Administration of orexin type 2 receptor agonists

Abstract

Disclosed is the use of orexin type 2 receptor (OX2R) agonists at non-wake concentrations. Also disclosed are compositions and methods for administering an OX2R agonist to a subject (e.g., a mammal) requiring such administration at a dose that keeps the plasma concentration of the OX2R agonist below the maximum non-wake plasma concentration of the OX2R agonist. Also disclosed are compositions and methods for treating narcolepsy type 1 (NT1) in a subject requiring such treatment by maintaining, after administration, the plasma concentration of the OX2R agonist below the maximum non-wake concentration of the OX2R agonist.

Description

[Background technology]

[0001] Narcolepsy is a severe neurological sleep disorder characterized by excessive daytime sleepiness (EDS). In some cases, narcolepsy may be accompanied by sudden loss of muscle tone and motor function (cataplexy). Narcolepsy with cataplexy is known as narcolepsy type 1 (NT1), while narcolepsy without cataplexy is known as narcolepsy type 2 (NT2). In addition to EDS and cataplexy, other symptoms include hypnagogic / wakefulness hallucinations, sleep paralysis, and nocturnal sleep disturbances (sleep fragmentation), which constitute the five symptoms of narcolepsy. There are few effective treatments for narcolepsy, and most address only one or two of the five symptoms. For example, stimulants (e.g., modafinil) may be used to treat EDS, antidepressants (e.g., clomipramine) may be used to treat cataplexy, and sodium oxybate and pitrisant may be used to treat both EDS and cataplexy. However, these drugs are known to have side effects such as insomnia, rebound symptoms, and the potential for drug abuse (Trends in Pharmacol. Sci., Vol. 27, No. 7, 368-374, (2006)).

[0002] Orexin (hypocretin) is a neuropeptide produced by specific neurons scattered throughout the lateral hypothalamus and surrounding regions, and consists of two subtypes: orexin A and orexin B. Both orexin A and orexin B are endogenous ligands for orexin receptors, which are G protein-coupled receptors mainly found in the brain. Two subtypes of orexin receptors are known: type 1 (OX1R) and type 2 (OX2R). Both orexin A and orexin B bind to OX2R with similar affinity (Cell, Vol. 92, 573-585, (1998)).

[0003] Orexin-producing neurons (orexin neurons) are localized near the feeding center, and since intravenous administration of orexin peptides increases food intake, orexin was initially noted as a neuropeptide involved in regulating feeding behavior. Subsequently, scientists reported that canine narcolepsy is caused by genetic mutations in the orexin 2 receptor (Cell, Vol. 98, 365-376, (1999)), and researchers focused on the role of orexin in regulating sleep and wakefulness. Other studies have shown that narcolepsy type 1 is associated with the irreversible loss of orexin-producing neurons, and therefore, agonists targeting the orexin 2 receptor (OX2R) are considered a promising treatment for NT1.

[0004] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice obtained by crossing these mice with transgenic mice overexpressing orexin demonstrated that sustained expression of orexin reduces narcolepsy-like symptoms caused by orexin neuron degeneration. Similarly, intracerebroventricular administration of orexin peptide to transgenic mice with degenerated orexin neurons also resulted in improvement of narcolepsy-like symptoms (Proc. Natl Acad. Sci. USA, Vol. 101, 4649-4654, (2004)). Studies using orexin type 2 receptor knockout mice suggest that OX2R is important for maintaining wakefulness (Cell, Vol. 98, 437-451, (1999), Neuron, Vol. 38, 715-730, (2003)). In summary, these studies suggest that orexin type 2 receptor agonists may be useful in treating narcolepsy or other sleep disorders characterized by excessive sleepiness (CNS Drugs, Vol. 27, 83-90, (2013), Ther. Adv. Neurol. Disord., Vol. .12,1-12,(2019)).

[0005] Numerous orexin type 2 receptor agonists have been proposed in this field (J.Med.Chem.No.58,7931-7937,(2015), Proc.Natl Acad.Sci.Vol.119,No.35,e2207531119,(2002), Ther.Adv.Neurol.Disord.,Vol.12,1-12,(2019)). To date, trials evaluating OX2R agonists for the treatment of narcolepsy have been designed to stimulate orexin type 2 receptors at dose levels sufficient to promote arousal or state of arousal in the subjects. In patients diagnosed with narcolepsy type 1, administration of wakefulness-promoting doses of OX2R agonists has been shown to improve daytime symptoms such as excessive sleepiness and cataplexy (J Sleep Res. 32(5):e13878.(2023), N Engl J Med. 389(4):309-321.(2023)). The administration of OX2R agonists at dose levels significantly lower than wakefulness-promoting dose levels (i.e., "low doses"), and the therapeutic effects of such low doses, are unknown. [Overview of the Initiative]

[0006] The present invention provides a method for treating narcolepsy type 1 in a person requiring treatment, the method comprising administering to the person a dosage form comprising an orexin type 2 receptor agonist, the dosage form thereby maintaining the plasma concentration of the agonist after administration at or below the maximum non-awake plasma concentration of the agonist over the administration interval.

[0007] One aspect of the present invention provides a method for achieving and maintaining a plasma concentration of an orexin type 2 receptor agonist after administration at a rate of 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 non-wake plasma concentration of the agonist over the dosing interval.

[0008] Another aspect of the present invention provides the above method, wherein the administration interval of the orexin type 2 receptor agonist is 1 day, 2 days, 1 week, 2 weeks, 4 weeks, 6 weeks, or 8 weeks.

[0009] Further aspects of the present invention provide the above method for improving nocturnal symptoms of one or more NT1s selected from sleep fragmentation, sleep paralysis and hallucinations, and for improving daytime symptoms of one or more NT1s selected from symptoms of wakefulness fragmentation and cataplexy.

[0010] Further aspects of the present invention provide the above method, wherein the dosage form includes a sustained-release formulation. The sustained-release formulation may be a depot formulation for subcutaneous administration of the OX2R agonist, or an infusion system designed to provide continuous subcutaneous delivery of the OX2R agonist.

[0011] Another aspect of the present invention provides the above method, wherein the plasma concentration of the orexin type 2 receptor agonist is selected as follows: i) To determine the non-awakened plasma concentration of orexin type 2 receptor agonists that do not induce an arousal response in humans, and ii) Determine the dose of orexin type 2 receptor agonist that yields a plasma concentration below the maximum non-awake plasma concentration. The arousal response can be determined by measuring the sleep latency of one or more subjects diagnosed with narcolepsy type 1.

[0012] A further aspect of the present invention provides the above method, wherein the plasma concentration of the orexin type 2 receptor agonist is selected as follows: i) To determine the maximum non-awakening concentration of orexin type 2 receptor agonists that do not induce an arousal response in humans. ii) determining the amount of OX2R agonist that yields the maximum non-wake concentration of the agonist, and iii) selecting a dose of the agonist that yields a level of the agonist that is below the maximum non-wake plasma concentration of the OX2R agonist. The arousal response can be determined by measuring the sleep latency of one or more subjects diagnosed with narcolepsy type 1.

[0013] A further aspect of the present invention is that 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)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, (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((3S,4R)-1-(5-fluoropyrimidine-2-yl)-3-methyl (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,3R,5S)-3-((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1) Octan-8-yl)-2-cyclopropylacetamide, (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-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)-cyclohexanacyclooctafan-5 3 -yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof, to provide the above method.

Brief Description of the Drawings

[0014] [Figure 1] Shows the time of the waking state detected by EEG / EMG recording in NT1 model mice after administration of Compound B. [Figure 2] Shows the plasma concentration over time in NT1 model mice after administration of Compound B. [Figure 3] Shows the time of the waking state detected by EEG / EMG recording in NT1 model mice after administration of Compound A. [Figure 4] Shows the plasma concentration over time in NT1 model mice after administration of Compound A. [Figure 5] Shows the time of the waking state detected by EEG / EMG recording in cynomolgus monkeys after administration of Compound A. [Figure 6] Shows the plasma concentration over time in cynomolgus monkeys after administration of Compound A. [Figure 7] Shows the plasma (BP) concentration over time of Compound A at a dose that gives a plasma (BP) concentration below the non-waking concentration. [Figure 8] Shows the sleep / wake state episodes observed in mice after administration of Compound A. [Figure 9]This shows the duration of wakefulness detected by EEG / EMG recordings in NT1 model mice after administration of compound D. [Figure 10] This shows the time course of BP concentration in NT1 model mice after administration of compound D. [Figure 11] This shows the time course of BP concentration of compound D at doses that yield BP concentrations below the non-awakened concentration. [Figure 12] This shows episodes of sleep / wake states observed in mice after administration of compound D. [Figure 13] This shows the duration of wakefulness detected by EEG / EMG recordings in NT1 model mice after administration of compound B. [Figure 14] This shows the time course of BP concentration in NT1 model mice after administration of compound B. [Figure 15] This shows the time course of BP concentration of compound B at doses that produce BP concentrations below the non-awakened concentration. [Figure 16] This shows episodes of sleep / wake states observed in mice after administration of compound B. [Figure 17] This shows the duration of wakefulness detected by EEG / EMG recordings in NT1 model mice after administration of compound E. [Figure 18] This shows the time course of BP concentration in NT1 model mice after administration of compound E. [Figure 19] This shows the time course of BP concentration of compound E at doses that produce BP concentrations below the non-awakened concentration. [Figure 20] This shows sleep / wake episodes observed in mice after administration of compound E. [Figure 21] This shows the duration of wakefulness detected by EEG / EMG recordings in NT1 model mice after administration of compound F. [Figure 22] This shows the time course of BP concentration in NT1 model mice after administration of compound F. [Figure 23] This shows the time course of BP concentration of compound F at doses that yield BP concentrations below the non-awakened concentration. [Figure 24]This shows episodes of sleep / wake states observed in mice after administration of compound F. [Modes for carrying out the invention]

[0015] The methods, compositions, and uses disclosed herein involve the use of OX2R agonists at non-awakened plasma concentrations.

[0016] Generally, when a pharmacological substance is administered to a subject, its plasma concentration temporarily increases, reaches a maximum concentration, and then decreases. Therefore, the efficacy of a substance generally depends on its plasma concentration. When an OX2R agonist is administered to promote awakening in a subject with NT1, the subject experiences critical awakening after the plasma concentration of the agonist exceeds the maximum non-awakening concentration, and then experiences full awakening when the concentration exceeds a certain threshold (awakening-promoting concentration). Certain OX2R agonists have been shown to have a potent effect on the awakened state in subjects with NT1 when the plasma concentration of the OX2R agonist exceeds the awakening-promoting concentration.

[0017] This invention relates to the use of orexin type 2 receptor (OX2R) agonists at non-awake concentrations in subjects (e.g., mammals). The invention also relates to a method for administering an OX2R agonist to subjects (e.g., mammals) requiring such an agonist at a dose that causes the plasma concentration of the agonist after administration to be below its maximum non-awake plasma concentration. The invention also relates to narcolepsy type 1 (NT1). The present invention relates to a method for treating narcolepsy type 1 (NT1) in subjects (e.g., mammals) requiring treatment, by maintaining the post-administered non-zero plasma concentration of the OX2R agonist below the maximum non-awake plasma concentration of the agonist over multiple dosing intervals (i.e., chronically). In some embodiments, the post-administered plasma concentration of the OX2R agonist is approximately 1 / 20 to approximately 1 / 1 of the maximum non-awake concentration of the agonist over the dosing intervals.

[0018] The present invention also relates to a dosage regimen for the treatment of NT1 in a subject (e.g., a mammal), comprising administering a first OX2R agonist in a dose sufficient to raise the plasma concentration of the OX2R agonist above the non-awakened plasma concentration, preferably above the awakening-promoting concentration, and administering a second OX2R agonist, which may be the same as or different from the first OX2R agonist, in a dose sufficient to raise the plasma concentration to or below the maximum non-awakened concentration.

[0019] As described above, current approaches to treating NT1 with OX2R agonists aim to induce and promote wakefulness in subjects with NT1, requiring doses to exceed the maximum non-wake plasma concentration and reach the wakefulness-promoting concentration. This invention focuses on the effects of OX2R agonists at non-wake plasma concentrations. Continuous or repeated administration of OX2R agonists at non-wake plasma concentrations unexpectedly improves multiple daytime and nocturnal symptoms in subjects with narcolepsy type 1. The use of the OX2R agonist of this invention is expected to provide new methods and strategies for treating NT1 and other sleep-related symptoms. Furthermore, the use of the OX2R agonist of this invention is expected to have fewer side effects compared to the use of the agonist at wakefulness-promoting concentrations.

[0020] In one embodiment, the methods, compositions and uses of the present disclosure may be used in [1] subjects (e.g., mammals) at plasma concentrations below the maximum non-wake plasma concentration of the orexin type 2 receptor agonist.

[0021] In another embodiment, the methods, compositions and uses of the present disclosure may be used in subjects (e.g., mammals) at doses that result in plasma concentrations below the maximum non-wake plasma concentration of the orexin type 2 receptor agonist.

[0022] In another embodiment, the methods, compositions and uses of the present disclosure may include a method comprising administering an OX2R agonist to a subject (e.g., a mammal) at a plasma concentration below the maximum non-wake plasma concentration of the orexin type 2 receptor agonist.

[0023] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method of administering an OX2R agonist to a subject (e.g., a mammal) at a dose that results in a plasma concentration below the maximum non-wake plasma concentration of the orexin type 2 receptor agonist.

[0024] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method for treating narcolepsy type 1 in a subject (e.g., a mammal). The method comprises administering to the subject an OX2R agonist in a dose that results in a plasma concentration below the maximum non-awake plasma concentration of orexin type 2 receptor agonist after administration.

[0025] In another embodiment, the methods, compositions and uses of the present disclosure may relate to methods for treating, in a subject (e.g., a mammal), episodes of excessive sleepiness and / or cataplexy during the active phase (generally daytime), and / or symptoms of sleep fragmentation and / or sleep paralysis / hallucinations during the sleep phase (generally nighttime). The method comprises administering to the subject an OX2R agonist in a dose that, after administration, results in a plasma concentration below the maximum non-wake plasma concentration of the orexin type 2 receptor agonist.

[0026] Excessive sleepiness can occur even in individuals who do not have an orexin deficiency. This disclosure also applies to the treatment of disorders, conditions, and / or symptoms of excessive sleepiness unrelated to decreased orexin levels.

[0027] In one embodiment, the methods, compositions and uses of the present disclosure may be used for the treatment of narcolepsy type 1 in a subject (e.g., a mammal) at a plasma concentration below the maximum non-awake plasma concentration of the orexin type 2 receptor agonist.

[0028] In one embodiment, the methods, compositions and uses of the present disclosure may be used in subjects (e.g., mammals) to treat symptoms of excessive sleepiness and / or cataplexy episodes during the active phase and / or sleep fragmentation and / or sleep paralysis / hallucinations in the active phase.

[0029] In one embodiment, the methods, compositions and uses of the present disclosure may relate to a method of administering the OX2R agonist to a subject (e.g., a mammal) for the treatment of narcolepsy type 1 in the subject, at a dose that results in a plasma concentration of the orexin type 2 receptor agonist below the maximum non-awake plasma concentration after administration.

[0030] In one embodiment, the methods, compositions and uses of the present disclosure may relate to a method of administering an orexin type 2 receptor agonist to a subject (e.g., a mammal) at a dose that, after administration, results in a plasma concentration of the orexin type 2 receptor agonist below the maximum non-wake plasma concentration of the agonist, for the treatment of symptoms of excessive sleepiness and / or cataplexy episodes during the active phase and / or sleep fragmentation and / or sleep paralysis / hallucinations in the subject.

[0031] In one embodiment, the methods, compositions and uses of the present disclosure may relate to the administration methods described in [9] or

[10] , wherein the orexin type 2 receptor agonist is administered in a sustained-release formulation.

[0032] In one embodiment, the methods, compositions and uses of the present disclosure may relate to the administration methods described in [9] or

[10] , wherein the orexin type 2 receptor agonist is administered in an oral formulation.

[0033] In embodiments, the methods, compositions and uses of the present disclosure may be intended for repeated or continuous use of the OX2R agonist at plasma concentrations below the maximum non-awake plasma concentration of the orexin type 2 receptor agonist in a subject (e.g., a mammal) for the treatment of narcolepsy type 1 in the subject.

[0034] In another embodiment, the methods, compositions and uses of the present disclosure may be intended for repeated or continuous use in a subject (e.g., a mammal) to treat symptoms of excessive sleepiness and / or cataplexy episodes during the active phase and / or sleep fragmentation and / or sleep paralysis / hallucinations in the subject, at plasma concentrations below the maximum non-wake plasma concentration of the orexin type 2 receptor agonist.

[0035] In embodiments, the methods, compositions and uses of the present disclosure may be applied to methods for treating narcolepsy type 1 in a person requiring treatment. The method comprises administering to the person a dosage form comprising an orexin type 2 receptor agonist, wherein the dosage form causes the plasma concentration of the OX2R agonist after administration to be less than or equal to the maximum non-awake plasma concentration of the agonist over the dosing interval.

[0036] In one embodiment, the method according to

[15] , wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches and maintains over the dosing interval about 5 percent to about 100 percent, about 10 percent to about 100 percent, about 15 percent to about 100 percent, about 20 percent to about 100 percent, about 30 percent to about 100 percent, or about 50 percent to about 100 percent of the maximum non-awakened plasma concentration of the agonist.

[0037] In one embodiment, the method according to

[15] , wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches and maintains approximately 33 percent to approximately 100 percent of the maximum non-awakened plasma concentration of the agonist over the dosing interval.

[0038] In one embodiment,

[18] the method according to any one of embodiments

[15] to

[17] , wherein the administration interval of the 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).

[0039] In one embodiment, the method according to

[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.

[0040] 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 non-awake plasma concentration of the orexin type 2 receptor agonist.

[0041] In one embodiment, the method according to

[15] , wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches its maximum non-wake concentration.

[0042] In one embodiment,

[22] the method according to any one of embodiments

[15] to

[21] , which improves one or more nocturnal symptoms selected from sleep fragmentation, sleep paralysis and hallucinations.

[0043] In one embodiment, the method according to any one of embodiments

[15] to

[21] , which improves one or more daytime symptoms selected from symptoms of awake state fragmentation and cataplexy.

[0044] 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 narcolepsy type 1.

[0045] In one embodiment, the method according to any one of embodiments

[15] to

[21] , which improves one or more nocturnal symptoms selected from sleep fragmentation, sleep paralysis and hallucinations, and one or more daytime symptoms selected from symptoms of wakefulness fragmentation and cataplexy.

[0046] In one embodiment,

[26] the method according to any one of embodiments

[15] to

[25] , wherein the orexin type 2 receptor agonist is administered to the human in a sustained-release formulation.

[0047] In one embodiment, the method according to

[26] , wherein the sustained-release formulation is a depot formulation for subcutaneous administration.

[0048] In one embodiment,

[28] the orexin type 2 receptor agonist is used in humans The method according to

[26] , administered by an infusion system designed to result in continuous subcutaneous delivery of the OX2R agonist.

[0049] In one embodiment, the method according to

[26] , wherein the orexin type 2 receptor agonist is a compound having a short half-life.

[0050] In one embodiment,

[30] 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)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, (R)-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,3R,5S)-3-((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1] Octan-8-yl)-2-cyclopropylacetamide, (R)-2-cyclopropyl-2-((1R,3S,5S)-3-((2S,4S)-1-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-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)-cyclohexanacyclooctafane-5 3 -yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof, the method according to any one of embodiments

[15] to

[29] .

[0051] In one embodiment,

[31] 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 or hydrate thereof, the method according to any one of embodiments

[15] to

[29] .

[0052] In one embodiment,

[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, the method according to any one of embodiments

[15] to

[29] .

[0053] In one embodiment,

[33] the method according to any one of the embodiments

[15] to

[29] , 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 or hydrate thereof.

[0054] In one embodiment,

[34] the method according to any one of the embodiments

[15] to

[29] , wherein the 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 pharmaceutically acceptable salts or hydrates thereof.

[0055] In one embodiment,

[35] the orexin type 2 receptor agonist is (R)-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,3R,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.

[0056] In one embodiment,

[36] the 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 the embodiments

[15] to

[29] , wherein the methanesulfonamide is -yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof.

[0057] 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 a non-awakened plasma concentration of the orexin type 2 receptor agonist that does not produce an arousal response in humans, and ii) determining a dose of the agonist that results in a plasma concentration less than or equal to the maximum non-awakened plasma concentration of the orexin type 2 agonist determined in i).

[0058] 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 non-awakening 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 yields the maximum non-awakening concentration of the OX2R agonist determined in i), and iii) selecting a dose of the agonist that yields a plasma concentration of the agonist that is less than or equal to the maximum non-awakening plasma concentration of the OX2R agonist.

[0059] In one embodiment, the method according to Embodiment

[37] or

[38] , wherein the arousal response may be determined by measuring sleep latency in one or more persons diagnosed with narcolepsy type 1.

[0060] In one embodiment, the method according to any one of embodiments

[15] to

[36] , wherein the plasma concentration of the orexin type 2 receptor agonist is selected from concentrations less than or equal to the maximum plasma concentration of the orexin type 2 receptor agonist that does not induce an arousal response in humans.

[0061] In another embodiment, the methods, compositions and uses of the present disclosure may be used in humans,

[41] in combination with an orexin type 2 receptor agonist at a plasma concentration less than or equal to the maximum non-awake plasma concentration of the agonist, and with a further orexin type 2 receptor agonist at a plasma concentration exceeding the maximum non-awake plasma concentration of the further OX2R agonist.

[0062] In one embodiment, the methods, compositions and uses of the present disclosure may be for a method of treating narcolepsy type 1 in a subject (e.g., a mammal). The method includes: i) acute treatment of NT1 symptoms by administering to the subject an orexin type 2 receptor agonist at a plasma concentration exceeding the maximum non-awake concentration of the OX2R agonist; and ii) maintenance therapy thereafter administering to the subject repeatedly or consecutively with the OX2R agonist at a plasma concentration below the maximum non-awake concentration of the OX2R agonist.

[0063] In another embodiment, the methods, compositions and uses of the present disclosure are described in

[43] WO2019 / 027058, WO2017 / 135306, WO2020 / 158958, WO2021 / 107023, WO2022 / 014680, WO2020 / 167701, WO2020 / 167706, WO2021 / 026047, WO2022 / 040070 The target may be 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.

[0064] In another embodiment, the methods, compositions and uses of the present disclosure may relate to pharmaceutical compositions comprising an orexin type 2 receptor agonist in doses that result in a plasma concentration of the agonist at or below the maximum non-wake plasma concentration over a

[44] administration interval.

[0065] In one embodiment, the dose of the orexin type 2 receptor agonist described in

[45]

[44] results in a plasma concentration of about 1 / 20 or more of the maximum non-awake plasma concentration.

[0066] In one embodiment, the dose of the orexin type 2 receptor agonist described in

[46]

[44] results in a plasma concentration of about 1 / 10 or more of the maximum non-awake plasma concentration.

[0067] In one embodiment, the dose of the orexin type 2 receptor agonist described in

[47]

[44] results in a plasma concentration of about 1 / 5 or more of the maximum non-awake plasma concentration.

[0068] In one embodiment, the dose of the orexin type 2 receptor agonist described in

[48]

[44] results in a plasma concentration of about one-third or more of the maximum non-awake plasma concentration.

[0069] In one embodiment, the dose of the orexin type 2 receptor agonist described in

[49]

[44] results in a plasma concentration of about half or more of the maximum non-awake plasma concentration.

[0070] In one embodiment, the dose of the orexin type 2 receptor agonist described in

[50]

[44] results in a plasma concentration approximately equal to or greater than the maximum non-awake plasma concentration.

[0071] In one embodiment, the methods, compositions and uses of the present disclosure may be for doses ranging from about 1 mg to about 5 mg of an orexin type 2 receptor agonist for administration to humans.

[0072] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method for administering a

[52] orexin type 2 receptor agonist to a mammal in need thereof. The method includes maintaining the mean plasma concentration of the agonist in the mammal above 0 ng / mL, but below about 100 ng / mL, below about 50 ng / mL, below about 30 ng / mL, below about 10 ng / mL, below about 5 ng / mL, below about 3 ng / mL, or below about 1 ng / mL, over the course of the administration interval.

[0073] Another aspect of the present invention relates to a method for producing a therapeutic dosage form for a person requiring treatment of

[53] NT1, the dosage form comprising about 1 mg to about 5 mg of an orexin type 2 receptor agonist, the dosage form being a sustained-release formulation for infusion.

[0074] Another aspect of the present invention relates to the use of an orexin type 2 receptor agonist in the manufacture of a therapeutic dosage form for a person requiring treatment of

[54] NT1, wherein the agonist yields a plasma concentration below the maximum non-wake concentration of the agonist after administration, and the dosage form is a sustained-release formulation for infusion.

[0075] In one embodiment of use described in

[54]

[55] , the amount of the orexin type 2 receptor agonist in the dosage form is about 1 mg to about 5 mg.

[0076] In another embodiment, the methods, compositions and uses of the present disclosure may relate to pharmaceutical compositions comprising a

[56] orexin type 2 receptor agonist in a dose that, after administration, results in a plasma concentration below the maximum non-awakened plasma concentration in a subject (i.e., a mammal).

[0077] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method of treating a person requiring treatment for narcolepsy type 1 by administering a

[57] orexin type 2 receptor agonist. The method comprises i) obtaining a maximum non-awake plasma concentration of the agonist in the person, ii) selecting a dose of the agonist that yields a plasma concentration less than or equal to the maximum non-awake plasma concentration in the person, and iii) administering the dose of the agonist selected in ii) to the person repeatedly or consecutively.

[0078] In another embodiment, the methods, compositions and uses of the present disclosure may relate to a method of treating a person requiring treatment for narcolepsy type 1 by administering a

[58] orexin type 2 receptor agonist. The method comprises i) obtaining a maximum non-awake plasma concentration of the agonist in the person, ii) selecting a plasma concentration less than or equal to the maximum non-awake plasma concentration in the person, and iii) administering the agonist to the person repeatedly or consecutively at a dose that gives the plasma concentration selected in ii).

[0079] 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 narcolepsy type 1 (NT1) in a person requiring treatment, comprising

[59] orexin type 2 receptor agonist. The method comprises i) determining the maximum non-awake concentration of orexin type 2 receptor agonist in a person with NT1; ii) selecting a dose of the agonist that yields a plasma concentration less than or equal to the maximum non-awake plasma concentration in a person with NT1; and iii) formulating the pharmaceutical composition by mixing a unit dose of the agonist with a pharmaceutically acceptable carrier.

[0080] In another embodiment, the methods, compositions and uses disclosed herein are used in patients with

[60] NT1 This may be used for the purposes described in [1], as it reduces dark-phase sleep fragmentation by approximately 10% to 20%.

[0081] In another embodiment, the methods, compositions and uses described herein may be intended for use as described in [1], for reducing light-phase cataplexy-like symptoms by about 15% to about 50% in patients with

[61] NT1.

[0082] Method and Use The methods and uses disclosed herein may treat narcolepsy type 1 in subjects requiring treatment. The methods and uses disclosed herein may also treat symptoms such as excessive daytime sleepiness (EDS), cataplexy, hypnagogic / wakefulness hallucinations, sleep paralysis, and nocturnal sleep disturbances (sleep fragmentation). In some embodiments, treatment of narcolepsy type 1 may include reducing or alleviating one or more symptoms of narcolepsy type 1. These one or more symptoms of narcolepsy type 1 may be selected from excessive daytime sleepiness (EDS), cataplexy, hypnagogic / wakefulness hallucinations, sleep paralysis, and nocturnal sleep disturbances (sleep fragmentation). In some embodiments, these one or more symptoms of narcolepsy type 1 may be selected from excessive daytime sleepiness (EDS), active phase cataplexy (including cataplexy-like symptoms), and sleep phase sleep fragmentation. The methods and uses disclosed herein may also treat comorbidities of narcolepsy type 1, such as obesity, type 2 diabetes, cardiovascular disease, sleep apnea, mood disorders, anxiety, attention deficit hyperactivity disorder (ADHD), restless legs syndrome, and parasomnias. Narcolepsy can be diagnosed by commonly used diagnostic criteria in the field, such as the International Classification of Sleep Disorders, Third Edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (Current Medical Research and Opinion, 32:10, 1611-1622, (2016)). Furthermore, nocturnal sleep can be improved, for example, by reducing the number of arousal events in the sleep-wake cycle.

[0083] The methods and uses disclosed herein may increase active arousal, and / or reduce excessive sleepiness, and / or treat it, and / or reduce the occurrence of cataplexy episodes, in subjects requiring it. In some embodiments, excessive sleepiness as used herein is also known as excessive daytime sleepiness (EDS) or excessive need for sleep (ENS). The methods and uses disclosed herein may also reduce sleep fragmentation of the sleep phase and / or reduce the occurrence of sleep paralysis / hallucinations. In some embodiments, arousal, excessive sleepiness, symptoms of cataplexy, sleep fragmentation, and / or sleep paralysis / hallucinations are determined by known methods, for example, using any one or more of the following: electroencephalography (EEG), electromyography (EMG), maintenance of wakefulness 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, a decrease in wakefulness and / or sleepiness is assessed 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. MSLT and polysomnography have been used to assess sleep in patients with potential narcolepsy, and several electrophysiological features appearing in NT1 patients have been previously reported (Nat Rev Dis Primers). 3,16100 (2017). In some embodiments, treatment of excessive daytime sleepiness may include reducing or alleviating one or more symptoms of excessive daytime sleepiness. The one or more symptoms of excessive daytime sleepiness may be selected from sleepiness, weakness, irritability, fatigue, and lethargy.

[0084] In some embodiments, the subject has a disease, disorder, or condition related to excessive sleepiness. In some embodiments, the subject is sleep-deprived, has excessive sleepiness, has a disrupted sleep-wake cycle, or needs to reduce sleepiness.

[0085] definition Unless otherwise defined, all technical and scientific terms used herein have meanings that are generally understood by those skilled in the art in which this disclosure pertains. The following references provide general definitions of many terms used in this invention: 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 y of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used in the present invention, the following terms have the meanings of those below unless otherwise specified. The terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the present disclosure.

[0086] As used herein, the singular forms "a," "an," and "the" are intended to include the plural form unless the context clearly indicates otherwise.

[0087] As used herein, the terms “about” or “approximately” mean within an acceptable margin of error of a particular value as determined by those skilled in the art, which 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 standard deviation of 3 or less or greater than 3, according to convention in the art. Alternatively, “about” may mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within one order of magnitude, up to five times, or up to two times the value.

[0088] 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 can be carried out by any suitable parenteral route, including but not limited to intravenous, intramuscular, intraperitoneal, subcutaneous, and other suitable routes described herein. Administration includes self-administration and administration by another person. Administration of OX2R agonists for therapeutic purposes in this invention is generally long-term, continuous, chronic, and / or repetitive. “Post-administration” of an OX2R agonist in this invention means a period of time that has elapsed since the OX2R agonist was administered to the subject. Typically, this means about 24 to about 48 hours after the initial administration.

[0089] As used herein, the terms “dosage form” or “pharmaceutical composition” mean a composition comprising a drug molecule. Examples of such dosage forms include oral preparations, e.g., 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), and parenteral preparations, e.g., 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 the present invention are each administered orally or parenterally. These formulations can be safely administered orally (e.g., rectally, intravenously, intra-arterially, intramuscularly, subcutaneously, intra-organally, intranasally, intradermally, intra-dermally, intra-infusionally, intracerebrally, intravaginally, intraperitoneally, intratumorally, proximal tumorly, and to lesions). These formulations may be controlled-release formulations (e.g., sustained-release microcapsules), such as immediate-release formulations or sustained-release formulations.

[0090] 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 the context of therapeutic use, the amount of compound administered to a subject may depend on the type and severity of the disease or symptom, as well as individual characteristics such as overall health, age, sex, weight, and tolerance to the drug. Those skilled in the art will be able to determine an appropriate dose in accordance with these and other factors.

[0091] 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%.

[0092] As used herein, the term “increase” means a positive change of at least about 5%, including, but not limited to, a positive change of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0093] As used herein, the term “reduce” means to change to a negative value of at least about 5%, including, but not limited to, changing to a negative value of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0094] 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 and orexin 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 danaborexton 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.

[0095] As used herein, the term “awakening” (including “awakening” in “awakening-promoting concentration”) means that the subject’s state is in a near-complete state of wakefulness, which is assessed by known measures such as the Maintenance of Wakefulness Test (MWT) and EEG / EMG recordings.

[0096] 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 invention, "post-administration plasma concentration" means the plasma concentration of the pharmaceutical substance at a point approximately 24 hours or more after administration of the pharmaceutical substance. "Average plasma concentration" means the average of the plasma concentrations at different points in time 24 hours or more after administration of the pharmaceutical to the subject.

[0097] As used herein, the terms “non-awakened plasma concentration” or “non-awakened concentration” refer to the plasma concentration of an orexin type 2 receptor agonist that does not induce awakening in a subject. Non-awakened 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. Of the non-awakened plasma concentrations, “maximum non-awakened plasma concentration” is the highest concentration above which a critical awakening effect occurs. The phrase “below the maximum non-awakened 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 non-awakened plasma concentration. In some embodiments, the plasma concentration of the OX2R agonist is below the maximum non-awakened plasma concentration of the agonist over the dosing interval in the subject, 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 non-awakened 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-awakened concentration of the agonist. In some embodiments, the mean plasma concentration of the OX2R agonist below the maximum non-awakened plasma concentration is approximately 1 / 60, 1 / 40, 1 / 36, 1 / 30, 1 / 20, or 1 / 10 of the awakening-promoting plasma concentration.

[0098] As used herein, the term “awakening-enhancing concentration” of an OX2R agonist refers to the critical plasma concentration of the agonist that elicits a near-complete awakening effect in a subject (i.e., maintenance of more than 75% awakening in a 10-minute vial). Certain OX2R agonists have been shown to elicit a potent awakening effect in NT1 subjects when the plasma concentration of the OX2R agonist exceeds its awakening-enhancing concentration. The awakening-enhancing concentration of an OX2R agonist is significantly higher than the maximum non-awakening concentration of the OX2R agonist.

[0099] Plasma concentrations can be determined by measurements known to those skilled in the art, including high-performance liquid chromatography-tandem mass spectrometry. These levels are typically expressed as ng / mL of the analyte. The maximum non-awakened and awakening-promoting concentrations of OX2R agonists 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 the maximum non-awakened or awakening-promoting concentrations of OX2R agonists in non-NT1 subjects, the measurement is performed at night, when the subject's auto-orexin A levels are generally low.

[0100] As used herein, the term “actigraphy” refers to a method of using a small, computerized, watch-like device to monitor and collect data generated by motion. Most actigraphs include analog systems for detecting motion. In some devices, a piezoelectric beam is used to detect motion.

[0101] 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. In one embodiment, the methods and uses disclosed herein may improve one or more nocturnal symptoms selected from sleep fragmentation, sleep paralysis, and hallucinations, and / or one or more daytime symptoms selected from wakefulness fragmentation and cataplexy. 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: MWT, MALT, EEG, or EMG, or by comparing the state of a subject administered a placebo with that of a subject administered an OX2R agonist. In one embodiment, the OX2R agonist of the present invention improves nocturnal sleep fragmentation in NT1 patients, as indicated by reducing the number of wakefulness episodes in the sleep phase (dark phase) by about 10% to about 20%, and / or increasing the duration of NREM sleep in the light phase by 10% to about 30%.

[0102] As used herein, the term “dosing interval” refers to the time between administrations of an OX2R agonist to a subject. The dosing interval of an OX2R agonist may depend, in ways known to those skilled in the art, on the pharmacokinetic profile of the OX2R agonist and on the dosage form of the OX2R agonist. If the dosage form is a sustained-release formulation for subcutaneous injection, preferred dosing intervals may, among other things, be once a week, once every two weeks, once every four weeks, once every six weeks, or once every eight weeks.

[0103] As used herein, the term “subject” refers to mammals, including humans, cattle, horses, dogs, cats, monkeys, mice, and rats, and preferably refers to humans.

[0104] As used herein, the term “medically acceptable” refers to a substance suitable for administration to a subject.

[0105] As used herein, the term “light phase” refers to the active phase or daytime in humans and monkeys, and to the sleep phase or nighttime in mice.

[0106] As used herein, the term “dark period” refers to the sleep phase or nighttime in humans and monkeys, and to the active period or daytime in mice.

[0107] The methods, compositions, and uses of the present invention are characterized in that the plasma concentration of an orexin type 2 receptor (OX2R) agonist in a subject is less than or equal to the maximum non-awakened plasma concentration of the agonist. In one embodiment, when an OX2R agonist is administered to a subject in need, 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 non-awakened plasma concentration of the agonist. By using certain formulations, such as intravenous and sustained-release formulations, the initial release of the OX2R agonist continues for about 24 to 48 hours after administration, and the plasma concentration of the OX2R agonist may exceed the maximum non-awakened concentration but not reach the arousal-promoting concentration. When the plasma concentration of the OX2R agonist is less than or equal to the maximum non-awakened concentration, it is greater than 0 (zero) and equal to or less than the maximum non-awakened 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-awakened concentration of the agonist.

[0108] In one embodiment, the OX2R agonist is administered to a subject over multiple dosing intervals for the treatment of NT1 and / or sleep-related symptoms, and throughout each dosing interval, the plasma concentration of the agonist is less than or equal to the maximum non-awake plasma concentration of the agonist. The terms “repeated,” “recurring,” “repeatedly,” “sequentially,” “continuously,” “chronic,” “chronically,” or “long-term” as used in this disclosure in relation to the administration of the OX2R agonist mean that the OX2R agonist is administered over multiple dosing intervals.

[0109] In one embodiment, the OX2R agonist is administered to a subject by repeated oral administration, by infusion, or by using a sustained-release formulation of the OX2R agonist. The appropriate formulation may be selected based on the characteristics of the OX2R agonist. Sustained-release formulations may be particularly useful for 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).

[0110] The dose of an OX2R agonist may be determined by i) identifying the maximum non-wake 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 non-wake 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 blood of the agonist is less than or equal to the maximum non-wake plasma concentration of the OX2R agonist in humans. The plasma concentrations are 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. In some embodiments, the dose of the agonist that yields a plasma concentration below the maximum non-wake 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.

[0111] Tests for increased alertness and / or reduced excessive sleepiness The methods and uses disclosed herein may treat narcolepsy type 1 in subjects requiring treatment. In some embodiments, treatment of narcolepsy type 1 may include reducing or alleviating one or more symptoms of narcolepsy type 1. The one or more symptoms of narcolepsy type 1 may be selected from excessive daytime sleepiness (EDS) and cataplexy. Narcolepsy may be diagnosed by diagnostic criteria commonly used in the art, such as the International Classification of Sleep Disorders, Third Edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Furthermore, nocturnal sleep is expected to be improved, for example, by reducing the number of arousal events in the sleep-wake cycle.

[0112] The methods and uses disclosed herein may increase alertness and / or reduce excessive sleepiness in subjects requiring such action. In some embodiments, the reduction in alertness and / or excessive sleepiness is determined by electroencephalography (EEG) and / or electromyography (EMG). These tests may also be used to identify the critical concentration for potent alertness and the non-alert concentration of a particular OX2R agonist. In some embodiments, the reduction in alertness and / or sleepiness is determined using a maintenance of alertness test (MWT) with 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 the Oxford sleep resistance test (OSLER). In some embodiments, the test may be the Karolinska sleepiness scale (KSS), the Epworth sleepiness scale (ESS), or the Stanford sleepiness scale.

[0113] In some embodiments, actigraphy can be used to test the effects of OX2R agonists on sleep and wake patterns. The term actigraphy refers to a method of using a small, computerized, watch-like device to monitor and collect motion-generated data. Most actigraphs include an analog system for detecting motion. Some devices use a piezoelectric beam to detect motion. See Sadeh et al., Sleep Medicine Reviews 6(2);113-124(2002).

[0114] The methods and uses disclosed herein may reduce excessive sleepiness or improve Karolinska Sleepiness Scale (KSS) scores in subjects requiring them. In some embodiments, the KSS score improves to a score of 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.

[0115] The methods and uses disclosed herein may include performing one or more tests to quantify the sleepiness of a subject. In some embodiments, the test is 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 test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, the Uranlinna Narcolepsy Scale (UNS), and the Work Limit The tests used are the WS Questionnaire (WLQ), SF-8 (a subset of the SF-36 questionnaire), or a combination of these tests.

[0116] Method of administration The methods and uses disclosed herein involve administering an OX2R agonist to a subject requiring it. In some embodiments, the OX2R agonist is administered orally. In some embodiments, the OX2R agonist is administered parenterally. In some embodiments, the parenteral administration is intravenous, subcutaneous, transdermal, intradermal, or transmucosal. In some embodiments, the parenteral administration is intravenous. In some embodiments, the parenteral administration is subcutaneous.

[0117] Dosage forms and delivery devices for specific routes are described in more detail below.

[0118] In some embodiments, the plasma concentration of the OX2R agonist represents the mean plasma concentration of the treated subject group, and the period of one hour or more is started at any point after administration. Plasma concentrations of individually treated subjects may deviate from the condition as long as the mean plasma concentration of the treated subject group satisfies the condition of "approximately XX ng / mL or more over a period of approximately one hour or more."

[0119] Frequency of administration The OX2R agonist of the present invention is used and administered over multiple dosing intervals. In some embodiments, the OX2R agonist of the present invention may be administered once daily, every other day, once weekly, twice weekly, once every two weeks, monthly, or once every two months.

[0120] Combination therapy The present invention may further include a combination of administering an OX2R agonist at a dose below the maximum non-awake plasma concentration and administering a further OX2R agonist at a dose that induces an awake plasma concentration. The further OX2R agonist and the OX2R agonist may be different or the same. In this treatment, the further OX2R agonist is administered to the subject as needed to provide acute treatment for NT1 symptoms, followed by administration of the OX2R agonist for maintenance therapy. There may be an administration interval of 1 to 5 days between the administrations of the two OX2R agonists, depending on the clearance profile of the further OX2R agonist.

[0121] OX2R agonist OX2R agonists useful in the methods, uses, or compositions of the present invention are chemical molecules (compounds) having OX2R agonist activity. Such compounds may be selected from known compounds or from newly designed / synthesized compounds. Compounds 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) are particularly useful when formulated as sustained-release formulations.

[0122] 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 and its pharmaceutically acceptable salts and hydrates (also referred to herein as Compound A). Compound A is described in WO2019 / 027058.

[0123] Another useful OX2R agonist is methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate and its pharmaceutically acceptable salts and hydrates (also known herein as Compound B or danaborexton). Compound B is classified under WO2017 / 13. It is described in 5306.

[0124] Another useful OX2R agonist is N-((2S,3S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-3-yl)ethanesulfonamide and its pharmaceutically acceptable salts and hydrates (also referred to herein as Compound C). Compound C is described in WO2019 / 027058.

[0125] 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 and its pharmaceutically acceptable salts and hydrates (also referred to herein as Compound D). Compound D is described in WO2020 / 158958.

[0126] Useful OX2R agonists include JZP441 / DSP-0187, ALKS2680, and E2086.

[0127] Useful OX2R agonists are described in PCT Publication Application WO2021 / 107023, which is incorporated herein by reference in whole, 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 (I):

[0128] [ka]

[0129] 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 (II):

[0130] [ka]

[0131] Useful OX2R agonists are described in PCT Publication Application WO2022 / 014680, which is incorporated herein by reference in whole, and comprises the following compounds and their pharmaceutically acceptable salts and hydrates: (R)-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 (III):

[0132] [ka]

[0133] (Also referred to as compound F in this specification), (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 (IV):

[0134] [ka]

[0135] (R)-2-((1R,3R,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 (V):

[0136] [ka]

[0137] 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 (VI):

[0138] [ka]

[0139] 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 as a whole.

[0140] Useful OX2R agonists are described in PCT publication applications WO2022 / 051583 and WO2022 / 051596, which are incorporated herein by reference as a whole.

[0141] Useful OX2R agonists are described in PCT Publication Application WO2021 / 108628, which is incorporated herein by reference in whole and comprises the following compounds represented by formula IA, as well as pharmaceutically acceptable salts and hydrates thereof:

[0142] [ka]

[0143] 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 10The 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 13 These 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.

[0144] An example of a suitable OX2R agonist listed in WO2019 / 027058 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 -yl)methanesulfonamide:

[0145] [ka]

[0146] or a pharmaceutically acceptable salt thereof (also referred to herein as compound E), and N-((2 represented by the following formula (VIII) 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)methanesulfonamide:

[0147] [ka]

[0148] This includes pharmaceutically acceptable salts or hydrates thereof.

[0149] The OX2R agonist may exist as a pharmaceutically acceptable salt. 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.

[0150] The OX2R agonist may exist as a hydrate, a nonhydrate, a nonsolvate (e.g., an anhydrous), or a solvate (e.g., a hydrate).

[0151] Furthermore, the OX2R agonist exists as a pharmaceutically acceptable cocrystal or cocrystal salt. This is possible. The cocrystal or cocrystalline salt refers to a crystalline substance composed of two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). The cocrystal or cocrystalline salt can be produced by known methods.

[0152] 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 the pharmaceutically acceptable carrier. 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.

[0153] 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.

[0154] 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.

[0155] 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 non-wake plasma concentration.

[0156] In some embodiments, the pharmaceutical composition yields mean plasma concentrations of 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, or approximately 1 ng / mL to approximately 30 ng / mL after administration of the OX2R agonist. [Examples]

[0157] The following non-limiting examples will provide to those skilled in the art a complete disclosure and description 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.

[0158] Example 1: Identification of plasma concentrations of OX2R agonists that promote wakefulness in NT1 model mice.

[0159] Orexin / ataxin-3 mice in a C57BL / 6J background (Neuron, 30(2), 345-54, (2001)) were provided by the University of Tsukuba. The mice were housed under laboratory conditions (12-hour light / dark cycle). Electroencephalogram (EEG) and electromyogram (EMG) electrode implantation and EEG / EMG recording were performed as previously described (Pharmacol. Biochem. Behav., (2019) 187, 172794). Compound B (1 mg / kg with a volume of 10 mL / kg body weight) was suspended in physiological saline containing 0.5% (w / v) methylcellulose (MC) and administered subcutaneously to mice at a Zeitgeber time (ZT) of 12 or ZT5 (start of the illumination period being ZT0). EEG / EMG was recorded using VitalRecorder (Kissei Comtec Co. Ltd, Nagano, Japan), and spontaneous movement was measured using an infrared activity sensor (Biotex, Kyoto, Japan). Sleep / wake states were classified every 4 seconds using SleepSign (Kissei Comtec). Each stage was characterized as follows: (1) wakeful state, low amplitude EEG and high voltage EMG activity or moving movement score, (2) NREM sleep, high amplitude slow wave EEG and low voltage EMG activity, and (3) REM sleep, theta-dominant EEG and EMG atonia. A total of 4-5 animals were used.

[0160] After oral administration of compound B at a dose of 1 mg / kg, blood samples were collected from the tail vein of C57BL / 6J mice at 0.25, 0.5, 1, 2, and 4 hours. Plasma was separated from these blood samples by centrifugation. The concentration of compound B in the plasma was quantified by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS).

[0161] As shown in Figure 1, compound B induced strong awakening (defined as maintaining more than 75% of an awakened state in a 10-minute vial) up to 70 and 90 minutes post-administration during the dark period (administered at ZT12) (Figure 1 left) and the light period (administered at ZT5) (Figure 1 right), respectively. From Figure 2, this shows the plasma concentration of compound B over time, and the awakening-promoting concentration of compound B in mice was estimated to be approximately 20–40 ng / mL.

[0162] Example 2: Identification of non-awakened plasma concentrations of OX2R agonists in NT1 model mice.

[0163] These experiments were performed using male orexin-tTA;TetO DTA mice (J Neurosci., 34(19), 6495-509, (2014)). Orexin-tTA mice with a C57BL / 6J genetic background were obtained from Nagoya University. Orexin-tTA mice were crossed with TetO diphtheria toxin A(DTA) mice (B6.Cg-Tg(tetO-DTA)1Gfi / J, The Jackson Laboratory, Bar Harbor, ME, USA) to produce orexin-tTA;TetO DTA mice. Mice were housed under laboratory conditions (12-hour light / dark cycle). Implantation of electroencephalogram (EEG) and electromyogram (EMG) electrodes and EEG / EMG recording were performed as previously described (Pharmacol. Biochem. Behav., (2019) 187, 172794). The effects of compound A on the sleep / wake state of mice were evaluated using a crossover design. Compound A (1, 3, or 10 mg / kg, with a volume of 10 mL / kg body weight) was suspended in distilled water containing 0.5% (w / v) methylcellulose (MC) (Fujifilm Wako pure chemical Co., Osaka, Japan) and administered orally to mice at a Zeitgeber time (ZT) of 5 (the start of the illumination period was ZT0). EEG / EMG was recorded using VitalRecorder (Kissei Comtec Co, Ltd, Nagano, Japan), and spontaneous movement was measured using an infrared activity sensor (Biotex, Kyoto, Japan). Sleep / wake states were classified every 4 seconds using SleepSign (Kissei Comtec). Each stage was characterized as follows: (1) wakefulness, low-amplitude EEG and high-voltage EMG activity or moving motion score; (2) NREM sleep, high-amplitude slow-wave EEG and low-voltage EMG activity; and (3) REM sleep, theta-dominant EEG and EMG atonia. A total of eight animals were used. The results are shown in Figure 3.

[0164] After oral administration of compound A at 1 and 10 mg / kg, blood samples were collected from the tail veins of mice at 0.25, 0.5, 1, 1.5, 2, 3, 4, and 8 hours. Plasma was separated from these blood samples by centrifugation. The concentration of compound A in the plasma was determined by high-performance liquid chromatography. The results were quantified by tandem mass spectrometry (HPLC-MS). The results are shown in Figure 4.

[0165] The minimum effective dose of compound A required to induce awakening (defined as maintaining a state of wakefulness exceeding 75% in a 10-minute vial) was 10 mg / kg. The plasma concentration of compound A at 10 mg / kg at the last time point in time when compound A induced strong awakening (110 minutes after administration) was 1128.9 ng / mL (Figure 4). The peak plasma concentration at which compound A at 1 mg / kg produced almost no awakening-promoting effect was 371.6 ng / mL (Figure 4). Therefore, the difference between the awakening-promoting plasma concentration and the non-awakening plasma concentration was identified as 3.04 times (approximately 3 times).

[0166] Example 3: Identification of non-awakened plasma concentrations of OX2R agonists in monkeys.

[0167] Male cynomolgus monkeys (Macaca fascicularis) implanted with wireless telemetry transmitters (TL10M3-D70-EEE, Data Sciences International Inc., MN, USA) were obtained from Hamuri Co., Ltd. (Ibaraki, Japan). The monkeys were housed under laboratory conditions (12-hour light / dark cycle). The effects of compound A on sleep / wake states were evaluated in a crossover design. Compound A was suspended in distilled water containing 0.5% (w / v) methylcellulose (MC) (Fujifilm Wako pure chemical Co., Osaka, Japan) and orally administered to the monkeys at a Zeitgeber time (ZT) of 12 (start of the light-on period at ZT12) (3, 10 kg / mg in volume of 5 mL / kg body weight). Compound A at 3 mg / kg was selected as the dose that yielded the potential maximum non-wake concentration of compound A. Cortical electroencephalography (EEG), electromyography (EMG), and spontaneous movement were recorded using Dataquest ART software (Data Sciences International Inc.). Sleep / wake states were classified every 20 seconds using SleepSign (Kissei Comtec). Wakefulness was determined by the presence of spontaneous movement and / or EMG signals in the absence of high-amplitude slow-wave EEG. A total of eight animals were used.

[0168] After oral administration of compound A at doses of 3 and 10 mg / kg, blood samples were collected from three monkeys at 0.25, 0.5, 1, 2, 4, 6, and 8 hours. Plasma was separated from these blood samples by centrifugation. The concentration of compound A in the plasma was quantified by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS).

[0169] C max and its vicinity (approximately 1 hour after administration) and T maxCompound A at a dose of 3 mg / kg approximately 1 hour before / after the specified time did not induce an awakening effect in these monkeys (Figure 5). Compound A induced awakening (defined as maintaining more than 75% awakening in a 1-hour vial) for up to approximately 3.5 hours after oral administration of 10 mg / kg. The plasma concentration of compound A at 3.5 hours post-administration was approximately 654.7 ng / mL (Figure 6). The Cmax at the non-awakened dose (3 mg / kg) was approximately 235 ng / mL (Figure 6). Therefore, the potential difference between the awakening-promoting plasma concentration and the maximum non-awakened plasma concentration was more than 2.79 times (approximately 3 times).

[0170] Example 4: Identification of awakening-promoting plasma concentrations and maximum non-awakening concentrations of OX2R agonists in humans.

[0171] In a Phase I single-dose escalation-dose (SRD) study evaluating the efficacy of compound B for daytime sleepiness in patients with narcolepsy type 1 (NT1), administration of compound B at doses of 11.2 mg or higher resulted in near-complete wakefulness during a wakefulness maintenance test (MWT) conducted using a 40-minute protocol (MWT40) (Proc. Natl Acad. Sci. USA., 119(35), e2207531119, (2022)). Therefore, the wakefulness-promoting plasma concentration of compound B in NT1 patients was determined to be around 20 ng / mL, which is the mean plasma exposure level of compound B at 11.2 mg (Proc. Natl Acad. Sci. USA.). ,119(35),e2207531119,(2022)).

[0172] The maximum non-awakened dose of compound B in NT1 patients was selected to be approximately 7 ng / mL, which is about one-third of the awakening-promoting concentration (20 ng / mL).

[0173] Example 5: Efficacy of OX2R agonists at plasma concentrations below non-awakened levels

[0174] These experiments were performed using male orexin-tTA;TetO DTA mice (J Neurosci., 34(19), 6495-509, (2014)). Orexin-tTA mice with a C57BL / 6J genetic background were obtained from Nagoya University. Orexin-tTA mice were crossed with TetO diphtheria toxin A(DTA) mice (B6.Cg-Tg(tetO-DTA)1Gfi / J, The Jackson Laboratory, Bar Harbor, ME, USA) to produce orexin-tTA;TetO DTA mice. Mice were housed under laboratory conditions (12-hour light / dark cycle). Implantation of electroencephalogram (EEG) and electromyogram (EMG) electrodes and EEG / EMG recording were performed as previously described (Pharmacol. Biochem. Behav., (2019) 187, 172794). The effects of compound A on the sleep / wake state of mice were evaluated using a crossover design.

[0175] Administration by injection of compound A

[0176] Compound A was dissolved in distilled water containing 40% captisol / 0.1% polysorbate 80 at concentrations of 7.5 mg / mL (dose 1) and 17.5 mg / mL (dose 2), and packed into Alzet osmotic pumps (Alzet Model 2002, Muromachi). These pumps were immersed in 0.9% physiological saline and incubated at 37°C for at least 16 hours before being implanted in mice. The pumps were inserted through a small incision made in the skin at the back of the mouse's neck. Plasma samples were collected on days 1, 4, 7, and 15 after pump implantation, and the concentration of compound A in the plasma was quantified by high-performance liquid chromatography-tandem mass spectrometry.

[0177] Plasma concentrations of compound A were maintained at approximately 90 ng / mL (dose 1) and 320 ng / mL (dose 2) from 7 to 15 days after pump implantation. This corresponds to 1 / 5 (dose 1) and the same amount (dose 2) of the maximum non-awake plasma concentration. The results are shown in Figure 7.

[0178] EEG analysis

[0179] This experiment consisted of four groups: wild-type (WT) mice (also called Non-Tg) administered the medium (with a pump filled with the medium implanted), orexin-tTA;TetO DTA mice administered the medium, and orexin-tTA;TetO DTA mice (also called Tg) administered compound A at doses 1 and 2. The compound was administered by infusion using the osmotic pump described above. Sleep stages were analyzed by EEG / EMG recording 14 days after pump implantation. Using SleepSign (Kissei Comtec), sleep / wake states were classified every 4 seconds as wakefulness, non-REM (NREM) sleep, or REM (REM) sleep, and the total time, number of episodes, and duration of each sleep stage were calculated. Effects between dark and light phases were analyzed in 12-hour bins. The scores of WT mice administered the medium or orexin-tTA;TetO DTA mice administered compound A (dose 1 or dose 2) were compared with those of orexin-tTA;TetO DTA mice administered the medium using Dunnett's multiple comparison test. A total of 14 to 16 mice were used in each treatment group.

[0180] As shown in Figure 8, orexin-tTA;TetO DTA mice administered the medium, Compared to WT mice administered the medium, these mice showed significantly increased daytime wakefulness fragmentation and significantly increased nocturnal sleep fragmentation, indicated by an increase in the number of wakefulness episodes and a decrease in episode duration during the dark phase, as well as an increase in the number of NREM sleep episodes and a decrease in episode duration during the light phase. When compound A was administered to orexin-tTA;TetO DTA mice at two different plasma concentrations (dose 1: approximately 90 ng / mL, dose 2: approximately 320 ng / mL), compared to orexin-tTA;TetO DTA mice administered the medium, the number of wakefulness episodes during the dark phase decreased significantly, and their duration increased significantly, as did the number of NREM sleep episodes during the light phase.

[0181] Direct transition from wakefulness to REM sleep (DREM) is considered a mouse analogue of human cataplexy (Exp. Neurol., 217(1):46-54, (2009)). DREM was analyzed as previously described (Proc. Natl Acad. Sci USA., 119(35):e2207531119, (2022)). Briefly, DREM was defined according to the criteria of a sudden EMG atonia episode lasting more than 20 seconds, lack of spontaneous movement, dominance of theta EEG activity, and wakefulness lasting more than 40 seconds prior to the episode. Orexin-tTA;TetO DTA mice administered a dose of compound A that resulted in plasma concentrations below non-wake plasma concentrations after administration had a significantly lower mean number of DREM episodes during the dark and light phases compared to orexin-tTA;TetO DTA mice administered the medium. Therefore, the doses of these compounds A improved cataplexy symptoms in orexin-tTA;TetO DTA mice during both the dark and light phases.

[0182] Example 6: Efficacy of OX2R agonists at non-wake plasma concentrations

[0183] The efficacy of compound D at doses that yield plasma concentrations of compound D below the non-awakened concentration was evaluated using orexin-tTA;TetO DTA mice in the same manner as described in Example 5. To determine the non-awakened dose of compound D, compound D (0.1, 0.3, and 1 mg / kg at a volume of 10 mL / kg body weight) was suspended in distilled water containing 0.5% (w / v) methylcellulose (MC) (Fujifilm Wako pure chemical Co., Osaka, Japan) and orally administered to mice at ZT5. From this study, the maximum non-awakened dose was determined to be 0.1 mg / kg (Figure 9).

[0184] After orally administering compound D at 0.1 mg / kg, blood samples were collected from the tail veins of mice at 0.25, 0.5, 1, 2, 4, and 7 hours. The Cmax at 0.1 mg / kg was determined to be approximately 83.7 ng / mL (Figure 10).

[0185] Administration by injection of compound D

[0186] Compound D was dissolved at a concentration of 2 mg / mL in distilled water containing 20% ​​captisol / 0.1% polysorbate 80 and packed into Alzet osmotic pumps (Alzet Model 2004, Muromachi). These pumps were immersed in 0.9% physiological saline and incubated at 37°C for at least 40 hours before being implanted in mice. The pumps were inserted through a small incision made in the skin at the back of the mouse's neck. Plasma samples were collected on days 1, 2, 5, 7, 14, 21, and 28 after pump implantation, and the concentration of compound D in the plasma was quantified by high-performance liquid chromatography-tandem mass spectrometry.

[0187] Plasma concentrations of compound D were maintained below non-wake levels (approximately 40 and 60 ng / mL) from 7 to 28 days after pump implantation (Figure 11).

[0188] EEG analysis

[0189] This experiment consisted of three groups: wild-type (WT) mice administered the medium (with a pump filled with the medium implanted), orexin-tTA;TetO DTA mice administered the medium, and orexin-tTA;TetO DTA mice injected with compound D. The scores of the WT mice administered the medium or the orexin-tTA;TetO DTA mice injected with compound D were compared with the orexin-tTA;TetO DTA mice administered the medium using Dunnett's multiple comparison test on day 28 of administration. A total of 8 to 12 mice were used in each administration group.

[0190] As shown in Figure 12, infusion of compound D at doses resulting in plasma concentrations below the maximum non-awake plasma concentration did not increase total wakefulness time during the dark / light phase. Orexin-tTA;TetO DTA mice administered with the medium showed significantly increased diurnal wakefulness fragmentation and significantly increased nocturnal sleep fragmentation compared to WT mice administered with the medium, which is indicated by an increase in the number of wakefulness episodes and a decrease in episode duration during the dark phase, as well as an increase in the number of NREM sleep episodes and a decrease in episode duration during the light phase. When compound D was infused into orexin-tTA;TetO DTA mice at doses below the maximum non-awake plasma concentration, the number of wakefulness episodes and their duration during the dark phase were significantly reduced and their duration prolonged, and the number of NREM sleep episodes and their duration prolonged during the light phase were significantly reduced and their duration prolonged, compared to orexin-tTA;TetO DTA mice administered with the medium. Orexin-tTA;TetO DTA mice administered compound D at concentrations below maximum non-awakened plasma levels had a significantly lower mean number of DREM episodes during the dark and light phases compared to orexin-tTA;TetO DTA mice administered the medium.

[0191] Example 7: Efficacy of OX2R agonists at plasma concentrations below non-awakened levels

[0192] The efficacy of compound B at doses that yield plasma concentrations of compound B below the non-awakened concentration was evaluated using orexin-tTA;TetO DTA mice in the same manner as described in Example 5. To determine the non-awakened dose of compound B, compound B (0.03, 0.1, and 0.3 mg / kg at a volume of 10 mL / kg body weight) was suspended in distilled water containing 10.5% (w / v) captisol / 1.5 mM Na2HPO4 and administered subcutaneously to mice at ZT5. From this study, the maximum non-awakened dose was determined to be 0.03 mg / kg (Figure 13).

[0193] After orally administering compound B at a dose of 0.03 mg / kg, blood samples were collected from the tail veins of mice at 0.25, 0.5, 1, 2, 4, and 8 hours. The Cmax at 0.03 mg / kg was determined to be approximately 7.2 ng / mL (Figure 14).

[0194] Administration by compound injection

[0195] Compound B was dissolved at a concentration of 1.3 mg / mL in distilled water containing 20% ​​captisol / 0.1% polysorbate 80 and packed into Alzet osmotic pumps (Alzet Model 2004, Muromachi). These pumps were immersed in 0.9% physiological saline and incubated at 37°C for at least 40 hours before being implanted in mice. The pumps were inserted through a small incision made in the skin at the back of the mouse's neck. Plasma samples were collected on days 1, 4, 7, 14, 21, and 28 after pump implantation, and the concentration of compound B in the plasma was quantified by high-performance liquid chromatography-tandem mass spectrometry.

[0196] Plasma concentrations of compound B on days 7, 14, 21, and 28 after pump implantation were maintained at doses below the non-awakened concentration from day 4 to day 28 after pump implantation (approximately 1.5 and 5 ng / mL) (Figure 15).

[0197] EEG analysis

[0198] This experiment consisted of three groups: wild-type (WT) mice administered the medium (with a pump filled with the medium implanted), orexin-tTA;TetO DTA mice administered the medium, and orexin-tTA;TetO DTA mice injected with compound B. The scores of the WT mice administered the medium or the orexin-tTA;TetO DTA mice injected with compound B were compared with the orexin-tTA;TetO DTA mice administered the medium using Dunnett's multiple comparison test on day 28 after administration. A total of 8 to 12 mice were used in each administration group.

[0199] Infusion of compound B at doses resulting in plasma concentrations below the maximum non-awake plasma concentration did not increase total wakefulness time during the dark / light phase. As shown in Figure 16, orexin-tTA;TetO DTA mice administered the medium showed significantly increased diurnal wakefulness fragmentation and significantly increased nocturnal sleep fragmentation compared to WT mice administered the medium, which is indicated by an increase in the number of wakefulness episodes and a decrease in episode duration during the dark phase, as well as an increase in the number of NREM sleep episodes and a decrease in episode duration during the light phase. When orexin-tTA;TetO DTA mice were infused with compound B at doses below the maximum non-awake plasma concentration, the number of wakefulness episodes and their duration during the dark phase were significantly reduced and their duration was extended, and the number of NREM sleep episodes and their duration were significantly reduced and their duration was extended during the light phase, compared to orexin-tTA;TetO DTA mice administered the medium. Orexin-tTA;TetO DTA mice administered compound B via infusion at concentrations below maximum non-awakened plasma levels had a significantly lower mean number of DREM episodes during the dark and light phases compared to orexin-tTA;TetO DTA mice administered the medium.

[0200] Example 8: Efficacy of OX2R agonists at plasma concentrations below non-awakened levels

[0201] The efficacy of compound E at doses that yield plasma concentrations of compound E below the non-awakened concentration was evaluated using orexin-tTA;TetO DTA mice in the same manner as described in Example 5. To determine the non-awakened dose of compound E, compound E (0.03, 0.1, and 0.3 mg / kg at a volume of 10 mL / kg body weight) was suspended in distilled water containing 0.5% (w / v) methylcellulose (MC) (Fujifilm Wako pure chemical Co., Osaka, Japan) and administered orally to mice at ZT5. From this study, the maximum non-awakened dose was determined to be 0.03 mg / kg (Figure 17).

[0202] After orally administering compound E at a dose of 0.03 mg / kg, blood samples were collected from the tail veins of mice at 0.25, 0.5, 1, 2, 4, and 8 hours. The Cmax at 0.03 mg / kg was determined to be approximately 2.9 ng / mL (Figure 18).

[0203] Administration by compound injection

[0204] Compound E was dissolved at a concentration of 1 mg / mL in distilled water containing 20% ​​captisol / 0.1% polysorbate 80 and packed into Alzet osmotic pumps (Alzet Model 2004, Muromachi). These pumps were immersed in 0.9% physiological saline and incubated at 37°C for at least 40 hours before being implanted in mice. The pumps were inserted through a small incision in the skin at the back of the mouse's neck. Plasma samples were collected on days 4, 7, 14, and 28 after pump implantation, and the concentration of compound E in the plasma was quantified by high-performance liquid chromatography-tandem mass spectrometry.

[0205] Plasma concentrations of compound E were maintained below the non-awake concentration on day 14 after pump implantation (1.9 ng / mL) (Figure 19).

[0206] EEG analysis

[0207] This experiment consisted of three groups: wild-type (WT) mice administered the medium (with a pump filled with the medium implanted), orexin-tTA;TetO DTA mice administered the medium, and orexin-tTA;TetO DTA mice injected with compound E. The scores of the WT mice administered the medium or the orexin-tTA;TetO DTA mice injected with compound E were compared with the orexin-tTA;TetO DTA mice administered the medium using Dunnett's multiple comparison test on day 14 after administration. A total of 8 to 12 mice were used in each administration group.

[0208] Infusion of compound E at doses resulting in plasma concentrations below the maximum non-awake plasma concentration did not increase total wakefulness time during the dark / light phase. As shown in Figure 20, orexin-tTA;TetO DTA mice administered the medium showed significantly increased diurnal wakefulness fragmentation and significantly increased nocturnal sleep fragmentation compared to WT mice administered the medium, which is indicated by an increase in the number of wakefulness episodes and a decrease in episode duration during the dark phase, as well as an increase in the number of NREM sleep episodes and a decrease in episode duration during the light phase. When orexin-tTA;TetO DTA mice were infused with compound E at doses below the maximum non-awake plasma concentration, the number of wakefulness episodes and their duration during the dark phase were significantly reduced and their duration prolonged, and the number of NREM sleep episodes and their duration prolonged during the light phase were significantly reduced and their duration prolonged, compared to orexin-tTA;TetO DTA mice administered the medium. Orexin-tTA;TetO DTA mice administered compound E at concentrations below maximum non-awakened plasma levels had a significantly lower mean number of DREM episodes during the dark and light phases compared to orexin-tTA;TetO DTA mice administered the medium.

[0209] Example 9: Efficacy of OX2R agonists at plasma concentrations below non-awakened levels

[0210] The efficacy of compound F at doses that yield plasma concentrations of compound F below the non-awakened concentration was evaluated using orexin-tTA;TetO DTA mice in the same manner as described in Example 5. To determine the non-awakened dose of compound F, compound F (0.03, 0.1, and 0.3 mg / kg at a volume of 10 mL / kg body weight) was suspended in distilled water containing 10.5% (w / v) captisol / 1.5 mM Na2HPO4 and administered subcutaneously to mice at ZT5. From this study, the maximum non-awakened dose was determined to be 0.03 mg / kg (Figure 21).

[0211] After orally administering compound F at a dose of 0.03 mg / kg, blood samples were collected from the tail veins of mice at 0.25, 0.5, 1, 2, 4, and 8 hours. The Cmax at 0.1 mg / kg was determined to be approximately 3.3 ng / mL (Figure 22).

[0212] Administration by compound injection

[0213] Compound F was dissolved at a concentration of 3 mg / mL in distilled water containing 20% ​​captisol / 0.1% polysorbate 80 and packed into Alzet osmotic pumps (Alzet Model 2004, Muromachi). These pumps were immersed in 0.9% physiological saline and incubated at 37°C for at least 40 hours before being implanted in mice. The pumps were inserted through a small incision made in the skin at the back of the mouse's neck. Plasma samples were collected on days 4, 7, 14, and 28 after pump implantation, and the concentration of compound F in the plasma was quantified by high-performance liquid chromatography-tandem mass spectrometry.

[0214] Plasma concentrations of compound F were maintained below the non-awake concentration on day 14 after pump implantation (2.8 ng / mL) (Figure 23).

[0215] EEG analysis

[0216] This experiment consisted of three groups: wild-type (WT) mice administered the medium (with a pump filled with the medium implanted), orexin-tTA;TetO DTA mice administered the medium, and orexin-tTA;TetO DTA mice injected with compound F. The scores of the WT mice administered the medium or the orexin-tTA;TetO DTA mice injected with compound F were compared with the orexin-tTA;TetO DTA mice administered the medium using Dunnett's multiple comparison test on day 14 after administration. A total of 8 to 12 mice were used in each administration group.

[0217] Infusion of compound F at doses resulting in plasma concentrations below the maximum non-awake plasma concentration did not increase total wakefulness time during the dark / light phase. As shown in Figure 24, orexin-tTA;TetO DTA mice administered the medium showed significantly increased diurnal wakefulness fragmentation and significantly increased nocturnal sleep fragmentation compared to WT mice administered the medium, which is indicated by an increase in the number of wakefulness episodes and a tendency toward shorter episode durations during the dark phase, as well as an increase in the number of NREM sleep episodes and a tendency toward shorter episode durations during the light phase. When orexin-tTA;TetO DTA mice were infused with compound F at doses below the maximum non-awake plasma concentration, they showed a significant decrease in the number of wakefulness episodes and a tendency toward longer durations during the dark phase, and a significant decrease in the number of NREM sleep episodes and a tendency toward longer durations during the light phase, compared to orexin-tTA;TetO DTA mice administered the medium. Orexin-tTA;TetO DTA mice administered compound F at concentrations below maximum non-awakened plasma levels had a significantly lower mean number of DREM episodes during the dark and light phases compared to orexin-tTA;TetO DTA mice administered the medium.

[0218] Example 10: Formulation of a sustained-release formulation of an OX2R agonist Microcapsules 1)Compound B 90mg 2) Polylactic acid-glycolic acid copolymer (PLGA) 210 mg 3) Mannitol 52.94 mg Total 352.94 mg Diluent Carboxymethylcellulose 5 mg, Polysorbate 80 0.3 mg, and Mannitol 15mg, In 1 mL of distilled water

[0219] Microcapsule powders containing 1), 2), and 3) were formulated using the underwater drying method (O / W) described in WO03 / 002092. The entire amounts of 1) and 2) were dissolved in dichloromethane and then added to the aqueous phase to prepare an emulsion. Microcapsules were obtained during the emulsification process and were recovered after the dichloromethane was evaporated. The recovered microcapsules were washed and freeze-dried together with the entire amount of 3) to obtain microcapsule powder. The obtained microcapsule powder (45.63 mg) was dispersed in a diluent (0.12 mL) and administered to rats by subcutaneous injection. The formulation using microcapsules was confirmed to achieve sustained release of compound B over a period of 4 weeks.

[0220] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

[0221] This disclosure is not limited to the specific embodiments described in this application, but is intended as a single illustrative example of the individual embodiments of this disclosure. All various embodiments of this disclosure are not limited to the specific embodiments described in this application. This is not described in the book. Any modifications and variations of this disclosure may be made without departing from its intent and scope and will be obvious to those skilled in the art. Functionally equivalent methods and apparatus within the scope of this disclosure will be obvious 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.

[0222] 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.

[0223] Furthermore, if any feature or aspect of the present disclosure is described in terms of a Markush group, a person skilled in the art will recognize that the present disclosure is also described in terms of any individual component or subgroup of any component of that Markush group.

[0224] 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 any possible partial scopes and combinations thereof. Any enumerated scope can be readily recognized as sufficiently described and enabling the same scope to be divided into at least two, three, four, five, ten, etc. As a non-limiting example, each scope discussed herein can be readily divided into a lower third, a middle third, and an upper third, etc. Similarly, as will be understood by those skilled in the art, all language such as “maximum,” “at least,” “greater than,” “less than,” etc., includes the enumerated number and refers to a scope, which, as described above, can be subsequently divided into partial scopes. 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, etc.

Claims

1. A method for treating narcolepsy type 1 in a person requiring treatment, comprising administering a dosage form containing an orexin type 2 receptor agonist to the person, wherein the dosage form maintains the plasma concentration of the agonist after administration at or below the maximum non-awake plasma concentration of the agonist over the administration interval.

2. The method according to claim 1, wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches and maintains over the dosing interval about 5 percent to about 100 percent, about 10 percent to about 100 percent, about 15 percent to about 100 percent, about 20 percent to about 100 percent, about 30 percent to about 100 percent, or about 50 percent to about 100 percent of the maximum non-awake plasma concentration of the agonist.

3. The method according to claim 1, wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches and maintains approximately 33 percent to approximately 100 percent of the maximum non-awakened plasma concentration of the agonist over the administration interval.

4. The method according to claim 1, 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 non-awake plasma concentration of the orexin type 2 receptor agonist.

5. The method according to claim 1, wherein the plasma concentration of the orexin type 2 receptor agonist after administration reaches its maximum non-wake concentration.

6. The method according to any one of claims 1 to 5, wherein the administration interval of the orexin type 2 receptor agonist is 1 day, 2 days, 1 week, 2 weeks, 4 weeks, 6 weeks, or 8 weeks.

7. The method according to any one of claims 1 to 5, wherein the plasma concentration of the orexin type 2 receptor agonist after administration is maintained for at least two weeks, at least four weeks, at least six weeks, or at least eight weeks.

8. The method according to any one of claims 1 to 7, for improving one or more nocturnal symptoms selected from sleep fragmentation, sleep paralysis, and hallucinations.

9. The method according to any one of claims 1 to 7, for improving one or more daytime symptoms selected from symptoms of awake state fragmentation and cataplexy.

10. The method according to any one of claims 1 to 7, for improving one or more daytime symptoms and one or more nocturnal symptoms in a patient with narcolepsy type 1.

11. The method according to any one of claims 1 to 7, for improving one or more nocturnal symptoms selected from sleep fragmentation, sleep paralysis and hallucinations, and one or more daytime symptoms selected from symptoms of wakefulness fragmentation and cataplexy.

12. The method according to any one of claims 1 to 11, wherein the dosage form includes a sustained-release formulation.

13. The method according to claim 12, wherein the sustained-release formulation is a depot formulation for subcutaneous administration.

14. The method according to claim 12, wherein the dosage form includes an infusion system designed to provide continuous subcutaneous delivery of the OX2R agonist to the human.

15. The plasma concentration of the orexin type 2 receptor agonist is i) To determine the non-awakened plasma concentration of the orexin type 2 receptor agonist that does not induce an arousal response in humans, and ii) Determining the dose of the orexin type 2 receptor agonist that yields a plasma concentration below the maximum non-awake plasma concentration. The method according to any one of claims 1 to 14, as selected by...

16. The plasma concentration of the orexin type 2 receptor agonist is i) To determine the maximum non-awakening concentration of the orexin type 2 receptor agonist that does not induce an arousal response in humans. ii) Determining the amount of the OX2R agonist that yields the maximum non-wake concentration of the agonist, and iii) Selecting a dose of the agonist that results in a level of the agonist that is below the maximum non-awake plasma concentration of the OX2R agonist. The method according to any one of claims 1 to 14, as selected by...

17. The method according to claim 15 or 16, wherein the arousal response is determined by measuring the sleep latency of one or more subjects diagnosed with narcolepsy type 1.

18. 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 )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,(R)-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,3R,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 Any of claims 1 to 17, selected from -yl)methanesulfonamide, or pharmaceutically acceptable salts or hydrates thereof. The method described in paragraph 1.

19. The method according to any one of claims 1 to 17, 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 or hydrate thereof.

20. The method according to any one of claims 1 to 17, wherein 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.

21. The method according to any one of claims 1 to 17, 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 or hydrate thereof.

22. The method according to any one of claims 1 to 17, 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.

23. The method according to any one of claims 1 to 17, wherein the 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 pharmaceutically acceptable salts or hydrates thereof.

24. The orexin type 2 receptor agonist is (R)-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,3R,5S)-3- The method according to any one of claims 1 to 17, selected from ((3S,4R)-1-(5-chloropyrimidine-2-yl)-3-ethoxypiperidine-4-yl)-8-azabicyclo[3.2.1]octane-8-yl)-2-cyclopropylacetamide 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]octane-8-yl)acetamide, or pharmaceutically acceptable salts or hydrates thereof.

25. The 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)-pyrazina-5(2,1)-piperidina-2(1,4)-cyclohexanacyclooctafan-5 ３ -yl)methanesulfonamide, or a pharmaceutically acceptable salt or hydrate thereof, any one of claims 1 to 17 Methods used.

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