Negative allosteric modulators of NMDA receptors with GluN2B subunit: Alanine‐derived benzoxazolone bioisosteres of 2‐methyl‐3‐benzazepine‐1,7‐diols

Abstract

Inspired by besonprodil, the phenol of potent negative allosteric modulators of GluN2B‐N‐methyl‐d‐aspartate (NMDA) receptors was replaced by a benzoxazolone system. To increase the similarity to the lead compounds, an additional methyl moiety was installed in the 8‐position of tricyclic oxazolobenzazepines, resulting in compounds 6. The additional methyl moiety originates from alanine, which was introduced by a Mitsunobu reaction of benzoxazolylethanol 7 with N‐triflyl‐protected alanine methyl ester. A crucial feature of the synthesis was the protection of the oxazolone ring by an allyl moiety, which was cleaved off at the end of the synthesis by RhCl3‐catalyzed isomerization. Due to the additional methyl moiety, the intramolecular Friedel–Crafts acylation of acid 10 to afford ketone 11 required careful optimization to minimize the formation of the side product tetrahydroisoquinoline 16. Alkylation or reductive alkylation of secondary amine 13 led to diastereomeric oxazolobenzazepines cis‐14 and trans‐14, which were separated by flash chromatography. Phenylbutyl derivatives cis‐6a and trans‐6a revealed twofold higher GluN2B affinity than analog 5a without 8‐CH3 group. The methylated oxazolobenzazepines 6 and 14 did not interact with the phencyclidine binding site of NMDA receptors and σ2 receptors. However, the σ1 receptor preferred cis‐configured oxazolobenzazepines. The highest σ1 receptor affinities were obtained for cis‐14a (Ki = 26 nM) and cis‐6b (Ki = 30 nM).

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] The test compounds 78-79 (Figure 20) showed a two-fold higher affinity toward GLuN2B as compared to their analogs 81 without a methyl group at eight-position. Similarly, compounds 78-79 showed no binding with the phencyclidine binding site of NMDA receptors and the σ 2 receptors.…”

“…The absence of allyl protective groups in compound 81 (Figure 20) resulted in a complete loss of the interactions with ifenprodil binding site. [62] Compound 75 through an unusual ring contraction to provide the products 84 and 85 (Figure 21). Reportedly, the trans isomer of ringcontracted compounds with allyl group 84 (Figure 21) showed a significant affinity toward GluN2B with K i = 89 nM as compared to its analog 85 (Figure 21) without allyl moiety.…”

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

“…Then, H 2 O (30 ml) and brine (30 ml) were added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried (Na 2 SO 4 ) and the solvent was removed under reduced pressure giving a yellow oil, which was purified by flash column chromatography (Ø 4 cm, 18 cm, ethyl acetate/n-hexane 1:1 + 1% Under N 2 atmosphere, N-triflylketone 12 [37] (50.3 mg, 0.12 mmol) was dissolved in dry acetonitrile (1.5 ml) and K 2 CO 3 (51.0 mg, 0.37 mmol) was added. The suspension was stirred at 60 °C for 3 h. Then H 2 O (5 ml) was added and the solution was extracted with CH 2 Cl 2 (3×).…”

“…without substituent at the oxazolone ring. For the synthesis of the methylated analog 6, the methylated building block 12 [37] was employed as starting material. K 2 CO 3 induced Both trans-18 and cis-18 were isolated as mixtures of diastereomers.…”