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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.

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.

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

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. "

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.

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).

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.