Download Ibuprofen

Chapter 6
Antipyretic Analgesics
&
Nonsteroidal Anti-inflammatory
Agents
1
Section 2
Nonsteroidal
Antiinflammatory Agents
2
Request and propose



Master the classification of NSAIDs, the
chemical structure and name, physicochemical property, metabolism, and synthesis
of Oxyphenbutazone, Indometacin, and
Ibuprofen.
Familiar with Mefenamic acid, Piroxicam,
Diclofenac sodium and Naproxen.
Get some information of Celecoxib.
3
O
Classification
pyrazolone
Oxyphenbutazone
N
O
N
OH
O
OH
O
N
Indoleacetic acid
Indometacin
O
Cl
O
Anthranilic acid
1,2-benzothiazine
OH
Mefenamic acid
H
N
OH
Piroxicam
O
NH
N
N
S
O
Phenylacetic acid
ONa
Diclofenac sodium
O
NH
Cl
Arylpropionic acid
O
Cl
O
Ibuprofen
OH
4
Oxyphenbutazone（羟布宗）
4
3
O
5
2
O
N1
N
OH

4-Butyl-1-(4-hydroxyphenyl)-2-phenyl-3,5pyrazolidinedione
5
Development
While researching for antipyretics of the quinoline type,
in 1884, Ludwig Knorr discovered the 5-pyrazolone
now known as antipyrine。
N
N
N
N
O
°² Ìæ±ÈÁÖ
Phenazone
antipyrine
N
O
°±»ù±ÈÁÖ
Aminophenazone
aminophenazone
N
N
O
O- Na+
N
S
O
O
°² Ä˾²
Metamizole Sodium
Metamizole sodium
Hypoleucocytosis（白细胞减少）and agranulocytosis（粒细胞缺乏症）
6
Development

In 1946, Swiss developed Phenylbutazone with
the basic structure of 3,5-pyrazolidinedione.
O
O
O
O
N
N
O
O
N
N
±£Ì©ËÉ
Pheny lbutazone
-ͪ ±£Ì©ËÉ
-ketopheny lbutazone
phenylbutazone
γ-ketophenylbutazone
S
O
O
N
N
»ÇßÁͪ
Sulf inpy razone
sulfinpyrazone
7
O
N
Development
O
N
OH
oxyphenbutazone


In 1961, the metabolite of phenylbutazone
is oxyphenbutazone,which is also antiinflammatory with less side effect.
Later, Sulfinpyrazone and γ-ketophenylbutazone were found to treat gout (痛风)and
rheumatic arthritis (风湿性关节炎).
8
Relation between
anti-inflammation and acidity
H
R
4
O 5 N
H
3
O
O
R
H
O
R
NH
NH + H
O
N
H
NH + H
O
N
H
The proton was active due to the influence of
ketones in position 3 and 5.
9
Metabolism
O
O
N
O
N
O
N
N
OH
OH
OGlu
OH
O
ôDz¼×Ú¡¡ Oxy phenbutazone
oxyphenbutazone
O
O
N
O
N
N
OH
OH
OH
O
N
O
N
N
O
O
±£Ì©ËÉ
pheny lbutazone
phenylbutazone
γ-hydrophenylbutazone
OH
Glu
O
- ôÇ»ù±£Ì©ËÉ
-hy dropheny lbutazone
Glu
O
O
N
N
O
N
N
O
N
N
-ͪ ±£Ì©ËÉ
γ-ketophenylbutazone
-ketopheny lbutazone
10
Physico-chemical property

Heated with glacial acetic acid and hydrochloric acid, then
sodium nitrite was added, the solution presents yellow; finally
β-naphthol was added, some orange precipitation forms.
OH
O
OH
O
N
N
O
O
OH
H
N
+
N
H
OH
HO
HO
NH2 +
NH2
N
H
NH2
11
Mefenamic Acid
(甲芬那酸)
O
OH
NH
1
2
3
2-[(2,3-Dimethylphenyl)amino]benzoic acid
12
Derivatives
O
O
OH
OH
NH
O
Aspirin
O
O
O
HO
OH
NH
Cl
O
O
O
O
OH
OH
NH
NH
Cl
Cl
F
F
¼×ÂÈ·ÒÄÇËá
Meclof enamic acid
F
·ú·ÒÄÇËá
Fluf enamic acid
ÂÈ·ÒÄÇËá
Chlof enamic acid
13
Diclofenac Sodium（双氯芬酸钠）
ONa
O
NH
Cl
Cl
Sodium 2-[(2,6-dichloroanilino)phenyl]acetate
Indicated for short- and long-term treatment of RA,
OA, and ankylosing spondylitis（强直性脊柱炎）.
Available as delayed-release tablets.
14
Chemosynthesis
OH
Cl
Cl
H
N
NH2
Cl
O
ClCH2COCl
ONa
Cl
N
AlCl3
Cl
O
NH
NaOH
Cl
Cl
Cl
Derivatives
O
O
Cl
HO
O
N
O
OH
O
Cl
·ÒÂÈËá
Fenclof enac
ÍÐÃÀÍ¡
Tolmetin
N
OH
O
Cl
×ôÃÀËá
Zomepirac
15
Indomethacin（吲哚美辛）
O
5
4
OH
3
1
2
O
N
O
Cl
1-(4- Chlorobenzoyl)-5-methoxy-2-methyl-1Hindole-3-acetic acid
A pale-white to yellow-tan crystalline powder.
Soluble in ethanol and acetone and practically insoluble in water.
Unstable in alkaline solution and sunlight.
16
Development



Serotonin（5-羟色胺，血清素）may be the chemical painproducing substance of inflammation
Serotonin is concerned with Tryptophan（色氨酸）in vivo
At the same time metabolic level of Tryptophan in the
patients with rheumatalgia（风湿痛）is higher
O
HO
NH2
N
H
5-ôÇÉ«°·
Serotonin
HO
OH
N
H
NH2
É«°±Ëá
Try ptophan
17
Pharmacologic action

Mechanism:
Not anti-serotonin, but an inhibition of the biosynthesis of
prostaglandins.

In clinic:
Widely used as an anti-inflammatory analgesic in RA,
spondylitis（脊椎炎), and OA, and to a lesser extent in gout.

Side effects:
The most commons are gastric distress and headache.
Also associated with peptic ulceration（消化性溃疡）, blood
disorders, and possible deaths.
Appear to be dose related. Not recommended for use in children.
18
O
OH
O
N
Derivatives
O
Indomethacin
Cl
F
OH
O
OH
O
O
OH
O
O
N
O
S
O
Cl
Sulindac
N3
MK-715
Zidometacin
Stronger anti-inflammatory action,
and weaker toxicity.
19
Ibuprofen（布洛芬）
O
OH
S-(+) isomer
α-Methyl-4-(2-methyl propyl)phenylacetic acid
 2-(4-isobutylphenyl)propionic acid

20
Development of ibuprofen
While researching for auxine(生长素）, discovered that arylacetic
acid possessed anti-inflammatory action.
 Ibufenac firstly go on the market.
 Introduction of the a-methy group on the acetic acid moiety to
get Ibuprofen.
 A methy group was replaced by an ethyl group to get Butibufen
whose anti-inflammation was similar as Ibuprofen with less
gastrointestinal irritation.

O
O
OH
4-Ò춡»ù±½ÒÒ
Ëá
Ibuf enac
Ibufenac
OH
²¼Ìæ²¼·Ò
Butibufen
Butibuf en
21
Development of ibuprofen
O
O
OH
Ibufenac
OH
Ibuprofen
Although ibufenac was several times more potent than
aspirin, it showed occasional hepatotoxicity in humans.
 When a methyl group was added to the acetic acid subunit,
a much safer drug resulted (ibuprofen)with diminished
gastrointestinal irritation and no hepato-toxicity, even in
large doses.

22
Drugs commonly used
name
Chemical structure
potency
name
Chemical structure
O
O
OH
Ibuprofen
F
1/10
N
O
OH
Fluprofen
Cl
5
N
Pirprofen
O
OH
O
1.5
Naproxen
2
O
OH
O
Ketoprofen
O
OH
Indoprofen
potency
1
O
OH
1
23
Metabolism of Ibuprofen
O

O
O
O
HO
(±)Ibuprofen



HO
OH
(+)isomer major
(+)isomer
O

O
O

OH
HO
O
24
SAR of Ibuprofen
S-isomer
may replaced by other aryl,
heterocycle group.
O
OH
Ar
may be methyl or ethyl
X
substituted by flurine and chlorine,
best activity
25
Chemical synthesis
Friedel-Crafts
reaction
CH3COCl
CH2=CHCH3
O
AlCl3
Na-C
O
1.NaOH
O
ClCH2COOC2H5
O
CH3CH2ONa
Hydrolysis,
De-carboxyl,
rearrangement
2. HCl
αß-epoxy ester
O
H
1. AgNO3, OH-
O
OH
2. H+
Darzens Reaction：hydrolysis, decarboxyl, rearrangement
26
Darzens Reaction
ClCH2COOC2H5
Na
Cl-CHCOOC2H5
+ RONa
Cl
CHCOOC2H5
O
O
CHCOONa
CHCOOC2H5
-Cl
NaOH
O
O
CH3
-CO2
HCl
C
H
CHO
27
Naproxen（萘普生）
1
H
OH
2
O
6
3
5
O
S(+)isomer
4
(+)6-Methoxy-α-methyl-2-naphthaleneacetic acid
 White to off-white crystal.
 Sparingly soluble in acidic solutions, freely soluble in
alkaline solutions, and higly soluble in organic or lipid-like
solutions.
28
SAR
Replace by other group such as alcohol, aldehyde, ketone, keep the activity.
OH
O
O
Remove the methoxyl group, reduce the activity.
Replace by smaller group such as Cl, CH3, F2CHO, keep the activity.
Replace by larger group, reduce the activity.
29
Metabolism of Nabumetone
OH
O
ÆÏÌ ÑÌÇËáÜÕ
O
O
O
OH

O
HO
HO
Nabumetone
OH
O
O
ÆÏÌ ÑÌÇËáÜÕ
Nabumetone serves as a prodrug to it metabolite,
6-methxoxy-2-naphthylacetic acid.
30
Pharmacologic action

Like aspirin, inhibits prostaglandin synthetase and prolongs
blood-clotting time.
Recommended for use in rheumatoid and gouty arthritis.
Also available over-the-counter (OTC).
Its potency for inhibit prostaglandin synthetase
is stronger 12 times than Asprin,
stronger 10 times than phenylbutazone,
stronger 3-4 times than ibuprofen,
but is weaker 300 times than indomethacin.
31
Naproxen
 Side effects:
Dizziness(头晕), drowsiness(困倦), and nausea, with
infrequent mention of gastrointestinal tract irritation.
Not recommended for pregnant or lactating（泌乳）
women or children under 16.
Risk of heart attack or stroke.
32
Piroxicam（吡罗昔康）
OH
4
O
3
NH
N
2
N
S
O


1
O
4-Hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine
-3-carboxamide-1,1- dioxide
Systematic (IUPAC) name :
(8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9methyl-10,10-dioxo-10λ6-thia-9-azabicyclo[4.4.0]deca1,3,5-trien-7-one
from:http://en.wikipedia.org/wiki/Piroxicam 33
Piroxicam
 Piroxicam is a non-steroidal anti-inflammatory drug used
to relieve the symptoms of rheumatoid and osteoarthritis;
act as an analgesic.
 Used in veterinary medicine（兽药）to treat certain
neoplasias expressing cyclooxygenase (COX) receptors,
such as bladder(膀胱), colon(结肠), and prostate(前列腺)cancers.
 Manufacturerd by Pfizer under the tradename Feldene.
 Other brand names "Brexidol", "Brexin", "Erazon",
"Felden", "Feldoral", "Hotemin", "Pirox von ct",
"Proponol", "Reumador", "Tracam", "Veral", "Vurdon".
34
Mechanism:
 Represents a class of acidic inhibitors of
prostaglandin synthetase.
 Non-steroidal anti-inflammatory drug.
 A non-selective COX inhibitor possessing both
analgesic and antipyretic properties.
 It undergoes enterohepatic circulation(肠肝循环).
 Very long acting, with a plasma half-life of 50h.
Requiring a dose of only 20 to 30mg once daily.
Giving results similar to those from 25 mg of
indometacin or 40mg ibuprofen 3 times a day.
35
Adverse effects
 Result in gastrointestinal toxicity, tinnitus(耳鸣),
dizziness(头晕), headache, rash(疹), and pruritus(瘙痒).
The most severe adverse reactions are peptic
ulceration(消化性溃疡)and gastrointestinal bleeding.
 Approximately 30% of all patients receiving daily
doses of 20 mg of piroxicam experience side effects.
 May cause skin to become more sensitive to sunlight.
Avoidance of sunlight and use of sunscreen is
recommended.
36
OH
NH
Derivatives
OH
O S
O
N
O
OH
S
N
S O
O
N
O
O
S
Êæ¶àÎô¿µ
Sudoxicam
sudoxicam
O
O
OH
O
S
N
H
àç·ÔÎô¿µ
Tenoxicam
tenoxicam
O
S
O
ÒÀË÷Îô¿µ
Isoxicam
Isoxicam
O
OH
N
N
N
H
N
N
Piroxicam
S
N
N
H
O
O
N
O
N
N
H
S
ÃÀÂåÎô¿µ
meloxicam
Meloxicam
Methyl
m group was introduced, no gastrointestinal tract irritation.
37
r
Celecoxib
O
（塞来昔布）
O
S
H2N
F-substitution is best

N
F
F
F
Other name: Celebrex.
It is a COX-2 inhibitor
5-m ring with an electrowithdrawing group
38
O
OH
O
N
O
N
NH
N
N
OH
S
O
Oxyphenbutazone
O
Piroxicam
O
ONa
OH
O
O
OH
NH
Cl
NH
O
Cl
N
O
Cl
Diclofenac Sodium
Indomethacin
Mefenamic Acid
O
H
OH
OH
O
O
Naproxen
Ibuprofen
39
Exercise(1)

Which of the following drugs only relieve
fever and pain,without antiinflammatory
A. Metamizole sodium
B. Aspirin
C.
√
Paracetamol
D. Naproxen
E. Piroxicam
40
Exercise (2)

Whose activity in the
following drugs is
similar to the structure
A. Phenobarbital
B. adrenalin
O
OH
O
D. Diphenhydramine
E. Nifedipine
C. Ibuprofen
√
41
Exercise (3)
A. Diclofenac sodium
D. Indometacin
B. Ibuprofen
E. Paracetamol
C. Aspirin
A  Sodium [O-(2,6-dichloroanilino) phenyl]acetate
D  1-(4-chlorobenzoyl)-5-methoxy-2methylindole-3-acetic acid
42
Exercise (4)

Which of the following items match Ibuprofen
A.
√
Belong to NSAIDs
B. Be used for gout
C. Possesses a chiral carbon, and racemic
√ body used in clinic
D. Contains isobutyl in its chemical structure
√
E. Used as an anti-ulcerative drug
43
Exercise (5)
O
ONa
OH
OH
O
O
O
NH
N
NH
N
Cl
Cl
N
O
S
O
Cl
A
O
B
N
H
D



Piroxicam
Ibuprofen
Naproxen
O
H
O
HO
C
OH
OH
O
O
E
B
F
E
F
44
Case study (1)



Six months ago, GZ began playing tennis
ball during his lunch hour with one of his
colleagues.
Today, he visited his physician
complaining of sore elbow.
His physician has diagnosed the problem
as bursitis, and wants to prescribe
treatment for the problem.
45
Q
CH3

Which of the agents
should not be used in
the patient? Explain
your answer using the
chemistry
of
the
compounds.
O
OH
O
36.2
NH
CH3
O
HO
36.4
OH
CH3O
O
CH3
N
CH3
OH
O
O
CH3O
Cl
36.3
36.5
46
Case study (2)



A two-year-old child is rushed to the emergency
room of your hospital by his distraught mother.
She tells the E.R. staff that her boy ate
approximately half of a full bottle of Tylenol
(acetaminophen) tablets.
Along with gastric lavage, you recommend the
po administration of a 5% solution of Cysteine
NH
CH3
O
HO
SH
O
CH3
OH
NH
O
37.1
37.2
47
Q1 and Q2

How is acetaminophen normally metabolized?
Based on this metabolic route, what medical
emergency is facing this child?

What is the chemical rational for the
administration of Cysteine
48