Flumexadol

Flumexadol
Clinical data
ATC code	None;
Identifiers
	IUPAC name 2-(3-(Trifluoromethyl)phenyl)morpholine;
CAS Number	30914-89-7;
PubChem CID	65774;
ChemSpider	59194;
UNII	V9783UEL0F;
CompTox Dashboard (EPA)	DTXSID00865570 ;
Chemical and physical data
Formula	C11H12F3NO
Molar mass	231.218 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1COC(CN1)C2=CC(=CC=C2)C(F)(F)F;
	InChI InChI=1S/C11H12F3NO/c12-11(13,14)9-3-1-2-8(6-9)10-7-15-4-5-16-10/h1-3,6,10,15H,4-5,7H2; Key:GXPYCYWPUGKQIJ-UHFFFAOYSA-N;

Flumexadol (INN) (developmental code name CERM-1841 or 1841-CERM) is a drug described and researched as a non-opioid analgesic which was never marketed.^[1]^[2]^[3]^[4] It has been found to act as an agonist of the serotonin 5-HT_1A (pK_i = 7.1) and 5-HT_2C (pK_i = 7.5) receptors and, to a much lesser extent, of the 5-HT_2A (pK_i = 6.0) receptor.^[5]^[6] According to Nilsson (2006) in a paper on 5-HT_2C receptor agonists as potential anorectics, "The (+)-enantiomer of this compound showed [...] affinity for the 5-HT_2C receptor (K_i) 25 nM) [...] and was 40-fold selective over the 5-HT_2A receptor in receptor binding studies. The racemic version [...], also known as 1841 CERM, was originally reported to possess analgesic properties while no association with 5-HT_2C receptor activity was mentioned."^[4] It is implied that flumexadol might be employable as an anorectic in addition to analgesic.^[4] Though flumexadol itself has never been approved for medical use, oxaflozane (brand name Conflictan) is a prodrug of the compound that was formerly used clinically in France as an antidepressant and anxiolytic agent.^[5]^[7]^[8]

Synthesis

Ex 1: Halogenation of 2-chloro ethyl vinyl ether [110-75-8] (1) with molecular bromine gives 1,2-dibromo-1-(2-chloroethoxy)ethane [14689-94-2] (2). Grignard reaction with 3-bromobenzotrifluoride [401-78-5] (3) gives 1-[2-Bromo-1-(2-chloroethoxy)ethyl]-3-(trifluoromethyl)benzene, CID:12343529 (4).

Ex 4: Treatment with benzylamine gives 4-benzyl-2-[3-(trifluoromethyl) phenyl]morpholine, CID:213531 (5).

Ex 6: Catalytric hydrogenation strips the benzyl protecting group completing the synthesis of flumexadol (6).

References

^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 561–. ISBN 978-1-4757-2085-3.
^ Hache J, Diamantis W, Sofia D, Streichenberger G (1978). "The pharmacology of 1841 CERM, a new analgesic". Arzneimittel-Forschung. 28 (4): 642–645. PMID 312104.
^ Kucharczyk N, Yang JT, Valia KH, Stiefel FJ, Sofia RD (November 1979). "Metabolites of 2-(3-trifluoromethylphenyl)tetrahydro-1,4-oxazine (CERM) 1841) in rats and dogs". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 9 (11): 703–711. doi:10.3109/00498257909042338. PMID 532219.
^ ^a ^b ^c Nilsson BM (July 2006). "5-Hydroxytryptamine 2C (5-HT2C) receptor agonists as potential antiobesity agents". Journal of Medicinal Chemistry. 49 (14): 4023–4034. doi:10.1021/jm058240i. PMID 16821762.
^ ^a ^b Bégué JP, Bonnet-Delpon D (2 June 2008). Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons. pp. 303–. ISBN 978-0-470-28187-1.
^ Leysen DC (February 1999). "Selective 5-HT2C agonists as potential antidepressants". IDrugs. 2 (2): 109–120. PMID 16160946.
^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 909–. ISBN 978-1-4757-2085-3.
^ Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory (Book with CD-ROM). Boca Raton: Medpharm Scientific Publishers. p. 766. ISBN 3-88763-075-0.
^ Busch N, Moleyre J, Simond J, Bondivenne R, Labrid C (1976). "Tetrahydro-1, 4-Oxazines. I. New Synthesis Method and a Study of Their Interaction With Tryptaminergic D Receptors". European Journal of Medicinal Chemistry. 11: 201–207.
^ FR 95182, "Process for the synthesis of 2-4-disubstituted tetrahydro 1,4-oxazines", assigned to Centre Europeen de Recherches Mauvernay CERM

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[Elks2014a-1] Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 561–. ISBN 978-1-4757-2085-3.

[pmid312104-2] Hache J, Diamantis W, Sofia D, Streichenberger G (1978). "The pharmacology of 1841 CERM, a new analgesic". Arzneimittel-Forschung. 28 (4): 642–645. PMID 312104.

[KucharczykYang1979-3] Kucharczyk N, Yang JT, Valia KH, Stiefel FJ, Sofia RD (November 1979). "Metabolites of 2-(3-trifluoromethylphenyl)tetrahydro-1,4-oxazine (CERM) 1841) in rats and dogs". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 9 (11): 703–711. doi:10.3109/00498257909042338. PMID 532219.

[Nilsson2006-4] Nilsson BM (July 2006). "5-Hydroxytryptamine 2C (5-HT2C) receptor agonists as potential antiobesity agents". Journal of Medicinal Chemistry. 49 (14): 4023–4034. doi:10.1021/jm058240i. PMID 16821762.

[BéguéBonnet-Delpon2008-5] Bégué JP, Bonnet-Delpon D (2 June 2008). Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons. pp. 303–. ISBN 978-0-470-28187-1.

[pmid16160946-6] Leysen DC (February 1999). "Selective 5-HT2C agonists as potential antidepressants". IDrugs. 2 (2): 109–120. PMID 16160946.

[Elks2014b-7] Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 909–. ISBN 978-1-4757-2085-3.

[isbn3-88763-075-0-8] Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory (Book with CD-ROM). Boca Raton: Medpharm Scientific Publishers. p. 766. ISBN 3-88763-075-0.

[9] Busch N, Moleyre J, Simond J, Bondivenne R, Labrid C (1976). "Tetrahydro-1, 4-Oxazines. I. New Synthesis Method and a Study of Their Interaction With Tryptaminergic D Receptors". European Journal of Medicinal Chemistry. 11: 201–207.

[10] FR 95182, "Process for the synthesis of 2-4-disubstituted tetrahydro 1,4-oxazines", assigned to Centre Europeen de Recherches Mauvernay CERM

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Synthesis

See also

References