Treatment of CNS disorders associated with sleep disorders

Abstract

1. A compound for use in treating a CNS disorder associated with a sleep disorder in a subject, such as narcolepsy or Angelman syndrome, comprising the compound according to formula I: [Formula 1] TIFF2022538569000058.tif37162 or any of its isomers, tautomers, enantiomers, racemic or deuterated forms, or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to the fields of medicine, pharmacologically active compounds, and pharmaceutical compositions containing such compounds. Specifically, the invention relates to the treatment of CNS disorders associated with cognitive impairment and sleep disorders. This includes central hypersomnias such as narcolepsy, and neurodevelopmental disorders such as Angelman syndrome.

Background Art

[0002] Sleep-wake regulation is closely related to synaptic function and plasticity, and recent findings suggest that the cycle of protein phosphorylation and dephosphorylation in neurons is the central molecular mechanism of sleep-wake regulation (Wang et al. Nature 2018, 558:435-439). So far, it is not known whether compounds targeting CaMK2a play a role in stabilizing sleep disorders or other CNS symptoms where there is an imbalance in neuronal activation and inhibition.

[0003] Narcolepsy is a chronic neurological disorder caused by the brain's inability to regulate the sleep-wake cycle. It causes fragmented nighttime sleep and excessive daytime sleepiness (EDS). Throughout the day at various times, people with narcolepsy experience very strong sleep attacks. When the urge becomes overwhelming, people will fall asleep for periods lasting from seconds to minutes, but rarely, some may remain asleep for over an hour.

[0004] Narcolepsy is a central hypersomnia. This disorder group includes idiopathic hypersomnia, recurrent hypersomnias such as Kleine-Levin syndrome, and narcolepsy with cataplexy (narcolepsy type 1; narcolepsy-cataplexy syndrome; NRCLP1; narcolepsy with low hypocretin) and narcolepsy without cataplexy (narcolepsy type 2; narcolepsy with normal hypocretin).

[0005] All central hypersomnias are characterized by excessive daytime sleepiness (EDS), a persistent underlying sense of sleepiness that occurs periodically throughout the day and often at inappropriate times. These are known as sleep attacks. It can lead to feelings of heaviness in the head, lack of concentration, reduced energy, memory decline, fatigue, and depression.

[0006] In addition to EDS, people with narcolepsy experience some or all of the typical symptoms of cataplexy (sudden loss of voluntary muscle tone), abnormal rapid eye movement (REM) sleep, vivid hallucinations during falling asleep or waking, and brief episodes of complete paralysis at the beginning or end of sleep (called sleep paralysis). Cataplexy is specific to narcolepsy type 1, and the remaining symptoms can occur in both narcolepsy type 1 and type 2.

[0007] In a typical sleep cycle, a person enters the initial stage of sleep, followed by a deeper sleep stage for 90 minutes, where REM sleep finally occurs. In people with narcolepsy, REM sleep occurs within 15 minutes in the sleep cycle and intermittently during wakefulness. Dreams and muscle paralysis occur during REM sleep.

[0008] Hallucinations are vivid, often terrifying sensory hallucinations (hypnogogic hallucinations) that occur during falling asleep and can be caused by the merging of dreams that occur with wakefulness and REM sleep.

[0009] Sleep paralysis is the inability to move or talk for a short time during falling asleep or waking. These episodes can last from seconds to minutes. After the episode ends, people quickly regain their full ability to move and talk.

[0010] Actions under unconsciousness can also occur. A person may fall asleep instantaneously but continue, unconsciously, with a previous action, such as driving.

[0011] Cataplexy is a sudden muscle weakness in the whole body or part, such as the face. Some people have only mild weakness, such as the head or jaw drooping, while others collapse completely to the ground. These episodes are often triggered by strong emotions, such as surprise, laughter, or anger. The weakness is typically temporary, lasting less than two minutes, but may last longer in severe cases.

[0012] Narcolepsy can range in severity from mild to severe.In severe cases, it can negatively affect social activities, school, work, and overall health and well-being.People with narcolepsy can fall asleep at any time, often without warning, for example while talking, standing, or driving.

[0013] Symptoms tend to appear in the teenage years, or in the 20s and early 30s. Men and women are affected equally, and the prevalence of narcolepsy is about 1 in 2,000.

[0014] Similar symptoms are seen by individuals affected by a group of disorders also known as Narcolepsy Due to Medical Conditions (NDMC), secondary or symptomatic narcolepsy. Examples of medical conditions that cause narcoleptic symptoms including cataplexy are: tumors, ischemic stroke, sarcoidosis, arteriovenous malformations affecting the hypothalamus, multiple sclerosis plaques affecting the hypothalamus, paraneoplastic syndromes antt-Ma2 antibodies, Neimann-Pick type C or Coffin-Lowry syndrome. Examples of medical conditions that commonly cause narcoleptic symptoms without cataplexy are: head trauma, myotonic dystrophy, Prader-Willi syndrome, Parkinson's disease or multiple system atrophy.

[0015] GHB is a metabolite and neuromodulator of naturally occurring γ-aminobutyric acid (GABA), which is present in micromolar concentrations in the mammalian brain. GHB (sodium oxybate) is clinically prescribed in narcolepsy and is also misused as a recreational drug (e.g., Fantasy). GHB acts at B both low affinity (millimolar) binding to the GABA receptor and high affinity (nanomolar to micromolar) binding to a specific protein in neurons (recently identified as CaMK2a (PCT / DK2019 / 050041)). One established pharmacological effect of GHB mediated by the GABA B receptor is a decrease in body temperature. In contrast, the neurophysiological and neuropharmacological effects associated with the CaMK2a binding site remain unknown.

[0016] CaMK2a is one of the most abundant proteins in postsynaptic membrane thickenings. It is a major regulator of synaptic signaling by phosphorylation of its ion channels and neurotransmitter receptors and is closely involved in higher brain functions such as synaptic plasticity and thus cognitive processes, which are processes occurring in postsynaptic membrane thickenings. Because of its central role in regulating synaptic function, CaMK2a is involved in most neurological disorders and is a promising drug target, but remains unexplored because no small molecule brain penetrant ligands with selectivity for the 2a subtype are available.

[0017] GHB is highly effective in treating the cataplexy associated with narcolepsy and excessive daytime sleepiness. This effect is widely believed to be due to the effect of GHB on the GABA B receptor. The effect of GHB on sleep parameters is similar between wild-type mice and GABA B receptor knockout mice (Vienne et al. J Neurosci 2010, 30:14194-14204), and further studies have shown that the GABA BThe receptor agonist baclofen has also been shown to be effective against narcolepsy symptoms in a mouse model of narcolepsy type 1 (Black et al. J Neurosci 2014, 34:6485-6494). Compounds related to GHB may thus be effective in narcolepsy due to their effects on CaMK2a and / or B GABA A receptors. This may be through downstream effects on

[0018] GABA

[0019] Wellendorph et al. (J Pharmacol Exp Ther 2005, 315:346-351) disclose cyclic GHB analogs and their affinities for their natural binding sites.

[0020] Krall et al. (J Med Chem 2019, 60:9022-9039) disclose structure-affinity relationship studies for ligands targeting the binding site of the neuroactive compound GHB.

[0021] Thiesen et al. (J Pharmacol Exp Ther 2015, 354:166-174) disclose the facilitation of brain uptake of 3-hydroxycyclopent-1-ene carboxylic acid (HOCPCA) by the monocarboxylate transporter 1 (MCT1), demonstrating that MCT1 is an important brain entry site for this compound.

[0022] PCT / DK2019 / 050041 discloses that GHB analogs bind to CaMK2a with high affinity and that compounds targeting this kinase are useful for the treatment of brain injury.

[0023] WO / 2019 / 055369 discloses the use of gaboxadol in the treatment of narcolepsy. The GABA A receptor agonist gaboxadol has been clinically developed for various diseases in the 1980s and 1990s, but patients with a history of drug abuse who received gaboxadol experienced an increased incidence of adverse mental events.

[0024] There is a need for new, effective and safe treatment options for CNS disorders associated with sleep disorders. There is also a need for new drugs for the treatment of central hypersomnias, including narcolepsy, which have no potential for abuse or have better pharmacokinetics compared to, for example, sodium oxybate. Furthermore, treatment options for neurodevelopmental disorders such as Angelman and Down syndromes are needed. For these syndromes, there is no targeted treatment, and cognitive and sleep disorders are dominant in them. Thus, specific options for treating sleep disorders would be suitable for all neurodevelopmental disorders. SUMMARY OF THE INVENTION

[0025] The inventors have shown that a wide range of GHB analogs bind to Ca 2+ / calmodulin-dependent protein kinase 2a (CaMK2a), and thus compounds of formula I are promising for the treatment of CNS disorders associated with sleep disorders, such as central hypersomnias exemplified by narcolepsy type 1 and neurodevelopmental disorders involving CaMK2a dysfunction exemplified by Angelman syndrome.

[0026] In its first aspect, the invention is a compound for use in the treatment of a CNS disorder associated with a sleep disorder in a subject, according to formula I

Chemical formula

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[0027] In one embodiment of the invention, the compound of formula I has the structure of formula II:

Chemical formula

[0028] In another embodiment of the invention, the compound of formula I is 3-hydroxycyclopent-1-ene carboxylic acid (HOCPCA), for example (RS)-3-hydroxycyclopent-1-ene carboxylic acid.

[0029] In another embodiment, the CNS disorder associated with the sleep disorder is a central hypersomnia such as narcolepsy.

[0030] In another embodiment, the CNS disorder associated with the sleep disorder is a neurodevelopmental disorder associated with CaMK2a dysfunction such as Angelman syndrome.

[0031] Compounds targeting the novel GHB binding site in CaMK2a have not been suggested as drug candidates in Angelman syndrome or other neurodevelopmental disorders. Herein, the inventors demonstrate that the binding site is located in the central organizing (hub) domain of CaMK2a. This is in contrast to other known CaMK2a ligands. The inventors further show that the compound targets CaMK2a in the Angelman syndrome mouse brain.

[0032] Surprisingly, the inventors have identified small molecule compounds that directly bind to CaMK2a and modulate its function. Compounds according to Formula I are the first example of compounds that selectively target CaMK2a and are thus promising in the treatment of central hypersomnias such as narcolepsy and in the treatment of neurodevelopmental disorders associated with CaMK2a dysfunction such as Angelman syndrome. This suggests the use of compounds of Formula I for the treatment of disorders related to CaMK2a dysfunction, such as Angelman syndrome. The availability of first-in-class small molecule compounds with selectivity for CaMK2a and the fact that these compounds bind at a novel site of the protein make this a completely new proposition. The proposed use of compounds of Formula I is clinically relevant and as such has useful applications, since there are currently no target medical treatments available for Angelman syndrome patients including severe sleep disorders and an improved treatment for central hypersomnias is needed.

[0033] In a second aspect, the present invention provides a pharmaceutical composition for use in the treatment of central hypersomnia or a neurodevelopmental disorder in a subject, said composition comprising a compound according to Formula I.

[0034] In one embodiment, the pharmaceutical composition has a single dosage of the pharmaceutical composition comprising from about 0.1 mg to about 1.0 g of the compound of Formula I above.

[0035] In a third aspect, the present invention provides a method for the treatment of a central hypersomnia such as narcolepsy or a neurodevelopmental disorder such as Angelman syndrome, comprising administration of an effective amount of a compound of Formula I.

[0036] In a fourth aspect, the present invention provides a method for the treatment of a CaMK2a-regulated sensitivity disorder, comprising administration of an effective amount of a compound of Formula I. BRIEF DESCRIPTION OF THE DRAWINGS

[0037]

Figure 1

Figure 2

Figure 3

Figures 4-5

Mode for Carrying Out the Invention

[0038] In a first aspect, the present invention is a compound for use in the treatment of a CNS disorder associated with a sleep disorder, such as central hypersomnia or a neurodevelopmental disorder such as Angelman syndrome, in a subject, According to formula I

Chemical formula

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Chem.

Chem.

Chem.

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[0039] Its isomers, tautomers, enantiomers, racemic forms, deuterated forms or mixtures are within the scope of the present invention. Thus, for example, the compound of formula I may exist in R or S form, and all such forms as well as racemic mixtures are included within the scope of the present invention.

[0040] The compounds of formula I can be prepared as described in PCT / DK2019 / 050041. A method for the synthesis of (RS)-3-hydroxycyclopent-1-ene carboxylic acid is also described in Wellendorph et al. J. Pharmacol. Exp. Therap. 2005, 315:346-351.

[0041] Based on radioligand binding studies, it has now been found that the compounds of formula I bind to a novel site in CaMK2a.

[0042] The inventors have identified CaMK2a as a specific high-affinity target for small molecules GHB and its analogs having the structure of formula I. Further studies exemplified herein have shown that the GHB analogs bind to a specific site of CaMK2a, more precisely the hub domain, and thus are the first small molecule compounds with selectivity for this very important brain kinase. CaMK2a is involved in important processes in the brain such as synaptic plasticity and learning and memory, and its precise regulation is essential for normal intellectual development. Since the kinase is calcium-dependent, it is also centrally involved in pathological conditions of calcium dysregulation such as epilepsy, as well as sleep and ischemia. Mechanistically, CaMK2a is regulated by its own phosphorylation (autophosphorylation), and both mouse models and patients with mutations in these sites show clear deficits in learning and memory and have epileptic seizures and inadequate sleep regulation (Elgersma et al., Neuron 2002, 36:493-505; Kury et al. Am. J. Human Genetics 2017, 101:768‐788).

[0043] Although CaMK2a has never been suggested to be involved in narcolepsy, the inventors have shown that the compounds of formula I targeting CaMK2a are very effective in treating narcoleptic symptoms.

[0044] Biochemical analysis of the mouse model of AS has shown that CaMK2 activity is reduced, in particular, the autophosphorylation of the inhibitory sites Thr305 and Thr306 of the CaMK2a site is increased, resulting in a decrease in hippocampal cell processes correlated with long-term potentiation (LTP), learning, and memory / cognition. Thus, it has been found that the motor function deficits, seizures, learning disabilities, and LTP in AS mice can be rescued by crossing Ube3a mice with mice having the T305V / 306A mutation and reducing the increased inhibitory phosphorylation level (van Woerden et al. Nature Neurosci 2007, 10, 280-282). The inventors have shown that the binding of the compound of formula I is increased in the hippocampus of mice with Angelman syndrome, suggesting that the compound of formula I is effective in treating Angelman syndrome symptoms.

[0045] Similarly, an increase in the phosphorylation level of CaMK2a has been reported in a mouse model of Down syndrome, another chronic neurodevelopmental human disease in which mental retardation is the main phenotype. Such mice exhibit learning and behavioral deficits, including sleep disorders (Siarey et al., J Neurochem. 98:1266-1277). CaMK2a dysfunction may also be part of the pathophysiology in other neurodevelopmental disorders characterized by one or more of the following symptoms: learning and behavioral deficits, seizure tendency, and sleep disorders. Such disorders include: fragile X, neurofibromatosis type 1, cat cry syndrome, succinic semialdehyde dehydrogenase (SSADH) deficiency with abnormal GHB levels, and Rett syndrome in which CaMK2 dysfunction has been shown (Shioda et al., Int J Mol Sci 2018, 19, 20; doi:10.3390 / ijms19010020).

[0046] Compounds targeting the novel GHB binding site in CaMK2a have not been suggested as drug candidates in Angelman syndrome or other neurodevelopmental disorders. Here, the inventors show that the binding site is located in the central organizing (hub) domain of CaMK2a. The inventors suggest that the compounds may be suitable for the treatment of cognitive and / or sleep-related symptoms mediated by CaMK2a in Angelman syndrome. For this reason, compounds of the formula targeting CaMK2a are suggested as drug candidates for treating Angelman syndrome symptoms and potentially other neurodevelopmental disorders with CaMK2a dysfunction.

[0047] Definitions: Autophosphorylation As used herein, the term "autophosphorylation" refers to the phosphorylation of CaMK2a on residue Thr286, Thr305, or Thr306.

[0048] CaMK2a As used herein, the term "CaMK2a" refers to Ca 2+ / calmodulin-dependent protein kinase type 2α.

[0049] Cataplexy As used herein, the term "cataplexy" is a sudden, transient episode of muscle weakness with full awareness, typically triggered by emotions such as laughter, crying, or fear.

[0050] Central hypersomnia Disorders of excessive daytime sleepiness related to the central nervous system, i.e., the brain. These disorders share the main symptom of daytime sleepiness. There are various types of central hypersomnia, including idiopathic hypersomnia, recurrent hypersomnia such as Kleine-Levin syndrome, and narcolepsy.

[0051] In one embodiment, the compound of formula I is contemplated to have beneficial effects in preventing and / or reducing central hypersomnia and cataplexy. Central hypersomnia includes idiopathic hypersomnia, recurrent hypersomnia such as Kleine-Levin syndrome, and narcolepsy with cataplexy (narcolepsy type 1; narcolepsy-cataplexy syndrome; NRCLP1; narcolepsy with low hypocretin) and narcolepsy without cataplexy (narcolepsy type 2; narcolepsy with normal hypocretin).

[0052] Narcolepsy types 1 and 2 are sleep disorders characterized by excessive daytime sleepiness, and narcolepsy type 1 is further characterized by cataplexy. Cataplexy is characterized by a sudden loss of muscle tone. The duration of a cataplectic attack is usually short, ranging from a few seconds to a few minutes, and recovery is immediate and complete. The loss of muscle tone varies in severity, ranging from a mild sense of weakness with head dropping, facial drooping, jaw dropping, slurred speech, and knee buckling to complete postural collapse with falling to the ground. Cataplectic attacks are usually triggered by emotions that typically have an enjoyable or stimulating element, such as laughter, elation, pride, anger, or surprise.

[0053] In addition to excessive daytime sleepiness and cataplexy (in narcolepsy type 1), individuals affected by narcolepsy often exhibit symptoms such as sleep fragmentation, abnormal REM sleep, nocturnal insomnia, paralysis during sleep onset or wakefulness; and / or hypnagogic hallucinations. Similar symptoms are also shown by individuals affected by narcolepsy secondary to a medical condition (NDMC), a group of disorders also known as secondary or symptomatic narcolepsy.

[0054] Examples of medical conditions that cause narcolepsy symptoms including cataplexy are as follows: tumors, ischemic stroke, sarcoidosis, arteriovenous malformations affecting the hypothalamus, multiple sclerosis plaques that damage the hypothalamus, tumor-associated syndrome anti-Ma2 antibody, Niemann-Pick disease type C or Coffin-Lowry syndrome. Examples of medical conditions that generally cause narcolepsy symptoms without cataplexy are as follows: head trauma, myotonic dystrophy, Prader-Willi syndrome, Parkinson's disease or multiple system atrophy.

[0055] Cataplexy is a prominent feature of narcolepsy but may also be associated with specific lesions mainly located in the lateral and posterior hypothalamus, such as tumors (astrocytoma, glioblastoma, glioma, craniopharyngioma and subependymoma) and arteriovenous malformations. Medical conditions in which cataplexy may be seen include ischemic events, multiple sclerosis, head trauma, tumor-associated syndromes, and infectious diseases such as encephalitis. Cataplexy can occur transiently or permanently due to hypothalamic lesions caused by surgery, especially difficult tumor resections. In childhood, cataplexy may be seen in association with other neurological syndromes such as Niemann-Pick disease type C.

[0056] GHB analogs The term "GHB analogs" as used herein refers to compounds that share a common GHB-related structure and bind to specific sites of CaMK2a.

[0057] Neurodevelopmental disorders involving CaMK2a dysfunction This term refers to human diseases that are mostly genetic and have elements of CaMK2a dysfunction. The disorders share common overall symptoms of learning deficits and behavioral deficits, increased tendency for epileptic seizures and sleep disorders. CaMK2 mutations causing the diseases, Angelman syndrome, Down syndrome, fragile X, neurofibromatosis type 1, cat meowing syndrome, SSADH deficiency, and Rett syndrome are included in this definition.

[0058] Pharmaceutical compositions containing the compounds of the invention: The present invention also provides a pharmaceutical composition comprising the compound of the invention together with one or more pharmaceutically acceptable diluents or carriers.

[0059] The compound of the invention or its formulation can be administered by any conventional method, for example, but not limited to, parenterally, orally, topically (including buccal, sublingual or transdermal), via a medical device (such as a stent), by inhalation or via injection (subcutaneous or intramuscular). The treatment can consist of a single administration or multiple administrations over a period of time. The treatment can be, for example, once a day, twice a day, three times a day, four times a day, etc. The treatment can also be by continuous administration, for example by intravenous drip infusion.

[0060] The compound of the invention may be administered alone, but it is preferably provided as a pharmaceutical formulation together with one or more acceptable carriers. The carrier(s) must be "acceptable" in the sense of being compatible with the compound of the invention and not harmful to its recipient. Examples of suitable carriers are described in more detail below.

[0061] For convenience, the formulation can be provided in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. Such methods include the step of bringing the active ingredient (the compound of the invention) into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0062] The compound of the invention will generally be administered in the form of a pharmaceutical formulation containing the active ingredient, optionally in the form of a non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form, intravenously, orally or by any parenteral route. Depending on the disorder being treated, the patient, and the route of administration, the composition can be administered in various dosages.

[0063] The pharmaceutical composition must be stable under the conditions of manufacture and storage; thus, it must preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium including water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0064] For example, the compounds of the invention may also be administered orally, buccally or sublingually, in the form of tablets, capsules, ovules, elixirs, solutions or suspensions for immediate, delayed or controlled release applications, which may contain flavor or coloring agents.

[0065] Formulations according to the invention suitable for oral administration may be provided as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be provided as a bolus, lozenge or paste.

[0066] Solutions or suspensions of the compounds of the invention suitable for oral administration may also contain excipients such as Ν,Ν-dimethylacetamide, dispersing agents such as polysorbate 80, surfactants, and solubilizing agents such as polyethylene glycol, Phosal 50PG (composed of phosphatidylcholine, soybean oil fatty acids, ethanol, mono / diglycerides, propylene glycol and ascorbyl palmitate). Formulations according to the invention may also be in the form of an emulsion, in which case the compound according to formula I may be present in an oil-in-water emulsion. The oil may be any oily substance, such as soybean oil or safflower oil by way of example, medium chain triglycerides (MCT - oil), such as coconut oil, palm oil etc. by way of example, or combinations thereof.

[0067] The tablets may contain excipients such as microcrystalline cellulose, lactose (e.g., lactose monohydrate or anhydrous lactose), sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, butylated hydroxytoluene (E321), crospovidone, hypromellose, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium, and certain complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), macrogol 8000, sucrose, gelatin and gum arabic. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

[0068] Tablets can be manufactured by compression or molding, optionally together with one or more accessory material components. Compressed tablets can be prepared by compressing, in a suitable machine, an active material component in a flowable form, such as a powder or granule, which is optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), a surfactant or dispersant. Wet tablets can be manufactured by molding, in a suitable machine, a mixture of a powdered compound moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can be formulated, for example, to provide sustained or controlled release of the active material component therein, using hydroxypropyl methylcellulose in various proportions to provide a desired release profile. Solid compositions of the same type can also be employed as fillers in gelatin capsules. Preferred excipients in this context include lactose, starch, cellulose, lactitol or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the compounds of the invention can be combined with various sweetening or flavoring agents, coloring substances or dyes, and an emulsifying and / or suspending agent, and a diluent such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0069] Formulations suitable for topical administration in the mouth include lozenges flavored base, usually containing the active material component in sucrose and gum arabic or tragacanth; troches containing the active material component in an inert base such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active material component in a suitable liquid carrier.

[0070] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils, transdermal devices, dusting powders, etc. These compositions can be prepared by conventional methods containing an active agent. Thus, they can also contain conventional carriers and additives of suitability, such as preservatives, solvents to assist drug penetration, emollients in creams or ointments and ethanol or oleyl alcohol for lotions. Such carriers can be present in about 1% to up to about 98% of the composition. More commonly they form up to about 80% of the composition. By way of example only, creams or ointments are prepared by mixing a sufficient amount of a hydrophilic material and water containing about 5-10% by weight of the compound in an amount sufficient to produce a cream or ointment having the desired consistency.

[0071] Pharmaceutical compositions suitable for transdermal administration can be provided as individual patches intended to remain in intimate contact with the recipient's epidermis for an extended period. For example, the active agent can be delivered from the patch by iontophoresis.

[0072] For application to external tissues such as the mouth and skin, the composition is preferably applied as a topical ointment or cream. When formulated as an ointment, the active agent can be employed with either a paraffinic or water-miscible ointment base.

[0073] Alternatively, the active agent can be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

[0074] For parenteral administration, fluid unit dosage forms are prepared using an active material component and a sterile vehicle such as, but not limited to, water, alcohol, polyols, glycerin and vegetable oils (water being preferred). The active material component can be colloidal suspended or dissolved in the vehicle depending on the vehicle and concentration used. In the preparation of solutions, the active material component is dissolved in water for injection, filtered sterilized and then filled into suitable vials or ampoules and sealed.

[0075] Inexpensively, active agents such as local anesthetics, preservatives, and buffers can be dissolved in the vehicle. To enhance stability, the composition may be frozen after filling into the vial, and water is removed under vacuum. The dried lyophilized powder is then sealed in the vial, and an accompanying vial of water for injection may be provided to reconstitute the liquid prior to use.

[0076] The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Further, the composition may be in the form of sterile powders for the immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid in order to be easily injectable.

[0077] Parenteral suspensions are prepared in substantially the same manner as solutions, except that the active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be achieved by filtration. The active ingredient can be sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Optionally, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.

[0078] In addition to the materials specifically mentioned above, the formulations of this invention may contain other active agents standard in the art relevant to the type of formulation in question, for example, those suitable for oral administration may contain flavoring agents, as will be understood by those skilled in the art. Those skilled in the art will know how to select a suitable formulation and how to prepare it (see, for example, Remington’s Pharmaceutical Sciences, 18th edition and later). Those skilled in the art will also know how to select a suitable route of administration and dosage.

[0079] The optimal amounts and intervals of individual administrations of the compounds of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, as well as the age and condition of the particular subject being treated, and it will be appreciated by those skilled in the art that the physician will ultimately determine the appropriate dosage to be used. This administration can often be repeated as appropriate. If side effects occur, the dosage and / or frequency of administration can be altered or reduced according to standard clinical practice.

[0080] All % values referred to herein are % w / w unless otherwise required by the context.

[0081] The following embodiments illustrate the invention: 1. A compound for use in the treatment of a CNS disorder associated with a sleep disorder in a subject, according to formula I

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[0082] 2. A compound according to Embodiment 1 having Formula II.

[0083] 3. A compound according to Embodiment 1 having Formula II or III, wherein n is 0.

[0084] 4. A compound according to any of the above embodiments, wherein both R3 and R4 are H.

[0085] 5. A compound according to any of the above embodiments,

Chemical formula

[0086] 6. A compound according to any of the above embodiments, [Chemistry] [Chemistry] [Chemistry] or a pharmaceutically acceptable salt thereof, a compound.

[0087] 7. [Chemistry] or a pharmaceutically acceptable salt thereof, the compound according to Embodiment 6.

[0088] 8. The compound according to Embodiment 7, which is a sodium salt or a potassium salt.

[0089] 9. A compound according to any of Embodiments 1-8 in a crystalline state.

[0090] 10. A compound according to any of Embodiments 1-9, administered to the subject at a dose of about 0.01 mg / kg to about 100 mg / kg.

[0091] 11. A compound according to any of the above embodiments, administered to the subject at a dose of about 0.1 mg / kg to about 10 mg / kg.

[0092] 12. A compound according to any of the above embodiments, wherein the above compound in an amount of about 0.1 mg to about 1.0 g is administered to the above subject.

[0093] 13. A compound according to embodiment 12, wherein the above compound in an amount of about 1 mg to about 1000 mg is administered to the above subject.

[0094] 14. A compound according to any of the above embodiments, wherein the CNS disorder accompanied by the above sleep disorder is central hypersomnia.

[0095] 15. A compound according to embodiment 14, wherein the above central hypersomnia is selected from the group consisting of idiopathic hypersomnia, recurrent hypersomnia, Kleine - Levin syndrome, and narcolepsy.

[0096] 16. A compound according to any of the above embodiments, wherein the CNS disorder accompanied by the above sleep disorder is narcolepsy.

[0097] 17. A compound according to any of the above embodiments, wherein the use reduces at least one of the symptoms of narcolepsy in the above subject.

[0098] 18. A compound according to embodiment 17, wherein the above symptoms are selected from daytime excessive sleepiness, cataplexy, abnormal REM sleep, sleep paralysis, or nocturnal awakening.

[0099] 19. A compound according to any of the above embodiments, wherein the treatment of the above narcolepsy is the treatment of narcolepsy with cataplexy (type 1 narcolepsy).

[0100] 20. A compound according to any one of embodiments 1 - 18, wherein the treatment of the above narcolepsy is the treatment of narcolepsy without cataplexy (type 2 narcolepsy).

[0101] 21. A compound according to any one of embodiments 1 - 18, wherein the treatment of the above narcolepsy is the treatment of secondary narcolepsy.

[0102] 22. A compound according to any of embodiments 1-13, wherein the CNS disorder is a neurodevelopmental disorder.

[0103] 23. A compound according to any of embodiments 1-13, wherein the CNS disorder is caused by a genetic CaMK2 mutation.

[0104] 24. A compound according to any of embodiments 1-13, wherein the CNS disorder is Angelman syndrome or Down syndrome.

[0105] 25. Use of a compound according to any of the above embodiments, wherein the use further comprises administration of a CNS stimulant, an antidepressant, or a GABA receptor agonist.

[0106] 26. A compound according to embodiment 25, wherein the CNS stimulant is selected from the group consisting of modafinil, armodafinil, methylphenidate, amphetamine, dextroamphetamine, methamphetamine, phentermine, phentermine, diethylpropion, lisdexamfetamine, benzfetamine, atomoxetine, caffeine, and ephedrine.

[0107] 27. A compound according to embodiment 25, wherein the antidepressant is selected from the group consisting of serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs).

[0108] 28. A compound according to embodiment 25, wherein the GABA receptor agonist is selected from the group consisting of sodium oxybate, baclofen, phenibut, and gaboxadol.

[0109] 29. A pharmaceutical composition for use in the treatment of a CNS disorder associated with a sleep disorder in a subject, comprising a compound according to any of embodiments 1-29.

[0110] 30. The pharmaceutical composition according to embodiment 29, wherein the CNS disorder accompanied by the sleep disorder is central hypersomnia.

[0111] 31. The pharmaceutical composition according to embodiment 30, wherein the central hypersomnia is narcolepsy.

[0112] 32. The pharmaceutical composition according to embodiment 29, wherein the CNS disorder accompanied by the sleep disorder is a neurodevelopmental disorder.

[0113] 33. The pharmaceutical composition according to embodiment 32, wherein the neurodevelopmental disorder is Angelman syndrome or Down syndrome, or is caused by a genetic CaMK2 mutation.

[0114] 34. The pharmaceutical composition according to any one of embodiments 28 - 33, wherein a single dose of the pharmaceutical composition contains about 0.1 mg to about 5.0 g of the above - mentioned compound.

[0115] 35. The pharmaceutical composition according to embodiment 34, wherein a single dose of the pharmaceutical composition contains about 10 mg to about 1.0 g of the above - mentioned compound.

[0116] 36. The pharmaceutical composition according to embodiment 34, wherein a single dose of the pharmaceutical composition contains about 50 mg to about 500 mg of the above - mentioned compound.

[0117] 37. The pharmaceutical composition according to embodiment 34, wherein a single dose of the pharmaceutical composition contains about 250 mg to about 5.0 g of the above - mentioned compound.

[0118] 38. The pharmaceutical composition according to embodiment 34, wherein a single dose of the pharmaceutical composition contains about 0.5 mg to about 50 mg of the above - mentioned compound.

[0119] 30. A method for the treatment of a CNS disorder accompanied by a sleep disorder, comprising administering an effective amount of a compound defined in any one of embodiments 1 - 28.

[0120] 40. The method according to embodiment 39, wherein the CNS disorder accompanied by the sleep disorder is central hypersomnia.

[0121] 41. The method according to embodiment 40, wherein the central hypersomnia is narcolepsy.

[0122] 42. The method according to any one of embodiments 40 - 41, wherein the central hypersomnia is selected from the group consisting of type 1 narcolepsy, type 2 narcolepsy, and secondary narcolepsy.

[0123] 43. The method according to embodiment 39, wherein the CNS disorder with the sleep disorder is a neurodevelopmental disorder.

[0124] 44. The method according to embodiment 43, wherein the neurodevelopmental disorder is Angelman syndrome or Down syndrome.

[0125] 45. The method according to any one of embodiments 39 - 44, further comprising administering a CNS stimulant, an antidepressant, a GABA A receptor agonist or a GABA B receptor agonist.

[0126] 46. The method according to embodiment 45, wherein the CNS stimulant is selected from the group consisting of modafinil, armodafinil, methylphenidate, amphetamine, dextroamphetamine, methamphetamine, phentermine, phentermine / diethylpropion, diethylpropion, lisdexamfetamine, benzfetamine, atomoxetine, caffeine, and ephedrine.

[0127] 47. The method according to embodiment 45, wherein the antidepressant is selected from the group consisting of serotonin - norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI), and noradrenergic and specific serotonergic antidepressants (NASSA).

[0128] 48. The above - mentioned GABA BThe method according to embodiment 45, wherein the receptor agonist is selected from the group consisting of sodium oxybate, baclofen and phenibut.

[0129] 49. The above GABA A The method according to embodiment 45, wherein the receptor agonist is gaboxadol.

[0130] 50. A method for the treatment of a disease sensitive to CaMK2a modulation, comprising administration of an effective amount of a compound as defined in any of embodiments 1-28.

[0131] Examples Materials and methods Mouse brain 3 H-HOCPCA autoradiography According to a previously published protocol, the mouse brain from either (Ube3a m- / p+ ) or wild-type mice was dissected, sliced on a cryostat, placed on glass slides, 3 H-HOCPCA autoradiography was performed as described (Griem-Krey et al. 2019, J Vis Exp Ther, 145:e58879). The binding protocol was performed using a 1 nM 3 H-HOCPCA radioligand prepared in-house (Vogensen et al., 2013, J Med Chem 56:8201-8205) and 1 mM GHB for non-specific binding. The buffer was 50 mM potassium phosphate, pH 6.0. The washed and dried sections were 3Exposed together with the H microscale to a phosphor imaging plate (Science Imaging Scandinavia AB, Nacka, Sweden) for 3 days and converted to tissue equivalent (TE). The imaging plate was scanned on a CR35Bio Scanner (Durr Medical). Subsequently, densitometric analysis was performed using Image J (NIH), and the data (nmol / mg TE) were further analyzed using GraphPad Prism 7, GraphPad Prism Software, San Diego, CA, USA.

[0132] Binding to recombinant CaMK2a expressed in HEK293T cells 3 H-HOCPCA binding HEK293T cells were cultured using standard conditions with Dulbecco's modified Eagle's medium having GlutaMax, 10% fetal bovine serum, and 1% penicillin-streptomycin and incubated at 37 °C in a humidified atmosphere of 95% O2 and 5% CO2. Site-directed mutagenesis was performed using point mutations and carried out by GenScript USA Inc. The cells were transfected with wild-type or mutant cmyc-tagged rat CaMK2a (Origene construct RR201121) using polyethimine, linear, MW25000 (Polysciences Inc., Warrington, PA, USA). Whole cell homogenates were prepared 48 hours after transfection by washing the cells with ice-cold 1× PBS and recovering them by scraping. The cells were collected and centrifuged at 1000×g for 10 minutes. The cell pellet was resuspended in ice-cold 1× PBS and homogenized using 2× 1 mm zirconium beads in a bead beater at maximum speed for 20 seconds (NextAdvance, NY, USA). The homogenate was clarified by centrifugation (10 minutes, 4 °C, 14,000×g). Protein concentration was determined using the Bradford protein assay. 150 - 200 μg of protein was used at 5 nM 3H-HOCPCA (Vogensen et al., 2013, J Med Chem 56:8201-8205) and the test compound were incubated in a total volume of 1 ml for 1 h at 0 - 4 °C. Nonspecific binding was determined using 1 - 10 mM GHB. The protein was then precipitated by the addition of ice-cold acetone (4× the assay volume), vortexing, and incubation at -20 °C for 1 h. The protein was rapidly filtered 30 times through a GF / C unifilter (Whatman) and washed using a 48-well harvester. Scintillation fluid was added to the dried filter, and radioactivity was measured using a Tricarb 2100 scintillation counter (Packard). Data analysis was performed using GraphPad Prism 7, GraphPad Prism Software, San Diego, CA, USA.

[0133] The total expression level of CaMK2a was evaluated by Western blot using anti-myc-Alexa488 (MA1980-A488, ThermoFisher Scientific).

[0134] Example 1 - Specific CaMK2a Radioligand 3 H-HOCPCA shows increased binding to the Angelman syndrome brain. Angelman syndrome mice (Ube3a m- / p+ , HET) brain sections were 3 compared to control mice (WT) using H-HOCPCA autoradiography. The observed differences were most prominent in the hippocampus where CaMK2a is highly expressed. The data highlight that GHB-related compounds may have an effect in Angelman syndrome by binding to the form of CaMK2a that accumulates in this disorder (Figure 1).

[0135] Example 2 - 3 The binding site of H-HOCPCA is limited to the hub domain cavity of CaMK2a as shown by mutagenesis analysis. A CaMK2a construct having the specific mutations Arg433Gln, Arg453Gln, and Arg469Cys, Arg469Gln, or a construct with the triple mutant or the hub deleted (delta hub) was expressed in HEK cells, and the whole cell homogenate was self- 3 Exposed to the H-HOCPCA filtration binding assay. Each of the three mutations completely abolished binding compared to the wild type, but expression was confirmed by WB (Figure 2).

[0136] Example 3 - In Narcolepsy 3 Evaluation of H-HOCPCA Binding Levels Mouse brain sections from a narcolepsy mouse model were used using the method described in Example 1 3 Compared to control mice (WT) using H-HOCPCA autoradiography.

[0137] Example 4 - Evaluation of the Spontaneous Motor Activity of Selected Compounds in Mice To determine the spontaneous motor effect (e.g., sedation or hyperactivity), the compound is evaluated after systemic administration to mice. Mice (typically n = 5 - 8) are administered the compound of Formula I and a vehicle control, and the mice are placed in a transparent cage (L: 37 cm × W: 21 cm × H: 15 cm). The spontaneous motor activity is then measured by a camera placed above the activity area. The mice are recorded for approximately 120 minutes, and the data are collected at 5-minute intervals.

[0138] Example 5 - Evaluation of Selected Compounds in the DTA Mouse Model of Narcolepsy Using the DTA narcolepsy mouse model, we have determined the changes in sleep-wake EEG / EMG patterns (including cataplexy episodes) at different time points (1 day to 3 weeks) under the influence of the compound of formula I (Ph-HTBA). After drug withdrawal, the EEG / EMG changes are then further mapped for up to 4 weeks. Under anesthesia with isoflurane (2% - 2.5% in O2), electrodes are inserted into the mouse skull and neck muscles. After a 5 - 10 day recovery, the electrodes are connected to a recording system and the EEG / EMG signals are recorded using synchronized video recording. From the data, sleep / wake parameters and cataplexy episodes are scored and calculated (Figures 4 - 5). The treatment has an overall statistically significant effect in a two-way ANOVA model, p = 0.0017, n = 5 - 6.

[0139] Example 6 - Evaluation of Selected Compounds in a Hypocretin Knockout Mouse Model of Narcolepsy Using the hypocretin knockout mouse model, we determine the changes in sleep-wake EEG / EMG patterns (including cataplexy episodes) at different time points (1 day to 3 weeks) under the influence of the compound of formula I (HOCPCA). After drug withdrawal, the EEG / EMG changes are then further mapped for up to 4 weeks. Under anesthesia with isoflurane (2% - 2.5% in O2), electrodes are inserted into the mouse skull and neck muscles. After a 5 - 10 day recovery, the electrodes are connected to a recording system and the EEG / EMG signals are recorded using synchronized video recording. From the data, sleep / wake parameters and cataplexy episodes are scored and calculated (Figures 4 - 5). The treatment significantly reduces cataplexy on day 8, p = 0.044 and on day 15, p = 0.010 (mixed effects model with post hoc Sidak comparison, Figure 4). The treatment has a two-way ANOVA with post hoc Dunnett comparison, p = 0.01, which further stabilizes wakefulness and significantly reduces medium- to long-term wakefulness episodes in the narcolepsy model.

Claims

1. A pharmaceutical composition for use in the treatment of CNS disorders associated with sleep disorders in a subject, said pharmaceutical composition comprising a compound of formula I 【Chemical 1】 wherein i) R ５ is H, R １ and R ２ form a ring system, and the compound has formula II, 【Chemical Formula 2】 wherein n is 0; X is O; R ３ is H, straight-chain or branched C １ -C ６ -alkyl, -benzyl, polyethylene glycolyl (PEG), [Chemical Formula 3] or 【Chemical Formula 4】 selected from wherein R ９ is selected from linear or branched C1-C6-alkyl, and R １０ is H and linear or branched C １ -C ６ -alkyl; R ４ is H, -C(=O)-C １ -C ６ -alkyl, wherein the alkyl is straight-chain or branched; -C(=O)-benzyl, polyethylene glycolyl (PEG), 【Chemical Formula 5】 or 【Chemical Formula 6】 selected from wherein R １１ is selected from linear or branched C1-C6-alkyl, and R １２ is H and linear or branched C １ -C ６ -alkyl; or ii) R ２ is H, R １ and R ５ form a ring system and the compound has formula III, 【Chemical Formula 7】 wherein n is 0; X is O m is 0 or 1; R ３ is H, linear or branched C １ -C ６ -alkyl, -benzyl, polyethylene glycolyl (PEG), 【Chemical 8】 or 【Chemical Formula 9】 selected from wherein R ９ is selected from linear or branched C1-C6-alkyl, and R １０ is H and linear or branched C １ -C ６ -alkyl; R ４ is H, -C(=O)-C １ -C ６ -alkyl, -C(=O)-benzyl, polyethylene glycolyl (PEG), 【Chemical Formula 10】 or 【Chemical 11】 selected from wherein R １１ is selected from linear or branched C1-C6-alkyl, and R １２ is H and linear or branched C １ -C ６ -alkyl; R １３ and R １４ are each independently selected from H, F, Cl, Br, I, aryl, linear or branched C １－８ alkyl, -CH ２ (CH ２ ) ｐ -aryl, -CH=CH-aryl, NH ２ , NO ２ , OH, SH, linear or branched -O-C １－８ alkyl, linear or branched -S-C １－８ alkyl, linear or branched -NH-C １－８ alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein said aryl may contain one or more heteroatoms selected from O, N or S, and p is 0 or 1; and the alkyl is linear or branched, a compound, or a tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof comprising, wherein the CNS disorder associated with the sleep disorder is central hypersomnia, neurodevelopmental disorder, narcolepsy, or Angelman syndrome. Pharmaceutical composition.

2. The pharmaceutical composition for use according to claim 1, wherein the compound has formula II.

3. R ３ and R ４ Both of which are H, a pharmaceutical composition for use according to any one of claims 1 to 2.

4. The compound is 【Chemical 12】 or a tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof is the pharmaceutical composition for use according to claim 3.

5. The pharmaceutical composition for use according to claim 1, wherein the compound is administered to the subject at a dose of about 0.01 mg / kg to about 100.0 mg / kg.

6. The pharmaceutical composition for use according to claim 1, wherein the CNS disorder associated with the sleep disorder is central hypersomnia or neurodevelopmental disorder.

7. The pharmaceutical composition for use according to claim 1, wherein the CNS disorder associated with the sleep disorder is narcolepsy.

8. The pharmaceutical composition for use according to claim 7, wherein the use reduces at least one of the symptoms of narcolepsy in the subject.

9. The pharmaceutical composition for use according to claim 8, wherein the narcolepsy is narcolepsy with cataplexy (narcolepsy type 1).

10. The pharmaceutical composition for use according to claim 8, wherein the narcolepsy is narcolepsy without cataplexy (narcolepsy type 2).

11. The pharmaceutical composition for use according to claim 8, wherein the narcolepsy is secondary narcolepsy.

12. The pharmaceutical composition for use according to claim 1, wherein the CNS disorder associated with the sleep disorder is Angelman syndrome.

13. The pharmaceutical composition for use according to claim 1, wherein the CNS disorder is caused by a genetic CaMK2 mutation.

14. The use according to claim 1, wherein the use further comprises administration of a CNS stimulant, an antidepressant or a GABA receptor agonist, for a pharmaceutical composition for such use.

15. The pharmaceutical composition for the use according to claim 1, wherein a single dose of the pharmaceutical composition comprises from about 0.1 mg to about 1.0 g of the compound.

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