52-86-8 Usage
Description
Haloperidol, also known as Haldol, is a potent antipsychotic medication belonging to the butyrophenone class. It is an odorless white to yellow crystalline powder with a long duration of action. Haloperidol is well and rapidly absorbed, with high bioavailability and more than 90% bound to plasma proteins. It is primarily used for the long-term treatment of psychosis and is especially useful in patients who are noncompliant with their drug treatment. The precise mechanism of its antipsychotic action is unclear but is considered to be associated with the potent dopamine D2 receptor-blocking activity in the mesolimbic system and the resulting adaptive changes in the brain.
Uses
Used in Pharmaceutical Industry:
Haloperidol is used as an antipsychotic drug for the treatment of schizophrenic psychoses, manic, paranoid, and delirious conditions, depression, psychomotor excitement of various origins, and for delirium and hallucinations of different origins.
Used in Research Applications:
Haloperidol is used in ethanol to serve as an inhibitor of Erg2p to address the mechanism of haloperidol in ferroptosis using hepatocellular carcinoma cells (Hep G2 and Huh-7 cell lines) and in receptor internalization assays.
Used in Medical Treatment:
Haloperidol is 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 24–48 hours.
Used in Drug Delivery Systems:
Haloperidol has been used in Dulbecco's Modified Eagle medium for various applications in drug delivery systems.
Chemical Properties:
Haloperidol is a white crystalline powder with the chemical name 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone. It has minimal effect on the cardiovascular system and is an effective antiemetic but has a high incidence of extrapyramidal adverse effects.
Brand Name:
Haloperidol is marketed under the brand name Haldol (OrthoMcNeil).
Originator
Haldol,Janssen-Le Brun,France,1960
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.
Therapeutic Function
Antidyskinetic, Antipsychotic
Pharmaceutical Applications
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.
Biological Activity
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
Synthesis
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) [41–46].
Drug interactions
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.
Metabolism
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).
Check Digit Verification of cas no
The CAS Registry Mumber 52-86-8 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 2 respectively; the second part has 2 digits, 8 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 52-86:
(4*5)+(3*2)+(2*8)+(1*6)=48
48 % 10 = 8
So 52-86-8 is a valid CAS Registry Number.
InChI:InChI=1/C21H23ClFNO2/c22-18-7-5-17(6-8-18)21(26)11-14-24(15-12-21)13-1-2-20(25)16-3-9-19(23)10-4-16/h3-10,26H,1-2,11-15H2/p+1
52-86-8Relevant articles and documents
An Improved Purification Method for the Rapid Synthesis of High Purity Fluorobutyrophenone Neuroleptics from Nitro and Chloro Precursors Suitable for PET Study
Hashizume, Kazunari,Hashimoto, Naoto,Cork, David G.,Miyake, Yoshihiro
, p. 2295 - 2298 (1994)
A rapid micro-scale synthesis of fluorinated neuroleptics with extremely high chemical purity was accomplished using a new single column reverse-phase HPLC purification procedure that employs a strongly alkaline eluent to clearly separate F-labeled compounds from the large excess of nitro or chloro precursor.The method is applicable to the production of 18F-labeled positron emission tomography (PET) tracer with high specific activity.
Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from: Mycobacterium tuberculosis to overcome kanamycin resistance
Garneau-Tsodikova, Sylvie,Garzan, Atefeh,Green, Keith D.,Holbrook, Selina Y. L.,Hou, Caixia,Krieger, Kyle,Pang, Allan H.,Parish, Tanya,Posey, James E.,Punetha, Ankita,Thamban Chandrika, Nishad,Tsodikov, Oleg V.,Willby, Melisa J.
supporting information, p. 1894 - 1909 (2022/01/12)
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a deadly bacterial disease. Drug-resistant strains of Mtb make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtb confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1), was a potent Eis inhibitor with IC50 = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol (1) complex, which guided synthesis of 34 analogues. The structure-activity relationship study showed that in addition to haloperidol (1), eight analogues, some of which were smaller than 1, potently inhibited Eis (IC50 ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant Mtb strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition. This journal is
Antifungal Compositions
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Paragraph 0171; 0199-0200, (2019/02/01)
Provided herein are antifungal compositions and methods of use thereof. The antifungal compositions include an antifungal agent and an antipsychotic agent or an antihistamine. The methods of use thereof include administering a composition including an antifungal agent and an antipsychotic or an antihistamine to a plant or animal in need thereof.