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HomeProduct name list1-(2,6-Dichlorophenyl)-2-indolinone

1-(2,6-Dichlorophenyl)-2-indolinone

Synonym(s):2-(2,6-dichloranilino) phenylacetic acid;2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid

  • CAS NO.:15307-86-5
  • Empirical Formula: C14H11Cl2NO2
  • Molecular Weight: 296.15
  • MDL number: MFCD00056694
  • EINECS: 239-348-5
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-05 11:59:05
1-(2,6-Dichlorophenyl)-2-indolinone Structural

What is 1-(2,6-Dichlorophenyl)-2-indolinone?

Absorption

Diclofenac is completely absorbed from the GI tract but likely undergoes significant first pass metabolism with only 60% of the drug reaching systemic circulation unchanged . Many topical formulations are absorbed percutaneous and produce clinically significant plasma concentrations. Absorption is dose proportional over the range of 25-150 mg. Tmax varies between formulations with the oral solution reaching peak plasma concentrations in 10-40min, the enteric coated tablet in 1.5-2h, and the sustained- and extended-release formulations prolonging Tmax even further. Administration with food has no significant effects on AUC but does delay Tmax to 2.5-12h.

Toxicity

Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, and gastrointestinal bleeding. Hypertension, acute renal failure, respiratory depression and coma occur rarely. In case of overdose, provide supportive care and consider inducing emesis and administering activated charcoal if overdose occurred less than 4 hours prior.

Originator

Voltaren,Fujisawa,Japan,1974

The Uses of 1-(2,6-Dichlorophenyl)-2-indolinone

prostaglandin synthetic inhibitor

The Uses of 1-(2,6-Dichlorophenyl)-2-indolinone

Diclofenac possesses all of the properties unique to the series of propionic acid drugs, yet in terms of anti-inflammatory and analgesic strength it exceeds that of aspirin, analgin, and ibuprofen. It is used in acute rheumatism, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, arthrosis, back pain, neuralgia, and myalgia. It rarely causes side effects. The most common synonym is voltaren.

Background

Diclofenac is a phenylacetic acid derivative and non-steroidal anti-inflammatory drug (NSAID). NSAIDs inhibit cyclooxygenase (COX)-1 and-2 which are the enzyme responsible for producing prostaglandins (PGs). PGs contribute to inflammation and pain signalling. Diclofenac, like other NSAIDs, is often used as first line therapy for acute and chronic pain and inflammation from a variety of causes. Diclofenac was the product of rational drug design based on the structures of phenylbutazone, mefenamic acid, and indomethacin. The addition of two chlorine groups in the ortho position of the phenyl ring locks the ring in maximal torsion which appears to be related to increased potency. It is often used in combination with misoprostol to prevent NSAID-induced gastric ulcers. Diclofenac was first approved by the FDA in July 1988 under the trade name Voltaren, marketed by Novartis (previously Ciba-Geigy).

Indications

Diclofenac is indicated for use in the treatment of pain and inflammation from varying sources including inflammatory conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, as well as injury-related inflammation due to surgery and physical trauma. It is often used in combination with misoprostol as a gastro-protective agent in patients with high risk of developing NSAID-induced ulcers.

Indications

Diclofenac (Voltaren, Cataflam) is approved for use in rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, dysmenorrhea, and topically for the treatment treatment of ocular inflammation and actinic keratosis. Diclofenac exhibits approximately equal selectivity for COX-1 and COX-2. The most common adverse reactions are GI disturbances and headache.A reversible elevation of serum transaminases occurs in 15% of patients.

Definition

ChEBI: Diclofenac is a monocarboxylic acid consisting of phenylacetic acid having a (2,6-dichlorophenyl)amino group at the 2-position. It has a role as a non-narcotic analgesic, an antipyretic, an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor, a xenobiotic, an environmental contaminant, a drug allergen and a non-steroidal anti-inflammatory drug. It is a secondary amino compound, an amino acid, a dichlorobenzene, an aromatic amine and a monocarboxylic acid. It is functionally related to a phenylacetic acid and a diphenylamine. It is a conjugate acid of a diclofenac(1-).

Manufacturing Process

Four grams of N-chloroacetyl-N-phenyl-2,6-dichloroaniline and 4 grams of aluminum chloride are well mixed together and heated for 2 hours at 160°C. The melt is cooled and poured onto about 50 grams of ice while it is still warm. The oil which separates is dissolved in 50 ml of chloroform, the chloroform solution is washed with 10 ml of water, dried over sodium sulfate and concentrated under 11 torr. The residue is distilled. The 1-(2,6- dichlorophenyl)-2-indolinone melts at 126°-127°C.
A solution of 186 grams of 1-(2,6-dichlorophenyl)-2-indolinone in 660 ml of ethanol and 660 ml of 2 N sodium hydroxide solution is refluxed for 4 hours. The solution is then cooled and left to stand for 4 hours at 0°-5°C. The crystals which form are filtered off and recrystallized from water. The sodium salt of 2-(2,6-dichloroanilino)-phenylacetic acid melts at 283°-285°C. The yield is 97% of theoretical, according to US Patent 3,558,690.

Therapeutic Function

Antiinflammatory

Biological Functions

Diclofenac (Voltaren) is a phenylacetic acid derivative that is a potent inhibitor of COX and that has analgesic, antiinflammatory, and antipyretic effects. Its use is accompanied by side effects similar to those of other NSAIDs. Indications for the drug include rheumatoid arthritis, osteoarthritis, and ophthalmic inflammation (use of an ophthalmic preparation).

Mechanism of action

Diclofenac is unique among the NSAIDs in that it possesses three possible mechanisms of action: 1) inhibition of the arachidonic acid cyclooxygenase system (3 to 1,000 times more potent than other NSAIDs on a molar basis), resulting in a decreased production of prostaglandins and thromboxanes; 2) inhibition of the lipoxygenase pathway, resulting in decreased production of leukotrienes, particularly the pro-inflammatory LKB4; and 3) inhibition of arachidonic acid release and stimulation of its reuptake, resulting in a reduction of arachidonic acid availability.

Pharmacokinetics

Diclofenac reduces inflammation and by extension reduces nociceptive pain and combats fever. It also increases the risk of developing a gastrointestinal ulcer by inhibiting the production of protective mucus in the stomach.

Pharmacokinetics

Diclofenac is rapidly and completely (~100%) absorbed on oral administration, with peak plasma levels being reached within 1.5 to 2.5 hours. The free acid (pKa = 4.0) is highly bound to serum proteins (99.5%), primarily albumin. Only 50 to 60% of an oral dose is bioavailable because of extensive hepatic metabolism.

Clinical Use

Diclofenac is synthesized from N-phenyl-2,6-dichloroaniline. It is available in 120 different countries and, perhaps, is the most widely used NSAID in the world. It was introduced in the United States in 1989 but was first marketed in Japan in 1974. It ranks among the top prescription drugs in the United States. Diclofenac possesses structural characteristics of both arylalkanoic acid and the anthranilic acid classes of anti-inflammatory drugs, and it displays anti-inflammatory, analgetic, and antipyretic properties.

Synthesis

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].

Synthesis_15307-86-5

Metabolism

Diclofenac undergoes oxidative metabolism to hydroxy metabolites as well as conjugation to glucuronic acid, sulfate, and taurine. The primary metabolite is 4'-hydroxy diclofenac which is generated by CYP2C9. This metabolite is very weakly active with one thirtieth the activity of diclofenac. Other metabolites include 3'-hydroxy diclofenac, 3'-hydroxy-4'methoxy diclofenac, 4',5-dihydroxy diclofenac, an acylglucuronide conjugate, and other conjugate metabolites.

Metabolism

Four major metabolites resulting from aromatic hydroxylation have been identified. The major metabolite via CYP3A4 is the 4′-hydroxy derivative and accounts for 20 to 30% of the dose excreted, whereas the 5-hydroxy, 3′-hydroxy, and 4′,5-dihydroxy metabolites via CYP2C9 account for 10 to 20% of the excreted dose. The remaining drug is excreted in the form of sulfate conjugates. Although the major metabolite is much less active than the parent compound, it may exhibit significant biological activity, because it accounts for 30 to 40% of all of the metabolic products.

Properties of 1-(2,6-Dichlorophenyl)-2-indolinone

Melting point: 156-158°
Boiling point: 412.0±45.0 °C(Predicted)
Density  1.431±0.06 g/cm3(Predicted)
storage temp.  Sealed in dry,Room Temperature
solubility  soluble in Methanol
form  powder to crystal
pka pKa 4 (Uncertain)
color  White to Almost white
Water Solubility  1.278mg/L(30 ºC)
Merck  14,3081
CAS DataBase Reference 15307-86-5(CAS DataBase Reference)
NIST Chemistry Reference Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]-(15307-86-5)
EPA Substance Registry System Benzeneacetic acid, 2-[(2,6-dichlorophenyl)amino]- (15307-86-5)

Safety information for 1-(2,6-Dichlorophenyl)-2-indolinone

Signal word Danger
Pictogram(s)
ghs
Skull and Crossbones
Acute Toxicity
GHS06
ghs
Health Hazard
GHS08
ghs
Environment
GHS09
GHS Hazard Statements H301:Acute toxicity,oral
H372:Specific target organ toxicity, repeated exposure
H411:Hazardous to the aquatic environment, long-term hazard
Precautionary Statement Codes P202:Do not handle until all safety precautions have been read and understood.
P260:Do not breathe dust/fume/gas/mist/vapours/spray.
P264:Wash hands thoroughly after handling.
P264:Wash skin thouroughly after handling.
P270:Do not eat, drink or smoke when using this product.
P273:Avoid release to the environment.
P301+P310:IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.

Computed Descriptors for 1-(2,6-Dichlorophenyl)-2-indolinone

InChIKey DCOPUUMXTXDBNB-UHFFFAOYSA-N

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