gratia) 11-hydroxylation; also insulin, interferon, antibodies, peptide hormones, enzymes, vaccines4.Partial synthetic modification of natural products (semisynthetic agents):Alkaloid compounds; semisynthetic -lactam antibiotics; steroids; human insulin表1 药品制备的可能产物方法例子1.全合成超过75%的药物制剂（合成物）2.从天然资源中分离（天然产品）2.1植物生物碱类；酶类；苷类；多糖类；生育酚；甾类前体类（薯蓣皂苷配基，谷甾醇）；柠檬醛（生产维生素A，E和K的中间体）2.2动物器官酶；激素肽；胆汁中获得的胆酸；胰腺中获得的胰岛素；血浆和疫苗2.3其它资源羊毛油中获得的胆固醇；角蛋白和动物胶水解产物中获得的左旋氨基酸3.发酵物抗生素；左旋氨基酸；葡聚糖；甾类的定向修饰物，如11位的羟基化；以及胰岛素，干扰素，抗体，激素肽，酶，疫苗4.半合成修饰产品生物碱类化合物；半合成内酰胺类抗生素；甾类；人胰岛素4 Several therapeutically significant具有重要治疗作用的 natural products which were originally obtained from natural sources are today more effectively i.e.id/est(id est) 拉(=that is (to say)略作i.e.即, 那就是 more economically prepared by total synthesis. Such examples include L-amino acids , Chloramphenicol, Caffeine, Dopamine, Epinephrine, Levodopa, peptide hormones, Prostaglandins, D-Penicillaminepenicill(in) -amine, Vincamine, and Practically all vitamins. 通过全合成，一些从天然资源中获得的有重要治疗作用的天然产品在今天被更加有效，即更加经济的制备了。例如：包括L-氨基酸、氯霉素、咖啡因、多巴胺、肾上腺素、左旋多巴、激素肽、前列腺素、D-青霉胺、长春蔓胺和几乎所有的维生素。5 Over the last few years fermentation i.e. microbiological微生物学的 processes has become extremely important. Through modern technology and results from genetic selection leading to the creation of high performance mutants of microorganisms, fermentation has already become the method of choice for a wide range of substances. Both Eukaryont真核细胞s (yeasts and moulds) and Prokaryont原核生物s ( single bacterial cells, and actinomycetes ) are used as microorganisms. The following product types can be obtained:近年来，发酵，也就是微生物发酵过程，已经变得极为重要。现代技术和基因选择的结果导致了高性能微生物突变体的产生，发酵已经成为许多物质的精选方法。包括真核生物（酵母和霉菌）和原核生物（单细胞细菌和放线菌）都被用做发酵用微生物。通过发酵可以得到以下类型产品：1.cell material (single cell protein),2.enzymes, 3.primary degradation products (primary metabolites),4.secondary degradation products ( secondary metabolites ).1.细胞物质（单细胞蛋白质）2.酶3.初级的降解产品（初级代谢物）4.次级的降解产品（次级代谢物）6 Disregarding the production of dextran from the mucous membranes of certain microorganisms, e.g. Leuconostoc mesenteroides, classes 2 and 3 are the relevant ones for the preparation of drugs. Dextran itself , with a molecular weight of 50,000100,000, is used as a blood plasma substitute, Among the primary metabolites the L-amino acids from mutants of Corynebacterium glutamicum and Brevibacterium flavum are especially interesting. From these organisms some 350,000 tones of monosodium L-glutamate (food additive) and some 70,000 tones of L-lysine (supplement for vegetable proteins )are produced. Further important primary metabolites are the purina nucleotides, organic acids, lactic acid, citric acid, and vitamins, for example vitamin B12 from Propionibacterium丙酸杆菌属 sherman谢尔曼(姓氏,男子名)ii.除了从某些微生物，如明串珠肠球菌的黏膜中产生的葡聚糖外，第2和第3类产品也是与制备药物相关的。葡聚糖本身，分子量为50000100000，被用来作为血浆的代用品。在初级代谢产物中，谷氨酸棒杆菌和黄色短杆菌突变体产生的L-氨基酸是尤其令人注意的。在这些生物体中，大约350000吨的L-谷氨酸单纳盐（食品添加剂）和70000吨的L-赖氨酸（植物蛋白补充物）被生产。更重要的初级代谢产物是嘌呤核苷，有机酸，乳酸，柠檬酸和维生素，如从谢氏丙酸杆柄菌获得的维生素B12。7 Among the secondary metabolites the antibiotics must be mentioned first. The following five groups represent a yearly worldwide value of US-$ 17 billion: penicillins (Penicillium chrysogenum产黄青霉：可产生许多种青霉素 ), cephalosporins (Cephalosporium acremonium念珠菌目 ), tetracyclines (streptomyces aureofaciens )erythromycins (streptomyces erythreus ) aminoglycosides (e.g. streptomycin from Streptomyces griseus ).在次级代谢物中首先要说抗生素。以下五类抗生素在全世界每年的产值达一百七十亿： 盘尼西林(产黄青霉) 头孢菌素(支顶头孢子菌 ), 四环素 (金霉素 )红霉素 (红链霉菌) 氨基糖苷类抗生素 (e.g. 链霉菌 from Streptomyces griseus ).8About 5000 antibiotics have already been isolated from microorganisms ,but of these only somewhat fewer than 100 are in therapeutic use. It must be remembered, however, that many derivatives have been modified by partial synthesis for therapeutic use; some 50,000 agents have been semisynthetically obtained from-lactam alone in the last decade. Fermentations are carried out in stainless steel fermentors with volumes up to 400m3. To avoid contamination of the microorganisms with phages etc.及其他 et cetera etc the whole process has to be under sterile conditions. Since the more important fermentations occur exclusively under aerobic conditions a good supply of oxygen or air (sterile) is needed. Carbon dioxide sources include carbohydrates, e.g. molasses, saccharides, and glucose. Additionally the microorganisms must be supplied in the growth medium培养基 with nitrogen-containing compounds such as ammonium sulfate, ammonia, or urea, as well as with inorganic phosphates. Furthermore, constant optimal Ph and temperature are required. In the case of penicillin G, the fermentation is finished after 200 hours, and the cell mass is separated by filtration. The desired active agent动因，因子：任何能产生物理、化学或生物学效应的力、成分或物质s are isolated from the filtrate by absorption or extraction processes. The cell mass , if not the desired product, can be further used as an animal feedstuff owing to its high protein content.大约有5000种抗生素已经从微生物中分离出来，但只有将近100种被用于治疗。然而，应该记住，通过部分合成的方法许多衍生物经改良后用于治疗。在近10年中，仅用-内酰胺就通过半合成的办法获得了大约50000种药剂。发酵是在容积达400立方米的不锈钢发酵罐内进行的，为了避免噬菌体等微生物的感染，整个过程必须在无菌的环境下进行。由于更重要的发酵过程必须在需氧的条件下发生，因此需要良好的氧气或空气(无菌的)的供应，二氧化碳的来源包括碳水化合物，如糖浆、糖类和葡萄糖。此外，微生物的培养基中必须供应含氮化合物，如，硫酸铵、氨、尿素，以及磷酸无机盐。另外，还需要恒定的最适PH和温度。以青霉素G为例，发酵过程在200小时后完成，细胞团块通过过滤分离。想要得到的活性成分通过吸附和提取的过程从滤液中分离得到。细胞团块，如果不是想要的产品，由于其蛋白质的含量很高可以进一步作为动物饲料使用。 By modern recombinant techniques microorganisms have been obtained which also allow production of peptides which were not encoded in the original genes. Modified E. coli bacteria make it thus possible to produce A- and B-chains of human insulin or proinsulin analogs. The disulfide bridge二硫键s are formed selectively after isolation, and the final purification is effectvt.招致, 实现, 达到(目的等)ed by chromatographic procedures. In this way human insulin is obtained totally independently from any pancreatic material taken from animals.通过现代的重组技术也可以得到不是由原始基因组所编码的肽产品。因此可以用经过修饰了的大肠杆菌生产人胰岛素或胰岛素原类似物的A链和B链，分离后选择性地形成二硫键，最终通过色谱程序实现纯化。通过这种方法可以完全独立的从任意动物胰腺的原料中获得人胰岛素。9 Other important peptides, hormones, and enzymes, such as human growth houmone( HGH ), neuroactiveadj.刺激神经组织的 peptides, somatostatin, interferons, tissue plasminogen activator( TPA ), lymphokines, calcium regulators like calmodulin, protein vaccines, as well as monoclonal antibodies used as diagnostics, are synthesized in this way.其他的重要的肽类、激素和酶，如人生长激素（HGH），神经活性肽，生长激素抑制素，干扰素类，组织纤维蛋白酶原活化剂（TPA），淋巴因子，钙调节剂如钙调蛋白，蛋白疫苗，以及诊断用单克隆抗体，都是通过这种方法合成的。10 The enzymes or enzymatic systems which are present in a single microorganism can be used for directed定向的 stereospecific and regiospecifec chemical reactions. This principle is especially useful in steroid chemistry. Here we may refer only to the microbiological 11-hydroxylation羟基化作用 of progesterone to 11-hydroxyprogesterone, a key product used in the synthesis of cortisonen.可的松 又称“11-脱氢-17-羟皮质酮”。. Isolated enzymes are important today not only because of the technical importance of the enzymatic saccharification of starch , and the isomerization of glucose to fructose, They are also significant in the countless test procedures used in diagnosing illness , and in enzymatic analysis which is used in the monitoring of therapy.在微生物体内的专一性的酶或酶系统可用于立体专一性或区域专一性定向反应。这一原则尤其适用于甾体化学。在这里我们只提一下微生物的11位羟基化作用使黄体酮羟化为11-羟基黄体酮，它是在可的松合成中的一个关键产品。单体酶在现在如此重要，不仅是由于淀粉的酶的糖基化技术的重要性，也是由于其对葡萄糖到果糖的异构化作用。他们在无数的疾病的诊断检测，以及治疗监控中的酶分析中也具有重要的意义11 A number of enzymes are themselves used as active ingredients. Thus preparations containing proteases (e.g. chymotrypsin , pepsin , and trypsin ), amylases and lipases, mostly in combination with synthetic antacids, promote digestion. Streptokinase 链激酶,溶栓酶(略作 SK)and urokinase are important in thrombolytic溶血栓药s, and asparaginase is used as a cytostatic agent in the treatment of leukemia. 许多酶类本身也作为活性成分应用。这样的制剂包含蛋白酶（例如：糜蛋白酶，胃蛋白酶和胰蛋白酶），淀粉酶和脂肪酶，大部分与合成的抗酸剂结合，促进消化。链激酶和尿激酶在溶栓剂中很重要，天冬酰胺酶在治疗白血病中作为抑制细胞生长的制剂。12 Finally mention must be made of the important use of enzymes as biocatalysts in chemical reactions where their stereospecificity立体专一性 and selectivity can be used. Known examples are the enzymatic cleavage of racemates of N-acetyl-D, L-amino acids to give L-amino acids, the production of 6-aminopenicillanic acid from benzylpenicillin by means of penicillinamidase酰胺酶 and the aspartase-catalysed stereospecific addition of ammonia to fumaric acid in order to produce L-aspartic acid. 在酶的重要作用中必须提到的是，在化学反应中可以应用其立体专一性和选择性使用酶作为生物催化剂。大家知道的例子是酶对于外消旋N-乙酰基-D，L氨基酸的裂解，得到L氨基酸，用青霉素酰氨酶催化从苄基青霉素得到6-氨基青霉酸以及在有氨水的条件下用天冬酰氨酶的立体专一性催化反丁烯乙酸以生产天冬氨酸。13 In these applications the enzymes can be used in immobilized forms固定化酶somehow bound to carriers and so used as heterogeneous catalysts. This is advantageous because they can then easily be separated from the reaction medium and recycled for further use.在这些应用中，酶可以以固定的形式使用以某种方式与载体结合作为不同种类的催化剂。这样做是有利的，因为它们可以轻松地从反应介质中分离出来，以进一步循环利用。酶的来源不仅包括微生物，而且包括蔬菜和动物原料14 Another important process depending on the specific action of proteases is applied for the productiong of semisynthetic human inlulin. This starts weth pig insulin in which the alanine in the 30-position of the B-chain is replaced by a threonine terttertiary adj.第三的, 第三位的, 第三世纪的-butyl ester by the selective action of trypsin. The insulin ester is separated, hydrolyzed to human insulin and finally purified by chromatographic procedures. 另一个重要的基于蛋白酶专一性反应的过程被应用于半合成生产人胰岛素。这个生产过程是从猪的胰岛素开始的。猪的胰岛素B链30位上的丙氨酸，通过胰蛋白酶的选择性反应被苏氨酸叔丁基酯所取代，然后这个胰岛素酯被分离、水解成人胰岛素，并最终通过色谱过程纯化。 Sources for enzymes include not only microorganisms but also vegetable and animal materials. 酶的来源不仅包括微生物，也包括蔬菜及动物资源。15 In Table 1 it was already shown that over 75% of all pharmaceutical agents are obtained by total synthesis. Therefore knowledge of the synthetic routes is useful . Understanding also makes it possible to recognize contamination of the agents by intermediates and by products. For the reason of effective quality control the registration authorities in many countries demand as essentials for registrat ion a thorough documentation on the production process. Knowledge of drug syntheses provides the R&DResearch and Development chemist with valuable stimulation as well.表1中已经表明，超过75%的药物制剂是通过合成途径获得的。因此，关于合成路线的知识是有用的。理解了这一点也使我们有可能认识到药物被中间体污染和被生成物污染。基于有效质量控制的原因，许多国家的注册机构把有关药品生产过程的全部的文件资料作为药品注册的基本要求。药物合成的知识也能提供给药物研究与开发人员有价值的参考。16 There are neither preferred structural class结构类es for all pharmaceutically active compounds nor preferred reaction types. This implies that practically the whole field of organic and in part also organometallic chemistry is covered. Nevertheless, a larger number of starting materials and intermediates are more frequently used, and so it is useful to know the possibilities for their preparation from primary chemical. For this reason it is appropriate somewhere in this book to illustrate tree of especially important intermediates. These latter intermediates are the key compounds used in synthetic processes leading to an enormous number of agents. For the most part chemicals are involved which are produced in large amounts. In a similar way this is also true for the intermediates based on the industrial aromatic compounds toluene, phenol and chlorobenzene. Further key compounds may be shown in a table which can be useful in tracing cross-relationships in syntheses. 本书对所有的药用活性化合物既没有提出它们的结构分类，也没有提出它们的反应类型。这意味着本书实际上涵盖了几乎所有有机化学和部分有机金属化学内容。然而尽管如此，由于大量的起始物质和中间体被更加频繁地使用着，所以了解它们由最初的化学产品制备制剂的可能性是有用的。因此在书中某处插入了特别重要的中间体的树状图。这些中间体是合成反应中的关键化合物，大部分有关的化学药品被大量生产并最终产生了庞大种类的药剂。对于以工业芳香化合物甲苯、苯酚、氯苯为基础的中间体也是如此。更多的关键化合物可能列于书中的一个表里，这张表可用于追查合成的交叉关系。17 In addition to the actual starting materials and intermediates solvents are required both as a reaction medium and for purification via recrystallization. Frequently used solvents are methanol, ethanol, isopropanol, butanol , acetone , ethyl acetate, benzene, toluene and xylene. To a lesser extent diethyl ether, tetrahydrofuran, glycol ethers, dimethyl formamide ( DMF ) and dimethyl sulphoxide (DMSO) are used in special reactions. 除了实际的起始物质和中间体之外，还需要溶剂。溶剂既是反应的媒介，用于重结晶纯化。常用的溶剂有甲醇、乙醇、异丙醇、丁醇、丙酮、乙酸乙酯、苯、甲苯和二甲苯。在较小范围内应用的二乙基醚，四氢呋喃，乙二醇醚，二甲基甲酰胺( DMF )和二甲基亚砜。18 Reagents used in larger amounts are not only acids (hydrochloric acid , sulfuric acid, nitric acid, acetic acid ) but also inorganic and organic base基底：任何东西的最低部分或基础部分；基质：化合物的主要部分；碱(旧名盐基)：在化学中，指盐的非酸部分；与酸结合形成盐类的物质；在水溶液中离解放出氢氧离子的物质；其分子或离子能与质子(氢离子)结合的物质；能供给一对电子(对酸)以形成共价键的物质。基托：一种可摘假体，既可支持义齿和支托，又接受基座组织的支持s (sodium hydroxide potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, triethylamine, pyridine ). Further auxiliary chemicals include active charcoal and catalysts. All of these supplementary chemicals (like the intermediates )can be a source of impurities in the final product. 大量应用的试剂除了酸(盐酸，硫酸，硝酸，醋酸 )之外还有无机的和有机的碱 (氢氧化纳，氢氧化钾，碳酸钾，碳酸氢钠，氨水，三乙胺，吡啶)。19 In 1969 the WHO published a treatise on Safeguarding Quality in drugs. Appendix 2 is concerned with the Proper Practice for Reparation and Safeguarding Quality in Drugs has in the meantime become known as Good Manufacturing Practices or GMP rules, and these should now be obeyed in drug production. They form the basis for mutual recognition of quality certificates relation to the production of pharmaceuticals and for inspections of the production facilities. 1969年世界卫生组织（WHO）出版了关于“维护药品质量”的论文集，附录2的内容是关于“恢复和维护药品质量管理规范”（WHO学术报道第418、1969号，附录2；第567，1975号，附录1A）。这也同时成为了著名的“药品生产管理规范”或GMP规则，在现代，它们在药品生产过程中是必须要遵守的。它们构成了对药品生产互认品质证明书和对生产设备检查的基础。20 For a long time the US drug authority, the Food and Drug Administration (FDA), has