gamma-(4-(p-Chlorphenyl)4-hydroxy-piperidino)-p-fluorbutyrophenon

Bezeichnung:gamma-(4-(p-Chlorphenyl)4-hydroxy-piperidino)-p-fluorbutyrophenon

CAS-Nr52-86-8

Englisch Name:Haloperidol

CBNumberCB7774829

SummenformelC21H23ClFNO2

Molgewicht375.86

MOL-Datei52-86-8.mol

Synonyma

Haloperidol

gamma-(4-(p-Chlorphenyl)4-hydroxy-piperidino)-p-fluorbutyrophenon

gamma-(4-(p-Chlorphenyl)4-hydroxy-piperidino)-p-fluorbutyrophenon physikalisch-chemischer Eigenschaften

Schmelzpunkt	152 °C
Siedepunkt	529.0±50.0 °C(Predicted)
Dichte	1.1820 (estimate)
Flammpunkt	9℃
storage temp.	2-8°C
Löslichkeit	45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 0.39 mg/mL
Aggregatzustand	powder
pka	8.3(at 25℃)
Farbe	white
Wasserlöslichkeit	2.058mg/L(22.5 ºC)
Merck	14,4598
BCS Class	4/3
CAS Datenbank	52-86-8(CAS DataBase Reference)
NIST chemische Informationen	Haloperidol(52-86-8)
EPA chemische Informationen	Haloperidol (52-86-8)

Sicherheit

Kennzeichnung gefährlicher	T,F
R-Sätze:	60-61-25-36/37/38-43-39/23/24/25-23/24/25-11
S-Sätze:	53-26-36/37/39-45-36/37-16
RIDADR	UN 2811 6.1/PG 3
WGK Germany	3
RTECS-Nr.	EU1575000
HazardClass	6.1(b)
PackingGroup	III
HS Code	2933399090
Giftige Stoffe Daten	52-86-8(Hazardous Substances Data)
Toxizität	LD50 orally in rats: 165 mg/kg (Goldenthal); i.p. in mice: 60 mg/kg (Collins, Horlington)

Gefahreninformationscode (GHS)

Haloperidol Chemische Eigenschaften,Einsatz,Produktion Methoden

R-Sätze Betriebsanweisung:
R60:Kann die Fortpflanzungsfähigkeit beeinträchtigen.
R61:Kann das Kind im Mutterleib schädigen.
R25:Giftig beim Verschlucken.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
R43:Sensibilisierung durch Hautkontakt möglich.
S-Sätze Betriebsanweisung:
S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
Beschreibung
Haloperidol is a butyrophenone with a long duration of action. It has lile α- adrenoceptor blocking activity and minimal effect on the cardiovascular system. It is an effective antiemetic but has a high incidence of extrapyramidal adverse effects. Haloperidol may be used in the short-term management of the acutely agitated patient (when sinister causes of confusion such as hypoxaemia and sepsis have been excluded) and in the management of delirium in ICU. The duration of action of haloperidol is approximately 24–48h.
Chemische Eigenschaften
White Crystalline Powder
Originator
Haldol,Janssen-Le Brun,France,1960
Verwenden
Antidyskinetic; antipsychotic
Verwenden
Haloperidol is one of the most actively used modern neuroleptics. Its high antipsychotic activity is combined with a moderate sedative effect. It effectively stops various types of psychomotor excitement. It is used for schizophrenic psychoses, manic, paranoid, and delirious conditions, depression, psychomotor excitement of various origins, and for delirium and hallucinations of different origin.
Verwenden
Haloperidol has been used:
- in ethanol to serves as an inhibitor of Erg2p
- to address the mechanism of haloperidol in ferroptosis using hepatocellular carcinoma cells: Hep G2 and Huh-7 cell lines
- in receptor internalization assay
- as an antipsychotic drug in Dulbecco′s Modified Eagle medium
Definition
ChEBI: A compound composed of a central piperidine structure with hydroxy and p-chlorophenyl substituents at position 4 and an N-linked p-fluorobutyrophenone moiety.
Manufacturing Process
A stirred slurry of 120.0 parts 4-(4-chlorophenyl)-piperidin-4-ol hydrochloride and 40.0 parts of potassium iodide in 500 parts of water is warmed to a temperature of about 35°C under a nitrogen atmosphere. Then, 70.0 parts of potassium hydroxide is added. After further heating to about 55°C. 138.0 parts of 1,1 dimethoxy-1-(4-fluorophenyl)-4-chlorobutane is added. The temperature is then raised to about 102°C and heating continued for 3.5 hours. After cooling to about 75°C. 785 parts of toluene is added to the reaction mixture and stirred for about 5 minutes. An additional 320 parts of toluene is added and the water and organic layers separated. 102 parts of methanol is used to rinse the flask and added to the organic layer to provide a solution of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4,4-dimethoxybutyl]- piperidin-4-ol. Then, 59 parts of concentrated hydrochloric acid is added to a stirred solution of the organic layer to precipitate a solid. The solid is filtered, rinsed twice with 550 parts by volume portions of a 10:9:1 acetone-toluenemethanol mixture, twice with 400 parts by volume portions of a 10:l acetonemethanol mixture, and air-dried. The dried solid is then dissolved in 1,950 parts of methanol with gentle heating on a steam bath. The resulting solution is filtered and 300 parts by volume of concentrated ammonium hydroxide is added. Heating is continued to reflux and maintained thereat for about 1 hour.Then, 2,520 parts of water is added and the slurry stirred at about 75°C for 1.5 hours. After cooling to about 25°C. the solid is filtered, washed twice with 600 parts by volume portions of a 3:1 mixture of water-methanol, and airdried. The resulting product, 4-[4-chlorophenyl)-4-hydroxypiperidino]-4'- fluorobutyrophenone, is obtained in 32.5% yield. This product melts at about 148.5°C to 150.5°C.
Trademarks
Haldol (OrthoMcNeil).
Therapeutic Function
Antidyskinetic, Antipsychotic
Allgemeine Beschreibung
Haloperidol, 4[4-(p-chlorophenyl)-4-hydroxypiperidone]-4' -n-fluorobutyrophenone (Haldol),the representative of several related classes of aromaticbutylpiperidine derivatives, is a potent antipsychotic usefulin schizophrenia and in psychoses associated with braindamage. It is frequently chosen as the agent to terminatemania and often used in therapy for Gilles de la Tourettesyndrome. Haloperidol-induced dyskinesias may involveneurotoxicological metabolite similar to dopaminergic toxicantMPP⁺.
Allgemeine Beschreibung
Haloperidol, 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone (Haldol), is anodorless white to yellow crystalline powder. Haloperidol iswell and rapidly absorbed and has a high bioavailability. It ismore than 90% bound to plasma proteins. Haloperidol is excretedslowly in the urine and feces. About 30% of a dose isexcreted in urine and about 20% of a dose in feces via biliaryelimination,and only 1% of a dose is excreted as unchangeddrug in the urine.Haloperidol is a minor substrate of CYP1A2 and a major substrate of CYP2D6 and CYP3A4.CYP2D6 inhibitors may increase the levels/effects ofhaloperidol.Haloperidol may increase the levels/effects ofCYP2D6 substrates and it may decrease the bioactivationof CYP2D6 prodrugs substrates. Haloperidol also is a moderateinhibitor of CYP2D6 and CYP3A4. CYP3A4 inducersmay decrease the levels/effects of haloperidol, whereasCYP3A4 inhibitors may increase the levels/effects ofhaloperidol. Centrally acting acetylcholinesterase inhibitorsmay increase the risk of antipsychotic-related EPS. The precisemechanism of antipsychotic action is unclear but isconsidered to be associated with the potent DA D₂receptor–blocking activity in the mesolimbic system and theresulting adaptive changes in the brain. Haloperidol is usedprimarily for the long-term treatment of psychosis and is especiallyuseful in patients who are noncompliant with theirdrug treatment.
Pharmazeutische Anwendungen
Haloperidol is an analogue of the dopamine D2 receptor antagonist and is an older antipsychotic drug. The drug is used in the treatment of schizophrenia, a neuropsychiatric disorder. In general, antipsychotic drugs work by blocking the dopamine D₂ receptors.
Haloperidol is such an antipsychotic drug, which was developed in the 1950s and entered the clinic soon after that. Its use is limited by the high incidence of extrapyramidal symptoms (movement disorders caused by drugs affecting the extrapyramidal system, a neural network which is part of the motor system). Nevertheless, haloperidol may be used for the rapid control of hyperactive psychotic states and is popular for treating restlessness in the elderly.
Biologische Aktivität
Dopamine antagonist with selectivity for D 2 -like receptors (K i values are 1.2, ~ 7, 2.3, ~ 80 and ~ 100 nM for D 2 , D 3 , D 4 , D 1 and D 5 receptors respectively). Subtype-selective NMDA antagonist.
Biochem/physiol Actions
Haloperidol is a butyrophenone antipsychotic. It is also classified as a neuroleptic (powerful tranquilizer). Haloperidol acts as a D2, D3, and D4 dopamine receptor antagonist and thus causes Parkinson′s disorder. It also has a negative effect on the central nervous system.
Clinical Use
Sedative in severe anxiety
Intractable hiccup
Motor tics
Nausea and vomiting
Schizophrenia and other psychoses
Synthese
Haloperidol, 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4??-fluorobutyrophenone (6.3.8), is synthesized by the alkylation of 4-(4-chlorophenyl)-4-hydroxypiperidine (6.3.7) using 4??-chloro-4-fluorobutyrophenone (6.3.4). 4-(4-Chlorophenyl) -4-hydroxypiperidine (6.3.7) is synthesized from 2-(4-chlorophenyl)propene, which on reaction with formaldehyde and ammonium chloride gives the intermediate 4-methyl-4-(4-chlorophenyl)-1, 3-oxazine (6.3.5), evidently through stages postulated for the Prince reaction. Treatment of the resulting product with hydrochloric acid leads to the formation of 4-(4-chlorophenyl)-1,2,3,6- tetrahydropiperidine (6.3.6), probably through a stage of opening of the hydrogenated 1,3-oxazine ring, followed by dehydration, and subsequent recyclization. Addition of hydrogen bromide to the double bond of 4-(4-chlorophenyl)1,2,3,6-tetrahydropipidine (6.3.6) and the subsequent alkaline hydrolysis of the 4-(4-chlorophenyl)-4-bromopiperidine formed during the reaction, gives 4-(4-chlorophenyl)-4-hydroxypiperidine (6.3.7), the reaction of which with 4??-chloro-4-fluorobutyrophenone (6.3.4) gives the desired haloperidol (6.3.6) [41¨C46].
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effects.
Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; possibly severe drowsiness with indometacin or acemetacin; increased risk of ventricular arrhythmias with methadone.
Anti-arrhythmics: increased risk of ventricular arrhythmias with anti-arrhythmics that prolong the QT interval; increased risk of ventricular arrhythmias with amiodarone or disopyramide - avoid.
Antibacterials: increased risk of ventricular arrhythmias with moxifloxacin and delamanid - avoid with moxifloxacin; concentration reduced by rifampicin.
Antidepressants: increased risk of ventricular arrhythmias with citalopram, escitalopram and tricyclics - avoid; concentration increased by fluoxetine and venlafaxine and possibly fluvoxamine; possible increased risk of convulsions with vortioxetine; concentration of tricyclics increased.
Antiepileptics: metabolism increased by carbamazepine, phenobarbital and primidone; lowered seizure threshold; concentration reduced by fosphenytoin and phenytoin.
Antifungals: concentration possibly increased by itraconazole.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol; possible increased risk of ventricular arrhythmias with mefloquine or quinine - avoid.
Antipsychotics: avoid concomitant use of depot formulations with clozapine (cannot be withdrawn quickly if neutropenia occurs); increased risk of ventricular arrhythmias with sulpiride and droperidol and possibly risperidone - avoid with droperidol; concentration possibly increased by chlorpromazine.
Antivirals: concentration possibly increased with ritonavir; increased risk of ventricular arrhythmias with saquinavir - avoid.
Anxiolytics and hypnotics: increased sedative effects; concentration increased by alprazolam and buspirone.
Atomoxetine: increased risk of ventricular arrhythmias.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Cytotoxics: increased risk of ventricular arrhythmias with bosutinib, ceritinib and vandetanib - avoid with vandetanib; increased risk of ventricular arrhythmias with arsenic trioxide.
Lithium: increased risk of extrapyramidal side effects and possibly neurotoxicity.
Stoffwechsel
Haloperidol is metabolised in the liver and is excreted in the urine and, via the bile in the faeces; there is evidence of enterohepatic recycling. Routes of metabolism of haloperidol include oxidative N-dealkylation, particularly via the cytochrome P450 isoenzymes CYP3A4 and CYP2D6, glucuronidation, and reduction of the ketone group to form an alcohol known as reduced haloperidol. Metabolites are ultimately conjugated with glycine and excreted in the urine. There is debate over the pharmacological activity of the metabolites.
Dosage forms
Dosage for haloperidol is as follows:
? Sedation: 2–10 mg i.v. or i.m. (max. 18 mg per 24 h).
? Antiemesis: 1.25 mg i.v. for prevention of postoperative nausea and vomiting (PONV).
Einzelnachweise
[1] dr ananya mandal, md .haloperidol pharmacology.

Haloperidol Upstream-Materialien And Downstream Produkte

gamma-(4-(p-Chlorphenyl)4-hydroxy-piperidino)-p-fluorbutyrophenon Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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