An approach to di- and trihetera[3.3.n]propellanes
(n = 2–4 ), advanced morpholine and piperazine
analogues, is developed. The key step of the reaction sequence included
a [3 + 2] cycloaddition reaction of unsaturated vicinal
dicarboxylic acid derivatives and in situ generated
azomethine ylide resulting in the formation of the pyrrolidine ring.
One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran)
was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic
intermediates. There were 11 examples of the title products obtained
in 3–5 steps on a multigram scale with 10–72% overall
yields. Additionally, molecular structures of homologous dihetera[3.3.n]propellanes, analogues of morpholine, were obtained from
X-ray diffraction studies and analyzed using exit vector plots (EVPs).
It was shown that the scaffolds obtained are somewhat larger as compared
to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane.
Moreover, despite very similar chemical structures, they provide a
very distinct spatial position of heteroatoms, which is clearly seen
from the conformation adopted by a formal eight-membered ring including
both N and O atoms (i.e., crown, boat–chair, twist chair–chair,
and boat–boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes,
and 3-oxa-7-azabicyclo[3.3.0]octane, respectively).
Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT(6) receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT(6)R antagonists. The most active 5-HT(6)R antagonists have IC(50) <100 nM in a functional assay, and K(i) <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin receptors.
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