Aminorex

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 It was withdrawn from the market after it was found to cause pulmonary hypertension.[1] In the U.S., it is an illegal Schedule I drug, meaning it has high abuse potential, no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
Clinical data
ATC code
  • none
Legal status
Legal status
  • 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
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard100.164.420
Chemical and physical data
FormulaC9H10N2O
Molar mass162.192 g·mol−1
3D model (JSmol)
ChiralityRacemic 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) Y
  • Key:SYAKTDIEAPMBAL-UHFFFAOYSA-N Y
  (verify)

Aminorex, in the 2-amino-5-aryl oxazoline class, was developed by McNeil Laboratories in 1962.[2] 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.[3] It can be produced as a metabolite of the worming medication levamisole, which is sometimes used as a cutting agent of illicitly produced cocaine.[4][5]

History

It was discovered in 1962 by Edward John Hurlburt,[6] 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 It was introduced as a prescription appetite suppressant in Germany, Switzerland and Austria in 1965, but was withdrawn in 1972 after it was found to cause pulmonary hypertension in approximately 0.2% of patients, and was linked to a number of deaths.[3][7]

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.[8] A similar synthesis has been also published.[9] In a search for a cheaper synthetic route, a German team developed an alternative route[10] which, by using chiral styrene oxide, allows an enantiopure product.

See also

References
  1. Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA (November 2000). "Recreational use of aminorex and pulmonary hypertension". Chest. 118 (5): 1496–7. doi:10.1378/chest.118.5.1496. PMID 11083709. Archived from the original on 2013-01-12.
  2. US 3161650, "2-Amino-5-Aryloxazoline Products"
  3. Fishman AP. (Jan 1991). "Aminorex to fen/phen - An epidemic foretold". Circulation. 99 (1): 156–161. doi:10.1161/01.CIR.99.1.156. ISSN 0009-7322. PMID 9884392.
  4. Ho EN, Leung DK, Leung GN, Wan TS, Wong AS, Wong CH, Soma LR, Rudy JA, Uboh C, Sams R (April 2009). "Aminorex and rexamino as metabolites of levamisole in the horse". Analytica Chimica Acta. 638 (1): 58–68. doi:10.1016/j.aca.2009.02.033. PMID 19298880.
  5. 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): 1186–9. doi:10.1016/j.jpba.2011.03.039. PMID 21531521.
  6. US 3115494, "2-amino-5, 6-dihydro-4ii-1, 3-oxazines and a process for their preparation"
  7. Weigle, DS (June 2003). "Pharmacological therapy of obesity: past, present, and future". The Journal of Clinical Endocrinology and Metabolism. 88 (6): 2462–9. doi:10.1210/jc.2003-030151. PMID 12788841.
  8. Poos GI, Carson JR, Rosenau JD, Roszowski 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.
  9. Ueda S, Terauchi H, Yano A, Ido M, Matsumoto M, Kawasaki M (Jan 2004). "4,5-Disubstituted-1,3-oxazolidin-2-imine derivatives: a new class of orally bioavailable nitric oxide synthase inhibitor". Bioorg. Med. Chem. Lett. 14 (2): 313–316. doi:10.1016/j.bmcl.2003.11.010. PMID 14698148.
  10. DE Patent 2101424 2-amino-5-phenyl-2-oxazoline preparation
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