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制药工程专业英语翻译吴达俊

Unit 1 Production of Drugs

Depending on their production or origin pharmaceutical agents can be split into three groups:

I .Totally synthetic materials (synthetics),

Ⅱ.Natural products,and

Ⅲ.Products from partial syntheses (semi-synthetic products).

The emphasis of the present book is on the most important compounds of groups I and Ⅲ一thus Drug synthesis. This does not mean,however,that natural products or other agents are less important. They can serve as valuable lead structures,and they are frequently needed as starting materials or as intermediates for important synthetic products.

Table 1 gives an overview of the different methods for obtaining pharmaceutical agents.

1单元生产的药品

其生产或出身不同药剂可以分为三类:

1。完全(合成纤维)合成材料,

Ⅱ。天然产物,和

Ⅲ。产品从(半合成产品)的部分合成。

本书的重点是团体的最重要的化合物Ⅰ和Ⅲ一所以药物合成。这并不意味着,但是,天然产品或其他代理人并不太

重要。它们可以作为有价值的领导结构,他们常常为原料,或作为重要的合成中间体产品的需要。

表1给出了获取药剂的不同方法的概述。

Table 1 Possibilities for the preparation of drugs Methods Examples

1. Total synthesis -over 75 % of all pharmaceutical agents (synthetics)

2. Isolation from natural sources (natural products):

2.1 Plants -alkaloids;enzymes;heart glycosides;polysaccharides;tocopherol;

steroid precursors (diosgenin, sitosterin);citral (intermediate product for

vitamins A, E,and K) 2.2 Animal organs一enzymes;peptide hormones;cholic acid from gall; insulin) from the

pancreas;sera and vaccines

2. 3 Other sources一cholesterol from wool oils;L-amino acids from keratin and gelatine

hydrolysates

3. Fermentation一antibiotics;L-amino acids;dextran; targeted modifications on steroids,

e.g. 11-hydroxylation; also insulin, interferon, antibodies, peptide

hormones,enzymes,vaccines

4. Partial synthetic modification of natural products (semisynthetic agents):

一alkaloid compounds;semisynthetic /3-lactam antibiotics;steroids;human insulin

表1对药物的可能性准备

方法举例

1。全合成,超过75%的药剂(合成纤维)

2。分离(天然产物)天然来源:

2.1植物-生物碱;酶;心甙,多糖,维生素E;

类固醇的前体(薯蓣皂素,sitosterin),柠檬醛(中间产品

维生素A,E和K)

2.2动物器官一酶;肽激素;胆酸从胆;胰岛素)从

胰脏;血清和疫苗

2。从角蛋白和明胶L -氨基酸;三一胆固醇从羊毛油脂的其他来源水解

3。一抗生素发酵; L -氨基酸,葡聚糖,对类固醇有针对性的

修改,

例如11 -羟基化;也胰岛素,干扰素,抗体,肽

激素,酶,疫苗

4。部分合成修改(半合成剂)天然产品:一生物碱化合物;半合成/ 3-内酰胺类抗生素;类固醇;人胰岛素

Several therapeutically significant natural products which were originally obtained from natural sources are today more effectively -i. e. more economically -prepared.. by total synthesis. Such examples include L-amino acids,Chloramphenicol,Caffeine, Dopamine,Epinephrine,Levodopa, peptide hormones,Prostaglandins,D-Penicillamine,Vincamine,and practically all vitamins.

其中几个重要的治疗作用最初是从天然产品天然来源获得更有效的今天,我。大肠杆菌更经济的准备..由全合成。这样的例子包括L-氨基酸,氯霉素,咖啡因,多巴胺,肾上腺素,左旋多巴,肽类激素,前列腺素,D -青霉胺,长春胺,以及几乎所有的维生素。

Over the last few years fermentation - i. e. microbiological 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 Eukaryonts (yeasts and moulds)and Prokaryonts(single bacterial cells,and actinomycetes)are used microorganisms. The following product types can be obtained:

1. cell material (single cell protein),

2. enzymes,

3. primary degradation products (primary metabolites),

4. secondary degradation products (secondary metabolites). 在过去的几年里发酵-岛大肠杆菌微生物过程变得极其重要。通过现代技术和基因选择的结果导致了突变体的微生物创

造高性能,发酵,已成为首选方法各种各样的物质。这两个Eukaryonts(酵母菌和霉菌)和Prokaryonts(单细胞细菌,放线菌和)用于微生物。下列产品类型可以得到:

1。细胞的物质(单细胞蛋白),

2。酶,

3。主要降解产物(主要代谢物),

4。二级降解产物(次生代谢物)。

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 50,000 ~ 100,000,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 B,2 from Propionibacterium shermanii.

Among the secondary metabolites the antibiotics must be mentioned first. The following five groups represent a yearly worldwide value of US-$17 billion:

不顾来自某些微生物,大肠杆菌粘膜生产的葡聚糖克明串珠mesenteroides,2和3级是毒品有关的准备工作。葡聚糖本身5万?10万分子量,是用作血浆代用品。其中主要来自谷氨酸棒杆菌代谢产物和黄色短杆菌突变体的L -氨基酸特别有趣。从这些味精约35万吨L -谷氨酸(食品添加剂)生物体和L -赖氨酸(用于植物蛋白补充)约70,000吨的生产。此外重要的初级代谢产物的普瑞纳核苷酸,有机酸,乳酸,柠檬酸和维生素,例如维生素B,从丙酸shermanii 2。

其中次生代谢产物的抗生素必须首先提到。以下五组代表了美国每年170亿美元的全球价值:

penicillins ( Penicillium chrysogenum ),

cephalosporins ( Cephalosporium acremonium ),

tetracyclines ( Streptomyces aureofaciens ),

erythromycins ( Streptomyces erythreus ),

aminoglycosides (e. g. streptomycin from Streptomyces griseus).

青霉素(青霉)

头孢菌素(头孢枝顶)

四环素(金色链霉菌)

erythromycins(链霉菌)

氨基糖苷类(如链霉素从灰色链霉菌)。

About 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户lactams alone in the last decade. Fermentations are carried out in stainless steel fermentors with volumes up to 400 m3. To avoid contamination of the microorganisms with phages etc. the whole process has to be performed 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 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 agents 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.

关于5000抗生素已经分离出的微生物,但其中只有不到100有些治疗使用。必须记住,但是,许多衍生工具已被用

于治疗使用部分合成修改;约50,000剂已被semisynthetically取得户内酰胺在过去十年孤独。发酵都是在不锈钢发酵罐出来的量高达400立方米。为了避免与噬菌体等微生物污染的全过程都必须在无菌条件下进行。由于更重要的发酵只发生在有氧条件下的氧气或空气好电源(无菌)是必要的。二氧化碳的来源包括碳水化合物,大肠杆菌克糖蜜,糖和葡萄糖。另外必须提供的微生物在与含氮如硫酸铵,氨水或尿素化合物生长介质,以及与无机磷酸盐。此外,不断最适pH和温度是必需的。在青霉素G的情况下,发酵完成200小时后,细胞的质量是由过滤分离。所需的活性剂是隔离的滤液吸收或提取工艺。大规模的细胞,如果不理想的产品,可进一步用作动物,由于其蛋白质含量高的饲料。

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 bridges are formed selectively after isolation,and the final purification is effected by chromatographic procedures. In this way human insulin is obtained totally independently from any pancreatic material taken from animals.

Other important peptides,hormones,and enzymes,such as human growth hormone (HGH),neuroactive 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.

利用现代微生物重组技术已获得这也让其中不是在原来的基因编码多肽的生产。改性大肠杆菌从而使可能产生A型和B -人胰岛素或胰岛素原类似物链。二硫键形成的选择性

分离后,最终由色谱净化工序的影响。通过这种方式获得的人类胰岛素完全独立采取任何从动物胰腺材料。

其他重要肽,激素和酶,如人类生长激素(hGH),神经活性肽,生长抑素,干扰素,组织型纤溶酶原激活物(tPA),淋巴因子,如钙调节钙调蛋白,蛋白疫苗,以及作为诊断用单克隆抗体是合成了这种方式。

The enzymes or enzymatic systems which are present in a single microorganism can be used for directed stereospecific and regiospecific chemical reactions. This principle is especially useful in steroid chemistry. Here we may refer only to the microbiological 11-a- hydro xylation of progesterone to 11-a-hydroxyprogesterone,a key product used in the synthesis of cortisone. 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.

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 and urokinase are important in thrombolytics,and asparaginase is used as a cytostatic agent in the treatment of leukemia.

这些酶或微生物在一个单一的酶系统,目前可用于立体定向和regiospecific化学反应。这个原则是有用的,尤其是在化学类固醇。在这里,我们只能引用的微生物十一水电黄体酮xylation至11人羟,一个关键的产品在可的松合成。隔离酶是重要的,不仅因为淀粉的酶法糖化技术重要性的今天,和葡萄糖异构果糖,他们也都在无数次试验在诊断疾病所用的程序显着,在酶的分析,在使用监测治疗。

数量的酶本身作为活性成分。因此,含有蛋白酶制剂(如糜蛋白酶,胃蛋白酶和胰蛋白酶),淀粉酶和脂肪酶的合成

主要是在与抗酸药相结合,促进消化。链激酶和尿激酶溶栓是重要的,是天冬酰胺酶在治疗白血病细胞生长剂。

Finally mention must be made of the important use of enzymes as `biocatalysts’in chemical reactions where their stereospecificity 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 8-aminopenicillanic acid from benzylpenicillin by means of penicillinamidase and the aspartase-catalysed stereospecific addition of ammonia to fumaric acid in order to produce L-aspartic acid.

最后必须提到的,作为他们在那里`biocatalysts'in化学stereospecificity和选择性反应的酶可用于制造重要的用途。著名的例子是对N -乙酰- D,L -氨基酸消旋给予L -氨基酸酶裂解,从青霉素生产8 -氨基青霉烷酸的penicillinamidase 手段和天冬氨酸酶,催化氨立体除了富马酸为了酸生产L -天门冬氨酸。

In these applications the enzymes can be used in immobilized forms-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.

Another important process depending on the specific action of proteases is applied for the production of semisynthetic human insulin. This starts with pig insulin in which the alanine in the 30-position of the B-chain is replaced by a threonine tert-butyl ester by the selective action of trypsin. The insulin ester is separated,hydrolyzed to human insulin and finally purified by chromatographic procedures.

Sources for enzymes include not only microorganisms but also vegetable and animal materials.

在这些酶可以在固定的形式使用的应用程序,在某种程度上势必运营商- 等为异构催化剂。这是有利的,因为他们可以很容易地分离反应介质和回收再利用。

另一个重要进程的具体行动蛋白酶是根据申请的半合成人胰岛素的生产。与猪胰岛素这将启动,其中在30的B

链的位置被替换为丙氨酸苏氨酸叔丁基由胰蛋白酶选择性作用酯。胰岛素酯分离,水解为人体胰岛素和程序,最后由色谱纯化。

对酶的来源不仅包括微生物,而且蔬菜和动物材料。

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 registration a thorough documentation on the production process. Knowledge of drug syntheses provides the R&D chemist with valuable stimulation as well.

There are neither preferred structural classes 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 chemicals. For this reason it is appropriate somewhere in this book to illustrate a 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.f

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,dimethylformamide (DMF) and dimethyl sulphoxide (DMSO) are used in special reactions.

在表1,已经显示,有超过75%是由药剂全合成获得。因此,合成路线的知识是有用的。认识也使我们能够认识到污染。按中间体和副产品代理。为了有效的质量控制在许多国家的登记要领对生产过程的完整的文档要求登记机关的原因。药物合成知识提供了宝贵的刺激研发化学家以及。

有没有首选的所有药学活性化合物,也反应类型结构类型的首选。这意味着几乎全部领域的有机和有机金属化学中的一部分也被覆盖。不过,也有较大的起始原料和中间体数量较常用,所以它是非常有用的知道他们准备从初级品的可能性。基于这个原因,它是在适当的地方,说明这本书的重要中间体,尤其是树。后面这些中间体领导到数目庞大的代理商合成工艺中的关键化合物。对于大多数的化学品是在涉及大量生产。以类似的方式,这也是对工业芳香族化合物甲苯,苯酚和氯苯中间体为基础的真实。另一个关键的化合物可能会显示在表格可在追踪syntheses.f交叉关系很有用除了实际的起始原料和中间体溶剂作为反应介质要求和通过再结晶纯化,两者。常用的溶剂是甲醇,乙醇,异丙醇,丁醇,丙酮,醋酸乙酯,苯,甲苯和二甲苯。在较小程度上乙醚,四氢呋喃,乙二醇醚,二甲基甲酰胺(DMF)和二甲基亚砜(DMSO)的使用在特殊的反应。

Reagents used in larger amounts are not only acids (hydrochloric acid,sulfuric acid,nitric acid,acetic acid) but also inorganic and organic bases (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.

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' (WHO Technical Report No. 418,1969,Appendix 2;No. 567,1975,Appendix 1A). This 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 relating to the production of pharmaceuticals and for inspections of the production. facilities.

在较大的数额使用的试剂,不仅酸(盐酸,硫酸,硝酸,

醋酸),而且无机和有机碱(氢氧化钠,氢氧化钾,碳酸钾,碳酸氢钠,氨,三乙胺,吡啶)。进一步的辅助化学品包括活性炭和催化剂。这些(如中间体)补充品都可以成为最终产品中杂质的来源。

1969年,世界卫生组织发表了`保障药品质量的论文中(WHO技术报告号418,1969,附录二,附录二是有关`适当的做法的赔偿和保障药品质量。';号567,1975,附件1A)。这已成为在此期间为'良好生产规范'或GMP规则众所周知的,现在应在这些药品生产服从。它们构成的质量有关的药品生产证书互认的生产和检验的基础。设施。

For a long time the US drug authority,the Food and Drug Administration (FDA),has issued regulations for the preparation of drugs analogous to the WHO rules,and it applies these strictly. Exports of drugs to the USA,like those of finished products,require regular inspection of the production facilities by the FDA. 5

It may merely be noted here that such careful control applies not only to the products,but also to the raw materials (control of starting Materials),and also to the intermediates. Clearly. the technical and hygienic equipment of the production and the storage areas have to fulfill set conditions.

Since only a few compounds,such as acetylsalicylic acid,paracetamol and vitamins,are prepared in large amounts,most of the actual production takes place in multi-purpose (multi-product) facilities. .Special care has to be taken to avoid cross-contamination by other products what can be effected by good cleansing of used apparatus. A careful description and definition of all stored intermediates and products is needed. Selected -from H. J. Roth and A. Kleemann, Pharmaceutical Chemistry, Vol. 1,Drug Synthesis,

Ellis Horwood Limited,England, 1988.

长期以来,美国药品管理局,美国食品和药物管理局(FDA)已发出的药品制剂类似于谁的规则规定,而且适用于这些严格。向美国药物如成品者外,出口由FDA要求的生产设施进行定期检查。 5

它可能只是在此指出,这种严格控制不仅适用于产品,而且对原材料(原辅料控制),同时还以中间体。清楚。对生

产和储存方面的技术和设备必须符合卫生规定的条件。

由于只有少数的化合物,如乙酰水杨酸,对乙酰氨基酚和维生素,是在大量的准备,在实际生产中最需要的多用途(多产品)设施的地方。。特别小心,注意避免交叉通过什么可以按所使用的仪器良好的清洁影响其他产品的污染。经过仔细的描述和所有储存的中间体和产品的定义是必要的。

选择从黄建忠罗斯和A. Kleemann,药物化学,卷。 1,药物合成,

埃利斯霍伍德有限公司,英国,1988年。

6 Exercises

1. Answer the following questions:

(1)How many groups can pharmaceutical agents be split into depending on their production or origin?

(2)Can you illustrate any significant examples of pharmaceutical agents obtained by total synthesis?

(3) What is the difference between the synthetic drugs and traditional Chinese herbal medicine?

2. Put the following into English:

3. Put the following into Chinese:

Polysaccharide peptide hormone vaccine

heterogeneous catalyst

contamination plasma steroid penicillin

metabolite

4. Fill in the blanks with the following verb words:

derive term distinguish present compose

Nucleic acids are polyanionic molecules of high molecular weight. These polymers are _____ of a sequence of subunits or nucleotides so that the whole is usually _____ a polynucleotide. The nucleic acids are of two main varieties,ribonucleic(RNA)and deoxyribonucleic (DNA).DNA is found primarily in the chromatin of the cell nucleus,whereas 90%of RNA is _____ in the cell cytoplasm and 10 0 o in the nucleolus. The two classes of nucleic acids are _____ primary on the basis of the five-carbon atom sugar or pentose present. Two general kinds of bases are found in all nucleic acids. One type is a derivative of the parent compound purine. Principle examples are guanine and adenine. The second class of bases found in all nucleic acids is _____ from the parent compound pyrimidine.

6习题

1。回答下列问题:

(1)有多少组可以药剂成其生产或出身而定分裂?

(2)你能说明所取得的全合成药剂任何重大的例子吗?(3)什么是之间的合成药物和传统中药的区别?

2。把以下内容翻译成英语:

3。把成中文如下:

多糖肽类激素疫苗非均相催化剂

青霉素类固醇代谢物污染血浆

4。填写以下动词的单词填空:

目前构成派生词区别

核酸是超高分子量聚阴离子分子。这些聚合物的一个亚基或核苷酸,使整个通常是一个多核苷酸序列__________。核酸是两个主要品种,核糖核酸(RNA)和脱氧核糖核酸(DNA)的。DNA是主要存在于细胞核内的染色质,而90%是_____的RNA在细胞的细胞质和细胞核中的10 0?。核酸类_____两对五碳糖或戊糖原子现有基础上小学。一般两个种基地发现,在所有核酸。一类是母体化合物嘌呤的衍生物。原理是鸟嘌呤和腺嘌呤的例子。在所有发现核酸碱基第二类是从母体化合物嘧啶_____。

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