Eszopiclone CAS 138729-47-2

Introduction：Basic information about Eszopiclone CAS 138729-47-2, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Eszopiclone Basic information

• Product Name: Eszopiclone
• Synonyms: ESOPICLONE;ESZOPICLONE;(S)-(+)-ZOPICLONE;Dexzopiclone;[(9S)-8-(5-Chloropyridin-2-yl)-7-oxo-2,5,8-triazabicyclo[4.3.0]nona-1,3,5-trien-9-yl]4-methylpiperazine-1-carboxylate;Lunesta;ESZOPICLONE CIV;1-Piperazinecarboxylic acid, 4-methyl-, (5S)-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester (9CI)
• CAS: 138729-47-2
• MF: C17H17ClN6O3
• MW: 388.81
• EINECS: 202-303-5
• Product Categories: GABA/Glycine receptor;Intermediates & Fine Chemicals;Sedative, Hypnotic;Pharmaceuticals
• Mol File: 138729-47-2.mol

Eszopiclone Chemical Properties

• Melting point: 202-204°C
• alpha: D20 +135 ±3° (c = 1.0 in acetone)
• Boiling point: 580.7±50.0 °C(Predicted)
• density: 1.54±0.1 g/cm3(Predicted)
• storage temp.: -20°C Freezer
• solubility: Chloroform (Slightly, Heated), Methanol (Slightly, Heated)
• pka: 6.70±0.10(Predicted)
• form: Solid
• color: White to Light Beige
• Major Application: pharmaceutical
• InChI: InChI=1S/C17H17ClN6O3/c1-22-6-8-23(9-7-22)17(26)27-16-14-13(19-4-5-20-14)15(25)24(16)12-3-2-11(18)10-21-12/h2-5,10,16H,6-9H2,1H3/t16-/m0/s1
• InChIKey: GBBSUAFBMRNDJC-INIZCTEOSA-N
• SMILES: N1(C(O[C@H]2C3=NC=CN=C3C(=O)N2C2=NC=C(Cl)C=C2)=O)CCN(C)CC1
• CAS DataBase Reference: 138729-47-2(CAS DataBase Reference)

Safety Information

• Hazard Codes: Xn
• Risk Statements: 20/21/22-36/37/38-62
• Safety Statements: 26-36
• WGK Germany: WGK 3
• HS Code: 2933790002
• Storage Class: 13 - Non Combustible Solids
• Hazard Classifications: Acute Tox. 4 Oral Aquatic Chronic 2 Repr. 2 STOT SE 3
• Hazardous Substances Data: 138729-47-2(Hazardous Substances Data)

Eszopiclone Usage And Synthesis

Description

Approved by the FDA in December 2004, Eszopiclone is a non-benzodiazepine drug with hypnotic and sedative activity which is effective for the treatment of insomnia characterized by difficulty falling asleep, difficulty maintaining sleep or awakening frequently during the night, waking up too early, an inability to fall back to sleep and awakening in the morning not feeling refreshed. Eszopiclone belongs to cyclopyrrolone and dextrorotatory stereoisomer of zopiclone, which was the first non-benzodiazepine approved for insomnia in over 20 years. However, Eszopiclone is a controlled pharmaceuticals. Long-term intake of this substance or any other sedative drug probably induces drug dependence. Patients may experience withdrawal symptoms if the drug is stopped abruptly.

References

https://en.wikipedia.org/wiki/Eszopiclone
http://www.medicinenet.com/eszopiclone/article.htm
https://pubchem.ncbi.nlm.nih.gov/compound/969472#section=Top

Description

Eszopiclone is a non-benzodiazepine hypnotic agent indicated for the treatment ofinsomnia to induce sleep and for sleep maintenance. It has similar pharmacokineticand pharmacodynamic parameters as the previously marketed non-benzodiazepinehypnotics zolpidem and zaleplon. However, unlike its predecessors, eszopiclone isnot restricted to short-term treatment of insomnia. Clinical studies of up to 6months of use show that patients do not develop tolerance to its effect. Eszopicloneis the (S)-enantiomer of zopiclone, which has been marketed as the racemic mixturein Europe for almost 20 years. These agents belong to the cyclopyrrolone class ofdrugs that act as agonists at the type A GABA receptor. Eszopiclone has approximately50-fold higher binding affinity than its antipode (R)-zopiclone for GABA-Areceptor (IC₅₀=21 and 1130 nM, respectively). In addition, the two enantiomersexhibit significant differences in their pharmacokinetic parameters and in vivo efficacy.In healthy volunteers, eszopiclone has 2-fold higher C_max and 2-fold greaterelimination half-life than the (R)-enantiomer.The two most frequent adverse events associated with eszopiclonetreatment are unpleasant taste and headache. Other less frequent side effects includesomnolence, dry mouth, and nausea.

Chemical Properties

White To Pale Yellow

Originator

Aventis (France)

Uses

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-tem use.

Brand name

(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 andα1β2γ3, because it potentiates the GABA-gated current more than the benzodiazepine (flunitrazepam) referenceagonist. 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 andmoderate duration (half-life, ~6 hours) of hypnotic-sedative effect. Less than 10% of orally administeredeszopiclone is excreted unchanged, because it undergoes extensive CYP3A4- and CYP2E1-catalyzed oxidation anddemethylation to metabolites excreted primarily in urine."

Pharmacokinetics

Zoplicone was originally marketed as a racemic mixture; however, because the sedative activity is primarilyassociated 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 α1subunit of GABAA, but it binds broadly, like the benzodiazepines (Table 19.2). Its pharmacological andpharmacodynamic activities, however, are more closely related to those of the nonbenzodiazepines. It israpidly absorbed, with an oral bioavailability of approximately 80%, reaching peak concentrations in 1 h andhaving a relatively long elimination half-life of approximately 6 hours (Table 19.2). Eszopliclone is primarilymetabolized 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-dailyadministration, 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 notbe affected by drug–drug interactions caused by protein binding. Up to 75% of an oral dose of racemiczopiclone 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 isexcreted in the urine as unchanged drug. After a high-fat meal, peak plasma concentrations can be delayed byapproximately 1 hour without affecting its half-life.

Synthesis

The synthesis of eszopicolone involves enzymatic resolutionof a zopicolone derivative to give the chiral compoundas 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 treatingwith 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 KBH4in 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 chloroformatein pyridine to give corresponding vinyl acetate 65 in75% yield. The racemic 65 was then subjected to kineticresolution by a highly enantioselective enzymatic hydrolysisprocess. Chiral vinyl acetate 67 with desired stereochemistrywas obtained when candida antarctica lipase was employedfor hydrolysis of 65 in dioxane/water at 60oC for 2 days.Interestingly, the enzymatic hydrolysis stopped at 50% conversionand the hydrolyzed alcohol was recovered as thestarting substrate 65 because of spontaneous racemization ofthe alcohol in the reaction medium. Therefore, although amaximum yield of kinetic resolution is 50%, the overall efficiencyof this enzymatic process is 100% because of substraterecycling. Finally, the chiral vinyl acetate 67 was condensedwith methyl piperazine in acetone to give eszopicolone(IX).

Metabolism

The effects of eszoplicone on sleep onset may be reduced ifit is taken either with or immediately after a high-fat/heavy meal. In elderly subjects, the elimination half-lifewas prolonged to approximately 5 to 9 hours. Therefore, in elderly patients, the starting dose should bedecreased to 1 mg, and the dose should not exceed 2 mg. No dose adjustment is necessary in patients withrenal impairment, because less than 10% of the orally administered eszopiclone dose is excreted in the urine asparent drug. Although no pharmacokinetic or pharmacodynamic or drug interactions have been reported foreszopiclone, potent inhibitors of CYP3A4 could increase plasma levels of eszopiclone. Eszopiclone does notalter 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 wheneszopiclone 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-termtreatment) in measures of sleep latency, total sleep time, and wake time after sleep onset without developmentof tolerance. Eszoplicone would appear to be most effectively used for patients who tend to awaken duringthe night rather than patients for whom the primary problem is initiating sleep.