Eszopiclone

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P281：Vorgeschriebene persönliche Schutzausrüstung verwenden.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P321：Besondere Behandlung

  P332+P313：Bei Hautreizung: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P362：Kontaminierte Kleidung ausziehen und vor erneutem Tragen waschen.

  P405：Unter Verschluss aufbewahren.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Eszopiclone Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R20/21/22:Gesundheitsschädlich beim Einatmen,Verschlucken und Berührung mit der Haut.
  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
  R62:Kann möglicherweise die Fortpflanzungsfähigkeit beeinträchtigen.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.

• Beschreibung

  Eszopiclone is a non-benzodiazepine hypnotic agent indicated for the treatment of insomnia to induce sleep and for sleep maintenance. It has similar pharmacokinetic and pharmacodynamic parameters as the previously marketed non-benzodiazepine hypnotics zolpidem and zaleplon. However, unlike its predecessors, eszopiclone is not restricted to short-term treatment of insomnia. Clinical studies of up to 6 months of use show that patients do not develop tolerance to its effect. Eszopiclone is the (S)-enantiomer of zopiclone, which has been marketed as the racemic mixture in Europe for almost 20 years. These agents belong to the cyclopyrrolone class of drugs that act as agonists at the type A GABA receptor. Eszopiclone has approximately 50-fold higher binding affinity than its antipode (R)-zopiclone for GABA-A receptor (IC₅₀=21 and 1130 nM, respectively). In addition, the two enantiomers exhibit significant differences in their pharmacokinetic parameters and in vivo efficacy. In healthy volunteers, eszopiclone has 2-fold higher C_max and 2-fold greater elimination half-life than the (R)-enantiomer.The two most frequent adverse events associated with eszopiclone treatment are unpleasant taste and headache. Other less frequent side effects include somnolence, dry mouth, and nausea.

• Chemische Eigenschaften

  White To Pale Yellow

• Originator

  Aventis (France)

• Verwenden

  Eszopiclone is the active stereoizomer of Zopiclone and belongs to the class of drug known as cyclopyrrones. It is a nonbenzodiazepine hypnotic agent used as a treatment for insomnia. This is a controlled substance (depressant) in the US but not in Canada.

• Definition

  ChEBI: The (5S)- (active) enantiomer of zopiclone. Unlike almost all other hypnotic sedatives, which are approved only for the relief of short-term (6-8 weeks) insomnia, eszopiclone is approved by the U.S. Food and Drug Administration for long-te m use.

• Trademarks

  (Pharmacia & Upjohn); Ortho-EST (Sun)Lunesta (Sepracor).

• Mechanism of action

  The cyclopyrrole zopiclone is described as a “superagonist” at BZRs with the subunit composition α1β2γ2 and α1β2γ3, because it potentiates the GABA-gated current more than the benzodiazepine (flunitrazepam) reference agonist. Racemic zopiclone has been available in Europe since 199,2 and the higher affinity S-enantiomer (eszopiclone) was marketed in the United States in 2005, primarily to treat insomnia, because of its rapid onset and moderate duration (half-life, ~6 hours) of hypnotic-sedative effect. Less than 10% of orally administered eszopiclone is excreted unchanged, because it undergoes extensive CYP3A4- and CYP2E1-catalyzed oxidation and demethylation to metabolites excreted primarily in urine. "

• Pharmakokinetik

  Zoplicone was originally marketed as a racemic mixture; however, because the sedative activity is primarily associated with the S-isomer, only the S-isomer is currently marketed in the United States (as esozoplicone) (36). It is soluble in dilute mineral acids. Unlike zolpidem and zaleplon, eszoplicone is not as specific for the α1 subunit of GABAA, but it binds broadly, like the benzodiazepines (Table 19.2). Its pharmacological and pharmacodynamic activities, however, are more closely related to those of the nonbenzodiazepines. It is rapidly absorbed, with an oral bioavailability of approximately 80%, reaching peak concentrations in 1 h and having a relatively long elimination half-life of approximately 6 hours (Table 19.2). Eszopliclone is primarily metabolized to (S)-zoplicone N-oxide and (S)-N-desmethylzoplicone by the CYP3A4. (S)-Ndesmethylzopiclone binds to GABA receptors with substantially lower potency than eszopiclone, and (S)-zopiclone-N-oxide shows no significant binding to this receptor. It does not accumulate with once-daily administration, and it exhibits linear (dose-proportional) pharmacokinetics over the range of 1 to 6 mg. Eszopiclone is weakly bound to plasma protein (52–60%), suggesting that eszopiclone distribution should not be affected by drug–drug interactions caused by protein binding. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for eszopiclone. Less than 10% of the orally administered eszopiclone dose is excreted in the urine as unchanged drug. After a high-fat meal, peak plasma concentrations can be delayed by approximately 1 hour without affecting its half-life.

• Synthese

  The synthesis of eszopicolone involves enzymatic resolution of a zopicolone derivative to give the chiral compound as depicted in the Scheme 12. Pyrazine-2,3- dicarboxylic acid anhydride was reacted with 2-amino- 5-chloropyridine (61) in refluxing acetonitrile to generate 3- (5-chloro-2-pyridyl)carbamoyl pyrazine-2-carboxylic acid (62) in 95% yield. Compound 62 was cyclized by treating with refluxing SOCl2 to give 6-(5-chloropyrid-2-yl)-5,7- dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (63) in 79% yield.Compound 63 was subjected to partial reduction with KBH4 in dioxane-water at low temperature to give 6-(5-chloro-2- pyridyl)-7-hydroxy-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one (64) in 64% yield, which was esterified with vinyl chloroformate in pyridine to give corresponding vinyl acetate 65 in 75% yield. The racemic 65 was then subjected to kinetic resolution by a highly enantioselective enzymatic hydrolysis process. Chiral vinyl acetate 67 with desired stereochemistry was obtained when candida antarctica lipase was employed for hydrolysis of 65 in dioxane/water at 60oC for 2 days. Interestingly, the enzymatic hydrolysis stopped at 50% conversion and the hydrolyzed alcohol was recovered as the starting substrate 65 because of spontaneous racemization of the alcohol in the reaction medium. Therefore, although a maximum yield of kinetic resolution is 50%, the overall efficiency of this enzymatic process is 100% because of substrate recycling. Finally, the chiral vinyl acetate 67 was condensed with methyl piperazine in acetone to give eszopicolone (IX).

  

• Stoffwechsel

  The effects of eszoplicone on sleep onset may be reduced if it is taken either with or immediately after a high-fat/heavy meal. In elderly subjects, the elimination half-life was prolonged to approximately 5 to 9 hours. Therefore, in elderly patients, the starting dose should be decreased to 1 mg, and the dose should not exceed 2 mg. No dose adjustment is necessary in patients with renal impairment, because less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug. Although no pharmacokinetic or pharmacodynamic or drug interactions have been reported for eszopiclone, potent inhibitors of CYP3A4 could increase plasma levels of eszopiclone. Eszopiclone does not alter the clearance of drugs metabolized by common CYP450 enzymes. Potential pharmacodynamic interactions (additive pharmacological effects) with CNS depressants such as alcohol, anticonvulsants, antihistamines, antidepressants, or other psychotropic drugs could occur. Dosage adjustment may be necessary when eszopiclone is administered with CNS depressants; concomitant use with alcohol should be avoided.
  The primary advantage of eszoplicone is that it has been shown to be effective in chronic insomnia (long-term treatment) in measures of sleep latency, total sleep time, and wake time after sleep onset without development of tolerance. Eszoplicone would appear to be most effectively used for patients who tend to awaken during the night rather than patients for whom the primary problem is initiating sleep.

Eszopiclone Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(221)Suppliers

138729-47-2, Eszopiclone Verwandte Suche: