5104-49-4 Usage
Uses
1. Used in Pharmaceutical Industry:
Flurbiprofen is used as an anti-inflammatory drug for the treatment of chronic arthritis and pain, inflammation of Deformation joint disease, and pain after surgery and tooth extraction.
2. Used in Pain Management:
Flurbiprofen is used as an analgesic to help manage pain associated with various conditions, such as arthritis and post-surgical pain.
3. Used as a Cyclooxygenase Inhibitor:
Flurbiprofen is used as a cyclooxygenase (COX) inhibitor, which helps in reducing inflammation and pain by blocking the production of prostaglandins.
4. Used in Ophthalmology:
Flurbiprofen, under the brand name Ocufen, is used as a topical NSAID to inhibit intraoperative miosis induced by prostaglandins in cataract surgery.
5. Used in Alzheimer's Disease Research:
(R)-flurbiprofen is being investigated as a potential treatment for Alzheimer's disease due to its ability to reduce Aβ42 production by human cells.
Anti-inflammatory analgesics
Flibanserin , also known as flurbiprofen, flurbiprofen, is a potent Phenylalanine anti-inflammatory and antipyretic analgesics,it can inhibit prostaglandin synthesizing cyclooxygenase to have analgesic, anti-inflammatory and antipyretic effects. Its anti-inflammatory and analgesic effects are 250 times and 50 times of aspirin (also known as acetylsalicylic acid) . The oral absorption is rapid , peak plasma concentration achieves after 1.5 hours , half-life is 3.5 hours, it has wide tissue distribution, PPB is 99.4%, it can compete with drugs having a high plasma protein binding rate to bind plasma protein .it Metabolizes in the liver and becomes flurbiprofen hydroxy and its aldehyde acid conjugates. T1/2 is 3.5 h. Urine and fecal excretion,account for approximately 60% and 40% respectively . Age has no effect on drug metabolism. It is Mainly used for rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis. It is also used in preventing aphakic cystoid patchy edema After surgical removal of the lens, inhibiting pupillary constrictionsurgery, treatment of inflammation after cataract and trabeculoplasty argon laser eye surgery. It Also applies to pain caused by some other reasons such as trauma, sprains, surgery.
Toxicity
Non-steroidal anti-inflammatory drug (NSAID) has anti-inflammatory, analgesic and antipyretic effects, toxicity ascending ranking is nabumetone, salsalate, sulindac, diclofenac, ibuprofen, one fabric ibuprofen, aspirin, naproxen, tolmetin, flurbiprofen, piroxicam, a phenoxy ibuprofen, indomethacin, mefenamic acid chlorine. Traditional NSAID medications may be the preferred aspirin, if children in the course of treatment can not tolerate its adverse reactions, use of other non-steroidal anti-inflammatory drugs is taken. a selective COX-2 inhibitor Has been developed, which will replace all traditional NSAID. Selective COX-2 inhibitors which has been listed are nimesulide (Nimeng Shu), rofecoxib (Vioxx), celecoxib (Celebrex), etodolac (Rodin), meloxicam. A recent large-scale, international, multi-center, randomized, double-blind technology, prospective study has shown that selective COX-2 inhibitors have few side effects on the gastrointestinal tract, kidneys, having no significant effect on platelet function,it can be used as drug of choice for early combination therapy of JRA children replacing aspirin .
The above information is edited by the lookchem of Tian Ye.
Adverse reactions
The most common adverse reactions are indigestion, stomach discomfort, occasional headache, skin rash. Peptic ulcer, bronchial asthma patients and pregnant women, lactating women should not take.
Other adverse reactions are nausea, diarrhea, abdominal pain, blurred vision, urinary tract infection symptoms, dermatitis. Few have elevated liver transaminases, continuing medication, may develop, or remain unchanged or disappear. Mild tingling and burning sensations and (or) visual disturbances when it is dropped into the eye.because it leads to platelet aggregation and prolongs bleeding time, it is reported that the application of the drug in the eye surgery increases intraocular hemorrhage tendency.in Animal experiments, Flibanserin 50~100 mg/kg, medication for three months, can cause renal papillary necrosis. For Humans,it also has this effect.
production method
It is obtained by 2-fluoro-linked acetophenone through oxidation, esterification, transesterification, hydrolysis, decarboxylation reaction.
Originator
Froben, Boots,UK ,1977
Indications
Flurbiprofen (Ansaid) is indicated for the treatment
of rheumatoid arthritis and osteoarthritis. Its half-life,
longer than that of many of the NSAIDs, allows for
twice daily dosing.The most common adverse effects of
flurbiprofen are similar to those of the other acidic
NSAIDs. Flurbiprofen inhibits both COX isoforms
about equally.
Manufacturing Process
A mixture of 3-acetyl-2-fluorobiphenyl, MP 95°C to 96°C, (73.5 g) [prepared from 4.bromo-3-nitroacetophenone (Oelschlage, Ann., 1961, 641, 81) via-4acetyl-2-nitrobiphenyl, MP 106°C to 108°C (Ullman reaction), 4-acetyl-2aminobiphenyl, MP 124°C to 125°C (reduction), and finally the Schiemann reaction], sulfur (17.4 g) and morpholine (87 ml) was refluxed for 16.5 hr, and then the resulting thiomorpholide was hydrolyzed by refluxing with glacial acetic acid (340 ml) concentrated sulfuric acid (54 ml) and water (78 ml) for 24 hr. The cooled solution was diluted with water, and the precipitated crude 2-fluoro-4-biphenylylacetic acid was collected. (A sample was purified by recrystallization to give MP 143°C to 144.5°C; Found (%): C, 73.2; H, 4.8. C14H11FO2 requires C, 73.1; H, 4.8.)A sodium carbonate solution of the crude acetic acid was washed with ether and then acidified with hydrochloric acid; the required acid was isolated via an ether extraction and was esterified by refluxing for 6 hr with ethanol (370 ml) and concentrated sulfuric acid (15 ml). Excess alcohol was distilled, the residue diluted with water and the required ester isolated in ether. Distillation finally gave ethyl 2-fluoro-4-biphenylacetate, BP 134°C to 136°C/0.25 mm.This ester (70g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (154 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5 N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acidto give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°C for 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4biphenylyl)propionic acid, MP 110°C to 111°C
Therapeutic Function
Antiinflammatory
Biological Activity
Potent inhibitor of cyclooxygenase (IC 50 values are 0.1 and 0.4 μ M for inhibition of human COX-1 and COX-2 respectively). Analgesic, anti-inflammatory and antipyretic in vivo . Inhibits tumor cell growth in vitro and in vivo . Also inhibits fibroblast proliferation in vitro .
Pharmacokinetics
Flurbiprofen is well absorbed after oral administration, with peak plasma levels being attained within 1.5 hours. Food
alters the rate of absorption but not the extent of its bioavailability. It is extensively bound to plasma proteins (99%).and has a plasma half-life of 2 to 4 hours. Metabolism is extensive, with 60 to 70% of flurbiprofen and its metabolites
being excreted as sulfate and glucuronide conjugates. Flurbiprofen shows some interesting metabolic patterns, with
40 to 47% as the 4′-hydroxy metabolite, 5% as the 3′,4′-dihydroxy metabolite, 20 to 30% as the 3′-hydroxy-
4′-methoxy metabolite, and the remaining 20 to 25% of the drug being excreted unchanged. None of these
metabolites demonstrates significant anti-inflammatory activity.
Clinical Use
Flurbiprofen is indicated as an oral formulation for the acute or long-term treatment of rheumatoid arthritis and
osteoarthritis and as an ophthalmic solution for the inhibition of intraoperative miosis.
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 with other
NSAIDs or aspirin; avoid concomitant use with
ketorolac (increased 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 heparin, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs or venlafaxine.
Antidiabetics: effects of sulphonylureas enhanced.
Antiepileptics: possibly enhanced effect of phenytoin.
Antivirals: concentration possibly increased by
ritonavir; increased risk of haematological toxicity
with zidovudine.
Ciclosporin: may potentiate nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate;
increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity;
antagonism of diuretic effect; hyperkalaemia with
potassium-sparing diuretics.
Lithium: excretion reduced (risk of lithium toxicity).
Pentoxifylline: increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity
Metabolism
Flurbiprofen is metabolised mainly by hydroxylation (via the
cytochrome P450 isoenzyme CYP2C9) and conjugation
in the liver and excreted in the urine. The rate of urinary
excretion of flurbiprofen and its two major metabolites
([2-(2-fluoro-4′-hydroxy-4-biphenylyl) propionic acid] and
[2-(2-fluoro-3′-hydroxy-4′-methoxy-4-biphenylyl) propionic
acid]) in both free and conjugated states is similar for both
the oral and rectal routes of administration.
Check Digit Verification of cas no
The CAS Registry Mumber 5104-49-4 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 5,1,0 and 4 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 5104-49:
(6*5)+(5*1)+(4*0)+(3*4)+(2*4)+(1*9)=64
64 % 10 = 4
So 5104-49-4 is a valid CAS Registry Number.
InChI:InChI=1/C12H4F14/c13-7(9(15,16)17,10(18,19)20)5-1-2-6(4-3-5)8(14,11(21,22)23)12(24,25)26/h1-4H
5104-49-4Relevant articles and documents
Biotransformation with whole microbial systems in a continuous flow reactor: Resolution of (RS)-flurbiprofen using Aspergillus oryzae by direct esterification with ethanol in organic solvent
Tamborini, Lucia,Romano, Diego,Pinto, Andrea,Contente, Martina,Iannuzzi, Maria C.,Conti, Paola,Molinari, Francesco
, p. 6090 - 6093 (2013)
Cell-bound lipases of dry mycelium of Aspergillus oryzae were used in organic solvent for the resolution of racemic flurbiprofen by direct esterification with ethanol in a flow-chemistry reactor. Under flow conditions a significant reduction of the reaction time and an increase of the enantioselectivity were achieved compared to the batch mode. Moreover, the process was implemented by adding an in-line purification step integrated with the racemization of the unreacted flurbiprofen directly into a polymer-supported resin.
Improvement of dissolution and suppository release characteristics of flurbiprofen by inclusion complexation with heptakis(2,6-di-O-methyl)-β-cyclodextrin
Uekama,Imai,Maeda,Irie,Hirayama,Otagiri
, p. 841 - 845 (1985)
The inclusion behavior of methylated β-cyclodextrins, heptakis(2,6-di-O-methyl)-β-cyclodextrin (2), and heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (3) in solution and the solid state was compared with that of natural β-cyclodextrin (1) using an anti-inflammatory drug, flurbiprofen, as a guest molecule. Stability constants were determined by the solubility method at various temperatures, and the thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. The solid complexes were obtained in a molar ratio of 1:1, and their dissolution behavior and release from suppository bases were examined. The data suggest that the inclusion mode of the complex with 3 is somewhat different from that of the complexes with 1 and 2. From a practical point of view, 2 seems to be particularly useful for improving the pharmaceutical properties of flurbiprofen in various dosage forms.
Method for determination of optical purity of 2-arylpropanoic acids using urea derivatives based on a 1,1′-binaphthalene skeleton as chiral NMR solvating agents: Advantages and limitations thereof
Cu?ínová, Petra,Hájek, Peter,Jank?, Kristyna,Holakovsky, Roman
, p. 410 - 417 (2019)
Five optically active urea derivatives (1-5) were used as NMR solvating agents for analysis of the optical purity of different 2-arylpropanoic acids commonly used as nonsteroidal anti-inflammatory drugs. These novel chiral solvating agents were more efficient at discriminating the respective enantiomers of targets than the chiral solvating agents known so far, without the need to add a base for achieving the signal splitting. The advantages and limits of the use of these novel chiral solvating agents were studied.
An efficient method for the lipase-catalysed resolution and in-line purification of racemic flurbiprofen in a continuous-flow reactor
Tamborini, Lucia,Romano, Diego,Pinto, Andrea,Bertolani, Arianna,Molinari, Francesco,Conti, Paola
, p. 78 - 82 (2012)
The lipase-catalysed kinetic resolution of flurbiprofen was performed in a flow-chemistry reactor allowing for a significant reduction of the reaction time compared to the classical batch method. The process was implemented by adding an in-line purification step of the exiting solution, consisting in a catch and release protocol, which allows easy separation and recovery of both (S)-flurbiprofen and (R)-flurbiprofen butyl ester with an enantiomeric excess ≥90% and a chemical purity >98%.
Direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen
Ghanem, Ashraf
, p. 597 - 603 (2010)
The solvent versatility of Chiralpak IB, a 3,5-dimethylphenylcarbamate derivative of cellulose-based chiral stationary phase, is demonstrated in the direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen in nonstandard HPLC organic solvents. Nonstandard HPLC organic solvents were used as the reaction media for the lipase-catalysis and in mean time as diluent to dissolve the difficult to dissolve enzyme substrate (the acid) and as eluent for the simultaneous enantioselective HPLC baseline separation of both substrate and product in one run without any further derivatization.
Resolution of (R,S)-flurbiprofen catalysed by dry mycelia in organic solvent
Spizzo, Patrizia,Basso, Alessandra,Ebert, Cynthia,Gardossi, Lucia,Ferrario, Valerio,Romano, Diego,Molinari, Francesco
, p. 11005 - 11010 (2007)
Mycelia of Aspergillus oryzae display high enantioselectivity towards (R)-flurbiprofen and can be efficiently used in pure organic solvent for the resolution of (R,S)-flurbiprofen through esterification. The use of the lyophilized mycelia facilitates the separation process so that in one step the two enantiomers of flurbiprofen, which are both valuable for pharmaceutical applications, can be easily separated. The biotransformation can be carried out in different apolar solvents using different primary alcohols as nucleophiles under very mild conditions.
A Highly Enantioselective Alkene Methoxycarbonylation Enables a Concise Synthesis of (S)-Flurbiprofen
Harkness, Gavin J.,Clarke, Matthew L.
, p. 4859 - 4863 (2017)
A highly enantioselective synthesis of (S)-flurbiprofen methyl ester in two steps from commercially available 4-bromo-2-fluoro-1,1′-biphenyl is shown. [PdCl2((S)-xylyl-phanephos)] catalyst is used to accomplish both Grignard cross-coupling and the highly enantioselective intermolecular methoxycarbonylation reaction.
Enantioseparation of Racemic Flurbiprofen by Aqueous Two-Phase Extraction With Binary Chiral Selectors of L-dioctyl Tartrate and L-tryptophan
Chen, Zhi,Zhang, Wei,Wang, Liping,Fan, Huajun,Wan, Qiang,Wu, Xuehao,Tang, Xunyou,Tang, James Z.
, p. 650 - 657 (2015)
A novel method for chiral separation of flurbiprofen enantiomers was developed using aqueous two-phase extraction (ATPE) coupled with biphasic recognition chiral extraction (BRCE). An aqueous two-phase system (ATPS) was used as an extracting solvent which was composed of ethanol (35.0% w/w) and ammonium sulfate (18.0% w/w). The chiral selectors in ATPS for BRCE consideration were L-dioctyl tartrate and L-tryptophan, which were screened from amino acids, β-cyclodextrin derivatives, and L-tartrate esters. Factors such as the amounts of L-dioctyl tartrate and L-tryptophan, pH, flurbiprofen concentration, and the operation temperature were investigated in terms of chiral separation of flurbiprofen enantiomers. The optimum conditions were as follows: L-dioctyl tartrate, 80 mg; L-tryptophan, 40 mg; pH, 4.0; flurbiprofen concentration, 0.10 mmol/L; and temperature, 25 C. The maximum separation factor α for flurbiprofen enantiomers could reach 2.34. The mechanism of chiral separation of flurbiprofen enantiomers is discussed and studied. The results showed that synergistic extraction has been established by L-dioctyl tartrate and L-tryptophan, which enantioselectively recognized R- and S-enantiomers in top and bottom phases, respectively. Compared to conventional liquid-liquid extraction, ATPE coupled with BRCE possessed higher separation efficiency and enantioselectivity without the use of any other organic solvents. The proposed method is a potential and powerful alternative to conventional extraction for separation of various enantiomers. Chirality 27:650-657, 2015.
Different in vitro activity of flurbiprofen and its enantiomers on human articular cartilage
Panico,Cardile,Vittorio,Ronsisvalle,Scoto,Parenti,Gentile,Morrone,Nicolosi
, p. 1339 - 1344 (2003)
The 2-arylpropionic acid derivatives or 'profens' are an important group of non-steroidal anti-inflammatory drugs that have been used for the symptomatic treatment of various forms of arthritis. These compounds are chiral and the majority of them are stil
Chiral liquid chromatography-mass spectrometry (LC-MS/MS) method development with β-cyclodextrin (β-CD) derivatized chiral stationary phase for the enhanced separation and determination of flurbiprofen enantiomers: Application to a stereoselective pharmacokinetic study
Cai, Liangzhao,Guo, Xingjie,Liu, Beibei,Sun, Jiayi,Yu, Jia
, p. 10334 - 10342 (2020)
A method was developed and validated for the enantioselective determination of flurbiprofen in rat plasma using liquid chromatography/electrospray ionization-tandem mass spectrometry under reversed-phase elution mode. Two polysaccharide derivatized chiral stationary phases and a homemade β-cyclodextrin (β-CD) derivatized based chiral column were evaluated. The latter one, a per-4-chlorophenylcarbamate-β-cyclodextrin bonded chiral stationary phase which was synthesized in our laboratory, enabled the highly sensitive detection and complete separation (resolution 2.0) of the flurbiprofen enantiomers. The assay was carried out after the solid-phase extraction procedure with C18 cartridges, and with R-(-)-ibuprofen used as the internal standard. The developed method has been validated for specificity, linearity, accuracy, precision, recovery, matrix effect, stability, carryover effect and dilution effect. The lower limit of quantification for R-flurbiprofen and S-flurbiprofen was 10 ng mL-1 in rat plasma, respectively. Linearity was confirmed in the range of 10.0-20000.0 ng mL-1 with a correlation coefficient (r2) greater than 0.996. The established method was successfully applied to a stereoselective pharmacokinetic study of flurbiprofen enantiomers in rat plasma following oral administration. This journal is
