Design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as potent orexin receptor antagonists

Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of orexin receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.

In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists such as 8c. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.Figure optionsDownload as PowerPoint slide