WO2020185711A1 - Méthode de traitement des troubles de la fragmentation du sommeil au moyen d'agonistes/antagonistes inverses à double action de h1 et 5ht2a - Google Patents

Méthode de traitement des troubles de la fragmentation du sommeil au moyen d'agonistes/antagonistes inverses à double action de h1 et 5ht2a Download PDF

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WO2020185711A1
WO2020185711A1 PCT/US2020/021768 US2020021768W WO2020185711A1 WO 2020185711 A1 WO2020185711 A1 WO 2020185711A1 US 2020021768 W US2020021768 W US 2020021768W WO 2020185711 A1 WO2020185711 A1 WO 2020185711A1
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sleep
compound
disorder
disease
administered
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PCT/US2020/021768
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English (en)
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Dale M. Edgar
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Alairion, Inc.
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Publication of WO2020185711A1 publication Critical patent/WO2020185711A1/fr

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present disclosure relates to methods of alleviating a symptom of, treating, or preventing a sleep disorder (e.g., increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold) by administering a dual Hi receptor inverse agonist and 5HT2A receptor antagonist, or pharmaceutically acceptable salt thereof.
  • a sleep disorder e.g., increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold
  • a dual Hi receptor inverse agonist and 5HT2A receptor antagonist e.g., increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold
  • poor sleep Whilst the daytime impairment caused by poor sleep has long been appreciated, poor sleep also has cascading negative impact upon alertness, cognition, learning and memory, vigilance, performance, and a broad range of co-morbid health conditions including acute and chrome pain and pain disorders, psychiatric conditions, neurodegenerative disease, developmental disorders, metabolic disease and diabetes, obesity, cardiovascular disease, immunological disorders, and many other medical conditions.
  • the present disclosure provides compounds for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold. In some embodiments, the sleep disorder is increased disturbed sleep. In some embodiments, the sleep disorder is increased sleep fragmentation. In some embodiments, the sleep disorder is increased arousals. In some embodiments, the sleep disorder is decreased arousal threshold.
  • the present disclosure provides the identification of a pharmacological compound class having dual Hi receptor inverse agonist and 5HT2A receptor antagonist activity to alleviate the symptom of, treat, or prevent a sleep disorder.
  • the sleep disorder is characterized in whole or in part by sleep fragmentation.
  • Compounds with dual Hi receptor inverse agonist and 5HT2A receptor antagonist pharmacology were studied for their effects on EEG sleep-wakefulness, locomotor activity, drink- and food-related activity, and body- temperature in rats using an enhanced and expanded version of SC()RE-2000 liy , a sleep- wake bioassay and analysis system known as“SCORETM”
  • a compound of the present disclosure is a dual Hi receptor inverse agonist and SHTZA receptor antagonist.
  • the dual Hi receptor inverse agonist and SHTZA receptor antagonist is selected from: HY-10275, mirtazapine (HY10521), S- mirtazapine (HY 10378), quetiapine (HY10625), and amitriptyline, or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering one or more compound of the present disclosure selected from: HY-10275, mirtazapine (HY10521), S-mirtazapine (HY10378), quetiapine (HY 10625), and amitriptyline, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • one or more compound of the present disclosure selected from: HY-10275, mirtazapine (HY10521), S-mirtazapine (HY10378), quetiapine (HY 10625), and amitriptyline, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering HY-10275, or a pharmaceutically acceptable salt thereof
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering mirtazapine, or a pharmaceutically acceptable salt thereof
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering S-mirtazapine, or a pharmaceutically acceptable salt thereof
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering quetiapine, or a pharmaceutically acceptable salt thereof.
  • the present discl osure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering amitriptyline, or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • RDI respiratory disturbance index
  • PLMD periodic leg movement disorder
  • REM behavior disorder elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with sleep apnea.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with restless legs syndrome.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a high respiratory disturbance index (RDI).
  • RDI respiratory disturbance index
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a neurological disease.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a circadian rhythm disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with pain.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with periodic leg movement disorder (PLMD).
  • PLMD periodic leg movement disorder
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with REM behavior disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with elderly fragmented sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with age-related sleep fragmentation.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with post-menopausal sleep disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse withdrawal.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with narcolepsy.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a mental disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with snoring.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with idiopathic hypersomnia.
  • the methods of the present disclosure the subject is administered a pharmaceutical composition.
  • the pharmaceutical composition comprises a compound of the present disclosure and an additional active agent.
  • the additional active agent is a sedative-hypnotic.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering a pharmaceutical composition comprising an Hi inverse agonist or antagonist and 5HT2A antagonist or inverse activity, or a pharmaceutically acceptable derivative thereof, in combination with an additional active agent.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering the compounds of the present disclosure and any additional active agents, if present, either hora somni, h.s. (at bedtime) or between about 0-4 hours before bedtime to a subject in need thereof.
  • compositions and methods of using such pharmaceutical therapies are provided herein for sleep fragmentation.
  • Pharmaceutical therapies and methods of using such pharmaceutical therapies are provided for a sleep disorder in a subject with one or more co- morbid medical conditions.
  • these therapies and methods of using such therapies include pharmaceutical therapies to decrease disturbed sleep, decrease sleep fragmentation, decrease arousais, or increase arousal threshold.
  • a subject may have one or more of the following medical conditions: sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • RDI respiratory disturbance index
  • PLMD periodic leg movement disorder
  • REM behavior disorder elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • LMAi Locomotor Activity' Intensity
  • LMAi Locomotor Activity Intensity
  • EMG electromyograph
  • “uninterrupted bouts of sleep” (average sleep bout duration) refers to the average duration of all bouts of uninterrupted sleep that occurred each hour, measured in minutes.“Interruption” of sleep refers to 2 or more consecutive 10 second epochs of
  • wakefulness.“Interruption” of wake refers to 2 or more consecutive 10 second epochs of sleep. The value for the length of a bout that extends into the subsequent hour is assigned to the hour in which it began. Analogous quantification was carried out for bouts of wakefulness. Sleep bout length may reflect the human tendency to awaken periodically through the night (such awakenings are normally not recalled), which in turn may be an important factor in determining the restorative value of sleep in a subject (e.g., humans). Pre-clinical measures of sleep bout duration are also strong predictors of soporific efficacy in a subject (e.g., humans).
  • NREM and“nonREM” refers to non-rapid eye movement sleep stages.
  • “reduced number of arousals” refers to the reduced number of wake bouts per hour.
  • REM refers to the rapid eye movement sleep stage.
  • CT refers to circadian time
  • “sleep consolidation” refers to the measurement of the average sleep bout duration per hour.
  • “sleep continuity” refers to the measurement of sleep-bout length.
  • the“depth” of sleep is characterized by EEG slow wave activity, which may subserve sleep continuity or sleep consolidation, which is one of several determinants of sleep quality.
  • “SWA” refers to slow wave activity, which may be exemplified as EEG delta po was by use of Fourier analysis.
  • “LMA intensity” (LMAi) refers to locomotor activity (LMA) counts per minute of EEG-defined wakefulness. This variate allows an assessment of LMA that is independent of the amount of time awake, which may be used to quantify the specificity of a wake- or sleep-promoting effect.
  • number of wake bouts refers to the number of uninterrupted bouts of wakefulness that occurred each hour, measured in minutes. Number of wake bouts are of interest because it may closely reflect the number of arousais from sleep that occur at the time of measurement. Interpreted together, average sleep bout duration and number of wake bouts provide a highly reliable assessment of a drug or novel molecular entity (NME) effect on sleep fragmentation. Drugs that improve sleep fragmentation have been shown to improve the restorative benefits of sleep.
  • NME novel molecular entity
  • the term“co-morbid” refers to a disease or disorder which is concurrent with a sleep disorder, but may not be the cause, in whole or m part, of the sleep disorder.
  • the term“pharmaceutically acceptable” refers to compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • the term“pharmaceutical composition” is a formulation comprising a compound of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants in some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • the term“preventing,”“prevent,” or“protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • rat and“laboratory rat” are used interchangeably.
  • references to“treating” or“treatment” include the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclimcal symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclimcal symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclimcal symptoms.
  • the term“subject” is interchangeable with the term“subject in need thereof’, both of which refer to a subject having a disease or having an increased risk of developing the disease.
  • A“subject” includes a mammal.
  • the mammal can be, for example, a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the mammal is a rat.
  • the mammal is a human.
  • a subject in need has been previously diagnosed or identified as having a disease or disorder disclosed herein.
  • a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
  • a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may he resistant at start of treatment or may become resistant during treatment.
  • the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein.
  • the subject m need thereof received at least one prior therapy.
  • “approximately” and“about” are synonymous.
  • “approximately” and“about” refer to the recited value, amount, dose or duration ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 8%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 2%, ⁇ 1%, or ⁇ 0.5%.
  • “approximately” and“about” refer to the listed amount, value, dose, or duration ⁇ 10%, ⁇ 8%, ⁇ 6%, ⁇ 5%, ⁇ 4%, or ⁇ 2%.
  • “approximately” and“about” refer to the listed amount, value, dose, or duration ⁇ 5%. In some embodiments,“approximately” and“about” refer to the listed amount, value, dose, or duration ⁇ 2%. In some embodiments,“approximately” and“about” refer to the listed amount, value, dose, or duration ⁇ 1%.
  • a“compound” is the same as an“active ingredient”, an“
  • H1/5HT2A molecule an“Hi inverse agonist”, an“HI/SHTIA antagonist”, a“dual acting Hi inverse agonist”, a“5HT2A antagonist molecule (HI/5HT2A) “a dual Hi receptor inverse agonist and 5-HT2A receptor antagonist”, and a“compound of the present disclosure”.
  • “HY-10275” may also be referred to as 3-(4- Dibenzo[b,f][l,4]oxazepin-l 1 -yl-piperazin-l-yl)-2,2-dimethyl-propionic acid; di-hydrogen
  • “mirtazapine” may also be referred to as HY10521, 2-methyl-
  • “S-mirtazapine” may also be referred to as HY10378, (S)-2- methyl- 1 ,2,3,4, 10, 14b-hexahydrobenzo[c]pyrazino[l ,2-a]pyrido[3,2-f]azepine (i.e. ,
  • “quetiapme” may also be referred to as HY10625, 2-(2-(4- (dibenzo[b,f
  • “amitriptyline” is 3-(10,11 -dihydro- 5H-dibenzo[a,d][7]annulen-5-
  • zolpidem may also be referred to as Ambien®, HY-10131 , N,N- dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[l ,2-a]pyridin-3-yl]acetamide (i.e.,
  • zolpidem is a pharmaceutically acceptable salt.
  • zolpidem is zolpidem tartrate.
  • S-zopiclone may also be referred to as Lunesta®, eszopiclone,
  • suvorexant may also be referred to as Be!somra®, [(7i?)-4-(5- chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4-diazepan-l-yl]-[5-methyl-2-(triazol-2-
  • Sleep fragmentation a condition m humans characterized by poor sleep consolidation, frequent brief arousals or microarousals (defined by the American Academy of Sleep Medicine as episodes of cortical EEG activation lasting at least 2 seconds and up to 16 seconds in duration and interrupting sleep), and frequent transitions to lighter stages of sleep, results in significant daytime impairment that may include impaired attention and concentration, excessive sleepiness, impaired judgement, impaired memory and learning, increased risk of accidents, and secondary morbidity and mortality when sleep fragmentation is a concomitant of pain, sleep disordered breathing, and other disease states. Patients suffering from sleep fragmentation are often unaware of the hundreds of brief arousals that may occur during the night, and primarily complain of severe daytime impairment. Sleep fragmentation patients often complain that their sleep is not beneficial, refreshing, or restorative.
  • insomnia is a separate and distinct medical diagnosis.
  • Insomnia is typically characterized by patient awareness and dissatisfaction with their sleep.
  • Most insomnia patients have a hyperarousal disorder that makes it difficult to fall asleep and/or difficult to stay asleep but enable them to function well during the daytime.
  • Insomnia is diagnosed by measuring the latency to persistent sleep, i.e., LPS (LPS of >30 minutes satisfies the definition of sleep-onset insomnia) and/or measuring the amount of time awake after sleep onset, i.e., WASO (WASO of >50 minutes satisfies the definition of sleep-maintenance insomnia).
  • LPS LPS of >30 minutes satisfies the definition of sleep-onset insomnia
  • WASO WASO of >50 minutes satisfies the definition of sleep-maintenance insomnia
  • insomnia patients It is common for insomnia patients, and particularly the elderly, to awaken m the middle of the night and be unable to return to sleep. Unlike patients suffering from sleep fragmentation, insomnia patients are almost always highly aware of their inability to fall asleep or stay asleep at night and complain about their nighttime experience, and typically do not complain about daytime impairment.
  • the utility of dual acting Hi inverse agonist and 5HT2A antagonist molecules to alleviate a symptom of, treat, or prevent a sleep disorder may be assessed by evaluating the sleep architecture and sleep quality endpoints of compounds with affinity and inverse
  • rat sleep and human sleep have all of the necessary fundamental similarities to permit the rat to be used as a preciinical model.
  • compounds that are soporific m a human may have soporific effects in a rat
  • compounds that are soporific in a rat may have soporific effects in a human.
  • Both rat and human exhibit robust circadian modulation of sleep tendency and sleep architecture.
  • The“homeostatic” control of sleep shares similarity across mammalian species, including humans, in that loss of sleep increases a homeostatic drive for sleep evidenced by a reduction in latency to sleep onset, increase in the depth of sleep that can be reflected by the amount of low- frequency“delta” EEG (“EEG slow waves”) during nonREM, an increase in sleep consolidation as measured by sleep bout duration, or an increase in total sleep time.
  • Sleep deprivation in a subject may cause the subject to fall asleep faster, sleep deeper, sleep more efficiently (e.g., more consolidated bouts of sleep), or sleep more (e.g., an increase of sleep time) until the homeostatic drive for sleep becomes adequately discharged through the sleeping process.
  • Uninterrupted, well consolidated sleep can determine sleep quality in both a rat and a human. Without wishing to be bound by theory, no matter how much a subject sleeps or what frequency of EEG dominates during sleep, the beneficial work of the sleeping process requires that sleep is not fragmented (interrupted) by frequent arousals.
  • compounds of the present disclosure which affect REM sleep by decreasing the latency to sleep onset, increasing sleep time, increasing the depth and/or consolidation of sleep, or reduce arousals, or a combination of the aforementioned effects in a subject have the same effects in a different subject.
  • the compounds of the present disclosure, which affect REM sleep by decreasing the latency to sleep onset effects in a subject may have the same effects on a subject of a different species.
  • the compounds of the present disclosure, which affect ITEM sleep by decreasing the latency to sleep onset effects in rats may have the same effects on a subject of different species.
  • the compounds of the present disclosure, which affect REM sleep by decreasing the latency to sleep onset effects m rats may have the same effects on a human.
  • compounds of the present disclosure which affect REM sleep by increasing sleep time in a subject have the same effects on a different subject.
  • the compounds of the present disclosure which affect REM sleep by increasing sleep time in a subject may have the same effects on a subject of a different species.
  • the compounds of the present disclosure which affect REM sleep by increasing sleep time in rats may have the same effects on a subject of a different species.
  • the compounds of the present disclosure which affect REM sleep by increasing sleep time in rats may have the same effects on a human.
  • compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in rats may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth and/or consolidation of sleep in rats may have the same effects in a human.
  • compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in rats may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth and consolidation of sleep in rats may have the same effects in a human.
  • compounds of the present disclosure which affect REM sleep by increasing the depth or consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure winch affect REM sleep by increasing the depth or consolidation of sleep in a subject, may have the same effects in a subject of a different species.
  • Compounds of the present disclosure winch affect REM sleep by increasing the depth or consolidation of sleep in rats, may have the same effects in a subject of a different species.
  • Compounds of the present disclosure winch affect REM sleep by increasing the depth or consolidation of sleep in rats, may have the same effects in a human.
  • compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in rats may have the same effects m a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the depth of sleep in rats may have the same effects in a human.
  • compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in rats may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by increasing the consolidation of sleep in rats may- have the same effects in a human.
  • compounds of the present disclosure which affect REM sleep by reducing arousals in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect REM sleep by reducing arousals in a subject have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by reducing arousals in rats have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect REM sleep by reducing arousals in rats have the same effects in a human.
  • compounds of the present disclosure which affect NREM sleep by decreasing the latency to sleep onset, increasing sleep time, increasing the depth and/or consolidation of sleep, or reduce arousals, or a combination of the aforementioned effects in a subject have the same effects in a different subject.
  • the compounds of the present disclosure, which affect NREM sleep by decreasing the latency to sleep onset effects in a subject may have the same effects on a subject of a different species.
  • the compounds of the present disclosure, which affect NREM sleep by decreasing the latency to sleep onset effects m rats may have the same effects on a subject of different species.
  • the compounds of the present disclosure, which affect NREM sleep by decreasing the latency to sleep onset effects in rats may have the same effects on a human.
  • compounds of the present disclosure which affect NREM sleep by increasing sleep time in a subject have the same effects on a different subject.
  • the compounds of the present disclosure which affect NREM sleep by increasing sleep time in a subject may have the same effects on a subject of a different species.
  • the compounds of the present disclosure which affect NREM sleep by increasing sleep time in rats may have the same effects on a subject of a different species.
  • the compounds of the present disclosure which affect NREM sleep by increasing sleep time in rats may have the same effects on a human.
  • compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in rats may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth and/or consolidation of sleep in rats may have the same effects in a human.
  • compounds of the present disclosure which affect NREM sleep by increasing the depth and consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth and consolidation of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by- increasing the depth and consolidation of sleep in rats may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth and consolidation of sleep in rats may have the same effects in a human.
  • compounds of the present disclosure winch affect NREM sleep by increasing the depth or consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth or consolidation of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth or consolidation of sleep in rats may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth or consolidation of sleep in rats may have the same effects in a human.
  • compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep m a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep in rats may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the depth of sleep in rats may have the same effects in a human.
  • compounds of the present disclosure which affect NREM sleep by increasing the consolidation of sleep in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect NREM sleep by increasing the consolidation of sleep in a subject may have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by increasing the consolidation of sleep in rats may have the same effects in a subject of a different species.
  • compounds of the present disclosure which affect NREM sleep by reducing arousals in a subject have the same effects in a different subject.
  • Compounds of the present disclosure which affect NREM sleep by reducing arousals in a subject have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by reducing arousals in rats have the same effects in a subject of a different species.
  • Compounds of the present disclosure which affect NREM sleep by- reducing arousals in rats have the same effects m a human.
  • sleep continuity can be measured as the duration of NREM“bouts” or the duration of REM bouts, or the duration NREM+REM“bouts”, wherein an arousal or bout of wakefulness interrupts the NREM-REM cycle.
  • sleep bout can he comprised of NREM, REM, or NREM+REM.
  • sleep bout can be comprised of NREM. In some embodiments, sleep bout can be comprised of REM. In some embodiments, sleep bout can be comprised of NREM+REM.
  • NREM and REM sleep alternate in what may be called the NREM-REM cycle. In some embodiments, NREM precedes REM.
  • the proportion of time spent in NREM versus REM is the same for different subjects. In some embodiments, the proportion of time spent in NREM versus REM is the same for different subjects of different species. In some embodiments, the proportion of time spent in NREM versus REM is the same for a rat and a subject of a different species. In some embodiments, the proportion of time spent in NREM versus REM is the same for a rat and a human.
  • the proportion of time spent in NREM versus REM is about 5:1.
  • the proportion of time spent in NREM versus REM is about 4: 1. In some embodiments, the proportion of time spent in NREM versus REM is about 3: 1. In some embodiments, the proportion of time spent in NREM versus REM is about 2: 1.
  • the proportion of time spent in NREM versus REM is from about 100: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 90: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 80: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 70: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 60: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 50: 1 to about 1 : 1.
  • the proportion of time spent in NREM versus REM is from about 40: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 30: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 20: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 10: 1 to about 1 : 1. In some embodiments, the proportion of time spent in NREM versus REM is from about 5: 1 to about 1 : 1. In some embodiments, the species is a mouse. In some embodiments, the species is a hoofed animal. In some embodiments, the hoofed animal is a horse or cow. In some embodiments, the species is not a laboratory rat. In some embodiments, the species is not a human.
  • hypnotics reduce REM sleep to some degree, and several classes of sleep disorder medicines can strongly suppress REM sleep.
  • REM sleep suppression is relevant to learning, memory, and/or psychiatric health.
  • the relative effect of some classes of medicines for sleep disorders, neuropsychiatric disorders, and cardiovascular disease that either inhibit or stimulate REM sleep translates from a subject to a different subject.
  • the relative effect of some classes of medicines for sleep disorders, neuropsychiatric disorders, and cardiovascular disease that either inhibit or stimulate REM sleep translates from a subject to a subject of a different species.
  • the relative effect of some classes of medicines for sleep disorders, neuropsychiatric disorders, and cardiovascular disease that either inhibit or stimulate ITEM sleep translates from a rat to a subject of a different species.
  • the relative effect of some classes of medicines for sleep disorders that either inhibit or stimulate REM sleep translate from a rat to a human.
  • a class of medicine which may inhibit or stimulate REM or NREM sleep is selected from a sleep therapeutic, a neuropsychiatric antidepressant, and a cardiovascular medicine.
  • a sleep therapeutic is a sedative hypnotic GABAA positive allosteric modulators that binds to the GABAA benzodiazepine receptor.
  • a neuropsychiatric antidepressant is a selective serotonin reuptake inhibitor (SSRI) or an atypical antipsychotics.
  • SSRI selective serotonin reuptake inhibitor
  • a cardiovascular medicine is a therapeutic that may bind to an alpha-adrenergic receptor.
  • rat and human sleep There are two differences which may be present between rat and human sleep. First, rats are night-active, whereas humans are day-active. This difference may have no importance per se for testing drug effects on sleep and wakefulness. The timing of the dose relative to the normal sleep period can be relied upon when evaluating drug efficacy on certain sleep related variables (e.g. inhibition of REM sleep) when comparing rat and human sleep.
  • sleep related variables e.g. inhibition of REM sleep
  • the difference between a rat and a human is sleep-bout length, also referred to as“sleep continuity.”
  • humans may consolidate sleep into a single period per day, interrupted normally only by very short (e.g., less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute) bouts of wakefulness.
  • the abnormal conditions may result in human sleep becoming fragmented, diminishing the restorative benefits of sleep.
  • Rats may have shorter bouts of sleep that occur throughout the 24-hour day (e.g., on average, every 20 minutes, a rat completes a sleep-wake cycle).
  • sleep typically occupies about 1/3 of each 20-minute cycle, and REM sleep is rare.
  • the rat typically sleeps about 2/3 of each 20-minute cycle.
  • the polyphasic nature of sleep and shorter spontaneous sleep bout durations in the rat enable highly sensitive assessments of drug effects such as those that increase sleep consolidation (sleep bout duration), decrease the number of arousals (number of wake bouts), and a variety of secondary but desirable measures of sleep quality, for example such as EEG slow wave activity' in nonREM sleep, and measures of wake maintenance as measured by wake bout duration.
  • Sleep bout-length may also be a sensitive measure of physiological sleepiness and is a pre-clinica! predictor of soporific efficacy in humans.
  • Empirical optimization can be performed by assessing sleep-related compounds by administering such compounds at two circadian times of day, CT-18 and CT-5, wherein CT-0 is defined as lights-on.
  • CT-18 is the mid-point of the activity phase of the rat’s circadian cycle, 6 hours after lights-off, and may be sensitive to soporific drug effects on sleep bout length, although such effects can be observed at both CT-18 and CT-5.
  • CT-5 begins several hours of peak abundance of REM sleep and thus is a sensitive time to reveal drug-related inhibition of REM sleep.
  • Both CT-18 and CT-5 are suitable times of the day for the assessment of drug effects on sleep fragmentation as measured by arousals (number of wake bouts), sleep consolidation (sleep bout duration), as well as assessments of maintenance of wakefulness (wake bout length) and drug-related side effects.
  • the subject is surgically prepared for EEG and EMG recording and administered an analgesic with an antibiotic, followed by therapeutic delivery via intraperitoneal or oral administration.
  • the sleep and wakefulness is determined using SCORETM.
  • the compounds of the present disclosure exhibit improved sleep fragmentation, as assessed by evaluating the sleep architecture and sleep quality endpoints of several neurosteroid molecules with established affinity and functional activity at this target.
  • sleep fragmentation is improved by (i) reducing the number of arousals (as measured by the number of wake bouts per hour), or (ii) increasing sleep consolidation (as measured by average sleep bout duration per hour). In some embodiments, sleep fragmentation is improved by (i) reducing the number of arousals (as measured by the number of wake bouts per hour), and (ii) increasing sleep consolidation (as measured by average sleep bout duration per hour). In some embodiments, sleep fragmentation is improved by reducing the number of arousals (as measured by the number of wake bouts per hour. In some embodiments, sleep fragmentation is improved by increasing sleep consolidation (as measured by average sleep bout duration per hour).
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder.
  • the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold.
  • the sleep disorder is increased disturbed sleep. In some embodiments, the sleep disorder is increased sleep fragmentation. In some embodiments, the sleep disorder is increased arousals. In some embodiments, the sleep disorder is decreased arousal threshold. [0142] The present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering one or more compounds of the present disclosure or pharmaceutically acceptable salt thereof to a subject in need thereof
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering a dual acting H inverse agonist and SHTYi antagonist molecules (HI/5HT2A), or pharmaceutically acceptable salts thereof, to a subject m need thereof.
  • a dual acting H inverse agonist and SHTYi antagonist molecules HI/5HT2A
  • pharmaceutically acceptable salts thereof to a subject m need thereof.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering one or more compound selected from: HY- 10275, mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure is directed to a method of alleviating a symptom of or treating a sleep disorder by administering one or more compound selected from: HY-10275, mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure is directed to a method of alleviating a symptom of a sleep disorder by administering one or more compound selected from: HY-10275, mirtazapine, S -mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure provides one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a
  • the present disclosure provides one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a
  • the present disclosure provides one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a
  • the present disclosure provides use of one or more compound selected from: HY-10275, nurtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the present disclosure provides use of one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of or treating a sleep disorder.
  • the present disclosure provides use of one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of a sleep disorder.
  • the present disclosure provides use of one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the present disclosure provides use of one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for alleviating a symptom of or treating a sleep disorder.
  • the present disclosure provides use of a one or more compound selected from: HY-10275, mirtazapine, S-mirtazapine, amitriptyline, and quetiapine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for alleviating a symptom of a sleep disorder.
  • the compound is HY-10275, mirtazapine (HY10521), S- mirtazapine (HY 10378), quetiapine (HY10625), or amitriptyline, or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering HY-10275, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure provides HY-10275, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing a sleep disorder.
  • the present disclosure provides use of HY-10275, or a
  • the present disclosure provides use of HY-10275, or a
  • the compound is HY-10275, or a pharmaceutically acceptable salt thereof.
  • HY-10275 is administered at a dose between about 0.010 mg/kg and about 50 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.05 mg/kg and about 50 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.1 mg/kg and about 50 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.1 mg/kg and about 45 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.1 mg/kg and about 40 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0. 1 mg/kg and about 35 mg/kg.
  • HY-10275 is administered at a dose between about 0.1 mg/kg and about 30 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.1 mg/kg and about 25 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.1 rng/kg and about 20 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.1 mg/kg and about 15 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.5 mg/kg and about 50 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.5 mg/kg and about 45 mg/kg.
  • HY-10275 is administered at a dose between about 0.5 mg/kg and about 40 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.5 mg/kg and about 35 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.5 mg/kg and about 30 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.5 mg/kg and about 25 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.5 mg/kg and about 20 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 0.5 mg/kg and about 15 mg/kg.
  • HY- 10275 is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 1 mg/kg and about 25 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 1 mg/kg and about 20 mg/kg. In some embodiments, HY- 10275 is administered at a dose between about 1 mg/kg and about 15 mg/kg. In some
  • HY-10275 is administered at a dose between about 3 mg/kg and about 30 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 3 mg/kg and about 25 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 3 mg/kg and about 20 mg/kg. In some embodiments, HY-10275 is administered at a dose between about 3 mg/kg and about 15 mg/kg.
  • HY-10275 is administered at a dose of about 0.010 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.015 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.020 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.025 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.05 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.1 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.2 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.3 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.4 mg/kg. In some
  • HY-10275 is administered at a dose of about 0.5 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.6 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0 7 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.8 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 0.9 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 1 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 3 mg/kg. In some embodiments, HY- 10275 is administered at a dose of about 5 mg/kg.
  • HY-10275 is administered at a dose of about 10 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 15 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 20 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 25 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 30 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 35 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 40 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 45 mg/kg. In some embodiments, HY-10275 is administered at a dose of about 50 mg/kg.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering mirtazapine, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure provides mirtazapine, or a pharmaceutically acceptable salt thereof for use in alleviating a symptom of treating, or preventing a sleep disorder.
  • the present disclosure provides use of mirtazapine, or a pharmaceutically acceptable salt thereof for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the present disclosure provides use of mirtazapine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the compound is mirtazapine, or a pharmaceutically acceptable salt thereof.
  • mirtazapine is administered at a dose between about 0.010 mg/kg and about 50 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 0.05 mg/kg and about 50 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 0.1 mg/kg and about 50 mg/kg. In some embodiments, mirtazapine is
  • mirtazapine is administered at a dose between about 0.5 mg/kg and about 50 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 1 mg/kg and about 50 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 1 mg/kg and about 45 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 1 mg/kg and about 35 g/kg. In some embodiments, mirtazapine is administered at a dose between about 1 mg/kg and about 30 mg/kg.
  • mirtazapine is administered at a dose between about 1 mg/kg and about 25 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 1 mg/kg and about 20 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 1 mg/kg and about 15 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 5 mg/kg and about 25 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 5 mg/kg and about 20 mg/kg.
  • mirtazapine is administered at a dose between about 5 mg/kg and about 15 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 10 mg/kg and about 30 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 10 mg/kg and about 25 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 10 mg/kg and about 20 mg/kg. In some embodiments, mirtazapine is administered at a dose between about 10 mg/kg and about 15 mg/kg.
  • mirtazapine is administered at a dose of about 0.010 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.015 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.020 mg/kg. In some
  • mirtazapine is administered at a dose of about 0.025 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.025 mg/kg.
  • mirtazapine is administered at a dose of about 0.05 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.1 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.2 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.3 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.4 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.5 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 1 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.05 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.1 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.2 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 0.3
  • mirtazapine is administered at a dose of about 1.5 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 2 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 2 5 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 3 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 3.5 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 4 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 4.5 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 5 mg/kg.
  • mirtazapine is administered at a dose of about 10 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 15 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 20 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 25 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 30 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 35 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 40 mg/kg. In some embodiments. mirtazapine is administered at a dose of about 45 mg/kg. In some embodiments, mirtazapine is administered at a dose of about 50 mg/kg.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering S-mirtazapme, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure provides S-mirtazapine, or a
  • the present disclosure provides use of S-mirtazapme, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the present disclosure provides use of S-mirtazapme, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the compound is S-mirtazapine, or a pharmaceutically acceptable salt thereof.
  • S-mirtazapine is administered at a dose between about 0.010 mg/kg and about 50 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 0.05 mg/kg and about 50 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 0.1 mg/kg and about 50 mg/kg. In some embodiments, S- mirtazapine is administered at a dose between about 0 5 mg/kg and about 50 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 1 mg/kg and about 50 mg/kg.
  • S-mirtazapine is administered at a dose between about 1 mg/kg and about 45 g/kg. In some embodiments, S-mirtazapine is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 1 mg/kg and about 35 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, S- mirtazapme is administered at a dose between about 1 mg/kg and about 25 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 1 mg/kg and about 20 mg/kg.
  • S-mirtazapine is administered at a dose between about 1 mg/kg and about 15 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 5 mg/kg and about 25 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 5 mg/kg and about 20 mg/kg. In some embodiments, S- mirtazapine is administered at a dose between about 5 mg/kg and about 15 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 10 mg/kg and about 30 mg/kg.
  • S-mirtazapine is administered at a dose between about 10 mg/kg and about 25 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 10 mg/kg and about 20 mg/kg. In some embodiments, S-mirtazapine is administered at a dose between about 10 mg/kg and about 15 mg/kg.
  • S-mirtazapine is administered at a dose of about 0.010 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 0.015 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 0.020 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 0.025 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 0.05 mg/kg. In some
  • S-mirtazapine is administered at a dose of about 0.1 mg/kg.
  • S-mirtazapine is administered at a dose of about 0.2 mg/kg.
  • S-mirtazapine is administered at a dose of about 0.3 mg/kg.
  • S-mirtazapine is administered at a dose of about 0.4 mg/kg.
  • S-mirtazapine is administered at a dose of about 0.5 mg/kg.
  • S-mirtazapine is administered at a dose of about 1 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 1.5 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 2 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 2.5 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 3 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 3.5 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 4 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 4.5 mg/kg. In some
  • S-mirtazapine is administered at a dose of about 5 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 10 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 1 5 mg/kg. In some embodiments, S-mirtazapine is
  • S-mirtazapine is administered at a dose of about 20 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 25 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 30 mg/kg. In some embodiments, S-mirtazapme is administered at a dose of about 35 mg/kg. In some embodiments, S-mirtazapme is administered at a dose of about 40 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 45 mg/kg. In some embodiments, S-mirtazapine is administered at a dose of about 50 mg/kg.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering amitriptyline, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure provides amitriptyline, or a
  • the present disclosure provides use of amitriptyline, or a pharmaceutically acceptable salt thereof, for alleviating a symptom of treating, or preventing a sleep disorder.
  • the present disclosure provides use of amitriptyline, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for alleviating a symptom of, treating, or preventing a sleep disorder.
  • the compound is amitriptyline, or a pharmaceutically acceptable salt thereof.
  • amitriptyline is administered at a dose between about 0.010 mg/kg and about 50 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 0.05 mg/kg and about 50 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 0.1 mg/kg and about 50 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 0.5 mg/kg and about 50 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 1 mg/kg and about 50 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 1 mg/kg and about 45 mg/kg.
  • amitriptyline is administered at a dose between about 1 mg/kg and about 40 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 1 mg/kg and about 35 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 1 mg/kg and about 25 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 1 mg/kg and about 20 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 1 mg/kg and about 15 mg/kg.
  • amitriptyline is administered at a dose between about 5 mg/kg and about 30 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 5 mg/kg and about 25 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 5 mg/kg and about 20 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 5 mg/kg and about 15 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 10 mg/kg and about 30 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 10 mg/kg and about 25 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 10 mg/kg and about 20 mg/kg. In some embodiments, amitriptyline is administered at a dose between about 10 mg/kg and about 15 mg/kg.
  • amitriptyline is administered at a dose of about 0.010 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 0.015 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 0.020 mg/kg. In some
  • amitriptyline is administered at a dose of about 0.025 mg/kg.
  • amitriptyline is administered at a dose of about 0.05 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 0.05 mg/kg.
  • amitriptyline is administered at a dose of about 0.1 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 0 2 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 0.3 mg/kg. In some embodiments, amitriptyline is
  • amitriptyline is administered at a dose of about 0.4 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 0.5 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 1 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 1.5 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 2 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 2.5 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 3 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 3.5 mg/kg.
  • amitriptyline is administered at a dose of about 4 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 4.5 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 5 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 10 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 15 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 20 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 25 mg/kg.
  • amitriptyline is administered at a dose of about 30 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 35 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 40 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 45 mg/kg. In some embodiments, amitriptyline is administered at a dose of about 50 mg/kg.
  • the present disclosure is directed to a method of alleviating a symptom of, treating, or preventing a sleep disorder by administering quetiapine, or a
  • the present disclosure provides quetiapine, or a pharmaceutically acceptable salt thereof, for use in alleviating a symptom of, treating, or preventing a sleep disorder.
  • the present disclosure provides use of quetiapine, or a
  • the present disclosure provides use of quetiapine, or a
  • the compound is quetiapine, or a pharmaceutically acceptable salt thereof
  • quetiapine is administered at a dose between about 0.010 mg/kg and about 50 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.05 mg/kg and about 50 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.1 mg/kg and about 50 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.5 mg/kg and about 50 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.1 mg/kg and about 45 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.1 mg/kg and about 40 mg/kg.
  • quetiapine is administered at a dose between about 0.1 mg/kg and about 35 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.1 mg/kg and about 30 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.1 mg/kg and about 25 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.1 mg/kg and about 20 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.1 mg/kg and about 15 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.5 mg/kg and about 50 mg/kg.
  • quetiapine is administered at a dose between about 0.5 mg/kg and about 45 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.5 mg/kg and about 40 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.5 mg/kg and about 35 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.5 mg/kg and about 30 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.5 mg/kg and about 25 mg/kg. In some embodiments, quetiapine is administered at a dose between about 0.5 mg/kg and about 20 mg/kg.
  • quetiapine is administered at a dose between about 0.5 mg/kg and about 15 mg/kg. In some embodiments, quetiapine is administered at a dose between about 1 mg/kg and about 30 mg/kg. In some embodiments, quetiapine is administered at a dose between about 1 mg/kg and about 25 mg/kg. In some embodiments, quetiapine is administered at a dose between about 1 mg/kg and about 20 mg/kg. In some embodiments, quetiapine is administered at a dose between about I mg/kg and about 15 mg/kg. In some embodiments, quetiapine is administered at a dose between about 3 mg/kg and about 30 mg/kg.
  • quetiapine is administered at a dose between about 3 mg/kg and about 25 mg/kg. In some embodiments, quetiapine is administered at a dose between about 3 mg/kg and about 20 mg/kg. In some embodiments, quetiapine is administered at a dose between about 3 mg/kg and about 1 5 mg/kg.
  • quetiapine is adm imstered at a dose of about 0.010 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.015 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.020 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.025 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.05 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.1 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.2 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.3 mg kg. In some embodiments, quetiapine is administered at a dose of about 0.4 mg/kg. In some
  • quetiapine is administered at a dose of about 0.5 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.6 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.7 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.8 mg/kg. In some embodiments, quetiapine is administered at a dose of about 0.9 mg/kg. In some embodiments, quetiapine is administered at a dose of about 1 mg/kg. In some embodiments, quetiapine is administered at a dose of about 3 mg/kg.
  • quetiapine is administered at a dose of about 5 mg/kg. In some embodiments, quetiapine is administered at a dose of about 10 mg/kg. In some embodiments, quetiapine is administered at a dose of about 15 mg/kg. In some embodiments, quetiapine is administered at a dose of about 20 mg/kg. In some embodiments, quetiapine is administered at a dose of about 25 mg/kg. In some embodiments, quetiapine is administered at a dose of about 30 mg/kg. In some embodiments, quetiapine is administered at a dose of about 35 mg/kg.
  • quetiapine is administered at a dose of about 40 nig/kg. In some embodiments, quetiapine is administered at a dose of about 45 mg/kg. In some embodiments, quetiapine is administered at a dose of about 50 mg/kg.
  • the compound is administered orally. In some embodiments, the compound is administered parenterally. In some embodiments, the compound is administered transdermally. In some embodiments, the compound is administered subcutaneously. In some embodiments, the compound is administered intravenously.
  • a compound of the present disclosure is not suvorexant, zolpidem, S-zopiclone, or a pharmaceutically acceptable salt thereof.
  • a compound of the present disclosure is not suvorexant or a pharmaceutically acceptable salt thereof.
  • a compound of the present disclosure is not zolpidem or a pharmaceutically acceptable salt thereof.
  • a compound of the present disclosure is not S-zopiclone or a pharmaceutically acceptable salt thereof.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder f PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • RDI respiratory disturbance index
  • REM behavior disorder elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by sleep apnea, restless legs syndrome, a high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • RDI respiratory disturbance index
  • PLMD periodic leg movement disorder
  • REM behavior disorder elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with sleep apnea, restless legs syndrome, high respiratory disturbance index (RDI), neurological disease, circadian rhythm disorder, pain, periodic leg movement disorder (PLMD), REM behavior disorder, elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • RDI respiratory disturbance index
  • PLMD periodic leg movement disorder
  • REM behavior disorder elderly fragmented sleep, age-related sleep fragmentation, post-menopausal sleep disorder, substance abuse, substance abuse withdrawal, narcolepsy, mental disorder, or non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with sleep apnea.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by sleep apnea.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with sleep apnea.
  • sleep apnea is obstructive sleep apnea.
  • sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with or without a concomitant apnea.
  • RRI respiratory disturbance index
  • RERA elevated respiratory event related arousal
  • sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with a concomitant apnea.
  • RRI respiratory disturbance index
  • RERA elevated respiratory event related arousal
  • sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with or without a concomitant hypopnea.
  • RRI respiratory disturbance index
  • RERA elevated respiratory event related arousal
  • sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with a concomitant hypopnea.
  • RRI respiratory disturbance index
  • RERA elevated respiratory event related arousal
  • sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory' event related arousal (RERA) with or without concomitant acute hemoglobin desaturation.
  • RDI high respiratory disturbance index
  • RERA elevated respiratory' event related arousal
  • sleep apnea is obstructive sleep apnea due to a high respiratory disturbance index (RDI) associated with an elevated respiratory event related arousal (RERA) with concomitant acute hemoglobin desaturation.
  • RRI respiratory disturbance index
  • RERA elevated respiratory event related arousal
  • sleep apnea is central sleep apnea.
  • sleep apnea is low-arousal threshold sleep apnea.
  • sleep apnea is hypopnea.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with restless legs syndrome.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by restless legs syndrome.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with restless legs syndrome.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a high respiratory disturbance index
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a high respiratory disturbance index (RDI).
  • RDI respiratory disturbance index
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with a high respiratory' disturbance index (RDI).
  • RDI respiratory' disturbance index
  • the RDI is associated with an elevated respiratory' event related arousal (RERA) with or without a concomitant apnea.
  • RERA respiratory' event related arousal
  • the RDI is associated with an elevated respiratory' event related arousal (RERA) with a concomitant apnea.
  • RERA respiratory' event related arousal
  • the RDI is associated with an elevated respiratory event related arousal (RERA) with or without a concomitant hypopnea.
  • RERA respiratory event related arousal
  • the RDI is associated with an elevated respiratory event related arousal (RERA) with a concomitant hypopnea.
  • RERA respiratory event related arousal
  • the RDI is associated with an elevated respiratory event related arousal (RERA) with or without concomitant acute hemoglobin desaturation.
  • RERA respiratory event related arousal
  • the RDI is associated with an elevated respiratory event related arousal (RERA) with concomitant acute hemoglobin desaturation.
  • RERA respiratory event related arousal
  • the RDI is associated with an elevated respiratory event related arousal (RERA) with or without concomitant hemoglobin desaturation.
  • RERA respiratory event related arousal
  • the RDI is associated with an elevated respiratory event related arousal (RERA) with concomitant hemoglobin desaturation.
  • RERA elevated respiratory event related arousal
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a neurological disease.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a neurological disease.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with a neurological disease.
  • the neurological disease is a neurodegenerative disease.
  • the neurodegenerative disease is Lewy body disease (i.e., Lewy body dementia). In some embodiments, the Lewy body disease is diffuse.
  • the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is Huntington’s disease. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is a synucleinopathy.
  • ALS amyotrophic lateral sclerosis
  • the neurodegenerative disease is Huntington’s disease.
  • the neurodegenerative disease is Parkinson’s disease.
  • the neurodegenerative disease is Alzheimer’s disease.
  • the neurodegenerative disease is a synucleinopathy.
  • a synucleinopathy is Alzheimer’s disease, Parkinson’s disease, or Lewy body dementia. In some embodiments, a synucleinopathy is Alzheimer’s disease. In some embodiments, a synucleinopathy is Parkinson’s disease. In some embodiments, a synucleinopathy is dementia with Lewy bodies. In some embodiments, a synucleinopathy is multiple system atrophy.
  • the neurological disease is a neurodevelopmental disease. In some embodiments, the neurodevelopmental disease is autism. In some embodiments, the neurological disease is a muscular dystonia. In some embodiments, the dystonia is neuromuscular dystonia. In some embodiments, the neuromuscular dystonia is spasmodic torticollis.
  • the neurological disease is multiple sclerosis (MS).
  • MS multiple sclerosis
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a circadian rhythm disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a circadian rhythm disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with a circadian rhythm disorder.
  • the circadian rhythm disorder is advanced sleep- wake phase disorder. In some embodiments, the circadian rhythm disorder is irregular sleep-wake rhythm disorder. In some embodiments, the circadian rhythm disorder is jet lag. In some embodiments, the circadian rhythm disorder is shift work sleep disorder. In some embodiments, the circadian rhythm disorder is delayed sleep phase syndrome. In some embodiments, the circadian rhythm disorder is non-24 hour rhythm disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with pain.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by pain.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with pain.
  • the pain is selected from an inflammatory pain, a nociceptive pain, a neuropathic pain, a mixed nociceptive and neuropathic pain, a post-operative pain, a post herpetic pain, a traumatic pain, a phantom-limb pam, a fibromyalgia, a back pain, a cancer pain, and an osteoarthritic pam.
  • the pam is an inflammatory pain.
  • the inflammatory pain is arthritis.
  • the arthritis is rheumatoid arthritis.
  • the arthritis is osteoarthritis.
  • the pain is a nociceptive pam.
  • the nociceptive pain is acute.
  • the nociceptive pain is chronic.
  • the nociceptive pam is caused by a cancer therapy.
  • the nociceptive pain is caused by a surgery.
  • the pain is a neuropathic pain.
  • the neuropathic pam is chronic.
  • the neuropathic pain is acute.
  • the neuropathic pain is back pain.
  • the neuropathic pain is caused by a spinal cord injury .
  • the neuropathic pain is caused by multiple sclerosis.
  • the neuropathic pam is caused by a stroke.
  • the neuropathic pain is caused by diabetes. In some embodiments, the neuropathic pain is caused by a metabolic condition.
  • the pam is a mixed nociceptive and neuropathic pain
  • the pain is a post-operative pam.
  • the pain is a post-herpetic pain
  • the pam is a traumatic pain.
  • traumatic pain is caused by causalgia.
  • the pam is a phantom-limb pain.
  • the pain is a fibromyalgia.
  • the pam is a back pam. In some embodiments, the pam is a low back pam.
  • the pam is a cancer pain.
  • the cancer pam is cancer.
  • the cancer pain is caused by a tumor.
  • the cancer pain is caused by a cancer treatment.
  • the cancer pain is caused by chemotherapy.
  • the cancer pain is radiation therapy.
  • the cancer pain is caused by surgery.
  • the pam is an osteoarthritic pain.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with periodic leg movement disorder
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by periodic leg movement disorder (PLMD).
  • PLMD periodic leg movement disorder
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with periodic leg movement disorder (PLMD).
  • PLMD periodic leg movement disorder
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with REM behavior disorder
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by REM behavior disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with REM behavior disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with elderly fragmented sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by elderly fragmented sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with elderly fragmented sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with age-related sleep fragmentation.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by age-related sleep fragmentation.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with age-related sleep fragmentation
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with post-menopausal sleep disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by post-menopausal sleep disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with post-menopausal sleep disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by substance abuse.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with substance abuse.
  • the substance abuse is opioid abuse or alcoholism. In some embodiments, the substance abuse is opioid abuse. In some embodiments, the substance abuse is alcoholism.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with substance abuse withdrawal.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by substance abuse withdrawal.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with substance abuse withdrawal.
  • the substance abuse withdrawal is opioid withdrawal or alcohol withdrawal. In some embodiments, the substance abuse withdrawal is opioid withdrawal. In some embodiments, the substance abuse is alcohol withdrawal.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with narcolepsy.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by narcolepsy.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with narcolepsy.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with a mental disorder.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by a mental disorder
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with a mental disorder.
  • the mental disorder is depression, major depressive disorder, post- traumatic stress disorder, anxiety disorder, bipolar disorder, or schizophrenia.
  • the mental disorder is depression. In some embodiments, the mental disorder is major depressive disorder. In some embodiments, the mental disorder is post- traumatic stress disorder. In some embodiments, the mental disorder is anxiety disorder. In some embodiments, the mental disorder is bipolar disorder. In some embodiments, the mental disorder is schizophrenia.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with non-restorative sleep.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with snoring.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by snoring.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with snoring.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousals, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by or co-morbid with idiopathic hypersomnia.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousafs, or decreased arousal threshold in a subject, wherein the sleep disorder is caused by idiopathic hypersomnia.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder wherein the sleep disorder is increased disturbed sleep, increased sleep fragmentation, increased arousais, or decreased arousal threshold in a subject, wherein the sleep disorder is co-morbid with idiopathic hypersomnia.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering to a subject in need thereof a pharmaceutical composition comprising an Hi inverse agonist or antagonist and 5HT'2A antagonist or inverse activity and an additional active agent.
  • the additional active agent is a sedative-hypnotic.
  • the sedative-hypnotic is selected from: zo!pidem, suvorexant, butabarbital, quazepam, triazolam, tasimelteon, eszopiclone, temazepam, ramelteon, secobarbital, doxepin, estazolam, or flurazepam.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering a pharmaceutical composition comprising an Hi inverse agonist or antagonist and 5HT2A antagonist or inverse activity, or a pharmaceutically acceptable derivative thereof, either alone, or in combination with a single additional active agent.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering a pharmaceutical composition comprising an Hi inverse agonist or antagonist and 5HT2A antagonist or inverse activity, or a pharmaceutically acceptable derivative thereof, in combination with a single additional active agent.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering a pharmaceutical composition comprising an Hi inverse agonist or antagonist and 5HT2A antagonist or inverse activity, or a pharmaceutically acceptable derivative thereof, either alone, or in combination with one or more additional active agent.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering a pharmaceutical composition comprising an Hi inverse agonist or antagonist and 5HT2A antagonist or inverse activity, or a pharmaceutically acceptable derivative thereof, in combination with one or more additional active agent.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering one or more compound of the present disclosure either hora somni, h.s. (at bedtime) or between 0-4 hours before bedtime.
  • the present disclosure is directed to alleviating a symptom of, treating, or preventing a sleep disorder by administering one or more compound of the present disclosure and an additional active agents, if present, either hora somni, h.s. (at bedtime) or between 0-4 hours before bedtime.
  • the number of arousals is decreased by up to about 99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment.
  • HY-10275 alleviates a symptom of, treats, or prevents a sleep disorder.
  • HY-10275 reduces sleep fragmentation .
  • HY-10275 decreases the number of arousals (e.g., about up to 50% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment) and increases sleep consolidation (e.g., about 10-fold in average sleep bout duration per hour post-treatment relative to vehicle treatment).
  • HY-10275 reduces wake bout length.
  • mirtazapine alleviates a symptom of, treats, or prevents a sleep disorder.
  • mirtazapine reduces sleep fragmentation .
  • mirtazapine decreases the number of arousals (e.g., about up to 50% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment) and increases sleep consolidation (e.g., about 10-fold in average sleep bout duration per hour post-treatment relative to vehicle treatment).
  • mirtazapine reduces wake bout length.
  • S-mirtazapine alleviates a symptom of, treats, or prevents a sleep disorder.
  • S-mirtazapine reduces sleep fragmentation .
  • S-mirtazapine decreases the number of arousals (e.g., about up to 50% reduction m the number of wake bouts per hour post-treatment relative to vehicle treatment) and increases sleep consolidation (e.g., about 10-fold m average sleep bout duration per hour post-treatment relative to vehicle treatment).
  • S-mirtazapine reduces wake bout length.
  • quetiapine alleviates a symptom of) treats, or prevents a sleep disorder.
  • quetiapine reduces sleep fragmentation . In some embodiments, quetiapine decreases the number of arousals (e.g., about up to 50% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment) and increases sleep
  • consolidation e.g., about 10-fold in average sleep bout duration per hour post-treatment relative to vehicle treatment.
  • quetiapine reduces wake bout length.
  • amitriptyline alleviates a symptom of, treats, or prevents a sleep disorder.
  • amitriptyline reduces sleep fragmentation .
  • amitriptyline decreases the number of arousals (e.g., about up to 50% reduction in the number of wake bouts per hour post-treatment relative to vehicle treatment) and increases sleep
  • consolidation e.g., about 10-fold in average sleep bout duration per hour post-treatment relative to vehicle treatment.
  • amitriptyline reduces wake bout length.
  • one or more compound of the present disclosure produces improvements in sleep fragmentation in comparison to compounds prescribed comprising the pharmacological standard of care for insomnia.
  • the standard of care compounds for insomnia are, for example, but not limited to, the orexin antagonists (e.g., suvorexant (BELSOMRA®)) and non-benzodiazepine, benzodiazepine receptor dependent GABAA allosteric modulators (e.g., zolpidem (AMBIEN®) and eszopiclone (LUNESTA®)), which do not adequately improve the requisite preclmical measures of sleep fragmentation.
  • the orexin antagonists e.g., suvorexant (BELSOMRA®)
  • non-benzodiazepine benzodiazepine receptor dependent GABAA allosteric modulators
  • benzodiazepine receptor dependent GABAA allosteric modulators e.g., zolpidem (AMBIEN®) and eszopiclone (LUNESTA®
  • orexin OX1/OX2 antagonist suvorexant fails to improve sleep fragmentation at 3 mg/kg, 10 mg/kg, and 30 mg/kg.
  • suvorexant does not reduce the number of arousals as measured by the number of wake bouts per hour, but instead, increases the number of arousals.
  • suvorexant produces small
  • zolpidem at doses sufficient to produce increases m soporific efficacy as measured by EEG slow wave activity (EEG delta power in nonREM sleep), fails to reduce the number of arousals as measured by the number of wake bouts per hour and fails to produce improvement in sleep consolidation as measured by average sleep bout duration per hour.
  • Zolpidem can produce sedative effects (up to and including non-responsiveness of the subject); however, increasing the dose of zolpidem may be complicated by a short kinetic half- life and can be contraindicated due to significant unwanted side effects including, but not limited to, REM sleep inhibition, severe motor coordination impairment, memory impairment, rebound insomnia, and other unwanted adverse effects, or a combination thereof.
  • S-zopiclone (marketed as LUNESTA®) fails to reduce the number of arousals as measured by the number of wake bouts per hour and produces only small improvements in sleep consolidation as measured by average sleep bout duration per hour.
  • the dose of S-zopiclone tested i.e., from about 5 mg/kg to about 30 mg/kg
  • S- zopiclone decreases Locomotor Activity Intensity (LMAi).
  • S-zopiclone dose-dependently inhibits REM sleep, which may be important for memory and learning.
  • standard of care insomnia drugs e.g., zolpidem and S-zopiclone
  • relaxation of upper airway muscles is undesirable as it could worsen obstructive sleep apnea and its comorbid health risks.
  • Direct electromyographic (EMG) assessment of muscle tone may reveal unwanted myorelaxation (decrease in skeletal muscle electrical activity) after treatment with S-zopie!one.
  • EMG Direct electromyographic
  • Example 1 Experimental details and methods for determining sleep continuity, wakefulness, number of arousals, locomotor activity, and soporific efficacy
  • EEG chrome electro-encephalogram
  • EMG electromyogram
  • Body temperature and locomotor activity were monitored via a miniature transmitter (Minimitter Series 4000 E-Mitter, Bend, OR) surgically placed m the abdomen during the same anesthetic event the cranial portion was implanted.
  • the cranial implant consisted of stainless steel screws (2 frontal [+3.9 AP from bregma, ⁇ 2.0 ML] and 2 occipital [-6.4 AP, ⁇ 5.5 ML]) for EEG recording.
  • cyanoacrylate applied between the hermetically sealed implant connector and skull, and dental acrylic.
  • An analgesic (buprinorphine 0.3 mg/kg IP) was administered pre-operatively and daily SC for 2 days post-surgery.
  • An antibiotic was administered before surgery' (chloramphenicol 40 mg/kg IM) and for 7-10 days after surgery' (Clavamox b.i.d). At least three weeks were allowed for surgical recovery' prior to any data collection.
  • Rats were housed individually within specially modified Nalgene ® microisolator cages equipped with an ultra-low-torque slip-ring commutator and a custom polycarbonate filter-top riser. These cages were located within separate, ventilated compartments of a stainless steel sleep-wake recording chamber. Food and water were available ad libitum and the ambient temperature was 23 ⁇ 1° C. A 24-hr light-dark cycle (LD 12: 12) was maintained throughout the study using fluorescent light. Light intensity averaged 35-40 lux at mid-level inside the cage. Relative humidity averaged 50% approximately. Animals were undisturbed for two days before and after each treatment.
  • SCORETM a microcomputer-based sleep- wake and physiological monitoring system. Validation of the SCORETM sleep stage identification algorithm in rodents and utility in pre-cimical drug evaluation have been previously described (Van Gelder et al. 1991 ; Edgar et ai. Psychopharmacology 1991 , 105, 374; J. Pharmacology & Experimental Therapeutics 1997, 283, 757; Seidel et al J Pharmacology & Experimental Therapeutics 275, 263; J. Pharmacology & Experimental Therapeutics, 285,
  • the system monitored amplified EEG (xl 0,000, bandpass 1-30 Hz; initial digitization rate 400 Hz [Grass Corp., Quincy, MA]), integrated EMG (bandpass 10-100 Hz, RMS integration), and telemetered body temperature and non-specific locomotor activity (LMA), and drink- and food-related activity, from up to 150 rodents simultaneously.
  • EEG amplified EEG
  • REM sleep REM sleep
  • LMA telemetered body temperature and non-specific locomotor activity
  • drink- and food-related activity from up to 150 rodents simultaneously.
  • Arousal states were classified on-line as NREM sleep, REM sleep, wake, or theta-dominated wake every 10 seconds using EEG period and amplitude feature extraction and ranked membership algorithms.
  • Individually taught EEG-arousal-state templates and EMG criteria differentiated states of arousal.
  • LMA and drink-related activity were automatically recorded as counts per minute, and body temperature was recorded each minute.
  • LMA was detected in both horizontal and vertical planes by a customized telemetry receiver (ER4000, Minimitter, Bend, OR) beneath the cage.
  • Drink-related activity and food-related activity were detected by beam break sensors closely situated around recessed access portals to the lixit and the food bin, respectively.
  • the beam break area for the food bin was, however, relatively large, and these data have not been validated as an endpoint for food consumption per se.
  • Telemetry measures (LMA and body temperature) were not part of the SCORE arousal-state determination algorithm; thus, sleep-scoring and telemetry' data were concurrent but independent measures.
  • methyleeliulose vehicle was prepared as a sterile 0.25% solution of methyleeliulose ( 15 centipoise, Sigma, St. Louis, MO., USA).
  • D-a-Tocopheryl polyethylene glycol 1000 succinate TPGS, HY-16388
  • the standard recording duration for SCORE data was not less than 30 hours before and after treatment.
  • the 30 hours pre-treatment baseline recording was itself preceded by at least 24 hours in which the animal was undisturbed in the home/recording cage.
  • Rats were randomly assigned to treatments in parallel groups. Some rats received more than one active treatment, in which cases at least 7 days“washout” elapsed between each treatment.
  • Post-treatment detail plots the first five hours post-treatment. Variables were computed in 5-minute bins, aligned to the minute of treatment. The first time bin, labeled 0, represents the first 5 minutes post treatment.
  • Pre- and post-treatment time series plot ⁇ 30 hours before and after CT-18 treatments (or 29 hr before and 31 hr after CT- 5 treatments). Treatment occurred at the beginning of the hour marked by an arrow. Variables w3 ⁇ 4re computed in hourly bins.
  • Example 2 HY-10275 effect on number of arousals, sleep continuity, depth of sleep, and maintenance of wakefulness
  • HY-10275 reduces number of arousals
  • HY-10275 increases sleep continuity/consolidation at CT5
  • HY-10275 increases sleep continuity/consolidation at CT-18
  • Hi inverse agonist and 5HT?.A antagonist HY-10275 administered to Wistar rats at CT-18 (6 hours after lights-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation (indicated by the arrow), as measured by the longest sleep bout duration observed per hour.
  • HY-10275 produced a statistically significant increase in sleep consolidation as exemplified by a 2-fold increase in the longest sleep bout-length per hour as compared to vehicle controls.
  • HY-10275 increases depth of sleep as measured by EEG slow wave activity
  • methyicellulose vehicle control are indicated by asterisks.
  • HY-10275 reduces maintenance of wakefulness
  • Hi inverse agonist and 5HT2A antagonist HY-10275 administered to male Wistar rats at CT-18 (6 hours after lights-off; time of treatment indicated by the triangle on the abscissa), decreased wake bout length (a measure of maintenance of wakefulness, and indirect measure of latency to return to sleep; indicated by the arrow), as measured by the longest wake bout duration per hour.
  • Statistically significant differences from methyicellulose vehicle control are indicated by asterisks. 24 hour light-dark cycle (LD 12: 12) is indicated on the abscissa (FIG. 5).
  • Example 3 Mirtazapine effects on number of arousals and sleep continuity
  • Mirtazapine reduces number of arousals
  • Hi inverse agonist and SHITA antagonist racemic mirtazapine (HY- 10521) administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation (indicated by the arrow), as measured by the average sleep bout duration per hour.
  • Hi inverse agonist and 5HT2A antagonist S-mirtazapine (HY-10378; the single S- enantiomer of mirtazapine) administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), reduced the number of arousals (indicated by the arrow), as measured by the number of wake bouts.
  • Number of wake bouts plotted as the population (N 9) hourly mean ⁇ SEM 30 hours before (baseline) and after treatment.
  • Amitriptyline reduces number of arousals
  • the Hi inverse agonist and 51 GG. ⁇ antagonist tricyclic antidepressant amitriptyline administered to Wistar rats at CT-5 can reduce the number of arousals (indicated by the arrow), as measured by the number of wake bouts.
  • Number of wake bouts ploted as population (N 9) hourly mean ⁇ SEM 30 hours before (baseline) and after treatment.
  • Statistically significant differences from methylcelluiose vehicle control are indicated by asterisks.
  • 24 hour light-dark cycle (LD 12: 12) is indicated on the abscissa (FIG. 10). Amitriptyline significantly reduced the number of arousals during the initial 6 hours post- treatment (arrow).
  • Amitriptyline increases sleep conti nuiiy /consolidation
  • Hi inverse agonist and 5HT2A antagonist tricyclic antidepressant amitriptyline administered to male Wistar rats at CT-5 (5 hours after light-on; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation (indicated by the arrow), as measured by the average sleep bout duration per hour.
  • Quetiapine reduces number of arousals
  • Hi inverse agonist and 5HT?A antagonist antidepressant/antipsychotic quetiapine administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), increased sleep consolidation (indicated by the arrow), as measured by the average sleep bout duration per hour.
  • Statistically significant differences from methyicellulose vehicle control are indicated by asterisks.
  • 24 hour light-dark cycle (LD 12: 12) is indicated on the abscissa (FIG. 13).
  • Quetiapine increased sleep continuity/ consolidation as evidenced by a statistically significant >50% increase in average sleep bout lengths relative to vehicle control treatment (arrow).
  • Example 7 Suvorexant effects on number of arousals and sleep continuity
  • methylcellu!ose vehicle control are indicated by asterisks.
  • 24 hour light-dark cycle (LD 12: 12) is indicated on the abscissa (FIG. 15).
  • Example 8 Zolpidem effects on EEG slow wave activity, number of arousals, sleep
  • zolpidem administered at a dose that produces robust efficacy as measured by EEG slow wave activity (FIG.16) failed to reduce the number of arousals as measured by the number of wake bouts per hour (indicated by the arrow).
  • Zolpidem is a GAB AA positive allosteric modulator acting at the benzodiazepine binding site on GABAA.
  • zolpidem (HY-10131) was administered to Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa). These are the same animals and the same drug treatment above.
  • methylcellulose vehicle control are indicated by asterisks.
  • 24 hour light-dark cycle (LD 12: 12) is indicated on the abscissa (FIG 19).
  • Zolpidem interferes with locomotor activity [0354]
  • LMAi reveals changes m motor activity (movements) that are disproportionate from that normally observed during wakefulness.
  • hypoactivity during w3 ⁇ 4kefulness is indicative of motor coordination impairment and/or myorelaxant properties of zolpidem and related benzodiazepine receptor ligand sedative hypnotics.
  • the magnitude of undesirable motor impairment increases with dose and is evident 4-5 hours post-treatment in this zolpidem 30 mg/kg example (arrow).
  • Example 9 S-zopiclone effects on number of arousals, sleep continuity, locomotor activity, muscle tone, and rebound sleep disturbance
  • Locomotor Activity Intensity (LMAi) as measured by the counts of locomotor activity per minute of wakefulness, averaged hourly for each animal. LMAi reveals whether changes m motor activity (movements) are disproportionate from that normally observed during wakefulness. A disproportionate reduction in locomotor activity during wakefulness, as shown here, is indicative of motor impairment that may be due in part to the skeletal muscle myorelaxant properties of S-zopiclone (see also FIG.
  • EMG electromyogram
  • insomnia standard of care sedative hypnotic s-zopiclone administered to male Wistar rats at CT-18 (6 hours after light-off; time of treatment indicated by the triangle on the abscissa), initially increased the amount of nonREM (NREM) sleep per hour post-treatment, but these initial soporific effects were follo wed by an interval of sleep interference (6-18 hours post treatment) characterized by a reduction in sleep time (indicated by the arrow '" ).
  • This“rebound” sleep disturbance corresponded with other markers of sleep disturbance such as concomitant reductions in sleep bout durations during the next circadian sleep phase (circadian time 0: GO- 12: 00; also see FIG. 22).

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Abstract

L'invention concerne des méthodes destinées à atténuer un symptôme d'un trouble du sommeil, ou à prévenir ou traiter ledit trouble, par administration à un individu le nécessitant d'au moins une molécule à double activité fonctionnelle présentant une activité agoniste ou antagoniste inverse de H1 et une activité antagoniste de 5HT2A ou inverse, ou un sel pharmaceutiquement acceptable de celle-ci.
PCT/US2020/021768 2019-03-08 2020-03-09 Méthode de traitement des troubles de la fragmentation du sommeil au moyen d'agonistes/antagonistes inverses à double action de h1 et 5ht2a WO2020185711A1 (fr)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
US20060094705A1 (en) * 2004-10-29 2006-05-04 Dale Edgar Quetiapine analogs and methods of use thereof

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US20060094705A1 (en) * 2004-10-29 2006-05-04 Dale Edgar Quetiapine analogs and methods of use thereof

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Title
CARLEY ET AL.: "Efficacy of Mirtazapine in Obstructive Sleep Apnea Syndrome", SLEEP, vol. 3, no. 1, 2007, pages 35 - 41, XP055739268 *

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