Aminorex

Aminorex
Clinical data
ATC code	none;
Legal status
Legal status	BR: Class B2 (Anorectic drugs); CA: Schedule III; DE: Anlage II (Authorized trade only, not prescriptible); UK: Class C; US: Schedule I;
Identifiers
	IUPAC name (RS)-5-Phenyl-4,5-dihydro-1,3-oxazol-2-amine;
CAS Number	2207-50-3 ;
PubChem CID	16630;
DrugBank	DB01490 ;
ChemSpider	15767 ;
UNII	2SH16612I9;
KEGG	D02909 ;
ChEMBL	ChEMBL106258 ;
CompTox Dashboard (EPA)	DTXSID00862867 ;
ECHA InfoCard	100.164.420
Chemical and physical data
Formula	C9H10N2O
Molar mass	162.192 g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
	SMILES NC1=NCC(C2=CC=CC=C2)O1;
	InChI InChI=1S/C9H10N2O/c10-9-11-6-8(12-9)7-4-2-1-3-5-7/h1-5,8H,6H2,(H2,10,11) ; Key:SYAKTDIEAPMBAL-UHFFFAOYSA-N ;
	(verify)

Aminorex (Menocil, Apiquel, aminoxaphen, aminoxafen, McN-742) is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension.^[2] In the U.S., it is an illegal Schedule I drug, meaning it has high abuse potential, no accepted medical use, and a poor safety profile.

Aminorex, in the 2-amino-5-aryl oxazoline class, was developed by McNeil Laboratories in 1962.^[3] It is closely related to 4-methylaminorex. Aminorex has been shown to have locomotor stimulant effects, lying midway between dextroamphetamine and methamphetamine. Aminorex effects have been attributed to the release of catecholamines.^[4] It can be produced as a metabolite of the worming medication levamisole, which is sometimes used as a cutting agent of illicitly produced cocaine.^[5]^[6]

Pharmacology

Aminorex has been found to act as a reuptake inhibitor at the dopamine and norepinephrine transporters, with releasing agent properties at the serotonin transporter.^[7]

History

It was discovered in 1962 by Edward John Hurlburt,^[8] and was quickly found in 1963 to have an anorectic effect in rats. It was introduced as a prescription appetite suppressant in Germany, Switzerland and Austria in 1965, but was withdrawn in 1972 after it was found to cause pulmonary hypertension in approximately 0.2% of patients, and was linked to a number of deaths.^[4]^[9]

Synthesis

The synthesis was first reported in a structure-activity relationship study of 2-amino-5-aryl-2-oxazolines, where aminorex was found to be approximately 2.5 times more potent than D-amphetamine sulfate in inducing anorexia in rats, and was also reported to have CNS stimulant effects.

The racemic synthesis involves addition/cyclization reaction of 2-amino-1-phenylethanol with cyanogen bromide.^[10] A similar synthesis has been also published.^[11] In a search for a cheaper synthetic route, a German team developed an alternative route^[12] which, by using chiral styrene oxide, allows an enantiopure product.

References

^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
^ Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA (November 2000). "Recreational use of aminorex and pulmonary hypertension". Chest. 118 (5): 1496–1497. doi:10.1378/chest.118.5.1496. PMID 11083709. Archived from the original on 2013-01-12.
^ US 3161650, Ireland PG, "2-Amino-5-Aryloxazoline Products", issued 15 December 1964, assigned to Janssen Pharmaceuticals Inc.
^ ^a ^b Fishman AP (Jan 1991). "Aminorex to fen/phen: an epidemic foretold". Circulation. 99 (1): 156–161. doi:10.1161/01.CIR.99.1.156. PMID 9884392.
^ Ho EN, Leung DK, Leung GN, Wan TS, Wong AS, Wong CH, et al. (April 2009). "Aminorex and rexamino as metabolites of levamisole in the horse". Analytica Chimica Acta. 638 (1): 58–68. Bibcode:2009AcAC..638...58H. doi:10.1016/j.aca.2009.02.033. PMID 19298880.
^ Bertol E, Mari F, Milia MG, Politi L, Furlanetto S, Karch SB (July 2011). "Determination of aminorex in human urine samples by GC-MS after use of levamisole". Journal of Pharmaceutical and Biomedical Analysis. 55 (5): 1186–1189. doi:10.1016/j.jpba.2011.03.039. PMID 21531521.
^ Hofmaier T, Luf A, Seddik A, Stockner T, Holy M, Freissmuth M, et al. (July 2014). "Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters". Neurochemistry International. 73 (100): 32–41. doi:10.1016/j.neuint.2013.11.010. PMC 4077236. PMID 24296074.
^ US 3115494, Albert MG, Ireland PG, "2-amino-5, 6-dihydro-4ii-1, 3-oxazines and a process for their preparation", issued 2 December 1963, assigned to Janssen Pharmaceuticals Inc.
^ Weigle DS (June 2003). "Pharmacological therapy of obesity: past, present, and future". The Journal of Clinical Endocrinology and Metabolism. 88 (6): 2462–2469. doi:10.1210/jc.2003-030151. PMID 12788841.
^ Poos GI, Carson JR, Rosenau JD, Roszkowski AP, Kelley NM, Mcgowin J (May 1963). "2-Amino-5-aryl-2-oxazolines. Potent New Anorectic Agents". Journal of Medicinal Chemistry. 6 (3): 266–272. doi:10.1021/jm00339a011. PMID 14185981.
^ Ueda S, Terauchi H, Yano A, Ido M, Matsumoto M, Kawasaki M (January 2004). "4,5-Disubstituted-1,3-oxazolidin-2-imine derivatives: a new class of orally bioavailable nitric oxide synthase inhibitor". Bioorganic & Medicinal Chemistry Letters. 14 (2): 313–316. doi:10.1016/j.bmcl.2003.11.010. PMID 14698148.
^ DE 2101424, "2-Amino-5-phenyl-2-oxazoline preparation", assigned to Polska Akademia Nauk Instytut Chemn Organicznej, Warschau