Zopiclone

Description

Zopiclone is an agonist at the type A γ-aminobutyric acid (GABA) receptor. It is a non-benzodiazepine hypnotic which was first reviewed in Drugs in 1986 and it is indicated for short-term treatment of insomnia. Zopiclone has a relatively low propensity to cause residual clinical effects (such as difficulty in waking or reduced morning concentration).

References

[1] Stuart Noble, Heather D. Langtry and Harriet M. Lamb, Drugs, 1998, vol. 55, 277-302
[2] G. Hajak, W. E. Müller, H. U. Wittchen, D. Pittrow, W. Kirch, Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data, Addiction, 2003, vol. 98, 1371-1378

Description

Zopiclone is an effective hypnotic agent with a short duration of action. Although it interacts with the benzodiazepine receptor complex, it is reported to have minimal effects on memory, little synergy with alcohol, and low abuse potential.

Chemical Properties

Crystalline Solid

Originator

Rhone-Poulenc (France)

Uses

antihyperammonemic,antineoplastic

Uses

inhibits tyrosinase and prevents melanin formation used to whiten and lighten skin

Uses

Cyclopyrrolone member of a family of non-benzodiazepine GABAA receptor agonists. This is a controlled substance (depressant) in the US but not in Canada. Sedative, hypnotic

Definition

ChEBI: A pyrrolo[3,4-b]pyrazine compound having a 4-methylpiperazine-1-carboxyl group at the 5-position, a 5-chloropyridin-2-yl group at the 6-position and an oxo-substituent at the 7-position.

Manufacturing Process

Producing of 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)-carbonyloxy-7- oxo-5,6-dihydropyrrolo[3,4-b]pyrazine by two methods.
1). A solution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6- dihydropyrrolo[3,4-b]pyrazine (12.0 g) in anhydrous dimethylformamide (360 ml) is added to a suspension of sodium hydride (50% dispersion in mineral oil) (2.4 g) in anhydrous dimethylformamide (60 ml), whilst maintaining the temperature at about -10°C. When the evolution of gas has ceased, a solution of 1-chlorocarbonyl-4-methylpiperazine (8.1 g) in anhydrous dimethylformamide (20 ml) is added, whilst maintaining the temperature at about -10°C. The reaction mixture is stirred for a further 3 h whilst allowing it to heat up gradually to a temperature of about 20°C, and then it is poured into ice-water (1540 ml). The product which crystallizes is filtered off, washed with water (150 ml) and then with diisopropyl ether (100 ml). After drying, a product is obtained and is dissolved in ethyl acetate (600 ml). The solution obtained is filtered through silica gel (250.0 g). Elution is then carried out with ethyl acetate (3200 ml) followed by a mixture of ethyl acetate and methanol The eluates are combined and concentrated to dryness under reduced pressure. So 8.3 g of the 6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)- carbonyloxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine are obtained, melting point 178°C (recrystallisation from a mixture of acetonitrile and diisopropyl ether 1:1; 190 ml).
2). 1-Methylpiperazine (155.0 g) is added to a suspension of 6-(5-chloropyrid- 2-yl)-7-oxo-5-phenoxycarbonyloxy-5,6-dihydropyrrolo[3,4-b]pyrazine (194.0 g) in acetone (970 ml) cooled to a temperature of about 3°C. The reaction mixture is stirred for 3 h at a temperature of about 3°C and is then poured into water (5000 ml). The product which precipitates is filtered off and then washed with water (600 ml) and dried. This product is treated with methylene chloride (1100 ml) at a temperature of about 20°C. The insoluble material is filtered off and then the filtrate is washed with 1 N sodium hydroxide solution (3x200 ml) and with water (3x200 ml). The organic phase is treated with decolorizing charcoal (10.0 g), dried over potassium carbonate, filtered and then concentrated to dryness under reduced pressure. The oily residue obtained is dissolved in boiling acetonitrile (500 ml). The 101.0 g of 6-(5- chloropyrid-2-yl)-5-(4-methylpiperazin-l-yl)carbonyloxy-7-oxo-5,6- dihydropyrrolo[3,4-b]-pyrazine are obtained, melting point 178°C (washed with ice cold acetonitrile, 50 ml, and then crystallizes with diisopropyl ether, 50 ml).

brand name

IMOVANE

Therapeutic Function

Sedative, Hypnotic

World Health Organization (WHO)

Zopiclone was introduced as a sedative in 1985. It remains registered in several countries and the World Health Organization is not aware of any other country that has refused registration.

Clinical Use

Hypnotic

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism inhibited by erythromycin; concentration significantly reduced by rifampicin.
Antipsychotics: enhanced sedative effects.
Antivirals: concentration possibly increased by ritonavir.

Metabolism

Zopiclone is extensively metabolised in the liver via the cytochrome P450 isoenzyme CYP3A4 and, to a lesser extent, CYP2C8; the 2 major metabolites, the less active zopiclone N-oxide and the inactive N-desmethylzopiclone, are excreted mainly in the urine. About 50
% of a dose is converted by decarboxylation to inactive metabolites, which are partly eliminated via the lungs as carbon dioxide.