KR102037937B1 - Composition for protecting kidney containing chalcone derivatives - Google Patents

Abstract

The present specification relates to a composition for protecting kidneys or a composition for improving kidney disease, including a chalcone derivative, and when the compound according to the present specification is used to protect the kidneys from nephrotoxicity due to drugs, etc., effectively improving kidney disease related to drugs. Since the present invention can be used, the present specification can be used to make a great contribution in the field of patient care and welfare.

Description

Composition for kidney protection containing chalcone derivatives {COMPOSITION FOR PROTECTING KIDNEY CONTAINING CHALCONE DERIVATIVES}

The present specification relates to a composition for protecting kidneys or a composition for improving kidney disease, including a chalcone derivative.

Kidney is an important excretory organ responsible for urine excretion in the human body. Various medicines and environmental pollutants show toxicity to the kidney, and representative drugs that cause kidney toxicity include nonsteroidal antipyretic analgesic anti-inflammatory drugs such as phenacetin, aspirin and indomethacin; Anticancer agents such as puromycin, daunomycin, cyclophosphamide, penicillamine, adriamycin, cisplatin, immunosuppressants, amikacin, gentamycin, kanamycin, neomycin, sisomycin, streptomycin, tobramycin Aminoglycoside antibiotics such as these; Cephalosporin antibiotics; Carbapenem antibiotics such as imipenem and melopenem; Heavy metals such as cadmium, lead, mercury, and chromium; And inorganic and organic heavy metal compounds, compounds such as chloroform, D-serine, sulfonamide, 2-bromoethylene, hydrobromide and mold toxins such as okaratoxin and citrinin. Renal diseases caused by nephrotoxicity to these drugs include nephritis, pyelonephritis, nephrotic syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, kidney tuberculosis, urinary tract infections, urinary tract stones, ureter stones, acute kidney failure, chronic kidney failure, Diabetic Nephropathy, Chronic Glomerulonephritis, Acute Progressive Nephritis, Neproje Syndrome, Microglomerulosclerosis, Membrane Nephritis, or Membrane Proliferative Glomerulonephritis and the like, but are not limited thereto.

Therefore, research has been conducted for the prevention or treatment of the disease, but to date, commercialization of a renal protective material that can effectively prevent or treat renal toxicity caused by a renal toxicity-inducing substance is insufficient compared to the demand.

Republic of Korea Patent Publication No. 10-2014-0037633 (2014.03.27)

The present specification is to provide a substance for renal protection and renal disease improvement that is insufficient compared to the demand, to prevent drug side effects and to achieve the treatment objectives of the relevant patients early.

In order to solve the above problems, the present disclosure provides a chalcone derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof having a structure of Formula 16 below.

[Formula 16]

In one embodiment, wherein R ₁ is H, OH or OC _n H _{2n +1} (n is one integer selected from 1 to 5) and R ₂ is H, OH or C _n H _{2n +1} (n is one integer selected from 1 to 5), R ₃ is H, OC _n H _{2n +1} (n is one integer selected from 1 to 5) or a halogen group, R ₄ is H, OH Or C _n H _{2n +1} (n is one integer selected from 1 to 5), R ₅ is H, OH or C _n H _{2n +1} (n is one integer selected from 1 to 5), R ₆ is H or a halogen group, R ₇ is H, a methyl group or an ethyl group, R ₈ is H, OC _n H _{2n +1} (n is one integer selected from 1 to 5) or a halogen group, R ₉ may be H, OH or C _n H _{2n +1} (n is one integer selected from 1 to 5).

In addition, the present specification provides a composition for kidney protection, or a composition for preventing, treating and improving kidney disease, including the chalcone derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient.

When the compound according to the present specification is used, the kidney can be protected from nephrotoxicity, and thus effective improvement of the kidney disease associated with the drug can be utilized. Therefore, the present specification can be used to make a great contribution in the field of patient treatment and welfare. There will be.

1A to 1O are graphs showing nephroprotective efficacy of chalcone derivatives 1 to 15 according to one aspect of the present invention.
Figure 2 is an image analysis of the neoprotective efficacy of the chalcone derivative 3 (Compound 3) according to an aspect of the present invention.

As used herein, the term "platinum-based anticancer agent" refers to an anticancer agent containing a platinum Pt atom and includes a platinum derivative series and a platinum group. Platinum anticancer agents include cisplatin, oxaliplatin, and carboplatin.

"Alkyl" as used herein means a monovalent saturated aliphatic hydrocarbon chain. The hydrocarbon chain may be straight or branched chain. In one aspect of the invention an "alkyl" may have from 1 to 6 carbon atoms ("C ₁ to C ₅ alkyl") and in another aspect from 1 to 5 carbon atoms ("C ₁ to C ₅ alkyl" ), And may have 1 to 4 carbon atoms (“C ₁ to C ₄ alkyl”), and in another aspect may have 1 to 3 carbon atoms (“C ₁ to C ₃ alkyl”). Specifically "alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl or t-amyl.

As used herein, “isomers” in particular are not only optical isomers (eg, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof), but also form isomers ( conformation isomers (ie, isomers that differ only by their angles of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (eg, cis-trans isomers) do.

As used herein, "essentially pure" means at least about 90%, preferably at least about 95%, of a specific compound, for example enantiomers or diastereomers, when used in connection with an enantiomer or diastereomer. More preferably at least about 97% or at least about 98%, even more preferably at least about 99%, even more preferably at least about 99.5% (w / w).

As used herein, "pharmaceutically acceptable" means the approval of a government or equivalent regulatory body to use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional medicinal dosages. It can be received or approved, or listed in a pharmacopoeia or recognized as another general pharmacopeia.

As used herein, a "pharmaceutically acceptable salt" is a concentration that has a relatively nontoxic and harmless effective action in a patient, and the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by Formula 1, and are pharmaceutically acceptable. By any and all organic or inorganic addition salts of the compounds that are possible and have the desired pharmacological activity of the parent compound.

The salt is formed from (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic protons present in the parent compound are substituted.

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

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid may be used as the organic acid. (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, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, etc. It is not limited to these.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium, or calcium salt, but is not limited thereto. Corresponding silver salts can also be obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

As used herein, "hydrate" refers to a compound to which water is bound, and is a broad concept including an inclusion compound having no chemical bonding force between water and the compound.

As used herein, the term "solvate" means a higher order compound produced between molecules or ions of a solute and molecules or ions of a solvent.

In one aspect, the present invention may be a chalcone derivative having the structure of Formula 16, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[Formula 16]

Wherein R ₁ is H, OH or OC _n H _{2n +1} (n is one integer selected from 1 to 5), and R ₂ is H, OH or C _n H _{2n +1} (n is 1 to 5) One integer selected from), R ₃ is H, OC _n H _{2n +1} (n is one integer selected from 1 to 5) or a halogen group, and R ₄ is H, OH or C _n H _{2n + 1} (n is one integer selected from 1 to 5), R ₅ is H, OH or C _n H _{2n +1} (n is one integer selected from 1 to 5), R ₆ is H, or A halogen group, R ₇ is H, a methyl group or an ethyl group, R ₈ is H, OC _n H _{2n +1} (n is one integer selected from 1 to 5) or a halogen group, R ₉ is H, OH or C _n H _{2n +1} (n is one integer selected from 1 to 5).

In one embodiment, when at least one of R ₃ , R ₆ and R ₈ is a halogen group, the halogen group may be F, Cl, or Br.

In another embodiment, the chalcone derivative is selected from (E) -3 (2-bromo-4,5-dimethoxyphenyl) -1-phenylpro-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (3,4-dimethoxyphenyl) pro-2-en-1-one; E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-5-methylphenyl) pro-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2,6-dihydroxyphenyl) pro-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) propo-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1-phenylpropo-2-en-1one; (E) -3- (4-chlorophenyl) -1- (3,4-dimethoxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2-hydroxy-5-methylphenyl) propo-2-en-1-one; (E) -1- (4-bromophenyl) -3- (4-chlorophenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2,6-dihydroxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2-hydroxyphenyl) propo-2-en-1-one; (E) -1,3-bis (4-chlorophenyl) propo-2-en-1-one; And (E) -3- (4-chlorophenyl) -1- (4-fluorophenyl) propo-2-en-1-one.

The present invention may be, in one aspect, a composition for protecting kidneys comprising a chalcone derivative having a structure of Formula 16, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

[Formula 16]

Wherein R ₁ is H, OH or OC _n H _{2n +1} (n is one integer selected from 1 to 5), and R ₂ is H, OH or C _n H _{2n +1} (n is 1 to 5) One integer selected from), R ₃ is H, OC _n H _{2n +1} (n is one integer selected from 1 to 5) or a halogen group, and R ₄ is H, OH or C _n H _{2n + 1} (n is one integer selected from 1 to 5), R ₅ is H, OH or C _n H _{2n + 1} (n is one integer selected from 1 to 5), R ₆ is H, or A halogen group, R ₇ is H, a methyl group or an ethyl group, R ₈ is H, OC _n H _{2n +1} (n is one integer selected from 1 to 5) or a halogen group, R ₉ is H, OH or C _n H _{2n +1} (n is one integer selected from 1 to 5).

In another aspect, the present invention may be a composition for improving kidney disease comprising a chalcone derivative having the structure of Formula 16, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient. In one embodiment the improvement includes treatment, prevention, alleviation of symptoms, and the like.

In one aspect, when at least one of R ₃ , R ₆ and R ₈ is a halogen group, the halogen group may be F, Cl, or Br.

In another aspect, pharmaceutically acceptable salts of the chalcone derivatives include salts of acidic or basic groups which may be present in the chalcone derivative, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, Hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like. It may be prepared through a known method for preparing a salt.

In another aspect, the chalcone derivative is selected from (E) -3 (2-bromo-4,5-dimethoxyphenyl) -1-phenylpro-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (3,4-dimethoxyphenyl) pro-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-5-methylphenyl) pro-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2,6-dihydroxyphenyl) pro-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) propo-2-en-1-one; (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1-phenylpropo-2-en-1one; (E) -3- (4-chlorophenyl) -1- (3,4-dimethoxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2-hydroxy-5-methylphenyl) propo-2-en-1-one; (E) -1- (4-bromophenyl) -3- (4-chlorophenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2,6-dihydroxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) propo-2-en-1-one; (E) -3- (4-chlorophenyl) -1- (2-hydroxyphenyl) propo-2-en-1-one; (E) -1,3-bis (4-chlorophenyl) propo-2-en-1-one; And (E) -3- (4-chlorophenyl) -1- (4-fluorophenyl) propo-2-en-1-one.

In another aspect, the concentration of the chalcone derivative, isomer thereof, pharmaceutically acceptable salt thereof, hydrate thereof or solvate thereof in the composition may be 0.001 μM to 5M. In one embodiment, the concentration is at least 0.001μM, at least 0.01μM, at least 0.1μM, at least 1μM, at least 10μM, at least 25μM, at least 50μM, at least 100μM, at least 125μM, at least 150μM, at least 200μM, at least 250μM, at least 300μM, It may be at least 400μM, at least 500μM, at least 1mM, at least 50mM, at least 100mM, at least 500mM, at least 1M, or at least 5M. As another embodiment, the concentration is 5M or less, 1M or less, 500mM or less, 100mM or less, 50mM or less, 1mM or less, 500μM or less, 400μM or less, 300μM or less, 250μM or less, 200μM or less, 150μM or less, 125μM or less, 100μM or less, 50μM or less Or less than 25 μM, less than 10 μM, less than 1 μM, less than 0.1 μM, less than 0.01 μM, or less than 0.005 μM.

In another aspect, the dosage of the chalcone derivative, isomer thereof, pharmaceutically acceptable salt thereof, hydrate thereof or solvate thereof may be from 0.0001 mg / kg / day to 80 mg / kg / day. In one embodiment, the dosage is at least 0.0001 mg / kg / day, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg / day, at least 0.5 mg / kg / day, 1 mg / kg / day or more, 5mg / kg / day or more, 10mg / kg / day or more, 20mg / kg / day or more, 30mg / kg / day or more, 50mg / kg / day or more, 60mg / kg / day or more, or 70mg It may be more than / kg / day. In another embodiment, the dosage is 80 mg / kg / day or less, 70 mg / kg / day or less, 60 mg / kg / day or less, 50 mg / kg / day or less, 40 mg / kg / day or less, 30 mg / kg / day or less , 20 mg / kg / day or less, 10 mg / kg / day or less, 5 mg / kg / day or less, 3 mg / kg / day or less, 1 mg / kg / day or less, 0.5 mg / kg / day or less, 0.1 mg / kg / day Or less, 0.05 mg / kg / day or less, 0.01 mg / kg / day or less, 0.005 mg / kg / day or less, 0.001 mg / kg / day or less, or 0.0005 mg / kg / day or less.

In one embodiment, the composition may be a pharmaceutical composition or a food composition.

In another embodiment, the kidney protection may be kidney protection from nephrotoxicity by drugs. In one aspect, the nephrotoxicity may be nephrotoxicity due to oxidative stress.

In another embodiment, the kidney disease may be kidney disease due to drug side effects.

In one aspect of the invention, the drug is a nonsteroidal antipyretic analgesic anti-inflammatory agent such as phenacetin, aspirin, indomethacin; Aminoglycoside antibiotics such as puromycin, daunomycin, cyclophosphamide, penicillamine, adriamycin, amikacin, gentamycin, kanamycin, neomycin, sisomycin, streptomycin, and tobramycin; Cephalosporin antibiotics; Carbapenem antibiotics such as imipenem and melopenem; Immunosuppressants; Heavy metals such as cadmium, lead, mercury, and chromium; And compounds such as inorganic and organic heavy metal compounds, chloroform, D-serine, sulfonamide, 2-bromoethylene and hydrobromide; Or fungal toxins such as okaratoxin, citrinin.

In one embodiment, the drug may be an anticancer agent.

In one aspect, the anticancer agent may be a platinum-based anticancer agent. The platinum-based anticancer agent may be, for example, at least one selected from the group consisting of cisplatin, oxaliplatin, and carboplatin.

In another aspect, the kidney disease is nephritis, pyelonephritis, nephrotic syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, kidney tuberculosis, urinary tract infections, urinary tract stones, ureteral stones, acute kidney failure, chronic kidney failure, diabetic nephropathy, chronic glomeruli One or more selected from the group consisting of nephritis, acute progressive nephritis, neprogen syndrome, microglomerular sclerosis, melanoma, and melanoma proliferative nephritis. In one embodiment, the disease may be a disease as a side effect of drugs or anticancer agents.

In one aspect of the invention, the nephrotoxicity may be characterized in that the nephrotoxicity by the drug. Specifically, in one aspect of the invention, the nephrotoxicity may be nephrotoxic induced by an anticancer agent, i.e. as an anticancer side effect.

The pharmaceutical composition according to the present disclosure may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, soft or hard capsules, and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, or the like. Or lactose, gelatin, or the like is mixed. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Pharmaceutical dosage forms of the compositions of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection. The salt is not particularly limited as long as it is pharmaceutically acceptable. For example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid , Benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid and the like can be used.

The composition of the present invention may be parenterally or orally administered as desired, and may be administered in divided doses one to several times a day. The dosage for a particular patient may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, severity of the disease, and the like.

The pharmaceutical compositions according to the present invention may be prepared in the form of powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, aerosols, oral formulations, ointments, creams, etc. It can be formulated into any form suitable for pharmaceutical preparations, including sterile injectable solutions and the like.

The composition according to the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes, such as parenteral, oral, and all modes of administration can be expected, for example, oral administration, Administration by rectal administration, intravenous, intramuscular, subcutaneous injection and the like.

On the other hand, the composition according to the present invention, there is no serious toxicity and side effects can be used with confidence even for long-term use for the purpose of prevention.

The formulation of the food composition according to the present disclosure is not particularly limited, but may be, for example, formulated as a tablet, granule, powder, liquid such as drink, caramel, gel, bar, or the like. In addition to the chalcone derivatives, the food composition of each formulation may be appropriately selected and blended by those skilled in the art according to the formulation or use purpose without difficulty, and synergistic effects may occur when simultaneously applied with other raw materials.

In the food composition according to the present specification, the dosage determination of the chalcone derivative is within the level of those skilled in the art and may vary depending on various factors such as age, health condition, complications, etc. of the subject to be administered.

The food composition according to the present disclosure may be, for example, various functional foods such as chewing gum, caramel products, candy, ice cream, confectionery, beverage products such as soft drinks, mineral water, alcoholic drinks, vitamins and minerals, and the like. Can be.

Beverages containing chalcone derivatives according to an aspect of the present invention is not particularly limited to other ingredients other than including the chalcone derivative as an essential ingredient in the indicated ratio, and additional ingredients such as various flavors or natural carbohydrates, such as ordinary drinks It may be included as.

In addition to the above, the health food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (such as cheese, chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the functional food compositions of the present invention may include a natural fruit juice and a pulp for the production of fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is typically included in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, the method of the present invention will be specifically described with reference to Examples, Experimental Examples, and Formulation Examples. However, the following examples are only for illustrating one aspect of the present invention, and the scope of the present invention is not limited only to these examples.

Example 1 Synthesis of (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1-phenylpro-2-en-1-one (1)

A general process for preparing a chalcone derivative according to an aspect of the present invention is as follows.

That is, Compound 1 (1 in the figure) and Compound 2 (2 in the figure) are dissolved in ethyl alcohol, and then reacted by treating with 8N sodium hydroxide solution to obtain compound 3 (3 in the figure) by column chromatography. Serve At this time, it is sufficient to use the equipment that is commonly used in the art.

The obtained compound 3 was treated with 1N HCl / MeOH to reflux, and then purified by column chromatography to obtain compound 4 (4 in the above figure).

(E) -3 (2-bromo-4,5-dimethoxyphenyl) -1-phenylpro-2-en-1-one represented by the following formula (1) in the same manner as described above ((E) -3 -(2-bromo-4,5-dimethoxyphenyl) -1-phenylprop-2-en-1-one) (1) was synthesized.

[Formula 1]

Specifically, acetophenone (40 mg, 0.33 mmol) was dissolved in ethyl alcohol (4 ml), 2-bromo-4,5-dimethoxyphenylaldehyde (80.52 mg, 0.33 mmol) was added, followed by 8N sodium hydroxide (0.5) ml) solution was treated and stirred at room temperature for 24 hours. After the reaction proceeded completely, the pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified using a silica gel column and ethyl acetate: hexane = 1: 5 to obtain Compound 1 (42 mg, 37.8%).

Detailed NMR data are as follows.

¹ H-NMR (CDCl 3): 8.07 ppm (d, J = 15.6 Hz, 1H), 8.04 ppm-7.98 ppm (m, 2H), 7.63 ppm-7.55 ppm (m, 1H), 7.54 ppm-7.47 ppm (m , 2H), 7.29 ppm (d, J = 15.2 Hz, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 3.95 ppm (s, 3H), 3.92 ppm (s, 3H).

ESI-MS: m / z calcd for C ₁₇ H ₁₆ BrO ₃ [M + H] = 347.02 found 347.0.

Example 2 (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (3,4-dimethoxyphenyl) pro-2-en-1-one ((E) Synthesis of -3- (2-bromo-4,5-dimethoxyphenyl) -1- (3,4-dimethoxyphenyl) prop-2-en-1-one) (2)

3,4-dimethoxyacetophenone (30 mg, 0.167 mmol) was dissolved in ethyl alcohol (4 ml), and then 2-bromo-4,5-dimethoxyphenylaldehyde (40.7 mg, 0.167 mmol) was added, followed by 8N. The sodium hydroxide (0.5 ml) solution was treated and stirred at room temperature for 24 hours. Thereafter, the pH was adjusted to 7.0, followed by extraction with ethyl acetate, which was purified by a silica gel column and ethyl acetate: hexane = 1: 5 to obtain Compound 2 (38.2 mg, 56.3%) represented by the following Chemical Formula 2.

[Formula 2]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 8.05 ppm (d, J = 15.6 Hz, 1H), 7.66 ppm (dd, J = 8.4 Hz, 2 Hz, 1H), 7.30 ppm (d, J = 15.6 Hz, 1H) , 7.19 (s, 1H), 7.09 (s, 1H), 6.94 ppm (d, J = 8.4 Hz, 1H), 3.98 ppm (s, 3H), 3.98 ppm (s, 3H), 3.95 ppm (s, 3H ), 3.92 ppm (s, 3 H).

ESI-MS: m / z calcd for C ₁₉ H ₂₀ BrO ₅ [M + H] = 407.04 found 407.0.

Example 3 (E) -3- (2-Bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-5-methylphenyl) pro-2-en-1-one ((E Synthesis of) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-5-methylphenyl) prop-2-en-1-one) (3)

2-hydroxy-5-methylacetophenone (30 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), and then 2-bromo-4,5-dimethoxyphenylaldehyde (48.8 mg, 0.2 mmol) was added. The 8N sodium hydroxide (0.5 ml) solution was treated and stirred at rt for 24 h. Thereafter, the pH was adjusted to 7.0, followed by extraction with ethyl acetate, which was then purified by a silica gel column and ethyl acetate: hexane = 1: 5 to obtain compound 3 (42.1 mg, 56.0%) represented by the following formula (3).

[Formula 3]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 12.60 ppm (s, 1H), 12.6 ppm (s, 1H), 8.20 ppm (d, J = 15.2 Hz, CH = CH, 1H), 7.66 ppm (d, J = 1.2 Hz, 1H), 7.44 ppm (d, J = 15.2 Hz, 1H), 7.32 ppm (dd, J = 8.4 ppm, 2 Hz, 1H), 7.21 ppm (s, 1H), 7. 11 ppm (s, 1H ), 6.94 ppm (d, J = 8.4 Hz, 1H), 3.98 ppm (s, 3H), 3.93 ppm (s, 3H). ESI-MS: m / z calcd for C ₁₈ H ₁₈ BrO ₄ [M + H] = 377.04 found 377.0.

Example 4 (E) -3- (2-Bromo-4,5-dimethoxyphenyl) -1- (2,6-dihydroxyphenyl) pro-2-en-1-one ((E Synthesis of) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2,6-dihydroxyphenyl) prop-2-en-1-one) (4)

1- (2,6-bis (methoxymethoxy) acetophenone (48 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml) and then 2-bromo-4,5-dimethoxyphenylaldehyde (48.8, 0.2 mmol) was added and the solution was treated with 8N sodium hydroxide (0.5 ml) solution and stirred at room temperature for 24 hours, the pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified by a silica gel column and ethyl acetate: hexane = 1; 5. Then, it was dissolved in 1N hydrochloric acid solution (1.5 ml) / methanol (5 ml) and refluxed for 1 hour, and then purified by silica gel column using ethyl acetate: hexane = 1: 2 to obtain a compound represented by the following formula (4). 4 (42.1 mg, 55.7%) was obtained.

[Formula 4]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 9.56 ppm (s, 2H), 8.16 ppm (d, J = 15.6 Hz, 1H), 7.85 ppm (d, J = 15.2 Hz, 1H), 7.25 ppm (m, 1H) , 7.19 ppm (s, 1H), 7.09 ppm (s, 1H), 6.44 ppm (d, J = 8 Hz, 2H), 3.92 ppm (s, 3H), 3.91 ppm (s, 3H). ESI-MS: m / z calcd for C ₁₇ H ₁₆ BrO ₅ [M + H] = 379.04 found 379.0.

Example 5 (E) -3- (2-Bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) propo-2-ene-1 Synthesis of -one ((E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) prop-2-en-1-one) (5)

2-hydroxy-4,6-dimethoxyacetophenone (38.8 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml) and then 2-bromo-4,5-dimethoxyphenylaldehyde (48.8 mg, 0.2 mmol) After addition of 8N sodium hydroxide (0.5 ml) solution was treated and stirred at room temperature for 24 hours. The pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified using a silica gel column and ethyl acetate: hexane = 1: 5 to obtain Compound 5 (48.6 mg, 57.6%) represented by Chemical Formula 5.

[Formula 5]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 14.28 ppm (s, 1H, phenolic OH), 8.07 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.75 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.17 ppm (s, 1H), 7.09 ppm (s, 1H), 6.12 ppm (d, J = 2.4, 1H), 5.96 ppm (d, J = 2.4 Hz, 1H), 3.93 ppm (s, 3H), 3.92 ppm (s, 3H), 3.90 (s, 3H), 3.84 ppm (s, 3H). ESI-MS: m / z calcd for C ₁₉ H ₂₀ BrO ₆ [M + H] = 423.04 found 423.0.

Example 6 (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxyphenyl) propo-2-en-1-one ((E)- Synthesis of 3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxyphenyl) prop-2-en-1-one) (6)

2-hydroxyacetophenone (27.2 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), followed by addition of 2-bromo-4,5-dimethoxyphenylaldehyde (48.8 mg, 0.2 mmol) followed by 8N sodium hydroxide ( 0.5 ml) solution was treated and stirred at room temperature for 24 hours. The pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified using a silica gel column and ethyl acetate: hexane = 1: 5 to obtain compound 6 (36.9 mg, 51.0%) represented by Chemical Formula 6.

[Formula 6]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 12.8 ppm (s, 1H), 8.24 ppm (d, J = 15.2 Hz, 1H), 7.93 ppm (d, J = 8.0 Hz, 1H), 7.52 ppm (m, 1H) , 7.49 (d, J = 15.2 Hz, 1H), 7.28 ppm (s, 1H), 7.10-7.00 ppm (m 2H), 6.97 ppm (t, J = 8.0 Hz, 1H), 3.99 ppm (s, 3H) , 3. 93 ppm (s, 3 H). ESI-MS: m / z calcd for C ₁₇ H ₁₆ BrO ₄ [M + H] = 363.02 found 263.0.

Example 7 (E) -3- (4-chlorophenyl) -1-phenylpropo-2-en-1one ((E) -3- (4-chlorophenyl) -1-phenylprop-2-en Synthesis of -1-one) (7)

Acetophenone (24 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), 4-chlorophenylaldehyde (28 mg, 0.2 mmol) was added, and 8N sodium hydroxide (0.5 ml) solution was treated and stirred at room temperature for 24 hours. It was. The pH was adjusted to 7.0, followed by extraction with ethyl acetate (100 ml), which was then purified using a silica gel column and ethyl acetate: hexane = 1: 5 to obtain compound 7 (22.1 mg, 49.3%) represented by the following formula (7): Obtained.

[Formula 7]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 8.40 ppm-7.99 ppm (m, 2H), 7.76 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.64 ppm-7.55 ppm (m, 3H), 7.56 ppm -7.46 ppm (m, 3H), 7.44 ppm-7.37 ppm (m, 2H). ESI-MS: m / z calcd for C ₁₅ H ₁₂ ClO [M + H] = 243.06 found 243.1.

Example 8 (E) -3- (4-chlorophenyl) -1- (3,4-dimethoxyphenyl) propo-2-en-1-one ((E) -3- (4-chlorophenyl Synthesis of) -1- (3,4-dimethoxyphenyl) prop-2-en-1-one) (8)

Dissolve 3,4-dihydroxyacetophenone (36 mg, 0.22 mmol) in ethyl alcohol (4 ml), add 4-chlorophenylaldehyde (28 mg, 0.22 mmol), and then add 8N sodium hydroxide (0.5 ml) solution. The treatment was stirred for 24 hours at room temperature. The pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified using a silica gel column and ethyl acetate: hexane = 1: 5 to obtain compound 8 (38.2 mg, 63.24%) represented by the following formula (8).

[Formula 8]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 7.74 ppm (d, J = 15.6 Hz, 1H), 7.67 ppm (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.62 ppm (d, J = 1.6 Hz, 1H) , 7.59 ppm-7.48 ppm (m, 3H), 7.38 ppm (d, J = 8.4 Hz, 2H), 6.62 ppm (d, J = 8.4 Hz, 1H), 3.97 ppm (s, 6H). ESI-MS: m / z calcd for C ₁₇ H ₁₅ ClO ₃ [M + H] = 303.08 found 303.1.

Example 9 (E) -3- (4-chlorophenyl) -1- (2-hydroxy-5-methylphenyl) propo-2-en-1-one ((E) -3- (4- Synthesis of chlorophenyl) -1- (2-hydroxy-5-methylphenyl) prop-2-en-1-one) (9)

2-hydroxy-5-methylacetophenone (38.8 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), and 4-chlorophenylaldehyde (29.4 mg, 0.2 mmol) was added, followed by 8N sodium hydroxide (0.5 ml) solution. Treated and stirred at room temperature for 24 hours. The pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified using a silica gel column and ethyl acetate: hexane = 1: 5 to obtain compound 9 (31.7 mg, 58.2%) represented by the following formula (9).

[Formula 9]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 12.56 ppm (s, 1H), 7.86 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.67 (s, 1H), 7.68 ppm-7.59 ppm (m, 3H ), 7.45 ppm-7.40 ppm (m, 2H), 7.33 ppm (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.94 ppm (d, J = 8.4 Hz, 1H), 2.36 ppm (s, 3H). ESI-MS: m / z calcd for C ₁₆ H ₁₄ ClO ₂ [M + H] = 273.07 found 273.1.

Example 10 (E) -1- (4-bromophenyl) -3- (4-chlorophenyl) propo-2-en-1-one ((E) -1- (4-bromophenyl)- Synthesis of 3- (4-chlorophenyl) prop-2-en-1-one) (10)

4-bromoacetophenone (39.6 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), 4-chlorophenylaldehyde (28 mg, 0.2 mmol) was added, followed by 8N sodium hydroxide (0.5 ml) solution treatment. Stir at room temperature for hours. The pH was adjusted to 7.0 and extracted with ethyl acetate (100 ml), which was then purified by a silica gel column and ethyl acetate: hexane = 1: 6 to obtain compound 10 (42.6 mg, 66.56%) represented by Chemical Formula 10 below. .

[Formula 10]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 7.88 ppm (ddd, J = 8.8 Hz, 4.4 Hz, 2.4 Hz, 1H), 7.77 ppm (d, J = 16 Hz, 1H, CH = CH), 7.67 ppm (m, 2H), 7.61 ppm-7.55 ppm (m, 2H), 7.45 ppm (d, J = 16 Hz, 1H, CH = CH), 7.48 ppm-7.380 ppm (m, 2H). ESI-MS: m / z calcd for C ₁₅ H ₁₁ ClO [M + H] = 320.97 found 320.9.

Example 11 (E) -3- (4-chlorophenyl) -1- (2,6-dihydroxyphenyl) propo-2-en-1-one ((E) -3- (4- Synthesis of chlorophenyl) -1- (2,6-dihydroxyphenyl) prop-2-en-1-one) (11)

2,6-dihydroxyacetophenone (30.4 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), 4-chlorophenylaldehyde (28 mg, 0.2 mmol) was added, followed by 8N sodium hydroxide (0.5 ml) solution. The treatment was stirred for 24 hours at room temperature. The pH was adjusted to 7.0 and extracted with ethyl acetate (110 ml), which was then purified by a silica gel column and ethyl acetate: hexane = 1: 5 to obtain compound 11 (34.5 mg, 62.9%) represented by the following formula (11). .

[Formula 11]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 9.36 ppm (s, 2H), 7.99 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.80 ppm (d, J = 15.6 Hz, 1H, CH = CH) , 7.55 ppm (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.25 ppm (m, 1H), 6.44 ppm (d, J = 8.0 Hz, 2H). ESI-MS: m / z calcd for C ₁₅ H ₁₂ ClO ₃ [M + H] = 275.05 found 275.1.

Example 12 (E) -3- (4-chlorophenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) propo-2-en-1-one ((E) -3 Synthesis of-(4-chlorophenyl) -1- (2-hydroxy-4,6-dimethoxyphenyl) prop-2-en-1-one) (12)

2-hydroxy-4,6-dimethoxyacetophenone (39.2 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), 4-chlorophenylaldehyde (28 mg, 0.2 mmol) was added, followed by 8N sodium hydroxide (0.5 ml) solution was treated and stirred at room temperature for 24 hours. After adjusting the pH to 7.0 and extracted with ethyl acetate and purified by a silica gel column and ethyl acetate: hexane = 1: 5 to obtain a compound 12 (41.5 mg, 65.3%) represented by the following formula (12).

[Formula 12]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 14.2 ppm (s, 1H), 7.86 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.72 ppm (d, J = 15.6 Hz, 1H, CH = CH) , 7.53 ppm (d, J = 8.6 Hz, 2H), 7.38 ppm (d, J = 8.8 Hz, 1H), 6.12 ppm (d, J = 2.4 Hz, 1H), 5.97 (d, J = 2.4 Hz, 1H ), 3.92 (s, 3H), 3.84 ppm (s, 3H). ESI-MS: m / z calcd for C ₁₇ H ₁₆ ClO ₄ [M + H] = 319.07 found 319.1.

Example 13 (E) -3- (4-chlorophenyl) -1- (2-hydroxyphenyl) propo-2-en-1-one ((E) -3- (4-chlorophenyl)- Synthesis of 1- (2-hydroxyphenyl) prop-2-en-1-one) (13)

2-hydroxyacetophenone (27.2 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), 4-chlorophenylaldehyde (28 mg, 0.2 mmol) was added, and 8N sodium hydroxide (0.5 ml) solution was treated to give 24 Stir at room temperature for hours. The pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified by a silica gel column and ethyl acetate: hexane = 1: 5 to obtain compound 13 (38.7 mg, 75.0%) represented by Chemical Formula 13.

[Formula 13]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 12.78 ppm (s, 1H), 7.93 ppm (dd, J = 8 Hz, 1.2 Hz, 1H), 7.99 (d, J = 15.2 Hz, 1H), 7.65 ppm (d, J = 15.2 Hz, 1H), 7.62 ppm (d, J = 8.4 Hz, 2H), 7.54 ppm (t, J = 8.4 Hz, 1H), 7.43 ppm (d, J = 8.4 Hz, 2H), 7.06 ppm ( dd, J = 8.4 Hz, 0.8 Hz, 1H), 6.98 ppm (t, J = 8.0 Hz, 0.8 Hz, 1H). ESI-MS: m / z calcd for C ₁₅ H ₁₂ ClO ₂ [M + H] 259.04, found 259.0.

Example 14 (E) -1,3-bis (4-chlorophenyl) propo-2-en-1-one ((E) -1,3-bis (4-chlorophenyl) prop-2-en Synthesis of -1-one) (14)

4-chloroacetophenone (30.8 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), 4-chlorophenylaldehyde (28 mg, 0.2 mmol) was added, and 8N sodium hydroxide (0.5 ml) solution was treated for 24 hours. Stir at room temperature. The pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified by a silica gel column and ethyl acetate: hexane = 1: 6 to obtain compound 14 (32.8 mg, 59.4%) represented by the following formula (14).

[Formula 14]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 7.96 ppm (d, J = 8.8 Hz, 2H), 7.77 ppm (d, J = 16.0 Hz, 1H), 7.58 ppm (d, J = 8.8 Hz, 2H), 7.52 ppm -7.43 ppm (m, 3H), 7.43 ppm-7.38 ppm (m, 2H). ESI-MS: m / z calcd for C ₁₅ H ₁₁ Cl ₂ O [M + H] = 277.02 found 277.0.

Example 15 (E) -3- (4-chlorophenyl) -1- (4-fluorophenyl) propo-2-en-1-one ((E) -3- (4-chlorophenyl)- Synthesis of 1- (4-fluorophenyl) prop-2-en-1-one) (15)

4-Fluoroacetophenone (27.6 mg, 0.2 mmol) was dissolved in ethyl alcohol (4 ml), 4-chlorophenylaldehyde (28 mg, 0.2 mmol) was added, followed by treatment with 8N sodium hydroxide (0.5 ml) solution. Stir at room temperature for hours. The pH was adjusted to 7.0 and extracted with ethyl acetate, which was then purified by a silica gel column and ethyl acetate: hexane = 1: 6 to obtain compound 15 (31.3 mg, 60.2%) represented by Chemical Formula 15.

[Formula 15]

Detailed NMR data are as follows.

¹ H-NMR (CDCl ₃ ): 8.08 ppm-8.03 ppm (m, 2H), 7.76 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.57 (d, J = 8.36 Hz, 2H), 7.48 ppm (d, J = 15.6 Hz, 1H, CH = CH), 7.40 ppm (d, J = 8.4 Hz, 2H), 7.18 ppm (m, 2H). ESI-MS: m / z calcd for C ₁₅ H ₁₁ ClFO [M + H] = 261.05 found 261.1.

Experimental Example 1 Kidney Cell Survival Rate Experiment

Porcine kidney epithelial cells (LLC-PK1, ATCC) were passaged once every 3 days while incubated in DMEM medium, 10% fetal bovine serum, 1% penicillin-streptomycin at 37 ^° C., 5% CO ₂ .

After injecting 5000 cells into a 96-well plate and incubating for 24 hours, the compound of Experimental Example was treated with a sample, treated with 25 μM cisplatin, and cultured for 24 hours, and then cell viability was confirmed with MTT reagent.

As a result, it was confirmed that the chalcone derivatives represented by Chemical Formulas 1 to 15 (1 to 15 in FIG. 1) exhibited nephroprotective efficacy, as shown in FIG. In comparison with other derivatives, the efficacy was higher, and the cell survival rate was 98% at 50 μM. In FIG. 1, the X-axis value of each graph indicates the concentration of each compound, and the unit is μM. Values indicate cell viability (%)). Specific values were as shown in Table 1 below. In Table 1 below, the number of the chalcone derivative represents a compound according to each chemical formula number according to the above Examples. (Eg, “1” is a compound represented by Formula 1 in the above examples)

Chalcone derivatives Concentration (μM) activation(%) One 0 60 10 76 25 78 50 79 100 38 200 34 2 0 62 10 63 25 67 50 68 100 64 200 65 3 0 60 10 68 25 79 50 98 100 36 200 32 4 0 60 10 58 25 60 50 82 100 98 200 97 5 0 60 10 60 25 61 50 63 100 67 200 72 6 0 62 10 63 25 60 50 59 100 58 200 57 7 0 60 10 78 25 79 50 58 100 10 200 8 8 0 60 10 62 25 67 50 67 100 82 200 10 9 0 62 10 63 25 74 50 76 100 76 200 78 10 0 61 10 61 25 78 50 78 100 80 200 98 11 0 60 10 62 25 61 50 63 100 65 200 73 12 0 62 10 63 25 60 50 59 100 58 200 59 13 0 60 10 60 25 60 50 26 100 20 200 20 14 0 60 10 70 25 70 50 72 100 80 200 79 15 0 60 10 62 25 70 50 75 100 82 200 61

That is, chalcone derivatives according to one aspect of the present invention have been shown to inhibit kidney damage caused by anticancer agents. As a result, it was found that the chalcone derivatives according to an aspect of the present invention effectively protects renal cells from nephrotoxicity caused by anticancer agents, and these results can protect the renal cell damage caused by oxidative stress. It also means that there is.

Experimental Example 2 Image-Based Cell Viability Confirmation

Pig epithelial cells (LLC-PK1), such as Experimental Example 1, were added to a 10 cm culture plate and then cultured for 24 hours, and then treated with the compound of the Experimental Example as a sample, followed by cisplatin for 2 hours. Was treated. Thereafter, the cells were stained with propidium iodide (PI) and Annexin V to confirm cell viability.

Since PI stained dead cells and annexin V stained live cells, the number of dead cells was confirmed by checking the number of cells stained with PI. The results are shown in FIG. 2, and when the sample was not treated, the dead cells were 33% of the total, 17% at 25 uM of sample, and 7% at 50 uM of sample. That is, when the compound 3 was treated, it was clearly seen that the bright green point tended to decrease.

Hereinafter will be described in more detail the formulation example of a pharmaceutical composition for reducing toxicity, or a food composition comprising a chalcone derivative according to one aspect of the invention as an active ingredient, which is intended to explain the invention in detail, The invention is not limited to the following examples.

Formulation Example 1 Soft Capsule

8 mg of the chalcone derivative of the above embodiment, vitamin E 9 mg, vitamin C 9 mg, palm oil 2 mg, vegetable hardened oil 8 mg, lead 4 mg and lecithin 9 mg are mixed and mixed according to a conventional method to prepare a soft capsule filler. 400 mg per capsule is filled to prepare a soft capsule. In addition, a soft capsule sheet is prepared at a ratio of 66 parts by weight of gelatin, 24 parts by weight of glycerine, and 10 parts by weight of sorbitol solution and filled with the filler to prepare a soft capsule containing 400 mg of the composition according to the present invention.

Formulation Example 2 Tablet

The chalcone derivative 8 mg, vitamin E 9 mg, vitamin C 9 mg, galactooligosaccharide 200 mg, lactose 60 mg and maltose 140 mg are mixed and granulated using a fluidized bed dryer, and then 6 mg of sugar ester is added. Tablets are prepared by tableting 500 mg of these compositions in a conventional manner.

[Formulation Example 3] Drinks

The chalcone derivative 8 mg, vitamin E 9 mg, vitamin C 9 mg, glucose 10 g, citric acid 0.6 g, and 25 g of liquid oligosaccharides were mixed, and 300 ml of purified water was added to each bottle to make 200 ml. After filling the bottle sterilized for 4-5 seconds at 130 ℃ to prepare a drink.

Formulation Example 4 Granules

The chalcone derivatives 8 mg, vitamin E 9 mg, vitamin C 9 mg, 250 mg of anhydrous glucose and 550 mg of starch were mixed, molded into granules using a fluidized bed granulator, and then filled into fabrics to prepare granules.

Formulation Example 5 Injection

Injectables were prepared by conventional methods according to the compositions set forth in Table 2 below.

Compounding ingredient content Chalcone Derivatives of Examples 10-50 mg Sterile Distilled Water for Injection Quantity pH regulator Quantity

Formulation Example 6 Health Functional Food

To prepare a health functional food in a conventional manner according to the composition shown in Table 3.

Compounding ingredient content Chalcone Derivatives of Examples 20mg Vitamin A Acetate 70 μg Vitamin E 1.0mg Vitamin B1 0.13mg Vitamin B2 0.15mg Vitamin B6 0.5mg Vitamin B12 0.2 μg Vitamin c 10mg Biotin 10 μg Nicotinic acid amide 1.7mg Folic acid1 50 μg Calcium Pantothenate 0.5mg Ferrous sulfate 1.75mg Zinc oxide 0.82 mg Magnesium carbonate 25.3 mg Potassium phosphate monobasic 15 mg Dicalcium Phosphate 55 mg Potassium citrate 90 mg Calcium carbonate 100mg Magnesium chloride 24.8 mg

Although the composition ratio of the said vitamin and mineral mixture was mixed and consisted with the component suitable for a health functional food in a preferable Example, you may change arbitrarily the compounding ratio.

Formulation Example 7 Healthy Drink

To prepare a health drink in a conventional manner according to the composition shown in Table 4.

Compounding ingredient content Chalcone Derivatives of Examples 1000 mg Citric acid 1000 mg oligosaccharide 100 g Taurine 1 g Purified water Remaining amount

The above ingredients are mixed according to a conventional method for preparing a health beverage, then stirred and heated at 85 ° C. for about 1 hour, and then the resulting solution is filtered and sterilized.

Claims (16)

delete delete delete (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-5-methylphenyl) pro-2-en-1-one;
(E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2,6-dihydroxyphenyl) pro-2-en-1-one; And
(E) -1- (4-bromophenyl) -3- (4-chlorophenyl) propo-2-en-1-one; one or more chalcone derivatives selected from the group consisting of, isomers thereof, and pharmaceuticals thereof Comprising an acceptable salt, a hydrate thereof or a solvate thereof as an active ingredient,
Nephritis, pyelonephritis, nephrotic syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, kidney tuberculosis, urinary tract infection, urinary tract stones, ureteral stones, acute kidney failure, chronic kidney failure, diabetic nephropathy, chronic glomerulonephritis, acute progressive nephritis syndrome A food composition for renal protection from nephrotoxicity by cisplatin in at least one kidney disease selected from the group consisting of microglomerular sclerosis, mesothelial nephropathy, and membranous proliferative glomerulonephritis. The food composition for kidney protection according to claim 4, wherein the concentration of the chalcone derivative, isomer thereof, pharmaceutically acceptable salt thereof, hydrate thereof or solvate thereof in the composition is 50 to 200μM. The food composition for kidney protection according to claim 4, wherein the dosage of the chalcone derivative, isomer thereof, pharmaceutically acceptable salt thereof, hydrate thereof or solvate thereof is 0.0001 mg / kg / day to 80 mg / kg / day. The food composition for kidney protection according to claim 4, wherein the nephrotoxicity is nephrotoxicity due to oxidative stress. (E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2-hydroxy-5-methylphenyl) pro-2-en-1-one;
(E) -3- (2-bromo-4,5-dimethoxyphenyl) -1- (2,6-dihydroxyphenyl) pro-2-en-1-one; And
(E) -1- (4-bromophenyl) -3- (4-chlorophenyl) propo-2-en-1-one; one or more chalcone derivatives selected from the group consisting of, isomers thereof, and pharmaceuticals thereof Comprising an acceptable salt, a hydrate thereof or a solvate thereof as an active ingredient,
Nephritis, pyelonephritis, nephrotic syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, kidney tuberculosis, urinary tract infection, urinary tract stones, ureteral stones, acute kidney failure, chronic kidney failure, diabetic nephropathy, chronic glomerulonephritis, acute progressive nephritis syndrome A pharmaceutical composition for improving, preventing or treating kidney disease by at least one cisplatin side effect selected from the group consisting of microglomerular sclerosis, mesothelial nephropathy, and membranous proliferative glomerulonephritis. The pharmaceutical composition of claim 8, wherein the concentration of the chalcone derivative, isomer thereof, pharmaceutically acceptable salt thereof, hydrate thereof, or solvate thereof in the composition is 50 to 200 μM. The method of claim 8, wherein the dosage of the chalcone derivative, isomer thereof, pharmaceutically acceptable salt thereof, hydrate thereof or solvate thereof is from 0.0001 mg / kg / day to 80 mg / kg / day, improving, preventing or Therapeutic pharmaceutical composition. delete delete delete delete delete delete

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