KR102144628B1 - Composition for preventing, improving or treating of bladder cancer comprising lauric acid derivatives - Google Patents

Abstract

The present invention relates to a lauric acid derivative, a method for preparing the same, and a composition for preventing, improving or treating bladder cancer comprising the same, wherein the compound represented by Formula 1 according to the present invention has excellent anti-bladder cancer activity, and thus prevents, improves and improves bladder cancer. May be useful for therapeutic use.

Description

Composition for preventing, improving or treating bladder cancer comprising lauric acid derivatives}

The present invention relates to a composition for preventing, improving or treating bladder cancer comprising a lauric acid derivative.

Cancer cells differ from normal cells in several ways. Normal cells proliferate according to their needs and where they are needed. Normal cells are attached to each other and appear to be together. In addition, normal cells destroy themselves if they are too old or damaged. However, cancer cells lack all of these functions and ultimately continue to divide, forming a tumor, a mass of cancer cells.

Bladder cancer is a malignant tumor of the bladder. Most of bladder cancers are epithelial cell tumors derived from epithelial cells, and malignant epithelial tumors include urinary tract cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Bladder cancer is divided into non-muscularly invasive (superficial) bladder cancer, which is limited to the bladder mucosa or the lower mucosa, according to the progression stage, and metastatic bladder cancer, in which the bladder cancer invades the muscle layer. Recently, TiCentrick has been used as a treatment for metastatic bladder cancer.

The side effects of injection of drugs into the bladder vary depending on the drug used, but chemotherapy drugs can cause systemic side effects and symptoms of bladder irritation due to absorption from the bladder mucosa. Overall, existing anti-bladder cancer drugs are accompanied by loss of appetite, nausea, vomiting, diarrhea, general weakness, and hair loss, and are very cytotoxic and can destroy healthy cells. Accordingly, there is a need to develop anti-bladder cancer drugs that can minimize the side effects of existing anti-bladder cancer drugs and exhibit excellent anti-bladder cancer activity in trace amounts.

The present inventors devised a lauric acid derivative compound and synthesized a total of five types of lauric acid derivatives, and confirmed that the lauric acid derivative compound showed excellent bladder cancer cell line killing effect and completed the present invention.

Korean Patent Registration No. 10-1797813

It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of bladder cancer comprising a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a health functional food and health food composition for preventing or improving bladder cancer, including the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the compound represented by Formula 1.

To achieve the above object,

The present invention provides a pharmaceutical composition for preventing or treating bladder cancer comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

,

,

,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

,

,

And

It is a substituent selected from the group consisting of.

In addition, the present invention provides a health functional food composition for preventing or improving bladder cancer comprising the compound represented by Chemical Formula 1 or a food pharmaceutically acceptable salt thereof.

In addition, the present invention provides a health food composition for preventing or improving bladder cancer comprising the compound represented by Chemical Formula 1 or a food pharmaceutically acceptable salt thereof.

Further, the present invention, as shown in the following scheme 1,

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

It provides a method for preparing the compound represented by Formula 1 including.

[Scheme 1]

In Scheme 1 above,

또는

이다.R ¹ is

or

to be.

Furthermore, the present invention is as shown in the following scheme 2,

Dissolving lauric acid and compound 2 in an organic solvent, refluxing, and stirring to obtain compound 1 (step 1);

It provides a method for preparing the compound represented by Formula 1 including.

[Scheme 2]

In Scheme 2 above,

,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

And

It is a substituent selected from the group consisting of.

Since the compound represented by Formula 1 according to the present invention has excellent anti-bladder cancer activity, it may be useful for preventing, improving and treating bladder cancer.

1 is an image obtained by observing a change in cell morphology of a bladder cancer cell line according to the compound treatment concentration of Example 1 under a microscope.
2 is a graph (a) showing the survival rate (%) of cells through the MTT assay of the bladder cancer cell line according to the compound treatment concentration of Example 1 (example 1) and a graph (b) showing the IC ₅₀ value.
3 is a result of confirming apoptosis through Annexin V staining of the bladder cancer cell line according to the compound treatment concentration of Example 1 (Live: cell survival, Early Apoptosis: early death, Late Apop./Dead: late death and cell death, Dead: cell death).
4 is a graph showing the degree of death (% Gated) of the bladder cancer cell line according to the compound treatment concentration of Example 1 (Live: cell survival, Early Apoptosis: early death, Late Apop./Dead: late death and cell death, Dead: cell death).

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition for preventing or treating bladder cancer

The present invention provides a pharmaceutical composition for preventing or treating bladder cancer comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof.

In Formula 1,

,

,

,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

,

,

And

It is a substituent selected from the group consisting of.

In the pharmaceutical composition of the present invention, preferred examples of the compound represented by Formula 1 according to the present invention include the following compound groups.

1) (E)-5-(4-hydroxystyryl)-1,3-phenylene didodecanoate;

2) (E)-5-(4-(dodecanoyloxy)styryl)-1,3-phenylene didodecanoate;

3) 4-acetamidophenyldodecanoate;

4) 2-acetoxybenzoic dodecanoic anhydride; And

5) Dodecanoic 2-(4-isobutylphenyl)propanoic anhydride.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The expression of a pharmaceutically acceptable salt is a concentration that is relatively non-toxic and harmless to the patient, and side effects caused by this salt do not degrade the beneficial efficacy of the basic compound of formula (1). It means inorganic addition salt. As these salts, inorganic acids and organic acids can be used as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, fumarin Acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesol Ponic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, malonic acid, and the like can be used. In addition, these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.), and the like. For example, as an acid addition salt, acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hybenzate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, Isethionate, Lactate, Malate, Mali Eate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccha Rate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, and zinc salts may be included.

The acid addition salt according to the present invention is a precipitate produced by dissolving the compound represented by Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid in a conventional method, for example, May be prepared by filtration and drying, or may be prepared by distilling a solvent and an excess of acid under reduced pressure and then drying or crystallizing in an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal 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 evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. Further, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Furthermore, the present invention includes not only the compound of Formula 1 and a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, isomers, optical isomers, and the like that may be prepared therefrom.

The compounds of the present invention can be administered in various oral and parenteral dosage forms at the time of clinical administration, and when formulated, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used. Is manufactured.

Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and these solid preparations include at least one excipient, such as starch, calcium carbonate, and water, in one or more compounds of the present invention. It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, or syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives are included. I can.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyloleate may be used as the non-aqueous solvent and the suspension. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease degree, and is generally about 0.001 to 100 mg/kg/day, preferably It is 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and from once a day at regular time intervals according to the judgment of a doctor or pharmacist. It can also be administered in several divided doses.

Health functional food and health food composition for preventing or improving bladder cancer

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

[Formula 1]

In Formula 1,

,

,

,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

,

,

And

It is a substituent selected from the group consisting of.

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

1) (E)-5-(4-hydroxystyryl)-1,3-phenylene didodecanoate;

2) (E)-5-(4-(dodecanoyloxy)styryl)-1,3-phenylene didodecanoate;

3) 4-acetamidophenyldodecanoate;

4) 2-acetoxybenzoic dodecanoic anhydride; And

5) Dodecanoic 2-(4-isobutylphenyl)propanoic anhydride.

The health functional food composition or health food composition according to the present invention is a compound represented by Chemical Formula 1, a food pharmaceutically acceptable salt thereof, or an optical isomer thereof for the purpose of preventing or improving bladder cancer. It can be added to functional foods or health foods.

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

The health food and health functional food composition containing the compound according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the compound according to the present invention may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in health foods and health functional foods may be added in an amount of 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of maintaining health or controlling health, the amount may be less than the above range, and there is no problem in terms of safety, so the active ingredient may be used in an amount above the above range.

The health food and health functional food composition of the present invention is not particularly limited to other ingredients except for containing the compound according to the present invention as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates, etc. It can contain as. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. 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 health functional food composition containing the compound according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.) ), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health food and health functional food composition of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverage and vegetable beverage.

These components may be used independently or in combination. Although the proportion of these additives is not so important, it is generally selected from 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.

Manufacturing method 1 and 2

The present invention is shown in the following scheme 1,

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

It provides a method for preparing the compound represented by Formula 1 including.

[Scheme 1]

In Scheme 1 above,

또는

이다.R ¹ is

or

to be.

Preferably, preferred examples of the compound represented by Formula 1 prepared from Scheme 1 include the following compound groups.

1) (E)-5-(4-hydroxystyryl)-1,3-phenylene didodecanoate; And

2) (E)-5-(4-(dodecanoyloxy)styryl)-1,3-phenylene didodecanoate.

In addition, the present invention, as shown in the following scheme 2,

Dissolving lauric acid and compound 2 in an organic solvent, refluxing, and stirring to obtain compound 1 (step 1);

It provides a method for preparing the compound represented by Formula 1 including.

[Scheme 2]

In Scheme 2 above,

,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

,

And

It is a substituent selected from the group consisting of.

Preferably, preferred examples of the compound represented by Formula 1 prepared from Scheme 2 include the following compound groups.

3) 4-acetamidophenyldodecanoate;

4) 2-acetoxybenzoic dodecanoic anhydride; And

5) Dodecanoic 2-(4-isobutylphenyl)propanoic anhydride.

In the production 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), dimethyl sulfoxide (DMSO), acetone, chlorobenzene, etc. may be used alone or in combination. Preferably, tetrahydrofuran (THF) may be used as the organic solvent in Step 1 of Scheme 1 and Scheme 2.

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Lauric acid Preparation of derivatives

< Example 1-2> Preparation of lauric acid derivative 1

The method for synthesizing the lauric acid derivatives of Examples 1 and 2 is as shown in Scheme 1 below.

Specifically, lauric acid (6.06 g, 0.03 mol) and resveratrol (resveratrol; 2.28 g, 0.01 mol) were added to tetrahydrofuran in a 250 mL one necked round-bottomed flask sufficiently dried at room temperature using a Deanstark instrument. It was refluxed using 20 mL of tetrahydrofuran; THF) as a solvent. After stirring for 24 hours, the water removed by deanstark was checked, and the degree and completion of the reaction were confirmed by TLC. The obtained solid reactant was subjected to flash column chromatography to prepare the compounds of Examples 1 and 2 represented by Chemical Formula 1.

[Scheme 1]

Example 1: (E)-5-(4- Hydroxystyryl )-1,3- Phenylene Daidodecanoate ((E)-5-(4-Hydroxystyryl)-1,3-phenylene didodecanoate)

The properties of the compound of Example 1 as a brown solid obtained through the above method (1.60 g, yield 27.0%) are as follows.

Yield: 27.0%;

mp: 513 to 514°C;

R _f : 0.4 (TLC eluent; EA:n-Hexane = 3:7 v/v);

MASS (70eV), m/z (rel. intensity %); 592.4(100), 593.4(41.2), 591.4(8.2);

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.87 (s, 6H), 1.25 (m, 32H), 1.61 (d, 4H), 2.55 (d, 4H), 6.17 (t, 4H), 6.87 (s, 1H) 6.91 (t, 4H);

¹³ C NMR (CDCl ₃ , 100 MHz): δ 178.997 (1C), 173.920 (1C), 156.390 (1C), 148.537 (2C), 138.889 (2C), 133.671 (2C), 129.835 (2C), 121.185 (1C) , 115.238 (4C), 33.963 (1C) 31.914 (1C), 29.607 (12C), 24.725 (1C), 22.695 (1C), 14.133 (2C);

Anal. calc. for C ₃₈ H ₅₆ O ₅ : C 76.99, H 9.52, O 13.49; Found: C 77.02, H 9.52, O 13.48.

Example 2: (E)-5-(4-( Dodecanoyloxy ) Styryl )-1,3- Phenylene Daidodekanoei T ((E)-5-(4-(Dodecanoyloxy)styryl)-1,3-phenylene didodecanoate )

The properties of the compound of Example 2 (3.02g, yield 50.7%) as a light brown liquid obtained through the above method are as follows.

Yield: 50.7%;

mp: sticky oil,

R _f : 0.3 (TLC eluent; EA:n-Hexane = 3:7 v/v);

MASS (70eV), m/z (rel. intensity %); 774.6(100) 775.6(54.1) 776.6(14.3);

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.79 (t, 9H), 1.17 (s, 48H), 1.61 (m, 6H), 2.40 (m, 6H), 6.17 (s, 3H), 6.67 (s, 2H), 6.91 (s, 4H);

¹³ C NMR (CDCl ₃ , 100 MHz): δ 180.363 (3C), 156.451 (1C), 156.400 (1C), 153.653 (1C), 133.457 (2C), 129.432 (2C), 115.295 (7C), 34.150 (1C) , 31.942 (1C), 29.637 (24C) 24.725 (1C), 22.718 (1C), 14.132 (3C);

Anal. calc. for C ₅₀ H ₇₈ O ₆ : C 77.47, H 10.14, O 12.38, Found: C 77.44, H 10.12, O 12.37.

< Example 3-5> Preparation of lauric acid derivative 2

The method of synthesizing the lauric acid derivatives of Examples 3 to 5 is as shown in Scheme 2 below.

Specifically, it was prepared by carrying out substantially the same method as in Example 1-2, but the lauric acid was added at a different concentration (2.00 g, 0.01 mol), and compound 2 instead of resveratrol (Example 3: R ¹ =4 -Acetamidophenyl-, 1.51 g, 0.01 mol; Example 4: R ¹ =2-acetoxybenzoyl-, 1.80 g, 0.01 mol; Example 5: R ¹ =2-(4-isobutylphenyl) pro Panoyl-, 2.06g, 0.01mol) was used to prepare the compounds of Examples 3, 4 and 5 represented by Chemical Formula 1.

[Scheme 2]

Example 3: 4 - Acetamidophenyldodecanoate (4-Acetamidophenyldodecanoate)

The properties of the compound of Example 3 (0.35g, yield 10.5%) as a white solid obtained through the above method are as follows.

Yield: 10.5%;

mp: 289 to 290°C;

R _f : 0.3 (TLC eluent; EA:n-Hexane = 3:7 v/v);

MASS (70eV), m/z (rel. intensity %); 332.2(100), 334.2(21.6), 335.2(2.2);

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.81 (s, 3H), 1.12 (m, 24H), 1.69 (d, 2H), 2.05 (s, 3H), 2.47 (d, 2H), 6.92 (s, 2H), 7.38 (s, 2H), 7.59 (s, 1H);

¹³ C NMR (CDCl ₃ , 100 MHz): δ 172.770 (1C), 168.559 (1C), 146.797 (1C), 135.441 (1C), 121.899 (2C), 120.824 (2C), 34.350 (1C), 31.895 (1C) , 29.590 (6C), 24.913 (1C) 24.311 (1C), 22.677 (1C), 14.119 (1C);

Anal. calc. for C ₂₀ H ₃₁ NO ₃ : C 72.04, H 9.37, N 4.20, O 14.39; Found: C 72.02, H 9.35, N 4.21, O 14.38.

Example 4: 2 - Acetoxybenzoic Dodecanoic Anhydride (2- Acetoxybenzoic dodecanoic anhydride)

The properties of the compound of Example 4 (2.31g, yield 47.0%) as a white solid obtained through the above method are as follows.

Yield: 47.0%;

mp: 218 to 219°C;

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

MASS (70eV), m/z (rel. intensity %); 362.2(100), 363.2(22.7), 364.2(2.5);

¹ H NMR (CDCl ₃ , 400MHz): δ 0.92 (t, 3H), 1.26 (m, 16H), 1.57 (t, 2H), 2.15 (s, 3H), 2.57 (t, 2H), 7.31 (d, 2H), 7.84 (d, 2H);

¹³ C NMR (CDCl ₃ , 100 MHz): δ 175.521 (2C), 151.101 (1C), 150.897 (1C), 134.732 (1C), 132.553 (1C), 126.004 (1C), 124.136 (1C), 123.809 (1C) , 31.920 (1C), 34.141 (1C), 29.655 (14C), 24.491 (1C), 22.698 (1C), 14.139 (1C);

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: Dodecanoic 2-(4- Isobutylphenyl ) Propanoic Anhydride (Dodecanoic 2-(4- isobutylphenyl ) propanoic anhydride)

The properties of the compound of Example 3 (1.16g, yield 29.9%) as a brown solid obtained through the above method are as follows.

Yield: 29.9%;

mp: 218 to 219°C;

R _f : 0.8 (TLC eluent; EA:n-Hexane = 3:7 v/v);

MASS (70eV), m/z (rel. intensity %); 388.3(100), 389.3(27.0), 390.3(2.7);

¹ H NMR (MeOD, 400MHz): δ 0.87 (t, 9H), 1.28 (s, 16H), 1.59 (dd, 6H), 2.26 (m, 2H), 2.42 (t, 2H), 4.08 (d, 1H) ), 7.08 (d, 2H), 7.16 (d, 2H);

¹³ C NMR (MeOD, 100 MHz): δ 175.145 (1C), 173.952 (1C), 137.977 (1C), 128.980 (1C), 126.815 (4C), 44.663 (1C), 33.695 (1C), 31.716 (1C), 29.393 (1C), 25.845 (1C), 24.728 (1C), 21.415 (3C), 17.423 (1C), 13.164 (1C);

Anal. calc. for C ₂₅ H ₄₀ O ₃ : C 77.27, H 10.38, O 12.35; Found: C 77.28, H 10.37, O 12.35.

< Experimental example 1> Evaluation of apoptosis effect on bladder cancer cell lines

In order to evaluate the anti-bladder cancer effect of the lauric acid derivative compound according to Example 1, cell morphology change analysis and apoptosis effect analysis were performed on the bladder cancer cell line (5637) as follows. Bladder cancer cell line (5637) was RPMI1640 medium (Capricorn Scientific GmbH) to which 10% bovine serum (FBS, Capricorn Scientific GmbH, Ebsdorfergrund, Germany) and penicillin/streptomycin (100 U/ml, 100 μg/ml, Capricorn Scientific GmbH, respectively) were added. ) Was used in the following experimental examples by culturing in a humidified incubator under conditions of 37°C and 5% CO _{2 in} which 95% humidity is maintained.

1-1. Analysis of cell morphology change

The bladder cancer cell line (5637) was cultured in a 24 compartment culture dish at a density of 4×10 ⁴ for 24 hours, and then the lauric acid derivative compound according to Example 1 was respectively at a concentration of 0, 1, 1.5, 2, 2.5 and 3 mM. After treatment and further culture for 24 hours, the morphology of the cells was observed under a microscope, and the results are shown in FIG. 1.

As a result, it was confirmed that the morphology of the cells changed as compared with the untreated group (0 mM) as the compound treatment concentration increased, and the number of cells decreased.

1-2. MTT Cell activity analysis through assay

The bladder cancer cell line (5637) was cultured in a 96-cell culture dish at a density of 1 Х10 ⁴ for 24 hours, and then the lauric acid derivative compound according to Example 1 was treated at a concentration of 0, 1, 2, 3, 4 and 5 mM, respectively, and , Incubated for an additional 24 hours. Then, MTT (final 0.5 mg/mL) solution dissolved in PBS buffer was dispensed to each cell and cultured for 4 hours to induce formazan formation. After the reaction, the supernatant (medium) was removed so that the formazan (purple precipitate) formed on the bottom of the well was not scattered, and dimethylsulfoxide was dispensed and shaken for 10 minutes, and the absorbance was measured at 550 nm wavelength using an ELISA reader. . Cell viability (%) was calculated according to Equation 1 below.

[Equation 1]

Cell viability (%) = {1-(absorbance of compound treated group/absorbance of untreated group)}×100

As a result, as shown in FIG. 2, bladder cancer cells were killed by the treatment of the compound of Example 1, and the survival rate (cell activity) of the bladder cancer cells was decreased in a concentration-dependent manner. It was confirmed that the number of viable cells decreased very dramatically. In addition, IC ₅₀ (halfmaximalinhibitoryconcentration) was calculated to be 2.267 mM.

Accordingly, it was found that the lauric acid derivative compound according to Example 1 of the present invention has an anti-bladder cancer effect that specifically acts on bladder cancer cells and kills the cells.

1-3. Annexin Cell death assay via V

The bladder cancer cell line (5637) was cultured in a 6-cell culture dish at a density of 2 to 10 ⁵ for 24 hours, and then the lauric acid derivative compound according to Example 1 was treated at concentrations of 0, 1, 2, 3, 4 and 5 mM, respectively. And cultured for an additional 24 hours. Then, phosphadidylserine moved to the outside of the cell membrane using Muse ^TM Annexin V & Dead cell kit (Millipore, Billerica, MA, USA) to confirm the degree of death of bladder cancer cell lines according to the compound treatment of Example 1 Was measured by Annexin-V staining, and the results are shown in FIGS. 3 and 4 (Live: cell survival, Early Apoptosis: early death, Late Apop./Dead: late death and cell death, Dead: cell death).

As a result, it was confirmed that the apoptosis of the bladder cancer cell line was increased in a concentration-dependent manner by the treatment of the lauric acid derivative compound of Example 1.

Therefore, it was found that the lauric acid derivative compound according to Example 1 of the present invention has an anti-bladder cancer effect of killing cells by acting on bladder cancer cells.

The above results suggest that the compound according to the embodiment of the present invention has anti-bladder cancer activity.

<Formulation Example 1> Preparation of pharmaceutical formulation

<1-1> Preparation of powder

2 g of compound of formula 1

1 g lactose

After mixing the above ingredients, the powder was prepared by filling the airtight cloth.

<1-2> Preparation of tablets

100 mg of the compound of formula 1

Corn starch 100 mg

100 mg lactose

Magnesium stearate 2 mg

After mixing the above ingredients, tablets were prepared by tableting according to a conventional tablet preparation method.

<1-3> Preparation of capsules

100 mg of the compound of formula 1

Corn starch 100 mg

100 mg lactose

Magnesium stearate 2 mg

After mixing the above ingredients, a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule formulation.

<1-4> Preparation of injection solution

10 ㎍ / ㎖ compound of formula 1

Dilute hydrochloric acid BP until pH 3.5

Sodium chloride BP for injection up to 1 ml

Dissolve the compound of formula 1 according to the present invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with diluted hydrochloric acid BP, adjust the volume with sodium chloride BP for injection, and sufficiently Mixed. The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120° C. for 15 minutes or longer to prepare an injection solution.

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

<2-1> Manufacture of health functional food

100 mg of the compound of formula 1

Vitamin mixture right amount

Vitamin A acetate 70 μg

1.0 mg of vitamin E

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

0.5 mg of vitamin B6

Vitamin B12 0.2 μg

10 mg of vitamin C

Biotin 10 μg

1.7 mg of nicotinic acid amide

50 μg folic acid

0.5 mg of calcium pantothenate

Suitable amount of inorganic mixture

1.75 mg ferrous sulfate

Zinc oxide 0.82 mg

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Dicalcium phosphate 55 mg

90 mg of potassium citrate

100 mg of calcium carbonate

Magnesium chloride 24.8 mg

The composition ratio of the vitamin and mineral mixture is a mixture of ingredients suitable for a health functional food in a preferred embodiment, but the mixing ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health functional food manufacturing method. Then, the granules are prepared, and can be used to prepare a health functional food composition according to a conventional method.

<2-2> Production of health functional beverages

100 mg of the compound of formula 1

100 mg citric acid

100 mg oligosaccharide

Plum Concentrate 2 mg

100 mg taurine

Total 500 mL with purified water

After mixing the above ingredients according to a normal health drink manufacturing method, stirring and heating at 85°C for about 1 hour, the resulting solution is filtered and obtained in one sterilized container, sealed and sterilized, and then stored in a refrigerator. It is used in the manufacture of health drink composition. The composition ratio is composed of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the blending ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the intended use.

<2-3> Manufacture of dairy products

0.01-1 parts by weight of the lauric acid derivative compound of 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> Linear Produce

Brown rice, barley, glutinous rice, and adlay were gelatinized and dried by a known method, and then roasted and prepared into a powder having a particle size of 60 mesh with a grinder. Black soybeans, black sesame seeds, and perilla seeds were also steamed and dried by a known method, and then roasted, and then prepared into a powder having a particle size of 60 mesh with a grinder. It was prepared by mixing the dry powder of the grains and seeds prepared above and the lauric acid derivative compound of Formula 1 of the present invention in the following ratio.

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

Seeds (perilla 7 parts by weight, black soybean 8 parts by weight, black sesame 7 parts by weight),

A compound of formula 1 (2 parts by weight),

Ganoderma lucidum (1.5 parts by weight), and

Rehmannia (1.5 parts by weight).

Claims (7)

A pharmaceutical composition for preventing or treating bladder cancer comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula 1,
R ¹ is

,

,

,

And

It is a substituent selected from the group consisting of).
The method of claim 1,
The compound represented by Formula 1 is a pharmaceutical composition for preventing or treating bladder cancer, characterized in that it is any one selected from the following compound group:
1) (E)-5-(4-hydroxystyryl)-1,3-phenylene didodecanoate;
2) (E)-5-(4-(dodecanoyloxy)styryl)-1,3-phenylene didodecanoate;
3) 4-acetamidophenyldodecanoate;
4) 2-acetoxybenzoic dodecanoic anhydride; And
5) Dodecanoic 2-(4-isobutylphenyl)propanoic anhydride.
A health functional food composition for preventing or improving bladder cancer comprising a compound represented by the following Formula 1 or a food pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula 1,
R ¹ is

,

,

,

And

It is a substituent selected from the group consisting of).
A health food composition for preventing or improving bladder cancer comprising a compound represented by the following Formula 1 or a food pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula 1,
R ¹ is

,

,

,

And

It is a substituent selected from the group consisting of).
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