Alvameline
Alvameline.png
Clinical data
ATC code
  • None
Identifiers
  • 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)
  • n1nn(nc1\C2=C\CCN(C)C2)CC
  • 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 checkY
  • Key:RNMOMKCRCIRYCZ-UHFFFAOYSA-N checkY
  (verify)

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.

Synthesis

Synthesis:[3] Patent:[4]
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