EA044821B1 - METHOD OF INCREASING BIOLOGICAL AVAILABILITY AND DEGREE OF INFLUENCE OF VOLTAGE-DEPENDENT POTASSIUM CHANNEL ACTIVATOR - Google Patents

Description

1. State of the art

Epilepsy is a fairly common condition; its prevalence is estimated at 0.7%, meaning it affects approximately 50 million people worldwide (see Hirtz, D. et al., Neurology. (2007), 68:326337). This disease is characterized by abnormal electrical activity in the brain, causing characteristic seizures. For epidemiological reasons, recognition of epilepsy in an individual requires reliable knowledge of more than one episode of unprovoked seizures of any type (epileptic seizure).

Patients with epilepsy have an increased risk of death compared to the general population, which is determined mainly by the etiology of the disease. Without treatment, epilepsy has the greatest risk of seizure-related death due to sudden death syndrome (SUDEP) (see Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376). Clinical trials of antiepileptic drugs (AEDs) typically enroll patients who have had epilepsy for more than 10 years and have not received relief from various drug therapy options.

The pathophysiological mechanisms of most forms of epilepsy remain poorly understood, but it is known that seizures in this disease occur due to excessive simultaneous and persistent discharge of a group of neurons. In all epileptic syndromes, there is usually a persistently increased level of neuronal excitability. The main treatment strategy for epilepsy involves reducing neuronal excitability through various biochemical mechanisms. In the last two decades, several new antiepileptic drugs have been developed and marketed, expanding the treatment options for this disease by targeting different mechanisms, thereby improving the benefit/risk ratio. The antiepileptic drugs currently available for use are thought to act by inhibiting synaptic vesicle glycoproteins, enhancing the inhibitory effect of gamma-aminobutyric acid (GABA)-mediated neurotransmission, reducing the excitatory effect of glutamic acid-mediated neurotransmission, or inhibition of voltage-gated sodium or calcium channels. But despite the use of such therapeutic agents, up to 30% of cases of epilepsy do not respond to currently available treatments, and patients do not undergo uncontrollable seizures (see Brown, D.A. et al., Nature (1980), 283:673-676, and Elger, C. E. et al., Epilepsy Behav (2008), 12:501-539). People with untreatable epilepsy have a poor quality of life: they cannot drive, they find it difficult to work and lead an independent lifestyle. Many of them also have neurological disorders, as well as behavioral and/or mental disorders caused by seizures. Modern antiepileptic drugs do not affect or have very little effect on voltage-gated ion channels of neurons, but these structures play an important role in regulating the excitability of nerve cells. Therefore, in order to meet the significant need for seizure control in patients with epilepsy refractory to existing treatments, drugs with a new mechanism of action or agents that improve the effect of commercially available antiepileptic drugs are needed.

Recently, a small molecule compound called N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (in it is also referred to herein as compound A). This substance and its use as a potassium channel modulator are described in US Patent Nos. 8,293,911 and 8,993,593, the contents of which are incorporated herein by reference in their entirety.

Voltage-dependent potassium channels Kv7.2 and Kv7.3 (Kv7.2/Kv7.3) play an important role in the regulation of neuronal excitability. The Kv7.2/Kv7.3 channels are central to the neuronal M-current mechanism, which is named for its blocking of muscarine-sensitive acetylcholine A receptors (see Brown, D.A. et al., Nature (1980), 283:673- 676). It is known that the M-current, being non-inactivating and hyper-polarizing, serves as a break in the hyperexcitability of neurons. Consequently, a decrease in the M-current in which Kv7.2 is involved, for example, with a genetically determined loss of functionality of these channels, can lead to depolarization, a shift of the membrane potential to the (+) side and an increase in neuronal excitability, which leads to the emergence and propagation of an action potential - discharges of neurons, manifested as epileptic convulsions. Conversely, an increase in M-current with the participation of Xy7.2 channels will lead to hyperpolarization of the nerve cell membrane and, accordingly, to a decrease in the excitability of neurons, and therefore will prevent the occurrence/propagation of action potentials and thereby the appearance of seizures. Activation (increasing the probability of an open state) of Kv7.2/Kv7.3 channels in neurons promotes a state of hyperpolarization in which an action potential is not generated, thus reducing the possibility of a rapid spike in membrane potential, that is, neuronal discharge. Such activation may create a stabilizing effect in excitable, especially hyperexcitable neurons, and thus help treat some seizure disorders. There is clinical evidence of the effectiveness of a known Kv7.2/Kv7.3 channel activator called retigabine (ezogabine) for the treatment of seizure disorders such as partial seizures in adult patients with epilepsy.

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The retigabine molecule has the following structure:

Retigabine was first identified as an analogue of the analgesic flupirtine in the late 1980s. Studies using various experimental rodent seizure models conducted to identify new anticonvulsant agents have demonstrated the broad spectrum of action of retigabine (see Kupferberg, H., Epilepsia (1989), 30 (Suppl. 1):S51-S56). The drug was approved for partial seizures in epilepsy in 2011, but was withdrawn from the market in 2017 due to commercial concerns due to labeling indicating negative side effects such as discoloration of the skin, lips, and nails, as well as pigmentary changes in the retina, which are associated with the formation of chromophoric dimers of retigabine with long-term use of the drug (Prescott, J.S. and Evans, S.L., Pigmentary abnormalities (discoloration) associated with ezogabine/retigabine treatment: nonclinical aspects, Poster 2.324 presented at the 68th Annual Meeting of the American Epilepsy Society (AES), Seattle, Washington, U.S.A., December 5-9, 2014).

Although significant advances have been made in the art, particularly with respect to Compound A and its use in the treatment of seizure disorders, there remains a great need for improved methods of increasing the bioavailability and oral exposure of Compound A in patients with seizure disorders, such as epilepsy.

2. Disclosure of the invention

In certain embodiments, the present disclosure relates to a method of treating a disease, disorder, or condition associated with dysfunction of Kv7 potassium channels in individuals in need thereof, which comprises administering to the patient a therapeutically effective amount of Compound A orally during or after a meal, or during from 30 minutes before meals to 2 hours after that. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as epilepsy with focal seizures at disease onset.

In certain embodiments, the present disclosure relates to a substance used in the treatment of a disease, disorder or condition associated with dysfunction of Kv7 potassium channels in individuals in need thereof, which comprises administering to the patient a therapeutically effective amount of Compound A orally during or after a meal, or in the period from 30 minutes before a meal to 2 hours after that. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as epilepsy with focal seizures at disease onset.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a person in need thereof, which comprises administering to the patient an amount of Compound A orally during or after a meal, or between 30 minutes before a meal and 2 hours thereafter, wherein the amount of Compound A administered is sufficient to treat a seizure disorder in a given individual.

In one embodiment, the present disclosure provides a substance for use in the treatment of a seizure disorder in a person in need, wherein the substance is Compound A of the present invention and is administered orally to the patient during or after a meal, or 30 minutes before a meal. up to 2 hours after that.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a person in need, which comprises administering to the patient an amount of Compound A orally during or after a meal, or from 30 minutes before a meal to 2 hours thereafter, wherein the administered the amount of compound A is from 2 mg to 200 mg.

In one embodiment, the present disclosure provides a method of increasing one or more of the following pharmacokinetic parameters for Compound A of this invention in a human taking Compound A orally: _Cmax , _AUCinf , Tmax, or ί1/ _2λΖ , which comprises administering to said individual orally some amount of Compound A orally during or after a meal, or from 30 minutes before a meal to 2 hours thereafter, which method increases one or more of the Cmax, AUC _inf , _Tmax or ί1/ _2λΖ , compared when the same amount of Compound A is taken orally by the individual on an empty stomach.

In one embodiment of the present disclosure, a substance is provided for use in increasing one or more of the following pharmacokinetic parameters for that substance in an orally administered human: C _max , AUC _inf , Tmax, or ί ¹ / _2λΖ , wherein said substance is compound A and is administered orally into the body during or after a meal, or in the period from 30 minutes before a meal to 2 hours after that, and oral administration of this substance leads to an increase in one or more of the _Cmax , AUC _inf , _Tmax , or ?/ _2λΖ , compared to when the same amount of compound A is taken orally by the individual on an empty stomach.

Some embodiments of the present disclosure provide a method of increasing the bioavailability of Compound A or improving one or more of its pharmacokinetic parameters _Cmax , AUCinf, _Tmax , or ?/ _2λΖ in a human taking Compound A orally, the method comprising:

(a) informing the individual that administration of Compound A orally during or after a meal, or from 30 minutes before a meal to 2 hours thereafter, increases the bioavailability of the substance or improves one or more of its pharmacokinetic parameters Cmax, AUCinf, Tmax or t%z, and (b) subject to step (a) administering Compound A to the subject orally during or after a meal, or from 30 minutes before a meal to 2 hours thereafter.

In some embodiments of the present invention, the likelihood of step (b) (i.e., taking Compound A during or after a meal, or from 30 minutes before a meal to 2 hours thereafter) is greater than if step (a) is not present in the method. ).

In one embodiment, the present disclosure provides a method of orally administering Compound A to a person in need thereof, comprising administering Compound A orally to the body during or after a meal, or from 30 minutes before a meal to 2 hours thereafter, and improving one or more from the pharmacokinetic parameters of the compound AC _max , AUCinf, T _max or ?/ _2λΖ in a given individual compared to when he takes the same amount of compound A orally on an empty stomach.

In one embodiment, the present disclosure provides a method of reducing the dose of Compound A taken orally by a person in need as part of a treatment regimen comprising administering Compound A at a reduced dose orally during or after a meal, or from 30 minutes before a meal to 2 h after this, and this reduced dose is less than the dose that would be required for the pharmacokinetic parameters of the compound AC _max , AUCinf, T _max or ?/ _2λΖ to reach the same values if the specified substance was taken orally on an empty stomach.

In one embodiment, the present disclosure provides a substance for use in reducing the dose of the substance that is administered orally to a person in need as part of a treatment regimen in which the substance is Compound A of this invention is administered orally during or after a meal, or in the period from 30 minutes before a meal to 2 hours after this, and this reduced dose is less than the dose that would be required for the pharmacokinetic parameters of the compound AC _max , AUCinf, T _max or ? / _2λΖ to reach the same values, when taking compound A orally on an empty stomach.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a person in need, which includes administering a therapeutically effective amount of Compound A. In some embodiments of the present disclosure, the method achieves one or more of the following pharmacokinetics for Compound A:

C _max >or=40 ng/ml,

AUC _inf >or=2500 ng-h-ml' ¹ ,

T _max >or=3.25 h or t ¹ / _2λZ >or=130 h.

In one embodiment, the present disclosure provides a substance for use in the treatment of a seizure disorder in a person in need, which is Compound A of the present invention and is administered orally. In some embodiments of the present invention, oral administration of Compound A results in the achievement of one or more of the following pharmacokinetic properties of the compound:

C _max >or=40 ng/ml,

AUC _in f>or=2500 ng-h-ml' ¹ ,

T _max >or=3.25 h or t ¹ / _2λZ >or= 130 h.

In one embodiment, the present disclosure provides a method of increasing passive motor response threshold (RMT) or active motor threshold (AMT) in individuals in need thereof, comprising administering an amount of Compound A orally, as appropriate, during or after a meal, or from 30 minutes before a meal to 2 hours thereafter, wherein the amount of Compound A administered is sufficient to cause an individual's RMT or AMT to increase, or the amount is between 2 mg and 200 mg.

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In one embodiment, the present disclosure provides a substance for use in increasing the passive motor response threshold (RMT) or active motor response threshold (AMT) in individuals in need, which is Compound A of the present invention and an amount thereof is administered to the individual in need thereof. person orally as needed during or after a meal, or from 30 minutes before a meal to 2 hours thereafter, wherein the amount of Compound A administered is sufficient to cause the individual's RMT or AMT to increase, or the amount is between 2 mg to 200 mg.

In one embodiment, the present disclosure provides a method of reducing corticospinal or cortical excitability in a person in need, comprising administering an amount of Compound A orally, as appropriate, during or after a meal, or from 30 minutes before a meal to 2 hours after a meal. wherein the amount of Compound A administered is sufficient to cause an increase in corticospinal or cortical excitability in the subject, or between 2 mg and 200 mg.

In one embodiment, the present disclosure provides a substance for use in reducing corticospinal or cortical excitability in a person in need, which is Compound A of this invention, which is administered orally to the body as appropriate during or after a meal, or from 30 minutes before meal up to 2 hours thereafter, the amount of Compound A administered being sufficient to cause an increase in corticospinal or cortical excitability in the individual, or ranging from 2 mg to 200 mg.

Some embodiments of the present disclosure generally provide methods for increasing the bioavailability and exposure of Compound A when administered orally to a subject in need thereof.

Thus, one aspect of the present invention is a method of treating a seizure disorder in a human, comprising orally (during or subsequent to) administering a therapeutically effective amount of Compound A to an individual in need thereof.

Another aspect of the present invention is a method of increasing the bioavailability and effect of Compound A in a human taking orally a therapeutically effective amount of Compound A for the treatment of a seizure disorder; the method comprises orally administering to the individual a therapeutically effective amount of Compound A during or after a meal.

Another aspect of the present invention is a method of increasing the absorption and exposure of Compound A in a human after oral administration of the substance; the method comprises orally administering to the individual a therapeutically effective amount of Compound A during or after a meal.

These and other aspects of the present invention are disclosed in the following Detailed Description of the Invention. For the sake of clarity, various references are provided throughout this document to provide more detailed information of both theoretical and practical nature; the contents of these publications are incorporated herein by reference in their entirety.

3. Brief description of drawings

Fig. 1 represents the change in the plasma concentration of Compound A in cynomolgus monkeys over time under different conditions of oral administration of the drug (fasting or after a meal), as described in Example 1 (see also Table 5). The ordinate axis is the concentration of compound A (ng/ml), the abscissa axis is time (in hours).

Fig. 2 represents the change in the concentration of compound A in human plasma over time under different conditions of oral administration of the drug (on an empty stomach or after a meal), as described in example 2. The y-axis is the concentration of compound A (ng/ml), the x-axis is time (in hours).

Fig. 3 is a graph showing Compound A-induced changes in passive motor response threshold (A) and active motor response threshold (B) at different drug doses (10 mg, 15 mg and 20 mg) at 2 hours and 4 hours after oral administration. The y-axis is the difference in the threshold value measured before and after drug administration (see text).

Fig. 4 is a graphical representation of the results of spatio-temporal analysis of potentials evoked by transcranial magnetic stimulation after administration of placebo and compound A. FIG. A shows butterfly plots of the overall mean (n=16) amplitude of TMS-evoked oscillations before and after administration of placebo (left) and compound A (right). Each trace corresponds to TMS-evoked potentials recorded from one EEG channel. In fig. B and C show the amplitude (μV) distribution over the surface of the head of oscillations of the main components of TMS-evoked potentials (N15-P25, N45, N100 and P180) before (B) and after (C) drug administration. In fig. D shows maps of the amplitude distribution of TMS-evoked potentials, demonstrating the difference between the results obtained before and after drug administration (statistical processing using a t-test). Results that are not statistically significant are indicated by n.s.; on the maps of the amplitude distribution over the surface of the head, areas of positive potential values are marked with a white cross, dark areas without a cross are areas of negative potential values.

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Fig. 5 is a graphical representation of the change in amplitude of TMS-evoked potentials at the highest concentration of Compound A in blood plasma. The overall average of this value across the EEG channels demonstrates a significant effect of compound A. Compared with the data obtained before drug administration, administration of compound A caused suppression of the N15-P25, N45 and P180 components. Data were averaged for 16 subjects who received TMS at the highest plasma concentration of Compound A. On the maps of the amplitude distribution over the surface of the head, areas with positive results of statistical analysis using the t-criterion are marked with a white cross; dark areas without a cross are areas for which the results of statistical analysis were negative.

Fig. 6 graphically illustrates the effect of Compound A on TMS-evoked potentials measured after administration compared to placebo. Data are presented on the amplitude (µV along the ordinate) at the moments of the appearance of components N15-P25, N45 and P180 after a magnetic pulse.

Fig. 7 contains graphs illustrating the effect of Compound A on TMS-evoked potentials 2, 4 and 6 hours after its administration. Averaged data (overall average) are presented for TMS-evoked potentials recorded before and 2, 4 and 6 hours after dosing. Compound A-specific signatures, which include suppression of the N15P25, N45 and P180 components, reflect an increase in the concentration of Compound A in the blood plasma .

Fig. Figure 8 illustrates changes in spontaneous oscillatory brain activity induced by compound A (oscillations were compared before and after taking the drug). In fig. A shows spectral power data (overall mean; n=16) before and after administration of Compound A. Significant increases in oscillation in the delta, theta, and beta frequency bands are marked with an asterisk and are shown for each band below in FIG. A1, A2 and A3.

Fig. 9 illustrates changes in spontaneous oscillatory brain activity induced by compound A (oscillations were compared before taking the drug and 2, 4 and 6 hours after that). In fig. A shows spectral power data (overall average; n=16) before administration of Compound A and 2, 4 and 6 hours thereafter. Significant increases in oscillation in the delta, theta, and beta frequency bands are indicated by an asterisk and are shown for each band below in FIG. A1, A2 and A3.

Fig. 10 graphically depicts the effect of compound A on the passive threshold of the motor response over time, the left ordinate axis shows changes in RMT compared to the initial level (percentage ratio to the maximum stimulant output [%MSO]), the right ordinate axis shows the concentration of compound A (ng/ ml), along the x-axis - time (h). In the case of compound A, n=19, 20 and 16 after 2, 4 and 6 hours, respectively. For placebo, n=20, 20 and 16 at 2, 4 and 6 hours, respectively. Means ± standard error of the mean (SEM) are shown.

Fig. 11 graphically represents the effect of Compound A on the passive motor response threshold. The y-axis represents the difference in RMT levels before and after drug administration, expressed as a ratio (in percent) to the maximum stimulant output (%MSO), for compound A and for placebo. The concentration of compound A (average highest) is 45 ng/ml.

Fig. 12 graphically represents the effect of compound A (average highest concentration 45 ng/ml) on the total average EEG field power [the ordinate is the total average field power (GMFP; μV ² ), the abscissa is time (seconds)]. In fig. A comparison of data before and after taking the drug. In fig. Compare data before taking the drug and 2 and 4 hours after that.

4. Carrying out the invention

The effect of a drug often depends significantly on the individual's food intake, which affects the pharmacokinetics and pharmacodynamics of the drug substance. This effect may manifest itself in worsening the absorption of the drug and reducing its effectiveness, or in enhancing absorption and increasing effectiveness. Food can also have either a positive or a negative effect on the incidence and severity of adverse drug events. Without careful experimental testing, it is impossible to predict whether food intake will affect the bioavailability of a drug and the extent of its effect on the body (see, for example, Heimbach, T. et al., Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data, The AAPS Journal (2012), Vol. 15, No. 1, pp. 143-158).

In some embodiments of the present invention, improved methods of treatment and administration of therapeutic agents are provided based on the unexpected observation that if a person takes Compound A orally during or after a meal (ie, swallowed with or shortly after food), the bioavailability of it is significantly increased. the substance and the extent to which it affects the individual compared to when taken on an empty stomach (namely, without food or before swallowing it). This fact was not expected, since studies in other primates indicated that the bioavailability of Compound A and the extent of its exposure to the body when taken orally during or after food do not exceed those when taken on an empty stomach.

The fact that we discovered the influence of food intake on the effect of compound A also seems unexpected in light of the fact that food does not in any way affect the bioavailability and degree of effect

- 5 044821 another potassium channel activator - retigabine (see page 2 of the US Food, Drug and Cosmetic Administration (FDA) Approved Labeling Text from

3/15/2012 about the drug Potiga (trade name for retigabine), as well as the work of Harris, J.A., Murphy, J.A.,

Retigabine (ezogabine) as add-on therapy for partial onset seizures: an update for clinicians, Therapeutic Advances in Chronic Disease (2011), 2(6), pp. 371-376).

In addition, compound A is not capable of forming chromophoric dimers, which exist with retigabine. This means that the grayish-blue coloration of the skin, lips and nails and retinal pigment changes in people that appear after long-term use of retigabine should not occur after long-term use of compound A.

Hereinafter, certain specific details are set forth herein for a better understanding of the various embodiments of the present invention. However, it will be apparent to one skilled in the art that the methods and applications thereof described herein can be practiced without these details. In other cases, items well known in the art are not shown or described in order to avoid unnecessary clutter in the descriptions of embodiments of the invention. As used herein and in the claims, the word (includes/contains and its derivatives (e.g., including/containing) has the meaning of an open set (that is, includes, but is not limited to included), unless the context otherwise requires. Also note that available in this document, headings and headings are for convenience only and do not in any way affect the scope or content of the subject matter of the invention as defined in its claims.

When the phrases "a" or "one" are used herein, it is meant that a particular feature, or a particular structure, or a particular property described in connection with that embodiment is included in at least one embodiment of this invention. Thus, the use of the specified phrase in different places in this description does not mean at all that we are talking about the same embodiment. In addition, specific features, structures, or properties may be combined in any suitable manner in one or more embodiments of the invention. Also in the present specification and the accompanying claims, singular articles (a, an, the) include the plural sense unless the context requires a different meaning. It should also be noted that the conjunction or is used, as a rule, in a sense that includes the meaning and/or, unless the context requires a different meaning. The preposition about as used herein means ±20% of the given value, and in some embodiments of the present invention it means ±10%, ±5%, ±2% and ±1% of the given value.

4.1. Definitions.

In this specification and the accompanying claims, terms and abbreviations are used with the meanings given below (unless specifically stated otherwise).

The term Compound A refers to a compound corresponding to the following formula:

and called according to the chemical nomenclature N[4-(6-fluoro-3,4-dihydro-III-isoquinolin-2-yl)2,6-dimethylphenyl]-3,3-dimethylbutanamide. The preparation of Compound A and its use as an activator of Kv7.2/Kv7.3 (KCNQ2/3) are described in US Patent Nos. 8293911 and 8993593. The mechanism of action of Compound A differs from the mechanism of action of most known antiepileptic drugs in that it includes potentiation or increases the probability of the open state of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2/Kv7.3), which play an important role in the regulation of neuronal excitability. Compound A is used in the methods and applications described herein.

The abbreviation AUC denotes the area under the curve of the concentration of a substance in the blood plasma versus time. This value reflects the actual overall effect (systemic effect) of compound A on the body after its extravascular administration at a given dose; AUC is expressed as the product of the plasma concentration of a substance (for example, mg/L or mmol/L) and time (in hours). According to this invention, the AUC dimension is ng-h-ml' ¹ .

AUC _inf is AUC from zero to infinity.

AUC _{inf obs} is the AUC from zero to infinity from observational data.

AUC _last is the AUC from zero to the last detectable concentration of a substance in the blood plasma.

%AUC _ext is the AUC extrapolated from zero to infinity as a percentage of the total AUC.

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Bioavailability is the rate and extent of absorption of Compound A, resulting in it being released into the bloodstream and able to be further distributed to the site of action.

_Cmax is the observed maximum concentration of a substance in the blood plasma.

The abbreviation h means hour or hours.

The term high-fat food refers to any food (solid or liquid) in which approximately 50% of its total energy (calories) comes from fat.

The term high-calorie food refers to any food that has an energy content of 800-1000 calories. In a typical high-fat, high-calorie meal, protein accounts for approximately 150 calories, carbohydrates 250 calories, and fat 500-600.

The abbreviation SD stands for standard deviation.

The term seizure disorder refers to seizures and conditions associated with seizures, such as partial seizure disorder, photogenic epilepsy, spontaneous syncope, incurable or drug-resistant epilepsy, Angelman syndrome, benign epilepsy with peaks in the central temporal region, syndrome caused by a mutation in the cyclin-dependent kinase 5 gene, childhood and juvenile absence epilepsy, Dravet syndrome, frontal epilepsy, glucose transporter deficiency syndrome type 1, hypothalamic hamartoma, infantile seizures/West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, syndrome Lennox-Gastaut (LGS), epilepsy with myoclonic absence seizures, Ohtahara syndrome, Panagiotopoulos syndrome, epilepsy due to mutation in the protocaderin 19 gene, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, early onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus (GEFS+), Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia and paroxysmal dyskinesias. In some embodiments of the present invention, the term seizure disorder refers to partial (also called focal or localized) epileptic seizures.

The designation ν/ _2λΖ is an abbreviation for the term terminal half-life; it refers to the period of time during which the concentration of compound A in the blood plasma is halved during the final elimination phase.

_Tmax is the period of time during which the maximum concentration (peak concentration) of compound A in the blood plasma is reached after its extravascular administration into the body.

The term therapeutically effective amount as used herein refers to an amount of Compound A that is sufficient to treat a specified disease, disorder or condition or produce a desired effect, including reducing the severity of or preventing the disease, disorder or condition or one or more mechanisms underlying the disease. , disorder or condition. In some embodiments of the present invention, when Compound A is administered to a human for the treatment of a seizure disorder, the term therapeutically effective amount refers to the range of amounts of Compound A upon administration of which to a human, the seizure disorder from which he is suffering is treated, ameliorated, or prevented, or in In these amounts, Compound A has a detectable therapeutic or prophylactic effect. The effect of compound A is detected, for example, by a decrease in the severity (qualitative assessment) or frequency of occurrence (quantitative assessment) of seizures. The exact therapeutically effective amount of Compound A for a given individual will depend on the individual's body weight and general health, the nature and severity of the seizure disorder, concomitant drug treatment, and other varying factors known to those skilled in the art. In each specific case, the therapeutically effective amount is determined experimentally by the attending physician using standard procedures.

The term treatment as used herein refers to treatments associated with the administration of Compound A to a human body that attenuate or prevent the specified disease, disorder or condition or the action of one or more mechanisms underlying the disease, disorder or condition, including slowing or stopping the progression of the disease, disorder or condition or the action of one or more mechanisms causing the disease, disorder or condition. In some embodiments of this invention in those cases. When Compound A is administered to a human for the treatment of a seizure disorder, the term treatment refers to therapeutic uses to slow or stop the progression of a seizure disorder, prophylactic uses to prevent the development of a seizure disorder, and/or treatment of a seizure disorder. Cure as used herein is not the same as therapeutic use: therapeutic measures slow or stop a seizure disorder, but to cure means not only to stop the progression of the disease, but also to restore to some extent the normal cellular activity that would be observed in the absence of the disorder. .

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The expression during or after a meal/meal refers to the state when the food is in the body from about 4 hours before oral administration of an effective amount (ie, in the therapeutically effective dose range) of Compound A until about 4 hours after administration. Food can be solid, liquid or mixed, but in sufficient volume and with sufficient fat content so as not to be diluted and absorbed too quickly in the gastrointestinal tract. In some cases, a meal is a regular meal of the day (breakfast, lunch or dinner) or the act of feeding an infant (breast milk or formula). A therapeutically effective amount of Compound A can be taken by an individual, for example, over a period of about 30 minutes. before a meal until about 2 hours after a meal, it is most preferable that a single dose of Compound A be taken (orally) by the individual during a meal or no later than 15 minutes thereafter.

The expression fasting refers to situations where the body is without food for a period of time from at least 4 hours prior to oral administration of a therapeutically effective amount of Compound A until about 4 hours thereafter.

4.2. Embodiments of the invention.

In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with dysfunction of Kv7 potassium channels in individuals in need thereof, which comprises administering to the patient a therapeutically effective amount of Compound A orally during or after a meal. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as epilepsy with focal seizures at disease onset.

In some embodiments, the present disclosure relates to a method of treating a disease, disorder, or condition associated with dysfunction of Kv7 potassium channels in individuals in need thereof, which comprises administering to the individual a therapeutically effective amount of Compound A orally at a time period of about 30 minutes prior to dosing. food up to 2 hours after it. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as epilepsy with focal seizures at disease onset.

In certain embodiments, the present disclosure provides a substance for use in the treatment of a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in individuals in need thereof, which is Compound A of this invention and is administered to the individual in a therapeutically effective amount orally at time or after meals. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as epilepsy with focal seizures at disease onset.

In certain embodiments, the present disclosure provides a substance for use in the treatment of a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in individuals in need thereof, which is Compound A of this invention and is administered to the individual in a therapeutically effective amount orally at a period of time from about 30 minutes before a meal to 2 hours after it. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is a seizure disorder, such as epilepsy with focal seizures at disease onset.

In embodiments of the present invention relating to a disease, disorder or condition associated with dysfunction of Kv7 potassium channels, in some cases the method of the present invention increases the likelihood of an open state of Kv7 potassium channels, for example one or more of the following types: Kv7.2, Kv7.3 , Kv7.4 and Kv7.5. In some cases, the method or use of the present invention is selective for activation of the Kv7 potassium channel which is selected from one or more of the following types: Kv7.2, Kv7.3, Kv7.4 and Kv7.5 and in addition Kv7.1. In some embodiments of the present invention, the method or use is selective for Kv7.2 and optionally also Kv7.1. In other embodiments of the present invention, the method or use is selective for Kv7.3 and optionally also Kv7.1. In still some other embodiments of the present invention, the method or use is selective for Kv7.4 and optionally also Kv7.1. In still some other embodiments of the present invention, the method or use is selective for Kv7.5 and optionally also Kv7.1. In certain embodiments of the present invention, the method or use is selective for Kv7.2 and Kv7.3 and, if necessary, also Kv7.1.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a person in need thereof, comprising orally administering an amount of Compound A during or after a meal, the amount of Compound A administered being sufficient to treat the seizure disorder in that individual. In some embodiments of the present invention, the amount of Compound A administered to a human is sufficient to reduce the frequency or severity of seizures, or both.

In one embodiment, the present disclosure provides a substance for use in the treatment of a seizure disorder in individuals in need, which is Compound A of this

- 8 044821 of the invention and is administered to the individual in a therapeutically effective amount orally during or after a meal. In some embodiments of this invention, the amount of compound

A administered to an individual is sufficient to reduce the frequency or severity of seizures, or both.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a person in need thereof, comprising orally administering an amount of Compound A to the body from about 30 minutes before a meal to 2 hours thereafter, wherein the amount of Compound A administered is sufficient to treat seizure disorder in the individual. In some embodiments of the present invention, the amount of Compound A administered to a human is sufficient to reduce the frequency or severity of seizures, or both.

In one embodiment, the present disclosure provides a substance for use in the treatment of a convulsive condition in a person in need, which is Compound A of the present invention and is administered to the individual by the oral route from about 30 minutes before a meal to 2 hours thereafter. In some embodiments of the present invention, the amount of Compound A administered to a subject is sufficient to reduce the frequency or severity of seizures, or both.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a person in need thereof, comprising orally administering an amount of Compound A during or after a meal, wherein the amount of Compound A administered is from 2 mg to 200 mg.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a person in need thereof, comprising orally administering an amount of Compound A to the body from about 30 minutes before a meal to 2 hours thereafter. B, wherein the administered amount of compound A is from 2 mg to 200 mg.

In one embodiment, the present disclosure provides a method of increasing one or more of the following pharmacokinetic parameters of Compound A in a human taking it orally: Cmax, AUC _inf , Tmax or t ¹ /2λZ, this method includes administering an amount of Compound A to the body orally at time or after meals. In some embodiments of the present invention, the method results in an increase in one or more of Cmax, AUCinf, Tmax, or t ¹ /2λZ, compared to when the same amount of Compound A is taken orally by a given individual on an empty stomach.

In one embodiment, the present disclosure provides a substance for use to increase one or more of the following pharmacokinetic parameters of Compound A in an orally administered human: _Cmax , AUCinf, _Tmax , or ί1/ _2λΖ , wherein the substance is Compound A and is administered to a human orally during or after meals. In some embodiments of the present invention, as a result of said administration of Compound A, one or more of the following pharmacokinetic parameters of Compound A are increased: _Cmax , AUCinf, _Tmax , or ί1/ _2λΖ , compared to when the same amount of Compound A is taken orally by a given individual on an empty stomach .

In one embodiment, the present disclosure provides a method of increasing one or more of the following pharmacokinetic parameters of Compound A in a human taking it orally: _Cmax , AUCinf, _Tmax or ί1/ _2λΖ , which method includes administering an amount of Compound A to the body orally at a period of time from about 30 minutes before a meal to 2 hours after it. In some embodiments of the present invention, the method results in an increase in one or more of _Cmax , AUCinf, _Tmax , or ί1/ _2λΖ compared to when the same amount of Compound A is taken orally by a given individual on an empty stomach.

In one embodiment, the present disclosure provides a substance for use to increase one or more of the following pharmacokinetic parameters of Compound A in an orally administered human: _Cmax , AUCinf, _Tmax , or ί1/ _2λΖ , wherein the substance is Compound A and is administered to a human orally for a period of time from about 30 minutes before a meal to 2 hours after it. In some embodiments of the present invention, as a result of said administration of Compound A, one or more of the following pharmacokinetic parameters of Compound A are increased: _Cmax , AUCinf, _Tmax , or ^t1 / _2λZ , compared to when the same amount of Compound A is administered orally by a given individual on an empty stomach.

In one embodiment, the present disclosure provides a method of increasing the bioavailability of one or more of the following pharmacokinetic parameters of Compound A in a human taking it orally: _Cmax , AUCinf, _Tmax , or ^t1 /^, the method comprising:

(a) informing the individual that administration of Compound A orally during or after a meal, or from 30 minutes before a meal to 2 hours thereafter, increases the bioavailability of the substance or improves one or more of its pharmacokinetic parameters Cmax, AUCinf, Tmax or t ¹ /2λz, and (b) subject to step (a) administering Compound A to the subject orally during or after a meal, or from 30 minutes before a meal to 2 hours thereafter. In some incarnations

- 9 044821 of this invention, the probability of performing step (b) (that is, taking compound A during or after a meal, or in the period from 30 minutes before a meal to 2 hours after that) is greater than in the absence of step (a) in the specified method ).

In one embodiment, the present disclosure provides a method of orally administering Compound A to a human in need, comprising administering Compound A orally to the body during or after a meal. In some embodiments of the present invention, the method results in an increase in one or more of the pharmacokinetic parameters of the compound AC _max , AUC _inf , T _max or t ¹ / _2λZ in a given individual compared to when he takes the same amount of compound A orally on an empty stomach .

In one embodiment, the present disclosure provides a method of orally administering Compound A to a human in need, comprising administering Compound A orally to the body at a time period from about 30 minutes before a meal to 2 hours thereafter. In some embodiments of the present invention, the method results in an increase in one or more of the pharmacokinetic parameters of the compound, _ACmax , _AUCinf , _Tmax , or ?/ _2λΖ , in a given individual compared to taking the same amount of Compound A orally on an empty stomach.

In one embodiment, the present disclosure provides a method of reducing the dose of Compound A taken orally by a person in need as part of a treatment regimen comprising administering Compound A at a reduced dose orally during or after a meal. In some embodiments of the present invention, this reduced dose is less than the dose that would be required for the compound's pharmacokinetics AC _max , AUCinf, _Tmax , or ?/ _2λΖ to reach the same values when administered orally on an empty stomach.

In one embodiment, the present disclosure provides a substance for use in reducing the dose of the substance that is administered orally to a person in need as part of a treatment regimen in which the substance is Compound A of this invention and is administered orally during or after dosing. food. In some embodiments of the present invention, this reduced dose is less than the dose that would be required for the pharmacokinetic parameters of compound AC _max , AUCinf, T _max or ?/ _2λΖ to reach the same values when compound A was administered orally on an empty stomach.

In one embodiment, the present disclosure provides a method of reducing the dose of Compound A administered orally to a person in need as part of a treatment regimen comprising administering Compound A at a reduced dose orally from about 30 minutes before a meal to 2 hours thereafter. In some embodiments of the present invention, this reduced dose is less than the dose that would be required for the compound's AC _max , AUCinf, Tmax, or ?/ _2λΖ pharmacokinetics to reach the same values when administered orally on an empty stomach.

In one embodiment, the present disclosure provides a substance for use in reducing the dosage of the substance, which is administered orally to a person in need as part of a treatment regimen in which the substance is Compound A of this invention and is administered orally to the body over a period of time from about 30 minutes before meals until 2 hours after. In some embodiments of the present invention, this reduced dose is less than the dose that would be required to achieve the same pharmacokinetic parameters of Compound A Cmax, AUCinf, Tmax or ?/ _2λΖ if Compound A was administered orally on an empty stomach.

In one embodiment, the present disclosure provides a method of treating a seizure disorder in a subject in need thereof, which comprises orally administering to the individual a therapeutically effective amount of Compound A. In some embodiments of the present invention, the method comprises the following pharmacokinetic parameters for Compound A:

C _max =or>40 ng/ml, for example=or>45, 50, 55, 60, 65, 70, 75 or 80 ng/ml;

AUC _inf =or>2500 ng-h- ^ml'1 , for example=or>2600, 2700, 2800, 2900, 3000, 3100, 3300, 3500, 3700 or 4000 ng-h- ^ml'1 ;

T _max =or>3.25 hours, for example=or>3.5;3.75;4; 4.25 or 4.5 hours or t ¹ / _2λZ =or>130 hours, for example=or>150, 170, 190 or 210.

In one embodiment, the present disclosure provides a substance for use in the treatment of a seizure disorder in individuals in need, which is Compound A and is administered orally to the individual. In some embodiments of the present invention, oral administration of Compound A results in the following pharmacokinetic parameters for Compound A:

C _max =or>40 ng/ml, for example=or>45, 50, 55, 60, 65, 70, 75 or 80 ng/ml;

AUC _inf =or>2500 ng-h- ^ml'1 , for example=or>2600, 2700, 2800, 2900, 3000, 3100, 3300, 3500, 3700 or 4000 ng-h-ml-1;

T _max =or>3.25 hours, for example=or>3.5;3.75;4; 4.25 or 4.5 hours or ί ¹ / _2λΖ =or>130 hours, for example=or>150, 170, 190 or 210.

In some embodiments of the present invention, the increase in one or more of the following parameters for compound A: C _max , AUCinf, T _max or ί ¹ / _2λΖ , resulting from the use of the methods of this invention, is independent of the nature of the food eaten by the person , for example, these foods may or may not include high-calorie or high-fat foods.

In one embodiment, the present disclosure provides a method of increasing passive motor response threshold (RMT) or active motor response threshold (AMT) in individuals in need thereof, comprising administering an amount of Compound A orally, as appropriate, during or after a meal, or at period from 30 minutes before a meal to 2 hours after it. In some embodiments of the present invention, the amount of Compound A administered to a subject is sufficient to increase the subject's passive motor response threshold (RMT) or active motor response threshold (AMT).

In one embodiment, the present disclosure provides a substance for use in increasing passive motor response threshold (RMT) or active motor response threshold (AMT) in individuals in need, which is Compound A and an amount thereof is administered to the individual orally as needed during or after a meal, or in the period from 30 minutes before a meal to 2 hours after it. In some embodiments of the present invention, the amount of Compound A administered to a subject is sufficient to increase the subject's passive motor response threshold (RMT) or active motor response threshold (AMT). In some embodiments of the present invention, Compound A is administered to an individual in an amount of from 2 mg to 200 mg.

In one embodiment, the present disclosure provides a method of increasing passive motor response threshold (RMT) or active motor threshold (AMT) in individuals in need thereof, comprising administering an amount of Compound A orally, as appropriate, during or after a meal, or at period from 30 minutes before a meal to 2 hours after it. In some embodiments of the present invention, the amount of Compound A administered to a subject is from 2 mg to 200 mg.

In one embodiment, the present disclosure provides a method of reducing corticospinal or cortical excitability in individuals in need thereof, comprising administering an amount of Compound A orally, as appropriate, during or after a meal, or between 30 minutes before a meal and 2 hours after it. In some embodiments of the present invention, the amount of Compound A administered to a subject is sufficient to increase the subject's corticospinal or cortical excitability.

In one embodiment, the present disclosure provides a substance for use in reducing corticospinal or cortical excitability in individuals in need, which is Compound A and an amount thereof is administered to the individual orally as appropriate during or after a meal, or within 30 minutes before a meal to 2 hours after it, and this amount is sufficient to increase corticospinal or cortical excitability in a given person. In some embodiments of the present invention, the amount of Compound A administered to a subject is from 2 mg to 200 mg.

In one embodiment, the present disclosure provides a method of reducing corticospinal or cortical excitability in individuals in need thereof, comprising administering an amount of Compound A orally, as appropriate, during or after a meal, or between 30 minutes before a meal and 2 h after it, and the amount of compound A administered to the individual is from 2 mg to 200 mg.

In one embodiment of the present disclosure, oral administration of Compound A to a human during or after a meal results in increased bioavailability and exposure of Compound A following oral administration. Such administration conditions have been found to significantly increase the bioavailability and exposure of Compound A following oral administration. In more particular embodiments of the present invention, the during or after meal condition includes eating the food product at or near the same time as the oral administration of Compound A.

In some (but not all) embodiments of the present disclosure, the food product is high in calories and high in fat. In a typical food of this type, 50% of the total energy content (in calories) comes from fat. A typical high-calorie meal provides the body with approximately 800-1000 calories. Of these, approximately 150 calories come from proteins, 250 from carbohydrates and 500-600 from fats. The amount of food consumed concomitantly with oral administration of Compound A should be sufficient to increase the bioavailability and exposure of Compound A in a given individual.

In some embodiments of the present invention, the oral administration of Compound A to a person in need according to the methods and uses set forth herein occurs from 30 minutes before a meal to 2 hours after a meal. In some embodiments, oral administration of Compound A occurs at a time period from about 60, 45, 30, 25, 20, 15, 10, or 5 minutes before a meal to about 5, 10, 15, 30, 45, 60, 75, 90. 105, 120, 135, 150, 165, 180, 195, 210, 225 or 240 after it. In some embodiments, Compound A is administered simultaneously with or no more than 15 minutes after a meal.

- 11 044821

In some embodiments of this invention, as a result of oral administration of Compound A to a person in need according to the methods and uses set forth herein, the _Cmax , _AUCinf , _Tmax , or ?/ _2λΖ for Compound A is increased compared to when the same amount compounds A is taken orally by the individual on an empty stomach. In some embodiments of the present invention, oral administration of Compound A in an individual results in an increase in the _Cmax for Compound A compared to when the same amount of Compound A is administered orally by the individual on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in AUC _inf compared to administration in the fasted state. In some embodiments, oral administration of Compound A results in an increase in _Tmax compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in ι/ _2λζ compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in C _max and AUC _inf compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in _Cmax and _Tmax compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in C _max and ί ¹ /2λΖ compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in increased AUCinf and Tmax compared to fasting. In some embodiments, oral administration of Compound A results in an increase in AUCinf and t ¹ /2λζ compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in Tmax and ?/ _2λΖ compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in Cmax, AUCinf, and Tmax compared to administration in the fasted state. In some embodiments, oral administration of Compound A results in increased Cmax, AUCinf, and ί1/ _2λΖ compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in _Cmax , _Tmax , and ί1/ _2λζ compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in an increase in AUCinf, _Tmax , and ύ/ _2λζ compared to administration on an empty stomach. In some embodiments, oral administration of Compound A results in increased _Cmax , AUCinf, _Tmax , and ί1/ _2λζ compared to administration on an empty stomach.

In some embodiments of the present invention, by orally administering Compound A to an individual in need according to the methods and uses set forth herein, the Cmax for Compound A is increased compared to when the same amount of Compound A is administered orally to that individual on an empty stomach. In some embodiments, the increase in _Cmax is at least 50%, such as at least 60%, 75%, 85%, 100%, 125%, 150%, 200%, 250%, or 300%. In some embodiments, the increase in C _max is at least 100%, 150%, or 200%, such as at least 100%. In some embodiments, the increase in _Cmax may vary from about 50% to about 500%, such as from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80% to about 250% or from about 100% to about 200%, for example from about 50%, 60%, 70%, 80%, 90% or 100% to about 200%, 250%, 300%, 350%, 400%, 450% or 500%, including about or at least about 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170% , 180%, 190% or 200%.

In one embodiment of the present disclosure, the ratio of the Cmax value after oral administration of Compound A to a human subject during or after a meal to the value after oral administration of Compound A on an empty stomach is greater than 1.2. In some embodiments of this invention, the ratio is greater than 1.3; exceeds 1.5; exceeds 2.0; exceeds 2.5; exceeds 3.0; exceeds 3.5; exceeds 4.0; exceeds 4.5; exceeds 5.0; exceeds 5.5; exceeds 6.0 or exceeds 6.5.

In some embodiments of this invention, the C _max for compound A is increased to at least 40 ng/ml. In some embodiments, the C _max for Compound A is increased from 20 ng/mL to about 200 ng/mL, such as from about 25 to about 200 ng/mL, from about 30 to about 200 ng/mL, from about 35 to about 200 ng/mL ml, from about 40 to about 175 ng/ml, from about 40 to about 150 ng/ml, from about 40 to about 125 ng/ml, from about 40 to about 100 ng/ml, from about 40 to about 90 ng/ml ml, from about 40 to about 80 ng/ml, from about 40 to about 70 ng/ml, from about 40 to about 60 ng/ml, or from about 40 to about 50 ng/ml, for example about 40 ng/ml, 41 ng/ml, 42 ng/ml, 43 ng/ml, 44 ng/ml, 45 ng/ml, 46 ng/ml, 47 ng/ml, 48 ng/ml, 49 ng/ml, 50 ng/ml, 51 ng/ml, 52 ng/ml, 53 ng/ml, 54 ng/ml, 55 ng/ml, 56 ng/ml, 57 ng/ml, 58 ng/ml, 59 ng/ml, 60 ng/ml, 61 ng/ml, 62 ng/ml, 63 ng/ml, 64 ng/ml, 65 ng/ml, 66 ng/ml, 67 ng/ml, 68 ng/ml, 69 ng/ml, 70 ng/ml, 71 ng/ml, 72 ng/ml, 73 ng/ml, 74 ng/ml, 75 ng/ml, 76 ng/ml, 77 ng/ml, 78 ng/ml, 79 ng/ml, 80 ng/ml, 81 ng/ml, 82 ng/ml, 83 ng/ml, 84 ng/ml, 85 ng/ml, 86 ng/ml, 87 ng/ml, 88 ng/ml, 89 ng/ml, 90 ng/ml, 91 ng/ml, 92 ng/ml, 93 ng/ml, 94 ng/ml, 95 ng/ml, 96 ng/ml, 97 ng/ml, 98 ng/ml, 99 ng/ml, or 100 ng/ml .

In some embodiments of the present invention, by orally administering Compound A to an individual in need according to the methods set forth herein, the AUCinf for Compound A is increased compared to when the same amount of Compound A is administered orally to that individual on an empty stomach. In some embodiments, the increase in AUCinf is at least 50%, such as at least 60%, 75%, 85%, 100%, 125%, 150%, 200%, or 250%. In some embodiments, the increase in AUCinf is at least 75% or 100%. In some countries

- 12 044821 anta increase in AUC _inf can vary from about 50% to about 500%, for example from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80% to about 250% or from about 100% to about 200%, for example from about 50%, 60%, 70%, 80%, 90% or 100% to about 200%, 250%, 300%, 350%, 400% , 450% or 500%, including about or at least about 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140 %, 150%, 160%, 170%, 180%, 190% or 200%.

In some embodiments of the present invention, the ratio of the AUC _inf value after oral administration of Compound A to a human subject during or after a meal to the value after oral administration of Compound A on an empty stomach is greater than 1.2. In some embodiments of this invention, the ratio is greater than 1.3; exceeds 1.5; exceeds 1.8; exceeds 2.0; exceeds 2.5; exceeds 3.0; exceeds 3.5; exceeds 4.0; exceeds 4.5; exceeds 5.0; exceeds 5.5; exceeds 6.0 or exceeds 6.5.

In one embodiment of the present disclosure, the ratio of the AUC value after oral administration of Compound A to a human subject during or after a meal to the value after oral administration of Compound A on an empty stomach is greater than 1.2. In some embodiments of this invention, the ratio is greater than 1.3; exceeds 1.5; exceeds 1.8; exceeds 2.0; exceeds 2.5; exceeds 3.0; exceeds 3.5; exceeds 4.0; exceeds 4.5; exceeds 5.0; exceeds 5.5; exceeds 6.0 or exceeds 6.5.

In some embodiments of this invention, the AUC _inf value for compound A is increased to at least 2500 ng-h-ml ^-1 . In some embodiments, the AUCinf value for compound A increases from about 2000 ng-h-ml ^-1 to about 5000 ng-h-ml ^-1 , for example from about 2500 to about 5000 ng-h-ml ^-1 , from about 2500 to about 4500 ng-h-ml ^-1 , from about 2500 to about 4250 ng-h-ml ^-1 , from about 2500 to about 4000 ng-h-ml ^-1 , from about 2500 to about 3750 ng-h-ml ^-1 , from about 2500 to about 3500 ng-h-ml ^-1 , from about 2500 to about 3250 ng-h-ml ^-1 , from about 2500 to about 3000 ng-h-ml ^-1 , or from about 2500 to about 2750 ng-h-ml ^-1 , for example about 2500 ng-h-ml ^-1 , 2600 ng-h-ml ^-1 , 2700 ng-h-ml ^-1 , 2800 ng-h-ml ^-1 , 2900 ng-h -ml ^-1 , 3000 ng-h-ml ^-1 ,

3100 ng-h-ml ^-1 , 3200 ng-h-ml ^-1 , 3300 ng-h-ml ^-1 , 3400 ng-h-ml ^-1 , 3500 ng-h-ml ^-1 , 3600 ng-h- ml ^-1 , 3700 ng-h-ml ^-1 ,

3800 ng-h-ml ^-1 , 3900 ng-h-ml ^-1 , 4000 ng-h-ml ^-1 , 4100 ng-h-ml ^-1 , 4200 ng-h-ml ^-1 , 4300 ng-h- ml ^-1 , 4400 ng-h-ml ^-1 ,

4500 ng-h-ml ^-1 , 4600 ng-h-ml ^-1 , 4700 ng-h-ml ^-1 , 4800 ng-h-ml ^-1 , 4900 ng-h-ml ^-1 or 5000 ng-h- ml ^-1 .

In some embodiments of the present invention, by orally administering Compound A to an individual in need according to the methods set forth herein, the T _max for Compound A is increased compared to when the same amount of Compound A is administered orally to that individual on an empty stomach. In some embodiments, the increase in T _max is at least 50%, such as at least 60%, 75%, 85%, 100%, 125%, 150%, 200%, or 250%. In some embodiments, the increase _{in Tmax} is at least 75% or 100%. In some embodiments, the increase in T _max ranges from at least about 50% to about 500%, such as from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80 % to about 250% or from about 100% to about 200%, for example from about 50%, 60%, 70%, 80%, 90% or 100% to about 200%, 250%, 300%, 350%, 400 %, 450%, or 500%, including about or at least about 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130% , 140%, 150%, 160%, 170%, 180%, 190%, or 200%.

In some embodiments of the present invention, the ratio of the _Tmax value after oral administration of Compound A during or after a meal to the _Tmax value after oral administration of Compound A on an empty stomach is greater than 1.2. In some embodiments of this invention, the ratio is greater than 1.3, greater than 1.5, greater than 1.8, greater than 2.0, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 4, 5, exceeds 5.0, exceeds 5.5, exceeds 6.0, or exceeds 6.5.

In some embodiments of the present invention, the Tmax for Compound A is increased to at least 3.25 hours. In some embodiments, the Tmax for Compound A is increased to between 3 hours and about 15 hours, such as between about 3.25 hours and about 15 hours. from about 3.25 hours to about 14.5 hours, from about 3.25 hours to about 14 hours, from about 3.25 hours to about 13.5 hours, from about 3.25 hours to about 13 hours, from about 3.25 hours to about 12.5 hours, from about 3.25 hours to about 12 hours, from about 3.25 hours to about 11.5 hours, from about 3.25 hours to about 11 hours, from about 3, 25 hours to about 10.5 hours, from about 3.25 hours to about 10 hours, from about 3.25 hours to about 9.5 hours, from about 3.25 hours to about 9 hours, from about 3.25 hours to about 8.5 hours, from about 3.25 hours to about 8 hours, from about 3.25 hours to about 7.5 hours, from about 3.25 hours to about 7 hours, from about 3.25 hours to about 6.5 hours, from about 3.25 hours to about 6 hours, from about 3.25 hours to about 5.5 hours, from about 3.25 hours to about 5 hours, or from about 3.25 hours to about 4, 5 hours, for example about 3.25 hours, 3.5 hours, 3.75 hours, 4 hours, 4.25 hours, 4.5 hours, 4.75 hours, 5 hours, 5.25 hours, 5.5 hours , 5.75 h, 6 h, 6.25 h, 6.5 h, 6.75 h, 7 h, 7.25 h, 7.5 h, 7.75 h, 8 h, 8.25 h, 8.5 hours, 8.75 hours, 9 hours, 9.25 hours, 9.5 hours, 9.75 hours or 10 hours.

In some embodiments of the present invention, as a result of oral administration of Compound A to a person in need according to the methods set forth herein, the ί1/ _2λΖ value for Compound A increases compared to when the same amount of Compound A is administered orally to that individual on an empty stomach, at least by 40% or 50%, for example at least

- 13 044821 for 60%, 75%, or 100%. In some embodiments, the increase in t ¹ /^ is at least 75%. In some embodiments, the increase in ί ¹ / _2λ ζ varies from about 50% to about 500%, such as from about 50% to about 400%, from about 60% to about 350%, from about 70% to about 300%, from about 80 % to about 250% or from about 100% to about 200%, for example from about 50%, 60%, 70%, 80%, 90% or 100% to about 200%, 250%, 300%, 350%, 400 %, 450% or 500%, including about or at least about 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%.

In some embodiments of the present invention, the ratio of the ?/ _2λΖ value after oral administration of Compound A during or after a meal to the _Tmax value after oral administration of Compound A on an empty stomach is greater than 1.2. In some embodiments of this invention, the ratio is greater than 1.3, greater than 1.5, greater than 1.8, greater than 2.0, greater than 2.5, greater than 3.0, greater than 3.5, greater than 4.0, greater than 4, 5, exceeds 5.0, exceeds 5.5, exceeds 6.0, or exceeds 6.5.

In some embodiments of this invention, the t ¹ / ₂ ^Z value for compound A is increased to at least 3.25 hours. In some embodiments, the ? / _2λΖ for compound A is increased to a value from 100 hours to about 500 hours, for example from about 110 h to about 500 h, from about 120 h to about 500 h, from about 130 h to about 500 h, from about 130 h to about 490 h, from about 130 h to about 480 h, from about 130 h to about 470 h , from about 130 hours to about 460 hours, from about 130 hours to about 450 hours, from about 130 hours to about 440 hours, from about 130 hours to about 430 hours, from about 130 hours to about 420 hours, from about 130 hours to about 410 hours, from about 130 hours to about 400 hours, from about 130 hours to about 390 hours, from about 130 hours to about 380 hours, from about 130 hours to about 370 hours, from about 130 hours to about 360 hours, from about 130 hours to about 350 hours, from about 130 hours to about 340 hours, from about 130 hours to about 330 hours, from about 130 hours to about 320 hours, from about 130 hours to about 310 hours, from about 130 hours to about 300 hours, from about 130 hours to about 290 hours, from about 130 hours to about 280 hours, from about 130 hours to about 270 hours, from about 130 hours to about 260 hours, from about 130 hours to about 250 hours, from about 130 hours to about 240 hours, from about 130 hours to about 230 hours, from about 130 hours to about 220 hours, from about 130 hours to about 210 hours, or from about 130 hours to about 200 hours, for example about 130 hours, 140 h, 150 h, 160 h, 170 h, 180 h, 190 h, 200 h, 210 h, 220 h, 230 h, 240 h, 250 h, 260 h, 270 h, 280 h, 290 h, 300 h , 310 h, 320 h, 330 h, 340 h, 350 h, 360 h, 370 h, 380 h, 390 h or 400 h.

In one embodiment of the present invention, a dosage form in single dosage units suitable for oral administration is provided. Dosage levels range from about 0.05 mg/kg to about 2.0 mg/kg. More specific examples of dosage levels in the proposed dosage form include 0.05 mg/kg, 0.10 mg/kg, 0.20 mg/kg, 0.30 mg/kg, 0.40 mg/kg, 0.5 mg/kg kg, 0.6 mg/kg, 0.7 mg/kg, 0.80 mg/kg, 0.90 mg/kg, 1.0 mg/kg, 1.1 mg/kg, 1.2 mg/kg , 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg and 2.0 mg/kg. In some embodiments, the method of this invention comprises orally administering Compound A at a dose of 0.1-1.0 mg/kg. In some embodiments, the method of this invention comprises orally administering Compound A at a dose of 0.2-0.5 mg/kg.

In some embodiments of the present invention, the methods and uses described herein, such as a method of treating or using in the treatment of a seizure disorder in a person in need thereof, are accomplished by orally administering Compound A in an amount of 2-200 mg to an individual. For example, such a method involves orally administering Compound A in amounts of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg. , about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg , about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg , about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg , about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg , about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg , about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg , about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about

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176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg , about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg or about 200 mg. In some embodiments, 5 to 50 mg of Compound A is orally administered. In some embodiments, 10, 20, or 25 mg of Compound A is orally administered. In some embodiments, 20 mg of Compound A is orally administered. In some embodiments, at least 20 mg of Compound A is orally administered.

In some embodiments of the present invention, the methods and uses described herein, for example, a method of treatment or use in the treatment of a seizure disorder in a person in need thereof, are accomplished by oral administration by an individual of Compound A in an amount of 5 to 1000 mg of Compound A per day, for example 5 to 500 mg/day or 5 - 250 mg/day. For example, such a method involves orally administering Compound A in amounts of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg. , about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg , about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg , about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg , about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg or about 1000 mg per day. In some embodiments, 10-200 mg of Compound A is administered orally per day, such as 10, 15, 20, 25, 30, 35, or 40 mg/day to 75, 100, 125, 150, 175, or 200 mg/day, including including 20 - 150 m/day. In some embodiments, 50, 75, 100, or 125 mg of Compound A are administered orally per day, such as 100 mg/day.

In some cases, the above daily doses of Compound A are administered orally in divided doses, for example two, three, four or five times a day. For example, a daily dose of 100 mg is administered in four 25 mg doses distributed throughout the day.

In some embodiments of the present invention, the above daily doses of Compound A are administered in one dose. For example, once daily a person takes from about 5, 10, 15, 20, 25 or 30 mg to about 50, 65, 75, 100, 125 or 150 mg of Compound A, including 10-25 mg, 10-30 mg and 10-40 mg per day in one dose, for example 10-25 mg/day in one dose.

In some embodiments of the present invention, the methods and uses described herein, including the use of the daily dosage specified herein, allow Compound A to reach equilibrium in the body within 6-9 days, such as 1 week or so.

In some cases, the present invention provides a method of increasing the level of Compound A in the blood serum of a person in need of treatment with this substance, comprising orally administering Compound A to the subject during or after a meal or during a period of time from 30 minutes before a meal to 2 hours after a meal. In similar embodiments of the present invention, Compound A is provided for use in increasing the level of Compound A in the blood serum of a person in need of treatment with this substance, wherein Compound A is administered to the individual orally during or after a meal or during a period of time from 30 minutes before a meal to 2 hours after it.

In one embodiment of the present invention, administration of Compound A is provided, for example for the treatment of a seizure disorder in which it would be beneficial to increase the open state of Kv7.2/Kv7.3 potassium channels (KCNQ2/3). Compound A is an activator of Kv7.2/Kv7.3 channels (KCNQ2/3). Some embodiments of the present disclosure provide a method of activating Kv7.2/Kv7.3 potassium channels (KCNQ2/3) in individuals in need, comprising administering to the human body an amount of Compound A. Similar embodiments of the present invention provide Compound A for use in activating potassium channels Kv7.2/Kv7.3 (KCNQ2/3) in people in need.

Some embodiments of the present disclosure provide a method of treating, ameliorating, or preventing a disease, disorder, or condition that is affected by altered functioning of at least one potassium channel selected from Kv7.2, Kv7.3, Kv7.4 (KCNQ4), and Kv7 channels. 5 (KCNQ5), in people in need, by, for example, activating one or more of these potassium channels; said method involves orally administering Compound A, as appropriate, during or after a meal or during a period of time from 30 minutes before a meal to 2 hours after a meal. In similar embodiments, the present disclosure provides Compound A for use in the treatment, amelioration, or prevention of a disease, disorder, or condition that is affected by alterations in the functioning of at least one potassium channel selected from the channels

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Kv7.2, Kv7.3, Kv7.4 and Kv7.5 in individuals in need, by, for example, activating one or more of these potassium channels, wherein Compound A is administered orally to the individual as needed during or after meals or during from 30 minutes before a meal to 2 hours after it. In some embodiments of the present invention, oral administration of Compound A does not result in activation of the Kv7.1 potassium channel (KCNQ1). That is, in some cases, Compound A acts selectively on one or more of the potassium channels Kv7.2, Kv7.3, Kv7.4 and Kv7.5, as well as Kv7.1.

In some embodiments of the present invention, oral administration of Compound A to a human in need according to the methods described herein results in an increase in the passive motor response threshold (RMT) or active motor response threshold (AMT). In some embodiments of the present invention, the increase in RMT or AMT is proportional to the plasma concentration of Compound A. In some embodiments of the present invention, oral administration of Compound A to a human in need results in a decrease in corticospinal or cortical excitability as measured by transcranial magnetic stimulation (TMS).

Some embodiments of the present disclosure provide a method of orally administering Compound A to a human who has a lower passive motor response threshold (RMT) or active motor threshold (AMT) than the human average; the method involves orally administering Compound A, as appropriate, during or after a meal, or from 30 minutes before a meal to 2 hours after a meal, thereby increasing the RMT or AMT of an individual with a decreased RMT or AMT.

In some embodiments of the present invention, oral administration of Compound A to a human according to the methods and uses described herein results in changes in transcranial magnetic stimulation-evoked potentials (TMS-evoked potentials) in combination with electroencephalography (EEG) and a decrease in cortical excitability. In some embodiments, at certain plasma concentrations of Compound A (e.g., 50 ng/mL or greater), there is a decrease (compared to placebo) in the amplitude of one or more early components of transcranial magnetic stimulation (TES)-evoked potentials, including those occurring 15 days later. 35 ms (N15-P25), 45 ms (N45) or 180 ms (P180) after the magnetic pulse (eg 50% or more). In some embodiments, at 2, 4, and 6 hours after dosing of Compound A, there is a decrease (compared to placebo) in the amplitude of one or earlier components of TMS-evoked potentials, including those occurring at 15-35 ms (N15-P25), 45 ms (N45 ) or 180 ms (P180) after the magnetic pulse (eg 30% or more).

In some embodiments of the present invention, oral administration of Compound A to a human according to the methods and uses described herein results in a change in transcranial magnetic stimulation-induced electrical potential oscillations (oscillations) and subsequent oscillatory activity. In some embodiments, at certain plasma concentrations of Compound A (eg, 50 ng/mL or greater), there is a reduction (40% or greater compared to placebo) in TMS-induced early (30-390 ms post-stimulus magnetic pulse) oscillations in theta band (4-7 Hz) or oscillations (220-400 ms post-stimulus) in the alpha band (8-12 Hz) and/or an increase (40% or more compared to placebo) in oscillation power (220-310 ms post-stimulus) stimulus) in the beta range (13-30 Hz). In some embodiments, a reduction (30% or more relative to placebo) in magnetic stimulus-induced early oscillation in the theta band is observed 2 hours after dosing of Compound A. In some embodiments, a reduction (30%) is observed 4 hours after dosing of Compound A and more compared to placebo) magnetic stimulus-induced oscillations in the alpha range. In some embodiments, a reduction (30% or more compared to placebo) in magnetic stimulus-induced oscillation in the theta band is observed 6 hours after dosing of Compound A.

In some embodiments of the present invention, oral administration of Compound A to a human according to the methods and uses described herein results in a change in background electroencephalogram (resting EEG). In some embodiments, at certain plasma concentrations of Compound A (e.g., 50 ng/mL or more), there is an increase (e.g., 50% or more compared to placebo) in the power of electrical activity in one or more delta, theta, or beta frequency bands . In some embodiments, 2, 4, and 6 hours after administration of Compound A, there is an increase (eg, 40% or more compared to placebo) in the power of electrical activity in one or more delta, theta, beta, or alpha frequency bands.

In certain embodiments of the present invention, the methods and uses described herein involve the administration of Compound A to a human in the form of a pharmaceutically acceptable composition for oral administration containing Compound A and one or more pharmaceutically acceptable carriers or other excipients. The amount of Compound A in such a composition corresponds to one or more of the amounts of Compound A administered to a person as set forth herein. In some embodiments of the present invention, the composition is provided in a dosage form in discrete unit doses.

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Examples of pharmaceutically acceptable oral compositions containing Compound A include solid dosage forms (e.g., tablets, capsules, lozenges, dragees, granules, powders, multiparticulates and films) and liquid formulations (e.g., aqueous solutions , elixirs, tinctures, suspensions and dispersions). In one embodiment of the present invention, the proposed pharmaceutically acceptable oral composition containing Compound A includes pediatric suspensions or granules. In such preparations, Compound A may be contained in all of the above amounts, for example, one capsule may contain 5, 10, 15, 10, 25, 30 or 35 mg of Compound A.

In another embodiment of the present invention, kits are provided for oral administration of Compound A during or after meals to increase the bioavailability and exposure of Compound A when administered orally. Such kits include a quantity of the drug containing Compound A in individual unit doses and instructions for oral administration with or after meals.

In one embodiment of the present disclosure, oral administration of a therapeutically effective amount of Compound A increases the maximum plasma concentration of Compound A (C _max ) and its exposure, as measured by the area under the concentration-time curve (AUC), compared to the values of these parameters when administered orally. administration of compound A on an empty stomach.

In one embodiment of the present disclosure, the ratio of the _Cmax value after oral administration of a therapeutically effective amount of Compound A during or after a meal to the value after oral administration of the same amount of Compound A on an empty stomach is greater than 1.3.

In one embodiment of the present disclosure, the ratio of the AUC value after oral administration of a therapeutically effective amount of Compound A during or after a meal to the value after oral administration of the same amount of Compound A on an empty stomach is greater than 1.3.

In one embodiment of the present disclosure, the therapeutically effective amount of Compound A is from about 0.05 mg/kg to about 2 mg/kg.

In certain embodiments of the invention described herein, the results of oral administration of Compound A in humans were compared to administration of the substance on an empty stomach; similarly, a comparison can be made with oral administration of Compound A such that the individual does not eat for a period of about 4 hours before administration of Compound A to 4 hours after administration, for example from about 4, 3, 2, 1.5, 1 or 0.5 h before oral administration of the compound to about 0.5; 1; 1.5; 2; 3 or 4 hours after oral administration of Compound A.

In some embodiments of the present invention, the seizure disorder to be treated herein is selected from the following disorders: partial seizure disorder, photogenic epilepsy, spontaneous syncope, incurable or drug-resistant epilepsy, Angelman syndrome, benign epilepsy with central peaks. -temporal region, syndrome caused by a mutation in the cyclin-dependent kinase 5 (CDKL5) gene, childhood and juvenile absence epilepsy, Dravet syndrome, frontal epilepsy, glucose transporter deficiency syndrome type 1., hypothalamic hamartoma, infantile seizures/West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic absence seizures, Ohtahara syndrome, Panagiotopoulos syndrome, epilepsy due to mutation in the protocaderin 19 gene (PCDH19), progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome syndrome 20, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis complex, early-onset epileptic encephalopathy (including childhood), generalized epilepsy with febrile seizures plus (GEFS+), Rett syndrome, multiple sclerosis, Alzheimer's disease , autism, ataxia, hypotension and paroxysmal dyskinesias. In some embodiments of the present invention, the term seizure disorder refers to partial (also called focal or localized) epileptic seizures.

Additional embodiments of the present invention and examples are also described herein. These embodiments and examples are illustrative in nature and do not limit the scope of the invention as defined by its claims.

4.3. Numbered incarnations.

Embodiment 1. A method of treating a disease, disorder or condition associated with Kv7 potassium channel dysfunction in individuals in need thereof, which comprises administering to the patient a therapeutically effective amount of Compound A orally during or after a meal, wherein Compound A is N-[4 -(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]3,3-dimethylbutanamide.

Embodiment 2. A method of treating a disease, disorder or condition associated with Kv7 potassium channel dysfunction in individuals in need thereof, which comprises administering to the patient a therapeutically effective amount of Compound A by the oral route from 30 minutes before a meal to 2 hours after a meal. food, and compound A is K-[4-(6-fluoro-3,4dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

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Embodiment 3. The method of embodiment 1 or 2, which increases the probability of an open state of Kv7 potassium channels.

Embodiment 4. The method of Embodiment 3, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5 channels.

Embodiment 5. The method of embodiment 4, which is selective for activation of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5 channels, as well as Kv7.1.

Embodiment 6. The method of any one of embodiments 1-5, wherein the disease, disorder or condition is a seizure disorder.

Embodiment 7. The method of embodiment 6, wherein the seizure disorder is epilepsy with focal seizures at disease onset.

Embodiment 8. A method of treating a seizure disorder in a person in need, comprising administering to that person an amount of Compound A orally during or after a meal, wherein Compound A is N[4-(6-fluoro-3,4-dihydro-1H- isoquinolin-2-yl)-2,6dimethylphenyl]-3,3-dimethylbutanamide, and the amount administered is sufficient to treat a seizure disorder in a given individual.

Embodiment 9. A method of treating a seizure disorder in a person in need, comprising administering to that person an amount of Compound A orally from 30 minutes before a meal to 2 hours after a meal, wherein Compound A is N-[4(6- fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the amount administered is sufficient to treat a seizure disorder in a given individual.

A method of treating a seizure disorder in a person in need, comprising administering to that person an amount of Compound A orally during or after a meal, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline- 2-yl)-2,6-dimethylphenyl]-3,3dimethylbutanamide, and the administered amount of compound A is from 2 mg to 200 mg.

Embodiment 11. A method of treating a seizure disorder in a person in need, comprising administering to that person an amount of Compound A orally from 30 minutes before a meal to 2 hours after a meal, wherein Compound A is N-[4(6- fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the administered amount of compound A is from 2 mg to 200 mg.

Embodiment 12. A method of treating a seizure disorder in a person in need, comprising administering Compound A to the body orally, wherein Compound A is N-[4-(6fluoro-3,4-dihydro-1H-isoquinolin-2-yl)- 2,6-dimethylphenyl]-3,3-dimethylbutanamide, and oral administration of this substance to the specified individual is carried out during or after a meal.

Embodiment 13. A method of treating a seizure disorder in a person in need thereof, comprising administering Compound A to the body orally, wherein Compound A is N-[4-(6fluoro-3,4-dihydro-1H-isoquinolin-2-yl)- 2,6-dimethylphenyl]-3,3-dimethylbutanamide, and oral administration of this substance to the specified individual is carried out in a period of time from 30 minutes before a meal to 2 hours after a meal.

Embodiment 14. A method of orally administering Compound A to a human in need, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]- 3,3dimethylbutanamide, and oral administration of this substance to the specified individual is carried out during or after meals.

Embodiment 15. A method of orally administering Compound A to a human in need, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]- 3,3dimethylbutanamide, and oral administration of this substance to the specified individual is carried out in a period of time from 30 minutes before a meal to 2 hours after a meal.

Embodiment 16. The method of any one of embodiments 8-15, wherein one or more of the C _max , AUC _inf , T _max or ί1/ _2λΖ parameters for Compound A are increased compared to orally administering the same amount of Compound A to a human on an empty stomach.

Embodiment 17. A method of increasing one or more _Cmax , _AUCinf , Tmax or ί1/ _2λΖ for compound A in a human taking the substance orally, which comprises orally administering compound A to the human during or after a meal, wherein compound A is N -[4-(6-fluoro-3,4dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide and as a result of using this method, one or more of the _Cmax , AUCinf indicators increase , _Tmax or ί1/ _2λΖ , for compound A compared to oral administration of the same amount of compound A to a person on an empty stomach.

Embodiment 18. A method of increasing one or more _Cmax , AUCinf, _Tmax or ί1/ _2λΖ for Compound A in a human taking the substance orally, which comprises orally administering Compound A to the human during a period of time from 30 minutes before a meal to 2 h after meals, and compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]3,3-dimethylbutanamide and as a result of the use of the specified way increase one or more

- 18 044821 from C _max , AUC _inf , T _max or ?/ _2λΖ , for compound A compared to oral administration of the same amount of compound A to a person on an empty stomach.

Embodiment 19. A method of orally administering Compound A to a person in need thereof, comprising administering Compound A orally to the body during or after a meal, wherein Compound A is K-[4-(6-fluoro-3,4-dihydro-1H- isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3dimethylbutanamide, and as a result of using this method, one or more of the _Cmax , AUCinf, _Tmax or t'/.Z indicators for compound A increases compared to by orally administering the same amount of Compound A to a person on an empty stomach.

Embodiment 20 A method of orally administering Compound A to a person in need, comprising administering Compound A orally to the body during a period of time from 30 minutes before a meal to 2 hours after a meal, wherein Compound A is K-[4-(6-fluoro -3,4-dihydro1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and as a result of using this method, one or more of the C _max , AUCinf, T _max or t'/ indicators increase .Z, for Compound A compared to orally administering the same amount of Compound A to a human on an empty stomach.

Embodiment 21. A method of reducing the dose of Compound A that is administered orally to a person in need thereof as part of a treatment regimen comprising orally administering a reduced dose of Compound A during or after a meal, wherein Compound A is P-[4-(6-fluoro-3 ,4-dihydro-1Nisoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the reduced dose is less than the dose that would be required to achieve the same values of one or more of the _Cmax values, AUCinf, _Tmax or t'/.Z, for compound A when administered orally to a given individual on an empty stomach.

Embodiment 22. A method of reducing the dose of Compound A that is administered orally to a person in need thereof as part of a treatment regimen comprising orally administering a reduced dose of Compound A during a period of time from 30 minutes before a meal to 2 hours after a meal, wherein Compound A is K -[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3dimethylbutanamide, and the reduced dose is less than the dose that would be required to achieve these the same values of one or more of _Cmax , AUCinf, _Tmax or t'/.Z, for compound A when administered orally to a given individual on an empty stomach.

Embodiment 23. The method of any one of embodiments 16-22, wherein oral administration of Compound A to a human results in an increase in the Cmax for Compound A compared to oral administration of the same amount of the substance on an empty stomach.

Embodiment 24. The method according to embodiment 23, wherein the ratio of the _Cmax value of compound A after oral administration to the Cmax value after oral administration on an empty stomach is greater than 1.3.

Embodiment 25. The method of Embodiment 23, wherein the ratio of the C _max value for compound A after oral administration to the C _max value after oral administration on an empty stomach is greater than 2.

Embodiment 26. The method of Embodiment 23, wherein the ratio of the C _max value of compound A after oral administration to the C _max value after oral administration on an empty stomach is greater than 3.

Embodiment 27. The method of embodiment 23, wherein the increase in C _max for compound A is at least 50%.

Embodiment 28. The method of embodiment 23, wherein the increase in C _max for compound A is at least 100%.

Embodiment 29. The method of any one of embodiments 16-28, wherein oral administration of compound A to a human results in an increase in the AUC _inf for compound A compared to oral administration of the same amount of the substance on an empty stomach.

Embodiment 30. The method of embodiment 29, wherein the ratio of the AUCinf value of compound A after oral administration to the AUC _inf value after oral administration on an empty stomach is greater than 1.3.

Embodiment 31. The method of embodiment 29, wherein the ratio of the AUCinf value of compound A after oral administration to the AUCinf value after oral administration on an empty stomach is greater than 1.5.

Embodiment 32. The method of embodiment 29, wherein the ratio of the AUCinf value of compound A after oral administration to the AUCinf value after oral administration on an empty stomach is greater than 1.8.

Embodiment 33. The method of embodiment 29, wherein the increase in AUCinf for compound A is at least 50%.

Embodiment 34. The method of embodiment 29, wherein the increase in AUCinf for Compound A is at least 75%.

Embodiment 35. The method of any one of embodiments 16-34, wherein oral administration of compound A to a human results in an increase in the T _max for compound A compared to oral administration of the same amount of the substance on an empty stomach.

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Embodiment 36. The method of Embodiment 35, wherein the ratio of the T _max value of compound A after oral administration to the T _max value after oral administration on an empty stomach is greater than

1.3.

Embodiment 37. The method according to embodiment 35, wherein the ratio of the T _max value of compound A after oral administration to the T _max value after oral administration on an empty stomach is greater than 1.8.

Embodiment 38. The method of Embodiment 35, wherein the ratio of the T _max value of compound A after oral administration to the T _max value after oral administration on an empty stomach is greater than 2.

Embodiment 39. The method of embodiment 35, wherein the increase in T _max for compound A is at least 50%.

Embodiment 40. The method of embodiment 35, wherein the increase in T _max for compound A is at least 75%.

Embodiment 41. The method of any one of embodiments 16-40, wherein oral administration of compound A to a human results in an increase in the t ¹ / ₂ ^Z value for compound A compared to oral administration of the same amount of the substance on an empty stomach.

Embodiment 42. The method according to embodiment 41, in which the ratio of the υ/ _2λΖ value for compound A after its oral administration to the t ¹ / ₂ ^Z value after its oral administration on an empty stomach exceeds 1.2.

Embodiment 43. The method according to embodiment 41, wherein the ratio of the ?/ _2λΖ value for compound A after its oral administration to the ?/ _2λΖ value after its oral administration on an empty stomach exceeds 1.4.

Embodiment 44. The method of embodiment 41, wherein the increase in ?/ _2λΖ for compound A is at least 20%.

Embodiment 45. The method of embodiment 41, wherein the increase in t ¹ / ₂ ^ _Z for compound A is at least 35%.

Embodiment 46. A method of treating a seizure disorder in a person in need thereof, comprising orally administering compound A to the body, wherein compound A is K-[4-(6-fluoro3,4-dihydro-1H-isoquinolin-2-yl)-2, 6-dimethylphenyl]-3,3-dimethylbutanamide, and as a result of using this method, one or more of the pharmacokinetic parameters for compound A takes on the following values:

C _max =or>40 ng/ml;

AUC _inf =or>2500 ng-h-ml' ¹

T _max =or>3.25 hours or t ¹ / _2λZ =or>130 hours.

Embodiment 47. A method of increasing the passive motor response threshold (RMT) or the active motor response threshold (AMT) in a person in need thereof, comprising orally administering an amount of Compound A to the body, wherein Compound A is K-[4-(6-fluoro- 3,4-dihydro1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the administered amount of this substance is sufficient to cause an increase in RMT or AMT in a given individual.

Embodiment 48. A method of increasing the passive motor response threshold (RMT) or the active motor response threshold (AMT) in a person in need thereof, comprising orally administering an amount of Compound A to the body, wherein Compound A is K-[4-(6-fluoro- 3,4-dihydro1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and the administered amount of this substance is 2-200 mg.

Embodiment 49. The method of Embodiment 47 or 48, wherein the increases in the passive motor response threshold (RMT) or active motor response threshold (AMT) are proportional to the concentration of compound A in the blood plasma.

Embodiment 50. A method of reducing corticospinal or cortical excitability in a person in need thereof, comprising orally administering an amount of Compound A to the body, wherein Compound A is K-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline -2-yl)-2,6dimethylphenyl]-3,3-dimethylbutanamide, and the administered amount of this substance is sufficient to reduce corticospinal or cortical excitability in a given individual.

Embodiment 51. A method of reducing corticospinal or cortical excitability in a person in need thereof, comprising orally administering an amount of Compound A to the body, wherein Compound A is K-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline -2-yl)-2,6dimethylphenyl]-3,3-dimethylbutanamide, and the administered amount of this substance is 2-200 mg.

Embodiment 52. The method according to any of embodiments 1-7, comprising orally administering Compound A to a human in an amount of 2-200 mg.

Embodiment 53. The method of any one of embodiments 8-52, comprising orally administering Compound A to a human in an amount of 2-100 mg.

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Embodiment 54. The method of embodiment 53, comprising orally administering Compound A to a human in an amount of 5-50 mg.

Embodiment 55. The method of Embodiment 53 comprising orally administering Compound A to a human in an amount of 10, 20 or 25 mg.

Embodiment 56. The method of Embodiment 53 comprising orally administering Compound A to a human in an amount of 20 mg.

Embodiment 57. The method of any one of embodiments 8-54, comprising orally administering Compound A to a human in an amount of at least 20 mg.

Embodiment 58. The method of any one of embodiments 8-57, comprising orally administering Compound A to a human in an amount of 5-500 mg per day.

Embodiment 59. The method of embodiment 58, comprising orally administering Compound A to a human in an amount of 20-150 mg per day.

Embodiment 60. The method of Embodiment 58 comprising orally administering Compound A to a human in an amount of 100 mg per day.

Embodiment 61. The method according to any of embodiments 1-60, comprising orally administering Compound A to a human at a dose of 0.05-2.0 mg/kg.

Embodiment 62. The method of embodiment 61, comprising orally administering Compound A to a human at a dose of 0.1-1.0 mg/kg.

Embodiment 63. The method of embodiment 61, comprising orally administering Compound A to a human at a dose of 0.2-0.5 mg/kg.

Embodiment 64. An agent for use in treating a disease, disorder or condition associated with dysfunction of Kv7 potassium channels in a human in need thereof, which is K-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline -2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide and is administered orally to the individual during or after a meal.

Embodiment 65. An agent for use in treating a disease, disorder or condition associated with dysfunction of Kv7 potassium channels in a human in need thereof, which is K-[4-(6-fluoro-3,4-dihydro-N-isoquinoline- 2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide and is administered to the specified individual orally during a period of time from 30 minutes before a meal to 2 hours after a meal.

Embodiment 66. A substance for use according to embodiment 63 or 64, wherein the method of this invention results in activation of Kv7 potassium channels.

Embodiment 67. The substance for use according to embodiment 65, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5 channels.

Embodiment 68. The substance for use according to embodiment 66, wherein the method of this invention is selective for activation of the Kv7 potassium channel selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5, as well as Kv7.1.

Embodiment 69. The substance for use according to any of embodiments 63-67, wherein the disease, disorder or condition is a seizure disorder.

Embodiment 70. The substance for use according to embodiment 68, wherein the seizure disorder is epilepsy with focal seizures at disease onset.

Embodiment 71. A substance for use in the treatment of a seizure disorder in a person in need, which is K-[4-(6-fluoro-3,4-dihydro-N-isoquinolin-2-yl)-2,6-dimethylphenyl]3, 3-dimethylbutanamide and is administered to said individual orally during or after a meal.

Embodiment 72. A substance for use in the treatment of a seizure disorder in a person in need, which is K-[4-(6-fluoro-3,4-dihydro-N-isoquinolin-2-yl)-2,6-dimethylphenyl]3, 3-dimethylbutanamide and is administered to the specified individual orally during a period of time from 30 minutes before a meal to 2 hours after a meal.

Embodiment 73. A substance for use in embodiment 56 or 57, the oral administration of which to a human results in an increase in the values of one or more of the C _max , AUC _inf , T _max or t ¹ / ₂ λ _ζ for that substance in that individual compared to the values of these indicators when taking the same amount of this substance orally on an empty stomach.

Embodiment 74. A substance for use in increasing the values of one or more of the C _max , AUCinf, T _max or ί ¹ / _2λ ζ for that substance in a person orally ingesting the substance, which is K-[4-(6-fluoro- 3,4-dihydro-III-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3dimethylbutanamide and is administered to the specified individual orally during or after a meal, resulting in an increase in the values of one or more of the C _max values. AUCinf, _Tmax or t1/ _24Z for a substance in a given individual compared with the values of these indicators when taking the same amount of the substance orally on an empty stomach.

Embodiment 75 A substance for use when one or more of the _Cmax , AUCinf, _Tmax , or ?/ _2λζ values for that substance increase in a person orally ingesting the substance, which is K-[4-(6-fluoro-3, 4-dihydro-III-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethyl- 21 044821 butanamide and is administered to the specified individual orally during a period of time from 30 minutes before a meal to 2 hours after a meal , resulting in an increase in the values of one or more of the _Cmax , _AUCinf , _Tmax or ί ¹ / _2λΖ indicators for that substance in a given individual compared to the values of these indicators when taking the same amount of the substance orally on an empty stomach.

Embodiment 76. A substance for use in reducing its dose, which is administered orally to a person in need as part of a treatment regimen and is K-[4-(6-fluoro-3,4dihydro-1H-isoquinolin-2-yl)-2, 6-dimethylphenyl]-3,3-dimethylbutanamide, wherein the reduced dose is administered orally during or after a meal and is less than the dose that would be required to achieve the same values of one or more of _Cmax , AUCinf, _Tmax or ?/ _2λΖ , for this substance when administered orally to a given individual on an empty stomach.

Embodiment 77. A substance for use in reducing its dose, which is administered orally to a person in need as part of a treatment regimen and is K-[4-(6-fluoro-3,4dihydro-1H-isoquinolin-2-yl)-2, 6-dimethylphenyl]-3,3-dimethylbutanamide, wherein the reduced dose is administered orally from 30 minutes before a meal to 2 hours after a meal, and is less than the dose that would be required to achieve the same values of one or more more of the _Cmax , AUCinf, _Tmax or ί1/ _2λΖ indicators for this substance when administered orally to a given individual on an empty stomach.

Embodiment 78. A substance for use according to any one of embodiments 73-77, wherein oral administration of the substance to a human results in an increase in the C _max for that substance in that individual compared to the value of that value when the same amount of the substance is orally administered on an empty stomach.

Embodiment 79. A substance for use according to embodiment 78, wherein the ratio of the _Cmax value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.3.

Embodiment 80. A substance for use according to embodiment 78, wherein the ratio of the _Cmax value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 2.

Embodiment 81. A substance for use according to embodiment 78, wherein the ratio of the _Cmax value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 3.

Embodiment 82. The substance for use according to embodiment 78, wherein the increase in the _Cmax value is at least 50%.

Embodiment 83. The substance for use according to embodiment 78, wherein the increase in the _Cmax value is at least 100%.

Embodiment 84. A substance for use according to any one of embodiments 73-78, wherein oral administration of the substance of this invention to a human results in an increase in the AUC _inf for that substance in that individual compared to the value of the indicated value when the same amount of the substance is taken orally on an empty stomach. .

Embodiment 85. The substance for use according to embodiment 84, wherein the ratio of the AUCinf value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.3.

Embodiment 86. A substance for use according to embodiment 84, wherein the ratio of the AUC _inf value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.5.

Embodiment 87. A substance for use according to embodiment 84, wherein the ratio of the AUC _inf value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.8.

Embodiment 88. The substance for use according to embodiment 84, wherein the increase in the AUCinf value is at least 50%.

Embodiment 89. A substance for use according to embodiment 84, wherein the increase in AUCinf value is at least 75%.

Embodiment 90. A substance for use according to any one of embodiments 73-89, wherein oral administration of the substance of this invention to a human results in an increase in the Tmax for that substance in that individual compared to the value of the same value when the same amount of the substance is taken orally on an empty stomach.

Embodiment 91. A substance for use according to embodiment 90, wherein the ratio of the _Tmax value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.3.

Embodiment 92. A substance for use according to embodiment 90, wherein the ratio of the Tmax value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.8.

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Embodiment 93. A substance for use according to embodiment 90, wherein the ratio of the _Tmax value after oral administration of this substance according to this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 2.

Embodiment 94. A substance for use according to embodiment 75, wherein the increase in T _max is at least 50%.

Embodiment 95. The substance for use according to embodiment 90, wherein the increase in T _max is at least 75%.

Embodiment 96. A substance for use according to any of embodiments 73-95, in which oral administration to a person of this substance according to this invention leads to an increase in t ¹ / ₂ λ _Z for this substance in a given individual compared to the value of the specified indicator when taking it orally the same amount of this substance on an empty stomach.

Embodiment 97. A substance for use according to embodiment 96, wherein the ratio of the t ¹ / ₂ λ _Z value after oral administration of a substance of this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.2.

Embodiment 98. A substance for use according to embodiment 96, wherein the ratio of the t ¹ / ₂ λ _Z value after oral administration of a substance of this invention to the value of the specified indicator after oral administration of the same amount of this substance on an empty stomach exceeds 1.4.

Embodiment 99. The substance for use according to embodiment 96, wherein the increase in t ¹ / ₂ λ _Z value is at least 20%.

Embodiment 100. The substance for use according to embodiment 96, wherein the increase in t ¹ / ₂ λ _Z value is at least 35%.

Embodiment 101. A substance for use in the treatment of a seizure disorder in a person in need, which is K-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6dimethylphenyl]-3, 3-dimethylbutanamide and is administered orally into the body, as a result of which one or more of the pharmacokinetic parameters for this substance takes on the following values:

C _max =or>40 ng/ml;

AUC _in f=or>2500 ng-h-ml' ¹

Tmax=or>3.25 h or t ¹ / _2λZ =or>130 h.

Embodiment 102. An agent for use in increasing the passive motor response threshold (RMT) or active motor response threshold (AMT) in a person in need that is K-[4-(6-fluoro-3,4-dihydro-1H- isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide and is administered orally.

Embodiment 103. The substance for use according to embodiment 102, wherein the increase in the passive motor response threshold (RMT) or active motor response threshold (AMT) is proportional to the concentration of the substance in the blood plasma.

Embodiment 104. A substance for use in reducing corticospinal or cortical excitability in a person in need, which is K-[4-(6-fluoro-3,4-dihydro-1Nisoquinolin-2-yl)-2,6-dimethylphenyl]- 3,3-dimethylbutanamide and is administered orally.

Embodiment 105. A substance for use according to any of embodiments 64-89, which is administered to a person in an amount of 2-200 mg.

Embodiment 106. The substance for use according to embodiment 105, which is administered to a person in an amount of 2-100 mg.

Embodiment 107. The substance for use according to embodiment 105, which is administered to a person in an amount of 5-50 mg.

Embodiment 108. The substance for use according to embodiment 105, which is administered to a person in an amount of 10, 20 or 25 mg.

Embodiment 109. The substance for use according to embodiment 105, which is administered to a person in an amount of 20 mg.

Embodiment 110. A substance for use in any one of embodiments 64-107, which is administered to a human in an amount of at least 20 mg.

Embodiment 111. A substance for use according to any of embodiments 64-110, which is administered to a person in an amount of 5-500 mg per day.

Embodiment 112. A substance for use according to embodiment 111, which is administered to a person in an amount of 20-150 mg per day.

Embodiment 113. The substance for use according to embodiment 111, which is administered to a person in an amount of 100 mg per day.

Embodiment 114. A substance for use according to any of embodiments 64-113, which is administered to a person at a dose of 0.05-2.0 mg/kg.

Embodiment 115. A substance for use according to embodiment 114, which is administered to a person at a dose of 0.1-1.0 mg/kg.

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Embodiment 116. A substance for use according to embodiment 114, which is administered to a person in a dose

0.2-0.5 mg/kg.

4.4. Additional numbered embodiments.

Embodiment 1a. A method of treating a seizure disorder in a person in need, comprising administering to the person a therapeutically effective amount of Compound A orally during or after a meal.

Embodiment 2a. The method of embodiment 1a, wherein the oral administration of a therapeutically effective amount of Compound A to a human results in an increase in the bioavailability and extent of exposure of Compound A compared to those when the substance is administered orally on an empty stomach.

Embodiment 3a. The method of embodiment 2a, wherein the oral administration of a therapeutically effective amount of Compound A to a human results in an increase in the maximum plasma concentration of that substance (C _max ) and the degree of its exposure to the body, assessed by the area under the concentration-time curve (AUC) compared with the indicated indicators upon oral administration of Compound A on an empty stomach.

Embodiment 4a. The method according to embodiment 3a, wherein the ratio of the _Cmax value after oral administration of a therapeutically effective amount of compound A during or after a meal to the value of the specified value after oral administration of a therapeutically effective amount of this substance on an empty stomach exceeds 1.3.

Embodiment 5a. The method of embodiment 3a, wherein the ratio of the AUC value after oral administration of a therapeutically effective amount of Compound A during or after a meal to the AUC value after oral administration of a therapeutically effective amount of the substance on an empty stomach is greater than 1.3.

Embodiment 6a. The method of any one of embodiments 1a-5a, wherein the therapeutically effective amount of compound A is from about 0.05 mg/kg to about 2.0 mg/kg.

Embodiment 7a. A method of increasing the bioavailability and potency of Compound A in a human taking the compound orally in a therapeutically effective amount for the treatment of a seizure disorder, the method comprising administering a therapeutically effective amount of Compound A orally during or after a meal.

Embodiment 8a. The method of embodiment 7a, wherein the oral administration of a therapeutically effective amount of Compound A results in an increase in the maximum plasma concentration of that substance (Cmax) and the degree of its exposure to the body, assessed by the area under the concentration-time curve (AUC) compared to these indicators when compound A is administered orally on an empty stomach.

Incarnation 9a. The method according to embodiment 8a, wherein the ratio of the _Cmax value after oral administration of a therapeutically effective amount of compound A during or after a meal to the value of the specified value after oral administration of a therapeutically effective amount of this substance on an empty stomach exceeds 1.3.

Embodiment 10a. The method of embodiment 8a, wherein the ratio of the AUC value after oral administration of a therapeutically effective amount of Compound A during or after a meal to the AUC value after oral administration of a therapeutically effective amount of the compound on an empty stomach is greater than 1.3.

Embodiment 11a. The method of any one of embodiments 7a-10a, wherein the therapeutically effective amount of Compound A is from about 0.05 mg/kg to about 2.0 mg/kg.

5. Examples

The studies described below were conducted to determine the effect of food (if any) on the bioavailability and exposure of Compound A when administered orally in humans. Further studies were conducted to evaluate the effect of Compound A (if present) on cortical excitability using transcranial magnetic stimulation (TMS).

5.1. Example 1: Non-human primate study.

The study described below was conducted to determine the effect of food upon oral administration of Compound A to non-human primates.

5.1.1. Experimental animals.

Cynomolgus macaques (Masaca fascicularis) from Vietnam were used in this study (n=3). At the time of the study, these three individuals were approximately 4.5 years old, with a body weight of 4.7-5.1 kg.

During the study, experimental animals were fed a certified primate diet (Teklad® Certified Diet 2050C). In group 1, three monkeys were fasted overnight and given food 4 h after drug administration. In group 2, the same three individuals fasted overnight and then received food approximately 1 h before drug administration and then 4 h after drug administration. In table Figure 1 presents data on the consumption of food offered by animals in group 2.

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Table 1

Food consumption in group 2

Group 2 Individual #1 Individual #2 Individual#3 Meal time ¹ 8:19 8: 19 8:19 Number of biscuits offered 7 7 7 Uneaten biscuits? 7 7 4 Uneaten bananas? (yes/no) No No No Uneaten bread? (yes/no) Partially No No Time point of food consumption assessment 9.07 9.07 9.07 Time of administration of the drug dose 9.34 9.37 9.39

The monkeys had not eaten since the evening before the drug was administered. Approximately 1 hour before the drug was administered, the animals were given half a banana, a slice of bread and half the daily allowance of biscuits. They recorded how much of something was eaten. 4 hours after drug administration, the animals were given food again.

5.1.2. Oral dosage units.

The oral dosage units were capsules containing Compound A in an amount of about 3 mg/kg. Capsules were filled in the morning before drug administration and kept at room temperature until the moment of administration to the animal. The remaining capsules were stored at 20°C.

5.1.3. Administration of the drug.

The capsules were injected into the animals as deep as possible into the oral cavity using a syringe-gun for administering tablets to animals or a modified tube for force-feeding. To ensure complete swallowing of the capsule, 10 ml of water was injected into the monkey’s mouth with a syringe. Each individual received one capsule per dose. The same individuals took the drug twice with an interval of 96 hours between doses (washing). (See Table 2.)

Group 1. All monkeys were weighed in the afternoon before drug administration. Individual #2 resisted drug administration. After several attempts, this animal was given a break, after which the drug was administered.

Group 2. On the day of drug administration, all animals were weighed in the morning. All individuals took the drug without incident.

Table 2 Injected amount and dose of the drug

Group # Individual # Body weight (kg) Amount administered (mg) Dose (mg/kg) 1 1 4.695 14.30 3.05 1 2 5.116 15.40 3.01 1 3 5.217 16.40 3.14 2 1 4,698 14.30 3.04 2 2 5.057 15.40 3.05 2 3 5.133 15.30 2.98

5.1.4. Blood collection.

From experimental animals, using a syringe with a needle, blood samples (about 2.0 ml) were taken from the great saphenous vein of the thigh or the lateral saphenous vein of the forearm, placed in vacuum tubes containing potassium ethylenediaminetetraacetate (K ₂ EDTA) and kept on wet ice until separation plasma. Blood sampling was carried out at the time of drug administration (time zero; 0.0 hours) and after 0.5; 1; 2; 4; 8; 12; 24 and 48 hours after drug administration.

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5.1.5. Processing of blood samples.

Whole blood was placed into K2EDTA tubes and centrifuged at 3200 rpm for 10 min at approximately 5°C. The resulting plasma samples were each divided into two aliquots and each aliquot was immediately transferred to a labeled tube; the inscription contained the experiment number, time of blood sampling, identification number (ID) of the animal and description of the sample. One of two aliquots of each sample was kept at -20±5°C until sent for analysis. Another aliquot was stored at -20±5°C. The red blood cells were disposed of.

All samples were subjected to standard processing for research using bioanalytical methods.

5. 6. Results.

Table 3

Concentration of compound A in blood plasma in male cynomolgus monkeys after oral administration of compound A in a single dose of 3 mg/kg on an empty stomach

Group Individual# Time (h) Concentration (ng/ml) 1 1 0 0 0.5 0 1 0 2 6.00 4 12.6 8 38.4 12 38.3 24 22.5 48 3.13 2 0 0 0.5 0 1 15.6 2 23.5 4 19.2 8 63.1 12 75.1 24 53.2 48 12.5 3 0 0 0.5 0 1 5.07 2 16.4 4 18.1 8 48.1 12 53.7 24 51.8 48 AND 2

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Table 4

Concentration of compound A in blood plasma in male cynomolgus monkeys after oral administration of a capsule with compound A at a dose of 3 mg/kg after a meal

Group Individual # Time (h) Concentration (ng/ml) 1 1 0 0 0.5 0 1 1.48 2 I,8 4 34.8 8 50.4 12 48.8 24 24.2 48 4.26 2 0 0 0.5 1.05 1 1.05 2 0 4 19.9 8 52.2 12 67.5 24 61.9 48 16.9 3 0 0 0.5 0 1 1.21 2 I,4 4 78.2 8 63.7 12 42.2 24 48.8 48 13.5

Table 5

Summary of plasma pharmacokinetic parameters for compound A in male cynomolgus monkeys following oral administration of the compound in capsule form at a dose of 3 mg/kg during or after a meal (group 2) or fasting (group 1)

Time (h) Average value (ng/ml) Standard Deviation (ng/ml) N 1 0 0 0 3 0.5 0 0 3 1 6.89 7.96 3 2 15.3 8.8 3 4 16.6 3.54 3 8 49.9 12.4 3 12 55.7 18.5 3

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24 42.5 17.3 3 48 8.94 5.08 3 2 0 0 0 3 0.5 0.35 0.61 3 1 1.25 0.22 3 2 7.73 6.7 3 4 44.3 30.3 3 8 55.4 7.22 3 12 52.8 13.1 3 24 45 19.1 3 48 I,6 6.54 3

N is the number of individuals.

Table 6

Summary of plasma pharmacokinetic parameters for compound A in male cynomolgus monkeys following oral administration of the compound in capsule form at a dose of 3 mg/kg during or after a meal (group 2) or fasting (group 1)

Group Individual t^z (h) Ttah (h) Stach (ng/ml) AUClast (ng-h-ml ⁴ ) AU Cinfobs (ng-ch-ml' ¹ ) 1 1 9.7 8 38.4 869 913 2 — 12 75.1 1940 — 3 — 12 53.7 1650 — Average 9.7 10.7 55.7 1490 913 SD — 2.3 18.4 556 — 2 1 10.1 8 50.4 1120 1180 2 — 12 67.5 2010 — 3 — 4 78.2 1790 — Average 10.1 8 65.4 1640 1180 SD — 4 14 466 —

SD - standard deviation.

5.1.7. Discussion.

In a study in non-human primates, there was no significant effect of food on _Cmax or AUC for Compound A when administered orally. The data given in Table 5 is presented in graphical form in Fig. 1.

5.2. Example 2: Human Research.

To determine the effect of food on the bioavailability and exposure of Compound A in humans, an open, randomized, two-period crossover study was conducted comparing dosing conditions (fasting/with or after a meal) in 9 healthy adult non-smoking men and women. (the latter - only without childbearing potential) not younger than 18 and not older than 55 years.

This study consisted of two exposure periods - period 1 and period 2. Each of them lasted 7 days; compound A was administered on day 1. Between these two periods there was an interval (washout period) of 10 days. The subjects were randomly divided into two groups. During Period 1, subjects in one group received an oral drug (compound A) on an empty stomach, and in the other group, the same dose of the drug was administered with or after a meal. The group that was given the drug on an empty stomach in period 1 received it during or after a meal in period 2; and vice versa.

In both study periods, on Day 1, each subject took 20 mg of Compound A orally (4 capsules containing 5 mg of Compound A).

During the period when the subject took the drug (compound A capsules) on a full stomach, he did not eat overnight (at least 10 hours), after which he received a high-calorie, high-fat meal for breakfast according to FDA recommendations. US Food, Drug and Cosmetics (FDA). Breakfast began 30 minutes before and ended 10 minutes before taking the drug. Typically, breakfast included 2 slices of toasted bread with butter, 2 scrambled eggs, 2 pieces of bacon, 4 ounces of fried potatoes and 8 ounces of whole milk. After taking the drug, the subject did not eat for at least 4 hours.

During the period in which the subject took Compound A capsules on an empty stomach, he did not eat overnight (at least 10 hours), after which he swallowed the drug and did not eat for another 4 hours. In both periods, subjects were allowed to drink water as desired, with the exception of 1 hour before and 1 hour after taking the drug.

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Blood samples were taken from all subjects to determine plasma concentrations of Compound A.

Blood sampling was carried out at the time of drug administration (time zero; 0.0 hours) and after 0.5; 1.0; 1.5; 2.0; 3.0;

4.0; 6.0; 8.0; 12.0; 24.0; 32.0; 48.0 and 144.0 hours after taking the drug.

5.2.1. Results.

Data on the concentration of compound A in blood plasma (ng/ml) in subjects who took compound A orally after meals are presented in table. 7.

Data on the concentration of compound A in blood plasma (ng/ml) in subjects taking compound A orally on an empty stomach are presented in table. 8.

A comparison of the mean plasma concentrations of Compound A (ng/ml) between subjects who took it after a meal and those who took the same drug on an empty stomach is illustrated in FIG. 2.

Pharmacokinetic parameters for compound A in subjects taking 20 mg of this substance after meals are presented in table. 9.

Pharmacokinetic parameters for compound A in subjects taking 20 mg of this substance on an empty stomach are presented in Table. 10.

Table 7

Concentration of compound A in the blood plasma of subjects who took 20 mg of this substance orally after meals

Nominal time (h) 0.00 0.50 1.0 1.5 2.0 h,o 4.0 6.0 8.0 12.0 24.0 32.0 48.0 144.0 Individual (No.) Period Admission conditions Compound A concentration (ng/ml) 1 1 after meal 0.00 0.00 1.07 6.07 23.8 57.5 60.0 31.0 22.3 14.7 I,9 11.6 8.76 5.06 2 2 after meal 1.28 1.16 4.66 I,7 23.7 70.6 77.5 63.6 41.9 24.5 12.5 10.6 7.89 3.68 3 2 after meal 1.71 1.56 4.59 18.7 37.2 66.1 59.7 46.3 25.6 15.6 13.5 11.3 9.54 6.15 4 2 after meal 2.92 2.56 2.74 4.34 5.63 12.1 39.2 38.1 52.0 35.6 15.8 12.6 12.3 8.82 5 1 after meal 0.00 0.00 7.27 22.3 24.6 58.5 52.7 44.6 33.1 24.6 14.5 10.9 8.44 3.99 6 2 after meal 2.05 4.06 30.6 58.3 57.7 104 81.0 56.7 36.5 23.0 17.4 15.6 13.6 7.91 7 1 after meal 0.00 0.00 0.00 0.00 3.94 46.1 39.2 33.3 22.1 17.7 10.5 8.60 6.77 5.33 8 2 after meal 1.43 1.30 1.62 1.91 2.90 7.50 14.7 16.4 39.2 24.0 I,4 10.0 8.03 5.56 9 1 after meal 0.00 0.00 5.89 33.3 60.6 90.3 66.7 46.4 35.3 28.0 16.9 14.6 12.5 6.89 Number of subjects 9 9 9 9 9 9 9 9 9 9 9 9 9 9 Average 1.04 1.18 6.49 17.4 26.7 57.0 54.5 41.8 34.2 23.1 13.8 11.8 9.76 5.93 Standard deviation 1.09 1.41 9.34 18.8 21.7 32.0 20.9 14.1 9.82 6.53 2.48 2.21 2.42 1.71 Standard error 0.36 0.47 h,i 6.26 7.24 10.7 6.97 4.71 3.27 2.18 0.83 0.74 0.81 0.57 Minimum value 0.00 0.00 0.00 0.00 2.90 7.50 14.7 16.4 22.1 14.7 10.5 8.60 6.77 3.68 Median value 1.28 1.16 4.59 I,7 23.8 58.5 59.7 44.6 35.3 24.0 13.5 from 8.76 5.56 Maximum value 2.92 4.06 30.6 58.3 60.6 104 81.0 63.6 52.0 35.6 17.4 15.6 13.6 8.82 Geometric mean 17.0 44.0 49.5 39.3 33.0 22.3 13.6 I,6 9.50 5.72 The coefficient of variation (%) 166 FROM 56.1 41.7 29.9 29.1 18.1 18.6 24.6 29.7 geometric mean

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Table 8

Concentration of compound A in the blood plasma of subjects who took 20 mg of this substance orally on an empty stomach

Nominal time (h) 0.00 0.50 1.00 1.50 2.00 3.00 4.00 6.00 8.00 12.0 24.0 32.0 48.0 144.0 Individual (No.) Period Admission conditions Compound A concentration (ng/ml) 1 2 on an empty stomach 2.05 4.02 Legal entity 14.5 13.8 9.72 8.27 6.15 5.75 7.65 11.7 9.37 8.66 4.24 2 1 on an empty stomach 0.00 0.00 10.7 12.7 11.7 8.61 8.03 5.08 6.08 9.05 8.87 10.8 6.42 1.95 3 1 on an empty stomach 0.00 0.00 4.66 9.21 10.9 10.6 6.93 3.75 3.62 4.28 4.28 5.67 4.74 2.64 4 1 on an empty stomach 0.00 0.00 33.3 37.1 29.8 21.4 15.6 10.2 8.32 8.62 9.53 7.60 7.14 4.21 5 2 on an empty stomach 1.82 2.47 17.4 I,6 13.9 I,1 10.5 8.59 8.97 8.78 9.83 8.81 8.19 3.09 6 1 on an empty stomach 0.00 0.00 12.3 15.7 19.8 22.4 17.6 9.46 7.26 6.25 AND 2 9.30 8.80 3.16 7 2 on an empty stomach 4.45 4.48 10.3 15.6 16.2 16.0 15.4 9.35 8.65 Yu, 1 12.3 12.0 Yu, 1 - 8 1 on an empty stomach 0.00 0.00 8.24 9.62 10.2 8.21 7.10 4.16 3.71 2.71 6.09 5.09 4.42 2.06 9 2 on an empty stomach 2.44 2.96 7.62 I,9 21.1 15.8 18.0 12.7 9.97 13.2 13.0 from 12.1 5.91 Number of subjects 9 9 9 9 9 9 9 9 9 9 9 9 9 8 Average 1.20 1.55 12.7 15.3 16.4 13.8 P,9 7.72 6.93 7.85 9.64 8.88 7.84 3.41 Standard deviation 1.60 1.92 8.47 8.50 6.30 5.40 4.66 3.07 2.29 3.13 2.89 2.40 2.47 1.33 Standard error 0.532 0.640 2.82 2.83 2.10 1.80 1.55 1.02 0.762 1.04 0.965 0.799 0.823 0.468 Minimum value 0.00 0.00 4.66 9.21 10.2 8.21 6.93 3.75 3.62 2.71 4.28 5.09 4.42 1.95 Median value 0.00 0.00 10.3 12.7 13.9 I,1 10.5 8.59 7.26 8.62 9.83 9.30 8.19 3.13 Maximum value 4.45 4.48 33.3 37.1 29.8 22.4 18.0 12.7 9.97 13.2 13.0 12.0 12.1 5.91 Geometric mean and about 14.0 15.5 12.9 I,1 7.14 6.54 7.18 9.16 8.56 7.48 3.20 Coefficient of variation (%) of geometric mean 59.4 43.1 36.3 39.4 41.7 45.2 38.7 51.1 37.7 30.6 34.3 39.4

Table 9

Pharmacokinetic parameters in subjects taking 20 mg of Compound A orally after meals

Individual # Period Admission conditions Tmax (h) Stach (ng/ml) AUClast (ng/) AUCinf (ng-h-ml' ¹ ) %AUCext (%) t^z (h) After meal 1 after meal 4.00 60.0 1410 2130 33.9 98.7 2 after meal 4.00 77.5 1530 1950 21.2 77.7 2 after meal 3.00 66.1 1590 2790 43.0 135 2 after meal 8.00 52.0 2020 4710 57.1 211 1 after meal 3.00 58.5 1500 1960 23.7 80.9 2 after meal 3.00 104 2230 3560 37.5 117 1 after meal 3.00 46.1 1230 2690 54.3 190 2 after meal 8.00 39.2 1330 2500 46.9 146 1 after meal 3.00 90.3 2050 3110 33.9 106 Average 4.33 66.0 1650 2820 39.1 129 Standard error 0.707 7.04 119 296 4.16 15.5 Minimum value 3.00 39.2 1230 1950 21.2 77.7 Median value 3.00 60.0 1530 2690 37.5 117 Maximum value 8.00 104 2230 4710 57.1 211 Geometric mean 3.98 63.1 1620 2710 37.2 122

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Table 10

Pharmacokinetic parameters in subjects taking 20 mg of Compound A orally on an empty stomach

Individual # Period Admission conditions Tmax (h) Stach (ng/ml) AUClast ng-h-ml ⁴ ) AUCinf (ng-h-ml ⁴ ) %AUC _ext (%) ΐ%λζ (h) 1 2 on an empty stomach 1.50 14.5 1060 1640 35.8 96.2 2 1 on an empty stomach 1.50 12.7 816 960 15.0 51.1 3 1 on an empty stomach 2.00 10.9 593 995 40.4 105 4 1 on an empty stomach 1.50 37.1 1010 1800 43.7 129 5 2 on an empty stomach 1.00 17.4 979 1300 24.7 72.1 6 1 on an empty stomach 3.00 22.4 1040 1350 22.9 67.7 7 2 on an empty stomach 2.00 16.2 541 1720 68.5 80.8 8 1 on an empty stomach 2.00 10.2 547 803 31.9 86.3 9 2 on an empty stomach 2.00 21.1 1460 2410 39.5 111 Average 1.83 18.1 894 1440 35.8 89.0 Standard error 0.10 2.76 101 169 5.14 8.09 Minimum value 1.00 10.2 541 803 15.0 51.1 Median value 2.00 16.2 979 1350 35.8 86.3 Maximum value 3.00 37.1 1460 2410 68.5 129 Geometric mean 1.76 16.7 848 1370 33.0 85.9

As evidenced by the pharmacokinetic data obtained in this study, the bioavailability and exposure of Compound A was significantly increased when the compound was administered orally after a meal compared to when administered on an empty stomach. This result would not have been expected based on similar experiments with other non-Homo sapiens primates, the results of which, presented in Example 1 above, showed no effect of food.

5.3. Example 3. Study of the effect of single and multicardial increasing doses of compound A in humans.

The first human study of Compound A was conducted to evaluate the safety, tolerability, and pharmacokinetics of this compound when administered orally in single and multiple ascending doses (SAD and MAD, respectively).

5.3.1. Methods.

In the single-dose phase (SAD), 32 healthy volunteers were randomized (3:1 randomization ratio) into two groups: one group received compound A orally at an ascending dose (5, 15, 20, 25, or 30 mg) and in the other - a placebo. This study employed an adaptive design. In a crossover food effect design cohort (N=10), subjects received a single dose of 20 mg. Also, in a subgroup of 8 male subjects, cortical excitability was determined by transcranial magnetic stimulation (TMS) (see examples 4 and 5).

The effect of repeated oral administration of compound A (15 mg once daily) on an empty stomach (for 7 days) and after meals (for 10 days) was assessed. The effect of repeated administration of compound A at 25 mg once daily after meals for 10 days was also determined.

Subjects received Compound A in the form of immediate release capsules. In all cohorts, serial plasma samples were collected to determine pharmacokinetic parameters. Safety assessments throughout the study included adverse event monitoring (AEs), clinical laboratory tests, vital signs, electrocardiography, physical examination, and the Columbia University Suicidality Scale.

5.3.2. Pharmacokinetics.

When Compound A was administered once daily, the pharmacokinetic profile was characterized by a low peak to trough ratio. When administered in the fasted state, the effect of Compound A was less dose proportional, with Compound A absorption being increased by food (AUCinf increased approximately 1.8-fold). When Compound A was administered repeatedly orally after meals, the effect increased proportionally to the dose. A clear steady-state was achieved between days 6 and 9, as the 90% confidence interval (CI) for the drug exposure ratio (AUC) on consecutive days was 0.8-1.25.

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Table 11

Plasma pharmacokinetic parameters (mean ± SD) for the single ascending dose (SAD) cohort

Index Compound A 5 mg ^a (N=3) Compound A 15 mg ^a (N=3) Compound A 20 mg ^a (N=6) Compound A 25 mg ^b (N=6) Compound A 30 mg ^a (N=6) Tmax (h) 3.17 ±2.47 4.50 ± 2.60 3.69 ±2.05 4.51 ± 1.22 3.17 ± 1.48 Stach (ng/ml) 7.13 ±6.12 27.3 ± 11.1 31.5 ±21.1 45.8 ± 14.3 35.5 ±33.5 T1/2 (h) 49.2 ±31.1 41.9 ± 31.1 48.9 ± 14.7 97.2 ± 18.0 63.4 ± 28.2 AUCo-24 (ng-h-ml ⁴ ) 74.6 ± 50.5 328±141 376 ±220 482±130 369 ±219 AUCo-t (ng-h-ml ⁴ ) ^s 91.3 ± 54.2 397±166 709 ±337 1470 ±270 837 ±280

a The subject did not eat 8 hours before and 1 hour after taking the drug.

The subject ate a standard breakfast 30 minutes before taking the drug, and did not eat for 4 hours after taking the drug.

^c tL _a st=32 hours in the 5 and 15 mg dose cohorts; 72 hours in the 20 and 30 mg dose cohorts; 146 hours in the 25 mg dose cohort.

SD - standard deviation.

Table 12

Plasma pharmacokinetic parameters (mean ± SD) for the multiple ascending dose (MAD) cohort

Index Compound A 15 mg once daily on ^an empty stomach (N=6) Compound A 15 mg after meal ^a (N=6) Compound A 25 mg once daily after ^meals (N=6) Day Day 1 Day 7 Day 1 Day 10 Day 1 Day 10 Tmax(h) 2.68 ± 1.15 2.69 ± 1.19 4.37 ± 1.85 3.69 ± 0.506 4.38 ± 1.86 4.99 ± 1.69 Stakh (ng/mL) 10.5 ± 2.01 45.1 ± 11.4 35.9 ± I.9 60.8 ± 11.2 49.6 ± 15.7 96.7 ± 8.6 Ti/2(h) — 167 ±36.8 — 239±179 — 218 ±136 AUCo-24 (ng-h-ml ⁴ ) 125 ± 32.9 757 ±200 353 ±105 1020 ±246 592± 133 1720± 198 AUCo-t (ng-h-ml ¹ ) — 4260 ±992 — 4950 ± 1250 — 8010 ± 1520

^a On days 1 and 7, the subject did not eat for 8 hours before and 4 hours after taking the drug; on days 2-6, the subject did not eat for 8 hours before and 1 hour after taking the drug.

The subject ate a standard breakfast 30 minutes before taking the drug, and did not eat for 4 hours after taking the drug.

SD - standard deviation.

5.3.3. Safety.

Both single and multiple administrations of compound A were well tolerated by subjects with Cmax up to 104 ng/ml (with a single administration) and 107 ng/ml (with multiple administrations). The negative phenomena that took place were mostly moderate or mild and went away on their own; these effects were similar to the negative effects of antiepileptic drugs of the same type as Compound A (eg, dizziness, sedation). There were no serious side effects, no deaths, no clinically significant changes in the electrocardiogram, or abnormal laboratory test results.

The results obtained indicate that Compound A is safe and well tolerated at the doses studied (up to 30 mg for a single dose and up to 25 mg once daily for multiple doses).

The observed pharmacokinetic profile (including an effective half-life of >24 hours) indicates the preference for a once-daily, immediate-release formulation of Compound A to achieve steady-state after one week of dosing without the need for titration.

5.4. Example 4: Pilot study using transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) in combination with electromyography (EMG) and electroencephalography (EEG) allows the determination of passive and active motor response thresholds (RMT/AMT) and TMS-evoked brain potentials (TEP), and these data indicate the effect of the drug on corticospinal and cortical excitability. Some antiepileptic drugs have been shown to cause significant increases in passive motor response thresholds and affect magnetic stimulation-evoked potentials, indicating a shift toward corticospinal/cortical inhibition.

A pilot study used TMS to non-invasively determine whether Compound A (at doses of 10, 15 and 20 mg) affected cortical excitability. This study was intended to inform sample size calculations in a larger randomized, double-blind, crossover study of the effect of Compound A with placebo control and method

TMS (N=20).

5.4.1. Methods.

This open-label TMS pilot study recruited eight healthy, right-handed men aged 21–35 years, weighing 62.4–95.4 kg, who were participating in the first phase 1 human study of the effect of oral administration of Compound A. Before the subject took compound A, and 2 and 4 hours after this, the passive motor response threshold, evoked potentials and electroencephalogram were recorded. Spectral analysis of the resting electroencephalogram was performed. To determine the effect of Compound A on the amplitude of TMS-evoked potentials, a single-subject design was analyzed using a multiple independent samples t test. Multiple comparisons and permutation tests were used for cluster analysis.

5.4.2. Results.

4 hours after administration of 20 mg of compound A ( _plasma C = 50 ± 10 ng/ml), a decrease in the amplitude of long-latency (late) potentials evoked by magnetic stimulation was observed (for example, peaks at the 180th millisecond (P180) after the stimulus 1.92 ±0.03 µV; p<0.01; N=3). At doses of 10 mg (N=2) and 15 mg (N=3) with an average plasma concentration of 23.1 ng/ml and 36.3 ng/ml, respectively, compound A did not cause significant and persistent changes 4 hours after stimulation TMS-evoked potentials. At a dose of compound A of 20 mg 4 hours after stimulation, the passive threshold (RMT) of the motor response increased by 4.3 ± 0 < 6% compared to the initial level (poster presentation 3.282) and the power of oscillations in theta increased on the electroencephalogram at rest. range. A dose of 20 mg of Compound A was selected for a double-blind, placebo-controlled crossover study using transcranial magnetic stimulation.

In fig. 3 it can be seen that compound A causes an increase in motor response thresholds (but not short interval intracortical inhibition (SICI)) determined by transcranial magnetic stimulation combined with electromyography (TMS/EMG). Black bars correspond to the effect (change in threshold value compared to the initial value, expressed as a percentage of the maximum possible output of the magnetic stimulator; mean value ± standard error of the mean) 2 hours after dosing, gray bars - after 4 hours. At a dose of 10 mg N=2; at a dose of 15 mg N=3. At a dose of 10 mg, compound A did not cause a change in the active threshold of the motor response. At a dose of 10 mg N=2; at doses of 15 and 20 mg N=3).

5.5. Example 5: Crossover study using transcranial magnetic stimulation.

A randomized, double-blind, placebo-controlled study using transcranial magnetic stimulation examined the safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of Compound A in healthy right-handed men.

The objectives of the study were 1) to evaluate the safety and tolerability, and to determine the pharmacokinetic parameters for compound A when administered a single oral dose in healthy men; 2) characterize the effects of compound A based on cortical excitability data obtained by using transcranial stimulation in combination with electroencephalography and electromyography, in comparison with placebo.

This study involved 20 healthy right-handed men who were randomly assigned to groups (randomization ratio 1:1). On Day 1, subjects in one group took a single dose of 20 mg of Compound A, and in the other, placebo. Then on day 7, those taking the drug were given a placebo and vice versa (crossover study).

Subjects began recruiting 27 days before Day 1. For Period 1 of the study, recruited individuals were invited to the study site where they received drug (Compound A or placebo) on Day 1 and left on Day 2. This was followed by a washout period of 6 days, after which for period 2 of the study the same subjects were again invited to the laboratory and on day 7 they were given the drug or placebo in the above order and on day 8 they left. On day 14, all subjects visited the clinical department for an outpatient examination, and on day 37 they were interviewed by telephone.

The subjects took the drug during or after meals, but the time of its administration relative to the meal changed throughout the study: high-fat food was given from 2 hours before drug administration to 1 hour after administration, standard food was given from 30 min before drug administration to 2.5 hours after administration.

The safety study included adverse event recording, clinical laboratory tests, vital signs, electrocardiography, physical examination, and the Columbia University Suicidality Scale.

The study of pharmacokinetics included the determination of the following indicators: the maximum concentration of the substance in the blood plasma (C _max ), the period of time during which the maximum concentration is reached (T _max ), the final half-life (t _1/2 ), the elimination rate constant ( λ _Z ), area under the concentration-time curve from 0 to 24 h (AUC _0-24h ), area under the concentration-time curve from 0 until the last quantifiable concentration is reached (AUC _0-tlast ), area under the concentration-time curve from 0 to infinity (AUC _{0. inf} ), fraction (percentage) of the area under the concentration-time curve due to extrapolation from t _last to infinity infinity (%AUC _extrap ), apparent total clearance after oral administration (CL/F), CL/ F normalized by body weight, mean retention time from 0 to last quantifiable concentration (MRT _last ), mean retention time extrapolated to infinity (MRT _inf ), apparent volume of distribution in the final phase (VZ/F) and VZ/F, normalized by body weight.

Pharmacodynamic studies included resting-state electroencephalography (RS-EEG); determination of passive and active motor response thresholds (RMT and AMT) and short-interval intracortical inhibition (SICI)) using transcranial magnetic stimulation in combination with electromyography (TMS-EMG), as well as experiments using transcranial magnetic stimulation in combination with electroencephalography (TMS-EEG ).

5.5.1. Pharmacokinetic analysis.

In this study, pharmacokinetic parameters were summarized in two ways. First, they were calculated, where possible, using blood samples collected during each of the 24-hour (24-hour post-dose) sampling periods for Study Periods 1 and 2 separately. Second, pharmacokinetic parameters were determined using samples collected outside of the 24-hour sampling periods (eg, days 7/8 and/or 14). For those subjects who received Compound A in the first study period, pharmacokinetic samples taken before placebo administration provided additional time points after the 24 hour period. For those individuals who received Compound A in the second study period, there were no additional points for pharmacokinetic determinations after the 24-hour period until Day 14, when an additional sample was taken. Thus, for subjects who were assigned to the Compound A arm in the second study period, before additional sampling on day 14, no pharmacokinetic data were available for time points outside the 24-hour period. The complete data set for the pharmacokinetic profile consisted of data obtained from 16 individuals whose samples were taken beyond the 24-hour period. In the following discussion of pharmacokinetic parameters, the complete data set for the pharmacokinetic profile was generally used because it allowed for more accurate determination of pharmacokinetic parameters.

Initially, subjects received the drug 2 hours after eating a high-fat meal and ate a relatively high-fat lunch 1 hour after drug administration. After reviewing the pharmacokinetic profiles (blindly, that is, without reference to individuals) for the first 8 subjects, it was decided to reduce the fat content of the lunch meal in order to shorten the period of time to _Tmax , so that _Cmax was within the time frame of measurements using transcranial magnetic stimulation . The meal schedule was also changed relative to the time of drug administration: before drug administration, meals were scheduled not 2 hours before, but 30 minutes before. In addition, they reduced the fat content in breakfast food. All of these changes were made to ensure that plasma levels of the drug were higher during periods of transcranial magnetic stimulation. The schedule and nature of food for each individual are indicated in the table. 13. In general, despite changes in the composition of food and the time of its intake relative to the moment of drug administration, there was no clear difference in _Cmax or _Tmax . Pharmacokinetic data are presented here without categorization by food content or timing of food intake relative to the time of drug administration.

Table 13

Characteristics of food and schedule of its intake relative to the moment of drug administration

Individuals Eating before drug administration Eating after drug administration Food Time of receipt Food Time of receipt 901, 908, 910, 907 High in ^fat 2 hours before drug administration High fat 1 hour after drug administration 912, 919, 914, 918 With high fat content 2 hours before drug administration Standard 1 hour after drug administration 927, 925, 928, 924 With high fat content 0.5 hour before drug administration Standard 2.5 hours after drug administration

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930, 934, 933, 937, 938, 941, 940, 942 Standard 0.5 hour before drug administration Standard 2.5 hours after drug administration

''Except for individual 910, who received standard food prior to drug administration.

5.5.1.1. Concentration of compound A in blood plasma.

To compile the pharmacokinetic profile, the concentration of compound A in the blood plasma was determined depending on time. At those time points when transcranial magnetic stimulation was performed (2, 4 and 6 hours after drug administration), the mean concentrations of compound A were (± standard deviation) 15.9 ± 21.4 ng/ml, respectively; 30.2 ± 21.1 ng/ml and 42.1 ± 19.1 ng/ml.

There were no differences in mean C _max or T _max values between study periods 1 and 2 (see Table 14). The total time to reach the maximum plasma concentration of Compound A ranged from 1.9 to 12 hours, with an average time of 7.8 hours; this indicated that in the majority of subjects, transcranial stimulation 2, 4 and 6 hours after administration of compound A falls within the period before Tmax.

Subjects who received placebo in Period 2 of the study had low but measurable levels of Compound A early in the period, with C _max ranging from 3.34 ng/mL to 9.61 ng/mL (mean 5.84 ng/mL). ml).

Table 14

Pharmacokinetic parameters by study periods, overall and for the full pharmacokinetic profile

Index Statistical parameter Dose of compound A 20 mg Period 1 (N=10) Period 2 (N=10) Both periods (N=20) Full pharmacokinetic profile (N=16) Stach (ng/ml) Mean ± SD 60.2±17.3 58.3± 9.94 59.2± 13.8 60.1± 14.9 From to 29.9-77.1 46.2-79.4 29.9-79.4 29.9-79.4 Ttah (h) Median 6.94 7.83 7.83 6.83 From to 1.9 -12 1.92-8.15 1.92-12 1.92-12 AUCo-24 (ng-h-ml ^-1 ) Mean ± SD 693±184 681± 142 687± 160 692± 151 From to 383-951 358-869 358-951 383-951 Clast (ng/ml) Mean ± SD 16.4±5.61 16.4± 3.87 16.4± 4.69 4.52± 1.82 From to 10.1-27.8 7.1-21.3 7.1-27.8 1.33-7.67 Tiast (h) Mean ± SD 23.8± 0.375 23.8± 0.213 23.8± 0.299 23 5± 81.5 From to 23.1-24.3 23.5-24.1 23.1-24.3 142-360 T1/2 (h) Mean ± SD 11.4±2.6 10.6±2.9 11.1±2.6 127± 84.6 From to 8.46-14.9 8.01-14.3 8.01-14.9 48.2-306

SD - standard deviation.

5.5.1.2. Other indicators for the complete pharmacokinetic profile.

A summary of other pharmacokinetic parameters is presented in Table. 15. The average AUC _last value was 2370 ng-h-ml ^-1 , including samples obtained during observation of subjects after periods 1 and 2 of the study, if any were taken. The AUCinf value for the same amount of data was 3155 ng-h-ml ^-1 ; the median extrapolated area fraction was 19.9% (range 10.6 to 40.5%). The relatively high value of the extrapolated portion of the area in some subjects indicates that parameters calculated from λZ (eg, half-life, MRT _inf , clearance and volume of distribution) should be analyzed with caution; they may have greater natural variability between individuals.

The mean normalized volume of distribution (VZ/F) of 16.3 L/kg is much higher than the total blood volume at a mean body weight of 72.3 kg, indicating that Compound A is distributed not only in the blood plasma, but also in surrounding tissues .

Body weight normalized clearance (CL/F) was 97.5 ml/h/kg (equivalent to approximately 1.6 ml/min/kg). This value reflects clearance from plasma and not from whole blood. However, even taking into account the hematocrit, it is much less than the total hepatic blood flow of 17 ml/min/kg (Carlisle K.M. et al., Gut 1992, 33:92-97), indicating low elimination of the substance.

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Table 15

Pharmacokinetic parameters (full data set)

Index Full pharmacokinetic profile data at a dose of compound A 20 mg (N=16) Mean ± SD From to AUClast (ng-h-ml ⁴ ) 2370 ± 680 1583 -4400 AUCinf (ng-h-ml ⁴ ) 3155 ±1341 1923 -7393 Vz/F normalized (l/kg) 16.3 ± 9.06 6.4-33.8 tl/2 (h) 127 ± 84.6 48.2-306 MRTiast (h) 77.4 ± 23.7 48.2 - 122 MRTinf (h) 102 ± 84.8 33 -304 CL/F normalized(ml/h/kg) 97.5 ±25.7 40.3 - 136

SD - standard deviation.

5.5.1.3. Conclusions.

Compound A, after oral administration in an amount of 20 mg, is slowly absorbed, and the median maximum plasma concentration is reached approximately 8 hours after administration. Once absorbed, it is distributed from the blood plasma into the surrounding tissues and slowly disappears from the general circulation at a rate below the hepatic blood flow, indicating minimal elimination (metabolic conversion) in the liver. The average half-life of compound A is 127 hours (from 48.2 hours to 306 hours), the average retention time is 102 hours (from 33 to 304 hours), and these values may be underestimated, since a number of subjects had %AUC values _extrap more than 20% up to 40%.

The washout period between periods 1 and 2 of the study was not sufficient to ensure that subjects receiving placebo in period 2 had a body level of Compound A that averaged 3.1 ng/mL (range: 1.3 ng/mL to 6.0 ng/mL). 8 ng/ml) became below the limit of quantitation.

5.5.2. Pharmacodynamic analysis.

All 20 subjects underwent transcranial magnetic stimulation in combination with electromyography and electroencephalography on day 1 and day 7 before drug administration and 2 and 4 hours after administration. Because the pharmacokinetic analysis revealed a prolonged absorption phase of Compound A, additional measurements were taken 6 hours after drug administration. Additional measurements after 6 hours included determination of passive motor response threshold in 16 subjects, determination of active motor response threshold in 8 subjects, who also underwent a resting electroencephalogram and transcranial magnetic stimulation in combination with electroencephalography.

Subject 912 did not undergo any pharmacodynamic analysis 2 hours after administration of Compound A due to a significant side effect (vomiting). Subject 940 did not receive transcranial magnetic stimulation during the placebo period 2 hours after dosing due to technical problems; He only had a resting electroencephalogram and a passive motor response threshold was determined.

We determined how the effect of compound A changes, namely its effect on pharmacodynamic markers, over time (the results of measurements taken 2, 4 and 6 hours after administration of the drug were compared with similar data obtained before taking the drug) and depending on its concentration ( compared the results of measurements taken after administration of the drug during the phase of its greatest effect with the initial values).

These analytical methods were applied to all subjects (n=20) and to those individuals (n=16) whose plasma levels of Compound A exceeded the highest concentration established as a carryover effect during the placebo period (see Table 16).

Table 16. Individual values of the concentration of compound A in the blood plasma, obtained 5 minutes before the application of the transcranial magnetic stimulation method in combination with electromyography and electroencephalography.

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Individual Concentration of compound A in blood plasma Connection A reception period Placebo period 2h 4h 6 hours 2h 4h 6 hours 901 ^a 0 6.08 __b 0 0 __b 908 64.2 76.5 __b 6.05 7 __b 910 47.2 38.7 __b 0 0 __b 907 1.55 8.92 __b 4.96 4.35 __b 912 34 48.4 49.7 0 0 0 919 0 16.5 71.2 5.27 4.48 5.56 914 55.2 50 48.5 6.28 5.51 5.75 918 10.6 24.5 47.0 0 0 0 927 47.1 38 39.1 3.81 3.6 3.42 925 ^a 0 4.91 37.6 0 0 0 928 ^a 0 2.54 4.43 0 0 0 924 3.1 29.8 51.9 5.74 5.36 5.61 93 0 ^a 1.95 4.06 6.23 3.94 3.66 3.44 934 25.7 60.7 57.6 0 0 0 933 0 22.3 53.2 0 0 0 937 2.74 32.7 54.9 7.44 6.83 6.67 938 10.7 52.1 52.2 0 0 0 941 0 8.77 25.1 8.04 8.15 8.22 940 2.52 41.9 79.4 0 0 0 942 8.01 35.7 32.8 h,i 2.77 2.87 Average 15.88 30.15 42.08 5.46 5.17 5.28 Standard deviation 21.41 21.09 19.13 1.58 1.73 1.70

^a Individuals whose plasma concentrations of Compound A did not exceed the carryover level observed during the placebo period (carryover level of 8.22 ng/mL observed in subject 941 6 hours after drug administration during the placebo period). Individuals 901, 925, 928, and 930 were not included in the analyzes of TMS-evoked potentials and oscillations versus time and drug concentration, and did not have a resting electroencephalogram (n=16). In individual 925, the concentration of compound A in the blood plasma 6 hours after its administration reached 37.6 ng/ml, but only the passive threshold of the motor response was determined at this point in time.

^b These individuals received the drug and treatments before the additional time point for measurements (6 hours after drug administration) was included in the study protocol.

5.5.2.1. Electrical potentials evoked by transcranial magnetic stimulation.

Electrical potentials evoked by transcranial magnetic stimulation (TER) were calculated by averaging electroencephalograms without artifacts taken under various experimental conditions (see Table 17).

Table 17

Electroencephalograms without artifacts

Number of electroencephalograms without artifacts (mean +/- SD) Before drug administration 2 hours after drug administration 4 hours after drug administration 6 hours after drug administration Placebo 128±13 121±Yu 125±10 125±13 Compound A 130±11 124±11 123±11 131±11

SD - standard deviation.

The following components of TMS-evoked potentials were considered (P - positive peaks, N - negative) according to literature sources: P25 (15-35 ms), N45 (35-70 ms), P70 (70-80 ms), N100 (80-145 ms) and P180 (145-230 ms), where the time interval taken (TOI) is indicated in parentheses. TOI values were selected based on the pooled mean obtained by averaging the evoked potentials, and these values were maintained during the analysis of predose and postdose measurements. To analyze changes in TMS-evoked potentials as a result of drug administration, we selected a region of interest (ROI) consisting of 27 channels above and around the stimulation point (left point Ml) and the corresponding contralateral point ('FC1', 'FC3', 'FC5', 'C1', 'C3', 'C5', 'C1', 'CP3', 'CP5', 'P1', 'P3', 'P5', 'Cz', 'CPz', 'Pz', 'FC2 ', 'FC4', 'FC6', 'C2', 'C4', 'C6', 'CP2', 'CP4', 'CP6', 'P2', 'P4', 'P6').

To analyze the significance of changes in the amplitude of TMS-evoked potentials under the influence of compound A, multiple comparisons and dependent samples t-tests (pre-drug data versus post-drug data) were used for each TOI value for all electrodes within the specified target region ( ROI). For correction of multiple

- 37 044821 comparisons (eg, electrodes, time points) were performed with cluster analysis using nonparametric and permutation criteria, as done in the FieldTrip software package.

The resulting set of spatiotemporal parameters of electrical potentials evoked by transcranial magnetic stimulation is consistent with what was previously described in the literature (Fig. 4-A). The early components of the potentials (N15, P25) are localized predominantly in the stimulated left point M1, followed by a pronounced negativity over the contralateral point, corresponding to N45. The N100 and P180 components confirm optimal topographic reproducibility over the left central and central frontal regions, respectively (Fig. 4-B). When comparing data obtained before drug administration (placebo versus compound A), no significant difference was revealed (p>0.05). These results are for data sets of 20 (n=20) and 16 (n=16) subjects. Fig. 4 demonstrates that administration of Compound A results in a significant change in early TMS-evoked potentials (N45 and P180).

Concentration analysis (N=16). To assess the effect of compound A at its highest plasma concentration observed at those time points at which transcranial magnetic stimulation was administered, data obtained before and after administration of the drug were compared using cluster analysis and using a permutation test. The corresponding data for placebo did not show any significant changes, but for compound A there was a decrease in the amplitude of the early components of TMS-evoked potentials measured after 15-35 ms (peak-to-peak amplitude of the early N15-P25 complex: 4.5 μV compared with 6 .0 μV; p<0.05), after 45 ms (N45: -2.3 μV vs. -3.0 μV; p<0.01) and after 180 ms (P180: 2.2 μV vs. with 3.0 μV; p<0.01) after a magnetic pulse (Fig. 4-D, Fig. 5). Fig. 6 demonstrates that Compound A causes significant changes in TMS-evoked potentials and a decrease in cortical excitability.

Time course analysis (individuals exposed to Compound A at the time of measurement). Measurements taken before and after Compound A were compared to assess the effect at 2 hours (n=15), 4 hours (n=16) and 6 hours (n=7) post-dose in individuals with adequate exposure to the compound. And in the first 6 hours; In this case, cluster analysis and permutation test were used. Compared with the data obtained before administration of compound A, 2 and 4 hours after administration, the first N15-P25 complex was reduced (p = 0.008 and p = 0.02, respectively). Also, 4 hours after administration of Compound A, significant suppression of N45 (p=0.03), N100 (p=0.04) and P180 (p=0.004) was observed (see Fig. 7).

Other comparisons were not statistically significant (p>0.05). Placebo did not cause significant changes (p>0.05).

Time analysis (all individuals available for TMS). Measurements taken before and after administration of Compound A were compared to assess the effect at 2 hours (n=19), 4 hours (n=20) and 6 hours (n=8) after drug administration in all subjects available for testing. conducting TMS; In this case, cluster analysis and permutation test were used. Compared with the data obtained before administration of compound A, 2 and 4 hours after administration, the first N15-P25 complex was reduced (p = 0.006 and p = 0.01, respectively). Also, 4 hours after administration of compound A, a significant suppression of N45 (p = 0.03), and P180 (p = 0.02) was observed. These results suggest that Compound A affects TMS-evoked potentials and reduces cortical excitability.

Other comparisons were not statistically significant (p>0.05). Placebo did not cause significant changes (p>0.05).

5.5.2.2. Electrical activity evoked by transcranial magnetic stimulation.

When the motor cortex of the left hemisphere was stimulated with single magnetic pulses, a number of changes in subsequent oscillatory activity were observed. Before administration of Compound A (baseline activity), magnetic pulses caused an early increase in theta/alpha oscillation power, followed by a decrease in beta oscillation power (desynchronization) and a late increase in beta oscillation power.

Data on the effect of Compound A on TMS-evoked oscillations were assessed by cluster analysis using a permutation test in the same manner as for TMS-evoked potentials. TMS-evoked oscillations before and after administration of compound A were compared in the theta (4-7 Hz), alpha (8-12 Hz) and beta (13-30 Hz) frequency ranges in the time interval from 30 ms (the first point of the time-frequency planes without artifacts) up to 800 ms. We preferred this method over a predefined set of time windows because there was no consensus on which time windows were needed when analyzing TMS-evoked oscillation. In addition, the statistical approach we used based on cluster analysis is suitable for preliminary analysis of drug effect, as it minimizes false-positive results in the case of multiple time points.

Concentration analysis (N=16). Transcranial magnetic stimulation measurements taken before and after administration of Compound A were compared to evaluate the effect of the drug at its highest plasma concentration at the time of measurement; In this case, cluster analysis and permutation test were used. Compound A suppressed early TMS-evoked oscillations in the theta frequency range (p<0.001; a significant effect was observed from

- 38 044821 ms to 390 ms), in the alpha frequency range (p = 0.02; a significant effect was observed from 220 ms to 400 ms) and an increase in the power of TMS-evoked oscillations in the beta frequency range (p = 0.04; significant the effect was observed from 220 ms to 310 ms).

Other comparisons were not statistically significant (p>0.05). Placebo did not cause significant changes (p>0.05).

Time course analysis (individuals exposed to Compound A at the time of measurement). Measurements taken before and after administration of Compound A were compared to assess the effect at 2 hours (n=15), 4 hours (n=16) and 6 hours (n=7) after drug administration; In this case, cluster analysis and permutation test were used. Compared with data obtained before administration of Compound A, 2 hours after administration Compound A had no effect on TMS-evoked oscillation, whereas after 4 hours it caused a suppression of early TMS-evoked oscillation in the theta frequency range (p=0.03 ; a significant effect was observed from 30 ms to 180 ms), in the alpha frequency range (p = 0.03; a significant effect was observed from 250 ms to 390 ms) and an increase in TMS-induced desynchronization in the beta frequency range (p = 0.04 ; a significant effect was observed from 250 ms to 330 ms). Finally, 6 hours after administration of compound A, there was a significant suppression of oscillations in the theta band (p < 0.001; significant effect observed from 30 ms to 280 ms).

Other comparisons were not statistically significant (p>0.05). Placebo did not cause significant changes (p>0.05).

Time analysis (all individuals available for TMS). Measurements taken before and after administration of Compound A were compared to assess the effect at 2 hours (n=19), 4 hours (n=20) and 6 hours (n=8) after drug administration; In this case, cluster analysis and permutation test were used. Compared with data obtained before administration of compound A, a trend towards suppression of TMS-evoked oscillations in the theta range was observed 2 hours after administration. 4 hours after administration of the compound, there was a suppression of TMS-evoked oscillations in the alpha range (p = 0.03; a significant effect was observed from 250 ms to 400 ms). 6 hours after administration of compound A, a significant suppression of oscillations in the theta range was observed (p =0.03; a significant effect was observed from 80 ms to 300 ms) and a tendency to suppress in the alpha range (for the tendency to suppress p = 0.07; 270390 ms).

Other comparisons were not statistically significant (p>0.05). Placebo did not cause significant changes (p>0.05).

5.5.2.3. Electroencephalogram at rest.

Concentration analysis (N=16). At a high concentration of compound A in the blood plasma, oscillatory activity at rest changed significantly, namely, oscillation in the delta (p < 0.001), theta (p = 0.01) and beta (p = 0.005) frequency ranges increased. Placebo caused an increase in oscillations in the theta range (p = 0.001); all other comparisons showed no significant results.

The difference between the data obtained before and after administration of Compound A was calculated, and then the calculated difference values (value after administration minus value before administration) for Compound A and placebo were statistically compared. Compared to placebo, Compound A caused an overall increase in oscillatory activity in the delta (p < 0.001), theta (p = 0.02) and beta (p = 0.003) frequency ranges (see Fig. 8).

Time course analysis (individuals exposed to Compound A at the time of measurement). Measurements taken before and after administration of Compound A were compared to assess the effect at 2 hours (n=15), 4 hours (n=16) and 6 hours (n=7) after drug administration; In this case, cluster analysis and permutation test were used.

When comparing data obtained before and after administration of compound A, a significant increase in low-frequency oscillation was found (for the difference 2 hours after dosing in the delta range p = 0.001, in the theta range p = 0.01; for the difference 4 h after dosing in the delta range p<0.001, in the theta range p=0.01) and oscillations in the beta frequency range (for the difference 2 hours after taking the drug p=0.01; for the difference 4 hours after taking the drug p<0.001) (see Fig . 9).

As for the placebo, 4 hours after its administration there was an increase in oscillations in the theta range (p = 0.003). Other comparisons were not statistically significant (p>0.05).

Time analysis (all individuals available for TMS). Measurements taken before and after administration of Compound A were compared to assess the effect at 2 hours (n=19), 4 hours (n=20) and 6 hours (n=8) after drug administration; In this case, cluster analysis and permutation test were used.

When comparing data obtained before and after administration of compound A, a significant increase in low-frequency oscillation was found (for the difference 2 hours after dosing in the delta range p < 0.001, in the theta range p = 0.006; for the difference 4 hours after dosing in the delta range p<0.001, in the theta range there are two clusters - with p=0.08 and p=0.03) and oscillations in the beta frequency range (for the difference 2 hours after taking the drug p=0.005; for the difference 4 hours after taking the drug p<0.001; for the difference 6 hours after taking the drug p=0.009).

After taking placebo, oscillation in the delta range increased (for the difference 2 hours after taking placebo, two clusters - with p = 0.02 and p = 0.04; for the difference 4 hours after taking placebo, two clusters - with p=0.004 and p=0.01), in the theta range (for the difference 4 hours after taking placebo p<0.001; for the difference 6 hours after taking placebo p=0.009), in the alpha range (for the difference after 6 h after taking placebo p=0.04) and in the beta range (for the difference 6 hours after taking placebo p=0.04). Other comparisons were not statistically significant (p>0.05).

5.5.2.4. Transcranial magnetic stimulation combined with electromyography.

Passive and active motor response thresholds are expressed as a ratio to the maximum stimulator output (%MSO). Drug (Compound A)-induced changes in transcranial stimulation-electromyography (TMS-EMG)-induced changes were assessed at three time points (2, 4, and 6 hours after drug administration) and at the drug exposure time point. on the body is greatest (at the highest concentration of compound A in the blood plasma).

5.5.2.4.1. Passive motor response threshold.

Separate and averaged values of the initial level of the passive motor response threshold (RMT) and its changes at each of the specified time points for all 20 subjects are presented in Table. 18. Four individuals (901, 925, 928 and 930) showed no significant effect of Compound A as measured by transcranial magnetic stimulation. In individual 912, it was not possible to register a passive motor response threshold 2 hours after taking compound A.

Table 18

Passive motor response threshold (RMT) values, expressed as a ratio (percentage) to maximum stimulant output (%MSO), before and after administration of Compound A/placebo

Individual Passive Motor Response Threshold (%MSO) Placebo Compound A Before your appointment Change after taking Before your appointment Change after taking 2h 4h 6 hours 2h 4h 6 hours 901 ^a 47 0 0 __b 47 0 1 __b 908 49 -1 -1 __b 51 3 7 __b 910 44 -3 -3 __b 41 1 1 __b 907 62 1 3 __b 62 0 0 __b 912 63 0 0 0 61 __With 6 8 919 65 0 0 1 66 0 0 4 914 39 0 0 0 38 2 3 4 918 52 2 3 2 52 3 5 6 927 78 1 1 1 77 3 10 10 925 ^a 49 -1 0 0 48 1 1 4 928 ^a 52 4 5 3 52 2 1 1 924 47 2 3 2 47 1 2 1 93 0 ^a 48 1 1 1 49 0 0 0 934 45 0 2 2 46 3 3 7 933 48 0 0 0 48 0 0 3 937 66 0 0 2 63 0 2 7 938 57 0 0 1 55 0 3 3 941 79 0 0 0 77 6 6 6 940 39 0 -1 -1 39 2 4 8 942 54 1 1 2 54 1 7 7 Average 54.2 0.4 0.7 0.9 53.7 1.5 3.1 4.9 SD I,4 1.4 1.8 1.1 11.1 1.6 2.9 2.8

a Individuals who had low plasma levels of Compound A at the time of transcranial magnetic stimulation (see Table 16).

^b Individuals treated with the drug before the 6 h post-dose time point was added to the experimental design.

^c In individual 912, it was not possible to register the passive threshold of the motor response at this point in time.

SD - standard deviation.

There was no significant difference in baseline RMT values between individuals taking Compound A and those taking placebo. Compound A caused a significant increase in the passive threshold of the motor response, which indicated a decrease in cortical excitability (see Fig. 10 and 11). There was a clear relationship between the effect of Compound A and its mean plasma concentration, with RMT changing by more than 4% 6 hours after administration of Compound A. Fig. Figure 8 demonstrates that the passive motor response threshold increases proportionally to the plasma concentration of Compound A, with an average (± standard error of the mean) increase in RMT 6 hours after administration of Compound A of 4.9 ± 0.7%. This significant increase in the passive threshold of the motor response indicates a decrease in corticospinal excitability and thereby the relationship between the pharmacokinetics and pharmacodynamics of the drug.

5.5.2.4.2. Active motor response threshold.

To determine the active motor response threshold (AMT), the subject was asked to squeeze the pressure gauge balloon with his hand with a force equal to 20% of his individual maximum grip force. Table 19 presents individual and mean AMT values for each time point (2, 4 and 6 hours) before and after administration of Compound A or placebo. In individual 912 taking compound A, and 940 taking placebo, AMT could not be recorded 2 hours after taking the drug.

There was no significant difference in baseline AMT values between Compound A and placebo. After taking compound A, an increase in AMT was observed. 6 hours after administration of compound A, the change in AMT was significantly different from that for placebo (p < 0.01).

Table 19

Active Motor Response Threshold (AMT) values expressed as a ratio (percentage) to the maximum stimulant output (%MSO), before and after administration of Compound A/placebo

Individual Active Motor Response Threshold (%MSO) Placebo Compound A Before your appointment Change after taking Before your appointment Change after taking 2h 4h 6 hours 2h 4h 6 hours 901 ^a 37 0 0 __b 38 0 0 __b 908 39 1 1 __b 40 2 2 __b 910 34 0 0 __b 31 4 4 __b 907 46 -1 -1 __b 46 0 0 __b 912 52 -4 -12 -12 45 __With 0 0 919 50 0 0 0 50 0 0 0 914 thirty 1 1 1 29 3 3 6 918 42 1 1 0 41 1 1 1 927 55 0 0 0 57 2 3 0 925 ^a 37 0 0 0 37 1 0 0 928 ^a 37 5 5 5 38 0 0 2 924 37 0 2 1 35 1 3 3 93 0 ^a 39 0 0 0 40 0 0 1 934 36 1 1 1 36 0 2 3 933 36 0 1 1 36 0 0 4 937 53 -1 -1 -1 51 0 0 1 938 43 0 0 0 41 0 2 3 941 55 0 0 0 56 1 1 2 940 33 __With -1 -1 35 2 2 3 942 42 0 0 0 41 1 3 3 Average 41.7 0.2 -0.2 -0.3 41.2 0.9 1.3 2.0 SD 7.7 1.6 3.1 3.3 7.6 1.2 1.4 1.7

^a Individuals who had low plasma levels of Compound A at the time of transcranial magnetic stimulation (see Table 16).

^b Individuals who received the drug before the time point 6 hours after drug administration was added to the experimental design, ^c Individuals for whom the active motor response threshold could not be recorded at this time point.

SD - standard deviation.

5.5.2.4.3. Short-interval intracortical inhibition (SICI). Short-interval intracortical inhibition (SICI) was determined using 15 stimulus pairs (conditioning-test) that were presented in random order with an inter-stimulus interval (ISI) of 2 ms. The conditioning stimulus was 80% of the AMT, and the suprathreshold stimulus was 120% of the RMT.

The SICI calculation used custom scripts to measure the amplitudes of motor potentials evoked by conditioning and nonconditioning stimuli (MEP); the SICI value was expressed as the ratio of the mean MEP value to the conditioning stimulus to the mean MEP value to the non-conditioning stimulus.

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SICI values (average MEP per conditioning stimulus/average MEP per non-conditioning stimulus) were obtained for each individual, each run and each dose of Compound A (see Table 20). The mean and standard deviation were also calculated for each item. No significant facts were discovered.

Table 20

Values of short-interval intracortical inhibition before and after taking compound A/placebo

Individual Short-interval intracortical inhibition (average MEP to conditioning stimulus / average MEP to non-conditioning stimulus) Placebo Compound A Before your appointment 2 hours after administration 4 hours after administration Before your appointment 2 hours after administration 4 hours after administration 901 ^a 1.32 1.18 0.91 1.56 0.85 1.07 908 0.79 0.76 0.54 0.53 0.67 1.02 910 1D1 0.83 0.86 0.90 0.71 1.03 907 0.90 0.98 0.86 0.75 0.72 0.93 912 1.12 0.96 0.91 1.15 __b __b 919 1.09 1.33 0.82 0.94 1.29 0.54 914 1.03 1.04 1.08 1.48 0.91 1.20 918 1.02 0.83 0.75 0.79 0.94 1.68 927 1,Yu 0.59 0.93 1.18 1,I 1.64 925 ^a 1.17 1.22 0.85 1.20 0.96 0.86 928 ^a 1.13 1.20 0.78 1.22 1.18 0.61 924 1.38 1.14 1.18 0.79 2.68 1.01 93 0 ^a 1.02 1.00 1.22 0.84 0.92 1.53 934 1.13 0.77 1.05 1.32 0.91 1.04 933 0.83 1.22 0.91 1.18 0.92 1.03 937 0.63 1.08 2.03 1.20 0.97 1.17 938 0.62 1.34 1.06 1.13 1.12 0.89 941 0.53 0.86 0.87 1.47 1.31 1.27 940 1.29 __b __b 0.78 1.09 0.87 942 1.18 0.71 1.00 1.65 1.03 0.75 Average 1.02 1.00 0.98 1.05 1.07 1.06 SD 0.23 0.22 0.30 0.29 0.43 0.31

a Individuals who had low plasma levels of Compound A at the time of transcranial magnetic stimulation (see Table 16).

^b There is no information available for this point in time.

SD - standard deviation; MEP - motor evoked potential.

5.5.2.5. Conclusion.

A pharmacodynamic study was conducted to evaluate the immediate effect of Compound A, which increases potassium channel open probability, on corticospinal cortical excitability using transcranial magnetic stimulation combined with electromyography and electroencephalography.

5.5.3. Application of the method of transcranial magnetic stimulation in combination with electromyography.

Motor response thresholds (passive and during active muscle contraction) are associated with the conductance of ion channels, and therefore with the excitability of the cell membrane of neurons, as they have been shown to increase under the influence of a number of antiepileptic drugs that affect sodium channels (for example, lamotrigine, carbamazepine; see Ziemann U. et al., J. Int. Fed. Clin. Neurophys. 2015, 126:1847-1868) and potassium channels (eg, retigabine; see Ossemann M. et al., Epilepsy Res. 2016, 126 :78-82).

Also, by determining short-interval intracortical inhibition (SICI) using paired magnetic stimuli, it is possible to study inhibition processes in the cortex. SICI makes it possible to assess the synaptic excitability of interneurons in stimulated areas of the motor cortex, and intracortical inhibition is associated with the transmission of nerve impulses with the participation of gamma-aminobutyric acid A receptors.

As the results obtained by this method show, compound A significantly increases motor thresholds, which indicates a decrease in corticospinal excitability. Particularly strong (according to

- 42 044821 compared to placebo) the passive threshold of the motor response changes in a time- and concentration-dependent manner of compound A. RMT values measured 2, 4, and 6 hours after a single 20 mg dose of Compound A were significantly higher than baseline, which was not observed with placebo. Also, at each of these time points, an increase in RMT correlated with an increase in total exposure (plasma concentration) of Compound A.

Compound A has less effect on the active motor response threshold. However, its value 6 hours after administration of Compound A is significantly different from that of placebo. It is not known why the results for RMT and AMT differ, but this pattern is consistent with data on the effects of other anti-epidemic drugs (Ziemann U. et al., Ann. Neuro. 1996, 40:367-378). It is believed that during voluntary muscle contraction, a decrease in the threshold of the motor response occurs due to an increase in the excitability of corticospinal outputs. neurons or spinal motor. neurons, or both together. The fact that under the influence of substances acting on ion channels of the cell membrane, the active threshold of the motor response increases less than the passive one is explained by subthreshold stimulation of corticospinal outputs. neurons, which are also likely to be the target of transcranial magnetic stimulation. During voluntary muscle activation, many physiological and anatomical elements play a role in addition to those directly activated by transcranial magnetic stimulation; This should explain why the change in the active threshold of the motor response caused by drugs is less pronounced than the passive one. Finally, the lack of effect of compound A on short-interval intracortical inhibition suggests that this substance does not affect intracortical inhibition mediated by gamma-aminobutyric acid A receptors. This result of ours is consistent with data obtained by transcranial magnetic stimulation in combination with electromyography in the case of retigabine (Ossemann M. et al., 2016) and sodium channel blockers (Ziemann et al., 1996).

5.5.4. Application of the transcranial magnetic stimulation method in combination with electroencephalography.

According to our data, compound A significantly affects the results of transcranial stimulation in combination with electroencephalography and the electroencephalogram at rest, and at the highest concentration of this substance in the blood plasma, the EEG characteristics are individual. In addition, the changes caused by compound A occurred after reaching its greatest effect (determined by the concentration in the blood plasma), and the maximum effect was observed 4 hours after taking the drug (see Table 21).

Table 21

Changes in TMS-evoked potentials, TMS-evoked oscillation and resting EEG components under the influence of compound A

Changes caused by compound A At maximum concentration of compound A in blood plasma Point in time after receiving connection A After 2 hours After 4 hours TMS-evoked potentials fN15-P25 fN15-P25 fN15-P25 1 N45 The effect is insignificant 1 Ν45 1 Р180 The effect is insignificant 1 Р180 TMS-evoked oscillation f Theta 30-390 ms The effect is insignificant f Theta 30-180 ms 1 Alpha 220-400 ms The effect is insignificant J, Alpha 250-390 ms T Beta 210-310 ms The effect is insignificant T Beta 250-330 ms Electroencephalogram at rest ΐ Delta ΐ Delta ΐ Delta ΐ Theta ΐ Theta ΐ Theta ΐ Beta ΐ Beta

Additional parameters allowing us to judge cortical excitability were changed in a similar way. Total mean field power (GMFP) quantifies the total electrical activity induced by TMS. Fig. 12 demonstrates that Compound A causes a decrease in cortical excitability over time with prolonged uptake. Compound A also causes a shift in the power spectra of the electroencephalogram at rest towards lower frequencies.

The method of transcranial magnetic stimulation in combination with electroencephalography makes it possible to quantify the pharmacological effect of a drug acting in the brain. It's special

- 43 044821 is valuable for the study of epilepsy, which, despite the presence of a variety of antiepileptic drugs, is not treatable in 30% of cases, and the long-term effect of therapy cannot be predicted (Kwan P., Brodie M.J., N. Engl. J. Med. 2000, 342:314 -319). Previously, using this method, the effect of two drugs most often prescribed to patients with epilepsy, namely lamotrigine and levetiracetam, was studied. Lamotrigine is a voltage-gated sodium (Na+) channel blocker, and levetiracetam binds to synaptic vesicle protein 2A (SV2A) and thereby inhibits excitatory neurotransmitter release (Rogawski M.A., Loscher W., Nat. Rev. Neurosci. 2004, 5:553564) . As for the effect at the systemic level, both drugs cause an increase in the amplitude of the N45 component and a suppression of the P180 component (Premoli I. et al., Epilepsia 2016, 58:42-50).

In the TMS-EEG portion of our study, Compound A 20 mg produced statistically significant changes in TMS-evoked potentials consistent with a decrease in cortical excitability. Compared with the effect of placebo, determined at the same time points, compound A, at its highest concentration in the blood plasma at the time of measurements by TMS-EEG method, caused a decrease in the amplitude of the first N15-P25 complex, and the characteristics of the N45 and P180 potentials were individual. The N15 component is generated in the ipsilateral premotor cortex; the origin of the P25 component is unclear - perhaps it reflects activity near the border between the ipsilateral sensorimotor and premotor areas, in the superior wall of the ipsilateral cingulate cortex or in the supplementary motor area and in the cortex of the other hemisphere (Maki H., Ilmoniemi R.J., Neurosci. Lett. 2010, 478 :24-28). The N15-P25 complex shows an inverse correlation with the amplitude of motor evoked potentials (MEP), which provides information about excitability in the stimulated brain region. It follows that the decrease in the peak-to-peak amplitude of these early components may reflect a decrease in cortical excitability caused by drug administration. Over time, after administration of compound A, a decrease in N45 amplitude occurs, which is associated with the transmission of nerve impulses with the participation of gamma-aminobutyric acid A receptors, as was shown in a study of the effect of benzodiazepines (which potentiate the effect of gamma-aminobutyric acid) on TMS-evoked potentials. (Premoli I. et al., J. Neurosci.: J. Soc. Neurosci. 2014, 34:5603-5612; Darmani G. et al., J. Neurosci.: J. Soc. Neurosci. 2016, 36:12312 -12320). The decrease in N45 amplitude may reflect a weakening of inhibition with the participation of the gamma-aminobutyric acid A receptor due to the activation of presynaptic A receptors, which reduces the release of this neurotransmitter into the synaptic cleft. There is an alternative explanation: the response to transcranial magnetic stimulation does not spread to the contralateral cerebral hemisphere due to a general increase in cortical inhibition and, consequently, the N45 amplitude in remote areas decreases. Finally, the decrease in the P180 component is consistent with observations made for other antiepileptic drugs (Premoli I. et al., 2016).

In addition to TMS-evoked potentials, brain responses to transcranial magnetic stimulation can be studied by time-frequency analysis at the individual response level, excluding the evoked component (i.e., TMS-evoked potential) from the signal. This approach results in TMS-evoked oscillations that provide phase-unlocked information (Premoli et al., Neuroimage 2017, 163:1-12). Data on the effects of compounds affecting gamma-aminobutyric acid transmission on TMS-evoked oscillations indicate that early alpha oscillation synchronization is increased by compounds affecting gamma-aminobutyric acid A-receptor synaptic transmission and decreased Under the influence of B receptor modulators, late alpha desynchronization is increased by B receptor modulators, and late beta desynchronization is increased by both A and B receptor modulators.

Compound A has a specific evoked response profile consisting of a suppression of TMS-evoked oscillation power in the theta and alpha bands and a further increase in TMS-evoked beta oscillation desynchronization. Without transcranial magnetic stimulation at rest, the spontaneous oscillatory activity of the brain changes, namely, the power of oscillations in the delta, theta and beta ranges increases.

Data obtained by transcranial magnetic stimulation in combination with electroencephalography and electromyography show that compound A, administered orally in an amount of 20 mg, penetrates the blood-brain barrier and affects cortical excitability, as demonstrated by changes in a number of pharmacodynamic parameters. The development of epilepsy is related to the natural properties of the cell membrane of neurons and the level of excitation and inhibition processes in the cerebral cortex. Thus, the endpoints of this study may play an important role in determining the therapeutic effect of Compound A in patients with epilepsy. For example, in individuals suffering from this disease who have not received treatment with Compound A, the passive motor response threshold is lower than in healthy individuals, and intracortical inhibition is impaired. Specifically for Compound A, changes in passive motor response threshold and other pharmacodynamic parameters before and after its administration can be used to assess response to therapy using this substance.

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Claims (22)

All patents, patent applications and patent application publications, foreign patents and patent applications, and non-patent publications mentioned herein are incorporated herein by reference in their entirety, including U.S. Provisional Patent Application No. 62/670,354, filed May 11, 2018 G. Although the compositions, methods and uses set forth herein have been described in some detail to facilitate a better understanding of the present invention, it is clear that certain changes and modifications thereof are possible within the scope of the invention as claimed. Accordingly, the embodiments of the present invention described herein are to be considered as illustrative and non-limiting in nature, and the claimed invention is not limited to the details set forth herein, but may be varied within the scope and scope of the claims appended hereto. CLAIM 1. The use of a substance which is K-[4-(6-fluoro-3,4-dihydro-III-isoquinolin-2-yl)-2,6dimethylphenyl]-3,3-dimethylbutanamide, for the treatment of a seizure disorder in a person in need of This treatment of a person in which the specified substance is administered to the specified person orally during or after a meal. 2. Use according to claim 1, in which the specified substance is administered to the specified person orally during a period of time from 30 minutes before a meal to 2 hours after a meal. 3. Use according to claim 1 or 2, wherein the seizure disorder is epilepsy with focal seizures. 4. Use according to any one of claims 1-3, which leads to activation of Kv7 potassium channels. 5. The use of claim 4, wherein the Kv7 potassium channel is selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5 channels. 6. Use according to claim 4, which enhances the opening of Kv7.2/Kv7.3 potassium channels. 7. Use according to claim 4, which is selective for activation of the Kv7 potassium channel selected from one or more of the Kv7.2, Kv7.3, Kv7.4 and Kv7.5 channels, as well as Kv7.1. 8. Use according to any one of claims 1 to 7, which includes administering to a human a dose of said substance that is lower than that required to achieve one or more of the same C _max or AUC _inf of the compound when administered orally to a human on an empty stomach. 9. Use according to any one of claims 1 to 7, wherein oral administration of said substance to a person results in an increase in the values of one or more of the _Cmax or AUCinf values for that substance in that person compared to the values of these indicators when taking the same amount orally of this substance on an empty stomach. 10. Use according to claim 9, wherein the C _max values for that substance in a given person are increased compared to the values of these parameters when taking the same amount of the substance orally on an empty stomach, and wherein the ratio of C _max after oral administration of the compound to C _max after oral administration of the compound on an empty stomach exceeds 1.3. 11. Use according to claim 9, wherein the AUCinf value for that substance in a given person is increased compared to the values of these indicators when taking the same amount of that substance orally on an empty stomach, and the ratio of AUCinf after oral administration of the compound to AUCinf after oral administration of the compound on an empty stomach exceeds 1.2. 12. Use according to claim 11, wherein the ratio of AUCinf after oral administration of the compound to AUC _inf after oral administration of the compound on an empty stomach is greater than 1.3. 13. Use according to any one of claims 1 to 12 for increasing the passive motor response threshold (RMT) or active motor response threshold (AMT) in a person in need thereof. 14. Use according to claim 13, wherein the increase in RMT or AMT is proportional to the concentration of this substance in the blood plasma. 15. Use according to any one of claims 1 to 12 for reducing corticospinal or cortical excitability in a person in need. 16. Use according to any one of claims 1-9, in which the specified substance is administered to a person in an amount of 2-200 mg. 17. Use according to claim 16, in which the specified substance is administered to a person in an amount of 2-100 mg. 18. Use according to claim 16, in which the specified substance is administered to a person in an amount of 5-50 mg. 19. Use according to claim 16, in which the specified substance is administered to a person in an amount of 10, 20 or 25 mg. 20. Use according to claim 16, in which the specified substance is administered to a person in an amount of 20 mg. 21. Use according to any one of claims 1 to 18, wherein said substance is administered to a human in an amount of at least 20 mg. 22. Use according to any one of claims 1-21, in which the specified substance is administered to a person in an amount of 5-500 mg per day. -