Novel 5-Alkyl Pyrrolidine Orexin Receptor Agonists for Treating Sleep Disorders

Important Compound Classes

Title

5-Alkyl Pyrrolidine Orexin Receptor Agonists

Patent Publication Number

WO 2020/167706 A1

Publication Date

August 20, 2020

Priority Application

US 62/805,007 and US 62/949,672

Priority Date

February 13, 2019 and December 18, 2019

Inventors

Bogen, S. L.; Clausen, D. J.; Guiadeen, D. G.; Rudd, M. T.; Yang, D.

Assignee Company

Merck Sharp & Dohme Corp., USA

Disease Area

Sleep disorders

Biological Target

Orexin

Summary

The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcolepsy, idiopathic hypersomnia, excessive daytime sleepiness, shift work disorder, obstructive sleep apnea, and insomnia. Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior. Orexins have also been indicated as playing a role in arousal, emotion, energy homeostasis, reward, learning and memory. Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors: the orexin-1 receptor (OX or OX1R) is partially selective for OX-A, and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B with similar affinity. The physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.

The present application describes a series of novel 5-alkyl pyrrolidine compounds as orexin receptor agonists for the treatment or prevention of neurological and psychiatric disorders and diseases, particularly sleep disorders. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = -O-, -NH-, or X may be a direct bond to R₁;

Y = N or CH;

R₁ is selected from -C_1–6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R₄, and -C_3–6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R₄;

R₂ is selected from H, -C_1–6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R₄, -C_3–6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R₄, -phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R₄, and -heteroaryl, where the heteroaryl is selected from pyridyl, pyrimidinyl, and pyrazinyl and the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R₄;

R_2a and R_2b are independently selected from H, OH, halogen, and -C_1–6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from halogen;

R₃ is selected from -C_1–6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R₄, -C_3–6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R₄, -phenyl, where the phenyl is unsubstituted or substituted with one to three substituents independently selected from R₄, -NR₁₀R₁₁, where R₁₀ and R₁₁ are independently selected from H and -C_1–6alkyl, which is unsubstituted or substituted with one to six R₄;

R₄ is selected from OH, halogen, -C_1–6alkyl, which is unsubstituted or substituted with one to six fluoro, C_2–4alkenyl, C_2–4alkynyl, -C_3–6cycloalkyl, -O-C_1–6alkyl, -O(C=O)-C_1–6alkyl, -NH₂, -NH-C_1–6alkyl, -NO₂, phenyl, -CO₂H, -SO₂–C_1–6alkyl, -C_3–5cycloalkyl(SO₂), and -CN;

R₅ and R₆ are independently selected from H, -C_1–6alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R₄, and -C_3–6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R₄.

Key Structures

Biological Assay

The human orexin-2 receptor IPOne assay was performed. The compounds described in this application were tested for their orexin-2 receptor agonists activity. The hOX2R-IP IC₅₀ (nM) and Emax (%) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for human orexin-2 receptor agonists activity. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 14

Compound claims: 11

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Recent Review Articles

• 1.Hwang Y. T.; Piguet O.; Hodges J. R.; Grunstein R.; Burrell J. R.. Sleep Med. Rev. 2020, 54, 101361.
• 2.Perrey D. A.; Zhang Y.. Brain Res. 2020, 1731, 145922.
• 3.Clark J. W.; Brain M. L.; Drummond S. P. A.; Hoyer D.; Jacobson L. H.. Sleep Med. Rev. 2020, 53, 101332.
• 4.Takenoshita S.; Nishino S.. Sleep Med. Clin. 2020, 15, 177.
• 5.Owen J. E.; Veasey S. C.. Neurobiol. Dis. 2020, 139, 104820.
• 6.Wei Y.; Van Someren E. J. W.. Curr. Opin. Behav. Sci. 2020, 33, 1.

The author declares no competing financial interest.