BUDIPINE

Description

Parkinsan was launched in Germany as a centrally-active anti-Parkinsonian agent. It can be prepared in three steps: a Mannich-aldol sequence to assemble the 4-phenylpiperidine scaffold followed by a Friedel-Crafts reaction to introduce the second phenyl ring. Parkinsan is effective for the treatment of Parkinsonian tremors and is similar in action to, but more potent than, biperiden. It exhibits use-dependent, open channel, uncompetitive NMDA receptor antagonistic activity. This may occur by binding to the PCP site in addition to interacting with sigma, binding sites in the frontal cortex. Parkinsan is also an antagonist at presynaptic muscarinic autoreceptors but facilitation of direct or indirect dopaminergic transmission does not contribute to its actions. While its mechanism of action is not completely understood, it has a weak inhibitory effect on dopamine reuptake, inhibits evoked GABA release (with low affinity for GABA-A receptors and a lower affinity for benzodiazepine receptors), and has a weak inhibitory effect on MAO-B.

Originator

Byk Gulden (Germany)

Definition

ChEBI: Budipine is a diarylmethane.

Manufacturing Process

24.4 g of 1-(t-butyl)-4-hydroxy-4-phenylpiperidine are suspended in 150 ml of anhydrous benzene. 61.5 g of finely pulverized anhydrous aluminum chloride are added in portions thereto within 25 min while stirring. The reaction temperature increases on starting addition of aluminum chloride to about 45°C. After about 20 min the temperature is increased to and maintained at about 50° to 55°C for about 1 hour. The resulting reaction solution is cooled to about 20°C and is poured into a mixture of ice and concentrated hydrochloric acid. After warming the mixture to room temperature, the hydrochloric acid layer together with the dark oil formed on decomposition is separated from the benzene layer and is washed with benzene. Water is added to said hydrochloric acid -oil phase, while stirring, in portions and in an amount sufficient to produce an almost clear solution. Said acid solution is rendered alkaline by the addition of 40% sodium hydroxide solution whereby the mixture is well cooled. The alkalized mixture is repeatedly extracted with ether. The combined ether extracts are dried over anhydrous potassium carbonate and are concentrated by evaporation of the ether. 24 g of the crude base are obtained as residue in the form of yellowish oil. A water clear oil boiling at 129-131°C/0.005 mm Hg is recovered by distillation of said crude oil in a high vacuum. The oil solidifies to crystals on standing for a short period of time. After recrystallization from aqueous dimethylformamide, the resulting 1-methyl-4,4-diphenylpiperidine has a melting point of 72-74°C.
Its hydrochloride is produced by dissolving the base in acetic acid ethyl ester and adding an ethereal hydrochloric acid solution thereto. After recrystallization from acetic acid ethyl ester, the melting point of the hydrochloride is 152-154°C.

brand name

Parkinsan

Therapeutic Function

Antiparkinsonian, Antidepressant