TW202302100A - Use of an orexin 2 receptor agonist for the treatment of an orexin-mediated disease or disorder - Google Patents

Abstract

Described herein are methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy) methyl)-piperidine-1-carboxylate (Compound (I)), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, compositions comprising Compound (I), and the use of Compound (I) for the treatment of an orexin-mediated disease or disorder, such as idiopathic hypersomnia and excessive daytime sleepiness, in a human in need thereof.

Description

Use of Orexin 2 Receptor Agonist in the Treatment of Orexin-Mediated Diseases or Conditions

This article relates to 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)-hexahydropyridine-1-carboxylic acid methyl ester (compound (I) ) or a pharmaceutically acceptable salt, hydrate or solvate thereof, a composition comprising Compound (I), and the use of Compound (I) in the treatment of a disease or condition mediated by human appetite hormones in need thereof, Examples include idiopathic narcolepsy and excessive daytime sleepiness.

Orexin (OX) is a neuropeptide, and the orexinergic system is the main wake-promoting system of the brain. Two orexinergic neuropeptides, OX-A and OX-B, have been identified to date. These neuropeptides exert their effects through two types of receptors: the type 1 orexin receptor (OX1R) and the type 2 orexin receptor (OX2R). OX-A has high affinity for OX1R and OX2R, and OX-B has high affinity for OX2R. The two types of OX receptors have different distributions in the arousal network: the locus coeruleus nucleus only contains OX1R, and the tuberomastoid nucleus only contains OX2R, and both receptor types appear in the dorsal raphe nucleus and ventral tegmental area middle. The two types of OX receptors also have different contributions to the regulation of arousal. OX2R in the tuberomastoid nucleus is required for the maintenance of wakefulness, and both receptor types are required for suppression of rapid eye movement (REM) sleep.

Excessive sleepiness or excessive diurnal sleepiness (EDS) is characterized by persistent lethargy and often a general lack of energy even during the day after an apparently adequate or even prolonged night's sleep. Excessive sleepiness can interfere with ability to function in family, social, occupational, or other settings. Current therapies are insufficient to address the full extent and scope of excessive sleepiness in clinical practice.

Idiopathic narcolepsy (IH) is a chronic neurological disorder that causes excessive daytime sleepiness often accompanied by long nocturnal or daytime sleep, unrefreshing sleep, difficulty waking, cognitive dysfunction, and autonomic symptoms. Orexin levels in patients with IH were within normal limits. IH is considered a relatively rare disease.

Drugs used to treat IH include stimulants such as modafinil, armodafinil methylphenidate, dextroamphetamine, and pemoline, as well as in some In patients, sodium oxybate (sodium oxybate), clarithromycin (clarithromycin) and fumazhen (flumazenil). Antidepressants with activating effects, such as bupropion and venlafaxine, may also be used. Modafinil is the only drug with marketing authorization in some European countries for the treatment of humans with IH. However, the European Medicines Agency withdrew modafinil for the treatment of IH because the risk of developing skin or allergic reactions and neuropsychiatric disorders outweighed the evidence of clinically important efficacy. There is no gold standard treatment for IH in the industry. Therefore, there is a great and urgent medical need to effectively treat excessive daytime sleepiness (EDS) under this condition.

The present disclosure addresses the needs mentioned above and involves the use of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate (compound (I)) or its medicine Pharmaceutically acceptable salts, hydrates or solvates, and compositions containing compound (I) or pharmaceutically acceptable salts, hydrates or solvates thereof for treatment. The disclosure also includes embodiments wherein compound (I) is the specific compound (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl )oxy)methyl)methyl hexahydropyridine-1-carboxylate (compound A).

In one aspect there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl Base)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvent compound, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexa Methyl hydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increased sleep latency more than placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating diseases or diseases mediated by orexin hormones in humans with normal levels of orexin hormones, wherein a therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Its pharmaceutically acceptable salt, hydrate or solvate increases sleep latency more than placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of drugs for diseases or conditions mediated by orexin in humans with normal levels of orexin, wherein Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate or a pharmaceutically acceptable salt, hydrate or solvate thereof increased sleep latency more than placebo.

In another aspect there is provided a method of treating idiopathic narcolepsy in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino) -2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate or a pharmaceutically acceptable salt, hydrate or solvate thereof increased sleep latency more than placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3 -((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates or solvates of the drug increased sleep latency more than placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its medicine A pharmaceutically acceptable salt, hydrate or solvate increased sleep latency more than placebo.

In another aspect there is provided a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)- Methyl 2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is therapeutically effective Amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) Methyl oxy)methyl)pyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency more than placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate, or solvate increased sleep latency more than placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutical The above acceptable salts, hydrates or solvates increased sleep latency more than placebo.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 2.8 minutes compared to placebo. In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 29.4 minutes compared to placebo.

In one aspect there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methyl Sulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable salt, hydrate Or a solvate, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep onset latency by more than about 10.5 minutes.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating diseases or diseases mediated by orexin hormones in humans with normal levels of orexin hormones, wherein a therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 10.5 minutes.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of drugs for diseases or conditions mediated by orexin in humans with normal levels of orexin, wherein Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, increases sleep latency by more than about 10.5 minutes.

In another aspect there is provided a method of treating idiopathic narcolepsy in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino) -2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, increases sleep latency by more than about 10.5 minutes.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3 -((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates or solvates of , increase sleep latency by more than about 10.5 minutes.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its medicine A pharmaceutically acceptable salt, hydrate or solvate increases sleep latency by more than about 10.5 minutes.

In another aspect there is provided a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)- Methyl 2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is therapeutically effective Quantity of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid The methyl ester, or a pharmaceutically acceptable salt, hydrate or solvate thereof, increases sleep latency by more than about 10.5 minutes.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-methanol Acetate methyl ester, or a pharmaceutically acceptable salt, hydrate or solvate thereof, increases sleep latency by more than about 10.5 minutes.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutical The above acceptable salts, hydrates or solvates increase sleep latency by more than about 10.5 minutes.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than 13.3 minutes. In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by 39.9 minutes or longer.

In one aspect there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl Base)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvent compound, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexa Methyl hydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof can increase sleep latency more than modafinil.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or its pharmaceutically acceptable salt, hydrate or Solvates for the treatment of orexin-mediated diseases or conditions in humans with normal orexin levels, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)- Methyl 2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable salt, hydrate or solvate than modafinil Ni can increase the latency to fall asleep.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of drugs for diseases or conditions mediated by orexin in humans with normal levels of orexin, wherein Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate or its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil.

In another aspect there is provided a method of treating idiopathic narcolepsy in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino) -2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate or its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3 -((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates or solvates of modafinil increase sleep latency more than modafinil.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its medicine Pharmaceutically acceptable salts, hydrates or solvates increased sleep latency more than modafinil.

In one aspect there is provided a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2 -(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein a therapeutically effective amount (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or their pharmaceutically acceptable salts, hydrates or solvates can increase sleep latency more than modafinil.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate, or solvate increased sleep latency more than modafinil.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine Methyl pyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof can increase sleep latency more than modafinil.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 26.6 minutes compared to modafinil.

In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is from about 5 mg to about 500 mg, from about 5 mg to about 400 mg, from about 5 mg to about 300 mg, from about 5 mg to about 275 mg , about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is about 70 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg , about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, or about 50 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg , about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or about 45 mg to about 115 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is from about 80 mg to about 160 mg, from about 85 mg to about 155 mg, from about 90 mg to about 150 mg, from about 95 mg to about 145 mg , about 90mg to about 140mg, about 95mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof is about 112 mg.

In some embodiments, the administration is oral administration. In some embodiments, the administration is parenteral. In some embodiments, parenteral administration is intravenous administration. In some embodiments, intravenous administration is a single dose. In some embodiments, intravenous administration is in multiple doses. In some embodiments, the single dose is at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours Hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours. In some embodiments, a single dose is administered within 9 hours. In some embodiments, the method increases sleep latency in the Maintenance of Wakefulness Test (MWT).

In one aspect there is provided a pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) Oxy)methyl)hexahydropyridine-1-carboxylate methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition provides Greater increase in sleep onset latency than placebo.

In some embodiments, the composition increases sleep onset latency by more than about 2.8 minutes compared to placebo. In some embodiments, the composition increases sleep onset latency by more than about 24.9 minutes compared to placebo.

In another aspect there is provided a pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl ) oxy)methyl) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition carry Provides an increase in sleep latency over 10.5 minutes.

In some embodiments, the composition increases sleep onset latency by more than about 13.3 minutes. In some embodiments, the composition increases sleep onset latency by 39.9 minutes or greater.

In one aspect there is provided a pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) Oxy)methyl)hexahydropyridine-1-carboxylate methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition provides Greater increase in sleep onset latency than modafinil.

In some embodiments, the composition increases sleep onset latency by more than about 26.6 minutes compared to modafinil.

In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 275 mg, about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 70 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, or about 50 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125mg, about 40mg to about 115mg, about 40mg to about 120mg, about 40mg to about 125mg, Or about 45 mg to about 115 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 90 mg to about 140 mg, about 95 mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in an amount of about 112 mg.

In another aspect there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonate Acyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or Solvates, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) Methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale compared to placebo Sleepiness Scale, KSS) measured.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating diseases or diseases mediated by orexin hormones in humans with normal levels of orexin hormones, wherein a therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-benzene Use of methyl cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of human Drugs for diseases or disorders mediated by orexin, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl )oxy)methyl)pyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reduces excessive daytime sleepiness compared to placebo, as demonstrated by Caroline Measured by the Skas Sleepiness Scale (KSS).

In another aspect there is provided a method of treating idiopathic narcolepsy in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino) -2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3 -((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates or solvates of ® reduce excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine Methyl pyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo Measure.

In another aspect there is provided a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)- Methyl 2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is therapeutically effective Quantity of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Methyl esters or pharmaceutically acceptable salts, hydrates or solvates thereof reduce excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate or solvate reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutical The above acceptable salts, hydrates or solvates reduce excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate or solvate reduced excessive daytime sleepiness by about 3.3 compared to placebo, as measured by the Karolinska Sleepiness Scale (KSS).

In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is from about 5 mg to about 500 mg, from about 5 mg to about 400 mg, from about 5 mg to about 300 mg, from about 5 mg to about 275 mg , about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is about 70 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg , about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, or about 50 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg , about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or about 45 mg to about 115 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - The therapeutically effective amount of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is from about 80 mg to about 160 mg, from about 85 mg to about 155 mg, from about 90 mg to about 150 mg, from about 95 mg to about 145 mg , about 90 mg to about 140 mg, about 95 mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or its pharmaceutically acceptable salt, hydrate or solvent A therapeutically effective amount of the compound is about 112 mg.

In some embodiments, administration is oral. In some embodiments, the administration is parenteral. In some embodiments, parenteral administration is intravenous administration. In some embodiments, intravenous administration is a single dose. In some embodiments, intravenous administration is in multiple doses. In some embodiments, the single dose is at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours Hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours. In some embodiments, a single dose is administered within 9 hours.

In another aspect there is provided a pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl ) oxy)methyl) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition Reduced excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In some embodiments, the composition reduces excessive daytime sleepiness by about 3.3 compared to placebo, as measured by the Karolinska Sleepiness Scale (KSS).

In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 275 mg, about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 70 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300mg, about 50mg to about 275mg, about 50mg to about 240 mg, about 50 mg to about 200 mg, or about 50 mg to about 150 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg, about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or about 45 mg to about 115 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 90 mg to about 140 mg, about 95 mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. In some embodiments, (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in an amount of about 112 mg.

In another aspect there is provided a method of treating a human suffering from the symptoms of idiopathic narcolepsy or excessive daytime sleepiness comprising: (a) determining the concentration of orexin in a biological sample from the human, and (b) if When the concentration of orexin is greater than about 110 pg/mL, an effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof. In some embodiments, the method comprises (a) obtaining a cerebrospinal fluid sample from a human; and/or (b) measuring the concentration of orexin in the cerebrospinal fluid sample, and if the concentration of orexin is greater than about 110 pg/mL, the human has Idiopathic narcolepsy, or excessive daytime sleepiness.

Figure 1 shows LS mean post-dose sleep latencies for certain examples of the 4 MWT trials. The mean sleep onset latency was estimated from the main treatment effect at the 4 post-dose time points (2 hours, 4 hours, 6 hours and 8 hours) in the model. Differences in LS means between Compound A and placebo were derived from repeated measures linear mixed effects models. ***=p-value<0.001.

Figure 2 shows the LS mean (95% CI) of post-dose sleep onset latency from MWT by time point for certain embodiments. ***=p-value<0.001.

Fig. 3 shows LS mean values of KSS (Karolinska Sleepiness Scale) after administration of certain embodiments. Mean KSS was estimated from the main treatment effect at the 4 post-dose time points (2 hours, 4 hours, 6 hours and 8 hours) in the model. Differences in LS means between Compound A and placebo were derived from repeated measures linear mixed effects models. ***=p-value<0.001.

Figure 4 shows the LS mean (95% CI) of post-dose KSS according to time point for certain embodiments. ***=p-value<0.001.

The methods, compositions and uses disclosed herein include the treatment of orexin-mediated diseases or conditions (such as idiopathic narcolepsy and excessive daytime sleepiness) in humans in need thereof, as well as the treatment of undiagnosed patients with either disease or Symptoms in humans suffering from excessive sleepiness.

There is no approved therapy for IH worldwide, except modafinil, which has been approved in Japan. This approval is based on a double-blind placebo-controlled crossover study in 33 drug-free adult IH patients without protracted sleep, each taking 200 mg of modafinil versus placebo for a treatment period of 3 weeks. Mayer et al., J Sleep Res. (2015) 24, 74-81. This study found that modafinil reduced the Epworth Sleepiness Scale (ESS) by 4.5 points, but the sleep latency of the wakefulness maintenance test (MWT) was not significantly changed by the placebo, specifically Word improvement 2.8min. However, the European Medicines Agency has withdrawn modafinil for the treatment of IH because the risk of developing skin or allergic reactions and neuropsychiatric disorders outweighed the evidence of clinically important efficacy.

In embodiments, the methods, compositions and uses of the present disclosure may relate to the treatment of excessive sleepiness in individuals who are not deficient in orexin, such as humans with normal orexin levels. The disclosure also relates to the treatment of diseases, disorders and/or symptoms of excessive sleepiness unrelated to decreased levels of orexin hormones.

Examples of the disclosure relate to methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate (Compound (I)) or a pharmaceutically acceptable salt, hydrate or solvate thereof, compositions and sets comprising Compound (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof , and a method of using compound (I) or a salt, hydrate or solvate thereof. In some embodiments, compound (I) is (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol base) methyl hexahydropyridine-1-carboxylate (compound A) or a pharmaceutically acceptable salt, hydrate or solvate thereof. Compound A can also be represented by the following structure:

Method and use

The methods and uses disclosed herein can include performing one or more tests to quantify sleepiness in humans. Examples of such tests include, but are not limited to, the multiple sleep latency test (MSLT), the maintenance of wakefulness test (MWT), and the Oxford Sleep Resistance (OSLER) test. Other examples include Karolinska Sleepiness Scale (KSS), Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (Stanford Sleepiness Scale), Ullanlinna Narcolepsy Scale (Ullanlinna Narcolepsy Scale, UNS), Work Limitation Questionnaire (WLQ), SF-8 (a subgroup of SF-36 questionnaire) or a combination thereof.

The methods and uses disclosed herein can increase sleep onset latency in the Maintenance of Wakefulness Test (MWT) in humans in need thereof. The MWT is a validated objective measure that assesses a person's ability to remain awake for a defined period of time under hypnotic conditions, and is commonly used in clinical studies as the primary efficacy endpoint for measuring excessive daytime sleepiness. Since no biological measure of wakefulness maintenance exists, the MWT indirectly measures this wakefulness maintenance by the human tendency to avoid or delay falling asleep. This propensity to sleep was measured by electroencephalogram (EEG) derived criteria of sleep latency in each MWT session.

In one embodiment there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)- 2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or Solvates, wherein a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate Ester (Compound (I)) or Compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof increased sleep latency more than placebo.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating diseases or diseases mediated by orexin hormones in humans with normal levels of orexin hormones, wherein a therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Its pharmaceutically acceptable salt, hydrate or solvate increases sleep latency more than placebo.

In one embodiment provides (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- Use of methyl phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of humans with normal levels of appetite hormones Drugs for diseases or disorders mediated by orexin, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclo Hexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency more than placebo.

In another embodiment there is provided a method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-((( 4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I) ) or Compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof can increase sleep latency more than placebo.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3 -((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates or solvates of the drug increased sleep latency more than placebo.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its medicine Pharmaceutically acceptable salts, hydrates or solvates more potent than placebo Added sleep latency.

In another embodiment there is provided a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-((((4 -phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I) ) or Compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof can increase sleep latency more than placebo.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate, or solvate increased sleep latency more than placebo.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutical The above acceptable salts, hydrates or solvates increased sleep latency more than placebo.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency in the Maintenance of Wakefulness Test (MWT). in some implementations In the example, method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 0.1 minutes, more than about 0.5 minutes, more than about 1.0 minutes, more than about 1.5 minutes, over 2.0 minutes, over about 2.5 minutes, over about 2.8 minutes, over about 3.0 minutes, over about 3.5 minutes, over about 4.0 minutes, over about 4.5 minutes, over about 5.0 minutes, over about 5.5 minutes, over about 6.0 minutes, over about 6.5 minutes, over about 7.0 minutes, over about 7.5 minutes, over about 8.0 minutes, over about 8.5 minutes, over about 9.0 minutes, over about 9.5 minutes, over about 10.0 minutes, over about 10.5 minutes, over about 11.0 minutes, over about 11.5 minutes, over about 12.0 minutes, over about 12.5 minutes, over about 13.0 minutes, over about 13.5 minutes, over about 14.0 minutes, over about 14.5 minutes, over about 15.0 minutes, over about 15.5 minutes, over about 20 minutes, over about 20.5 minutes, over about 21.0 minutes, over about 21.5 minutes, over about 22.0 minutes, over about 22.5 minutes, over about 23.0 minutes, over about 23.5 minutes, over about 24.0 minutes, over about 24.5 minutes, over about 25.0 minutes, over about 25.5 minutes, over about 26.0 minutes, over about 26.5 minutes, over about 27.0 minutes, over 27.5 minutes, over 28.0 minutes, over about 28.5 minutes, over about 29.0 minutes, over about 29.4 minutes, over about 29.5 minutes, More than about 30.0 minutes, more than about 30.5 minutes, more than about 31.0 minutes, more than about 31.5 minutes, more than about 32.0 minutes, more than about 32.5 minutes, more than about 33.0 minutes, more than about 33.5 minutes, more than about 34.0 minutes, more than about 34.5 minutes, More than about 35.0 minutes, more than about 40.0 minutes, more than about 45.0 minutes, or more than about 50.0 minutes (or a range between any of these values). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 2.8 minutes compared to placebo. In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amine Base)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate and Sleep onset latency was increased by approximately 29.4 minutes over placebo.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by about 0.1 minutes to about 50 minutes, including about 0.5 minutes, about 1.0 minutes, about 1.5 minutes, about 2.0 minutes, about 2.5 minutes, about 2.8 minutes, about 3.0 minutes, about 3.5 minutes, about 4.0 minutes, about 4.5 minutes, about 5.0 minutes, about 5.5 minutes, about 6.0 minutes, about 6.5 minutes , about 7.0 minutes, about 7.5 minutes, about 8.0 minutes, about 8.5 minutes, about 9.0 minutes, about 9.5 minutes, about 10.0 minutes, about 10.5 minutes, about 11.0 minutes, about 11.5 minutes, about 12.0 minutes, about 12.5 minutes, about 13.0 minutes, about 13.5 minutes, about 14.0 minutes, about 14.5 minutes, about 15.0 minutes, about 15.5 minutes, about 20 minutes, about 20.5 minutes, about 21.0 minutes, about 21.5 minutes, about 22.0 minutes, about 22.5 minutes, about 23.0 minutes , about 23.5 minutes, about 24.0 minutes, about 24.5 minutes, about 25.0 minutes, about 25.5 minutes, about 26.0 minutes, about 26.5 minutes, about 27.0 minutes, about 27.5 minutes, about 28.0 minutes, about 28.5 minutes, about 29.0 minutes, about 29.4 minutes, about 29.5 minutes, about 30.0 minutes, about 30.5 minutes, about 31.0 minutes, about 31.5 minutes, about 32.0 minutes, about 32.5 minutes, about 33.0 minutes, about 33.5 minutes, about 34.0 minutes, about 34.5 minutes, about 35.0 minutes , about 40.0 minutes, about 45.0 minutes, and about 50.0 minutes (or a range between any of these values). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by about 2.5 minutes to about 3.0 minutes, about 2.0 minutes to about 3.5 minutes compared to placebo minutes, about 1.5 minutes to about 4.0 minutes, about 0.5 minutes to about 4.5 minutes, about 0.5 minutes to about 5.0 minutes, about 0.5 minutes to about 10.0 minutes, about 0.5 minutes to about 20.0 minutes, about 0.5 minutes to about 30.0 minutes, or about 0.5 minutes to about 40.0 minutes, including about 2.8 minutes. In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by about 27.5 minutes to about 32.5 minutes, about 25.0 minutes to about 35.0 minutes compared to placebo minutes, from about 20.0 minutes to about 40.0 minutes, from about 15.0 minutes to about 45.0 minutes, from about 10.0 minutes to about 50.0 minutes, from about 5.0 minutes to about 50.0 minutes, including about 29.4 minutes.

In one embodiment there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)- Methyl 2-(((4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvent Compounds, wherein a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate or solvate thereof, increases sleep latency by more than about 10.5 minutes.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating diseases or diseases mediated by orexin hormones in humans with normal levels of orexin hormones, wherein a therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 10.5 minutes.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of human appetite hormone-mediated hormones with normal levels of appetite hormone A drug for a disease or condition, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) Methyl)pyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 10.5 minutes.

In another embodiment there is provided a method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-((( 4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I) ) or Compound A, or a pharmaceutically acceptable salt, hydrate or solvate thereof, increases sleep latency by more than about 10.5 minutes.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3 -((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates or solvates of , increase sleep latency by more than about 10.5 minutes.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its medicine A pharmaceutically acceptable salt, hydrate or solvate increases sleep latency by more than about 10.5 minutes.

In another embodiment there is provided a method of treating excessive daytime sleepiness in a human in need thereof, It comprises administering to humans a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein the therapeutically effective amount of 3-((methylsulfonyl)amino)-2-(( (4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate Sleep latency increases over about 10.5 minutes.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates, or solvates increased sleep latency by more than about 10.5 minutes.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutical The above acceptable salts, hydrates or solvates increase sleep latency by more than about 10.5 minutes.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency in the Maintenance of Wakefulness Test (MWT). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or its pharmaceutically acceptable salt, hydrate or solvate for sleep Latency increased by more than about 0.1 minutes, by more than about 0.5 minutes, by more than about 1.0 minutes, by more than about 1.5 minutes, by more than 2.0 minutes, by more than about 2.5 minutes, by more than about 2.8 minutes, by more than about 3.0 minutes, by more than about 3.5 minutes, by more than about 4.0 minutes minutes, over about 4.5 minutes, over about 5.0 minutes, over about 5.5 minutes, over about 6.0 minutes, over about 6.5 minutes, over about 7.0 minutes, over about 7.5 minutes, over about 8.0 minutes, over about 8.5 minutes, over about 9.0 minutes, more than about 9.5 minutes, more than about 10.0 minutes, more than about 10.5 minutes, more than about 11.0 minutes, more than about 11.5 minutes, more than about 12.0 minutes, more than about 12.5 minutes, more than about 13.0 minutes, more than about 13.3 minutes, more than about 13.5 minutes minutes, more than about 14.0 minutes, more than about 14.5 minutes, more than about 15.0 minutes, more than about 15.5 minutes, more than about 20 minutes, more than about 20.5 minutes, more than about 21.0 minutes, more than about 21.5 minutes, more than about 22.0 minutes, more than about 22.5 minutes minutes, over about 23.0 minutes, over about 23.5 minutes, over about 24.0 minutes, over about 24.5 minutes, over about 25.0 minutes, over about 25.5 minutes, over about 26.0 minutes, over about 26.5 minutes, over about 27.0 minutes, over 27.5 minutes , over 28.0 minutes, over about 28.5 minutes, over about 29.0 minutes, over about 29.4 minutes, over about 29.5 minutes, over about 30.0 minutes, over about 30.5 minutes, over about 31.0 minutes, over about 31.5 minutes, over about 32.0 minutes, More than about 32.5 minutes, more than about 33.0 minutes, more than about 33.5 minutes, more than about 34.0 minutes, more than about 34.5 minutes, more than about 35.0 minutes, more than about 40.0 minutes, more than about 45.0, or more than about 50.0 minutes (or between range between any of the values). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 13.3 minutes.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or its pharmaceutically acceptable The salt, hydrate, or solvate increases sleep onset latency by about 0.1 minutes to about 50 minutes, including about 0.5 minutes, about 1.0 minutes, about 1.5 minutes, about 2.0 minutes, about 2.5 minutes, about 2.8 minutes, about 3.0 minutes, About 3.5 minutes, about 4.0 minutes, about 4.5 minutes, about 5.0 minutes, about 5.5 minutes, about 6.0 minutes, about 6.5 minutes, about 7.0 minutes, about 7.5 minutes, about 8.0 minutes, about 8.5 minutes, about 9.0 minutes, about 9.5 minutes, about 10.0 minutes, about 10.5 minutes, about 11.0 minutes, about 11.5 minutes, about 12.0 minutes, about 12.5 minutes, about 13.0 minutes, about 13.3 minutes, about 13.5 minutes, about 14.0 minutes, about 14.5 minutes, about 15.0 minutes, About 15.5 minutes, about 20 minutes, about 20.5 minutes, about 21.0 minutes, about 21.5 minutes, about 22.0 minutes, about 22.5 minutes, about 23.0 minutes, about 23.5 minutes, about 24.0 minutes, about 24.5 minutes, about 25.0 minutes, about 25.5 minutes minutes, about 26.0 minutes, about 26.5 minutes, about 27.0 minutes, about 27.5 minutes, about 28.0 minutes, about 28.5 minutes, about 29.0 minutes, about 29.4 minutes, about 29.5 minutes, about 30.0 minutes, about 30.5 minutes, about 31.0 minutes, About 31.5 minutes, about 32.0 minutes, about 32.5 minutes, about 33.0 minutes, about 33.5 minutes, about 34.0 minutes, about 34.5 minutes, about 35.0 minutes, about 40.0 minutes, about 45.0 minutes and about 50.0 minutes (or between range between any of them). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by about 12.5 minutes to about 15.0 minutes, about 10.0 minutes to about 20.0 minutes, about 5.0 minutes to about 25.0 minutes, about 5.0 minutes to about 30.0 minutes, about 5.0 minutes to about 35.0 minutes, about 5.0 minutes to about 40.0 minutes, about 5.0 minutes to about 45.0 minutes, or about 5.0 minutes to about 50.0 minutes, including about 13.3 minutes .

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increased by about 0.5 minutes, about 1.0 minutes, about 1.5 minutes, about 2.0 minutes, About 2.5 minutes, about 2.8 minutes, about 3.0 minutes, about 3.5 minutes, about 4.0 minutes, about 4.5 minutes, about 5.0 minutes, about 5.5 minutes, about 6.0 minutes, about 6.5 minutes, about 7.0 minutes, about 7.5 minutes, about 8.0 minute, about 8.5 minutes, about 9.0 minutes, about 9.5 minutes, about 10.0 minutes, about 10.5 minutes, about 11.0 minutes, about 11.5 minutes, about 12.0 minutes, about 12.5 minutes, about 13.0 minutes, about 13.5 minutes, about 14.0 minutes, About 14.5 minutes, about 15.0 minutes, about 15.5 minutes, about 20 minutes, about 20.5 minutes, about 21.0 minutes, about 21.5 minutes, about 22.0 minutes, about 22.5 minutes, about 23.0 minutes, about 23.5 minutes, about 24.0 minutes, about 24.5 minutes minutes, about 25.0 minutes, about 25.5 minutes, about 26.0 minutes, about 26.5 minutes, about 27.0 minutes, about 27.5 minutes, about 28.0 minutes, about 28.5 minutes, about 29.0 minutes, about 29.4 minutes, about 29.5 minutes, about 30.0 minutes, About 30.5 minutes, about 31.0 minutes, about 31.5 minutes, about 32.0 minutes, about 32.5 minutes, about 33.0 minutes, about 33.5 minutes, about 34.0 minutes, about 34.5 minutes, about 35.0 minutes, about 39.9 minutes, about 40.0 minutes, about 45.0 minutes, a sleep latency of about 50.0 minutes or longer (or a range between any of these values). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by 39.9 minutes or longer.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increased from about 37.5 minutes to about 42.5 minutes, from about 35.0 minutes to about 45.0 minutes, or from about 30.0 minutes to about 50.0 minutes, including about 39.9 minutes of latency to fall asleep.

In one embodiment there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)- 2-(((4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound Compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl )oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate can increase sleepiness more than modafinil incubation time.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating diseases or diseases mediated by orexin hormones in humans with normal levels of orexin hormones, wherein a therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of drugs for diseases or conditions mediated by orexin in humans with normal levels of orexin, wherein Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate or its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil.

In another embodiment there is provided a method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-((( 4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I) ) or compound A or its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3 -((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates or solvates of modafinil increase sleep latency more than modafinil.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its medicine Pharmaceutically acceptable salts, hydrates or solvates increased sleep latency more than modafinil.

In another embodiment there is provided a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-((((4 -phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein therapeutically effective Amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) Or compound A or its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-methanol Methyl ester or its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutical The above acceptable salts, hydrates or solvates increased sleep latency more than modafinil.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency in the Maintenance of Wakefulness Test (MWT). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 0.1, more than about 0.5, more than about 1.0, compared to modafinil More than about 1.5, more than 2.0, more than about 2.5, more than about 2.8, more than about 3.0, more than about 3.5, more than about 4.0, more than about 4.5, more than about 5.0, more than about 5.5, more than about 6.0, more than about 6.5, more than about 7.0 , more than about 7.5, more than about 8.0, more than about 8.5, more than about 9.0, more than about 9.5, more than about 10.0, more than about 10.5, more than about 11.0, more than about 11.5, more than about 12.0, more than about 12.5, more than about 13.0, more than About 13.5, over about 14.0, over about 14.5, over about 15.0, over about 15.5, over about 20, over about 20.5, over about 21.0, over about 21.5, over about 22.0, over about 22.5, over about 23.0, over about 23.5 , over about 24.0, over about 24.5, over about 25.0, over about 25.5, over about 26.0, over about 26.5, over about 26.6, over about 27.0, over 27.5, over 28.0, over about 28.5, over about 29.0, over More than about 29.4, more than about 29.5, more than about 30.0, more than about 30.5, more than about 31.0, more than about 31.5, more than about 32.0, more than about 32.5, more than about 33.0, more than about 33.5, more than about 34.0, more than about 34.5, more than about 35.0, more than about 40.0, more than about 45.0, more than about 50.0 (or a range between any of these values). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 26.6 minutes compared to modafinil.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep onset latency by about 0.1 minutes to about 50 minutes, including about 0.5 minutes, compared to modafinil , about 1.0 minutes, about 1.5 minutes, about 2.0 minutes, about 2.5 minutes, about 2.8 minutes, about 3.0 minutes, about 3.5 minutes, about 4.0 minutes, about 4.5 minutes, about 5.0 minutes, about 5.5 minutes, about 6.0 minutes, about 6.5 minutes, about 7.0 minutes, about 7.5 minutes, about 8.0 minutes, about 8.5 minutes, about 9.0 minutes, about 9.5 minutes, about 10.0 minutes, about 10.5 minutes, about 11.0 minutes, about 11.5 minutes, about 12.0 minutes, about 12.5 minutes , about 13.0 minutes, about 13.5 minutes, about 14.0 minutes, about 14.5 minutes, about 15.0 minutes, about 15.5 minutes, about 20 minutes, about 20.5 minutes, about 21.0 minutes, about 21.5 minutes, about 22.0 minutes, about 22.5 minutes, about 23.0 minutes, about 23.5 minutes, about 24.0 minutes, about 24.5 minutes, about 25.0 minutes, about 25.5 minutes, about 26.0 minutes, about 26.5 minutes, about 26.6 minutes, about 27.0 minutes, about 27.5 minutes, about 28.0 minutes, about 28.5 minutes , about 29.0 minutes, about 29.4 minutes, about 29.5 minutes, about 30.0 minutes, about 30.5 minutes, about 31.0 minutes, about 31.5 minutes, about 32.0 minutes, about 32.5 minutes, about 33.0 minutes, about 33.5 minutes, about 34.0 minutes, about 34.5 minutes, about 35.0 minutes, about 40.0 minutes, about 45 minutes, about 50.0 minutes. In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- Phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate increases sleep latency by about 25.0% compared with modafinil minutes to about 27.5 minutes, about 25.0 minutes to about 30.0 minutes, about 20.0 minutes to about 35.0 minutes, about 15.0 minutes to about 40.0 minutes, about 10.0 minutes to about 45.0 minutes, about 5.0 minutes to about 50.0 minutes, including about 26.6 minutes .

The methods and uses disclosed herein can reduce excessive sleepiness or improve Karolinska Sleepiness Scale (KSS) ratings in humans in need thereof. The Karolinska Sleepiness Scale (KSS) is a 10-item Likert-type rating scale used to evaluate subjective sleepiness. This self-rating scale measures subjective sleepiness levels at specific times of the day. Humans indicate that this scale best reflects the level of sleepiness they experienced in the last 10 minutes. KSS is useful for evaluating changes in response to drug effects and is a measure of contextual sleepiness. It is more sensitive to fluctuations. It has been used in studies of shift work, jet lag, driving ability, concentration and performance, as well as in clinical settings. It helps evaluate changes in response to environmental factors, circadian rhythms, and drug effects. Humans who are asleep and unable to wake will have a KSS score of 10 entered. KSS scores are on a 10-point scale where 1=extremely alert, 2=very alert, 3=alert, 4=quite alert, 5=neither alert nor sleepy, 6=some signs of lethargy, 7=sleepy but without effort Staying awake, 8=sleepy but takes effort to stay awake, 9=very sleepy and takes extreme effort to stay awake and resists sleep, and 10=extremely sleepy and unable to stay awake.

In one embodiment there is provided a method of treating an orexin-mediated disease or condition in a human having normal orexin levels comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)- Methyl 2-(((4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvent Compounds, wherein a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate (Compound (I)) or Compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS ) as measured by

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used for treating diseases or diseases mediated by orexin hormones in humans with normal levels of orexin hormones, wherein a therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of drugs for diseases or conditions mediated by orexin in humans with normal levels of orexin, wherein Effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1- Methyl formate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In another embodiment there is provided a method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-((( 4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein the treatment Effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I) ) or Compound A, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one embodiment provides (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- Phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of idiopathic sleepiness in humans in need thereof disease, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo Measure.

In one embodiment there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicine for idiopathic narcolepsy in humans in need, wherein a therapeutically effective amount of (2R, 3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its medicine A pharmaceutically acceptable salt, hydrate or solvate reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In another embodiment there is provided a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of 3-((methylsulfonyl)amino)-2-((((4 -phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or compound A or its pharmaceutically acceptable salt, hydrate or solvate, wherein therapeutically effective Amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3- ((Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-methanol Methyl ester, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In one aspect there is provided (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Use of methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R, 3S )-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutical The above acceptable salts, hydrates or solvates reduce excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo.

In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness by about 0.5 to about 5.9, including about 0.5, about 0.6, About 0.7, About 0.8, About 0.9, About 1.0, About 1.1, About 1.2, About 1.3, About 1.4, About 1.5, About 1.6, About 1.7, About 1.8, About 1.9, About 2.0, About 2.1, About 2.2, About 2.3 , about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, About 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.7, about 6.8, or about 6.9, as measured by the Karolinska Sleepiness Scale (KSS) Measured. In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness by about 1.0 to about 5.5, about 1.5 to about 5.5, about 2.0 to about 5.5, about 2.5 to about 5.5, about 2.5 to 4.5, about 2.0 to about 3.5, or about 3.0 to about 3.5, as by Caroline Measured by the Skas Sleepiness Scale (KSS). In some embodiments, the method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduced excessive daytime sleepiness by about 3.3% compared to placebo, as measured by the Karolinska Sleepiness Scale Table (KSS) measured.

This paper further discloses methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate (compound (I) ) or Compound A, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of orexin-mediated diseases or conditions in humans with normal orexin levels, and in the treatment of idiopathic orexin in humans in need thereof Narcolepsy, or the treatment of excessive daytime sleepiness in humans in need thereof.

Disclosed herein is 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester (compound (I)) or The use of compound A or its pharmaceutically acceptable salt, hydrate or solvate, which is used for the manufacture of orexin-mediated diseases or diseases in humans with normal orexin levels, and the treatment of idiopathic human diseases in need Drugs for narcolepsy or the treatment of excessive daytime sleepiness in humans in need thereof.

In some embodiments, treating an orexin-mediated disease or condition may include alleviating or alleviating one or more symptoms of excessive sleepiness. The one or more symptoms of excessive sleepiness may be selected from fatigue, tiredness, laziness, lethargy, inactivity.

In some embodiments, the human suffers from a disease or disorder or condition associated with excessive sleepiness. In some embodiments, the human is a sleep deprived human, a human with excessive sleepiness, a human with disruptive regular sleep cycles, or a human in need of reduced sleepiness.

Orexin or hypocretin is a neuropeptide that regulates arousal, wakefulness, and appetite. In some embodiments, excessive sleepiness may be associated with a deficiency of orexin. In some embodiments, excessive sleepiness Not associated with decreased levels of orexin hormones. In some embodiments, orexin levels in humans are unimpaired or partially impaired. In some embodiments, the level of orexin in the human is normal. Orexin levels in humans refer to cerebrospinal fluid (CSF) hypocretin 1 (orexin A) concentrations as measured by immunoreactivity. In some embodiments, the human having normal (or unimpaired or partially impaired) orexin hormone levels has an orexin hormone level of greater than about 110 pg/mL or greater than about 190 pg/mL. In some embodiments, the human with normal (or unimpaired or partially impaired) orexin hormone levels has an orexin hormone level greater than about 110 pg/mL, greater than about 150 pg/mL, greater than about 190 pg/mL, greater than about 200 pg/mL, Greater than about 250 pg/mL, or greater than about 300 pg/mL. In some embodiments, the orexin level of a human with normal (or unimpaired or partially impaired) orexin hormone levels is about 110 pg/mL to about 900 pg/mL, about 110 pg/mL to about 850 pg/mL, about 110 pg/mL mL to about 800pg/mL, about 110pg/mL to about 750pg/mL, about 110pg/mL to about 700pg/mL, about 110pg/mL to about 650pg/mL, about 110pg/mL to about 600pg/mL, about 190pg/mL mL to about 700 pg/mL, about 190 pg/mL to about 650 pg/mL, or about 190 pg/mL to about 600 pg/mL, about 200 pg/mL to about 700 pg/mL, about 200 pg/mL to about 650 pg/mL, about 600 pg /mL to about 700pg/mL, or about 200pg/mL to about 600pg/mL. In some embodiments, the patient's orexin level is about 110 pg/mL, about 190 pg/mL, about 200 pg/mL, about 250 pg/mL, about 300 pg/mL, about 350 pg/mL, about 400 pg/mL, about 500 pg/mL mL, about 600pg/mL, about 700pg/mL, about 800pg/mL, about 900pg/mL or any range therebetween.

Examples of orexin-mediated diseases or conditions in humans with normal orexin levels include excessive daytime sleepiness (EDS) in myotonic dystrophy type I, EDS in Prader Willi syndrome, EDS in sleep apnea (OSA), EDS in multiple sclerosis, EDS in Mobius syndrome, EDS in Guillain-Barre syndrome, Smith-Lay-Osan Syndrome (Smith-Lemli-Opitz syndrome) EDS in central diabetes insipidus, EDS in central diabetes insipidus and EDS in type 1 X-linked Carcot-Marie-Tooth disease (X-linked Carcot-Marie-Tooth disease).

Other examples of orexin-mediated diseases or conditions in humans with normal orexin levels include, but are not limited to, narcolepsy type 2 (NT2), idiopathic narcolepsy (IH), adequately treated with CPAP but still EDS in sleep apnea (OSA) with residual excessive daytime sleepiness (EDS), sleep-wake disorder (SWD) and Parkinson's disease.

Idiopathic hypersomnia (IH) as used herein is as defined by the International Classification of Sleep Disorders-3 (ICSD-3). The diagnostic criteria for idiopathic narcolepsy are:

a) Human beings have a period of uncontrollable sleep need every day or enter sleep during the day for at least 3 months.

b) Absence of cataplexy.

15分鐘，則多重睡眠潛伏期測試(MSLT)顯示少於2個入睡快速眼球轉動(REM)時段或無入睡REM時段。 c) If the REM latency on the previous polysomnography

15 minutes, the Multiple Sleep Latency Test (MSLT) shows less than 2 sleep-onset rapid eye movement (REM) periods or no sleep-onset REM periods.

d) There is at least one of the following:

8分鐘之平均睡眠潛伏期。 a) MSLT display

Average sleep latency of 8 minutes.

660分鐘。 b) Total 24-hour sleep on 24-hour polysomnographic monitoring (performed after correction for chronic sleep deprivation) or by wrist activity records associated with sleep diary (average of at least 7 days in the case of unrestricted sleep) time

660 minutes.

e) Rule out sleep deprivation syndrome.

f) Narcolepsy and/or MSLT findings are not better explained by another sleep disorder, other medical or psychiatric condition, or use of drugs or medication.

In some embodiments, the human in need thereof has the International Sleep Disorder of Essential Narcolepsy At least one or more of the diagnostic criteria described in Classification of Disorders-3 (ICSD-3).

In another aspect there is provided a method of treating a human suffering from the symptoms of idiopathic narcolepsy or excessive daytime sleepiness comprising: (a) determining the concentration of orexin in a biological sample from the human, and (b) if When the concentration of orexin is greater than about 110 pg/mL, an effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexa Methyl hydropyridine-1-carboxylate (Compound I) or Compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof. In some embodiments, the method comprises (a) obtaining a cerebrospinal fluid sample from a human; and/or (b) measuring the concentration of orexin in the cerebrospinal fluid sample, and if the concentration of orexin is greater than about 110 pg/mL, the human has Idiopathic narcolepsy, or excessive daytime sleepiness.

In some embodiments, the human has an orexin level of greater than about 110 pg/mL, greater than about 150 pg/mL, greater than about 190 pg/mL, greater than about 200 pg/mL, greater than about 250 pg/mL, or greater than about 300 pg/mL. In some embodiments, the patient's orexin level is from about 110 pg/mL to about 900 pg/mL, from about 110 pg/mL to about 850 pg/mL, from about 110 pg/mL to about 800 pg/mL, from about 110 pg/mL to about 750 pg/mL mL, about 110pg/mL to about 700pg/mL, about 110pg/mL to about 650pg/mL, about 110pg/mL to about 600pg/mL, about 190pg/mL to about 700pg/mL, about 190pg/mL to about 650pg/mL mL, or about 190 pg/mL to about 600 pg/mL, about 200 pg/mL to about 700 pg/mL, about 200 pg/mL to about 650 pg/mL, or about 200 pg/mL to about 600 pg/mL. In some embodiments, the patient's orexin level is about 110 pg/mL, about 190 pg/mL, about 200 pg/mL, about 250 pg/mL, about 300 pg/mL, about 350 pg/mL, about 400 pg/mL, about 500 pg/mL mL, about 600pg/mL, about 700pg/mL, about 800pg/mL, about 900pg/mL or any range therebetween.

Mode of administration

The methods and uses disclosed herein include administering Compound (I) or Compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof to humans in need. In some embodiments, the Compound (I) or Compound A was administered orally. In some embodiments, Compound (I) or Compound A is not administered orally. In some embodiments, parenteral administration is intravenous, subcutaneous, transdermal, intradermal, or transmucosal administration. In some embodiments, parenteral administration is intravenous administration. In some embodiments, parenteral administration is subcutaneous administration. In some embodiments, parenteral administration is transdermal administration. In some embodiments, Compound (I) or Compound A is administered intravenously. Alternatively or additionally, Compound (I) or Compound A may be administered as an infusion. Administering Compound (I) or Compound A as an infusion may comprise administering Compound (I) or Compound A via a needle or catheter.

Compound (I) or Compound A can be administered orally and parenterally, such as intramuscular, intraperitoneal, intravenous, intraarterial, intraventricular, intracisternal injection or infusion; subcutaneous injection; or implantation; or inhalation spray , intratracheal, nasal, vaginal, rectal, subdermal, percutaneous, intradermal, epidural, ophthalmic insertion or eye drop injection, containing pharmaceutically acceptable conventional non-toxic Suitable unit dosage forms of carriers, adjuvants and vehicles.

In some embodiments, Compound (I) or Compound A is administered as a single dose. In some embodiments, Compound (I) or Compound A is administered in multiple doses. In some embodiments, Compound (I) or Compound A is administered intravenously as a single dose. In some embodiments, Compound (I) or Compound A is administered intravenously in multiple doses.

In some embodiments, Compound (I) or Compound A is administered for about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours Hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours or 20 hours. Compound (I) or Compound A can be administered as an infusion in a single dose for about 9 hours. In some embodiments, the total period of administration of Compound (I) or Compound A is continuous (eg, Compound (I) or Compound A is administered continuously as an infusion for about 9 hours). Alternatively, the total time of administration of Compound (I) or Compound A is intermittent (eg, Compound (I) or Compound A given as an infusion for 1 hour, then the infusion is stopped for a period of time, and the infusion is started for another hour).

Alternatively or additionally, administering Compound (I) or Compound A may comprise administering an effective amount of Compound (I) or Compound A. In some embodiments, administering Compound (I) or Compound A may comprise administering a therapeutically effective amount of Compound (I) or Compound A.

The effective amount of compound (I) or compound A can be about 5 mg to about 500 mg, including about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 275 mg, about 5 mg to about 240 mg, about 5 mg to about 200 mg, and From about 5 mg to about 150 mg. In some embodiments, the effective amount of Compound (I) or Compound A may be from about 70 mg to about 250 mg. In some embodiments, the effective amount of compound (I) or compound A can be about 50 mg to about 500 mg, including about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, and about 50 mg to about 150 mg. In some embodiments, the effective amount of compound (I) or compound A can be about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg, about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or about 45 mg to about 115 mg. In some embodiments, the effective amount of Compound (I) or Compound A can be about 80 mg to about 500 mg, including about 80 mg to about 400 mg, about 80 mg to about 300 mg, about 80 mg to about 200 mg, and about 80 mg to about 150 mg. In some embodiments, the effective amount of Compound (I) or Compound A can be about 90 mg to about 500 mg, including about 90 mg to about 400 mg, about 90 mg to about 300 mg, about 90 mg to about 200 mg, and about 90 mg to about 150 mg.

The effective amount of compound (I) or compound A can be about 30 mg to about 160 mg or about 80 mg to about 160 mg, including about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42 mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, About 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg , about 76mg, about 77mg, about 78mg, about 79mg, about 80mg, about 81mg, about 82mg, about 83mg, about 84mg, about 85mg, about 86mg, about 87mg, about 88mg, about 89mg, about 90mg, about 91mg, about 92mg, about 93mg, about 94mg, about 95mg, about 96mg, about 97mg, about 98mg, about 99mg, about 100mg, about 101mg, about 102mg, about 103mg, about 104mg, about 105mg, about 106mg, about 107mg, about 108mg, About 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg , about 126mg, about 127mg, about 128mg, about 129mg, about 130mg, about 131mg, about 132mg, about 133mg, about 134mg, about 135mg, about 136mg, about 137mg, about 138mg, about 139mg, about 140mg, about 141mg, About 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg , about 159mg and 160mg. In some embodiments, the effective amount of Compound (I) or Compound A is from about 80 mg to about 160 mg, from about 85 mg to about 155 mg, from about 90 mg to about 150 mg, from about 95 mg to about 145 mg, from about 90 mg to about 140 mg, from about 95 mg to About 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. In some embodiments, the effective amount of Compound (I) or Compound A may be about 112 mg.

PK parameters

The plasma concentration of Compound (I) or Compound A may be at least 25ng/mL, 30ng/mL, 35ng/mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng /mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL, 100ng/mL, 105ng/mL, 110ng/mL, 115ng/mL, 120ng/mL, 125ng/mL, 130ng/mL , 135ng/mL, 140ng/mL, 145ng/mL, 150ng/mL, 160ng/mL, 170ng/mL, 180ng/mL, 190ng/mL, 200ng/mL, 210ng/mL, 220ng/mL, 230ng/mL, 240ng /mL, 250ng/mL, 300ng/mL, 310ng/mL, 320ng/mL, 330ng/mL, 340ng/mL, or 350ng/mL for at least 1 hour. The plasma concentration of Compound (I) or Compound A may be at least 25ng/mL, 30ng/mL, 35ng/mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng /mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL, 100ng/mL, 105ng/mL, 110ng/mL, 115ng/mL, 120ng/mL, 125ng/mL, 130ng/mL , 135ng/mL, 140ng/mL, 145ng/mL, 150ng/mL, 160ng/mL, 170ng/mL, 180ng/mL, 190ng/mL, 200ng/mL, 210ng/mL, 220ng/mL, 230ng/mL, 240ng /mL, 250ng/mL, 300ng/mL, 310ng/mL, 320ng/mL, 330ng/mL, 340ng/mL, or 350ng/mL for at least 2 hours. The plasma concentration of Compound (I) or Compound A may be at least 25ng/mL, 30ng/mL, 35ng/mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng /mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL, 100ng/mL, 105ng/mL, 110ng/mL, 115ng/mL, 120ng/mL, 125ng/mL, 130ng/mL , 135ng/mL, 140ng/mL, 145ng/mL, 150ng/mL, 160ng/mL, 170ng/mL, 180ng/mL, 190ng/mL, 200ng/mL, 210ng/mL, 220ng/mL, 230ng/mL, 240ng /mL, 250ng/mL, 300ng/mL, 310ng/mL, 320ng/mL, 330ng/mL, 340ng/mL or 350ng/mL, Lasts for at least 4 hours. The plasma concentration of Compound (I) or Compound A may be at least 25ng/mL, 30ng/mL, 35ng/mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng /mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL, 100ng/mL, 105ng/mL, 110ng/mL, 115ng/mL, 120ng/mL, 125ng/mL, 130ng/mL , 135ng/mL, 140ng/mL, 145ng/mL, 150ng/mL, 160ng/mL, 170ng/mL, 180ng/mL, 190ng/mL, 200ng/mL, 210ng/mL, 220ng/mL, 230ng/mL, 240ng /mL, 250ng/mL, 300ng/mL, 310ng/mL, 320ng/mL, 330ng/mL, 340ng/mL, or 350ng/mL for at least 6 hours. The plasma concentration of Compound (I) or Compound A may be at least 25ng/mL, 30ng/mL, 35ng/mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng /mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL, 100ng/mL, 105ng/mL, 110ng/mL, 115ng/mL, 120ng/mL, 125ng/mL, 130ng/mL , 135ng/mL, 140ng/mL, 145ng/mL, 150ng/mL, 160ng/mL, 170ng/mL, 180ng/mL, 190ng/mL, 200ng/mL, 210ng/mL, 220ng/mL, 230ng/mL, 240ng /mL, 250ng/mL, 300ng/mL, 310ng/mL, 320ng/mL, 330ng/mL, 340ng/mL, or 350ng/mL for at least 8 hours. The plasma concentration of Compound (I) or Compound A may be at least 25ng/mL, 30ng/mL, 35ng/mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng /mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL, 100ng/mL, 105ng/mL, 110ng/mL, 115ng/mL, 120ng/mL, 125ng/mL, 130ng/mL , 135ng/mL, 140ng/mL, 145ng/mL, 150ng/mL, 160ng/mL, 170ng/mL, 180ng/mL, 190ng/mL, 200ng/mL, 210ng/mL, 220ng/mL, 230ng/mL, 240ng /mL, 250ng/mL, 300ng/mL, 310ng/mL, 320ng/mL, 330ng/mL, 340ng/mL, or 350ng/mL for at least 12 hours.

Dosing frequency

Compound (I) or Compound A may be administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times per day. In some embodiments , Compound (I) or Compound A is administered at least once a day. In some embodiments, Compound (I) or Compound A is administered at least twice daily.

Compound (I) or Compound A can be administered at least 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times a week times or 14 or more times. In some embodiments, Compound (I) or Compound A is administered weekly. In some embodiments, Compound (I) or Compound A is administered at least twice a week. In some embodiments, Compound (I) or Compound A is administered at least 3 times per week. In some embodiments, Compound (I) or Compound A is administered at least 4 times per week.

Compound (I) or compound A can be administered at least 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times per month times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times or 20 times or more. Compound (I) or Compound A may be administered at least 4 times per month.

combination therapy

The methods disclosed herein can further comprise administering one or more other therapies. The kits and compositions disclosed herein may further comprise one or more other therapies. One or more additional therapies may be selected from stimulants, antidepressants, central nervous system depressants, histamine 3 (H3) receptor antagonists, agents for reducing the metabolism of Compound (I) or Compound A and those described below Any concomitant drug. In some embodiments, the stimulating agent is modafinil. In some embodiments, the antidepressant is clomipramine. In some embodiments, the central nervous system depressant is sodium oxybate. In some embodiments, the one or more other therapies are venlafaxine or desvenlafaxine. In some embodiments, the H3 receptor antagonist is tilolide Health (pitolisant). In some embodiments, the agent used to reduce the metabolism of Compound (I) or Compound A is cobicistat.

Agents for reducing the metabolism of Compound (I) or Compound A can increase the bioavailability of Compound (I) or Compound A or the systemic exposure of Compound (I) or Compound A. In some embodiments, the agent for reducing the metabolism of Compound (I) is an inhibitor of one or more enzymes of the cytochrome P450 enzyme system. In some embodiments, the agent for reducing the metabolism of Compound (I) or Compound A is a CYP3A4 inhibitor. In some embodiments, the CYP3A4 inhibitor is selected from the group consisting of atazanavir, boceprevir, clarithromycin, cobicistat, conivaptan, turmeric Curcumin, Danazol, Danoprevir, Darunavir, Delavirdine, Diltiazem, Ditiocarb, Econazole, efavirenz, elvitegravir, ergotamine, idelalisib, indinavir, itraconazole (itraconazole), ketoconazole, loperamide, lopinavir, methimazole, midostaurin, naloxone, naphthalene Nefazodone, nelfinavir, nilotinib, posaconazole, ribociclib, ritonavir, saquina Saquinavir, stiripentol, telaprevir, telithromycin, terfenadine, tipranavir, troleandomycin ( troleandomycin) and voriconazole (voriconazole). In some embodiments, the CYP3A4 inhibitor is selected from the group consisting of ritonavir and cobicistat. In some embodiments, the CYP3A4 inhibitor is cobicistat.

Examples of concomitant medications include, but are not limited to, the following medications. Therapeutic drugs for narcolepsy (such as methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine , tirolisan, solriamfertol), weight loss drugs (amphetamine, benzfetamine, bromocriptine, bupropion, diethylpropion, Ezema Exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, octreotide, ori Orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide ( pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin , metformin), acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galanthamine, zanapezil, idebenone (idebenone, tacrine), antidementia agents (such as memantine), inhibitors of β-amyloid production, secretion, accumulation, aggregation and/or deposition, β-secretase Inhibitors (such as 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methyl Oxy-2-(N,N-dimethylamino)methyl-tetralin, 6-(4-biphenyl)methoxy-2-(N,N-dipropylamino)methyl Tetrahydronaphthalene, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)tetrahydronaphthalene, 6-(4-biphenyl Phenyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-Dimethylamino)ethyl]- 6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxy ylbiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4- base)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxole-5- base)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4- base)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, its optically active form, its pharmaceutically acceptable salt, hydrate or solvate and Its hydrate, OM99-2 (WO01/00663)), γ-secretase inhibitors, β -amyloid aggregation inhibitors (such as PTI-00703, ALZHEMED (NC-531), PPI-368 (International Patent Application National Publication No. 11-514333), PPI-558 (National Publication of International Patent Application No. 2001-500852), SKF-74652 (Biochem.J.(1999), 340(1), 283-289 )), beta -amyloid vaccines, beta -amyloid-degrading enzymes and the like, brain function enhancers (eg aniracetam, nicergoline), therapeutic drugs for Parkinson's disease [(e.g. dopamine receptor agonists (e.g. L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, adamantane amantadine), monoamine oxidase (MAO) inhibitors (e.g. deprenyl, selegiline, remacemide, riluzole), antiparasympathetic agents (e.g. Trihexyphenidyl, biperiden, COMT inhibitors (such as entacapone (entacapone)], therapeutic drugs for amyotrophic lateral sclerosis (such as riruthiazole, etc., neurotrophic factors), therapeutic drugs (e.g., sedatives, anxiolytics), inhibitors of apoptosis (e.g., CPI-1189, IDN-6556, CEP-1347 ), neuronal differentiation/regeneration promoters (eg, leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853, proxatide ( prosaptide), 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzene Furan-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylbenzene base)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropyl Phenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3] Dioxole[4,5-f]isoindole and its optically active forms, salts or hydrates), non-steroidal anti-inflammatory agents (meloxicam, tenoxicam , indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroid drugs (dexamethasone (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-intermediate drugs (such as TNF inhibitors, MAP kinase inhibitors) , therapeutic agents for incontinence and urinary frequency (such as flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (such as sildenamate sildenafil (citric acid), dopamine agonists (such as apomorphine), antiarrhythmic drugs (such as mexiletine), sex hormones or their derivatives (such as progesterone (progesterone, estradiol, estradiol benzoate), therapeutic agents for osteoporosis (such as alfacalcidol, calcitriol, elcatonin, salmon Calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium )), parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drugs for insomnia (such as benzodiazepine drugs, non-benzodiazepine drugs, melatonin agonists, orexin receptors antagonists), therapeutic drugs for schizophrenia (e.g. typical antipsychotics such as haloperidol and the like; atypical antipsychotics such as clozapine, olanzapine, Risperidone, aripiprazole iprazole) and the like; drugs acting on metabotropic glutamate receptors or ion channel-binding glutamate receptors; phosphodiesterase inhibitors), benzodiazepines (chlordiazepoxide ), diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitors (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, hydrochloride clomipramine, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, citalopram hydrochloride Sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-norepinephrine reuptake inhibitors (venlafaxine hydrochloride, duloxyl hydrochloride (duloxetine hydrochloride, venlafaxine hydrochloride, etc.), norepinephrine reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine (mirtazapine), trazodone hydrochloride ( trazodone hydrochloride), nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT _1A agonists (buspirone hydrochloride, Spirone (tandospirone citrate), osemozotan hydrochloride (osemozotan hydrochloride, etc.), 5-HT _2A antagonists, 5-HT _2A inverse agonists, 5-HT ₃ antagonists (cyamemazine etc.), cardiac nonselective β inhibitors (propranolol hydrochloride, oxprenolol hydrochloride, etc.), histamine _H1 antagonists (hydroxyzine hydrochloride (hydroxyzi ne hydrochloride, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), acting on metabotropic gluten Drugs for amino acid salt receptors, CCK antagonists, β3 adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium Channel inhibitors, carbonic anhydrase II inhibitors, NMDA glycine partial agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4 ), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), COMT inhibitors (entacapone, etc.), therapeutic drugs for bipolar disorders ( Lithium carbonate, sodium valproate, lamotrigine, riruthiazole, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, Sodium channel inhibitors, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), therapeutic drugs for alcoholism, therapeutic drugs for autism, therapeutic drugs for chronic fatigue syndrome, therapeutic drugs for spasticity , Therapeutic drugs for fibromyalgia syndrome, therapeutic drugs for headache, therapeutic drugs for smoking cessation, therapeutic drugs for myasthenia gravis, therapeutic drugs for cerebral infarction, therapeutic drugs for mania, therapeutic drugs for hypersomnia , therapeutic drugs for pain, therapeutic drugs for hypodepression, therapeutic drugs for autonomic ataxia, therapeutic drugs for male and female sexual dysfunction, therapeutic drugs for migraine, therapeutic drugs for pathological gamblers , Therapeutic drugs for restless legs syndrome, therapeutic drugs for substance addiction, therapeutic drugs for alcohol-related syndrome, therapeutic drugs for irritable bowel syndrome, therapeutic drugs for ALS (riruthiazole, etc., neurotrophic factors, etc. ), therapeutic drugs for lipid abnormalities such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), Fibrate (clofibrate, etc.), squalene synthase inhibitors), therapeutic drugs for abnormal behaviors caused by dementia or wandering disorder inhibitors (sedatives, anti-anxiety drugs, etc.), reduce Obesity drugs, therapeutic drugs for diabetes, therapeutic agents for diabetic complications, therapeutic drugs for hypertension, therapeutic drugs for hypotension, diuretics, chemotherapeutic agents, immunotherapeutic agents, antithrombotic agents, anticancer agents, and the like .

Two or more of the above-mentioned combined drugs may be used in admixture at an appropriate ratio.

Compound (I) can also be used in combination with biological agents (such as antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), or can be combined with gene therapy methods and the like and administered as combination therapy, or can also be combined with Therapeutic combination use in the field of psychiatry without the use of drugs.

Examples of treatments in the field of psychiatry that do not use drugs include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, psychotherapy (including cognitive behavioral for therapy) and the like.

pharmaceutical composition

Further disclosed herein are pharmaceutical compositions comprising Compound (I) or Compound A. In some embodiments, the pharmaceutical composition comprises (a) 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine- Methyl 1-formate (compound (I)) or compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable carrier thereof.

In one embodiment there is provided a pharmaceutical composition comprising (a) 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate (compound (I)) or compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition Provided a greater increase in sleep onset latency than placebo.

In one embodiment there is provided a pharmaceutical composition comprising (a) 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate (compound (I)) or compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition Provides an increase in sleep latency over 10.5 minutes.

In one embodiment there is provided a pharmaceutical composition comprising (a) 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate (compound (I)) or compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition Provides a greater increase in sleep onset latency than modafinil.

In one embodiment there is provided a pharmaceutical composition comprising (a) 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydro Methyl pyridine-1-carboxylate (compound (I)) or compound A or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition Reduces excessive daytime sleepiness compared to placebo, as measured by the Karolinska Sleepiness Scale (KSS) measured.

The pharmaceutically acceptable carrier can be cyclodextrin. The cyclodextrin may be sodium beta cyclodextrin sulfobutyl ether.

Various organic or inorganic carrier substances generally used as preparation materials can be used as the pharmaceutically acceptable carrier. These substances are incorporated as excipients, lubricants, binders and disintegrants for solid preparations; or as solvents, solubilizers, suspending agents, isotonic agents, buffers and soothing agents for liquid preparations; and the like; Formulation additives such as preservatives, antioxidants, colorants, sweeteners, and the like may need to be added.

Examples of dosage forms of the above-mentioned pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, orally disintegrating tablets), capsules (including soft capsules, microcapsules), granules, powder, lozenge, syrup, emulsion, suspension, film (e.g., orally disintegrable film), injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, instillation), topical (e.g., dermal ointments), suppositories (e.g. rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalation), eye drops and the like, which may be safely administered orally or parenterally respectively (e.g. topical, rectal, intravenous administration). Such formulations may be release controlled formulations (eg sustained release microcapsules), eg immediate release formulations, sustained release formulations and the like.

In some embodiments, pharmaceutical compositions are formulated for oral administration. In some embodiments, pharmaceutical compositions are formulated for parenteral administration. In some embodiments, pharmaceutical compositions are formulated for intravenous, subcutaneous, transdermal, intradermal, or transmucosal administration. In some embodiments, pharmaceutical compositions are formulated for intravenous administration. In some embodiments, pharmaceutical compositions are formulated for subcutaneous administration. In some embodiments, pharmaceutical compositions are formulated for transdermal administration.

optically active compound

In some embodiments, Compound (I) is an optically active compound. In some embodiments, compound (I) is (2R,3S)-3-((methylsulfonyl)amino)-2- in any one of the methods, uses and pharmaceutical compositions disclosed herein Methyl (((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate (Compound A). Compound (I), including salts thereof and optically active compounds thereof, can be produced as disclosed in WO2017/135306.

set

Further disclosed herein are kits comprising Compound (I), including Compound A. In some embodiments, the kit comprises (a) a compound containing 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1 - a container for methyl formate (compound (I)) or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) instructions for administering compound (I).

The kits disclosed herein may further comprise another container containing saline.

The container can be a glass bottle. Alternatively, the container can be a syringe.

The disclosure is not to be limited to the specific embodiments described in this application, which are intended as separate illustrations of individual aspects of the disclosure. Not all individual embodiments of the disclosure are described herein. Many modifications and variations of this disclosure can be made without departing from the spirit and scope of the disclosure, as will be apparent to those skilled in the art. Functionally equivalent methods and devices within the scope of the disclosure, in addition to those methods and devices enumerated herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The disclosure is to be limited only by the appended claims, and the full scope of equivalents to which such claims are entitled.

It is to be understood that this disclosure is not limited to particular uses, methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

Additionally, where features or aspects of the disclosure are described in terms of the Markush group, those skilled in the art should recognize that any individual member or subgroup of members of the Markush group is also thereby To illustrate this disclosure.

As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range is readily identifiable as adequately formulated and capable of breaking down the same range into at least equal one-half, one-third, one-fourth, one-fifth, one-tenth, etc. As a non-limiting example, each range discussed herein can be easily broken down into a lower third, a middle third, an upper third, and so on. Those skilled in the art will also understand that all language (e.g., "up to," "at least," "greater than," "less than," and the like) includes the recited numerical value and refers to values that can then be broken down into subranges as discussed above. scope. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2 or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4 or 5 cells, etc.

definition

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide those skilled in the art with general definitions of many of the terms used in the present invention: Singleton et al ., Dictionary of Microbiology and Molecular Biology (2nd Ed., 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale and Marham, The Harper Collins Dictionary of Biology (1991). Unless otherwise stated, the following terms as used herein have the meanings assigned below. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well unless the context clearly dictates otherwise.

As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one skilled in the art, which will depend in part on the manner in which the value was measured or determined, i.e. measuring System Limitations. For example, "about" can mean within 3 standard deviations or more than 3 standard deviations, as practiced in the art. Alternatively, "about" may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value. Alternatively, especially for biological systems or processes, these terms may mean within a certain order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

The term "administering" an agent to a human as used herein includes any means by which an agent is introduced or delivered to a human to perform its intended function. Administration can be by any suitable parenteral route, including but not limited to intravenous, intramuscular, intraperitoneal, subcutaneous and other suitable routes as described herein. Administration includes self-administration as well as administration by another person.

The term "effective amount" or "therapeutically effective amount" as used herein refers to the amount of Compound (I) (or Compound A) sufficient to achieve a desired effect or a desired therapeutic effect. In the context of therapeutic applications, the amount of Compound (I) or Compound A administered to humans may depend on the type and severity of the disease or symptoms, as well as on individual characteristics (such as general health, age, sex, body weight, and drug resistance). Receptivity) depends. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors.

The term "modulation" as used herein refers to positive or negative changes. Exemplary adjustments include changes of about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100%.

The term "increase" as used herein 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%.

The term "decrease" as used herein means a negative change of at least about 5%, including but not limited to a negative change of about 5%, about 10%, about 25%, about 30%, about 50%, about 75% Or about 100%.

The term "OX2R agonist" as used herein refers to 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)hexahydropyridine- Methyl 1-formate ("compound (I)") or a pharmaceutically acceptable salt, hydrate or solvate thereof. In some embodiments, compound (I) is (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol base) methyl hexahydropyridine-1-carboxylate (compound A).

A "pharmaceutically acceptable excipient or carrier" refers to an excipient that is optionally included in the compositions of the present disclosure and that does not produce significant adverse toxicological effects in humans.

A "composition", "pharmaceutical composition" as used herein is intended to be an active agent, such as a compound as disclosed herein, and an inert or active carrier. The carrier can be, but is not limited to, a solid such as beads or resins, or a liquid such as phosphate buffered saline.

"Pharmaceutically acceptable salt" means a salt of a compound that is suitable for pharmaceutical use and is derived from a variety of organic and inorganic counterions well known in the art, and includes when the compound contains an acidic functional group ( By way of example only) sodium, potassium, calcium, magnesium, ammonium and tetraalkylammonium; and when the molecule contains basic functional groups, including salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate , mesylate, acetate, maleate and oxalate (for a discussion of pharmaceutical salts, their selection, preparation and use, see Stahl and Wermuth, eds., "Handbook of Pharmaceutically Acceptable Salts", (2002), Verlag Helvetica Chimica Acta, Zürich, Switzerland).

In general, pharmaceutically acceptable salts are those salts that substantially retain one or more of the desired pharmacological activities of the parent compound and are suitable for in vivo administration. Pharmaceutically acceptable salts include and inorganic Acid addition salts formed with acids or organic acids. Inorganic acids suitable for the formation of pharmaceutically acceptable acid addition salts include, for example, but are not limited to, hydrohalic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like), sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids suitable for the formation of pharmaceutically acceptable acid addition salts include, for example and without limitation, acetic acid, trifluoroacetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid , malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid , alkylsulfonic acids (such as methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, etc.) acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include those when the acidic proton present in the parent compound is passed on by a metal ion (such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or by an ammonium ion (such as derived from an organic base (such as ethanolamine, ethanolamine, Diethanolamine, triethanolamine, morpholine, hexahydropyridine, dimethylamine, diethylamine, triethylamine, and ammonium ions of ammonia) are substituted for salts.

A solvate of a compound is a solid form of the compound that crystallizes within the crystal lattice using less than one, one or more than one molecule of solvent. A few examples of solvents that can be used to generate solvates such as pharmaceutically acceptable solvates generally include, but are not limited to, water, C1-C6 alcohols such as methanol, ethanol, isopropanol, butanol, and optionally substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, and solvent mixtures thereof. Other such biocompatible solvents that facilitate the manufacture of pharmaceutically acceptable solvates are well known in the art. In addition, various organic and inorganic acids and bases can be added to produce the desired solvates. Such acids and bases are known in the art. When the solvent is water, the solvate may be referred to as a hydrate. In some embodiments, one molecule of compound can form a solvent with 0.1 to 5 molecules of solvent One molecule of solvent (hemisolvate, eg, hemihydrate), one molecule of solvent (monosolvate, eg, monohydrate), and two molecules of solvent (disolvate, eg, dihydrate).

An "effective amount" or "pharmaceutically acceptable amount" is an amount sufficient to achieve a beneficial or desired result. An effective amount can be one or more of administration, administration, or dosage administration and is determined by the system in which the drug or compound is delivered, eg, an effective amount for in vitro purposes is different from an effective amount for in vivo purposes. For in vivo purposes, delivery and an "effective amount" depend on a number of variables including the time period over which the individual dosage unit is intended to be used, the bioavailability of the therapeutic agent, the route of administration, and the like. It is understood, however, that specific dosage levels for the therapeutic agents disclosed herein for any given human will depend on a variety of factors, including the activity of the particular compound used, the bioavailability of the compound, the route of administration, the age of the animal and its body weight, general health, sex, diet of the animal, time of administration, rate of excretion, combination of drugs and severity of the specific condition being treated, and form of administration. In general, one would expect to administer an amount of compound effective to achieve serum levels commensurate with concentrations considered effective in vivo. Such considerations, as well as effective formulation and administration procedures, are well known in the art and are described in standard textbooks.

As used herein, "treating" or "treatment" of a human disease refers to (1) inhibiting the disease or arresting its development; or (2) improving or causing regression of the disease or symptoms of the disease. As understood in the art, "treatment" is a means of obtaining beneficial or desired results, including clinical results. For the purposes of this technique, beneficial or desired results may include, but are not limited to, one or more of the following: relief or alleviation of one or more symptoms, reduction in the severity of a disorder (including a disease), Stability of state (ie no deterioration), delay or slowdown of disease (including disease), progression, remission or alleviation of disease (including disease), state and decline (partial or complete), detectable or undetectable.

example

The following non-limiting examples are presented to provide those skilled in the art how to make and use The complete disclosure and description of the compositions and methods of analysis, screening and treatment of the present disclosure are not intended to limit the scope of what the inventors regard as their invention.

Example 1: Phase 1b randomized, double-blind, placebo-controlled, crossover study of a single intravenous infusion dose of an orexin 2 receptor (OX2R) agonist in patients with idiopathic narcolepsy

main target

The primary objective of this study was to evaluate the administration of Compound A ((2R,3S)-3-((methylsulfonyl)amino)-2- Safety and tolerability of a single IV infusion of (((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate).

secondary goal

The secondary objective of this study was to investigate the pharmacokinetic (PK) parameters of a single IV infusion of Compound A in adult subjects with IH.

exploratory goals

The exploratory objectives of this study are as follows:

1. To evaluate the effect of compound A on daytime sleepiness as measured by the 40-minute maintenance of wakefulness test (MWT).

2. Evaluation of the effect of Compound A on daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS).

3. To evaluate the effect of Compound A on attention and alertness as measured by the Psychomotor Vigilance Task (PVT).

4. Evaluate the effect of Compound A on vital signs.

5. Evaluation of PK of compound A metabolites.

Research Design and Planning

This is a Phase 1b, randomized, double-blind, placebo-controlled, 2-period, 2-treatment crossover study to evaluate the PK, pharmacodynamics (PD), pharmacodynamics (PD), Safety and Tolerability. The subjects were male and female aged 18 to 75 years old (including 18 and 75 years old), diagnosed with IH according to the International Classification of Sleep Disorders-3 (ICSD-3) criteria, such as by Validation of previous nocturnal polysomnography (nPSG) and multiple sleep latency testing (MSLT) studies performed.

The treatment period started on Day 1 of treatment period 1 (study day 1), and treatment period 2 started on study day 3, where treatment period 1 was study days 1 and 2 and treatment period 2 was study days 3 and 4. On the morning of Day 1 of Treatment Period 1, eligible subjects were randomized to 1 of 2 sequence groups as listed in Table 1. After randomization, the subject is dosed for 2 treatment periods according to the order defined by the sequence group to which he/she is randomized. Compound A (or placebo) was administered as a single 9-hour IV infusion starting at approximately 0800 hours on Day 1 of each treatment period. The infusion was stopped at approximately 1700. On Day 1 of each treatment period, four 40-minute MWT sessions were performed at 2 hours, 4 hours, 6 hours, and 8 hours after the start of the infusion. Subjects were asked to remain awake between MWT sessions and during the day on the first washout day (Study Day 2).

11之合格受試者完成病史及身體檢查、半臥生命徵象評價、12導程心電圖(ECG)、貝克抑鬱症清單II(Beck Depression Inventory，BDI-II)、哥倫比亞自殺嚴重程度評級量表(Columbia Suicide Severity Rating Scale，C-SSRS)及臨床安全性實驗室測試。在篩選時正在服用刺激劑之ESS評分<11之受試者繼續篩選過程且在洗滌後在研 究日-2時重複ESS。將總共40個受試者隨機化，以使得至少36個受試者完成研究。為避免具有慢性睡眠剝奪之短睡眠者入選，前瞻性參與者完成睡眠日記支持之大約連續7天之活動記錄，在研究日-9開始且在研究日-3結束(即在其入住臨床單位之研究日-2前一天)，以確保受試者之正常夜間睡眠時段期間之平均夜間睡眠持續時間

420分鐘(7小時)，且若受試者之平均夜間睡眠持續時間

480分鐘(8小時)，則該受試者未患睡眠不足症候群(在「非工作日」比「工作日」多睡>2小時/夜)。在篩選期間，合格受試者中斷其用於治療IH之刺激藥物。在給藥之第一天(治療期1之第1天)之前，使藥物中斷最短7天或每一藥物之至少5個半衰期，以較長者為準。在篩選前中斷羥丁酸鈉至少4週。 Epworth Sleepiness Scale (ESS) score at Screening Visit

11 qualified subjects completed medical history and physical examination, semi-recumbent vital sign evaluation, 12-lead electrocardiogram (ECG), Beck Depression Inventory II (Beck Depression Inventory, BDI-II), Columbia Suicide Severity Rating Scale (Columbia Suicide Severity Rating Scale, C-SSRS) and clinical safety laboratory tests. Subjects with an ESS score <11 on the stimulant at Screening continued with the Screening process and repeated the ESS on Study Day-2 after washing. A total of 40 subjects were randomized such that at least 36 subjects completed the study. To avoid enrollment of short sleepers with chronic sleep deprivation, prospective participants completed approximately 7 consecutive days of activity recording supported by sleep diaries, beginning on Study Day-9 and ending on Study Day-3 (i.e., before their admission to the clinical unit). Study Day-2 the day before) to ensure the average duration of nocturnal sleep during the subjects' normal nocturnal sleep period

420 minutes (7 hours), and if the subject's average nighttime sleep duration

480 minutes (8 hours), then the subject does not suffer from sleep deprivation syndrome (sleep more than 2 hours/night on "non-working days" than "working days"). During the screening period, eligible subjects discontinued their stimulatory medications for the treatment of IH. Prior to the first day of dosing (Day 1 of Treatment Period 1), drug was interrupted for a minimum of 7 days or at least 5 half-lives for each drug, whichever was longer. Discontinue sodium oxybate for at least 4 weeks prior to screening.

5%之總睡眠時間，O₂飽和

80%)，並確認呼吸暫停低通氣指數(AHI)

10/小時且與喚起相關之週期性肢體移動指數(PLMAI)

15/小時。 The screening period is up to 28 days. After screening, subjects who met all screening entry criteria were admitted to clinical units (Study Day-2). Semi-recumbent vital signs were obtained after admission and ESS was recorded in the late afternoon. Overnight 8-hour nPSG was administered around the subject's normal bedtime (e.g., between 2200 and 2300) to confirm that the subject did have other comorbid sleep disorders or clinically significant nocturnal hypoxemia (for

5% of total sleep time, _O2 saturation

80%), and confirm the apnea-hypopnea index (AHI)

10/hour and arousal-related periodic limb movement index (PLMAI)

15/hour.

Study Day-1 was the assigned baseline evaluation day and also intended to acclimate to sleeping in the clinical unit. Four 40-minute MWT sessions were administered, timed to match the planned times of the MWT sessions scheduled after study drug administration on dosing days (Study Days 1 and 3). Complete KSS and PVT after MWT. Safety evaluations including blood pressure (BP), pulse, respiration rate and ECG were also collected.

On Day 1 of Treatment Period 1 (Study Day 1), all eligible subjects were randomized and received the first dose of study drug. Compound A or placebo was administered as a single 9 hour IV infusion starting at approximately 08:00. On each dosing day (study days 1 and 3), at 2 hours, 4 hours, 6 hours and 8 hours to conduct 40-minute MWT sessions. A minimum 24-hour washout interval between the end of the Compound A infusion and initiation of treatment in the subsequent treatment period allowed for complete elimination of the effects of previous treatment. Study days 2 and 4 were wash days. Collect KSS and PVT. Blood samples for determination of Compound A plasma concentrations are collected pre-dose and at indicated time points post-dose, ideally via an internal venous catheter, so as not to interfere with MWT testing. Safety assessments were recorded, including adverse events (AEs), vital signs, and ECG. During the study, AEs were recorded and clinical laboratory results, vital signs and safety ECGs were obtained. Subjects were discharged from the hospital after completion of the study exit procedure in the afternoon of Study Day 4 (Day 2 of Treatment Period 2).

Subjects returned to the study site approximately 7 days (±2 days) after discharge or contacted by telephone for a safety check, and all females of childbearing potential returned to the study site at the end of the study visit to complete a urine pregnancy test.

An overview of the inpatient unit study schedule is presented in Table 2.

Diet and Fluids

Subjects received 3 standard meals per day during unit confinement, each meal consisting of approximately 30% fat (relative to total calories). Breakfast at approximately 0700 each morning; lunch and dinner at standard time to avoid overlap or interference with clinical tests (MWT, KSS, PVT).

Subjects were restricted from using tobacco and nicotine-containing products, alcohol, xanthine and/or coffee before and during the screening period (days -28 to -3) and during hospitalization day -2 to discharge day 4.

Subjects refrained from grapefruit/grapefruit juice and Seville orange, mustard greens for 7 days prior to dosing during the screening period (days -28 to -3) and during hospitalization day -2 to discharge day 4 Vegetables (i.e. kale, broccoli, watercress, green kale, kohlrabi, Brussels sprouts and mustard greens) and roasted meat.

Activity

Subjects refrained from unaccustomed strenuous physical activity (i.e. weightlifting, running, cycling, etc.). Short supervised walks outside the unit are permitted on wash days.

Primary and Secondary Endpoints

The primary endpoints were as follows:

˙Percentage of subjects experiencing at least 1 treatment-emergent adverse event (TEAE).

˙Percentage of subjects meeting the criteria for significant abnormalities in clinical safety laboratory tests at least once after the protocol.

˙Percentage of subjects meeting the criteria for significantly abnormal vital sign measurements at least once post-protocol.

˙Percentage of subjects meeting the significantly abnormal criteria for 12-lead safety electrocardiogram (ECG) parameters at least once after the protocol.

Secondary endpoints:

˙Compound A PK parameters:

- Observed plasma concentration at the end of the infusion (C _eoi ).

- Area under the plasma concentration-time curve ( _AUC∞ ) from time 0 to infinity.

- Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC _last ).

exploratory endpoint

The following PD endpoints were measured to explore the effect of Compound A in subjects with IH:

˙Average sleep latency of 4 MWT sessions after dosing in each treatment period.

˙KSS score measured at each time point in each treatment period.

˙PVT score after administration in each treatment period.

The following PK parameters were estimated to assess the PK of Compound A metabolites in subjects with IH:

˙C _eoi .

_˙AUC∞ .

˙AUC _{last time} .

As data permit, the following safety endpoints were estimated for Compound A in subjects with IH:

Body checkup.

˙Vital signs, including semi-recumbent blood pressure (BP), heart rate (HR) and respiratory rate.

˙12 lead ECG.

˙Clinical laboratory safety assessment (hematology, serum chemistry and urinalysis).

research group

Main inclusion criteria:

˙IH diagnosis as defined by ICSD-3, as validated by previous nocturnal polysomnography (nPSG) and multiple sleep latency testing (MSLT) studies performed within the past 10 years.

˙Hypersomnia begins between the age of 10 and the age of 30.

˙The body mass index (BMI) is 18 to 33 (including 18 and 33) kg/m ² .

420分鐘。 ˙Seven consecutive days of activity recordings obtained prior to nPSG (Study Day-2) backed by sleep diaries (recorded while subjects were wearing actigraphy) showing mean nocturnal sleep duration during subjects' normal nighttime sleep periods

420 minutes.

5%之總睡眠時間，O₂飽和

80%)，且其呼吸暫停低通氣指數(AHI)

10/小時，其週期性肢體移動喚起指數(PLMAI)

15/小時，且總睡眠時間

6.5小時。 ˙nPSG (Study Day-2) demonstrated that the subject did not suffer from other comorbid sleep disorders or clinically significant nocturnal hypoxemia (for

5% of total sleep time, _O2 saturation

80%), and its apnea-hypopnea index (AHI)

10/hour, its periodic limb movement arousal index (PLMAI)

15/hour, and total sleep time

6.5 hours.

˙Average (over 4 sessions) baseline MWT sleep latency less than or equal to 20 minutes and a single session of sleep The sleep latency does not exceed 30 minutes, as determined by the field investigator or qualified designer.

˙Subjects taking medication for excessive daytime sleepiness were willing to discontinue medication prior to randomization into the study.

11。在篩選時正在服用刺激劑之ESS評分<11之受試者可繼續篩選過程且在洗滌後在研究日-2時重複ESS。 ˙Epworth Sleepiness Scale (ESS) score at Screening and Day -2

11. Subjects with an ESS score < 11 who were taking a stimulant at Screening may continue with the Screening process and repeat the ESS on Study Day-2 after washing.

˙Blood pressure (BP) must be <140mmHg (systolic) and <90mmHg (diastolic) at screening and study day-2. BP measurements were obtained after the subject rested for a minimum of 10 minutes and could be repeated 3 times while BP was above these parameters. Use the median BP reading.

Key exclusion criteria:

8小時(480分鐘)且受試者患有睡眠不足症候群，如藉由在nPSG(研究日-2)之前獲得之活動記錄及睡眠日記所確定之「非工作日」比「工作日」多睡>2小時/夜所證實。 ˙Average nighttime sleep duration

8 hours (480 minutes) and the subject suffered from sleep deprivation syndrome, as determined by the activity records and sleep diaries obtained before nPSG (study day-2) "Non-working days" sleep more than "Working days">2 hours/night demonstrated.

˙The resting heart rate (HR) exceeds the range of 40 to 90 beats per minute, and no stimulants are taken.

˙Screening ECG revealing QT interval >450ms (male) or >470ms (female) using Fridericia correction method.

˙Usual bedtime later than 2400 (midnight) or had an occupation requiring night shift work or variable shift work within the past 6 months, or had travel with significant jet lag within the 14 days prior to Study Day-2.

˙History of sleep disorders other than IH, such as sleep apnea (OSA), restless legs syndrome, or periodic limb movements associated with arousal of sleep (PLMS), based on the interview at the screening visit.

˙Use of any stimulant over-the-counter or prescription drug within 7 days prior to dosing or 5 half-lives (whichever is longer) that may have affected the assessment of excessive daytime sleepiness, or oxybutyrate within 4 weeks of screening Any use of sodium.

10隻香煙/天)及/或不願意中斷所有吸煙及尼古丁使用。 ˙During the confinement portion of the study (days -2 to 4), nicotine dependence that may have had an effect on sleep (eg, subjects typically smoked awake at night) or challenged the conduct of the study (smoking

10 cigarettes/day) and/or unwillingness to discontinue all smoking and nicotine use.

˙Consumption of caffeine greater than 600 mg/day (1 serving of coffee approximately equivalent to 120 mg caffeine) in the 7 days prior to Study Day 1, and/or not during the confinement portion of the study (Days -2 to 4) Willing to cut off all caffeine.

˙From 72 hours before admission to discharge on study day 4, alcohol use that may have an effect on sleep and/or unwillingness to discontinue all alcohol use.

˙Any history or existence of unstable medical disorders, behavioral or mental disorders (including major depressive disorder or active suicidal ideation), or according to the investigator's judgment, may have affected the safety of the subject or interfered with the efficacy, safety, PK assessment or surgical history of subject's ability to complete the study.

Statistical Considerations

Implement standard summarization of TEAE, Adverse Events of Special Interest (AESI), clinical safety laboratory results, vital signs and ECG. BP and QT parameters (N, mean, SD, median, minimum, and maximum) were pooled for baseline, post-dose, change from baseline, and change from time-matched baseline to post-dose treatment, as appropriate.

Observed HR and BP were analyzed using linear mixed effects models for repeated measures in a crossover study. Models included sequence, time period, treatment, time point, and treatment interacting by time point as fixed and random effects for subjects. Estimated mean HR and BP and associated standard errors and 95% CIs for each treatment, as well as all pairwise differences and associated standard errors, 95% CIs and p-values from placebo were extracted from the model at each time. The same amount averaged over all time points during the infusion and after the end of the infusion was extracted from the model using appropriate contrasts.

List the individual plasma concentrations and PK of Compound A (and its metabolites) for each subject Parameter estimates and summary using descriptive statistics where appropriate.

Summary of Top Line Results

Twenty-eight patients were randomized, and 25 patients completed the study. All patients were experiencing excessive daytime sleepiness (EDS) at entry (mean Epworth Sleepiness Scale (ESS) = 18.3 points and mean sleep onset latency of 4 maintenance of wakefulness test (MWT) trials was 9.2 min). Tables 3 and 4 show the demographic and baseline disease characteristics of the study population.

In conclusion, Compound A was well tolerated with no serious adverse events (AEs), no discontinuations due to AEs, and no clinically significant ECG or laboratory values. The percentage of patients with at least one treatment-emergent AE (TEAE) was 15% in the placebo group and 40% in the Compound A 112 mg group. All Compound A 112 mg TEAEs were mild except for one report of insomnia classified as severe and one report of anxiety classified as moderate. TEAEs related to "any urinary event" were reported in 16% of patients (4 patients) in the Compound A 112 mg group, all of which were mild in severity.

No TEAEs of increased blood pressure were reported. No significantly abnormal BP elevations (>160/100 or >20 change from pre-dose) or HR>115 were reported.

70%確定性。圖1顯示4次MWT試驗之給藥後睡眠潛伏期之LS平均值。圖2顯示根據時間點來自MWT之給藥後入睡潛伏期之LS平均值(95% CI)。 With regard to the pharmacodynamics of excessive daytime sleepiness, Compound A 112 mg showed significant improvements in objective and subjective measures of wakefulness in patients with idiopathic narcolepsy (IH). In the MWT with a 40-minute ceiling effect, unadjusted mean sleep latency values were approximately 10.5 minutes and 39.9 minutes for placebo and Compound A 112 mg, respectively. A mean placebo-adjusted increase in sleep onset latency of 29.4 minutes was statistically significant. This study complied with the ePOC guidelines, and based on the data, the true difference between MWT and placebo > 6min has

70% certainty. Figure 1 shows the LS mean values of post-dose sleep latencies for 4 MWT trials. Figure 2 shows the LS mean (95% CI) of post-dose sleep onset latency from MWT according to time point.

Compound A 112 mg also reduced subjective sleepiness as measured by KSS (Karolinska Sleepiness Scale). A mean placebo-adjusted KSS reduction of -3.3 points was statistically significant. Fig. 3 shows LS mean values of KSS (Karolinska Sleepiness Scale) after administration. Figure 4 shows the LS mean (95% CI) of KSS after dosing according to time point.

Objective and subjective pharmacodynamic effects were evident as early as 2 hours after dosing and remained stable over time.

In conclusion, a single dose of Compound A administered as an infusion of 112 mg over 9 hours in IH patients was well tolerated in most people without major safety concerns and demonstrated a significant effect on maintaining daytime wakefulness in patients with IH Positive objective and subjective pharmacodynamic effects.

112 mg of Compound A administered by IV infusion demonstrated near-maximal levels of wakefulness as measured by MWT in previous clinical tests.

There is no approved therapy for IH worldwide, except modafinil, which has been approved in Japan. The only published pivotal study supporting this approval showed an improvement in MWT of 2.8 min in a 33 patient study which was found not to be significant (Mayer et al ., J Sleep Res. (2015) 24, 74-81).

Claims (88)

A method of treating an orexin-mediated disease or condition in a human having normal orexin levels, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino )-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine- Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof increased sleep latency more than placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof, which are used to treat orexin-mediated diseases or conditions in humans with normal orexin levels, wherein a therapeutically effective amount of (2R,3S)- 3-((Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable The received salt, hydrate or solvate increased sleep latency more than placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of the ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for a human orexin-mediated disease or disease with normal orexin levels, wherein a therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Pharmaceutically acceptable salts, hydrates or solvates increased sleep latency more than placebo. A method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(( (cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, which The therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine - Methyl 1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency more than placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof, which are used for the treatment of idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methyl Sulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable salt, hydrate Or solvates increased sleep latency more than placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of an ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for human idiopathic narcolepsy in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate, or solvate increased sleep latency more than placebo. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-((( cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Pharmaceutically acceptable salts, hydrates or solvates increased sleep latency more than placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or their pharmaceutically acceptable salts, hydrates or solvates, which For the treatment of excessive daytime sleepiness in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl Methyl cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency more than placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of the ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3-( (Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt thereof , hydrate, or solvate increased sleep latency more than placebo. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 9 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester, wherein the therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis Formula-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate increases sleep latency compared with placebo Over about 2.8 minutes. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-((cis-4-phenyl ring) as described in any one of claims 1 to 10 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester, wherein the therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis Formula-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate increases sleep latency compared with placebo Over about 29.4 minutes. A method of treating an orexin-mediated disease or condition in a human having normal orexin levels, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino )-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Accepted salts, hydrates or solvates, wherein the therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclo Hexyl)oxy)methyl)pyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 10.5 minutes. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof, which are used to treat orexin-mediated diseases or conditions in humans with normal orexin levels, wherein a therapeutically effective amount of (2R,3S)- 3-((Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Received salts, hydrates or solvates increased sleep latency by more than about 10.5 minutes. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of the ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for a human orexin-mediated disease or disease with normal orexin levels, wherein a therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate increases sleep latency by more than about 10.5 minutes. A method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(( (cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate thereof increases sleep latency by more than about 10.5 minutes. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof, which are used for the treatment of idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methyl Sulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable salt, hydrate or solvates increased sleep latency by more than about 10.5 minutes. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of an ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for human idiopathic narcolepsy in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salts, hydrates, or solvates increased sleep latency by more than about 10.5 minutes. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-((( cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate increases sleep latency by more than about 10.5 minutes. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof for the treatment of excessive daytime sleepiness in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonate Acyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or The solvate increased sleep latency by more than about 10.5 minutes. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of the ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3-( (Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt thereof , hydrate or solvate increases sleep latency by more than about 10.5 minutes. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 12 to 20 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R,3S)-3-(( Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt thereof, Hydration or solvation increased sleep latency by more than 13.3 minutes. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 12 to 21 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R,3S)-3-(( Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt thereof, Hydrates or solvates increased sleep latency by 39.9 minutes or longer. A method of treating an orexin-mediated disease or condition in a human having normal orexin levels, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino )-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine- Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof can increase sleep latency more than modafinil. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof, which are used to treat orexin-mediated diseases or conditions in humans with normal orexin levels, wherein a therapeutically effective amount of (2R,3S)- 3-((Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable The received salts, hydrates or solvates increased sleep latency more than modafinil. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of the ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for a human orexin-mediated disease or disease with normal orexin levels, wherein a therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Pharmaceutically acceptable salts, hydrates or solvates increase sleep latency more than modafinil. A method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(( (cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof, which are used for the treatment of idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methyl Sulfur Acyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or Solvates increased sleep latency more than modafinil. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of an ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for human idiopathic narcolepsy in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate, or solvate increased sleep latency more than modafinil. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-((( cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or Pharmaceutically acceptable salts, hydrates or solvates increased sleep latency more than modafinil. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof for the treatment of excessive daytime sleepiness in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonate Acyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or Solvates increased sleep latency more than modafinil. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of an ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in a human being in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate Or its pharmaceutically acceptable salt, hydrate or solvate can increase sleep latency more than modafinil. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 23 to 31 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R,3S)-3-(( Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt thereof, Hydrate or solvate increased sleep onset latency by more than about 26.6 minutes compared to modafinil. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 33 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein (2R,3S)-3-((methylsulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate The therapeutically effective amount of a substance is about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 275 mg, about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 33 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylate, in which (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-benzene The therapeutically effective amount of methyl cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof is from about 70 mg to about 250 mg, from about 50 mg to about 500mg, about 50mg to about 400mg, about 50mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, or about 50 mg to about 150 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 33 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylate, in which (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-benzene The therapeutically effective amount of methyl cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof is from about 30 mg to about 130 mg, from about 35 mg to About 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg, about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or about 45 mg to about 115 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 33 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylate, in which (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-benzene The therapeutically effective amount of methyl cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof is from about 80 mg to about 160 mg, from about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 90 mg to about 140 mg, about 95 mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 33 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein (2R,3S)-3-((methylsulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate The therapeutically effective amount of the substance is about 112 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 37 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the administration is oral administration. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 37 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the administration is parenteral administration. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 39 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the parenteral administration is intravenous administration. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 40 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the intravenous administration is a single dose. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 40 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the intravenous administration is administered in multiple doses. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 41 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the single dose is within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours Administration within 1 hour, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 41 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the single dose is administered within 9 hours. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 1 to 44 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R,3S)-3-(( Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt thereof, Hydrates or solvates increase sleep latency in the Maintenance of Wakefulness Test (MWT). A pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition provides greater Large increase in latency to fall asleep. The pharmaceutical composition of claim 46, wherein the composition increases sleep latency by more than about 2.8 minutes compared to a placebo. The pharmaceutical composition of claim 47, wherein the composition increases sleep latency by more than about 24.9 minutes compared to a placebo. A pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition provides Increased sleep latency. The pharmaceutical composition of claim 49, wherein the composition increases sleep latency by more than about 13.3 minutes. The pharmaceutical composition according to claim 50, wherein the composition increases the latency of falling asleep by 39.9 minutes or longer. A pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition provides Increased latency to sleep onset in Niger. The pharmaceutical composition of claim 52, wherein the composition increases sleep latency by more than about 26.6 minutes compared to modafinil. The pharmaceutical composition as described in any one of claims 46 to 53, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl Cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amounts: about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 275 mg, about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. The pharmaceutical composition as described in any one of claims 46 to 53, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl Cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is present in the following amounts: about 70 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, or about 50 mg to about 150 mg. The pharmaceutical composition as described in any one of claims 46 to 53, wherein the (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-benzene Cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is present in the following amount: about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg, about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or about 45 mg to about 115 mg. The pharmaceutical composition as described in any one of claims 46 to 53, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl Cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is present in the following amounts: about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 90 mg to about 140 mg, about 95 mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. The pharmaceutical composition as described in any one of claims 46 to 53, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl Methyl cyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof was present in an amount of about 112 mg. A method of treating an orexin-mediated disease or condition in a human having normal orexin levels, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino )-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein The therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine- Methyl 1-formate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS ) as measured by A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof for use in the treatment of orexin-mediated diseases or conditions in humans having normal orexin levels, wherein Therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1 - Methyl formate or a pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of the ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for a human orexin-mediated disease or disease with normal orexin levels, wherein a therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. A method of treating idiopathic narcolepsy in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-(( (cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of ( 2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate thereof reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof, which are used for the treatment of idiopathic narcolepsy in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methyl Sulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable salt, hydrate or solvate reduced excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of an ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a drug for human idiopathic narcolepsy in need, wherein a therapeutically effective amount of (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or its pharmaceutically acceptable Salt, hydrate or solvate reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of (2R,3S)-3-((methylsulfonyl)amino)-2-((( cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R ,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or A pharmaceutically acceptable salt, hydrate or solvate reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Esters or pharmaceutically acceptable salts, hydrates or solvates thereof for the treatment of excessive daytime sleepiness in humans in need thereof, wherein a therapeutically effective amount of (2R,3S)-3-((methylsulfonate Acyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or Solvates reduced excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. A (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid Use of the ester or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for excessive daytime sleepiness in humans in need, wherein a therapeutically effective amount of (2R,3S)-3-( (Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-methanol Methyl ester, or a pharmaceutically acceptable salt, hydrate or solvate thereof, reduces excessive daytime sleepiness as measured by the Karolinska Sleepiness Scale (KSS) compared to placebo. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 59 to 67 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the therapeutically effective amount of (2R,3S)-3-(( Methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt thereof, Hydrate or solvate reduced excessive daytime sleepiness by about 3.3 compared to placebo, as measured by the Karolinska Sleepiness Scale (KSS). The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 59 to 68 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein (2R,3S)-3-((methylsulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate The therapeutically effective amount of a substance is about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 275 mg, about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 59 to 68 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein (2R,3S)-3-((methylsulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate The therapeutically effective amount of the substance is about 70 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, or From about 50 mg to about 150 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 59 to 68 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein (2R,3S)-3-((methylsulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate The therapeutically effective amount of the substance is about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg, about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or From about 45 mg to about 115 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 59 to 68 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein (2R,3S)-3-((methylsulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate The therapeutically effective amount of the substance is about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 90 mg to about 140 mg, about 95 mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenyl ring) as described in any one of claims 59 to 68 Hexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate, wherein (2R,3S)-3-((methylsulfonyl )amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, hydrate or solvate The therapeutically effective amount of the substance is about 112 mg. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) as described in claims 59 to 73 ) methyl) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the administration is orally. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) as described in claims 59 to 73 ) methyl) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the administration is parenteral. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 75 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the parenteral administration is intravenous administration. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 76 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the intravenous administration is a single dose. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 76 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the intravenous administration is administered in multiple doses. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 77 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the single dose is within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours Administration within 1 hour, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours. The method, use or (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methanol as described in Claim 77 base) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the single dose is administered within 9 hours. A pharmaceutical composition comprising (a) (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl ) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (b) a pharmaceutically acceptable excipient, wherein the composition is compared to a placebo Reduces excessive daytime sleepiness, as measured by the Karolinska Sleepiness Scale (KSS). The pharmaceutical composition of claim 81, wherein the composition reduces excessive daytime sleepiness by about 3.3 compared to a placebo, as measured by the Karolinska Sleepiness Scale (KSS). The pharmaceutical composition as described in claim 81 or 82, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy yl)methyl)pyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is present in the following amounts: about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 275 mg, about 5 mg to about 240 mg, about 5 mg to about 200 mg, or about 5 mg to about 150 mg. The pharmaceutical composition as described in claim 81 or 82, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy yl)methyl)pyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is present in the following amounts: about 70 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 275 mg, about 50 mg to about 240 mg, about 50 mg to about 200 mg, or about 50 mg to about 150 mg. The pharmaceutical composition as described in claim 81 or 82, wherein the (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) Oxy)methyl)hexahydropyridine-1-carboxylic acid methyl ester or its medicine A pharmaceutically acceptable salt, hydrate or solvate is present in the following amounts: about 30 mg to about 130 mg, about 35 mg to about 115 mg, about 35 mg to about 120 mg, about 35 mg to about 125 mg, about 40 mg to about 115 mg, about 40 mg to about 120 mg, about 40 mg to about 125 mg, or about 45 mg to about 115 mg. The pharmaceutical composition as described in claim 81 or 82, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy yl)methyl)pyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is present in the following amounts: about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 90 mg to about 140 mg, about 95 mg to about 135 mg, about 100 mg to about 130 mg, about 105 mg to about 125 mg, or about 110 mg to about 120 mg. The pharmaceutical composition as described in claim 81 or 82, wherein (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy yl)methyl)pyridine-1-carboxylate, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is present in an amount of about 112 mg. A method of treating a human suffering from the symptoms of idiopathic narcolepsy or excessive daytime sleepiness comprising: (a) determining the concentration of orexin in a biological sample from the human being, and (b) If the concentration of orexin is greater than about 110 pg/mL, administer an effective amount of 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy ) methyl) methyl hexahydropyridine-1-carboxylate or a pharmaceutically acceptable salt, hydrate or solvate thereof.

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