Flumexadol (
INN) (developmental code name CERM-1841 or 1841-CERM) is a
drug described and researched as a non-
opioidanalgesic which was never marketed.[1][2][3][4] It has been found to act as an
agonist of the
serotonin5-HT1A (pKi = 7.1) and
5-HT2C (pKi = 7.5)
receptors and, to a much lesser extent, of the
5-HT2A (pKi = 6.0) receptor.[5][6] According to Nilsson (2006) in a paper on 5-HT2C receptor agonists as potential
anorectics, "The (+)-enantiomer of this compound showed [...] affinity for the 5-HT2C receptor (Ki) 25 nM) [...] and was 40-fold selective over the 5-HT2A receptor in receptor binding studies. Curiously, the racemic version [...], also known as 1841 CERM, was originally reported to possess analgesic properties while no association with 5-HT2C 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).
^Hache J, Diamantis W, Sofia D, Streichenberger G (1978). "The pharmacology of 1841 CERM, a new analgesic". Arzneimittel-Forschung. 28 (4): 642–645.
PMID312104.
^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.
PMID532219.
^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
Flumexadol (
INN) (developmental code name CERM-1841 or 1841-CERM) is a
drug described and researched as a non-
opioidanalgesic which was never marketed.[1][2][3][4] It has been found to act as an
agonist of the
serotonin5-HT1A (pKi = 7.1) and
5-HT2C (pKi = 7.5)
receptors and, to a much lesser extent, of the
5-HT2A (pKi = 6.0) receptor.[5][6] According to Nilsson (2006) in a paper on 5-HT2C receptor agonists as potential
anorectics, "The (+)-enantiomer of this compound showed [...] affinity for the 5-HT2C receptor (Ki) 25 nM) [...] and was 40-fold selective over the 5-HT2A receptor in receptor binding studies. Curiously, the racemic version [...], also known as 1841 CERM, was originally reported to possess analgesic properties while no association with 5-HT2C 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).
^Hache J, Diamantis W, Sofia D, Streichenberger G (1978). "The pharmacology of 1841 CERM, a new analgesic". Arzneimittel-Forschung. 28 (4): 642–645.
PMID312104.
^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.
PMID532219.
^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