Azaperone

Azaperone
Clinical data
AHFS/Drugs.com	International Drug Names
Routes of; administration	IM
ATCvet code	QN01AX91 (WHO) QN05AD90 (WHO);
Pharmacokinetic data
Metabolism	Hepatic
Elimination half-life	4 hours
Identifiers
	IUPAC name 1-(4-fluorophenyl)-4-[4-(pyridin-2-yl)piperazin-1-yl]butan-1-one;
CAS Number	1649-18-9 ;
PubChem CID	15443;
DrugBank	DB11376;
ChemSpider	14695 ;
UNII	19BV78AK7W;
KEGG	D02620 ;
ChEBI	CHEBI:88301 ;
ChEMBL	ChEMBL340211 ;
CompTox Dashboard (EPA)	DTXSID2045361 ;
ECHA InfoCard	100.015.197
Chemical and physical data
Formula	C19H22FN3O
Molar mass	327.403 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	90 to 95 °C (194 to 203 °F)
	SMILES Fc1ccc(cc1)C(=O)CCCN3CCN(c2ncccc2)CC3;
	InChI InChI=1S/C19H22FN3O/c20-17-8-6-16(7-9-17)18(24)4-3-11-22-12-14-23(15-13-22)19-5-1-2-10-21-19/h1-2,5-10H,3-4,11-15H2 ; Key:XTKDAFGWCDAMPY-UHFFFAOYSA-N ;
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Azaperone is a pyridinylpiperazine and butyrophenone neuroleptic drug with sedative and antiemetic effects, which is used mainly as a tranquilizer in veterinary medicine.^[1] It is uncommonly used in humans as an antipsychotic drug.

Azaperone acts primarily as a dopamine antagonist but also has some antihistaminic and anticholinergic properties as seen with similar drugs such as haloperidol. Azaperone may cause hypotension and while it has minimal effects on respiration in pigs, high doses in humans can cause respiratory depression.

Veterinary use

The most common use for azaperone is in relatively small doses as a "serenic" (to reduce aggression) in farmed pigs, either to stop them fighting or to encourage sows to accept piglets. Higher doses are used for anesthesia in combination with other drugs such as xylazine, tiletamine and zolazepam. Azaperone is also used in combination with strong narcotics such as etorphine or carfentanil for tranquilizing large animals such as elephants.^[2] Use in horses is avoided as adverse reactions may occur.

The European Medicines Agency has established a maximum residue limit for azaperone when administered to pigs.^[3]

Azaperone (under the brand name Stresnil) was approved for use in pigs in the USA in 1983, under NADA 115-732.^[4]

Synthesis

The alkylation of 2-chloropyridine (1) with piperazine gives 1-(pyridin-2-yl)piperazine [67980-77-2] (2). The attachement of the sidechain by reaction with 4-chloro-4'-fluorobutyrophenone [3874-54-2] (3) completed the synthesis of azaperone (4).

References

^ Posner LP, Burns P (2013). "Sedative agents: tranquilizers, alpha-2 agonists, and related agents. Veterinary pharmacology and therapeutics. 2009:.". In Riviere JE, Papich MG (eds.). Veterinary Pharmacology and Therapeutics (9th ed.). Somerset: Wiley. pp. 337–380 (366). ISBN 978-1-118-68590-7.
^ "The Elephant Formulary". Archived from the original on 2012-02-05. Retrieved 2007-04-30.
^ "Azaperone Summary Report (2)" (PDF). European Medicines Agency. Committee for Veterinary Medicinal Products. November 1997. Archived from the original (PDF) on 2017-01-16. Retrieved 2017-01-15.
^ "Rules and Regulations" (PDF). Federal Register. 48 (202): 48229. 18 October 1983. Retrieved 2017-01-15.
^ Jaen, Juan C.; Caprathe, Bradley W.; Pugsley, Thomas A.; Wise, Lawrence D.; Akunne, Hyacinth (1993). "Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and .sigma. receptors". Journal of Medicinal Chemistry. 36 (24): 3929–3936. doi:10.1021/jm00076a022.
^ Janssen Paul Adriaan Jan, U.S. patent 2,958,694 (1960).
^ Taghizadeh, M. J., Mohammadnia, M. S., Ghalkhani, M., Sohouli, E. (April 2022). "Improved Method for the Total Synthesis of Azaperone and Investigation of Its Electrochemical Behavior in Aqueous Solution". Chemical Research in Chinese Universities. 38 (2): 546–551. doi:10.1007/s40242-021-1061-2. ISSN 1005-9040. S2CID 235614834.
^ Soudijn, W.; van Wijngaarden, I. (1968). "A rapid and convenient method for the synthesis of labelled tertiary amines". Journal of Labelled Compounds. 4 (2): 159–163. doi:10.1002/jlcr.2590040209.

[1] Posner LP, Burns P (2013). "Sedative agents: tranquilizers, alpha-2 agonists, and related agents. Veterinary pharmacology and therapeutics. 2009:.". In Riviere JE, Papich MG (eds.). Veterinary Pharmacology and Therapeutics (9th ed.). Somerset: Wiley. pp. 337–380 (366). ISBN 978-1-118-68590-7.

[2] "The Elephant Formulary". Archived from the original on 2012-02-05. Retrieved 2007-04-30.

[3] "Azaperone Summary Report (2)" (PDF). European Medicines Agency. Committee for Veterinary Medicinal Products. November 1997. Archived from the original (PDF) on 2017-01-16. Retrieved 2017-01-15.

[4] "Rules and Regulations" (PDF). Federal Register. 48 (202): 48229. 18 October 1983. Retrieved 2017-01-15.

[5] Jaen, Juan C.; Caprathe, Bradley W.; Pugsley, Thomas A.; Wise, Lawrence D.; Akunne, Hyacinth (1993). "Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and .sigma. receptors". Journal of Medicinal Chemistry. 36 (24): 3929–3936. doi:10.1021/jm00076a022.

[6] Janssen Paul Adriaan Jan, U.S. patent 2,958,694 (1960).

[7] Taghizadeh, M. J., Mohammadnia, M. S., Ghalkhani, M., Sohouli, E. (April 2022). "Improved Method for the Total Synthesis of Azaperone and Investigation of Its Electrochemical Behavior in Aqueous Solution". Chemical Research in Chinese Universities. 38 (2): 546–551. doi:10.1007/s40242-021-1061-2. ISSN 1005-9040. S2CID 235614834.

[8] Soudijn, W.; van Wijngaarden, I. (1968). "A rapid and convenient method for the synthesis of labelled tertiary amines". Journal of Labelled Compounds. 4 (2): 159–163. doi:10.1002/jlcr.2590040209.

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v t e Antipsychotics (N05A)
Typical	Butyrophenones: Benperidol Bromperidol Bromperidol decanoate Droperidol Haloperidol^# Haloperidol decanoate Moperone Pipamperone Spiperone Timiperone Trifluperidol Diphenylbutylpiperidines: Fluspirilene Penfluridol Pimozide Phenothiazines: Acepromazine Acetophenazine Butaperazine Carphenazine (carfenazine)^‡ Chlorpromazine Cyamemazine Dixyrazine Fluphenazine Fluphenazine decanoate Fluphenazine enanthate Levomepromazine (methotrimeprazine) Mesoridazine Perazine Periciazine Perphenazine BL-1020 Perphenazine decanoate Perphenazine enanthate Piperacetazine Pipotiazine Pipotiazine palmitate Pipotiazine undecylenate Prochlorperazine Promazine Sulforidazine Thiopropazate Thioproperazine Thioridazine Trifluoperazine Triflupromazine Thioxanthenes: Chlorprothixene Clopenthixol Clopenthixol decanoate Flupentixol Flupentixol decanoate Tiotixene (thiothixene) Zuclopenthixol Zuclopenthixol acetate Zuclopenthixol decanoate
Disputed	Benzamides: Amisulpride Levosulpiride Nemonapride Remoxipride^‡ Sulpiride Sultopride Tiapride Veralipride^‡ Butyrophenones: Melperone Tricyclics: Carpipramine Clocapramine Clorotepine Clotiapine Loxapine Mosapramine Oxyprothepin decanoate Others: Molindone
Atypical	Benzisoxazole/benzisothiazoles: Iloperidone Lurasidone Paliperidone Paliperidone palmitate Perospirone Risperidone^# Ziprasidone Butyrophenones: Lumateperone Phenylpiperazines/quinolinones: Aripiprazole Aripiprazole lauroxil Brilaroxazine^† Brexpiprazole Cariprazine Tricyclics: Asenapine Clozapine^# Olanzapine (+samidorphan) Quetiapine Zotepine Others: Blonanserin Pimavanserin Sertindole
Others	Monoamine-depleting agents: Oxypertine Reserpine Tetrabenazine Muscarinic agonists: Xanomeline/trospium chloride Others/unknown: Azacyclonol
^#WHO-EM ^‡Withdrawn from market Clinical trials: ^†Phase III ^§Never to phase III

v t e Arylpiperazines
Phenylpiperazines	1-Phenylpiperazine (1-PP; PP) 3,4-CFP 2C-B-PP Acaprazine Antrafenine Aripiprazole Batoprazine Bifeprunox BRL-15,572 Ciprofloxacin Dapiprazole DCPP DMPP Diphenylpiperazine Dropropizine EGIS-7625 EGIS-12,233 Elopiprazole Eltoprazine Enpiprazole Ensaculin Etoperidone Flesinoxan Fluanisone Flibanserin Fluprazine Itraconazole Ketoconazole Levodropropizine Lorpiprazole mCPP Mefway MeOPP Mepiprazole Naftopidil Naluzotan Nefazodone Niaprazine Oxypertine Pardoprunox pCPP pFPP Posaconazole S-14,506 S-14,671 S-15,535 SB-258,585 SB-271,046 SB-357,134 SB-399,885 Sonepiprazole TFMPP Tolpiprazole Trazodone Urapidil Vesnarinone Vilazodone Vortioxetine WAY-100,135 WAY-100,635
Benzylpiperazines	2C-B-BZP 3-Methylbenzylpiperazine Befuraline Bifeprunox Buclizine BZP Chlorbenzoxamine DBZP EGIS-7625 Fipexide Imatinib MBZP MDBZP Meclozine Methoxypiperamide NSI-189 Piberaline Piribedil RN-1747 Sunifiram Trimetazidine Vesnarinone
Naphthylpiperazines	1-Naphthylpiperazine (1-NP) 2-Naphthylpiperazine (2-NP) CSP-2503 F-11,461 S-14,506 S-14671
Quinolinylpiperazines	FPPQ 6-Nitroquipazine Isoquipazine Quipazine
Diphenylalkylpiperazines	AD-1211 Almitrine Amperozide BRL-15,572 Buclizine BW373U86 Cetirizine Chlorbenzoxamine Chlorcyclizine Cinnarizine Clocinizine Cyclizine DBL-583 Diphenpipenol Diphenylmethylpiperazine Dotarizine DPI-221 DPI-287 DPI-3290 GBR-12,783 GBR-12,935 GBR-13,069 GBR-13,098 GBR-13,119 Hydroxyzine JJC8-088 Lidoflazine Manidipine Meclozine MT-45 Oxatomide SNC-80 Vanoxerine
Pyrimidinylpiperazines	Buspirone Dasatinib Eptapirone Gepirone Ipsapirone Piribedil Pyrimidinylpiperazine Revospirone Tandospirone Tirilazad Trimazosin Umespirone Zalospirone
Pyridinylpiperazines	Atevirdine Azaperone Delavirdine Mirtazapine ORG-12962 Pyridinylpiperazine
Benzo(iso)thiazolyl piperazines	Lurasidone Perospirone Revospirone Tiospirone Ziprasidone
Tricyclic-linked piperazines	Amoxapine Clopenthixol Clorotepine Clozapine Cyanothepin Doclothepin Docloxythepin Flupentixol Fluphenazine Isofloxythepin Loxapine Meperathiepin Metitepine Octomethothepin Olanzapine Opipramol Oxyclothepin Oxyprothepin Peradithiepin Perathiepin Perazine Perphenazine Pirenzepine Prochlorperazine Thiethylperazine Thiothixene Trifluoperazine Trifluthepin Zuclopenthixol
Others/uncategorized	AP-238 Azimilide Bucinnazine Cinepazet Cinepazic acid Cinepazide CPD-1 Cyclohexylpiperazine Hexocyclium Indinavir JNJ-7777120 Lodenafil MK-212 Mirodenafil PB-28 Ranolazine SA-4503 Sildenafil Tadalafil Vardenafil VUF-6002 WY-46824 Zipeprol

Veterinary use

Synthesis

See also

References