Unit 1 Production of Drugs

Unit1ProductionofDrugs1单元药物制造1Dependingontheirproductionororiginpharmaceuticalagentscanbesplitintothreegroups:1.Totallysyntheticmaterials(synthetics)2.Naturalproducts,and3.Productsfrompartialsyntheses(semi-syntheticproducts)2Theemphasisofthepresentbookisonthemostimportantcompoundsofgroups1and3-thusDrugsynthesis.Thisdoesnotmean,however,thatnaturalproductsorotheragentsarelessimportant.Theycanserveasvaluableleadstructures,andtheyarefrequentlyneededasstartingmaterialsorasintermediatesforimportantsyntheticproducts.3Table1givesanoverviewofthedifferentmethodsforobtainingpharmaceuticalagents.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Table1PossibilitiesforthepreparationofdrugsMethodsExamples1.Totalsynthesisover75%ofallpharmaceuticalagents(synthetics).2.Isolationfromnaturalsources(naturalproducts)2.1Plantsalkaloids;enzymes;heartglycosides;polysaccharides;tocopherol;steroidprecursors(diosgenin,sitosterin);citral(intermediateproductforvitaminsA,E,andK)2.2AnimalorgansEnzymes;peptidehormones;cholicacidfromgall;insulinfromthepancreas;seraandvaccines2.3OthersourcesCholesterolfromwooloils;L-aminoacidsfromkeratinandgelatinehydrolysates3.FermentationAntibiotics;L-aminoacids;dextran;targetedmodificationsonsteroids,e.g.11-hydroxylation;alsoinsulin,interferon,antibodies,peptidehormones,enzymes,vaccines4.Partialsyntheticmodificationofnaturalproducts(semisyntheticagents):Alkaloidcompounds;semisyntheticβ-lactamantibiotics;steroids;humaninsulin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β内酰胺类抗生素；甾类；人胰岛素4Severaltherapeuticallysignificantnaturalproductswhichwereoriginallyobtainedfromnaturalsourcesaretodaymoreeffectively–i.e.moreeconomically–preparedbytotalsynthesis.SuchexamplesincludeL-aminoacids,Chloramphenicol,Caffeine,Dopamine,Epinephrine,Levodopa,peptidehormones,Prostaglandins,D-Penicillamine,Vincamine,andPracticallyallvitamins.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。5Overthelastfewyearsfermentation–i.e.microbiologicalprocesses–hasbecomeextremelyimportant.Throughmoderntechnologyandresultsfromgeneticselectionleadingtothecreationofhighperformancemutantsofmicroorganisms,fermentationhasalreadybecomethemethodofchoiceforawiderangeofsubstances.BothEukaryonts(yeastsandmoulds)andProkaryonts(singlebacterialcells,andactinomycetes)areusedasmicroorganisms.Thefollowingproducttypescanbeobtained: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.cellmaterial(singlecellprotein),2.enzymes,3.primarydegradationproducts(primarymetabolites),4.secondarydegradationproducts(secondarymetabolites).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）6Disregardingtheproductionofdextranfromthemucousmembranesofcertainmicroorganisms,e.g.Leuconostocmesenteroides,classes2and3aretherelevantonesforthepreparationofdrugs.Dextranitself,withamolecularweightof50,000~100,000,isusedasabloodplasmasubstitute,AmongtheprimarymetabolitestheL-aminoacidsfrommutantsofCorynebacteriumglutamicumandBrevibacteriumflavumareespeciallyinteresting.Fromtheseorganismssome350,000tonesofmonosodiumL-glutamate(foodadditive)andsome70,000tonesofL-lysine(supplementforvegetableproteins)areproduced.Furtherimportantprimarymetabolitesarethepurinanucleotides,organicacids,lacticacid,citricacid,andvitamins,forexamplevitaminB12fromPropionibacteriumshermanii.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50000~100000，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。7Amongthesecondarymetabolitestheantibioticsmustbementionedfirst.ThefollowingfivegroupsrepresentayearlyworldwidevalueofUS-$17billion:penicillins(Penicilliumchrysogenum),cephalosporins(Cephalosporiumacremonium),tetracyclines(streptomycesaureofaciens)erythromycins(streptomyceserythreus)aminoglycosides(e.g.streptomycinfromStreptomycesgriseus).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fromStreptomycesgriseus).8About5000antibioticshavealreadybeenisolatedfrommicroorganisms,butoftheseonlysomewhatfewerthan100areintherapeuticuse.Itmustberemembered,however,thatmanyderivativeshavebeenmodifiedbypartialsynthesisfortherapeuticuse;some50,000agentshavebeensemisyntheticallyobtainedfromβ-lactamaloneinthelastdecade.Fermentationsarecarriedoutinstainlesssteelfermentorswithvolumesupto400m3.Toavoidcontaminationofthemicroorganismswithphagesetc.thewholeprocesshastobeundersterileconditions.Sincethemoreimportantfermentationsoccurexclusivelyunderaerobicconditionsagoodsupplyofoxygenorair(sterile)isneeded.C