Use of SIK inhibitor in the preparation of a medicament for preventing and / or treating sleep disorders

Abstract

This application relates to the use of SIK inhibitors in the preparation of a medicament for preventing and / or treating sleep disorders. This application also relates to a method for preventing and / or treating sleep disorders in mammals, the method comprising: administering to a mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] This application relates to the field of biomedicine, and particularly to a compound for preventing and / or treating sleep disorders and its applications. Background Art

[0002] Sleep is a natural resting state that commonly exists in organisms such as mammals, birds, and fish, and even occurs in invertebrate mammals such as Drosophila. Healthy sleep plays an important regulatory and protective role in the body. Sleep disorder refers to abnormal sleep quantity and abnormal behaviors during sleep, and is also an indication of the disorder of the normal rhythmic alternation between sleep and wakefulness. Sleep disorder has become a major affliction that plagues modern people and seriously affects the physical and mental health of the human body.

[0003] Multiple reasons can lead to sleep disorders. For example, sleep apnea syndrome, narcolepsy, stroke, heart failure, etc. can disrupt the nocturnal sleep structure, reduce sleep quality, and result in excessive daytime sleepiness (EDS). EDS is a neurofunctional disorder, usually caused by endocrine disorders, various brain diseases, metabolic abnormalities, etc. It refers to an uncontrollable sleep tendency during the day. In mild cases, it is only manifested as daytime fatigue or drowsiness, with a decline in alertness when watching TV, reading newspapers, taking a car, or attending a meeting, or dozing off. In severe cases, the patient suddenly falls asleep during conversation, eating, or even driving, and can only be awakened by moving or strong stimulation. The daytime sleepiness of patients can seriously impair their daily living ability and increase the risk of accidents.

[0004] Salt-inducible kinases (SIKs) constitute a serine / threonine kinase (STK) subfamily that belongs to the AMP-activated kinase (AMPK) family. Three members (SIK1, -2, and -3) have been identified to date. SIK3 is associated with a variety of biological processes, such as glucose and lipid homeostasis in mice (Uebi et al., 2012, PloS ONE 7: e37803), chondrocyte hypertrophy during skeletal development in mice (Sasagawa et al., 2012, Development 139: 1153), osteoarthritis in mice (Yahara et al., 2016, Nature Commun 7: 10959), SIK3 deficiency in mice exacerbates lipopolysaccharide (LPS)-induced endotoxin shock with elevated levels of pro-inflammatory molecules (Sanosaka et al., 2015, Immunology 145: 268), SIK as a tumor antigen associated with the tumorigenesis of ovarian cancer (Chareonfuprasert et al., 2011, Oncogene 20: 3570), and as a novel mitotic regulator and target for enhancing mitotic therapeutic agent-mediated cell death (Chen et al., 2014, Cell Death and Disease 5: e1177), and overexpression of SIK3 induces upregulation of cyclin D and E, leading to acceleration of the G1 / S cell cycle progression (Du et al., 2015, Exp Opin Therap Targ 4: 477).

[0005] Dasatinib (trade name Sprycel) is a novel small molecule multi-target tyrosine kinase inhibitor (TKI) developed by Bristol-Myers Squibb Company in the United States. It inhibits the tyrosine kinases (RTKs) of multiple receptors. Currently, dasatinib is mainly used clinically for patients with chronic myeloid leukemia (CML) who have failed or are intolerant to Imatinib treatment, and also for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to other therapies. Its efficacy exceeds that of high-dose Imatinib treatment, and no drug resistance has been found, so it has important clinical application value. Summary of the Invention

[0006] No reports on SIK inhibitors and dasatinib for the treatment of sleep disorder-related diseases have been found. In this application, in a sleep-deprived mouse model, dasatinib can significantly reduce the lethargy of mice. In addition, dasatinib has been on the market and has a large amount of clinical trial data. If it is used as a therapeutic drug for sleep disorder diseases, it can significantly reduce the clinical trial time and save a large amount of costs. Therefore, dasatinib has great potential in the prevention and / or treatment of sleep disorder-related diseases.

[0007] On the one hand, the present application provides the use of SIK inhibitors in the preparation of a medicament for preventing and / or treating sleep disorders.

[0008] In certain embodiments, the sleep disorders include: hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, post-sleep restriction or deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof.

[0009] In certain embodiments, the hypersomnia disorders include insufficient sleep syndrome.

[0010] In certain embodiments, the symptoms of narcolepsy include: excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakenings, or any combination thereof.

[0011] In certain embodiments, the circadian rhythm sleep-wake disorders include: delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, or any combination thereof.

[0012] In certain embodiments, the post-sleep restriction or deprivation disorders include: attention disorders, alertness disorders, sleepiness, or any combination thereof.

[0013] In certain embodiments, the insomnia disorders include: insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder, or any combination thereof.

[0014] In certain embodiments, the drug-induced sleep disorders include sleep disorders induced by hypnotics, antidepressants, or antipsychotics.

[0015] In certain embodiments, the SIK inhibitor can cross the blood-brain barrier and reach a therapeutically effective amount.

[0016] In certain embodiments, the treatment is mediated by inhibiting the activity of SIK in cells related to the sleep disorder.

[0017] In certain embodiments, the SIK inhibitor is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells related to the sleep disorder.

[0018] In certain embodiments, the cells related to the sleep disorder include neuronal cells.

[0019] In certain embodiments, the SIK inhibitor includes small molecules.

[0020] In certain embodiments, the SIK inhibitor includes a SIK3-specific inhibitor.

[0021] In certain embodiments, the SIK inhibitor includes dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof, and one or more pharmaceutically acceptable additives.

[0022] On the other hand, the present application provides a method for preventing and / or treating sleep disorders in mammals, the method comprising: administering to a mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof.

[0023] In certain embodiments, the sleep disorders include: excessive daytime sleepiness, hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, post-sleep restriction or sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drowsiness or lethargy in patients with rheumatic diseases, drug-induced sleep disorders, or any combination thereof.

[0024] In certain embodiments, the hypersomnia disorder includes a sleep insufficiency syndrome.

[0025] In certain embodiments, the symptoms of narcolepsy include: excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakening, or any combination thereof.

[0026] In certain embodiments, the circadian rhythm sleep-wake disorder includes: delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, or any combination thereof.

[0027] In certain embodiments, the post-sleep restriction or sleep deprivation disorder includes: attention disorder, alertness disorder, drowsiness, or any combination thereof.

[0028] In certain embodiments, the insomnia disorder includes: insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder, or any combination thereof.

[0029] In certain embodiments, the drug-induced sleep disorder includes a sleep disorder induced by a sleeping pill, antidepressant, or antipsychotic.

[0030] In certain embodiments, the mammal administered with a therapeutically effective amount exhibits a reduced degree of excessive daytime sleepiness.

[0031] In certain embodiments, the method comprises: administering a pharmaceutical composition comprising the SIK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0032] In certain embodiments, the SIK inhibitor is able to cross the blood-brain barrier and reach a therapeutically effective amount.

[0033] In certain embodiments, wherein the method is mediated by inhibiting the activity of SIK in cells associated with the sleep disorder.

[0034] In certain embodiments, wherein the SIK inhibitor is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells associated with the sleep disorder.

[0035] In certain embodiments, the cells associated with the sleep disorder include neuronal cells.

[0036] In certain embodiments, wherein the SIK inhibitor comprises a small molecule.

[0037] In certain embodiments, wherein the SIK inhibitor comprises a SIK3-specific inhibitor.

[0038] In certain embodiments, wherein the SIK inhibitor is dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof, and one or more pharmaceutically acceptable additives.

[0039] In certain embodiments, the therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is about 1 to about 2000 mg.

[0040] In certain embodiments, wherein based on the body weight of the mammal to which a therapeutically effective amount is administered, the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg.

[0041] In certain embodiments, wherein the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day or every other day.

[0042] In certain embodiments, wherein the administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof comprises at least one of the following routes: oral, parenteral, intravenous, intramuscular, oral, gingival, sublingual, intraocular, transdermal or transmucosal.

[0043] Those skilled in the art can easily gain insights into other aspects and advantages of this application from the following detailed description. Only exemplary embodiments of this application are shown and described in the following detailed description. As those skilled in the art will recognize, the content of this application enables those skilled in the art to make changes to the disclosed specific embodiments without departing from the spirit and scope of the invention involved in this application. Accordingly, the descriptions in the drawings and the specification of this application are merely exemplary and not restrictive. Brief Description of the Drawings

[0044] The specific features of the invention involved in this application are shown in the appended claims. The characteristics and advantages of the invention involved in this application can be better understood by referring to the exemplary embodiments and the drawings described in detail below. A brief description of the drawings is as follows:

[0045] Figure 1 Shows the dose-response curves of different SIK inhibitors of this application inhibiting SIK3 activity;

[0046] Figure 2 Shows the dose-response curves of Dasatinib of this application inhibiting SIK3 activity in 293 cells overexpressing sik3;

[0047] Figure 3 A-3B shows the awake duration curve of mice within 24 hours before and after sleep deprivation of this application;

[0048] Figure 3 C-3D shows the REM duration curve of mice within 24 hours before and after sleep deprivation of this application;

[0049] Figure 3 E-3F shows the NREM duration curve of mice within 24 hours before and after sleep deprivation of this application. Detailed Embodiments

[0050] The following specific embodiments illustrate the implementation manners of the invention of this application. Those familiar with this technology can easily understand other advantages and effects of the invention of this application from the content disclosed in this specification.

[0051] Term Definitions

[0052] In the present application, the term "NREM sleep" refers to the non-rapid eye movement sleep stage, during which the muscles of the whole body are relaxed, there is no eye movement, and the activity of the visceral parasympathetic nerve predominates. The heart rate and respiration both slow down, blood pressure decreases, gastrointestinal peristalsis increases, the basal metabolic rate is low, the brain temperature is slightly lower than when awake, and the total blood flow in the brain is reduced compared to when awake. Non-rapid eye movement sleep is divided into four stages according to its electroencephalogram characteristics: Stage 1 (N1), the brain waves are mainly theta waves, and spindle waves or K complexes do not appear. In fact, it is a transitional stage from full wakefulness to sleep, the response to external stimuli weakens, mental activities enter a floating state, and thinking is disconnected from reality; Stage 2 (N2), the brain waves are spindle waves and K complexes, and the delta waves are less than 20%. In fact, a person has entered true sleep and belongs to light sleep; Stage 3 (N3), the delta waves in the brain waves account for 20% - 50%, which is medium-depth sleep; Stage 4 (N4), the delta waves in the brain waves account for more than 50%, belonging to deep sleep and not easily awakened.

[0053] In the present application, the term "REM sleep", also known as "dream sleep", refers to the rapid eye movement sleep stage, during which desynchronized low-amplitude brain waves of mixed frequencies appear. The eyes move rapidly, and there are many episodic small twitches in the facial and limb muscles. Sometimes, there may be sucking movements of the lips, short sounds emitted from the larynx, athetoid movements, highly unstable visceral activities, irregular breathing, frequent changes in heart rate, increased gastric acid secretion, and sometimes penile erection. The blood flow in each part of the brain is significantly increased compared to when awake; it is most obvious in the diencephalon and brainstem, and in the brain, it increases more in the hippocampus and the area around the anterior commissure. The oxygen consumption of the brain is also significantly increased compared to when awake.

[0054] Each of the above sleep types and stages has an indicative EEG pattern, and during a night's sleep, the sleeper usually cycles through these types and stages multiple times. Each 30-second time unit during sleep can be called an "epoch", and based on the EEG map obtained during sleep, a sleep technician can assign a sleep type and / or stage (or wakefulness indication) to each such epoch.

[0055] For a 30-minute period included in a specific graph, the percentage of NREM sleep is calculated as 100×(the number of minutes of NREM sleep in that minute period) / 30. For a 30-minute period included in a specific graph, the percentage of REM sleep is calculated as 100×(the number of minutes of REM sleep in that 30-minute period) / 30; for a 30-minute period included in a specific graph, the percentage of "wakefulness" is calculated as 100×(the number of minutes spent in wakefulness (i.e., not in REM sleep or NREM sleep) in 30 minutes) / 30.

[0056] In the present application, the term "salt-inducible kinase" or "SIK" (also known as QSK and KIAA0999) is a member of a serine / threonine protein kinase subfamily that includes SIK1, SIK2, and SIK3, and this subfamily belongs to the AMP-activated protein kinase (AMPK) family. In the present application, the SIK3 protein is generally a protein kinase. Information regarding the human SIK3 protein can be accessed on UniProt: Q9Y2K2 (entry version 138 as of March 15, 2017). SIK3 is a cytoplasmic protein with serine / threonine kinase activity that is regulated by phosphorylation of a conserved threonine residue (position 163) in the T-loop of the kinase domain by the LKB1 complex, and this phosphorylation has been reported to be essential for the catalytic activity of SIK (Lizcano, J.M. et al., EMBO J. 23, 833-843 (2004)). At least four protein isoforms (SIK-001 to SIK-004) are known to be produced by alternative splicing of the SIK gene product. The human SIK3 gene is located at chromosomal position 11q23.3 (HGNC gene symbol accession number: HGNC: 29165) and is conserved in many species such as chimpanzee, rhesus macaque, dog, cow, mouse, rat, chicken, zebrafish, and frog. In the present application, the SIK3 protein is not the SIK1 (also known as SIK and SNF1LK) protein and / or is not the SIK2 (also known as QIK, KIAA0781, and SNF1LK2) protein. When applicable to the context (if not more specifically specified), the term SIK3 can mean the SIK3 protein (such as the SIK3 protein described above) or the mRNA molecule encoding this SIK3 protein.

[0057] In the present application, the term "inhibitor of SIK" (or "SIK inhibitor") refers to any component that inhibits SIK, which can mean inhibition of the expression (e.g., amount), function, activity, and / or stability of SIK, particularly the mRNA and / or protein of SIK, especially phosphorylated SIK. A SIK inhibitor can attenuate, inhibit, reduce, and / or decrease the expression of SIK (e.g., SIK mRNA or protein) in a cell. In such a case, the term "expression" means the cellular process of transcribing a gene into mRNA and subsequently translating said mRNA into a protein (and in certain embodiments, the subsequent trafficking and localization of such a protein). Thus, "gene expression" can refer solely to the production of mRNA regardless of the fate of the mRNA so produced, or alternatively / additionally to the translation of the expressed mRNA into a protein (or the trafficking and localization of such a protein). On the other hand, the term "protein expression" can include the entire cellular process of protein synthesis and / or its trafficking / localization to certain cellular compartments. A SIK inhibitor can attenuate (e.g., cause its reduction or decrease) the efficiency, effectiveness, amount, or rate of one or more activities of SIK (by way of example, by attenuating the expression of SIK protein and / or the amount of phosphorylated SIK protein), such as one or more of the activities described in the present application, e.g., the activity of SIK3 to phosphorylate class II (such as IIa) HDACs (such as HDAC4) and / or the activity of rendering cells associated with a proliferative disorder sensitive to a cell-mediated immune response. A SIK inhibitor may have a negative impact on the stability of SIK (e.g., SIK mRNA or protein), which should be understood in its broadest sense and will include inhibitors that interfere with and reduce the half-life of the SIK protein intracellularly or interfere with and disrupt the folding, presentation, or trafficking / localization of the SIK protein.

[0058] In the present application, the term "hypersomnia disorder (sometimes also referred to as narcolepsy)" generally refers to excessive sleepiness, and a person suffering from a hypersomnia disorder may lack energy, have difficulty thinking clearly, and / or fall asleep at inconvenient or even dangerous times (such as while working or driving).

[0059] In the present application, the term "narcolepsy" refers to a chronic neurological disorder that includes conditions with reduced ability to regulate the sleep-wake cycle. The most typical symptoms are excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, and hallucinations. Other symptoms can include automatic behavior and nocturnal awakenings. Not all patients exhibit all symptoms. During a normal sleep cycle, people enter rapid eye movement (REM) sleep after about 60 to 90 minutes. Dreams occur during REM sleep, and during this sleep stage, the brain keeps the muscles weak. Patients with narcolepsy often enter REM sleep rapidly within 15 minutes after falling asleep. In addition, the muscle weakness or dream activity of REM sleep can occur during wakefulness and may also be absent during sleep. In narcolepsy, excessive daytime sleepiness (EDS) can last from seconds to minutes or longer and can occur at any time. EDS is characterized by persistent sleepiness regardless of how much a person sleeps at night. Due to the strong sense of sleepiness that can appear rapidly, the sleepiness in narcolepsy can occur suddenly.

[0060] In the present application, the term "circadian rhythm sleep-wake disorder" involves sleep times that are inconsistent with the normal day / night cycle and / or 24-hour clock, including delayed sleep-wake phase, i.e., the sleep pattern is delayed by two hours or more, so that sleep occurs later at night and waking occurs later in the morning; advanced sleep-wake phase, i.e., falling asleep several hours before the normal bedtime and, correspondingly, waking up earlier; irregular sleep-wake rhythm, i.e., the sleep pattern is so disrupted that there is no clear sleep-wake schedule; non-24-hour sleep-wake rhythm, i.e., the sleeper's sleep time becomes later each day so that over time, the sleep time is inconsistent with the desired sleep pattern; shift work syndrome, i.e., a work schedule with periodically changing start and end times, resulting in poor sleep quality and a consistent feeling of fatigue or exhaustion; and jet lag, i.e., difficulty adjusting the sleep schedule after crossing multiple time zones.

[0061] In the present application, the term "post-sleep restriction or sleep deprivation disorder" generally refers to sleep disorders caused by sleep restriction or sleep deprivation; sleep restriction refers to restricting the daily sleep time to a level below normal during a period, resulting in a reduction in total sleep time; sleep deprivation refers to a complete lack of sleep or failure to reach the ideal sleep time during a certain period. In the present application, sleep deprivation of mice is achieved by observing the behavior of mice or by electroencephalogram monitoring to detect when the mice enter sleep, and then gently patting the mouse cage or applying stimuli such as sound and light to keep the mice awake. When necessary, a paper roll, pencil, or direct touch with the hand can also be used to prevent the mice from entering sleep.

[0062] In the present application, the term "insomnia disorder" generally refers to the inability to fall asleep or stay asleep, including insomnia (adult insomnia), which is sometimes also referred to as sleep-onset insomnia, insomnia disorder, or "primary insomnia" to distinguish it from insomnia disorders where adults are unable to fall asleep at the desired onset of sleep; child insomnia, where children are unable to stay asleep or fall asleep, for example, because they refuse to go to bed or are reluctant to let their parents leave the bedside; middle-of-the-night insomnia (or MOTN insomnia), also known as sleep maintenance insomnia, middle insomnia, middle-of-the-night awakening (or MOTN awakening), and / or nocturnal awakening, that is, waking up during the night and then having difficulty resuming sleep; and short sleeper disorder, where adults feel refreshed and alert after less than 6 hours of sleep per night. Adult insomnia / early insomnia / insomnia disorder / primary insomnia is not caused by a disease or the use / abuse of substances.

[0063] In the present application, the term "breathing-related sleep disorder" or "breathing-related sleep disorder" generally refers to difficulty breathing during sleep, including obstructive sleep apnea, where breathing stops during sleep due to airway blockage; snoring, which is a loud noise caused by the vibration of tissues at the back of the throat during sleep; central sleep apnea, where there is a reduction or cessation of breathing during sleep caused by brain or heart problems rather than airway obstruction; pediatric sleep apnea, where breathing stops during sleep in children due to the large size of the tonsils and adenoids compared to the throat; infant sleep apnea, where breathing stops during sleep in infants due to developmental problems caused by an immature brainstem or other diseases; and sleep-related groaning, which is an extended noise similar to groaning caused by exhalation during sleep.

[0064] In the present application, the term "idiopathic hypersomnia" is also known as "NREM narcolepsy", "idiopathic central hypersomnia", "functional hypersomnia", or "coordinated hypersomnia", and refers to persistent or recurrent daytime hypersomnolence, the hypersomnolent periods of which consist of non-rapid eye movement (NREM) phases.

[0065] In the present application, the term "Kleine-Levin syndrome" generally refers to recurrent (more than once a year) periods of two to five weeks involving hypersomnolence.

[0066] In the present application, the term "deep sleep state" refers to some clinical manifestations that occur during slow-wave sleep, mostly during sleep stages III and IV, but the sleep process itself is normal. One of them is somnambulism, which is more common in children and adult hysterics. Somnambulism often occurs during sleep stages III and IV. That is, after the patient has slept for a period of time at night, he or she will sit up in bed, or even get out of bed and walk around. The behavior is rather rigid, the consciousness is trance, and he or she will not answer or respond when asked or called. After walking around for a while, he or she will go back to sleep and cannot remember the next day.

[0067] In the present application, the term "sleep deprivation syndrome" refers to the situation where sufficient sleep cannot be obtained regularly at night, resulting in sleep deprivation; and long-sleeper disorder, that is, normal and good-quality regular sleep, but the length is much longer than other similar situations (for example, similar age).

[0068] In the present application, the term "excessive daytime sleepiness" or "EDS" refers to persistent sleepiness during the time when an individual is expected to be awake and alert, even during the day after apparently sufficient or even extended nocturnal sleep. EDS may be the result of a sleep disorder or a symptom of other underlying disorders (such as narcolepsy, sleep apnea, circadian rhythm sleep disorder, or idiopathic hypersomnia). Although the name includes "daytime", it should be understood that sleepiness may also occur at other times when the subject should be awake (such as at night or other times, when the subject is working the night shift). It should also be understood that EDS is medically different from fatigue and disorders related to fatigue.

[0069] In the present application, the terms "small molecule" and similar terms include: peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic substances with a molecular weight of less than about 10,000 grams per mole (i.e., including heterologous organic substances and organometallic compounds), and salts, esters, and other pharmaceutically acceptable forms of such drugs.

[0070] In the present application, the term "therapeutically effective amount" or "effective amount" refers to an amount of a composition, compound, or agent of the present application that can modulate a subject afflicted with a disorder, disease, or illness. For example, such modulation can include beneficial effects, including, as is well known in the art, improving the condition of the subject (e.g., one or more symptoms), delaying or alleviating the progression of the disorder, preventing or delaying onset, and / or causing a change in clinical parameters, disease, or illness. For example, a therapeutically effective amount or effective amount can refer to an amount of a composition, compound, or agent that can improve the disorder of a subject by at least 5%, such as at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0071] In the present application, the term "prevention and / or treatment" not only includes the prevention and / or treatment of diseases, but also generally includes preventing the onset of a disease, slowing or reversing the progression of a disease, preventing or slowing the onset of one or more symptoms associated with a disease, reducing and / or alleviating one or more symptoms associated with a disease, reducing the severity and / or duration of a disease and / or any symptoms associated therewith and / or preventing a further increase in the severity of a disease and / or any symptoms associated therewith, preventing, reducing, or reversing any physiological damage caused by a disease, and any pharmacological effect generally beneficial to the patient being treated. The compositions of the present application forming viable therapeutic agents need not achieve complete cure or eradication of any symptoms or manifestations of a disease. As recognized in the relevant art, a drug used as a therapeutic agent can reduce the severity of a given disease state, but need not eliminate every manifestation of the disease to be considered a useful therapeutic agent. Similarly, prophylactic administration of a treatment constituting a viable prophylactic agent need not be completely effective in preventing the onset of a disorder. Simply reducing the impact of a disease in a subject (e.g., by reducing the number or severity of its symptoms, or by enhancing the effectiveness of another treatment, or by producing another beneficial effect), or reducing the likelihood of the occurrence or worsening of a disease is sufficient.

[0072] In the present application, the term "mammal" generally refers to any animal classified as a mammal, including but not limited to, humans, rodents, sport animals, zoo animals, pet animals, and domestic or farm animals, such as dogs, cats, cows, sheep, pigs, horses; non-human primates, such as monkeys. Rodents can include mice or rats. Humans are also referred to as patients or subjects in the present application.

[0073] In the present application, the terms "reduce" and "decrease" are used interchangeably and mean any change that is less than the original. "Reduce" and "decrease" are relative terms and require comparison between before and after measurement. The change can include 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100%.

[0074] In the present application, the term "pharmaceutically acceptable" generally refers to one or more non-toxic substances that do not interfere with the effectiveness of the biological activity of the active ingredient. Such preparations usually may contain salts, buffers, preservatives, compatible carriers and optionally other therapeutic agents. Such pharmaceutically acceptable preparations usually may also contain compatible solid or liquid fillers, diluents or encapsulating materials suitable for administration to humans. When used in medicine, the salts should be pharmaceutically acceptable salts, but non-pharmaceutically acceptable salts can be conveniently used to prepare pharmaceutically acceptable salts and they cannot be excluded from the scope of the present application. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, salts prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, citric acid, boric acid, formic acid, malonic acid, succinic acid, etc. Pharmaceutically acceptable salts can also be prepared as alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts or calcium salts.

[0075] In the present application, "specificity" refers to the selective reactivity of the interaction in the case of the interaction between members of a specific binding pair (such as between an antigen and an antibody). In the present application, the specificity of the SIK3 inhibitor means that the inhibitory effect of the SIK inhibitor on SIK activity is higher compared to the inhibitory effects on SIK1 and SIK2 activities. For example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or even 100%.

[0076] In the present application, the term "about" means within an acceptable error range of a specific value as determined by a person of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. The term "about" is intended to cover variations deviating from the specified value by ±20%, or in some cases ±10%, or in some cases ±5%, or in some cases ±1%, or in some cases ±0.1%, since such variations are appropriate for carrying out the disclosed methods. Detailed Description of the Invention

[0078] On the one hand, the present application provides the use of SIK inhibitors in the preparation of a medicament for preventing and / or treating sleep disorders.

[0079] In the present application, the sleep disorder may include hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, sleep restriction or post-sleep deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drowsiness or somnolence in patients with rheumatic diseases, drug-induced sleep disorder, or any combination thereof.

[0080] In certain embodiments, the hypersomnia disorder may include insufficient sleep syndrome.

[0081] In certain embodiments, the symptoms of narcolepsy may include excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakening, or any combination thereof.

[0082] In certain embodiments, the circadian rhythm sleep-wake disorder may include delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, or any combination thereof.

[0083] In certain embodiments, the sleep restriction or post-sleep deprivation disorder may include attention disorder, alertness disorder, somnolence, or any combination thereof.

[0084] In certain embodiments, the insomnia disorder may include insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder, or any combination thereof.

[0085] In certain embodiments, the drug-induced sleep disorder may include sleep disorder induced by hypnotics, antidepressants, or antipsychotics.

[0086] In the present application, the SIK inhibitor can be prepared for use in the preparation of a medicament for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, sleep restriction or post-sleep deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof.

[0087] For example, the hypersomnia disorder may include insufficient sleep syndrome; and the symptoms of narcolepsy may include excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakening, or any combination thereof; and the circadian rhythm sleep-wake disorder may include delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, or any combination thereof; and the disorder after sleep restriction or sleep deprivation may include attention disorder, alertness disorder, drowsiness, or any combination thereof; and the insomnia disorder may include insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder, or any combination thereof; and the drug-induced sleep disorder may include hypnotic, antidepressant, or antipsychotic-induced sleep disorder.

[0088] The SIK inhibitor described in the present application can cross the blood-brain barrier and reach a therapeutically effective amount.

[0089] In the present application, the SIK inhibitor can cross the blood-brain barrier and reach a therapeutically effective amount, and the SIK inhibitor can be prepared for use in the prevention and / or treatment of hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, disorder after sleep restriction or sleep deprivation, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof.

[0090] The treatment described in the present application can be mediated by inhibiting the activity of SIK in cells related to the sleep disorder.

[0091] In the present application, the SIK inhibitor can be prepared for use in the prevention and / or treatment of hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, disorder after sleep restriction or sleep deprivation, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof; and the treatment can be mediated by inhibiting the activity of SIK in cells related to the sleep disorder.

[0092] The SIK inhibitor described in the present application is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells related to the sleep disorder.

[0093] In the present application, the SIK inhibitor can be prepared for use in the preparation of a medicament for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof; the SIK inhibitor is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells associated with the sleep disorder.

[0094] The SIK inhibitor described in the present application may include small molecules.

[0095] In the present application, the SIK inhibitor can be prepared for use in the preparation of a medicament for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof; and the SIK inhibitor may include small molecules.

[0096] The SIK inhibitor described in the present application may include an SIK3-specific inhibitor.

[0097] In the present application, the SIK inhibitor can be prepared for use in the preparation of a medicament for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof; and the SIK inhibitor may include an SIK3-specific inhibitor.

[0098] In the present application, the SIK inhibitor can be prepared for use in the preparation of a medicament for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof; and the SIK inhibitor may include an SIK-specific inhibitor; and the SIK inhibitor can cross the blood-brain barrier and reach a therapeutically effective amount; and the treatment can be mediated by inhibiting the activity of SIK in cells associated with the sleep disorder; and the SIK inhibitor is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells associated with the sleep disorder; and the SIK inhibitor may include an SIK3-specific inhibitor; and the SIK inhibitor may include small molecules.

[0099] In certain embodiments, the SIK inhibitor may include dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof.

[0100] In certain embodiments, the SIK inhibitor may further include one or more pharmaceutically acceptable additives.

[0101] For example, the present application provides the use of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof in the preparation of a medicament for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders or any combination thereof.

[0102] On the other hand, the present application provides a method for preventing and / or treating sleep disorders in mammals, the method may include: administering to a mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof.

[0103] In the present application, the sleep disorders may include: hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders or any combination thereof.

[0104] In certain embodiments, the hypersomnia disorder may include sleep insufficiency syndrome.

[0105] In certain embodiments, the symptoms of narcolepsy may include excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakening or any combination thereof.

[0106] In certain embodiments, the circadian rhythm sleep-wake disorder may include delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag or any combination thereof.

[0107] In certain embodiments, the sleep restriction or post-sleep deprivation disorder may include attention disorder, alertness disorder, sleepiness or any combination thereof.

[0108] In certain embodiments, the insomnia disorder may include insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder or any combination thereof.

[0109] In certain embodiments, the drug-induced sleep disorder may include a sleep disorder induced by a sleeping pill, an antidepressant, or an antipsychotic.

[0110] In the present application, the method for preventing and / or treating hypersomnia, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or sleep deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof.

[0111] For example, the hypersomnia may include sleep insufficiency syndrome; and the symptoms of narcolepsy may include excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakening, or any combination thereof; and the circadian rhythm sleep-wake disorder may include delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, or any combination thereof; and the post-sleep restriction or sleep deprivation disorder may include attention disorder, alertness disorder, sleepiness, or any combination thereof; and the insomnia disorder may include insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder, or any combination thereof; and the drug-induced sleep disorder may include a sleep disorder induced by a sleeping pill, an antidepressant, or an antipsychotic.

[0112] The mammal to which a therapeutically effective amount of the SIK inhibitor is administered according to the present application may exhibit a reduced degree of excessive daytime sleepiness.

[0113] In the present application, the method for preventing and / or treating hypersomnia, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or sleep deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and the mammal to which a therapeutically effective amount of the SIK inhibitor is administered may exhibit a reduced degree of excessive daytime sleepiness.

[0114] For example, the sleep time of mice after sleep deprivation can be reduced by at least 5%, such as at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0115] The method described in the present application further includes administering a pharmaceutical composition comprising the SIK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0116] In the present application, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, sleep restriction or post-sleep deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of an SIK inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the SIK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0117] The SIK inhibitor described in the present application can cross the blood-brain barrier and reach a therapeutically effective amount.

[0118] In the present application, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, sleep restriction or post-sleep deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of an SIK inhibitor or a pharmaceutically acceptable salt thereof; and the SIK inhibitor can cross the blood-brain barrier and reach a therapeutically effective amount.

[0119] The treatment described in the present application may be mediated by inhibiting the activity of SIK in cells related to the sleep disorder.

[0120] In the present application, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, sleep restriction or post-sleep deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of an SIK inhibitor or a pharmaceutically acceptable salt thereof; and the treatment may be mediated by inhibiting the activity of SIK in cells related to the sleep disorder.

[0121] The SIK inhibitor described in the present application may be administered in a therapeutically effective amount that reduces the activity of SIK in cells related to the sleep disorder.

[0122] In the present application, the method for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, post-sleep restriction or deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in mammals may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and the SIK inhibitor may be administered in a therapeutically effective amount to reduce the activity of SIK in cells associated with the sleep disorder.

[0123] The SIK inhibitor described in the present application may include small molecules.

[0124] In the present application, the method for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, post-sleep restriction or deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in mammals may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and the SIK inhibitor may include small molecules.

[0125] The SIK inhibitor described in the present application may include a SIK3-specific inhibitor.

[0126] In the present application, the method for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, post-sleep restriction or deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in mammals may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and the SIK inhibitor may include a SIK3-specific inhibitor.

[0127] In the present application, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the SIK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and the mammal administered with the therapeutically effective amount of the SIK inhibitor may exhibit a reduced degree of excessive daytime sleepiness; and the SIK inhibitor can cross the blood-brain barrier and reach a therapeutically effective amount; and the treatment may be mediated by inhibiting the activity of SIK in cells associated with the sleep disorder; the SIK inhibitor may be administered in a therapeutically effective amount to reduce the activity of SIK in cells associated with the sleep disorder; and the SIK inhibitor may include a SIK3-specific inhibitor; and the SIK inhibitor may include a small molecule.

[0128] In certain embodiments, the SIK inhibitor may include dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof.

[0129] For example, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof.

[0130] The therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof described in the present application is about 1 to about 2000 mg.

[0131] In the present application, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and the therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is about 1 to about 2000 mg.

[0132] In certain embodiments, a suitable therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof administered as a single dose is from about 0.06 mg to about 600 mg, from about 0.05 mg to about 50 mg, from about 0.12 mg to about 600 mg, from about 0.10 mg to about 30 mg, from about 0.10 mg to about 20 mg, from about 0.10 mg to about 15 mg, from about 0.10 mg to about 10 mg, from about 0.10 mg to about 8 mg, from about 0.10 mg to about 7 mg, from about 0.15 mg to about 30 mg, from about 0.15 mg to about 20 mg, from about 0.15 mg to about 15 mg, from about 0.15 mg to about 10 mg, from about 0.15 mg to about 8 mg, from about 0.15 mg to about 7 mg, from about 0.18 mg to about 9 mg, from about 0.18 mg to about 6 mg, from about 0.18 mg to about 4.0 mg, from about 0.2 mg to about 30 mg, from about 0.2 mg to about 20 mg, from about 0.2 mg to about 15 mg, from about 0.2 mg to about 10 mg, from about 0.2 mg to about 8 mg, from about 0.2 mg to about 7 mg, from about 0.2 mg to about 6.0 mg, from about 0.2 mg to about 4.0 mg, from about 0.2 mg to about 3.0 mg, from about 0.2 mg to about 2.0 mg, from about 0.2 mg to about 1.0 mg, from about 0.5 mg to about 6.0 mg, from about 0.5 mg to about 4.0 mg, from about 0.5 mg to about 3.0 mg, from about 0.5 mg to about 2.0 mg, from about 0.5 mg to about 1.0 mg, from about 0.6 mg to about 6.0 mg, or from about 0.6 mg to about 4.0 mg, but in certain embodiments, it is about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.100 mg, about 0.120 mg, about 0.125 mg, about 0.150 mg, about 0.175 mg, about 0.200 mg, about 0.225 mg, about 0.250 mg, about 0.275 mg, about 0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.50 mg, about 0.55 mg, about 0.60 mg, about 0.65 mg, about 0.70 mg, about 0.75 mg, about 0.80 mg, about 0.85 mg, about 0.90 mg, about 0.95 mg, about 1.00 mg, about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.00 mg, about 2.25 mg, about 2.50 mg, about 2.75 mg, about 3.00 mg, about 3.25 mg, about 3.50 mg, about 3.75 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 9.0 mg, about 10 mg, about 12 mg, about 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 70 mg, about 100 mg, about 120 mg, about 150 mg, about 175 mg, or about 200 mg. As is known to those skilled in the art, for human mammals, the single daily dose (mg) can be converted to mg / kg / day dose by dividing the mg dose by 60 kg (the average mass of human mammals recognized in the art). For example, converting a single human daily dose of 1.25 mg to a dose of about 0.021 mg / kg / day.

[0133] In certain embodiments, the method of preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof; and the therapeutically effective amount of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof is about 1 to about 2000 mg.

[0134] This application is based on the weight of the mammal to which a therapeutically effective amount is administered, and the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg.

[0135] In this application, the method of preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and based on the weight of the mammal to which a therapeutically effective amount is administered, the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg.

[0136] In certain embodiments, a suitable therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is, in one embodiment, from about 0.0002 mg / kg to about 25 mg / kg of mammalian body weight per day, in another embodiment from about 0.00025 mg / kg / day to about 20 mg / kg / day, in another embodiment from about 15 mg / kg / day to about 600 mg / kg / day, in another embodiment from about 20 mg / kg / day to about 600 mg / kg / day, in another embodiment from about 25 mg / kg / day to about 600 mg / kg / day, in another embodiment from about 30 mg / kg / day to about 600 mg / kg / day. In another embodiment, the therapeutically effective amount is about 10.0 mg / kg / day or less. In certain embodiments, a suitable therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is from about 0.0002 mg / kg / day to about 10 mg / kg / day, from about 0.001 mg / kg / day to about 10 mg / kg / day, from about 0.002 mg / kg / day to about 10 mg / kg / day, from about 0.003 mg / kg / day to about 10 mg / kg / day, from about 0.0005 mg / kg / day to about 5.0 mg / kg / day, from about 0.001 mg / kg / day to about 2.5 mg / kg / day, from about 0.002 mg / kg / day to about 2.0 mg / kg / day, or from about 0.002 mg / kg / day to about 1.0 mg / kg / day. In another embodiment, the therapeutically effective amount is about 1.0 mg / kg / day or less. In certain other embodiments, a suitable therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is from about 0.001 mg / kg / day to about 1.0 mg / kg / day, from about 0.002 mg / kg / day to about 0.8 mg / kg / day, from about 0.0025 mg / kg / day to about 0.5 mg / kg / day, from about 0.003 mg / kg / day to about 0.15 mg / kg / day, from about 0.006 mg / kg / day to about 0.12 mg / kg / day, or from about 0.010 mg / kg / day to about 0.10 mg / kg / day. It is understood that for these doses, the term "day" refers to a 24-hour period starting from the time of administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof. For example, for a normal night's sleep cycle, if the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at 9:30 PM, the "day" ends at 9:29 PM on the next calendar day.

[0137] In certain embodiments, the method for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof; and the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg based on the body weight of the mammal to which the therapeutically effective amount is administered.

[0138] The SIK inhibitor or a pharmaceutically acceptable salt thereof described in the present application is administered once a day, twice a day, three times a day or every other day.

[0139] In the present application, the method for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day or every other day.

[0140] In certain embodiments, the method for preventing and / or treating hypersomnia disorders, narcolepsy, circadian rhythm sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof; and the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day or every other day.

[0141] The administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof described in the present application includes at least one of the following routes: oral, parenteral, intravenous, intramuscular, oral, gingival, sublingual, intraocular, transdermal or transmucosal.

[0142] In the present application, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof; and the administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof includes at least one of the following routes: oral, parenteral, intravenous, intramuscular, oral, gingival, sublingual, intraocular, transdermal, or transmucosal.

[0143] In certain embodiments, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof; and the administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof includes at least one of the following routes: oral, parenteral, intravenous, intramuscular, oral, gingival, sublingual, intraocular, transdermal, or transmucosal.

[0144] In the present application, the method for preventing and / or treating hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof in a mammal may include: administering to the mammal a therapeutically effective amount of a SIK inhibitor, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the SIK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and the therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is about 1 to about 2000 mg; and based on the body weight of the mammal to which the therapeutically effective amount is administered, the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg; and the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, or every other day; and the administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof includes at least one of the following routes: oral, parenteral, intravenous, intramuscular, oral, gingival, sublingual, intraocular, transdermal, or transmucosal.

[0145] In certain embodiments, the method for preventing and / or treating hypersomnia disorders, narcolepsy, circadian sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof in mammals may include: administering to the mammal a therapeutically effective amount of dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof; and the therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is from about 1 to about 2000 mg; and based on the body weight of the mammal to which the therapeutically effective amount is administered, the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg; and the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day or every other day; and the administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof includes at least one of the following routes: oral, parenteral, intravenous, intramuscular, oral, gingival, sublingual, intraocular, transdermal or transmucosal.

[0146] The present application also discloses the following embodiments:

[0147] 1. Use of an SIK inhibitor in the preparation of a medicament for preventing and / or treating sleep disorders.

[0148] 2. The use according to embodiment 1, wherein the sleep disorder includes: hypersomnia disorders, narcolepsy, circadian sleep-wake disorders, sleep restriction or post-sleep deprivation disorders, insomnia disorders, breathing-related sleep disorders, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorders, or any combination thereof.

[0149] 3. The use according to embodiment 2, wherein the hypersomnia disorder includes a sleep insufficiency syndrome.

[0150] 4. The use according to any one of embodiments 2-3, wherein the symptoms of narcolepsy include: excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakening, or any combination thereof.

[0151] 5. The use according to any one of embodiments 2-4, wherein the circadian sleep-wake disorder includes: delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, or any combination thereof.

[0152] 6. The application according to any one of Embodiments 2-5, wherein the post-sleep restriction or sleep deprivation disorder includes: attention disorder, alertness disorder, drowsiness, or any combination thereof.

[0153] 7. The application according to any one of Embodiments 2-6, wherein the insomnia disorder includes: insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder, or any combination thereof.

[0154] 8. The application according to any one of Embodiments 2-7, wherein the drug-induced sleep disorder includes a sleep disorder induced by a sleeping pill, an antidepressant, or an antipsychotic.

[0155] 9. The application according to any one of Embodiments 1-8, wherein the SIK inhibitor is able to cross the blood-brain barrier and reach a therapeutically effective amount.

[0156] 10. The application according to any one of Embodiments 1-9, wherein the treatment is mediated by inhibiting the activity of SIK in cells related to the sleep disorder.

[0157] 11. The application according to any one of Embodiments 1-10, wherein the SIK inhibitor is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells related to the sleep disorder.

[0158] 12. The application according to any one of Embodiments 1-11, wherein the SIK inhibitor includes small molecules.

[0159] 13. The application according to any one of Embodiments 1-12, wherein the SIK inhibitor includes a SIK3-specific inhibitor.

[0160] 14. The application according to any one of Embodiments 1-13, wherein the SIK inhibitor includes dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate, or solvate of a salt, ester, or ether thereof, a precursor, or a metabolite.

[0161] 15. The application according to any one of Embodiments 1-14, wherein the SIK inhibitor further includes one or more pharmaceutically acceptable additives.

[0162] 16. A method for preventing and / or treating a sleep disorder in a mammal, the method comprising: administering to the mammal a therapeutically effective amount of a SIK inhibitor or a pharmaceutically acceptable salt thereof.

[0163] 17. The method according to embodiment 16, wherein the sleep disorder includes: hypersomnia disorder, narcolepsy, circadian rhythm sleep-wake disorder, post-sleep restriction or deprivation disorder, insomnia disorder, breathing-related sleep disorder, idiopathic hypersomnia, Kleine-Levin syndrome, deep sleep state, drug-induced sleep disorder, or any combination thereof.

[0164] 18. The method according to any one of embodiments 16-17, wherein the hypersomnia disorder includes sleep insufficiency syndrome.

[0165] 19. The method according to any one of embodiments 16-18, wherein the symptoms of narcolepsy include: excessive daytime sleepiness, abnormal REM sleep, cataplexy, sleep paralysis, hallucinations, automatic behavior, nocturnal awakening, or any combination thereof.

[0166] 20. The method according to any one of embodiments 16-19, wherein the circadian rhythm sleep-wake disorder includes: delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, or any combination thereof.

[0167] 21. The method according to any one of embodiments 16-20, wherein the post-sleep restriction or deprivation disorder includes: attention disorder, alertness disorder, sleepiness, or any combination thereof.

[0168] 22. The method according to any one of embodiments 16-21, wherein the insomnia disorder includes: insomnia, childhood insomnia, nocturnal insomnia, short sleeper disorder, or any combination thereof.

[0169] 23. The method according to any one of embodiments 16-22, wherein the drug-induced sleep disorder includes sleep disorders induced by hypnotics, antidepressants, or antipsychotics.

[0170] 24. The method according to any one of embodiments 16-23, wherein the mammal administered with a therapeutically effective amount of the SIK inhibitor exhibits a reduced degree of excessive daytime sleepiness.

[0171] 25. The method according to any one of embodiments 16-24, the method comprising: administering a pharmaceutical composition comprising the SIK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0172] 26. The method according to any one of embodiments 16-25, wherein the SIK inhibitor is capable of passing through the blood-brain barrier and reaching a therapeutically effective amount.

[0173] 27. The method according to any one of embodiments 16 - 26, wherein the method is mediated by inhibiting the activity of SIK in cells associated with the sleep disorder.

[0174] 28. The method according to any one of embodiments 16 - 27, wherein the SIK inhibitor is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells associated with the sleep disorder.

[0175] 29. The method according to any one of embodiments 16 - 28, wherein the SIK inhibitor comprises a small molecule.

[0176] 30. The method according to any one of embodiments 16 - 29, wherein the SIK inhibitor is a SIK3 - specific inhibitor.

[0177] 31. The method according to any one of embodiments 16 - 30, wherein the SIK inhibitor comprises dasatinib or a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a salt, ester or ether, precursor or metabolite thereof.

[0178] 32. The method according to any one of embodiments 16 - 31, wherein the therapeutically effective amount of the SIK inhibitor or a pharmaceutically acceptable salt thereof is about 1 to about 2000 mg.

[0179] 33. The method according to any one of embodiments 16 - 32, wherein based on the body weight of the mammal to which a therapeutically effective amount is administered, the SIK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg.

[0180] 34. The method according to any one of embodiments 16 - 33, wherein the administration of the SIK inhibitor or a pharmaceutically acceptable salt thereof comprises at least one of the following routes: oral, parenteral, intravenous, intramuscular, oral, gingival, sublingual, intraocular, transdermal or transmucosal.

[0181] Examples

[0182] Example 1

[0183] To evaluate the ability of SIK inhibitors to inhibit SIK3. The compound, ADP - Glo, was evaluated using an IC50 property test. TM is a luminescent kinase assay developed by Promega Corporation that measures the amount of ADP formed in a kinase reaction to reflect kinase activity. In this assay, the remaining ATP in the kinase reaction is first consumed by the ADP - Glo reagent; next, the ADP generated in the kinase reaction is reduced to ATP by the kinase detection reagent; then, the ATP is detected in Ultra - Glo.TM In the presence of luciferase, it reacts with luciferin to emit light, and the luminescence signal is positively correlated with kinase activity. ADP-Glo TM It can be used to detect the activity of almost any enzyme that can generate ADP, without the participation of antibodies and radioactive labeling. This detection method is quite sensitive, and the lower limit of the concentration of ADP that can be detected is 20 nM.

[0184] Such as Figure 1 As shown, Dasatinib (IC50 = 39.05 nM), YKL06-061 (IC50 = 18.35 nM), YKL05-009 (IC50 = 48.01 nM), HG-9-91-01 (IC50 = 3.366 nM) all have excellent kinase inhibitory effects on SIK3.

[0185] Example 2:

[0186] In this example, the luciferase reporter gene method was used to determine the EC50 of dasatinib. In order to screen for Sik3 agonists and antagonists, an EC experiment was established. SIKs phosphorylate CRTCs, sequestering CRTCs in the cytoplasm and eliminating their function. CRTC activates CREB in the nucleus, binds to CRE (cAMP response element), and promotes downstream gene transcription. When Sik3 is inhibited, CRTCs are dephosphorylated, enter the nucleus, and activate the transcription of downstream genes of CRE. After co-transfecting Sik3, CRE-firefly luciferase, and Renilla luciferase (internal control) in 293T cells, an inhibitor was added, and then detected using the Dual luciferase reporter gene assay kit. The specific steps are as follows:

[0187] (1) Observe that the 293T cells are at 60% confluence. A total of 96 * 7 wells need to be transfected; [[ID=I9]]

[0188] (2) Dilute Lipofectamine 3000 reagent with Opti-MEM medium and mix well;

[0189] (3) Dilute DNA with Opti-MEM medium to prepare a DNA premix, and then add P3000 reagent and mix well;

[0190] (4) Add the diluted DNA (1:1) to each tube of the diluted Lipofectamine 3000 reagent;

[0191] (5) Incubate at room temperature for 15 min;

[0192] (6) Add 10 μl of the DNA-lipid complex to each well of the 96-well plate;

[0193] (7) After culturing for 24 h, first detect the cell growth under a microscope. At this time, the cells in most wells should be confluent;

[0194] (8) Prepare dasatinib (10 mM), and use DMSO to serially dilute the 10 mM drug by a factor of 3 to prepare drug concentrations (mM): 10 / 3.3 / 1.1 / 0.37 / 0.19 / 0;

[0195] (9) Take 3 μl of the prepared dasatinib and add it to 997 μl of DMEM + 10% FBS + 1% PS medium;

[0196] (10) Aspirate the original medium from the 12-well plate and add 1 ml of the drug-containing medium to each well;

[0197] (11) Remove the cells, aspirate all the cell culture medium, wash once with 1xPBS, and add 300 μl of cell lysis buffer to each well. Gently rotate the culture dish or plate to ensure that the lysis buffer completely covers the cells;

[0198] (12) Incubate on ice for 5 min to fully lyse the cells;

[0199] (13) Centrifuge at 10000 - 16000 rpm for 1 min and take the supernatant;

[0200] (14) Take 20 μl of the cell lysate and add it to a white microplate. Set up 2 replicates per well;

[0201] (15) Prepare the working solution for the firefly luciferase reaction and the reaction solution for the Renilla luciferase, that is, dilute the firefly luciferase substrate (50×) and the Renilla luciferase substrate (50×) to 1× working solution with the corresponding buffer respectively, and incubate to room temperature. 50 μl of the enzyme substrate + 2450 μl of the buffer = 2.5 ml;

[0202] (16) Add 100 μl of the firefly luciferase reaction solution, shake the plate to mix well, and detect the activity of the firefly luciferase. Try to complete the detection within 30 min;

[0203] (17) Add 100 μl of the Renilla luciferase reaction solution, shake the plate to mix well, and detect the activity of the Renilla luciferase. Try to complete the detection within 30 min;

[0204] (18) Use Excel to statistically analyze the data, calculate the ratio of the firefly luciferase value to the Renilla luciferase value, and plot the ratio against the Log10 drug concentration.

[0205] Such as Figure 2As shown, the EC50 value of dasatinib for inhibiting SIK3 activity in 293 cells overexpressing sik3 is 2826 nM.

[0206] Example 3

[0207] Eight C57 / BL6 mice were selected, SPF grade, weighing 20 ± 2 g, with half males and half females (Beijing Vital River Laboratory Animal Technology Co., Ltd.). Breeding conditions: (25 ± 2) °C, relative humidity (50 ± 10)%, natural light, free access to food and water.

[0208] Grouping and administration: Randomly divided into 2 groups, namely the control group and the experimental group, with 4 mice in each group. During the experiment, the animals in the administration group were respectively given the corresponding dasatinib (0.2 mg / 10 g by gavage), once a day, and the control group was given an equal volume of distilled water.

[0209] When the experimenter observed that the mice entered sleep by observing the behavior of the mice or through electroencephalogram monitoring, the mice were gently patted on the cage or stimulated with sound and light to keep them awake. If necessary, a paper roll, pencil or direct touch with the hand could also be used to prevent the mice from entering sleep. After the mice were implanted with recording electrodes through surgical procedures, they waited for 1 week in the recording box to complete recovery and adapt to the electrode recording operation. First, the sleep situation under unoperated conditions was recorded for 1 day. Then, after turning on the light, sleep was continuously deprived for 6 hours using the above method, and then drugs or solvents were injected respectively, and the recording continued for 1 day.

[0210] First, the signals were filtered, and the filtering parameters were as follows: The EEG signal was high-pass filtered with a cut-off of 0.75 Hz, and the EMG signal was band-pass filtered with a cut-off of 0.75 - 50 Hz; the sleep state was determined according to the following criteria: If the electromyogram activity intensity was high or there was movement, it was the awake state; if Delta waves (0.65 - 4 Hz) were dominant, the amplitude was large, and the electromyogram was quiet, it was NREM; if Theta waves (6 - 10 Hz) were dominant, the amplitude was small, the fluctuations were synchronous, and the electromyogram was the lowest, it was REM.

[0211] Figure 3 A is the awake duration of untreated wild mice, and there was no significant difference between the experimental group and the control group; as Figure 3 shown in B, after sleep deprivation, compared with the control group, Dasatinib could significantly increase the awake time; Figure 3 C is the REM duration of untreated wild mice, and there was no significant difference between the experimental group and the control group; as Figure 3 shown in D, after sleep deprivation, compared with the control group, Dasatinib could significantly shorten the REM time; Figure 3 E is the NREM duration of untreated wild mice, and there was no significant difference between the experimental group and the control group; as Figure 3As shown in F, after sleep deprivation, Dasatinib can significantly shorten the NREM time compared with the control group; in summary, it shows that Dasatinib can effectively reduce the daytime sleepiness of sleep-deprived mice.

[0212] In the description of this specification, the descriptions of terms such as "one embodiment", "some embodiments", "certain implementations", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0213] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, or variations to the above embodiments within the scope of the present invention.

[0214] It is easy for those skilled in the art to understand that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of dasatinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating sleep disorders, wherein the sleep disorder is daytime sleepiness after sleep deprivation.

2. The use according to claim 1, wherein the dasatinib or a pharmaceutically acceptable salt thereof can cross the blood-brain barrier and reach a therapeutically effective amount.

3. The use according to claim 1, wherein the treatment is mediated by inhibiting the activity of SIK in cells related to the sleep disorder.

4. The use according to claim 1, wherein the dasatinib or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount capable of reducing the activity of SIK in cells related to the sleep disorder.

5. The use according to claim 1, wherein the therapeutically effective amount of the dasatinib or a pharmaceutically acceptable salt thereof is 1 mg to 2000 mg.

6. The use according to claim 1, wherein based on the body weight of a mammal administered a therapeutically effective amount, the dasatinib or a pharmaceutically acceptable salt thereof is administered at a dose in the range of 0.001 mg / kg to 1000 mg / kg.

7. The use according to claim 1, wherein the medicament further comprises one or more pharmaceutically acceptable additives.

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