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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5648_Библиотеки_им_академика_М_И_Перельмана.pdf
52 Pharmaceutical Chemistry
Compound C: Alkylation of an enolate is the most favourable approach to synthesize
compound C.
FGI
COOH
Hydrolysis
COOEt
Synthons
COOEt
Synthetic equivalents
Case 14: Plan the retrosynthetic approach of the given circled compound
Br
COOEt
COOEt
Case 15: Plan the retrosynthetic approach for antihypertensive drug, captopril and also
synthesize the same using synthetic equivalence.
Cl
+
O
OH
O
Cl
FGI
ClO
N
O
Captopril
COOH
SH
FGI
COOH
N
O
Cl
OH
COOH
N
H
Synthesis of captopril
COOH
OH
O
HCl
OH
O
SOCl
Cl O
Cl
2
N
H
Cl
O
COOH
N
NH4SH
O
THF, H
Cl
O
2
COOH
N
Captopril
SH
Basic Retrosynthetic Approach 53
Case 16: Retrosynthesis of potent antimigraine drug sumatriptan
Retrosynthetic analysis 1
H
N
S
O
O
H
N
S
O
O
Cl
S
O
O
N
H
N
H
NO
NH
2
N
_
Me
FGI
2
FGI
H
N
S
O
H
N
NaO
O
S
O
O
NH
S
O
O
N
2
NO
Cl
FGI
N
H
FGI
2
_
2
Na2SO
H
N
S
O
O
H
N
S
O
O
NO
2
N
H
_
MeNH
OH
O
_
2
Br
NO
3
2
Synthesis of sumatriptan using synthetic equivalents from retrosynthetic analysis 1
H
N
2
O
SO
2
S
O
O
H
N
S
4
O
NO
2
O
N
H
N
N
H
Br
H
N
O
MsCl
Et3N
1. Na2SO
TBAB, H
NO
2
S
O
NH
2
H
N
S
O
O
2. PCl
1. NaNO
2.SnCl
3
Cl
/HCl
2
2
S
O
Cl
O
H
N
S
O
O
Nal, DIPEA
NHMe
2
O
2
5
N
H
NO
aq. MeNH
DCM, 0°C
2
N
H
H
N
NH
2
H
S
O
O
OH
Retrosynthetic analysis 2
PhO
PhO
H
N
S
O
O
S
O
O
S
O
O
N
H
N
H
NH
N
CN
FGI
2
_
2 Me
PhO
PhO
H
N
S
O
O
NH
2
HCHO
N
H
FGI
CN
S
O
O
N
H
S
O
O
NO
FGI
H
O
FGI FGI
Cl
S
O
2
O
CN
+
NO
H
N
O
PhO
S
O
S
O
O
Br
2
CN
_
N
H
MeNH
2
NH
2
N
H
NO
2
54 Pharmaceutical Chemistry
Synthesis of sumatriptan using synthetic equivalents from retrosynthetic analysis 2
SO
Br
PhO
PPA
O
S
PhO
1. Na
TBAB, H2O
NO
2
O
NH
S
O
O
2
2. PCl
1. NaNO
2.SnCl
2
N
H
3
5
/HCl
2
2
CN
aq. MeNH
Py
Cl
S
O
PhO
N
Et
3
EtO CN
EtO
2
CN
PhO
H2SO
H2/Pd
S
O
O
NO
2
,Pd
H
2
MeOH
CN
PhO
S
O
4
O
H
N
S
O
O
N
H
NH
N
H
PhOH
O
S
O
O
H
N
2
NO
2
NH
N
H
S
O
O
N
H
2
HCHO
NaBH
H
N
4
S
O
O
N
N
H
Retrosynthetic analysis 3
O
H
N
S
O
O
H
N
O
O
+
Cl
Cl
H
O
SPh
O
N
FGI
N
H
S
O
+
N
H
H
N
S
O
O
FGI
H
N
S
O
O
H
N
NH
2
N
H
O
N
Me
N
H
SPh
S
O
O
FGI
N
H
H
N
S
O
O
H
NH
N
2
H
N
NH
S
O
O
S
O
O
2
O
O
Cl
N
H
SPh
N
H
Synthesis of sumatriptan using synthetic equivalents from retrosynthetic analysis 3
H
O
NH
2
N
H
O O
ClCl
SPh
H
N
S
O
O
O
H
N
S
O
O
N
H
SPh
HCl
N
H
O
Me2NH
Cl
O
H
2
N
N
H
2
LiAlH
H
N
S
O
O
H
N
S
O
O
H
N
4
N
H
S
O
O
H
N
S
O
O
H
N
S
O
O
H
N
S
O
O
1. NaNO2/HCl
2.SnCl
NH
2
SPh
Raney-Ni
N
H
O
O
N
N
H
H
2
Retrosynthetic analysis 4
Basic Retrosynthetic Approach 55
_
H
N
Na
FGI
S
O
O
Br
2CO3
O
MeO
N
N
H
_
N
H
O
O
N
H
MeNH
N
N
2
_
MeNH
Cl
O
FGI
S
O
HO
O
MeO
2
N
N
H
N
H
O
N
H
FGI
HO
S
O
O
O
N
FGI
MeO
O
O O
Cl
ClCl
MeO
N
H
N
N
H
O
N
H
Synthesis of sumatriptan using synthetic equivalents from retrosynthetic analysis 4
O
O
N
N
H
S
O
O
LiAlH
4
HO
H
N
PCl
N
H
DCM
MeNH
N
5
S
O
O
2
N
PBr
N
H
N
N
H
MeO
Br
O
N
H
O O
ClCl
N
H
N
Na2SO
TBAB, H2O
MeO
3
O
HO
Cl
3
QUESTIONS
1. How does retrosynthetic analysis work, explain with a suitable example.
2. What is retrosynthesis?
3. What are synthons?
4. What are synthetic equivalents?
5. How is linear synthesis different from convergent synthesis?
6. Explain the strategies that could lead to desired simplification.
7. How will you explain retrosynthetic approach, explain with an example.
8. What is disconnection approach, explain with an example.
56 Pharmaceutical Chemistry
9. Which of the synthons (A-D) represents the following reagent?
O
R
OH
R
AB C D
R R
O
O
R
Ans: D
10. Carry out a retrosynthetic analysis of ropivacaine and identify which of the reagents
(A-D) is least likely to be useful.
Me
O
N
N
H
H
N
H2N
Br
AB C D
I
Ans: D
11. What is the difference between synthon and synthetic equivalents? Explain with
suitable examples.
12. What are the key factors responsible to plan a retrosynthetic approach?
13. Design disconnection approach for the given compound:
O
14. What are the synthetic equivalents for the given organic compound and explain
what type of addition reaction leads to this product?
O
OMe
OMe
O
3
Analgesics, Antipyretic and
Anti-Inflammatory Agents
3.1 INTRODUCTION
The therapeutic molecules have been broadly classified by traditional medical observers
based on their effect on human physiology. It is basically in terms of lowering in temperature,
inhibition of pain and arrest of inflammation, if any, in the body. Analogous therapeutic
molecules are classified as analgesic, antipyretic and anti-inflammatory, respectively.
Antipyretics refer to varying types of medication that may be primarily used to reduce
fever (rise in temperature—an external symptom of internal disorder) of patient with
overly high body temperatures, usually as due to viral or bacterial infection. People may
have familiarity with many of these drugs. Widely available over the counter types of
drugs include non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, aspirin
and Paracetamol/Acetaminophen. All of these medications can be used to lower fevers or
reduce the temperature of the body and there are other medications that might be tried if
these do not work.
One of the distinctive parts of the definition of antipyretics is that they are the medications
that lower body temperature only when fever is present. This is why, the over the counter
drugs listed above are applicable for other things like treatment of inflammation, pain, or
in the case of salicylates, daily treatment for stroke prevention. Fever reducers could not
be particularly effective for other treatments, if they always lowered body temperature.
Their use might mean dropping the temperature of the body below safe levels. The reason
that these medications typically only work on temperature when required, has to do with
the way the body responds to infection. When infection of any type occurs, the body may
begin reducing a substance called interleukin, which sends a message to the hypothalamus
to increase the temperature. Antipyretics essentially override this message and the
hypothalamus responds by lowering the temperature to normal.
In metaphor, it is as though interleukin and antipyretic are two roommates who can’t
agree about the temperature of the house since infection came for a visit. Interleukin is
constantly trying to turn up the thermostat. Antipyretic keeps turning it back down. Note
this battle can continue for a while, until infection leaves.
58 Pharmaceutical Chemistry
It’s often necessary for people to continue to take antipyretics for a few days or more to
keep a fever from coming back. Other medications like antibiotics might be useful in
bacterial infections too, as these may help reduce infection and reduce release of interleukin.
On the other hand, some viral infections quickly leave and people might only need a single
dose of antipyretics to regulate the temperature.
There are many potent antipyretics, available over the counter with chemists. They have
been made available in forms like pill, chewable tablets, quick dissolve strips or in liquid.
Many people may take suppository types of medications and this is particularly helpful
when controlling fever of someone who is vomiting.
There are some general things to remember about the common antipyretics. Aspirin
should never be allowed for children unless it is particularly prescribed. Acetaminophen/
Paracetamol is usually contraindicated in patients with liver disease. Ibuprofen or
other NSAIDs need to be avoided by people with NSAID allergy or who are on any blood
thinner therapy. Excess of antipyretics are not advisable and overdose can be fatal.
Usage of antipyretics is of particular interest along with fever reducers. It is a typical
situation for doctors especially when treating infants and young children who are suffering
with high fevers. A balanced approach must be practised while evaluating the benefits of
the fever fighting infection and the risks and comfort level of the person under treatment.
The most commonly used drugs, as antipyretics, are Acetanilide, Phenacetin
(Acetophentidin), and Paracetamol (Acetaminophen). Interestingly, the aforesaid three
drug entities are interrelated to one another at the level of metabolism:
O
HNOMe HNOMe
OH
Acetanilide Paracetamol Phenacetin
HN
Me
OEt
Phenacetin was dropped as a drug in 1982 in the US by virtue of the fact that it earned
a bad reputation for causing nephrotoxicity due to its chronic high dose abuse in several
parts of the world. It was also reported to cause cancer in the kidney and liver. Paracetamol
is still a preferred drug candidate which belongs to aniline-based analgesic-antipyretic
family for its abundant utility in controlling fever in most non-inflammatory conditions
which is very similar to aspirin.
Analgesics, Antipyretic and Anti-Inflammatory Agents 59
3.2 CLASSIFICATION
Antipyretic analgesics may be classified on the basis of their chemical structures as follows:
1. Aniline and p-Aminophenol analogues: The antipyretic activities of this family were
first reported by Cohn & Hepp in 1886. These drugs are also called coal tar analgesics.
Aminophenols are less toxic than the aniline while p-Aminophenols are less toxic
than other isomers, thus p-Aminophenols were used preferably as a drug choice.
Examples of a few salicyclic acid aniline and p-aminophenol analogues are as follows:
O
HN
OH
Paracetamol
Me
O
HN
Me
OEt
Phenacetin
NH
2
OEt
p-Phenetidine
O
HN
Acetanilide
Me
2. Salicyclic acid analogues: Salicyclic acid was first prepared by Paira in 1838;
however, the structure was reported by Hoffmann in 1899 who studied a detailed
pharmacodynamic property. Later on, Dresser introduced it as aspirin. The name
aspirin was derived from ‘a’ for acetyl and spirin which comes from spiric acid (old
name of salicyclic acid obtained from Spirea plants). Examples of a few salicyclic
acid analogues:
COOH
OCOCH
3
Aspirin Salol or
OH
O
O
Phenyl salicylate
OH
O OH
O
Salsalate
COONa
OH
Sodium salicylate
CONH
OH
Salicylamide
2
OCOCH
O
O
Benorilate
3
NHCOCH
F
3
Flufenisal
COOH
OCOCH
COO
3
Choline Salicylate
.HO(CH2)2NMe
OH
2
3. Quinoline analogues: Since long, Quinoline analogues have been used as a potent
antipyretic agent along with its remarkable effects on malarial fever. Nevertheless
possessing significant antipyretic action, firstly synthesized two Quinoline
derivatives could not gain attention as an effective drug due to their high toxic
effects on the red blood corpuscles and damaging effect on the kidneys. These were
60 Pharmaceutical Chemistry
Thalline and 6-Methoxy quinoline. Some other examples of Quinoline analogues
are as follows:
COOH
N
MeO
Thalline 6-Methoxyquinoline
MeO
N
H
COOH
Me
N
N
Cinchophen
Neocinchophen
4. Pyrazolones and Pyrazolodiones: Many heterocyclic compounds are known for
their medicinal uses. A few of them showing antipyretic activity are given:
Me
N
O
N
Phenazone
Me
N
2
O
Me
Aminophenazone
or aminopyrine
NaO2S
Me
.H2O
N
Me
N
Me
N
O
N
Dipyrone
N
Me
Me
Me
Phenylbutazone
Me
O
N
O
N
Oxyphenbutazone
O
N
O
N
OH
5. N-Arylanthranilic acids: These analogues open the door for new horizons of
antipyretic, analgesic and anti-inflammatory compounds which have recently
gained attention. Here are some examples:
Me
HOOC
H
N
CF
3
HOOC Me
H
N
NaOOC Cl
Me
H
N
Cl
Flufenamic acidMeclofenamate sodiumMefenamic acid
3.3 MECHANISM OF ACTION
The antipyretic activity is generally caused due to the direct interference with the pyrogenic
factors responsible for fever where the body temperature is more than 98.4°F. It has been
established that the antipyretics exert their activities very much within the central nervous
system (CNS) which is directly related to hypothalamic thermoregulatory centre. It can be
explained by the following conclusions:
(a) Endogenous leukocytic pyrogenes: They are released from the cells that have been
activated by host stimuli and these activated cells are inhibited by antipyretics with
the help of exogenous pyrogens as activator.
(b) Inhibition of the release of endogenous leukocytic pyrogenes from the cells activated
by the exogenous pyrogens.
Analgesics, Antipyretic and Anti-Inflammatory Agents 61
In 1979, Clark reported some evidences to prove central antipyretic mechanism which
specifically affords antagonism due to the following reasons:
(a) A direct competitive affinity between pyrogen and the antipyretic drug prevailing
at the CNS receptors.
(b) An inhibition of prostaglandin synthesis occurring in CNS.
3.4 ANALGESIC AGENTS
The terms analgesics and analgesic drugs are often used interchangeably to describe a
diverse group of pain medications such as opioids, nonsteroidal anti-inflammatory drugs
(NSAIDs), and triptans. Each of these produces analgesic effect with different mechanisms
of action for a wide array of causes. It can be broadly categorized, according to their
therapeutic use, into several drug classes:
The opioids or narcotic analgesics play a major role in the relief of acute pain and in
the management of moderate to severe chronic pain.
The NSAIDs and acetaminophen are the most widely used analgesic drugs for
relieving mild to moderate pain and reducing fever.
The triptans (the antimigraine medications) are specifically designed and targeted
for acute and abortive treatment of migraine and cluster headaches.
Newly emerged class of analgesics such as tricyclic antidepressants (viz.,
Amitriptyline), anticonvulsants (viz., Gabapentin and Pregabalin), and topical
analgesics (viz., Lidocaine patches) can be used to treat neuropathic pains.
Pain, one of the most common complaints for which patients seek medical attention, is
also the hardest symptom to manage despite the availability of many analgesic medications
as well as other nonpharmacologic treatment options. To understand how and when this
broad class of drugs is and should be used in the management of pain requires a brief
review of pain. Pain has been categorized as the following types: Inflammatory (viz.,
infection and tissue injuries), physiological (viz., touching hot water) and neuropathic
(viz., injury in peripheral or central nervous system). Within these classes of pain there are
different levels of pain such as acute, chronic, arthritic, cancer, neuropathic, etc.
The World Health Organization (WHO) brought together an international, as well as
multidisciplinary group of experts to discuss and formulate a series of WHO guidelines,
including the “three-step analgesic ladder” on pain management in Access to Controlled
Medications Programme. Thus, according to this analgesic ladder model (Fig. 3.1), the choice
of analgesic therapy is based on the assessment of pain intensity that was adopted. This
guideline has now been adapted for treating other noncancer pains.
For moderate pain, a combination of an NSAID (or acetaminophen) and a weak opioid
such as codeine may generally be prescribed. Morphine, fentanyl, and other potent opioids
are reserved only for severe pain, especially in patients who are terminally ill, to control
pain and to improve their quality of life.