Bevantolol hydrochloride

Description

Bevantolol hydrochloride is a cardioselective (β₁) adrenergic blocker, devoid of intrinsic sympathomimetic and local anesthetic activities. As with other agents of this category, it is useful in the treatment of hypertension and angina.

Description

Bevantolol is an antagonist of the β1-adrenergic receptor (β₁-AR; K_i = 14.79 nM in rat cortical membranes). It is selective for β₁- over β₂-ARs (K_i = 588.84 nM), as well as α₂-ARs up to 100 μM, but is an antagonist of α₁-ARs (K_i = 125.89 nM). Bevantolol inhibits low voltage-activated calcium currents (LVA-I_Ca) in dissociated rat ventro-medial hypothalamic neurons (IC₅₀ = 40 μM). It inhibits norepinephrine-induced contraction of isolated rabbit thoracic aorta (pA₂ = 4.77), isoprenaline-induced inotropic effects in isolated guinea pig right atria (pA₂ = 7.74), and isoprenaline-induced relaxation of isolated guinea pig trachea (pA₂ = 6.69). Bevantolol (250 mg/kg per day) prevents immobilization stress-induced increases in systolic blood pressure in a rat model of stress-induced hypertension.

Chemical properties

Off-White Solid

Originator

Warner-Lambert (USA)

The Uses of Bevantolol hydrochloride

Bevantolol is a cardioselective β-adrenergic blocker. Bevantolol is used as an antianginal, antihypertensive, antiarrhythmic.

Definition

ChEBI: The hydrochloride salt of bevantolol.

Manufacturing Process

To a solution of 50 g (1.25 mol) of NaOH in 1200 ml H2O was added 108 g (1 mol) of m-cresol freshly distilled and at 15°C in one lot 117ml (1.5 mol) of epichlorohydrin. The emulsion was stirred at room temperature for 16 hours in a creased flask. The product was taken up in 1000 ml of toluene and washed with 500 ml water. Distillation yielded 135.7 g=82% of 3-(m-tolyloxy)-1,2- epoxypropane, b.p. 61°C at 0.05 mm.
Preparation of bevantolol hydrochloride:
To a suitable reactor under a nitrogen blanket is added 13.7 kg of β-(3,4- dimethoxyphenyl)ethylamine. The amine is cooled to 5°C and 12.5 kg of 3- (m-tolyloxy)-1,2-epoxypropane is added maintaining the temperature between 5-10°C. After 10 hours, the mixture is seeded with bevantolol free base; seeding is repeated approximately every 2 hours until it is evident that crystallization has started. After stirring for 48 hours at 10°C, 26 L of hexane is added. The temperature is raised to 25°C and stirring is continued for 48 hours. The slurry is filtered and the collected solid is dried under vacuum. The product is dissolved in 60 L of isopropyl alcohol and the solution is filtered. The reactor and filter are rinsed with 186 L of isopropyl alcohol and 2.7 kg of anhydrous hydrogen chloride is added to the combined filtrate. The batch is heated to reflux for 2 hours. The temperature is adjusted to 65°C and the solution is seeded with bevantolol hydrochloride crystals. The mixture is held at this temperature with stirring until a heavy sand-like slurry is present. The mixture is allowed to cool to ambient temperature without stirring or artificial cooling. It is then cooled to 20°C. The slurry is centrifuged and the product rinsed with isopropyl alcohol until the filtrate is colorless. After being vacuum dried at 50-55°C the product is milled if necessary; yield of bevantolol hydrochloride 22.7 kg (78.6%); melting point 137-138°C.

brand name

Vantol (Parke-Davis);Ranestol.

Therapeutic Function

Antiarrhythmic, Beta-adrenergic blocker

Hazard

Moderately toxic by ingestion.

Safety Profile

A poison by intraperitoneal andintravenous route. Moderately toxic by ingestion. Whenheated to decomposition it emits toxic vapors of NOx,HCl, and Cl-.