GABA receptor modulators for use in the treatment of absence seizures

Abstract

Methods for treating and / or preventing absence seizures are provided herein. The present invention relates to methods for treating and preventing absence epilepsy and absence seizures. Surprisingly, the inventors have found that known GABA A We found that the receptor modulator, 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, compound 1, has a modulating effect on spike-and-slow-wave firing and absence seizure activity.

Description

[Technical Field]

[0001] The present invention relates to the use of 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, a known GABA receptor modulator, or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of absence seizures. [Background technology]

[0002] Absence seizure Absence seizure is a term for a type of seizure accompanied by staring. This type of seizure is a short-lived (usually less than 15 seconds) disturbance of brain function due to abnormal electrical activity in the brain. The seizure is caused by hyperactivity in the brain. Absence seizures occur most frequently in people under 21 years of age, usually in children between 4 and 12 years of age.

[0003] A generalized absence seizure (non-motor seizure) is a type of unconscious seizure with electrophotographic generalized seizures. It is a generalized seizure characterized by interruption of activity, a blank stare, and usually the person is unresponsive when spoken to, which can be mistaken for a brief period of inattention. The seizure lasts about 10 seconds, but may last up to 30 seconds. Typically, there is no confusion, headache, or drowsiness after the seizure.

[0004] Symptoms of absence seizures include the following: • Sudden cessation of activity without falls. • Lip clicking. • Eyelid spasms. ·Chewing movements. • Rub your fingers together. • Small movements of both hands.

[0005] Afterward, there is usually no memory of the event. However, if the seizure is longer, the person may be aware of the time they missed. Some people have many episodes every day. When it happens, it can interfere with school or daily activities.

[0006] Absence seizures typically occur in children between the ages of 4 and 14. A child may experience 10, 50, or even 100 absence seizures in a given day, and these may go unnoticed.

[0007] The electrophotographic EEG signature of absence seizures is a spike-and-wave discharge of 2-4 Hz. Several epileptic disorders are characterized by both spike-and-wave discharge and the occurrence of absence seizures. Therefore, there is a need for effective methods that can control both spike-and-wave discharge and absence seizures. [Overview of the project] [Means for solving the problem]

[0008] This invention relates to a method for treating and preventing absence epilepsy and absence seizures. Surprisingly, the inventors have discovered that the known GABA A We found that the receptor modulator, 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, compound 1, has a modulating effect on spike-and-slow-wave firing and absence seizure activity.

[0009] Therefore, in its primary embodiment, the present invention relates to compound 1, which is 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol (shown in formula 1), for use in the treatment and / or prevention of absence seizures. [ka]

[0010] In particular, compound 1 may be included in the treatment of epileptic disorders or conditions, such as slow-wave sleep status epilepticus (ESES), developmental / epileptic encephalopathy with sleep spike-slow wave activation (DEE-SWAS), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, or idiopathic generalized epilepsy, focal-origin seizures, and / or childhood epilepsy exhibiting central temporal spike waves.

[0011] In one embodiment, the present invention relates to a method for treating and / or preventing absence seizures, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0012] In one embodiment, the present invention relates to a method for regulating or reducing spike-and-slow wave emission in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject requiring such regulation.

[0013] In one embodiment, the present invention relates to the use of compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical for the treatment and / or prevention of absence seizures in a subject.

[0014] In one embodiment, the present invention relates to a method for reducing the time, number, and / or duration of absence seizures in a subject, wherein the method comprises administering compound 1 or a pharmaceutically acceptable salt thereof to a subject in need.

[0015] In one embodiment, the present invention relates to a method for treating childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) in human subjects, comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject requiring its use.

[0016] In one aspect, the present invention relates to a method for treating absence epilepsy or absence seizure in a human subject in need thereof, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject in need thereof.

[0017] In one aspect, the present invention relates to a method for treating an epilepsy syndrome or seizure disorder associated with reduced sleep spindle activity in a human subject in need thereof, comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject in need thereof.

[0018] Compound 1 is a α3-containing GABA A A PAM at R, has minimal affinity for α2 and α5 subunits, and does not have an effect on α1-containing GABA A R. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] [Figure 1] These are EEG recordings obtained from GAERS rats systemically injected with vehicle or Compound 1. Effect of administration of the indicated doses of Compound 1 on absence seizures in GAERS rats. A: Vehicle. B: 1 mg / kg. C: 3 mg / kg. D: 10 mg / kg. A typical enlarged section is shown below each trace. The voltage and time calibration in the upper left recording applies to all traces. Conclusion: Administration of Compound 1 reduces spike-and-wave discharges in GAERS rats, a rodent model of spontaneous, genetically determined absence seizures. [Figure 2] Total time spent in absence seizures by GAERS rats after systemic administration of Compound 1. A. Total time spent in absence seizures by GAERS rats after systemic administration of the indicated doses of Compound 1 (time 0). Each data point represents the total time in seizures observed during the indicated 20-minute period. B. Total time in seizures normalized to vehicle-injected rats. *p < 0.05, ****p < 0.0001. Conclusion: Compound 1 significantly reduces the time spent in absence seizures. The anti-absence effect of Compound 1 is rapid, potent, and long-lasting. [Figure 3] The total time spent in absence seizures in GAERS rats after systemic administration of compound 1 is shown as the statistical significance of the anti-absence effect of compound 1 at different time points after injection. The same data as in Figure 2A shows the statistical significance of the total time spent in seizures at each time point after systemic injection of compound 1 at the indicated doses (Tukey post-hoc test compared to vehicle-treated GAERS rats). A. 1 mg / kg (n=8). B. 3 mg / kg (n=8). C. 10 mg / kg (n=9). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. [Figure 4] This is an area-of-curve analysis of the antiabsence effect of compound 1. Total time in the area-of-curve normalized for seizures. The data shown in Figure 2 is analyzed by calculating the area-of-curve for compound 1 for each injected dose. *p<0.05, **p<0.01, ****p<0.0001. [Figure 5] This is the number of absence seizures in GAERS rats after systemic administration of compound 1. A. Number of absence seizures in GAERS rats after systemic administration of compound 1 at the indicated dose (time 0). Each data point represents the number of seizures observed during the indicated 20-minute time period. Same as BA, but normalized to vehicle-treated rats. *p<0.05, **p<0.01, ****p<0.0001. Conclusion: Compound 1 significantly reduces the number of absence seizures. [Figure 6] This is the seizure duration in GAERS rats after systemic administration of compound 1. A. Mean duration of absence seizures in GAERS rats after systemic administration of compound 1 at the indicated dose (time 0). Each data point represents the mean duration of absence seizures observed during the indicated 20-minute period. Same as BA, but normalized to vehicle-treated rats. *p<0.05, ***p<0.001, ****p<0.0001. Conclusion: Compound 1 reduces the duration of absence seizures. [Figure 7]This is the long-term anti-absence effect of compound 1. Total time spent in absence seizures in GAERS rats (normalized to vehicle-treated rats) after systemic administration of compound 1 at 10 mg / kg (time 0). Each data point represents the total time spent in seizures observed during the indicated 1-hour period. *p<0.05, ***p<0.001. Conclusion: Compound 1 exhibits a significant long-term anti-absence effect. [Figure 8] Compound 1 increases sleep spindles. Each graph shows the effect (normalized to the pre-injection period) on the indicated sleep spindle parameters of a systemic administration of 10 mg / kg of Compound 1 in normal Wistar rats during spontaneous sleep, respectively: A. spindle count per minute, B. spindle frequency, C. spindle power, and D. spindle duration (injection time is indicated by a dashed line). Each data point is the mean for a 20-minute vial. *p<0.05, **p<0.01. Conclusion: Compound 1 significantly increases sleep spindles. [Modes for carrying out the invention]

[0020] This disclosure is based, at least in part, on the finding that administration of compound 1 provides modulation of spike-and-slow discharge and absence seizure activity, including a reduction in total time in absence seizures, a reduction in the number of absence seizures, and a reduction in the duration of absence seizures.

[0021] Compound 1 was demonstrated to reduce spike-and-slow-wave firing in a rodent model of spontaneous, genetically determined absence seizures (Genetic Absence Epilepsy Rats from Strasbourg, GAERS), thereby demonstrating a positive effect on the treatment of generalized absence seizures and diseases and disorders associated with absence seizures (Example 1). These results demonstrate a positive effect on the treatment of generalized absence seizures and diseases and disorders associated with absence seizures.

[0022] The compounds of the present invention are useful for treating neurological conditions such as epilepsy, including simple partial seizures, compound partial seizures, secondary generalized seizures, and further including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures.

[0023] Furthermore, it has been demonstrated that compound 1 results in increases in sleep spindles, including an increased number of sleep spindles and an increased duration of sleep spindles (Example 2).

[0024] In one embodiment, the present invention relates to a method for treating and / or preventing absence seizures, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol (compound 1), or a pharmaceutically acceptable salt thereof, to a subject in need.

[0025] Epileptic disorders and absence seizures Epileptic disorders, such as absence epileptic disorders, are characterized by the occurrence of spike-and-slow wave discharges and absence seizure activity. Examples of absence epileptic disorders, including both typical and atypical absence disorders, are as follows: -ESES / DEE-SWAS - Childhood absence epilepsy - Youth absence epilepsy - Juvenile myoclonic epilepsy - Lennox-Gastaut (atypical absence seizures) - Dravet syndrome (atypical absence seizures) - Idiopathic generalized epilepsy In some embodiments, absence seizures are a symptom of an epileptic disorder or disability. In some embodiments, the epileptic disorder or disability is characterized by spike-and-slow discharges. In some embodiments, the epileptic disorder or disability is slow-wave status epilepticus during sleep (ESES), developmental / epileptic encephalopathy with sleep-induced spike-and-slow activation (DEE-SWAS), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome (atypical absence seizures), or idiopathic generalized epilepsy. In some embodiments, the epileptic disorder includes simple partial seizures, compound partial seizures, secondary generalized seizures, and further includes absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and / or atonic seizures.

[0026] In some embodiments, absence seizures are typical. In some embodiments, absence seizures are atypical.

[0027] In one embodiment, the present invention relates to a method for treating childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) in a human subject, comprising administering a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0028] Epileptic disorders and sleep spindles Several epileptic disorders, including epilepsy syndromes and seizure disorders, are further associated with reduced sleep spindle activity. For example, patients with focal epilepsy show reduced sleep spindle activity (Schiller et al., 2022, Roliz and Kothare, 2023).

[0029] Examples of epileptic syndromes and seizure disorders associated with reduced sleep spindle activity include the following: - Childhood absence epilepsy - Youth absence epilepsy - Juvenile myoclonic epilepsy Lennox-Gastaut syndrome - Developmental and epileptic encephalopathy (DEE) - Focal-origin seizures - Childhood epilepsy showing central temporal lobe spike waves In one embodiment, the present invention relates to a method for treating epileptic syndrome or seizure disorder associated with reduced sleep spindle activity in a human subject requiring such treatment, comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to the subject requiring such treatment.

[0030] In one embodiment, epileptic syndrome or seizure disorder is associated with reduced sleep spindle activity. In one embodiment, epileptic syndrome or seizure disorder is childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy (DEE), focal-origin seizures, and / or childhood epilepsy exhibiting central temporal spikes.

[0031] Sleep spindles are bursts of oscillatory brain activity generated in the reticular nucleus of the thalamus during sleep. Sleep spindles consist of bursts of 12-15 Hz and occur during stage 2 non-rapid eye movement (NREM) sleep (N2).

[0032] Sleep spindle activity is a characteristic transient feature of the sleep electroencephalogram (EEG) of mammals during sleep, possessing a well-recognizable, burst-like sequence of 10-15 Hz sinusoidal cycles with a duration of 0.5-2 seconds during the N2 sleep phase. Sleep spindles characterize the N2 stage of non-rapid eye movement sleep (NREMS) and belong to the most heritable EEG signature. Higher sleep spindle density correlates with longer N2 sleep duration and greater resilience to external perturbations. Sleep spindles generate a massive influx of Ca2+ into cortical pyramidal neurons, initiating an intracellular cascade involved in generating synaptic plasticity. Sleep plays a crucial role in cognitive function. Sleep spindle density correlates with markers of intelligence, but also with cognitive impairments and several disorders that can lead to neurological conditions such as epilepsy and epileptic disorders.

[0033] biological activity Compound 1 of the present invention is GABA A It can regulate the receptor complex, GABA A Compound 1 is a proven positive allosteric modulator (PAM) of the receptor. Compound 1 is a GABA containing the a3 subunit, and to a small extent, the a2 and a5 subunits. A It is selective for receptors.

[0034] Compound 1 is demonstrated herein to reduce absence seizure activity, including by reducing the total time in absence seizures, reducing the number of absence seizures, and reducing the duration of absence seizures.

[0035] Furthermore, compound 1 is demonstrated herein to increase the number of sleep spindles, and further to increase the spindle frequency, spindle power, and spindle duration.

[0036] Therapy methods GABA A As a receptor ligand, compound 1 is useful for treating, preventing, and / or alleviating disorders in living organisms, including humans.

[0037] In one embodiment, the present invention relates to a method for treating and / or preventing absence seizures, wherein the method comprises administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0038] In some embodiments, the total duration of absence seizures decreases. In some embodiments, the number of absence seizures decreases. In some embodiments, the duration of absence seizures decreases. In some embodiments, absence seizure activity decreases within 20 minutes after administration, for example, within 10 minutes after administration. In some embodiments, absence seizure activity decreases for at least 3 hours after administration, for example, 4 hours, for example, 5 hours, for example, 6 hours, for example, 7 hours.

[0039] In one embodiment of the present invention, treatment with compound 1 is acute.

[0040] In one embodiment of the present invention, treatment with compound 1 is prophylactic. In one embodiment of the present invention, treatment with compound 1 is preventive. In one embodiment of the present invention, treatment with compound 1 is corrective. In one embodiment of the present invention, treatment with compound 1 is symptomatic.

[0041] Preferably, the subject is a mammal such as a human. In some embodiments, the subject suffers from an epileptic disorder or disability. In some embodiments, the epileptic disorder or disability is absence epilepsy.

[0042] In some embodiments, subjects are administered compound 1 or a pharmaceutically acceptable salt thereof in doses ranging from 0.001 to 100 mg / kg. In some embodiments, compound 1 is administered to subjects in doses ranging from 0.001 mg / kg to 100 mg / kg, for example, 0.001 to 0.01 mg / kg, for example, 0.01 to 0.05 mg / kg, for example, 0.05 to 1.0 mg / kg, for example, 1 to 5 mg / kg, for example, 5 to 10 mg / kg, for example, 10 to 25 mg / kg, for example, 25 to 50 mg / kg, for example, 50 to 100 mg / kg. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered via oral route. In one embodiment of the present invention, treatment with compound 1 is administered orally to the subject at a dose in the range of 0.001 mg / kg to 100 mg / kg, for example, 0.001 to 0.01 mg / kg, for example, 0.01 to 0.05 mg / kg, for example, 0.05 to 1.0 mg / kg, for example, 1 to 5 mg / kg, for example, 5 to 10 mg / kg, for example, 10 to 25 mg / kg, for example, 25 to 50 mg / kg, for example, 50 to 100 mg / kg.

[0043] In one embodiment, compound 1 is administered in combination with one or more additional therapeutic active ingredients. In one embodiment, the additional therapeutic active ingredients are known to treat epilepsy and epileptic disorders.

[0044] In some embodiments, the subjects are under 21 years of age. In some embodiments, the subjects exhibit generalized polyspike-slow wave or spike-slow wave firing at 2–6 Hz when measured by electroencephalography (EEG). In some embodiments, the subjects exhibit generalized spike-slow wave firing at 3 Hz when measured by electroencephalography (EEG). In some embodiments, the number of spike-slow wave firings decreases.

[0045] In one embodiment, the present invention relates to a method for regulating or reducing spike-and-slow wave emission in a subject, the method comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject requiring such regulation.

[0046] In some embodiments, the subject is a human subject who has, is suspected of having, or is at risk of developing absence seizures.

[0047] In one embodiment, the present invention relates to the use of compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical for the treatment and / or prevention of absence seizures in a subject.

[0048] In one embodiment, the present invention relates to Compound 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of absence seizures.

[0049] In one embodiment, the present invention relates to a method for treating absence epilepsy or absence seizures in a human subject requiring the treatment, comprising administering compound 1, or a pharmaceutically acceptable salt thereof, to a subject requiring the treatment.

[0050] Treatment of absence seizures In one embodiment, the present invention relates to a method for reducing the time, number, and / or duration of absence seizures in a subject, wherein the method comprises administering compound 1 or a pharmaceutically acceptable salt thereof to a subject in need.

[0051] Pharmaceutically acceptable salts The compounds of the present invention may be provided in any form suitable for the intended administration, including pharmaceutically (i.e., physiologically) acceptable salts. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts, such as hydrochlorides, hydrobroms, nitrates, perchlorates, phosphates, sulfates, formates, acetates, aconitates, ascorbicates, benzenesulfons, benzoates, cinnamates, citrates, embonates, enanates, fumarates, glutamates, glycolates, lactates, maleates, malons, mandelates, methanesulfons, naphthalene-2-sulfons, phthalates, salicylates, sorbates, stearates, succinates, tartrates, toluene-p-sulfons, and the like. Such salts are well known in the art and can be formed by the procedures described. Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts that serve as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0052] Examples of pharmaceutically acceptable cationic salts of compound 1 of the present invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysinium, and ammonium salts of compound 1 of the present invention containing an anionic group. Such cationic salts are well known in the art and can be formed by the procedures described. In the context of the present invention, "onium salts" of N-containing compounds are also intended as pharmaceutically acceptable salts. Preferred "onium salts" include alkyl-onium salts, cycloalkyl-onium salts, and cycloalkylalkyl-onium salts.

[0053] Labeled Compounds The compounds of the present invention may be used in their labeled or unlabeled form. In the context of the present invention, a labeled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. The label will allow easy quantitative detection of the compound.

[0054] The labeled compounds of the present invention may be useful as diagnostic tools, radiation tracers, or monitoring agents in various diagnostic methods and for in vivo receptor imaging. The labeled isomers of the present invention preferably contain at least one radionuclide as a label. Positron-emitting radionuclides are all candidates for use. In the context of the present invention, the radionuclide is preferably 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 131 I, 125 I, 123 I, and 18 selected from F.

[0055] Physical methods for detecting the labeled isomers of the present invention may be selected from positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed axial tomography (CAT), or combinations thereof.

[0056] Pharmaceutical Compositions The present invention also provides the use of a pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0057] Compound 1 of the present invention for use in therapy may be administered in the form of the crude compound, but it is preferred to incorporate the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other conventional pharmaceutical adjuvants.

[0058] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising one or more pharmaceutically acceptable compounds of the present invention, or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers, and optionally, other therapeutic and / or prophylactic components known and used in the art. The carriers should be “acceptable” in the sense that they are compatible with the other components of the formulation and are not harmful to their receptors. The pharmaceutical compositions of the present invention may be in forms suitable for oral, rectal, bronchial, nasal, pulmonary, topical (including buccal and sublingual), transdermal, vaginal, or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intra-arterial, intracerebral, intraocular injection or infusion), or in forms suitable for inhalation or insufflation, including powder and liquid aerosol administration, or in the form of a sustained-release system. A preferred example of a sustained-release system is a semipermeable matrix of a solid hydrophobic polymer containing the compound of the present invention, which may be in the form of a molded article, e.g., a film or microcapsules.

[0059] Therefore, Compound 1 of the present invention may be arranged in the form of pharmaceutical compositions and unit doses thereof, together with conventional adjuvants, carriers, or diluents. Such forms include solids, particularly tablets, filled capsules, powders, and pellets, all for oral use, and liquids, particularly aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with them, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may contain conventional components in conventional proportions, with or without additional active compounds or components, and such unit dosage forms may contain any suitable effective amount of the active component corresponding to the intended daily dose range used. Compound 1 of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain, as the active component, either the compound of the present invention or a pharmaceutically acceptable salt of the compound of the present invention.

[0060] To prepare a pharmaceutical composition from compound 1 of the present invention, the pharmaceutically acceptable carrier may be either a solid or a liquid. Examples of solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material.

[0061] In one embodiment of the present invention, compound 1, or a pharmaceutically acceptable salt thereof, is the sole active pharmaceutical ingredient. In one embodiment of the present invention, compound 1 is present in a pharmaceutical composition, the composition comprising one or more adjuvants, excipients, carriers, buffers, diluents, and / or other pharmaceutical auxiliary agents. In one embodiment of the present invention, the pharmaceutical composition comprises compound 1, or a pharmaceutically acceptable salt thereof, and one or more adjuvants, excipients, carriers, buffers, diluents, and / or other pharmaceutical auxiliary agents.

[0062] Pharmaceutical preparations are preferably in unit dosage forms. In such forms, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. A unit dosage form may be a packaged preparation, the package containing separate amounts of the preparation, for example, packaged tablets, capsules, and powder in vials or ampoules. Alternatively, a unit dosage form may be a capsule, tablet, cache, or lozenge itself, or any of these in an appropriate number of packaged forms.

[0063] The therapeutically effective dose refers to the amount of the active ingredient that improves the symptoms or condition. Therapeutic efficacy and toxicity, e.g., ED. 50 This can be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose-to-toxicity ratio is the therapeutic index, which can be expressed as the ratio between the plasma level that produces the therapeutic effect and the plasma ratio that produces the toxic effect. Pharmaceutical compositions exhibiting a large therapeutic index are preferred.

[0064] The dose administered may be adjusted to the age, weight, and condition of the individual being treated, as well as the route of administration, dosage form, and regimen, and the desired outcome. The exact dosage can be determined by a physician.

[0065] The actual dosage depends on the nature and severity of the disease being treated and is at the physician's discretion, and may be varied by titration of the dosage for the specific situation of the present invention to produce the desired therapeutic effect. However, pharmaceutical compositions containing about 0.1 to about 10,000 mg, preferably about 1 to about 1,000 mg, and most preferably about 10 to about 500 mg of the active ingredient per individual dose are currently intended to be suitable for therapeutic treatment. The active ingredient may be administered in one or several doses per day. Satisfactory results may be obtained in certain cases at low doses of 0.1 μg / kg iv and 1 μg / kg po. The upper limit of the dosage range is currently considered to be about 10 mg / kg iv and 100 mg / kg po. Preferred ranges are about 0.1 μg / kg to about 10 mg / kg / day iv and about 1 μg / kg to about 100 mg / kg / day po.

[0066] definition As used herein, the term “absence seizure activity” generally refers to absence seizures, such as the total time in an absence seizure, the duration of an absence seizure, and the number of absence seizures.

[0067] As used herein to describe the present invention, the term “preventive treatment” means that a compound, pharmaceutical composition, or combination administered to a subject inhibits, cessates, or reduces the risk of an associated condition or symptoms of such condition occurring in the subject.

[0068] As used herein to describe the present invention, the term “prophylactic treatment” refers to the treatment of a subject who has or is at risk of having a particular condition or symptoms of a condition, but who does not currently have or have not experienced symptoms of a condition.

[0069] As used herein to describe the present invention, the term “corrective treatment” refers to the treatment of a subject who has or is at risk of having a particular condition, the subject currently having or experiencing the symptoms of the condition.

[0070] As used herein to describe the present invention, the term “symptomatic treatment” refers to significantly improving a particular condition, disorder, or symptom associated with it.

[0071] item 1. A method for treating and / or preventing absence seizures, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0072] 2. The method according to item 1, wherein absence seizures are a symptom of an epileptic disorder or disability.

[0073] 3. The method described in any one of the preceding items, for subjects suffering from epileptic disease or disability.

[0074] 4. The method according to either item 2 or 3, wherein the epileptic disorder or disability is characterized by spike-and-slow discharge.

[0075] 5. The method described in any one of items 2-4, wherein the epileptic disorder or disability is slow-wave sleep status epilepticus (ESES), developmental / epileptic encephalopathy with sleep spike-slow wave activation (DEE-SWAS), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome (atypical absence seizures), or idiopathic generalized epilepsy.

[0076] 6. The method according to any one of items 2 to 5, wherein the epileptic disorder includes simple partial seizures, compound partial seizures, secondary generalized seizures, and further includes absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and / or atonic seizures.

[0077] 7. Absence seizures are typical, as described in any one of the preceding items.

[0078] 8. Absence seizures are atypical, as described in any one of the preceding items.

[0079] 9. The method described in any one of the preceding items, wherein absence seizure activity is reduced.

[0080] 10. The method described in any one of the preceding items, which reduces the total duration of absence seizures.

[0081] 11. The method described in any one of the preceding items, wherein the number of absence seizures decreases.

[0082] 12. The method described in any one of the preceding items, which reduces the duration of absence seizures.

[0083] 13. The method according to any one of the preceding items, wherein absence seizure activity is reduced within 20 minutes after administration, for example, within 10 minutes after administration.

[0084] 14. The method according to any one of the preceding items, wherein absence seizure activity decreases for at least 3 hours, e.g., 4 hours, e.g., 5 hours, e.g., 6 hours, e.g., 7 hours after administration.

[0085] 15. The method described in any one of the preceding items, wherein the subject is under 21 years of age.

[0086] 16. The method described in any one of the preceding items, wherein the subject exhibits generalized polyspike-slow wave or spike-slow wave emission at 2-6 Hz when measured by electroencephalography (EEG).

[0087] 17. The method described in item 16, wherein the subject exhibits generalized spike-and-slow wave emission at 3 Hz when measured by electroencephalography (EEG).

[0088] 18. The method described in any one of the preceding items, wherein the number of spike-slow wave emission is reduced.

[0089] 19. The method described in any one of the preceding items, relating to a subject who has, is suspected of having, or is at risk of developing absence seizures.

[0090] 20. The method described in any one of the preceding items, wherein the subject is a human subject who has absence seizures, is suspected of having absence seizures, or is at risk of developing absence seizures.

[0091] 21. The method described in any one of the preceding items, wherein the subject is administered 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol in doses ranging from 0.001 to 100 mg / kg.

[0092] 22. The method according to any one of the preceding items, wherein 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, is administered by oral route.

[0093] 23. The method described in any one of the preceding items, wherein the treatment is curative, preventive, protective, palliative, prophylactic, symptomatic, and / or ameliorative.

[0094] 24. A method for regulating or reducing spike-and-slow wave firing in a subject, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0095] 25. Use of 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol or a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product for the treatment and / or prevention of absence seizures in a subject.

[0096] 26. 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of absence seizures.

[0097] 27. A method for reducing the time, number, and / or duration of absence seizures in a subject, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0098] 28. A method for treating childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE) in a human subject, comprising administering to a subject in need of the therapeutically effective dose of 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to the subject in need of the therapeutically effective dose.

[0099] 29. A method for treating absence epilepsy or absence seizures in a human subject requiring the use of 29.2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject requiring the use of the same.

[0100] 30. A method for treating an epileptic syndrome or seizure disorder in a human subject requiring the treatment of reduced sleep spindle activity, comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject requiring the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of epileptic syndrome or seizure disorder in a human subject requiring the treatment of the treatment of the treatment of reduced sleep spindle activity, comprising administering the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of reduced sleep spindle activity in a human subject requiring the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of reduced sleep spindle activity in a human subject requiring the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of the treatment of reduced sleep spindle activity in a human subject requiring reduced sleep spindle activity in a human subject requiring the treatment of reduced sleep spindle activity in a human subject requiring the treatment of reduced sleep spindle activity in a human subject requiring the treatment of reduced sleep spindle activity in a human subject requiring the treatment of reduced sleep spindle activity in a human subject requiring the treatment of reduced sleep spindle activity in a human subject requiring the treatment of reduced sleep spindle activity in a human subject requiring the treatment of reduced sleep spindle activity in a human subject

[0101] 31. The method according to item 30, wherein the epileptic syndrome or seizure disorder associated with reduced sleep spindle activity is childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy (DEE), focal-origin seizures, and / or childhood epilepsy exhibiting central temporal spikes. [Examples]

[0102] Example 1 - Treatment of absence seizures with compound 1 In this example, the effect of compound 1 on spontaneous absence seizures in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) (a polygenetic model of absence seizures with strong superficial, constructive, and substantive validity (Crunelli et al., 2002)).

[0103] Materials and methods animal: Male GAERS rats and male Wistar rats (purchased from Charles River, UK) bred at Cardiff University were provided with free access to normal food and water and kept under a 12:12 light-dark cycle with lights turned on at 7:00 a.m. All experimental procedures were conducted in accordance with the UK Animal (Scientific Procedures) Act (1986), the Council Directive of the European Community (2010 / 63 / EU), local ethics committees, and expert group guidelines (Lidster et al., 2015). All efforts were made to minimize animal suffering and the number of animals used.

[0104] Recording and analysis of absence seizures Adult (250-300g) male GAERS rats were anesthetized with isoflurane (2-5%), placed in a stereotactic frame, and their body temperature was maintained at 37°C with a heating pad. Gold-plated epidural screws (Svenska Dentorama AB, Sweden) were implanted bilaterally in the frontal lobe (AP: +2.0mm, ML: ±2.0mm), parietal lobe (AP: -2.2mm, ML: ±5.5mm), and cerebellar cortex to record EEG, as previously described by Kronland-Martinet et al, 1987. Animals were allowed to recover from surgery for at least 5 days before starting any experiment.

[0105] For several days prior to the experiment, GAERS rats were connected to recording devices and placed individually in plexiglass boxes within Faraday cages for 1-2 hours of acclimatization. On the day of recording, animals were placed in the plexiglass boxes (9am) for 30 minutes (acclimatization period), followed by 1 hour of recording (control period), after which they were intraperitoneally (ip) injected with either a vehicle (5% DMSO + 0.03% HpbCD (0.03% hydroxypropyl-beta-cyclodextrin) solution) or different doses of compound 1. They were then recorded for 3 hours while being continuously monitored by researchers. Treatment was assigned in a pseudo-randomized manner in a crossover design: each animal received up to four different treatments with at least 5 days between each treatment. In some experiments, GAERS rats were recorded for up to 7 hours after compound 1 injection.

[0106] The EEG signal was acquired through a 4-channel differential preamplifier (high-pass filter 0.1Hz, SuperTech, Hungary) connected to a 4-channel BioAmp amplifier (1000 gain, low-pass filter 500Hz, SuperTech, Hungary), and digitized at 1000Hz using a CED Mk3 1401 (Cambridge Electronic Design, UK). Spike-slow wave firings (SWDs) were first semi-automatically detected in the EEG recording using the SeizureDetect script (kindly provided by Steve Clifford, CED) in Spike2 v7.03 (Cambridge Electronic Design, UK), and then confirmed by visual inspection. The data was digitally processed, and the inter-seizure EEG period of wakefulness was manually selected and used to set a threshold of ±5 SD of the baseline EEG. To identify SWDs, all crossovers above or below the threshold were then grouped into bursts according to five pre-set parameters. Maximum onset interval (0.2s), maximum interval (0.75s), minimum spike count (5), minimum interval within burst (1s), and minimum duration (0.6s). Identified bursts lasting less than 1 second were discarded. Estimated bursts were ultimately classified into SWD according to frequency, which was manually set to 5–12 Hz to exclude deep non-REM sleep and artifact epochs. This semi-automatic detection was further refined by visual inspection. The following parameters were extracted from EEG data in a 20-minute epoch: total time spent in seizures, total number of seizures, and mean seizure duration. Data were plotted as raw data or normalized to vehicle-injected rat results.

[0107] Statistical evaluation: Statistical analysis was performed using GraphPad Prism version 9.0 (GraphPad Software, San Diego, USA). Normality of the data was verified using QQ plots. The effect of each dose was evaluated by repeated measures (RM) two-way analysis of variance (ANOVA) with Sidac correction for multiple comparisons. The main effect of treatment versus vehicle was also measured as area under the curve (AUC) and analyzed by one-way ANOVA using Dunnett's multiple comparison test. Unless otherwise specified, all quantitative data in the text and figures are reported as mean ± SEM.

[0108] result: Absence seizure As shown in Figures 1 and 2, systemic injection of compound 1 blocked spontaneous absence seizures in GAERS rats in a dose-dependent manner. Compound 1 at 1 mg / kg did not have a significant effect, while 3 mg / kg reduced the total amount spent in seizures by approximately 50%, and the maximum effect of approximately 95% was observed at 10 mg / kg (Figure 2A). This anti-absence effect was rapid, already present within the first 20 minutes after injection at all doses and still present at the end of the recording session (3 hours post-injection) (Figures 2A and 3). The strength of these results is supported by the statistical significance observed in the raw data (Figures 2A and 3A-C), the results normalized to vehicle-injected animals (Figure 2B), and the area under the curve analysis (Figure 4). The anti-absence effect of compound 1 at 10 mg / kg was attributed to reductions in both the number of seizures (Figure 5) and the mean duration of seizures (Figure 6).

[0109] The anti-absence effect of compound 1 was investigated in different sets of GAERS rats to determine if it lasted for more than 3 hours (Figure 7). A single injection of 10 mg / kg of compound 1 remained effective up to 7 hours post-injection, with statistically significant differences only at 1, 2, and 3 hours post-injection.

[0110] conclusion Antiabsence effect of compound 1 The results presented demonstrate that compound 1 rapidly, potently, and dose-dependently reduces spontaneous, genetically determined absence seizures in a well-established model of these non-convulsive seizures, namely GAERS rats. This finding is consistent with GABA containing the α3 subunit. A This definitively demonstrates that increasing R activity has an anti-absence effect.

[0111] The lack of statistical significance in the anti-absence effect of compound 1 4–7 hours after injection is likely related to the small number of observations (n=2).

[0112] Example 2 - Sleep spindle-enhancing activity of Compound 1 In this example, sleep spindles generated during spontaneous sleep in normal, non-epileptic Wistar rats were examined.

[0113] Materials and methods: animal: Male Wistar rats as described in Example 1 were used.

[0114] Recording and analysis of sleep spindles during natural sleep. Adult (250-300g) male Wistar rats were anesthetized and EEG electrodes were implanted. In addition, Wistar rats had electrodes placed in the neck muscles to provide EMG data necessary for proper classification of sleep stages, as previously described (Roux et al., 2007). Animals were allowed to recover from surgery for at least 5 days before starting any experiment.

[0115] For several days prior to the experiment, Wistar rats were connected to recording devices and individually placed in plexiglass boxes within Faraday cages for 4–6 hours of acclimatization. On the day of recording, animals were placed in the plexiglass boxes (9:00 AM) for 30 minutes (acclimatization period), followed by 120 minutes of recording (control period), after which they were systemically injected with either 5% DMSO + 0.03% HpbCD (0.03% hydroxypropyl-beta-cyclodextrin) or compound 1. They were then recorded for 140 minutes while being continuously monitored by researchers. Treatment was assigned in a pseudo-randomized manner in a crossover design: each animal received up to two injections at least 5 days apart.

[0116] The EEG signal was acquired through a 4-channel differential preamplifier (high-pass filter 0.1Hz, SuperTech, Hungary) connected to a 4-channel BioAmp amplifier (1000 gain, low-pass filter 500Hz, SuperTech, Hungary), and digitized at 1000Hz using a CED Mk3 1401 (Cambridge Electronic Design, UK). The EEG signal was convolved with a 2.5-cycle complex Morley wavelet with a frequency resolution of 0.1Hz (Kronland-Martinet et al., 1987). Using wavelet ridge extraction, each oscillation epoch of the EEG was extracted at an energy threshold to detect its start and end (Roux et al., 2007, Garcia S. and Fourcaud-Trocme, N. 2009). The boundary frequencies for wave detection were selected as 6–14Hz for spindle oscillations. The threshold was defined as three times the average energy during non-REM sleep periods in a control session. Spindles with fewer than 3 cycles were discarded.

[0117] Statistical analysis was performed using GraphPad Prism version 9.0 (GraphPad Software, San Diego, USA). Data normality was verified using QQ plots. The effect of compound 1 was evaluated for each time bottle (20 minutes) using Student's t-test. Unless otherwise specified, all quantitative data in the text and figures are reported as mean ± SEM.

[0118] result: sleep spindles As shown in Figure 8, systemic injection of compound 1 at a dose of 10 mg / kg significantly enhanced sleep spindles recorded during spontaneous sleep in Wistar rats, as indicated by an increase in spindle number, which was statistically significant from 100 to 140 minutes post-injection (Figure 8A). Statistically significant increases in spindle frequency (Figure 1B) and power (Figure 8C) were present at 60 and 140 minutes post-injection, respectively. Furthermore, increases in mean spindle duration (Figure 8D) were observed at 80 and 140 minutes post-injection.

[0119] conclusion Sleep spindle-enhancing activity of compound 1. Data obtained during spontaneous sleep in Wistar rats indicate that compound 1 can increase sleep spindles at a later time (>100 minutes) after injection. In particular, there is an increase in spindle count at earlier times (60 and 80 minutes) after injection, although this is not significant due to the large SEM size of the available data.

[0120] References Crunelli V,Leresche N.Childhood absence epilepsy: genes, channels, neurons and networks.Nat Rev Neurosci.2002;3:371-382. Garcia S,Fourcaud-Trocme´ N.Open Electrophy:an electrophysiological data-and analysis-sharing framework.Front Neuroinform.2009;3:14. Kronland-Martinet R,Morlet J,Grossmann A.Analysis of sound patterns through wavelet transforms.Int J Pattern Recogn.1987;1:273-283. Roliz,A.H.,Kothare,S.The Relationship Between Sleep,Epilepsy,and Development:a Review.Curr Neurol Neurosci Rep 23,469-477(2023) Roux SG,Cenier T,Garcia S,Litaudon P,Buonviso N(2007)A wavelet-based method for local phase extraction from a multi-frequency oscillatory signal.J Neurosci Methods.2007;160:135-143. Schiller,K.,Avigdor,T.,Abdallah,C.et al.Focal epilepsy disrupts spindle structure and function.Sci Rep 12,11137(2022).

Claims

1. A compound for use in the treatment or prevention of absence seizures in a subject, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol or a pharmaceutically acceptable salt thereof.

2. The compound for use according to claim 1, wherein the absence seizure is a symptom of an epileptic disorder or disability.

3. The compound for use according to any one of the prior claims, wherein the subject is suffering from an epileptic disorder or disability.

4. The compound for use according to claim 2 or 3, wherein the epileptic disorder or disorder is characterized by spike-and-slow wave emission.

5. The compound for use according to any one of claims 2 to 4, wherein the epileptic disorder or disability is slow-wave status epilepticus during sleep (ESES), developmental / epileptic encephalopathy with spike-slow-wave activation during sleep (DEE-SWAS), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, or idiopathic generalized epilepsy.

6. A compound for use according to any one of the prior claims, which reduces absence seizure activity.

7. The compound for use according to any one of the prior claims, wherein the absence seizure activity decreases within 20 minutes after administration, for example, within 10 minutes after administration.

8. The compound for use according to any one of the prior claims, wherein the absence seizure activity decreases for at least three hours, for example, four hours, for example, five hours, for example, six hours, for example, seven hours after administration.

9. The compound for use according to any one of the prior claims, wherein the number of spike-slow wave emission is reduced.

10. The compound for use according to any one of the prior claims, wherein the subject is a human subject having, suspected of having, or at risk of developing absence seizures.

11. The compound for use according to any one of the prior claims, wherein the subject is administered 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol in a dose in the range of 0.001 to 100 mg / kg.

12. The compound for use according to any one of the prior claims, wherein 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, is administered by oral route.

13. A compound for use according to any one of the prior claims, wherein the treatment is curative, preventive, protective, palliative, prophylactic, symptomatic, and / or ameliorative.

14. A method for treating and / or preventing absence seizures, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

15. A method for reducing the duration of absence seizures, the number of absence seizures, and / or the duration of absence seizures, the method comprising administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

16. A method for regulating or reducing spike-and-slow wave emission in a subject, wherein the method comprises administering 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, to the subject in need thereof.

17. Use of 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicinal product for the treatment and / or prevention of absence seizures.

18. Compounds for use in the treatment or prevention of epileptic syndromes or seizure disorders associated with reduced sleep spindle activity, wherein the compound is 2-(3-(3-(2,4-dimethoxypyrimidine-5-yl)phenyl)-3H-imidazo[4,5-b]pyridine-6-yl)propan-2-ol or a pharmaceutically acceptable salt thereof.

19. The compound for use according to claim 18, wherein the epileptic syndrome or seizure disorder associated with the reduced sleep spindle activity is selected from childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy (DEE), focal-origin seizures, and / or childhood epilepsy exhibiting central temporal spike waves.

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