Guidechem | China Chemical Manufacturers,suppliers,B2B Marketplace
Encyclop..
  • Products
  • Encyclopedia
  • Buy offers
  • Suppliers
Home> Encyclopedia >   /  Antipyretic Analgesics and NSAIDs  /  Pharmaceutical Intermediates  /  Pharmaceutical
Indometacin structure
Indometacin structure

Indometacin

Iupac Name:2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid
CAS No.: 53-86-1
Molecular Weight:357.78764
Modify Date.: 2022-10-30 19:14
Introduction: 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 aceticacid and subsequentacylation after protection of the carboxyl group as the t-butyl ester. It was introduced in the United States in 1965. Itis still one of the most potent NSAIDs in use. It also is a more potent antipyretic than either aspirin oracetaminophen, and it possesses approximately 10 times the analgetic potency of aspirin. View more+
1. Names and Identifiers
1.1 Name
Indometacin
1.2 Synonyms

1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic Acid 1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetic acid 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid Amuno AURORA KA-6542 Bonidin Catlep Dolovin EINECS 200-186-5 Inacid Indacin INDOCIN INDOMETACINE Indomethacin indomethacin crystalline indomethacin methanol solution indomethacin usp Lausit MFCD00057095 Tannex Vonum

1.3 CAS No.
53-86-1
1.4 CID
3715
1.5 EINECS(EC#)
200-186-5
1.6 Molecular Formula
C19H16ClNO4 (isomer)
1.7 Inchi
InChI=1S/C19H16ClNO4/c1-11-15(10-18(22)23)16-9-14(25-2)7-8-17(16)21(11)19(24)12-3-5-13(20)6-4-12/h3-9H,10H2,1-2H3,(H,22,23)
1.8 InChkey
CGIGDMFJXJATDK-UHFFFAOYSA-N
1.9 Canonical Smiles
CC1=C(C2=C(N1C(=O)C3=CC=C(C=C3)Cl)C=CC(=C2)OC)CC(=O)O
1.10 Isomers Smiles
CC1=C(C2=C(N1C(=O)C3=CC=C(C=C3)Cl)C=CC(=C2)OC)CC(=O)O
2. Properties
3.1 Density
1.32
3.1 Melting point
155-162℃
3.1 Boiling point
499.4 °C at 760 mmHg
3.1 Refractive index
1.6800 (estimate)
3.1 Flash Point
255.8 °C
3.1 Precise Quality
357.07700
3.1 PSA
68.53000
3.1 logP
3.92730
3.1 Solubility
ethanol: 50?mg/mL, clear, yellow-green
3.2 Appearance
White crystalline powder
3.3 Storage
Light Sensitive. Ambient temperatures.
3.4 Chemical Properties
Crystalline Solid
3.5 Color/Form
PALE-YELLOW TO YELLOW-TAN, CRYSTALLINE POWDER
CRYSTALS EXHIBIT POLYMORPHISM
3.6 Odor
Odorless, or has slight odor
3.7 pKa
4.5(at 25℃)
3.8 Water Solubility
ethanol: 50?mg/mL, clear, yellow-green
3.9 Spectral Properties
MAX ABSORPTION (ETHANOL): 230, 260, 319 NM (E= 20,800, 16,200, 6,290)
Intense mass spectral peaks: 111 m/z, 139 m/z, 313 m/z
3.10 Stability
Stable. Incompatible with strong oxidizing agents.
3.11 StorageTemp
Store at RT
3. Use and Manufacturing
4.1 Definition
The antiinflammatory drug indomethacin.
4.2 General Description
From the time of its introduction in 1965, indomethacin(Indocin) has been widely used as an analgesic to relieve inflammatorypain associated with RA, OA and ankylosingspondylitis, and, to a lesser extent, in gout. Although both itsanalgesic and anti-inflammatory activities are well established,its use is often limited because of frequent GI distressand potential drug interactions, especially with warfarinfurosemide, and lithium (i.e., it elevates blood levels oflithium as a result of reducing renal blood flow and thereforeincreases lithium toxicities).Following oral administration, indomethacin is rapidlyabsorbed and is 90% protein bound at therapeutic plasmaconcentrations. The drug has a biological half-life ofabout 5 to 10 hours and a plasma clearance of 1 to 2.5 ml/kgper minute. It is metabolized to its inactive, O-desmethyl,N-deschlorobenzoyl-, and O-desmethyl, N-deschlorobenzoylindomethacinmetabolites.
4.3 Usage
1.The product is anti-inflammatory, and antipyretic effect is obvious, mainly is used for salicylates to tolerance or the effect is not significant rheumatism and arthritis, ankylosing light spondylitis, osteoarthritis.2.Non steroid anti-inflammatory analgesic
4. Safety and Handling
5.1 Symbol
GHS06;
5.1 Hazard Codes
T+
5.1 Signal Word
DANGER
5.1 Risk Statements
R28
5.1 Safety Statements
S28;S36/37;S45
5.1 Exposure Standards and Regulations
Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
5.2 Packing Group
I
5.2 Octanol/Water Partition Coefficient
LogP= 4.27 at pH 2.0
5.3 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.
5.4 Hazard Class
6.1
5.4 Hazard Declaration
H300
5.4 DisposalMethods
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.
5.5 RIDADR
UN 2811
5.5 Caution Statement
Missing Phrase - N15.00950417
5.5 WGK Germany
3
5.5 RTECS
NL3500000
5.5 Report

Reported in EPA TSCA Inventory.

5.6 Safety

A poison by ingestion, intravenous, intraperitoneal, and subcutaneous routes. Human systemic effects by ingestion: aplastic anemia, changes in kidney tubules, decreased urine volume, diarrhea, fibrous hepatitis, hemorrhage, hypermotility, liver changes, necrotic stomach changes, retinal changes. Human teratogenic effects by ingestion and intravenous routes: developmental abnormalities of the respiratory system and urogenital system, homeostasis, other neonatal effects. Experimental teratogenic and reproductive effects. Mutation data reported. When heated to decomposition it emits very toxic Cl? and NOx.
Hazard Codes of Indomethacin (CAS NO.53-86-1):?T+,Xi
Risk Statements: 28-36/37/38?
R28: Very toxic if swallowed.?
R36/37/38: Irritating to eyes, respiratory system and skin.
Safety Statements: 28-36/37-45-26?
S28: After contact with skin, wash immediately with plenty of soap-suds.?
S36/37: Wear suitable protective clothing and gloves.?
S45: In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
RIDADR: UN 2811 6.1/PG 1
WGK Germany: 3
F: 8-10
HazardClass:? 6.1
PackingGroup:? I

5.7 Specification

?Synonyms of Indomethacin (CAS NO.53-86-1) are (1-p-Chlorobenzoyl-5-methoxy-2-methylindol-3-yl)acetic acid ; 1-(p-Chlorbenzoyl)-5-methoxy-2-methylindol-3-essigsaeure ; 1-(p-Chlorbenzoyl)-5-methoxy-2-methylindol-3-essigsaeure [German] ; 1-(p-Chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetic acid ; 1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid ; 1-p-Cloro-benzoil-5-metoxi-2-metilindol-3-acido acetico ; 1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl- ; Indole-3-acetic acid, 1-(p-chlorobenzoyl)-5-methoxy-2-methyl- .

5.8 Toxicity

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
cat LD50 oral 320mg/kg (320mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 30, Pg. 1398, 1980.
cat LDLo intravenous 20200ug/kg (20.2mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 33, Pg. 726, 1983.
dog LD50 intravenous 100mg/kg (100mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 30, Pg. 1398, 1980.
dog LD50 oral 160mg/kg (160mg/kg) ? Oyo Yakuri. Pharmacometrics. Vol. 2, Pg. 70, 1968.
guinea pig LD skin > 100mg/kg (100mg/kg) BEHAVIORAL: EXCITEMENT Yakuri to Chiryo. Pharmacology and Therapeutics. Vol. 14, Pg. 3185, 1986.
guinea pig LD50 intraperitoneal 143mg/kg (143mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 30, Pg. 1398, 1980.
guinea pig LD50 intravenous 180mg/kg (180mg/kg) ? Journal de Pharmacologie. Vol. 2, Pg. 259, 1971.
guinea pig LD50 oral 100mg/kg (100mg/kg) ? Oyo Yakuri. Pharmacometrics. Vol. 2, Pg. 70, 1968.
hamster LD50 oral 81mg/kg (81mg/kg) ? Archives of Toxicology, Supplement. Vol. 7, Pg. 365, 1984.
human TDLo oral 113mg/kg/8W-I (113mg/kg) GASTROINTESTINAL: "HYPERMOTILITY, DIARRHEA"

GASTROINTESTINAL: OTHER CHANGES
Arzneimittel-Forschung. Drug Research. Vol. 33, Pg. 636, 1983.
infant TDLo intravenous 200ug/kg (0.2mg/kg) BLOOD: HEMORRHAGE Journal of Pediatrics. Vol. 107, Pg. 312, 1985.
infant TDLo oral 400ug/kg/2D-I (0.4mg/kg) GASTROINTESTINAL: NECROTIC GHANGES Journal of Pediatrics. Vol. 107, Pg. 484, 1985.
mammal (species unspecified) LD50 oral 8mg/kg (8mg/kg) ? Indian Journal of Medical Research. Vol. 81, Pg. 621, 1985.
man LDLo oral 15mg/kg/2W-I (15mg/kg) BLOOD: APLASTIC ANEMIA Israel Journal of Medical Sciences. Vol. 17, Pg. 433, 1981.
man TDLo multiple routes 3557mg/kg/5Y- (3557mg/kg) SENSE ORGANS AND SPECIAL SENSES: "RETINAL CHANGES (PIGMENTARY DEPOSITIONS, RETINITIS, OTHER): EYE" American Journal of Ophthalmology. Vol. 73, Pg. 846, 1972.
man TDLo oral 714ug/kg (0.714mg/kg) BEHAVIORAL: GENERAL ANESTHETIC

BEHAVIORAL: ATAXIA

BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
Allergy. Vol. 54, Pg. 90, 1999.
man TDLo oral 4286ug/kg/2D- (4.286mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE" Postgraduate Medical Journal. Vol. 72, Pg. 186, 1996.
man TDLo oral 22500ug/kg/3W (22.5mg/kg) LIVER: "HEPATITIS, FIBROUS (CIRRHOSIS, POST-NECROTIC SCARRING)"

LIVER: OTHER CHANGES
British Medical Journal. Vol. 3, Pg. 155, 1967.
man TDLo oral 22500ug/kg/3W (22.5mg/kg) GASTROINTESTINAL: ULCERATION OR BLEEDING FROM LARGE INTESTINE Annals of Pharmacotherpy. Vol. 29, Pg. 883, 1994.
man TDLo rectal 2586mg/kg/3.5 (2586mg/kg) SENSE ORGANS AND SPECIAL SENSES: "RETINAL CHANGES (PIGMENTARY DEPOSITIONS, RETINITIS, OTHER): EYE" American Journal of Ophthalmology. Vol. 73, Pg. 846, 1972.
man TDLo unreported 499mg/kg/87W- (499mg/kg) BEHAVIORAL: STIFFNESS

KIDNEY, URETER, AND BLADDER: HEMATURIA
Arthritis and Rheumatism. Vol. 20, Pg. 917, 1977.
mouse LD50 intramuscular 18200ug/kg (18.2mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 30, Pg. 1398, 1980.
mouse LD50 intraperitoneal 10mg/kg (10mg/kg) ? Archivos de Farmacologia y Toxicologia. Vol. 8, Pg. 201, 1982.
mouse LD50 intravenous 30mg/kg (30mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 19, Pg. 1198, 1969.
mouse LD50 oral 11841ug/kg (11.841mg/kg) ? German Offenlegungsschrift Patent Document. Vol. #3005827,
mouse LD50 subcutaneous 18300ug/kg (18.3mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 30, Pg. 1398, 1980.
rabbit LD50 oral 135mg/kg (135mg/kg) ? Drugs in Japan Vol. 6, Pg. 90, 1982.
rat LD skin > 250mg/kg (250mg/kg) ? Yakuri to Chiryo. Pharmacology and Therapeutics. Vol. 14, Pg. 3185, 1986.
rat LD50 intramuscular 26300ug/kg (26.3mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 30, Pg. 1398, 1980.
rat LD50 intraperitoneal 13mg/kg (13mg/kg) ? Toxicology and Applied Pharmacology. Vol. 38, Pg. 127, 1976.
rat LD50 intravenous 21mg/kg (21mg/kg) ? Arzneimittel-Forschung. Drug Research. Vol. 31, Pg. 655, 1981.
rat LD50 oral 2420ug/kg (2.42mg/kg) GASTROINTESTINAL: ULCERATION OR BLEEDING FROM STOMACH Arzneimittel-Forschung. Drug Research. Vol. 25, Pg. 1526, 1975.
rat LD50 rectal 31900ug/kg (31.9mg/kg) ? Yakuri to Chiryo. Pharmacology and Therapeutics. Vol. 14, Pg. 2259, 1986.
rat LD50 subcutaneous 12mg/kg (12mg/kg) ? Oyo Yakuri. Pharmacometrics. Vol. 2, Pg. 70, 1968.
women TDLo oral 2098ug/kg/1D- (2.098mg/kg) KIDNEY, URETER, AND BLADDER: "CHANGES IN TUBULES (INCLUDING ACUTE RENAL FAILURE, ACUTE TUBULAR NECROSIS)"

KIDNEY, URETER, AND BLADDER: URINE VOLUME DECREASED
Southern Medical Journal. Vol. 78, Pg. 1390, 1985.
women TDLo oral 10mg/kg (10mg/kg) BEHAVIORAL: COMA Japanese Journal of Toxicology. Vol. 12, Pg. 337, 1999.

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 2

Skin sensitization, Category 1

Reproductive toxicity, Category 1B

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word

Danger

Hazard statement(s)

H300 Fatal if swallowed

H317 May cause an allergic skin reaction

H360 May damage fertility or the unborn child

Precautionary statement(s)
Prevention

P264 Wash ... thoroughly after handling.

P270 Do not eat, drink or smoke when using this product.

P261 Avoid breathing dust/fume/gas/mist/vapours/spray.

P272 Contaminated work clothing should not be allowed out of the workplace.

P280 Wear protective gloves/protective clothing/eye protection/face protection.

P201 Obtain special instructions before use.

P202 Do not handle until all safety precautions have been read and understood.

Response

P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/\u2026

P321 Specific treatment (see ... on this label).

P330 Rinse mouth.

P302+P352 IF ON SKIN: Wash with plenty of water/...

P333+P313 If skin irritation or rash occurs: Get medical advice/attention.

P362+P364 Take off contaminated clothing and wash it before reuse.

P308+P313 IF exposed or concerned: Get medical advice/ attention.

Storage

P405 Store locked up.

Disposal

P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

9. Other Information
9.0 Merck
14,4968
9.1 BRN
497341
9.2 anti-inflammatory analgesic
Indomethacin is a kind of stronger corticoid anti-inflammatory and antipyretic and analgesic, by inhibiting cyclooxygenase reducing the synthesis of prostaglandin (PG), to prevent the formation of the nere impulses, inflammation tissue inhibiting inflammatory reaction, including inhibition of leukocyte chemotaxis and lysosomal enzyme release, etc., and produce antipyretic, analgesic and anti-inflammatory effects. Indomethacin anti-inflammatory, antipyretic effect is very strong, its anti-inflammatory effect is better than bute, 84 times better than hydrocortisone, and sugar cortical hormone, used in combination with aspirin, bute, can reduce their dosage, toxic and side effects, improve curative effect; Second is antipyretic effect, 10 times than amidopyrine ;its analgesic action is weak , only to the inflammatory pain has obvious analgesic effect, but the effect is good for inflammatory pain than Baotai loose, analgin and salicylic acid. Clinical is mainly used for the salicylic acid, drugs are less tolerance or curative effect is not obvious in the acute and chronic rheumatic or rheumatoid arthritis, ankylosing spondylitis, slippery bursa phlogistic, tenosynovitis, articular capsulitis, osteoarthritis and acute gout and cancerous pain, etc.In recent years, the researchers try to use indomethacin biliary colic, dysmenorrhea, migraine, glomerulonephritis, polyuria, salmonella gastroenteritis, orthostatic hypotension, bart syndrome and so on, all have good curative effect.It can also be used to treat eye pigment meningitis, keratitis, scleritis, glaucoma and fever caused by cancer or other difficult to control the fever. Dermatologist for lupus erythematosus (sle), white plug syndrome, scleroderma, nodular erythema, herpes zoster, joint type of psoriasis, etc. photosensitive dermatitis induced by topical treatment of eczema, allergic dermatitis, and local pain.
9.3 Pharmacokinetics
Oral medicine absorbed quickly and completely, can absorb more than 90% of the dosage of food with in 4 h, take medicine of acid containing aluminum and magnesium can be slightly slowed absorption, plasma protein conjugation rate is about 99%. After oral 25 mg, tmax is 1~4 h, the blood medicine peak concentration (Cmax) is 1.4 mu g/ml, when 50 mg, Cmax is 2.8 mu g/ml; Half-life (t1/2) of an average is 4.5 h, premature extended obviously. A small amount of indomethacin can through the blood-brain barrier. And through the placenta.This article in the liver metabolism go methyl chloride and chlorobenzene formyl chloride, and can be hydrolyzed into recycle indomethacin to absorb. Renal excretion from 60%, 10%~20% in prototype discharge; Part with droppings.33% from the bile excretion, 1.5% were prototype;In the breast milk also has a discharge (up to 0.5~2.0 mg daily).This product can not be dialysis to remove.
9.4 usage and dosage
1.Anti-rheumatism: adult dosage: oral: early quantity from 25 to 50 mg each time, 2~4 times a day, immediately take at food service or after a meal. Such as good tolerance, the daily dosage can be increased from 25 to 50 mg per week, the most mount should not be more than 200 mg a day. Arthritis patients such as persistent pain at night or morning stiffness, can give quantity of 100 mg in bed all day.
2. Resistance to gout: oral: At the beginning quantity is 100 mg once, then 50 mg, three times a day, until the pain relief, and then gradually reduced as soon as possible, until the drug withdrawal.
3. Antifebrile: adult dosage: oral: 25~50 mg each time, 3~4 times daily.Rectal drug delivery: every time 50 mg, 50 to 100 mg per day. Pediatric dosage: oral: 0.5~1 mg/kg each time, 3 times a day.
9.5 Side effects
Adverse reactions of Indomethacin are high incidence , common adverse reactions are as follows:
1. nausea, vomiting, abdominal pain, diarrhea, anorexia, serious ulcers can occur and cause bleeding and perforation. After dinner, that can reduce the incidence.
2. common headache, dizziness, fatigue, occasional seizures, mental derangement, syncope, etc. Should be paid attention to in due course.
3.the skin pruritus, erythema, urticaria, and one of the few of asthma, breathing problems and even breathing, circulation inhibition.
4.Inhibition of hematopoietic system such as granulocytopenia, aplastic anemia, thrombocytopenia, and so on. Although rare, but more severe consequences.There are also some other similar to aspirin reaction, notes are also the same.
9.6 matters need attention
1.indomethacin and aspirin have cross allergic. Caused by aspirin allergic asthmatic patients, the application of this product can be induced bronchospasm. Other non steroidal anti-inflammatory drugs to which are allergic may also be allergic to this product.
2.This product is contraindicated with active ulcer disease, ulcerative colitis and history, epilepsy, Parkinson's disease, mental disease, liver and kidney function, the goods or aspirin or other nonsteroidal anti-inflammatory drug allergic person, angioedema or bronchial asthma. This product for the last 3 months of pregnancy can make fetal ductus arteriosus closure and result in persistent pulmonary hypertension, so pregnant women, disabled. This product can be discharged from the milk, breast-feeding women also disable.
3.This product is used for patients with cardiac insufficiency, and hypertension (because this product sodium can lead to water retention, hemophilia and other patients with hemorrhagic disease (because this product can make the bleeding time prolonged, aggravate bleeding tendency), aplastic anemia, granulocytopenia disease patients (this product is inhibition of hematopoietic system).Age < 14 years old children should not be commonly used drug, When it is applied,it should be closely observed.Easily occur in elderly patients with renal toxicity, which should also be careful.
4.Because indomethacin has inhibition to the platelet aggregation, which can make the bleeding time prolonged, the role after the drug was stopped sustainable. During the blood urea nitrogen and serum creatinine,levels are also often higher. During the medication,it should be regularly check routine blood and liver and kidney function. Case reports referred to in this article that the product can lead to corneal composure and retinal change (including macular degeneration), if it comes to the blurred vision eye exams should be done immediately.
5.Drug overdose (especially when dose > 150 mg a day) is easy to cause toxic reactions such as nausea, vomiting, tension headaches, sleepiness, spirit, behavior disorders, etc., with vomiting or gastric lavage, symptomatic and supportive treatment.
9.7 chemical property
White or slightly yellow crystalline powder. Melting point is 158-162℃, soluble in acetone, slightly soluble in ethanol, chloroform, ether, almost insoluble in water.
9.8 Uses
1.The product is anti-inflammatory, and antipyretic effect is obvious, mainly is used for salicylates to tolerance or the effect is not significant rheumatism and arthritis, ankylosing light spondylitis, osteoarthritis.
2.Non steroid anti-inflammatory analgesic
9.9 Used in Particular Diseases
Acute Gouty Arthritis:
Dosage and Frequency: 25–50 mg four times a day for 3 days, then taper to twice daily for 4–7 days
9.10 methods of production
Para aminophenylmethylether is through diazotization, reduction, cyclization, hydrolysis, acidification to get indomethacin.
9.11 Category
Poisonous
9.12 classification of toxicity
Highly toxic.
9.13 acute toxicity
Oral administration: LD50 2.42 mg/kg in rats; oral administration of 11.84 mg/kg of LD50: in mice.
9.14 Combustible hazard characteristics
Open flame fuel; high heat decomposition of toxic chloride and nitrogen oxide gas.
9.15 Storage and transportation characteristics
Low temperature and dry air ventilation; and oxidant, food additives separately.
9.16 Extinguisher
Foam, fog water, sand, carbon dioxide.
9.17 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.
9.18 Chemical Properties
Crystalline Solid
9.19 Originator
Indocin,MSD,US,1965
9.20 Uses
Indomethacin is used in rheumatoid arthritis, nonspecific infectious polyarthritis, gouty arthritis, osteoarthritis, ankylosing spondylitis, arthrosis, back pain, neuralgia, myalgia, and other diseases accompanied by inflammation.
9.21 Uses
Inhibits cyclooxygenase (IC50=0.1uM) selectively over liposygenases (IC50=100uM for 5-,12- and 15-LO). A clinically useful NAISD
9.22 Uses
antiinflammatory, antipyretic, analgesic
9.23 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.
9.24 Definition
The antiinflammatory drug indomethacin.
9.25 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.
9.26 Brand name
Indocin (Merck);Argan.
9.27 Therapeutic Function
Antiinflammatory
9.28 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.
9.29 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.
9.30 General Description
From the time of its introduction in 1965, indomethacin(Indocin) has been widely used as an analgesic to relieve inflammatorypain associated with RA, OA and ankylosingspondylitis, and, to a lesser extent, in gout. Although both itsanalgesic and anti-inflammatory activities are well established,its use is often limited because of frequent GI distressand potential drug interactions, especially with warfarinfurosemide, and lithium (i.e., it elevates blood levels oflithium as a result of reducing renal blood flow and thereforeincreases lithium toxicities).
Following oral administration, indomethacin is rapidlyabsorbed and is 90% protein bound at therapeutic plasmaconcentrations. The drug has a biological half-life ofabout 5 to 10 hours and a plasma clearance of 1 to 2.5 ml/kgper minute. It is metabolized to its inactive, O-desmethyl,N-deschlorobenzoyl-, and O-desmethyl, N-deschlorobenzoylindomethacinmetabolites.
9.31 General Description
Crystals.
9.32 Air & Water Reactions
Practically insoluble in water. Decomposes in alkali.
9.33 Reactivity Profile
A weak organic acid.
9.34 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.
9.35 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 .
9.36 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.
9.37 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.
9.38 Biochem/physiol Actions
Cyclooxygenase (COX) inhibitor that is relatively selective for COX-1.
9.39 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.
9.40 Side effects
All of these drugs produce analgesic effects, antipyresis, and antiinflammatory effects.Due to the high incidence of gastric irritation, headache, nausea, and other side effects, including hematological effects and coronary vasoconstriction, they are not useful as an initial treatment for pain. GI irritation and ulceration occur to a lesser extent with etodolac. Indomethacin is useful in the treatment of acute gout, osteoarthritis, ankylosing spondylitis, and acceleration of the closure of the ductus arteriosus in premature infants. The tocolytic effects of indomethacin to prevent preterm labor are the result of its effects on prostaglandin synthesis. However, the toxicity of the drug limits such application, since it increases fetal morbidity. Indomethacin is contraindicated in pregnancy, in asthmatics, and in those with gastric ulcers or other ulceration of the GI tract. Indomethacin may increase the symptoms associated with depression or other psychiatric disturbances and those associated with epilepsy and Parkinson’s disease. The drug should be used with caution in such patients.
9.41 Chemical 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’s 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].

9.42 Usage
It is a non-steroidal anti-inflammatory drug, it is used in the treatment of musculoskeletal and joint disorders including osteoarthritis, rheumatoid arthritis, gout, bursitis and tendinitis. It finds its application as gout suppressant, non-steroidal anti-inflammatory drug and analgesic. It also plays many biological roles. Additionally, Indomethacin displays adipogenic actions via binding and activation of PPARγ (peroxisome proliferator-activated receptor γ), a ligand-activated transcription factor known to play an important role in adipogenesis.
9.43 Usage
Non-selective cyclooxygenase inhibitorIndomethacin acts as an antiinflammatory, antipyretic and analgesic. It serves as an inhibitor cyclooxygenase such as Cox-1 and Cox-2. In addition to this, it is used as a prescription medication in order to reduce fever, stiffness, swelling and pain.
10. Computational chemical data
  • Molecular Weight: 357.78764g/mol
  • Molecular Formula: C19H16ClNO4
  • Compound Is Canonicalized: True
  • XLogP3-AA: null
  • Exact Mass: 357.0767857
  • Monoisotopic Mass: 357.0767857
  • Complexity: 506
  • Rotatable Bond Count: 4
  • Hydrogen Bond Donor Count: 1
  • Hydrogen Bond Acceptor Count: 4
  • Topological Polar Surface Area: 68.5
  • Heavy Atom Count: 25
  • Defined Atom Stereocenter Count: 0
  • Undefined Atom Stereocenter Count: 0
  • Defined Bond Stereocenter Count: 0
  • Undefined Bond Stereocenter Count: 0
  • Isotope Atom Count: 0
  • Covalently-Bonded Unit Count: 1
  • CACTVS Substructure Key Fingerprint: AAADceB6OAAEAAAAAAAAAAAAAAAAAWAAAAAwYAAAAAAAAFgB9AAAHgIACAAADA6BniIyzvMMFgCoAyXyXACCiCAlJyAImCE2btgMJvLFt5uEcShkxBHI6Ye82fOehEABAAACAAAIgAIAAAQAAAAAAAAAAA==
11. Recommended Suppliers
Global330SuppliersView all >>
  • Products:5413-05-8 Ethyl 2-phenylacetoacetate; 20320-59-6/5449-12-7 BMK powder; 28578-16-7 Pmk glycidate; 79099-07-3 N-BOC-4-piperidone; 49851-31-2 2-bromo-1-phenylpentan-1-one; 288573-56-8
  • Tel:86-27-18672397182
  • Email:Selena@hanhong-api.com
Top Quality Pharmaceutical Chemical Raw Powder Indometacin CAS 53-86-1
  • Purity:99%Packing: 200kg/bag FOB
  • Price: 15 USD/kilogram
  • Time: 2022/11/29
Inquire
  • Products:API,fine chemical&its intermediates,biological chemistry
  • Tel:0086-27-59207850
  • Email:info@fortunachem.com
Trade assurance guaranteed Indometacin CAS 53-86-1 with good quality
  • Purity:99%Packing: 200kg/bag FOB
  • Price: 50 USD/kilogram
  • Time: 2022/11/29
Inquire
  • Products:Organic intermediates, Organic solvents,Cosmetic raw materials ...
  • Tel:00-86-19930553744
  • Email:Berry@hbzebo.com
Indometacin
  • Purity:99%Packing: 200kg/bag FOB
  • Price: 1 USD/g
  • Time: 2022/11/26
Inquire
  • Products:biotechnology pharmaceutical intermediates biotechnology medical intermediates
  • Tel:0086-0310-15343106358
  • Email:guide@cnyouze.com
Wholesale price API Indometacin CAS NO.53-86-1
  • Purity:99%Packing: 200kg/bag FOB
  • Price: 8.9 USD/kg
  • Time: 2022/11/25
Inquire
  • Products:chemical raw materials, veterinary drug raw materials, animal and plant extracts, pharmaceutical excipients, pharmaceutical products, food additives
  • Tel:86-155-03787326
  • Email:hnkanbeichemical@126.com
Indomethacin 53-86-1
  • Purity:99%Packing: 200kg/bag FOB
  • Price: 1 USD/kilogram
  • Time: 2022/11/15
Inquire
12. Realated Product Infomation