WO2020009403A1 - Pharmaceutical composition for preventing or treating sleep disorders - Google Patents

Abstract

The present invention pertains to a pharmaceutical composition for preventing or treating sleep disorders. The pharmaceutical composition provided according to an aspect of the present invention can exhibit high sleep-inducing activity with low toxicity and side effects, and thus has the effect of being usable as a sleep therapeutic agent.

Description

Pharmaceutical compositions for the prevention or treatment of sleep disorders

It relates to a pharmaceutical composition for the prevention or treatment of sleep disorders.

Sleep accounts for one third of human life and is the most fundamental and essential physiological phenomenon, which is very important for health maintenance and mental stability. Chronic sleep deprivation and disability have a negative impact on overall physical and mental health including cardiovascular disease, high blood pressure, memory, learning, metabolic control, weight, immunity, cancer resistance, diabetes, safety and mood. Currently, about 30% of the world's population experiences insomnia and 10% have chronic problems.

The lifetime prevalence of insomnia has increased from 36% to 49% over the last few years. The problem was so severe that a joint study conducted by the International Health Organization found that on average, 4.4 days for patients with physical illness averaged 5.2 days for people with physical disabilities, compared to 5.2 days for people with sleep disorders. It has been shown that the impact of disability on our lives is very serious. In addition, according to a 1995 Gallup survey conducted in the United States, 52% of adults surveyed said they had drowsy driving during the past year, and only 3 out of 10 adults who reported having sleep disorders discussed their problems with their medical practitioners. . Even if insomnia patients complain of their symptoms to doctors, most doctors have a limited knowledge of sleep disorders, so doctors often improperly use sleeping pills.

Hypnotics are generally effective for short-term treatment of insomnia, but there are various side effects such as drug dependence and cognitive decline. Therefore, non-pharmaceutical treatment is recommended at the beginning.

Therapeutic drugs include, but are not limited to, benzodiazepine-based drugs (Korea Patent 10-2001-7014366), non-benzodiazepine-based drugs, benzodiazepine receptor agonists and antidepressants with sedative effects. In addition to the side effects of dependence, symptoms may be similar to anxiety, excitement, and withdrawal, which can lead to not only daily life difficulties but also other diseases such as cognitive impairment and depression.

Therefore, it is urgent to develop drugs that can treat anxiety and insomnia with little side effects.

It is an object in one aspect of the present invention to provide a compound usable in the prevention or treatment of sleep disorders.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of sleep disorders comprising the compound as an active ingredient.

Another object of the present invention is to provide a dietary supplement for preventing or improving sleep disorders comprising the compound as an active ingredient.

It is an object of another aspect of the present invention to provide a method for treating a sleep disorder by administering the compound to a patient or a subject in need thereof (ie, a sleep disorder patient).

Another object of the present invention is to provide a use of the pharmaceutical composition or nutraceutical composition comprising the compound in the treatment of sleep disorders.

It is an object in another aspect of the present invention to provide a use of the compound for the manufacture of a medicament for the prevention or treatment of sleep disorders.

In order to achieve the above object,

One aspect of the present invention provides a pharmaceutical composition for preventing or treating sleep disorders comprising any one compound selected from the following compound groups, or a pharmaceutically acceptable salt thereof as an active ingredient:

(1) N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) benzamide; And

(2) 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benzamide.

In addition, another aspect of the present invention provides a health functional food composition for preventing or improving sleep disorders comprising the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.

Furthermore, another aspect of the present invention provides a method for preventing or treating a sleep disorder comprising administering the compound, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

In addition, another aspect of the present invention, a method for preventing or treating a sleep disorder comprising administering to a subject in need thereof a pharmaceutical composition or a health functional food containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.

Furthermore, another aspect of the present invention provides a use of the pharmaceutical composition or health functional food containing the compound or a pharmaceutically acceptable salt thereof in the prevention or treatment of sleep disorders.

In another aspect, the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of sleep disorders.

Embodiment compounds provided in one aspect of the present invention has a low toxicity and side effects, and can exhibit high sleep-inducing activity, there is an effect that can be usefully used as a pharmaceutical composition for the prevention or treatment of sleep disorders.

1 is a graph showing the sleep induction rate by the compound of Preparation Example 1 or Preparation Example 2.

2 is a graph showing sleep start time by Preparation Example 1 or Preparation Example 2 compound.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a pharmaceutical composition for preventing or treating sleep disorders comprising any one compound selected from the following compound groups, or a pharmaceutically acceptable salt thereof as an active ingredient.

(1) N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) benzamide; And

(2) 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benzamide.

Sleep is an increase in the threshold of response to external stimuli while the activity of the organism remains static. The physiological functions of sleep include recovery of homeostasis of the central nervous system, energy storage, temperature control, and memory adjustment, and long-term sleep deprivation causes various mental problems. Sleep is divided into NREM (non-rapid eye movement) and REM (rapid eye movement) on the basis of physiological state.Regarding NREM, most physiological functions are significantly lowered in pulse or respiration compared to arousal state. It is similar to, and is characterized by the expression of caring active brain function. Typically, 90 minutes after sleep, the NREM sleep transitions to REM sleep.

Sleep disorders are generally known to affect about one third of adults once in their lifetime. These sleep disorders include insomnia, sleepy (excessive somnolence), and sleep-wake schedule disorders depending on symptoms. Current clinical trials use the Sleep Disorders classification, classified by the American Psychiatric Association, to classify primary (primary) sleep disorders, sleep disorders associated with other mental disorders, and other sleep disorders. Primary sleep disorders are divided into dyssomia and paracomnia, and sleep disorders are divided into insomnia, hypersomnia, narcolepsy, respiratory related sleep disorders (sleep apnea), and circadian rhythm sleep disorders. Sleep accompaniment is subdivided into nightmares, night terrors and sleepwalking. Other sleep disorders are generally somatic or substance-like sleep disorders. Insomnia usually manifests as a sleep initiation, sleep maintenance or a combination of the two. That's why sleep initiation and sleep duration are the most important factors in evaluating insomnia.

Compounds provided in one aspect of the present invention can be used in the form of pharmaceutically acceptable salts, as salts are acid addition salts formed by pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids and the like, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro Zensulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving an example compound derivative in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like by adding an organic acid or an inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention encompasses not only the compound and its pharmaceutically acceptable salts, but also all solvates, stereoisomers, hydrates and the like that can be prepared therefrom.

The compound can prevent or treat sleep disorders by decreasing the sleep time or increasing sleep duration in a concentration-dependent manner, and specific disease names of the sleep disorders include insomnia, narcolepsy, abnormal behavior during sleep, and hypersleep. However, the present invention is not particularly limited thereto.

In the pharmaceutical composition according to the present invention, the compound, or a pharmaceutically acceptable salt thereof, may be administered in a variety of oral and parenteral formulations for clinical administration, and when formulated, commonly used fillers, extenders, It can be prepared using diluents or excipients such as binders, wetting agents, disintegrants, surfactants and the like.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

Pharmaceutical compositions comprising the compound as an active ingredient may be administered parenterally, and parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

In this case, the compound or a pharmaceutically acceptable salt thereof may be mixed with water together with a stabilizer or a buffer to prepare a parenteral formulation, and may be prepared as a solution or suspension, which may be prepared in an ampule or vial unit dosage form. . The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

Furthermore, the dosage of the compound of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and the adult patient weighs 70 kg. On the basis of the standard, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, and may be divided once or several times a day at regular intervals according to the judgment of a doctor or a pharmacist. .

In addition, one aspect of the present invention, a health functional food composition for preventing or improving sleep disorders comprising the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.

Example compound provided in one aspect of the present invention has a low toxicity and side effects, can exhibit high sleep-inducing activity, there is an effect that can be usefully used as a pharmaceutical composition for the prevention or treatment of sleep disorders, which will be described later Yes, supported by the experimental example.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following Examples and Experimental Examples are only illustrative of the present invention in detail, and the present invention is not limited by the following Examples and Experimental Examples.

Preparation Example 1 N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin -1-yl) benzamide preparation

The compound of Preparation Example 1 was prepared by referring to Korean Patent Registration No. 10-1753654.

Preparation Example 2 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benz Amide manufacturers

The compound of Preparation Example 2 was prepared with reference to Korean Patent Registration 10-1753654.

Example 1 Evaluation of Sleep Induction Activity

<1-1> experimental material

(1) Experimental animal: Sprague Dawley (SD) rats (male, 5 weeks, Orient Bio, South Korea Inc.)

(2) Compound: Preparation Example 1, Preparation Example 2 Compound

(3) Solvent: Polyethylene Glycol 400 (SAMCHUN, Cat #: 25322-68-3), D.W

<1-2> Experimental method

(1) Experimental animals SD rats are screened one day before the start of the experiment, after adaptation at 24 ° C (± 1) and 56% (± 0.5%) humidity for three days, to check for abnormal behavior or physical abnormalities.

(2) Selected experimental animals should be limited to feeding for more than 2 hours to minimize food interaction before oral administration, but not negative.

(3) Selected animals were dissolved in 30% PEG 400 in Preparation Example 1 or Preparation 2 compound orally and the drug was administered, and only 30% PEG 400 was administered to the vehicle group. At this time, the dose was calculated by calculating 10μl / g according to the individual body weight.

(4) Observe the animal for abnormal behavior in the cage after drug administration.

(5) After 30 minutes, each subject was placed in a separate chamber, and after 5 minutes of adaptation, observation was performed. More specifically, after 30 minutes was moved to a chamber divided into six compartments that do not affect each other, and the vehicle group and the drug group was not observed at the same time. The test was continued for 30 minutes and 1 hour.

(6) Sleep was judged as maintaining the relative static state and increasing the threshold of response to external stimuli, and the repetitive and regular behavior of the animal's behavior. Responses to external stimuli were stimulated using von-Frey filaments.

(7) The sleep initiation was used by measuring the time when the eyes were closed and the static state was started.

(8) In this experiment, we analyzed NREM based on the physiological state of sleep consisting of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.

<1-3> Experimental Results

Experimental results are shown in FIGS. 1 and 2.

1 is a graph showing sleep induction rate by the compound of Preparation Example 1 or Preparation Example 2; 2 is a graph showing sleep start time by Preparation Example 1 or Preparation Example 2 compound.

For Preparation Example 1 compound, the sleep effect was confirmed in three out of four, the sleep start time was found to be 60 minutes.

In the case of Preparation 2 compound, the sleep effect was confirmed in two out of four, and the sleep start time was found to be the same 60 minutes.

Preparation Example 1 Preparation of Pharmaceutical Formulation

1-1. Manufacture of powder

Compound 500 mg

Lactose 100mg

Talc 10mg

The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

1-2. Manufacture of tablets

Compound 500 mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.

1-3. Manufacture of capsule

Compound 500 mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.

1-4. Preparation of Injectables

Compound 500 mg

Appropriate sterile distilled water for injection

pH adjuster

According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

1-5. Preparation of liquid

100 mg of compound

10 g of isomerized sugar

Mannitol 5g

Purified water

According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve it, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled into a brown bottle. The liquid is prepared by sterilization.

Embodiment compounds provided in one aspect of the present invention is low toxicity and side effects, and can exhibit high sleep-inducing activity, it is useful as a pharmaceutical composition for the prevention or treatment of sleep disorders.

Claims (7)

A pharmaceutical composition for preventing or treating sleep disorders comprising any one compound selected from the following compound groups, or a pharmaceutically acceptable salt thereof as an active ingredient: (1) N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) benzamide; And (2) 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benzamide. The method of claim 1, The compound is a pharmaceutical composition, characterized in that to reduce the sleep time or increase the sleep duration in a concentration dependent. The method of claim 1, The sleep disorder is a pharmaceutical composition, characterized in that at least one sleep disorder selected from the group consisting of insomnia, narcolepsy, abnormal behavior during sleep and hypersomnia. Health functional food composition for the prevention or improvement of sleep disorders comprising any one compound selected from the following compound, or a pharmaceutically acceptable salt thereof as an active ingredient: (1) N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) benzamide; And (2) 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benzamide. A method of treating a sleep disorder comprising administering to a subject in need thereof a pharmaceutically effective amount of any one compound selected from the group of compounds, or a pharmaceutically acceptable salt thereof: (1) N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) benzamide; And (2) 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benzamide. For use in the prevention or treatment of sleep disorders, Any one compound selected from the following group of compounds, or a pharmaceutically acceptable salt thereof: (1) N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) benzamide; And (2) 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benzamide. For the manufacture of drugs for the prevention or treatment of sleep disorders, Use of any one compound selected from the following compound group, or a pharmaceutically acceptable salt thereof. (1) N- (5- (3- (3-isopropylureido) phenyl) -1H-pyrazolo [3,4-b] pyridin-3-yl) -4- (4-methylpiperazin-1 -Yl) benzamide; And (2) 4- (4-methylpiperazin-1-yl) -N- (5- (pyridin-3-yl) -1H-pyrazolo [3,4-b] pyridin-3-yl) benzamide.

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