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手 性 药 物 Chiral Drugs. 参考书. 曾苏主编, 《 手性药物与手性药理学 》 ,浙江大学出版社, 2002 年出版 郭宗儒编著, 《 药物化学总论 》 第 2 版,中国医药科技出版社, 2003 年出版 Camille Georges Wermuth, The Practice of Medicinal Chemistry, 2 th ed. Elsevier, 2003. 卡米尔 · 乔治 · 微尔穆特主编,迟玉明主译, 《 创新药物化学 》 ,广东世界图书出版公司, 2005 年出版. 本章内容. 手性药物的研究意义 手性药物的一般概念

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Chiral Drugs


  • 2002

  • 22003

  • Camille Georges Wermuth, The Practice of Medicinal Chemistry, 2th ed. Elsevier, 2003.

    2005



1. 1

6

523

509

517

8

1850

799

1327

61

528

467


1. 2


1. 3


1997 100852

50428

1993 9720%


2.

2.1

2.2

2.3


2.1 1

  • enantiomerchirality


2.1 2

  • chiral centerchiral axischiral plane

  • 4

  • n2n2n-1diastereomer, diastereoisomer


2.1 3


2.1 4

  • RS


1


2


Gossypol


3

  • Spiral Chirality


1,4-Benzodiazepines

P M

C2-C3-N4-C5PplusMminus


2.2 1

    • dextrotatoryd-(+)-levorotatoryl-(-)-racematedl-()-


2.2 2

  • DL

    • D-L-

    • RRXHC1FisherXDD-(+)-XLL-(-)-DL-


2.2 2

  • DL

    • D/Ldl


2.2 3

  • RS

    • a>b>c>ddabc3RS


Determination of absolute configuration

  • X-ray diffraction (XRD)

  • Vibrational circular dichroism (VCD)

  • Other methods


Determination of enantiomeric purity

  • Polarimetry

  • Nuclear magnetic resonance (NMR)

  • Direct enantioselective chromatography/electrophoresis

  • Indirect enantioselective chromatography/electrophoresis


2.3

  • eutomer, Eu

  • distomer, Dis

  • eudismic ratio, ER

  • eudismic index, EIlogER



    • > 2Eu Rac > 2

    • 2Eu Rac = 2

    • < 2Eu Rac < 2

    • = 1Eu Rac = 1



abc

abcab


Pfeiffer


3.

3.1

3.2

3.3

3.4



3.1

  • pKapKa


Methotrexate

  • MTX

  • L-MTXGlu

  • D-MTX


Levodopa, L-Dopa

  • l-Dopad-Dopa


Melphalan

  • L-PheDSarcolysin



3.2


1


2

  • 1


  • III

  • WarfarinS-(-)-R-(+)-6825S-(-)-R-(+)-


Phenprocoumon

  • S-(-)-ER=2

  • 136R-(+)- > S-(-)-4S-(-)- > R-(+)-3


  • S-

  • S-S-Oxazepam succinate40

  • S-S-TofisopamPMR-


Tryptophan

  • L-D-100


1

  • 13

  • 1

  • 1


S- S- Propranolol

  • (S)-

  • 1(R)-< (S)-

  • (R)-> (S)-

  • 1

  • 1



  • S-RS-R-


  • S-Folinic acid R-


3.3

  • P450CYP

  • III


  • -


  • 25



  • Propranolol

R-(+)-

4

R-(+)-

S-(-)-


  • MephenytoinRSP450


Warfarin


S




  • chiral inversion


2-

  • SRSR10800S-R1601.4

  • RS2-

  • S-(+)-Ibuprofen


R-

  • R-(-)-AAAAAR-(-)-S-(+)-

  • S-(+)-ARS

  • R-(-)-S-(+)-


-



IcPropafenone

  • RSS

  • S-

  • P4502D6S-

    R-

    S

    S-

    2


p-Chloroamphetamine

  • S-(+)-R-(-)-

  • S-(+)-R-(-)-9 R-(-)-S-(+)-2


Methorphan


3.4

  • S-(-)-VerapamilS-R-(+)-


3.4

  • R-(+)-S-(-)-S-


4.



Flecainide

  • RS


  • S-(-)-IIR-(+)-9.31.3SR8128


  • S-(+)-NaproxenR-(-)-1020S-(+)-



  • R

  • S


  • 3,5-S


Methyldopa

  • S-




  • R-(-)-1S-(+)-R-(-)-

l

dl

d

10-5

10-4

10-3

10-2


  • Dobutamine

    R-(-)-1S-(+)-S-(+)-


  • S-(-)-R-(+)-


  • Ketamine

    S-(+)-R-(-)-


  • Pentazocine


  • Selegiline(+)-AmphetamineR-(-)-

Amphetamine

Selegiline


  • DextropropoxypheneLevopropoxyphene


  • quininequinidine


  • levamisoledextramisole


  • S-(-)-R-(+)-100



  • PenicillamineD-L-

D-Penicillamine


  • PrilocaineS-(+)-R-(-)-


Thalidomide

  • 2060

  • R-(+)-S-(-)- S-(-)-


Thalidomide

  • S-(-)-R-(+)-


Thalidomide

  • DMFpH 7.437Ct1/2=2.5h37C pH 9.0t1/23.6minR-S-


  • 3



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