Application of serotonin 5-HT1A receptor stimulant to treatment of diseases related to sudden epilepsy death

Abstract

The present application relates to the treatment and prevention of diseases associated with increased risk of sudden epilepsy death, such as Fragile X Syndrome, by administering a selective 5-HT1A receptor agonist.

Description

[0001] The present application relates to the field of treatment of diseases associated with sudden unexpected death in epilepsy (SUDEP), such as fragile X syndrome (FXS).

[0002] An epileptic seizure is a period of symptoms caused by abnormal excessive or synchronized neuronal activity in the brain. Fatal complications of epilepsy may result in SUDEP, which is defined as the sudden, unexpected, non-traumatic, and non-drowning death of a person with epilepsy without a toxicological or anatomical cause of death. Not all epileptic seizures result in SUDEP. It has been hypothesized that certain types of seizures or seizures that occur in certain patients may be associated with an increased risk of SUDEP.

[0003] Seizures associated with SUDEP often occur in the setting of certain medical conditions.

[0004] These include Fragile X syndrome (FXS), a rare genetic disorder caused by mutations in the FMR1 gene, which results in loss of function of the FMRP protein, which is important for brain development. Individuals with FXS experience a range of symptoms, including sensory hypersensitivity and a tendency to seizures.

[0005] Transgenic mice lacking FMRP function (i.e., FMR1 knockout mice) are an animal model of FXS and are prone to audiogenic seizures (i.e., seizures induced by loud noises), which can lead to death if they persist for too long.

[0006] Mutations that can cause SUDEP also occur in the SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5, and DEPDC5 genes.

[0007] Other disorders associated with epileptic seizures include Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic-cataplexy epilepsy (MAE), and Lennox-Gastaut syndrome.

[0008] Therefore, it is desirable to provide new drug candidates for treating diseases associated with SUDEP.It is also desirable to provide new drug candidates for treating SUDEP.

[0009] In terms of brain neurobiology, the relationship between epileptic seizures and serotonin (5-hydroxytryptamine: 5-HT) receptors is well established. 1A The role of specific subtypes of serotonin receptors, including serotonin, remains controversial.

[0010] In fact, about 5-HT 1A Receptor agonists (i.e., activating 5-HT1A Previous reports of the effects of agonists of leukemia / associated peptides (ligands for leukemia / associated peptide receptors) on seizures in wild-type rodents (i.e., those without genetic abnormalities that predispose to seizures) have been conflicting: some have shown increases, while others have shown decreases:

[0011] Studies have reported that 8-OH-DPAT (a dual 5-HT 1A / 5-HT 7 Receptor agonists) have shown conflicting results on seizure activity (Yang et al. Neurosci-Bull. 2014Jun; 30(3):401-8. doi:10.1007 / s12264-013-1396-x. Epub 2014Jan 15. PMID:224429728; Fujii et al. Yakubussu Seishin Kodo. 1991Feb; 11(1):29-35. PMID:1831945). In addition, when 8-OH-DPAT was electrophysiologically and cellularly tested in FMR1 knockout mice, its effects were found to be mediated by 5-HT. 7 Instead of 5-HT 1A Receptor-mediated (Costa et al., Biol Psychiatry. 2012 Dec 1; 72(11):924-33. doi:10.1016 / j.biopsych.2012.06.008. Epub 2012 Jul 18. PMID:22817866).

[0012] Obniska et al. reported that 5-HT has anticonvulsant activity 1A / 5-HT 7 Compounds, but it is not clear whether these compounds are agonists or antagonists (Pharmacol Rep. 2005 May-Jun; 57(3):336-44. PMID:15985716). In addition, the authors also reported other 5-HT 1A / 5-HT 7 The ligands showed no correlation between their anticonvulsant activity and their serotonergic properties (Pharmacol Rep. 2005 May-Jun; 57(3):336-44. PMID: 15985716).

[0013] Recently, some authors reported that vilazodone, as a 5-HT 1A Receptor agonists that induce epileptic seizures in humans (McKean et al., Pharmaceutical. 2015 Mar; 35(3): e6-8. doi: 10.1002 / par.1549. PMID: 25809181).

[0014] Therefore, for 5-HT 1A The role of 5-HT receptors in epilepsy, especially selective 5-HT 1A There is no clear consensus on the possible effects of agonists on seizures associated with SUDEP.

[0015] WO2016 / 138138 also discloses the use of 5-HT receptor agonists to treat epilepsy, which are 2A and 5-HT 2B Receptor binding but not 5-HT 1A In any case, there is no mention of selective 5-HT 1A Agonist.

[0016] Overall, although serotonin may be considered important in the pathophysiology of seizures in disorders such as FXS, 5-HT has not been shown to 1A The exact role of the receptors and selective 5-HT 1A Effects of receptor agonists in preclinical models of FXS or other diseases associated with SUDEP.

[0017] NLX-101 (also known as F-15599) has been disclosed in WO03 / 106449. It is a highly selective serotonin 5-HT 1A The compound, which targets the 5-HT receptor, has been tested in preclinical and clinical studies. It has a unique property known as "biased agonism," whereby it directs the 5-HT 1A The receptor preferentially activates specific intracellular signaling pathways, particularly ERK1 / 2 phosphorylation, over other signaling pathways. The biased agonist properties of NLX-101 are associated with activation of specific brain regions (Lladó-Pelfort et al. J Pharmacol. 2010 Aug;160(8):1929-40. doi:10.1111 / j.1476-5381.2010.00738.x. PMID:20649591).

[0018] Levitt et al. J. Appli. Physiol. 115: 1626-1633 2013 reported that NLX-101 improved respiratory abnormalities in a mouse model of Rett syndrome. However, the possible effect of NLX-101 on SUDEP has not been studied.

[0019] The inventors have now found that NLX-101 unexpectedly reduces audiogenic seizures in FMR1 knockout mice and have identified a selective 5-HT 1AReceptor agonists may therefore be useful in the treatment of FXS and other SUDEP-related disorders.

[0020] Therefore, the present application provides a method for treating or preventing a disease associated with SUDEP, wherein the disease is selected from the group consisting of epileptic seizures, fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic cataplexy epilepsy (MAE), Lennox-Gastaut syndrome, and a disease associated with FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 or DEPDC5 gene dysfunction, the method comprising administering a therapeutically effective amount of a selective 5-HT inhibitor. 1A Receptor agonists are administered to patients suffering from this disease.

[0021] The present application also provides a method for treating or preventing epileptic seizures, comprising administering a therapeutically effective amount of a selective 5-HT 1A Receptor agonists are administered to patients suffering from a disease in which SUDEP occurs.

[0022] According to one embodiment of the present application, the diseases in which SUDEP occurs include fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome, Angelman syndrome, Rett syndrome, myoclonic cataplexy epilepsy (MAE), Lennox-Gastaut syndrome, and diseases associated with FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 or DEPDC5 gene dysfunction.

[0023] More preferably, the disease is selected from the group consisting of Fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome and Ohtahara syndrome.

[0024] In particular, using two widely used epileptic seizure models induced by corneal electrical stimulation, the inventors found that NLX-101 did not exhibit any anti-epileptic activity in wild-type (i.e., non-transgenic) mice. In contrast, when tested at a similar dose range in an audiogenic tonic-clonic seizure model in FMR1 knockout mice, NLX-101 potently and effectively reduced seizures and protected more than 75% of mice from death.

[0025] NLX-101 had no effect on electrically induced seizures in the cornea of ​​wild-type mice, suggesting a general lack of antiseizure activity for this compound. Therefore, the antiseizure activity of NLX-101 against audiogenic seizures in transgenic FMR1 mice was unexpected and suggests a selective 5-HT 1A Receptor agonists are active against certain seizure types, particularly those associated with SUDEP.

[0026] The ability of NLX-101 to reduce seizures and mortality in FMR1 knockout mice may result from the effects of NLX-101 on 5-HT 1A Very selective agonist properties of the receptor. In addition, its biased agonist activity towards activation of ERK1 / 2 phosphorylation may contribute to its anti-seizure and anti-SUDEP properties.

[0027] As used herein, "associated with SUDEP" refers to a disease that may result in an increased risk of SUDEP compared to the general patient population, typically at least 10% more SUDEP than the general patient population, more preferably at least 20% more SUDEP, more preferably at least 30% more SUDEP. This increased risk may correspond to certain seizure types and / or may occur in certain patient populations.

[0028] As used herein, the term "disease" refers to health disorders, including established medical symptoms with a clear cause, as well as syndromes, which are a collection of symptoms that do not necessarily have an identifiable cause.

[0029] Treatment of this disease involves eliminating the cause and / or alleviating the symptoms.

[0030] According to one embodiment of the present application, the 5-HT 1A Receptor agonists are biased towards 5-HT 1A Receptor agonists.

[0031] According to one embodiment of the present application, the 5-HT 1A The receptor agonist is selected from the compounds of formula (I):

[0032]

[0033] in

[0034] X represents a halogen atom;

[0035] Z represents -(CH 2 -Y) n -Ar group, wherein:

[0036] n is 0 or 1;

[0037] Y is selected from -CH 2 -, -NH-, -S-, or -O-; and

[0038] Ar represents one or more C 1 -C 6 an alkyl-substituted 5- to 10-membered aryl or heteroaryl ring;

[0039] or one of its pharmaceutically acceptable salts or esters.

[0040] As used herein, "alkyl" refers to a straight or branched aliphatic hydrocarbon group having about 1 to about 6 carbon atoms in the chain, optionally substituted with one or more substituents which may be the same or different, including halogen, hydroxy, cyano, amino, alkoxy. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl.

[0041] "Aryl" refers to an aromatic monocyclic or bicyclic ring system having 5 to about 10 carbon atoms, preferably having about 6 to about 10 carbon atoms. Exemplary aryl groups include phenyl or naphthyl.

[0042] "Heteroaryl" refers to an aromatic monocyclic or bicyclic ring system having about 5 to about 10 atoms, preferably about 5 to 10 carbon atoms, wherein one or more atoms in the ring system are heteroelements other than carbon, such as nitrogen, oxygen or sulfur. Preferred ring sizes for the rings of the ring system include about 5 to about 6 ring atoms. In the heteroaryl prefix, the designation of aza, oxa or thia means that at least one nitrogen, oxygen or sulfur atom is present as a ring atom, respectively. The nitrogen atom of the heteroaryl group can be a basic nitrogen atom and can also be optionally oxidized to the corresponding N-oxide. Exemplary heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazolyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazolyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridinyl, thienopyrimidinyl, pyrazolyl, pyridaz ... The preferred heteroaryl groups include pyrazinyl, pyrid ...

[0043] According to a preferred embodiment, the compound of formula (I) is selected from the following compounds (IA) and (II), which are closely related and also exhibit similar biased agonist properties for activation of ERK1 / 2 phosphorylation:

[0044] NLX-101 of formula (IA):

[0045]

[0046] or one of its pharmaceutically acceptable salts or esters; and

[0047] Compounds of formula (II):

[0048]

[0049] in

[0050] X is selected from F and Cl;

[0051] Y is selected from -CH 2 -, -NH-, -S-, or -O-; and

[0052] Ar is selected from the group consisting of one or more C 1 -C 6 Alkyl-substituted phenyl and N-containing 6-membered monocyclic heteroaryl;

[0053] or one of its pharmaceutically acceptable salts or esters.

[0054] According to one embodiment of the present application, in formula (II),

[0055] X is selected from F and Cl; and

[0056] Group Select from the following group:

[0057]

[0058] According to a further embodiment, in formula (II),

[0059] X = F;

[0060] Y=-O-; and

[0061] Ar is selected from the group consisting of:

[0062]

[0063] According to a particular embodiment, the compound of formula (II) may be selected from:

[0064]

[0065] or one of its pharmaceutically acceptable salts or esters.

[0066] Compounds of formula (II), their effects on serotonin 5-HT 1A The high selectivity of the receptors, their biased agonistic properties of ERK1 / 2 phosphorylation and their synthesis are disclosed in Sniecikowska et al. Journal of Medicinal Chemistry, 2019, 627750-2771, PMID 30721053.

[0067] According to one embodiment of the present application, the compound may be in the form of its free base, or alternatively, in the form of a pharmaceutically acceptable salt, such as hydrochloride, oxalate, dihydrochloride, fumarate, maleate, toluenesulfonate, salicylate, sulfonate or benzoate.

[0068] It is well within the ability and knowledge of those skilled in the art to determine the subjects who need treatment for the above-mentioned diseases. Clinicians in the art can easily identify those subjects who need such treatment by using clinical trials, physical examinations, genetic testing and medical history / family history. These subjects usually suffer from diseases associated with SUDEP, such as epileptic seizures, fragile X syndrome (FXS), Rett syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome and Angelman syndrome, or diseases associated with FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 or DEPDC5 gene dysfunction.

[0069] According to one embodiment, a patient suffering from a disease associated with SUDEP may exhibit FRM1 gene dysfunction.

[0070] The actual dosage level of the compound can be varied to obtain an amount of active ingredient that is effective to obtain the desired therapeutic response for a particular composition and method of administration. Therefore, the selected dosage level depends on the desired therapeutic effect, route of administration, desired course of treatment and other factors, such as the patient's condition.

[0071] The therapeutically effective amount can be readily determined by an attending diagnostician with expertise according to routine techniques and by reference to the results of similar situations. In determining the therapeutically effective amount, the attending diagnostician considers many factors, including, but not limited to: the type of subject; his / her size, age and general health; the specific disease involved; the extent or severity of the disease; the response of the individual subject; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; concomitant medications; and other relevant circumstances.

[0072] The amount of compound required to achieve the desired biological effect will vary depending on many factors, including the type of formulation of the drug being administered, the type of disease, the disease state of the patient, and the route of administration.

[0073] In general, the preferred dosage of the drug to be administered may depend on such variables as the type and extent of the disease or condition developed, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the compound excipients and its route of administration.

[0074] In human patients, selective 5-HT 1AThe daily dose of the receptor agonist is generally between 0.1 mg / day and 10 mg / day, more particularly between 0.5 mg / day and 3 mg / day.

[0075] According to another embodiment, the method of the present application further comprises administering one or more other active ingredients, typically administered for the treatment or prevention of epileptic seizures.

[0076] Selective 5-HT 1A The receptor agonist can be formulated into a pharmaceutical composition by mixing with one or more pharmaceutically acceptable excipients. The composition can be conveniently administered in unit dosage form and can be prepared by any method well known in the pharmaceutical field, for example, as described in Remington: The Science and Practice of Pharmacy, 20 th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.

[0077] Selective 5-HT 1A Receptor agonists can be administered by various routes of administration: for example, orally; parenterally, including subcutaneous injection, intramuscular injection, intravenous injection; sublingually, topically, locally; intratracheally; intranasally; transdermally or rectally; the active ingredient is combined with a pharmaceutically acceptable excipient or carrier in one or two pharmaceutical compositions.

[0078] In particular, formulations suitable for parenteral administration are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending agents, thickening agents and antioxidants, buffers, bacteriostats and solutes to make the formulation isotonic with the blood of the intended recipient and have a suitably adjusted pH. For topical application, the compositions of the present application can be used as creams, gels, ointments or emulsions.

[0079] According to the present application, oral administration of suitable formulations is advantageously used. Formulations suitable for oral administration to patients include discrete units, such as capsules, such as soft gel or hard gel; tablets, each containing a predetermined amount of selective 5-HT 1A Receptor agonists. They also include powders; granules; solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil emulsions. For oral preparations, especially duloxetine, gastrointestinal resistant preparations are also considered.

[0080] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans, as the case may be.

[0081] As used herein, "pharmaceutically acceptable excipient" includes, inter alia, a diluent, an adjuvant, a carrier or an excipient. The use of such ingredients for pharmaceutically active substances is well known in the art.

[0082] In the context of this application, the term "treat", "treat", or "treating" as used herein means to reverse, alleviate, inhibit the progression of, or prevent the disease or condition to which the term applies, or to reverse, alleviate, inhibit, or prevent one or more symptoms of the disease or condition.

[0083] As used herein, "prevention" refers to preventing a condition, particularly with the intent to reduce the risk of the condition occurring or to reduce the extent of the condition occurring.

[0084] "Therapeutically effective amount" refers to an effective amount of the compound / pharmaceutical composition according to the present application to produce the desired therapeutic effect.

[0085] According to the present application, the term "patient" or "patient in need thereof" refers to a human or non-human mammal that is affected by or may be affected by the above-mentioned disease. Preferably, the patient is a human.

[0086] These compounds can be administered in unit doses, wherein the term "unit dose" refers to a single dose that can be administered to a patient and can be easily handled and packaged, and is physically and chemically stable, and includes the active compound itself, or one or two pharmaceutically acceptable compositions.

[0087] Suitable unit dosage forms include oral dosage forms; sublingual, buccal, intratracheal, intraocular, intranasal dosage forms, by inhalation, topically, transdermally, subcutaneously, intramuscularly or intravenously, as well as rectal forms and implants.

[0088] It should be noted that the alternative embodiments described above are not mutually exclusive and can be considered in addition to each other. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] This application will be described in conjunction with the accompanying drawings:

[0090] Figure 1 We show that NLX-101 lacks anti-seizure activity in two seizure models in wild-type mice.

[0091] Figure 2 NLX-101 was shown to dose-dependently reduce tonic-clonic seizures (TCS) and mortality in FRM1 transgenic mice (ns: not significant; ***p<0.001, ****p<0.0001, log-rank (Mantel-Cox) test).

[0092] The present application will be further understood by reference to the following illustrative examples: Example

[0093] method

[0094] Corneal electrical stimulation (CES)-induced epilepsy attack

[0095] The experiment was conducted in accordance with the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Treatment Screening Program (https: / / panache.ninds.nih.gov / TestDescription / Test6HZ). Wild-type male CF-1 mice were used for CES testing. Epileptic seizures were induced by delivering low-frequency (6 Hz, 0.2 msec rectangular pulses), long duration (3 seconds), 44 mA current (the current that produced epileptic seizures in 97% of animals was twice the current) through corneal electrodes (Barton ME, Klein BD, Wolf HH, White HS. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 2001; 47: 217-27). Before placing the corneal electrodes, 0.5% tetracaine hydrochloride in a 0.9% saline (anesthetic / electrolyte) solution was instilled into the eyes. Seizures in mice are characterized by an initial brief vertigo, followed immediately by jaw clonus, forelimb clonus, vibrissa twitching, and a "straub tail." Animals that did not display this behavior during the one-minute observation period were considered "protected" from seizures.

[0096] Anti-seizure activity was tested in the CES model using 4 male mice / dose / time point. Six doses of NLX-101 (0.02, 0.06, 0.5, 1 and 2 mg / kg ip) and two time points (30 and 120 min after dosing) were tested.

[0097] Maximum electric shock epilepsy Seizure (MES) test induced epilepsy attack

[0098] The study was conducted under the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Treatment Screening Program ( https: / / panache.ninds.nih.gov / TestDescription / Test6HZ). Wild-type male mice were used for MES testing. MES is a model of systemic tonic-clonic seizures, which is used to indicate the ability of a compound to prevent the spread of seizures when all neuronal circuits in the brain are maximally active (White HS, Johnson M, Wolf HH, Kupferberg HJ. The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. Ital J Neurol sci. 1995; 16: 73-7). These seizures are highly reproducible and electrophysiologically consistent with human epileptic seizures. A short-term (0.2 second), 50mA high-frequency (60Hz) alternating current was applied through corneal electrodes to induce epileptic seizures. Before stimulation, the cornea was rinsed with 0.5% tetracaine hydrochloride for local anesthesia, and the cornea was rinsed with 0.9% saline to increase conductivity. MES-induced seizures are characterized by tonic extension of the forelimbs and hindlimbs, followed by brief episodes of clonic activity in the forelimbs and hindlimbs. Animals are considered "protected" from MES-induced seizures after the hindlimb tonic extensor component of the seizure is eliminated. When testing anti-epileptic activity in the MES model, 4 male mice were used per dose / time point. Six doses of NLX-101 (0.02, 0.06, 0.5, 1 and 2 mg / kg ip) and two time points (30 and 120 min after dosing) were tested.

[0099] Audiogenic tonic-clonic dyscrasias in FMR1 transgenic mice epilepsy Seizure (TCS)

[0100] FMR1 knockout (KO) mice were bred and weaned at postnatal day 21 (P21), and all mice were tested between P21 and P23. NLX-101 was administered at doses of 0.6, 1.2, 1.8, and 2.4 mg / kg ip. Control FMR1 KO mice received saline. NLX-101 or saline was injected 10 minutes before auditory stimulation of mice.

[0101] To distinguish each mouse in subsequent video analysis, mice were color-coded before administration of drugs or saline. Mice (up to 4 / cage) were then placed in a covered cage; after 10 minutes, a speaker was placed on top of the lid and the cage was placed in a sound-attenuating chamber (Gretch-Ken, OR); auditory stimulation was a continuous alternating up and down frequency modulation sweep with a frequency between 2-8kHz, presented at an intensity of 105-110dB for 15 minutes. The process lasted a total of 20 minutes, starting with a 5-minute habituation training (without sound stimulation). The entire 20-minute process was video recorded for offline analysis.

[0102] Typical behaviors of FMR1 knockout mice in response to loud audio stimulation include tonic-clonic seizures (TCS: mice lying on the cage floor with hind limbs extended) and death from respiratory arrest (manifested by deep gasps for breath and relaxed auricles).

[0103] The waiting time (from the start of stimulation) to the time of TCS and death was recorded with a stopwatch (accuracy: 1 sec). Survival analysis was performed and the probability of TCS or death was analyzed by log-rank test.

[0104] The results are as follows Figure 1 and Figure 2 As shown:

[0105] In wild-type mice, NLX-101 did not affect seizure activity in the maximal electroconvulsive seizure (MES) test over a wide dose range (0.02 to 2 mg / kg ip) and at 30 and 120 min after injection (left). In the corneal electrical stimulation (CES) seizure test (right), NLX-101 reduced seizure activity in only 1 of 4 mice at the highest dose tested and at only one time point (30 min after injection). The minimal activity of NLX-101 in both the MES and CES tests suggests that it does not have anti-seizure activity ( Figure 1 ).

[0106] In contrast, NLX-101 dose-dependently reduced the percentage of FMR1 knockout mice that developed tonic-clonic seizures, with significant effects at 1.8 and 2.4 mg / kg (left panel). NLX-101 also dose-dependently reduced the number of deaths in FMR1 knockout mice, with significant effects at doses of 1.2, 1.8, and 2.4 mg / kg (right panel). Each experimental group consisted of 14 or 16 mice (half of which were male and half were female). These data indicate that NLX-101 exhibits potent anti-seizure and anti-SUDEP activity in FMR1 knockout mice ( Figure 2 ).

Claims

1. A method for treating or preventing a disease associated with sudden unexpected death in epilepsy (SUDEP), the disease being selected from the group consisting of fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic cataplexy epilepsy (MAE), Lennox-Gastaut syndrome, and a disease associated with dysfunction of the FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 or DEPDC5 genes, The method comprises administering a therapeutically effective amount of a selective 5-HT 1A Receptor agonists are administered to patients suffering from this disease.

2. A method for treating or preventing epileptic seizures, comprising administering a therapeutically effective amount of a selective 5-HT 1A Receptor agonists are administered to patients suffering from a disease in which SUDEP occurs.

3. The method of treatment according to claim 1 or 2, wherein the patient exhibits FRM1 gene dysfunction.

4. The method of claim 2, wherein the patient suffers from a disease selected from the group consisting of fragile X syndrome, Rett syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome and Angelman syndrome, myoclonic cataplexy epilepsy (MAE), Lennox-Gastaut syndrome, and diseases associated with dysfunction of the FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 and DEPDC5 genes.

5. The method according to any one of the preceding claims, wherein the patient suffers from a disease selected from the group consisting of Fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome and Ohtahara syndrome.

6. A method according to any one of the preceding claims, wherein the 5-HT 1A Receptor agonists are biased towards 5-HT 1A Receptor agonists.

7. A method according to any one of the preceding claims, wherein the 5-HT 1A The receptor agonist is selected from the compounds of formula (I): in X represents a halogen atom; Z represents -(CH2-Y) n -Ar group, wherein: n is 0 or 1; Y is selected from -CH2-, -NH-, -S- or -O-; and Ar represents a 5- to 10-membered aryl or heteroaryl ring optionally substituted by one or more C1-C6 alkyl groups; or one of its pharmaceutically acceptable salts or esters.

8. The method of claim 7, wherein the compound of formula (I) is NLX-101 (also known as F-15599) of formula (IA): or one of its pharmaceutically acceptable salts or esters.

9. The method according to claim 7, wherein the compound of formula (I) is a compound of formula (II): in X is selected from F and Cl; Y is defined in claim 5; and Ar is selected from phenyl optionally substituted with one or more C1-C6 alkyl groups and 6-membered monocyclic heteroaryl groups containing N; or one of its pharmaceutically acceptable salts or esters.

10. The method according to claim 9, wherein the compound of formula (I) is selected from: or one of its pharmaceutically acceptable salts or esters.

11. A method according to any one of the preceding claims, comprising administering the selective 5-HT in a human patient at a dose of 0.1 to 10 mg / day. 1A Receptor agonists.

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