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HomeProduct name listSibutramine

Sibutramine

Sibutramine Structural

What is Sibutramine?

Absorption

Rapid absorption following oral administration. Absolute bioavailability is not known, but at least 77% of a single oral dose of sibutramine is absorbed.

Toxicity

Side effects include dry mouth, anorexia, insomnia, constipation and headache.

Originator

Meridia,Abbott Laboratories,USA

The Uses of Sibutramine

Anorexic; antidepressant.

Indications

For the treatment of obesity.

Background

Sibutramine (trade name Meridia in the USA, Reductil in Europe and other countries), usually as sibutramide hydrochloride monohydrate, is an orally administered agent for the treatment of obesity. It is a centrally acting stimulant chemically related to amphetamines thus it is classified as a Schedule IV controlled substance in the United States. In October 2010, Sibutramine was withdrawn from Canadian and U.S. markets due to concerns that the drug increases the risk of heart attack and stroke in patients with a history of heart disease.

Definition

ChEBI: A tertiary amino compound that is N,N,3-trimethylbutan-1-amine substituted by a (4-chlorophenyl)cyclobutyl group at position 1.

Manufacturing Process

A solution of 4-chlorobenzyl cyanide and 1,3-dibromopropane in dry dimethylsulfoxide was added dropwise under nitrogen to a stirred mixture of sodium hydride dispersed in mineral oil and dimethylsulfoxide at a temperature in the range 30° to 35°C. The mixture was stirred at room temperature for 2 h and propan-2-ol and then water were added dropwise. The mixture was filtered through a diatomaceous earth sold under the Registered Trade Mark CELITE and the solid residue washed with ether. The ether layer was separated, washed with water, dried and evaporated. 1-(4- Chlorophenyl)-1-cyclobutanecarbonitrile was isolated by distillation.
1-(4-Chlorophenyl)-1-cyclobutanecarbonitrile (37.6 g) was added to a solution of potassium hydroxide (32.4 g) in diethyleneglycol (370 ml) and the mixture heated under reflux for three and a 0.5 h The reaction mixture was poured into an ice/water mixture and the resulting solution was washed with ether. The aqueous layer was added to a mixture of concentrated hydrochloric acid (100 ml) and ice and the resulting precipitate of 1-(4-chlorophenyl)-1- cyclobutanecarboxylic acid (melting point 86°-88°C) collected, washed with water and dried.
1-(4-Chlorophenyl)-1-cyclobutane carboxylic acid (10.5 g) was heated under reflux with thionyl chloride (20 ml) for 2.5 h. Excess thionyl chloride was evaporated off and the acid chloride of the above acid distilled (boiling point 82°-96°C /0.2 mm Hg). A solution of the acid chloride in dry tetrahydrofuran was added slowly to the product of the reaction of magnesium turnings and ethyl bromide in dry tetrahydrofuran. Water was added followed by 5 N hydrochloric acid with cooling. The reaction mixture was extracted with ether, washed with water, sodium bicarbonate solution, dried. The solvent was removed by evaporation and 1-isobutyl-1-(4-chlorophenyl)cyclobutane obtained by distillation. The 1-isobutyl-1-(4-chlorophenyl)cyclobutane, diethylene glycoldimethyl ether, water and concentrated hydrochloric acid were mixed and heated under reflux. The mixture was poured into water aqueous NaOH was added and the product extracted into ether. Evaporation gave a dark oil. A sample of this oil, water and formic acid were mixed and formaldehyde added. The mixture was heated under reflux and then concentrated hydrochloric acid and propan-2-ol were added. Evaporation to dryness gave N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]isobutyl hydrochloride as a white solid.

brand name

Meridia (Abbott).

Therapeutic Function

Antidepressant, Anorexic

General Description

Sibutramine (Meridia) is said to be an uptake inhibitor ofNE and 5-HT. These mechanisms fit its structure. It is reportedlyan antidepressant and an anorexiant drug. Thismechanism implies that activation of all presynaptic andpostsynaptic receptors in NE and 5-HT systems is possible.The data are not completely clear, but studies to date indicatethat the receptors principally involved are α1, β1, and5-HT2C.

Pharmacokinetics

Sibutramine is an orally administered agent for the treatment of obesity. Sibutramine exerts its pharmacological actions predominantly via its secondary (M1) and primary (M2) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin and norepinephrine reuptake in vivo, but not in vitro. However, metabolites M1 and M2 inhibit the reuptake of these neurotransmitters both in vitro and in vivo. In human brain tissue, M1 and M2 also inhibit dopamine reuptake in vitro, but with ~3-fold lower potency than for the reuptake inhibition of serotonin or norepinephrine. Sibutramine, M1 and M2 exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M1 and M2 have low affinity for serotonin (5-HT1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), norepinephrine (b, b1, b3, a1 and a2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

Metabolism

Hepatic

Properties of Sibutramine

Melting point: 191-192°C
Boiling point: 342.6±25.0 °C(Predicted)
Density  1.031±0.06 g/cm3(Predicted)
solubility  Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly)
pka 9.69±0.50(Predicted)
form  Solid
color  White to Off-White
Water Solubility  2.9 mg/mL
CAS DataBase Reference 106650-56-0(CAS DataBase Reference)

Safety information for Sibutramine

Computed Descriptors for Sibutramine

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