22204-53-1 Usage
Uses
Used in Pharmaceutical Industry:
Naproxen is used as an anti-inflammatory, analgesic, and antipyretic agent for the treatment of various conditions such as arthritis, gout, and dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes, which are involved in the production of prostaglandins, inflammatory mediators that cause pain, fever, and inflammation.
Used in Over-the-Counter (OTC) Medicines:
Naproxen is available as an OTC medication in the form of 200-mg tablets (Aleve) for the relief of pain, fever, and inflammation associated with various conditions.
Used in Prescription Medicines:
Naproxen is also used in prescription medications such as Naprosyn and Anaprox for the treatment of more severe or chronic conditions like rheumatoid arthritis, osteoarthritis, and acute gouty inflammation.
Used in Research and Development:
Naproxen serves as a reference compound in the development and testing of new NSAIDs and other anti-inflammatory drugs, due to its well-established potency and efficacy.
Used in Veterinary Medicine:
Naproxen is also used in veterinary medicine for the treatment of pain and inflammation in animals, similar to its use in humans.
Non-steroidal anti-inflammatory drugs
Naproxen is a non-steroidal anti-inflammatory drug ,it is a PG synthase inhibitor, which can inhibit prostaglandin synthetase, it has significant analgesic and antipyretic effects, oral absorption is rapid and complete, 2 to 4 hours after a dose ,plasma concentration reaches the peak, in the blood , more than 99% is bound to plasma proteins, t1/2 is 13 to 14 hours, about 95% is discharged from the urine with the prototype and metabolites.it is clinically used For the treatment of rheumatic and rheumatoid arthritis , osteoarthritis, ankylosing spondylitis, gout, arthritis, tenosynovitis.it can also be used to alleviate pain caused by musculoskeletal sprains, contusions,damages and dysmenorrhea . But it should be noted that like other non-steroidal anti-inflammatory drugs, the same serious gastrointestinal adverse reactions could occur at any time while taking naproxen during treatment, so the active gastroduodenal ulcer patients are hanged, other gastrointestinal tract disease patients should take this drug under close medical supervision.
The above information is edited by the lookchem of Tian Ye.
Used in Particular Diseases
Acute Gouty Arthritis:
Dosage and Frequency:?500 mg twice daily for 3 days, then 250–500 mg daily for 4–7 days
production method
by methylation, acetylation With 2-naphthol , 6-methoxy-2-acetonaphthone is produced, then it is condensed with acid ester, then generate the product through isomerization, hydrolysis, oxidation, and split and other reactions.
Toxicity grading
Highly toxic
Acute toxicity
Oral-rat LD50 248 mg/kg; Oral-Mouse LD50: 360 mg/kg
Flammability and hazard characteristics
Combustible; combustion produces toxic and acrid smoke.
Storage Characteristics
Ventilated, low-temperature ,dry storeroom, it should be stored and transported from food raw materials separately.
Extinguishing agent
Water, dry powder, foam,sand
Originator
Naprosyn,Syntex,UK,1973
Indications
Naproxen (Naprosyn) also has pharmacological
properties and clinical uses similar to those of ibuprofen.
It exhibits approximately equal selectivity for
COX-1 and COX-2 and is better tolerated than certain
NSAIDs, such as indomethacin. Adverse reactions related
to the GI tract occur in about 14% of all patients,
and severe GI bleeding has been reported. CNS complaints
(headache, dizziness, drowsiness), dermatological
effects (pruritus, skin eruptions, echinoses), tinnitus,
edema, and dyspnea also occur.
Manufacturing Process
According to US Patent 3,658,858, a solution of 24 grams of 2-bromo-6-
methoxynaphthalene in 300 ml of tetrahydrofuran is slowly added to 2.5
grams of magnesium turnings and 100 ml of tetrahydrofuran at reflux
temperature. After the addition is complete, 20 grams of cadium chloride is
added, and the resultant mixture is refluxed for 10 minutes to yield a solution
of di-(6-methoxy-2-naphthyl)cadmium (which can be separated by
conventional chromatography, although separation is unnecessary).A solution of 18 grams of ethyl 2-bromopropionate in 20 ml of tetrahydrofuran
is then added to the cooled reaction mixture. After 24 hours at 20°C, the
product is hydrolyzed by adding 200 ml of 5 weight percent methanolic
sodium hydroxide followed by heating to reflux for 1 hour. The reaction
mixture is then diluted with excess 1 N sulfuric acid and extracted with ether.
The ether phase is separated, evaporated to dryness and the residue is
recrystallized from acetone-hexane to yield 2-(6-methoxy-2-
naphthyl)propionic acid.
Therapeutic Function
Antiinflammatory
Synthesis Reference(s)
Tetrahedron, 49, p. 8433, 1993 DOI: 10.1016/S0040-4020(01)81926-8
Pharmacokinetics
Naproxen is almost completely absorbed following oral administration. Peak plasma levels are achieved within 2 to 4
hours following administration. Like most of the acidic NSAIDs (pKa = 4.2), it is highly bound (99.6%) to plasma
proteins. Approximately 70% of an administered dose is eliminated as either unchanged drug (60%) or as conjugates
of unchanged drug (10%). The remainder is converted to the 6-O-desmethyl metabolite by both CYP3A4 and CYP1A2
and, further, to the glucuronide conjugate of the demethylated metabolite. The 6-O-desmethyl metabolite lacks
anti-inflammatory activity. Like most of the arylalkanoic acids, the most common side effect associated with the use
of naproxen is irritation to the GI tract. The most common other adverse reactions are associated with CNS
disturbances (e.g., nausea and dizziness).
Clinical Use
Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing
spondylitis, tendinitis, bursitis, acute gout, and primary dysmenorrhea and for the relief of mild to moderate pain.
Synthesis
Naproxene, 2-(6-methoxy-2-naphthyl)-propionic acid (3.2.15) can be synthesized by the methods of synthesis described for ibuprofen as well as by the methods of
fenoprofen (3.2.21) and ketoprofen (3.2.27) synthesis that will be described below from
2-acetyl or 2-chloromethyl-6-methoxynaphthaline [99–101].
Veterinary Drugs and Treatments
The manufacturer lists the following indications: “…for the relief
of inflammation and associated pain and lameness exhibited with
myositis and other soft tissue diseases of the musculoskeletal system
of the horse.” (Package Insert; Equiproxen?—Syntex). It has
also been used as an antiinflammatory/analgesic in dogs for the
treatment of osteoarthritis and other musculoskeletal inflammatory
diseases (see adverse reactions below).
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 of 2 or more
NSAIDs, including aspirin (increased side effects);
avoid with ketorolac (increased risk of 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 heparins, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas
enhanced.
Antiepileptics: possibly increased phenytoin
concentration.
Antivirals: increased risk of haematological toxicity
with zidovudine; concentration possibly increased by
ritonavir.
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 decreased.
Pentoxifylline: increased risk of bleeding.
Probenecid: excretion reduced by probenecid.
Tacrolimus: increased risk of nephrotoxicity.
Metabolism
Naproxen is extensively metabolised in the liver
to 6-0-desmethyl naproxen. Both naproxen and
6-0-desmethyl naproxen are further metabolised to their
respective acylglucuronide conjugated metabolites.
About 95% of a dose is excreted in urine as naproxen and
6-O-desmethylnaproxen and their conjugates. Less than
5% of a dose appears in the faeces.
references
[1] barnett j, chow j, ives d, et al. purification, characterization and selective inhibition of human prostaglandin g/h synthase 1 and 2 expressed in the baculovirus system[j]. biochimica et biophysica acta (bba)-protein structure and molecular enzymology, 1994, 1209(1): 130-139.[2] laneuville o, breuer d k, dewitt d l, et al. differential inhibition of human prostaglandin endoperoxide h synthases-1 and-2 by nonsteroidal anti-inflammatory drugs[j]. journal of pharmacology and experimental therapeutics, 1994, 271(2): 927-934.[3] dubois r n, abramson s b, crofford l, et al. cyclooxygenase in biology and disease[j]. the faseb journal, 1998, 12(12): 1063-1073.[4] agdeppa e d, kepe v, petri a, et al. in vitro detection of (s)-naproxen and ibuprofen binding to plaques in the alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18 f] fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene) malononitrile[j]. neuroscience, 2003, 117(3): 723-730.
Check Digit Verification of cas no
The CAS Registry Mumber 22204-53-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,2,2,0 and 4 respectively; the second part has 2 digits, 5 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 22204-53:
(7*2)+(6*2)+(5*2)+(4*0)+(3*4)+(2*5)+(1*3)=61
61 % 10 = 1
So 22204-53-1 is a valid CAS Registry Number.
InChI:InChI=1/C14H14O3/c1-9(14(15)16)10-3-4-12-8-13(17-2)6-5-11(12)7-10/h3-9H,1-2H3,(H,15,16)/p-1/t9-/m0/s1
22204-53-1Relevant articles and documents
Asymmetric Synthesis of (S)-2-(6-methoxy-2-naphthyl)propanoic Acid
Hiyama, Tamejiro,Saito, Kumi,Sato, Ken-ichi,Wakasa, Noriko,Inoue, Masuo
, p. 1471 - 1472 (1986)
For the synthesis of the title compound of 60 percent ee, a new method is established which involves cyanation of an acetal derived from 1-(6-methoxy-2-naphthyl)ethanone and (S,S)-2,4-pentanediol, alkaline hydrolysis, and finally hydrogenolysis with palladium catalyst.
Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver
Lo,Addison,Hooper,Dickinson
, p. 309 - 319 (2001)
1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 μg NAP equivalents ml-1 perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t1/2) of 13.4 ± 4.4 h. No metabolites were detected in perfusate, while NAG was the only metabolite present in bile in measurable amounts (3.9 ± 0.8% of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t1/2 in perfusate = 57 ± 3 and 75 ± 14 min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.
New synthesis of optically active α-arylpropanoic acid: The asymmetric hydrogenation of atropic acid over cinchona-modified Pd/Fe2O3 catalysts
Ma,Wang,Shi
, p. 175 - 182 (2003)
The first satisfactory application of the heterogeneous cinchona-modified Pd/Fe2O3 catalyst system in the synthesis of optically active α-arylpropanoic acid, namely, the highly enantioselective (up to 87% ee) hydrogenation of atropic acid to S-(+)-naproxen is described.
Catalytically distinct antibodies prepared by the reactive immunization versus transition state analogue hapten manifolds
Datta, Anita,Wentworth Jr., Paul,Shaw, Joanne P.,Simeonov, Anton,Janda, Kim D.
, p. 10461 - 10467 (1999)
This report describes the first direct comparison between the reactive immunization and transition state analogue hapten manifolds for catalytic antibody production. In an initial communication (Janda et al J. Am. Chem. Soc. 1997, 119, 10251) we described the use of a phosphonate diester hapten 5, in a reactive immunization approach, that elicited a panel of proficient biocatalysts for the hydrolysis of S-(+)-naproxen p-methylsulfonylphenyl ester (3b) [k(cat)(3b)/k(uncat)(3b) = 0.05-6.60 x 105]. However, only moderate enantioselectivity was obtained when the panel of antibody catalysts was studied in a kinetic resolution of rac-3a, the best result leading to S- (+)-4a in 90% ee for 35% conversion of rac-3a. This report details a transition state analogue hapten approach to elicit antibody catalysts for this same process by employment of phosphonate monoester 6. This strategy has yielded a library of catalysts with excellent turnover numbers [k(cat)(3b)/k(uncat)(3b) = 0.14-19.0 x 105] and enantioselectivities. Three of these catalysts, 6G6, 12C8, and 12D9, perform a useful kinetic resolution of rac-3a, generating S-(+)-naproxen 4a in >98% ee with up to 50% conversion. Comparing the two hapten strategies reveals that the antibodies, although elicited for the same reaction with the same substrate, exhibit quite different catalytic behavior. The transition state analogue approach has furnished better catalysts, in terms of turnover numbers and enantiomeric discrimination, but which possess varying degrees of product inhibition by phenol 9. Thermodynamic evaluation reveals that their catalytic power is derived almost entirely as a function of differential stabilization of the transition state over the ground state: K(m)(3b)/K(i)(8). By contrast, the reactive immunization approach has elicited more proficient biocatalysts that couple an efficient 'catalytic' mechanism and improved substrate recognition with no product inhibition.
Fabrication of a nano-drug delivery system based on layered rare-earth hydroxides integrating drug-loading and fluorescence properties
Gu, Qingyang,Chen, Wen,Duan, Fei,Ju, Ruijun
, p. 12137 - 12143 (2016)
We demonstrate the first example of intercalation of naproxen (abbr. NPX) into layered europium hydroxide (LEuH) and investigate the structure, chemical composition, thermostability, morphology, luminescence properties, cytotoxic effect, and controlled-release behaviors. Different deprotonation degrees lead to NPX-LEuH composites with diverse structures (horizontal or vertical arrangement), and the thermal stability of organics is enhanced after intercalation. The Eu3+ luminescence in NPX-LEuH composites is enhanced, especially for the NPX-LEuH-1: 0.5 composite. The content of naproxen in the intercalation material can be confirmed by HPLC. The cytotoxic effect of LEuH is observed with a sulforhodamine B (SRB) colorimetric assay, which reveals that the LEuH has low cytotoxic effects on most cells. In addition, the NPX-LEuH nanocomposites can control the release of NPX in Na2HPO4-NaH2PO4 buffer solution at pH 6.86 and 37 °C, and the complete release needs about 200 min. The release mechanism can be ascribed to the ion-exchange reaction between NPX and HPO42-/H2PO4- in bulk solution. The ion-exchange velocity is fast at the beginning and slows down gradually with the exchange reaction. The construction of LRH composites with drug molecules provides a beneficial pathway for preparing a nano-drug delivery system based on LRHs integrating drug-loading and fluorescence properties.
Efficient resolution of naproxen by inclusion crystallization with N-octyl-glucamine and structure characterization of the inclusion complex
Yuan, Xuejun,Li, Jiguo,Tian, Yunqi,Lee, Gene-Hsiang,Peng, Xie-Ming,Zhu, Rongguang,You, Xiaozeng
, p. 3015 - 3018 (2001)
(S)-(+)-Naproxen was directly resolved from the racemate with high enantiopurity (>95% e.e.) by inclusion crystallization using N-octyl-D-(-)-glucamine as the chiral host. The crystal structure of the inclusion complex was determined.
Asymmetric dihydroxylation in an approach to the enantioselective synthesis of 2-arylpropanoic acid non-steroidal anti-inflammatory drugs
Griesbach, Robert C.,Hamon, David P. G.,Kennedy, Rebecca J.
, p. 507 - 510 (1997)
Naproxen ((S)-2-(6-methoxy-2-naphthyl)propanoic acid) and flurbiprofen ((S)2-3 -fluoro-4-phenylphenyl) propanoic acid) have been synthesised in high en antiomeric excess. The synthetic strategy employed waste introduce asymmetry into the molecules by Sharpless asymmetric dihydroxylation of the appropriate methyl styrenes. The resultant diols were then converted into optically active epoxides and the required stereogenic centre was assembled by catalytic hydrogenolysis of the introduced benzylic epoxide oxygen bond, followed by oxidation of the derived optically active primary alcohol.
Polymer-supported chiral catalysts with positive support effects
Fan, Qing-Hua,Wang, Rui,Chan, Albert S.C
, p. 1867 - 1871 (2002)
In this paper, we discuss the rational design of polymeric catalysts and the positive effect of polymer supports on the catalytic asymmetric reactions. The attachment of chiral catalysts to soluble polymers, particularly dendritic polymers, offered a potential combination of the advantages of homogeneous and heterogeneous asymmetric catalysis.
Preparation of One-Pot Immobilized Lipase with Fe3O4 Nanoparticles Into Metal-Organic Framework For Enantioselective Hydrolysis of (R,S)-Naproxen Methyl Ester
Ozyilmaz, Elif,Ascioglu, Sebahat,Yilmaz, Mustafa
, p. 3687 - 3694 (2021)
Immobilization of enzyme to magnetic metal-organic frameworks (MOF) can preserve biological functionality in harsh environments to increase enzymes activity, stability, and improve reusability. The magnetic Fe3O4 nanoparticles were treated with calix[4]arene tetracarboxylic acid (Calix) and Candida rugosa lipase (CRL), and then encapsulated into the zeolitic imidazole framework-8 (Fe3O4@Calix-ZIF-8@CRL). The lipase activity data of Fe3O4@Calix-ZIF-8@CRL was 2.88 times higher than that of the Fe3O4@ZIF-8@CRL (without Calix). The catalytic properties of immobilized lipases were studied on the enantioselective hydrolysis of R/S-naproxen methyl ester. It was also observed that Fe3O4@Calix-ZIF-8@CRL has excellent enantioselectivity (E=371) compared to Fe3O4@ZIF-8@CRL (E=131). Furthermore, Fe3O4@Calix-ZIF-8@CRL was seen to still retain 30 % of the conversion rate after the fifth reuse. This work may also be useful for the pharmaceutical industry due to the increased reusability and stability of enzymes, the enantiomeric selectivity exhibited by MOF-enzyme biocomposites, and the significant differences in the biological activities of the enantiomers.
ASYMMETRIC COUPLING OF ARYLMAGNESIUM BROMIDES WITH ALLYLIC ESTERS
Hiyama, Tamejiro,Wakasa, Noriko
, p. 3259 - 3262 (1985)
Arylmagnesium bromides were allowed to react with 3-penten-2-yl (or 2-buten-1-yl) acetate (pivaloate, carbonate, or methyl ether) in the presence of NiCl2 catalyst to afford (R)-4-aryl-2-pentene (or 3-aryl-1-butene) in high chemical and optical yields.
