Manifaxine

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 ;
PubChem CID	60829;
ChemSpider	54816 ;
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 ; Key:OZGPVYJHWWPEFT-RGNHYFCHSA-N ;
	(what is this?) (verify)

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]

Synthesis

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).

References

^ ^a ^b "Manifaxine - AdisInsight".
^ 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.
^ 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.
^ 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.
^ James Leroy Kelley, et al. EP0426416 (1991 to Wellcome Foundation Ltd).
^ Frank Ivy Carroll, et al. US9562001 (2012 to Research Triangle Institute).
^ Frank Ivy Carroll, et al. US20180215701 (Research Triangle Institute).

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[AdisInsight-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).

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Manifaxine

Synthesis

See also

References

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