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WO2025046050A1 - Méthodes de traitement d'un trouble du sommeil à l'aide d'un inhibiteur de recapture triple - Google Patents

Méthodes de traitement d'un trouble du sommeil à l'aide d'un inhibiteur de recapture triple Download PDF

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Publication number
WO2025046050A1
WO2025046050A1 PCT/EP2024/074250 EP2024074250W WO2025046050A1 WO 2025046050 A1 WO2025046050 A1 WO 2025046050A1 EP 2024074250 W EP2024074250 W EP 2024074250W WO 2025046050 A1 WO2025046050 A1 WO 2025046050A1
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Prior art keywords
sleep
disorder
compound
narcolepsy
subject
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PCT/EP2024/074250
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English (en)
Inventor
George GARIBALDI
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Noema Pharma Ag
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Publication of WO2025046050A1 publication Critical patent/WO2025046050A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • Difficulties in falling asleep, remaining asleep, sleeping for adequate lengths of time, and abnormal sleep behaviors are common symptoms for those suffering with a sleep disorder.
  • Current treatment of many sleep disorders include the use of prescription hypnotics, e.g., benzodiazapines, that may be habit-forming, lose their effectiveness after extended use, and metabolize more slowly for certain designated groups, e.g., elderly persons, resulting in persisting medicative effects.
  • Other, milder treatments include over-the-counter antihistamines, e.g., diphenhydramine or dimenhydrinate, which are not designed to be strictly sedative in their activity.
  • This method of treatment is also associated with a number of adverse side effects, e.g., persistence of the sedating medication after the prescribed time of treatment, or the so-called “hangover effect”.
  • Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, including cataplexy (sudden loss of muscle tone triggered by strong emotions), direct transition from wakefulness to REM sleep (DREMs) periods, sleep paralysis and hypnagogic hallucinations.
  • REM rapid eye movement
  • Patients with narcolepsy experience irresistible attacks of sleep at any time during the day and may fall asleep for a period lasting from seconds to few hours. Such attacks can occur without any warning, which can cause serious problems in daily routines.
  • There is currently no cure for narcolepsy and narcolepsy patients depend on medicines and lifestyle changes to manage their symtpoms. Therefore, there is an unmet medical need for new methods that address treating individuals suffering from narcolepsy and other sleep disorders.
  • composition comprising a therapeutically effective amount of Compound 1 : or a pharmaceutically acceptable salt thereof.
  • the sleep disorder is a disorder selected from the group consisting of insomnia, hypersomnolence, narcolepsy, cataplexy, idiopathic hypersomnia, sleep paralysis, hypnagogic hallucinations, hypnopompic hallucinations, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a non-24-hour sleep wake disorder, a non-rapid eye movement sleep arousal disorder, a nightmare disorder, a rapid eye movement sleep behavior disorder, restless leg syndrome, a medication-induced sleep disorder, a substance-induced sleep disorder, excessive daytime sleepiness, excessive need for sleep, shift work sleep disorder, and Kleine Levin syndrome.
  • Also provided herein is a method of treating or preventing hypersomnolence in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the hypersomnolence is a disorder selected from the group consisting of idiopathic hypersomnia, recurrent hypersomnia, narcolepsy, shift work sleeping disorder, endozepine induced-recurrent stupor and amphetamine-resistant hypersomnia.
  • Also provided herein is a method of treating or preventing narcolepsy in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the narcolepsy is narcolepsy type 1 or narcolepsy type 2.
  • the treating or preventing comprises: (a) reducing one or more symptoms of narcolepsy in the subject; and/or (b) modulating an rapid eye movement REM sleep in the subject.
  • the one or more symptoms of narcolepsy is selected from the group consisting of: (a) excessive daytime sleepiness; (b) cataplexy; (c) sleep paralysis; (d) hallucinations; (e) deficiency of the hormone hypocretin; (f) changes in rapid eye movement (REM) sleep; (g) excessive need for sleep; (h) metabolic-syndrome- related disorder.
  • the modulation of REM sleep comprises decreasing the rate of eye movement, reducing the density and latency of REM sleep, disrupting REM sleep or increasing non-REM sleep, decreasing ratio of REM:non-REM sleep, or REM sleep onset latency.
  • the narcolepsy is associated with a metabolic- syndrome-related disorder.
  • the metabolic-syndrome-related disorder is selected from the group consisting of hypertension, diabetes, and dyslipidemia.
  • the subject experienced weight gain, obesity, high body mass index, or cardiometabolic risks.
  • the therapeutically effective amount is between about 3 mg to about 60 mg.
  • Compound 1 is administered once daily.
  • FIG. 1 depicts an exemplary X-ray powder diffraction pattern of a hydrochloride quarterhydrate of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Compound 1).
  • FIG. 2 depicts an exemplary X-ray powder diffraction pattern of a hydrochloride of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Compound 1).
  • FIG. 3 depicts latency (mean ⁇ standard error of mean) to the first 6 continuous epochs of non-rapid eye movement sleep “NR” (top) and latency (mean ⁇ standard error of mean) to the first 3 continuous epochs of rapid eye movement sleep “REM” (bottom) measurements for Compound 1 at three concentrations (1-10 mg/kg), RO5186582 (“6582”) at three concentrations (3-30 mg/kg), caffeine “CAF” at one concentration (10 mg/kg), and a vehicle control (purified H2O), all administered by mouth. means condition is significantly different from vehicle 1, and “+” means condition is significantly different from CAF. [00015] FIG. 4A, FIG. 4B and FIG.
  • FIG. 4A depicts percent time in W. ANOVA is significant for treatment and for treatment by time.
  • FIG. 4B depicts percent time in NR. ANOVA is significant for treatment and for treatment by time.
  • FIG. 4C depicts percent time in REM. ANOVA is significant for treatment (see legend) and for treatment by time.
  • FIG. 5 depicts average cumulative time in W, NR, and REM over the 6 h recording period for 6582, Compound 1, CAF, and vehicle. means significantly different from vehicle (p ⁇ 0.05), and “+” means significantly different from CAF (p ⁇ 0.05).
  • FIG. 6 depicts REM:NR ratio for the entire 6 h recording period for 6582, Compound 1, CAF, and vehicle. means significantly different from vehicle, and “+” means significantly different from CAF (p ⁇ 0.05).
  • FIG. 7A and FIG. 7B depict hourly NRD normalized to the 6 h average following treatment with vehicle control (“vehicle”), CAF, or three different doses of Compound 1 or 6582. Dosing occurred during the first part of ZT7.
  • FIG. 7A depicts 3 concentrations of Compound 1 vs. CAF and vehicle.
  • FIG. 7B depicts 3 concentrations of 6582 vs. CAF and vehicle.
  • FIGS 8A-8F depict measures of sleep-wake consolidation for 3 concentrations of Compound 1 vs. CAF and vehicle.
  • the asterisks above the graphs represent time points with significant differences. In the legends, means treatment is significantly different overall from vehicle and “+” means treatment is significantly different overall from CAF (p ⁇ 0.05).
  • FIG. 8A and FIG. 8B depict average hourly W bout duration “WBD.”
  • FIG. 8C and FIG. 8D depict average hourly NR bout duration “NRBD.”
  • FIG. 8E and FIG. 8F depict average hourly REM bout duration “RBD.”
  • FIG. 9A and FIG. 9B depict average hourly locomotor activity (EMA) and relative core body temperature (Tb) for 3 concentrations of Compound 1 vs. CAF and vehicle.
  • EMA hourly locomotor activity
  • Tb relative core body temperature
  • FIG. 9A depicts average hourly LMA.
  • FIG. 9B depicts average hourly Tb.
  • FIG. 10A, FIG. 10B and FIG. 10C depict hourly percent time spent in W, NR, and REM for 3 concentrations of 6582 vs. CAF and vehicle. Dosing occurred during the first part of ZT7. The asterisks above the graphs represent time points with significant differences. In the legends, means condition is significantly different from vehicle and “+” means condition is significantly different from CAF (p ⁇ 0.05).
  • FIGS 11A-11F depict measures of sleep-wake consolidation for 3 concentrations of 6582 vs. CAF and vehicle.
  • the asterisks above the graphs represent time points with significant differences. In the legends, means treatment is overall significantly different from vehicle and “+” means treatment is overall significantly different from CAF (p ⁇ 0.05).
  • FIG. 11A and FIG. 11B depict average hourly WBD.
  • FIG. 11C and FIG. 11D depict average hourly NRBD.
  • FIG. HE and FIG. HF depict average hourly RNB.
  • FIG. 12A and FIG. 12B depict average hourly EMA and relative Tb for 3 concentrations of 6582 vs. CAF and vehicle.
  • the asterisks above the graphs represent time points with significant differences. In the legends, means treatment is significantly different from vehicle and “+” means treatment is significantly different from CAF (p ⁇ 0.05).
  • FIG. 12A depicts average hourly LMA.
  • FIG. 12B depicts average hourly Tb.
  • the present disclosure provides methods of treating a sleep disorder (e.g., narcolepsy) in a subject in need thereof.
  • the methods comprise administering to a subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating a sleep disorder (e.g., narcolepsy) with a crystalline form of either Compound 1 or a pharmaceutically acceptable salt thereof.
  • compositions comprising a therapeutically effective amount of Compound 1 : (Compound 1), or a pharmaceutically acceptable salt thereof.
  • the sleep disorder is a disorder selected from the group consisting of insomnia, hypersomnolence, narcolepsy, cataplexy, idiopathic hypersomnia, sleep paralysis, hypnagogic hallucinations, hypnopompic hallucinations, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a non-24-hour sleep wake disorder, a non-rapid eye movement sleep arousal disorder, a nightmare disorder, a rapid eye movement sleep behavior disorder, restless leg syndrome, a medication-induced sleep disorder, a substance-induced sleep disorder, excessive daytime sleepiness, excessive need for sleep, shift work sleep disorder, and Kleine Levin syndrome.
  • Also provided herein is a method of treating or preventing hypersomnolence in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 : (Compound 1), or a pharmaceutically acceptable salt thereof.
  • the hypersomnolence is a disorder selected from the group consisting of idiopathic hypersomnia, recurrent hypersomnia, narcolepsy, shift work sleeping disorder, endozepine induced-recurrent stupor, and amphetamine-resistant hypersomnia.
  • a method of treating or preventing narcolepsy in a subject in need thereof comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 : (Compound 1), or a pharmaceutically acceptable salt thereof.
  • the narcolepsy is narcolepsy type 1 or narcolepsy type 2.
  • the treating or preventing comprises: a. reducing one or more symptoms of narcolepsy in the subject; and/or b. modulating an rapid eye movement REM sleep in the subject.
  • the one or more symptoms of narcolepsy is selected from the group consisting of: a. excessive daytime sleepiness; b. cataplexy; c. sleep paralysis; d. hallucinations; e. deficiency of the hormone hypocretin; f. changes in rapid eye movement (REM) sleep; g. excessive need for sleep; and h. metabolic-syndrome-related disorder.
  • the modulation of REM sleep comprises decreasing the rate of eye movement, reducing the density and latency of REM sleep, disrupting REM sleep or increasing non-REM sleep, decreasing ratio of REM:non-REM sleep, or REM sleep onset latency.
  • the narcolepsy is associated with a metabolic-syndrome-related disorder.
  • the metabolic-syndrome-related disorder is selected from the group consisting of hypertension, diabetes, and dyslipidemia.
  • the subject experienced weight gain, obesity, high body mass index, or cardiometabolic risks.
  • the therapeutically effective amount is between about 3 mg to about 60 mg.
  • the therapeutically effective amount is about 3 mg, about 9 mg, or about 30 mg.
  • Compound 1 is administered once daily.
  • the compounds and compositions of the disclosure are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount.
  • the quantity to be administered depends on the subject to be treated, in some embodiments. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each subject. Suitable regimes for initial administration, but are typified by an initial administration followed by repeated doses at one hour intervals or longer by a subsequent administration. Alternatively, continuous administration that is sufficient to maintain concentrations in the blood are contemplated.
  • the amounts of the active ingredients (e.g., compound of the disclosure or a pharmaceutically acceptable salt thereof) in the compositions, the composition formulation, and the mode of administration are among the factors that are varied to provide an amount of the active ingredient that is effective to achieve the desired therapeutic response for each subject, without being unduly toxic to the subject.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health, diet and prior medical history of the subject being treated, and like factors well known in the medical arts.
  • the compound described herein or a pharmaceutically acceptable salt thereof is administered to a subject in various dosing amounts and over various time frames.
  • the dose(s) of a compound is administered, in some embodiments, twice a week, weekly, every two weeks, every three weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 12 weeks, or any combination of weeks therein.
  • Dosing cycles are also contemplated, such as, e.g. , administering the compound once or twice a week for 4 weeks, followed by two weeks without therapy. Additional dosing cycles including, e.g., different combinations of the doses and weekly cycles described herein are also contemplated within the disclosure.
  • Therapeutically effective amounts of a composition vary and depend on the severity of the disease, the subject’s weight, and general state of the subject being treated. Administration is, in some embodiments, daily, on alternating days, weekly, twice a month, monthly, or more or less frequently, as necessary depending on the response of the disorder or condition and the subject’s tolerance to the therapy. In some embodiments, maintenance dosages over a longer period of time, such as 4, 5, 6, 7, 8, 10, or 12 weeks or longer, are needed until a desired suppression of disorder symptoms occurs, and dosages are adjusted as necessary. The progress of this therapy is easily monitored by conventional techniques and assays.
  • ED50 effective dose
  • the physician could start doses of the compounds employed in the composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a dose remains constant in some embodiments.
  • unit dosage forms may be presented in unit dosage forms to facilitate accurate dosing.
  • unit dose or “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the pharmaceutical dosage forms described herein can be administered as a unit dose.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the dosage of the compound of the disclosure or compositions comprising the compound can vary depending on multiple factors, such as, e.g., the pharmacodynamic properties of the compound, the mode of administration, age, health, or weight of the recipient, the nature and extent of the symptoms, frequency of the treatment, the type of concurrent treatment, if any, and the clearance rate of the compound in the animal to be treated.
  • factors such as, e.g., the pharmacodynamic properties of the compound, the mode of administration, age, health, or weight of the recipient, the nature and extent of the symptoms, frequency of the treatment, the type of concurrent treatment, if any, and the clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compound of the disclosure or a pharmaceutically acceptable salt thereof may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • the compounds of the disclosure are administered to a human at a daily dosage of, e.g., between 0.05 mg and 3000 mg (measured as the solid form).
  • Dose ranges include, for example, between 0.1-1000 mg (e.g., 0.2-950, 0.4-900, 0.6-850, 0.8-800, 1-750, 1-20, 2-16, 2-700, 4-650, 6-600, 8-550, 10-500, 15-450, 20-400, 30-350, 40-300, 50-250, 75-200, or 100-150 mg).
  • about 1, 2, 2.5, 4, 5, 8, 10, 15, or 20 mg of the compound of the disclosure or a pharmaceutically acceptable salt thereof is administered, e.g., per day.
  • a single dose or multiple doses may be administered in a 24-hour period.
  • between 0.5-8 mg (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 mg) of the compound is administered to the subject once or more than once, e.g., twice, daily.
  • the dosage amount can be calculated using the body weight of the patient.
  • the dose of a compound, or pharmaceutical composition thereof, administered to a patient may be 0.005-5 (0.01-4.8, 0.02-4.6, 0.04-4.4, 0.06-4.2, 0.08-4.0, 0.1-3.8, 0.2-3.6, 0.3-3.4, 0.4-3.2, 0.5-3.0, 0.6, 2.8, 0.7-2.6, 0.8-2.4, 0.9-2.2, 1-2, 1.1-1.9, 1.2- 1.8, 1.3-1.7, or 1.4-1.6) mg/kg.
  • the dose may range from 0.005-1 mg/kg e.g., 0.01-0.5, 0.01-0.2, or 0.01-0.1 mg/kg).
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • reference to a range of 1-5,000 fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5 fold, etc., 2. ⁇ , 2.2, 2.3, 2.4, 2.5 fold, etc., and so forth.
  • variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
  • an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40
  • an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • the term “administration” refers to delivery of an agent or composition disclosed herein to a subject by any acceptable route.
  • acceptable administration routes include oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • a slow-release device e.g., a mini-osmotic pump
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.
  • “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate, and/or that are approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., Compound 1), which salt is compatible with pharmaceutical administration.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid.
  • acids such as oxalic
  • bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4 + , wherein W is Ci-4 alkyl, and the like.
  • salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
  • salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , K + , Ca 2+ , NH4 + , and NW4 + (where W can be a Ci-4 alkyl group), and the like.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • pharmaceutically acceptable excipient refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline (PBS) solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • PBS phosphate buffered saline
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • solid dosage form means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.
  • the terms “subject” and “patient” refer to an animal (e.g., a mammal, such as a human).
  • a subject to be treated according to the methods described herein may be one who has been diagnosed with a particular condition, or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art.
  • a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.
  • the subject is a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey, and the like), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the term “therapeutically effective amount” of an agent or composition described herein refers to a quantity sufficient to, when administered to a subject, including a mammal (e.g., a human), effect beneficial or desired results, including effects at the cellular level, tissue level, or clinical results, and, as such, an “therapeutically effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating a sleep disorder, it is an amount of the agent or composition sufficient to achieve a treatment response as compared to the response obtained without administration of the agent or composition.
  • a “therapeutically effective amount” of agent or composition of the present disclosure is an amount that results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of an agent or composition of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.
  • Treatment refers to the medical management of a subject with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent or cure a disease, pathological condition, or disorder.
  • This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy).
  • Treatment also includes diminishment of the extent of the disease or condition; preventing spread of the disease or condition; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable.
  • “Ameliorating” or “palliating” a disease or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • sleep disorder in general refers to any condition that would benefit from treatment with the agents of the present invention, including any sleep disease or disorder that can be treated by effective amounts of agents described herein.
  • Sleep disorder may comprise intrinsic sleep disorders, extrinsic sleep disorders, and circadian rhythm sleep disorders.
  • intrinsic sleep disorders include, but not limited to, psychophysiological insomnia, sleep state misperception, idiopathic insomnia, narcolepsy, recurrent hypersomnia, idiopathic hypersomnia, posttraumatic hypersomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation, periodic limb movement disorder, restless leg syndrome (RLS), etc.
  • extrinsic sleep disorders include inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, food allergy insomnia, nocturnal eating/drinking syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcoholdependent sleep disorder, toxin-induced sleep disorder, etc.
  • circadian rhythm sleep disorders include time-zone change (jet lag) syndrome, shiftwork sleep disorder, irregular sleep/wake pattern, delayed sleep-phase syndrome, advanced sleep-phase syndrome, non-24-hour sleep/wake disorder, etc.
  • hypersomnolence may be understood to indicate a group of disorders characterized by excessive daytime sleepiness, which occurs despite the subject generally experiencing a normal quality and timing of nocturnal sleep.
  • excessive daytime sleepiness may be defined as the inability to stay awake and alert during major waking episodes of the day, resulting in periods of irrepressible need for sleep or unintended lapses into drowsiness or sleep.
  • hypersomnolence may be assessed and diagnosed, and treatments evaluated, according to a range of scales and/or tests as known in the art.
  • TRI triple reuptake inhibitor
  • SERT serotonin transporter
  • NAT noradrenaline transporter
  • DAT dopamine transporter
  • each of serotonin, noradrenaline, and/or dopamine can independently be by any amount, such as at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or
  • narcolepsy refers to a chronic neurological disorder characterized by recurring episodes of sleep during the day and it also referred as a rare longterm brain disorder that causes a person to suddenly fall asleep at inappropriate times. The brain is unable to regulate sleeping and waking patterns normally, which can result in irregular sleep features, overwhelming episodes of sleep, excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, and excessive dreaming and waking in the night.
  • the narcolepsy is narcolepsy type 1 or narcolepsy type 2.
  • cataplexy refers to a sudden muscle weakness that occurs when one is awake.
  • diabetes refers to a disease characterized by high blood sugar levels over a prolonged period.
  • the term “diabetes” and its grammatical equivalents as used herein can refer to all or any type of diabetes, including, but not limited to, type 1, type 2, cystic fibrosis-related, surgical, gestational diabetes, and mitochondrial diabetes. In some cases, diabetes can be a form of hereditary diabetes.
  • lipids and/or lipid proteins refers to an abnormal level and/or profile of lipids and/or lipid proteins in the blood. For example, an amount of one or more lipids may be increased or decreased with respect to the levels thereof in a healthy subject.
  • lipids and lipid proteins may include, for example, cholesterol, glycerides (such as triglycerides), and lipoproteins (such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL).
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • hypertension is synonymous with elevated high blood pressure. In some embodiments, the term is defined as systolic blood pressure of 120 mmHg or higher.
  • hypocretin or “orexin” refers to a neurotransmitter that regulates arousal, wakefulness, and appetite. Narcolepsy may be caused by a lack of orexin in the brain due to the destruction of the cells that produce it.
  • hallucinations refers to vivid images or other sensory experiences that may occur when a subject is falling asleep or waking up.
  • insomnia refers to difficulty in falling or staying asleep at night.
  • REM sleep refers to a stage of sleep that is often associated with very vivid dreams due to the increase in brain activity.
  • the REM sleep may be characterized by relaxed muscles, quick eye movement, irregular breathing, elevated heart rate, and increased brain activity.
  • sleep paralysis refers to a temporary inability to speak or move that may occur when a subject is falling asleep or waking up.
  • narcolepsy is associated with a metabolic-syndrome- related disorder.
  • people with narcolepsy have a higher risk for developing metabolic disorders, which relate to energy, weight, and sexual development.
  • Overweight and obesity are common in people with narcolepsy, with adults weighing on average 15 percent to 20 percent more than those without narcolepsy.
  • Children who develop narcolepsy often gain significant weight in the months following the emergence of symptoms. Obesity was nearly twice as likely in children with narcolepsy — 74 percent compared with 36 percent in the general population.
  • a 2007 study including 13 people with narcolepsy found that those with type 1 narcolepsy (narcolepsy with cataplexy) had a lower metabolism and tended to eat less than people without narcolepsy.
  • the researchers theorized that the changes in metabolism may be connected to low levels of hypocretin (also referred to as orexin), a brain chemical connected with the cause of narcolepsy.
  • hypocretin also referred to as orexin
  • narcolepsy is associated with cardiometabolic risks.
  • a subject with narcolepsy may experience weight gain, obesity, high body mass index, or cardiometabolic risks.
  • Disrupted nighttime sleep and excessive daytime sleepiness, which are characteristic of narcolepsy may increase cardiovascular risk.
  • Patients with narcolepsy also often present with other comorbidities (e.g., obesity, diabetes, depression, other sleep disorders) that may contribute to increased cardiovascular risk. Often these disorders are overlooked, but they have important implications in the management of this condition.
  • Some medications used to treat symptoms of narcolepsy may have potential negative effects on cardiovascular health, including in patients that are sensitive to sodium, such as those with hypertension, heart failure, or impaired renal function.
  • Compound 1 is a triple reuptake inhibitor, also known as (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone. [00085] The chemical structure of Compound 1 is: (Compound 1).
  • methods described herein comprise administering Compound 1 or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p- toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • physiologically compatible mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid
  • organic acids such as methanesulphonic acid, p- toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt, being in a hydrate or an anhydrate form (e.g., anhydrate, hemihydrate, monohydrate, or quarterhydrate). In certain embodiments, the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt, being in a quarterhydrate form.
  • the pharmaceutically acceptable salt of Compound 1 is , or a hydrate thereof.
  • Compound 1 or a pharmaceutically acceptable salt thereof is in an amorphous form. In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in a crystalline form. In certain embodiments, the crystalline form is a crystalline polymorph or a hydrate thereof. In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarterhydrate (Form 1). In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (Form 2).
  • the compound is in a crystalline quarterhydrate form (Form 1) of a hydrochloride salt of Compound 1, wherein Form 1 has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 1.
  • Form 1 X-ray powder diffraction
  • Form 1 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cu ⁇ a radiation at 20 (2 Theta): 5.5+0.20°, 9.4+0.20°, 10.6+0.20°, 12.5+0.20°, 14.6+0.20°, 16.2+0.20°, 16.6+0.20°, 17.3+0.20°, 18.6+0.20°, 19.6+0.20°, 22.2+0.20°, 22.7+0.20°, 23.1+0.20°, 23.7+0.20°, and 25.3+0.20°.
  • the compound is in a crystalline form (Form 2) of a hydrochloride salt of Compound 1 , wherein Form 2 has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 2.
  • Form 2 has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 2.
  • Form 2 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cu ⁇ a radiation at 26 (2 Theta): 5.2+0.20°, 10.5+0.20°, 12.3+0.20°, 15.3+0.20°, 15.6+0.20°, 16.0+0.20°, 17.1+0.20°, 18.8+0.20°, 23.0+0.20°, 23.9+0.20°, 27.2+0.20°, 28.2+0.20°, and 30.5+0.20°.
  • the present disclosure relates to a composition, such as a pharmaceutical composition comprising Compound 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of a sleep disorder in a subject in need thereof.
  • the sleep disorder is narcolepsy.
  • the present disclosure relates to a composition such as a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of a medical condition associated with a sleep disorder in a subject in need thereof.
  • the sleep disorder is narcolepsy.
  • the composition is a solid pharmaceutical composition.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 1 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the composition comprises from about 1 mg to about 60 mg. In some embodiments, the composition comprises from about 1 mg to about 45 mg. In some embodiments, the composition comprises from about 1 mg to about 30 mg. In some embodiments, the composition comprises from about 1 mg to about 15 mg. In some embodiments, the composition comprises from about 1 mg to about 5 mg.
  • the composition comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, or about 70 mg.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 3 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 3 mg to about
  • the composition comprises from about 3 mg to about 50 mg. In some embodiments, the composition comprises from about 3 mg to about 40 mg. In some embodiments, the composition comprises from about 3 mg to about 30 mg. In some embodiments, the composition comprises from about 3 mg to about 20 mg. In some embodiments, the composition comprises from about 3 mg to about 10 mg.
  • the composition comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 13 mg, about 16 mg, about 19 mg, about 22 mg, about 25 mg, about 28 mg, about 31 mg, about 34 mg, about 37 mg, about 40 mg, about 43 mg, about 46 mg, about 49 mg, about 52 mg, about 55 mg, or about 58 mg.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be administered at a dose of from about 1 mg/kg to about 70 mg/kg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the composition can be administered at a dose of from about 1 mg/kg to about 60 mg/kg.
  • the composition can be administered at a dose of from about 1 mg/kg to about 45 mg/kg.
  • the composition can be administered at a dose of from about 1 mg/kg to about 30 mg/kg.
  • the composition can be administered at a dose of from about 1 mg/kg to about 15 mg/kg.
  • the composition can be administered at a dose of from about 1 mg/kg to about 5 mg/kg. In some embodiments, the composition can be administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, or about 70 mg/kg.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be administered at a dose of from about 3 mg/kg to about 70 mg/kg of Compound 1, or a pharmaceutically acceptable salt thereof. In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be administered at a dose of from about 3 mg/kg to about 60 mg/kg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition can be administered at a dose of from about 3 mg/kg to about 50 mg/kg. In some embodiments, the composition can be administered at a dose of from about 3 mg/kg to about 40 mg/kg.
  • the composition can be administered at a dose of from about 3 mg/kg to about 30 mg/kg. In some embodiments, the composition can be administered at a dose of from about 3 mg/kg to about 20 mg/kg. In some embodiments, the composition can be administered at a dose of from about 3 mg/kg to about 10 mg/kg.
  • the composition can be administered at a dose of about 1 mg/kg, about 2 mg/kg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 13 mg/kg, about 16 mg/kg, about 19 mg/kg, about 22 mg/kg, about 25 mg/kg, about 28 mg/kg, about 31 mg/kg, about 34 mg/kg, about 37 mg/kg, about 40 mg/kg, about 43 mg/kg, about 46 mg/kg, about 49 mg/kg, about 52 mg/kg, about 55 mg/kg, or about 58 mg/kg.
  • compositions described herein comprise a therapeutically effective amount of the free base form of Compound 1.
  • the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of Compound 1.
  • the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • physiologically compatible mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid
  • organic acids such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicy
  • compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • oral (enteral) administration parenteral (by injection) administration
  • rectal administration transdermal administration
  • intradermal administration intrathecal administration
  • SC subcutaneous
  • IV intravenous
  • IM intramuscular
  • intranasal administration intranasal administration.
  • the pharmaceutical compositions disclosed herein are administered orally.
  • the pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”).
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • the pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing.
  • unit dose or “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the pharmaceutical dosage forms described herein can be administered as a unit dose.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the pharmaceutical compositions provided herein are administered to the patient as a solid dosage form.
  • the solid dosage form is a capsule.
  • the solid dosage form is a tablet.
  • compositions provided herein comprise Compound 1 as the sole active agent, or in combination with other active agents.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005. EXAMPLES
  • Cmpd 1 refers to Compound 1; “ANOVA” refers to analysis of variance test; “AP” refers to anteroposterior; “EEG” refers to electroencephalograph; “EMG” refers to electromyograph; “LMA” refers to locomotor activity; “ML” refers to medial-lateral; “CAF” refers to caffeine; “NR” refers to non-rapid eye movement sleep; “NRBD” refers to NR bout duration; “NRD” refers to EEG delta power (1-4 Hz) within NR; “NRNB” refers to number of NR bouts; “RBD” refers to REM bout duration; “REM” refers to rapid eye movement sleep; “RNB” refers to number of REM bouts; “SEM” refers to standard error of mean; “Tb” refers to core body temperature; “W” refers to waking; “WBD” refers to W bout duration; “WN
  • the organic phase was separated and washed with a mixture consisting of 500 mL 2 M HC1 (aq), 300 mL saturated NaCl (aq) and 300 mL ethanol.
  • the organic phase was washed with 400 mL of IM NaOH (aq) and twice with 150 mL 10% NaCl (aq).
  • the organic phase was concentrated under reduced pressure to an oil, taken up in 100 mL toluene and concentrated again to give 87 g of crude (14) with 80% purity.
  • X-ray diffraction powder patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu ⁇ a radiation, primary monochromator, position sensitive detector, angular range 3° to 42° (2 Theta), approximately 60 minutes total measurement time). The samples were prepared and analyzed without further processing (e.g., grinding or sieving) of the substance.
  • the hydrochloride quarterhydrate of (3,4-dichloro-phenyl)-((S)-3-propyl- pyrrolidin-3-yl)-methanone solid (Form 1) can be identified by as few as one characteristic peak in its powder X-ray diffraction patterns as shown in FIG. 1.
  • Exemplary X-ray powder diffraction patterns of hydrochloride of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone solid (Form 2) in terms of 20 (2 Theta) are: 5.2+0.20°, 10.5+0.20°, 12.3+0.20°, 15.3+0.20°, 15.6+0.20°, 16.0+0.20°, 17.1+0.20°, 18.8+0.20°, 23.0+0.20°, 23.9+0.20°, 27.2+0.20°, 28.2+0.20°, and 30.5+0.20°.
  • thermogravimetric analyses approximately 5-10 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to the measurement, the lids were automatically pierced resulting in approximately 1.5 mm pin holes. The samples were then heated under a flow of nitrogen of about 50 mL/min using a heating rate of 5 K/min.
  • EEG, EMG, Tb, and LMA were recorded via telemetry using DQ ART 4.1 software (Data Sciences Inc., St Paul, MN). Animals were acclimated to the handling procedures and were given two separate 1 mL doses of vehicle, one 7 days and the other 3 days before the first experimental day. Following completion of the data collection, expert scorers determined states of sleep and wakefulness in 10 s epochs by examining the recordings visually using NeuroScore software (Data Sciences Inc., St Paul, MN). The EEG and EMG data were scored for waking (W), rapid eye movement sleep (REM), and non-rapid eye movement sleep (NR). Tb and LMA (counts per minute) were analyzed as mean counts per hour.
  • EEG and EMG data were scored visually in 10 s epochs for W, REM, and NR. Scored data were analyzed and expressed as time spent in each state per hour. Latency to NR onset for each rat was calculated from the time of drug injection to the first six continuous 10 s epochs scored as NR. Latency to REM onset for each rat was calculated from the time of drug injection to the first three continuous 10 s epochs scored as REM. Cumulative time spent in W, NR, and REM, as well as the REM:NR ratios, were calculated for the 6 h recording period.
  • the duration and number of bouts for each state were calculated in hourly bins.
  • a “bout” consisted of a minimum of two consecutive 10 s epochs of a given state and ended with any single state change epoch.
  • the EEG spectra during NR sleep were analyzed offline with a fast Fourier transform algorithm (NeuroScore software, Data Sciences Inc., St Paul, MN) on all epochs without a visually detectable artifact.
  • EEG delta power (1-4 Hz) within NR (NRD) was then calculated in hourly bins. Tb and LMA (counts per minute) were analyzed as mean values per hour (hourly means).
  • Latency to NR and REM, REM:NR ratios, and cumulative state data were analyzed using one-way repeated-measures analysis of variance (ANOVA); all other data were analyzed using two-way repeated-measures ANOVA.
  • ANOVA analysis of variance
  • t-tests were performed for post hoc analysis.
  • ANOVA both a treatment effect and an effect that changed over time were predicted.
  • WBD was increased during ZT7 and RBD increased during ZT12 following 6582 at 10 mg/kg while RBD was increased during ZT7 following 6582 at 30 mg/kg. No effect on LMA or Tb were found following any concentration of 6582 (FIG. 12A, FIG. 12B).
  • CAF produced the expected effects on sleep/wake parameters, LMA, and Tb.
  • W bout duration was increased while the number of W bouts, the number of NR bouts and the number of REM bouts were all decreased for the entire recording period following Compound 1 at 10 mg/kg compared to vehicle.
  • LMA was increased across the entire recording period following Compound 1 at 10 mg/kg compared to vehicle.
  • Tb was decreased during ZT9-ZT10 following administration of Compound 1 at 1 and 3 mg/kg compared to vehicle.
  • REM:NR ratios following 6582 at any concentration Only very small effects on NRD and in measures of sleep/wake consolidation were found compared to vehicle. No effects on LMA or Tb were found following any concentration of 6582.
  • CAF produced the expected effects on sleep/wake parameters, LMA, and Tb.

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Abstract

L'invention concerne des méthodes de traitement d'un trouble du sommeil (par exemple, la narcolepsie) chez un sujet en ayant besoin par l'administration au sujet de compositions comprenant un inhibiteur de recapture triple.
PCT/EP2024/074250 2023-08-30 2024-08-30 Méthodes de traitement d'un trouble du sommeil à l'aide d'un inhibiteur de recapture triple WO2025046050A1 (fr)

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