Abstract Lecture Jean-Philippe Bouillon, Masaryk University, April 10, 2014.
COBRA, UMR CNRS 6014, Université et INSA de Rouen, 1 rue Tesnière, 76130 Mont-SaintAignan,
France, jean-philippe.bouillon@univ-rouen.fr
Synthesis of new fused fluorinated tricyclic diazine heterocycles and their use as ligands
for 5-HT4 serotoninergic receptors
Despite few symptomatic treatments, there is not at the present time a drug which is able to
cure or stop the progression of Alzheimer’s disease. Among the different approaches for the
development of curative treatments, serotonin 5-HT4 receptor (5-HT4R) agonists have recently
emerged as promising compounds. Recent works have allowed synthesizing 5-HT4R ligands
such as phenanthridines and benzonaphthyridines showing nanomolar affinity. Based on these
results, we aimed at developing new fluorinated tricyclic ligands containing a diazine cycle in
order to increase their affinity and selectivity toward 5-HT4R and determinate their
pharmacological profile.
Our targets A and B were prepared from the corresponding diazino[c](iso)quinolinones.
Two different methodologies involving on a palladium cross-coupling (Suzuki or Stille)
reaction and a KOH mediated anionic ring closure have been developed.
N
R1
Diazine
B
C
R2
R1
, R2
= H, Ph, OMe, Cl, F, I, CF3
O
Target A
N
R1
B
R2
Target B
A
Diazine
O
N
N
(2N)
(2N)
Thus, 20 final compounds were obtained in the three diazine series (pyrazine, pyrimidine
and pyridazine) and evaluated on guinea pig and human 5-HT4R. Pyrazino[2,3-c]isoquinoline
derivatives showed a better affinity for 5-HT4R than phenanthridines and benzonaphthyridines
series and four selected targets were selective against others 5-HT receptors.
Keywords: Alzheimer’s disease, Serotonin 5-HT4 receptors, Diazines, Phenanthridines,
nitrogen fused heterocycles.