Phenol—Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B‐selective N‐methyl‐d‐aspartate receptor antagonists

Abstract

Tricyclic tetrahydrooxazolo[4,5-h]-[3]benzazepin-9-ols 22 were designed as phenol bioisosteres of tetrahydro-3-benzazepine-1,7-diols. Key features of the synthesis are the introduction of the trifluoromethylsulfonyl and allyl protective groups at the heterocyclic N-atoms. Two methods were developed to convert the triflyl-protected ketone 16 into tricyclic alcohols 21 bearing various N-substituents. According to the first method, trifluoromethanesulfinate was removed by K 2 CO 3 . Following the selective reduction of the imino moiety of 17 with NaBH(OAc) 3 afforded the aminoketone 18, which was reductively alkylated and reduced. According to the second method, both the imine and the ketone of the iminoketone 17 were reduced with NaBH 4 to yield the aminoalcohol 20, which was alkylated or reductively alkylated to form tertiary amines 21f-21r. In the last step, the allyl protective group of 21 was removed with RhCl 3 and HCl to obtain oxazolones 22. In receptor binding studies using [ 3 H]ifenprodil as radioligand ketone, 22m showed the highest GluN2B affinity (K i = 88 nM). However, a reduced affinity toward GluN2B subunit-containing N-methyl-D-aspartate (NMDA) receptors was observed for oxazolones 22 compared to bioisosteric 3-benzazepine-1,7-diols. High selectivity of 22m for the ifenprodil binding site of GluN2B-NMDA receptors over the 1-(1-phenylcyclohexyl)piperidine binding site and σ 2 receptors was observed, but only negligible selectivity over σ 1 receptors. In two-electrode voltage clamp experiments, the 4-phenylbutyl derivative 22d (K i = 422 nM) demonstrated 80% inhibition of ion flux at a concentration of 1 µM. The differences in GluN2B affinity and inhibitory activity are explained by docking studies. In conclusion, 22d is regarded as a novel scaffold of highly potent GluN1/GluN2B antagonists.

Synthesis and biological profile of benzoxazolone derivatives

“…The removal of allyl protective group by its isomerization into prop‐1‐en‐1‐yl with RhCl 3 and subsequent hydrolysis of the resultant enamine functionality resulted in the synthesis of final compounds 78–79 (Figure 20). [ 62 ]…”

Phenol‐benzoxazolone bioisosteres of GluN2B‐NMDA receptor antagonists: Unexpected rearrangement during reductive alkylation with phenylcyclohexanone

“…For the synthesis of oxazolo-benzazepine 5 without methyl moiety in 8position, the same one-pot strategy as for the synthesis of the 4-phenylbutyl substituted analog was pursued. [33] Upon release of trifluoromethanesulfinate (CF 3 SO 2…”

“…To investigate, whether the high GluN2B affinity of 5 in the binding assay translates into a blockade of the ion channel, twoelectrode voltage clamp (TEVC) experiments were conducted. [27,33,39] In these experiments, the cRNA of GluN1a and GluN2B subunits were injected into Xenopus laevis oocytes, which were incubated afterward for 5 days until the NMDA receptor with the desired subunits was expressed.…”

“…Under N 2 atmosphere, N-triflylketone 7 [33] (507 mg, 1.3 mmol) was dissolved in dry acetone (52 ml) and K 2 CO 3 (360 mg, 2.6 mmol) was added. The suspension was stirred at 40 °C for 18 h. Then, H 2 O (50 ml) was added and the solution was extracted with CH 2 Cl 2 (3×).…”

“…[32] The benzoxazolone analog of 3 with a 4-phenylbutyl side chain showed promising GluN2B affinity and inhibition of the ion channel. [33] To increase the GluN2B affinity, we envisaged the bioisosteric replacement of the phenol of 4 with the benzoxazolone system, which should result in compounds 5 and 6 (Figure 1).…”