WO2020046020A1 - Inhibitory material against human body-derived nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase-like, and anticancer agent comprising same as effective ingredient or pharmaceutical composition comprising same as effective ingredient for treatment of hyperlipidemia - Google Patents

Abstract

A nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase-like (NSDHL) inhibitor provided according to an aspect of the present invention can be used not only as an anticancer agent capable of overcoming resistance to EGFR-targeting anticancer agents, but also advantageously in the treatment of hyperlipidemia.

Description

Nicotineamide Adenine Dinucleotide Phosphate-dependent Steroid Dehydrogenase Inhibitors Derived from the Human Body and Pharmaceutical Compositions for the Treatment of Anticancer Agents or Hyperlipidemia Containing the Same as Active Ingredients

The present invention relates to a nicotine amide adenine dinucleotide phosphate-dependent steroid dehydrogenase inhibitor derived from a human body, and an anticancer agent or a hyperlipidemic pharmaceutical composition containing the same as an active ingredient.

Recently, the problem of resistance of epidermal growth factor receptor (EGFR) target anticancer drugs known as blockbusters has emerged, and thus, development of new anticancer drugs is required.

Meanwhile, nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NSDHL), which acts on the cholesterol synthesis pathway in the human body, is basically known as a sterol synthase, but has recently been inhibited by EGF (epidermal). growth factor) The inhibition of cancer growth through the elimination of resistance and metabolic regulation of receptor-targeted anticancer drugs has been found to attract attention as a new anticancer drug target (Non-Patent Document 1, Nat Commun. 2015 Oct 12; 6: 8613). The nicotinamide adenine dinucleotide phosphate dependent steroid dehydrogenase has also been reported to play an important role in the metastasis of breast cancer.

In addition, if there is an abnormality in the nicotine amide adenine dinucleotide phosphate-dependent steroid dehydrogenase gene, the keratinocyte envelope membrane is modified and abnormal accumulation of steroid precursors leads to CK syndrome and CHILD (congenital hemidysplasia with ichthyosiform nevus and limb). defects are known to develop, and are expected to give important clues to the treatment of congenital hereditary diseases.

Furthermore, nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase is closely related to hyperlipidemia, and compounds that inhibit the function of nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase protein with high activity are used for the treatment of important human diseases in the future. It is possible.

An object of one aspect of the present invention is to provide a compound that effectively inhibits nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NADP-dependent steroid dehydrogenase-like; NSDHL).

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.

An object in another aspect of the present invention is to provide a pharmaceutical composition for preventing or treating hyperlipidemia containing the compound as an active ingredient.

Another object of the present invention is to provide a nutraceutical composition for the prevention or improvement of cancer containing the compound as an active ingredient.

Another object of the present invention is to provide a dietary supplement for the prevention or improvement of hyperlipidemia containing the compound as an active ingredient.

It is an object of another aspect of the present invention to provide a method for treating cancer comprising administering the compound to a subject in need thereof.

It is another object of the present invention to provide a method for treating hyperlipidemia comprising administering the compound to a subject in need thereof.

It is an object of another aspect of the present invention to provide the compound for use in the prevention or treatment of cancer.

It is an object in another aspect of the present invention to provide the compound for use in the prevention or treatment of hyperlipidemia.

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

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

In order to achieve the above object,

One aspect of the invention provides a compound represented by the following formula (1), solvates, hydrates, or pharmaceutically acceptable salts thereof.

[Formula 1]

In Chemical Formula 1,

R is as defined herein.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.

Another aspect of the invention provides a pharmaceutical composition for the prevention or treatment of hyperlipidemia containing the compound as an active ingredient.

Another aspect of the present invention provides a nutraceutical composition for preventing or improving cancer containing the compound as an active ingredient.

Another aspect of the invention provides a dietary supplement for the prevention or improvement of hyperlipidemia containing the compound as an active ingredient.

Another aspect of the invention provides a method of treating cancer comprising administering the compound to a subject in need thereof.

Another aspect of the invention provides a method of treating hyperlipidemia comprising administering the compound to a subject in need thereof.

Another aspect of the invention provides the compound for use in the prevention or treatment of cancer.

Another aspect of the present invention provides the compound for use in the prevention or treatment of hyperlipidemia.

Another aspect of the invention provides the use of said compound for the manufacture of a medicament for use in the prevention or treatment of cancer.

Another aspect of the invention provides the use of said compound for the manufacture of a medicament for use in the prevention or treatment of hyperlipidemia.

The nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NSDHL) inhibitor provided in one aspect of the present invention is not only usable as an anticancer agent capable of overcoming the resistance of an EGFR target anticancer agent, but also has an effect that can be used to treat hyperlipidemia.

1 is a graph showing a measurement result of fluorescence intensity of NADH for each NSDHL concentration.

Figure 2 is a graph showing the results of NSDHL and NADH conjugate inhibition experiment using NAD +.

Hereinafter, the present invention will be described in detail.

One aspect of the invention provides a compound represented by the following formula (1), solvates, hydrates, or pharmaceutically acceptable salts thereof.

[Formula 1]

In Chemical Formula 1,

R is

or

ego,

A ¹ is —H or unsubstituted or substituted C _6-10 aryl C _1-5 straight or branched alkoxy, wherein substituted C _6-10 aryl C _1-5 straight or branched alkoxy is C _6-10 aryl C _1-5 straight or branched chain substituted with one or more substituents selected from the group consisting of halogen (-F, -Cl, -Br, -I), nitro, nitrile and -COOH Alkoxy;

A ² is -H or -OH;

A ³ is —H, halogen or unsubstituted or substituted C _6-10 aryl, wherein the substituted C _6-10 aryl is one or more halogen-substituted aryl;

A ⁴ is —H or C _1-5 straight or branched alkoxy;

B ¹ is —H or unsubstituted or substituted C _6-10 aryl, wherein the substituted C _6-10 aryl is one or more halogen-substituted aryl; And

The B ² is -H or unsubstituted or substituted C _6-10 aryl, wherein the substituted C _6-10 aryl may be one or more halogen-substituted aryl.

On the other side,

A ¹ is unsubstituted or substituted benzyloxy, wherein substituted benzyloxy is benzyloxy substituted with one or more substituents selected from the group consisting of halogen and -COOH;

A ² is -H or -OH;

A ³ is —H, halogen or unsubstituted or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or more halogens;

A ⁴ is -H or methoxy;

B ¹ is phenyl substituted with one halogen; And

B ² may be phenyl substituted with one halogen.

In another aspect, the compound represented by Formula 1 may be a compound of any one of the following compound groups.

(1) (Z) -4-((3-((3- (carboxymethyl) -4-oxo-2-thioxothiazolidine-5-ylidene) methyl) -4'-fluorobiphenyl- 4-yloxy) methyl) benzoic acid;

(2) (Z) -2- (5-((3- (3-chlorophenyl) -1- (4-fluorophenyl) -1H-pyrazol-4-yl) methylene) -4-oxo-2 -Thioxothiazolidin-3-yl) acetic acid;

(3) (Z) -2- (5- (2- (benzyloxy) -6-methoxybenzylidene) -4-oxo-2-thioxothiazolidin-3-yl) acetic acid;

(4) (Z) -2- (5- (2- (2-bromobenzyloxy) -4-hydroxybenzylidene) -4-oxo-2-thioxothiazolidin-3-yl) acetic acid; And

(5) (Z) -2- (5- (5-bromo-2- (2-iodobenzyloxy) benzylidene) -4-oxo-2-thioxothiazolidin-3-yl) acetic acid.

The compound represented by Chemical Formula 1 of the present invention may 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. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, Fluoride, Acetate, Propionate, Decanoate, Caprylate, Acrylate, Formate, Isobutyrate, Caprate, Heptanoate, Propiolate, Oxalate, Malonate, Succinate, Sube Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobene Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 Sulfonates, naphthalene-2-sulfonates, mandelate and the like.

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

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

Furthermore, the present invention includes not only the compound represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In this case, the compound may be to inhibit or inhibit nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NADP-dependent steroid dehydrogenase-like; NSDHL) to exhibit a prophylactic or therapeutic activity of cancer. The pharmaceutical composition may be an anticancer composition. The cancer is kidney cancer, bladder cancer, liver cancer, thymic cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastases cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrotic Tumors, brain tumors, etc., but is not limited thereto.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating hyperlipidemia, which contains the compound represented by Formula 1, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. At this time, the compound may be to inhibit or inhibit nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NADP-dependent steroid dehydrogenase-like; NSDHL) to exhibit the prevention or treatment of hyperlipidemia.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration. 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, capsules and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose (at least one compound). lactose) and gelatin. 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 may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

A pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how to do it.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is an ampule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

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

Another aspect of the present invention provides a nutraceutical composition for preventing or improving cancer containing the compound represented by Formula 1, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention provides a health functional food composition for preventing or improving hyperlipidemia containing the compound represented by Formula 1, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound represented by Chemical Formula 1 according to the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). Generally, the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene or health control, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.

In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have. 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 conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Furthermore, in addition to the above, the compound represented by the formula (1) according to the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, colorants and neutralizing agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. In addition, the compound represented by the formula (1) of the present invention may contain a fruit flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.

Another aspect of the invention provides a method of treating cancer comprising administering the compound to a subject in need thereof. Another aspect of the invention provides a method for treating hyperlipidemia comprising administering the compound to a subject in need thereof.

Another aspect of the invention provides the compound for use in the prevention or treatment of cancer. Another aspect of the present invention provides the compound for use in the prevention or treatment of hyperlipidemia.

Another aspect of the invention provides the use of said compound for the manufacture of a medicament for use in the prevention or treatment of cancer. Another aspect of the invention provides the use of said compound for the manufacture of a medicament for use in the prevention or treatment of hyperlipidemia.

The nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NSDHL) inhibitor provided in one aspect of the present invention is not only usable as an anticancer agent capable of overcoming the resistance of an EGFR target anticancer agent, but also has an effect that can be used to treat hyperlipidemia. It is supported by the following Examples and Experimental Examples.

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

However, Examples and Experimental Examples described below are merely illustrative of the present invention in one aspect, the present invention is not limited thereto.

Example 1 (Z) -4-((3-((3- (carboxymethyl) -4-oxo-2-thioxothiazolidine-5-ylidene) methyl) -4'-fluorobi Phenyl-4-yloxy) methyl) benzoic acid

The title compound was obtained from the Korean Compound Bank.

(ID: 461974)

Example 2 (Z) -2- (5-((3- (3-chlorophenyl) -1- (4-fluorophenyl) -1H-pyrazol-4-yl) methylene) -4-oxo 2-thioxothiazolidin-3-yl) acetic acid

The title compound was obtained from the Korean Compound Bank.

(ID: 179862)

Example 3 (Z) -2- (5- (2- (benzyloxy) -6-methoxybenzylidene) -4-oxo-2-thioxothiazolidin-3-yl) acetic acid

The title compound was obtained from the Korean Compound Bank.

(ID: 118448)

Example 4 (Z) -2- (5- (2- (2-bromobenzyloxy) -4-hydroxybenzylidene) -4-oxo-2-thioxothiazolidin-3-yl) Acetic acid

The title compound was obtained from the Korean Compound Bank.

(ID: 129671)

Example 5 (Z) -2- (5- (5-Bromo-2- (2-iodobenzyloxy) benzylidene) -4-oxo-2-thioxothiazolidin-3-yl) Acetic acid

The title compound was obtained from the Korean Compound Bank.

(ID: 118459)

The structure of the compound prepared in Examples 1 to 5 are summarized in Table 1 below.

Example	rescue	Example
One		4
2		5
3

Experimental Example 1 Evaluation of Nicotinamide Adenine Dinucleotide Phosphate-dependent Steroid Dehydrogenase (NSDHL) Inhibitory Activity

In order to evaluate the nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NSDHL) inhibitory activity of the example compound provided in one aspect of the present invention, the following experiment was performed.

<1-1> NSDHL expression

Human-derived nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NADP-dependent steroid dehydrogenase-like; NSDHL) was expressed in large quantities through E. coli. The NSDHL gene was inserted into the pET21a plasmid and cloned into E. coli cell line C41 (DE3). After incubating E. coli in Luria Broth medium at 37 ° C, IPTG was added at a time point of OD600 of about 0.7 to express NSDHL and incubated at 37 ° C for 4 hours.

<1-2> Purification and Isolation of NSDHL Protein

The cultured E. coli was centrifuged, the cells were stored at minus 80 ° C., and then crushed by ultrasound, and then purified first using IMAC (Immobilized metallo-affinity chromatography), followed by SEC (Size exclusion chromatography) method. Final purification. The buffer solution for storing NSDHL was 40 mM HEPES (pH 8.0), 150 mM NaCl, 0.5 mM TCEP.

<1-3> Inhibitor Detection and IC Using Amplification of Fluorescence Intensity When Dehydrogenase Couples with NADH ₅₀ Measure

When dehydrogenase binds to NADH, fluorescence intensity is amplified compared to NADH alone. In other words, if the inhibitor is treated while NSDHL, which is a dehydrogenase, is bound to NADH, the intensity of fluorescence will be reduced because NADH is released alone. The fluorescence intensity measurement results of NADH for each NSDHL concentration are shown in FIG. 1. 1 is a graph showing a measurement result of fluorescence intensity of NADH for each NSDHL concentration.

As shown in FIG. 1, when the NSDHL is actually reacted with NADH by concentration, it can be seen that the fluorescence intensity is amplified.

In addition, it was confirmed again through FIG. 2 that the inhibition experiment is possible through NAD +, which is an oxidized form of NADH, but is not measured in the fluorescence measurement range of NADH. Figure 2 is a graph showing the results of NSDHL and NADH conjugate inhibition experiment using NAD +.

<1-4> Lead material screening

Activity assays were performed using 96 well plates, and experiments were performed such that each well contained 200 μM to 1 μM inhibitor at final concentration. Experiment was performed by adding 50 μl, 16 μM NSDHL, 50 mM HEPES (pH 8.0), 20% glycerol to each well, and adding 50 ul, 50 uM NADH, and reacting at room temperature for 10 minutes, followed by SpectraMax M5 (Molecular Devices) Using the instrument, the fluorescence values of each well were read at fluorescence Ex: 340 nm and Em: 460 nm, and the values were corrected by measuring the absorbance of the compound and buffer solution separately. Inhibition of NSDHL of each compound was measured.

The IC ₅₀ (inhibitory concentration at 50%) was calculated using GraphPad Prism software. The results are shown in Table 2 below.

Example	IC 50 (μM)
One	10.43
2	12.78
3	19.85
4	17.78
5	27.13

As shown in Table 2, Examples 1 to 5 can be seen that the compound effectively inhibits nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase.

Preparation Example 1 Preparation of Pharmaceutical Formulation

1-1. Manufacture of powder

500 mg of compound of formula 1

Lactose 100 mg

Talc 10 mg

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

1-2. Manufacture of tablets

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components and tableting according to the manufacturing method of the conventional tablet to prepare a tablet.

1-3. Manufacture of capsule

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

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

1-4. Preparation of Injectables

500 mg of compound of formula 1

Appropriate sterile distilled water for injection

pH adjuster

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

1-5. Preparation of liquid

100 mg of compound of formula 1

10 g of isomerized sugar

5 g of mannitol

Purified water

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

The nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NSDHL) inhibitor provided in one aspect of the present invention is not only usable as an anticancer agent capable of overcoming the resistance of an EGFR target anticancer agent, but also has an effect that can be used to treat hyperlipidemia.

Claims (9)

1. A compound represented by the following formula (1), a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   (In Formula 1,

   R is

   

   or

   

   ego,

   A ¹ is —H or unsubstituted or substituted C _6-10 aryl C _1-5 straight or branched alkoxy, wherein substituted C _6-10 aryl C _1-5 straight or branched alkoxy is C _6-10 aryl C _1-5 straight or branched chain substituted with one or more substituents selected from the group consisting of halogen (-F, -Cl, -Br, -I), nitro, nitrile and -COOH Alkoxy;

   A ² is -H or -OH;

   A ³ is —H, halogen or unsubstituted or substituted C _6-10 aryl, wherein the substituted C _6-10 aryl is one or more halogen-substituted aryl;

   A ⁴ is —H or C _1-5 straight or branched alkoxy;

   B ¹ is —H or unsubstituted or substituted C _6-10 aryl, wherein the substituted C _6-10 aryl is one or more halogen-substituted aryl; And

   B ² is —H or unsubstituted or substituted C _6-10 aryl, wherein the substituted C _6-10 aryl is one or more halogen substituted aryl).
2. The method of claim 1,

   A ¹ is unsubstituted or substituted benzyloxy, wherein substituted benzyloxy is benzyloxy substituted with one or more substituents selected from the group consisting of halogen and -COOH;

   A ² is -H or -OH;

   A ³ is —H, halogen or unsubstituted or substituted phenyl, wherein substituted phenyl is phenyl substituted with one or more halogens;

   A ⁴ is -H or methoxy;

   B ¹ is phenyl substituted with one halogen; And

   Wherein B ² is one halogen substituted phenyl; a solvate, hydrate, or pharmaceutically acceptable salt thereof.
3. The method of claim 1,

   The compound represented by the formula (1) is any one selected from the group of compounds, solvates, hydrates, or pharmaceutically acceptable salts thereof:

   (1) (Z) -4-((3-((3- (carboxymethyl) -4-oxo-2-thioxothiazolidine-5-ylidene) methyl) -4'-fluorobiphenyl- 4-yloxy) methyl) benzoic acid;

   (2) (Z) -2- (5-((3- (3-chlorophenyl) -1- (4-fluorophenyl) -1H-pyrazol-4-yl) methylene) -4-oxo-2 -Thioxothiazolidin-3-yl) acetic acid;

   (3) (Z) -2- (5- (2- (benzyloxy) -6-methoxybenzylidene) -4-oxo-2-thioxothiazolidin-3-yl) acetic acid;

   (4) (Z) -2- (5- (2- (2-bromobenzyloxy) -4-hydroxybenzylidene) -4-oxo-2-thioxothiazolidin-3-yl) acetic acid; And

   (5) (Z) -2- (5- (5-bromo-2- (2-iodobenzyloxy) benzylidene) -4-oxo-2-thioxothiazolidin-3-yl) acetic acid.
4. A pharmaceutical composition for preventing or treating cancer, comprising the compound represented by the formula (1) of claim 1, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
5. The method of claim 4, wherein

   The compound is a pharmaceutical composition, characterized in that it inhibits or inhibits nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NADP-dependent steroid dehydrogenase-like; NSDHL).
6. The method of claim 4, wherein

   The cancer is kidney cancer, bladder cancer, liver cancer, thymic cancer, blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastases cancer, skin cancer, bladder cancer, prostate cancer, lung cancer, osteosarcoma, fibrotic A pharmaceutical composition, characterized in that at least one selected from the group consisting of tumors, brain tumors.
7. A pharmaceutical composition for preventing or treating hyperlipidemia, comprising the compound represented by Formula 1 of claim 1, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The method of claim 7, wherein

   The compound is a pharmaceutical composition, characterized in that it inhibits or inhibits nicotinamide adenine dinucleotide phosphate-dependent steroid dehydrogenase (NADP-dependent steroid dehydrogenase-like; NSDHL).
9. Claim 1, a health functional food composition for preventing or improving cancer or hyperlipidemia containing a compound represented by the formula (1), solvates, hydrates, or pharmaceutically acceptable salts thereof as an active ingredient.

Images