Untitled

Schepmann

Wünsch

2022

To improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil ( 2) and the 3-benzazepone moiety of WMS-1410 (3) were merged to obtain oxazolobenzazepines of type 4. The 5-(hydroxyethyl)benzoxazolone 7 representing the first key intermediate was prepared in four steps starting with the 4-(2-hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N-sulfonylated glycine esters established the necessary side chain. The intramolecular Friedel-Crafts acylation of acid 12a containing the N-tosyl protective group led upon decarbonylation exclusively to the tricyclic tetrahydroisoquinoline 14. Protection of the amino moiety by the stronger electron-withdrawing triflyl group resulted in the desired 3-benzazepine 15 without the formation of analogous isoquinoline. The triflyl protective group was cleaved off by K 2 CO 3 -induced elimination of trifluoromethanesulfinate. In a one-pot three-step procedure, various oxazolobenzazepinediones 15 were obtained, which were reduced to afford the desired secondary alcohols 18.

Section: Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators

Schepmann

Wünsch

2022

“…All three ionotropic glutamate receptors play a key role in excitatory neurotransmission in the central nervous system. [ 1–3 ]…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, drugs inhibiting the ion flux of Ca 2+ through the NMDA receptor are of great interest for the treatment of acute neuronal disease states (e.g., stroke, brain injury, epileptic seizure, and migraine) and chronic neurodegenerative processes (e.g., Parkinson's disease, Alzheimer's disease, and multiple sclerosis). [ 3,6–8 ]…”

Section: Introductionmentioning

confidence: 99%

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

Schreiber

Goerges

et al. 2022

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.

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

Frehland

Schepmann

et al. 2022

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).