FLUSPIRILENE

Description

Fluspirilene is a potent, non-competitive antagonist of agonist-activated L-type calcium channels (IC₅₀ = 0.03 μM). In addition to its use in research as a calcium channel blocker, fluspirilene has potential application as an antipsychotic in schizophrenia.

Chemical Properties

White or almost white powder.

Originator

Imap, Janssen W. ,Germany ,1972

Uses

This drug is primarily used for supportive therapy of patients suffering from chronic mental illnesses after treatment in the hospital. It is suitable for use in ambulatory practice because of the lack of expressed hypno-sedative effects.

Uses

Antipsychotic.

Uses

Fluspirilene has been used as a neuroleptic drug to study its effects on human ether-a-go-go related gene (HERG).

Definition

ChEBI: 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one is a diarylmethane.

Manufacturing Process

To a solution of 130 parts cyclopropyl-di-(4-fluorophenyl)-carbinol in 240 parts benzene are added dropwise 43 parts thionylchloride. The whole is refluxed until no more gas is evolved. The reaction mixture is then evaporated. The residue is distilled in vacuo, yielding 4-chloro-1,1-di-(4-fluorophenyl)-1butene, boiling point 165° to 167°C at 6 mm pressure; nD20= 1.5698; d2020= 1.2151.
A solution of 61 parts 4-chloro-1,1-di-(4-fluorophenyl)-1-butene in 400 parts 2-propanol is hydrogenated at normal pressure and at room temperature in the presence of 5.5 parts palladium-on-charcoal catalyst 10% (exothermic reaction, temperature rises to about 30°C). After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled in vacuo, yielding 1chloro-4,4-di-(4-fluorophenyl)-butane, boiling point 166° to 168°C at 6 mm pressure; nD20= 1.5425; d2020= 1,2039.
A mixture of 7.3 parts 1-chloro-4,4-di-(4-fluorophenyl)-butane, 5.1 parts 1phenyl-4-oxo-1,3,8-triaza-spiro[4,5]decane, 4 parts sodium carbonate, a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone is stirred and refluxed for 60 hours. After cooling the reaction mixture is treated with water. The organic layer is separated, dried, filtered and evaporated. The solid residue is recrystallized from 80 parts 4-methyl-2-pentanone, yielding 1phenyl-4-oxo-8-[4,4-di-(4-fluorophenyl)]butyl-1,3,8-triaza-spiro[4,5]decane, melting point 187.5° to 190°C.

brand name

Imap (OrthoMcNeil).

Therapeutic Function

Tranquilizer

Biochem/physiol Actions

Fluspirilene has a potential to inhibit the activity of cyclin-dependent kinase 2 (CDK2). It is an effective anti-cancer agent used for treating human hepatocellular carcinoma.

Synthesis

Fluspirilene, 8-[4,4-bis(p-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro [4,5]decan-4-one (6.6.9), is synthesized from 1-benzyl-4-anilino-4-cyanopiperidine (3.1.64) by the way of its acidic hydrolysis into the amide (6.6.6), and the subsequent heterocyclization of 4-aminocarbonyl and 4-aniline functional groups into imidazolone cycle, thus creating the desired spiroheterocyclic system, 8-benzyl-1-phenyl-1,3,8-triazaspiro[4,5] decan-4-one (6.6.7). Hydrogenation of this product using a palladium on carbon catalyst removes the N-benzyl protecting group, forming 1-phenyl-1,3,8-triazaspiro [4,5]decan-4-one (6.6.8). Alkylating this with 1,1-bis-(4-fluorophenyl)butyl bromide (6.6.3) gives fluspirilene (6.6.9) [64¨C66].

in vitro

fluspirilene was found to be weakly active as an antagonist of ca2(+)-induced contractions in k(+)-depolarized taenia. in addition, fluspirilene at 10-1000 nm was a potent non-competitive antagonist of the effects of bay k 8644 on ca2(+)-induced contractions and could selectively antagonise the effects of bay k 8644, without affecting the calcium antagonist effects of nitrendipine [1].

in vivo

in a previous animal study, adult male wistar rats were intramuscularly injected with a 8 mg/kg dose of fluspirilene. results showed that the excretion was slow but constant during the first 12 days. the identified metabolites of the urine and faeces showed oxidative n-dealkylation as the major metabolic pathway [2].

IC 50

0.03 μm

References

[1] kenny, b. a.,fraser, s.,kilpatrick, a.t., et al. selective antagonism of calcium channel activators by fluspirilene. br. j. pharmacol. 100(2), 211-216 (1990).
[2] heykants jp. the excretion and metabolism of the long-acting neuroleptic drug fluspirilene in the rat. life sci. 1969 oct 1;8(19):1029-39.
[3] chouinard g, annable l, steinberg s. a controlled

Raw materials

Preparation Products