1

Chapter 4Chapter 4

Circulatory System Agents

2

Section 1

β-Adrenergic Block Agents ( 肾上腺能 β- 受体阻滞剂 )

3

　Propranolol Hydrochloride( 盐酸普萘洛尔 )

1-Isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride

O NH

H OH. HCl

1

23

4

Structure Activity Relation (SAR)

O NH

H OH

Substituted by S,CH2 or NCH3,activity lower

S-configuration isomer¡s̄ activity is better

By tert-butyl and isopropyl ,activity highest.Or number of C more than 3.

Benzene,naphthalene,heterocycle and condensed ring.on the ring can be methyl,chloride,methoxyl and nitro-.2,4-or2,3,6-substitute simultaneously,best activity.

5

Section 2

Calcium Channel Blockers

6

Ion channel concept ：

classification ：

a kind of transmembrane biomacromolecule

take the action of ion pump like activating enzyme

and adjust many kinds of physiologic function

produce and transmit electrical signal

sodium channel potassium channel

calcium channel chlorine channel

7

Nifedipine ( 硝苯地平 )

IUPAC name: 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Other name: 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester

HN

O

O

O

O

NO2

1 2

34

5

6

Adalat / Procardia( 心痛定 )

INN:International Non-proprietary Names

8

Other 1,4-dihydropyridine agentsHN

O

O

O

O

NO2

HN

O

O

O

O O

NO2

N

HN

O

O

NO2

O

O

HN

O

O

O

O

NO2

HN

O

O

O

O

NO2

HN

O

O

O

O

Cl

ONH2

Nifedipine Nimodipine Nicardipine

Nisoldipine Nitrendipine Amlodipine

9

SAR of Nifedipine

HN

OO

OONO2

position 4 requires an aromatic substitution ortho- and/or meta-position requir

an electron-withdrawing group

position 3 and 5 must be carboxylic ester

nitro group is essential

position 2 and 6 substituted with an alkyl group

10

Section 3

Sodium and Potassium Channels Blockers

11

Mexiletine Hydrochloride( 盐酸美西律 )

1-(2,6-Dimethylphenoxy)-2-propanamine hydrochloride

ONH2 .HCl

1

2

3

1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride

12

　Amiodarone Hydrochloride( 盐酸胺碘酮 )

(2-Butyl-3-benzofuranyl)[4-(2-(diethyl- amino) ethoxy)-3,5-diiodophenyl] methanone hydrochloride

O

O

O

I

I

N

. HCl

3

2

1

1

41

2

13

Angiotensin( 血管紧张素 )Converting Enzyme Inhibitors (ACEI)

& Angiotensin Receptor Ⅱ

Antagonists( 拮抗剂 )

Section 4

14

　 Captopril ( 卡托普利 )

1-[ （ 2S） -3-Mercapto( 巯基 )-2-methyl-1- oxopropyl ） ]-L-proline( 脯氨酸 )

HS N

H

O

OHO

123

15

Its analogue

N

HN

H OO

OH

OO

HS NH

O

OHO

Enalapril

A non-thiol-containing ACE inhibitor

Act as prodrug

Converted to activation by hydrolysis of its ethyl ester to form the diacid enalaprilat.

OH

No thiol group, devoid of the side effects of rash and loss of taste sense with Captopril.

Captopril

16

Angiotensin( 血管紧张素 )ⅡReceptor Antagonists( 拮抗剂 )

17

　 Losartan ( 氯沙坦 )

2-Butyl-4-chloro-1-[[2’-(1H-tetrazol-5-yl)[1,1’-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol

N

NHN

N

N

N

OH

Cl

1

2

34

5

1′2′

1

4

18

Section 5

NO Donor Drugs

19

The Nobel Assembly at the Karolinska Institute in Stockholm, Sweden, has awarded the Nobel Prize in Physiology or Medicine for 1998 to Robert F Furchgott, Louis J Ignarro and Ferid Murad for their discoveries concerning "the nitric oxide as a signalling molecule in the cardiovascular system".

The Nobel Prize in Physiology or Medicine 1998

20

Mechanism of action

NitrovasodilatorsEndothelial Cells

NO

GC* Guanylate cyclase(GC)

GTP cGMP

MLCKMLCK* MLCK-PO4

NO formed in smooth muscle from nitrovasodilators ( 硝基血管扩张剂 )or from endothelial cell (EDRF) activates guanylate cyclase ( 鸟苷酸环化酶 ,GC*).

GC* activates cGMP-dependent protein kinases( 激酶 )that phosphorylate myosin light-chain kinase (MLCK, 肌凝蛋白 ), cause its inactivation and subsequent muscle relaxation.

21

Section 6

Cardiac Agents( 强心剂 )

22

Digoxin ( 地高辛 )

OH

Steroid structure

23

Section 7

Lipid Regulators

24

　 Lovastatin ( 洛伐他汀 )

2-methylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester

O

H

H

HO

OH

O

O

1

35

7

88a

25

Analogues of -statin

  

O O

H

H

HH

H

O

H OOH

H

Lovastatin

O O

H

HH

H

O

H OOH

H

Mevastatin Pravastatin

O O

H

HH

H

O

H OOH

H

Simvastatin

NOH OH

O

OH

F

Fluvastatin

O O

H

HO

H

HH

HO

H

HO

OH

OH

H

CH3

26

Section 8

Antithrombotic Drugs( 抗血栓药 )

27

ClassificationOH

O

O

O

N

S Cl

H

OO

O

OH O

O

Antiplatelet drug

Anticoagulant

Thrombolytic Urokinase

Clopidogrel

Warfarin SodiumAccording tomechanism

Aspirin

Dicoumarol( 双香豆素 )

Streptokinase

O O

OH OH

O O

28

Aspirin

More than 100 years for antipyretic analgesic( 解热止痛剂 ).

In 1954, discovered that it can extend bleeding time. In 1971, found its mechanism by inhibiting the synth

esis of PG.

Arachidonic acid( 花生四烯酸 )

Endoperoxide (EP)

Thromboxane A2

epoxidase

Aspirin Clopidogrel

inhibit inhibit

29

Warfarin Sodium

4-Hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one sodium salt.

3-(α-acetonylbenzyl)-4-hydroxycoumarin( 羟基香豆

素 )sodium salt

O

ONa O

O

43

21

30

Warfarin interacts with many commonly-used drugs, and the metabolism of warfarin varies greatly between patients.

Antibiotics, alcohol, herbs and some food have been reported to interact with warfarin.

Vitamin K.

31

Chapter 5

Digestive System Agents

32

Classification

AntiacidsAntiacids

Inhibit the different linkInhibit the different link of acid secretionof acid secretion

Mucous membraneMucous membrane(( 黏膜 )

protective drugsprotective drugs

Anticholinergic agents( 抗胆碱能药 )

H2-receptor antagonists

Antigastrin agents( 抗胃泌素 )

Proton pump inhibitors

Cimetidine( 西咪替丁 )

Omeprazole( 奥美拉唑 )

Pirenzepine( 哌仑西平 )

Proglumide( 丙谷胺 )

Prostaglandin E （前列腺素 E ） /Sucralfate （硫糖铝） /Alginic Acid （藻朊酸）

Mechanism of action

NaHCO3/MgO

33

Ranitidine Hydrochloride( 盐酸雷尼替丁 )

N-[2-[[[5-[(dimethylamino)methyl-2-furanyl] methyl]thio]ethyl]-N’- methyl-2-nitro-1,1-ethenediamine monohydrochloride

An aminoalkyl furan derivative with pKa values of 2.7 and 8.2.

. HClS

HN

NO2

HNO

N

(side chain and dimethylamino)

34

Proton pump (PP) inhibitors A group of drugs whose main action is a pronounced an

d long-lasting reduction of gastric acid production. Significantly more effective than H2 antagonists and red

uce gastric acid secretion by up to 99%. The most potent inhibitors of acid secretion, and the mo

st widely-selling drugs in the world. They are generally considered safe and effective.

Majority of these drugs are benzimidazole derivatives; however, new research indicates that imidazopyridine derivatives may be more effective.

35

　 Omeprazole ( 奥美拉唑 )

(R,S)-5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfinyl)benzimidazole

A white to off-white crystalline powder with very slight solubility in water

N

ONH

NOS

O

1

2

34

5

36

Section 3

Prokinetics( 促动力药 )

37

Concept and classification Prokinetics

Classification D2 receptor antagonists Metoclopramide( 甲氧氯普胺 )

Periphery D2 receptor antagonists Domperidone( 多潘立酮 )

Acetylcholine agonists Cisapride( 西沙必利 )

Promote GI content to push forward, used in the treatment of GI dyskinesis( 动力障碍 ) such as reflux esophagitis( 返流食道炎 ), dyspepsia( 消化不良 ), intestinal obstruction( 肠梗阻 ), etc.

38

Common Prokinetics

NH

NO

H2N

Cl

O

HN

NO

Cl

NN

HN

O

NO

O

FCl

H2N

O

NH

O

Metoclopramide Domperidone

Cisapride

39

　 Cisapride ( 西沙必利 )

N

Cl

H2N

O

NH

O

O

FO

1

2

3

4

5

1

234

3 and 4-C are both chiral C

3 and 4-substituents on the same side of pyridine ring

4-amino-5-chloro-N-((3S,4S)-1-[3-(4-fluoro phenoxy)propyl]-3-methoxypiperidin-4-yl)-2-methoxybenzamide

40

NH

O

Cl

H2N O

N O

FO

NH

O

Cl

H2N O

N O

FO

NH

O

Cl

H2N O

N O

FO

NH

O

Cl

H2N O

N O

FO

34

2-cis isomers in

clinic

4-isomersof

Cisapride

41

Domperidone ( 多潘立酮 )

N

HN

N

N

HN

OCl

O

5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl] piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

吗丁啉

42

Section 4

Adjuvant for Hepatic and Biliary Diseases

( 肝胆疾病辅助治疗药物 )

43

Common drugs

   

HO OH

O

NH2

O

Glutamic Acid( 谷氨酸 )

O

OO

HO

OH

OH

Glucurolactone( 葡醛内酯 )

OH

HO

OH

OHO

HOOH

O

HOOH

Lactulose( 乳果糖 )

O O

O

OO

OO

O

OO

Bifendate( 联苯双酯 )

OHO

OH OOH

O

O

OHO

OH

2

2`

3

3`

Silibinin( 水飞蓟宾 )

44

Chapter 6

Antipyretic Analgesics &

Nonsteroidal Anti-inflammatory Agents

45

HO O

O ONomenclature:Acetylsalicylic acid; 2-Acetoxy benzoic acid; (Aspro, Empirin)

White crystal or white crystalline powerHydrolyzed to form salicylic acid

Aspirin—AcetylAcetylsalicylic acid It is more potent, less irritating.

46

　 Paracetamol ( 对乙酰氨基酚 )

N -(4-Hydroxyphenyl) acetamide; Acetaminophen; N-Acetal-p-aminopheno

l; 4-Hydroxyacetanilide; APAP

NH

O

HO

It is Aniline and p-Aminophenol derivative. It isn’t anti-inflammatory, different with Aspirin. Not to exceed the recommended dosages.

47

Metabolic Pathway of Paracetamol

N

O

OH

HO

NH

OHO

Paracetamol

Ferrihemoglobin and hepatotoxicity

NH

O

NH

OO

NH2

O

NH

OS

HOO

OONH

OOGlu

Acetanilide Phenacetin

Ferrihemoglobin

children

adults

48

N

O

OH

HO

Ferrihemoglobin and hepatotoxicity

O

N

O

HO

N

O

HO

N

O

O

N

OSG

orgatein

S

O

HO

NH

O

GSH

Toxicity metabolite

N-Acetylethylenimine quinone

acetylcysteine

kidneyHepatonecrosis, renal failure

49

Salicylic acid

OH

OH

OHO O

O O

NH

O

HO

ParacetamolAspirinSalicylic acid

Antipyretic Analgesics

50

Diclofenac Sodium( 双氯芬酸钠 )

Sodium 2-[(2,6-dichloroanilino)phenyl]acetate

ONa

NH

ClCl

O

Indicated for short- and long-term treatment of RA, OA, and ankylosing spondylitis（强直性脊柱炎） .Available as delayed-release tablets.

51

　 Ibuprofen （布洛芬）

α-Methyl-4-(2-methyl propyl)phenylacetic acid 2-(4-isobutylphenyl)propionic acid

O

OHS-(+) isomer

52

　 Naproxen （萘普生）

(+)6-Methoxy-α-methyl-2-naphthaleneacetic acid

OO

OHH1

2

3

456

White to off-white crystal. Sparingly soluble in acidic solutions, freely soluble in alkaline solutions, and higly soluble in organic or lipid-like solutions.

S(+)isomer

53

NN

OH

O

O

NH

OH

O ONa

NH

ClCl

O

Oxyphenbutazone

Mefenamic AcidDiclofenac Sodium

NO

OHO

O

Cl

Indomethacin

O

OH

Ibuprofen

OO

OHH

Naproxen

SN

NH N

OOH

O O

Piroxicam

N

F F

F

S

OO

H2N

Celecoxib

54

Chapter 10

Diuretics and Synthetic Hypoglycemic Drugs

55

Type 1 Diabetes (insulin-dependent)

Formerly known as insulin-dependent diabetes mellitus (IDDM, 胰岛素依赖性糖尿病 ).

The β–cells of the pancreatic islets of Langerhans are destroyed, probably by an autoimmune process, such that insulin production is grossly deficient.

There exists only a weak genetic link in the etiologyof this form of diabetes.

Type 1 diabetes is invariably treated with insulin.

56

Type 2 Diabetes (noninsulin-dependent)

Formerly known as noninsulin-dependent diabetes mellitus (NIDDM).

Frequently associated with obesity in its mainly adult victims. Serum insulin levels are normal or elevated, so in essence this is a disease of insulin resistance.

There is a strong genetic link in the etiology of the condition, and insulin therapy is not always required.

57

Classification of Hypoglycemic Drug

Sulfonylureas( 磺酰脲类 ) Biguanides( 双胍类 ) α-Glucosidase inhibitors(α- 葡萄糖苷酶抑制

剂 ) Thiazolindiones( 噻唑烷二酮类 )

58

Glibenclamide( 格列本脲 )

1-[[p-[2-(5-chloro-o-anisamido)ethyl]-phenyl]sulfonyl] -3-cyclohexylurea.

Second-generation oral hypoglycemic agent. The drug has a half-life elimination of 10h, but its hyp

oglycemic effect remains for up to 24h.

59

Glimepiride( 格列美脲 )

1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl] phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.

The third-generation oral hypoglycemic agent. It is metabolized primarily through oxidation of the alkyl side chain of the pyr

rolidine, with a minor metabolic route involving acetylation of the amine.

60

Biguanide (( 双胍类双胍类 ) ) :

N ， N-Dimethylimidodicarbonimidic diamide hydrochloride

Metformin Hydrochloride （盐酸二甲双胍）

61

α-Glucosidase Inhibitors

1-(2-Hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

O

HO

HO

OH

OH

OH

pyranose

Miglitol ( 米格列醇 )

62

Thiazolindiones( 噻唑烷二酮类 )

N

O

S

NH

O

O

COOH

COOH

H

H

Chemical Name:(5-[[4-[2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl] -2,4-thiazolidinedione maleate

Rosiglitazone Maleate( 马来酸罗格列酮 )

63

Diuretics ( 利尿剂 )

64

Furosemide

Name:

5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl ）amino] benzoic acid

S

OO

H2N

Cl

O

OH

NH

O

Most effective,Strongest diuretic!

65

A negative feature of all above-discussed diuretics is that they increase the renal excretion rate of K+ and thus can induce hypokalemia( 低钾血 ).

The K+-sparing diuretics including Spironolactone and Triameterene.

Other: Potassium-sparing diuretics

Keep K+

66

Prostaglandins Peptide Hormones Steroid Hormones Natural hormones and their analogues

Chapter 11 Hormones

67

1. Prostaglandins ( 前列腺素 , PG)

68

Basic chemical Structure

This acid contains 20 carbon atoms.

7 carbons and carboxyl group in the upside chain

8 carbons in the downside chain

5-m-alicyclic

69

2. Peptide Hormones ( 肽类激素 )

70

Insulin ( 胰岛素 )

Insulin’s MW. 5807.69 Insulin molecule consists of chain A and B, with 21 and 30 amino acid residue, respectively. The chains are connected by two disulfide linkages, and an additional disulfide linkage within chain A.

71

3. Steroid Hormones( 甾体激素 )

Estradiol ( 雌二醇 )

Testosterone propionate ( 丙酸睾酮 )

Progesterone ( 黄体酮 )

Dexamethasone acetate ( 醋酸地塞米松 )

72

Backbone of Structure

甾SteroidSteroid

73

3.1 Steroid Estrogen( 雌激素 )

Natural estrogens : Estradiol ( 雌二醇 ), Estrone ( 雌酮 ) and Estriol ( 雌三醇 ).

Estradiol > Estrone > Estriol Ratio of activity is 1 ： 0.3 ： 0.1

Estrogens Classify: Steroid estrogen and Non-steroid estrogen .

74

Estradiol ( 雌二醇 )

75

3.2 Non-Steroidal Estrogen and Selective Estrogen Receptor Modulator

Non-Steroidal estrogen are mainly biphenylethylene compounds.

SERMs compounds mainly

triphenylethylene compounds.

76

　 Diethylstilbestrol ( 己烯雌酚 )

Chemical name : （ E)-4, 4’-(1, 2-Diethyl-1, 2-ethenediyl)bisphenol Non-Steroidal Estrogen

77

Tamoxifen Citrate( 枸橼酸他莫昔芬 )

Chemical name: (Z)-2-[4-(1, 2-diphenyl-1-butenyl)-phenoxy]-

N, N-dimethyl ethanamine citrate. Dimethylamino-ethoxyphenyl group exists i

n many drugs’ structure.

78

Selectivity of Anti-estrogens’ Target Organ

Antioestrogens

Target organs Indication

Clomifen sex organ Sterility( 不孕 )

Tamoxifen lacteal gland Breast cancer ( 乳癌 )

Roloxifen skeleton Osteoporosis ( 骨质疏松 )

79

Structure features

Differences of structure

Progesterone 17β-acetyl

Testosterone 17β-hydroxyl

Testosterone ( 睾酮 )Progesterone ( 黄体酮 )

80

　 Levonorgestrel( 左炔诺孕酮 )

Chemical name: D-(-) 17-Ethynyl-17- hydroxy-18-methyl-estro-4-en-3-one

O

OH

H

H H

18

17

3.5 Steroid Contraceptive agents3.5 Steroid Contraceptive agents(( 避孕药避孕药 ))

81

Hormone, its excitomotor and antagonist

( 激素、激动剂和拮抗剂 ) 激素 合成激动剂 激素拮抗剂

孕激素 （拮抗剂）

O

O

黄体酮

Progesterone

O

OH

炔诺酮

Norethisterone

O

OHN

米非司酮

Mifepristone

雌激素 （拮抗剂）

OH

HO

雌二醇 Estradiol

HO

OH

己烯雌酚 Diethylstilbestrol

HO

ON

4-羟基他莫昔芬

Hydroxytamoxifen

pregnancy (hormone antagonist)

estrogen (hormone antagonist)

Hormones synthesized excitomotor

Hormone antagonist

82

1 ． Mineralcorticoids （盐皮质激素）： Oxygen atoms do not exist at C-11 and C-17 at the same time.

Aldosterone( 醛甾酮 ) , Deoxycorticosterone( 去氧皮质酮 )

2 ． Glucocorticoids （糖皮质激素）： Oxygen atoms do exist at C-11 and C-17 at the same time. Hydrocortisone( 氢化可的松 ), Cortisone( 可的松 )

3.7 Adrenocorticoids3.7 Adrenocorticoids(( 肾上腺皮质激素肾上腺皮质激素 ))

83

Dexamethasone Acetate( 醋酸地塞米松 )

Chemical name: 9--Fluoro-11, 17, 21-

trihydroxypregna-16-methylpregna-1, 4-diene-3,20- dione-21-acetate.

O

O

OHO

O

F

HO

84

Chapter 12 Vitamin

85

Classification and Effect of Vitamin

Lipid soluble vitamin Daily dose (mg)

Main effect

Vitamin A (retinol) 1.5 Used for xerophthalmia( 干眼症 ), vitamin A deficiency disease

Vitamin D2 (ergocalciferol) vitamin D deficiency disease, osteoporosis （骨质疏松症）Vitamin D3 (colecalciferol) 0.025

Vitamin E

(tocopherol)

Vitamin E deficiency, intermittent limp （间歇性跛行）

Vitamin K1 (phyonadione) 1 Antihemorrhagic( 止血 )vitamin, can resist newborn hemorrhage (出血 ), low plasminogen disease( 低凝血酶原症 ), vitamin K deficiency

Vitamin K2

Vitamin K3

(Menadione Sodium Bisulfite)

86

Water-soluble vitamin

Daily dose (mg)

Main effect

Vitamin B1

(thiamine hydrochloride)

1.5 Vitamin B deficiency, peripheral neuritis（周围神经炎）

Vitamin B2 (riboflavine) 2 Lactochrome(核黄素 )deficiency disease

Vitamin B6

(pyridoxine hydrochloride) 3

Vitamin B dependence syndrome, deficiency, congenital dysbolism(先天代谢障碍 )

Vitamin B12 　 (cyanocobalamine) 0.005

Malignant anaemia(恶性贫血 ), megaloblastic anemia(巨幼红细胞性贫血 ), anaemia(贫血 )and spirit system disease caused by anti-folic drugs( 抗叶酸药 )

Vitamin H (biotin) 0.25 Vitamin H deficiency

Vitamin C

(ascorbic acid) 60Vitamin C deficiency, acidation urine, idiopathic methemoglobinemia (特发性高铁血红蛋白血症 )

87

Vitamin A Acetate

Chemical name: (All-trans)-3,7-Dimethyl-9-(2,6,6-trimethyl-

1-cyclohexene-1-yl)-2,4,6,8-nonatetraen-1-ol acetate.

All-trans retinol acetate.

O

O

24681'

2'

6'

88

Vitamin E Acetate

Chemical name : (±)3, 4-Dihydro-2, 5, 7, 8-tetramethyl -2-(4, 8, 12-trimethyl-tridecyl)-2H-

benzopyran-6-ol acetate. -Tocopherol Acetate

89

Vitamin C

Chemical name ： 2-oxo-L-threo-hexono-1,4- lactone-2,3-enediol. (R)-3,4-dihydroxy-5-[(S)- 1,2-dihydroxyethyl] fu

ran-2(5H)-one. Ascorbic Acid.

OO

HO

H OH

OH

OH

90

4 Optical Isomers of Vitamin C

L-(+)antiscorbic acid has highest activity, which is 20 times of D-(-)-isoascorbic acid.

D-(-)- antiscorbic acid and L-(+)- isoascorbic acid are ineffective.

O O

HO

H OH

OH

OH

O O

H OH

OH

HO OH O O

HO

HO H

OH

OH

O O

HO H

OH

HO OH

L-(+)-¿¹»µÑªËá D-(-)-¿¹»µÑªËá D-(-)-Ò쿹»µÑªËá L-(+)-Ò쿹»µÑªËáL-(+)antiscorbic acidL-(+)antiscorbic acid D-(-)-antiscorbic acidD-(-)-antiscorbic acid D-(-)-isoantiscorbic acidD-(-)-isoantiscorbic acid L-(+)-isoantiscorbic acidL-(+)-isoantiscorbic acid