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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
72 Pharmaceutical Chemistry
Ibuprofen was developed and discovered by the Boots Company. Dr Stewart Adams
and his colleagues John Nicholson, Colin Burrows and hundreds of people were involved.
Work started in the 1950s to find a drug to treat rheumatoid arthritis (inflammed joints)
that had fewer side effects than aspirin. However, ibuprofen was not launched until 1969.
This timescale is not unusual for development and testing of a drug. The timeline was
as follows:
1955 The discovery is made that anti-inflammatory drugs reduce inflammation of the
skin caused by ultraviolet light. This gives a simple screening test for new chemical
compounds (called new chemical entities or NCEs in the jargon) that the research chemists
produced.
1958 After some 600 compounds had been synthesized and screened for activity, a
promising compound code named BTS 8402 is given a clinical trial on patients. It was
found to be no better than aspirin.
1961 A patent was filed for the compound 2-(4-isobutylphenyl) propanoic acid which
was later known as ibuprofen.
1964 Ibuprofen was selected for further development.
1966 Clinical trials of ibuprofen took place at the Northern general hospital in Edinburgh
and showed its anti-inflammatory effect on patients.
1969 Ibuprofen was launched in the UK on prescription only.
1983 Because of its safety record, ibuprofen was made available without prescription.
Ibuprofen is a NSAID having anti-inflammatory, analgesic and antipyretic effects. It
inhibits the activities of COX1 and COX2 resulting in a decreased formation of precursors
of prostaglandins and thromboxanes. This leads to decreased prostaglandin synthesis by
prostaglandin synthatase as the main physiologic effect of ibuprofen. It also caused a
decrease in the formation of thromboxane A2 synthesis, by thromboxane synthase, thereby
inhibiting platelet aggregation.
3.8.1 Specification
Name : (RS)-2-(4-(2-methylpropyl)phenyl)propionic acid
Molecular Formula : C
18H18O2
Molecular Weight : 206.29 g/mol
Melting Point : 75-77°C
Physical State : Colourless crystalline solid
Solubility : Slightly soluble in water and readily soluble in ethanol and acetone.
3.8.2 Synthesis of Ibuprofen
There have been many commercial methods for the synthesis of ibuprofen but two most
popular ways to obtain ibuprofen are the Boot process and the Hoechst process. The Boot
process is an older commercial process developed by the Boot Pure Drug Company, and
Analgesics, Antipyretic and Anti-Inflammatory Agents 73
the Hoechst process is a newer process developed by the Hoechst Company. Most of these
routes to ibuprofen begin with isobutylbenzene by using Friedel-Crafts acylation. The
Boot process requires six steps, while the Hoechst process, with the assistance of catalysts,
is completed in only three steps.
Me
Me
Boot
process
Me
Hoechst
Process
Me O
(CH3CO)2O
AlCl
Me
CH3COCl
AlCl
Me
Me
O
3
3
Me
CH
H
2
Raney-Ni
Me
NaOEt
ClCOOEt
2
Me
Me
Me
OH
Me
CO/Pd
Me
CO2Et
O
Me COOH
Me
Alternative synthesis of ibuprofen by green chemistry
Me
Me
Ac
HF
OMe
H
2
Me
Me
Raney-Ni
COOH
CH
3
O
2
OHMe
Me
Ibuprofen
CO/Pd
Me
+
H
O
H
2
Me CHO
Me
NH2OH
Me
Me
O
-H
2
Me
H2O
Me CN
Me
COOH
Me
Me
Me
Ibuprofen
Me
N
OH
Me
3.8.3 Mode of Action
When a part of the body is injured, protective mechanisms get into action. White blood
cells accumulate at the site of the injury and this causes swelling, heat, redness, loss of
function, fever and pain together called inflammation. All these effects are potentially
beneficial. Swelling can help to immobilise injured joints, heat and increased blood flow
promote healing and pain alerts the injured person that there is a problem (so that he or
she will quickly remove their hand from a hot stove, for example, to prevent further injury).
However, they can often be too much of a good thing—once we know we are injured, the
pain no longer has a function and we wish to get rid of it; often the inflammatory response
is too powerful and can do more harm than good.
74 Pharmaceutical Chemistry
Ibuprofen is classed as a non-steroidal anti-inflammatory drug or NSAID. It works by
acting on a group of compounds called prostaglandins. Prostaglandins are sometimes
called local hormones because they act close to where they are produced rather than all
over the body. They have a remarkably wide range of effects. One of their actions is to
cause inflammation. Ibuprofen’s action as a painkiller and antipyretic (fever-reducing)
compound is due to its ability to inhibit the synthesis of prostaglandins. It does this by
interfering with the action of an enzyme called cyclooxygenase (COX) which catalyses the
conversion of a compound called arachidonic acid into prostaglandins. Aspirin and other
NSAIDs work in a similar way.
Nonsteroidal anti-inflammatory drugs such as ibuprofen work by inhibiting the COX
enzymes which convert arachidonic acid to prostaglandin H
(PGH2). PGH2, in turn, is
2
converted by other enzymes to several other prostaglandins (which are mediators of pain,
inflammation, and fever) and to thromboxane-A
(which stimulates platelet aggregation
2
leading to the formation of blood clots). The exact mechanism of action of ibuprofen is still
under investigation. Ibuprofen is a nonselective inhibitor of COX, an enzyme involved in
prostaglandin synthesis via the arachidonic acid pathway (Fig 3.7). Its pharmacological
effects are believed to be due to inhibition of COX-2 which decreases the synthesis of
prostaglandins involved in mediating inflammation, pain, fever, and swelling. Antipyretic
effects may be due to action on the hypothalamus, resulting in an increased peripheral
blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 is thought
to cause some of the side effects of ibuprofen including gastrointestinal ulceration.
Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive
interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be a more
pharmacologically active enantiomer.
Like aspirin and indomethacin, ibuprofen is a nonselective COX inhibitor that inhibits
two isoforms of COX (COX-1 and COX-2). The analgesic, antipyretic, and anti-inflammatory
activity of NSAIDs appears to operate mainly through inhibition of COX-2, whereas
inhibition of COX-1 would be responsible for unwanted effects on the gastrointestinal
tract. However, the role of the individual COX isoforms in the analgesic, anti-inflammatory
and gastric damage effects of NSAIDs is uncertain and different compounds cause different
degrees of analgesia and gastric damage.
8
HOOC
12
Arachidonic Acid
Enzyme
(inhibited by NSAID's)
1
20
Fig 3.7: Synthesis of prostaglandin
O
HO
COOH
OH
Prostaglandin
Analgesics, Antipyretic and Anti-Inflammatory Agents 75
The structures of arachidonic acid and prostaglandins are different. It was expected that
when C-8 and C-12 of arachidonic acid was connected with each other, resulting in
5-membered ring which seems to be similar as the prostaglandin.
3.8.4 Metabolism of Ibuprofen
Ibuprofen is rapidly absorbed on oral administration, with peak plasma levels being
usually attained within 2 hours and duration of action of less than 6 hours. As with most
of these acidic NSAIDs, ibuprofen (pK
(99%) and interacts with other acidic drugs that are protein bound. Metabolism occurs
rapidly and the drug is nearly completely excreted in the urine as unchanged drug and
oxidative metabolites within 24 hours after administration. Metabolism by CYP2C9 (90%)
and CYP2C19 (10%) involves primarily Z, Z
followed by alcohol oxidation of the primary alcohol resulting from Z-oxidation to the
corresponding carboxylic acid (Fig. 3.8). All metabolites are inactive. When ibuprofen is
administered as the individual enantiomer, the major metabolite isolated is the S-(+)-
enantiomer whatever the configuration of the starting enantiomer. Interestingly, the R-(-)-
enantiomer is inverted to the S-(+)-enantiomer in vivo via an acetyl coenzyme A intermediate,
accounting for the observation that the two enantiomers are bioequivalent in vivo. This is
a metabolic phenomenon that has been also observed for other arylpropionic acids, such
as ketoprofen, benoxaprofen, fenoprofen, and naproxen.
= 4.4) is extensively bound to plasma proteins
a
, Z2-oxidation of the p-isobutyl side chain,
1
O
OH
OH
1-Hydroxy ibuprofen
O
Glucuronic acid
conjugates
Ibuprofen
O
HO
3-Hydroxy ibuprofen Carboxy ibuprofen
Glucuronic acid
conjugates
OH
Fig. 3.8: Metabolism of ibuprofen
OH
HO
2-Hydroxy ibuprofen
Glucuronic acid
O
OH
Glucuronic acid
conjugates
O
OH
conjugates
O
OH
76 Pharmaceutical Chemistry
3.8.5 Adverse Effects
The most common (greater than 1%) adverse effects reported include: nausea, epigastric
pain, heartburn, diarrhoea, abdominal distress, nausea and vomiting, indigestion,
constipation, abdominal cramps or pain, fullness of the GI tract (bloating and flatulence),
tinnitus, oedema, fluid retention, dizziness, headache, nervousness, rash, pruritus and
decreased appetite. Other less common (less than 1%) reactions include: depression,
insomnia, confusion, somnolence, aseptic meningitis with fever and coma, vesiculobullous
eruptions, urticaria, alopecia, gastrointestinal haemorrhage, pancreatitis, gastritis, jaundice,
abnormal liver function tests, amblyopia, fever, chills, anaphylaxis, bronchospasm, melaena,
neutropenia, agranulocytosis, aplastic anaemia and decrease in haemoglobin and haematocrit.
3.8.6 Side Effects
It could lead to an allergic reaction such as nausea, upper stomach pain, itching, loss of
appetite, dark urine, clay-coloured stools, jaundice (yellowing of the skin or eyes), fever,
sore throat, and headache with severe blistering, peeling, and red skin rash; bruising,
severe tingling, numbness, pain, muscle weakness; or severe headache, neck stiffness,
chills, increased sensitivity to light, and/or seizure (convulsions). The common side effects
of ibuprofen may also include upset stomach, mild heartburn, nausea, vomiting, bloating,
gas, diarrhoea, constipation, dizziness, headache, nervousness, mild itching or rash; or
ringing in your ears.
3.9 PARACETAMOL
Paracetamol is an antipyretic class of drugs which exerts its action on the
hypothalamic heat regulating centre and analgesia by enhancing the pain
threshold profile appreciably. It is found to lack the anti-inflammatory
activity of the salicylates, therefore its therapeutic uses in inflammatory
disorders is very much limited and hence is not regarded as an NSAID agent.
Contrary to the action of aspirin, paracetamol possesses little effect in
antagonising the actions of uricosuric agents (such as increases the urinary
excretion of uric acid). It has also been observed that its large doses usually help in
potentiating the action of the anticoagulants, whereas the normal therapeutic dose regimes
exert hardly any effect on the prothrombin time or coagulating time.
It is metabolite of acetanilide and phenacetin employed as an antipyretic and analgesic.
It can also be used for the arthritic and rheumatic conditions linked with musculoskeletal
pain, headache, neuralgias, myalgias and dysmenorrhea. It is particularly useful in aspirinsensitive patient.
Nearly 2% of the drug is excreted almost unchanged in the urine, while approximately
95% is found as its corresponding glucuronide and sulphate conjugates that are absolutely
devoid of any toxicity. Furthermore, the remaining 3% gets oxidised via the hepatic cytoc hrome
P450 system into respective chemically reactive intermediates which eventually combine
specifically with the liver glutathione to give rise to the formation of a nontoxic entity.
HNOCH
OH
Paracetamol
3
Analgesics, Antipyretic and Anti-Inflammatory Agents 77
Paracetamol is widely used as an antipyretic-analgesic and fever-reducing agent.
Paracetamol is designed for moderate analgesia. It is also effective like aspirin and is used
in analgesia for headaches (from weak to moderate pain), myalgia, arthralgia, chronic
pain, for oncological and post-operational pain, etc. Synonyms for this drug are paracetamol,
tylenol, and many others.
3.9.1 Specification
Name : 4-Hydroxyacetanilide, Acetaminophen, Paracetamol
Molecular Formula : C
8H9NO2
Molecular Weight : 151.16 g/mol
Melting point : 169°C
Physical state : White crystalline powder
Solubility : Partially soluble in water; soluble in methanol and ethanol
3.9.2 Synthesis of Paracetamol
It may be prepared by the reduction of p-Nitrophenol in the presence of NaBH4 giving
p-aminophenol, which on acetylation in the presence of acetic anhydride and glacial acetic
acid gives 4-hydroxyacetanilide which is known as paracetamol. The pure product can be
purified by recrystallization from water ethanol (1:1) mixture.
NO
OH
2
Reduction
NH
2
O
Ac
2
glacial acetic acid
OH
p-Aminophenolp-Nitrophenol
HNOMe
OH
Paracetamol
An alternative industrial synthesis:
This method was developed by Hoechst–Celanese which involves direct acylation of
phenol with acetic anhydride catalyzed by HF, and followed by the conversion of the
ketone to a ketoxime with hydroxylamine, which further treated with SOCl
in CF3COOH
2
to afford paracetamol.
OH
Ac
HF
O
2
OH
OH
OH
NH
2
MeO
HO
CF
COOH/SOCl
3
Amberlyst 15
MeN
2
OH
HNOMe
Paracetamol
78 Pharmaceutical Chemistry
3.9.3 Mode of Action
Paracetamol differs from the nonsteroidal anti-inflammatory agents described in that it is
devoid of anti-inflammatory and antirheumatic properties. It was recently shown that
acetaminophen, like aspirin, inhibits COX action in the brain and is even stronger than
aspirin. On the other hand, the mechanism of analgesic action of acetaminophen is not
fully clear, since it acts poorly on peripheral COX. Paracetamol can be administered orally
or rectally in the form of suppositories and it does not associate with any gastric side
effects. It is efficacious against toothaches and headaches. However, unlike the antipyrines,
paracetamol is not effective for visceral pain. Unlike the other NSAIDs, it possesses no
anti-inflammatory activity. It has been confirmed that, provided the ambient concentration
of peroxides is kept low, paracetamol can inhibit COX. This consequently explains why
paracetamol is not active at the site of inflammation where the peroxide level is high,
however, the peroxide concentration in the brain is low. The in vivo effect of paracetamol
is comparable to those of the selective COX-2 inhibitors. Bertolini and Zygmunt in 2006
demonstrated that the analgesic effect of paracetamol is due to the indirect activation of
cannabinoid CB1 receptors in human. The active metabolite N-arachidonoylphenolamine
(AM404) is formed in the brain by conjugation of the primary amine (p-aminophenol) of
paracetamol with arachidonic acid in the presence of a fatty acid amide hydrolase (FAAH).
AM404 is an already known compound, previously described as an endogenous
cannabinoid. It is a TRPV1 (transient receptor potential vanilloid) ion channel receptor
agonist which indirectly activates the CB1 receptors by further increasing the levels of
endogenous cannabinoids; moreover, it inhibits COX in the brain at concentrations not
attainable with analgesic doses of paracetamol. Prior to renal elimination, the drug
undergoes conjugation at its phenolic hydroxyl moiety with glucuronic or sulphuric acid.
A small fraction is oxidised to N-acetyl-p-benzoquinone which is detoxified by coupling
with gluthathione. At high doses, the hepatic glutathione reserve is depleted and the
quinoneimine metabolite reacts with the liver cells, resulting in necrosis. As an antidote,
N-acetylcysteine is given intravenously within 6–8 hours.
3.9.4 Metabolism of Paracetamol
Paracetamol is metabolised primarily in the liver by converting into toxic and non-toxic
products. There are three metabolic pathways in action. First glucuronidation (45-55%),
second sulfation (sulfate conjugation) accounts for 20–30%, and third is N-hydroxylation
and dehydration, then GSH conjugation (<15%).
The hepatic cytochrome P450 enzyme system metabolises paracetamol, forming a minor
yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzoquinoneimine or
N-acetylimidoquinone). NAPQI is then irreversibly conjugated with the sulfhydryl groups
of glutathione. All the three pathways yield final products that are inactive, non-toxic, and
eventually excreted by the kidneys. In the third pathway, however, the intermediate
product NAPQI is toxic which is also responsible for the toxic effects of paracetamol; this
constitutes an example of toxication. Production of NAPQI is due primarily to two
Analgesics, Antipyretic and Anti-Inflammatory Agents 79
isoenzymes of cytochrome P450: CYP2E1 and CYP3A4. At usual doses, NAPQI is quickly
detoxified by conjugation with glutathione (Figs. 3.9 & 3.10).
HNOCH
3
in CNS
OH
Paracetamol
HN
P
h
+
e
g
l
u
t
a
O
CH
O
HOOC
HO
HO
l
y
s
o
e
n
s
o
a
r
r
u
e
c
f
u
s
l
n
g
a
r
t
PD
U
O
OH
Glucuronic acid conjugate
(predominant in adults)
Kidneys (low toxic, Elimination)
NH
2
Fatty acid amide hydrolase
(+arachidonic acid)
OH
p-Aminophenol
C
n
o
l
s
u
t
l
h
f
o
i
o
t
r
n
a
e
n
p
r
e
c
u
3
Y
P
4
5
0
+
N
A
D
P
H
+
2
CH
O
2
3
benzoquinoneimine
sf
e
r
a
se
r
so
r
HO
O
HN
O
O
S
O
Sulfuric acid conjugate
(predominant in fetus & children)
Fig. 3.9: Pathways of Paracetamol metabolism
NOCH
3
Detoxification
O
Np-acetyl- -
Toxic reactions
with protein and
nucleic acids
O
N
H
Me
N-
arachidonoylphenolamine
(AM404)
O
HN
CH
GSH,
macromolecule
OH
proteins
Non toxic
glutathione
conjugate
Cell death than
Hepatic necrosis
and Renal Failure
Liver
OH
3
NHCOCH
3
Paracetamol
NHCOCH
O
glucuronide
HOOC
HO
HO
O
H
OH
O
O
O
UDP Glucuronide
O
OH
NH
N
O
O
OPOPO
O
O
OH
-UDP
HOOC
HO
O
OH
HO
Paracetamol β−
Fig. 3.10: Glucuronidation of Paracetamol with UDP glucuronyl transferase
3.9.5 Side effects of Paracetamol
Paracetamol causes rare side effects. If at all, they, include allergic reactions like rashes or
swelling, hypotension (low blood pressure), higher dose than recommended could lead to
liver and kidney damage.
3
80 Pharmaceutical Chemistry
3.10 DICLOFENAC
Diclofenac belongs to a class of drugs called nonsteroidal anti-
Cl
inflammatory drugs (NSAIDs) that are used for the treatment of mild
to moderate pain (signs and symptoms of osteoarthritis or rheumatoid
arthritis), fever, sprains and strains, gout, migraine, dental pain, and
pain after surgical operations and inflammation.
NH
Cl OH
O
It was introduced in the US in 1989 but was first marketed in Japan
in 1974. Other members of this class include ibuprofen (Motrin),
Diclofenac
indomethacin (Indocin), nabumetone (Relafen), naproxen (Aleve) and several others.
Diclofenac works by blocking the effect of chemicals in your body, called COX enzymes.
These enzymes help to make other chemicals in the body, called prostaglandins.
Prostaglandins are produced at sites of injury or damage, and cause pain and inflammation.
By blocking the effect of COX enzymes, fewer prostaglandins are produced consequently
inflammation, pain and fever are reduced.
Diclofenac is not a suitable medicine for people who have heart disease (such as heart
failure), or who have circulatory problems, or who have had a heart attack or a stroke. This
is because it has been found that there is a small increased risk of heart attack and stroke
in this group of people. Other anti-inflammatory medicines are more suitable for people
with these conditions.
There are two forms of salts, diclofenac sodium and diclofenac potassium. The main
difference between the two is that diclofenac potassium is absorbed into the body more
quickly than diclofenac sodium. A quick action is useful where immediate pain relief is
required, and a prolonged action is more useful in reducing inflammation. Diclofenac
sodium is indicated for the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing
spondylitis.
3.10.1 Specification
Name : 2-(2,6-dichloranilino) phenylacetic acid, Aclonac, Cataflam, Voltaren
Molecular Formula : C
14H11Cl2NO2
Molecular Weight : 296.15 g/mol
Melting point : 160°C
Physical state : White crystalline powder
Solubility : Partially soluble in water; soluble in methanol and ethanol
3.10.2 Synthesis of Diclofenac
Catalytic hydroxylation in the presence of Cu and KOH, of 2-Chlorobenzoic acid and
2,6-dichloro aniline gives 2(2,6-dichloroaniline)benzoic acid which gets reduced in
presence of LiAlH
giving [2-(2,6-dichloro-phenylamino)-phenyl]-methanol. The alcohol
4
Analgesics, Antipyretic and Anti-Inflammatory Agents 81
counterpart on sulfonation followed by reaction with NaCN gives [2-(2,6-dichlorophenylamino)-phenyl]-acetonitrile which on hydrolysis in the presence of NaOH leads to
diclofenac.
Alternative synthesis of diclofenac
2(2,6-Dichloroaniline)benzoic acid on heating condition leads to 2,6-dichlorodiphenylamine which on reaction with oxalyl dichloride leads to [(2,6-dichloro-phenyl)phenyl-amino]-oxo-acetyl chloride. This scaffold on Friedel-Craft’s reaction leads to
cyclised product 1-(2,6-dichloro-phenyl)-1H-indole-2,3-dione which further reacts with
hydrazine under basic conditions leading to diclofenac.
Cl
AlCl
Cl
NH
COOH
3
Cl
Cl
N
280°C
2,6-Dichloro-
diphenylamine
O
O
Cl
NH
Cl
H2NNH
KOH
2
O
Cl
Cl
O
Cl
NH
Cl
Diclofenac
Cl
Cl
N
COOH
O
O
Cl