KR101864085B1 - Valproic acid derivatives, preparation method thereof and anticonvulsant comprising the same - Google Patents

Abstract

The present invention relates to a valproic acid derivative, a preparation method thereof, and a composition for preventing, alleviating, and treating epileptic seizures or seizures containing the valproic acid derivative. A compound represented by chemical formula 1 according to the present invention has excellent anticonvulsant activity, and thus can be useful for preventing, alleviating, and treating epileptic seizures or seizures.

Description

Valproic acid derivatives, a process for preparing the same, and an anticonvulsant comprising the same.

The present invention relates to a composition for the prevention, amelioration, or treatment of valproic acid derivatives, a method for producing the same, and interstitial seizures or convulsions comprising the same.

Seizures are the result of paroxysmal brain dysfunction associated with excessive neuronal activity resulting in changes in behavior or consciousness. Epilepsy is a recurrence of two or more unexplained seizures, which means chronic brain disease.

There are two main types of seizures: partial or focal seizures, which originate at one location in the brain but can spread during the course of an event; And generalized seizures that can affect both hemispheres simultaneously. Partial seizures are manifested in a number of ways depending on the area of the affected brain (confusion, spontaneous physical activity, hallucinations, etc.), generalized tonic-clonic events (convulsions) . There are several types of systemic seizures: spastic seizures (tension-liver seizures, tense seizures, hepatic seizures, myoclonic seizures) and non-convulsive seizures (syncope, no-tense seizures). Typically, all kinds of seizures last for a few minutes, usually less than 5 minutes. Spastic seizures, in particular tonic-clonicevent, usually result in impaired consciousness.

Epilepsy persistence (SE) is defined as a seizure that usually lasts for 30 minutes or more, or a series of seizures that occur for 30 minutes or more in a state in which the subject does not fully recover from unconsciousness. However, many doctors and a number of recent major research papers assume that the patient is in the SE if seizures last longer than 5 minutes. There are two main types of epilepsy persistence: systemic epilepsy, which can be spastic or non-convulsive, and persistent epilepsy. Generalized convulsive status is the most serious type and is associated with high morbidity and mortality. Epilepsy persistence can occur in patients with prior epilepsy diagnosis. However, the occurrence of SE is associated with more frequent and often severe acute brain disease (eg, encephalitis, or stroke) or trauma in subjects without prior history of epilepsy. In addition to these, diverse conditions can be the cause of SE, including hypoglycemia, hyperthermia, drug overdose and alcohol or drug withdrawal. Thus, for example, in patients with a complex partial seizure model or multiple partial seizures, the anticonvulsive activity of a compound or combination does not necessarily predict activity against SE. SE is not only a life-threatening disease, it also causes nerve cell loss and epileptogenesis.

The present inventors devised a novel valproic acid derivative compound to synthesize a total of six valproic acid derivatives and found that valproic acid derivative compounds have excellent anticonvulsant activity in nerve-derived cell lines and in an animal model that induces convulsions by electric shock And the present invention has been completed.

Korean Patent No. 10-1610972

It is an object of the present invention to provide a compound represented by the formula (1), or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the compound represented by the above formula (1).

Another object of the present invention is to provide a pharmaceutical, health functional food and health food composition for preventing, ameliorating or treating epileptic seizures or seizures comprising the compound represented by the above-mentioned formula 1 or a pharmaceutically acceptable salt thereof .

In order to achieve the above object,

The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

,

,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

,

,

And C _1-15 straight or branched alkylcarbonyl.

Also, as shown in the following Reaction Scheme 1,

Dissolving valproic acid and Compound 2 in an organic solvent, refluxing and stirring to obtain Compound 1 (Step 1);

Wherein R < 1 > and R < 2 >

[Reaction Scheme 1]

In the above Reaction Scheme 1,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다.Wherein R < ^{1 &}

,

And C _1-15 straight or branched alkylcarbonyl.

In addition, the present invention relates to a process for producing a compound represented by the formula

Dissolving valproic acid and resveratrol in an organic solvent, refluxing and stirring to obtain compound 1 (step 1);

Wherein R < 1 > and R < 2 >

[Reaction Scheme 2]

In the above Reaction Scheme 2,

또는

이다.Wherein R < ^{1 &}

or

to be.

Further, the present invention provides a pharmaceutical composition for preventing or treating seizures or seizures comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

,

,

,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

,

,

,

And C _1-15 straight or branched alkylcarbonyl.

Further, the present invention provides a health functional food and a health food composition for preventing or improving interstitial seizure or seizure comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

, ,

,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

, ,

,

,

And C _1-15 straight or branched alkylcarbonyl.

The compound represented by formula (I) according to the present invention is excellent in anticonvulsant activity, and thus may be useful for the prevention, improvement and treatment of seizures or seizures.

1 is an image showing the ¹ H-NMR and ¹³ C-NMR spectra of the compound of Example 1; (a) ¹ H-NMR (CDCl ₃ ) spectrum, (b) ¹ H-NMR (CDCl ₃ with one drop D ₂ O) spectrum and (c) ¹³ C-NMR (CDCl ₃ ) spectrum.
2 is an image showing the ¹ H-NMR and ¹³ C-NMR spectra of the compound of Example 2; (a) ¹ H-NMR (MeOD) spectrum and (b) ¹³ C-NMR (MeOD) spectrum.
3 is an image showing the ¹ H-NMR and ¹³ C-NMR spectra of the compound of Example 3; (a) ¹ H-NMR (MeOD) spectrum and (b) ¹³ C-NMR (MeOD) spectrum.
4 is an image showing the ¹ H-NMR and ¹³ C-NMR spectra of the compound of Example 4; (a) ¹ H-NMR (MeOD) spectrum and (b) ¹³ C-NMR (MeOD) spectrum.
5 is an image showing the ¹ H-NMR and ¹³ C-NMR spectra of the compound of Example 5; (a) ¹ H-NMR (CDCl ₃ ) spectrum, (b) ¹ H-NMR (CDCl ₃ with one drop D ₂ O) spectrum and (c) ¹³ C-NMR (CDCl ₃ ) spectrum.
6 is an image showing the ¹ H-NMR and ¹³ C-NMR spectra of the compound of Example 6; (a) ¹ H-NMR (CDCl ₃ ) spectrum and (b) ¹³ C-NMR (CDCl ₃ ) spectrum.
FIG. 7 is a graph showing the cell survival rate (%) of neural-derived cell lines according to solvent or compound treatment; (DW), the compound (LK1) of Example 1, the compound (LK2) of Example 6, and the compound (LK2) And topiramate (TM) treatment.
8 is a graph showing the cell survival rate (%) of neural-derived cell lines according to the treatment concentration of the compound (LK1) of Example 1 or the compound (LK2) of Example 6. FIG.
9 is a graph showing the cell viability (%) of neural-derived cell lines following treatment with glutamate (GLM) or potassium chloride (KCl).
FIG. 10 shows the cytoprotective effect of the compound (LK1) of Example 1, the compound of Example 6 (LK2) and topiramate on cytotoxicity induced by glutamate (GLM) Fig.
Fig. 11 shows the cytoprotective effect of the compound (LK1) of Example 1, the compound of Example 6 (LK2) and topiramate on cytotoxicity induced by potassium chloride (KCl) Fig.
12 shows the cytoprotective effect of the compound (LK1) of Example 1, the compound of Example 6 (LK2) and topiramate on cytotoxicity induced by hydrogen peroxide (H ₂ O ₂ ) %).

Hereinafter, the present invention will be described in detail.

Compound or a pharmaceutically acceptable salt thereof. Acceptable  salt

The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

In Formula 1,

,

,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

,

,

And C _1-15 straight or branched alkylcarbonyl.

Preferably, the C _1-15 straight or branched alkylcarbonyl may be lauroyl.

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

2) 2-acetoxybenzoic acid 2-propylpentanoic anhydride;

3) 2- (4-isobutylphenyl) propanoate 2-propylpentanoic anhydride;

4) Dodecanoic 2-propylpentanoic anhydride;

5) (E) -4- (3-hydroxy-5 - ((2-propylpentanoyl) oxy) styryl) phenyl-2-propyl pentanoate; And

6) (E) -5-4 - ((2-Propylpentanoyl) oxy) styryl) -1,3-phenylene-bis-2-propylpentanoate.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term pharmaceutically acceptable salt means a concentration that is relatively non-toxic to a patient and has a beneficial effect that is harmless to the patient, such that the side effects caused by the salt are any organic or inorganic salt of the base compound of Formula 1 that does not impair the beneficial effects of the base compound of Formula An inorganic addition salt. Examples of the inorganic acid include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, tartaric acid, succinic acid, malonic acid, succinic acid, malonic acid, glutamic acid, aspartic acid, oxalic acid, P-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid. These salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, the acid addition salt may be selected from the group consisting of acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camylate, citrate, eddylate, Hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, malate, glucoside, gluconate, gluconate, glucuronate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / Hydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydroxyacetate, Lactate, stearate, succinate, tartrate, tosylate, trifluoroacetate Agent, may be included in the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving the compound represented by the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Furthermore, the present invention encompasses the compounds of formula (I) and pharmaceutically acceptable salts thereof as well as possible solvates, hydrates, isomers, optical isomers and the like which can be prepared therefrom.

Production methods 1 and 2

As shown in the following Reaction Scheme 1,

Dissolving valproic acid and Compound 2 in an organic solvent, refluxing and stirring to obtain Compound 1 (Step 1);

(1), wherein R < 1 >

[Reaction Scheme 1]

In the above Reaction Scheme 1,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다.Wherein R < ^{1 &}

,

And C _1-15 straight or branched alkylcarbonyl.

Preferably, the C _1-15 straight or branched alkylcarbonyl may be lauroyl.

Preferable examples of the compound represented by the general formula (1) prepared from the above Reaction Scheme 1 include the following compounds.

2) 2-acetoxybenzoic acid 2-propylpentanoic anhydride;

3) 2- (4-isobutylphenyl) propanoate 2-propylpentanoic anhydride; And

4) Dodecanoic 2-propylpentanoic anhydride.

In addition, the present invention relates to a process for producing a compound represented by the formula

Dissolving valproic acid and resveratrol in an organic solvent, refluxing and stirring to obtain compound 1 (step 1);

(1), wherein R < 1 >

[Reaction Scheme 2]

In the above Reaction Scheme 2,

또는

이다.Wherein R < ^{1 &}

or

to be.

Preferable examples of the compound represented by the formula (1), which is prepared from the above reaction formula 2, include the following compounds.

5) (E) -4- (3-hydroxy-5 - ((2-propylpentanoyl) oxy) styryl) phenyl-2-propyl pentanoate; And

6) (E) -5-4 - ((2-Propylpentanoyl) oxy) styryl) -1,3-phenylene-bis-2-propylpentanoate.

In the preparation method according to the present invention, the organic solvent is ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH ₂ Cl _2, hexane, dimethylformamide (DMF), diisopropyl ether , Diethyl ether, dioxane, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetone, chlorobenzene, etc. may be used alone or in combination. Preferably, tetrahydrofuran (THF) may be used as the organic solvent in the step 1.

Pharmaceutical composition for the prevention or treatment of epileptic seizures or convulsions

The present invention provides a pharmaceutical composition for preventing or treating epileptic seizures or seizures comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1,

,

,

,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다. R ¹ is

,

,

,

,

And C _1-15 straight or branched alkylcarbonyl.

Preferably, the C _1-15 straight or branched alkylcarbonyl may be lauroyl.

In the pharmaceutical composition according to the present invention, the compound represented by Formula 1 may be any one selected from the following compounds.

1) 4-acetamidophenyl-2-propyl pentanoate;

2) 2-acetoxybenzoic acid 2-propylpentanoic anhydride;

3) 2- (4-isobutylphenyl) propanoate 2-propylpentanoic anhydride;

4) Dodecanoic 2-propylpentanoic anhydride;

5) (E) -4- (3-hydroxy-5 - ((2-propylpentanoyl) oxy) styryl) phenyl-2-propyl pentanoate; And

6) (E) -5-4 - ((2-Propylpentanoyl) oxy) styryl) -1,3-phenylene-bis-2-propylpentanoate.

In a pharmaceutical composition according to the present invention, the seizure is characterized by partial seizures with secondary generalization, partial seizures without secondary symptom enlargement, a status epilepticus, and a generalized tonic-clonic event.

The compound of the present invention may be administered orally or parenterally in various dosage forms during clinical administration. In the case of formulation, the diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, .

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients such as starch, calcium carbonate, It is prepared by mixing sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity, and is generally about 0.001 to 100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally 0.07 to 7000 mg / day, preferably 0.7 to 2500 mg / day, based on an adult patient weighing 70 kg, and may be administered once a day, It may be divided into several doses.

Health functional foods and health food compositions for preventing or improving epileptic seizures or seizures

The present invention provides a health functional food or a health food composition for preventing or improving interstitial seizure or seizure comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

,

,

,

,

및 C_1-15의 직쇄 또는 측쇄 알킬 카보닐로 이루어지는 군으로부터 선택되는 치환기이다. R ¹ is

,

,

,

,

And C _1-15 straight or branched alkylcarbonyl.

Preferably, the C _1-15 straight or branched alkylcarbonyl may be lauroyl.

In the health functional food composition or the health food composition according to the present invention, the compound represented by the formula (1) may be any one selected from the following group of compounds.

1) 4-acetamidophenyl-2-propyl pentanoate;

2) 2-acetoxybenzoic acid 2-propylpentanoic anhydride;

3) 2- (4-isobutylphenyl) propanoate 2-propylpentanoic anhydride;

4) Dodecanoic 2-propylpentanoic anhydride;

5) (E) -4- (3-hydroxy-5 - ((2-propylpentanoyl) oxy) styryl) phenyl-2-propyl pentanoate; And

6) (E) -5-4 - ((2-Propylpentanoyl) oxy) styryl) -1,3-phenylene-bis-2-propylpentanoate.

The health functional food composition or the health food composition according to the present invention may be used for preventing or improving interstitial seizure or seizure by administering a compound represented by the general formula (1), a pharmaceutically acceptable salt thereof, or an optical isomer thereof, It may be added to health functional foods such as beverages or health foods.

The epileptic seizures may include partial seizures with secondary generalization, partial seizures without secondary symptom enlargement, primarily generalized seizures, status epilepticus, and systemic tension- a generalized tonic-clonic event, or the like.

There is no particular limitation on the kind of the food. Examples of the food to which the compound according to the present invention can be added include food products such as drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Various soups, beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and includes health foods and health functional foods in a conventional sense.

The health food and health functional food composition containing the compound according to the present invention can be added directly to food or can be used together with other food or food ingredients and can be suitably used according to conventional methods. The mixing amount of the compound according to the present invention can be appropriately determined depending on the purpose of use (for prevention or improvement). Generally, the amount of the compound in the health food and the health functional food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term intake for the purpose of health maintenance or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

The health food and health functional food composition of the present invention is not particularly limited to the other ingredients other than the compound containing the compound according to the present invention as an essential ingredient in the indicated ratios and may contain various flavors or natural carbohydrates, . Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the health functional food composition of the present invention.

In addition to the above, the health food and the health functional food composition containing the compound according to the present invention can be used as a nutritional supplement, a vitamin, a mineral (electrolyte), a flavor such as a synthetic flavor and a natural flavor, ), Pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, the health food and health functional food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

These components may be used independently or in combination. The proportion of such additives is not so important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the effective substance of the present invention.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Valproic Mountain  Preparation of derivatives

< Example  1-4> Valproic Mountain  Preparation of derivatives 1

The methods for synthesizing the valproic acid derivatives of Examples 1 to 4 are as shown in the following Reaction Scheme 1.

Specifically, valproic acid (1.58 mL, 0.01 mol) and compound 2 (Example 1: R ¹ = 4-acetamido) were added to a 250 mL one necked round-bottomed flask thoroughly dried at room temperature using a Deanstark apparatus Phenyl-, 1.51 g, 0.01 mol Example 2: R ¹ = 2-acetoxybenzoyl-, 1.80 g, 0.01 mol Example 3: R ¹ = 2- (4-isobutylphenyl) propanoyl, 2.06 g, 0.01 mol; Example 4: R ¹ = lauroyl-, 2.00 g, 0.01 mol) was refluxed with 20 mL of tetrahydrofuran (THF) as a solvent. After stirring for 24 hours, the water removed by deanstark was confirmed and the degree of reaction and completion were confirmed by TLC. The obtained sticky oil or the solid reaction product was subjected to flash column chromatography to prepare the compounds of Examples 1 to 4 represented by the general formula (1).

[Reaction Scheme 1]

Example 1: 4 - Acetamidophenyl -2- Propyl pentanoate  (4- Acetamidophenyl -2-propylpentanoate)

The properties of the compound of Example 1 (1.664 g, yield 57.1%) as a pale brown solid obtained through the above method are as follows.

Yield: 57.1%;

mp: 229-230 占 폚;

R _f : 0.5 (TLC eluent; EA: n-Hexane = 5: 5 v / v);

MASS (70 eV), rel / intensity%: 277.2 (100), 278.2 (17.3), 279.2 (1.4);

_{^{1 H NMR (CDCl 3, 400MHz}} ): δ 0.89 (t, 6H), 1.56 (dd, 8H), 2.00 (s, 3H), 2.61 (s, 1H), 6.99 (s, 2H), 7.48 (s, 2H), 7.87 (s, 1 H);

¹³ C NMR (CDCl ₃ , 100 MHz):? 175.673 (1C), 168.718 (1C), 146.797 (1C), 135.527 (1C), 121.861 (2C), 120.920 , 22.755 (1C), 20.705 (2C), 14.023 (2C);

Anal. calc. for C ₁₆ H ₂₃ NO ₃ : C 69.23, H 8.36, N 5.05, O 17.30; Found: C 69.24, H 8.35, N 5.06, O 17.31.

Example 2: 2 - Acetoxybenzoic acid  2- Profile Penthouse Anhydride  (2- Acetoxybenzoic  2- propylpentanoic  anhydride)

The properties of the compound of Example 2 (1.38 g, yield 45.1%) obtained in the above procedure are as follows.

Yield: 45.1%;

mp: sticky oil,

R _f : 0.6 (TLC eluent; EA: n-Hexane = 1: 9 v / v);

MASS (70 eV), m / z rel. Intensity%: 306.1 (100), 307.2 (18.4), 308.2 (1.6);

^{1 H NMR (MeOD, 400MHz)} : δ 0.91 (t, 6H), 1.37 (m, 8H), 1.58 (t, 1H), 1.99 (s, 3H), 6.77 (t, 2H), 7.17 (t, 2H );

¹³ C NMR (MeOD, 100 MHz): δ 179.279 (1C), 171.787 (1C), 156.879 (1C), 129.048 (1C), 119.205 (4C), 114.877 20.341 (2C), 13.114 (2C);

Anal. calc. for C ₁₇ H ₂₂ O ₅ : C 66.65, H 7.24, O 26.11; Found: C 66.64, H 7.22, O 26.12.

Example 3: 2 -(4- Isobutylphenyl ) Propanoi  2- Profile Penthouse Anhydride  (2- (4-Isobutylphenyl) propanoic 2-propylpentanoic anhydride)

The properties of the compound of Example 3 (0.89 g, yield 26.8%) of the lemon-colored liquid phase obtained through the above method are as follows.

Yield: 26.8%;

mp: sticky oil,

R _f : 0.5 (TLC eluent; EA: n-Hexane = 1: 9 v / v);

MASS (70 eV), m / z rel. Intensity%): 332.2 (100), 333.2 (22.7), 334.2 (2.5);

^{1 H NMR (MeOD, 400MHz)} : δ 0.96 (t, 9H), 1.38 (dd, 6H), 1.78 (m, 2H), 1.89 (m, 2H), 2.47 (s, 3H), 3.77 (t, 1H ), 7.11 (t, 2 H) 7.13 (t, 2 H);

¹³ C NMR (MeOD, 100 MHz):? 176.254 (1C), 174.466 (1C), 140.168 (1C), 138.032 (1C), 129.045 (2C), 126.946 34.598 (1C), 30.098 (2C), 24.868 (1C), 21.713 (2C), 20.440 (2C), 17.866 (2C), 13.347 (1C);

Anal. calc. for C ₂₁ H ₃₂ O ₃ : C 75.86, H 9.70, O 14.44; Found: C 75.84, H 9.72, O 14.42.

Example  4 : Dodecanoi  2- Profile Penthouse Anhydride  ( Dodecanoic  2-propylpentanoic anhydride)

The characteristics of the compound of Example 4 (0.22 g, yield 6.1%) as a white solid obtained through the above method are as follows.

Yield: 6.1%;

mp: 110-112 &lt; 0 &gt; C,

_Rf : 0.1 (TLC eluent; EA: n-Hexane = 1: 9 v / v);

MASS (70 eV), m / z rel. Intensity%): 326.3 (100), 327.3 (21.6), 328.2 (2.2);

¹ H NMR (MeOD, 400 MHz):? 0.98 (t, 9H), 1.38 (m, 20H), 1.57 (m, 6H), 2.15 (s, 2H), 2.37

¹³ C NMR (MeOD, 100 MHz):? 176.221 (1C), 174.108 (1C), 34.521 (1C), 33.593 (1C), 31.713 (1C), 29.389 (7C), 24.722 20.322 (1C), 13.143 (3C);

Anal. calc. for C ₂₀ H ₃₈ O ₃ : C 73.57, H 11.73, O 14.70; Found: C 73.58, H 11.72, O 14.72.

< Example  5-6> Valproic Mountain  Preparation of derivatives 2

The method of synthesizing the valproic acid derivatives of Examples 5 and 6 is as shown in the following Reaction Scheme 2.

Specifically, resveratrol (resveratrol; 2.28 g, 0.01 mol) was used instead of compound 2, and the same procedure as in Example 1-4 was carried out, except that valproic acid was added at a different concentration (4.75 mL, 0.03 mol) The compounds of Example 5 and Example 6 represented by Formula 1 were prepared.

[Reaction Scheme 2]

Example  5: (E) -4- (3-Hydroxy-5 - ((2- Propylpentanoyl ) Oxy ) Stiryl ) Phenyl-2- The (E) -4- (3-tert-Butyl- Hydroxy -5 - ((2- propylpentanoyl ) oxy) styryl ) phenyl-2-propylpentanoate)

The properties of the yellow oil-like compound of Example 5 (1.25 g, yield 26.14%) obtained through the above method are as follows.

Yield: 26.14%;

mp: sticky oil;

_Rf : 0.7 (TLC eluent; EA: n-Hexane = 9: 1 v / v);

MASS (70 eV), m / z rel. Intensity%): 480.3 (100), 481.3 (32.4), 482.3 (2.7);

_{^{1 H NMR (CDCl 3, 400MHz}} ): δ 0.89 (m, 12H), 1.30 (d, 8H), 1.81 (d, 8H), 2.56 (t, 2H), 7.12 (m, 4H), 7.28 (m, 1H), 7.47 (m, 4H);

¹³ C NMR (CDCl ₃ , 100 MHz):? 174.878 (2C), 150.660 (1C), 129.208 (2C), 125.505 (2C), 121.460 (2C), 100.197 (4C), 94.554 , 34.652 (4C), 20.569 (4C), 13.898 (4C);

Anal. calc. _{for C 30 H 40 O 5:} C 74.97, H 8.39, O 16.64; Found: C 75.00, H 8.35, O 16.63.

Example  6: (E) -5-4 - ((2- Propylpentanoyl ) Oxy ) Stiryl ) -1,3- Phenylene - Bis -2- The ((E) -5- (4 - ((2- Propylpentanoyl ) oxy) styryl ) -1,3- henylene -bis-2-propylpentanoate)

The properties of the transparent oily product of Example 6 (1.48 g, yield 30.83%) obtained through the above method are as follows.

Yield: 30.83%;

mp: sticky oil;

_Rf : 0.3 (TLC eluent; EA: n-Hexane = 1: 9 v / v);

MASS (70 eV), m / z (rel. 606.4 (100), 607.4 (41.1), 608.4 (8.2);

¹ H NMR (CDCl ₃ , 400 MHz):? 0.89 (t, 18H), 1.30 (m, 12H), 1.81 (m, 12H), 2.38 2H), 7.27 (t, 3H);

¹³ C NMR (CDCl ₃ , 100 MHz):? 183.048 (3C), 155.476 (3C), 129.623 (2C), 120.706 (2C), 115.280 (7C), 45.115 (3C), 34.332 , 13.970 (6C);

Anal. calc. for C ₃₈ H ₅₄ O ₆ : C 75.21, H 8.97, O 15.82; Found: C 75.20, H 8.95, O 15.83.

< Experimental Example  1> Nervous origin Protection effect on cell line  evaluation

To evaluate the protective effects of the compounds according to Examples 1 and 6 on nerve-derived cell lines, the following experiment was conducted, and the results are shown in FIGS. 7 to 12.

Specifically, TE-671 cells, a human medulloblastoma cell line, were purchased from the American Type Culture Collection (ATCC) and used. Cells with 10% heat deactivated bovine fetal serum (heat-inactivated fetal bovine serum, HyClone) and 100mg / ml streptomycin and 100U / ml penicillin containing a Dulbecco's Modified Eagle's medium (DMEM ) with 5% CO ₂ with 37 ℃ culture medium containing the Lt; / RTI &gt;

Cytotoxic effects of samples (solvent, compound, drug, glutamate, potassium chloride or hydrogen peroxide) were investigated by 3,4,5-dimethyl thiazole-3, 5-diphenyl tetrazolium bromide (MTT) assay. MTT stock solution (10 mg / ml) was dissolved in PBS, and formazan crystals were removed with a 0.22 mm filter and stored at -20 ° C. 1 × 104 TE-671 cells were seeded on a 96-well culture plate and cultured for 2 days. After reaching confluence, the cells were cultured without serum for 4 hours before treatment with the drug. After 24-48 hours, 10 μl MTT (1 μl / well) was added per well and allowed to react for 4 hours. After the reaction was completed, the supernatant was removed and the formazan crystals were dissolved in MTT solubilization solution (10% Triton-X 100 plus 0.1 N HCl in anhydrous isopropanol). The microplate ELISA reader (El 312e, Bio-Tek) Was measured.

1-1. Solvent toxicity assessment

First, the cell survival rate of the nerve-derived cell lines following the solvent treatment was measured using four kinds of solvents as DMSO, THF, dichloromethane and distilled water (DW).

As a result, as shown in FIG. 7, it was confirmed that the cell survival rate was decreased in a concentration-dependent manner for each solvent.

(DMSO and DW), the compound according to Example 1 (LK1) and the compound according to Example 6 (LK2) and the antitumor topiramate (TM) at concentrations of 0.004 μM, 0.02 μM, 0.1 μM and 0.5 μM, To evaluate cytotoxicity against nerve-derived cell lines.

The survival rate of distilled water (DW) was significantly lowered to 66.3% on average. DMSO solvent was found to be a suitable solvent because it had no effect on cell viability at various concentrations. LK1, LK2 and TM did not significantly affect the survival rate of the cells (Fig. 7).

1-2. Toxicity Evaluation of Compounds

The cytotoxicity of the compound (LK1) according to Example 1 and the compound (LK2) according to Example 6 on the nerve-derived cell line was evaluated and it was found that the compound (LK2) ), The survival rate of the cells was relatively low, indicating that the toxicity was slightly stronger (Fig. 8).

1-3. Glutamate  And potassium chloride toxicity evaluation

Glutamate (GLM) causes excitatory toxicity by neurotransmitters, while potassium chloride (KCl) is known to cause cytotoxicity due to depolarization.

To confirm this, treatment of neurogenic cell lines with glutamate (GLM), 500 μM, 1 mM and 5 mM and potassium chloride (KCl) 5 mM, 7.5 mM and 10 mM resulted in increased toxicity with higher concentrations of glutamate (GLM) and KCl , And the survival rate of the cells was decreased (FIG. 9).

Accordingly, when the above-mentioned substances causing cytotoxicity and the compound of the present invention are treated together to show a high survival rate of the cells, it can be confirmed that the compound has a cytotoxic protective effect.

1-4. With glutamate  Cytoprotective effects of compounds on induced cytotoxicity

(GLM) was treated at a concentration of 2 mM and 10 mM to induce cytotoxicity. Then, 0.004 μM, 0.02 μM, 0.1 μM and 0.5 μM of the compound (LK1) according to Example 1, The cell viability was confirmed by treating the compound (LK2) at 0.0008 μM, 0.004 μM, 0.02 μM and 0.1 μM, and the antagonistic topiramate (TM) at 0.004 μM, 0.02 μM, 0.1 μM and 0.5 μM, respectively.

As a result, LK1 showed higher cell survival rate as LK1 concentration was lower regardless of glutamate concentration, but LK2 showed little effect on the concentration of glutamate in 2 mM treatment group and lower concentration in glutamate 10 mM treatment group (Fig. 10). As shown in Fig. In addition, LK2 showed a greater effect than LK1 at 0.0008 [mu] M, which is lower than LK1 in the glutamate 10 mM treatment group (Fig. 10).

1-5. Cytoprotective effect of compounds on cytotoxicity induced by potassium chloride

(KCl) was treated at a concentration of 7.5 mM and 15 mM to cause depolarization to induce toxicity. Then, 0.004 μM, 0.02 μM, 0.1 μM and 0.5 μM of the compound (LK1) according to Example 1, Cell viability was determined by treating each of 0.0008 μM, 0.004 μM, 0.02 μM and 0.1 μM of the compound (LK2) according to Example 6 and 0.004 μM, 0.02 μM, 0.1 μM and 0.5 μM of the premixed drugs topiramate (TM), respectively.

As a result, regardless of the concentration of KCl, the lower the concentration of both LK1 and LK2, the better the effect of preventing cytotoxicity (FIG. 11). In addition, the compounds LK1 and LK2 according to Examples 1 and 6 showed a toxic protective effect similar to that of topiramate (TM) in the 7.5 mM KCl treated group and more effective than topiratmate (TM) in the 15 mM KCl treated group (Fig. 11).

1-6. Cytoprotective effect of compounds on hydrogen peroxide-induced cytotoxicity

0.1 μM and 0.5 μM of hydrogen peroxide (H ₂ O ₂ ) were added to the nerve-derived cell line to induce oxidative stress toxicity, and then 0.004 μM, 0.02 μM, 0.1 μM and 0.5 μM of the compound (LK1) (LK2) according to the present invention were treated with 0.004 μM, 0.002 μM, 0.004 μM, 0.02 μM and 0.1 μM of the compound (LK2) and 0.004 μM, 0.02 μM, 0.1 μM and 0.5 μM of the premixed topiramate (TM), respectively.

As a result, the LK1 was most indicate a better protection effect than topiramate (TM), regardless of the H ₂ O ₂ concentration, is LK2 cells in H ₂ O ₂ treatment group compared to 0.5μM 0.1μM treatment group H ₂ O ₂ The survival rate was relatively decreased (FIG. 12).

As a result, the compound (LK2) according to Example 6 was superior to the cytotoxic effect caused by glutamate or KCl, and the compound (LK1) according to Example 1 for the cytotoxicity caused by hydrogen peroxide. Was superior to the cytoprotective effect.

< Experimental Example  2> Assessment of seizure inhibition in animal models

Maximal electroshock test (MES test) was conducted to examine the anticonvulsiveness of the compounds according to Examples 1 and 6 in animal models. The results are shown in Table 6.

Specifically, the animal models to be tested were purchased from Sam Taco Co., Ltd., ICR mice weighing about 20 g, and divided into 5 groups of 3 animals each. To prepare a control, three mice were injected with distilled water and subjected to electric shock. To confirm the anticonvulsant effect of the compound (LK1) according to Example 1 and the compound (LK2) according to Example 6, Were injected into the mice at a concentration of 25 mg / kg and 50 mg / kg, respectively, and then the number of mosquitoes caused by electric shock was measured.

Electrical stimulation was performed by dropping 0.9% saline into both eyes and using an ECT Unit (UGO Basline, Way). Electrical stimulation was applied to both eyes using an electrod for 0.2 sec at 50 mA and 60 cycles of intensity. For this test, the presence or absence of hind limb tonic extension was used as a criterion for convulsions.

group sample Mice Body weight MES Experiment Seizure Marisu / Seeds (3) Control group Distilled water (D.W.) One 37.2 O 3/3 2 36.8 O 3 36.0 O Experimental Example 2-1 Example 1
(LK 1)
25 mg / kg One 36.3 O 3/3 2 33.8 O 3 35.6 O EXPERIMENTAL EXAMPLE 2-2 Example 1
(LK 1)
50 mg / kg One 36.7 X 0/3 2 37.2 X 3 34.8 X Experimental Example 2-3 Example 6
(LK 2)
25 mg / kg One 36.6 X 1/3 2 37.2 X 3 34.6 O Experimental Example 2-4 Example 6
(LK 2)
50 mg / kg One 35.6 X 0/3 2 35.0 X 3 35.2 X

As shown in Table 1, seizures occurred in all three rats treated with distilled water, and rats treated with the compound (LK1) according to Example 1 also had seizures in all three rats, Compounds (LK2) did not develop seizures except for the one with the lowest weight. However, in the group injected with the compound (LK1) according to Example 1 and the compound according to Example 6 (LK2) at a concentration of 50 mg / kg, all rats did not develop seizures even when an electric shock was applied, (Table 1).

These results suggest that compounds according to the examples of the present invention have anticonvulsant activity.

&Lt; Formulation Example 1 > Preparation of pharmaceutical preparation

<1-1> Preparation of powder

2 g &lt; RTI ID = 0.0 &gt;

Lactose 1 g

After mixing the above components, the mixture was packed in an airtight container to prepare a powder.

<1-2> Preparation of tablets

100 mg of the compound of formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

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

&Lt; 1-3 > Preparation of capsules

100 mg of the compound of formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<1-4> Preparation of Injection Solution

10 [mu] g / ml of the compound of formula (1)

Until dilute hydrochloric acid BP pH 3.5

Sodium chloride BP injected up to 1 ml

The compound of formula 1 according to the invention is dissolved in a suitable volume of sodium chloride BP and the pH of the resulting solution is adjusted to pH 3.5 with diluted hydrochloric acid BP and the volume is adjusted using injectable sodium chloride BP . The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed in an upper lattice of air by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and an injection solution was prepared.

< Formulation example  2> Manufacture of health functional food and health food

<2-1> Production of Health Functional Food

100 mg of the compound of formula (1)

Vitamin mixture quantity

Vitamin A acetate 70 μg

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

0.15 mg of vitamin B2

Vitamin B6 0.5 mg

Vitamin B12 0.2 μg

Vitamin C 10 mg

Biotin 10 μg

Nicotinic acid amide 1.7 mg

Folic acid 50 μg

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a component suitable for a health functional food as a preferred embodiment, the compounding ratio may be arbitrarily changed, and the above components may be mixed , Granules may be prepared and used in the manufacture of health functional food compositions according to conventional methods.

<2-2> Preparation of Health Functional Drink

100 mg of the compound of formula (1)

Citric acid 100 mg

Oligosaccharide 100 mg

Plum concentrate 2 mg

Taurine 100 mg

Purified water was added to the whole 500 mL

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the solution thus prepared was filtered to obtain a sterilized container. The resulting solution was sealed and sterilized, &Lt; / RTI &gt; Although the composition ratio is a mixture of the components suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preferences such as the demand level, the demanding country, and the intended use.

<2-3> Manufacture of dairy products

0.01-1 parts by weight of the valproic acid derivative compound of the formula (1) of the present invention was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.

<2-4> Solar  Produce

Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh. Black soybeans, black sesame seeds, and perilla seeds were steamed and dried by a conventional method, and then they were prepared into powder having a particle size of 60 mesh by a pulverizer. The dry powders of the grains and seeds prepared above were mixed with the valproic acid derivative of the formula (1) in the following proportions.

Grain (34 parts by weight of brown rice, 19 parts by weight of yulmu, 20 parts by weight of barley)

Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds)

The compound of the formula (1) (2 parts by weight)

(1.5 parts by weight), and

Rhizome (1.5 parts by weight).

Claims (11)

1. A compound represented by the following formula (1): &lt; EMI ID =
[Chemical Formula 1]

(In the formula 1,
R ¹ is

,

,

,

And a straight chain or branched alkylcarbonyl of C _1-15 ;
Provided that R &lt; ¹ &gt;

Is not).
The method according to claim 1,
Or a pharmaceutically acceptable salt thereof, wherein the C _1-15 straight or branched alkylcarbonyl is lauroyl.
The method according to claim 1,
Wherein the compound represented by the formula (1) is any one selected from the group consisting of the following compounds: or a pharmaceutically acceptable salt thereof:
2) 2-acetoxybenzoic acid 2-propylpentanoic anhydride;
3) 2- (4-isobutylphenyl) propanoate 2-propylpentanoic anhydride;
4) Dodecanoic 2-propylpentanoic anhydride;
5) (E) -4- (3-hydroxy-5 - ((2-propylpentanoyl) oxy) styryl) phenyl-2-propyl pentanoate; And
6) (E) -5-4 - ((2-Propylpentanoyl) oxy) styryl) -1,3-phenylene-bis-2-propylpentanoate.
As shown in Scheme 1 below,
Dissolving valproic acid and Compound 2 in an organic solvent, refluxing and stirring to obtain Compound 1 (Step 1);
(1), wherein R &lt; 1 &gt; and R &lt; 2 &gt;
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
Wherein R &lt; ^{1 &}

,

And a straight chain or branched alkylcarbonyl of C _1-15 .
As shown in Scheme 2 below,
Dissolving valproic acid and resveratrol in an organic solvent, refluxing and stirring to obtain compound 1 (step 1);
(1), wherein R &lt; 1 &gt; and R &lt; 2 &gt;
[Reaction Scheme 2]

(In the above Reaction Scheme 2,
Wherein R &lt; ^{1 &}

or

to be).
The method according to claim 4 or 5,
The organic solvent of step 1 may be selected from the group consisting of ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, CH ₂ Cl ₂ , hexane, dimethylformamide (DMF), diisopropyl ether, Wherein the solvent is at least one selected from the group consisting of oxalic acid, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetone and chlorobenzene.
A pharmaceutical composition for preventing or treating epileptic seizures or convulsions comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ is

,

,

,

,

And a straight chain or branched alkylcarbonyl of C _1-15 .
8. The method of claim 7,
The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (1) is any one selected from the group consisting of the following compounds:
1) 4-acetamidophenyl-2-propyl pentanoate;
2) 2-acetoxybenzoic acid 2-propylpentanoic anhydride;
3) 2- (4-isobutylphenyl) propanoate 2-propylpentanoic anhydride;
4) Dodecanoic 2-propylpentanoic anhydride;
5) (E) -4- (3-hydroxy-5 - ((2-propylpentanoyl) oxy) styryl) phenyl-2-propyl pentanoate; And
6) (E) -5-4 - ((2-Propylpentanoyl) oxy) styryl) -1,3-phenylene-bis-2-propylpentanoate.
8. The method of claim 7,
The epileptic seizure may include partial seizures with secondary generalization, partial seizures without secondary symptom enlargement, primarily generalized seizures, status epilepticus, and systemic tension- a generalized tonic-clonic event, and the like.
A health functional food composition for preventing or improving interstitial seizures or seizures comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ is

,

,

,

,

And a straight or branched alkylcarbonyl of C _1-15 .
A health food composition for preventing or ameliorating an epileptic seizure or seizure comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ is

,

,

,

,

And a straight or branched alkylcarbonyl of C _1-15 .

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