Tazomeline

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".

Tazomeline
Clinical data
ATC code
  • None
Identifiers
IUPAC name
  • 5-[4-(hexylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-methyl-1,2,3,6-tetrahydropyridine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H23N3S2
Molar mass297.48 g·mol−1
3D model (JSmol)
SMILES
  • n2snc(/C1=C/CCN(C)C1)c2SCCCCCC

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
  1. 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.
  2. 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.
  3. 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.
  4. 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 1520-4804 0022-2623, 1520-4804. {{cite journal}}: Check |issn= value (help)
  5. Per Sauerberg & Preben H. Olesen, U.S. Patent 5,712,297 (1998 to Novo Nordisk AS).
  6. Klosa, J. (1956). "Über einige Kondensationen mit Pyridin- und Chinolinaldehyden". Archiv der Pharmazie. 289 (4): 177–188. doi:10.1002/ardp.19562890402. ISSN 1521-4184 0365-6233, 1521-4184. {{cite journal}}: Check |issn= value (help)
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