General Description
Crystals.
Reactivity Profile
A weak organic acid.
Air & Water Reactions
Practically insoluble in water. Decomposes in alkali.
Fire Hazard
Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated.
Description
Aqueous solutions of indomethacin are not stable because of the ease of hydrolysis of the p-chlorobenzoyl group.
The original synthesis of indomethacin by Shen et al. involved the formation of 2-methyl-5-methoxyindole acetic
acid and subsequent
acylation after protection of the carboxyl group as the t-butyl ester. It was introduced in the United States in 1965. It
is still one of the most potent NSAIDs in use. It also is a more potent antipyretic than either aspirin or
acetaminophen, and it possesses approximately 10 times the analgetic potency of aspirin.
Chemical Properties
Crystalline Solid
Originator
Indocin,MSD,US,1965
Indications
Indomethacin (Indocin) is used in the treatment of
acute gouty arthritis, rheumatoid arthritis, ankylosing
spondylitis, and osteoarthritis. It is not recommended
for use as a simple analgesic or antipyretic because of its
potential for toxicity.While indomethacin inhibits both
COX-1 and COX-2, it is moderately selective for COX-
1. It produces more CNS side effects than most of the
other NSAIDs. Severe headache occurs in 25 to 50% of
patients; vertigo, confusion, and psychological disturbances
occur with some regularity. GI symptoms also
are more frequent and severe than with most other NSAIDs. Hematopoietic side effects (e.g., leukopenia,
hemolytic anemia, aplastic anemia, purpura, thrombocytopenia,
and agranulocytosis) also may occur. Ocular
effects (blurred vision, corneal deposits) have been observed
in patients receiving indomethacin, and regular
ophthalmological examinations are necessary when the
drug is used for long periods. Hepatitis, jaundice, pancreatitis,
and hypersensitivity reactions also have been
noted.
Preparation
acylation of sodium 2-(4-
methoxyphenyl)hydrazine-1-sulfonate with
4-chlorobenzoyl chloride followed by
heating yields 1-(4- chlorobenzoyl)-1-(4-
methoxyphenyl)hydrazine. Condensation with
levulinic acid in a Fischer indole synthesis affords indomethacin.
Manufacturing Process
(A) 2-Methyl-5-Merhoxy-3-Indolylacetic Anhydride: Dicyclohexylcarbodiimide
(10 g, 0.049 mol) is dissolved in a solution of 2-methyl-5-methoxy-3-indolylacetic acid (22 g, 0.10 mol) in 200 ml of THF, and the solution is
allowed to stand at room temperature for 2 hours. The precipitated urea is
removed by filtration, and the filtrate is evaporated in vacuo to a residue and
flushed with Skellysolve 6. The residual oily anhydride is used without
purification in the next step.
(B) t-Butyl 2-Methyl-5-Merhoxy-3-Indolylacetate: t-Butyl alcohol (25 ml) and
fused zinc chloride (0.3 g) are added to the anhydride from Part A. The
solution is refluxed for 16 hours and excess alcohol is removed in vacuo. The
residue is dissolved in ether, washed several times with saturated bicarbonate,
water, and saturated salt solution. After drying over magnesium sulfate, the
solution is treated with charcoal, evaporated, and flushed several times with
Skellysolve B for complete removal of alcohol. The residual oily ester (18 g,
93%) is used without purification.
(C) t-Buryl 1-p-Chlorobenzoyl-2-Methyl-5-Mefhoxy-3-Indolylacetate: A stirred
solution of ester (18 g, 0.065 mol) in dry DMF (450 ml) is cooled to 4°C in an
ice bath, and sodium hydride (4.9 g, 0.098 mol, 50% susp.) is added in
portions. After 15 minutes, p-chlorobenzoyl chloride (15 g, 0.085 mol) is
added dropwise during 10 minutes, and the mixture is stirred for 9 hours
without replenishing the ice bath. The mixture is then poured into one liter of
5% acetic acid, extracted with a mixture of ether and benzene, washed
thoroughly with water, bicarbonate, saturated salt, dried over magnesium
sulfate, treated with charcoal, and evaporated to a residue which partly
crystallizes. This is shaken with ether, filtered and the filtrate is evaporated to
a residue (17 g) which solidifies after being refrigerated overnight.
The crude product is boiled with 300 ml of Skellysolve 6, cooled to room
temperature, decanted from some gummy material, treated with charcoal,
concentrated to 100 ml, and allowed to crystallize. The product thus obtained
(10 g) is recrystallized from 50 ml of methanol and gives 4.5 g of analytically
pure material, MP 103° to 104°C.
(D) 1 -p-Chlorobenzoyl-2-Methyl-5-Methoxy-3-Indolylacetic Acid: A mixture of
1 g ester and 0.1 g powdered porous plate is heated in an oil bath at 210°C
with magnetic stirring under a blanket of nitrogen for about 2 hours. No
intensification of color (pale yellow) occurs during this period. After cooling
under nitrogen, the product is dissolved in benzene and ether, filtered, and
extracted with bicarbonate. The aqueous solution is filtered with suction to
remove ether, neutralized with acetic acid, and then acidified weakly with
dilute hydrochloric acid. The crude product (0.4 g, 47%) is recrystallized from
aqueous ethanol and dried in vacuo at 65°C: MP 151°C.
Brand name
Indocin (Merck);Argan.
Therapeutic Function
Antiinflammatory
World Health Organization (WHO)
Indometacin was introduced in 1963 and it is one of the first
NSAIDs. Convulsions are rarely reported in relation with the use of this group of
agents. Indometacin farnesil is a pro-drug of indometacin, and the occurrence of
gastro-intestinal adverse effects could be expected. See also under nonsteroidal
antiinflammatory agents.
Biological Functions
Indomethacin (Indocin) is an acetic acid derivative related
functionally to sulindac (Clinoril), a prodrug with
a long half-life, and etodolac (Lodine).They are metabolized
in the liver and excreted as metabolites in the bile and via the kidney. They are potent inhibitors of
COX and thus extremely effective antiinflammatory
agents.
Pharmaceutical Applications
Indomethacin is a nonsteroidal anti-inflammatory agent used in pain and moderate to severe
inflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase)
inhibitor and therefore interrupts the production of prostaglandins.
A series of new silicon compounds, based on the structure of indomethacin, have been synthesised and
are under investigation as novel anticancer agents. The carboxyl group of indomethacin was reacted with
a series of amino-functionalised silanes. The resulting products have been shown to be significantly more
lipophilic and more selective to COX-2. Furthermore, in vitro testing has shown an increased uptake of the
new compounds at the tumour site. The silane-functionalised indomethacin derivatives exhibited a 15-fold
increased antiproliferative effect when tested against pancreatic cancer .
Pharmaceutical Applications
Indomethacinis a nonsteroidal anti-inflammatory agent used in pain and moderate to severe
inflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase)
inhibitor and therefore interrupts the production of prostaglandins.
Biological Activity
Cyclooxgenase (COX) inhibitor; displays selectivity for COX-1 (IC 50 values are 230 and 630 nM for human COX-1 and COX-2 respectively). Widely used anti-inflammatory agent.
Biochem/physiol Actions
Cyclooxygenase (COX) inhibitor that is relatively selective for COX-1.
Clinical Use
Indomethacin is available for the short-term treatment of acute gouty arthritis, acute pain of ankylosing spondylitis,
and osteoarthritis. An injectable form to be reconstituted also is available as the sodium trihydrate salt for IV use in
premature infants with patent ductus arteriosus. Because of its ability to suppress uterine activity by inhibiting
prostaglandin biosynthesis, indomethacin also has an unlabeled use to prevent premature labor.
Synthesis
Indomethacin, 1-(n-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetic acid
(3.2.51), has been synthesized by various methods. All of the proposed methods of synthesis start with 4-methoxyphenylhydrazine. According to the first method, a reaction is done to
make indole from phenylhydrazone (3.2.46) by Fischer?ˉs method, using levulinic acid
methyl ester as a carbonyl component, hydrogen chloride as a catalyst, and ethanol as a solvent, to give the methyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.47). This
product is hydrolyzed by an alkali into 5-methoxy-2-methyl-3-indolylacetic acid (3.2.48),
from which tert-butyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.49) is formed
by using tert-butyl alcohol and zinc chloride in the presence of dicyclohexylcarbodiimide.
The resulting product undergoes acylation at the indole nitrogen atom by p-chorobenzoyl
chloride in dimethylformamide, using sodium hydride as a base. The resulting tert-butyl
ester of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid (3.2.50), further
undergoes thermal decomposition to the desired acid, indomethacin (3.2.51) [111,112].
Drug interactions
Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:
antagonism of hypotensive effect; increased risk of
nephrotoxicity and hyperkalaemia.
Analgesics: avoid concomitant use of 2 or more
NSAIDs, including aspirin (increased side effects);
avoid with ketorolac (increased risk of side effects
and haemorrhage).
Antibacterials: possibly increased risk of convulsions
with quinolones.
Anticoagulants: effects of coumarins and
phenindione enhanced; possibly increased risk of
bleeding with heparins, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas
enhanced.
Antiepileptics: effects of phenytoin enhanced.
Antipsychotics: possible severe drowsiness with
haloperidol.
Antivirals: increased risk of haematological toxicity
with zidovudine; concentration possibly increased by
ritonavir.
Ciclosporin: increased risk of nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate.
Diuretics: increased risk of nephrotoxicity,
hyperkalaemia with potassium-sparing diuretics;
antagonism of diuretic effect
.
Lithium: lithium excretion reduced.
Pentoxifylline: possibly increased risk of bleeding.
Probenecid: excretion of indometacin reduced.
Tacrolimus: increased risk of nephrotoxicity.
Metabolism
Indometacin is metabolised in the liver primarily by
demethylation and deacetylation; it also undergoes
glucuronidation and enterohepatic circulation.
Indometacin is mainly excreted in the urine,
approximately 60%, the pH of the urine can affect this
amount. Lesser amounts are excreted in the faeces.
storage
4°C, protect from light
