Novel compound and pharmaceutical composition for preventing or treating metabolic diseases comprising same

Abstract

The present application relates to a compound represented by chemical formula 1: (wherein, in chemical formula 1, R1 to R3 are each independently hydrogen, substitutable linear or branched C1-C20 alkyl, substitutable C3-C20 cycloalkyl, substitutable C6-C20 aryl, or a halogen, wherein the substitution is substitution with oxygen, nitrogen, sulfur, linear or branched C1-C6 alkyl, C6-C20 aryl, a halogen, or a combination thereof.

Description

Novel compound and pharmaceutical composition containing the same for preventing or treating metabolic diseases

[0001] The present invention relates to a novel compound and a pharmaceutical composition containing the same for the prevention or treatment of metabolic diseases.

[0002] The global obesity population continues to increase, and the World Health Organization (WHO) predicts that metabolic disorders caused by overweight and obesity will also increase. Currently, approximately 34% of obese adults in the United States have non-alcoholic fatty liver disease (non-alcoholic fatty liver disease), which can eventually progress to chronic liver diseases such as liver failure, cirrhosis, and hepatocellular carcinoma (Cohen et al. 2011).

[0003] Nonalcoholic fatty liver disease includes simple nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), which are diseases in which fat accumulates in the liver. Steatohepatitis (NASH) is a progressive disease that includes inflammation, cellular fibrosis, and cell damage after going through the prodromal stage of simple fatty liver disease (NAFLD) in which excess fat accumulates in the liver. It has been reported that there is a significantly high possibility of causing cirrhosis and liver cancer later (Cohen, et al 2011), and it has been reported that 80% of adults with nonalcoholic fatty liver disease develop metabolic diseases such as insulin resistance, diabetes, and heart disease (Stefan, et al. 2008; Cohen, et al 2011).

[0004] Meanwhile, histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from specific histone sites in promoter and enhancer regions, which are essential for regulating cellular gene transcription. HDACs also indirectly regulate gene expression by mediating the acetylation of non-histone proteins, such as DNA-binding proteins, transcription factors, signal transduction factors, DNA repair proteins, and chaperone proteins.

[0005] HDAC inhibitors have been described to induce growth arrest with subsequent differentiation or apoptosis in tumor cells, while normal cells are unaffected. The efficacy of HDAC inhibitors has been demonstrated in animal models of various cancer types, including breast, prostate, lung, and stomach cancers, neuroblastoma, and leukemia. However, studies on the anti-fatty liver effects of HDAC inhibitors are limited.

[0006] Therefore, there is a need for the development of a compound having histone deacetylase inhibitory activity and a composition for preventing or treating metabolic diseases containing the compound as an active ingredient.

[0007] The background technology of this application, Korean Patent Publication No. 10-2024-0012958, relates to an anti-obesity composition containing an HDAC inhibitor.

[0008] The present invention is intended to solve the problems of the above-mentioned prior art and provides a novel compound having histone deacetylase inhibitory activity.

[0009] Additionally, a method for preparing the compound is provided.

[0010] In addition, a pharmaceutical composition for preventing or treating metabolic diseases containing the compound as an active ingredient is provided.

[0011] In addition, a health functional food for preventing or improving metabolic diseases, which contains the compound as an active ingredient, is provided.

[0012] However, the technical tasks to be achieved by the embodiments of the present invention are not limited to the technical tasks described above, and other technical tasks may exist.

[0013] As a technical means for achieving the above-mentioned technical task, the first aspect of the present invention provides a compound represented by the following chemical formula 1:

[0014] [Chemical Formula 1]

[0015]

[0016] (In the above chemical formula 1,

[0017] R 1 Inland R 3 are each independently hydrogen, linear or branched C1-C which may be substituted 20 Alkyl, which may be substituted C3-C 20 Cycloalkyl, optionally substituted C6-C 20 is aryl or halogen,

[0018] The above substitutions are oxygen, nitrogen, sulfur, linear or branched C1-C6 alkyl, C6-C 20 (substituted by aryl, halogen, or a combination thereof).

[0019] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may include, but is not limited to, the following compounds:

[0020] .

[0021] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may have an inhibitory activity against histone deacetylase, but is not limited thereto.

[0022] According to one embodiment of the present invention, the histone deacetylase may include, but is not limited to, HDAC11 (Histone Deacetylase 11).

[0023] According to one embodiment of the present invention, the expression of AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) may be suppressed by the compound represented by the chemical formula 1, but is not limited thereto.

[0024] According to one embodiment of the present invention, glucose clearance and glucose tolerance may be improved by the compound represented by the chemical formula 1, but are not limited thereto.

[0025] In addition, the second aspect of the present invention provides a method for preparing a compound represented by the following chemical formula 1, comprising the step of reacting a hydrazide compound and an aldehyde compound:

[0026] [Chemical Formula 1]

[0027]

[0028] (In the above chemical formula 1,

[0029] R 1 Inland R 3 are each independently hydrogen, linear or branched C1-C which may be substituted 20 Alkyl, which may be substituted C3-C 20 Cycloalkyl, optionally substituted C6-C 20 is aryl or halogen,

[0030] The above substitutions are oxygen, nitrogen, sulfur, linear or branched C1-C6 alkyl, C6-C 20 (substituted by aryl, halogen, or a combination thereof).

[0031] According to one embodiment of the present invention, the hydrazide compound may include, but is not limited to, thiazole-5-carbohydrazide hydrochloride.

[0032] According to one embodiment of the present invention, the aldehyde compound may include, but is not limited to, hexadecanal.

[0033] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may include, but is not limited to, the following compounds:

[0034] .

[0035] In addition, the third aspect of the present invention provides a pharmaceutical composition for preventing or treating a metabolic disease, comprising a compound according to the first aspect of the present invention as an active ingredient.

[0036] According to one embodiment of the present invention, the metabolic disease may include, but is not limited to, one selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, diabetes, hypertension, hyperlipidemia, and combinations thereof.

[0037] In addition, the fourth aspect of the present invention provides a health functional food for preventing or improving metabolic diseases, which comprises a compound according to the first aspect of the present invention as an active ingredient.

[0038] The above-described problem-solving methods are merely exemplary and should not be construed as limiting the present invention. In addition to the exemplary embodiments described above, additional embodiments may be included in the drawings and detailed description of the invention.

[0039] The compounds described herein exhibit remarkable fatty liver suppression effects in a high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) animal model, and thus can be used for the prevention or treatment of liver disease. Specifically, they can significantly reduce the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), markers of liver damage, in high-fat diet-fed mice, and improve insulin resistance induced by a high-fat diet.

[0040] In addition, although SIS17, a conventional HDAC11 inhibitor, has been shown to be effective in controlling non-alcoholic fatty liver disease (NAFLD), it has the problem of toxicity. On the other hand, the novel compound according to the present invention, which is a similar compound to SIS17, not only exhibits HDAC11 inhibitory activity but also has no side effects such as toxicity, and therefore has the advantage of being more effective in preventing or treating NAFLD than the conventional SIS17.

[0041] However, the effects that can be obtained from this center are not limited to the effects described above, and other effects may exist.

[0042] Figure 1 shows the structural formula and molecular weight of compounds according to examples and comparative examples of the present invention.

[0043] Figure 2 shows the results of evaluating the HDAC11 activity inhibition effect of compounds according to the examples and comparative examples of the present invention.

[0044] Figure 3 shows the results of a glucose tolerance test of mice administered compounds according to the examples and comparative examples of the present invention.

[0045] Figure 4 shows the results of an insulin sensitivity test of mice administered compounds according to the examples and comparative examples of the present invention.

[0046] Figure 5 shows the results of analyzing the ALT and AST expression levels of mice administered compounds according to the examples and comparative examples of the present invention.

[0047] Figure 6 shows the results of measuring the liver weight of mice administered with compounds according to the examples and comparative examples of the present invention.

[0048] Figure 7 shows the results of H&E staining of liver tissue of mice administered compounds according to the examples and comparative examples of the present invention.

[0049] Figure 8 shows the results of Oil Red O staining of liver tissue of mice administered compounds according to the examples and comparative examples of the present invention.

[0050] Below, with reference to the attached drawings, embodiments of the present invention are described in detail to facilitate easy implementation by those skilled in the art. However, the present invention can be implemented in various different forms and is not limited to the embodiments described herein. In the drawings, irrelevant parts have been omitted for clarity, and similar reference numerals have been used throughout the specification to indicate similar elements.

[0051] Throughout this specification, when a part is said to be "connected" to another part, this includes not only cases where it is "directly connected" but also cases where it is "electrically connected" with another element in between.

[0052] Throughout this specification, when it is said that a member is located “on,” “above,” “upper,” “lower,” “lower” or “lower” another member, this includes not only cases where the member is in contact with the other member, but also cases where another member exists between the two members.

[0053] Throughout this specification, whenever a part is said to "include" a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

[0054] The terms "about," "substantially," and the like, as used herein, are used to mean at or near the numerical value when manufacturing and material tolerances inherent to the meanings referred to are presented, and are used to prevent unscrupulous infringers from unfairly exploiting disclosures that contain precise or absolute numerical values ​​to aid understanding of the present disclosure. Furthermore, throughout the present disclosure, the terms "step of ~" or "step of ~" do not mean "step for ~."

[0055] Throughout this specification, the term "combination thereof" included in the expressions in the Makushi format means one or more mixtures or combinations selected from the group consisting of the components described in the expressions in the Makushi format, and means including one or more selected from the group consisting of said components.

[0056] Throughout this specification, references to “A and / or B” mean “A, B, or A and B.”

[0057] Hereinafter, the novel compounds of the present invention and pharmaceutical compositions containing them as active ingredients for the prevention or treatment of metabolic diseases will be described in detail with reference to embodiments, examples, and drawings. However, the present invention is not limited to these embodiments, examples, and drawings.

[0058]

[0059] As a technical means for achieving the above-mentioned technical task, the first aspect of the present invention provides a compound represented by the following chemical formula 1:

[0060] [Chemical Formula 1]

[0061]

[0062] (In the above chemical formula 1,

[0063] R 1 Inland R 3 are each independently hydrogen, linear or branched C1-C which may be substituted20 Alkyl, which may be substituted C3-C 20 Cycloalkyl, optionally substituted C6-C 20 is aryl or halogen,

[0064] The above substitutions are oxygen, nitrogen, sulfur, linear or branched C1-C6 alkyl, C6-C 20 (substituted by aryl, halogen, or a combination thereof).

[0065] The compounds described herein exhibit remarkable fatty liver suppression effects in a high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) animal model, and thus can be used for the prevention or treatment of liver disease. Specifically, they can significantly reduce the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), markers of liver damage, in high-fat diet-fed mice, and improve insulin resistance induced by a high-fat diet.

[0066] SIS17, a conventional HDAC11 inhibitor, has been shown to be effective in controlling non-alcoholic fatty liver disease (NAFLD), but has been associated with toxicity. In contrast, the novel compound disclosed herein, a similar compound to SIS17, not only exhibits HDAC11 inhibitory activity but also has no adverse side effects, such as toxicity, making it more effective than the conventional SIS17 in the prevention or treatment of NAFLD.

[0067] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may include, but is not limited to, the following compounds:

[0068] .

[0069] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may have an inhibitory activity against histone deacetylase, but is not limited thereto.

[0070] According to one embodiment of the present invention, the histone deacetylase may include, but is not limited to, HDAC11 (Histone Deacetylase 11).

[0071] The compound according to the present invention exhibits inhibitory activity of histone deacetylase (particularly, HDAC 11), and thus can be included as an active ingredient in a pharmaceutical composition for preventing or treating metabolic diseases, and exhibit effects such as regulating the pathogenesis of fatty liver, anti-inflammatory and antioxidant effects, improving insulin resistance, and inhibiting the progression of fibrosis.

[0072] According to one embodiment of the present invention, the expression of AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) may be suppressed by the compound represented by the chemical formula 1, but is not limited thereto.

[0073] The above AST and ALT are indicators indicating liver cell damage, and the compound according to the present invention can protect the liver by reducing hepatocyte damage by suppressing the expression of the above AST and ALT, and can prevent or improve the progression of diseases such as hepatitis, cirrhosis, fatty liver, and alcoholic liver disease, and can promote regeneration and functional recovery of the liver.

[0074] According to one embodiment of the present invention, glucose clearance and glucose tolerance may be improved by the compound represented by the chemical formula 1, but are not limited thereto.

[0075] The compound according to the present invention can improve glucose clearance rate and glucose tolerance, thereby increasing the responsiveness of cells to insulin, thereby improving insulin resistance, improving blood sugar control, and reducing the risk of developing metabolic diseases such as obesity, fatty liver, and hyperlipidemia.

[0076]

[0077] In addition, the second aspect of the present invention provides a method for preparing a compound represented by the following chemical formula 1, comprising the step of reacting a hydrazide compound and an aldehyde compound:

[0078] [Chemical Formula 1]

[0079]

[0080] (In the above chemical formula 1,

[0081] R 1 Inland R 3 are each independently hydrogen, linear or branched C1-C which may be substituted 20 Alkyl, which may be substituted C3-C 20 Cycloalkyl, optionally substituted C6-C 20 is aryl or halogen,

[0082] The above substitutions are oxygen, nitrogen, sulfur, linear or branched C1-C6 alkyl, C6-C 20 (substituted by aryl, halogen, or a combination thereof).

[0083] Regarding the manufacturing method according to the third aspect of the present application, detailed descriptions of parts overlapping with the first aspect of the present application have been omitted, but even if the descriptions have been omitted, the contents described in the first aspect of the present application can be equally applied to the second aspect of the present application.

[0084] According to one embodiment of the present invention, the hydrazide compound may include, but is not limited to, thiazole-5-carbohydrazide hydrochloride.

[0085] According to one embodiment of the present invention, the aldehyde compound may include, but is not limited to, hexadecanal.

[0086] According to one embodiment of the present invention, the compound represented by the chemical formula 1 may include, but is not limited to, the following compounds:

[0087] .

[0088]

[0089] In addition, the third aspect of the present invention provides a pharmaceutical composition for preventing or treating a metabolic disease, comprising a compound according to the first aspect of the present invention as an active ingredient.

[0090] Regarding the pharmaceutical composition for preventing or treating metabolic diseases according to the third aspect of the present invention, detailed descriptions of parts overlapping with the first aspect and / or the second aspect of the present invention are omitted, but even if the descriptions are omitted, the contents described in the first aspect and / or the second aspect of the present invention can be equally applied to the third aspect of the present invention.

[0091] According to one embodiment of the present invention, the metabolic disease may include, but is not limited to, one selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, diabetes, hypertension, hyperlipidemia, and combinations thereof.

[0092]

[0093] In addition, the fourth aspect of the present invention provides a health functional food for preventing or improving metabolic diseases, which comprises a compound according to the first aspect of the present invention as an active ingredient.

[0094] Regarding the health functional food for preventing or improving metabolic diseases according to the fourth aspect of the present invention, detailed descriptions of parts overlapping with the first aspect and / or the second aspect of the present invention have been omitted. However, even if the descriptions have been omitted, the contents described in the first aspect and / or the second aspect of the present invention may be equally applied to the fourth aspect of the present invention.

[0095] The present invention will be described in more detail through the following examples; however, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0096]

[0097] [Example] HS2204 synthesis

[0098] Figure 1 shows the structural formula and molecular weight of compounds according to examples and comparative examples of the present invention.

[0099] Referring to FIG. 1, SIS17, known as an inhibitor of HDAC11, exhibits excellent selectivity for HDAC11 and strong activity inhibition ability due to its structure. The following description describes the process of synthesizing a compound (HS2204) according to the example of the present disclosure having a structure similar to SIS17 by changing the process of synthesizing SIS17.

[0100] 1. Analysis equipment

[0101] To confirm the structure of the synthesized product, nuclear magnetic resonance spectrum ( 1 H NMR, 13 C NMR) was performed using Bruker Magnet System 500'54 Ascend, and CDCl3 was used as the solvent.

[0102] 2. Synthesis method

[0103] Method 1: Manufacturing process of thiazole carboxyhydrazide compound (3)

[0104] [Reaction Formula 1]

[0105]

[0106] First, 50 mg (0.39 mmol) of thiazole-5-carboxylic acid (1) was dissolved in 4 mL of methylene chloride, and 52.7 mg (0.40 mmol) of tert-butyl carbazate and 76.3 mg (0.40 mmol) of EDCI were added, and the mixture was stirred at room temperature overnight. H2O was added to quench the reaction, and the mixture was extracted with methylene chloride. The organic layer was washed with H2O and dried over anhydrous MgSO4. After removing the solvent under vacuum, the residue was purified by column chromatography using 50% ethyl acetate in n-hexane to obtain 87.1 mg (yield: 92%) of 2-(thiazole-5-carbonyl)hydrazine-1-carboxylate (2).

[0107] 1 H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.37 (s, 1H), 1.50 (s, 9H).

[0108] Next, 50 mg (0.21 mmol) of 2-(thiazole-5-carbonyl)hydrazine-1-carboxylate (2) was dissolved in 2 mL of MeOH, and 0.51 mL (2.06 mmol) of 4 M HCl in 1,4-Dioxane was added. The mixture was stirred at room temperature until the reaction was complete, as confirmed by TLC. After removing the solvent under vacuum, 36.9 mg of thiazole-5-carbohydrazide hydrochloride (3) was obtained, which was used for the next reaction without purification.

[0109] Method 2: Manufacturing process of Hexadecanal (5)

[0110] [Reaction Formula 2]

[0111]

[0112] 284.5 mg (1.32 mmol) of pyridinium chlorochromate was dissolved in 4 mL of methylene chloride, and a solution of 200 mg (0.83 mmol) of cetyl alcohol4 in 4 mL of methylene chloride was added. The mixture was stirred at room temperature until the reaction was complete, as confirmed by TLC. After removing the solvent under vacuum, the residue was purified by column chromatography using 16% ethyl acetate in n-hexane, obtaining 182.6 mg (yield: 92%) of hexadecanal (5).

[0113] Method 3: Preparation of N'-hexadecylthiazole-5-carbohydrazide (6) (HS2204)

[0114] [Reaction Formula 3]

[0115]

[0116] 49 mg (0.21 mmol) hexadecanal (5) was dissolved in 1 mL methylene chloride, 3.8 mg (0.021 mmol) p-toluenesulfonic acid monohydrate was added, and the mixture was stirred for 30 minutes. After stirring for 30 minutes, 36.9 mg (0.21 mmol) thiazole-5-carbohydrazide hydrochloride (3) dissolved in MeOH was added, and the mixture was stirred for 1 hour. Then, a solution of 38.6 mg (6.14 mmol) sodium cyanoborohydride in MeOH was added, and the mixture was stirred for 1 hour. The reaction was terminated by adding saturated aqueous NaHCO3, and the mixture was extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous Na2SO4. N'-hexadecylthiazole-5-carbohydrazide (6) was purified by column chromatography using 50% ethyl acetate in methylene chloride, and 12.8 mg (yield: 17% in 3 steps) was obtained.

[0117] The results of nuclear magnetic resonance spectrum analysis of the synthesized N'-hexadecylthiazole-5-carbohydrazide (6) are as follows:

[0118] 1 H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.29 (s, 1H), 2.97 - 2.92 (m, 2H), 1.56 - 1.50 (m, 2H), 1.25 (s, 26H), 0.88 (s, 3H);

[0119] 13 C NMR (126 MHz, CDCl3) δ 160.56, 159.82, 156.47, 143.98, 52.46, 32.07, 29.84, 29.80, 29.74, 29.71, 29.64, 29.57, 29.50, 28.12, 27.20, 22.83, 14.25.

[0120] Through this, it was confirmed that a compound (HS2204) represented by the following structural formula was synthesized:

[0121] .

[0122] [Comparative Example] SIS17

[0123] SIS17, a conventional HDAC inhibitor, was used as a comparative example.

[0124]

[0125] [Experimental Example 1] Confirmation of the HDAC11 activity inhibition effect of Example (HS2204)

[0126] To determine whether the compound (HS2204) according to the present example, which is a SIS17 derivative, has the ability to inhibit the activity of HDAC11, the HDAC11 Fluorogenic Assay Kit (BPS Bioscience) was used. Specifically, the principle of reacting Human HDAC11 with a Fluorogenic substrate and treating it with Lysine Developer to create a fluorophore and fluoresce was utilized, and screening was conducted in a modified 384-well plate type. Trichostatin A (TSA), a known HDAC inhibitor, was used as a control substance.

[0127] First, HS2204 was diluted in assay buffer to a final concentration of 50 μM (5X the final concentration of 10 μM), and the control substance, TSA (Test inhibitor), was also diluted in 15 μL buffer in the same manner as the sample.

[0128] Next, 2 μl of the diluted drug was dispensed into a 384-well black bottom plate, and 4 μl of the HDAC11 enzyme was diluted in assay buffer to 10 ng / well in a 384-well plate.

[0129] Next, the substrate (Fluorogenic HDAC substrate class 2A) was diluted in assay buffer to a final concentration of 2 μM, 4 μl was added to each well, and the reaction was performed at 37°C for 30 minutes. An equal amount of 10 μl of HDAC Developer (2x) was added and the reaction was performed at room temperature for 15 minutes.

[0130] Next, fluorescence was measured at Excitation 355 nm / Emission 460 nm using a microplate reader, SpectraMax iD3 (Molecular Devices), and the measured values ​​were analyzed using the Nonlinear curve fit (three parameters) method using the GraphPad Prism 10.2.1 program.

[0131] Figure 2 shows the results of evaluating the HDAC11 activity inhibition effect of compounds according to the examples and comparative examples of the present invention.

[0132] Referring to Figure 2, it was confirmed that the example (HS2204) had an active inhibitory effect on HDAC11.

[0133]

[0134] [Experimental Example 2] Confirmation of the effect of Example (HS2204) on improving high-fat diet-induced insulin resistance.

[0135] In liver tissue, insulin plays a crucial role in regulating gluconeogenesis. Therefore, we investigated whether SIS17 and HS2204 could reverse high-fat-induced insulin resistance using the insulin tolerance test (ITT) and the glucose tolerance test (GTT).

[0136] Glucose tolerance test (GTT)

[0137] Insulin tolerance tests were performed on mice administered SIS17 or HS2204 for 4 weeks, control (HFD), and normal (ND) mice. After fasting for 6 h, a total dose of 0.7 U / kg insulin (Novolin R, Novodisk, Denmark) was administered intraperitoneally. The blood glucose-lowering effect of insulin was measured using a simple blood glucose meter (Accucheck, Roche, Germany) from the tail vein before and 15, 30, 60, and 120 min after insulin injection.

[0138] Insulin sensitivity test (ITT, insulin tolerance test)

[0139] Glucose tolerance tests were performed on mice administered SIS17 or HS2204 for 15 weeks, control (HFD), and normal (ND) mice. After fasting for 6 h, 1 g / kg total glucose was administered intraperitoneally. Recovery after glucose-induced elevations in blood glucose was measured using a simple blood glucose meter (Accucheck, Roche, Germany) from the tail vein before and 15, 30, 60, and 120 min after glucose injection.

[0140] Figure 3 shows the results of a glycemic load test of compounds according to examples and comparative examples of the present disclosure, and Figure 4 shows the results of an insulin sensitivity test of compounds according to examples and comparative examples of the present disclosure. In this regard, ND and HFD represent the normal diet group and the high fat diet group, respectively.

[0141] Referring to Figures 3 and 4, it was confirmed that administration of SIS17 or HS2204 could significantly improve the blood sugar-lowering effect induced by insulin.

[0142]

[0143] [Experimental Example 3] Confirmation of the effect of controlling liver tissue damage of Example (HS2204)

[0144] To confirm liver tissue damage, ALT (alanine amino transferase) and AST (aspartate aminotransferase) were analyzed.

[0145] Figure 5 shows the results of analyzing the ALT and AST expression levels of high-fat diet mice administered compounds according to the examples and comparative examples of the present invention.

[0146] Referring to Figure 5, it was confirmed that the high-fat diet group (HFD) showed a significant increase in ALT and AST compared to the normal group (ND), and it was confirmed that the high-fat diet group administered SIS17 or HS2204 showed a significant decrease in AST and ALT present in the blood.

[0147]

[0148] [Experimental Example 4] Measurement of the efficacy of controlling high-fat diet-induced fatty liver disease in comparative examples (SIS17) and examples (HS2204).

[0149] Liver weight measurement

[0150] After sacrificing the mice and isolating the liver tissue, the liver weight was measured to determine whether fat was reduced.

[0151] Figure 6 shows the results of measuring the liver weight of mice administered with compounds according to the examples and comparative examples of the present invention.

[0152] Referring to Figure 6, it was confirmed that mice administered HS2204 showed reduced liver weight compared to the control group (HFD).

[0153] H&E staining method technology

[0154] First, the liver was removed by sacrificing the mouse, fixed with 4% paraformaldehyde at 4°C for 24 hours, washed with running water, embedded in paraffin, and sectioned into 5 μm thick tissues.

[0155] Next, the sectioned tissue was placed on a coated slide, deparaffinized with xylene, and dehydrated in a series of alcohols (100%, 95%, 90%, 80%, and 70% ethanol (EtOH)) before immunohistological staining.

[0156] Next, the sectioned tissue was stained with Harry's hematoxylin for 5 minutes, washed in running water for 5 minutes, and destained with 1% HCl alcohol and ammonia. After washing in running water for 10 minutes, it was counterstained with eosin stain for 1 minute, dehydrated in the reverse direction of the water flow, mounted, and observed under a microscope (Olympus).

[0157] Figure 7 shows the results of H&E staining of liver tissue of mice administered compounds according to the examples and comparative examples of the present invention.

[0158] Referring to Figure 7, it was confirmed that mice administered HS2204 showed a fatty liver reduction effect.

[0159] Oil Red O dyeing method technology

[0160] First, the liver tissue isolated from the mouse was washed, dried, and fixed in a frozen tissue embedding agent, Optical cutting temperature (OCT) compound (SAKURA, USA), to create a frozen tissue block, which was then stored in a -70°C freezer.

[0161] Next, liver tissue sections cut into 10 ㎛ thick sections using a microtome were quickly attached to slides, dried at room temperature for about 1 hour, and then stored in a -70℃ deep freezer.

[0162] Next, 3g / ℓ of Oil-red-O (Sigma, USA) powder was added to a 99% isopropanol solution and shaken at room temperature to make a saturated solution. The solution was stored in a 60℃ oven, and immediately before dyeing, the saturated solution and distilled water were mixed in a ratio of 6:4 and filtered through Whatman Filter Paper #2 (Whatman, England) for use.

[0163] Next, the slides stored in a -70℃ deep freezer were taken out just before the experiment and dried at room temperature for 1 to 2 hours. The slides were then washed in water and then in 70% isopropanol for 10 minutes.

[0164] Next, the slides were placed in filtered Oil-red-O and stained for 15 minutes, then placed in 70% isopropanol and destained for 3 minutes. The slides were then rinsed in running water for 5 minutes, stained in hematoxylin solution (Sigma, USA) for 5 minutes, and rinsed again in running water for 5 minutes. After staining, the slides were sealed with Faramount Aqueous Mounting Medium (Dako. cat. S3025, Japan) and observed under a microscope.

[0165] Figure 8 shows the results of Oil Red O staining of liver tissue of mice administered compounds according to the examples and comparative examples of the present invention.

[0166] Referring to Figure 8, it was confirmed that mice administered HS2204 showed a fatty liver reduction effect.

[0167]

[0168] The above description of the present invention is for illustrative purposes only, and those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single entity may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined manner.

[0169] The scope of the present invention is indicated by the claims described below rather than the detailed description above, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. A compound represented by the following chemical formula 1: [Chemical Formula 1] (In the above chemical formula 1, R 1 Inland R 3 are each independently hydrogen, linear or branched C1-C which may be substituted 20 Alkyl, which may be substituted C3-C 20 Cycloalkyl, optionally substituted C6-C 20 is aryl or halogen, The above substitutions are oxygen, nitrogen, sulfur, linear or branched C1-C6 alkyl, C6-C 20 (substituted by aryl, halogen, or a combination thereof).

2. In paragraph 1, The compound represented by the above chemical formula 1 is a compound including the following compounds: .

3. In paragraph 1, The compound represented by the above chemical formula 1 has an inhibitory activity against histone deacetylase. compound.

4. In paragraph 3, The above histone deacetylase comprises HDAC11 (Histone Deacetylase 11). compound.

5. In paragraph 1, The expression of AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) is inhibited by the compound represented by the above chemical formula 1. compound.

6. In paragraph 1, The glucose clearance and glucose tolerance are improved by the compound represented by the above chemical formula 1. compound.

7. Step of reacting a hydrazide compound and an aldehyde compound; including, A method for producing a compound represented by the following chemical formula 1: [Chemical Formula 1] (In the above chemical formula 1, R 1 Inland R 3 are each independently hydrogen, linear or branched C1-C which may be substituted 20 Alkyl, which may be substituted C3-C 20 Cycloalkyl, optionally substituted C6-C 20 is aryl or halogen, The above substitutions are oxygen, nitrogen, sulfur, linear or branched C1-C6 alkyl, C6-C 20 (substituted by aryl, halogen, or a combination thereof).

8. In paragraph 7, The above hydrazide compound comprises thiazole-5-carbohydrazide hydrochloride. Method for preparing a compound.

9. In paragraph 7, The above aldehyde compound comprises hexadecanal. Method for preparing a compound.

10. In paragraph 7, A method for producing a compound represented by the above chemical formula 1, which comprises the following compound: .

11. A pharmaceutical composition for preventing or treating metabolic diseases, comprising a compound according to any one of claims 1 to 6 as an active ingredient.

12. In paragraph 11, The above metabolic disease includes one selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), obesity, diabetes, hypertension, hyperlipidemia, and combinations thereof. A pharmaceutical composition for the prevention or treatment of metabolic diseases.

13. A health functional food for preventing or improving metabolic diseases, comprising a compound according to any one of clauses 1 to 6 as an active ingredient.

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