WO2022190060A1 - An orexin 2 receptor agonist for the treatment of an orexin-mediated disease or disorder - Google Patents

An orexin 2 receptor agonist for the treatment of an orexin-mediated disease or disorder Download PDF

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WO2022190060A1
WO2022190060A1 PCT/IB2022/052214 IB2022052214W WO2022190060A1 WO 2022190060 A1 WO2022190060 A1 WO 2022190060A1 IB 2022052214 W IB2022052214 W IB 2022052214W WO 2022190060 A1 WO2022190060 A1 WO 2022190060A1
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methyl
oxy
carboxylate
amino
solvate
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James CRONICAN
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Takeda Pharmaceutical Company Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

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  • a method of treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about modafmil.
  • composition comprising (a) methyl
  • the methyl (2R, 3 S)-3 -((methyl sulfony l)amino)-2-(((ci s-4- phenylcyclohexyl)oxy) methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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 methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of about 112 mg.
  • KSS Karolinska Sleepiness Scale
  • KSS Karolinska Sleepiness Scale
  • the methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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 methods, compositions and uses of this disclosure may be directed to treating excessive sleepiness in individuals who do not have deficiency of orexin (e.g ., humans with normal orexin levels). This disclosure is also directed to treating diseases, disorders, and/or symptoms of excessive sleepiness that are not associated with reduced orexin level.
  • Idiopathic hypersomnia is as defined by the International
  • Compound (I) is an optically active compound.
  • Compound (I) is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound A) in any of the methods, the uses and the pharmaceutical compositions disclosed herein.
  • Compound (I) including its salt and its optical active compound may be produced as disclosed in WO2017/135306.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • the term “effective amount” or “therapeutically effective amount” refers to a quantity of Compound (I) (or Compound A) sufficient to achieve a desired effect or a desired therapeutic effect.
  • the amount of Compound (I) or Compound A administered to the human can depend on the type and severity of the disease or symptom and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or by an ammonium ion (e.g., an ammonium ion derived from an organic base, such as, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).
  • a metal ion e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion
  • an ammonium ion e.g., an ammonium ion derived from an organic base, such as, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia.
  • Nicotine dependence that was likely to have an effect on sleep (e.g., a subject who routinely awakens at night to smoke) or challenge the conduct of this study (smokes >10 cigarettes/day) and/or an unwillingness to discontinue all smoking and nicotine use during the confinement portion of the study (Day -2 to Day 4).

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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

AN OREXIN 2 RECEPTOR AGONIST FOR THE TREATMENT OF AN OREXIN-MEDIATED DISEASE OR DISORDER
BACKGROUND
[0001] Orexin (OX) is a neuropeptide, and the orexinergic system is a major wake- promoting system of the brain. Two orexinergic neuropeptides, OX-A and OX-B, have been identified to date. These neuropeptides exert effects via 2 types of receptors: orexin type-1 receptor (OX1R) and orexin type-2 receptor (OX2R). OX-A has a high affinity to OX1R and OX2R, and OX-B has a high affinity to OX2R. The 2 types of OX receptors have a distinct distribution in the arousal network: the locus coeruleus contains only OXIRs, the tuberomammillary nucleus contains only OX2Rs, and both receptor types occur in the dorsal raphe nucleus and ventral tegmental area. The 2 types of OX receptors also make distinct contributions to the regulation of arousal. OX2Rs in the tuberomammillary nucleus are essential for the maintenance of wakefulness, whereas both receptor types are required for the inhibition of rapid eye movement (REM) sleep.
[0002] Excessive sleepiness, or excessive daytime sleepiness (EDS), is characterized by persistent sleepiness and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. Excessive sleepiness can affect the ability to function in family, social, occupational, or other settings. Current therapies do not adequately address the full extent and spectrum of excessive sleepiness in clinical practice.
[0003] Idiopathic hypersomnia (IH) is a chronic neurological disorder that results in excessive daytime sleepiness and is frequently accompanied by long nocturnal or daytime sleep, unrefreshing sleep, difficulty in awakening, cognitive dysfunction, and autonomic symptoms. Orexin levels in patients with IH are within normal limits. IH is thought to be a relatively rare disease.
[0004] Medications used for the treatment of IH include stimulants such as modafmil, armodafmil methylphenidate, dextroamphetamine, and pemoline as well as in some patients, sodium oxybate, clarithromycin, and flumazenil. Antidepressants with activating effects such a bupropion and venlafaxine may also be used. Modafmil is the only drug that had a marketing authorization in some European countries for the treatment of humans with IH. However, the European Medicines Agency withdrew modafmil for the treatment of IH because the risk for developing skin or hypersensitivity reactions and neuropsychiatric disorders outweighed the evidence for clinically important efficacy. There is no gold standard treatment for IH. As such, there is a huge unmet medical need for an effective treatment of the excessive daytime sleepiness (EDS) in this condition.
SUMMARY
[0005] The present disclosure addresses the aforementioned needs and includes a treatment using methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl) piperidine- 1-carboxylate (Compound (I)), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and compositions comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The present disclosure also includes embodiments wherein Compound (I) is the specific compound methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound A).
[0006] Provided in one aspect is a method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereofmcreases sleep onset latency time greater than placebo.
[0007] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0008] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2- (((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0009] Provided in another aspect is a method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl) piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
[0010] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0011] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0012] Provided in another aspect is a method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
[0013] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0014] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0015] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 2.8 minutes than placebo. In some embodiments, the method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 29.4 minutes than placebo.
[0016] Provided in one aspect is a method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
[0017] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0018] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-
2-(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0019] Provided in another aspect is a method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
[0020] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes. [0021] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0022] Provided in another aspect is a method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((ci s-4- phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
[0023] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0024] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes. [0025] In some embodiments, the method, use, or methyl (2R, 3 S)-3 -((methyl sulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than 13.3 minutes. In some embodiments, the method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time of 39.9 minutes or more.
[0026] Provided in one aspect is a method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-
1 -carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than modafmil.
[0027] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0028] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-
2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0029] Provided in another aspect is a method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than modafmil.
[0030] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0031] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0032] Provided in one aspect is a method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about modafmil.
[0033] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0034] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0035] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 26.6 minutes than modafmil.
[0036] In some embodiments, the therapeutically effective amount of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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. In some embodiments, the therapeutically effective amount of methyl (2R,3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, 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, the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, 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, the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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. In some embodiments, the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is about 112 mg.
[0037] In some embodiments, the administration is an oral administration. In some embodiments, the administration is a non-oral administration. In some embodiments, the non-oral administration is intravenous administration. In some embodiments, the intravenous administration is a single dose. In some embodiments, the intravenous administration is administered over multiple doses. In some embodiments, the single dose is administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours. In some embodiments, the single dose is administered over 9 hours. In some embodiments, the method increases sleep latency in maintenance of wakefulness test (MWT).
[0038] Provided in one aspect is a pharmaceutical composition comprising (a) methyl
(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater than placebo.
[0039] In some embodiments, the composition increases sleep onset latency greater than about 2.8 minutes than placebo. In some embodiments, the composition increases sleep onset latency greater than about 24.9 minutes than placebo.
[0040] Provided in another aspect is a pharmaceutical composition comprising (a) methyl
(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater 10.5 minutes. [0041] In some embodiments, the composition increases sleep onset latency greater than about 13.3 minutes. In some embodiments, the composition increases sleep onset latency of 39.9 minutes or more.
[0042] Provided in one aspect is a pharmaceutical composition comprising (a) methyl
(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater than modafmil.
[0043] In some embodiments, the composition increases sleep onset latency greater than about 26.6 minutes than modafmil.
[0044] In some embodiments, the methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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, the methyl (2R, 3 S)-3 -((methyl sulfony l)amino)-2-(((ci s-4- phenylcyclohexyl)oxy) methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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, the methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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 methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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, the methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of about 112 mg.
[0045] Provided in another aspect is a method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-
1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0046] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0047] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-
2-(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0048] Provided in another aspect is a method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0049] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0050] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0051] Provided in another aspect is a method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((ci s-4- phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0052] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0053] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0054] In some embodiments, the method, use, or methyl (2R, 3 S)-3 -((methyl sulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness by about 3.3 compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0055] In some embodiments, the therapeutically effective amount of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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. In some embodiments, the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, 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, the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, 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, the therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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. In some embodiments, the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is about 112 mg.
[0056] In some embodiments, the administration is oral. In some embodiments, the administration is non-oral. In some embodiments, the non-oral administration is intravenous administration. In some embodiments, the intravenous administration is a single dose. In some embodiments, the intravenous administration is administered over multiple doses. In some embodiments, the single dose is administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours. In some embodiments, the single dose is administered over 9 hours.
[0057] Provided in another aspect is a pharmaceutical composition comprising (a) methyl
(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, 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).
[0058] In some embodiments, the composition reduces excessive daytime sleepiness by about 3.3 compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0059] In some embodiments, the methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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, the methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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, the methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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 methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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, the methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of about 112 mg.
[0060] Provided in another aspect is a method of treating a human suffering from symptoms of idiopathic hypersomnia or excessive daytime sleepiness comprising: (a) ascertaining the concentration of orexin in a biological sample from the human and (b) if the concentration of orexin is greater than about 110 pg/mL, then administering an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the method comprises (a) obtaining a cerebral spinal fluid sample from the human; and/or (b) measuring the concentration of orexin in the cerebral spinal fluid sample, and if the concentration of orexin is greater than about 110 pg/mL, then the human has idiopathic hypersomnia or excessive daytime sleepiness. BRIEF DESCRIPTION OF THE DRAWINGS
[0061] FIG. 1 shows the LS mean post-dose sleep latency from for certain embodiments of 4 MWT Trials. The average sleep onset latency was estimated from the main treatment effect in the model over the 4 post dose timepoints (2, 4, 6, and 8 hours). The difference in the LS means between Compound A and placebo is from the linear mixed effect model for repeated measures. *** = p-value <0.001.
[0062] FIG. 2 shows the LS mean (95% Cl) for post-dose sleep onset latency from MWT by time point for certain embodiments. *** = p-value <0.001.
[0063] FIG. 3 shows the LS mean for post-dose KSS (Karolinska Sleepiness Scale) for certain embodiments. The average KSS was estimated from the main treatment effect in the model over the 4 post dose timepoints (2, 4, 6, and 8 hours). The difference in the LS means between Compound A and placebo is from the linear mixed effect model for repeated measures. *** = p-value <0.001.
[0064] FIG. 4 shows the LS mean (95% Cl) for post-dose KSS by time point for certain embodiments. *** = p-value <0.001.
DETAILED DESCRIPTION
[0065] The methods, compositions and uses disclosed herein include treating an orexin- mediated disease or disorder, such as idiopathic hypersomnia and excessive daytime sleepiness, in a human in need thereof, as well as treating humans suffering from excessive sleepiness who have not been diagnosed with any disease or disorder.
[0066] There are no therapies approved for IH worldwide except for modafmil which has been approved in Japan. This approval is based on a double-blind placebo-controlled crossover study with a treatment period of 3 weeks each with 200 mg of modafmil vs placebo in 33 drug-free adult IH patients without long sleep. Mayer et al. J Sleep Res. (2015) 24, 74-81. This study found that modafmil significantly decreased the Epworth Sleepiness Scale (ESS) by 4.5 points but the change in sleep latency on the Maintenance of Wakefulness Test (MWT) versus placebo, specifically a 2.8 min improvement, was not significant. However, the European Medicines Agency has withdrawn modafmil for treating IH because the risk for developing skin or hypersensitivity reactions and neuropsychiatric disorders outweighed the evidence for clinically important efficacy. [0067] In an embodiment, the methods, compositions and uses of this disclosure may be directed to treating excessive sleepiness in individuals who do not have deficiency of orexin ( e.g ., humans with normal orexin levels). This disclosure is also directed to treating diseases, disorders, and/or symptoms of excessive sleepiness that are not associated with reduced orexin level.
[0068] An embodiment of the disclosure relates to methyl 3 -((methyl sulfonyl)amino)-2-
(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, compositions and kits comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and methods of using Compound (I), or the salt, hydrate, or solvate thereof. In some embodiments, Compound (I) is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis- 4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound A), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. Compound A can also be represented by the following structure:
Figure imgf000019_0001
Methods and Uses
[0069] The methods and uses disclosed herein may comprise performing one or more tests to quantify a human’s sleepiness. Examples of such tests include but are not limited to multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT), and the Oxford Sleep Resistance (OSLER) test. Other examples include the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, Ullanlinna Narcolepsy Scale (UNS), Work Limitations Questionnaire (WLQ), SF- 8 (subset of SF-36 questionnaire) or a combination thereof.
[0070] The methods and uses disclosed herein may increase sleep onset latency in the maintenance of wakefulness test (MWT) in a human in need thereof. The MWT is a validated objective measure that evaluates a person’s ability to remain awake under soporific conditions for a defined period and has often been used as a primary efficacy endpoint to measure excessive daytime sleepiness in clinical studies. As there is no biological measure of the maintenance of wakefulness, the MWT measures this indirectly by the human’s inability to avoid or delay the tendency to fall asleep. This tendency to fall asleep is measured via electroencephalography (EEG)-derived criteria for time to sleep latency during each MWT session.
[0071] Provided in one embodiment is a method for treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
[0072] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0073] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0074] Provided in another embodiment is a method for treating idiopathic hypersomnia in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
[0075] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0076] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0077] Provided in another embodiment is a method for treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy) methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
[0078] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0079] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
[0080] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep latency in maintenance of wakefulness test (MWT). In some embodiments, the method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 0.1, greater than about 0.5, greater than about 1.0, greater than about 1.5, greater than 2.0, greater than about 2.5, greater than about 2.8, greater than about 3.0, greater than about 3.5, greater than about 4.0, greater than about 4.5, greater than about 5.0, greater than about 5.5, greater than about 6.0, greater than about 6.5, greater than about 7.0, greater than about
7.5, greater than about 8.0, greater than about 8.5, greater than about 9.0, greater than about 9.5, greater than about 10.0, greater than about 10.5, greater than about 11.0, greater than about 11.5, greater than about 12.0, greater than about 12.5, greater than about 13.0, greater than about 13.5, greater than about 14.0, greater than about 14.5, greater than about 15.0, greater than about 15.5, greater than about 20, greater than about
20.5, greater than about 21.0, greater than about 21.5, greater than about 22.0, greater than about 22.5, greater than about 23.0, greater than about 23.5, greater than about 24.0, greater than about 24.5, greater than about 25.0, greater than about 25.5, greater than about 26.0, greater than about 26.5, greater than about 27.0, greater than 27.5, greater than 28.0, greater than about 28.5, greater than about 29.0, greater than about 29.4, greater than about 29.5, greater than about 30.0, greater than about 30.5, greater than about 31.0, greater than about 31.5, greater than about 32.0, greater than about 32.5, greater than about 33.0, greater than about 33.5, greater than about 34.0, greater than about 34.5, greater than about 35.0, greater than about 40.0, greater than about 45.0, or greater than about 50.0 minutes (or a range in between any of these values) than placebo. In some embodiments, the method, use, or methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2- (((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 2.8 minutes than placebo. In some embodiments, the method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 29.4 minutes than placebo.
[0081] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by about 0.1 to about 50 minutes, including about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.8, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, about 12.0, about 12.5, about 13.0, about 13.5, about 14.0, about 14.5, about 15.0, about 15.5, about 20, about 20.5, about 21.0, about 21.5, about 22.0, about 22.5, about 23.0, about 23.5, about 24.0, about
24.5, about 25.0, about 25.5, about 26.0, about 26.5, about 27.0, about 27.5, about 28.0, about 28.5, about 29.0, about 29.4, about 29.5, about 30.0, about 30.5, about 31.0, about
31.5, about 32.0, g about 32.5, about 33.0, about 33.5, about 34.0, about 34.5, about 35.0, about 40.0, about 45.0, and about 50.0 minutes (or a range in between any of these values), than placebo. In some embodiments, the method, use, or methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by about 2.5 to about 3.0 minutes, about 2.0 to about 3.5 minutes, about 1.5 to about 4.0 minutes, about 0.5 to about 4.5 minutes, about 0.5 to about 5.0 minutes, about 0.5 to about 10.0 minutes, about 0.5 to about 20.0 minutes, about 0.5 to about 30.0 minutes, or about 0.5 to about 40.0 minutes, including about 2.8 minutes, than placebo. In some embodiments, the method, use, or methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by about 27.5 to about 32.5 minutes, about 25.0 to about 35.0 minutes, about 20.0 to about 40.0 minutes, about 15.0 to about 45.0 minutes, about 10.0 to about 50.0 minutes, about 5.0 to about 50.0 minutes, including about 29.4 minutes, than placebo.
[0082] Provided in one embodiment is a method for treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl 3 -((methyl sulfonyl)amino)-2-(((4-phenyl cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy) methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
[0083] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0084] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes. [0085] Provided in another embodiment is a method for treating idiopathic hypersomnia in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
[0086] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0087] Provided in one embodiment is the use of methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0088] Provided in another embodiment is a method for treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3 -((methyl sulfonyl)amino)-2-(((4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
[0089] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2- (((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0090] Provided in one embodiment is the use of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
[0091] In some embodiments, the method, use, or methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep latency in maintenance of wakefulness test (MWT). In some embodiments, the method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 0.1, greater than about 0.5, greater than about 1.0, greater than about 1.5, greater than 2.0, greater than about 2.5, greater than about 2.8, greater than about 3.0, greater than about 3.5, greater than about 4.0, greater than about 4.5, greater than about 5.0, greater than about 5.5, greater than about 6.0, greater than about 6.5, greater than about 7.0, greater than about 7.5, greater than about 8.0, greater than about 8.5, greater than about 9.0, greater than about 9.5, greater than about 10.0, greater than about 10.5, greater than about 11.0, greater than about 11.5, greater than about 12.0, greater than about 12.5, greater than about 13.0, greater than about 13.3, greater than about 13.5, greater than about 14.0, greater than about 14.5, greater than about 15.0, greater than about 15.5, greater than about 20, greater than about 20.5, greater than about 21.0, greater than about 21.5, greater than about 22.0, greater than about 22.5, greater than about 23.0, greater than about 23.5, greater than about 24.0, greater than about 24.5, greater than about 25.0, greater than about 25.5, greater than about 26.0, greater than about 26.5, greater than about 27.0, greater than 27.5, greater than 28.0, greater than about 28.5, greater than about 29.0, greater than about 29.4, greater than about 29.5, greater than about 30.0, greater than about 30.5, greater than about 31.0, greater than about 31.5, greater than about 32.0, greater than about 32.5, greater than about 33.0, greater than about 33.5, greater than about 34.0, greater than about 34.5, greater than about 35.0, greater than about 40.0, greater than about 45.0, or greater than about 50.0 minutes (or a range in between any of these values). In some embodiments, the method, use, or methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 13.3 minutes.
[0092] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by about 0.1 to about 50 minutes, including about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.8, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, about 12.0, about 12.5, about 13.0, about 13.3, about 13.5, about 14.0, about 14.5, about 15.0, about 15.5, about 20, about 20.5, about 21.0, about 21.5, about 22.0, about 22.5, about 23.0, about 23.5, about 24.0, about 24.5, about 25.0, about 25.5, about 26.0, about 26.5, about 27.0, about 27.5, about 28.0, about 28.5, about 29.0, about 29.4, about 29.5, about 30.0, about 30.5, about 31.0, about 31.5, about 32.0, g about 32.5, about 33.0, about 33.5, about 34.0, about 34.5, about 35.0, about 40.0, about 45.0, and about 50.0minutes (or a range in between any of these values). In some embodiments, the method, use, or methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by about 12.5 to about 15.0 minutes, about 10.0 to about 20.0 minutes, about 5.0 to about 25.0 minutes, about 5.0 to about 30.0 minutes, about 5.0 to about 35.0 minutes, about 5.0 to about 40.0 minutes, about 5.0 to about 45.0 minutes, or about 5.0 to about 50.0 minutes, including about 13.3 minutes.
[0093] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time of about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.8, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, about 12.0, about 12.5, about 13.0, about 13.5, about 14.0, about 14.5, about 15.0, about 15.5, about 20, about 20.5, about 21.0, about 21.5, about 22.0, about
22.5, about 23.0, about 23.5, about 24.0, about 24.5, about 25.0, about 25.5, about 26.0, about 26.5, about 27.0, about 27.5, about 28.0, about 28.5, about 29.0, about 29.4, about
29.5, about 30.0, about 30.5, about 31.0, about 31.5, about 32.0, g about 32.5, about 33.0, about 33.5, about 34.0, about 34.5, about 35.0, about 39.9, about 40.0, about 45.0, about 50.0 minutes, or more (or a range in between any of these values). In some embodiments, the method, use, or methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time of 39.9 minutes or more.
[0094] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time of about 37.5 to about 42.5 minutes, about 35.0 to about 45.0 minutes, or about 30.0 to about 50.0 minutes, including about 39.9 minutes.
[0095] Provided in one embodiment is a method for treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl 3 -((methyl sulfonyl)amino)-2-(((4-phenyl cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy) methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than modafmil.
[0096] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0097] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0098] Provided in another embodiment is a method for treating idiopathic hypersomnia in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than modafmil.
[0099] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil. [0100] Provided in one embodiment is the use of methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0101] Provided in another embodiment is a method for treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3 -((methyl sulfonyl)amino)-2-(((4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than modafmil.
[0102] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
[0103] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil. [0104] In some embodiments, the method, use, or methyl (2R, 3 S)-3 -((methyl sulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep latency in maintenance of wakefulness test (MWT). In some embodiments, the method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 0.1, greater than about 0.5, greater than about 1.0, greater than about 1.5, greater than 2.0, greater than about 2.5, greater than about 2.8, greater than about 3.0, greater than about 3.5, greater than about 4.0, greater than about 4.5, greater than about 5.0, greater than about 5.5, greater than about 6.0, greater than about 6.5, greater than about 7.0, greater than about 7.5, greater than about 8.0, greater than about 8.5, greater than about 9.0, greater than about 9.5, greater than about 10.0, greater than about 10.5, greater than about 11.0, greater than about 11.5, greater than about 12.0, greater than about 12.5, greater than about 13.0, greater than about 13.5, greater than about 14.0, greater than about 14.5, greater than about 15.0, greater than about 15.5, greater than about 20, greater than about 20.5, greater than about 21.0, greater than about 21.5, greater than about 22.0, greater than about 22.5, greater than about 23.0, greater than about 23.5, greater than about 24.0, greater than about 24.5, greater than about 25.0, greater than about 25.5, greater than about 26.0, greater than about 26.5, greater than about 26.6, greater than about 27.0, greater than 27.5, greater than 28.0, greater than about 28.5, greater than about 29.0, greater than about 29.4, greater than about 29.5, greater than about 30.0, greater than about 30.5, greater than about 31.0, greater than about 31.5, greater than about 32.0, greater than about 32.5, greater than about 33.0, greater than about 33.5, greater than about 34.0, greater than about 34.5, greater than about 35.0, greater than about 40.0, greater than about 45.0, greater than about 50.0, (or a range in between any of these values) than modafmil. In some embodiments, the method, use, or methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 26.6 minutes than modafmil.
[0105] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by about 0.1 to about 50 minutes, including about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 2.8, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, about 12.0, about 12.5, about 13.0, about 13.5, about 14.0, about 14.5, about 15.0, about 15.5, about 20, about 20.5, about 21.0, about 21.5, about 22.0, about 22.5, about 23.0, about 23.5, about 24.0, about 24.5, about 25.0, about 25.5, about 26.0, about 26.5, about 26.6, about 27.0, about 27.5, about 28.0, about 28.5, about 29.0, about 29.4, about 29.5, about 30.0, about 30.5, about 31.0, about 31.5, about 32.0, g about 32.5, about 33.0, about 33.5, about 34.0, about 34.5, about 35.0, about 40.0, about 45, about 50.0, minutes, than modafinil. In some embodiments, the method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl) oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by about 25.0 to about 27.5 minutes, about 25.0 to about 30.0 minutes, about 20.0 to about 35.0 minutes, about 15.0 to about 40.0 minutes, about 10.0 to about 45.0 minutes, about 5.0 to about 50.0 minutes, including about 26.6 minutes, than modafinil.
[0106] The methods and uses disclosed herein may decrease excessive sleepiness or improve Karolinska Sleepiness Scale (KSS) rating in a human in need thereof. The Karolinska Sleepiness Scale (KSS) is a 10-item Likert-type rating scale for assessing subjective sleepiness. This self-rating scale measures the subjective level of sleepiness at a specific time during the day. Humans indicate which level on this scale best reflects their sleepiness experienced in the last 10 minutes. The KSS is helpful in assessing the changes in response to the effects of drugs and is a measure of situational sleepiness. It is sensitive to fluctuations. It has been used in studies of shift work, jetlag, for driving abilities, attention and performance, and in clinical settings. It is helpful in assessing the changes in response to environmental factors, circadian rhythm, and effects of drugs. Humans who are asleep and unable to be aroused will have the KSS score imputed as 10. KSS scoring is on a 10-point scale with 1 = extremely alert, 2 = very alert, 3 = alert, 4= rather alert, 5 = neither alert nor sleepy, 6 = some signs of sleepiness, 7 = sleepy but no effort to remain awake, 8 = sleepy but some effort to keep awake, 9 = very sleepy with great effort to keep awake and fighting sleep, and 10 = extremely sleepy and can’t keep awake.
[0107] Provided in one embodiment is a method for treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl 3 -((methyl sulfonyl)amino)-2-(((4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0108] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0109] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0110] Provided in another embodiment is a method for treating idiopathic hypersomnia in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0111] Provided in one embodiment is methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0112] Provided in one embodiment is the use of methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0113] Provided in another embodiment is a method for treating excessive daytime sleepiness in a human in need thereof comprising administering to the human a therapeutically effective amount of methyl 3 -((methyl sulfonyl)amino)-2-(((4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l -carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS). [0114] Provided in one aspect is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0115] Provided in one aspect is the use of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-
(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0116] In some embodiments, the method, use, or methyl (2R,3S)-3-
((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- 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, compared to placebo as measured by the Karolinska Sleepiness Scale (KSS). In some embodiments, the method, use, or methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- 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 compared to placebo as measured by the Karolinska Sleepiness Scale (KSS). In some embodiments, the method, use, or methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2- (((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness by about 3.3 compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0117] Further disclosed herein is methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin- mediated disease or disorder in a human with normal orexin levels, treating idiopathic hypersomnia in a human in need thereof, or treating excessive daytime sleepiness in a human in need thereof.
[0118] Disclosed herein are uses of methyl 3 -((methyl sulfonyl)amino)-2-(((4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof for the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, treating idiopathic hypersomnia in a human in need thereof, or treating excessive daytime sleepiness in a human in need thereof.
[0119] In some embodiments, treating an orexin-mediated disease or disorder may comprise reducing or alleviating one or more symptoms of excessive sleepiness. The one or more symptoms of excessive sleepiness may be selected from drowsiness, languor, inertness, fatigue, sluggishness.
[0120] In some embodiments, the human suffers from the diseases or disorders or symptoms 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 cycle, or a human with a need to decrease sleepiness.
[0121] Orexin, or hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. In some embodiments, excessive sleepiness may be associated with orexin deficiency. In some embodiments, the excessive sleepiness is not associated with reduced orexin level. In some embodiments, the orexin level in the human is not compromised or partially compromised. In some embodiments, the orexin level in the human is normal. The orexin level of the human refers to the cerebral spinal fluid (CSF) hypocretin 1 (orexin A) concentration, measured by immunoreactivity. In some embodiments, a human with an orexin level that is normal (or not compromised or partially comprised) has an orexin level that is more than about 110 pg/mL or more than about 190 pg/mL. In some embodiments, a human with an orexin level that is normal (or not compromised or partially comprised) has an orexin level that is more than about 110 pg/mL, more than about 150 pg/mL, more than about 190 pg/mL, more than about 200 pg/mL, more than about 250 pg/mL, or more than about 300 pg/mL. In some embodiments, a human with an orexin level that is normal (or not compromised or partially comprised) has an orexin level of about 110 pg/mL to about 900 pg/mL, about 110 pg/mL to about 850 pg/mL, about 110 pg/mL to about 800 pg/mL, about 110 pg/mL to about 750 pg/mL, about 110 pg/mL to about 700 pg/mL, about 110 pg/mL to about 650 pg/mL, about 110 pg/mL to about 600 pg/mL, about 190 pg/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 700 pg/mL or about 200 pg/mL to about 600 pg/mL. In some embodiments, the patient has an orexin level of 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, about 600 pg/mL, about 700 pg/mL, about 800 pg/mL, about 900 pg/mL, or any range therein between.
[0122] Examples of orexin-mediated disease or disorder in a human with normal orexin levels include excessive daytime sleepiness (EDS) in myotonic dystrophy I, EDS in Prader Willi syndrome, EDS in obstructive sleep apnea (OSA), EDS in multiple sclerosis, EDS in Mobius syndrome, EDS in Guillain-Barre syndrome, EDS in Smith-Lemli-Opitz syndrome, EDS in central diabetes insipidus, and EDS in X-linked Carcot-Marie-Tooth disease type 1.
[0123] Additional examples of orexin-mediated disease or disorder in a human with normal orexin levels include but are not limited to narcolepsy type 2 (NT2), idiopathic hypersomnia (IH), obstructive sleep apnea (OSA) adequately treated with CPAP but still with residual excessive daytime sleepiness (EDS), sleep-wake disturbances (SWD), and EDS in Parkinson’s disease.
[0124] Idiopathic hypersomnia (IH), as used herein, is as defined by the International
Classification of Sleep Disorders-3 (ICSD-3). The diagnostic criteria for idiopathic hypersomnia are: a) Human has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months. b) Cataplexy is absent. c) Multiple sleep latency test (MSLT) shows fewer than 2 sleep onset rapid eye movement (REM) periods or no sleep onset REM periods if the REM latency on the preceding polysomnogram was <15 minutes. d) Presence of at least 1 of the following: a. MSLT shows a mean sleep latency of <8 minutes. b. Total 24-hour sleep time is >660 minutes on 24-hour polysomnographic monitoring (performed after correction of chronic sleep deprivation), or by wrist actigraphy in association with a sleep log (averaged over at least 7 days with unrestricted sleep). e) Insufficient sleep syndrome is ruled out. f) Hypersomnolence and/or MSLT findings are not better explained by another sleep disorder, other medical or psychiatric disorder, or use of drugs or medications.
[0125] In some embodiments, the human in need thereof has at least one or more of the diagnostic criteria set forth by the International Classification of Sleep Disorders-3 (ICSD-3) for idiopathic hypersomnia.
[0126] Provided in another aspect is a method of treating a human suffering from symptoms of idiopathic hypersomnia or excessive daytime sleepiness comprising: (a) ascertaining the concentration of orexin in a biological sample from the human and (b) if the concentration of orexin is greater than about 110 pg/mL, then administering an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound I) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the method comprises (a) obtaining a cerebral spinal fluid sample from the human; and/or (b) measuring the concentration of orexin in the cerebral spinal fluid sample, and if the concentration of orexin is greater than about 110 pg/mL, then the human has idiopathic hypersomnia or excessive daytime sleepiness.
[0127] In some embodiments, the human has an orexin level that is more than about 110 pg/mL, more than about 150 pg/mL, more than about 190 pg/mL, more than about 200 pg/mL, more than about 250 pg/mL, or more than about 300 pg/mL. In some embodiments, the patient has an orexin level of about 110 pg/mL to about 900 pg/mL, about 110 pg/mL to about 850 pg/mL, about 110 pg/mL to about 800 pg/mL, about 110 pg/mL to about 750 pg/mL, about 110 pg/mL to about 700 pg/mL, about 110 pg/mL to about 650 pg/mL, about 110 pg/mL to about 600 pg/mL, about 190 pg/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, or about 200 pg/mL to about 600 pg/mL. In some embodiments, the patient has an orexin level of 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, about 600 pg/mL, about 700 pg/mL, about 800 pg/mL, about 900 pg/mL, or any range therein between.
Modes of Administration
[0128] The methods and uses disclosed herein comprise administering Compound (I) or
Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to a human in need thereof. In some embodiments, Compound (I) or Compound A is administered orally. In some embodiments, Compound (I) or Compound A is administered non-orally. In some embodiments, the non-oral administration is intravenous administration, subcutaneous administration, transdermal administration, intradermal administration or transmucosal administration. In some embodiments, the non-oral administration is intravenous administration. In some embodiments, the non-oral administration is subcutaneous administration. In some embodiments, the non-oral 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 through a needle or catheter.
[0129] Compound (I) or Compound A can be administered orally and non-orally such as intramuscular, intraperitoneal, intravenous, intraarterial, intraventricular, intraci sternal injection or infusion; subcutaneous injection; or implant; or inhalation spray, intratracheal, nasal, vaginal, rectal, subdermal, transdermal, intradermal, epidural, ocular insert or ocular instillation administration, in a suitable unit dosage form containing a pharmaceutically acceptable conventional nontoxic carrier, adjuvant and vehicle suitable for each administration route. [0130] In some embodiments, Compound (I) or Compound A is administered in a single dose. In some embodiments, Compound (I) or Compound A is administered over multiple doses. In some embodiments, Compound (I) or Compound A is administered intravenously in a single dose. In some embodiments, Compound (I) or Compound A is administered intravenously over multiple doses.
[0131] In some embodiments, Compound (I) or Compound A is administered for about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours. Compound (I) or Compound A may be administered as an infusion in a single dose for about 9 hours. In some embodiments, the total time for administering Compound (I) or Compound A is consecutive (e.g., Compound (I) or Compound A is administered as an infusion for about 9 consecutive hours). Alternatively, the total time for administering Compound (I) or Compound A is intermittent (e.g., Compound (I) or Compound A is administered as an infusion for 1 hour, then the infusion is stopped for period of time, and the infusion is restarted for another hour).
[0132] 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.
[0133] The effective amount of Compound (I) or Compound A may 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 about 5 mg to about 150 mg. In some embodiments, the effective amount of Compound (I) or Compound A may be about 70 mg to about 250 mg. In some embodiments, the effective amount of Compound (I) or Compound A may 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 may 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 may 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 may 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.
[0134] The effective amount of Compound (I) or Compound A may be about 30 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 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, 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 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, abouy 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, 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 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about about 141 mg, 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 159 mg, and 160 mg. In some embodiments, the effective amount of Compound (I) or Compound A 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. In some embodiments, the effective amount of Compound (I) or Compound A may be about 112 mg.
PK Parameters
[0135] The plasma concentration for Compound (I) or Compound A may be at least 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 310, 320, 330, 340 or 350 ng/mL for at least 1 hours. The plasma concentration for Compound (I) or Compound A may be at least 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 310, 320, 330, 340 or 350 ng/mL for at least 2 hours. The plasma concentration for Compound (I) or Compound A may be at least 25, 30, 35, 40, 45, 50,
55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 310, 320, 330, 340 or 350 ng/mL for at least 4 hours. The plasma concentration for Compound (I) or Compound A may be at least 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 310, 320, 330, 340 or 350 ng/mL for at least 6 hours. The plasma concentration for Compound (I) or Compound A may be at least 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,
95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 310, 320, 330, 340 or 350 ng/mL for at least 8 hours. The plasma concentration for Compound (I) or Compound A may be at least 25, 30, 35, 40, 45, 50,
55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 310, 320, 330, 340 or 350 ng/mL for at least 12 hours.
Frequency of Administration
[0136] 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 per day. In some embodiments, Compound (I) or Compound A is administered at least twice per day.
[0137] Compound (I) or Compound A may be administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, or 14 or more times per week. In some embodiments, Compound (I) or Compound A is administered at once per week. In some embodiments, Compound (I) or Compound A is administered at least twice per 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.
[0138] Compound (I) or Compound A may be administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more times per month. Compound (I) or Compound A may be administered at least 4 times per month.
Combination Therapy
[0139] The methods disclosed herein may further comprise administering one or more additional therapies. The kits and compositions disclosed herein may further comprise one or more additional therapies. The one or more additional therapies may be selected from a stimulant, an antidepressant, a central nervous system depressant, a histamine 3 (H3) receptor antagonist, an agent for reducing the metabolism of Compound (I) or Compound A, and any one of the concomitant drugs described hereinafter. In some embodiments, the stimulant is modafmil. 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 additional therapies is venlafaxine or desvenlafaxine. In some embodiments, the H3 receptor antagonist is pitolisant. In some embodiments, the agent for reducing the metabolism of Compound (I) or Compound A is cobicistat.
[0140] The agent for reducing metabolism of Compound (I) or Compound A may increase bioavailability of Compound (I) or Compound A or systemic exposure of Compound (I) or Compound A. In some embodiments, the agent for reducing 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 metabolism of Compound (I) or Compound A is a CYP3 A4 inhibitor. In some embodiments, the CYP3 A4 inhibitor is selected from the group consisting of atazanavir, boceprevir, clarithromycin, cobicistat, conivaptan, curcumin, danazo!, danoprevir, darunavir, delavirdine, diltiazem, ditiocarb, econazole, efavirenz, elvitegravir, ergotamine, idelalisib, indinavir, itraconazole, ketoconazole, loperamide, lopinavir, methimazoie, midostaurin, naloxone, nefazodone, neifinavir, nilotinib, posaconazole, ribocidib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, terfenadine, tipranavir, troleandomycin, and voriconazole. In some embodiments, the CYP3 A4 inhibitor is selected from the group consisting of ritonavir and cobicistat. In some embodiments, the CYP3 A4 inhibitor is cobicistat.
[0141] Examples of the concomitant drug include, but are not limited to, the following. A therapeutic drug for narcolepsy (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafmil, caffeine, pitolisant, solriamfertol), antiobesity drug (amphetamine, benzfetamine, bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trade mark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, Lorcaserin, metformin), acetylcholine esterase inhibitor (e.g., donepezil, rivastigmine, galanthamine, zanapezil, idebenone, tacrine), antidementia agent (e.g., memantine), inhibitor of b-amyloid protein production, secretion, accumulation, aggregation and/or deposition, b-secretase inhibitor (e.g., 6-(4-biphenylyl) methoxy-2-[2-(N,N- dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethyl amino)methyl- tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino) methyltetralin, 2-(N,N- dimethylamino)methyl-6-(4’-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl) 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 biphenyl-4-yl)methoxytetralin, 6-(2’,4’-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N- dimethylamino)ethyl]tetralin, 6-[4-(l,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N- dimethylamino)ethyl]tetralin, 6-(3’,4’-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N- dimethylamino)ethyl]tetralin, an optically active form thereof, a pharmaceutically acceptable salt, hydrate, or solvate thereof and a hydrate thereof, OM99-2 (WOO 1/00663)), g-secretase inhibitor, b-amyloid protein aggregation inhibitor (e.g., RΊΊ- 00703, ALZHEMED (NC-531), PPI-368 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of International Patent Application No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), b- amyloid vaccine, b-amyloid-degrading enzyme and the like, brain function enhancer (e.g., aniracetam, nicergoline), therapeutic drug for Parkinson’ s disease [(e.g., dopamine receptor agonist (e.g., L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase enzyme (MAO) inhibitor (e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergic agent (e.g., trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)], therapeutic drug for amyotrophic lateral sclerosis (e.g., riluzole etc., neurotrophic factor), therapeutic drug for abnormal behavior accompanying progress of dementia, wandering and the like (e.g., sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation / regenerate promoter (e.g., leteprinim, xaliproden; SR-57746-A), SB- 216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4- methylphenyl)-2, 3 -dihydro- 1 -benzofuran-5 -yl]i soindoline, 5 , 6-dimethoxy-2- [3 -(4- isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-l-benzofuran-5-yl]isoindoline, 6-[3- (4-isopropylphenyl)-2, 2,4,6, 7-pentamethyl-2,3-dihydro-l-benzofuran-5-yl]-6,7-dihydro- 5H-[l,3]dioxolo[4,5-f isoindole and an optically active form, salt or hydrate thereof), non-steroidal antiinflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin etc.), steroid drug (dexamethasone, hexestrol, cortisone acetate etc.), disease-modifying anti-rheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor, MAP kinase inhibitor), therapeutic agent for incontinence, frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitor (e.g., sildenafil(citrate)), dopamine agonist (e.g., apomorphine), anti arrhythmic drugs (e.g., mexiletine), sex hormone or a derivative thereof (e.g., progesterone, estradiol, estradiol benzoate), therapeutic agent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drug for insomnia (e.g., benzodiazepines medicament, non-benzodiazepines medicament, melatonin agonist, orexin receptor antagonists), therapeutic drug for schizophrenia (e.g., typical antipsychotic agents such as haloperidol and the like; atypical antipsychotic agents such as clozapine, olanzapine, risperidone, aripiprazole and the like; medicament acting on metabotropic glutamate receptor or ion channel conjugated-type glutamate receptor; phosphodiesterase inhibitor), benzodiazepines medicament (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam etc.), L-type calcium channel inhibitor (pregabalin etc.), tricyclic or tetracyclic antidepressant (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate etc.), serotonin-noradrenaline reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride etc.), noradrenaline reuptake inhibitor (reboxetine mesylate etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HTIA agonist, (buspirone hydrochloride, tandospirone citrate, osemozotan hydrocloride etc.), 5-HT2A antagonist, 5-HT2A inverse agonist, 5-HT3 antagonist (cyamemazine etc.), heart non-selective b inhibitor (propranolol hydrochloride, oxprenolol hydrochloride etc.), histamine Hi antagonist (hydroxyzine hydrochloride etc.), CRF antagonist, other antianxiety drug (meprobamate etc.), tachykinin antagonist (MK-869, saredutant etc.), medicament that acts on metabotropic glutamate receptor, CCK antagonist, b3 adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor (tiagabine hydrochloride etc.), N-type calcium channel inhibitor, carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDA antagonist (memantine etc.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin Vlb antagonist, vasopressin Via antagonist, phosphodiesterase inhibitor, opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide etc.), COMT inhibitor (entacapone etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate etc.), cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHD drug (methylphenidate hydrochloride, methamphetamine hydrochloride etc.), therapeutic drug for alcoholism, therapeutic drug for autism, therapeutic drug for chronic fatigue syndrome, therapeutic drug for spasm, therapeutic drug for fibromyalgia syndrome, therapeutic drug for headache, therapeutic drug for quitting smoking, therapeutic drug for myasthenia gravis, therapeutic drug for cerebral infarction, therapeutic drug for mania, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic ataxia, therapeutic drug for male and female sexual dysfunction, therapeutic drug for migraine, therapeutic drug for pathological gambler, therapeutic drug for restless legs syndrome, therapeutic drug for substance addiction, therapeutic drug for alcohol -related syndrome, therapeutic drug for irritable bowel syndrome, therapeutic drug for ALS (riluzole etc., neurotrophic factor etc.), therapeutic drug for lipid abnormality such as cholesterol-lowering drug (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin etc.), fibrate (clofibrate etc.), squalene synthetase inhibitor), therapeutic drug for abnormal behavior or suppressant of dromomania due to dementia (sedatives, antianxiety drug etc.), antiobesity drug, therapeutic drug for diabetes, therapeutic agent for diabetic complications, therapeutic drug for hypertension, therapeutic drug for hypotension, diuretic, chemotherapeutic agent, immunotherapeutic agent, antithrombotic agent, anti-cancer agent and the like.
[0142] Two or more kinds of the above-mentioned concomitant drug may be used in a mixture at an appropriate ratio.
[0143] Compound (I) can also be used in combination with biologies (e.g., antibody drug, nucleic acid or nucleic acid derivative, aptamer drug, vaccine preparation), or can be combined with a gene therapy method and the like and applied as a combination therapy, or can also be used in combination with a treatment in psychiatric field without using drugs.
[0144] Examples of the treatment method in the psychiatric field without using drug include modified electroconvulsive therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, psychotherapy including cognitive behavioral therapy and the like.
Pharmaceutical Compositions
[0145] Further disclosed herein are pharmaceutical compositions comprising Compound
(I) or Compound A. In some embodiments, the pharmaceutical composition comprises (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmaceutically acceptable carrier therefor.
[0146] Provided in one embodiment is a pharmaceutical composition comprising (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater than placebo.
[0147] Provided in one embodiment is a pharmaceutical composition comprising (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater 10.5 minutes.
[0148] Provided in one embodiment is a pharmaceutical composition comprising (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater than modafmil.
[0149] Provided in one embodiment is a pharmaceutical composition comprising (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l- carboxylate (Compound (I)) or Compound A, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
[0150] The pharmaceutically acceptable carrier may be a cyclodextrin. The cyclodextrin may be betadex sulfobutyl ether sodium.
[0151] As pharmaceutically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations; and the like; and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary.
[0152] Examples of the dosage form of the aforementioned pharmaceutical composition include tablet (including sugar-coated tablet, film-coated tablet, orally disintegrating tablet), capsule (including soft capsule, microcapsule), granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films), injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., dermal preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like, which can be respectively safely administered orally or non-orally (e.g., topical, rectal, intravenous administration). These preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate- release preparation, a sustained-release preparation and the like. [0153] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for non-oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration, subcutaneous administration, transdermal administration, intradermal administration or transmucosal administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for transdermal administration.
Optically Active Compound
[0154] In some embodiments, Compound (I) is an optically active compound. In some embodiments, Compound (I) is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound A) in any of the methods, the uses and the pharmaceutical compositions disclosed herein. Compound (I) including its salt and its optical active compound may be produced as disclosed in WO2017/135306.
Kits
[0155] Further disclosed herein are kits comprising Compound (I), including Compound
A. In some embodiments, the kit comprises (a) a container comprising methyl 3-((methyl sulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) instructions for administering Compound (I).
[0156] The kits disclosed herein may further comprise an additional container comprising saline.
[0157] The container may be a glass vial. Alternatively, the container may be a syringe.
[0158] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the disclosure. All the various embodiments of the present disclosure will not be described herein. Many modifications and variations of the disclosure can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.
[0159] It is to be understood that the present 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.
[0160] In addition, where features or aspects of the disclosure are described in terms of
Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.
[0161] As will be understood by one 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 can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range 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, and so forth.
Definitions
[0162] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton etal, Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger etal. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.
[0163] As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.
[0164] As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
[0165] As used herein, the term “administration” of an agent to a human includes any route of introducing or delivering the agent to a human to perform its intended function. Administration can be carried out by any suitable non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and the administration by another.
[0166] As used herein, the term “effective amount” or “therapeutically effective amount” refers to a quantity 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 the human can depend on the type and severity of the disease or symptom and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
[0167] As used herein, the term “modulate” refers positively or negatively alter.
Exemplary modulations include an about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100% change. [0168] As used herein, the term “increase” refers to alter positively by at least about 5%, including, but not limited to, alter positively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.
[0169] As used herein, the term “reduce” refers to alter negatively by at least about 5% including, but not limited to, alter negatively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.
[0170] As used herein, the term “an OX2R agonist” refers to methyl 3-
((methylsulfonyl)amino)-2-(((4-phenyl-cyclohexyl)oxy)methyl)piperidine-l-carboxylate (“Compound (I)”), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, Compound (I) is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis- 4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate (Compound A).
[0171] “Pharmaceutically acceptable excipient or carrier” refers to an excipient that may optionally be included in the compositions of the disclosure and that causes no significant adverse toxicological effects to the human.
[0172] A “composition” “pharmaceutical composition” as used herein, intends an active agent, such as a compound as disclosed herein and a carrier, inert or active. The carrier can be, without limitation, solid such as a bead or resin, or liquid, such as phosphate buffered saline.
[0173] “Pharmaceutically acceptable salt” refers to salts of a compound, which salts are suitable for pharmaceutical use and are derived from a variety of organic and inorganic counter ions well known in the art and include, when the compound contains an acidic functionality, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate (see Stahl and Wermuth, eds., “Handbook of Pharmaceutically Acceptable Salts,” (2002), Verlag Helvetica Chimica Acta, Ziirich, Switzerland), for a discussion of pharmaceutical salts, their selection, preparation, and use.
[0174] Generally, pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for in vivo administration. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.
[0175] Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic 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 (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
[0176] Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or by an ammonium ion (e.g., an ammonium ion derived from an organic base, such as, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).
[0177] A solvate of a compound is a solid-form of a compound that crystallizes with less than one, one or more than one molecules of a solvent inside in the crystal lattice. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but are not limited to, water, C1-C6 alcohols (such as methanol, ethanol, isopropanol, butanol, and can be optionally substituted) in general, tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art. Additionally, various organic and inorganic acids and bases can be added to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate. In some embodiments, one molecule of a compound can form a solvate with from 0.1 to 5 molecules of a solvent, such as 0.5 molecules of a solvent (hemisolvate, such as hemihydrate), one molecule of a solvent (monosolvate, such as monohydrate) and 2 molecules of a solvent (disolvate, such as dihydrate).
[0178] An “effective amount” or a “pharmaceutically acceptable amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is determined by the system in which the drug or compound is delivered, e.g., an effective amount for in vitro purposes is not the same as an effective amount for in vivo purposes. For in vivo purposes, the delivery and “effective amount” is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents disclosed herein for any particular human depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal and its body weight, general health, sex, the diet of the animal, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vivo. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.
[0179] As used herein, “treating” or “treatment” of a disease in a human refers to (1) inhibiting the disease or arresting its development; or (2) ameliorating or causing regression of the disease or the symptoms of the disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of this technology, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease), stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of condition (including disease), progression, amelioration or palliation of the condition (including disease), states and remission (whether partial or total), whether detectable or undetectable. EXAMPLES
[0180] The following non-limiting examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compositions, and assay, screening, and therapeutic methods of the disclosure, and are not intended to limit the scope of what the inventors regard as their invention.
Example 1: A Phase lb Randomized, Double-Blind, Placebo-Controlled, Crossover Study of a Single Intravenous Infusion Dose of an Orexin 2 Receptor (OX2R) Agonist in Patients With Idiopathic Hypersomnia
Primary Objective
[0181] The primary objective of this study was to evaluate the safety and tolerability of administering a single IV infusion of Compound A (methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperi-dine-l-carboxylate) to adult subjects with idiopathic hypersomnia (IH).
Secondary Objective
[0182] 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 Objectives
[0183] The exploratory objectives of this study were as follows:
1. To assess the effects of Compound A on daytime sleepiness as measured by the 40-minute Maintenance of Wakefulness Test (MWT).
2. To assess the effects of Compound A on daytime sleepiness as measured by Karolinska Sleepiness Scale (KSS).
3. To assess the effects of Compound A on attention and vigilance as measured by Psychomotor Vigilance Task (PVT).
4. To assess the effects of Compound A on vital signs.
5. To assess the PK of Compound A metabolites. Study Design and Plan
[0184] This was a phase lb, randomized, double-blind, placebo-controlled, 2-period, 2- treatment crossover study to evaluate the PK, pharmacodynamics (PD), safety, and tolerability of a single IV infusion dose of Compound A in subjects with IH. Subjects were males and females aged 18 through 75 years, inclusive, with IH diagnosed according to the International Classification of Sleep Disorders-3 (ICSD-3) criteria as verified by a previous nocturnal polysomnography (nPSG) and multiple sleep latency test (MSLT) study performed within the last 10 years.
[0185] The treatment periods began on Day 1 of Treatment Period 1 (Study Day 1) with
Treatment Period 2 commencing on Study Day 3, where Treatment Period 1 was Study Days 1 and 2 and Treatment Period 2 was Study Days 3 and 4. In 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 was dosed in 2 treatment periods according to the order defined by the sequence group to which he/she was randomized. On Day 1 of each treatment period, Compound A (or placebo) was administered as a single 9-hour IV infusion commencing at approximately 0800. The infusion was terminated at approximately 1700. On Day 1 of each treatment period, four 40-minute MWT sessions were performed at 2, 4, 6, and 8 hours after the start of the infusion. Subjects were instructed to stay awake in between the MWT sessions and during the daytime hours of the first washout day (Study Day 2).
Table 1. Summary of Treatment Assignment for Each Sequence
Figure imgf000056_0001
[0186] At the screening visit, eligible subjects who had an Epworth Sleepiness Scale
(ESS) score of >11 completed medical histories and physical examinations, semi- recumbent vital signs assessment, a 12-lead electrocardiogram (ECG), Beck Depression Inventory II (BDI-II), Columbia Suicide Severity Rating Scale (C-SSRS), and clinical safety laboratory tests. Subjects with an ESS score of <11 who were taking stimulants at screening continued the screening process and repeated the ESS at Study Day -2 following washout. A total of 40 subjects were randomized so 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 actigraphy supported by a sleep diary beginning on Study Day -9 and ending on Study Day -3 (i.e., the day before their Study Day -2 admission to the clinical unit), to ensure an average nightly sleep duration of >420 minutes (7 hours) during the subject’s normal nocturnal sleep period, and, if the subject’s average nightly sleep duration was <480 minutes (8 hours), that the subject did not have insufficient sleep syndrome (sleeping >2 hours/night more on “off days” than on “work days”). During screening, eligible subjects discontinued their stimulant medications used for treatment of IH. Medications were discontinued for a minimum of 7 days or at least 5 halfdives of each medication, whichever is longer, before the first day of dosing (Day 1 of Treatment Period 1). Sodium oxybate was discontinued at least 4weeks before screening.
[0187] The screening period was up to 28 days. Following screening, subjects who met all screening entry criteria were admitted to the clinical unit (Study Day -2). Semi- recumbent vital signs were obtained following admission, and the ESS were recorded in the late afternoon. An overnight 8-hour nPSG was performed commencing at approximately 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 (O2 saturation <80% for >5% of total sleep time), and to confirm the apnea hypopnea index (AHI) is <10/hour and the periodic limb movement index associated with arousal s (PLMAI) is < 15/hour.
[0188] Study Day -1 was the designated baseline assessment day and was also intended for accommodation to sleeping in the clinical unit. Four 40-minute MWT sessions were performed, time-matched to the planned times of the MWT sessions that were scheduled post study drug administration on dosing days (Study Days 1 and 3). The KSS and the PVT were completed after MWT. Safety assessments including blood pressure (BP), pulse, respiration rate, and ECG were also collected.
[0189] 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 commencing at approximately 08:00. On each dosing day (Study Days 1 and 3), 40-minute MWT sessions were performed at 2, 4, 6, and 8 hours after the start of the infusion. There was a minimum 24-hour washout interval between the end of Compound A infusion and the commencement of treatment in the subsequent treatment period to allow for complete elimination of the preceding treatment effect. Study Days 2 and 4 were washout days. The KSS and PVT were collected. Blood samples for determination of Compound A plasma concentrations were collected predose and at specified time points postdose, ideally via an indwelling venous catheter so as not to interfere with MWT testing. Safety assessments including adverse events (AEs), vital signs, and ECGs were recorded. During the study, AEs were recorded, and clinical labs, vital signs, and safety ECGs were obtained. Subjects were discharged from the unit following completion of study exit procedures in the afternoon of Study Day 4 (Day 2 of Treatment Period 2).
[0190] Subjects returned to the study site or were contacted by telephone approximately 7 days (±2 days) following unit discharge for a safety check and all women of childbearing potential returned to the study site to complete a urine pregnancy test at the end-of-study visit.
[0191] An overview of the inpatient unit study schedule is presented in Table 2.
Table 2. Overview of Inpatient Unit Study Schedule
Figure imgf000058_0001
nPSG: nocturnal polysomnography; PD: pharmacodynamics; PK: pharmacokinetic. a nPSG only on Study Day -2. b Discharge from unit on Study Day 4. Diet and Fluids
[0192] Subjects received 3 standardized meals per day each including approximately 30% fat (relative to the total calories) during confinement in the unit. Breakfast was served at approximately 0700 each morning; lunch and dinner was served at standardized times so as not to coincide or interfere with clinical testing (MWT, KSS, PVT).
[0193] Subjects restricted using tobacco- and nicotine-containing products, alcohol, and xanthine and/or coffee before and during the Screening Period (Days -28 to -3) and during Inpatient Day -2 to Discharge Day 4.
[0194] Subjects refrained from consuming grapefruit/grapefruit juice and Seville oranges, mustard greens (i.e., kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, and mustard), and charbroiled meat 7 days before dosing in the Screening Period (Days - 28 to -3) and during Inpatient Day -2 to Discharge Day 4.
Activity
[0195] Subjects avoided unaccustomed strenuous physical activity (i.e., weight lifting, running, bicycling, etc.) from the screening visit until administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), and until the follow-up visit. Short supervised walks outside the unit were permitted on washout days.
Primary and Secondary Endpoints
[0196] The primary endpoints were as follows:
• Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).
• Percentage of subjects who meet the markedly abnormal criteria for clinical safety laboratory tests at least once post a regimen.
• Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at least once post a regimen.
• Percentage of subjects who meet the markedly abnormal criteria for 12-lead safety electrocardiogram (ECG) parameters at least once post a regimen.
[0197] The secondary endpoint:
• Compound A PK parameters: - Observed plasma concentration at the end of infusion (Ceoi).
- Area under the plasma concentration-time curve from time 0 to infinity (AUCoo).
- Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUCiast).
Exploratory Endpoints
[0198] The following PD endpoints were measured to explore the effect of Compound A in subjects with IH:
• Average sleep latency from the 4 MWT sessions post-dose in each treatment period.
• KSS score measured in each time point in each treatment period.
• PVT score post-dose in each treatment period.
[0199] The following PK parameters were estimated to evaluate the PK of Compound A metabolites in subjects with IH:
• Ceoi.
• AUCoo.
• AUCiast.
[0200] The following safety endpoints were estimated for Compound A in subjects with IH as data permitted:
• Physical examinations.
• Vital signs, including semi-recumbent blood pressure (BP), heart rate (HR), and respiratory rate.
• 12-lead ECGs.
• Clinical laboratory safety evaluations (hematology, serum chemistry, and urinalysis).
Study Population
[0201] Main Inclusion Criteria:
• A diagnosis of IH, as defined by the ICSD-3, as verified by a previous nocturnal polysomnography (nPSG) and multiple sleep latency test (MSLT) study performed within the last 10 years. • Onset of hypersomnia between 10 and 30 years of age.
• Body mass index (BMI) of 18 through 33 kg/m2 inclusive.
• Seven consecutive days of actigraphy supported by a sleep diary (recorded while the subject was wearing the actigraph) obtained prior to the nPSG (Study Day -2) shows an average nightly sleep duration of >420 minutes during the subject’s normal nocturnal sleep period.
• nPSG (Study Day -2) demonstrates that subject does not have other comorbid sleep disorders or clinically significant nocturnal hypoxemia (O2 saturation <80% for >5% of total sleep time) and that their Apnea-Hypopnea Index (AHI) was <10/hour, their periodic limb movement arousal index (PLMAI) was <15/hour, and total sleep time was >6.5 hours.
• Average (of 4 sessions) baseline MWT sleep latency was less than or equal to 20 minutes and no single session had a sleep latency of greater than 30 minutes as determined by the site investigator or qualified designee.
• Subjects taking medication for treatment of excessive daytime sleepiness were willing to discontinue medication prior to randomization into the study.
• Epworth Sleepiness Scale (ESS) score >11 at screening and on Day -2. Subjects with an ESS score of <11 who were taking stimulants at screening may continue the screening process and repeat the ESS at Study Day -2 following washout.
• Blood pressure (BP) must be <140 mmHg (systolic) and <90 mmHg (diastolic) at screening and Study Day -2. BP measures were obtained after the subject had been resting for a minimum of 10 minutes and may be repeated 3 times if the BP was elevated above these parameters. The median BP reading was used.
[0202] Main Exclusion Criteria:
• Average nightly sleep duration was <8 hours (480 minutes) and the subject had insufficient sleep syndrome as evidenced by sleeping >2 hours/night more on “off-days” relative to “work days” as determined by actigraphy and sleep diary obtained prior to the nPSG (Study Day -2).
• Resting heart rate (HR) outside of the range of 40 to 90 beats per minute, off stimulants. • Screening ECG revealed a QT interval with Fridericia correction method >450 ms (men) or >470 ms (women).
• Usual bedtime later than 2400 (midnight) or an occupation requiring nighttime shift work or variable shift work within the past 6 months, or travel with significant jet lag within 14 days before Study Day -2.
• History of sleep disorder other than IH, based on interviews at the screening visit, such as obstructive sleep apnea (OSA), restless legs syndrome, or periodic limb movements of sleep (PLMS) associated with arousals.
• Use of any over the counter or prescription medications with stimulating properties within 7 days prior to dosing or 5 half-lives (whichever is longer) that could have affected the evaluation of excessive daytime sleepiness, or any use of sodium oxybate within 4 weeks of screening.
• Nicotine dependence that was likely to have an effect on sleep (e.g., a subject who routinely awakens at night to smoke) or challenge the conduct of this study (smokes >10 cigarettes/day) and/or an unwillingness to discontinue all smoking and nicotine use during the confinement portion of the study (Day -2 to Day 4).
• Caffeine consumption of more than 600 mg/day for 7 days before Study Day 1 (1 serving of coffee is approximately equivalent to 120 mg of caffeine) and/or unwilling to discontinue all caffeine during the confinement portion of the study (Day -2 to Day 4).
• Alcohol use that was likely to have an effect on sleep and/or an unwillingness to discontinue all alcohol use from 72 hours before check-in through discharge on Study Day 4.
• History or presence of any unstable medical condition, behavioral or psychiatric disorder (including major depression or active suicidal ideation), or surgical history that could have affected the safety of the subject or interfered with study efficacy, safety, PK assessments, or the ability of the subject to complete the study per the judgment of the investigator. Statistical Considerations
[0203] Standard summaries of TEAEs, adverse events of special interest (AESIs), clinical safety labs, vital signs, and ECGs were performed. Where appropriate, BP and QT parameters were summarized (N, mean, SD, median, minimum and maximum) for baseline, post-dose, change from baseline, and change from time-matched baseline to post-dose by treatment.
[0204] The observed HR and BP were analyzed using linear mixed effect model for repeated measures in crossover studies. The model includes sequence, period, treatment, time points, and treatment by time point interaction as fixed effects and a random effect for subject. The estimated mean HR and BP for each treatment and the associated standard error and 95% Cl was extracted from the model at each time, along with all pairwise differences from placebo and associated standard errors, 95% CIs, and p-values. The same quantities, averaged over all timepoints during the infusion and post the end of the infusion, were extracted from the model using appropriate contrasts.
[0205] Individual plasma concentrations of Compound A (and its metabolites) and PK parameter estimates were listed for each subject and summarized using descriptive statistics, as appropriate.
Summary of Topline Results
[0206] Twenty-eight patients were randomized, and 25 patients completed the study. All patients at entry were experiencing excessive daytime sleepiness (EDS) (mean Epworth Sleepiness Scale (ESS) = 18.3 points and mean sleep onset latency from 4 Maintenance of Wakefulness Test (MWT) trials of 9.2 min). Tables 3 and 4 show the demographics and baseline disease characteristics of the study population.
Table 3. Demographics of Study Population (N = 27)
Figure imgf000063_0001
Figure imgf000064_0001
Table 4. Baseline Disease Characteristics of Study Population (N = 27)
Figure imgf000064_0002
*Discrepancy in scoring between Clinilabs (AHI 24) and the Site (AHI 8.4). Upon agreement with Sponsor's Sleep expert the subject was considered eligible for the study.
[0207] Overall, Compound A was well tolerated with no serious adverse events (AEs), no discontinuations due to AEs, and no clinically significant ECG or laboratory values. Percent of patients with at least one treatment emergent AEs (TEAEs) was 15% in the placebo group and 40% in the Compound A 112 mg group. All Compound A 112 mg TEAEs were mild except one report of insomnia classified as severe and one report of anxiety reported as moderate. 16% of patients (4 patients) in the Compound A 112 mg group reported a TEAE related to ‘any urinary event,’ all mild in severity.
[0208] There were no reported TEAEs of blood pressure increase. There were no reports of markedly abnormal BP elevation (>160/100 or change from pre-dose >20) or HR >
115.
[0209] Regarding the pharmacodynamics of Excessive Daytime Sleepiness, Compound A
112 mg demonstrated significant improvements in the objective and subjective measures of wakefulness in patients with idiopathic hypersomnia (IH). In the MWT, which has a ceiling effect of 40 minutes, the unadjusted mean sleep onset latency values were approximately 10.5 minutes and 39.9 minutes for placebo and Compound A 112 mg, respectively. The mean placebo-adjusted increase in sleep onset latency of 29.4 minutes was statistically significant. The study met the ePOC criteria, and based on the data, there is >70% certainty that the true difference from placebo in MWT is > 6 min. FIG. 1 shows the LS mean for post-dose sleep latency from 4 MWT Trials. FIG. 2 shows the LS mean (95% Cl) for post-dose sleep onset latency from MWT by time point.
[0210] Compound A 112 mg also reduced subjective sleepiness as measured by KSS
(Karolinska Sleepiness Scale). The mean placebo-adjusted decrease in KSS of -3.3 points was statistically significant. FIG. 3 shows the LS mean for post-dose KSS (Karolinska Sleepiness Scale). FIG. 4 shows the LS mean (95% Cl) for post-dose KSS by time point.
[0211] The objective and subjective pharmacodynamic effects were evident as early as 2 hours post dose and remained stable over time.
[0212] In summary, a single dose of Compound A at 112 mg administered as an infusion over nine hours in IH patients was well tolerated by most with no major safety concerns and demonstrated remarkable positive objective and subjective pharmacodynamic effects on maintenance of daytime wakefulness in patients with IH.
[0213] 112 mg of Compound A administered by IV infusion demonstrated near maximal levels of wakefulness as measured by the MWT in precedent clinical tests.
[0214] There are no therapies approved for IH worldwide except for modafmil which has been approved in Japan. The only published pivotal study supporting this approval showed in a 33 patient study a 2.8 min improvement on the MWT which was not found to be significant (Mayer et al. J Sleep Res. (2015) 24, 74-81).

Claims

WHAT IS CLAIMED IS:
1. A method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
2. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
3. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
4. A method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
5. Methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
6. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
7. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than placebo.
8. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
9. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than placebo.
10. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate according to any one of claims 1-
9, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 2.8 minutes than placebo.
11. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate according to any one of claims 1-
10, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcy cl ohexyl)oxy)methyl)piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 29.4 minutes than placebo.
12. A method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
13. Methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
14. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4-phenyl cyclohexyl)oxy)methyl)piperidine-l -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
15. A method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about 10.5 minutes.
16. Methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
17. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
18. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereofmcreases sleep onset latency time greater than about 10.5 minutes.
19. Methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
20. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than about 10.5 minutes.
21. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 12-20, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than 13.3 minutes.
22. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 12-21, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time of 39.9 minutes or more.
23. A method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than modafmil.
24. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
25. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
26. A method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than modafmil.
27. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
28. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
29. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time greater than about modafmil.
30. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
31. The use of methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, increases sleep onset latency time greater than modafmil.
32. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 23-31, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep onset latency time by greater than about 26.6 minutes than modafmil.
33. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1-33, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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.
34. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate according to any one of claims 1- 33, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, 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.
35. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate according to any one of claims 1- 33, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, 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.
36. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate according to any one of claims 1- 33, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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.
37. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1-33, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is about 112 mg.
38. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1-37, wherein the administration is an oral administration.
39. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1-37, wherein the administration is a non-oral administration.
40. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 39, wherein the non-oral administration is intravenous administration.
41. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 40, wherein the intravenous administration is a single dose.
42. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 40, wherein the intravenous administration is administered over multiple doses.
43. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 41, wherein the single dose is administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
44. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 41, wherein the single dose is administered over 9 hours.
45. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 1-44, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof increases sleep latency in maintenance of wakefulness test (MWT).
46. A pharmaceutical composition comprising (a) methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater than placebo.
47. The pharmaceutical composition according to claim 46, wherein the composition increases sleep onset latency greater than about 2.8 minutes than placebo.
48. The pharmaceutical composition according to claim 47, wherein the composition increases sleep onset latency greater than about 24.9 minutes than placebo.
49. A pharmaceutical composition comprising (a) methyl (2R, 3 S)-3 -((methyl sulfonyl) amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater 10.5 minutes.
50. The pharmaceutical composition according to claim 49, wherein the composition increases sleep onset latency greater than about 13.3 minutes.
51. The pharmaceutical composition according to claim 50, wherein the composition increases sleep onset latency of 39.9 minutes or more.
52. A pharmaceutical composition comprising (a) methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and (b) a pharmacuetically acceptable excipient, wherein the composition provides an increase in onset sleep latency greater than modafmil.
53. The pharmaceutical composition according to claim 52, wherein the composition increases sleep onset latency greater than about 26.6 minutes than modafmil.
54. The pharmaceutical composition according to any one of claims 46-53, wherein methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
55. The pharmaceutical composition according to any one of claims 46-53, wherein methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
56. The pharmaceutical composition according to any one of claims 46-53, wherein the methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
57. The pharmaceutical composition according to any one of claims 46-53, wherein methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
58. The pharmaceutical composition according to any one of claims 46-53, wherein methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of about 112 mg.
59. A method of treating an orexin-mediated disease or disorder in a human with normal orexin levels comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
60. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
61. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an orexin-mediated disease or disorder in a human with normal orexin levels, wherein a therapeutically effective amount of methyl (2R, 3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
62. A method of treating idiopathic hypersomnia in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
63. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
64. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl) oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating an idiopathic hypersomnia in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
65. A method of treating excessive daytime sleepiness in a human in need thereof, comprising administering to the human a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate or pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
66. Methyl (2R,3 S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
67. The use of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a medicament for treating excessive daytime sleepiness in a human in need thereof, wherein a therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, reduces excessive daytime sleepiness compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
68. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 59-67, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate or a pharmaceutically acceptable salt, hydrate, or solvate thereof reduces excessive daytime sleepiness by about 3.3 compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
69. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcy cl ohexyl)oxy)methyl)piperi dine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 59-68, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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.
70. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 59-68, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, 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.
71. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 59-68, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, 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.
72. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of claims 59-68, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof 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.
73. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the claims 59-68, wherein the therapeutically effective amount of methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is about 112 mg.
74. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claims 59-73, wherein the administration is oral.
75. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claims 59-73, wherein the administration is non-oral.
76. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 75, wherein the non-oral administration is intravenous administration.
77. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 76, wherein the intravenous administration is a single dose.
78. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 76, wherein the intravenous administration is administered over multiple doses.
79. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 77, wherein the single dose is administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours.
80. The method, use, or methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to claim 77, wherein the single dose is administered over 9 hours.
81. A pharmaceutical composition comprising (a) methyl (2R,3 S)-3 - ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, 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).
82. The pharmaceutical composition according to claim 81, wherein the composition reduces excessive daytime sleepiness by about 3.3 compared to placebo as measured by the Karolinska Sleepiness Scale (KSS).
83. The pharmaceutical composition according to claims 81 or 82, wherein methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
84. The pharmaceutical composition according to claims 81 or 82, wherein methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
85. The pharmaceutical composition according to claims 81 or 82, wherein the methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
86. The pharmaceutical composition according to claims 81 or 82, wherein methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy) methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of 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.
87. The pharmaceutical composition according to claims 81 or 82, wherein methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is present in an amount of about 112 mg.
88. A method of treating a human suffering from symptoms of idiopathic hypersomnia or excessive daytime sleepiness comprising: (a) ascertaining the concentration of orexin in a biological sample from the human and
(b) if the concentration of orexin is greater than about 110 pg/mL, then administering an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenyl- cyclohexyl)oxy)methyl)piperidine-l-carboxylate, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
PCT/IB2022/052214 2021-03-12 2022-03-11 An orexin 2 receptor agonist for the treatment of an orexin-mediated disease or disorder WO2022190060A1 (en)

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