Treatment of CNS disorders with sleep disturbances

Abstract

A compound for use in treating a CNS disorder (e.g., narcolepsy or Angelman syndrome) with sleep disturbances in a subject, wherein the compound is according to Formula I or any isomer, tautomer, enantiomer, racemic form, or deuterated form thereof, or a pharmaceutically acceptable salt thereof.

Description

Invention Field

[0001] This invention relates to the field of pharmaceuticals, pharmacologically active compounds, and pharmaceutical compositions comprising such compounds. Specifically, this invention relates to the treatment of CNS disorders accompanied by cognitive and sleep disturbances. This includes central hypersomnias (such as narcolepsy) and neurodevelopmental disorders (such as Angelman syndrome).

[0002] background

[0003] Sleep-wake regulation is closely related to synaptic function and plasticity. Recent research results indicate that the protein phosphorylation and dephosphorylation cycle in neurons is a core molecular mechanism of sleep-wake regulation (Wang et al. Nature 2018, 558:435-439). It remains unclear whether compounds targeting CaMK2a can play a role in stabilizing sleep disorders or other CNS symptoms with an imbalance between neuronal activation and inhibition.

[0004] Narcolepsy is a chronic neurological disorder caused by the brain's inability to regulate the sleep-wake cycle. It leads to fragmented sleep at night and excessive daytime sleepiness (EDS). People with narcolepsy experience intense waves of sleepiness at different times of the day. If the urge becomes irresistible, they fall asleep, lasting from a few seconds to a few minutes, but in rare cases, some may sleep for an hour or longer.

[0005] Narcolepsy is a central disorder of excessive sleep. This group of disorders includes idiopathic hypersomnia, recurrent hypersomnia (such as Klein-Levin syndrome), and narcolepsy, including narcolepsy with cataplexy (type 1 narcolepsy; narcolepsy-cataplexy syndrome; NRCLP1; narcolepsy with low hypothalamus) and narcolepsy without cataplexy (type 2 narcolepsy; narcolepsy with normal hypothalamus).

[0006] All forms of central hypersomnia are characterized by excessive daytime sleepiness (EDS), a persistent background drowsiness and a tendency to doze off at intervals throughout the day, often at inappropriate times. These are known as sleep attacks. They can lead to brain fog, poor concentration, decreased energy, memory problems, exhaustion, and low mood.

[0007] In addition to EDS, people with narcolepsy may experience some or all of the typical symptoms, including cataplexy (sudden loss of voluntary muscle tone), abnormally rapid eye movement (REM) sleep, vivid hallucinations during sleep onset or wakefulness, and brief episodes of complete 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.

[0008] In a typical sleep cycle, a person enters the early stages of sleep, then the deep sleep stage, which lasts for 90 minutes, and finally REM sleep. In individuals with narcolepsy, REM sleep occurs within 15 minutes of the sleep cycle and occurs intermittently during waking hours. Dreaming and muscle paralysis occur during REM sleep.

[0009] Hallucinations are vivid and often frightening sensory hallucinations that occur as one falls asleep (pre-sleep hallucinations), which may be caused by a mixture of dreaming that occurs during wakefulness and REM sleep.

[0010] Sleep paralysis is a brief loss of the ability to move or speak while falling asleep or waking up. These episodes can last from a few seconds to a few minutes. After the episode ends, people quickly regain their full ability to move and speak.

[0011] Automatic behavior can also occur. A person may fall asleep immediately but continue the previous activity without being aware of it, such as driving.

[0012] Sudden collapse is a sudden weakness of the muscles in the whole body or a specific area (such as the face). Some people experience only mild weakness, such as a drooping head or jaw, while others collapse completely to the ground. These episodes are often triggered by strong emotions, such as surprise, laughter, or anger. The weakness is usually brief, lasting two minutes or less, but can be longer in severe cases.

[0013] Narcolepsy ranges in severity from mild to severe. In severe cases, it can negatively impact social activities, school, work, and overall health and well-being. People with narcolepsy may fall asleep at any time, often without warning, such as while talking, standing, or driving.

[0014] Symptoms often appear in the teens, or early twenties and thirties. Men and women are equally susceptible, and the prevalence of narcolepsy is approximately 1 in 2,000 individuals.

[0015] Individuals affected by narcolepsy due to medical condition (NDMC, also known as a group of conditions of secondary or symptomatic narcolepsy) also exhibit similar symptoms. Examples of medical conditions that cause narcolepsy symptoms (including cataplexy) include: tumors, ischemic stroke, sarcoidosis, arteriovenous malformations affecting the hypothalamus, multiple sclerotic plaques damaging the hypothalamus, paraneoplastic syndromes, antt-Ma2 antibody, Neimann-Pick type C disease, or Coffin-Lowry syndrome. Examples of medical conditions that typically cause narcolepsy symptoms without cataplexy include: head trauma, myotonic dystrophy, Prader-Willi syndrome, Parkinson's disease, or multiple system atrophy.

[0016] GHB is a naturally occurring metabolite and neuromodulator of gamma-aminobutyric acid (GABA) present in the mammalian brain at micromolar concentrations. GHB (sodium oxybate) is clinically used as a prescription drug for narcolepsy and is also misused as a recreational drug (e.g., Fantasy). GHB shows similarities to GABA. B The receptor binds with low affinity (millimolar) and high affinity (nanomolar to micromolar) to specific proteins in neurons (recently identified as CaMK2a (PCT / DK2019 / 050041)). In GABA... B One confirmed pharmacological effect of GHB, mediated by its receptor, is the reduction of body temperature. In contrast, the neurophysiological and neuropharmacological effects associated with the CaMK2a binding site remain unknown.

[0017] CaMK2a is one of the most abundant proteins in the postsynaptic dense region. It is a major modulator of synaptic signaling via phosphorylated ion channels and neurotransmitter receptors, and is closely involved in synaptic plasticity (a process occurring in the postsynaptic dense region), thus participating in higher brain functions such as cognitive processes. Due to its central role in regulating synaptic function, CaMK2a is involved in most neurological diseases and is a promising drug target, but it has not yet been developed due to the unavailability of small-molecule brain-permeable ligands selective for the 2a isoform.

[0018] GHB is highly effective in treating cataplexy and excessive daytime sleepiness associated with narcolepsy. This effect is generally attributed to GHB's effect on GABA. BThe role of receptors. The effects of GHB on sleep parameters in wild-type mice and GABA. B Similarities were observed among receptor knockout mice (Vienne et al. J Neurosci 2010, 30:14194-14204). Further research has shown that in a mouse model of type 1 narcolepsy, GABA... B The receptor agonist baclofen is also effective for narcolepsy symptoms (Black et al. J Neurosci 2014, 34:6485-6494). Therefore, GHB-related compounds may be effective by stimulating CaMK2a and / or GABA. B It is effective against narcolepsy through the action of receptors. This may be through the action of GABA receptors. A Downstream effects of receptors.

[0019] Angelman syndrome (AS) is a rare, chronic neurodevelopmental disorder caused by the loss of function of the gene ubiquitin ligase E3A (UBE3A). It affects approximately 1 in 12,000 people and begins at birth. AS is characterized by intellectual disability, impaired motor coordination, seizures, sleep disturbances, and behavioral abnormalities, including features of autism spectrum disorder (ASD).

[0020] Wellendorph et al. (J Pharmacol Exp Ther 2005,315:346-351) disclosed cyclic GHB analogs and their affinity for natural binding sites.

[0021] Krall et al. (J Med Chem 2019, 60: 9022-9039) published a study on the structural affinity relationship of ligands targeting the binding site of the neuroactive compound GHB.

[0022] Thiesen et al. (J Pharmacol Exp Ther 2015, 354: 166-174) disclosed that monocarboxylic acid transporter 1 (MCT1) promotes the brain uptake of 3-hydroxycyclopent-1-carboxylic acid (HOCPCA) and demonstrated that MCT1 is an important brain entry site for this compound.

[0023] PCT / DK2019 / 050041 discloses that GHB analogs bind to CaMK2a with high affinity, and that compounds targeting this kinase can be used to treat brain injury.

[0024] WO / 2019 / 055369 discloses the use of gaboxadol in the treatment of narcolepsy. GABA AGabosadone, a receptor agonist, was in clinical development for a range of diseases in the 1980s and 1990s, but patients with a history of drug abuse who received gabosadone experienced an increase in adverse psychiatric events.

[0025] For CNS disorders accompanied by sleep disturbances, there is a need for effective and safe new treatment options. New drugs are also needed to treat central hypersomnia, including narcolepsy, that do not pose a risk of abuse or have better pharmacokinetics than, for example, sodium oxybutyrate. Furthermore, treatment options are needed for neurodevelopmental disorders such as Angelman syndrome and Down syndrome, for which there are no targeted therapies and where cognitive and sleep disturbances are central. Therefore, specific treatment options for sleep disorders will be relevant to all neurodevelopmental disorders. Summary of the Invention

[0026] The inventors have discovered that many GHB analogs exhibit similarities to Ca 2+ The binding of calmodulin-dependent protein kinase 2a (CaMK2a) makes the compound of Formula I a promising candidate for treating CNS disorders with sleep disturbances, such as central hypersomnia (e.g., narcolepsy type 1), and neurodevelopmental disorders involving CaMK2a dysfunction, such as Angelman syndrome.

[0027] In its first aspect, the present invention provides a compound for treating CNS conditions accompanied by sleep disorders in a subject, wherein the compound has the formula I:

[0028]

[0029] When R5 is H and R1 and R2 form a ring system, the compound is selected from compounds of formula II or IV:

[0030]

[0031] in

[0032] n is 0 or 1;

[0033] X is selected from O or NH;

[0034] Y represents NH, O, S, or CH2.

[0035] R3 is selected from H; straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, neopentyl, hexyl, branched hexyl; -benzyl; polyethylene glycol (PEG); or groups such as:

[0036]

[0037] Among them, R9 and R 10 Each is independently selected from straight or branched C1-C6, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; in particular, R 10 Selected from H, -Me, -Et, -iPr;

[0038] R4 is selected from H; –C(=O)-C1-C6-alkyl, wherein the alkyl group is straight-chain 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 groups such as:

[0039]

[0040] Where R 11 and R 12 Each is independently selected from straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; particularly, R 12 Selected from H, –Me, -Et, -iPr, -iBu;

[0041] R6 and R7 are each independently selected from H, F, Cl, Br, I, aryl, straight-chain or branched C. 1–8 Alkyl group, -CH2(CH2) p -aryl, -CH=CH-aryl, NH2, NO2, OH, SH, straight-chain or branched-OC 1–8 Alkyl, straight-chain or branched -SC 1–8 Alkyl, straight-chain or branched -NH-C 1–8 Alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein the aryl group includes an aryl group having one or more heteroatoms selected from O, N, or S, and wherein p is 0 or 1; and C 1–8 Alkyl groups include Me, Et, Pr, Bu, pentyl, hexyl, heptyl, and octyl – alkyl groups can be straight-chain or branched.

[0042] Alternatively, when R2 is H and R1 and R5 form a ring system, the compound has Formula III:

[0043]

[0044] in

[0045] n is 0 or 1;

[0046] X is O or NH;

[0047] m is 0 or 1;

[0048] R3 is selected from H; straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl, branched hexyl; -benzyl; polyethylene glycol (PEG); or groups such as:

[0049]

[0050] Among them, R9 and R 10 Each is independently selected from straight-chain or branched C1-C6-alkyl groups, wherein the alkyl group is straight-chain or branched, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; particularly, R 10 Selected from H, -Me, -Et, -iPr;

[0051] 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 glycol (PEG); or groups such as:

[0052]

[0053] Where R 11 and R 12 Each is independently selected from straight or branched C1-C6, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; R 12 Selected from H, -Me, -Et, -iPr;

[0054] R 13 and R 14 Each is independently selected from H, F, Cl, Br, I, aryl, straight-chain or branched C. 1–8 Alkyl group, -CH2(CH2) p -aryl, -CH=CH-aryl, NH2, NO2, OH, SH, straight-chain or branched-OC 1–8 Alkyl, straight-chain or branched -SC 1–8 Alkyl, straight-chain or branched -NH-C 1–8 Alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein the aryl group includes an aryl group having one or more heteroatoms selected from O, N, or S, and wherein p is 0 or 1; and C 1–8Alkyl groups include Me, Et, Pr, Bu, pentyl, hexyl, heptyl, and octyl – alkyl groups can be straight-chain or branched.

[0055] Or any of its isomers, tautomers, enantiomers, racemic forms, or deuterated forms.

[0056] Or its pharmaceutically acceptable salt.

[0057] In one embodiment of the invention, the compound of formula I has the structure of formula II:

[0058]

[0059] In another embodiment of the invention, the compound of formula I is 3-hydroxycyclopent-1-encarboxylic acid (HOCPCA), for example (RS)-3-hydroxycyclopent-1-encarboxylic acid.

[0060] In another embodiment, the CNS condition accompanied by sleep disturbance is central hypersomnia, such as narcolepsy.

[0061] In another embodiment, the CNS condition accompanied by sleep disturbance is a neurodevelopmental condition with CaMK2a dysfunction, such as Angelman syndrome.

[0062] Compounds targeting novel GHB binding sites in CaMK2a have never been proposed as drug candidates for Angelman syndrome or other neurodevelopmental disorders. The inventors have demonstrated that the binding site is located in the central tissue (central) domain of CaMK2a, unlike other known CaMK2a ligands. The inventors further demonstrate that these compounds target CaMK2a in the brains of Angelman syndrome mice.

[0063] The inventors have surprisingly identified small molecule compounds that directly bind to and regulate CaMK2a function. The compounds according to Formula I are the first group of examples of compounds selectively targeting CaMK2a, and therefore hold promise for treating central hypersomnia (such as narcolepsy) and neurodevelopmental disorders involving CaMK2a dysfunction (such as Angelman syndrome). This demonstrates the potential use of Formula I compounds for treating disorders involving CaMK2a dysfunction (such as Angelman syndrome). The availability of first-class small molecule compounds selective for CaMK2a and the fact that these compounds bind to novel sites on the protein make this a novel approach. The proposed use of Formula I compounds is clinically relevant and therefore has useful applications, as there is currently no targeted medical treatment available for patients with Angelman syndrome (including severe sleep disorders) and there is a need for improved treatments for central hypersomnia.

[0064] In a second aspect, the present invention provides a pharmaceutical composition for treating a subject with central hypersomnia or neurodevelopmental disorders, said composition comprising a compound according to Formula I.

[0065] In one embodiment, a dose of the pharmaceutical composition comprises about 0.1 mg to about 1.0 g of the compound of formula I.

[0066] In a third aspect, the present invention provides a method for treating central hypersomnia (e.g., narcolepsy) or neurodevelopmental disorders (e.g., Angelman syndrome), comprising administering an effective amount of a compound of formula I.

[0067] In a fourth aspect, the present invention provides a method for treating diseases sensitive to CaMK2a regulation, comprising administering an effective amount of a compound of formula I.

[0068] Brief description of the attached figures

[0069] Figure 1 Increased levels of [something] in brain slices of Ube3a (Angelman syndrome) mice 3 The H-HOCPCA binding level indicates that binding to the anomalous form of CaMK2a is preferred.

[0070] Figure 2 The elimination of 3H-HOCPCA in mutations of the CaMK2a hub domain shows the location of the binding site.

[0071] Figure 3 Evaluation of selected compounds in a DTA mouse model of narcolepsy

[0072] Figure 4-5 Evaluation of selected compounds in the Hcrt-KO mouse model of narcolepsy Invention Details

[0074] In a first aspect, the present invention provides a compound for treating a subject with a CNS disorder (e.g., central hypersomnia) or a neurodevelopmental disorder (e.g., Angelman syndrome) accompanied by sleep disturbances, wherein the compound is according to formula I:

[0075]

[0076] When R5 is H and R1 and R2 form a ring system, the compound is selected from compounds of formula II or IV.

[0077]

[0078] in:

[0079] n is 0 or 1;

[0080] X is selected from O or NH;

[0081] Y represents NH, O, S, or CH2.

[0082] R3 is selected from H; straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, neopentyl, hexyl, branched hexyl; -benzyl; polyethylene glycol (PEG); or groups such as:

[0083]

[0084] Among them, R9 and R 10 Each is independently selected from straight or branched C1-C6, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; in particular, R 10 Selected from H, -Me, -Et, -iPr;

[0085] R4 is selected from H; –C(=O)-C1-C6-alkyl, wherein the alkyl group is straight-chain 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 groups such as:

[0086]

[0087] Where R 11 and R 12 Each is independently selected from straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; particularly, R 12 Selected from H, –Me, -Et, -iPr, -iBu;

[0088] R6 and R7 are each independently selected from H, F, Cl, Br, I, aryl, straight-chain or branched C. 1–8 Alkyl group, -CH2(CH2) p -aryl, -CH=CH-aryl, NH2, NO2, OH, SH, straight-chain or branched-OC 1–8 Alkyl, straight-chain or branched -SC 1–8 Alkyl, straight-chain or branched -NH-C 1–8Alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein the aryl group includes an aryl group having one or more heteroatoms selected from O, N, or S, and wherein p is 0 or 1; and C 1–8 Alkyl groups include Me, Et, Pr, Bu, pentyl, hexyl, heptyl, and octyl – alkyl groups are straight-chain or branched;

[0089] Alternatively, when R2 is H and R1 and R5 form a ring system, the compound has Formula III.

[0090]

[0091] in:

[0092] n is 0 or 1;

[0093] X is O or NH;

[0094] m is 0 or 1;

[0095] R3 is selected from H; straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl, branched hexyl; -benzyl; polyethylene glycol (PEG); or groups such as:

[0096]

[0097] Among them, R9 and R 10 Each is independently selected from straight-chain or branched C1-C6-alkyl groups, wherein the alkyl group is straight-chain or branched, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; particularly, R 10 Selected from H, -Me, -Et, -iPr;

[0098] 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 glycol (PEG); or groups such as:

[0099]

[0100] Where R 11 and R 12 Each is independently selected from straight or branched C1-C6, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; R 12 Selected from H, –Me, -Et, -iPr;

[0101] R 13 and R 14 Each is independently selected from H, F, Cl, Br, I, aryl, straight-chain or branched C. 1–8 Alkyl group, -CH2(CH2) p -aryl, -CH=CH-aryl, NH2, NO2, OH, SH, straight-chain or branched-OC 1–8 Alkyl, straight-chain or branched -SC 1–8 Alkyl, straight-chain or branched -NH-C 1–8 Alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein the aryl group includes an aryl group having one or more heteroatoms selected from O, N, or S, and wherein p is 0 or 1; and C 1–8 Alkyl groups include Me, Et, Pr, Bu, pentyl, hexyl, heptyl, and octyl – alkyl groups can be straight-chain or branched.

[0102] Or any of its isomers, tautomers, enantiomers, racemic forms, or deuterated forms.

[0103] Or its pharmaceutically acceptable salt.

[0104] Isomers, tautomers, enantiomers, racemic forms, deuterated forms, or mixtures thereof are within the scope of this invention. Therefore, for example, compounds of formula I may exist in the R or S form, and all such forms, as well as racemic mixtures, are included within the scope of this invention.

[0105] Compound of Formula I can be prepared as described in PCT / DK2019 / 050041. A method for synthesizing (RS)-3-hydroxycyclopent-1-enecarboxylic acid is also described in Wellendorph et al. J. Pharmacol. Exp. Therap. 2005, 315:346-351.

[0106] Based on studies of radioligand binding, new sites in CaMK2a have been discovered to bind to compounds of formula I.

[0107] The inventors have identified CaMK2a as a specific high-affinity target for small-molecule GHB and its analogues having the structure of Formula I. Further studies, as illustrated herein, have demonstrated that GHB analogues bind to a unique site (more precisely, the central domain) in CaMK2a, thus representing the first class of small-molecule compounds selective for this crucial neurokinase. CaMK2a is involved in important brain processes such as synaptic plasticity and learning and memory, and its tight regulation is essential for normal intellectual development. Because this kinase is calcium-dependent, it is also centrally involved in calcium-disordered conditions such as epilepsy, sleep disturbances, and ischemia. Mechanistically, CaMK2a is regulated by its own phosphorylation (autophosphorylation), and mouse models and patients with mutations at these sites exhibit significant learning and memory deficits, seizures, and poor sleep regulation (Elgersma et al., Neuron 2002, 36:493-505; Küry et al. Am.J. Human Genetics 2017, 101:768–788).

[0108] While no link has ever been proposed between CaMK2a and narcolepsy, the inventors have demonstrated that compounds of formula I targeting CaMK2a are highly effective in treating narcolepsy symptoms.

[0109] Biochemical analysis of AS mouse models has shown that decreased CaMK2 activity, and especially increased autophosphorylation of the inhibitory sites Thr305 and Thr306 at the CaMK2a site, leads to reduced long-term potentiation (LTP), a hippocampal process associated with learning and memory / cognition. Therefore, it has been found that crossing Ube3a mice with mice carrying the T305V / 306A mutation can rescue AS mice from motor function, seizures, learning disabilities, and LTP deficiencies by mitigating the increased levels of inhibitory phosphorylation (van Woerden et al. Nature Neurosci 2007, 10, 280-282). The inventors have demonstrated that compounds of formula I bind more strongly in the hippocampus of Angelman syndrome mice, indicating that compounds of formula I are effective in treating symptoms of Angelman syndrome.

[0110] Similarly, increased CaMK2a phosphorylation levels have been reported in mouse models of Down syndrome, another chronic neurodevelopmental disorder in humans, in which intellectual disability is the predominant 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 of other neurodevelopmental disorders characterized by one or more of the following symptoms: learning and behavioral deficits, seizure tendency, and sleep disturbances. These conditions include Fragile X, neurofibromatosis type 1, Cri-du-Chat syndrome, succinate semialdehyde dehydrogenase (SSADH) deficiency with abnormal GHB levels, and Rett syndrome, which also includes CaMK2 dysfunction (Shioda et al., Int J Mol Sci 2018, 19, 20; doi:10.3390 / ijms19010020).

[0111] Compounds targeting novel GHB binding sites in CaMK2a have never been proposed as drug candidates for Angelman syndrome or other neurodevelopmental disorders. The inventors have demonstrated that this binding site is located in the central tissue (center) domain of CaMK2a. The inventors propose that this compound may be suitable for treating cognitive and / or sleep-related symptoms in Angelman syndrome via CaMK2a. For this reason, compounds targeting CaMK2a are proposed as drug candidates for treating symptoms of Angelman syndrome and potentially other neurodevelopmental disorders with CaMK2a dysfunction.

[0112] definition:

[0113] Autophosphorylation

[0114] As used herein, the term “autophosphorylation” refers to the phosphorylation of CaMK2a at residues Thr286, Thr305, or Thr306.

[0115] CaMK2a

[0116] As used in this article, the term "CaMK2a" refers to Ca 2+ Calmodulin-dependent protein kinase 2α.

[0117] sudden collapse

[0118] The term "cataplexy" is a sudden and brief episode of muscle weakness accompanied by full consciousness, usually triggered by emotions such as laughter, crying, or fear.

[0119] Central hypersomnia

[0120] Excessive daytime sleepiness is a disorder of the central nervous system (i.e., the brain). These disorders share the common symptom of pronounced daytime sleepiness. Various types of central hypersomnia exist, including idiopathic hypersomnia, recurrent hypersomnia (such as Klein-Levin syndrome), and narcolepsy.

[0121] In one embodiment, the compound of formulation I is expected to have a beneficial effect in preventing and / or alleviating central hypersomnia and cataplexy. Central hypersomnia includes idiopathic hypersomnia, recurrent hypersomnia (such as Klein-Levin syndrome), and narcolepsy, including narcolepsy with cataplexy (narcolepsy type 1; narcolepsy-cataplexy syndrome; NRCLP1; narcolepsy with low hypothalamus) and narcolepsy without cataplexy (narcolepsy type 2; narcolepsy with normal hypothalamus).

[0122] Type 1 and Type 2 narcolepsy are sleep disorders characterized by excessive daytime sleepiness, with Type 1 narcolepsy also featuring cataplexy. Cataplexy is characterized by a sudden loss of muscle tone. Cataplexy typically lasts only a few seconds to a few minutes, and recovery is immediate and complete. The severity of muscle tone loss varies, ranging from mild weakness accompanied by drooping head, facial relaxation, jaw drooping, slurred speech, and bent knees to complete postural collapse and falling to the ground. Cataplexy is often triggered by emotions that typically have a pleasurable or exciting component, such as laughter, happiness, pride, anger, or surprise.

[0123] In addition to excessive daytime sleepiness and cataplexy (in type 1 narcolepsy), individuals affected by narcolepsy typically experience symptoms such as sleep fragmentation, abnormally rapid eye movement (REM) sleep, nighttime sleep disruption, paralysis during sleep onset or wakefulness, and / or hypnagogic hallucinations. Individuals affected by medically induced narcolepsy (NDMC, also known as a group of conditions of secondary or symptomatic narcolepsy) also exhibit similar symptoms.

[0124] Examples of medical conditions that can cause narcolepsy symptoms (including cataplexy) include: tumors, ischemic stroke, sarcoidosis, arteriovenous malformations affecting the hypothalamus, multiple sclerotic plaques damaging the hypothalamus, paraneoplastic syndromes (ANTT-Ma2 antibody), Neimann-Pick type C disease, or Coffin-Lowry syndrome. Examples of medical conditions that typically cause narcolepsy symptoms without cataplexy include: head trauma, myotonic dystrophy, Prader-Willi syndrome, Parkinson's disease, or multiple system atrophy.

[0125] Cataplexy is a hallmark of narcolepsy, but it can also be associated with specific lesions primarily located in the lateral and posterior hypothalamus, such as tumors (astrocytomas, glioblastomas, gliomas, craniopharyngiomas, and subependymal tumors) and arteriovenous malformations. Conditions in which cataplexy can be observed include ischemic events, multiple sclerosis, head injury, paraneoplastic syndromes, and infections such as encephalitis. Cataplexy may occur temporarily or permanently due to hypothalamic lesions caused by surgery (especially in difficult tumor resections). In infancy, cataplexy can be observed in conjunction with other neurological syndromes, such as Niemann-Pick type C disease.

[0126] GHB analogues

[0127] The term “GHB analogue” as used in this article refers to compounds that share a common GHB-related structure and bind to a unique site in CaMK2a.

[0128] Neurodevelopmental disorders involving CaMK2a dysfunction

[0129] This term refers to human diseases, primarily of genetic origin, in which there is a component of CaMK2a dysfunction. These conditions share symptoms of learning and behavioral deficits, increased tendency to have seizures, and sleep disturbances. The definition includes disease-causing CaMK2 mutations, Angelman syndrome, Down syndrome, Fragile X, neurofibromatosis type 1, Cri-du-Chat syndrome, SSADH deficiency, and Rett syndrome.

[0130] Pharmaceutical compositions comprising the compounds of the present invention:

[0131] The present invention also provides a pharmaceutical composition comprising the compounds of the present invention and one or more pharmaceutically acceptable diluents or carriers.

[0132] The compounds or formulations thereof of the present invention can be administered by any conventional method, such as, but not limited to, parenteral, oral, topical (including oral, sublingual, or percutaneous), via medical devices (e.g., stents), by inhalation, or by injection (subcutaneous or intramuscular). Treatment may consist of a single dose or multiple doses 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 by intravenous infusion.

[0133] While the compounds of the present invention can be administered alone, they are preferably administered as pharmaceutical formulations in combination with one or more acceptable carriers. The carrier must be "acceptable" in the sense that it is compatible with the compounds of the present invention and harmless to its recipient. Examples of suitable carriers are described in more detail below.

[0134] The formulation can be conveniently present in unit dosage form and can be prepared by any method well known in the field of pharmaceutical science. This method involves the step of binding the active ingredient (the compound of the present invention) to a carrier constituting one or more auxiliary components. Typically, the formulation is prepared by uniformly and tightly binding the active ingredient to a liquid carrier or a subdivided solid carrier, or both, and then, if desired, shaping the product.

[0135] The compounds of the present invention are typically administered intravenously, orally, or via any parenteral route in pharmaceutically acceptable dosage forms comprising the active ingredient (optionally in the form of a non-toxic organic or inorganic acid or base addition salt). Depending on the disease to be treated and the patient, as well as the route of administration, the compositions may be administered at different doses.

[0136] Pharmaceutical compositions must be stable under manufacturing and storage conditions; therefore, they should preferably be preserved in a manner that prevents contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0137] For example, the compounds of the present invention can also be administered orally, sublingually, or in the form of tablets, capsules, ovules, elixirs, solutions, or suspensions, and may contain flavoring agents or coloring agents for immediate-release, sustained-release, or controlled-release applications.

[0138] The formulations suitable for oral administration according to the present invention may be in the following forms: discrete units, such as capsules, pouches, or tablets, each unit containing a predetermined amount of active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil emulsions. The active ingredient may also be in the form of pellets, saccharides, or pastes.

[0139] Solutions or suspensions of the compounds of the present invention suitable for oral administration may also contain excipients, such as N,N-dimethylacetamide; dispersants, such as polysorbate 80; surfactants; and solubilizers, such as polyethylene glycol, Phosal 50PG (which is composed of phosphatidylcholine, soybean fatty acids, ethanol, mono / diglycerides, propylene glycol, and ascorbyl palmitate). Formulations according to the invention may also be in the form of emulsions, wherein the compounds according to formula I may be present in an aqueous oil emulsion. The oil may be any oily substance, such as soybean oil or safflower oil, medium-chain triglycerides (MCT-oils), such as coconut oil, palm oil, etc., or combinations thereof.

[0140] The tablets may contain excipients such as microcrystalline cellulose, lactose (e.g., lactose monohydrate or anhydrous lactose), sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine, butylated hydroxytoluene (E321), crospovidone, and hydroxypropyl methylcellulose; disintegrants such as starch (preferably corn starch, potato starch, or tapioca starch), sodium glycolate starch, croscarmellose sodium, and certain complex silicates; and granulation binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene glycol 8000, sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included.

[0141] Tablets may optionally be made by compression or molding with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient (e.g., powder or granules) in a free-flowing form in a suitable machine, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium glycolate starch, crospovidone, crospovidone), surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and can be formulated with, for example, different proportions of hydroxypropyl methylcellulose to provide sustained or controlled release of the active ingredient, thereby providing the desired release profile. Similar types of solid compositions can also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar, or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the compounds of the present invention can be combined with various sweeteners or flavorings, colorants or dyes; with emulsifiers and / or suspending agents; and with diluents (e.g., water, ethanol, propylene glycol and glycerin) and combinations thereof.

[0142] Formulations suitable for topical application in the oral cavity include sugar tablets containing active ingredients in a flavoring matrix (typically sucrose and gum arabic or tragacanth); lozenges containing active ingredients in an inert matrix (e.g., gelatin and glycerin, or sucrose and gum arabic); and mouthwashes containing active ingredients in a suitable liquid carrier.

[0143] Pharmaceutical compositions suitable for topical application can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, dipping dressings, sprays, aerosols, or oils, transdermal devices, dusting powders, etc. These compositions can be prepared using conventional methods containing active agents. Therefore, they may also contain compatible conventional carriers and additives, such as preservatives, solvents to aid drug penetration, emollients in creams or ointments, and ethanol or oleyl alcohol in lotions. Such carriers can be present from about 1% to about 98% of the composition. More commonly, they will form up to about 80% of the composition. By way of illustration, creams or ointments are prepared by mixing sufficient amounts 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 with the desired consistency.

[0144] Pharmaceutical compositions suitable for transdermal application can exist as discrete patches designed to maintain close contact with the recipient's epidermis for an extended period. For example, the active agent can be delivered from the patch via iontophoresis.

[0145] 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 used with paraffin or a water-miscible ointment base.

[0146] Alternatively, the surfactant can be formulated into a cream together with an oil-in-water emulsion base or an oil-in-water emulsion base.

[0147] For parenteral administration, a fluid unit dosage form is prepared using the active ingredient and a sterile solvent, such as, but not limited to, water, alcohol, polyol, glycerol, and vegetable oil, with water being preferred. Depending on the solvent used and the concentration, the active ingredient may be in colloid, suspension, or dissolved in the solvent. In preparing the solution, the active ingredient may be dissolved in water for injection and sterilized by filtration, then filled into suitable vials or ampoules and sealed.

[0148] Advantageously, agents such as local anesthetics, preservatives, and buffers can be dissolved in the solvent. To improve stability, the composition can be frozen and the water removed under vacuum after being filled into a vial. The dried lyophilized powder is then sealed in a vial, and a matching vial of water for injection can be provided for reconstitution before use.

[0149] The pharmaceutical compositions of the present invention suitable for injection include sterile aqueous solutions or dispersions. Alternatively, the compositions may be in the form of sterile powders for immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be an easily injectable and effective fluid.

[0150] The preparation method of parenteral suspensions is basically the same as that of solutions, except that the active ingredient is suspended in the solvent rather than dissolved, and sterilization cannot be achieved by filtration. The active ingredient can be sterilized by exposure to ethylene oxide before being suspended in a sterile solvent. Advantageously, the composition contains surfactants or wetting agents to promote uniform distribution of the active ingredient.

[0151] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of this invention may include other conventional substances in the art concerning the types of formulations discussed, such as flavoring agents, those suitable for oral administration. 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 or later). Those skilled in the art will also know how to select a suitable route of administration and dosage.

[0152] Those skilled in the art will recognize that the optimal amount and interval of the individual dosage of the compounds of the present invention will be determined based on the nature and extent of the condition being treated, the form, route and site of administration, and the age and condition of the specific subject being treated. The physician will ultimately determine the appropriate dosage to be used. This dosage may be repeated as appropriate. If side effects occur, the amount and / or frequency of the dosage may be changed or reduced in accordance with normal clinical practice.

[0153] Unless the context requires otherwise, all % values ​​mentioned in this article are %w / w.

[0154] The following implementation scheme illustrates the present invention:

[0155] 1. A compound for treating a subject with CNS symptoms accompanied by sleep disturbances, wherein the compound has formula I:

[0156]

[0157] When R5 is H and R1 and R2 form a ring system, the compound is selected from compounds of formula II or IV.

[0158]

[0159] in

[0160] n is 0 or 1;

[0161] X is selected from O or NH;

[0162] Y represents NH, O, S, or CH2.

[0163] R3 is selected from H; straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, neopentyl, hexyl, branched hexyl; -benzyl; polyethylene glycol (PEG); or groups such as:

[0164]

[0165] Among them, R9 and R 10 Each is independently selected from straight or branched C1-C6, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; in particular, R 10 Selected from H, -Me, -Et, -iPr;

[0166] R4 is selected from H; wherein the alkyl group is a straight-chain or branched –C(=O)-C1-C6-alkyl group, 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 the following:

[0167]

[0168] Where R 11 and R 12 Each is independently selected from straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; particularly, R 12 Selected from H, –Me, -Et, -iPr, -iBu;

[0169] R6 and R7 are each independently selected from H, F, Cl, Br, I, aryl, straight-chain or branched C. 1–8 Alkyl group, -CH2(CH2) p -aryl, -CH=CH-aryl, NH2, NO2, OH, SH, straight-chain or branched-OC 1–8 Alkyl, straight-chain or branched -SC 1–8 Alkyl, straight-chain or branched -NH-C 1–8 Alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein the aryl group includes an aryl group having one or more heteroatoms selected from O, N, or S, and wherein p is 0 or 1; and C 1–8Alkyl groups include Me, Et, Pr, Bu, pentyl, hexyl, heptyl, and octyl – alkyl groups can be straight-chain or branched.

[0170] Alternatively, when R2 is H and R1 and R5 form a ring system, the compound has Formula III:

[0171]

[0172] in

[0173] n is 0 or 1;

[0174] X is O or NH;

[0175] m is 0 or 1;

[0176] R3 is selected from H; straight-chain or branched C1-C6-alkyl groups, including -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl, branched hexyl; -benzyl; polyethylene glycol (PEG); or groups such as:

[0177]

[0178] Among them, R9 and R 10 Each is independently selected from straight-chain or branched C1-C6-alkyl groups, wherein the alkyl group is straight-chain or branched, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; particularly, R 10 Selected from H, -Me, -Et, -iPr;

[0179] 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 glycol (PEG); or groups such as:

[0180]

[0181] Where R 11 and R 12 Each is independently selected from straight or branched C1-C6, including -Me, -Et, -Pr, -iPr, -Bu, -iBu, -tBu, pentyl, neopentyl, and hexyl; R 12 Selected from H, –Me, -Et, -iPr;

[0182] R 13 and R 14 Each is independently selected from H, F, Cl, Br, I, aryl, straight-chain or branched C.1–8 Alkyl group, -CH2(CH2) p -aryl, -CH=CH-aryl, NH2, NO2, OH, SH, straight-chain or branched-OC 1–8 Alkyl, straight-chain or branched -SC 1–8 Alkyl, straight-chain or branched -NH-C 1–8 Alkyl, -O-aryl, -S-aryl, -NH-aryl, wherein the aryl group includes an aryl group having one or more heteroatoms selected from O, N, or S, and wherein p is 0 or 1; and C 1–8 Alkyl groups include Me, Et, Pr, Bu, pentyl, hexyl, heptyl, and octyl – alkyl groups can be straight-chain or branched.

[0183] Or any of its isomers, tautomers, enantiomers, racemic forms, or deuterated forms.

[0184] Or its pharmaceutically acceptable salt.

[0185] 2. The compound according to embodiment 1 has formula II.

[0186] 3. The compound according to embodiment 1, having formula II or formula III, wherein n is 0.

[0187] 4. The compound according to any one of the foregoing embodiments, wherein R3 and R4 are both H.

[0188] 5. The compound according to any one of the foregoing embodiments, wherein the compound is selected from...

[0189]

[0190] Or its pharmaceutically acceptable salt.

[0191] Where R' is COOH, R” is H and R”' is OCH3, or

[0192] Where R' is COOH, R” is CH3 and R”' is OH.

[0193] 6. The compound according to any one of the foregoing embodiments, wherein the compound is selected from...

[0194]

[0195] Or its pharmaceutically acceptable salt.

[0196] 7. The compound according to embodiment 6, which is

[0197]

[0198] Or its pharmaceutically acceptable salt.

[0199] 8. The compound according to embodiment 7 is a sodium or potassium salt.

[0200] 9. The compound according to any one of embodiments 1-8, which is in a crystalline state.

[0201] 10. The compound according to any one of embodiments 1-9, wherein the compound is administered to the subject at a dose of about 0.01 mg / kg to about 100 mg / kg.

[0202] 11. The compound according to any one of the foregoing embodiments, wherein the compound is administered to the subject at a dose of about 0.1 mg / kg to about 10 mg / kg.

[0203] 12. The compound according to any one of the foregoing embodiments, wherein about 0.1 mg to about 1.0 g of the compound will be administered to the subject.

[0204] 13. The compound according to embodiment 12, wherein about 1 mg to about 1000 mg of the compound will be administered to the subject.

[0205] 14. The compound according to any one of the foregoing embodiments, wherein the CNS condition accompanied by sleep disorder is central hypersomnia.

[0206] 15. The compound according to embodiment 14, wherein the central hypersomnia is selected from idiopathic hypersomnia, recurrent hypersomnia, Klein-Levin syndrome, and narcolepsy.

[0207] 16. The compound according to any one of the foregoing embodiments, wherein the CNS condition accompanied by sleep disorder is narcolepsy.

[0208] 17. The compound according to any one of the foregoing embodiments, wherein the use alleviates at least one of the narcolepsy symptoms of the subject.

[0209] 18. The compound according to embodiment 17, wherein the symptoms are selected from excessive daytime sleepiness, cataplexy, abnormal REM sleep, sleep paralysis, or nighttime wakefulness.

[0210] 19. The compound according to any one of the foregoing embodiments, wherein the treatment of narcolepsy is treatment of narcolepsy with cataplexy (narcolepsy type 1).

[0211] 20. The compound according to any one of embodiments 1-18, wherein the treatment of narcolepsy is treatment of narcolepsy without cataplexy (narcolepsy type 2).

[0212] 21. The compound according to any one of embodiments 1-18, wherein the treatment of narcolepsy is a treatment of secondary narcolepsy.

[0213] 22. The compound according to any one of embodiments 1-13, wherein the CNS disorder is a neurodevelopmental disorder.

[0214] 23. The compound according to any one of embodiments 1-13, wherein the CNS condition is caused by a hereditary CaMK2 mutation.

[0215] 24. The compound according to any one of embodiments 1-13, wherein the CNS condition is Angelman syndrome or Down syndrome.

[0216] 25. The compound according to any one of the foregoing embodiments, wherein the use further includes administration of a CNS stimulant, an antidepressant, or a GABA receptor agonist.

[0217] 26. The compound according to embodiment 25, wherein the CNS stimulant is selected from modafinil, armofenil, methylphenidate, amphetamine, dextroamphetamine, methamphetamine, phentermine, phendimetrazine, diethylpropion, lisdexamfetamine, benzphetamine, atomoxetine, caffeine, and ephedrine.

[0218] 27. The compound according to embodiment 25, wherein the antidepressant is selected from serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and norepinephrine and specific serotonergic antidepressants (NASSAs).

[0219] 28. The compound according to embodiment 25, wherein the GABA receptor agonist is selected from sodium hydroxybutyrate, baclofen, phenibut, and gapoxetine.

[0220] 29. A pharmaceutical composition for treating a subject with CNS symptoms accompanied by sleep disturbances, comprising a compound according to any one of embodiments 1-29.

[0221] 30. The pharmaceutical composition according to embodiment 29, wherein the CNS condition accompanied by sleep disturbance is central hypersomnia.

[0222] 31. The pharmaceutical composition according to embodiment 30, wherein the central hypersomnia is narcolepsy.

[0223] 32. The pharmaceutical composition according to embodiment 29, wherein the CNS condition accompanied by sleep disturbance is a neurodevelopmental condition.

[0224] 33. The pharmaceutical composition according to embodiment 32, wherein the neurodevelopmental disorder is Angelman syndrome or Down syndrome or is caused by a hereditary CaMK2 mutation.

[0225] 34. The pharmaceutical composition according to any one of embodiments 28-33, wherein a dose of the pharmaceutical composition comprises about 0.1 mg to about 5.0 g of the compound.

[0226] 35. The pharmaceutical composition according to embodiment 34, wherein a dose of the pharmaceutical composition comprises about 10 mg to about 1.0 g of the compound.

[0227] 36. The pharmaceutical composition according to embodiment 34, wherein a dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of the compound.

[0228] 37. The pharmaceutical composition according to embodiment 34, wherein a dose of the pharmaceutical composition comprises about 250 mg to about 5.0 g of the compound.

[0229] 38. The pharmaceutical composition according to embodiment 34, wherein a dose of the pharmaceutical composition comprises about 0.5 mg to about 50 mg of the compound.

[0230] 30. A method of treating CNS conditions with sleep disturbances, comprising administering an effective amount of a compound as defined in any one of embodiments 1-28.

[0231] 40. The method according to embodiment 39, wherein the CNS condition accompanied by sleep disorder is central hypersomnia.

[0232] 41. The method according to embodiment 40, wherein the central hypersomnia is narcolepsy.

[0233] 42. The method according to any one of embodiments 40-41, wherein the central sleep excess is selected from narcolepsy type 1, narcolepsy type 2 and secondary narcolepsy.

[0234] 43. The method according to embodiment 39, wherein the CNS disorder accompanied by sleep disturbance is a neurodevelopmental disorder.

[0235] 44. The method according to embodiment 43, wherein the neurodevelopmental disorder is Angelman syndrome or Down syndrome.

[0236] 45. The method according to any one of embodiments 39-44, wherein the method further comprises administering a CNS stimulant, an antidepressant, or GABA. A receptor agonists or GABA B Receptor agonists.

[0237] 46. ​​The method according to embodiment 45, wherein the CNS stimulant is selected from modafinil, amofinil, methylphenidate, amphetamine, dextromethorphan, methamphetamine, phentermine, benzotriazine, amphetamine, lisdextromethorphan, benzphenamine, atomoxetine, caffeine, and ephedrine.

[0238] 47. The method according to embodiment 45, wherein the antidepressant is selected from serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and norepinephrine and specific serotonergic antidepressants (NASSAs).

[0239] 48. The method according to embodiment 45, wherein the GABA B The receptor agonist is selected from sodium hydroxybutyrate, baclofen, and fenibut.

[0240] 49. The method according to embodiment 45, wherein the GABA A The receptor agonist is gabosadol.

[0241] 50. A method of treating a disease sensitive to CaMK2a regulation, comprising administering an effective amount of a compound as defined in any one of embodiments 1-28. Example

[0242] Materials and methods

[0243] mouse brain 3 H-HOCPCA autoradiography

[0244] According to the previously announced procedure, the source (Ube3a) m- / p+ The brains of mice, either wild-type or terrestrial-type, were dissected, sliced ​​on a cryostat, mounted on a glass slide, and processed as described. 3 H-HOCPCA autoradiography (Griem-Krey et al. 2019, J Vis Exp Ther, 145:e58879). Combined with a procedure using internally prepared 1 nM... 3 H-HOCPCA radioligand (Vogensen et al., 2013, J Med Chem 56:8201-8205) was used for nonspecific binding with 1 mM GHB. The buffer was 50 mM potassium phosphate, pH 6.0. The washed and dried sections were then... 3 H micro-levels were exposed together with a phosphor imaging plate (Science Imaging Scandinavia AB, Nacka, Sweden) for 3 days to convert to tissue equivalent (TE). The sample was then scanned using a CR35 BioScanner. Medical imaging plate was scanned. Subsequently, optical density analysis was performed using Image J (NIH), and further analysis and data (nmol / mg TE) were obtained using GraphPad Prism 7, GraphPad Prism Software, San Diego, CA, USA.

[0245] 3 H-HOCPCA binding to recombinant CaMK2a expressed in HEK293T cells

[0246] HEK293T cells were cultured in Dulbecco-modified Eagle medium containing GlutaMax, 10% fetal bovine serum, and 1% penicillin-streptomycin under standard conditions and incubated at 37°C in a humid atmosphere of 95% O2 and 5% CO2. Site-directed mutagenesis was performed using point mutagenesis by GenScript USA Inc. Cells were transfected with wild-type or mutant CMYC-labeled rat CaMK2a (Origene construct RR201121) using linear polyethyleneimine (MW 25000, Polysciences Inc., Warrington, PA, USA). Forty-eight hours post-transfection, whole-cell homogenates were prepared by washing cells with ice-cold 1x PBS and harvesting by scraping. Cells were collected and centrifuged at 1000x g for 10 minutes. The cell pellet was resuspended in ice-cold 1x PBS and homogenized for 20 seconds at maximum speed using a bulletblender with 2x 1mm zirconium beads (NextAdvance, NY, USA). The homogenate was clarified by centrifugation (10 min, 4°C, 14,000 x 25 g). Protein concentration was determined using the Bradford protein assay. 150–200 μg of protein was mixed with 5 nM PBS. 3 H-HOCPCA (Vogensen et al., 2013, J Med Chem 56:8201-8205) and the test compound were incubated at 0–4 °C for 1 hour with a total volume of 1 mL. Nonspecific binding was determined using 1–10 mM GHB. Proteins were then precipitated by adding ice-cold acetone (4 times the test volume), vortexing, and incubation at -20 °C for 1 hour. Proteins were rapidly filtered through GF / Cunifilters (Whatman) 30 and washed using a 48-well collector. Scintillation solution was added to the dried filter, and radioactivity was measured on a Tricarb 2100 scintillation counter (Packard). Data analysis was performed using a GraphPadPrism 7, GraphPadPrism Software, San Diego, CA, USA.

[0247] The total expression level of CaMK2a was assessed using Western blot analysis with anti-myc-Alexa488 (MA1980-A488, ThermoFisherScientific).

[0248] Example 1 – Specific CaMK2a radioligand 3 H-HOCPCA showed increased binding to the brain in patients with Angelman syndrome.

[0249] use 3 H-HOCPCA autoradiography was used to visualize Angelman syndrome mice (Ube3a) m- / p+ HET brain slices were compared with control mice (WT). The observed differences were most pronounced in the hippocampus where CaMK2a was highly expressed. The data suggest that GHB-related compounds may affect Angelman syndrome by binding to the CaMK2a form accumulated in the disease. Figure 1 ).

[0250] Example 2 – Demonstrated by mutagenesis analysis 3 The binding site of H-HOCPCA is confined within the central structural domain cavity of CaMK2a.

[0251] CaMK2a constructs, triple mutants, or constructs lacking a center (Δ center) with specific mutations Arg433Gln, Arg453Gln, Arg469Cys, and Arg469Gln were expressed in HEK cells, and whole-cell homogenates were exposed to the cells. 3 H-HOCPCA filtration binding assay. Each of the three mutations completely eliminated binding compared to the wild type, although expression was confirmed by Western blotting. Figure 2 ).

[0252] Example 3 - Assessment in Narcolepsy 3 H-HOCPCA binding level

[0253] use 3 H-HOCPCA autoradiography was used to compare mouse brain slices from a narcolepsy mouse model with control mice (WT) using the method described in Example 1.

[0254] Example 4 - Evaluation of the autonomous activity of selected compounds in mice

[0255] To determine the effects of the compound on movement (e.g., sedation or hyperactivity), the compound was evaluated after systemic administration to mice. Mice (typically n = 5–8) were administered the compound of formula I and a solvent control and placed in transparent cages (L: 37 cm x W: 21 cm x H: 15 cm). Spontaneous activity was then measured using a camera mounted above the arena. Mice were recorded for approximately 120 minutes, with data collected every 5 minutes.

[0256] Example 5 - Evaluation of selected compounds in a DTA mouse model of narcolepsy

[0257] Using a DTA-induced narcolepsy mouse model, we determined changes in sleep-wake EEG / EMG patterns (including cataplexy) at different time points (day 1 to week 3) under the influence of compound I (Ph-HTBA). EEG / EMG changes were further mapped up to week 4 after drug withdrawal. Electrodes were placed in the skull and neck muscles of mice under isoflurane anesthesia (2% to 2.5% in O2). After 5–10 days of recovery, the electrodes were connected to a recording system, and EEG / EMG signals were recorded via synchronized video recording. Based on the data, sleep / wake parameters and cataplexy episodes were scored and calculated. Figure 3 In a two-factor ANOVA model, the treatment was found to have a statistically significant effect overall, p = 0.0017, n = 5-6.

[0258] Example 6 - Evaluation of selected compounds in a hypothalamic-pituitary-knockout mouse model of narcolepsy

[0259] Using a hypothalamic-pituitary-knockout mouse model, we determined changes in sleep-wake EEG / EMG patterns (including cataplexy) at different time points (day 1 to week 3) under the influence of compound I (HOCPCA). EEG / EMG changes were further mapped up to week 4 after drug withdrawal. Electrodes were placed in the skull and neck muscles of mice under isoflurane anesthesia (2% to 2.5% in O2). After 5–10 days of recovery, the electrodes were connected to a recording system, and EEG / EMG signals were recorded via synchronized video recording. Based on the data, sleep / wake parameters and cataplexy episodes were scored and calculated. Figure 4-5 Treatment on day 8 showed p = 0.044 and on day 15 p = 0.010 (mixed-effects model and post-hoc Sidak comparison). Figure 4 It significantly reduced cataplexy. In the narcolepsy model, treatment further stabilized wakefulness and significantly reduced wake bouts (p = 0.01), as shown by two-way ANOVA and post-hoc Dunnett comparison.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating CNS disorders accompanied by sleep disturbances, wherein the compound of formula I is: (Equation I) Where R5 is H and R1 and R2 form a ring system, the compound is a compound of formula II: (Formula II), in n is 0; X is O; R3 is H or a straight-chain or branched C1-C6-alkyl group; R4 is H; Alternatively, if R2 is H and R1 and R5 form a cyclic system, the compound is Ph-HTBA: (Ph-HTBA), The CNS conditions accompanied by sleep disorders mentioned above are central hypersomnia or neurodevelopmental disorders.

2. The use according to claim 1, wherein the compound has the structure of formula II.

3. The use according to claim 1, wherein the compound is Ph-HTBA.

4. The use according to claim 1, wherein R3 is -Me, -Et, -Pr, -iPr, -Bu, -tBu, -iBu, pentyl, isopentyl, neopentyl, hexyl or branched hexyl.

5. The use according to claim 1, wherein R3 and R4 are both H.

6. The use according to claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

7. The use according to claim 6, wherein the pharmaceutically acceptable salt is a sodium or potassium salt.

8. The use according to claim 1, wherein the compound is in a crystalline state.

9. The use according to claim 1, wherein the compound is administered at a dose of 0.01 mg / kg to 100.0 mg / kg.

10. The use according to claim 9, wherein the compound is administered at a dose of 0.1 mg / kg to 10 mg / kg.

11. The use according to claim 1, wherein the CNS condition accompanied by sleep disturbance is central hypersomnia.

12. The use according to claim 11, wherein the central hypersomnia is idiopathic hypersomnia, recurrent hypersomnia, or narcolepsy.

13. The use according to claim 12, wherein the recurrent hypersomnia is Klein-Levin syndrome.

14. The use according to claim 1, wherein the central hypersomnia is narcolepsy.

15. The use according to claim 14, wherein the use relieves at least one of the symptoms of narcolepsy.

16. The use according to claim 15, wherein the symptoms are selected from excessive daytime sleepiness, cataplexy, abnormal REM sleep, sleep paralysis, or nocturnal insomnia.

17. The use according to claim 14, wherein the narcolepsy is narcolepsy with cataplexy or narcolepsy type 1.

18. The use according to claim 14, wherein the narcolepsy is narcolepsy without cataplexy or narcolepsy type 2.

19. The use according to claim 14, wherein the narcolepsy is secondary narcolepsy.

20. The use according to claim 1, wherein the CNS disorder accompanied by sleep disturbance is a neurodevelopmental disorder.

21. The use according to claim 1, wherein the CNS condition with sleep disturbance is caused by a hereditary CaMK2 mutation.

22. The use according to claim 20, wherein the neurodevelopmental disorder is Angelman syndrome, Down syndrome, Fragile X, neurofibromatosis type 1, Cri-du-Chat syndrome, succinate semialdehyde dehydrogenase deficiency, or Rett syndrome.

23. The use according to claim 22, wherein the neurodevelopmental disorder is Angelman syndrome or Down syndrome.

24. The use according to claim 1, wherein the drug further comprises a CNS stimulant, an antidepressant, or a GABA receptor agonist.

25. The use according to claim 24, wherein the CNS stimulant is selected from modafinil, amofinil, methylphenidate, amphetamine, dextromethorphan, methamphetamine, phentermine, benzotriazine, amphetamine, lisdextromethorphan, benzphenamine, atomoxetine, caffeine, and ephedrine.

26. The use according to claim 24, wherein the antidepressant is selected from serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and norepinephrine and specific serotonergic antidepressants.

27. The use according to claim 24, wherein the GABA receptor agonist is selected from sodium hydroxybutyrate, baclofen, fenibutide, and gaposadol.

28. The use according to claim 1, wherein a dose of the drug comprises 0.1 mg to 5.0 g of the compound.

29. The use according to claim 28, wherein a dose of the drug comprises 0.1 mg to 1.0 g of the compound.

30. The use according to claim 28, wherein a dose of said drug comprises 1 mg to 1000 mg of said compound.

31. The use according to claim 28, wherein a dose of the drug comprises 10 mg to 1.0 g of the compound.

32. The use according to claim 28, wherein a dose of the drug comprises 50 mg to 500 mg of the compound.

33. The use according to claim 28, wherein a dose of the drug comprises 250 mg to 5.0 g of the compound.

34. The use according to claim 28, wherein a dose of the drug comprises 0.5 mg to 50 mg of the compound.

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