Mice treated with idazoxan, which blocks the α2A receptor which regulates norepinephrine, behaved similarly to control animals despite still having amyloid-beta plaques in the brain, as a proof-of-concept experiment that dramatically reduced Alzheimer's pathology and symptoms in two mouse models, potentially offering an immediate treatment for this devastating disease.[5]
Synthesis
Note that the literature method claims that the old original patented procedure gives a different reaction product formed through a rearrangement.
The reaction of catechol (1) with 2-Chloroacrylonitrile [920-37-6] (2) gives 2-cyano-1,4-benzodioxan [1008-92-0] (3). Pinner reaction with alcoholic hydrogen chloride leads to the iminoether,[11] (4). Treatment with ethylenediamine [107-15-3] (5) gives the imidazoline ring affording Idazoxin (6).
^Bousquet P, Bruban V, Schann S, Greney H, Ehrhardt JD, Dontenwill M, Feldman J (June 1999). "Participation of imidazoline receptors and alpha(2-)-adrenoceptors in the central hypotensive effects of imidazoline-like drugs". Annals of the New York Academy of Sciences. 881 (1): 272–8. Bibcode:1999NYASA.881..272B. doi:10.1111/j.1749-6632.1999.tb09369.x. PMID10415925. S2CID38772290.
^Yakubu MA, Hamilton CA, Howie CA, Reid JL (1988). "Idazoxan and brain alpha2-adrenoceptor in the rabbit". Brain Research. 436: 289–296. doi:10.1016/0006-8993(88)90402-7. PMID2848612.
^Hamilton CA, Yakubu MA, Jardine E, Reid JL (1991). "Imidazole binding sites in rabbit kidney and forebrain membranes". J Auton Pharmacol. 11 (4): 277–83. doi:10.1111/j.1474-8673.1991.tb00325.x. PMID1939285.
^Chapleo CB, Myers PL, Butler RC, Doxey JC, Roach AG, Smith CF (June 1983). "alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants". Journal of Medicinal Chemistry. 26 (6): 823–31. doi:10.1021/jm00360a008. PMID6133953.
^US 2979511, Krapcho J, Lott WA, "Certain 1, 4-benzodioxanyl imidazolines and corresponding pyrimidines and process", issued 11 April 1961, assigned to Olin Corp.
^US 7338970, Bougaret J, Avan JL, Segonds R, "Pharmaceutical composition based on idazoxan, salts, hydrates or polymorphs thereof", issued 3 March 2008, assigned to Pierre Fabre Medicament.