Alvameline

Alvameline (Lu 25-109) is a M1 receptor agonist and M2/M3 receptor antagonist[1] that was under investigation for the treatment of Alzheimer's disease, but produced poor results in clinical trials[2] and was subsequently discontinued.

Alvameline
Clinical data
ATC code
  • None
Identifiers
IUPAC name
  • 3-(2-ethyltetrazol-5-yl)-1-methyl-5,6-dihydro-2H-pyridine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC9H15N5
Molar mass193.254 g·mol−1
3D model (JSmol)
SMILES
  • n1nn(nc1\C2=C\CCN(C)C2)CC
InChI
  • InChI=1S/C9H15N5/c1-3-14-11-9(10-12-14)8-5-4-6-13(2)7-8/h5H,3-4,6-7H2,1-2H3 Y
  • Key:RNMOMKCRCIRYCZ-UHFFFAOYSA-N Y
  (verify)

Synthesis
Synthesis:[3] Patent:[4]

Alkylation of nicotinonitrile (accessible from nicotinamide)[5] (1) with methyl iodide affords the N-methylpyridinium salt (2). The reduction of this intermediate with sodium borohydride gives 3-cyano-N-methyl-1,2,5,6-tetrahydropyridine [5657-66-9] (3). Reaction with ethyl chloroformate results in N-demethylation and consequent formation of the corresponding carbamate [120241-16-9] (4). The nitrile group is then transformed to a tetrazole by reaction with sodium azide in the presence of aluminum chloride giving CID:9991151 (5). The surrogate acid is then alkylated with ethyl iodide to afford CID:10106197 (6). Treatment with acid then removes the carbamate on the ring nitrogen giving Lu-25-077 [221549-70-8] (7). The methyl group on the piperidine ring restored using formaldehyde and formic acid under standard Eschweiler–Clarke conditions, yielding alvameline (8).

See also

References
  1. Sánchez C, Arnt J, Didriksen M, Dragsted N, Moltzen Lenz S, Matz J (June 1998). "In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro". Psychopharmacology. 137 (3): 233–40. doi:10.1007/s002130050615. PMID 9683000. S2CID 20740372. Archived from the original on 2000-10-02. Retrieved 2009-12-03.
  2. Sramek JJ, Forrest M, Mengel H, Jhee SS, Hourani J, Cutler NR (1998). "A bridging study of LU 25-109 in patients with probable Alzheimer's disease". Life Sciences. 62 (3): 195–202. doi:10.1016/S0024-3205(97)01087-4. PMID 9488097.
  3. Moltzen, E. K.; Pedersen, H.; Boegesoe, K. P.; Meier, E.; Frederiksen, K.; Sanchez, C.; Lemboel, H. L. (1994). "Bioisosteres of Arecoline: 1,2,3,6-Tetrahydro-5-pyridyl-Substituted and 3-Piperidyl-Substituted Derivatives of Tetrazoles and 1,2,3-Triazoles. Synthesis and Muscarinic Activity". Journal of Medicinal Chemistry. 37 (24): 4085–4099. doi:10.1021/jm00050a006. PMID 7990109.
  4. EP0296721 idem Klaus P. Bogeso, Klaus G. Jensen, Ejner K. Moltzen, Henrik Pedersen, U.S. Patent 4,866,077 (1988 to H Lundbeck AS).
  5. "Nicotinonitrile". Organic Syntheses. 33: 52. 1953. doi:10.15227/orgsyn.033.0052.; Collective Volume, vol. 4, p. 706
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