1841-19-6

Usage

Uses

Used in Pharmaceutical Industry:
Fluspirilene is used as a supportive therapy for patients suffering from chronic mental illnesses after hospital treatment. It is suitable for use in ambulatory practice due to the lack of expressed hypno-sedative effects.
Used in Research:
Fluspirilene is used as a neuroleptic drug to study its effects on the human ether-a-go-go related gene (HERG), which is important for understanding its potential applications in various neurological conditions.
Used in Psychiatry:
Fluspirilene is used as an antipsychotic medication, particularly in the treatment of schizophrenia. Its action as a calcium channel blocker may contribute to its effectiveness in managing the symptoms of this mental disorder.

Originator

Imap, Janssen W. ,Germany ,1972

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.

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) [64–66].

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

InChI:InChI=1/C29H31F2N3O/c30-24-12-8-22(9-13-24)27(23-10-14-25(31)15-11-23)7-4-18-33-19-16-29(17-20-33)28(35)32-21-34(29)26-5-2-1-3-6-26/h1-3,5-6,8-15,27H,4,7,16-21H2,(H,32,35)

Upstream product

• 352-13-6 4-flourophenylmagnesium bromide 
• 337506-83-9 1,1-bis(4-fluorophenyl)butane-1,4-diol 
• 293729-65-4 5,5-bis-(4-fluoro-phenyl)-tetrahydro-furan-2-ol 
• 357-77-7 1,1-bis(4-fluorophenyl)prop-2-yn-1-ol 
• 50337-85-4 4,4-bis(4-fluorophenyl)butan-1-ol 
• 817642-33-4 8-[4,4-bis(p-fluorophenyl)-4-hydroxybutyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 
• 345-92-6 4,4'-Difluorobenzophenone 
• 99734-06-2 α,α-bis(4-fluorophenyl)allyl alcohol 
• 1841-17-4 8-[4,4-bis(4-fluorophenyl)-but-3-enyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 
• 57668-61-8 4,4'-(4-bromobutane-1,1-diyl)bis(fluorobenzene) 
• 1021-25-6 1-Phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 

Relevant academic research and scientific papers

Rhodium catalyzed hydroformylation of 1,1-bis(p-fluorophenyl)allyl or propargyl alcohol: A key step in the synthesis of Fluspirilen and Penfluridol

Fluspirilen (1) and Penfluridol (2), two neuroleptic agents, belong to a wide class of pharmaceuticals that contain in their molecules a 4,4-bis(p-fluorophenyl)butyl group bound to a nitrogen atom of a pyrrolidine, piperidine or piperazine moiety. A key intermediate for the synthesis of compounds 1 and 2,4,4-bis(p-fluorophenyl)butylbromide (15), has been prepared starting from commercially available 4,4′-difluorobenzophenone (7) following a preparative route involving the rhodium catalyzed hydroformylation in toluene or in the biphasic system toluene/water or cyclohexane/water of 1,1-bis(p-fluorophenyl)-2-propenol (8) and/or 1,1-bis(p-fluorophenyl)-2-propynol (12). Fluspirilen and Penfluridol were obtained in 70-80% yield by reaction of bromide 15 with 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (16) and 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol (17), respectively. The overall yields of the two pharmaceuticals 1 and 2, based on starting ketone 7, were about 35-40%.

Fluspirilene Analogs Activate the 20S Proteasome and Overcome Proteasome Impairment by Intrinsically Disordered Protein Oligomers

Oligomerization of aggregation-prone intrinsically disordered proteins (IDPs), such as α-synuclein, amyloid β, and tau, has been shown to be associated with the pathogenesis of several neurodegenerative diseases, including Parkinson's and Alzheimer's disease. The proteasome is charged with regulating cellular levels of IDPs, but this degradation pathway can become dysregulated leading to their accumulation and subsequent aggregation. Although the pathogenesis of these neurodegenerative diseases is still under intense investigation, it has been shown that the oligomeric forms of IDPs, including α-synuclein and amyloid β, can impair proteasome function. This leads to additional accumulation of the IDPs, further promoting disease progression. Herein, we report the use of small molecule activators of the 20S subcomplex of the proteasome to restore impaired 20S proteasome activity and prevent IDP accumulation and oligomerization. We found that fluspirilene and its new synthetic analog (16) show strong 20S proteasome enhancement (doubling 20S proteolytic activity at μ2 μM, with maximum fold enhancement of μ1000%), overcome impaired proteasome function, and prevent the accumulation of pathogenic IDPs. These findings provide support for the use of 20S enhancers as a possible therapeutic strategy to combat neurodegenerative diseases.

METHODS FOR TREATING CHRONIC FATIGUE SYNDROME AND MYALGIC ENCEPHALOMYELITIS

In one aspect the invention relates to a method of treatment selected from the group consisting of: (a) treating a symptom such as pain in a subject identified or diagnosed as having Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); (b) treating a symptom such as pain in a subject having dysfunctional TRPM3 ion channel activity; (c) restoring NK cell function in a subject having dysfunctional TRPM3 ion channel activity; and (d) restoring calcium homeostasis in a subject having dysfunctional TRPM3 ion channel activity. The method comprises the step of administering to the subject a therapeutically effective amount of at least one therapeutic compound selected from the group consisting of: (i) an opioid receptor antagonist; (ii) an opioid antagonist; and (iii) a therapeutic compound that restores TRPM3 ion channel activity. In some embodiments the therapeutic compound is naltrexone hydrochloride.

Synthesis and SAR study of diphenylbutylpiperidines as cell autophagy inducers

A novel series of diphenylbutylpiperidines as autophagy inducers was described and extensive SAR studies resulted in derivatives (15d-e, 15i-j) with 10-fold greater activity than the lead compounds 1 and 2. Meanwhile, a new synthetic route to diphenylbutyl bromide (6) from bromobenzene and γ-butyrolactone was also reported here.

DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS

Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.

Regioselective hydroaminomethylation of 1,1-diaryl-allyl-alcohols: A new access to 4,4-diarylbutylamines

Pharmacologically active 4,4-diarylbutylamines like Fluspirilene and 4-amino-1,1-diarylbutan-1-ols like Difenidol were prepared in high yields via rhodium catalysed hydroaminomethylation of 1,1-diaryl-allylalcohols. Conversion of these olefins with carbon monoxide, hydrogen and secondary amines proceeds with complete regioselectivity. This group can easily be removed under acidic and hydrogenating conditions, enabling the transformation of 4-amino-1,1-diarylbutan-1-ols to 4,4-diarylbutylamines in high yields. Thus Fluspirilene was synthesised in 88% yield in four steps starting from commercially available materials. Graphical Abstract.