Chiral drugs
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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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手 性 药 物 Chiral Drugs

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Chiral drugs

Chiral Drugs


Chiral drugs

  • 2002

  • 22003

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

    2005


Chiral drugs


Chiral drugs

1. 1

6

523

509

517

8

1850

799

1327

61

528

467


Chiral drugs

1. 2


Chiral drugs

1. 3


Chiral drugs

1997 100852

50428

1993 9720%


Chiral drugs

2.

2.1

2.2

2.3


2 1 1

2.1 1

  • enantiomerchirality


2 1 2

2.1 2

  • chiral centerchiral axischiral plane

  • 4

  • n2n2n-1diastereomer, diastereoisomer


2 1 3

2.1 3


2 1 4

2.1 4

  • RS


Chiral drugs

1


Chiral drugs

2


Gossypol

Gossypol


Chiral drugs

3

  • Spiral Chirality


1 4 benzodiazepines

1,4-Benzodiazepines

P M

C2-C3-N4-C5PplusMminus


2 2 1

2.2 1

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


2 2 2

2.2 2

  • DL

    • D-L-

    • RRXHC1FisherXDD-(+)-XLL-(-)-DL-


2 2 21

2.2 2

  • DL

    • D/Ldl


2 2 3

2.2 3

  • RS

    • a>b>c>ddabc3RS


Determination of absolute configuration

Determination of absolute configuration

  • X-ray diffraction (XRD)

  • Vibrational circular dichroism (VCD)

  • Other methods


Determination of enantiomeric purity

Determination of enantiomeric purity

  • Polarimetry

  • Nuclear magnetic resonance (NMR)

  • Direct enantioselective chromatography/electrophoresis

  • Indirect enantioselective chromatography/electrophoresis


Chiral drugs

2.3

  • eutomer, Eu

  • distomer, Dis

  • eudismic ratio, ER

  • eudismic index, EIlogER


Chiral drugs


Chiral drugs

    • > 2Eu Rac > 2

    • 2Eu Rac = 2

    • < 2Eu Rac < 2

    • = 1Eu Rac = 1


Chiral drugs


Chiral drugs

abc

abcab


Pfeiffer

Pfeiffer


Chiral drugs

3.

3.1

3.2

3.3

3.4


Chiral drugs


Chiral drugs

3.1

  • pKapKa


Methotrexate

Methotrexate

  • MTX

  • L-MTXGlu

  • D-MTX


Levodopa l dopa

Levodopa, L-Dopa

  • l-Dopad-Dopa


Melphalan

Melphalan

  • L-PheDSarcolysin


Chiral drugs


Chiral drugs

3.2


Chiral drugs

1


Chiral drugs

2

  • 1


Chiral drugs

  • III

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


Phenprocoumon

Phenprocoumon

  • S-(-)-ER=2

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


Chiral drugs

  • S-

  • S-S-Oxazepam succinate40

  • S-S-TofisopamPMR-


Tryptophan

Tryptophan

  • L-D-100


Chiral drugs

1

  • 13

  • 1

  • 1


S s propranolol

S- S- Propranolol

  • (S)-

  • 1(R)-< (S)-

  • (R)-> (S)-

  • 1

  • 1


Chiral drugs


Chiral drugs

  • S-RS-R-


Chiral drugs

  • S-Folinic acid R-


Chiral drugs

3.3

  • P450CYP

  • III


Chiral drugs

  • -


Chiral drugs

  • 25


Chiral drugs


Chiral drugs

  • Propranolol

R-(+)-

4

R-(+)-

S-(-)-


Chiral drugs

  • MephenytoinRSP450


Chiral drugs

Warfarin


Chiral drugs

S


Chiral drugs


Chiral drugs


Chiral drugs

  • chiral inversion


Chiral drugs

2-

  • SRSR10800S-R1601.4

  • RS2-

  • S-(+)-Ibuprofen


Chiral drugs

R-

  • R-(-)-AAAAAR-(-)-S-(+)-

  • S-(+)-ARS

  • R-(-)-S-(+)-


Chiral drugs

-


Chiral drugs


Ic propafenone

IcPropafenone

  • RSS

  • S-

  • P4502D6S-

    R-

    S

    S-

    2


P chloroamphetamine

p-Chloroamphetamine

  • S-(+)-R-(-)-

  • S-(+)-R-(-)-9 R-(-)-S-(+)-2


Methorphan

Methorphan


Chiral drugs

3.4

  • S-(-)-VerapamilS-R-(+)-


Chiral drugs

3.4

  • R-(+)-S-(-)-S-


Chiral drugs

4.


Chiral drugs


Flecainide

Flecainide

  • RS


Chiral drugs

  • S-(-)-IIR-(+)-9.31.3SR8128


Chiral drugs

  • S-(+)-NaproxenR-(-)-1020S-(+)-


Chiral drugs


Chiral drugs

  • R

  • S


Chiral drugs

  • 3,5-S


Methyldopa

Methyldopa

  • S-


Chiral drugs


Chiral drugs


Chiral drugs

  • R-(-)-1S-(+)-R-(-)-

l

dl

d

10-5

10-4

10-3

10-2


Chiral drugs

  • Dobutamine

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


Chiral drugs

  • S-(-)-R-(+)-


Chiral drugs

  • Ketamine

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


Chiral drugs

  • Pentazocine


Chiral drugs

  • Selegiline(+)-AmphetamineR-(-)-

Amphetamine

Selegiline


Chiral drugs

  • DextropropoxypheneLevopropoxyphene


Chiral drugs

  • quininequinidine


Chiral drugs

  • levamisoledextramisole


Chiral drugs

  • S-(-)-R-(+)-100


Chiral drugs


Chiral drugs

  • PenicillamineD-L-

D-Penicillamine


Chiral drugs

  • PrilocaineS-(+)-R-(-)-


Thalidomide

Thalidomide

  • 2060

  • R-(+)-S-(-)- S-(-)-


Thalidomide1

Thalidomide

  • S-(-)-R-(+)-


Thalidomide2

Thalidomide

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


Chiral drugs

  • 3


Chiral drugs


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