Abstract
Provided herein are novel compounds as orexin receptor agonists, pharmaceutical compositions, use of such compounds in treating sleep disorders, namely, narcolepsy and hypersomnia, and processes for preparing such compounds.
Important Compound Classes
Title
Orexin Receptor Agonists
Patent Publication Number
WO 2024/107615 A1
Publication Date
May 23, 2024
Priority Applications
US 63/426,087 and US 63/516,017
Priority Dates
November 17, 2022, and July 27, 2023
Inventors
Chiriac, M. I.; Hurzy, D. M.; Kern, J. C.; Manley, P. J.; Rudd, M. T.
Assignee Company
Merck Sharp & Dohme LLC, 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 roles in arousal, emotion, energy homeostasis, reward, learning and memory. Two orexin receptors have been cloned and characterized in mammals. They belong to the superfamily 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 the OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.
The present application describes a series of novel compounds as orexin receptor agonists for the treatment of sleep disorders, particularly narcolepsy and hypersomnia. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
ring A = aryl and heteroaryl;
Ra = C1–6 alkyl and C3–6 cycloalkyl;
R1 = (CR2)n-heteroaryl, (CR2)n-heterocyclyl, (CR2)n-C3–6 cycloalkyl, C1–6 alkyl, O(CR2)pR4, OR, halo, OCR2C(O)NR2, OCR2CF3, O(CR2)tOCR3, (CR2)nCN, (CR2)nR2, O(CR2)tNR2, C2–6 alkenyl, and C2–6 alkynyl;
R2 = H, C1–6 alkyl, halo, (CR2)sOR, (CR2)sCN, (CR2)sS(O)zR, (CR2)sC(O)OR, aryl, and (CR2)s-heterocyclyl;
R3 = C1–6 alkyl, C3–6 cycloalkyl, aryl, heteroaryl, (CR2)x-C2–6 alkenyl, (CR2)x-C2–6 alkynyl and OCF2CH3; and
m = 0, 1, 2, 3 and 4.
Key Structures
Biological Assay
The human orexin-2 receptor IP assay was performed. The compounds described in this application were tested for their orexin-2 receptor agonists activity. The hOX2R-IP IC50 values (nM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for human orexin-2 receptor agonists activity
and the biological data obtained from testing representative examples.
Claims
Total claims: 15
Compound claims: 12
Pharmaceutical composition claims: 1
Method of treatment claims: 2
Recent Review Articles
The author declares no competing financial interest.
References
- Huang L.; Zhu W.; Li N.; Zhang B.; Dai W.; Li S.; Xu H. Functions and mechanisms of adenosine and its receptors in sleep regulation. Sleep Med. 2024, 115, 210–217. 10.1016/j.sleep.2024.02.012. [DOI] [PubMed] [Google Scholar]
- Carpi M.; Palagini L.; Fernandes M.; Calvello C.; Geoffroy P. A.; Miniati M.; Pini S.; Gemignani A.; Mercuri N. B.; Liguori C. Clinical usefulness of dual orexin receptor antagonism beyond insomnia: Neurological and psychiatric comorbidities. Neuropharmacology 2024, 245, 109815. 10.1016/j.neuropharm.2023.109815. [DOI] [PubMed] [Google Scholar]
- Fagan H. A.; Huneke N. T. M.; Domschke K.; Baldwin D. S. The role of the orexin system in the neurobiology of anxiety disorders: Potential for a novel treatment target. Neurosci. Appl. 2024, 3, 103922. 10.1016/j.nsa.2023.103922. [DOI] [Google Scholar]
- Stark R. The olfactory bulb: A neuroendocrine spotlight on feeding and metabolism. J. Neuroendocrinol. 2024, 36, e13382. 10.1111/jne.13382. [DOI] [PubMed] [Google Scholar]
- Sabnis R. W. Sulfonamide Compounds as Orexin Receptor Agonists for Treating Sleep Disorders, Namely, Narcolepsy and Hypersomnia. ACS Med. Chem. Lett. 2024, 15, 17–18. 10.1021/acsmedchemlett.3c00546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Townsend L. T. J.; Anderson K. N.; Boeve B. F.; McKeith I.; Taylor J.-P. Sleep disorders in Lewy body dementia: Mechanisms, clinical relevance, and unanswered questions. Alzheimer’s Dement. 2023, 19, 5264–5283. 10.1002/alz.13350. [DOI] [PubMed] [Google Scholar]