TREATMENT OF CENTRAL NERVOUS SYSTEM (CNS) DISORDERS WITH SLEEP DISTURBANCES

Abstract

A compound is described for use in the treatment of CNS disorders with sleep disturbances, for example narcolepsy or Angelman syndrome, in an individual, wherein said compound is in accordance with formula (I) or any isomer, tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof.

Description

The present invention relates to the fields of medicine, pharmacologically active compounds, and pharmaceutical compositions comprising such compounds. Specifically, the invention relates to the treatment of central nervous system disorders with cognitive and sleep disturbances. This includes central hypersomnias such as narcolepsy, and neurodevelopmental disorders such as Angelman syndrome. BACKGROUND OF THE INVENTION The regulation of sleep-wake cycles is closely linked to synaptic function and plasticity, and recent findings have suggested that protein phosphorylation and dephosphorylation cycles in neurons are a central molecular mechanism for regulating sleep-wake cycles (Wang et al. Nature 2018, 558:435-439). It is currently unknown whether compounds that target CaMK2a might play a role in stabilizing sleep disturbances or other CNS symptoms in which there is an imbalance of neuronal activation and inhibition. Narcolepsy is a chronic neurological disorder caused by the brain's inability to regulate sleep-wake cycles. This results in fragmented nighttime sleep and excessive daytime sleepiness (EDS). At various times throughout the day, people with narcolepsy experience overwhelming sleep episodes. If the urge becomes overwhelming, they will fall asleep for periods ranging from a few seconds to several minutes, but in rare cases, some may remain asleep for an hour or longer. Narcolepsy is a central hypersomnia. This group of disorders includes idiopathic hypersomnia, recurrent hypersomnia such as Klein-Levin syndrome, and narcolepsy that includes cataplexy (type 1 narcolepsy; narcolepsy-cataplexy syndrome; NRCLP1; narcolepsy with low hypocretin) and narcolepsy without cataplexy (type 2 narcolepsy; narcolepsy with normal hypocretin). All central hypersomnias are characterized by excessive daytime sleepiness (EDS), a persistent background feeling of sleepiness with a tendency to fall asleep intermittently throughout the day, often at inappropriate times. This is known as sleep attacks. This can lead to brain fog, poor concentration, decreased energy, memory lapses, fatigue, and a depressed mood. In addition to EDS, people with narcolepsy experience some or all of the typical symptoms of cataplexy (the sudden loss of voluntary muscle tone), abnormal rapid eye movement (REM) sleep, vivid hallucinations during sleep onset or upon waking, and brief episodes of total paralysis at the beginning or end of sleep (called sleep paralysis). Cataplexy is specific to type 1 narcolepsy, while the other symptoms can occur in both type 1 and type 2 narcolepsy. In a typical sleep cycle, a person enters the early stages of sleep, followed by deeper sleep stages lasting 90 minutes, during which REM sleep finally occurs. For people with narcolepsy, REM sleep occurs within 15 minutes of the sleep cycle and intermittently during waking hours. It is during REM sleep that dreaming and muscle paralysis occur. The hallucinations are vivid, often terrifying sensory hallucinations that occur while falling asleep (hypnagogic hallucinations), which could be caused by the mixture of wakefulness and daydreaming that occurs in REM sleep. Sleep paralysis is a brief inability to move or speak while falling asleep or waking up. These episodes can last from a few seconds to several minutes. After the episode ends, people quickly regain their full ability to move and speak. Automatic behaviors can also occur. A person may momentarily fall asleep but continue performing the previous activity, such as driving, without being aware of it. Cataplexy is a sudden, full-body or partial muscle weakness, such as in the face. Some people experience only mild weakness, such as a dropped head or jaw, while others collapse completely. These episodes are often triggered by strong emotions, such as surprise, laughter, or anger. The weakness is typically temporary, lasting two minutes or less, but can last longer in severe cases. Narcolepsy can range in severity from mild to severe. In severe cases, it can negatively impact social activities, school, work, and overall health and well-being. A person with narcolepsy may fall asleep at any time, often without warning, for example, while talking, standing, or driving. Symptoms tend to appear during adolescence or in the early twenties and thirties. Men and women are equally susceptible, and the prevalence of narcolepsy is approximately 1 in 2,000 individuals. Similar symptoms are also exhibited by individuals with narcolepsy due to a medical condition (NDMC), a group of disorders also known as secondary or symptomatic narcolepsy. Examples of medical conditions that cause narcolepsy symptoms including cataplexy include tumors, ischemic stroke, sarcoidosis, arteriovenous malformations affecting the hypothalamus, multiple sclerosis plaques affecting the hypothalamus, paraneoplastic syndrome with anti-Ma2 antibodies, Neimann-Pick type C disease, or Coffin-Lowry syndrome. Examples of medical conditions that commonly cause narcolepsy symptoms without cataplexy include head trauma, myotonic dystrophy, Prader-Willi syndrome, Parkinson's disease, or multiple system atrophy. GHB is a naturally occurring metabolite of γ-aminobutyric acid (GABA) and a neuromodulator present in micromolar concentrations in the mammalian brain. GHB (sodium oxybate) is used clinically as a prescription drug for narcolepsy and as a recreational drug of abuse (e.g., "Fantasy"). GHB exhibits both low (millimolar) affinity for GABAb receptors and high (nanomolar to micromolar) affinity for a specific protein in neurons, recently identified as CaMK2a (PCT / DK2019 / 050041). Mediated by GABAb receptors, a well-established pharmacological effect of GHB is a reduction in body temperature. In contrast, the neurophysiological and neuropharmacological effects related to the CaMK2a binding site remain unknown. CaMK2a is one of the most abundant proteins in the postsynaptic density. It is a major regulator of synaptic signaling through its phosphorylation of ion channels and neurotransmitter receptors and is intimately involved in synaptic plasticity, a process that occurs in postsynaptic densities, and therefore in higher brain functions such as cognitive processes. Due to its central role in regulating synaptic function, CaMK2a is implicated in most neurological diseases and is a promising, though unexplored, pharmacological target due to the lack of small-molecule brain-penetrating ligands with selectivity for the 2a subtype. GHB is highly effective in treating cataplexy and excessive daytime sleepiness associated with narcolepsy. This effect is widely believed to be due to GHB's effects on GABAb receptors. The effect of GHB on sleep parameters is similar between wild-type mice and mice with suppressed GABAb receptor expression (Vienne et al. J Neurosci 2010, 30:14194-14204), and a study shows that the GABAb receptor agonist baclofen is also effective against narcolepsy symptoms in a mouse model of type 1 narcolepsy (Black et al. J Neurosci 2014, 34:6485-6494). GHB-related compounds may therefore be effective in narcolepsy through their effects on CaMK2a and / or GABAb receptors. This could be via downstream effects on the GABAa receptor. Angelman syndrome is a rare, chronic neurodevelopmental disorder caused by a loss of function in the ubiquitin protein ligase E3A (UBE3A) gene. The disorder affects 1 in 12,000–20,000 people and is present at birth. Angelman syndrome (AS) is characterized by intellectual disability, impaired motor coordination, epilepsy, sleep disturbances, and behavioral abnormalities that include features of autism spectrum disorder (ASD). Wellendorph et al (J Pharmacol Exp Ther 2005, 315:346-351) describe cyclic GHB analogues and their affinities for native binding sites. Krall et al (J Med Chem 2019, 60:9022-9039) describe a study of the structure-affinity relationship for ligands that target the binding sites for the neuroactive compound GHB. Thiesen et al (J Pharmacol Exp Ther 2015, 354:166-174) describe the facilitated brain uptake of 3-hydroxycyclopent-1-encarboxylic acid (HOCPCA) by means of the monocarboxylate transporter 1 (MCT1), and demonstrate that MCT1 is an important brain entry site for this compound. The document PCT / DK2019 / 050041 describes that GHB analogues bind with high affinity to CaMK2a and that compounds that target this kinase are useful for the treatment of brain injuries. Document WO / 2019 / 055369 describes the use of gaboxadol in the treatment of narcolepsy. The GABAa receptor agonist gaboxadol was in clinical development for a range of diseases in the 1980s and 1990s, but patients with a history of substance abuse who received gaboxadol experienced an increase in adverse psychiatric events. There is a need for new, effective, and safe treatment options for central nervous system disorders with sleep disturbances. There is also a need for a new drug to treat central hypersomnias, including narcolepsy, that has no potential for abuse or better pharmacokinetics compared to, for example, sodium oxybate. Furthermore, there is a need for treatment options in neurodevelopmental disorders such as Angelman and Down syndromes, for which there is no targeted treatment and in which cognitive and sleep disturbances are central. Therefore, a specific option for treating sleep disturbances would be relevant for all neurodevelopmental disorders. BRIEF DESCRIPTION OF THE INVENTION The present inventors have found that a wide range of GHB analogues exhibit Ca2+ / calmodulin-dependent protein kinase 2a (CaMK2a) binding, and therefore the compounds of Formula I are promising for the treatment of CNS disorders with sleep disturbances such as central hypersomnias, exemplified by type 1 narcolepsy, and neurodevelopmental disorders involving CaMK2a dysfunction, exemplified by Angelman syndrome. In its first aspect, the present invention provides a compound for use in the treatment of a CNS disorder with sleep disturbances in an individual, wherein said compound is in accordance with formula I (CH2)nCOXR3 / L / nzn / zznz / q / YL (Formula I) wherein when Rs is H, and Ri and R2 form a ring system, then said compound is selected from the following compounds of Formula II or Formula IV (CH2)nCOXR3(Formula II), or R? (Formula IV) / L / nzn / zznz / q / Yi in which n is 0 or 1; X is selected from O or NH Yes NH, O, S, CH2 R3 is selected from H, linear or branched Ci-Ce alkyl including -Me, -Et, -Pr, -iPr, Bu, -tBu, -iBu, pentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or a group such as in which Rg and R10 are independently selected from each other from linear or branched C1-C6 including -Me, -Et, -Pr, -iPr, -Bu, -¡Bu, -tBu, pentyl, neopentyl, hexyl; notably R10 is selected from H, -Me, -Et, -¡Pr; R4 is selected from H, -C(=O)-Ci-Cs alkyl, wherein the alkyl is linear or branched, including -C(=O)-Me, -C(=O)-Et, -C(=O)-Pr, -C(=O)-iPr, -C(=O)-Bu, -C(=O)-tBu; -C(=O)-benzyl, polyethylene glycol (PEG), or a group such as wherein Ru and R12 are independently selected from each other from linear or branched Ci-Ce alkyl including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably R12 is selected from H, -Me, -Et, -iPr; -iBu Rey R7 independently of each other are selected from H, F, Cl, Br, I, aryl, linear or branched C1-8 alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched C1-8 -O-alkyl, linear or branched C1-8 -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1; and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched or when R2 is H, and R1 and Rs form a ring system, then such compound has the formula III / L / nzn / zznz / q / Yi (CH2)nCOXR3 in which n is 0 or 1; X is O or NH m is 0 or 1; R3 is selected from H, linear or branched Ci-Cb alkyl including -Me, -Et, -Pr, -iPr, Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or wherein Rg and Rw are independently selected from each other from linear or branched Ci-Ce alkyl, wherein alkyl is linear or branched including -Me, -Et, -Pr, -iPr, -Bu, -iBu, tBu, pentyl, neopentyl, hexyl; notably R10 is selected from H, -Me, -Et, -iPr; R4 is selected from H, -C(=O)-Ci-Ce alkyl including -C(=O)-Me, -C(=O)-Et, C(=O)-Pr, -C(=O)-iPr, -C(=O)-Bu, -C(=O)-tBu; -C(=O)-benzyl, polyethylene glycolyl (PEG), or a group such as wherein Rn and R12 are independently selected from linear or branched Ci-Ce including -Me, -Et, -Pr, -IPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; R12 is selected from H, -Me, -Et, -iPr; R13 and R14 independently of each other are selected from H, F, Cl, Br, I, aryl, linear or branched C1-8 alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched C1-8 -O-alkyl, linear or branched Ci-b -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1; and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched, or any isomer, tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the compound of formula I has the structure of formula II: / L / nzn / zznz / q / Yi In another embodiment of the invention, the compound of formula I is 3-hydroxycyclopent-1-encarboxylic acid (HOCPCA), such as (RS)-3-hydroxycyclopent-1-encarboxylic acid. In another form, this CNS disorder with sleep disturbances is a central hypersomnia, such as narcolepsy. In another form, this CNS disorder with sleep disturbances is a neurodevelopmental disorder with CaMK2a dysfunction, such as Angelman syndrome. Compounds that target the novel GHB-binding site on CaMK2a have never been suggested as drug candidates for Angelman syndrome or other neurodevelopmental disorders. The inventors demonstrate in this application that the binding site is located in the central organizer domain (hub) of CaMK2a. This contrasts with other known CaMK2a ligands. The inventors also show that the compounds target CaMK2a in the brains of mice with Angelman syndrome. The inventors have surprisingly identified small-molecule compounds that bind directly to and regulate the function of CaMK2a. Compounds conforming to formula I are the first example of compounds that selectively target CaMK2a and are therefore promising for treating central hypersomnias such as narcolepsy and neurodevelopmental disorders with CaMK2a dysfunction, such as Angelman syndrome. This suggests the use of formula I compounds for the treatment of disorders involving 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 to a novel site on the protein, makes this a completely new approach.The proposed uses of the compounds in Formula I are clinically relevant and therefore have useful applications, as there is currently no targeted medical treatment available for patients with Angelman syndrome, including severe sleep disturbances, as improved treatments for central hypersomnia are needed. In a second aspect, the present invention provides pharmaceutical compositions to be used in the treatment of central hypersomnias or neurodevelopmental disorders in an individual, said composition comprising a compound in accordance with formula I. In one embodiment, the pharmaceutical composition has a dosage of said pharmaceutical composition comprising from approximately 0.1 mg to approximately 1.0 g of said compound of formula I. In a third aspect, the present invention provides a method for the treatment of central hypersomnias such as narcolepsy or neurodevelopmental disorders such as Angelman syndrome comprising the administration of an effective amount of a compound of formula I. In a fourth aspect, the present invention provides a method for treating a disease sensitive to CaMK2a modulation, comprising administering an effective amount of a compound of formula I. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Increased de3H-HOCPCA binding levels in brain sections from Ube3a mice (Angelman syndrome), indicating preferred binding to an aberrant form of CaMK2a. Figure 2: 3H-HOCPCA abolished in CaMK2a core domain mutations, showing the location of the binding site. Figure 3: Evaluation of a selected compound in the DTA mouse model of narcolepsy. Figures 4 and 5: Evaluation of a selected compound in the Hcrt-KO mouse narcolepsy model DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention provides a compound to be used in the treatment of CNS disorders with sleep disturbances such as central hypersomnias or neurodevelopmental disorders such as Angelman syndrome in an individual, wherein said compound is in accordance with formula I / L / nzn / zznz / q / Yi (CH2)nCOXR3 (Formula I) wherein when Rs is H, and Ri and R2 form a ring system, then said compound is selected from the following compounds of Formula II or Formula IV (Formula II), or (CH2)nCOXR3 / L / nzn / zznz / q / Yi (Formula IV) in which n is 0 or 1; X is selected from O or NH Yes NH, O, S, CH2 R3 is selected from H, linear or branched Ci-Ce alkyl including -Me, -Et, -Pr, -iPr, Bu, -tBu, -iBu, pentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or a group such as in which Rs and Rw are independently selected from each other from linear or branched Ci-Ce including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably Rw is selected from H, -Me, -Et, -iPr; R4 is selected from H, -C(=O)-alkyl of Ci-Ce, wherein the alkyl is linear or branched, including -C(=O)-Me, -C(=O)-Et, -C(=O)-Pr, -C(=O)-iPr, -C(=O)-Bu, -C(=O)-tBu; -C(=O)-benzyl, polyethylene glycol (PEG), or a group such as wherein Rn and R12 are independently selected from linear or branched C1-C6 alkyl including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably R12 is selected from H, -Me, -Et, -iPr; -iBu Rey R7 independently of each other are selected from H, F, Cl, Br, I, aryl, linear or branched Ci~b alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched Ci~b -O-alkyl, linear or branched Ci-b -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1; and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched or when R2 is H, and R1 and Rs form a ring system, then such compound has the formula III / L / nzn / zznz / q / Yi in which n is 0 or 1; X is O or NH m is 0 or 1; R3 is selected from H, linear or branched Ci-Ce alkyl including -Me, -Et, -Pr, -iPr, Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or a group such as wherein Rg and R10 are independently selected from each other from linear or branched Ci-Cs alkyl, wherein alkyl is linear or branched including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably R10 is selected from H, -Me, -Et, -iPr; R4 is selected from H, -C(=O)-Ci-Ce alkyl including -C(=O)-Me, -C(=O)-Et, C(=O)-Pr, -C(=O)-iPr, -C(=O)-Bu, -C(=O)-tBu; -C(=O)-benzyl, polyethylene glycolyl (PEG), or a group such as wherein Rn and R12 are independently selected from linear or branched Ci-Cb including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; R12 is selected from H, -Me, -Et, -iPr; R13, and R14 independently of each other are selected from H, F, Cl, Br, I, aryl, linear or branched Ci~b alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched Ci~b -O-alkyl, linear or branched Ci-b -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1; and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched, or any isomer, tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof. Within the scope of the present invention are isomers, tautomers, enantiomers, racemic forms, deuterated forms, or mixtures thereof. Therefore, for example, compounds of formula I, which may be present in forms R or S, are all included within the scope of the present invention, as are racemic mixtures. The compound of formula I can be prepared as described in document PCT / DK2019 / 050041. A method for the synthesis of (RS)-3-hydroxycyclopent-1-encarboxylic acid is also described in Wellendorph et al. J. Pharmacol. Exp. Therap. 2005, 315:346-351. Based on radioligand binding studies, it has now been found that compounds of formula I bind to a novel site on CaMK2a. The inventors have identified CaMK2a as the specific high-affinity target for the small molecule GHB and its analogues, which have a structure like that of Formula I. Further studies, as exemplified in this application, have shown that GHB analogues bind to a unique site on CaMK2a, more precisely the central domain, and thus represent the first small-molecule compounds with selectivity for this very important brain kinase. CaMK2a is involved in important brain processes such as synaptic plasticity, learning, and memory, and its tight regulation is crucial for normal intellectual development. Because the kinase is calcium-dependent, it is also centrally involved in calcium dysregulation disorders such as epilepsy, sleep disorders, and ischemia.From a mechanistic point of view, CaMK2a is regulated by its own phosphorylation (autophosphorylation), and both mouse models and patients with mutations at these sites exhibit various deficits in learning and memory, have seizures and poor sleep regulation (Elgersma et al., Neuron 2002, 36:493-505; Küry et al. Am. J. Human Genetics 2017,101:768-788). It has never been suggested that CaMK2a is involved in narcolepsy, but the inventors have shown that the compounds in Formula I that target CaMK2a are highly effective in treating the symptoms of narcolepsy. Chemical analysis of a mouse model of AS has shown that CaMK2 activity is reduced, and specifically, that autophosphorylation of the inhibitory sites Thr305 and Thr306 of CaMK2a is increased, leading to decreased long-term potentiation (LTP), a hippocampal cellular process correlated with learning and memory / cognition. Consequently, deficits in motor function, seizures, learning disability, and LTP in AS mice have been found to be rescued by crossing Ube3a mice with mice harboring a T305V / 306A mutation, thereby alleviating the increased level of inhibitory phosphorylation (van Woerden et al. Nature Neurosci 2007, 10, 280-282).The inventors have shown that the binding of the compounds in formula I is increased in the hippocampus of mice with Angelman syndrome, suggesting that the compounds in formula I are effective in treating the symptoms of Angelman syndrome. Similarly, increased phosphorylation levels of CaMK2a have been reported in mouse models of Down syndrome, another chronic human neurodevelopmental disorder in which intellectual disability is the primary phenotype. These mice exhibit learning and behavioral deficits, including sleep disturbances (Siarey et al., J Neurochem. 98:1266-1277). CaMK2a dysfunction may also be part of the pathology in other neurodevelopmental disorders characterized by one or more of the following symptoms: learning and behavioral deficits, seizure predisposition, and sleep disturbances. These disorders include fragile X, neurofibromatosis type 1, cri-du-chat syndromes, succinic semialdehyde dehydrogenase (SSADH) deficiency in which GHB levels are abnormal, and Rett syndrome in which CaMK2 dysfunction has also been proposed (Shioda et al., Int J Mol Sci 2018, 19, 20; doi:10.3390 / ijms19010020). Compounds that target the novel GHB binding site on CaMK2a have never been suggested as drug candidates for Angelman syndrome or other neurodevelopmental disorders. The inventors in this application demonstrate that the binding site is located in the central organizer (center) domain of CaMK2a. The inventors suggest that the compounds may be appropriate for treating cognitive and / or sleep-related symptoms involving CaMK2a in Angelman syndrome. For this reason, the compounds in the formulation that target CaMK2a are suggested drug candidates for treating symptoms of Angelman syndrome and potentially other neurodevelopmental disorders with CaMK2a dysfunction. Definitions Autophosphorylation The term “autophosphorylation” as used in this application refers to the phosphorylation of CaMK2a at residue Thr286, Thr305 or Thr306. CaMK2a The term “CaMK2a” as used in this application refers to the Ca27calmodulin-dependent type 2 alpha protein kinase. Cataplexy The term “cataplexy” is a sudden, transient episode of muscle weakness accompanied by full awareness, typically triggered by emotions such as laughter, crying, or terror. Central hypersomnia Disorders of excessive daytime sleepiness related to the central nervous system, that is, the brain. Such disorders share the predominant symptom of daytime sleepiness. There are several types of central hypersomnias, including idiopathic hypersomnia, recurrent hypersomnia such as Klein-Levin syndrome, and narcolepsy. In one formulation, the compounds in Formula I are considered to have beneficial effects in preventing and / or relieving central hypersomnias and cataplexy. Central hypersomnias include idiopathic hypersomnia, recurrent hypersomnia such as Klein-Levin syndrome, and narcolepsy, including cataplexy (type 1 narcolepsy; narcolepsy-cataplexy syndrome; NRCLP1; narcolepsy with low hypocretin) and narcolepsy without cataplexy (type 2 narcolepsy; narcolepsy with normal hypocretin). Type 1 and Type 2 narcolepsy are sleep disorders characterized by excessive daytime sleepiness, and Type 1 narcolepsy is further characterized by cataplexy. Cataplexy is characterized by a sudden loss of muscle tone. The duration of cataplexy is usually short, ranging from a few seconds to several minutes, and recovery is immediate and complete. The loss of muscle tone varies in severity, from a mild feeling of weakness with head drooping, facial slumping, jaw drop, slurred speech, and buckling knees, to complete postural collapse with a fall to the ground. Cataplexy is usually triggered by an emotion that typically has a pleasurable or exciting component, such as laughter, euphoria, pride, anger, or surprise. Aside from excessive daytime sleepiness and cataplexy (in type 1 narcolepsy), individuals with narcolepsy often experience symptoms such as sleep fragmentation, abnormal rapid eye movement sleep, disrupted nighttime sleep, sleep paralysis during sleep onset or awakening, and / or hypnagogic hallucinations. Similar symptoms are also seen in individuals with narcolepsy due to a medical condition (NDMC), a group of disorders also known as secondary or symptomatic narcolepsy. Examples of medical conditions that cause narcolepsy symptoms, including cataplexy, include tumors, ischemic stroke, sarcoidosis, arteriovenous malformations affecting the hypothalamus, multiple sclerosis plaques affecting the hypothalamus, paraneoplastic syndrome associated with anti-Ma2 antibodies, Neimann-Pick type C disease, and Coffin-Lowry syndrome. Examples of medical conditions that commonly cause narcolepsy symptoms without cataplexy include head trauma, myotonic dystrophy, Prader-Willi syndrome, Parkinson's disease, and multiple system atrophy. Cataplexy is a hallmark of narcolepsy but can also be associated with specific lesions located primarily in the lateral and posterior hypothalamus, such as tumors (astrocytoma, glioblastoma, glioma, craniopharyngioma, and subependinoma) and arteriovenous malformations. Conditions in which cataplexy may be observed include ischemic events, multiple sclerosis, head injury, paraneoplastic syndromes, and infections, such as encephalitis. Cataplexy can occur transiently or permanently due to hypothalamic lesions resulting from surgery, especially difficult tumor resections. In childhood, cataplexy may be observed in association with other neurological syndromes, such as Niemann-Pick type C disease. / L / nzn / zznz / q / Yi GHB Analogues The term “GHB analogue” as used in this application refers to compounds that share a common GHB-related structure and bind to a unique site on CaMK2a. Neurodevelopmental disorders involving CaMK2a dysfunction This term refers to human diseases, mostly of genetic origin, in which there is a dysfunctional component of CaMK2a. These disorders share common symptoms of learning and behavioral deficits, an increased propensity for seizures, and sleep disturbances. This definition includes CaMK2a mutations that cause disease, Angelman syndrome, Down syndrome, Fragile X syndrome, neurofibromatosis type 1, cri-du-chat syndromes, SSADH deficiency, and Rett syndrome. Pharmaceutical compositions comprising a compound 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 vehicles. The compound of the invention or a formulation thereof may be administered by any conventional method, including, but not limited to, parenteral, oral, or topical (including buccal, sublingual, or transdermal) administration, administration via a medical device (e.g., a stent), inhalation, or injection (subcutaneous or intramuscular). Treatment may consist of a single dose or multiple doses administered over a period of time. Treatment may be administered once daily, twice daily, three times daily, four times daily, etc. Treatment may also be administered continuously, such as intravenously by drip infusion. Although the compound of the invention may be administered alone, it is preferable to present it as a pharmaceutical formulation, together with one or more acceptable carriers. The carrier(s) must be “acceptable” in the sense that they are compatible with the compound of the invention and not harmful to its recipients. Examples of suitable carriers are described in more detail later. The formulations may be conveniently presented in unit-dose form and may be prepared by any of the well-known methods in the art of pharmacy. Such methods include the step of combining the active ingredient (compound of the invention) with the vehicle, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately combining the active ingredient with liquid vehicles or finely divided solid vehicles, or both, and then, if necessary, shaping the product. The compound of the invention is normally administered intravenously, orally, or by any parenteral route, in the form of a pharmaceutical formulation comprising the active ingredient, optionally in the form of an added salt of an acid or base, non-toxic organic or inorganic, in a pharmaceutically acceptable dosage form. Depending on the disorder and the patient being treated, as well as the route of administration, the compositions may be administered in varying doses. / L / nzn / zznz / q / Yi Pharmaceutical compositions must be stable under manufacturing and storage conditions; therefore, they should preferably be protected against contamination by microorganisms such as bacteria and fungi. The vehicle may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and appropriate mixtures thereof. For example, the compound of the invention can also be administered orally, buccally, or sublingually in the form of tablets, capsules, ovules, elixirs, solutions, or suspensions, which may contain flavoring or coloring agents, for immediate, delayed, or controlled release applications. The formulations according to the present invention suitable for oral administration may be presented as discrete units such as capsules, wafers, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous 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 presented as a bolus, electuary, or paste. Solutions or suspensions of the compound of the invention suitable for oral administration may also contain excipients, for example, N,N-dimethylacetamide; dispersants, for example, polysorbate 80; surfactants; and solubilizers, for example, polyethylene glycol, Phosal 50 PG (which consists of phosphatidylcholine, soybean fatty acids, ethanol, mono / diglycerides, propylene glycol, and ascorbyl palmitate). Formulations according to the present invention may also be in the form of emulsions, in which a compound according to Formula I is present in an aqueous-oil emulsion. The oil may be any oil-like substance, such as, for example, soybean oil or safflower oil, a medium-chain triglyceride (MCT oil), such as, for example, coconut oil, palm oil, etc., or combinations thereof. 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 cassava starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), macrogol 8000, sucrose, gelatin, and acacia. Lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate, and talc may also be included. A tablet can be manufactured by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethylcellulose), surfactant, or dispersing agent. Molded tablets can be manufactured by molding a mixture of the compound in powder form moistened with an inert liquid diluent in a suitable machine.The tablets may be optionally coated or scored and can be formulated to provide slow or controlled release of the active ingredient using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Solid compositions of a similar type can also be used as fillings in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the compounds of the invention can be combined with various sweetening or flavoring agents, coloring materials or colorants, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof. Appropriate formulations for topical administration in the mouth include medicated lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouth rinses comprising the active ingredient in an appropriate liquid vehicle. Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols, or oils, transdermal devices, medicated powders for external use, and the like. These compositions may be prepared using conventional methods containing the active agent. Therefore, they may also include compatible conventional vehicles and additives, such as preservatives, solvents to aid drug penetration, emollients in creams or ointments, and ethanol or oleyl alcohol for lotions. Such vehicles may be present from approximately 1% to approximately 98% of the composition. More commonly, they will constitute up to approximately 80% of the composition.As an illustration only, a cream or ointment is prepared by mixing sufficient quantities of hydrophilic material and water, containing approximately 5-10% by weight of the compound, in sufficient quantities to produce a cream or ointment having the desired consistency. Pharmaceutical compositions adapted for transdermal administration can be presented as discreet patches intended to remain in close contact with the recipient's epidermis for an extended period. For example, the active ingredient can be delivered from the patch via iontophoresis. For external tissue applications, such as to the mouth and skin, the preferred compositions are applied as a topical ointment or cream. When formulated as an ointment, the active agent may be used with either a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active agent can be formulated in a cream with an oil-in-water cream base or a water-in-oil base. For parenteral administration, fluid unit-dose forms are prepared using the active ingredient and a sterile vehicle, for example, but not limited to, water, alcohols, polyols, glycerin, and vegetable oils, with water being preferred. Depending on the vehicle and concentration used, the active ingredient may be in colloidal form, suspended, or dissolved in the vehicle. In the preparation of solutions, the active ingredient may be dissolved in water for injection and sterilized by filtration before being used to fill and seal an appropriate vial or ampoule. Conveniently, agents such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle. To increase stability, the composition can be frozen after use to fill the vial, and the water is then vacuum-sealed. The lyophilized powder is then sealed in the vial, and an accompanying vial of water for injection can be supplied for reconstitution of the liquid before use. The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. The compositions may also be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and effectively fluid for ease of administration with a syringe. Parenteral suspensions are prepared substantially the same way as solutions, except that the active ingredient is suspended in the vehicle rather than dissolved, and sterilization cannot be achieved by filtration. The active ingredient may be sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. Conveniently, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient. It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of this invention may include other conventional agents in the art, taking into consideration the type of formulation in question; for example, those suitable for oral administration may include flavoring agents. A person skilled in the art will know how to select an appropriate formulation and how to prepare it (see, for example, Remington's Pharmaceutical Sciences 18th Ed. or later). A person skilled in the art will also know how to select an appropriate route of administration and dosage. A person skilled in the art will recognize that the optimum quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and severity of the condition being treated, the form, route, and site of administration, and the age and condition of the individual being treated, and that a physician will ultimately determine the appropriate dosages to be used. This dosage may be repeated as frequently as appropriate. If side effects develop, the quantity and / or frequency of dosage may be altered or reduced in accordance with normal clinical practice. All % values ​​mentioned in this application are % p / p unless the context requires otherwise. The following embodiments illustrate the present invention: 1. A compound to be used in the treatment of a CNS disorder with sleep disturbances in an individual, wherein said compound is in accordance with the formula I / L / nzn / zznz / q / Yi (CH2)nCOXR3 / L / nzn / zznz / q / viAi wherein when Rs is H, and Ri and R2 form a ring system, then said compound is selected from the following compounds of formula II or formula IV (Formula IV) in which n is 0 or 1; X is selected from O or NH Yes NH, O, S, CH2 R3 is selected from H, linear or branched Ci-Ce alkyl including -Me, -Et, -Pr, -iPr, Bu, -tBu, -iBu, pentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or a group such as in which Rg and Rw are independently selected from each other from linear or branched Ci-Cb including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably Rw is selected from H, -Me, -Et, -iPr; R4 is selected from H, -C(=O)-alkyl of Ci-Cb, wherein the alkyl is linear or branched, including -C(=O)-Me, -C(=O)-Et, -C(=O)-Pr, -C(=O)-iPr, -C(=O)-Bu, -C(=O)-tBu; -C(=O)-benzyl, polyethylene glycol (PEG), or a group such as / L / nzn / zznz / q / Yi wherein Ru and R12 are independently selected from each other from linear or branched Ci-Cs alkyl including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably R12 is selected from H, -Me, -Et, -iPr; -iBu Rey R? independently of each other are selected from H, F, Cl, Br, I, aryl, linear or branched C1-8 alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched C1-8 -O-alkyl, linear or branched C1-8 -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1; and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched or when R2 is h, and R1 and Rs form a ring system, then such compound has formula III (Formula III) in which n is 0 or 1; X is O or NH m is 0 or 1; R3 is selected from H, linear or branched Ci-Cs alkyl including -Me, -Et, -Pr, -iPr, Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or a group such as wherein Rg and Rio independently of each other are selected from linear or branched Ci-C6 alkyl, wherein alkyl is linear or branched including -Me, -Et, -Pr, -iPr, -Bu, -iBu, tBu, pentyl, neopentyl, hexyl; notably Rw is selected from H, -Me, -Et, -iPr; R4 is selected from H, -C(=O)-C1-C6 alkyl including -C(=O)-Me, -C(=O)-Et, C(=O)-Pr, -C(=O)-iPr, -C(=O)-Bu, -C(=O)-tBu; -C(=O)-benzyl, polyethylene glycolyl (PEG), or a group such as / L / nzn / zznz / q / Yi in which Rn and R12 are independently selected from each other from linear or branched Ci-Cs including -Me, -Et, -Pr, -iPr, -Bu, -¡Bu, -tBu, pentyl, neopentyl, hexyl; R12 is selected from H, -Me, -Et, -iPr; R13 and Ru independently of each other are selected from H, F, Cl, Br, I, indigo, linear or branched Ci-b alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched C1-8 -O-alkyl, linear or branched C1-8 -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1; and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched, or any isomer, tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof. 2. A compound in accordance with modality 1 having formula II. 3. A compound in accordance with modality 1 having formula II or III, and in which n is 0. 4. The compound in accordance with any of the preceding forms, wherein both R3 and R4 are H. 5. The compound in accordance with any of the preceding modalities that is selected from or a pharmaceutically acceptable salt thereof, wherein R' is COOH, R” is H and R'' is OCH3, or wherein R' is COOH, R” is CH3 and R'' is OH. 6. The compound in accordance with any of the preceding methods, which is selected from / L / nzn / zznz / q / Yi or a pharmaceutically acceptable salt thereof. 7. The compound in accordance with modality 6, which is COOH or a pharmaceutically acceptable salt thereof. 8. The compound in accordance with modality 7, which is the sodium salt or the potassium salt. 9. The compound in accordance with any of the options 1 to 8, which is in a crystalline state. 10. The compound in accordance with any of the options 1 to 9, wherein said compound is to be administered to said individual at a dose of approximately 0.01 mg / kg up to approximately 100 mg / kg. 11. The compound in accordance with any of the preceding forms, wherein said compound is to be administered to said individual in a dose of approximately 0.1 mg / kg up to approximately 10 mg / kg. 12. The compound in accordance with any of the preceding modalities, wherein approximately 0.1 mg to approximately 1.0 g of said compound is to be administered to said individual. 13. The compound in accordance with modality 12, wherein said individual is to be administered approximately 1 mg up to approximately 1000 mg of said compound. 14. The compound in accordance with any of the preceding modalities, wherein said CNS disorder with sleep disturbances is a central hypersomnia. 15. The composite in accordance with modality 14, wherein said central hypersomnia is selected from the group consisting of idiopathic hypersomnia, recurrent hypersomnia, Klein-Levin syndrome, and narcolepsy. 16. The compound in accordance with any of the preceding modalities, wherein said CNS disorder with sleep disturbances is narcolepsy. 17. The compound in accordance with any of the preceding modalities, in which the use reduces at least one of the symptoms of narcolepsy in said individual. 18. The compound in accordance with modality 17, wherein said symptoms are selected from excessive daytime sleepiness, cataplexy, abnormal REM sleep, sleep paralysis, or nighttime wakefulness. 19. The compound in accordance with any of the preceding modalities, wherein said narcolepsy treatment is the treatment of narcolepsy with cataplexy (type 1 narcolepsy). 20. The compound in accordance with any of modalities 1 to 18, wherein said narcolepsy treatment is the treatment of narcolepsy without cataplexy (type 2 narcolepsy). 21. The compound in accordance with any of modalities 1 to 18, wherein said narcolepsy treatment is the treatment of secondary narcolepsy. 22. The compound in accordance with any of modalities 1 to 13, wherein said CNS disorder is a neurodevelopmental disorder. 23. The compound in accordance with any of modalities 1 to 13, wherein said CNS disorder is caused by a genetic mutation of CaMK2. 24. The compound in accordance with any of modalities 1 to 13, wherein said CNS disorder is Angelman syndrome or Down syndrome. 25. The compound in accordance with any of the preceding modalities, wherein the use also includes the administration of a CNS stimulant, an antidepressant, or a GABA receptor agonist. 26. The compound according to modality 25, wherein said CNS stimulant is selected from the group consisting of modafinil, armodafinil, methylphenidate, amphetamine, dextroamphetamine, methamphetamine, phentermine, phendimetrazine, diethylpropion, lisdexamfetamine, benzphetamine, atomoxetine, caffeine, and ephedrine. 27. The compound according to modality 25, wherein said 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 specific norepinephrine and serotonergic antidepressants (NASSAs). 28. The compound according to modality 25, wherein said GABA receptor agonist is selected from the group consisting of sodium oxybate, baclofen, phenibut, and gaboxadol. 29. A pharmaceutical composition for use in the treatment of a CNS disorder with sleep disturbances in an individual, comprising a compound in accordance with any of modalities 1 to 29. 30. The pharmaceutical composition in accordance with modality 29, in which said CNS disorder with sleep disturbances is a central hypersomnia. 31. The pharmaceutical composition in accordance with modality 30, in which said central hypersomnia is narcolepsy. / L / nzn / zznz / q / YL 32. The pharmaceutical composition in accordance with modality 29, in which said CNS disorder with sleep disturbances is a neurodevelopmental disorder. 33. The pharmaceutical composition in accordance with modality 32, wherein said neurodevelopmental disorder is Angelman syndrome or Down syndrome or is caused by genetic mutations of CaMK2. 34. The pharmaceutical composition in accordance with any of the forms 28-33, wherein a dosage of said pharmaceutical composition comprises from approximately 0.1 mg to approximately 5.0 g of said compound. 35. The pharmaceutical composition in accordance with modality 34, wherein a dosage of said pharmaceutical composition comprises from approximately 10 mg to approximately 1.0 g of said compound. 36. The pharmaceutical composition in accordance with modality 34, wherein a dosage of said pharmaceutical composition comprises from approximately 50 mg to approximately 500 mg of said compound. 37. The pharmaceutical composition in accordance with modality 34, wherein a dosage of said pharmaceutical composition comprises from approximately 250 mg to approximately 5.0 g of said compound. 38. The pharmaceutical composition in accordance with modality 34, wherein a dosage of said pharmaceutical composition comprises from approximately 0.5 mg to approximately 50 mg of said compound. 39. A method for treating a CNS disorder with sleep disturbances, comprising administering an effective amount of a compound as defined in any of modalities 1 to 28. 40. The method in accordance with modality 39, in which said CNS disorder with sleep disturbances is a central hypersomnia. 41. The method in accordance with modality 40, in which said central hypersomnia is narcolepsy. 42. The method in accordance with any of the modalities 40 to 41, wherein said central hypersomnia is selected from the group consisting of type 1 narcolepsy, type 2 narcolepsy, and secondary narcolepsy. 43. The method in accordance with modality 39, in which said CNS disorder with sleep disturbances is a neurodevelopmental disorder. 44. The method in accordance with modality 43, in which said neurodevelopmental disorder is Angelman syndrome or Down syndrome. 45. The method in accordance with any of modalities 39 to 44, wherein the method also comprises the administration of a CNS stimulant, an antidepressant, a GABAa receptor agonist or a GABAb receptor agonist. 46. ​​The method in accordance with modality 45, wherein said CNS stimulant is selected from the group consisting of modafinil, armodafinil, methylphenidate, amphetamine, dextroamphetamine, methamphetamine, phentermine, phendimetrazine, diethylpropion, lisdexamfetamine, benzphetamine, atomoxetine, caffeine, and ephedrine. 47. The method in accordance with modality 45, wherein said 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 specific norepinephrine and serotonergic antidepressants (NASSAs). 48. The method in accordance with modality 45, wherein said GABAb receptor agonist is selected from the group consisting of sodium oxybate, baclofen, and phenibut. 49. The method in accordance with modality 45, wherein said GABAa receptor agonist is gaboxadol. 50. A method for treating a disease sensitive to CaMK2a modulation, comprising administering an effective amount of a compound as defined in any of modalities 1 to 28. EXAMPLES Materials and methods 3H-HOCPCA autoradiography of the mouse brain In accordance with previously published protocols, mouse brains from either Ube3am7p+ or wild-type (WT) mice were dissected, sectioned in a cryostat, mounted on glass slides, and autoradiography was performed with 3H-HOCPCA as described (Griem-Krey et al. 2019, J Vis Exp Ther, 145:e58879). The binding protocol was performed using 1 nM of internally prepared 3H-HOCPCA radioligand (Vogensen et al., 2013, J Med Chem 56:8201-8205) and 1 mM of GHB for nonspecific binding. The buffer solution was 50 mM potassium phosphate, pH 6.0. The washed and dried sections are exposed to a phosphor plate for imaging (Science Imaging Scandinavia AB, Nacka, Sweden) for 3 days along with a 3H microscale to convert to tissue equivalents (TE). The imaging plate is scanned on a CR35 Bio-scanner (Dürr Medical).Subsequently, densitometric analysis was performed using Image J (NIH) and the data (nmol / mg of TE) were further analyzed using GraphPad Prism 7, GraphPad Prism Software, San Diego, CA, USA 3H-HOCPCA binding to recombinant CaMK2a expressed in HEK293T cells HEK293T cells are cultured under standard conditions using Dulbecco's modified Eagle medium with 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 using point mutations is performed by GenScript USA Inc. Cells are transfected with wild-type or mutated CMYC-labeled rat CaMK2a (Origine construct RR201121) using linear polyethylene, MW 25,000 (Polysciences Inc., Warrington, PA, USA). Whole-cell homogenates are prepared 48 hours post-transfection by washing cells with iced 1x PBS and collecting by scraping. The cells are collected and centrifuged for 10 minutes at 1000 x g.Cell tablets are resuspended in ice-cold 1x PBS and homogenized using 2 x 1 mm zirconium globules in a bullet blender for 20 seconds at maximum speed (NextAdvance, NY, USA). The homogenates are clarified by centrifugation (10 minutes, 4 °C, 14,000 x 25 g). Protein concentration is determined using the Bradford protein assay. 150–200 pg of protein are incubated with 5 nM 3H-HOCPCA (Vogensen et al., 2013, J Med Chem 56:8201–8205) and the test compound in 1 mL of total volume for 1 hour at 0–4 °C. Non-specific binding is determined with 1–10 mM GHB. The proteins are then precipitated by adding ice-cold acetone (4x the test volume), subjecting the mixture to swirling action, and incubating at -20 °C for 1 hour. The proteins are then rapidly filtered through GF / C unifilters (Whatman) and washed using a 48-cavity collector.Dry filters are treated with scintillation fluid, and radioactivity is measured using a Tricaré 2100 scintillation counter (Packard). Data analysis is performed using GraphPad Prism 7, GraphPad Prism Software, San Diego, CA, USA. Total CaMK2a expression levels are assessed by Western blot (WB) with anti-myc-Alexa488 (MA1980-A488, ThermoFisher Scientific). EXAMPLE 1 The CaMK2a3H-HOCPCA specific radioligand shows increased binding to brains with Angelman syndrome Brain sections from mice with Angelman syndrome (Ube3am7p+, HET) were compared with those from control mice (WT) using 3H-HOCPCA autoradiography. The observed difference was most pronounced in the hippocampus, where CaMK2a was highly expressed. The data suggest that GHB-related compounds may have effects on Angelman syndrome by binding to the form of CaMK2a that accumulates in this disorder (Figure 1). EXAMPLE 2 The 3H-HOCPCA binding site is confined to the cavity of the CaMK2a core domain as shown by mutagenesis analysis CaMK2a constructs with the specific mutations Arg433Gln, Arg453Gln, and Arg469Cys, Arg469Gln, or the triple mutant or a construct with the central domain deleted (delta hub), are expressed in HEK cells, and whole-cell homogenates are exposed to an internal filtration 3H-HOCPCA binding assay. Compared to the wild type, each of the three mutations completely abolishes binding, although expression is confirmed by WB (Figure 2). EXAMPLE 3 Evaluation of 3H-HOCPCA binding levels in narcolepsy Cuts in sections of mouse brain from a mouse narcolepsy model with control (WT) mice are compared using 3H-HOCPCA autoradiography using the methods as described in Example 1. EXAMPLE 4 Evaluation of the locomotor activity of selected compounds in mice To determine locomotor effects (e.g., sedation or hyperactivity), the compounds are evaluated after systemic administration to mice. Mice (typically n=5-8) are administered a compound from Formula I and vehicle controls and placed in transparent cages / L / nzn / zznz / q / Yi (Length: 37 cm x Width: 21 cm x Height: 15 cm). Locomotor activity is then measured using a camera mounted above the cage. The mice are recorded for approximately 120 minutes, and data are collected at 5-minute intervals. EXAMPLE 5 Evaluation of selected compounds in the DTA mouse model of narcolepsy Using the DTA mouse model of narcolepsy, changes in EEG / EMG sleep-wake patterns (including cataplexy) were determined at different time points (1 day to 3 weeks) under the influence of a compound from Formula I (Ph-HTBA). After discontinuation of the drug, EEG / EMG changes were further mapped for up to 4 weeks. Under isoflurane anesthesia (2% to 2.5% in O2), electrodes were placed on the skull and neck muscles of the mice. After 5–10 days of recovery, the electrodes were connected to a recording system, and the EEG / EMG signals were recorded with synchronized video recordings. From the data, sleep-wake parameters and cataplexy episodes were scored and calculated (Figures 4 and 5). The treatment has an overall statistically significant effect in a two-way ANADEVA model, p=0.0017, n=5-6. EXAMPLE 6 Evaluation of selected compounds in a mouse model of narcolepsy with suppressed hypocretin expression Using the hypocretin-suppressed mouse model, changes in sleep-wake EEG / EMG patterns (including cataplexy) were determined at different time points (1 day to 3 weeks) under the influence of a compound (HOCPCA) from Formula I. After discontinuation of the drug, EEG / EMG changes were further mapped for up to 4 weeks. Under isoflurane anesthesia (2% to 2.5% in O2), electrodes were placed on the skull and neck muscles of the mice. After 5–10 days of recovery, the electrodes were connected to a recording system, and the EEG / EMG signals were recorded with synchronized video recordings. From the data, sleep-wake parameters and cataplexy episodes were scored and calculated (Figures 4 and 5). The treatment significantly reduces cataplexy on day 8, p = 0.044 and on day 15 p = 0.010 (Sidak mixed effects model with post hoc comparisons, Figure 4).The treatment further stabilizes wakefulness with a significant decrease in medium-long wakefulness episodes in the narcolepsy model p=0.01, two-way ANADEVA with Dunnett's post hoc comparison.

Claims

1. A compound for use in the treatment of a central nervous system (CNS) disorder with sleep disturbances in an individual, wherein said compound is according to formula I (CH2)nCQXR3 where when Rs is H, and Ri and R2 form a ring system, then said compound is selected from the following compounds of formula II or formula IV (formula IV) where n is 0 or 1; X is selected from O or NH; Yes NH, O, S, CH2; R3 is selected from H, linear or branched Ci-Ce alkyl including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or a group such as wherein R9 and Rw are independently selected from each other from linear or branched Ci-Cb including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably Rw is selected from H, -Me, -Et, -iPr;R4 is selected from H, -C(=O)-Ci-Ce alkyl, wherein the alkyl is linear or branched, including -C(=O)-Me, -C(=O)-Et, -C(=O)-Pr, -C(=O)-iPr, -C(=O)-Bu, -C(=O)-tBu; -C(=O)-benzyl, polyethylene glycol (PEG), or a group such as / L / nzn / zznz / q / Yi R:1 wherein Rn and R12 are independently selected from linear or branched Ci-Ce alkyl, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably R12 is selected from H, -Me, -Et, -iPr; -iBu Re and R? independently of each other are selected from H, F, Cl, Br, I, aryl, linear or branched C1-s alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched C1-8 -O-alkyl, linear or branched C1-8 -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1;and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched or when R2 is H, and R1 and Rs form a ring system, then such compound has formula III where n is 0 or 1; X is O or NH; m is 0 or 1; R3 is selected from H, linear or branched Ci-Ce alkyl including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl, branched hexyl, -benzyl, polyethylene glycol (PEG), or a group such as wherein R9 and R10 are independently selected from each other from linear or branched Ci-Ce alkyl, wherein alkyl is linear or branched including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, hexyl; notably Rw is selected from H, -Me, -Et, -iPr; R4 is selected from H, -C(=0)-Ci-Cb alkyl including -C(=O)-Me, -C(=O)-Et, C(=O)-Pr, -C(=O)-¡Pr, -C(=O)-Bu, -C(=O)-tBu;-C(=O)-benzyl, polyethylene glycol (PEG), or a group such as / L / nzn / zznz / q / Yi wherein Rn and R12 are independently selected from linear or branched Ci-Cb including -Me, -Et, -Pr, -IPr, -Bu, -¡Bu, -tBu, pentyl, neopentyl, hexyl; R12 is selected from H, -Me, -Et, -¡Pr; R13, and R14 independently of each other are selected from H, F, Cl, Br, I, aryl, linear or branched C1-8 alkyl, -CH2(CH2)P-aryl, -CH=CH-aryl, NH2, NO2, OH, SH, linear or branched C1-8 -O-alkyl, linear or branched C1-8 -S-alkyl, linear or branched C1-8 -NH-alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein aryl includes aryl having one or more heteroatoms selected from O, N or S, and wherein p is 0 or 1;and C1-8 alkyl includes Me, Et, Pr, Bu, pentyl, hexyl, heptyl, octyl - alkyl is linear or branched, or any isomer, tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof.; 2. The compound to be used according to claim 1, wherein the compound is of formula II.

3. The compound to be used according to any of the preceding claims, wherein both R3 and R4 are H.

4. The compound to be used according to claim 3, wherein it is COOH or any isomer, tautomer, enantiomer, racemic form or deuterated form thereof, or a pharmaceutically acceptable salt thereof.

5. The compound for use according to any of the preceding claims, wherein said compound is adapted to be administered to said individual in a dose of 0.01 mg / kg up to 100.0 mg / kg.

6. The compound for use according to any of the preceding claims, wherein said CNS disorder with sleep disturbances is a central hypersomnia or a neurodevelopmental disorder.

7. The compound for use according to any of claims 1 to 5, wherein said CNS disorder with sleep disturbances is narcolepsy.

8. The compound for use according to claim 7, wherein the use reduces at least one of the symptoms of narcolepsy in said individual.

9. The compound for use according to any of claims 1 to 5, wherein said CNS disorder with sleep disturbances is Angelman syndrome.

10. The compound for use according to any of the preceding claims, wherein the use further comprises a CNS stimulant, an antidepressant, or a GABA receptor agonist adapted for administration.

11. A pharmaceutical composition for use in the treatment of CNS hypersomnia disorder with sleep disturbances in an individual, comprising the compound as defined in any one of claims 1 to 10.

12. The pharmaceutical composition for use according to claim 11, wherein a dosage of said pharmaceutical composition comprises from 0.1 mg to 1.0 g of said compound.

13. Use of the compound as defined in any of claims 1 to 10, for preparing a medicament for treating a CNS disorder with sleep disturbances, wherein the compound is adapted to be administered in an effective amount.

14. Use according to claim 13, wherein said CNS disorder with sleep disturbances is narcolepsy or Angelman syndrome.

15. Use of a compound as defined in any of claims 1 to 10, for preparing a medicament for treating a disease sensitive to CaMK2a modulation, wherein the compound is adapted to be administered in an effective amount.