Chemical compound
Tazomeline (LY-287,041 ) is a drug which acts as a non-selective muscarinic acetylcholine receptor agonist .[1] [2] It was in clinical trials for the treatment of cognitive dysfunction such as that seen in Alzheimer's disease and schizophrenia , but development was apparently scrapped for unknown reasons.[1] [2] [3] Another of the patented uses is for the treatment of "severe painful conditions".
Synthesis
Synthesis:
[4] Patent:
[5] Precursor (XXXV):
[6]
Ex 1 : A Strecker type alpha-amino nitrile between nicotinaldehyde , potassium cyanide and ammonium chloride gives amino(pyridin-3-yl)acetonitrile [131988-63-1] (2 ). The halogenation of this intermediate with sulfur monochloride [10025-67-9] in DMF led to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole [131986-28-2] (3 ).
Ex 64 : Thioether formation with 1-Hexanethiol [111-31-9] (4 ) in the presence of sodium hydrogen sulfide , DMF and K2CO3 gave 3-(4-hexylthio-1,2,5-thiadiazol-3-yl)pyridine, CID:10755149 (5 ). Alkylation with methyl iodide gives 3-(4-hexylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide, CID:19075299 (6 ). The reduction of the pyridine with sodium borohydride in alcohol gives the tetrahydropyridine and hence completed the synthesis of Tazomeline (7 ).
See also
References
^ a b Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacology & Therapeutics . 117 (2): 232–43. doi :10.1016/j.pharmthera.2007.09.009 . PMID 18082893 .
^ a b Amos D Korczyn (October 2000). "Muscarinic M1 Agonists in the Treatment of Alzheimer's Disease". Expert Opinion on Investigational Drugs . 9 (10): 2259–2267(9). doi :10.1517/13543784.9.10.2259 . PMID 11060805 . S2CID 32214700 .
^ Mashkovskii MD, Glushkov RG (April 2001). "Drugs for the Treatment of Alzheimer's Disease". Pharmaceutical Chemistry Journal . 35 (4): 179–182. doi :10.1023/A:1010474325601 . S2CID 39866378 .
^ Sauerberg, P., Olesen, P. H., Nielsen, S., Treppendahl, S., Sheardown, M. J., Honore, T., Mitch, C. H., Ward, J. S., Pike, A. J. (June 1992). "Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines". Journal of Medicinal Chemistry . 35 (12): 2274–2283. doi :10.1021/jm00090a019 . ISSN 0022-2623 . PMID 1613751 .
^ Per Sauerberg & Preben H. Olesen, U.S. Patent 5,712,297 (1998 to Novo Nordisk AS).
^ Klosa, J. (1956). "Über einige Kondensationen mit Pyridin- und Chinolinaldehyden". Archiv der Pharmazie . 289 (4): 177–188. doi :10.1002/ardp.19562890402 . ISSN 0365-6233 . PMID 13328069 . S2CID 98758459 .
mAChRs
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AQ-RA 741
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J-104,129
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RU-47,213
SCH-57,790
SCH-72,788
SCH-217,443
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Silahexacyclium
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Umeclidinium bromide (+vilanterol )
WIN-2299
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Zamifenacin
Precursors (and prodrugs )
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