Etoricoxib

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H310：Lebensgefahr bei Hautkontakt.

• Sicherheit

  P262：Nicht in die Augen, auf die Haut oder auf die Kleidung gelangen lassen.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P270：Bei Gebrauch nicht essen, trinken oder rauchen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P301+P312：BEI VERSCHLUCKEN: Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

Etoricoxib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Etoricoxib is a COX-2 inhibitor developed as a follow-up of rofecoxib for the treatment of osteoarthritis, rheumatoid arthritis, dysmenorrhoea, gout, ankylosing spondylitis and pain. Several processes describe the preparation of etoricoxib in 4 or 5 steps from 6- methylnicotinate. The key step is the novel pyridine construction using annulation of a ketosutfone with a vinamidinium synthon. In human whole blood, in vitro, the IC₅₀ value obtained for inhibition of COX-2 is 1 .I μM as compared to 116 μM obtained for inhibition of COX-1. Thus, etoricoxib is the most selective COX-2 inhibitor to date, with a COX-IKOX- 2 ratio of IC₅₀ values of 106 for etoricoxib as compared to 35, 30, 7.6 for rofecoxib, valdecoxib and celecoxib, respectively. Its in vivo potency is generally comparable to that of rofecoxib in animal models against inflammation (carrageenan-induced paw edema), pyrexia (LPS-induced pyresis), pain (carrageenan-induced hyperalgesia) and arthritis (adjuvant-induced arthritis). Etoricoxib is well tolerated with dose-proportional pharmacokinetics. It has no effect on bleeding time or platelet ag regation. The gastrointestinal tolerability of etoricoxib is excellent as demonstrated by [⁵¹Cr] models of excretion in rats and squirrel monkeys. Moreover, etoricoxib, unlike naproxen is not associated with significant inhibition of gastric mucosal PGE₂ synthesis compared to placebo. Etoricoxib is highly absorbed, has a t_max of 1.5 h and a half-life time of approximately 15-22h. Five metabolites, weak inhibitors of COX-1 and COX-2 have been identified after renal excretion. Finally, although multiple CYP enzymes are involved in the metabolism of etoricoxib (CYP3A4 being the major contributor), etoricoxib is not a potent CYP3A4 inhibitor or inducer. In patients undergoing molar extraction, etoricoxib showed similar efficacy to naproxen sodium with a longer duration of analgesia than acetaminophen/codeine (approximately ＞24 h, 22 h and 5.2 h, respectively) and a better total pain relief score over 8 h. Similar efficacy of etoricoxib and naproxen was also seen in patients suffering of osteoarthritis. In the treatment of rheumatoid arthritis and ankylosing spondylitis, etoricoxib demonstrated significantly superior efficacy compared to naproxen and placebo. Etoricoxib did not affect the pharmacokinetics of prednisolone (i.v. or p.0.) and its co-administration with antacids showed insignificant effects on the maximal concentration and its absorption. .

• Chemische Eigenschaften

  Off-White Powder

• Originator

  Merck & Co (USA)

• Verwenden

  For the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout.

• Verwenden

  anti-inflammatory, analgesic;cyclooxygenase inhibitor

• Verwenden

  Etoricoxib is a dipyridinyl compound that demonstrates high in vitro and ex vivo selectivity for COX-2 over COX-1 in several assays, e.g., in the production of PGE2 by CHO cells expressing either COX-2 (IC50 = 79 nM) or COX-1 (IC50 > 50 μM). Oral etoricoxib is well absorbed and metabolized extensively via oxidation, with metabolites excreted largely in the urine.[Cayman Chemical]

• Verwenden

  Labeled Etoricoxib, intended for use as an internal standard for the quantification of Etoricoxib by GC- or LC-mass spectrometry.

• Verwenden

  A specific inhibitor of COX-2 .

• Definition

  ChEBI: A member of the class of bipyridines that is 2,3'-bipyridine which is substituted at the 3, 5, and 6' positions by 4-(methylsulfonyl)phenyl, chlorine, and methyl groups, respectively.

• Trademarks

  Arcoxia

• Pharmakokinetik

  Etoricoxib is rapidly absorbed, with an oral bioavailability of 80 to 100%, and reaches maximum plasma concentrations in 1 to 2 hours after dosing. Food decreases the rate of absorption but has no effect on the extent of absorption. It exhibits a long elimination half-life of approximately 22 hours, demonstrating linear plasma pharmacokinetics with no accumulation during multiple dosing.

• Clinical Use

  Etoricoxib is a selective COX-2 inhibitor being developed for postsurgical treatment of dental pain (120 mg) and osteoarthritis. It has a methylsulfonyl group common to the other coxib inhibitors.

• Synthese

  The synthesis of etoricoxib (8) was explored extensively by the Merck process research group. Key intermediate 85 was synthesized through at least three different routes. In the Horner-Wittig approach, 6-methyl methylnicotinate (79) was converted into Weinreb amide 80 in 95% yield. Amide 80 was then converted to aldehyde 81 via a DIBAL-H mediated reduction. Subsequent treatment of a solution of aldehyde 81 in isopropyl acetate with aniline and diphenyl phosphite provided N,P-acetal 82 in 87% yield. The Horner-Wittig reaction of N,P-acetal 82 with 4-methanesulfonylbenzaldehyde (83) furnished enamine 84, which was hydrolyzed to ketosulfone 85. A Grignard approach was also developed in the preparation of ketosulfone 85. Addition of Grignard reagent 86 to Weinreb amide 80 in toluene/THF provided ketosulfide 85 in 80% yield. Tungstate-catalyzed oxidation of ketosulfide 87 using hydrogen peroxide provided ketosulfone 85 in 89% yield by simple filtration. Ketosulfone 85 was prepared through Claisen condensation protocol as well. Thus, reaction of 4-methanesulfonyl phenyl acetic acid (88) with methyl nicotinate 79 under Ivanoff condition, i.e., the magnesium dianion in THF, resulted 58% yield of ketosulfone 85. Treatment of ketosulfone 85 with a three-carbon electrophile, 2-chloro-N,Ndimethylaminotrimethinium hexafluorophos-phate (89) in the presence of potassium t-butoxide at ambient temperature resulted adduct 90. Inverse quench of adduct 90 into a mixture of HOAc /TFA led to the putative intermediate 91. Ring closure of the pyridine ring occurred upon heating at reflux in the presence of an excess of aqueous ammonium hydroxide to give desired etoricoxib (8) in 97% yield in a one-pot process from 85.

  

• Arzneimittelwechselwirkung

  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; concentration reduced by rifampicin.
  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 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; possibly reduced excretion of pemetrexed; 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.
  Tacrolimus: increased risk of nephrotoxicity.

• Stoffwechsel

  Etoricoxib is metabolized involving oxidation of its 6′-methyl group primarily by CYP3A4 but is not an inhibitor of CYP3A4. Other metabolites include 1′-N-oxide and glucuronides. Etoricoxib is primarily excreted as metabolites into the urine.

Etoricoxib Upstream-Materialien And Downstream Produkte

Etoricoxib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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