Manifaxine

Manifaxine (developmental code name GW-320,659) is a norepinephrine–dopamine reuptake inhibitor developed by GlaxoSmithKline through structural modification of radafaxine, an isomer of hydroxybupropion and one of the active metabolites of bupropion.^[1] Manifaxine was researched for treatment of attention deficit hyperactivity disorder (ADHD) and obesity and was found to be safe, reasonably effective, and well-tolerated for both applications.^[2][3] However, no results were reported following these initial trials and development was discontinued.^[1]

Manifaxine

Clinical data
Other names	GW-320,659
Routes of administration	Oral
ATC code	none
Identifiers
IUPAC name (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethylmorpholin-2-ol
CAS Number	135306-39-7 Y
PubChem CID	60829
ChemSpider	54816 N
UNII	J8IE53G2IV
CompTox Dashboard (EPA)	DTXSID60928953
Chemical and physical data
Formula	C12H15F2NO2
Molar mass	243.254 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@@H]1CO[C@]([C@@H](N1)C)(C2=CC(=CC(=C2)F)F)O
InChI InChI=1S/C12H15F2NO2/c1-7-6-17-12(16,8(2)15-7)9-3-10(13)5-11(14)4-9/h3-5,7-8,15-16H,6H2,1-2H3/t7-,8+,12-/m1/s1 N Key:OZGPVYJHWWPEFT-RGNHYFCHSA-N N
NY (what is this?)  (verify)

Synthesis

Synthesis:^[4] Patent:^[5] See also:^[6][7]

The Grignard reaction between 3,5-difluorobenzonitrile [64248-63-1] (1) and ethylmagnesium bromide gives 3,5-difluoropropiophenone [135306-45-5] (2). Halogenation with molecular bromine occurs at the alpha-keto position providing 2-bromo-3',5'-difluoropropiophenone [135306-46-6] (3). Intermolecular ring formation with DL-Alaninol (2-Aminopropanol) [6168-72-5] completed the synthesis of Manifaxine (4).

See also

• 3,5-Difluoromethcathinone
• 3-Fluorophenmetrazine

References

1. "Manifaxine - AdisInsight".
2. DeVeaugh-Geiss J, Conners CK, Sarkis EH, Winner PK, Ginsberg LD, Hemphill JM, et al. (August 2002). "GW320659 for the treatment of attention-deficit/hyperactivity disorder in children". Journal of the American Academy of Child and Adolescent Psychiatry. 41 (8): 914–20. doi:10.1097/00004583-200208000-00009. PMID 12162627.
3. Spraggs CF, Pillai SG, Dow D, Douglas C, McCarthy L, Manasco PK, et al. (December 2005). "Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects". Pharmacogenetics and Genomics. 15 (12): 883–9. doi:10.1097/01213011-200512000-00006. PMID 16272960. S2CID 40809351.
4. Kelley, J. L., Musso, D. L., Boswell, G. E., Soroko, F. E., Cooper, B. R. (1 January 1996). "(2 S ,3 S ,5 R )-2-(3,5-Difluorophenyl)-3,5- dimethyl-2-morpholinol: A Novel Antidepressant Agent and Selective Inhibitor of Norepinephrine Uptake". Journal of Medicinal Chemistry. 39 (2): 347–349. doi:10.1021/jm950630p. PMID 8558500.
5. James Leroy Kelley, et al. EP0426416 (1991 to Wellcome Foundation Ltd).
6. Frank Ivy Carroll, et al. US9562001 (2012 to Research Triangle Institute).
7. Frank Ivy Carroll, et al. US20180215701 (Research Triangle Institute).