KR102427769B1 - Composition for prevention or treatment of multiple sclerosis - Google Patents

Abstract

The present invention provides for the prevention of multiple sclerosis comprising (S)-2-((4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide or a pharmaceutically acceptable salt thereof as an active ingredient , improvement or therapeutic use.

Description

Composition for prevention or treatment of multiple sclerosis

The present invention provides for the prevention of multiple sclerosis comprising (S)-2-((4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide or a pharmaceutically acceptable salt thereof as an active ingredient , improvement or therapeutic use.

Multiple sclerosis (MS) occurs in genetically susceptible individuals, mediators of innate immune responses caused by environmental factors such as viruses, and autoimmune, chronic inflammatory and demyelination centers associated with immunological factors such as antibodies and complement It is a nervous system (CNS) disease. MS is classified as an inflammatory demyelinating disease and can occur in any age group, but it occurs most often in the 20-40 years of age, and it is known that the incidence rate in women is twice that of men. This neurological disorder is due to damage to the myelin sheath surrounding the axon of the nerve cell due to an inflammatory response in the central nervous system. Lesions appear scattered in the white matter regions of the brain and spinal cord, and are a typical symptom of primary inflammatory diseases in the lesions. Initially, the inflammation is transient and repair of damaged myelin occurs but does not persist. However, as time goes by, due to the intensive and chronic activation of microglia associated with neurodegeneration, pathological changes progress, and the clinical symptoms become increasingly serious.

The main symptoms of multiple sclerosis include movement disorders and sensory abnormalities, optic nerve damage, memory loss, and depression. also suffer It is possible to temporarily lead a normal life by relieving the condition through continuous drug treatment, but reducing the recurrence frequency is the key.

Autoreactive CD4+ T cells that respond to self myelin are activated after migrating from the blood to the central nervous system for various reasons. These CD4+ T cells secrete substances that attract other immune cells, such as macrophages and B cells, into the central nervous system, while also secreting substances that induce inflammation. Autoreactive CD8+ T cells are also reactivated when they enter the central nervous system from the blood, self-replicate and proliferate, and cytotoxically attack and destroy epitope-containing cells. Macrophages cooperate with microglia in the central nervous system to attract and activate CD4+ T cells and CD8+ T cells to the central nervous system, while secreting BAFF (B cell activating factor belonging to the TNF family) to activate B cells. . In addition, macrophages destroy myelin by secreting pro-inflammatory cytokines, and phagocytic and complement-labeled myelin are removed. It is known that multiple sclerosis is caused by this autoimmune reaction.

Current therapies to slow the progression of multiple sclerosis have many challenges. Many drugs have been shown to slow the progression of the disease in some people. These drugs work by inhibiting or altering the activity of the body's immune system. Therefore, these treatments are based on the partial theory that the cause of multiple sclerosis is an abnormal reaction of the body's immune system that causes it to attack the myelin sheaths lining the nerves. However, these existing drugs are not effective in some patients, or in many patients, it is difficult to cure, and at the same time, recurrence and side effects are accompanied. Therefore, there is an urgent need to develop effective drugs and treatment technologies that have fewer side effects and can be treated fundamentally.

Under this background, the present inventors found that the KDS2010 compound of the present invention significantly restores movement impairment in EAE mice, an animal model of multiple sclerosis, and also reduces CD4 T cells and F4/80 macrophages through the efficacy of reducing multiple sclerosis. It is useful for the treatment of multiple sclerosis. The present invention was completed by confirming that it can be utilized.

Korean Patent Publication No. 10-1795562 Korean Patent Publication No. 10-1781060

One object of the present invention is to provide a pharmaceutical composition for preventing or treating multiple sclerosis (MS) comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

.

.

Another object of the present invention is to provide a method for preventing or treating multiple sclerosis, comprising administering the pharmaceutical composition to a subject in need thereof.

Another object of the present invention is to provide a food composition for preventing or improving multiple sclerosis comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a feed composition for preventing or improving multiple sclerosis comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited by the specific descriptions described below.

As an aspect for achieving the above object, the present invention provides a pharmaceutical for preventing or treating multiple sclerosis (MS) comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. A composition is provided:

[Formula 1]

.

.

The compound represented by Formula 1 of the present invention is (S)-2-((4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide ((S)-2-((4) It is a compound with the IUPAC name of '-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide).

The specific pharmacological activity of the compound is still being studied, but it has not been revealed whether it has a direct preventive and therapeutic effect on multiple sclerosis.

In another aspect, the present invention provides a method for preventing or treating multiple sclerosis, comprising administering the pharmaceutical composition to an individual in need thereof.

The method for preventing or treating multiple sclerosis of the present invention may be combined with rehabilitation training.

The compound of Formula 1 contained as an active ingredient in the pharmaceutical composition of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid value formed by a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" means any and all organic or organic compounds of the compound at a concentration having an effective action that is relatively non-toxic and harmless to the patient, in which side effects attributable to the salt do not reduce the beneficial efficacy of the compound. means inorganic addition salts.

Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.

At this time, organic acids and inorganic acids can be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid as organic acids (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , but not limited to these.

In addition, bases can be used to prepare pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention, unless otherwise indicated, include salts of acidic or basic groups that may be present in the compounds. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate. , dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be prepared through a method.

In addition, the compound includes, without limitation, pharmaceutically acceptable salts thereof as well as solvates such as possible hydrates that can be prepared therefrom. Solvates of the compounds can be prepared using methods known in the art.

Furthermore, the compound may be prepared in crystalline or amorphous form, and when prepared in crystalline form, may optionally be hydrated or solvated. In the present invention, not only stoichiometric hydrates of the above compounds, but also compounds containing various amounts of water may be included. Solvates of the compounds according to the invention include both stoichiometric and non-stoichiometric solvates.

Specifically, (S)-2-((4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide used in the pharmaceutical composition of the present invention is (S)-2-(( 4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide methanesulfonate, but is not limited thereto.

On the other hand, a method for obtaining (S)-2-((4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide or a pharmaceutically acceptable salt thereof used in the pharmaceutical composition of the present invention is not particularly limited to, chemically synthesized by a method known in the art, or a commercially available material may be used.

As used herein, "multiple sclerosis (MS) is a demyelinating disease caused by damage to myelin, which is an insulating cover that protects nerve cells in the brain and spinal cord. Such damage is As it interferes with signaling in parts of the nervous system, it causes a wide range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. movement disorders (e.g., nystagmus), sensory symptoms (e.g., tingling, tingling, throbbing of the skin), weakness, convulsions, ataxia, bladder disorders, and cognitive disorders, emotional disorders and seizure disorders. Multiple sclerosis can take many forms, such as relapsing forms with isolated attacks or progressive forms that accumulate over time, although symptoms may disappear completely between attacks. , permanent neurological problems may still remain and, in particular, may accompany disease progression.The underlying mechanism of this multiple sclerosis is thought to be due to destruction by the immune system or errors in myelin-producing cells. Although known, environmental factors such as genetic factors and viral infection have been discussed as the cause of the occurrence, but it is not clear, and there is no known treatment.

For example, the pharmaceutical composition of the present invention can delay the onset of multiple sclerosis.

In addition, the pharmaceutical composition of the present invention can alleviate symptoms of multiple sclerosis.

Furthermore, the pharmaceutical composition of the present invention can reduce the spinal cord infiltration of immune cells caused by multiple sclerosis.

Specifically, the pharmaceutical composition of the present invention may promote recovery of motor function damaged due to multiple sclerosis, or reduce spinal cord infiltration of CD4 T cells and/or F4/80 macrophages.

In a specific embodiment of the present invention, when the methanesulfonate of the compound of Formula 1 of the present invention is treated in an animal model of multiple sclerosis, the recovery of motor function is accelerated compared to the control group not administered with the multiple sclerosis drug, and CD4 T cells and F4 /80 It was confirmed that the spinal cord infiltration of macrophages was reduced ( FIGS. 2 and 3 ).

This indicates that the composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention can exhibit excellent effects for the prevention or treatment of multiple sclerosis.

As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of multiple sclerosis by administration of the pharmaceutical composition of the present invention, and "treatment" refers to any action by administration of the pharmaceutical composition of the present invention. It refers to any action that improves or beneficially changes the symptoms of the above disease.

In a specific embodiment of the present invention, the treatment comprises reducing or alleviating the symptoms of multiple sclerosis, reducing the severity of the disease, delaying or slowing the disease, temporarily ameliorating or stabilizing the disease state, and may mean other beneficial results, but is not limited thereto.

As used herein, the term "individual" refers to an individual suspected of having multiple sclerosis, which is invented or may develop, including humans, monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, It refers to all animals, including mice, rats, rabbits, or guinea pigs, and by administering the pharmaceutical composition of the present invention to these individuals, the disease can be effectively prevented or treated. In addition, the pharmaceutical composition of the present invention may exhibit a synergistic effect by administering in parallel with the existing therapeutic agent.

The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. have. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, may be administered intrarectally, but is not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell. Preferred administration modes and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like. For injections, aqueous solvents such as physiological saline solution and Ringer's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) Stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, to inhibit microbial growth Pharmaceutical carriers such as preservatives (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.

For example, the composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and may be powder, granule, tablet, capsule, suspension, emulsion, It can be formulated and used in various forms such as oral formulations such as syrups and aerosols, injections of sterile injection solutions, etc. . Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the composition of the present invention may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

Liquid formulations for oral use may include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included. can

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. The suppositories are Witepsol, Macrogol, and Twin61. Cacao butter, laurin fat, glycerogelatin, etc. may be used. On the other hand, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

The formulation may be prepared by a conventional mixing, granulating or coating method and may contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of active ingredient.

At this time, the composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field. can The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

For example, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.

The preferred dosage of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for desirable effects, it is preferable to administer the compound of the present invention at 0.0001 to 100 mg/kg (body weight), preferably 0.001 to 100 mg/kg (body weight) per day. Administration may be administered once a day or in divided doses via oral or parenteral routes.

The composition for preventing or treating multiple sclerosis of the present invention may be prepared into a pharmaceutical formulation using a method well known in the art to provide rapid, sustained or delayed release of an active ingredient after administration to a mammal. In the preparation of the formulation, the active ingredient may be mixed or diluted with a carrier, or enclosed in a carrier in the form of a container.

Accordingly, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and powder, granule, tablet, capsule, suspension according to a conventional method according to each purpose of use. Oral formulations such as emulsions, syrups, aerosols, etc., can be formulated and used in various forms such as injections of sterile injection solutions. can be Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the composition of the present invention may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

Liquid formulations for oral use may include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included. can

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. The suppositories are Witepsol, Macrogol, and Twin61. Cacao butter, laurin fat, glycerogelatin, etc. may be used. On the other hand, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

The formulation may be prepared by a conventional mixing, granulating or coating method and may contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of active ingredient.

At this time, the composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field. can

The preferred dosage of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the form of the drug, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for desirable effects, it is preferable to administer the compound of the present invention at 0.0001 to 100 mg/kg (body weight), preferably 0.001 to 100 mg/kg (body weight) per day. Administration may be administered once a day or in divided doses via oral or parenteral routes.

For example, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.

In addition, the pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the prevention and treatment of multiple sclerosis. For the purposes of the present invention, the pharmaceutical composition according to the present invention may be administered in combination with one or more additional drugs commonly used for the treatment of multiple sclerosis.

When the pharmaceutical composition according to the present invention is administered for the treatment of multiple sclerosis, it may be administered in combination and/or in combination with one or more ingredients and/or agents effective for the treatment or prevention of multiple sclerosis. At this time, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects in consideration of all of the above factors, which can be easily determined by those skilled in the art.

Specifically, the combination and/or combination administration may include administering the compound of the present invention or a pharmaceutically acceptable salt thereof and the one or more additional drugs simultaneously, sequentially, or in reverse order, respectively, and simultaneously administering in an appropriate effective amount in combination, or , can be administered concurrently, sequentially, or in reverse order after storing each in a separate container.

In another aspect, the present invention provides a food composition for preventing or improving multiple sclerosis comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The "multiple sclerosis", and "prevention" are as described above.

In addition, as used herein, the term "food pharmaceutically acceptable salt" may be defined the same as the above-described pharmaceutically acceptable salt.

"Improvement" of the present invention refers to any action in which the symptoms of the subject disease and the subject's symptoms are improved or beneficial by using the composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The food composition according to the present invention includes the form of pills, powders, granules, needles, tablets, capsules or liquids, and the food to which the composition of the present invention can be added, for example, various foods, for example , beverages, gum, tea, vitamin complexes, and health supplements.

As an essential ingredient that can be included in the food composition of the present invention, other ingredients are not limited except for the inclusion of the compound of Formula 1 or a food pharmaceutically acceptable salt thereof. may be contained as an additional component.

In addition, the food supplement additives include food supplement additives conventional in the art, for example, flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like.

Examples of the natural carbohydrate include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavoring agents (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used as flavoring agents other than those described above.

In addition to the above, the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, it may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages. These components may be used independently or in combination.

In the present invention, the food composition includes health functional food and health supplement food.

The functional food (functional food) is the same term as food for special health use (FoSHU), and is a food manufactured and/or processed using raw materials or ingredients having useful functions in the human body. As such, it refers to foods with high medical and medical effects that are processed to efficiently exhibit bioregulatory functions in addition to nutritional supply. Here, "function (sex)" means to obtain a useful effect for health purposes such as regulating nutrients or physiological action with respect to the structure and function of the human body. As described above, foods that contain ingredients useful to the human body and whose functions and safety have been recognized by the Ministry of Food and Drug Safety are called health functional foods. It is classified as (auxiliary) food. The food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art. In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food. The food composition of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur during long-term administration of the drug using food as a raw material, and has excellent portability.

In another aspect, the present invention provides a feed composition for preventing or improving multiple sclerosis comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The "multiple sclerosis", "prevention", and "improvement" are as described above.

In addition, as used herein, the term "feedally acceptable salt" may be defined the same as the aforementioned pharmaceutically acceptable salt.

As used herein, the term "feed" means any natural or artificial diet, meal, etc., or a component of said meal, intended for or suitable for being eaten, consumed, and digested by an animal.

The type of feed is not particularly limited, and feed commonly used in the art may be used. Non-limiting examples of the feed include plant feeds such as grains, root fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, gourds or grain by-products; and animal feeds such as proteins, inorganic materials, oils and fats, minerals, oils and fats, single cell proteins, zooplankton, or food. These may be used alone or in combination of two or more.

The feed of the present invention may be powder feed, solid feed, moist pellet feed, dry pellet feed, EP (Extruder Pellet) feed, raw feed, etc., but is not limited thereto.

The composition for feed of the present invention may include a binder, an emulsifier, a preservative, etc. added to prevent quality deterioration, and the composition for feed may include a feed additive. There may be amino acids, vitamins, enzymes, flavoring agents, non-protein nitrogenous compounds, silicates, buffers, extractants, oligosaccharides, etc. added to the feed to increase the efficacy. In addition, it may further include a feed mixture and the like, but is not limited thereto.

The composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention suppresses symptoms such as loss of reflexes and/or paralysis accompanying the onset of multiple sclerosis, and suppresses infiltration of immune cells into the spinal cord, so multiple sclerosis It can be usefully used for the prevention or treatment of

1 shows the construction of a rodent multiple sclerosis model and administration of (S)-2-((4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide methanesulfonate (hereinafter, KDS2010). It is a diagram showing an outline.
2 is a diagram showing symptom relief of multiple sclerosis caused by KDS2010 administration in a rodent multiple sclerosis model. 2A shows the daily clinical symptom index, which quantifies the degree of paralysis of the tail and legs. B of FIG. 2 shows the area of the graph Ari by group A, and compares the severity of symptoms by administration concentration of the KDS2010-administered group compared to the control group (100%). 2C shows the time point and rate at which multiple sclerosis symptoms appeared for each group.
3 is a diagram showing the results of measuring the infiltration of inflammatory cells in the spinal cord, specifically, CD4 T cells, CD8 T cells, and F4/80 macrophages, in a rodent multiple sclerosis model by KDS2010 administration by flow cytometry.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Preparation Example 1: Preparation of drug for administration

(S)-2-((4'-(trifluoromethyl)biphenyl-4-yl)methylamino)propanamide methanesulfonate (hereinafter, KDS2010), the drug to be administered, was disclosed in Korean Patent Publication No. 10-1746060 It was prepared by synthesizing by the method described in No., specifically, by the method described in Example 9.

Preparation Example 2: Preparation of rodent multiple sclerosis model

A rodent model of myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE), which is the most used for the study of multiple sclerosis, was prepared.

Specifically, after acclimatizing 10-week-old C56BL6/J male mice in a breeding room controlled by temperature and humidity, a mixture of MOG _35-55 peptide and complete Freund's adjuvant (CFA) was injected subcutaneously. . Additionally, pertussis toxin dissolved in PBS was intraperitoneally injected on days 0 and 1. The multiple sclerosis (MOG-induced EAE) animal model production timeline and drug administration outline are shown in FIG. 1 .

Example 1: Drug administration and clinical symptom evaluation

In the rodent multiple sclerosis model prepared according to Preparation Example 2, KDS2010 prepared according to Preparation Example 1 was dissolved in tertiary distilled water and orally administered at a dose of 1 or 10 mg/kg daily. The control group was orally administered with the same amount of tertiary distilled water daily. At this time, in the experimental group and control model, the following symptom scales were used to evaluate and score daily until day 28:

0: No abnormality,

0.5: loss of tension in the tail,

1.0: loss of reflex of tail,

2.0: loss of reflexes of tail, perception of more than one leg,

3.0: paresthesia and paralysis of one leg;

3.5: Paralysis of both hind limbs,

4.0: paralysis of forelimbs and hindlimbs,

5.0: Moribund or dead.

The daily calculated scores are shown in Figure 2A. As shown in Figure 2A, in the control model, symptoms started to develop after 9 days, and the symptoms worsened rapidly over time, whereas in the KDS2010-administered group, the onset of symptoms itself was delayed after 13 days and time elapsed. The expression of symptoms was also weakened compared to the control group, and in particular, in the experimental group administered at a dose of 10 mg/kg, the severity of symptoms was significantly lower even after 28 days.

In addition, in order to more directly confirm symptom relief in the KDS2010-administered experimental group, the relative symptom severity of the experimental group was calculated by setting the symptom of the control group to 100%, and this is shown in FIG. 2B. As shown in FIG. 2B , the experimental group administered with KDS2010 at a dose of 1 mg/kg and 10 mg/kg, respectively, showed only symptoms significantly alleviated to 60% and 30% levels compared to the non-administered control group.

Furthermore, the incidence rate over time was calculated and shown in FIG. 2C. As shown in FIG. 2C , the onset of onset was generally delayed in the KDS2010-administered group compared to the non-administered control group, and in particular, as the dose increased, the delay was longer and the increase in the incidence rate was also lowered.

Example 2: Analysis of spinal cord infiltration of immune cells

After 28 days of clinical evaluation, mice were euthanized, spinal cord tissue was recovered, and the degree of infiltration of immune cells was confirmed by flow cytometry assay. Specifically, the recovered spinal cord tissue was chopped and lysed with collagenase D and DNase I, and only immune cells were collected by Percoll gradient centrifugation. After washing with PBS, staining with anti-CD4-FITC antibody, anti-CD8-PerCP-Cy5.5 antibody and anti-F4/40-PE antibody to measure the number and ratio of immune cells infiltrating the spinal cord by flow cytometry, , the results are shown in FIG. 3 . As shown in FIG. 3 , the infiltration of immune cells into the spinal cord was increased in the non-administered control group, but the number was decreased in all of the KDKS2010-administered experimental groups, and in particular, CD4 T cells and F4/80 macrophages were significantly reduced.

The above results indicate that KDS2010 can improve the neurological clinical symptom scale of the disease in the multiple sclerosis model, delay the onset, and inhibit the infiltration of immune cells into the spinal cord, so it can be usefully used for the prevention or treatment of multiple sclerosis. will indicate

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.

Claims (7)

A pharmaceutical composition for preventing or treating multiple sclerosis (MS) comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

.
According to claim 1,
The compound is in the form of a methanesulfonate, the pharmaceutical composition.
According to claim 1,
wherein the composition delays the onset of multiple sclerosis.
According to claim 1,
The composition is to alleviate the symptoms of multiple sclerosis, a pharmaceutical composition.
According to claim 1,
The composition is to reduce the spinal cord infiltration of immune cells by multiple sclerosis, a pharmaceutical composition.
A food composition for preventing or improving multiple sclerosis comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

.
A feed composition for preventing or improving multiple sclerosis comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

.

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