22494-42-4 Usage
Outline
Diflunisal, a nonsteroidal anti-inflammatory analgesic, is the most promising alternative to aspirin.It is used clinically for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, sprain, strain and analgesia. Researches have indicated that diflunisal and ibuprofen are effective in the treatment of rheumatoid arthritis and degenerative arthritis. It has also been observed that diflunisal is superior to ibuprofen in improving the grip strength and relieving joint pain and tenderness of rheumatoid arthritis and degenerative arthritis in patients with rheumatoid arthritis. At the same time, diflunisal can decrease and alleviate the rheumatoid factor titre in patients with rheumatoid arthritis and stiffness,The analgesic effect of diflunisal is 7.5 to 13 times as high as aspirin.Its antipyretic effect is 1.4 times as high as aspirin, and its therapeutic effect is about 3 times as strong as aspirin. Therefore, it is suitable for treating rheumatoid arthritis, osteoarthritis, muscle sprain, strain, meniscus surgery, orthopedic and oral surgery, and primary pain caused by dysmenorrhea. It is worthy of clinical application.Diflunisal is selected from more than 500 salicylic acid derivatives by American company Merck Sharp & Do hme using the flunisal as the leading compound in 1975. It was launched in 1975. Now it is one of the Merck Co's annual sales of over 100 million US dollars. And it has been listed in more than 70 countries, such as Britain, the United States, Japan, Italy, France and other countries. It has also been recorded by the United States Pharmacopoeia and the British Pharmacopoeia. In China, the tablets and capsules of diflunisal have been approved for production.
Pharmacokinetics
Different sources of media describe the Pharmacokinetics of 22494-42-4 differently. You can refer to the following data:
1. This product is well absorbed in oral administration, and the blood concentration 2 ~ 3H after taking will reach the peak.The half-life is proportional to the dosage, about 8 to 12h, and the binding rate of plasma protein is 90%. Oral administration of 125mg should be 3 ～ 4d and 500mg should be 7 to 9d. .The elimination of half-life of 125mg is 7 to 8h, and 500mg is 15h.Its binding rate with plasma protein in normal human body is up to 98% ~ 99%.The content of breast milk in lactating women is 2% ~ 7% of the blood concentration.It is not metabolized into salicylic acid in the body.80% to 95% of the drugs will be discharged from the urine in the form of 2 soluble glucoside complexes within 72-96h.
2. 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).
Clinical application
This product can inhibit the synthesis of prostaglandin with analgesic, anti-inflammatory and antipyretic effects. It is used to relieve the moderate pain in bone and rheumatoid arthritis.It is also used to relieve pain and joint, muscle sprain and cancer pain after meniscus and orthopedic surgery. The drug will take effect 1h after taking and the effect lasts for 8 ~ 12h.It can also be used to treat osteoarthritis and rheumatoid arthritis etc.
Precaution
The combined use with hydrochlorothiazine, indomethacin, and paracetamol can increase the plasma concentration of these drugs.?
Long-term application can cause renal function damage and drug accumulation, so the patients with renal insufficiency should be careful in application with reduced doses.
This drug is forbidden for patients with cardiac insufficiency, hypertension, edema, peptic ulcer and bleeding as well as for pregnant women and breast-feeding women.
It is forbidden for those who are allergic to this product and acetyl salicylic acid.
Used with anticoagulants, it can prolong the time of coagulation
Adverse reaction
Digestive system: anorexia, nausea, abdominal pain, abdominal distention, diarrhea, and constipation.
Nervous system: vertigo, headache, fatigue, insomnia, lethargy, etc.
Others: rare rash, edema, rhinitis, tinnitus, transient visual impairment, etc.
Description
Different sources of media describe the Description of 22494-42-4 differently. You can refer to the following data:
1. 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).
2. 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
Uses
Different sources of media describe the Uses of 22494-42-4 differently. You can refer to the following data:
1. 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.
2. Salicylate; non-selective cyclo-oxygenase inhibitor; antipyretic; analgesic; anti- inflammatory.
3. 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).
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
Dolobid (Merck).
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.
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.
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–Schmitt phenol carboxylation method, giving diflunisal (3.2.5) [64–67].
Check Digit Verification of cas no
The CAS Registry Mumber 22494-42-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,2,4,9 and 4 respectively; the second part has 2 digits, 4 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 22494-42:
(7*2)+(6*2)+(5*4)+(4*9)+(3*4)+(2*4)+(1*2)=104
104 % 10 = 4
So 22494-42-4 is a valid CAS Registry Number.
InChI:InChI=1/C13H8F2O3/c14-10-3-1-8(6-11(10)15)7-2-4-12(16)9(5-7)13(17)18/h1-6,16H,(H,17,18)
22494-42-4Relevant articles and documents
Functionally substituted isoxazoles and isothiazoles: Synthesis, palladium(II) complexes and their catalytic activity
Bumagin,Zelenkovskii,Kletskov,Petkevich,Dikusar,Potkin
, p. 68 - 81 (2016)
Functionally substituted 5-(p-tolyl)isoxazoles and 4,5-dichloroisothiazoles, whose molecules contain azomethine, amino, carboxyl, and ester moieties in various combinations in the aromatic ring in the position 3 of heterocycle, were synthesized. Synthesis of complexes of Pd(II) with carboxyl derivative of 1,2-azoles was performed. They show high catalytic activity in the Suzuki reaction in aqueous media.
3,5-[5-Arylisoxazol-3-yl(4,5-dichloroisothiazol-3-yl)]-substituted 1,2,4- and 1,3,4-oxadiazoles: synthesis, palladium complexes, and catalysis of Suzuki reactions in aqueous media
Bumagin, Nikolay A.,Petkevich, Sergey K.,Kletskov, Alexey V.,Potkin, Vladimir I.
, p. 1340 - 1349 (2017)
[Figure not available: see fulltext.] A reaction sequence involving transformations of 5-(4-methylphenyl)isoxazole and 4,5-dichloroisothiazole derivatives containing an amidoxime group at position 3 allowed to synthesize the respective 3,5-isoxazolyl(isothiazolyl)-substituted 1,2,4-oxadiazoles. Selective recyclization of 4,5-dichloro-3-(1Н-tetrazol-5-yl)isothiazole and 5-(4-methylphenyl)-3-(1Н-tetrazol-5-yl)isoxazole gave 2,5-isoxazolyl-(isothiazolyl)-substituted 1,3,4-oxadiazoles. The obtained compounds combining three azole heterocycles in one molecule formed palladium complexes that showed high catalytic activity in Suzuki reactions in aqueous and aqueous alcohol media. The bimetallic reusable Pd/Fe catalyst obtained from palladium polyazole complex retained high catalytic activity after five uses.
Mimics of Pincer Ligands: An Accessible Phosphine-Free N-(Pyrimidin-2-yl)-1,2-azole-3-carboxamide Framework for Binuclear Pd(II) Complexes and High-Turnover Catalysis in Water
Bumagin, Nikolay A.,Dikusar, Evgenij A.,Ivashkevich, Ludmila S.,Kletskov, Alexey V.,Kolesnik, Iryna A.,Lyakhov, Alexander S.,Petkevich, Sergey K.,Potkin, Vladimir I.
supporting information, (2020/08/12)
We report for the first time cyclic phosphine-free "head to tail"N,N,N pincer-like (pincer complexes mimicking) N-(pyrimidin-2-yl)-1,2-azole-3-carboxamide Pd(II) complexes with deprotonated amide groups as high-turnover catalysts (TON up to 106, TOF up to 1.2 × 107 h-1) for cross-coupling reactions on the background of up to quantitative yields under Green Chemistry conditions. The potency of the described catalyst family representatives was demonstrated in Suzuki-Miyaura, Mizoroki-Heck, and Sonogashira reactions on industrially practical examples. Corresponding ligands could be synthesized based on readily available reagents through simple chemical transformations. Within the complex structures, a highly unusual 1,3,5,7-tetraza-2,6-dipalladocane frame could be observed.
Iron-Catalyzed Room Temperature Cross-Couplings of Bromophenols with Aryl Grignard Reagents
Xu, Li-Chen,Liu, Kun-Ming,Duan, Xin-Fang
supporting information, p. 5421 - 5427 (2019/11/14)
Herein we report a room temperature Fe-catalyzed coupling reaction of various bromophenols with aryl Grignard reagents, which exhibits a wide substrate scope and high functional group tolerance. For the first time, the combination of simple Fe(acac)3/PBu3/Ti(OEt)4 has been used as an effective catalyst for the biaryl couplings of bromophenols or their Na or K salts with debromination and etherification side reactions being well suppressed. Various biphenols including natural product garcibiphenyl C as well as pharmaceutical diflunisal and its ethyl ester were facilely synthesized using the present protocol. (Figure presented.).
