Sibutramine

Pharmacological effects

Sibutramine is an orally administered centrally acting weight-loss pill and belongs to non-amphetamine appetite suppressant. Its metabolites in vivo can inhibit the re-uptake of norepinephrine, serotonin and dopamine, reduce appetite and increase the sense of fullness, and accelerate the body energy consumption, thereby reducing weight. The degree of causing weight loss was positively correlated with the dose. In addition, the product also has mild antidepressant effect. It can be absorbed through oral administration with the bioavailability being 77%; after 1.2 hours, its plasma concentration reaches peak. It has the protein binding rate being 97%. The highest concentration has been observed in the liver and kidney with being metabolized into two kinds of active metabolites in the liver: single nor-sibutramine and dual nor-sibutramine. The time for reaching metabolite peak is 3 to 4 hours. The half-life of the parental drug is 1.1 hours and the half life of the metabolites is 14 to 16 hours. 85% of the oral dose is excreted from the urine and feces. After the administration, the adverse reactions may include tachycardia, an increase in the number of premature pulse, increased blood pressure, and headache, insomnia, easy to wake up, dry mouth, constipation, irritability, dry skin, or skin rash. Gallstone patients, patients with history of hypertension or narrow-angle glaucoma, epilepsy, liver and kidney dysfunction should take it with caution. Patients of anorexia nervosa disease, arrhythmias, heart failure, coronary heart disease, severe liver, kidney dysfunction, uncontrolled hypertension and those who are allergic to the chemicals should be disabled for using it.

Sibutramine hydrochloride

Sibutramine hydrochloride is a weight loss drug and is the hydrochloride salt form of sibutramine with the pharmacological effects being fully consistent with that of sibutramine. However, it has a better stability and solubility than sibutramine.
Acid sibutramine was first used for treating depression. During its clinical application, people found that its weight-loss effect was significantly stronger than the effect of its antidepressant effect. On the one hand, through inhibiting the reuptake of serotonin, it can reduce hunger feeling of the body and suppress appetite for effectively controlling the caloric intake; on the other hand, through activating the adrenergic receptors, it increases the adipose tissue consumption, increases the metabolism and promotes the energy consumption with obviously weight-loss promoting effect. However, at the same time, it may cause high blood pressure, increased heart rate, anorexia, insomnia, abnormal liver function and other kinds of severe side effects.
The above information is edited by the Chemicalbook of Dai Xiongfeng.

Indications

It is suitable for the treatment of obesity which can’t be tackled through diet control or exercise. The treatment includes weight loss and maintenance of weight loss. The treatment should be applied in combination with low-calorie diet and exercise. It is recommended for being applied to the treatment of obesity patients with the body mass index being greater than or equal to 30kg/m2 or being equal to or greater than 27kg/m2 but accompanied with other risk factors such as hypertension, diabetes and dyslipidemia. The recommended starting amount is 10mg, qd. It can be used in single administration in the morning or be subject administration together with food. If the weight loss is less than expected, after four weeks, the dose can be adjusted to 15 mg per day. If the patient can’t tolerate the dose of 10 mg, the dose can be reduced to 5mg. The dose should be adjusted based on the patient's blood pressure and heart rate. It is not recommended for using the dose of over 15 mg/d.

Uses

It is 5-HT reuptake inhibitors and can be used for the treatment of obesity.
It can be used as an antidepressant.

Production method

Mix p-Chlorobenzene, acetonitrile and KOH at 25%: slowly add drop wise of 1, 3-dibromopropane. After the completion of the dropping, continue for stirring of 1h; add distilled water and further extracted with ethyl acetate. The extract was washed with water, brine and dried. It is then filtered, concentrated under reduced pressure and distilled, collect the 160 ℃/2.13kPa fraction to obtain the compound (Ⅰ) with the yield being 73% to 74%.
The magnesium sheet was dissolved in anhydrous THF. Add drop wise of isobutyl bromide followed by reaction of 1h. Then slowly add drop wise of the anhydrous THF solution of compound (I). After the completion of dropping, reflux for 4h and cool to room temperature. Add them drop wise into the isopropanol solution of KBH4, reflux for 4h. Cool, add water and extract with ethyl acetate. The extract was washed by water, brine and dried. It is then filtered with the filtrate being concentrated under reduced pressure before distillation. Collect the 170 ℃/0.67kPa fraction to obtain the compound (II) with the yield being 76% to 79%.
Compound (II), formic acid and the 1/2 formaldehyde solution were stirred at 90~92 ℃ for 1h. Further add another part of 1/2 formaldehyde solution and reaction was continued for 1h. Cool to room temperature and slowly pour into the crushed ice solution of sodium hydroxide, then extract with diethyl ether. The extract was washed with saturated brine, washed, and dried. Then it is filtered with the filtrate being concentrated to give khaki sibutramine with the yield of 94%. The analytical sample can be subject to recrystallization of diethyl ether with the m.p. of 52~53 ℃.
Sibutramine was dissolved in methanol, add concentrated hydrochloric acid for reaction at 50~60'C for 10min. Recover the methanol under reduced pressure until a small volume was crystallized, add water and stir, and cool at ice bath. Filter and wash to obtain the crude product of sibutramine hydrochloride. Use methanol-water of crystallization to obtain the white crystals of sibutramine hydrochloride with the melting point of 194 ℃ and yield of 83%.

Originator

Meridia,Abbott Laboratories,USA

Uses

Anorexic; antidepressant.

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-HT_2C.