Use of orexin 2 receptor agonists to improve respiratory function during sleep

Abstract

Disclosed are the use of orexin type 2 receptor (OX2R) agonists at anomalous concentrations for the treatment of sleep apnea. Also disclosed are compositions and methods for administering an OX2R agonist to a subject (e.g., a mammal) in need at a dose that provides a plasma concentration of the OX2R agonist below the maximum anomalous plasma concentration of the OX2R agonist. Also disclosed are compositions and methods for treating sleep apnea in subjects requiring treatment of sleep apnea by maintaining the plasma concentration of the OX2R agonist below the maximum anomalous concentration of the OX2R agonist after administration.

Description

[Technical Field]

[0001] Respiration is a crucial process involving the exchange of oxygen and carbon dioxide within the lungs. The efficiency of this exchange depends on ventilation, which is the movement of air into the lungs through inspiration and expiration. Ventilation requires precise control of the respiratory and airway muscles, including the diaphragm and genioglossus (the main upper airway dilator). The descending movement of the diaphragm into the abdominal cavity increases lung volume and induces inspiration (M. de Carvalho, et al., Diaphragmatic Neurophysiology and Respiratory Markers in ALS, Frontiers in Neurology 10 (2019)), and the forward movement of the tongue by the genioglossus widens the airway in the oropharynx (AS Jordan, DP White, Pharyngeal motor control and the pathogenesis of obstructive sleep apnea, Respir Physiol Neurobiol 160(1)(2008)1-7). Neurons in the Pre-Betzinger complex, located in the ventrolateral part of the medulla oblongata, regulate the coordinated activity of the diaphragm and genioglossus muscles by controlling the activity of phrenic motor neurons in the cervical spinal cord and hypoglossal motor neurons in the dorsomedial part of the medulla oblongata, respectively (JCSmith, APAbdala, A. Borgmann, IARybak, JFPaton, Brainstem respiratory networks: building blocks and microcircuits, Trends Neurosci 36(3)(2013), 152-62), playing a crucial role in the generation of inspiratory airflow. [Background technology]

[0002] Respiratory dysregulation includes opioid-induced respiratory depression after surgery (S. Ayad, AKKhanna, SUIqbal, N. Singla, Characterization and monitoring of postoperative respiratory depression: current approaches and future considerations, Br J Anaesth 123(3)(2019), 378-391), opioid overdose (M. Nagappa, TN Weingarten, G. Montandon, J. Sprung, F. Chung, Opioids, respiratory depression, and sleep-disordered breathing, Best Pract Res Clin Anaesthesiol 31(4)(2017), 469-485), and sleep apnea (obstructive, mixed, central) characterized by intermittent cessation of breathing during sleep, leading to hypoxia and cerebral cortical arousal (JA Dempsey, SCVeasey, BJ Morgan, CPO'Donnell, Pathophysiology of sleep) Opioids are associated with various medical conditions, including apnea (Physiol Rev 90(1)(2010)47-112). Postoperatively, opioids are administered for pain management, but opioid use can be accompanied by serious adverse events, including respiratory depression and CNS suppression (CJ van Dam, M.H. Algera, E. Olofsen, L. Aarts, T. Smith, M. van Velzen, E. Sarton, M. Niesters, A. Dahan, Opioid utility function: methods and implications, Ann Palliat Med 9(2)(2020)528-536). Naloxone, an opioid antagonist, reduces these adverse events, but it also suppresses the analgesic effect of opioids.Furthermore, due to life-threatening cardiovascular side effects, the use of naloxone must be carefully considered (A. Dahan, L. Aarts, TWSmith, Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression, Anesthesiology 112(1)(2010)226-38). Therefore, there is a need for drugs that suppress opioid-induced respiratory depression (OIRD) without impairing analgesic effects (MZImam, A. Kuo, MTSmith, Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants, F1000Res 9(2020)).

[0003] Sleep apnea includes several types: central sleep apnea (CSA), obstructive sleep apnea (OSA), mixed sleep apnea, and complex sleep apnea (TIMorgenthaler, V. Kagramanov, V. Hanak, PADcker, Complex sleep apnea syndrome: is it a unique clinical syndrome?, Sleep 29(9)(2006), 1203-9). CSA is associated with reduced respiratory signals from the brainstem respiratory center to the diaphragm (JADempsey, et al.). OSA is associated with upper airway obstruction (JADempsey, et al.). Complex sleep apnea is characterized by patients with obstructive sleep apnea who develop central sleep apnea after treatment. Continuous positive airway pressure (CPAP), the gold standard in the treatment of sleep apnea, is widely used to treat both CSA and OSA by securing the airway through a mask worn over the nose and / or mouth, physically keeping the upper airway open like a splint. However, CPAP has a problem of low adherence, with patients shortening the duration of use at night or even discontinuing treatment altogether (AMSawyer, NSGooneratne, CLMarcus, D.Ofer, KCRichards, TEWeaver, A systematic review of CPAP adherence across age groups: clinical and empiric insights for developing CPAP adherence interventions, Sleep Med Rev 15(6)(2011), 343-56).While several compounds have been reported to improve OSA (DWCarley, B.Prasad, KJReid, R.Malkani, H.Attarian, SMAbbott, B.Vern, H.Xie, C.Yuan, PCZee, Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea, Sleep 41(1)(2018); L.Taranto-Montemurro, L.Messineo, SASands, A.Azarbarzin, M.Marques, BAEdwards, DJEckert, DPWhite, A.Wellman, The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial, Am J Respir Crit Care) (Med 199(10)(2019)1267-1276) Currently, there are no drugs approved by the U.S. Food and Drug Administration for the treatment of CSA and OSA. Therefore, novel pharmaceutical approaches to treat sleep apnea are needed. [Overview of the Initiative]

[0004] In one embodiment, the present disclosure provides a method for improving respiratory function during sleep in a subject requiring improvement, the method comprising administering an orexin type 2 receptor agonist to the subject.

[0005] In some embodiments, administering an orexin type 2 receptor agonist modulates inspiratory airflow in the subject.

[0006] In some embodiments, orexin type 2 receptor agonists are administered in doses effective in improving respiratory function without inducing an arousal response or state of arousal in the subject.

[0007] In some embodiments, the arousal response or state of arousal is determined by measuring the sleep latency of one or more subjects diagnosed with sleep apnea.

[0008] In some embodiments, the subject has sleep apnea.

[0009] In some embodiments, sleep apnea is selected from obstructive sleep apnea (OSA), treatment-induced sleep apnea, and central sleep apnea (CSA).

[0010] In some embodiments, sleep apnea is obstructive sleep apnea (OSA).

[0011] In some embodiments, administration of an OX2R agonist reduces the subject's apnea-hypopnea index (AHI). In some embodiments, after administration, the subject's AHI is lower compared to when no orexin type 2 receptor agonist is administered.

[0012] In some embodiments, administration of an OX2R agonist reduces the hypoxic load of the subject. In some embodiments, the hypoxic load of the subject is reduced after administration compared to when no orexin 2 receptor agonist is administered.

[0013] In some embodiments, administration of an OX2R agonist provides a plasma concentration of the OX2R agonist below the maximum unaware plasma concentration of the agonist over a predetermined dosing interval.

[0014] In some embodiments, the plasma concentration of the OX2R agonist is selected by i) determining an unawakened plasma concentration of the OX2R agonist that does not induce an arousal response or state of arousal in humans, and ii) determining a dose of the OX2R agonist that provides a plasma concentration below the maximum unawakened plasma concentration.

[0015] In some embodiments, administration of an OX2R agonist provides a plasma concentration of the agonist that is bioequivalent to a plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate at approximately 5 ng / mL to approximately 100 ng / mL over a predetermined dosing interval following administration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate to the subject.

[0016] In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is approximately 10 ng / mL to approximately 30 ng / mL.

[0017] In some embodiments, the OX2R agonist is administered orally, intravenously, subcutaneously, transdermally, or transmucosally. In some embodiments, the OX2R agonist is administered orally.

[0018] In some embodiments, the OX2R agonist is administered once daily. In some embodiments, the OX2R agonist is administered approximately 5 minutes to 5 hours before the subject goes to bed.

[0019] In some embodiments, the orexin type 2 receptor agonist is a compound represented by formula (I):

[0020] [ka]

[0021] [In the formula, R 3~10 is (1) a hydrogen atom, (2) a C 1~6 alkyl-carbonyl group optionally substituted by 1 to 7 substituents selected from the following: (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) a C 3~10 cycloalkyl group, (v) a C 1~6 alkoxy group, (vi) a C 6~14 aryl group, (vii) a C 6~14 aryloxy group, (viii) a pyrazolyl group, thiazolyl group, pyrimidinyl group, or pyridazinyl group optionally substituted by an oxo group, (ix) a pyrazolyloxy group optionally substituted by 1 to 3 C 1~6 alkyl groups, (x) a C 1~6 alkyl-carbonyl group, (xi) a C 1~6 alkoxy-carbonyl group, (xii) a C 1~6 alkyl-carbonyloxy group, (xiii) a C 1~6 alkylsulfonyl group, (xiv) a mono- or di-C 1~6 alkylamino group, (xv) a C 1~6 alkyl-carbonylamino group, and (xvi) a (C 1~6 alkyl)(C 1~6 alkyl-carbonyl)amino group, (3) a halogen atom, cyano group, hydroxy group, oxo group, and a C 1~6 cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from an alkyl group, 3~10 (4) deuterium, a halogen atom, and a C (4) deuterium, a halogen atom, and a C 6~14 alkoxy-carbonyl group optionally substituted by 1 to 6 substituents selected from an aryl group, 1~6 (5) a C (5) a C 1~6 cycloalkyloxy-carbonyl group optionally substituted by 1 to 3 substituents selected from an alkyl group, 3~10 (6) a halogen atom and a C (6) a halogen atom and a C 6~14C may be substituted with 1 to 3 substituents selected from aryl groups. 6~14 Aryl-carbonyl group, (7)C 6~14 Aryloxy-carbonyl group, (8)C 1~6 A furylcarbonyl group, thienylcarbonyl group, pyrazolylcarbonyl group, isoxazolylcarbonyl group, or pyridylcarbonyl group, which may each be substituted by one to three substituents selected from alkyl groups. (9) Oxo group, C 1~6 Alkyl-carbonyl group, C 1~6 Alkoxy-carbonyl group, and C 1~6 Azetidinyl carbonyl group, oxetanyl carbonyl group, pyrrolidinyl carbonyl group, tetrahydrofuranyl carbonyl group, tetrahydropyranyl carbonyl group, or morpholinyl carbonyl group, which may each be substituted with 1 to 3 substituents selected from alkylsulfonyl groups. (10) Halogen atoms, cyano groups, hydroxyl groups, and C 1~6 Mono- or di-C12 1~6 Alkyl-carbamoyl group, (11) Mono- or di-C 3~10 Cycloalkyl-carbamoyl group, (12) Mono- or di-C 6~14 Aryl-carbamoyl group, (13)C 1~6 Alkyl sulfonyl group, (14)C 3~10 Cycloalkylsulfonyl group, (15) C which may be substituted with 1 to 3 halogen atoms 6~14 Aryl sulfonyl group, (16)C 1~6 A thienylsulfonyl group, pyrazolylsulfonyl group, imidazolylsulfonyl group, pyridylsulfonyl group, or dihydrochromenylsulfonyl group, which may each be substituted with 1 to 3 substituents selected from alkyl groups. (17) Mono- or di-C 1~6Alkyl-sulfamoyl group, or (18)C 1~6 It is an alkyl-carbonyl-carbonyl group, R 2 C may be substituted with 1 to 3 substituents selected from the following. 3~6 It is a cycloalkyl group, a pyrrolidinyl group, a piperidinyl group, or a dioxanyl group: (1) Deuterium, (2) Halogen atom, (3) Hydroxyl group, (4) Halogen atoms and C 6~14 C may be substituted with 1 to 3 substituents selected from aryl groups. 1~6 alkyl group, (5)C 3~10 Cycloalkyl groups, (6)C 3~10 C may be substituted with a cycloalkyl group. 1~6 Alkoxy group, (7) C which may be substituted with a halogen atom, a cyano group, or 1 to 3 halogen atoms. 1~6 C which may be substituted with alkyl groups or 1 to 3 halogen atoms. 1~6 C may be substituted with 1 to 3 substituents selected from alkoxy groups and hydroxyl groups. 6~14 Aryl group, (8)C 6~14 Aryloxy group, (9) Tri-C 1~6 Alkylsilyloxy group, (10) Halogen atom, C 1~6 Alkyl and C 1~6 Pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl, or isoquinolinyl groups, which may be substituted with 1 to 3 substituents selected from alkoxy groups, and (11)C 6~14 Aryl-carbonyl group; R 3 C 1~6 Alkyl groups, or mono- or di-C 1~6 It is an alkylamino group. or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, R 1 teeth, (1) Hydrogen atom, (2) C which may be substituted with a hydroxyl group 1~6 Alkyl-carbonyl group, (3) Cyclopropanecarbonyl group, (4)C 1~6 Alkoxy-carbonyl group, or (5) Mono- or di-C 1~6 It is an alkyl-carbamoyl group, R 2 teeth, (A) A cyclohexyl group which may be substituted with 1 to 3 substituents selected from the following: (1)C 1~6 alkyl groups, and (2) C which may be substituted with a halogen atom or 1 to 3 halogen atoms. 1~6 Alkyl alkyl groups, and C 1~6 A phenyl group which may be substituted with 1 to 3 substituents selected from alkoxy groups; or (B) A piperidinyl group which may be substituted with 1 to 3 pyrimidinyl groups, R 3 C 1~6 Alkyl alkyl group, or di-C 1~6 It is an alkylamino group, or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the orexin type 2 receptor agonist is selected from methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, N-((2R,3S)-1-glycoyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidine-3-yl)methanesulfonamide, and (2R,3S)-N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the orexin type 2 receptor agonist is selected from methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide, methyl(2R,3S)-3-((methylsulfonyl)amide (N)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piper [zin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide, N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide, (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-meth [Xypiperidine-4-yl]-8-azabicyclo[3.2.1]octane-8-yl]acetamide, (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-3-methylbutanamide, (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1]Octane-8-yl)-2-cyclopropylacetamide, (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidine-2-yl)-2-methylpiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)acetamide, and N-((2. 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-1(2,3)-pyrazine-5(2,1)-piperazine-2(1,4)-cyclohexanacyclooctaphane-5 3 Selected from -yl)methanesulfonamides or pharmaceutically acceptable salts thereof.

[0026] In some embodiments, the orexin type 2 receptor agonist is a compound represented by formula (II):

[0027] [ka]

[0028] [In the formula, R 1 teeth, (1) C which may be substituted with 1 to 3 substituents selected from the following 1~6 Alkyl group: (a) halogen atoms, and (b)C 1~6 Alkoxy group; (2) C which may be substituted with 1 to 3 halogen atoms 3~6 Cycloalkyl groups, or (3) Mono- or di-C 1~6 It is an alkylamino group, R 2 It is a hydrogen atom, R 3 teeth, (1)C 1~6 Alkoxy-carbonyl group, (2) C which may be substituted with 1 to 3 hydroxyl groups 1~6 Alkyl-carbonyl group, (3) Mono- or di-C 1~6 alkyl-carbamoyl group, (4) N-C 1~6 alkyl-N-C 1~6 alkoxy-carbamoyl group, (5) C which may be substituted by 1 to 3 substituents selected from the following 3~6 cycloalkyl-carbonyl group (C 3~6 in the cycloalkyl-carbonyl group C 3~6 cycloalkyl may be a bridged ring group): (a) halogen atom, (b) C which may be substituted by 1 to 3 halogen atoms 1~6 alkyl group, (c) hydroxy group, (d) C 1~6 alkoxy group, and (e) cyano group; (6) oxetanylcarbonyl group, (7) azetidinylcarbonyl group which may be substituted by 1 to 3 substituents selected from the following: (a) halogen atom, and (b) C 1~6 alkyl group; or (8) 5-azaspiro[2.3]hexylcarbonyl group, and R 4 and R 5 are both hydrogen atoms, ring A is (1) pyrrolidine ring, or (2) piperidine ring, ring B is (1) benzene ring further substituted by one phenyl group which may be substituted by 1 to 3 substituents selected from the following: (i) halogen atom, and (ii) C 1~6 alkyl group, and (which may be further substituted by one halogen atom), (2) pyridine ring further substituted by one phenyl group which may be substituted by 1 to 3 halogen atoms, (3) A thiazole ring further substituted by one phenyl group which may be substituted by 1 to 3 halogen atoms, or (4) A piperidine ring further substituted by one phenyl group. Or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3’,5’-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the orexin type 2 receptor agonist is N-((2S,3S)-2-((2,3’-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the orexin type 2 receptor agonist is a compound represented by formula (III):

[0032]

Chemical formula

[0033] [Wherein, R 1 is (1) A C 1~6 alkyl group, (2) A mono- or di-C 1~6 alkylamino group, or (3) A C 3~6 cycloalkyl group, and R 2 is (1) A hydrogen atom, (2) A fluorine atom, or (3) A C 1~6 alkyl group, and R 3teeth, (1) C which may be substituted with 1 to 3 substituents selected from the following 1~6 Alkyl-carbonyl group: (a) halogen atom, (b) Hydroxyl group, and (c) cyano group; (2)C 1~6 Alkoxy-carbonyl group, (3) C may be substituted with 1 to 3 substituents selected from the following. 3~10 Cycloalkyl-carbonyl group (C 3~10 Cycloalkyl-carbonyl group C 3~10 The cycloalkyl portion may be crosslinked. (a) halogen atom, (b) Hydroxyl group, (c) cyano group, and (d)C 1~6 alkyl group; (4) A 3- to 14-membered non-aromatic heterocyclylcarbonyl group which may be substituted with 1 to 3 substituents selected from the following: (a) halogen atom, (b) Hydroxyl group, and (c)C 1~6 alkyl group; (5) Mono- or di-C 1~6 Alkyl-carbamoyl group, or (6) NC 1~6 Alkyl-NC 1~6 It is an alkoxy-carbamoyl group, Ring A is, (1) A benzene ring which may be substituted with one substituent selected from the following: (a) C which may be substituted with 1 to 3 substituents selected from the following 6~14 Aryl group: (i) halogen atom, (ii) C may be halogenated 1~6 alkyl groups, and (iii) C which may be halogenated 1~6 Alkoxy groups; and (b) A 5- to 14-membered aromatic heterocyclyl group which may be substituted with 1 to 3 substituents selected from the following: (I C 1~6 alkyl groups, and (ii)C 1~6 Alkoxy groups, and (May be further substituted with 1 to 3 halogen atoms), or (2) One carbon atom which may be substituted with 1 to 3 halogen atoms. 6~14 It is a five- or six-membered aromatic heterocycle further substituted with an aryl group. or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the orexin 2 receptor agonist is N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the orexin 2 receptor agonist is N-((2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the orexin 2 receptor agonist is N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3-methyl[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}-N,N-dimethyl sulfate diamide, N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-methylpropanoyl)pyrrolidine-3-yl]ethanesulfonamide, N-{( 2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N-{(2S,3R)-1-(bicyclo[1,1.1]Pentan-1-carbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-((1S,3R)-3-fluorocyclobutane-1-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3 Selected from [(-yl)methyl]pyrrolidine-3-yl]ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-((1S,3R)-3-fluorocyclobutan-1-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-difluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}-N,N-dimethylsulfate diamide, or a pharmaceutically acceptable salt thereof.

[0037] In another aspect, the present invention provides the use of orexin type 2 receptor agonists in the manufacture of agents for improving respiratory function during sleep. In another aspect, the present invention provides orexin type 2 receptor agonists for use in improving respiratory function during sleep. [Brief explanation of the drawing]

[0038] [Figure 1]The images show how compounds A, B, and C activated neurons in the pre-Betzinger complex of rat medulla oblongata sections. Effect of compound A on burst frequency: N=2–11. Effect of compound B on burst frequency: N=7–21. Effect of compound C on burst frequency: N=7–21. Neuronal activity was recorded in the presence of a solvent, followed by application of the drugs. The mean burst frequency during the last 1–2 minutes in the presence of the solvent was used as the control value, and the percentage change from the control value was calculated using the mean burst frequency during the last 1–2 minutes after stimulation with each concentration of the drug. Data are shown as mean ± SEM. [Figure 2] This shows how compounds A, B, and C activated phrenic motor neurons in isolated rat brainstem-spinal cord specimens. Effect of compound A on burst frequency. N=5-6. Effect of compound B on burst frequency. N=4-8. Effect of compound C on burst frequency. Curve fitting was not performed as only two concentrations of compound C were tested. N=4-5. Neuronal activity was recorded in the presence of a solvent, followed by drug application. The mean burst frequency over the last 2 minutes in the presence of the solvent was used as the control value, and the percentage change from the control value was calculated using the mean burst frequency over the last 2 minutes of drug perfusion. Data are shown as mean ± SEM. [Figure 3] This shows how compounds A, B, and C activated hypoglossal motor neurons in rat medullary sections. Effect of compound A on burst frequency: N=5-9. Effect of compound B on burst frequency: N=4-15. Effect of compound C on burst frequency: N=20-21. Neuronal activity was recorded in the presence of a solvent, followed by application of the drugs. The mean burst frequency during the last 1-2 minutes in the presence of the solvent was used as the control value, and the percentage change from the control value was calculated using the mean burst frequency during the last 1-2 minutes after stimulation with each concentration of the drug. Data are shown as mean ± SEM. [Figure 4]This study shows that intravenous administration of compound C significantly increased the diaphragmatic burst frequency in anesthetized rats. The effect of compound C on diaphragmatic burst frequency was examined. The mean burst frequency 2 minutes before administration of the solvent or compound C was used as the control value, and the percentage of the control value was calculated using the mean burst frequency 10 minutes after administration of the solvent or compound C. N=8. Data are presented as mean ± SEM. Compared to solvent-treated rats, *P<0.05, ***P<0.001. [Figure 5] This study shows that intravenous administration of compound C significantly increased the burst amplitude of the genioglossus muscle in anesthetized rats. The effect of compound C on genioglossus muscle burst amplitude was examined. The mean burst amplitude 2 minutes before administration of the solvent or compound C was used as the control value, and the mean burst amplitude 10 minutes after administration of the solvent or compound C was used to calculate the percentage of the control value. N=8. Data are shown as mean ± SEM. Compared to solvent-treated rats, ***P<0.001. [Modes for carrying out the invention]

[0039] The methods, compositions, and uses disclosed herein include the use of OX2R agonists to improve sleep respiratory function in subjects requiring improvement of sleep respiratory function. The methods, compositions, and uses disclosed herein include the use of OX2R agonists at non-awakening plasma concentrations. Orexin type 2 receptor agonists can be administered in amounts effective in improving sleep respiratory function without inducing an arousal response or state of wakefulness in the subject.

[0040] The methods, compositions, and uses disclosed herein also include the use of orexin 1 receptor (OX1R) / OX2R dual agonists, for example, the use of OX1R / OX2R dual agonists to improve sleep respiratory function in subjects requiring improvement of sleep respiratory function.

[0041] Generally, when a drug is administered to a subject, its plasma concentration temporarily increases, reaches a maximum concentration, and then decreases. As a result, the efficacy of the substance generally follows its plasma concentration. In the case of an OX2R agonist administered to promote wakefulness in a subject (e.g., a subject with narcolepsy type 1 (NT1)), the subject experiences mild wakefulness after the plasma concentration of the agonist exceeds the maximum non-wakefulness concentration, and then experiences full wakefulness when the concentration exceeds a certain threshold (wakefulness-promoting concentration). Therefore, at concentrations higher than this, the OX2R agonist induces a wakefulness response or state of wakefulness in the subject. Certain OX2R agonists have been shown to have a strong effect on the state of wakefulness when the plasma concentration of the OX2R agonist exceeds the wakefulness-promoting concentration (e.g., in a subject with NT1).

[0042] This disclosure relates to the use of OX2R agonists to improve sleep respiratory function in subjects requiring improvement of sleep respiratory function. This disclosure also relates to the use of OX2R agonists at non-awakening concentrations that do not induce arousal responses or states of wakefulness in subjects (e.g., mammals). This disclosure further relates to a method of administering an OX2R agonist to a subject (e.g., a mammal) in need at a dose such that the plasma concentration of the agonist after administration is below its maximum non-awakening plasma concentration. This disclosure also relates to a method of regulating inspiratory airflow in a subject by administering an OX2R agonist. This disclosure also relates to a method of improving sleep respiratory function in a subject, wherein an orexin 2 receptor agonist is administered to the subject in an amount effective in improving sleep respiratory function without inducing arousal responses or states of wakefulness.

[0043] This disclosure also relates to a method for treating sleep apnea in subjects (e.g., mammals) requiring treatment for sleep apnea, by maintaining a post-administration non-zero plasma concentration of the OX2R agonist in the subject below the maximum unaware concentration of the agonist over multiple dosing intervals (i.e., over a long period). In some embodiments, the post-administration plasma concentration of the OX2R agonist is approximately 1 / 20 to approximately 1 / 1 of the maximum unaware concentration of the agonist over dosing intervals.

[0044] This disclosure also relates to a dosing regimen for improving sleep-related respiratory function in subjects (e.g., mammals) by administering an OX2R agonist at a dose sufficient to keep the plasma concentration of the OX2R agonist below the maximum awake plasma concentration of the agonist over a predetermined dosing interval.

[0045] The administration regimen may also be sufficient to provide a plasma concentration of the agonist equivalent to a plasma concentration of approximately 5 ng / mL to approximately 100 ng / mL of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate over a predetermined dosing interval after administration to a subject of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate. The administration regimen may further be sufficient to provide a plasma concentration of approximately 10 ng / mL or approximately 30 ng / mL of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate.

[0046] This disclosure focuses on the effects of OX2R agonists on improving respiratory function during sleep at non-awakening plasma concentrations, i.e., doses effective in improving respiratory function without inducing an arousal response or state of wakefulness in the subject. Administration of OX2R agonists at non-awakening plasma concentrations unexpectedly improves respiratory function during sleep and modulates inspiratory airflow in the subject. The use of OX2R agonists in this disclosure is expected to improve respiratory function during sleep and provide novel methods and strategies for treating sleep apnea syndromes, including obstructive sleep apnea (OSA), treatment-related sleep apnea, central sleep apnea (CSA), and mixed sleep apnea. Furthermore, the use of OX2R agonists in this disclosure is expected to have fewer side effects compared to the use of agonists at arousal-promoting concentrations.

[0047] In one embodiment, the present disclosure provides a method for improving respiratory function during sleep in a subject requiring improvement, the method comprising administering an OX2R agonist to the subject. In some embodiments, the administration of the OX2R agonist modulates the inspiratory airflow in the subject. In some embodiments, the administration of the OX2R agonist modulates the respiratory rhythm in the subject. In some embodiments, the administration of the OX2R agonist activates hypoglossal motor neurons. In some embodiments, the administration of the OX2R agonist modulates the activity of the genioglossus muscle. In some embodiments, the administration of the OX2R agonist activates neurons of the pre-Betzinger complex. In some embodiments, the administration of the OX2R agonist activates phrenic motor neurons. In some embodiments, the administration of the OX2R agonist modulates the activity of the diaphragm.

[0048] In some embodiments, the subjects are mammals. In some embodiments, the subjects are humans. In some embodiments, the subjects have not been diagnosed with narcolepsy type 1 (NT1). In some embodiments, the subjects have not undergone surgery requiring general anesthesia within 5 years, 4 years, 3 years, 2 years, or 1 year prior to administration of the OX2R agonist disclosed herein. In some embodiments, the subjects have not experienced opioid-induced sedation and respiratory depression.

[0049] In one embodiment, the disclosure provides a method for regulating inspiratory flow in a subject, comprising administering an OX2R agonist to the subject. In one embodiment, the disclosure provides a method for regulating respiratory rhythm in a subject, comprising administering an OX2R agonist to the subject.

[0050] In some embodiments, the subject has sleep apnea. In some embodiments, the subject has OSA. In some embodiments, the subject has CSA. In some embodiments, the subject has mixed sleep apnea. In some embodiments, the subject has treatment-related sleep apnea.

[0051] In some embodiments, the OX2R agonist is an OX1R / OX2R dual agonist. In some embodiments, the OX2R agonist is administered as a predetermined dose and / or over a predetermined dosing interval.

[0052] In some embodiments, the OX2R agonist is administered in a dose effective in improving sleep respiratory function without inducing an arousal response or state of wakefulness in the subject. In some embodiments, administration of the OX2R agonist provides a plasma concentration of the agonist below the maximum unaroused plasma concentration of the agonist. In some embodiments, administration of the OX2R agonist provides a plasma concentration of the agonist below the maximum unaroused plasma concentration of the agonist over a predetermined dosing interval.

[0053] In some embodiments, the arousal response or state of arousal is determined by measuring the sleep latency of one or more subjects diagnosed with sleep apnea during their usual bedtime.

[0054] In some embodiments, the plasma concentration of the OX2R agonist is selected by i) determining an unawakened plasma concentration of the OX2R agonist that does not induce an arousal response or state of arousal in humans, and ii) determining a dose of the OX2R agonist that provides a plasma concentration below the maximum unawakened plasma concentration.

[0055] In some embodiments, administration of an OX2R agonist reduces the apnea-hypopnea index (AHI) of the subject. In some embodiments, the methods disclosed herein reduce the apnea-hypopnea index (AHI) of the subject compared to the case where an orexin type 2 receptor agonist is not administered. In some embodiments, the reduction in AHI is about 1 to about 50 events per hour. In some embodiments, the reduction in AHI is about 1 to about 40 events per hour. In some embodiments, the reduction in AHI is about 1 to about 30 events per hour. In some embodiments, the reduction in AHI is about 1 to about 20 events per hour. In some embodiments, the reduction in AHI is about 5 to about 50 events per hour. In some embodiments, the reduction in AHI is about 5 to about 40 events per hour. In some embodiments, the reduction in AHI is about 5 to about 30 events per hour. In some embodiments, the reduction in AHI is about 5 to about 20 events per hour. In some embodiments, the reduction in AHI is about 10 to about 50 events per hour. In some embodiments, the decrease in AHI is approximately 10 to 40 events per hour. In some embodiments, the decrease in AHI is approximately 10 to 20 events per hour.

[0056] In some embodiments, the decrease in AHI is approximately 1 event per hour, or approximately 2 events per hour, or approximately 3 events per hour, or approximately 4 events per hour, or approximately 5 events per hour, or approximately 6 events per hour, or approximately 7 events per hour, or approximately 8 events per hour, or approximately 9 events per hour, or approximately 10 events per hour, or approximately 11 events per hour, or approximately 12 events per hour, or approximately 13 events per hour, or approximately 14 events per hour, or 1 hour This is approximately 15 events per interval, or approximately 16 events per hour, or approximately 17 events per hour, or approximately 18 events per hour, or approximately 19 events per hour, or approximately 20 events per hour, or approximately 22 events per hour, or approximately 24 events per hour, or approximately 26 events per hour, or approximately 28 events per hour, or approximately 30 events per hour, or approximately 35 events per hour, or approximately 40 events per hour, or approximately 45 events per hour, or approximately 50 events per hour. In some embodiments, the decrease in AHI is approximately 9 events per hour.

[0057] In some embodiments, administration of an OX2R agonist reduces the hypoxic load in a subject. In some embodiments, the methods disclosed herein reduce the hypoxic load in a subject compared to the case without administration of an orexin type 2 receptor agonist. In some embodiments, the hypoxic load is reduced by about 45% to 75%* min / hour. In some embodiments, the hypoxic load is reduced by about 50% to 70%* min / hour. In some embodiments, the hypoxic load is reduced by about 55% to 65%* min / hour. In some embodiments, the hypoxic load is reduced by about 60%* min / hour.

[0058] In some embodiments, administration of an OX2R agonist yields a post-administration plasma concentration of the agonist of approximately 1 / 50 to 1 / 1 of the maximum unceasing concentration of the agonist. In some embodiments, the post-administration plasma concentration of the agonist is approximately 1 / 40 to 1 / 1 of the maximum unceasing concentration of the agonist. In some embodiments, the post-administration plasma concentration of the agonist is approximately 1 / 30 to 1 / 1 of the maximum unceasing concentration of the agonist. In some embodiments, the post-administration plasma concentration of the agonist is approximately 1 / 20 to 1 / 1 of the maximum unceasing concentration of the agonist. In some embodiments, the post-administration plasma concentration of the agonist is approximately 1 / 10 to 1 / 1 of the maximum unceasing concentration of the agonist. In some embodiments, the post-administration plasma concentration of the agonist is approximately 1 / 5 to 1 / 1 of the maximum unceasing concentration of the agonist.

[0059] In some embodiments, administration of an OX2R agonist provides a plasma concentration of the agonist that is bioequivalent to the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate over a predetermined dosing interval following administration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, or any value in between, over a predetermined dosing interval following administration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 10 ng / mL to about 80 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 10 ng / mL to about 60 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 10 ng / mL to about 50 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 10 ng / mL to about 40 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 10 ng / mL to about 30 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 5 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 10 ng / mL.In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 20 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 30 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 40 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 50 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 60 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 70 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 80 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is about 90 ng / mL. In some embodiments, the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is approximately 100 ng / mL.

[0060] In some embodiments, the OX2R agonist may be administered using methods well known in the art. In some embodiments, the OX2R agonist is administered orally, intravenously, subcutaneously, transdermally, or transmucosally. In some embodiments, the OX2R agonist is administered orally. In some embodiments, the OX2R agonist is administered intravenously. In some embodiments, the OX2R agonist is administered subcutaneously. In some embodiments, the OX2R agonist is administered transdermally. In some embodiments, the OX2R agonist is administered transmucosally.

[0061] It will be understood that an appropriate dose of the OX2R agonist, and optionally one or more additional therapeutic agents, can be taken at any time of day or night. In some embodiments, the OX2R agonist is administered in the morning. In some embodiments, the OX2R agonist is administered in the middle of the day, for example, around 12:00 p.m. or the target lunchtime. In some embodiments, the OX2R agonist is administered in the evening. In some embodiments, the OX2R agonist is administered in the morning and evening. An appropriate dose of the OX2R agonist, and optionally one or more additional therapeutic agents, can be administered with or without food (i.e., while fasting). In some embodiments, the OX2R agonist is administered with or with food. In some embodiments, the OX2R agonist is administered while fasting.

[0062] In some embodiments, the OX2R agonist is administered on a once-daily schedule. In some embodiments, the OX2R agonist is administered every other day. In some embodiments, the OX2R agonist is administered every three days. In some embodiments, the OX2R agonist is administered on a twice-weekly schedule. In some embodiments, the OX2R agonist is administered on a three-times-weekly schedule. In some embodiments, the OX2R agonist is administered on a once-weekly schedule. In some embodiments, the OX2R agonist is administered on a bi-weekly schedule. In some embodiments, the OX2R agonist is administered on a three-weekly schedule. In some embodiments, the OX2R agonist is administered on a four-weekly schedule. In some embodiments, the OX2R agonist is administered on a monthly schedule.

[0063] In some embodiments, the OX2R agonist is administered once daily. In some embodiments, the OX2R agonist is administered twice daily. In some embodiments, the OX2R agonist is administered three times daily. In some embodiments, the OX2R agonist is administered four times daily.

[0064] In some embodiments, the OX2R agonist is administered before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 5 hours (or any value in between) before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 4 hours before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 3 hours before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 1 hour before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 1 hour before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 45 minutes before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 30 minutes before the subject goes to bed. In some embodiments, the OX2R agonist is administered about 5 minutes to about 20 minutes before the subject goes to bed. In some embodiments, the OX2R agonist is administered approximately 5 minutes before bedtime, or approximately 10 minutes before bedtime, or approximately 20 minutes before bedtime, or approximately 30 minutes before bedtime, or approximately 45 minutes before bedtime, or approximately 1 hour before bedtime, or approximately 2 hours before bedtime, or approximately 3 hours before bedtime, or approximately 4 hours before bedtime, or approximately 5 hours before bedtime.

[0065] In some embodiments, the OX2R agonist is administered in an amount of about 0.01 mg to about 1.0 g, or any value in between. In some embodiments, the OX2R agonist is administered in an amount of about 0.1 mg to about 500 mg. In some embodiments, the OX2R agonist is administered in an amount of about 1 mg to about 100 mg. In some embodiments, the OX2R agonist is administered in an amount of about 1 mg to about 50 mg. In some embodiments, the OX2R agonist is administered in an amount of about 1 mg to about 20 mg. In some embodiments, the OX2R agonist is administered in an amount of about 1 mg to about 10 mg. In some embodiments, the OX2R agonist is administered in an amount of about 1 mg to about 5 mg. In some embodiments, the OX2R agonist is administered in an amount of about 0.01 mg. In some embodiments, the OX2R agonist is administered in an amount of about 0.1 mg. In some embodiments, the OX2R agonist is administered in an amount of about 1 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 2 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 3 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 4 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 5 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 10 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 20 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 50 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 100 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 200 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 300 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 400 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 500 mg. In some embodiments, the OX2R agonist is administered in an amount of approximately 1.0 g.

[0066] In one embodiment, the methods, compositions and uses of the present disclosure may relate to (1) the use of an OX2R agonist in a subject (e.g., a mammal) at a plasma concentration below the maximum awake plasma concentration of an orexin type 2 receptor agonist.

[0067] In another embodiment, the methods, compositions and uses of the present disclosure may relate to (2) the use of an OX2R agonist in a subject (e.g., a mammal) at a dose that gives a plasma concentration below the maximum awake plasma concentration of an orexin 2 receptor agonist.

[0068] In another embodiment, the methods, compositions and uses of the present disclosure may relate to (3) the administration of an OX2R agonist to a subject (e.g., a mammal) at a plasma concentration below the maximum awake plasma concentration of an orexin 2 receptor agonist.

[0069] In another embodiment, the methods, compositions and uses of the present disclosure may relate to (4) a method for administering an OX2R agonist to a subject (e.g., a mammal) in a dose that gives a plasma concentration below the maximum awake plasma concentration of orexin type 2 receptor agonist.

[0070] In another embodiment, the methods, compositions and uses of the present disclosure may relate to (5) a method for treating sleep apnea in a subject (e.g., a mammal), comprising administering an OX2R agonist to the subject in a dose that gives a post-administration plasma concentration below the maximum awake plasma concentration of orexin type 2 receptor agonist.

[0071] In another embodiment, the methods, compositions and uses of the present disclosure may relate to (6) a method for treating obstructive sleep apnea, central sleep apnea, mixed sleep apnea, or treatment-related sleep apnea in a subject (e.g., a mammal), comprising administering an OX2R agonist to the subject in a dose that gives a post-administration plasma concentration below the maximum awake plasma concentration of an orexin 2 receptor agonist.

[0072] In one embodiment, the methods, compositions and uses of the present disclosure may relate to (7) the use of an OX2R agonist at a plasma concentration below the maximum awake plasma concentration of an orexin 2 receptor agonist for the treatment of sleep apnea in a subject (e.g., a mammal).

[0073] In one embodiment, the methods, compositions and uses of the present disclosure may relate to the use of an OX2R agonist in a subject (e.g., a mammal) at a plasma concentration below the maximum awake plasma concentration of an orexin 2 receptor agonist for the treatment of obstructive sleep apnea, central sleep apnea, mixed sleep apnea, or treatment-related sleep apnea during the sleep phase of the subject.

[0074] In one embodiment, the methods, compositions and uses of the present disclosure may relate to (9) a method of administering an OX2R agonist to a subject (e.g., a mammal) in a dose that gives a plasma concentration below the maximum awake plasma concentration of the orexin type 2 receptor agonist for the treatment of sleep apnea in the subject.

[0075] In one embodiment, the methods, compositions and uses of the present disclosure may relate to (10) a method of administering an agonist to a subject (e.g., a mammal) in a dose that gives a plasma concentration below the maximum awake plasma concentration of the orexin 2 receptor agonist for the treatment of obstructive sleep apnea, central sleep apnea, mixed sleep apnea, or treatment-related sleep apnea in the subject (e.g., a mammal).

[0076] In one embodiment, the methods, compositions and uses of the present disclosure may relate to the administration method described in (9) or (10), wherein (11) an orexin type 2 receptor agonist is administered as a sustained-release formulation.

[0077] In one embodiment, the methods, compositions and uses of the present disclosure may relate to the administration method described in (9) or (10), wherein (12) an orexin type 2 receptor agonist is administered as an oral formulation.

[0078] In some embodiments, the methods, compositions and uses of the present disclosure may relate to (13) repeated or continuous use of an OX2R agonist at a plasma concentration below the maximum awake plasma concentration of an orexin type 2 receptor agonist for the treatment of sleep apnea in a subject (e.g., a mammal).

[0079] In another embodiment, the methods, compositions and uses of the present disclosure may relate to the repeated or continuous use of an OX2R agonist in a subject (e.g., a mammal) at a plasma concentration below the maximum awake plasma concentration of the orexin type 2 receptor agonist for the treatment of obstructive sleep apnea, central sleep apnea, mixed sleep apnea, or treatment-related sleep apnea in the subject (e.g., a mammal) during the sleep phase of the subject.

[0080] In some embodiments, the methods, compositions and uses of the present disclosure may relate to (15) a method for treating sleep apnea in a person requiring treatment for sleep apnea, comprising administering to a person a dosage form comprising an orexin type 2 receptor agonist, wherein the dosage form provides a post-administration plasma concentration of the agonist below the maximum awake plasma concentration of the OX2R agonist over a predetermined dosing interval.

[0081] In one embodiment, the method according to (15), wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches and maintains the concentration at approximately 5 percent to approximately 100 percent, approximately 10 percent to approximately 100 percent, approximately 15 percent to approximately 100 percent, approximately 20 percent to approximately 100 percent, approximately 30 percent to approximately 100 percent, or approximately 50 percent to approximately 100 percent of the maximum uncooked plasma concentration of the agonist over a predetermined dosing interval.

[0082] In one embodiment, (17) the method of (15), wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches approximately 33 percent to approximately 100 percent of the maximum unceasing plasma concentration of the agonist over a predetermined dosing interval and maintains that concentration.

[0083] The method according to any one of embodiments (15) to (17), wherein in one embodiment, the administration interval of (18) orexin type 2 receptor agonist is 1 day (once daily), 2 days (once every other day), 1 week (once weekly), 2 weeks (once every 2 weeks), 4 weeks (once every 4 weeks), 6 weeks (once every 6 weeks), or 8 weeks (once every 8 weeks).

[0084] In one embodiment, the method of (18), wherein the plasma concentration of the orexin type 2 receptor agonist after administration is maintained for at least 2 weeks, at least 4 weeks, at least 6 weeks, or at least 8 weeks.

[0085] In one embodiment, the method according to (15), wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches about one-fifth, one-quarter, one-third, or half of the maximum uncaught plasma concentration of the orexin type 2 receptor agonist.

[0086] In one embodiment, the method according to (15), wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches its maximum asthma concentration.

[0087] In one embodiment, (22) the method according to any one of embodiments (15) to (21) for improving one or more nocturnal symptoms associated with sleep apnea.

[0088] In one embodiment, (23) the method according to any one of embodiments (15) to (21) for improving one or more daytime symptoms related to sleep apnea.

[0089] In one embodiment, (24) the method according to any one of embodiments (15) to (21) for improving one or more daytime symptoms and one or more nocturnal symptoms in a patient with sleep apnea.

[0090] In one embodiment, (25) the method according to any one of embodiments (15) to (21) for improving one or more daytime symptoms and one or more nocturnal symptoms in a patient with obstructive sleep apnea, central sleep apnea, mixed sleep apnea, or treatment-related sleep apnea.

[0091] In one embodiment, the method according to any one of embodiments (15) to (25), wherein (26) an orexin type 2 receptor agonist is administered to a human as a sustained-release formulation.

[0092] In one embodiment, the method of (26), wherein (27) the sustained-release formulation is a depot formulation for subcutaneous administration.

[0093] In one embodiment, the method of (26), (28) an orexin 2 receptor agonist is administered to a human by an infusion system designed to result in sequential subcutaneous delivery of an OX2R agonist.

[0094] In one embodiment, the method according to (26), wherein (29) the orexin type 2 receptor agonist is a compound having a short half-life.

[0095] In one embodiment, (30) an orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide, methyl(2R,3S)-3-((methylsulfonyl) Mino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)pi [Perazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide, N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide, (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidine-2-yl)-3- [Methoxypiperidine-4-yl]-8-azabicyclo[3.2.1]octane-8-yl]acetamide, I-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-3-methylbutanamide I(R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1]Octane-8-yl)-2-cyclopropylacetamide, (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidine-2-yl)-2-methylpiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)acetamide, and N-((2. 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-1(2,3)-pyrazine-5(2,1)-piperazine-2(1,4)-cyclohexanacyclooctaphane-5 3 The method according to any one of embodiments (15) to (29), selected from -yl)methanesulfonamide or pharmaceutically acceptable salts or hydrates thereof.

[0096] In one embodiment, the method according to any one of embodiments (15) to (29), wherein (31) the orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof.

[0097] The method according to any one of embodiments (15) to (29), wherein (32) the orexin type 2 receptor agonist is methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, or a pharmaceutically acceptable salt or hydrate thereof.

[0098] In one embodiment, the method according to any one of embodiments (15) to (29), wherein (33) the orexin type 2 receptor agonist is N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-3-yl}methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof.

[0099] In one embodiment, the method according to any one of embodiments (15) to (29), wherein the (34) orexin type 2 receptor agonist is selected from 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide and N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide, or a pharmaceutically acceptable salt or hydrate thereof.

[0100] In one embodiment, (35) an orexin type 2 receptor agonist is (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl]-8-azabicyclo[3.2.1]octane-8-yl}acetamide, (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-3-methylbutanamide, (R)-2-((1R,3S,5S The method according to any one of embodiments (15) to (29), selected from (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidine-2-yl)-2-methylpiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)acetamide, or pharmaceutically acceptable salts or hydrates thereof.

[0101] In one embodiment, (36) an orexin type 2 receptor agonist is N-((2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-1(2,3)-pyrazine-5(2,1)-piperazine-2(1,4)-cyclohexanacyclooctaphane-5 3 The method according to any one of embodiments (15) to (29), wherein the methanesulfonamide is -yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof.

[0102] In one embodiment, (37) the method according to any one of embodiments (15) to (36), wherein the plasma concentration of the orexin type 2 receptor agonist is selected by i) determining an unawakened plasma concentration of the orexin type 2 receptor agonist that does not elicit an arousal response in humans, and ii) determining a dose of the agonist that provides a plasma concentration less than or equal to the maximum unawakened plasma concentration of the orexin type 2 agonist determined in i).

[0103] In one embodiment, (38) the method according to any one of embodiments (15) to (36), wherein the plasma concentration of the orexin type 2 receptor agonist is selected by i) determining the maximum unawakened concentration of the orexin type 2 receptor agonist that does not produce an arousal response in humans, ii) determining the corresponding dose of the agonist that gives the maximum unawakened concentration of the OX2R agonist determined in i), and iii) selecting a dose of the agonist that gives a plasma concentration of the agonist that is less than or equal to the maximum unawakened plasma concentration of the OX2R agonist.

[0104] In one embodiment, the method according to embodiment (37) or (38), wherein the arousal response or state of arousal can be determined by measuring the sleep latency in one or more people diagnosed with sleep apnea.

[0105] In one embodiment, the method according to any one of embodiments (15) to (36), wherein the plasma concentration of (40) orexin type 2 receptor agonist is selected from a concentration less than or equal to the maximum plasma concentration of orexin type 2 receptor agonist that does not induce an arousal response or state of arousal in humans.

[0106] In another embodiment, the methods, compositions and uses of the present disclosure may relate to (41) the use in humans of an orexin 2 receptor agonist at a plasma concentration below the maximum awake plasma concentration of the agonist, in combination with a further orexin 2 receptor agonist at a plasma concentration below the maximum awake plasma concentration of the further OX2R agonist.

[0107] In one embodiment, the methods, compositions and uses of the present disclosure may relate to (42) a method for treating sleep apnea in a subject (e.g., a mammal), comprising: i) an acute treatment of sleep apnea, comprising administering an orexin type 2 receptor agonist to the subject at a plasma concentration exceeding the maximum unceasing concentration of an OX2R agonist; and ii) a maintenance therapy, comprising subsequently administering an OX2R agonist to the subject at a plasma concentration below the maximum unceasing concentration of an OX2R agonist, either repeatedly or consecutively.

[0108] In another embodiment, the methods, compositions and uses of the present disclosure are as described in (43) WO2019 / 027058, WO2017 / 135306, WO2020 / 158958, WO2021 / 107023, WO2022 / 014680, WO2020 / 167701, WO2020 / 167706, WO2021 / 026047, WO2022 / 040070 This may relate to an orexin type 2 receptor agonist selected from any of the compounds described in WO2022 / 094012, WO2022 / 040058, WO2022 / 109117, WO2022 / 119888, WO2022 / 132696, WO2022 / 051583, WO2022 / 051596, and WO2021 / 108628.

[0109] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a pharmaceutical composition comprising an agonist in a dose that provides a plasma concentration less than or equal to the maximum awake plasma concentration of orexin type 2 receptor agonist over a predetermined dosing interval.

[0110] In one embodiment, the dose of the orexin type 2 receptor agonist described in (45)(44) provides a plasma concentration of about 1 / 20 or more of the maximum unease plasma concentration.

[0111] In one embodiment, the dose of the orexin type 2 receptor agonist described in (46)(44) provides a plasma concentration of about 1 / 10 or more of the maximum unease plasma concentration.

[0112] In one embodiment, the dose of the orexin type 2 receptor agonist described in (47)(44) provides a plasma concentration of about 1 / 5 or more of the maximum unease plasma concentration.

[0113] In one embodiment, the dose of the orexin type 2 receptor agonist described in (48)(44) provides a plasma concentration of about one-third or more of the maximum unease plasma concentration.

[0114] In one embodiment, the dose of the orexin type 2 receptor agonist described in (49)(44) provides a plasma concentration of about half or more of the maximum unease plasma concentration.

[0115] In one embodiment, the dose of the orexin type 2 receptor agonist described in (50)(44) provides a plasma concentration approximately equal to or greater than the maximum awake plasma concentration.

[0116] In one embodiment, the methods, compositions and uses of the present disclosure may relate to (51) doses of orexin type 2 receptor agonists administered to humans in the range of about 1 mg to about 100 mg, or about 1 mg to about 50 mg, or about 1 mg to about 10 mg, or about 1 mg to about 5 mg.

[0117] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method of administering an (52) orexin type 2 receptor agonist to a mammal in need thereof, the method comprising maintaining the mean plasma concentration of the agonist in the mammal, after administration or over the interval between administrations, to less than about 100 ng / mL, less than about 50 ng / mL, less than about 30 ng / mL, less than about 10 ng / mL, less than about 5 ng / mL, less than about 3 ng / mL, or less than about 1 ng / mL, but greater than 0 ng / mL.

[0118] Another aspect of the present disclosure relates to a method for producing a dosage form for the treatment of sleep apnea in a person requiring treatment for sleep apnea, comprising about 1 mg to about 5 mg of an orexin type 2 receptor agonist, and being an oral dosage form or a sustained-release formulation for infusion.

[0119] Another aspect of the present disclosure relates to (54) the use of an orexin type 2 receptor agonist in the manufacture of a dosage form for treating sleep apnea in a person requiring treatment for sleep apnea, wherein the agonist provides a post-administration plasma concentration below the maximum non-awakening concentration of the agonist, and the dosage form is an oral dosage form or a sustained-release formulation for infusion.

[0120] In one embodiment of use described in (54) (55), the amount of orexin type 2 receptor agonist in the dosage form is approximately 1 mg to approximately 100 mg, or approximately 1 mg to approximately 50 mg, or approximately 1 mg to approximately 10 mg, or approximately 1 mg to approximately 5 mg.

[0121] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a pharmaceutical composition comprising (56) an orexin type 2 receptor agonist in a dose that gives a plasma concentration below the maximum asthmatic plasma concentration in a subject (i.e., a mammal).

[0122] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method for treating sleep apnea in a person requiring treatment by administering (57) an orexin type 2 receptor agonist, comprising: i) obtaining a maximum awake plasma concentration of the agonist in a person; ii) selecting a dose of the agonist that gives a plasma concentration less than or equal to the maximum awake plasma concentration in a person; and iii) administering the dose of the agonist selected in ii) to a person once, repeatedly or consecutively.

[0123] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method for treating sleep apnea in a person requiring treatment by administering (58) an orexin type 2 receptor agonist, comprising: i) obtaining a maximum awake plasma concentration of the agonist in a person; ii) selecting a plasma concentration less than or equal to the maximum awake plasma concentration in a person; and iii) administering to a person a dose of the agonist that gives the plasma concentration selected in ii) once, repeatedly, or consecutively.

[0124] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method for producing a pharmaceutical composition for the treatment of sleep apnea in a person requiring treatment, comprising (59) an orexin 2 receptor agonist, the method comprising: i) determining the maximum unawakened concentration of the orexin 2 receptor agonist in a person having sleep apnea; ii) selecting a dose of the agonist that provides a plasma concentration less than or equal to the maximum unawakened plasma concentration in a person having sleep apnea; and iii) formulating a pharmaceutical composition by mixing a unit dose of the agonist with a pharmaceutically acceptable carrier.

[0125] Method and Use The methods and uses disclosed herein can treat sleep apnea in subjects requiring treatment for sleep apnea. The methods and uses disclosed herein can also treat the symptoms of sleep apnea. In some embodiments, treating sleep apnea may include reducing or alleviating one or more symptoms of sleep apnea. One or more symptoms of sleep apnea may be selected from snoring, airway collapse, airway obstruction, gasping during sleep, dry mouth, headache, insomnia, excessive daytime sleepiness (EDS), hypersomnia, irritability, difficulty concentrating, fatigue, Cheyne-Stokes respiration, night sweats, sexual dysfunction, dizziness, nightmares, and restless sleep. In some embodiments, one or more symptoms of sleep apnea may be selected from excessive daytime sleepiness (EDS), snoring, airway collapse, airway obstruction, and gasping during sleep. The methods and uses disclosed herein can also be used to treat comorbidities of sleep apnea, such as hypertension, atrial fibrillation, congestive heart failure, stroke, metabolic syndrome, diabetes (including type 2 diabetes), obesity, depression, gastroesophageal reflux disease (GERD), hypercholesterolemia, and asthma. Sleep apnea can be diagnosed based on diagnostic criteria commonly used in the art, such as the International Classification of Sleep Disorders, Third Edition (ICSD-3). Furthermore, nighttime sleep can be improved, for example, by reducing the number of arousal responses and awakenings during the sleep cycle.

[0126] The methods and uses disclosed herein can treat sleep apnea, increase wakefulness outside the sleep cycle, and / or reduce and / or treat excessive sleepiness during the active period in subjects requiring treatment. In some embodiments, excessive sleepiness as used herein is also known as daytime sleepiness (EDS). The methods and uses disclosed herein can also reduce sleep fragmentation. In some embodiments, wakefulness, excessive sleepiness, and / or sleep fragmentation are determined by known methods, for example, using one or more of the following: electroencephalography (EEG), electromyography (EMG), wakefulness maintenance test (MWT), polysomnography, etc. (Sleep, Vol. 45, Issue 8, zsac091, (2022)). MWT is a valid objective measure of the time it takes for a subject to fall asleep under hypnosis (Electroencephalogr. Clin. Neurophysiol., 53(6):658-661, (1982). MWT is quantified by EEG, optionally in combination with EMG. Electroencephalography (EEG) is a test that detects electrical activity in the brain using small metallic discs or electrodes attached to the scalp. In some embodiments, the arousal response, state of arousal, and / or reduction of sleepiness are determined using the Multiple Sleep Latency Test (MSLT) or the Oxford Sleep Resistance (OSLER) test. In some embodiments, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), or the Stanford Sleepiness Scale. In some embodiments, treating sleep apnea may include reducing or alleviating one or more symptoms of sleep apnea. One or more symptoms of sleep apnea may be selected from the symptoms described herein.

[0127] In some embodiments, the subjects have a disease, disorder, or condition related to sleep apnea and excessive sleepiness. In some embodiments, the subjects are sleep-deprived subjects, subjects with excessive sleepiness, subjects with a disrupted sleep / wake cycle, or subjects who need to reduce sleepiness.

[0128] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which this disclosure pertains. The following references provide general definitions of many of the terms used herein: Singleton et al., Dictionary of Microbiology and Mo le cular Biology(2nd ed.1994), The Cambridge Dictionary of Science and Technology(Walker ed.,1988), The Gloss ar See *y of Genetics*, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, *The Harper Collins Dictionary of Biology* (1991). Where used herein, the following terms shall have the meanings given below unless otherwise specified. The terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit this disclosure.

[0129] As used herein, the singular forms "a," "an," and "the" are intended to include the plural form unless otherwise clearly indicated by the context.

[0130] As used herein, the terms “about” or “approximately” mean within the allowable margin of error for a particular value as determined by those skilled in the art. This range depends in part on how the value is measured or determined, i.e., on the limits of the measurement system. For example, “about” may mean a range of three standard deviations or more, according to convention in the art. Alternatively, “about” may mean a range of 20%, 10%, 5%, or 1% of a particular value. Or, particularly with respect to biological systems and processes, the term may mean a range of one order of magnitude, five times, or twice a given value.

[0131] As used herein, the term “administration” of a drug to a subject includes any route by which the drug is introduced or delivered to the subject in order to perform its intended function. Administration may be carried out by any suitable oral route, or by parenteral routes including, but not limited to, intravenous, intramuscular, intraperitoneal, subcutaneous, and other suitable routes as described herein. Administration may include self-administration and administration by another person. Administration of an OX2R agonist for therapeutic purposes in this disclosure may generally be a single, long-term, continuous, chronic, and / or repeated dose. “Post-administration” of an OX2R agonist in this disclosure means a certain amount of time has elapsed since the OX2R agonist was administered to the subject. Typically, this means approximately 24 to 48 hours after the first administration.

[0132] As used herein, the terms “dosage form” or “pharmaceutical composition” mean a composition comprising one or more drug molecules. Examples of dosage forms include oral preparations, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, and cheek tablets), capsules (including soft capsules and microcapsules), pills, granules, powders, lozenges, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal adhesive films), parenteral preparations, such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drips), topical preparations (e.g., transdermal preparations, ointments, lotions, and adhesive preparations), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal sprays, lung preparations (inhalants), and eye drops. The compounds and pharmaceuticals of this disclosure can be safely administered orally or parenterally (e.g., rectally, intravenously, intra-arterially, intramuscularly, subcutaneously, intra-organally, intranasally, intradermally, intra-infusionally, intracerebrally, intravaginally, intraperitoneally, intratumorally, proximal tumorly, and to a lesion). These formulations may be controlled-release formulations (e.g., sustained-release microcapsules), such as immediate-release formulations or sustained-release formulations.

[0133] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to an amount of compound sufficient to achieve the desired effect or therapeutic effect. In relation to therapeutic use, the amount of compound administered to a subject may depend on the type and severity of the disease or symptoms, as well as individual characteristics such as overall health, age, sex, weight, and tolerance to the drug. Those skilled in the art can determine an appropriate dose in accordance with these and other factors.

[0134] As used herein, the term “adjust” refers to changing something in a positive or negative direction. Illustrative adjustments include changes of approximately 1%, 2%, 5%, 10%, 25%, 50%, 75%, or 100%.

[0135] As used herein, the term “increase” means to change positively by at least about 5%, and this includes, but is not limited to, changing positively by about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0136] As used herein, the term “reduce” means to change by at least about 5% negative, and this includes, but is not limited to, changing by about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100% negative.

[0137] As used herein, the terms “orexin receptor 2 agonist” or “OX2R agonist” refer to drugs or substances, such as small molecules, that activate OX2R. OX2R is a G protein-coupled receptor (GPCR) that interacts with Gq class heterotrimeric G proteins and β-arrestin. Orexin A (OX-A) and orexin B (OX-B) peptides are known to increase calcium mobilization in OX2R-expressing recombinant cells (Cell, Vol. 92, 573-585, (1998)) and promote β-arrestin recruitment (J. Biol. Chem. Vol. 286, No. 19, 16726-16733, (2011)). OX2R agonists such as compound A and YNT-185 have also been shown to increase calcium mobilization and promote β-arrestin recruitment (Pharmacol. Biochem. Behav., 187(2019), 172794; Proc. Natl Acad. Sci. USA., 114(22), 5731-5736, (2017)). Therefore, the OX2R agonist activity of drug candidates can be evaluated by calcium mobilization assays or β-arrestin recruitment assays using OX2R-expressing cells. In some embodiments, the OX2R agonist is in the form of a pharmaceutically acceptable salt.

[0138] As used herein, the terms “arousal” (including “arousal response” and “arousal” in “arousal-promoting concentration”) and “state of arousal” mean that the state of the subject is a near-complete state of arousal, which is assessed by known measures such as the Maintenance of Arousal Test (MWT) and EEG / EMG recordings.

[0139] As used herein, “blood plasma concentration” (sometimes abbreviated as “plasma concentration”) refers to the concentration of a pharmaceutical substance in plasma obtained from the subject’s blood collected at a specific point in time. In this disclosure, “post-administration plasma concentration” means the plasma concentration of the pharmaceutical substance at a point in time after administration of the pharmaceutical substance, for example, approximately 24 hours after administration of the substance. “Mean plasma concentration” means the average of the plasma concentrations at different points in time from 24 hours after administration of the drug to the subject.

[0140] As used herein, the terms “unawakened plasma concentration” or “unawakened concentration” refer to the plasma concentration of an orexin 2 receptor agonist that does not induce awakening (e.g., an awakening response) or an awakened state in a subject. Unawakened plasma concentrations can be determined by conducting multi-dose studies. Such studies may be conducted as part of preclinical and clinical PK / PD studies during the drug discovery phase. Among unawakened plasma concentrations, the “maximum unawakened plasma concentration” is the highest concentration above which a mild awakening effect occurs. The phrase “below the maximum unawakened plasma concentration” for an OX2R agonist means that the plasma concentration of the OX2R agonist in the subject is greater than 0 (zero) and equal to or below the maximum unawakened plasma concentration. In some embodiments, the plasma concentration of the OX2R agonist is below the maximum unawakened plasma concentration of the agonist in the subject over a given dosing interval, but is about 1 / 20, about 1 / 12, about 1 / 10, about 1 / 8, about 1 / 5, or about 1 / 3 or more of the maximum unawakened concentration. The mean plasma concentration of the OX2R agonist may be approximately 1 / 20, 1 / 10, 1 / 8, 1 / 5, 1 / 4, 1 / 3, 1 / 2, or 1 / 1, ±5% of the maximum non-awakening concentration of the agonist. In some embodiments, the mean plasma concentration of the OX2R agonist below the maximum non-awakening concentration is approximately 1 / 60, 1 / 40, 1 / 36, 1 / 30, 1 / 20, or 1 / 10 of the awakening-promoting plasma concentration.

[0141] As used herein, the term “awakening-enhancing concentration” of an OX2R agonist refers to the threshold plasma concentration of the agonist that elicits a near-complete awakening effect in a subject (i.e., maintenance of more than 75% of the state of wakefulness in a 10-minute interval). Certain OX2R agonists have been shown to elicit a strong awakening effect when the plasma concentration of the OX2R agonist exceeds its awakening-enhancing concentration (e.g., in NT1 subjects). The awakening-enhancing concentration of an OX2R agonist is significantly higher than the maximum non-awakening concentration of the OX2R agonist.

[0142] Plasma concentrations can be determined by measurements known to those skilled in the art, including high-performance liquid chromatography-tandem mass spectrometry. Levels are typically expressed as ng / mL of the test substance. Maximum unaware and arousal-promoting concentrations of the OX2R agonist in a subject can be determined by combining time-series measurements of plasma concentrations with recordings of the subject's nocturnal and / or daytime sleep and wake patterns by known methods, including EEG / EMG recording and actigraphy. When detecting maximum unaware or arousal-promoting concentrations of the OX2R agonist in non-NT1 subjects, measurements are performed at night when the subject's auto-orexin A levels are generally low.

[0143] As used herein, the term “actigraphy” refers to a method of monitoring and collecting motion-generated data using a small, computerized device such as a wristwatch (also known as acceleration measurement). Most actigraphs include analog systems for detecting motion. Some devices detect motion using piezoelectric beams.

[0144] As used herein, the terms “treatment,” “to treat,” or “to treat” include improvement, reduction, mitigation, or amelioration of one or more symptoms associated with a disease. One embodiment of the methods and uses disclosed herein can improve one or more nocturnal symptoms of sleep apnea. Such improvement may be evaluated by comparing the state of a subject before and after administration of an OX2R agonist using one or more of the following: polysomnography with respiratory airflow and respiratory effort measurement (PSG), MWT, MSLT, EEG, or EMG, or by comparing the state of a subject administered a placebo with a subject administered an OX2R agonist. In one embodiment, the OX2R agonist of this disclosure improves symptoms of sleep apnea.

[0145] As used herein, the term “dosing interval” refers to the time between each administration of an OX2R agonist to a subject. The dosing interval of an OX2R agonist can be determined by its pharmacokinetic profile and dosage form in a manner well known to those skilled in the art. If the dosage form is an oral dosage form, preferred dosing intervals may, in particular, be three times daily, twice daily, once daily, every other day, once weekly, once every two weeks, once every four weeks, once every six weeks, or once every eight weeks. If the dosage form is a sustained-release formulation for subcutaneous injection, preferred dosing intervals may, in particular, be once weekly, once every two weeks, once every four weeks, once every six weeks, or once every eight weeks.

[0146] As used herein, the term “subject” refers to mammals, including humans, cattle, horses, dogs, cats, monkeys, mice, and rats, and preferably refers to humans. In some embodiments, the subject is human. In some embodiments, the subject has not been diagnosed with narcolepsy type 1 (NT1). In some embodiments, the subject has not undergone surgery requiring general anesthesia within 5 years, 4 years, 3 years, 2 years, or 1 year prior to administration of the OX2R agonist disclosed herein. In some embodiments, the subject has not experienced opioid-induced sedation and respiratory depression.

[0147] As used herein, the term “pharmaceutically acceptable” refers to a substance suitable for administration to a subject.

[0148] The methods, compositions, and uses described herein are characterized in that the plasma concentration of the orexin type 2 receptor (OX2R) agonist in the subject is less than or equal to the maximum unawakened plasma concentration of the agonist. In one embodiment, when an OX2R agonist is administered to a subject requiring it, the plasma concentration of the OX2R agonist in the subject, when measured 24 hours or more after administration, is less than or equal to the maximum unawakened plasma concentration of the agonist. By using certain formulations, such as oral formulations, intravenous formulations, and sustained-release formulations, the initial release of the OX2R agonist continues for approximately 24 to 48 hours after administration, and the plasma concentration of the OX2R agonist may exceed the maximum unawakened concentration but not reach an awakening-promoting concentration. When the plasma concentration of the OX2R agonist is less than or equal to the maximum unawakened concentration, the plasma concentration is greater than 0 (zero) and equal to or less than the maximum unawakened plasma concentration. In some embodiments, the plasma concentration of the OX2R agonist in the subject is approximately 1 / 20 to 1 / 1, approximately 1 / 12 to 1 / 1, approximately 1 / 10 to 1 / 1, approximately 1 / 8 to 1 / 1, approximately 1 / 5 to 1 / 1, or approximately 1 / 3 to 1 / 1 of the maximum non-awakening concentration of the agonist.

[0149] In one embodiment, an OX2R agonist is administered to a subject over multiple dosing intervals for the treatment of sleep apnea and / or symptoms of sleep apnea, wherein the plasma concentration of the agonist is less than or equal to the maximum awake plasma concentration of the agonist throughout each dosing interval. The terms “repeated,” “recurring,” “repeatedly,” “sequentially,” “continuously,” “chronic,” “chronically,” or “long-term” as used in this disclosure in relation to the administration of an OX2R agonist mean that the OX2R agonist is administered over multiple dosing intervals.

[0150] In one embodiment, the OX2R agonist is administered to the subject by a single oral dose, repeated oral doses, or by infusion, or by using a sustained-release or extended-release formulation of the OX2R agonist. The appropriate formulation may be selected based on the characteristics of the OX2R agonist. Sustained-release or extended-release formulations may be particularly useful when administering OX2R agonists with short half-lives (i.e., less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours).

[0151] The dose of an OX2R agonist may be determined by i) identifying the maximum anomalous concentration of the OX2R agonist in the subject (e.g., using EEG), and then ii) identifying the dose of the OX2R agonist that will achieve the maximum anomalous concentration after administration. Those skilled in the art in the pharmaceutical industry may select a dose less than the dose determined in step ii). In some embodiments, the plasma concentrations of agonists below the maximum non-awakening plasma concentration of OX2R agonists in humans are approximately 0.01 ng / mL to approximately 1 mg / mL, approximately 0.03 ng / mL to approximately 300 ng / mL, approximately 0.05 ng / mL to approximately 100 ng / mL, approximately 0.08 ng / mL to approximately 50 ng / mL, approximately 1 ng / mL to approximately 30 ng / mL, approximately 1 ng / mL to approximately 100 ng / mL, approximately 10 ng / mL, approximately 20 ng / mL, approximately 30 ng / mL, approximately 40 ng / mL, approximately 50 ng / mL, approximately 60 ng / mL, approximately 70 ng / mL, approximately 80 ng / mL, approximately 90 ng / mL, or approximately 100 ng / mL. In some embodiments, the agonist dose that delivers a plasma concentration below the maximum unaware plasma concentration of the OX2R agonist in humans is approximately 0.1 mg to 50 mg, approximately 0.5 mg to 30 mg, or approximately 1 mg to 20 mg.

[0152] As used herein, the term “bioequivalent” means, for example, that two products or active ingredients containing two OX2R agonists are equivalent in terms of the rate and extent to which the active pharmaceutical ingredient (API) of those products becomes available at the site of action.

[0153] Tests for increased alertness and / or reduced excessive sleepiness The methods and uses disclosed herein can treat sleep apnea in subjects requiring treatment for sleep apnea. In some embodiments, treating sleep apnea may involve reducing or alleviating one or more symptoms of sleep apnea. One or more symptoms of sleep apnea may include excessive daytime sleepiness (EDS). Furthermore, nighttime sleep is expected to be improved, for example, by reducing the number of wakefulness events in the sleep cycle.

[0154] The methods and uses disclosed herein may increase alertness and / or reduce excessive sleepiness during non-sleep or daytime hours in subjects where required. In some embodiments, the reduction in alertness and / or excessive sleepiness is determined by electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG), which together form the basis of a polysomnography (PSG). These tests can also be used to identify the concentration thresholds for strong alertness and non-alertness for specific OX2R agonists. In some embodiments, the reduction in alertness and / or sleepiness is determined using a maintenance of alertness test (MWT) on EEG, optionally combined with EMG. Electroencephalography (EEG) is a test that detects electrical activity in the brain using, for example, small metallic discs or electrodes attached to the scalp. In some embodiments, the reduction in alertness and / or sleepiness is determined using a multiple sleep latency test (MSLT) or Oxford sleep resistance (OSLER) test. In some embodiments, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), or the Stanford Sleepiness Scale.

[0155] In some embodiments, actigraphy (also known as acceleration measurement) can be used to test the effects of OX2R agonists on sleep and wake patterns. The term actigraphy refers to a method of monitoring and collecting motion-generated data using a small, computerized device such as a wristwatch. Most actigraphs include an analog system for detecting motion. Some devices detect motion using a piezoelectric beam. See Sadeh et al., Sleep Medicine Reviews 6(2);113-124(2002).

[0156] The methods and uses disclosed herein can reduce excessive sleepiness during non-sleep or daytime hours, or improve Karolinska Sleepiness Scale (KSS) scores, in subjects requiring such reduction. In some embodiments, KSS scores improve to 1, 2, 3, 4, or 5, or higher. In some embodiments, the subject has a KSS score of 1, 2, 3, 4, or 5 after treatment.

[0157] The methods and uses disclosed herein may involve performing one or more tests to quantify sleepiness in a subject during non-sleep time or daytime hours. In some embodiments, the tests are selected from the Multiple Sleep Latency Test (MSLT), the Maintenance of Wakefulness Test (MWT), and the Oxford Sleep Resistance (OSLER) test. In some embodiments, the test is the MWT. In some embodiments, the tests are the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, the Uranlinna Narcolepsy Scale (UNS), the Work Limitations Questionnaire (WLQ), the SF-8 (a subset of the SF-36 questionnaire), or a combination of these tests.

[0158] Method of administration The methods and uses disclosed herein include administering to a subject that requires an OX2R agonist. In some embodiments, the OX2R agonist is administered orally. In some embodiments, the OX2R agonist is administered parenterally. In some embodiments, parenteral administration is intravenous, subcutaneous, transdermal, intradermal, or transmucosal administration. In some embodiments, parenteral administration is intravenous administration. In some embodiments, parenteral administration is subcutaneous administration.

[0159] Dosage forms and delivery devices for specific routes are further described in detail below.

[0160] In some embodiments, the plasma concentration of the OX2R agonist represents the mean plasma concentration of the treated group of subjects, and the period of 1 hour or more starts at any point after administration. As long as the mean plasma concentration of the treated group of subjects meets the condition of "about XX ng / mL or more over a period of about 1 hour or more", the plasma concentration of an individual treated subject may deviate from this condition.

[0161] Frequency of administration The OX2R agonists of the present disclosure can be administered once or over multiple dosing intervals. In some embodiments, the OX2R agonists of the present disclosure can be administered three times a day, twice a day, once a day, every other day, once a week, twice a week, once every two weeks, once a month, or once every two months.

[0162] Combination therapy The method for treating sleep apnea of the present disclosure can further include the combined use of administration of an OX2R agonist at a plasma concentration below the maximum non-awakening plasma concentration and administration of a further OX2R agonist, and the combined plasma concentration of the two OX2R agonists is lower than the maximum non-awakening plasma concentration. The further OX2R agonist and the OX2R agonist may be different or the same. In this treatment method, after the further OX2R agonist is administered to a subject who requires acute treatment of the symptoms of sleep apnea, the OX2R agonist is administered for maintenance therapy. An administration interval of 1 to 5 days can be provided between the administrations of the two OX2R agonists according to the clearance profile of the further OX2R agonist.

[0163] OX2R agonist The OX2R agonist useful in the method, use, or composition of the present disclosure is a chemical molecule (compound) having OX2R agonist activity. Such a compound may be selected from known compounds or may be selected from newly designed / synthesized compounds. Compounds having a short half-life (i.e., less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours) are particularly useful when formulating it into a sustained release formulation.

[0164] In some embodiments, the OX2R agonist is an OX1R / OX2R dual agonist.

[0165] In some embodiments, the OX2R agonist is a pharmaceutically acceptable salt.

[0166] In some embodiments, the OX2R agonist is a compound represented by formula (I):

[0167] [In the formula,

[0168] [wherein, R 1 is (1) a hydrogen atom, (2) C may be substituted with 1 to 7 substituents selected from the following: 1~6 Alkyl-carbonyl group: (i) halogen atom, (ii) cyano group, (iii) hydroxyl group, (iv) C 3~10 Cycloalkyl groups, (v)C 1~6 Alkoxy group, (vi)C 6~14 Aryl group, (vii)C 6~14 (viii) Pyrazolyl group, thiazolyl group, pyrimidinyl group, or pyridadinyl group which may be substituted with an aryloxy group, (viii) an oxo group, (ix) 1 to 3 C 1~6 A pyrazolyloxy group which may be substituted with an alkyl group, (x)C 1~6 Alkyl-carbonyl group, (xi)C 1~6 Alkoxy-carbonyl group, (xii)C 1~6 Alkyl-carbonyloxy group, (xiii)C 1~6 Alkyl sulfonyl group, (xiv) mono- or di-C 1~6 Alkylamino group, (xv)C 1~6 Alkyl-carbonylamino group, and (xvi)(C 1~6 Alkyl)(C 1~6 Alkyl-carbonyl)amino group, (3) Halogen atoms, cyano groups, hydroxyl groups, oxo groups, and C 1~6 C may be substituted with 1 to 3 substituents selected from alkyl groups. 3~10 Cycloalkyl-carbonyl group, (4) Deuterium, halogen atoms, and C 6~14 C may be substituted with 1 to 6 substituents selected from aryl groups. 1~6 Alkoxy-carbonyl group, (5)C 1~6 C may be substituted with 1 to 3 substituents selected from alkyl groups. 3~10 Cycloalkyloxy-carbonyl group, (6) Halogen atoms and C 6~14 C may be substituted with 1 to 3 substituents selected from aryl groups. 6~14 Aryl-carbonyl group, (7)C 6~14Aryloxy-carbonyl group, (8)C 1~6 A furylcarbonyl group, thienylcarbonyl group, pyrazolylcarbonyl group, isoxazolylcarbonyl group, or pyridylcarbonyl group, which may each be substituted by one to three substituents selected from alkyl groups. (9) Oxo group, C 1~6 Alkyl-carbonyl group, C 1~6 Alkoxy-carbonyl group, and C 1~6 Azetidinyl carbonyl group, oxetanyl carbonyl group, pyrrolidinyl carbonyl group, tetrahydrofuranyl carbonyl group, tetrahydropyranyl carbonyl group, or morpholinyl carbonyl group, which may each be substituted with 1 to 3 substituents selected from alkylsulfonyl groups. (10) Halogen atoms, cyano groups, hydroxyl groups, and C 1~6 Mono- or di-C12 1~6 Alkyl-carbamoyl group, (11) Mono- or di-C 3~10 Cycloalkyl-carbamoyl group, (12) Mono- or di-C 6~14 Aryl-carbamoyl group, (13)C 1~6 Alkyl sulfonyl group, (14)C 3~10 Cycloalkylsulfonyl group, (15) C which may be substituted with 1 to 3 halogen atoms 6~14 Aryl sulfonyl group, (16)C 1~6 A thienylsulfonyl group, pyrazolylsulfonyl group, imidazolylsulfonyl group, pyridylsulfonyl group, or dihydrochromenylsulfonyl group, which may each be substituted with one to three substituents selected from alkyl groups. (17) Mono- or di-C 1~6 Alkyl-sulfamoyl group, or (18)C 1~6 It is an alkyl-carbonyl-carbonyl group, R2 C may be substituted with 1 to 3 substituents selected from the following. 3~6 It is a cycloalkyl group, a pyrrolidinyl group, a piperidinyl group, or a dioxanyl group: (1) Deuterium, (2) Halogen atom, (3) Hydroxyl group, (4) Halogen atoms and C 6~14 C may be substituted with 1 to 3 substituents selected from aryl groups. 1~6 alkyl group, (5)C 3~10 Cycloalkyl groups, (6)C 3~10 C may be substituted with a cycloalkyl group. 1~6 Alkoxy group, (7) C which may be substituted with a halogen atom, a cyano group, or 1 to 3 halogen atoms. 1~6 C which may be substituted with alkyl groups or 1 to 3 halogen atoms. 1~6 C may be substituted with 1 to 3 substituents selected from alkoxy groups and hydroxyl groups. 6~14 Aryl group, (8)C 6~14 Aryloxy group, (9) Tri-C 1~6 Alkylsilyloxy group, (10) Halogen atom, C 1~6 Alkyl and C 1~6 Pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl, or isoquinolinyl groups, which may be substituted with 1 to 3 substituents selected from alkoxy groups, and (11)C 6~14 Aryl-carbonyl group; R 3 C 1~6 Alkyl groups, or mono- or di-C 1~6 It is an alkylamino group. or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, R 1 teeth, (1) Hydrogen atom, (2) C optionally substituted with a hydroxy group 1~6 alkyl-carbonyl group, (3) cyclopropanecarbonyl group, (4) C 1~6 alkoxy-carbonyl group, or (5) mono- or di-C 1~6 alkyl-carbamoyl group, and R 2 is (A) a cyclohexyl group optionally substituted with 1 to 3 substituents selected from the following: (1) C 1~6 alkyl group, and (2) a halogen atom, a C optionally substituted with 1 to 3 halogen atoms 1~6 alkyl group, and a phenyl group optionally substituted with 1 to 3 substituents selected from a C 1~6 alkoxy group; or (B) a piperidinyl group optionally substituted with 1 to 3 pyrimidinyl groups, and R 3 is a C 1~6 alkyl group, or a di-C 1~6 alkylamino group, and or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the orexin type 2 receptor agonist is selected from methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, N-((2R,3S)-1-glycoloyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide, and (2R,3S)-N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the orexin type 2 receptor agonist is selected from methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a pharmaceutically acceptable salt thereof. Methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is also referred to herein as compound A.

[0172] In some embodiments, the orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide, methyl(2R,3S)-3-((methylsulfonyl)amide (N)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piper [zin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide, N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide, (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-meth [Xypiperidine-4-yl]-8-azabicyclo[3.2.1]octane-8-yl]acetamide, (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-3-methylbutanamide, (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1]Octane-8-yl)-2-cyclopropylacetamide, (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidine-2-yl)-2-methylpiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)acetamide, and N-((2. 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-1(2,3)-pyrazine-5(2,1)-piperazine-2(1,4)-cyclohexanacyclooctaphane-5 3 Selected from -yl)methanesulfonamides or pharmaceutically acceptable salts thereof.

[0173] In some embodiments, the orexin type 2 receptor agonist is a compound represented by formula (II):

[0174] [ka]

[0175] [In the formula, R 1 teeth, (1) C which may be substituted with 1 to 3 substituents selected from the following 1~6 Alkyl group: (a) halogen atoms, and (b)C 1~6 Alkoxy group; (2) C which may be substituted with 1 to 3 halogen atoms 3~6 Cycloalkyl groups, or (3) Mono- or di-C 1~6 It is an alkylamino group, R 2 It is a hydrogen atom, R 3 teeth, (1)C 1~6 Alkoxy-carbonyl group, (2) C which may be substituted with 1 to 3 hydroxyl groups 1~6 Alkyl-carbonyl group, (3) Mono- or di-C 1~6 Alkyl-carbamoyl group, (4) NC 1~6 Alkyl-NC 1~6 Alkoxy-carbamoyl group, (5) C which may be substituted with 1 to 3 substituents selected from the following 3~6 Cycloalkyl-carbonyl group (C 3~6 C in the cycloalkyl-carbonyl group 3~6 Cycloalkyl groups may also be crosslinking ring groups. (a) halogen atom, (b) C which may be substituted with 1 to 3 halogen atoms 1~6 alkyl group, (c) Hydroxyl group, (d)C 1~6 Alkoxy groups, and (e) cyano group; (6) Oxetanylcarbonyl group, (7) Azetidinyl carbonyl group which may be substituted with 1 to 3 substituents selected from the following: (a) halogen atoms, and (b)C 1~6 alkyl group; or (8) 5-azaspiro[2.3]hexylcarbonyl group, R 4 and R 5 Both are hydrogen atoms, Ring A is, (1) A pyrrolidine ring, or (2) A piperidine ring, Ring B is, (1) A benzene ring further substituted with one phenyl group, which may be substituted with one to three substituents selected from the following: (i) halogen atoms, and (ii)C 1~6 alkyl groups, and (It may be further substituted with one halogen atom), (2) A pyridine ring further substituted with one phenyl group which may be substituted with 1 to 3 halogen atoms, (3) A thiazole ring further substituted with one phenyl group which may be substituted with 1 to 3 halogen atoms, or (4) A piperidine ring further substituted with one phenyl group. or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the orexin 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof. N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide is also referred to herein as compound B.

[0177] In some embodiments, the orexin type 2 receptor agonist is N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the orexin type 2 receptor agonist is a compound represented by formula (III):

[0179] [ka]

[0180] [In the formula, R 1 teeth, (1)C 1~6 alkyl group, (2) Mono- or di-C 1~6 Alkylamino group, or (3)C 3~6 It is a cycloalkyl group, R 2 teeth, (1) Hydrogen atom, (2) A fluorine atom, or (3)C 1~6 It is an alkyl group, R 3 teeth, (1) C which may be substituted with 1 to 3 substituents selected from the following 1~6 Alkyl-carbonyl group: (a) halogen atom, (b) Hydroxyl group, and (c) cyano group; (2)C 1~6 Alkoxy-carbonyl group, (3) C may be substituted with 1 to 3 substituents selected from the following. 3~10 Cycloalkyl-carbonyl group (C 3~10 Cycloalkyl-carbonyl group C 3~10 The cycloalkyl portion may be crosslinked. (a) halogen atom, (b) Hydroxyl group, (c) cyano group, and (d)C 1~6 alkyl group; (4) A 3- to 14-membered non-aromatic heterocyclylcarbonyl group which may be substituted with 1 to 3 substituents selected from the following: (a) halogen atom, (b) Hydroxyl group, and (c)C 1~6 alkyl group; (5) Mono- or di-C 1~6 Alkyl-carbamoyl group, or (6) NC 1~6 Alkyl-NC 1~6 It is an alkoxy-carbamoyl group, Ring A is, (1) A benzene ring which may be substituted with one substituent selected from the following: (a) C which may be substituted with 1 to 3 substituents selected from the following 6~14 Aryl group: (i) halogen atom, (ii) C may be halogenated1~6 alkyl groups, and (iii) C which may be halogenated 1~6 Alkoxy groups; and (b) A 5- to 14-membered aromatic heterocyclyl group which may be substituted with 1 to 3 substituents selected from the following: (I C 1~6 alkyl groups, and (ii)C 1~6 Alkoxy groups, and (May be further substituted with 1 to 3 halogen atoms), or (2) One carbon atom which may be substituted with 1 to 3 halogen atoms. 6~14 It is a five- or six-membered aromatic heterocycle further substituted with an aryl group. or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the orexin 2 receptor agonist is N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the orexin 2 receptor agonist is N-((2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof. N-((2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide is also referred to herein as compound C.

[0183] In some embodiments, the orexin 2 receptor agonist is N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3-methyl[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}-N,N-dimethyl sulfate diamide, N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-methylpropanoyl)pyrrolidine-3-yl]ethanesulfonamide, N-{( 2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N-{(2S,3R)-1-(bicyclo[1,1.1]Pentan-1-carbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-((1S,3R)-3-fluorocyclobutane-1-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3 Selected from [(-yl)methyl]pyrrolidine-3-yl]ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-((1S,3R)-3-fluorocyclobutan-1-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-difluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}-N,N-dimethylsulfate diamide, or a pharmaceutically acceptable salt thereof.

[0184] One useful OX2R agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, as well as its pharmaceutically acceptable salts and hydrates. This compound is described in WO2019 / 027058.

[0185] Another useful OX2R agonist is methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, as well as its pharmaceutically acceptable salts and hydrates. This compound is described in WO2017 / 135306.

[0186] Another useful OX2R agonist is N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide, as well as its pharmaceutically acceptable salts and hydrates. This compound is described in WO2019 / 027058.

[0187] Another useful OX2R agonist is N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, as well as its pharmaceutically acceptable salts and hydrates. This compound is described in WO2020 / 158958.

[0188] Further useful OX2R agonists include JZP441 / DSP-0187, ALKS2680, and E2086.

[0189] Useful OX2R agonists are also described in PCT Publication Application WO2021 / 107023, which is incorporated herein by reference in its entirety, and include the following compounds and their pharmaceutically acceptable salts and hydrates: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide, represented by the following formula (IV):

[0190] [ka]

[0191] And, N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide, represented by the following formula (V):

[0192] [ka]

[0193] Useful OX2R agonists are described in PCT Publication Application WO2022 / 014680, which is incorporated herein by reference in its entirety, and include the following compounds and their pharmaceutically acceptable salts and hydrates: (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, represented by the following formula (VI):

[0194] [ka]

[0195] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-3-methylbutanamide, represented by the following formula (VII):

[0196] [ka]

[0197] (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-2-cyclopropylacetamide, represented by the following formula (VIII):

[0198] [ka]

[0199] And (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidine-2-yl)-2-methylpiperidine-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide represented by the following formula (IX):

[0200] [ka]

[0201] Useful OX2R agonists are described in PCT publication applications WO2020 / 167701, WO2020 / 167706, WO2021 / 026047, WO2022 / 040070, WO2022 / 040058, WO2022 / 109117, WO2022119888, WO2022 / 132696, and WO2022094012, which are incorporated herein by reference in their entirety.

[0202] Useful OX2R agonists are described in PCT publication applications WO2022 / 051583 and WO2022 / 051596, which are incorporated herein by reference as a whole.

[0203] Useful OX2R agonists are described in PCT Publication Application WO2021 / 108628, which is incorporated herein by reference in whole and includes the following compounds represented by formula IA, as well as their pharmaceutically acceptable salts and hydrates:

[0204] [ka]

[0205] In the formula, ring A is selected from the group consisting of phenyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, and triazinyl, and n is 1, 2, or 3. T is either CR1R2 or O. W is CR4R5 or O, U is CR6R7, X is CR8R9, V is either CR3 or N. Y is NR 10 , is O, or does not exist, Z is (CR 12 R 13 ) m And, R is a halogen or deuterium, p is 0, 1, 2, 3, or 4, and m is 1, 2, 3, or 4. R1, R2, R4, and R5 are each independently selected from the group consisting of H, halogens, and deuterium, or alternatively, R2 and R5 form a single bond with the carbon atom to which they are bonded. R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano, or alternatively, R3 and R1 together with the carbon atom to which they are bonded form a C3-C5 cycloalkyl group, or alternatively, R3 and R4 together with the carbon atom to which they are bonded form a C3-C5 cycloalkyl group. R6, R7, R8, R9, and R 11 Each is independently selected from the group consisting of H, halogens, and deuterium. R 10 The group consists of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen atoms, and each R 12 and R 13These are independently selected from the group consisting of H, halogens, deuterium, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogen atoms. R 12 and R 13 This is independently selected from the group consisting of H, halogens, deuterium, unsubstituted C1-C3 alkyls, and C1-C3 alkyls substituted with one or more halogen atoms.

[0206] An example of a suitable OX2R agonist is N-((2) represented by the following formula (X). 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-1(2,3)-pyrazine-5(2,1)-piperazine-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide:

[0207] [ka]

[0208] Alternatively, there may be a pharmaceutically acceptable salt or hydrate thereof.

[0209] OX2R agonists may exist as pharmaceutically acceptable salts. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Examples of salts with inorganic bases include alkali metal salts, such as sodium salts and potassium salts; alkaline earth metal salts, such as calcium salts and magnesium salts; aluminum salts; and ammonium salts. Examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, and N,N-dibenzylethylenediamine. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Examples of salts with basic amino acids include salts with arginine, lysine, and ornithine. Examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.

[0210] The OX2R agonist may exist as a hydrate or a nonhydrate, or as a nonsolvate (e.g., an anhydride) or a solvate (e.g., a hydrate).

[0211] Furthermore, the OX2R agonist may exist as a pharmaceutically acceptable cocrystal or cocrystalline salt. A cocrystal or cocrystalline salt refers to a crystalline substance composed of two or more specific solids at room temperature, each having different properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Such cocrystals or cocrystalline salts may be produced by known methods.

[0212] Pharmaceutical compositions, dosage forms, and delivery devices The pharmaceutical composition contains a pharmaceutically acceptable carrier. Various organic or inorganic carrier substances commonly used as preparation materials may be used as pharmaceutically acceptable carriers. These are incorporated as excipients, lubricants, binders, and disintegrants for solid formulations, or as solvents, solubilizers, suspending agents, isotonic agents, buffers, and analgesics for liquid formulations, and preparation additives, such as preservatives, antioxidants, colorants, and sweeteners, may be added as needed.

[0213] Examples of dosage forms of the aforementioned pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, lozenges, syrups, emulsions, suspensions, films (e.g., orally disintegrating films), injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip infusions), topical preparations (e.g., transdermal preparations and ointments), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal sprays, lung preparations (inhalants), and eye drops, each of which can be safely administered orally or parenterally (e.g., topically, rectally, or intravenously). These preparations may be controlled-release formulations, such as immediate-release formulations and sustained-release formulations.

[0214] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous, subcutaneous, transdermal, intradermal, or transmucosal administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for transdermal administration. In some embodiments, the pharmaceutical composition is formulated for transmucosal administration.

[0215] Sustained-release formulation In one embodiment, the pharmaceutical composition comprises (a) an orexin type 2 receptor (OX2R) agonist, and (b) one or more pharmaceutically acceptable carriers capable of providing sustained release of the OX2R agonist at or below the maximum uncreathable plasma concentration.

[0216] In some embodiments, the pharmaceutical composition yields mean plasma concentrations of approximately 0.01 ng / mL to 1 mg / mL, approximately 0.03 ng / mL to 300 ng / mL, approximately 0.05 ng / mL to 100 ng / mL, approximately 0.08 ng / mL to 50 ng / mL, or approximately 1 ng / mL to 30 ng / mL after administration of an OX2R agonist. [Examples]

[0217] The following non-limiting examples provide a complete disclosure and explanation of methods for preparing and using the compositions of the present invention, as well as assays, screenings, and therapeutic methods, and are not intended to limit the scope of what the inventors consider to be their invention.

[0218] Example 1. Effects of OX2R-selective agonists, Compound A and Compound C, on respiratory function using OX-A and OX-B as controls. method animal For in vitro electrophysiological recordings, neonatal Sprague-Dawley (SD) rats obtained from Charles River Laboratories Italia (Lecco, Italy) were used from 1 to 10 days postnatology (P1-10). For in vivo studies, male SD rats obtained from Charles River Laboratories Japan (Kanagawa, Japan) were used, and EMG recordings of the diaphragm and genioglossus muscle were performed at 7 weeks of age. All adult rats and mice were housed under laboratory conditions (12-hour light-dark cycle, lights on at 7am) and given ad libitum for feed (CE-2 (manufactured by CREA Nippon Co., Ltd.) for animals obtained in Japan, and Altromin R (A. Rieper SpA, Bolzano, Italy)), a rat and mouse maintenance diet, for animals obtained in Italy, and water.

[0219] Chemical substances and solutions Compound A, namely methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, compound B, namely N-((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, and compound C, namely N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, were synthesized by Takeda Pharmaceutical Company Limited. In in vitro studies, all drugs were dissolved in dimethyl sulfoxide (DMSO) and diluted in each experimental solution. In EMG studies of the rat diaphragm and genioglossus muscle, compound C was dissolved in 0.1% (w / v) polysorbate 80 and 20% (w / v) Captisol (CyDex Pharmaceuticals, KS, USA) and administered intravenously at a dose of 1 mL / kg body weight.

[0220] Electrophysiological recordings of neurons in the Pre-Betzinger complex and hypoglossal motor neurons in rat medulla oblongata slices. Neonatal rats (1-10 days old) were decapitated, and the neural axis was separated in a chamber filled with oxygenated artificial cerebrospinal fluid (ACSF: NaCl 125mM, KCl 2.5mM, MgCl2 1mM, CaCl2 2mM, NaHCO3 25mM, NaH2PO4 1.25mM, glucose 25mM, pH 7.4). After removing the cerebellum, the brainstem was fixed in a vibratome (VT1000S; Leica, Milan, Italy) chamber filled with oxygenated gluconate cleavage solution (K-gluconate 130mM, KCl 15mM, EGTA 0.2mM, HEPES 20mM, glucose 25mM, kynurenic acid 2mM, pH 7.4). Transverse medullary sections (400–600 μm thick) containing the Pre-Betzinger complex and hypoglossal nerve nuclei were prepared. The sections were transferred to oxygenated mannitol cutting solution (D-mannitol 225 mM, glucose 25 mM, KCl 2.5 mM, NaH2PO4 1.25 mM, NaHCO3 26 mM, CaCl2 0.8 mM, MgCl2 8 mM, kynurenic acid 2 mM, pH 7.4) at room temperature for 1 minute. The slices were then kept in ACSF solution at 30°C for 30 minutes, followed by 30 minutes at room temperature. At least 30 minutes before the start of recording, each section was transferred to a recording solution with the K+ concentration increased to 9 mM and the Mg2+ concentration decreased to 0.5 mM to ensure a long-term and stable rhythm. During recording, the sections were transferred to an immersion recording chamber and continuously perfused with fresh extracellular modified ACSF solution (mACSF: NaCl 125mM, MgCl2 0.5mM, KCl 9mM, CaCl2 1mM, NaHCO3 25mM, NaH2PO4 1.25mM, glucose 25mM, pH 7.4) using a peristaltic pump while maintaining a temperature of 27±2℃ and a flow rate of 2.3±0.2 mL / min.The pre-Boetzinger complex was located ventrally to the nucleus ambiguus (JCSmith, HHEllenberger, K. Ballanyi, DWRichter, JLFeldman, Pre-Boetzinger complex: a brainstem region that may generate respiratory rhythm in mammals, Science (New York, NY) 254(5032) (1991) 726-9). As previously reported (GDFunk, JJGreer, The rhythmic, transverse medullary slice preparation in respiratory neurobiology: contributions and caveats, Respir Physiol Neurobiol 186(2)(2013)236-53; JQPilarski, HEWakefield, AJFuglevand, RBLevine, RFFregosi, Increased nicotinic receptor desensitization in hypoglossal motor neurons following chronic developmental nicotine exposure, J Neurophysiol 107(1)(2012)257-64), hypoglossal motor neurons were identified based on their location within the hypoglossal nucleus, characteristic size (width 20-60 μm) and shape (multipolar neurons with unbranched axons extending ventrolaterally toward the root of the hypoglossal nerve), and physiological characteristics (input resistance 50-200 MΩ). Whole-cell voltage clamp recordings were performed at membrane potentials of -60mV and -55mV in Prebotzinger complex neurons and hypoglossal motor neurons, respectively, using borosilicate glass pipettes filled with intracellular solution (114mM K-gluconate, 6mM KCl, 4mM MgATP, 0.3mM NaGTP, 10mM Na-creatine phosphate, 10mM HEPES, 0.2mM EGTA, pH 7.25, osmotic pressure 300mOsm due to sucrose).Signals were acquired at a sampling rate of 10–20 kHz using Clampex 10.6 software (Axon, Molecular Devices, CA, USA), filtered to 2–10 kHz using the software's built-in 8-pole Bessel filter, and analyzed using Clampfit 10.6 software (pClamp 10.6; Axon, Molecular Devices). The baseline and threshold levels for bursts were set using the Clampfit software. Bursts were then automatically detected, and their frequency was measured.

[0221] To evaluate the effect of the solvent (0.1% DMSO) on neuronal activity, neuronal activity was recorded for 2–12 minutes in the basal state after 5 minutes of stabilization, followed by 30 minutes of recording in the presence of the solvent (0.1% DMSO). The mean burst frequency during the last 1–2 minutes of the basal state was used as the control value, and the percentage change from the control value was calculated using the mean burst frequency during the last 1–2 minutes of solvent perfusion. Since the solvent (0.1% DMSO) did not significantly affect the burst frequency of pre-Betzinger complex neurons and hypoglossal motor neurons, the effect of the drugs was evaluated under the solvent (0.1% DMSO). To evaluate the effect of each drug on neuronal activity, neuronal activity was recorded for each neuron for 2–20 minutes in the presence of the solvent after 5 minutes of stabilization, followed by recording after applying the drug at 2–3 progressively increasing concentrations (4–15 minutes each). The average burst frequency over the last 1-2 minutes in the presence of the solvent was used as the control value, and the percentage change from the control value was calculated using the average burst frequency over the last 1-2 minutes after stimulation with each concentration of the drug.

[0222] Electrophysiological recordings of phrenic nerve motor neurons in isolated rat brainstem-spinal cord specimens. Neonatal rats (1-4 days postnatally) were decapitated, and the brainstem and spinal cord were excised in a cistern containing ACSF. The cerebellum and pons were also resected. At least 30 minutes before the start of recording, the tissue was transferred to a recording solution (modified ACSF, NaCl 125mM, MgCl2 0.5mM, KCl 5mM, CaCl2 1mM, NaHCO3 25mM, NaH2PO4 1.25mM, glucose 30mM, pH 7.4) with increased K+ concentration to 5mM and decreased Mg2+ concentration to 0.5mM to ensure a stable rhythm over a long period. The tissue was attached to a coverslip and transferred to a recording chamber, where it was continuously perfused with mACSF at a flow rate of 2.3±0.2 mL / min at 27±2°C. The activity of phrenic motor neurons was measured by electrophysiological recording (output of phrenic motor neurons) from the C3-5 ventral root using glass aspiration electrodes (JJGreer, JCSmith, JLFeldman, Respiratory and locomotor patterns generated in the fetal rat brain stem-spinal cord in vitro, J Neurophysiol 67(4)(1992)996-9; JCSmith, JJGreer, GSLiiu, JLFeldman, Neural mechanisms generating respiratory pattern in mammalian brain stem-spinal cord in vitro. I. Spatiotemporal patterns of motor and medullary neuron activity, J Neurophysiol 64(4)(1990)1149-69). Signals were acquired using Clampex 10.6 software (Axon, Molecular Devices) in current-fixed mode at a sampling rate of 10-20 kHz, and filtered at 2-10 kHz using an 8-pole Bessel filter built into the software. The acquired signals were filtered using a bandpass filter (0.01-3000Hz), rectified, and integrated with a time constant decay (50-200ms) using LabChart software (AD Instruments, Dunedin, New Zealand).Spontaneous bursts detected by voltage signals consist of multiple positive and negative voltages from the baseline; therefore, rectification and integration were used to quantify the activity of phrenic motor neurons (T. Sugita, et al.). The burst threshold level was set using LabChart software (AD Instruments). Bursts were then automatically detected, and their frequency was measured.

[0223] To evaluate the effect of the solvent (0.1% DMSO) on neuronal activity, neuronal activity was recorded for 2–20 minutes in the basal state after 5 minutes of stabilization, followed by 30–40 minutes of recording in the presence of the solvent (0.1% DMSO). The average burst frequency during the last 2 minutes of the basal state was used as the control value, and the percentage change from the control value was calculated using the average burst frequency during the last 2 minutes of solvent perfusion. Since the solvent (0.1% DMSO) did not show a significant effect on the burst frequency of phrenic nerve neurons, the effect of the drugs was evaluated under the solvent (0.1% DMSO). To evaluate the effect of each drug on neuronal activity, neuronal activity was recorded for 5–30 minutes in the presence of the solvent after 5 minutes of stabilization, followed by 30–40 minutes of recording while perfusing with the drug until a plateau effect was obtained. The average burst frequency during the last 2 minutes in the presence of the solvent was used as the control value, and the percentage change from the control value was calculated using the average burst frequency during the last 2 minutes of drug perfusion.

[0224] EMG recording of the diaphragm in anesthetized rats Rats were anesthetized with isoflurane (induction: 2%, maintenance: 1.5%). Depth of anesthesia was assessed by the reflex response to pinching the feet. A cannula was inserted into the tail vein for intravenous drug administration. To prevent hypothermia, the rats were laid on disposable body warmers. The diaphragm was exposed, and then two needle electrodes were implanted in the costophrenic diaphragm to monitor diaphragmatic EMG. After 10 minutes of baseline recording, a solvent (0.1% [w / v] polysorbate 80 and 20% [w / v] Captisol solution) or compound C was administered intravenously, and EMG was recorded for another 10 minutes. The EMG was amplified using a Bio amp system (ML132, AD Instruments), passed through a high-pass filter (10 Hz), and then digitized and recorded using PowerLab software (AD Instruments). It was then rectified using LabChart software (AD Instruments) and integrated with a time constant decay (100 ms). The burst threshold level was set using LabChart software (AD Instruments). Bursts were then automatically detected, and their frequency was measured. The average burst frequency in the 2 minutes prior to administration of solvent or compound C was used as the control value, and the average burst frequency in the 10 minutes after administration of solvent or compound C was used to calculate the percentage of the control value.

[0225] EMG recording of the genioglossus muscle in anesthetized rats EMG recording of the genioglossal muscle was performed with slight modifications to a previously described method (GHZhang, et al.). Rats were anesthetized with urethane (2.0 g / kg, intraperitoneal injection). The depth of anesthesia was assessed by the reflex response to pinching the foot. A cannula was inserted into the tail vein for intravenous drug administration. Each rat was laid on a servo-controlled electric heating pad. The rats' body temperature was monitored with a rectal probe on the pad and maintained at approximately 37°C. Bilateral vagus nerves were severed to enhance genioglossal muscle activity (GHZhang, et al.; GM Stettner, L. Kubin, Antagonism of orexin receptors in the posterior hypothalamus reduces hypoglossal and cardiorespiratory excitation from the perifornical hypothalamus, J Appl Physiol (1985) 114(1) (2013) 119-30). Rats were tracheostomied to expose the genioglossus muscle. Two needle electrodes were then implanted on both sides of the genioglossus muscle to monitor EMG. After 10 minutes of baseline recording, a solvent (0.1% [w / v] polysorbate 80 and 20% [w / v] Captisol solution) or compound C was administered intravenously, and EMG was recorded for another 10 minutes. The EMG signal was amplified 1,000-fold using a Microelectrode AC Amplifier (Model 1800; AM Systems, Carlsborg, WA, USA), passed through a bandpass filter (100-5,000 Hz), digitized using an AD converter (Power 1401; Cambridge Electronic Design, Cambridge, UK), and recorded using Spike2 software (Cambridge Electronic Design). Subsequently, the signal was rectified using LabChart software (AD Instruments) and integrated with a time constant decay (100 ms). The burst threshold level was set using LabChart software (AD Instruments). Bursts were then automatically detected, and their amplitude was measured.The average burst amplitude over 2 minutes prior to drug administration was used as the control value, and the percentage of the control value was calculated using the average burst amplitude over 10 minutes after administration of the solvent or compound C.

[0226] result Effects of compounds A, B, and C on the activity of neurons involved in respiratory control The effects of compounds A, B, and C on the activity of pre-Betzinger complex neurons and hypoglossal motor neurons were investigated by measuring the burst frequency detected by voltage clamp recording.

[0227] Effects of compounds A, B, and C on neuronal activity in the Pre-Betzinger complex of rat medulla oblongata sections. To investigate the effects of compounds A, B, and C on the activity of pre-Betzinger complex neurons, whole-cell patch-clamp recordings were performed using rat medullary sections. Compounds A, B, and C all increased the burst frequency of pre-Betzinger complex neurons (Figure 1). These results suggest that compounds A, B, and C increase the activity of pre-Betzinger complex neurons in rat medullary sections.

[0228] The results are shown in Figure 1. The figure shows how compounds A, B, and C activated neurons in the pre-Betzinger complex of rat medulla oblongata sections.

[0229] Effects of compounds A, B, and C on the activity of phrenic nerve motor neurons in isolated rat brainstem-spinal cord specimens To investigate the effects of compounds A, B, and C on the activity of phrenic motor neurons, electrophysiological recordings were performed using isolated rat brainstem-spinal cord specimens. Compounds A, B, and C all increased the burst frequency of phrenic motor neurons (Figure 2). These results suggest that compounds A, B, and C increase the activity of phrenic motor neurons in isolated rat brainstem-spinal cord specimens.

[0230] The results are shown in Figure 2. The figure shows how compounds A, B, and C activated phrenic motor neurons in isolated rat brainstem-spinal cord specimens.

[0231] Effects of compounds A, B, and C on the activity of hypoglossal motor neurons in rat medullary sections. To investigate the effects of compounds A, B, and C on the activity of hypoglossal motor neurons, whole-cell patch-clamp recordings were performed using rat medullary sections. Compounds A, B, and C increased burst frequency (Figure 3). These results suggest that compounds A, B, and C increase the activity of hypoglossal motor neurons in rat medullary sections.

[0232] The results are shown in Figure 3. The figure shows how compounds A, B, and C activated hypoglossal motor neurons in rat medullary sections.

[0233] Effect of compound C on diaphragmatic activity in EMG recordings of anesthetized rats For the technical feasibility of this experiment, anesthetized rats were used for EMG recording of the diaphragm. In this experiment, compound C was administered intravenously to anesthetized rats. To understand the relationship between the plasma effective concentration of compound C for awakening and the plasma effective concentration of compound C for diaphragmatic activation, the plasma concentration of compound C was measured after intravenous administration. The maximum plasma concentrations of compound C after intravenous administration of 0.3 and 1 mg / kg were similar to the maximum plasma concentrations after oral administration of 3 mg / kg and 10 mg / kg, respectively. Since oral administration of compound C at doses of 10 mg / kg or higher resulted in a strong awakening effect in rats, the efficacy of intravenous administration of compound C at 0.3, 1, and 3 mg / kg was evaluated to activate the diaphragm in EMG recordings of anesthetized rats. As a result, intravenous administration of compound C at 1 and 3 mg / kg significantly increased the frequency of diaphragmatic bursts (Figure 4). These results suggest that compound C increases diaphragmatic activity in anesthetized rats.

[0234] The results are shown in Figure 4. The figure shows that intravenous administration of compound C significantly increased the diaphragmatic burst frequency in anesthetized rats.

[0235] Effect of compound C on genioglossus muscle activity in EMG recordings of anesthetized rats The effect of intravenous administration of compound C on genioglossus muscle activity in anesthetized rats was investigated using EMG recording. Burst amplitude indicates the peak of genioglossus muscle activity during bursts. As a result, intravenous administration of compound C at a dose of 1 mg / kg significantly increased the burst frequency (Figure 5). These results suggest that compound C increases genioglossus muscle activity in anesthetized rats, particularly in terms of burst amplitude.

[0236] Figure 5 shows that intravenous administration of compound C significantly increased the burst amplitude of the genioglossus muscle in anesthetized rats.

[0237] Neurons in the Pre-Betzinger complex, located in the ventrolateral medulla oblongata, are crucial for generating inspiratory airflow. Furthermore, these neurons regulate the activity of the diaphragm and genioglossus muscles by controlling the activity of phrenic motor neurons in the cervical spinal cord and hypoglossal motor neurons in the dorsomedial medulla oblongata, respectively (JCSmith, APAbdala, A. Borgmann, IARybak, JFPaton, Brainstem respiratory networks: building blocks and microcircuits, Trends Neurosci 36(3)(2013), 152-62).

[0238] Compounds A, B, and C all increased the activity of neurons in the pre-Betzinger complex and hypoglossal motor neurons in rat medulla oblongata sections. In these neurons, all three compounds significantly increased burst frequency. The OX2R protein is thought to be expressed in the pre-Betzinger complex in rat brain slices (K. Mitsukawa, H. Kimura, Orexin 2 receptor (OX2R) protein distribution measured by autoradiography using radiolabeled OX2R-selective antagonist EMPA in rodent brain and peripheral tissues, Sci Rep 12(1)(2022)8473), and therefore, OX2R agonists may directly stimulate neurons within the pre-Betzinger complex. Compounds A, B, and C also increased the activity of phrenic motor neurons in isolated rat brainstem-spinal cord specimens, primarily by increasing burst frequency.

[0239] The diaphragm and genioglossus muscles generate spontaneous bursts during inspiration, and therefore, the burst frequency of these muscles is thought to be related to the respiratory rate of these mice. Thus, an increase in burst frequency was observed in both the diaphragm and genioglossus muscles. However, in vivo studies revealed that compound C increased the burst frequency of the diaphragm in anesthetized rats, while primarily increasing the burst amplitude of the genioglossus muscle. Our results suggest that OX2R agonists can modulate respiratory function by increasing the activity of the diaphragm and genioglossus muscles through stimulation of neurons in the pre-Betzinger complex in rodents, as well as neural networks including phrenic motor neurons and hypoglossal motor neurons.

[0240] OX2R agonists are thought to have therapeutic effects on both CSA and OSA because they activate the diaphragm and genioglossus muscles.

[0241] OX2R agonists can modulate respiratory function by increasing the activity of the diaphragm and genioglossus muscles through stimulation of neurons in the pre-Betzinger complex, as well as neural networks including phrenic motor neurons and hypoglossal motor neurons.

[0242] Example 2. A clinical trial to evaluate the safety, tolerability, pharmacodynamic effects, and pharmacokinetic effects of overnight intravenous administration of compound A in patients with obstructive sleep apnea. A phase 1b, randomized, double-blind, placebo-controlled, 3-period crossover trial was conducted to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic effects of overnight intravenous administration of compound A in patients with obstructive sleep apnea (OSA). This trial was designed to further evaluate intravenous (IV) administration of compound A in adults with OSA, based on the hypothesis that unawakening-promoting exposure to compound A increases airway patency by increasing genioglossus muscle tone and hypoglossal motor neuron activity. The primary objective of this trial was to evaluate the potential mechanism of action of OX2R agonists for the treatment of OSA using IV infusion of compound A and to determine appropriate use in future trials using oral OX2R agonists.

[0243] Participants were men and women aged 18 to 75 years who were diagnosed with OSA according to the International Classification of Sleep Disorders, Third Revision (ICSD-3) criteria and had an apnea-hypopnea index (AHI) of 12 to 50 episodes per hour of sleep. The study consisted of a screening period, three treatment periods with two washout periods, and a follow-up period. A total of 13 participants were enrolled and randomized, and 12 participants (92.3%) completed all planned doses of the study drug and the study. One participant (7.7%) did not complete all planned doses of the study drug due to an adverse event and discontinued the study due to withdrawal.

[0244] Test plan Eligible participants were randomly assigned (in a double-blind manner) to one of six dosing sequences. During each treatment period, participants underwent three 10-minute UACI assessments to examine the primary biological mechanism of OSA (described in Osman, AM, et al., 2019, Sleep, 42(7), 1-10), followed by an overnight polysomnography (PSG). After the initial baseline UACI assessment (U1), an IV infusion regimen of compound A or placebo was administered over approximately 10 hours to specified plasma concentrations, and the effect of compound A on UACI and PSG metrics was evaluated. The target plasma concentrations for the low-dose compound A IV regimen were 10 ng / mL for the second UACI (U2), 30 ng / mL for the third UACI (U3), and 10 ng / mL for the overnight PSG. The target plasma concentrations for the high-dose compound A IV regimen were 30 ng / mL for U2, 90 ng / mL for U3, and 30 ng / mL for overnight PSG.

[0245] A 20-minute loading period followed by a 15-minute maintenance period was set for each UACI assessment (U2 and U3) to achieve the target exposure levels. The overnight maintenance dose (approximately 490 minutes) covered the duration of a standard overnight PSG (approximately 8 hours). Each dose was selected to include the potential pharmacologically active concentration range for upper airway obstruction. The study was double-blinded to ensure that all participants received the same amount of liquid by using solution concentrations of compound A for the low-dose compound A regimen, the high-dose compound A regimen, and placebo.

[0246] On the first day of each treatment period, participants were asked to check in approximately 3 hours before the scheduled administration time. To reduce confounding factors due to endogenous OX levels during evaluation, the procedure was initiated in the evening. The initiation time was adjusted based on the patient's usual bedtime. Following physical examination, urinalysis, and breath alcohol testing, each participant was fitted with an IV catheter for injecting placebo or compound A, electroencephalogram (EEG) electrodes to monitor alertness, pressure sensors in the posterior nostrils and epiglottis, and a nasal mask and pneumotachograph to measure airflow (Osman, et al. 2019).

[0247] After measuring baseline UACI, IV infusions of placebo or compound A were initiated. Compound A was tested in two concentrations in stages, each stage consisting of a 20-minute loading period followed by a 15-minute maintenance period. UACI was tested at each concentration during the maintenance period. Subjective sleepiness was measured using the Karolinska Sleepiness Scale (KSS) immediately before each UACI test period. After the U3 test, the KSS was performed, and then the UACI testing equipment (pressure sensor, genioglossus EMG electrode) was removed, except for the EEG electrode which was placed in position to record overnight PSG. A final KSS was performed before lights out. After lights out, participants were allowed to sleep until the following morning (day 2). Compound A / placebo infusions were maintained overnight during nocturnal PSG (nPSG) and terminated approximately 8 hours after lights out. Participants were then discharged on day 2. This procedure was repeated for each treatment period.

[0248] Safety assessments, including adverse events (AEs), safety tests, vital signs, and ECG, were recorded at specific time points. The interval between each treatment period was at least 48 hours to 14 days from the end of one infusion to the start of the next. Participants were contacted by telephone 7(±2) days after discharge from the third treatment period to inquire about concomitant medications and adverse events.

[0249] Treatment and medication During each treatment period, each participant received either a placebo or one of two dose regimens of compound A, each targeting a 3-fold range of exposure to compound A (see Table 1).

[0250] Each dose regimen was designed to achieve the target plasma concentrations of compound A for U2, U3, and PSG. Specifically, the low-dose regimens of compound A were 10, 30, and 10 ng / mL, and the high-dose regimens were 30, 90, and 30 ng / mL. A 20-minute loading period followed by a 15-minute maintenance period was set for each regimen to achieve the target exposure levels for UACI assessment (U2 and U3). The overnight maintenance dose (approximately 490 minutes) was designed to cover the duration of a standard overnight PSG (approximately 8 hours). Each dose was selected to include the potential pharmacologically active concentration range for upper airway obstruction. The solution concentrations of compound A were designed so that participants received the same volume of liquid for the low-dose compound A regimen, the high-dose compound A regimen, and placebo.

[0251] [Table 1]

[0252] Key evaluation criteria The primary endpoint was the number of participants experiencing at least one treatment-induced adverse event (TEAE).

[0253] Secondary outcome items Secondary endpoints included the percentage change from baseline in the upper airway collapse index (UACI) and AHI observed during overnight polysomnography (PSG).

[0254] Results and Conclusions Low-dose and high-dose regimens of compound A were generally well-tolerated in adult participants with OSA, and no safety concerns were observed. Three participants (23.1%) experienced four drug-related TEAEs, all of which were mild in severity. Specifically, one TEAE of elevated blood pressure occurred during administration of the low-dose regimen of compound A, two TEAEs of headache occurred during administration of the low-dose regimen of compound A and placebo, and one TEAE of muscle pain occurred during administration of the low-dose regimen of compound A.

[0255] In the case of elevated blood pressure (TEAE), the study drug was discontinued during the low-dose regimen of compound A. This participant was not exposed to placebo or the high-dose regimen of compound A, and the possible interpretation of this event is limited. TEAEs of drug-related headache occurred with both the low-dose regimen of compound A and placebo, but no drug-related TEAEs occurred with the high-dose regimen of compound A. This negates any association with the dose of compound A and reduces the clinical significance of these drug-related events.

[0256] No deaths or serious TEAEs were reported during the trial.

[0257] With the exception of one moderate TEAE (unrelated to the study drug or procedure) of headache reported with a low-dose regimen of compound A, all TEAEs were mild. Headache was the most frequently reported TEAE, but no dose-related trend was observed.

[0258] Before medication, the mean LS changes in SBP / DBP, adjusted for placebo, were 2.44 / 0.29 mmHg and 9.01 / 1.84 mmHg for the low-dose and high-dose regimens of compound A, respectively. The wide 95% confidence intervals (CIs) for SBP and DBP values ​​at this point reaffirm the high variability of the results. The lack of a clear trend in BP values ​​is supported by individual examinations of BP values ​​across all participants. The clinical significance of these results is limited due to the variability of BP values ​​at screening and before medication, as well as the inconsistent BP increases across each treatment period and time point.

[0259] The high-dose regimen of compound A (30 ng / mL overnight) resulted in a statistically and clinically significant reduction in AHI of approximately 9 events / hour. Responders showed a large decrease in AHI, while non-responders did not. The mean LS was less than 30 events per hour, which corresponds to a reduction from severe to moderate OSA.

[0260] This dose also showed a beneficial reduction in hypoxic load, which suggests a decrease in OSA severity as measured by measures affecting cardiovascular outcomes. In addition to the statistical significance obtained in the placebo-adjusted mean difference in LS of hypoxic load in the high-dose regimen of compound A, this difference was considered clinically significant in both the low-dose and high-dose regimens, as the estimated hypoxic load was ≤53%* min / hour. Such a reduction in high hypoxic load may correlate with improved survival rates in OSA participants, as this parameter has been reported to be relevant to the assessment of cardiovascular risk in both fatal and non-fatal cardiovascular events (Azarbarzin, A., et al., 2019, European Heart Journal, 40(14), 1149-1157; Martinez-Garcia, MA, 2023, Archivos de bronconeumologia, 59(1), 36-43).

[0261] There was no consistent improvement in upper airway collapse as measured by UACI during wakefulness. In the endotype of OSA, pharyngeal collapse during sleep is V 受動 and V 能動 The indicators showed a decrease, suggesting that the high-dose regimen of compound A improved upper airway collapse during sleep. Loop gain was also reduced at this dose, indicating stabilization of the central ventilatory response, which is thought to reduce central AHI. The arousal threshold for respiratory variability decreased, which is consistent with the arousal-promoting effect of compound A.

[0262] When administered continuously throughout the entire sleep period, compound A at 30 ng / ml significantly reduced REM sleep and increased awakenings after sleep onset, affecting sleep continuity and decreasing sleep efficiency, but this dose did not cause insomnia.

[0263] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

[0264] This disclosure is not limited to the specific embodiments described in this application, but is intended as a single illustrative example of the individual aspects of this disclosure. Not all of the various embodiments of this disclosure are described herein. Any modifications and variations of this disclosure may be made without departing from its spirit and scope and will be apparent to those skilled in the art. Functionally equivalent methods and apparatus within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description, in addition to those listed herein. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure, together with the entire scope of equivalents to which such claims are entitled, is limited only by the conditions of the appended claims.

[0265] This disclosure is not limited to any particular use, method, reagent, compound, composition, or biological system, and these are, of course, subject to change. It should also be understood that the terms used herein are for illustrative purposes only and are not intended to limit to any particular embodiment.

[0266] Furthermore, if any feature or aspect of the present disclosure is described in a Markush group, a person skilled in the art will recognize that the present disclosure may also be described in any individual component or subgroup of any component of that Markush group.

[0267] As will be understood by those skilled in the art, for all purposes, and especially in providing written descriptions, all scopes disclosed herein also encompass all possible subscopes and combinations thereof. It will be readily apparent to those skilled in the art that any scope described herein can be divided into at least equal fractions, such as half, one-third, one-quarter, one-fifth, one-tenth, etc. As a non-limiting example, each scope referred to herein can be readily divided into a lower third, middle third, upper third, etc. Furthermore, as will be understood by those skilled in the art, expressions such as “up to,” “at least,” “greater than,” and “less than” include the stated numerical values ​​and refer to scopes that include further subdivided subscopes as described above. Finally, as will be understood by those skilled in the art, a scope includes individual components. Thus, for example, a group having 1 to 3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to a group having 1, 2, 3, 4, or 5 cells, and so on.

Claims

1. A method for improving respiratory function in a subject requiring improvement of respiratory function during sleep, the method comprising administering an orexin type 2 receptor agonist to the subject.

2. The method according to claim 1, wherein administering the orexin type 2 receptor agonist modulates the inspiratory airflow in the subject.

3. The method according to claim 1 or 2, wherein the orexin type 2 receptor agonist is administered to the subject in an amount effective in improving respiratory function without causing an arousal response or state of arousal.

4. The method according to claim 3, wherein the arousal response or state of arousal is determined by measuring the sleep latency of one or more subjects diagnosed with sleep apnea.

5. The method according to any one of claims 1 to 3, wherein the subject has sleep apnea.

6. The method according to claim 5, wherein the sleep apnea is selected from obstructive sleep apnea (OSA), treatment-induced sleep apnea, and central sleep apnea (CSA).

7. The method according to claim 6, wherein the sleep apnea is obstructive sleep apnea (OSA).

8. The method according to any one of claims 1 to 7, wherein the administration of the OX2R agonist reduces the apnea-hypopnea index (AHI) of the subject.

9. The method according to any one of claims 1 to 7, wherein the administration of the OX2R agonist reduces the hypoxic load of the subject.

10. The method according to any one of claims 1 to 9, wherein the administration of the OX2R agonist provides a plasma concentration of the OX2R agonist at or below the maximum non-awakening plasma concentration of the agonist over a predetermined administration interval.

11. The plasma concentration of the OX2R agonist is i) To determine the non-awakened plasma concentration of the OX2R agonist that does not induce an arousal response or state of arousal in humans, ii) The method according to claim 10, selected by determining the dose of the OX2R agonist that provides a plasma concentration less than or equal to the maximum non-awakening plasma concentration.

12. The method according to claim 10, wherein the administration of the OX2R agonist gives a plasma concentration of the OX2R agonist after administration that is about 1 / 50 to about 1 / 1 of the maximum non-awakening concentration of the OX2R agonist.

13. The method according to claim 12, wherein the plasma concentration of the OX2R agonist is about 1 / 20 to about 1 / 1 of the maximum non-awakening concentration of the OX2R agonist.

14. The method according to any one of claims 1 to 13, wherein the agonist is administered orally, intravenously, subcutaneously, transdermally, or transmucosally.

15. The method according to claim 14, wherein the OX2R agonist is administered orally.

16. The method according to any one of claims 1 to 15, wherein the OX2R agonist is administered once daily.

17. The method according to any one of claims 1 to 15, wherein the OX2R agonist is administered to the subject approximately 5 minutes to approximately 5 hours before bedtime.

18. The orexin type 2 receptor agonist is a compound represented by formula (I): 【Chemistry 1】 [In the formula, R １ teeth, (1) Hydrogen atom, (2) C which may be substituted with 1 to 7 substituents selected from the following １～６ Alkyl-carbonyl group: (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) C ３～１０ a cycloalkyl group, (v) C １～６ an alkoxy group, (vi) C ６～１４ an aryl group, (vii) C ６～１４ an aryloxy group, (viii) a pyrazolyl group, a thiazolyl group, a pyrimidinyl group, or a pyridazinyl group which may each be substituted with an oxo group, (ix) a pyrazolyloxy group which may be substituted with 1 to 3 C １～６ alkyl groups, (x) C １～６ an alkyl-carbonyl group, (xi) C １～６ an alkoxy-carbonyl group, (xii) C １～６ an alkyl-carbonyloxy group, (xiii) C １～６ an alkylsulfonyl group, (xiv) a mono- or di-C １～６ alkylamino group, (xv) C １～６ an alkyl-carbonylamino group, and (xvi) (C １～６ alkyl)(C １～６ alkyl-carbonyl)amino group, (3) Halogen atoms, cyano groups, hydroxyl groups, oxo groups, and C １～６ C may be substituted with 1 to 3 substituents selected from alkyl groups. ３～１０ Cycloalkyl-carbonyl group, (4) Deuterium, halogen atoms, and C ６～１４ C may be substituted with 1 to 6 substituents selected from aryl groups. １～６ Alkoxy-carbonyl group, (5) C １～６ C may be substituted with 1 to 3 substituents selected from alkyl groups. ３～１０ Cycloalkyloxycarbonyl group, (6) Halogen atoms and C ６～１４ C may be substituted with 1 to 3 substituents selected from aryl groups. ６～１４ Aryl-carbonyl group, (7) C ６～１４ Aryloxy-carbonyl group, (8) C １～６ A furylcarbonyl group, thienylcarbonyl group, pyrazolylcarbonyl group, isoxazolylcarbonyl group, or pyridylcarbonyl group, which may each be substituted by one to three substituents selected from alkyl groups. (9) Oxo group, C １～６ Alkyl-carbonyl group, C １～６ Alkoxy-carbonyl group, and C １～６ Azetidinyl carbonyl group, oxetanyl carbonyl group, pyrrolidinyl carbonyl group, tetrahydrofuranyl carbonyl group, tetrahydropyranyl carbonyl group, or morpholinyl carbonyl group, which may each be substituted with one to three substituents selected from alkylsulfonyl groups. (10) Halogen atoms, cyano groups, hydroxyl groups, and C １～６ Mono- or di-C153 １～６ Alkyl-carbamoyl group, (11) Mono- or G-C ３～１０ Cycloalkyl-carbamoyl group, (12) Mono or G-C ６～１４ Aryl-carbamoyl group, (13) C １～６ Alkyl sulfonyl group, (14) C ３～１０ Cycloalkylsulfonyl group, (15) C which may be substituted with 1 to 3 halogen atoms ６～１４ Aryl sulfonyl group, (16) C １～６ A thienylsulfonyl group, pyrazolylsulfonyl group, imidazolylsulfonyl group, pyridylsulfonyl group, or dihydrochromenylsulfonyl group, which may each be substituted with one to three substituents selected from alkyl groups. (17) Mono or G-C １～６ Alkyl-sulfamoyl group, or (18) C １～６ It is an alkyl-carbonyl-carbonyl group, R ２ C may be substituted with one to three substituents selected from the following. ３～６ These are cycloalkyl groups, pyrrolidinyl groups, piperidinyl groups, or dioxanyl groups: (1) Deuterium, (2) Halogen atoms, (3) Hydroxyl group, (4) Halogen atoms and C ６～１４ C may be substituted with 1 to 3 substituents selected from aryl groups. １～６ alkyl group, (5) C ３～１０ Cycloalkyl groups, (6) C ３～１０ C may be substituted with a cycloalkyl group. １～６ Alkoxy group, (7) C which may be substituted with a halogen atom, a cyano group, or 1 to 3 halogen atoms. １～６ C may be substituted with alkyl groups or 1 to 3 halogen atoms. １～６ C may be substituted with 1 to 3 substituents selected from alkoxy groups and hydroxyl groups. ６～１４ Aryl group, (8) C ６～１４ Aryloxy group, (9) Tri-C １～６ Alkylsilyloxy group, (10) Halogen atom, C １～６ Alkyl and C １～６ Pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl, or isoquinolinyl groups, which may each be substituted with one to three substituents selected from alkoxy groups, and (11) C ６～１４ Aryl-carbonyl group; R ３ C １～６ Alkyl alkyl groups, or mono- or di-C １～６ [It is an alkylamino group.] The method according to any one of claims 1 to 17, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

19. In formula (I), R １ teeth, (1) Hydrogen atom, (2) C which may be substituted with a hydroxyl group １～６ Alkyl-carbonyl group, (3) Cyclopropanecarbonyl group, (4) C １～６ Alkoxy-carbonyl group, or (5) Mono or G-C １～６ It is an alkyl-carbamoyl group, R ２ teeth, (A) A cyclohexyl group which may be substituted with one to three substituents selected from the following: (1) C １～６ alkyl groups, and (2) C which may be substituted with a halogen atom or 1 to 3 halogen atoms. １～６ Alkyl groups, and C １～６ A phenyl group which may be substituted with one to three substituents selected from alkoxy groups; or (B) A piperidinyl group which may be substituted with 1 to 3 pyrimidinyl groups, R ３ C １～６ Alkyl alkyl group, or diC １～６ It is an alkylamino group, The method according to claim 18, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

20. The method according to claim 18, wherein the orexin type 2 receptor agonist is selected from methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, N-((2R,3S)-1-glycoyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidine-3-yl)methanesulfonamide, and (2R,3S)-N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

21. The method according to claim 20, wherein the orexin type 2 receptor agonist is selected from methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a pharmaceutically acceptable salt thereof.

22. The orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide, methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl (L)oxy)methyl)piperidine-1-carboxylate, N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide, (2R)-2-cyclopropyl-2-{(1R,3S,5S)-3-[(3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl]-8-azabicyclo[3.2.1]octan-8-yl}acetamide, (R)-2 - ((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-3-methylbutanamide, (R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-2-cyclopropylacetamide, (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidine-2-yl)-2-methylpiperidine-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide, and N-((2, １ S, 2 ４ S, 5 ２ R, 5 ３ S)-6-oxo-3,8-dioxa-1(2,3)-pyrazina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctaphane-5 ３ The method according to any one of claims 1 to 17, selected from -yl)methanesulfonamide or pharmaceutically acceptable salts thereof.

23. The orexin type 2 receptor agonist is a compound represented by formula (II): 【Chemistry 2】 [In the formula, R １ teeth, (1) C which may be substituted with 1 to 3 substituents selected from the following １～６ Alkyl group: (a) halogen atoms, and (b) C １～６ Alkoxy group; (2) C which may be substituted with 1 to 3 halogen atoms ３～６ Cycloalkyl groups, or (3) Mono or G-C １～６ It is an alkylamino group, R ２ It is a hydrogen atom, R ３ teeth, (1) C １～６ Alkoxy-carbonyl group, (2) C which may be substituted with 1 to 3 hydroxyl groups １～６ Alkyl-carbonyl group, (3) Mono or G-C １～６ Alkyl-carbamoyl group, (4) N-C １～６ Alkyl-N-C １～６ Alkoxycarbamoyl group, (5) C which may be substituted with 1 to 3 substituents selected from the following ３～６ Cycloalkyl-carbonyl group (the C ３～６ The C in the cycloalkyl-carbonyl group ３～６ Cycloalkyl groups may also be crosslinking ring groups. (a) Halogen atom, (b) C which may be substituted with 1 to 3 halogen atoms １～６ alkyl group, (c) Hydroxyl group, (d) C １～６ Alkoxy groups, and (e) cyano group; (6) Oxetanylcarbonyl group, (7) Azetidinyl carbonyl group which may be substituted with 1 to 3 substituents selected from the following: (a) halogen atoms, and (b) C １～６ an alkyl group; or (8) 5-azaspiro[2.3]hexylcarbonyl group, R ４ and R ５ Both are hydrogen atoms, Ring A is, (1) A pyrrolidine ring, or (2) A piperidine ring, Ring B is, (1) A benzene ring further substituted with one phenyl group which may be substituted with one to three substituents selected from the following: (i) halogen atoms, and (ii) C1-6 alkyl groups, and (It may be further substituted with one halogen atom.) (2) A pyridine ring further substituted with one phenyl group which may be substituted with one to three halogen atoms, (3) A thiazole ring further substituted with one phenyl group which may be substituted with one to three halogen atoms, or (4) A piperidine ring further substituted with one phenyl group. The method according to any one of claims 1 to 17, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23, wherein the orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide or a pharmaceutically acceptable salt thereof.

25. The method according to claim 23, wherein the orexin type 2 receptor agonist is N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide or a pharmaceutically acceptable salt thereof.

26. The orexin type 2 receptor agonist is a compound represented by formula (III): 【Transformation 3】 [R １ teeth, (1) C １～６ alkyl group, (2) Mono or G-C １～６ Alkylamino group, or (3) C ３～６ It is a cycloalkyl group, R ２ is (1) Hydrogen atom, (2) A fluorine atom, or (3) C １～６ It is an alkyl group, R ３ teeth, (1) C which may be substituted with 1 to 3 substituents selected from the following １～６ Alkyl-carbonyl group: (a) Halogen atom, (b) Hydroxyl group, and (c) cyano group; (2) C １～６ Alkoxy-carbonyl group, (3) C which may be substituted with 1 to 3 substituents selected from the following ３～１０ Cycloalkyl-carbonyl group (the C ３～１０ The C of the cycloalkyl-carbonyl group ３～１０ The cycloalkyl portion may be cross-linked. (a) Halogen atom, (b) Hydroxyl group, (c) cyano group, and (d) C １～６ alkyl group; (4) A 3- to 14-membered non-aromatic heterocyclylcarbonyl group which may be substituted with 1 to 3 substituents selected from the following: (a) Halogen atom, (b) Hydroxyl group, and (c) C １～６ alkyl group; (5) Mono or G-C １～６ Alkyl-carbamoyl group, or (6) N-C １～６ Alkyl-N-C １～６ It is an alkoxy-carbamoyl group, Ring A is, (1) A benzene ring which may be substituted with one substituent selected from the following: (a) C which may be substituted with 1 to 3 substituents selected from the following ６～１４ Aryl group: (i) Halogen atom, (ii) C which may be halogenated １～６ alkyl groups, and (iii) C which may be halogenated １～６ Alkoxy groups; and (b) A 5- to 14-membered aromatic heterocyclyl group which may be substituted with 1 to 3 substituents selected from the following: (i) C １～６ alkyl groups, and (ii) C １～６ Alkoxy groups, and (Further substitutions may be made with 1 to 3 halogen atoms), or (2) One carbon atom which may be substituted with one to three halogen atoms. ６～１４ It is a five- or six-membered aromatic heterocycle further substituted with an aryl group. The method according to any one of claims 1 to 17, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

27. The method according to claim 26, wherein the orexin type 2 receptor agonist is N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide or a pharmaceutically acceptable salt thereof.

28. The method according to claim 26, wherein the orexin type 2 receptor agonist is N-((2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl)pyrrolidine-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

29. The orexin type 2 receptor agonist is N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3-methyl[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}-N,N-dimethyl sulfate diamide, N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-methylpropanoyl)pyrrolidine-3-yl]ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1- (2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N-{(2S,3R)-1-(bicyclo[1.1.1]pentan-1-carbonyl)-4,4-difluoro-2- [(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-((1S,3R)-3-fluorocyclobutan-1-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl [2-3-yl)methyl]pyrrolidine-3-yl}ethanesulfonamide, N-{(2S,3R)-4,4-difluoro-1-((1S,3R)-3-fluorocyclobutan-1-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}methanesulfonamide, N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-difluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-3-yl}-N,The method according to claim 26, selected from N-dimethyl sulfate diamide or a pharmaceutically acceptable salt thereof.

30. Use of orexin type 2 receptor agonists in the manufacture of drugs to improve respiratory function during sleep.

31. An orexin type 2 receptor agonist for use in improving respiratory function during sleep.

Images