138729-47-2 Usage
Description
Eszopiclone, also known as the (5S)-enantiomer of zopiclone, is a non-benzodiazepine hypnotic agent that belongs to the cyclopyrrolone class of drugs. It is characterized by its white to pale yellow appearance and has a higher binding affinity for the GABA-A receptor compared to its antipode. Approved by the FDA in December 2004, Eszopiclone is effective in treating insomnia and is unique in that it is approved for long-term use, unlike most other hypnotic sedatives.
Uses
Used in Pharmaceutical Industry:
Eszopiclone is used as a hypnotic and sedative agent for the treatment of insomnia. It helps in addressing difficulty falling asleep, maintaining sleep, frequent awakenings during the night, waking up too early, inability to fall back asleep, and not feeling refreshed upon waking up in the morning.
Eszopiclone is used as a long-term treatment option for insomnia, as it does not lead to tolerance development in patients even after 6 months of use. This makes it a preferred choice for managing chronic insomnia.
Additionally, Eszopiclone is used as an active ingredient in various brand-name medications, such as Lunesta (Sepracor) and Ortho-EST (Sun), which are prescribed to patients suffering from insomnia.
References
https://en.wikipedia.org/wiki/Eszopiclone
http://www.medicinenet.com/eszopiclone/article.htm
https://pubchem.ncbi.nlm.nih.gov/compound/969472#section=Top
Originator
Aventis (France)
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.
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Pharmacokinetics
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.
Synthesis
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).
Metabolism
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.
Check Digit Verification of cas no
The CAS Registry Mumber 138729-47-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,8,7,2 and 9 respectively; the second part has 2 digits, 4 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 138729-47:
(8*1)+(7*3)+(6*8)+(5*7)+(4*2)+(3*9)+(2*4)+(1*7)=162
162 % 10 = 2
So 138729-47-2 is a valid CAS Registry Number.
InChI:InChI=1/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
138729-47-2Relevant articles and documents
Are Highly Stable Covalent Organic Frameworks the Key to Universal Chiral Stationary Phases for Liquid and Gas Chromatographic Separations?
Cui, Yong,Jia, Wenyan,Li, Yanan,Yu, Ziyun,Yuan, Chen,Yuan, Li-Ming,Zi, Min
, p. 891 - 900 (2022/02/03)
High-performance liquid chromatography (HPLC) and gas chromatography (GC) over chiral stationary phases (CSPs) represent the most popular and highly applicable technology in the field of chiral separation, but there are currently no CSPs that can be used for both liquid and gas chromatography simultaneously. We demonstrate here that two olefin-linked covalent organic frameworks (COFs) featuring chiral crown ether groups can be general CSPs for extensive separation not only in GC but also in normal-phase and reversed-phase HPLC. Both COFs have the same 2D layered porous structure but channels of different sizes and display high stability under different chemical environments including water, organic solvents, acids, and bases. Chiral crown ethers are periodically aligned within the COF channels, allowing for enantioselective recognition of guest molecules through intermolecular interactions. The COF-packed HPLC and GC columns show excellent complementarity and each affords high resolution, selectivity, and durability for the separation of a wide range of racemic compounds, including amino acids, esters, lactones, amides, alcohols, aldehydes, ketones, and drugs. The resolution performances are comparable to and the versatility is superior to those of the most widely used commercial chiral columns, showing promises for practical applications. This work thus advances COFs with high stability as potential universal CSPs for chromatography that are otherwise hard or impossible to produce.
Method for synthesizing eszopiclone
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Paragraph 0047-0049, (2018/04/02)
The invention provides a method for synthesizing eszopiclone. According to the method, chiral imidazo thiazole is taken as a catalyst to catalyze a racemic hemiacetal intermediate and chloro-formic ester to produce kinetic resolution reaction, and (S)-hemiacetal carbonic ester with good yield and enantioselectivity is obtained. The (S)-hemiacetal carbonic ester is reacted with N-methyl piperazine, so that eszopiclone can be obtained. The method has the advantages that the chiral imidazo thiazole which is low in cost and easy to obtain is used as the catalyst, operation procedures are simple, the production cost is low, and the method has very high application value for the industrial preparation of eszopiclone.
Strategy Approach for Direct Enantioseparation of Hyoscyamine Sulfate and Zopiclone on a Chiral αl-Acid Glycoprotein Column and Determination of Their Eutomers: Thermodynamic Study of Complexation
Zaazaa, Hala E.,Salama, Nahla N.,Abd El Halim, Lobna M.,Salem, Maissa Y.,Abd El Fattah, Laila E.
, p. 49 - 57 (2016/02/20)
Rapid and simple isocratic high-performance liquid chromatographic methods with UV detection were developed and validated for the direct resolution of racemic mixtures of hyoscyamine sulfate and zopiclone. The method involved the use of αl-acid glycoprotein (AGP) as chiral stationary phase. The stereochemical separation factor (Greek small letter alpha with tonos) and the stereochemical resolution factor (Rs) obtained were 1.29 and 1.60 for hyoscyamine sulfate and 1.47 and 2.45 for zopiclone, respectively. The method was used for determination of chiral switching (eutomer) isomers: S-hyoscyamine sulfate and eszopiclone. Several mobile phase parameters were investigated for controlling enantioselective retention and resolution on the chiral AGP column. The influence of mobile phase, concentration and type of uncharged organic modifier, ionic strength, and column temperature on enantioselectivity were studied. Calibration curves were linear in the ranges of 1-10 μg mL-1 and 0.5-5 μg mL-1 for S-hyoscyamine sulfate and eszopiclone, respectively. The method is specific and sensitive, with lower limits of detection and quantifications of 0.156, 0.515 and 0.106, 0.349 for S-hyoscyamine sulfate and eszopiclone, respectively. The method was used to identify quantitatively the enantiomers profile of the racemic mixtures of the studied drugs in their pharmaceutical preparations. Thermodynamic studies were performed to calculate the enthalpic ΔH and entropic ΔS terms. The results showed that enantiomer separation of the studied drugs were an enthalpic process.
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