Use of serotonin 5-HT1A receptor agonists to treat disorders associated with sudden unexpected death in epilepsy

Abstract

The present application relates to a selective 5-HT 1A The present invention relates to the treatment and prevention of diseases associated with an increased risk of sudden unexpected death in epilepsy, such as fragile X syndrome, by administering receptor agonists.

Description

[Technical field]

[0001] The present invention relates to the field of therapeutic treatment of disorders associated with Sudden Unexpected Death in Epilepsy (SUDEP), such as Fragile X Syndrome (FXS). [Background technology]

[0002] A seizure or epileptic seizure is a period of symptoms resulting from abnormally excessive or synchronized neuronal activity in the brain. A fatal complication of epilepsy can lead to SUDEP, which is defined as the sudden and unexpected non-traumatic and non-drowning death of a person with epilepsy without toxicological or anatomical causes of death. Not all seizures result in SUDEP. It has been hypothesized that certain seizure types or seizures occurring in certain patients may be associated with an increased risk of SUDEP.

[0003] Seizures associated with SUDEP typically occur in the setting of certain disorders.

[0004] Among them is fragile X syndrome (FXS), a rare genetic disorder caused by mutations in the FMR1 gene, resulting in loss of function of the FMRP protein, which is important for brain development. Subjects with FXS suffer from a range of symptoms, including sensory hypersensitivity and a tendency to epileptic seizures.

[0005] Transgenic mice lacking FMRP function (i.e., FMR1 knockout mice), a model of FXS, are prone to audiogenic seizures (i.e., seizures induced by loud noise), which if prolonged, can lead to death.

[0006] There are also mutations in the SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 and DEPDC5 genes that can result in SUDEP.

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

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

[0009] From the perspective of brain neurobiology, a link between seizures and serotonin (5-hydroxytryptamine: 5-HT) receptors has been established. However, 1A The role of specific subtypes of serotonin receptors, including those listed above, is controversial.

[0010] Indeed, previous reports have demonstrated the effect of 5-HT on seizures in wild-type rodents (i.e., not affected by genetic abnormalities that confer susceptibility to epilepsy). 1A Receptor agonists (i.e., 5-HT 1A The effects of acetylcholine (ligands that activate the receptor) are conflicting: some reports show an increase, others a decrease:

[0011] Studies have shown that 8-OH-DPAT, dual 5-HT 1A reported conflicting results regarding the activity of 5-HT7 receptor agonists (Yang et al Neurosci Bull. 2014 Jun;30(3):401-8. doi:10.1007 / s12264-013-1396-x. Epub 2014 Jan 15. PMID:24429728; Fujii et al Yakubutsu Seishin Kodo. 1991 Feb;11(1):29-35. PMID:1831945). Furthermore, 8-OH-DPAT was tested in FMR1 knockout mice in electrophysiological and cellular assays, and its effects were mediated by 5-HT7 receptors, but not by 5-HT 1AIt was found not to be mediated by the receptor (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 reported 5-HT7 compounds, but it is unclear whether these compounds are agonists or antagonists (Pharmacol Rep. 2005 May-Jun;57(3):336-44. PMID:15985716). Furthermore, the authors did not report any other 5-HT 1A also reported that 5-HT7 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 have reported that 5-HT 1A Vilazodone, which acts as a receptor agonist, has been reported to induce seizures in humans (McKean et al. Pharmacotherapy. 2015 Mar;35(3):e6-8. doi:10.1002 / phar.1549. PMID:25809181).

[0014] Therefore, 5-HT in seizures 1A The role of receptors, more specifically, selective 5-HT, in SUDEP-related seizures 1A There is no clear consensus regarding the possible effects of receptor agonists.

[0015] WO 2016 / 138138 also describes 5-HT 2A and 5-HT 2B Binds to receptors but not to 5-HT 1AThe patent also discloses the treatment of epilepsy with 5-HT receptor agonists that do not significantly bind to the receptor. 1A No mention of agonists.

[0016] Overall, serotonin can be considered important in the pathophysiology of seizures in disorders such as FXS, but 5-HT 1A No established role has been demonstrated for the receptor, and selective 5-HT 1A The effects of receptor agonists have not been investigated in preclinical models of FXS or other disorders related to SUDEP.

[0017] NLX-101 (also known as F-15599) is disclosed in WO 03 / 106449. It inhibits the serotonin 5-HT 1A It is a compound that highly selectively targets the 5-HT receptor and has been tested in preclinical and clinical studies. 1A It has a distinctive property known as "biased agonism," which directs the receptor to preferentially activate certain intracellular signaling pathways, particularly ERK1 / 2 phosphorylation, as opposed to other signaling pathways. The biased agonist property of NLX-101 is associated with the activation of specific brain regions (Llado-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 improves respiratory abnormalities in a mouse model of Rett syndrome. Nevertheless, the possible effects of NLX-101 on SUDEP have not been investigated. Summary of the Invention

[0019] We now unexpectedly found that NLX-101 reduced audiogenic seizures in FMR1 knockout mice, and selectively inhibited 5-HT 1A It has been established that receptor agonists may be useful in treating FXS and other disorders related to SUDEP.

[0020] Accordingly, the present invention provides a method for the treatment or prevention of a disease associated with SUDEP selected from the group consisting of seizures, fragile X syndrome, Dravet syndrome, Guillain-Barre syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, and diseases associated with FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 or DEPDC5 gene dysfunction, The method comprises administering a therapeutically effective amount of selective 5-HT 1A This involves administering a receptor agonist to a patient suffering from such a disease.

[0021] The present invention also provides a method for administering a therapeutically effective amount of selective 5-HT to a patient suffering from a disease in which SUDEP occurs. 1A Also provided is a method of treating or preventing stroke comprising administering a receptor agonist.

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

[0023] More preferably, the disease is selected from fragile X syndrome, Dravet syndrome, Guillain-Barre syndrome and Ohtahara syndrome.

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

[0025] The lack of effect of NLX-101 against corneal electrically induced seizures in wild-type mice suggests a general lack of antiseizure activity for this compound. As a result, the antiseizure activity of NLX-101 against audiogenic seizures in transgenic FMR1 mice was unexpected and suggests a selective 5-HT inhibitor against certain seizure types, particularly those associated with SUDEP. 1A This suggests receptor agonist activity.

[0026] The ability of NLX-101 to reduce seizures and death in FMR1 knockout mice was due to 5-HT 1A This may result from the highly selective agonist properties of NLX-101 at the receptor. Furthermore, its biased agonist activity for activating ERK1 / 2 phosphorylation may contribute to its anti-seizure and anti-SUDEP properties.

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

[0028] As used herein, the term "disease" refers to a health disorder and encompasses both established medical conditions with a defined reason and syndromes, or collections of symptoms that may not necessarily have the same cause.

[0029] Treatment of such diseases involves eliminating the cause and / or alleviating the symptoms.

[0030] According to one embodiment, 5-HT 1A Receptor agonists are selective, biased 5-HT 1A It is a receptor agonist.

[0031] According to a preferred embodiment, selective 5-HT 1A The receptor agonist has the formula (I): [ka] (In the formula, X represents a halogen atom; Z is -(CH2-Y) n represents an -Ar group, n is 0 or 1, Y is selected from -CH2-, -NH-, -S- or -O-; and Ar represents a 5-10 membered aryl or heteroaryl ring optionally substituted with one or more C1-C6 alkyl groups. or one of the pharma- ceutically acceptable salts or esters thereof.

[0032] As used herein, "alkyl" means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain, and which may be optionally substituted with one or more substituents, which may be the same or different, including halo, hydroxy, cyano, amino, alkoxy, etc. Exemplary alkyl groups include methyl, ethyl, n-propyl, and i-propyl.

[0033] "Aryl" means an aromatic monocyclic or bicyclic ring system of 5 to about 10 carbon atoms, preferably about 6 to about 10 carbon atoms. Exemplary aryl groups include phenyl or naphthyl.

[0034] "Heteroaryl" means an aromatic monocyclic or bicyclic ring system of about 5 to about 10 atoms, preferably about 5 to about 10 carbon atoms, in which one or more of the atoms in the ring system is a heteroatom(s) other than carbon, such as nitrogen, oxygen, or sulfur. Preferred ring sizes of the rings in the ring system include about 5 to about 6 ring atoms. The designation of aza, oxa, or thia as a prefix before heteroaryl clearly indicates that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of a heteroaryl may be a basic nitrogen atom or may be optionally oxidized to the corresponding N-oxide. Examples of heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, isoaryl, ... Heteroaryl groups include midazopyridyl, benzazaindole, 1,2,4-triazinyl, benzthiazolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl. Preferred heteroaryl groups include pyrazinyl, pyridyl and pyrimidinyl.

[0035] According to a preferred embodiment, the compound of formula (I) is selected from the group consisting of the following closely related compounds (IA) and (II) which also exhibit similar biased agonist properties towards the activation of ERK1 / 2 phosphorylation: NLX-101 of formula (IA): [ka] or one of its pharma- ceutically acceptable salts or esters, and Formula (II): [ka] (In the formula, X is selected from F and Cl; Y is selected from -CH2-, -NH-, -S-, or -O-; and Ar is selected from phenyl and N-containing 6-membered monocyclic heteroaryl groups, optionally substituted with one or more C1-C6 alkyl groups. or one of the pharma- ceutically acceptable salts or esters thereof, is selected from.

[0036] According to one embodiment, in formula (II): X is selected from F and Cl, and It is the basis [ka] teeth: [ka] is selected from the group consisting of:

[0037] According to a further embodiment, in formula (II): X=F, Y=-O-, and Ar is: [ka] is selected from the group consisting of:

[0038] According to a particular embodiment, the compound of formula (II) is: [ka] or one of their pharma- ceutically acceptable salts or esters.

[0039] Compounds of formula (II), serotonin 5-HT 1A Their high selectivity for the receptor, their biased agonism profile towards ERK1 / 2 phosphorylation and their synthesis are disclosed in Sniecikowska et al. Journal of Medicinal Chemistry, 2019, 62, 2750-2771, PMID 30721053.

[0040] According to one embodiment, the compounds may be in the form of their free base or alternatively may be in the form of a pharma- ceutically acceptable salt, such as, for example, a hydrochloride, oxalate, dihydrochloride, fumarate, maleate, tosylate, salicylate, sulfonate or benzoate salt.

[0041] Identifying subjects in need of treatment for the conditions described herein is well within the ability and knowledge of one of ordinary skill in the art. A skilled clinician can easily identify subjects in need of such treatment by using clinical tests, physical examinations, genetic tests, and medical / family history. These subjects typically suffer from diseases associated with SUDEP, such as seizures, fragile X syndrome (FXS), Rett syndrome, Dravet syndrome, Guillain-Barre syndrome, Ohtahara syndrome, and Angelman syndrome, or suffer from diseases associated with FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5, or DEPDC5 gene dysfunction.

[0042] According to one embodiment, a patient suffering from a disease associated with SUDEP may exhibit FRM1 gene dysfunction.

[0043] The actual dosage level of the compound may vary so as to obtain an amount of the active ingredient effective to obtain the desired therapeutic response for a particular composition and method of administration. Thus, the selected dosage level will depend on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors, such as the condition of the patient.

[0044] The therapeutically effective amount can be easily determined by the attending diagnostician who is skilled in the art by using conventional techniques and observing the results obtained under similar circumstances. In determining the therapeutically effective amount, the attending diagnostician takes into account a number of factors, including but not limited to the species of the subject; its size, age and general health; the specific disease involved; the extent or severity of the disease involved; the response of the individual subject; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; the use of concomitant drugs; and other relevant circumstances.

[0045] The amount of compound required to achieve a desired biological effect will vary depending on a number of factors, including the type of drug formulation to be administered, the type of disease, the disease state of the patient, and the route of administration.

[0046] Generally speaking, the preferred dosage of a drug to be administered will likely depend on variables such as the type and extent of the progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, and the compound's excipient formulation and its route of administration.

[0047] Selective 5-HT 1A The daily dose of the receptor agonist may generally be comprised between 0.1 mg / day and 10 mg / day, more particularly between 0.5 and 3 mg / day, in a human patient.

[0048] According to a further embodiment, the methods of the invention also comprise the administration of one or more further active ingredients, typically administered in the treatment or prevention of stroke.

[0049] Selective 5-HT 1AThe receptor agonist can be formulated into a pharmaceutical composition by admixture with one or more pharma- ceutically acceptable excipients.

[0050] The compositions can be conveniently administered in unit dosage form, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th ed.; Gennaro, AR, Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000, by any of the methods well known in the pharmaceutical art.

[0051] Selective 5-HT 1A The receptor agonists can be administered by various routes of administration, such as oral; parenteral, including subcutaneous, intramuscular, intravenous; sublingual, topical; local; intratracheal; intranasal; transdermal or rectal, and the active ingredient is combined with a pharma- ceutically acceptable excipient or vehicle in one or two pharmaceutical compositions.

[0052] In particular, formulations suitable for parenteral administration are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending agents and thickening agents, antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient and have a suitably adjusted pH. For topical application, the composition of the present invention may be used as a cream, gel, ointment or lotion.

[0053] According to the present invention, oral administration in a suitable formulation is advantageously used. Formulations suitable for oral administration to a patient include those each containing a predetermined amount of selective 5-HT 1AThese include discrete units such as capsules, tablets, etc., of soft or hard gelatin, which contain the receptor agonist. They also include powders, granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions. Gastrointestinal resistant formulations are contemplated for oral formulations, particularly for duloxetine.

[0054] "Pharmaceutically" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal, i.e., a human, as appropriate.

[0055] As used herein, "pharmaceutically acceptable excipients" include, inter alia, diluents, adjuvants, carriers, or vehicles. The use of such active ingredients for pharmaceutical active substances is well known in the art.

[0056] In the context of the present invention, the terms "treating" or "treatment" as used herein mean reversing, alleviating or inhibiting the progression of, or preventing, the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0057] As used herein, "prevention" refers to the prophylaxis of a condition, particularly with the aim of reducing the risk of the condition occurring or reducing the extent to which the condition occurs.

[0058] By "therapeutically effective amount" is meant an amount of a compound / pharmaceutical composition according to the invention effective to produce a desired therapeutic effect.

[0059] According to the present invention, the term "patient" or "patient in need thereof" refers to a human or non-human mammal suffering or potentially suffering from the above disorders. Preferably, the subject is a human.

[0060] The compound may be administered in unit dosage form, the term "unit dose" meaning a single dose that can be administered to a patient and that can be easily handled and packaged as a physically and chemically stable unitary dose containing either the active compound itself or as one or two pharma- ceutically acceptable compositions.

[0061] Suitable unit dosage forms include oral forms, sublingual, buccal, intratracheal, intraocular, intranasal forms, by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous, and rectal forms and implants.

[0062] It should be noted that the alternative embodiments described above are not mutually exclusive and may be considered in addition to one another. [Brief description of the drawings]

[0063] The present invention will now be described with reference to the accompanying drawings.

[0064] [Figure 1] FIG. 1 shows the lack of anti-seizure activity of NLX-101 in two models of seizures in wild-type mice. [Diagram 2] FIG. 1 shows dose-dependent reduction of tonic-clonic seizures (TCS) and mortality by NLX-101 in FRM1 transgenic mice (ns: not significant, ***p<0.001, ****p<0.0001, log-rank (Mantel-Cox) test). EXAMPLES

[0065] The invention will be further understood by reference to the following illustrative examples.

[0066] method Corneal Electrical Stimulation (CES)-induced seizures in wild-type mice Experiments were performed according to the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (https: / / panache.ninds.nih.gov / TestDescription / Test6HZ). CES tests were performed using wild-type male CF-1 mice. Seizures were induced by a low-frequency (6 Hz, 0.2 ms rectangular pulse), long duration (3 s), 44 mA current (twice the current that produces seizures in 97% of animals) delivered via a corneal electrode (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). Just before placing the corneal electrode, a drop of 0.5% tetracaine hydrochloride in 0.9% saline solution (anesthetic / electrolyte solution) was applied to the eye. Seizures in mice are characterized by an initial momentary fainting followed immediately by jaw clonus, forelimb clonus, twitching of the vibrissae, and "straub tail." Animals that do not exhibit this behavior within a 1-minute observation period are considered "protected" from seizures.

[0067] Tests for anti-seizure activity in the CES model are performed in 4 male mice / dose / time point. Six doses of NLX-101 (0.02, 0.06, 0.5, 1 and 2 mg / kg, intraperitoneally (ip)) and two time points (30 and 120 min after drug administration) were tested.

[0068] Seizures induced in the Maximal Electroshock Seizure (MES) test Experiments were performed according to the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (https: / / panache.ninds.nih.gov / TestDescription / TestMES). MES testing was performed using wild-type male mice. MES is a model of generalized tonic-clonic seizures and provides an indication of a compound's ability to prevent seizure spread when all neural 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 seizures. Seizures were induced by a brief (0.2 s) duration (50 mA) high-frequency (60 Hz) alternating current delivered through corneal electrodes. Prior to stimulation, the cornea was irrigated with 0.5% tetracaine hydrochloride for local anesthesia and 0.9% saline to improve electrical conductivity. MES-induced seizures are characterized by a brief episode of tonic extension of the forelimbs and hindlimbs followed by clonic activity of the forelimbs and hindlimbs. Animals are considered "protected" from MES-induced seizures upon disappearance of the hindlimb tonic extensor component of the seizures. Testing for anti-seizure activity in the MES model is performed on 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 drug administration) were tested.

[0069] Audiogenic tonic-clonic seizures (TCS) in FMR1 transgenic mice FMR1 knockout (KO) mice were bred and weaned on 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. Mice were injected with NLX-101 or saline 10 min before being subjected to auditory stimulation.

[0070] Mice were color-coded before drug or saline administration to distinguish each mouse in post-hoc video analysis. Mice (maximum 4 / cage) were then placed in a cage with a lid, and after 10 min, a speaker was placed on the lid and the cage was placed in a sound-attenuating booth (Gretch-Ken Inc., OR). The auditory stimulus was a frequency-modulated sweep that alternated continuously up and down at frequencies between 2 and 8 kHz, at an intensity of 105–110 dB for 15 min. The procedure began with 5 min of habituation (without sound stimulation) and continued for a total of 20 min. The entire 20 min procedure was video-recorded for offline analysis.

[0071] Typical behavior of FMR1 knockout mice exposed to loud acoustic stimuli includes tonic-clonic seizures (TCS: the mouse lies on the cage bottom with hind limbs extended) and death by respiratory arrest (displaying a deep respiratory gasp and flaccid ears).

[0072] The latency (from the onset of stimulation) to the occurrence of TCS and death was recorded with a stopwatch (precision: 1 s). Survival analysis was used to analyze the probability of TCS or death by the log-rank test.

[0073] The results are shown in Figures 1 and 2.

[0074] In wild-type mice, NLX-101 had no effect on the occurrence of seizures in the maximal electroshock seizure (MES) test at 30 and 120 min post-injection over a wide range of doses (0.02-2 mg / kg ip) (left panel). In the corneal electrical stimulation (CES) seizure test (right panel), NLX-101 reduced the occurrence of seizures in only one of four mice at the highest dose tested and at only one time point (30 min post-injection). The minimal activity of NLX-101 in the MES and CES tests suggests that it does not have anti-seizure activity (Figure 1).

[0075] In contrast, NLX-101 dose-dependently reduced the proportion of FMR1 knockout mice exhibiting 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 dead 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 suggest that NLX-101 exhibits strong anti-seizure and anti-SUDEP activity in FMR1 knockout mice (Figure 2).

Claims

1. A pharmaceutical composition for treating or preventing a disease associated with sudden unexpected death in epilepsy (SUDEP) in a patient, comprising a selective 5-HT 1A receptor agonist, The pharmaceutical composition, wherein the disease associated with SUDEP is selected from the group consisting of fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, and diseases associated with dysfunction of the FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5, or DEPDC5 genes.

2. The pharmaceutical composition according to claim 1 for treating or preventing attacks in patients suffering from a disease in which SUDEP occurs.

3. The pharmaceutical composition of claim 1 or 2, wherein the patient exhibits a FRM1 gene dysfunction.

4. 3. The pharmaceutical composition of claim 2, wherein the patient is suffering 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 astatic epilepsy (MAE), Lennox-Gastaut syndrome, and diseases associated with dysfunction of the FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 and DEPDC5 genes.

5. 3. The pharmaceutical composition according to claim 1, wherein the patient is suffering from a disease selected from the group consisting of fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, and Ohtahara syndrome.

6. The 5-HT １Ａ Receptor agonists are biased 5-HT １Ａ The pharmaceutical composition according to claim 1 or 2, which is a receptor agonist.

7. The 5-HT １Ａ The receptor agonist is represented by formula (I): 【Chemistry 1】 (In the formula, X represents a halogen atom; Z is -(CH ２ -Y) ｎ represents an —Ar group, n is 0 or 1; Y is -CH ２ is selected from —, —NH—, —S—, or —O—, and Ar represents a 5-10 membered aryl or heteroaryl ring optionally substituted with one or more C1-C6 alkyl groups.

3. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

8. The compound of formula (I) has formula (IA): 【Chemistry 2】 8. The pharmaceutical composition of claim 7, wherein the compound is NLX-101 (also known as F-15599) of the compound of Formula 1, or one of its pharmaceutically acceptable salts or esters.

9. The compound of formula (I) is represented by formula (II): 【Transformation 3】 (In the formula, X is selected from F and Cl; Y is defined in claim 7, and Ar is selected from phenyl and N-containing 6-membered monocyclic heteroaryl groups, optionally substituted with one or more C1-C6 alkyl groups.

8. The pharmaceutical composition of claim 7, wherein the compound is one of the following:

10. The compound of formula (I) 【Chemistry 4】 or one of the pharmaceutically acceptable salts or esters thereof.

11. The selective 5-HT agonist is administered in a dose of 0.1 to 10 mg / day in human patients. １Ａ The pharmaceutical composition of claim 1 or 2, wherein a receptor agonist is administered.

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