RanitidineHydrochloride盐酸雷尼替丁Carmustine卡莫司汀课件

MedicinalChemistry

Purpose

????1,Tofamiliarizethestudentswiththepropertiesofdrugsbasedontheirfunctionalgroups;2,Themolecularmodeofactionofdrugsandtheelementsofdrugdesign;3,Thechemicalnomenclatureofimportantdrugs4,ThechemicalprinciplesofdrugsGrading

????Totalpoints=100(middleexams:30;quizzes:20;finalexam:50).Middle:Exams:8:00–10:00a.m.inRoomA101;Quizzes:Therewillbe2-4quizzes(10-20minuteseach);FinalExam:BOOKS???TextBook:Foye'sPrinciplesofMedicinalChemistry,5th

References:Burger'sMedicinalChemistry

药物化学，主编

尤启冬

LearnABCofMed.Chem.Chapter1IntroductionDefinitionofMedicinalChemistry?

MCisachemistry-baseddiscipline,alsoinvolving?aspectsofbiological,medicalandpharmaceuticalsciences.Itisconcernedwiththediscovery,design,identificationandpreparationofbiologicallyactivecompounds;thestudyoftheirmetabolism;theinterpretationoftheirmodeofactionatthemolecularlevelandtheconstructionofstructure-activityrelationships.1.TheScopeandPurposeofMC

?1)Whatismedicine?

Biologicallyactivecompoundsareusedaspreventing,diagnosingandtreating

disease.Theyalsoinvolveinmodulating

functionofbody.

?

?Useas

preventing(预防药)

疫苗

diagnosing(诊断药)

血管造影剂

treating(治疗药)

modulating(保健药)Whatismedicine?Whatismedicine?汕头金石制药厂

对乙酰胺基酚片

粤卫药准字（1996）第306018号

?南京第三制药厂

盐酸雷尼替丁胶囊

苏卫药准字（1986）第337005号

?脑白金

卫食健字（1997）第723号

?CategorizingDrugsByeffect:antibiotics,antiviralsetc.?Bydrugstructure:steroids,penicillinsetc.?Bysiteofaction:specificenzyme,receptoretc.

???EnzymesandReceptorsarePROTEINS

Enzymes:Located‘anywhere'

Receptors:Cellmembrane(ornucleus)

2).ResearchfieldsofMC

?Appropriateadministrationofavailabledrugs

?Preparationofdrugs

?discoveryofnewdrugs

Appropriateadministration?Pharmaceuticalchemistry?Aspirin(阿斯匹林)

COOH

OCOCH3HOOOHPreparationofdrugs?Mifepristone(米菲司酮):OHCCCH3(H3C)2NOOCH3HOOH3OOCH3O????

CHCH

F

DexamethasoneAcetate(醋酸地塞米松)Roussel-Uclaf,天津天药药业有限公司

1999，costdecreases40%，600millionsperyearMarket:90%inChina,50%intheAsia；

3

Discoveryofnewdrugs

???About4500medicineinclinic

only30%illnessesarecompletelycuredNeeddrugsforcancer,virus,cardiovascularandneuraldiseasesHighrisk,Highreward?????Riskoffailure(1/5000-survived)2004,Merck,withdrawRofecoxib(万络)，2.55billion

Increasedcostsofdrugdevelopment:359milliondollarsin1991,1.36billiondollarsin2000

雷尼替丁,依那普利,奥美拉唑

Salesof2billionin1997

R&Dprocess???Pre-Clinic?Phase?ClinicPhase???药物制备工艺研究11.0%药理、药效学研究16.0%毒理和“三致”实验室6.0%药物剂型和稳定性研究9.6%生产和质量监控9.6%新药研究申请IND(InvestigationalNewDrug)和新药申请NDA(NewDrugApplication)3.8%临床评价I.II.III.Iv期34.5%其他9.4%

Consolidationinthepharmaceuticalindustry????MonsantowithPharmacia-UpjohntoformPharmaciaGlaxo-WellcomewithSmithKlineBeechamtoformGlaxoSmithKlineCibaGeigywithSandoztoformNovartisAstrawithZenecatoformAstraZeneca

2.OriginsofMC???1).Discovery(---1930)

2).Development(1932---1960)

3).Design(1960---)

?NaturalProductsasfolkremedies1).Discovery(---1930)

?神农，

神农本草经，本草纲目

?埃斯克雷庇斯，

药物学

（希腊），5册，900种

SomeancientmedicinalagentsstilluseintodayOH

H

NHCI

Ephedrine(麻黄碱),theearliestrecordedusesofplantmedicinesChina,over5000??SomeancientmedicinalagentsstilluseintodayNCH3ONHOCH3OCH3OOCOCOCH3OCH3OCH3Reserpine(利血平)IndiaSomeancientmedicinalagentsstilluseintoday

1800s,ChemistryexperimentationOpium,1803,Derosne

Serturner,Alkali-like,MorphiumLussac,alkaloid,thesuffix“ine”,

Morphine(吗啡)

SomeancientmedicinalagentsstilluseintodayJosephPelletier?JosephCaventou1820，isolatedQuinine(奎宁)fromcinchonabarkFormalaria(疟疾),1826,3600kg/y?PaulEhrlich“PrincipleChemotherapy”

NH2OHEarly20thCAsAsHN

HO

?Salvarasan---Firstsyntheticantimicrobial

Sleepingsicknessandsyphilis（梅毒）

?2

2).Development(1932---1960)

?Domagk?1932，

Prontosil(百浪多息)H2NNNSO2NH2NH2DevelopmentofDrugs???

30-40‘santibiotics40-50‘sDrugsaffectingNeuralsystem、anticancerdrugs50-60‘sNSAIA、steroid(甾体类)

AccidentofDevelopment?1961,“Thalidomide”

(反应停,致畸，短肢和无肢)

?ToxicologicalsafetyEvaluation

致畸，致癌，致突变

3).Design(1960---)

Design??60-70‘sβ1-Rblocker、H2-Rblocker

70-80‘sACEinhibitor、CalciumblockerDrugsandTargets????1.Receptorasdrugtarget;2.Enzymeasdrugtarget;3.Ionchannelasdrugtarget;;4.Nucleicacidasdrugtarget;

?Reversetranscriptase

AchievementsofPRCinMedicinalChemistryBefore1949

?1949---1993:仿制能力强，创新能力弱

?1993/1/1---对有关物质实行专利保护：加强创新

1992/1/16中美政府关于知识产权的谅解备忘录

?CH3HArtemisinin(青蒿素)OH3COOOHHCH3

OCH3?中国科学院上海药物研究所朱大元研究员，

他研制的一类新药蒿甲醚，是国际公认的、由我国

研制的新型抗疟药。

3.NomenclatureofDrugSubstances?GenericName(INN,通用名)

?ChemicalName(化学名)

?TradeName(商品名)

?GenericNameInternationalNon-ProprietaryNameForPharmaceuticalSubstance(INN，国际非专利药品名称):

Source:在新药申请(IND)时向政府主管部门提出的正式名称.User:producer,textbook,referenceet.al

?WorldHealthOrganization(WHO)-cillin,cef-,-vir,-caineCADN?ChineseApprovedDrugNames(CADN中国药品通用名称):translatedfromINN:音译、同类药物有相同的词头或词尾

?-cillin,cef-,-vir,-caine西林

头孢

韦

卡因

TradeName商品名R????头孢曲松

罗氏芬

头孢三嗪

丽珠芬

Cl

Sibutramine

Hydrochloride西布曲明

?美国雅培制药AbbottLaboratoriesN

诺美亭

?南京医药集团

可秀

HCl?太极集团

曲美

?南京长澳制药

澳曲轻

?桂林集琦药业

亭立

ChemicalName?????ChemicalAbstractsService,(CAS,美国化学文摘)

PrinciplesofNomenclature

IdentifyskeletonNumbertheatomofskeleton：S>O>NSequencerule(标注取代基并按次序排列)ThiamineHydrochloride,

VitaminB1（盐酸硫胺

）

N3NH2S1CIHCIOH1N53N5?Skeletonandnumber:thiazolum噻唑

Substituents(取代基):3，Pyrimidinyl,methyl嘧啶基，甲基;4,methyl甲基；

5，2-hydroxyethyl2-羟乙基

ThiamineHydrochlorideNNH2SCIHCINNOHChemicalname:?3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyehtyl)-4-methylthiazoliumchloridemonohydrochloride

氯化-4-甲基-3[（2-甲基-4-氨基-5-嘧啶基)甲基]-5-（2-羟乙基）噻唑盐酸盐

?Carmustine(卡莫司汀)

CIH2CH2CNONOCNHCH2CH2CI

NRanitidineHydrochloride(盐酸雷尼替丁)NO2SNH

NHO

Carmustine(卡莫司汀)CIH2CH2CNONOC1NHCH2CH2CI3?Skeletonandnumber：Urea(脲)?Substituents:1，3：2-chloroethyl(氯乙基)；