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Manifaxine - Revision history
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<p><b>New page</b></p><div>{{Short description|Chemical compound}}<br />
{{Drugbox<br />
| Verifiedfields = changed<br />
| Watchedfields = changed<br />
| verifiedrevid = 449582256<br />
| IUPAC_name = (2''S'',3''S'',5''R'')-2-(3,5-difluorophenyl)-3,5-dimethylmorpholin-2-ol<br />
| image = Manifaxine.svg<br />
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --><br />
| routes_of_administration = [[Oral administration|Oral]]<br />
<br />
<!--Identifiers--><br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 135306-39-7<br />
| ATC_prefix = none<br />
| PubChem = 60829<br />
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| UNII = J8IE53G2IV<br />
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| ChemSpiderID = 54816<br />
| synonyms = GW-320,659<br />
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<br />
'''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 metabolite]]s of [[bupropion]].<ref name="AdisInsight">{{Cite web|url=https://adisinsight.springer.com/drugs/800006906|title=Manifaxine - AdisInsight}}</ref> 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.<ref>{{cite journal | vauthors = DeVeaugh-Geiss J, Conners CK, Sarkis EH, Winner PK, Ginsberg LD, Hemphill JM, Laurenza A, Barrows CE, Webster CJ, Stotka CJ, Asgharnejad M | display-authors = 6 | title = GW320659 for the treatment of attention-deficit/hyperactivity disorder in children | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 41 | issue = 8 | pages = 914–20 | date = August 2002 | doi = 10.1097/00004583-200208000-00009 | pmid = 12162627 }}</ref><ref>{{cite journal | vauthors = Spraggs CF, Pillai SG, Dow D, Douglas C, McCarthy L, Manasco PK, Stubbins M, Roses AD | display-authors = 6 | title = Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects | journal = Pharmacogenetics and Genomics | volume = 15 | issue = 12 | pages = 883–9 | date = December 2005 | doi = 10.1097/01213011-200512000-00006 | pmid = 16272960 | s2cid = 40809351 }}</ref> However, no results were reported following these initial trials and development was discontinued.<ref name="AdisInsight" /><br />
==Synthesis==<br />
[[File:Manifaxine synthesis.svg|class=skin-invert-image|thumb|center|500px|Synthesis:<ref>{{cite journal | vauthors=((Kelley, J. L.)), ((Musso, D. L.)), ((Boswell, G. E.)), ((Soroko, F. E.)), ((Cooper, B. R.)) | journal=Journal of Medicinal Chemistry | title=(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 | volume=39 | issue=2 | pages=347–349 | date=1 January 1996 | doi=10.1021/jm950630p| pmid=8558500 }}</ref> Patent:<ref>James Leroy Kelley, et al. EP0426416 (1991 to Wellcome Foundation Ltd).</ref> See also:<ref>Frank Ivy Carroll, et al. US9562001 (2012 to Research Triangle Institute).</ref><ref>Frank Ivy Carroll, et al. US20180215701 (Research Triangle Institute).</ref>]]<br />
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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''').<br />
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==See also==<br />
* [[3,5-Difluoromethcathinone]]<br />
* [[3-Fluorophenmetrazine]]<br />
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==References==<br />
{{Reflist}}<br />
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{{Stimulants}}<br />
{{Monoamine reuptake inhibitors}}<br />
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[[Category:Abandoned drugs]]<br />
[[Category:Beta-Hydroxyamphetamines]]<br />
[[Category:Fluoroarenes]]<br />
[[Category:Drugs developed by GSK plc]]<br />
[[Category:Norepinephrine–dopamine reuptake inhibitors]]<br />
[[Category:Phenylmorpholines]]<br />
[[Category:Stimulants]]<br />
[[Category:Tertiary alcohols]]<br />
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{{Nervous-system-drug-stub}}</div>
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