Diflunisal
Synonym(s):2′,4′-Difluoro-4-hydroxy-[1,1′-biphenyl]-3-carboxylic acid;5-(2,4-Difluorophenyl)salicylic acid;Diflunisal
- CAS NO.:22494-42-4
- Empirical Formula: C13H8F2O3
- Molecular Weight: 250.2
- MDL number: MFCD00057834
- EINECS: 245-034-9
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-05 19:05:58
What is Diflunisal?
Absorption
Rapidly and completely absorbed following oral administration, with a bioavailability of 80-90%. Peak plasma concentrations are achieved 2 - 3 hours following oral administration.
Toxicity
Oral LD50 in rat, mouse, and rabbit is 392 mg/kg, 439 mg/kg, and 603 mg/kg, respectively. Symptoms of overdose include drowsiness, nausea, vomiting, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. As a monotherapy, the smallest dosage capable of causing death was reported as 15 grams.
Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of diflunisal. Short-term use does not appear to be associated with increased cardiovascular risk (except when used immediately following coronary artery bypass graft (CABG) surgery). Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Severe hepatic reactions, including cholestasis and/or jaundice, have been reported. May cause rash or hypersensitivity syndrome.
Description
Diflunisal is more potent than aspirin but produces fewer side effects and has a biological half-life three to four times greater than that of aspirin. It is rapidly and completely absorbed on oral administration, with peak plasma levels being achieved within 2 to 3 hours of administration. It is highly bound (99%) to plasma proteins after absorption. Its elimination half-life is 8 to 12 hours, and it is excreted into urine primarily as glucuronide conjugates. The most frequently reported side effects include disturbances of the GI system (e.g., nausea, dyspepsia, and diarrhea), dermatological reactions, and CNS effects (e.g., dizziness and headache).
Description
Diflunisal is a non-steroidal anti-inflammatory drug (NSAID) that inhibits both COX-1 (IC50 = 113 μM) and COX-2 (IC50s = 8.2 and 134 μM for human whole blood assay and human-modified whole blood assays, respectively). Peak plasma levels are achieved within two hours, with little metabolism before excretion in the urine. The terminal plasma half-life is approximately eight hours.
Chemical properties
White Solid
Originator
Dolobid,Morson,UK,1978
The Uses of Diflunisal
As a prostaglandin synthetase inhibitor, diflunisal exhibits analgesic, fever-reducing, and anti-inflammatory action. It is used for long- and short-lasting symptomatic relief of low to moderate pain in osteoarthritis and rheumatoid arthritis.
The Uses of Diflunisal
Salicylate; non-selective cyclo-oxygenase inhibitor; antipyretic; analgesic; anti- inflammatory.
The Uses of Diflunisal
Diflunisal acts as an analgesic agent, used in Alzheimer’s studies (1,2,3) as an anti-inflammatory. As well as in autolytic regulation of human kallikrein -related peptidase 6 (4).
Background
Diflunisal, a salicylate derivative, is a nonsteroidal anti-inflammatory agent (NSAIA) with pharmacologic actions similar to other prototypical NSAIAs. Diflunisal possesses anti-inflammatory, analgesic and antipyretic activity. Though its mechanism of action has not been clearly established, most of its actions appear to be associated with inhibition of prostaglandin synthesis via the arachidonic acid pathway. Diflunisal is used to relieve pain accompanied with inflammation and in the symptomatic treatment of rheumatoid arthritis and osteoarthritis.
Indications
For symptomatic treatment of mild to moderate pain accompanied by inflammation (e.g. musculoskeletal trauma, post-dental extraction, post-episiotomy), osteoarthritis, and rheumatoid arthritis.
What are the applications of Application
Diflunisal is an NSAID analgesic
Definition
ChEBI: Diflunisal is an organofluorine compound comprising salicylic acid having a 2,4-difluorophenyl group at the 5-position. It has a role as a non-steroidal anti-inflammatory drug and a non-narcotic analgesic. It is an organofluorine compound and a monohydroxybenzoic acid. It is functionally related to a salicylic acid and a 1,3-difluorobenzene.
Manufacturing Process
A mixture of 10 g of 4-(2',4'-difluorophenyl)-phenol and 27.2 g of potassium carbonate is exposed to carbon dioxide at 1,300 psi and 175°C. The dark mass obtained from this carbonation is then dissolved in 300 ml of water and 200 ml of methylene chloride and the two layers separated. The water layer is then extracted with 100 ml of methylene chloride and then acidified with 2.5 N hydrochloric acid. This mixture is then filtered and the cake dried in vacuo to yield 5.32 g of the crude product. The crude product is then recrystallized from benzene-methanol. An additional crystallization of this semipure material from benzene-methanol yields analytically pure 2-hydroxy-5-(2',4'- difluorophenyl)-benzoic acid (MP 210-211°C).
brand name
Biartac (Merck Sharp & Dohme, Belgium), Diflonid (Dumex, Denmark, Sweden), Diflusal (Merck Sharp & Dohme, Belgium), Dolobid (Frosst, Canada; Logos, South Africa; Merck, USA; Morson, UK), Dolobis (M.S.D.-Chibret, France), Fluniget (Merck Sharp & Dohme, Austria).
Therapeutic Function
Analgesic, Antiinflammatory
General Description
Diflunisal (Dolobid), is a longer acting and more potent drugthan aspirin because of its hydrophobic, 2,4-difluorophenylgroup attached to the 5-position of the salicyclic acid. In alarge-scale comparative study with aspirin, it was also bettertolerated with less GI complications than aspirin. It ismarketed in tablet form for treating mild to moderate postoperativepain as well as RA and OA.
Diflunisal is highly protein bound. Its metabolism is subjectto a dose-dependent, saturable, and capacity-limitedglucuronide formation. This unusual pharmacokineticprofile is a result of an enterohepatic circulation and the reabsorptionof 65% of the drug and its glucuronides, followedby cleavage of its unstable, acyl glucuronide back tothe active drug. Thus, diflunisal usage in patients with renalimpairment should be closely monitored.
General Description
Diflunisal is a salicylate with greater anti-inflammatory and analgesic potency and with a long plasma half-life that allows for twice-a-day dosage. Without an O-acetyl group it is a reversible inhibitor of cyclooxygenase. It is comparable in efficacy to aspirin in the treatment of osteoarthritis and rheumatoid arthritis but is much better tolerated.
Mechanism of action
Diflunisal is a weak inhibitor of both COX-1 and COX-2.
Pharmacokinetics
Diflunisal is a nonsteroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance and addiction have not been reported. Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the 0-acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.
Pharmacokinetics
Diflunisal is more potent than aspirin but produces fewer side effects and has a biological half-life three to four times greater than that of aspirin. It is rapidly and completely absorbed on oral administration, with peak plasma levels being achieved within 2 to 3 hours of administration. It is highly bound (99%) to plasma proteins after absorption. Its elimination half-life is 8 to 12 hours, and it is excreted into urine primarily as glucuronide conjugates. The most frequently reported side effects include disturbances of the GI system (e.g., nausea, dyspepsia, and diarrhea), dermatological reactions, and CNS effects (e.g., dizziness and headache).
Pharmacology
Peak plasma concentrations are reached within 2 to 3 h after oral dosing. Diflunisal is strongly bound to plasma protein (> 99 %), has a long elimination half-life (8–12 h) and nonlinear elimination kinetics. Hence, it is used with an initial loading dose (1000 mg) and a lower maintenance dose (500–1000 mg/d).
Clinical Use
Diflunisal (pKa 3.3) was introduced in the United States in 1982 and has gained considerable acceptance as an analgetic and as a treatment of rheumatoid arthritis and osteoarthritis. Diflunisal is metabolized primarily to ether and ester glucuronide conjugates.
Side Effects
The main side effects are gastrointestinal disturbances, headache and rash.
Safety Profile
Poison by ingestion, subcutaneous, and intraperitoneal routes. Human systemic effects by ingestion: tolerance, and cholestatic jaundce (due to the stoppage of the flow of bile), agranulocytosis, increased body temperature. An experimental teratogen. Other experimental reproductive effects. An analgesic and anti-inflammatory agent. When heated to decomposition it emits toxic fumes of F-. See also FLUORIDES.
Synthesis
Diflunisal, 2??,4??-difluoro-4-hydroxy-3-byphenylcarboxylic acid (3.2.5), is synthesized from a diazonium salt, which is synthesized from 2,4-difluoroaniline and isoamyl nitrite, and anisole in the presence of copper (I) salts by the classic scheme of making diaryls. The resulting 4-(2,4-difluorophenyl)anisole (3.2.3) is demethylated by hydrogen iodide into 4-(2,4-difluorophenyl)-phenol (3.2.4). This product is reacted with carbon dioxide in the presence of a base according to the Kolbe¨CSchmitt phenol carboxylation method, giving diflunisal (3.2.5) [64¨C67].
Metabolism
Hepatic, primarily via glucuronide conjugation (90% of administered dose).
Properties of Diflunisal
Melting point: | 207-209?C |
Boiling point: | 386.9±42.0 °C(Predicted) |
Density | 1.3505 (estimate) |
storage temp. | Keep in dark place,Sealed in dry,Room Temperature |
solubility | Practically insoluble in water, soluble in ethanol (96 per cent). It dissolves in dilute solutions of alkali hydroxides. |
form | neat |
pka | pKa 3.3 (H2O I=0.1) (Uncertain) |
form | Solid |
color | White |
Water Solubility | 6.186mg/L(24.99 ºC) |
CAS DataBase Reference | 22494-42-4(CAS DataBase Reference) |
NIST Chemistry Reference | Diflunisal(22494-42-4) |
Safety information for Diflunisal
Signal word | Warning |
Pictogram(s) |
Exclamation Mark Irritant GHS07 Health Hazard GHS08 |
GHS Hazard Statements |
H302:Acute toxicity,oral H315:Skin corrosion/irritation H319:Serious eye damage/eye irritation H335:Specific target organ toxicity, single exposure;Respiratory tract irritation H361:Reproductive toxicity |
Precautionary Statement Codes |
P201:Obtain special instructions before use. P302+P352:IF ON SKIN: wash with plenty of soap and water. P305+P351+P338:IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing. P308+P313:IF exposed or concerned: Get medical advice/attention. |
Computed Descriptors for Diflunisal
Abamectin manufacturer
Aarti Industries Limited (AIL)
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