NSAIDS

NSAIDS
Indole acetic acid Propanoic acid derivatives

IBUPROFEN
 The same mechanism & pharmacological actions of aspirin Except that it is reversible inhibitor for COX
enzymes. More potent as antiinflammatory than aspirin!!!
Ibuprofen, 2-(4-iso-butylphenyl)propionic acid (3.2.23), can be synthesized by various methods [88–

98]. The simplest way to synthesize ibuprofen is by the acylation of iso-butylbenzol by acetyl chloride.
The resulting iso-butylbenzophenone (3.2.21) is reacted with sodium cyanide, giving oxynitrile
(3.2.22), which upon reaction with hydroiodic acid in the presence of phosphorus is converted into 2-
(4-iso-butylphenyl)propionic acid (3.2.23), which subsequently undergoes phases of dehydration,
reduction, and hydrolysis.
Pharmacokinetics
Rapidly absorbed after oral ingestion.
Half-life 1-2 hours
Highly bound to plasma proteins
Excreted through kidney as metabolites
Diclofenac, 2-[(2,6-dichlorophenyl)-amino]-phenylacetic acid (3.2.42), is
synthesized from 2-chlorobenzoic acid and 2,6-dichloroaniline. The reaction of
these in the presence of sodium hydroxide and copper gives N-(2,6-
dichlorophenyl)anthranylic acid (3.2.38), the carboxylic group of which
undergoes reduction by lithium aluminum hydride. The resulting 2-[(2,6-
dicholorphenyl)-amino]-benzyl alcohol (3.2.39) undergoes further chlorination
by thionyl chloride into 2-[(2,6-dichlorophenyl)-amino]-benzylchloride (3.2.40)
and further, upon reaction with sodium cyanide converts into 2-[(2,6-
dicholorophenyl)-amino]benzyl cyanide (3.2.41). Hydrolysis of the nitrile
group leads to diclofenac (3.2.42) [107,108]
Clinical uses
 A) Analgesic
 B) Antipyretic
 C) Anti-inflammatory

• It is a shunt connecting the pulmonary artery to the D)Acute gouty arthritis
aortic arch  E) Patent ductus arteriosus
• Maintained by local PGE2 and PGI2
• Closes at birth • Failure to close – small doses of
NSAIDs (aspirin or indomethacin) – closes.
• NSAIDs is not used in late pregnancy in late

pregnancy – premature closure) Other action of
•NSAIDs: Aspirin can reduce diarrhea that occur

after radiation therapy. Sulindac , potent inhibitor of
Aldose reductase
Adverse effects
 1.Gastric upset (less frequent than aspirin).
 2.Fluid retention
 3.Hypersensetivity reactions
 4.Ocular disturbances
 5.Rare hematologic effects (agranulocytosis & aplastic
anaemia).
Contraindications
 1. Peptic ulcer
 2. Allergic patients to aspirin
 3. Kidney impairment
 4.Liver diseases
 5.Pregnancy
 6.Haemophilic patients
The concomitant administration of ibuprofen antagonizes the irrevesible platelet inhibition
of ASPIRIN (limit cardioprotective effect of aspirin).
.
 .
It is employed for acute and
long-term therapy for the
relief of symptoms of
osteoarthritis and
rheumatoid arthritis. It also
possesses uricosuric actions
and has been used in the
treatment of acute gout.
.
 .
Piroxicam synthesis
Piroxicam, 1,1-dioxid-4-hydroxy-2-methyl-N-2-pyradyl-2H-1,2-
benzothiazine-
3-carboxamide (3.2.78), is synthesized from saccharin (3.2.70). It usually
comes from toluene, which is sulfonated by chlorosulfonic acid, forming
isomeric 4- and 2-toluenesulfonyl chlorides. The isomeric products are
separated by freezing (chilling). The liquid part, 2-toluenesulfonyl chloride
(3.2.68) is separated from the crystallized 4-toluenesulfochloride and reacted
with ammonia, giving 2-toluenesulfonylamide (3.2.69). Oxidation of the
product with sodium permanganate or chromium (VI) oxide in sulfuric acid
gives saccharin—o-sulfobenzoic acid imide.]
The reaction of saccharin with sodium hydroxide results in substitution of
the imide hydrogen atom of saccharin with sodium, giving a sodium salt
(3.2.75). The resulting product is reacted with methyl chloroacetate, giving
the saccharin-substituted acetic acid methyl ester (3.2.76). Upon reaction
with sodium methoxide in dimethylsulfoxide, the product undergoes
rearrangement into 1,1-dioxide 3-methoxycarbonyl-3,4-dihydro-2-H-1,2-
benzothiazin-4- one (3.2.77). This product is methylated at the nitrogen
atom using methyl iodide, giving (3.2.78). Finally, reaction of the resulting
product with 2-aminopyridine gives piroxicam
(3.2.79)
SAR of piroxicam
The most active analogues have substituents CH3 on the nitrogen
and electron withdrawing substituents on the anilide phenyl
groups, such as Cl and CF3.
The introduction of heterocyclic ring in the amide chain
signiﬁcantly increases the anti-inﬂammatory activity.
Example—2-thiazolyl derivative sudoxicam is more potent than
indomethacin.
The most active benzothiazine have acidities in the pKa range of
6–8.
 Mechanism of actions:
 A) Non-selective inhibitors to COX1 & COX2
 B) Traps free radicals
 C) Inhibits polymorphonuclear leukocytes migration
 D) Inhibits lymphocyte function.
 Well absorbed orally
 Half- Life 45 hours
 Given once daily
Adverse effects
 Less frequent gastric upset (20%).
 Dizziness.
 Tinnitus.
 Headache.
 Allergy.
Quinoline Derivatives
Cinchophen INN, BAN, USAN,
Its antipyretic actions are very much akin to those of the
salicylates. Its major pharmacological
action was in the control and management of chronic gout
and rheumatic conditions, but by virtue of its relatively
high level of toxic effects, such as : hepatic dysfunction
ultimately leading to acute jaundice
Synthesis of Cincophin
The Schiff’s base is prepared by the

interaction of aniline and benzaldehyde
with the elimination
of a molecule of water. The resulting
base is treated with the lactim-form of
pyruvic acid thereby resulting into the
formation of cinchophen.

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NSAIDS

Indole acetic acid Propanoic acid derivatives

Ibuprofen, 2-(4-iso-butylphenyl)propionic acid (3.2.23), can be synthesized by various methods [88–

• NSAIDs is not used in late pregnancy in late

•NSAIDs: Aspirin can reduce diarrhea that occur

The Schiff’s base is prepared by the

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