KR20180010629A - A novel cinnamoyl derivative compounds and pharmaceutical composition comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to novel cinnamoyl derivative compounds and a pharmaceutical composition comprising the same as an active ingredient. The cinnamoyl derivatives which are effective components are obtained by separating and purifying a Solidago virgaurea extract using chromatography. Also, the compounds inhibit aldose reductase, thereby being used for treating and preventing diabetes, cataract, colon cancer, asthma or chronic obstructive pulmonary disease.

Description

TECHNICAL FIELD The present invention relates to novel cinnamoyl derivative compounds and pharmaceutical compositions containing them as active ingredients,

The present invention relates to a novel cinnamoyl derivative compound and a pharmaceutical composition containing the same as an active ingredient.

Recently, with the recent economic development and the high growth of science and technology, advanced age-type aging and adult diseases are increasing rapidly. The cause of this is the westernization of the stress and dietary habits of modern people, excessive nutrition and decreased physical activity, and the death rate of heart and cerebrovascular disease, which is a complication accompanied by actual obesity, is 1 or 2, Has been suggested as a cause of various adult diseases.

Among them, diabetes mellitus (DM) is a progressive disease associated with obesity, often characterized by insulin deficiency and insulin resistance, or both. Obesity is associated with more than half of adult diabetic patients and obesity is an important cause of diabetes mellitus.

Specifically, obesity is an important risk factor for type 2 diabetes, and the incidence increases with the degree and duration of obesity and body fat distribution. As the BMI increases, the incidence of diabetes increases. The incidence of diabetes is reported to be 40 times higher when the BMI exceeds 35 ㎏ / ㎡ compared to those with a body mass index of 23 ㎏ / ㎡. The report that the prevalence of obesity in Pima Indians is 80% and the incidence of diabetes is 40% reflects the close correlation between obesity and diabetes. In addition to fat mass, fat distribution is associated with the occurrence of diabetes and its frequency increases with central obesity. Obesity and the occurrence of diabetes mellitus are closely related, but in fact, only about 20% to 30% of obese patients develop diabetes. This is related to the degree of insulin secretion in the pancreas. Diabetes mellitus appears from the time insulin secretion can not overcome the insulin resistance seen in obesity. Also, although there is a difference according to race, most of the patients with type 2 diabetes are obese, but their weight decreases with the progression of diabetes and it develops into a non - obesity type. This increase in weight plays an important role in the development of diabetes, and the treatment of obesity plays an important role in the prevention and treatment of diabetes.

Accordingly, the market for obesity drugs in Korea is estimated to be over 80 billion won, which is growing by about 10% every year. Anti-obesity Functional food products have been scientifically recognized for their functionality. Pyrus Pusan and CLA (Conjugated Linolic Acid) are found in the market, and CLA induces the suicide mechanism of fat cells to reduce the number of fat cells. CLA's patent rights are sold in the market in foreign countries, and the products are produced and sold by paying royalties to foreign countries.

At one time, the advent of anti-obesity drugs, such as Xenical and Reductil, led to the formation of a 50 billion-dollar market, but sales were banned due to cardiovascular disease, damage to the large intestine mucosa and side effects.

Pancreatic lipase acts as a key enzyme that breaks down triglyceride into 2-monoacyl glycerol and fatty acids. Representative pancreatic lipase inhibitors are tetrahydrolipstatin, a derivative of lipstatin derived from Streptomyces toxitricini, which is excellent in efficacy to inhibit about 30% of the fat ingested and is currently on the market as a medicinal product, , Hypersensitivity, cholestasis, and other side effects.

On the other hand, in the case of diabetes and diabetic complications, an increase in fasting and postprandial blood glucose causes acute and chronic complications (including microvascular and macrovascular complications) which lead to blindness, kidney failure, heart disease, stroke and amputation macro-vascular). Improved blood glucose control has been shown to reduce the risk of such diabetic complications.

Because of the progressive nature of these diseases, an evolving therapeutic strategy is needed to maintain blood glucose control. There are two types of diabetes: type 1 diabetes, or childhood diabetes or insulin dependent diabetes mellitus (IDDM), and type 2 diabetes, or adult type diabetes or non-insulin dependent diabetes mellitus (NIDDM). Patients with type 1 diabetes are absolutely insulin deficient due to immunological destruction of pancreatic beta cells that synthesize and secrete insulin. Type 2 diabetes is characterized by a more complex and relative insulin deficiency, reduced insulin action, and insulin resistance. Early-onset NIDDM or adult-onset diabetes mellitus (MODY) share many of the most common forms of NIDDM in the middle-aged (Rotter et al., 1990). A clear mode of inheritance (autosomal dominant) was observed for MODY. At least three distinct mutations have been identified in the MODY family (Bell et al., 1996).

It is known that inhibition of the polyol pathway, Aldose reductase, which is one of the main causes of diabetic complications, plays an important role in the treatment and prevention of diabetic complications.

Here, aldose reductase is an enzyme which is generally present in a region leading to the eyes or the human body. In normal conditions, aldose reductase has a very low affinity for glucose. In high glucose concentration, aldose reductase is activated, excess glucose is reduced to sorbitol, and sorbitol is converted to fructose by sorbitol dehydrogenase. This fructose is about 10 times faster in the rate of nonenzymatic glycation of protein than glucose. Thus, a high concentration of fructose binds to the protein and ultimately accelerates the formation of the final glycation end product (AGE).

Aldose reductase is also known to be closely related to diseases such as diabetes, cataract, colon cancer, asthma or COPD. As described above, many studies have been made to treat diabetes by inhibiting Aldose reductase. In addition, Satish Srivastava, a professor at the University of Texas Medical School's Galveston Medical Center, confirmed that aldose reductase is the key to excessive mucus production in patients with asthma or chronic obstructive pulmonary disease According to the results, it was found that the aldose reductase was essential for the proliferation of goblet cells (mucus-producing endothelial cells) seen in asthma or COPD by cell culture using laboratory rats. In goblet cell proliferation, pollen, mold, Exposure to allergens, such as ticks, causes a series of biochemical reactions that transform cells that form the lungs from normal to goblet cells, resulting in excessive mucus production.

In healthy people's lungs, goblet cells are very few, but asthma patients die (about 5,000 people per year in the United States), and the fact that these goblet cells are so large that they cause asthma or chronic obstructive pulmonary disease And that the inhibition of Aldose reductase should be actively studied.

Aldose reductase has a close relationship with cataracts. Cataracts appear to accumulate in the lens of the eye with excessive aldose reductase. Therefore, it is known that the action of aldose reductase can be suppressed and treated.

In addition, researchers at the University of Texas Medical Branch recently reported that inhibiting the activity of major enzymes in rats can prevent colon cancer, and the researchers found that Aldose reductase inhibited inflammation and malignant cell growth , And reported that the inhibition of this enzyme, without any obvious side effects, in mice experiments with colon cancer resulted in complete interruption of tumor growth.

It has been reported that the aldose reductase inhibitors zopolrestat, ponalrestat, sorbinil, tolrestat, fidarestat, ranireatat and epalrestat, which have been developed so far, prevent and delay diabetic complications in various animal experiments.

However, in clinical practice, zopolrestat and ponalrestat were ineffective and stopped during development due to side effects such as sorbinil hypersensitivity and tolrestat liver dysfunction. Clinical trials of ranireatat and fidarestat are underway in Japan and the United States. Epalrestat has not been approved by the US Food and Drug Administration (FDA), but has been approved and marketed only in Japan in 1992.

Therefore, there is an increasing demand for the development of a pharmaceutical composition which can be used for the treatment and prevention of diabetes, cataract, colon cancer, asthma or chronic obstructive pulmonary disease with aldose reductase inhibitor as a natural product which is safe even with long-term use and has no side effects .

It is an object of the present invention to provide novel cinnamoyl derivatives.

Another object of the present invention is to provide a pharmaceutical composition comprising as an active ingredient a novel cinnamoyl derivative compound capable of treating and preventing diabetes, cataract, colon cancer, asthma or chronic obstructive pulmonary disease (COPD) as an aldose reductase inhibitor .

Another object of the present invention is to provide a pharmaceutical composition containing a novel cinnamoyl derivative compound as an active ingredient, which can have an excellent anti-obesity or body fat reducing effect.

In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions, and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms.

In one embodiment of the present invention, the present invention relates to a cinnamoyl derivative compound having a structure represented by the following formula (1).

≪ Formula 1 >

Wherein R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cyclo An alkyl group and a C ₆ to C ₆₀ aryl group, each of R ₂ to R ₄ is independently selected from the group consisting of H, halogen group, -COOR 'and -OR', and R 'is hydrogen or C ₁ -C ₅ alkyl group.

In one embodiment of the present invention, the present invention relates to a cinnamoyl derivative compound having a structure represented by the following formula (2).

(2)

here,

R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cycloalkyl, C ₆ to C ₆₀ aryl groups, R ₂ to R ₄ are each independently selected from the group consisting of H, halogen group, -COOR 'and -OR', R 'is hydrogen or C ₁ To C < ₅ >

&Quot; Alkyl " in the present invention means a monovalent substituent derived from a C ₁ to C ₄₀ linear or branched saturated hydrocarbon. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isobutyl, sec-butyl, pentyl, iso-amyl and hexyl.

&Quot; Alkenyl " in the present invention means a monovalent substituent derived from C ₂ to C ₄₀ linear or branched unsaturated hydrocarbons having at least one carbon-carbon double bond. Examples thereof include, but are not limited to, vinyl, allyl, isopropenyl, 2-butenyl, and the like.

&Quot; Alkynyl " in the present invention means a monovalent substituent derived from C ₂ to C ₄₀ linear or branched unsaturated hydrocarbons having at least one carbon-carbon triple bond. Examples thereof include, but are not limited to, ethynyl, 2-propynyl, and the like.

In the present invention, " cycloalkyl " means a monovalent substituent having ₃ to ₂₀ carbon atoms, although it is not particularly limited.

The term "alkyl", "alkenyl", "alkynyl", "aryl", and "cycloalkyl" in the present invention refers to a group selected from the group consisting of deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ An alkenyl group and a C ₂ to C ₄₀ alkynyl group.

In one embodiment of the present invention, the stereoisomer of the compound of Formula 1 may have the structure of Formula 3 below.

(3)

Wherein R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cyclo An alkyl group and a C ₆ to C ₆₀ aryl group, each of R ₂ to R ₄ is independently selected from the group consisting of H, halogen group, -COOR 'and -OR', and R 'is hydrogen or C ₁ -C ₅ alkyl group.

In one embodiment of the present invention, the stereoisomer of the compound of Formula 2 may have a structure represented by Formula 4 below.

≪ Formula 4 >

here,

R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cycloalkyl, C ₆ to C ₆₀ aryl groups, R ₂ to R ₄ are each independently selected from the group consisting of H, halogen group, -COOR 'and -OR', R 'is hydrogen or C ₁ To C < ₅ >

In one embodiment, the compound is directed to a compound in which the R _1, wherein an aryl group of C ₆ ~ C _60. Preferably, R < _{1 >} is phenylene, but is not limited thereto.

&Quot; Aryl " in the present invention means a monovalent substituent derived from a C ₆ to C ₄₀ aromatic hydrocarbon in which a single ring or two or more rings are combined. Also, a form in which two or more rings are pendant or condensed with each other may be included. Examples of such aryl include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, and the like.

In one embodiment of the invention, the compound is characterized in that R ₄ is -COOR 'and R' is hydrogen or a C ₁ -C ₅ alkyl group.

On the other hand, the compounds according to the present invention may have asymmetric carbon centers and therefore exist as R or S isomers or racemic compounds, and all of these optical isomers and mixtures may be included in the scope of the present invention.

In addition, the compounds according to the present invention may be isolated from the undiluted extract. Here, the Solidago virgaurea subspecies (asiatica Kitam. Ex Hara) is a chrysanthemum which is sometimes referred to as japonica, japonica, japonica, dumemi and pig herb. Its origins are Korea and Japan. The young leaves are edible as herbs, and are used in the private sector as dry foods, diuretics, and so on.

It is known that Ulleungdo and Jeonnam Goheung produce most of the domestic distribution. Among them, Ulleungdo is known to be cultivated much more than Keunheung in Jeonnam with annual average of 200M / T from 70ha area (Source: Technology Center, Goheung County Agricultural Technology Center). In the case of Gohung, Jeollanam-do, it is cultivated and distributed along with anchovy and ginger in the insects. In addition, most of the currently unseodorized products are distributed in the form of dried products, and some of them are distributed only in the form of foods such as soy sauce, and studies on melanin production inhibitory effect, antiinflammatory effect and osteoblast activation have been reported, And no attention has been paid to the inhibitory effect of the enzyme.

In one embodiment of the present invention, Is a pharmaceutical composition for inhibiting aldose reductase comprising any one of the compounds. Specifically, the present invention is a pharmaceutical composition for treating and preventing any one of diabetes, cataract, colon cancer, asthma, or COPD comprising any one of the compounds having the structures of Formulas 1 to 4 .

In one embodiment of the present invention, it is a pharmaceutical composition for anti-obesity comprising any one of the above-mentioned compounds. Specifically, it is an anti-obesity composition comprising any one of the compounds having the structures of the above formula (1) to (4).

In one embodiment of the invention, the composition provides a pharmaceutical composition comprising a pharmaceutical preparation.

Meanwhile, the pharmaceutical preparation may be in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration such as injection, Dosage form.

In addition, the pharmaceutical preparation may be formulated according to a conventional method by adding at least one selected from the group consisting of a carrier, a reinforcing agent and an excipient, in addition to the active ingredient, as a usual non-toxic pharmaceutically acceptable additive. have.

Examples of excipients include, but are not limited to, sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, perfumes and the like. Examples of the excipient include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, magnesium aluminum silicate, starch, gelatin, tragacanth gum, arginic acid, sodium alginate, methylcellulose, sodium carboxylmethyl Cellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like can be used.

When the composition of the present invention is orally administered, examples of the carrier to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, But is not limited thereto.

When the composition of the present invention is used as an injection, the carrier may include, but is not limited to, water, saline solution, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride and the like .

In order to use the compound according to the invention as a medicament, the latter is prepared in the form of pharmaceutical preparations, which are in addition to the active ingredients for oral or parenteral administration, suitable pharmaceutical organic or inorganic inert carrier substances, for example water, gelatin , Gum arabic, lactose, starch, vegetable oil, polyalkylene glycol and the like. The pharmaceutical preparations can be present in solid form, for example as tablets, dragees, suppositories or capsules, or in liquid form, for example as a liquid, a suspension or an emulsion. They may also optionally contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents; Salt or buffer for modifying the osmotic pressure. These pharmaceutical formulations are also the subject of the present invention.

For parenteral administration, aqueous solutions of the active compounds, especially in injection solutions or suspensions, in particular in polyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surfactant adjuvants such as bile salts or animal or plant phospholipids, and also mixtures thereof, and liposomes or components thereof, may also be used.

For oral administration, tablets, dragees or capsules containing, in particular, talc and / or hydrocarbon vehicles or binders, for example lactose, corn or potato starch, are suitable. It can also be administered in liquid form, for example, as a sweetened juice.

TECHNICAL FIELD The present invention relates to a novel cinnamoyl derivative compound and a pharmaceutical composition containing the same as an active ingredient, and was obtained by separating and purifying cinnamoyl derivative as an active ingredient from an undrawn extract using chromatography. In addition, the compounds can be used for the treatment and prevention of diabetes, cataract, colon cancer, asthma or chronic obstructive pulmonary disease by inhibiting Aldose reductase.

Fig. 1 shows HPLC results of the cinnamoyl derivative obtained in Production Example 3. Fig.
2 shows the ¹ H-NMR results of Compound 1 in cinnamoyl derivatives.
3 shows ¹ H-NMR results of Compound 2 in cinnamoyl derivatives.
4 shows ¹ H-NMR results of Compound 3 in cinnamoyl derivatives.
5 is the UV spectrum of compounds 1 to 3 of cinnamoyl derivatives.
6 shows ¹³ C-NMR results of Compound 3 in cinnamoyl derivatives.
FIG. 7 shows the results of COZY (Correlation spectroscopy) of the compound 3 in cinnamoyl derivatives.
8 is a result of HSQC (Heteronuclear single quantum coherence spectroscopy) of the compound 3 in cinnamoyl derivatives.
FIG. 9 shows the result of HMBC (Heteronuclear multiple bond correlation) of the compound 3 among the cinnamoyl derivatives.
FIG. 10 shows the NOESY (Nuclear Overhauser effect spectroscopy) of Compound 3 among the cinnamoyl derivatives.
Results.
Fig. 11 shows the result of inhibition of adipocyte differentiation of compound 1 in cinnamoyl derivatives.
Fig. 12 shows the evaluation results of inhibition of adipocyte differentiation of compound 2 in cinnamoyl derivatives.
Fig. 13 shows the evaluation results of inhibition of adipocyte differentiation of compound 3 in cinnamoyl derivatives.
Fig. 14 shows the results of the cytotoxicity test of Compound 1 in cinnamoyl derivatives.
Fig. 15 shows the result of cytotoxicity test of Compound 2 among cinnamoyl derivatives.
Fig. 16 shows the result of cytotoxicity test of Compound 3 among cinnamoyl derivatives.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Production Example 1: Extraction method

Seedlings containing crushed flowers and flowers were crushed and leached at room temperature for 48 hours using dichloromethane. The samples were filtered and then dried. The dried sample was extracted with 70% ethanol at room temperature for 48 hours. The sample was filtered, dried, and then leached at room temperature for 48 hours using water. The residue was separated by filtration. And then lyophilized.

Production Example 2: Fractionation method

15 g of the undiluted product extracted from Preparation Example 1 was dissolved in 500 ml of distilled water, and the product was fractionated five times using ethyl acetate (EtOAc). The separated water layer was fractionated three times using butanol (n-BuOH) And concentrated to obtain respective fractions.

Manufacturing example  3: Undisturbed From the fraction Cinnamoyl  derivative( Cinnamoyl  derivatives

The butanol (n-BuOH) fraction obtained from Preparation Example 2 was fractionated into 5 fractions (developing solvent: 20%, 40%, 60%, 80%, 100% MeOH) using Diaion HP-20 column chromatography A fraction was obtained. Five fraction fractions were obtained using sephadex LH-20 column chromatography and developing solvent 50% methanol (MeOH) to yield three novel cinnamoyl derivatives.

Manufacturing example  4: Undisturbed From the fraction Cinnamoyl  derivative( Cinnamoyl  derivatives

Agilent 1200 was used for liquid chromatography (HPLC) in order to concentrate the three new cinnamoyl derivatives obtained in Preparation Example 3 to secure the respective fractions. The column was Thermo Hypersil GOLD 4.6 x150 mm was used. The purification method is shown in Table 1 below. The flow rate was 0.7 ml / min, the temperature was 30 ° C, the injection volume was 10 μl, and the UV detector was 254 nm.

Time % A % B Water
(+ 0.1% TFA) MeOH 0 95 5 15 60 40 30 40 60 40 0 100 50 0 100 55 95 5 60 95 5

Fig. 1 shows the HPLC results of the cinnamoyl derivative obtained from Preparation Example 3. Fig. As shown in FIG. 1, at 254 nm, the three cinnamoyl derivatives had different retention times, thereby securing each fraction. Also, as shown in FIGS. 2 to 5, ¹ H-NMR and UV spectra of the compounds of the respective fractions were measured, and the structure of each compound was analyzed using the results. As a result of analysis, the structures of the compounds are shown in Table 2 below.

As shown in FIGS. 6 to 10, ¹³ C-NMR, COZY (Correlation Spectroscopy), HSQC (Heteronuclear single quantum coherence spectroscopy), HMBC (Heteronuclear multiple bond correlation) and NOESY (Nuclear Overhauser effect spectroscopy) 3 structure was analyzed precisely.

Compound 1 Compound 2 Compound 3

(1R,2S,3S,5R,7S)-2,3-dihydroxy-7-((((Z)-3-phenylacryloyl) oxy)methyl)-6,8 -dioxabicyclo[3.2.1]octane-5-carboxylic acid
(분자량 : 352.34g/mol)

(Z) -3-phenylacryloyl) oxy) methyl) -6,8-dioxabicyclo [3.2.1] octane-5-carboxylic acid; carboxylic acid
(Molecular weight: 352.34 g / mol)

(1R, 2S, 3S, 5S, 7S) -7 - ((cinnamoyloxy) methyl) -2,3-dihydroxy-methyl-6,8-dioxabicyclo [3.2.1] octane-
(Molecular weight: 352.34 g / mol)

(1R, 2S, 3S, 5R, 7S) -methyl-7- (cinnamoyloxy) methyl) -2,3-dihydroxy-6,8-dioxabicyclo [3.2.1] octane-
(Molecular weight: 366.36 g / mol)

Experimental Example 1: Inhibition of differentiation of 3T3-L1 cells for inhibiting lipid accumulation

3T3-L1 preadipocyte cells are purchased from the American Type Culture Collection (ATCC). Cell culture was performed in Dulbecco's modified Eagle's medium (DMEM) medium (Gibco) containing 10% fetal bovine serum (FBS), penicillin (100 U / ml) and streptomycin And cultured in a CO2 incubator at 37, 5% CO ₂ . 3T3-L1 cells were seeded on a 24-well plate and the cells were post-confluent. The cells were treated with 0.5 mM dexamethasone, 10 g / ml insulin, , And treated with 0.5 mM IBMX. After 4 days, the medium was changed to insulin (5 g / ml), and after 2 days, the medium was changed into normal medium to induce differentiation into adipocytes. The compounds shown in Table 2 were treated at the time of adipocyte differentiation (25, 50, 100 袖 g / ml) by concentration.

In order to confirm the inhibition of adipogenesis of the compounds shown in Table 2, which are three cinnamoyl derivatives separated from each Seaweed fraction, the fat differentiation medium and each compound were treated at the same time, ) Were discarded and washed three times with phosphate buffered saline (PBS), and the cells were fixed with 10% formalin reagent. After 1 hour, cells were stained with 0.6% Oil Red O reagent. The stained cells were photographed with a phase contrast microscope at 200X magnification and the relative TG OD values were measured. (Final concentration of all samples is 10 ug / ml). Here, the evaluation results thereof are shown in Figs. 11 to 13.

As shown in Fig. 11, the adipocyte treated with Compound 1 at 25, 50, and 100 쨉 g / ml showed that the DM treated with the differentiation inducing agent alone Fat accumulation was inhibited in a concentration - dependent manner.

As shown in FIG. 12, the fat cells treated with the compound 2 at the concentrations of 25, 50, and 100 μg / ml had higher fat accumulation than the DM treated with the differentiation inducer alone Dependent inhibition.

As shown in FIG. 13, the fat cells treated with the compound 3 at the concentrations of 25, 50, and 100 μg / ml had higher fat accumulation than DM treated with the differentiation inducing agent Dependent inhibition.

Experimental Example 2: Evaluation of toxicity of 3T3-L1 cells (MTT)

For cytotoxicity analysis, 5 × 10 ³ of 3T3-L1 cells were seeded in a 96-well microtiter plate for 16 hours, and then the compounds shown in Table 2 were added to each concentration ( 25, 50, 100 μg / ml) and cultured for 24 hours or 48 hours. Then, 50 ul of MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- sulfophenyl) -2H-tetrazolium, inner salt) (Promega, Madison, Wis., USA) was added and reacted for 20 minutes at a wavelength of 490 nm using a microplate reader (Sensident scan).

As a result of the cytotoxicity evaluation, as shown in Fig. 14, the adipocytes treated with the compound 1 at the concentrations of 25, 50 and 100 μg / ml were not toxic on the basis of the control group without any treatment.

As shown in FIG. 15, the adipocytes treated with the compound 2 at the concentrations of 25, 50 and 100 μg / ml were not toxic on the basis of the control group without any treatment.

As can be seen from FIG. 16, the adipocytes treated with the compound 3 at a concentration of 25, 50 μg / ml were not toxic on the basis of the control group without any treatment, and Compound 3 was administered at a dose of 100 μg / ml The adipocyte treated with the concentration showed a very weak toxicity.

Experimental Example 3 Evaluation of Aldose Reductase Inhibitory Activity

In order to measure the aldose reductase inhibitory effect of the cinnamoyl derivative isolated from the marine extract, in relation to the treatment or prevention effect of diabetes, cataract, colon cancer, asthma or chronic obstructive pulmonary disease, the aldose reductase And inhibition was measured. The inhibitory effect of aldose reductase was determined by the removal of a white crystalline lens. The compounds 1 to 3 were each prepared at a concentration of 1 mg / ml.

Six male WKY (wiatar Kyoto), 10 weeks old, were used in the experimental animals. Animal experiments were carried out using an ether and anesthetized. Then, the lens was extracted from the experimental animal, and a phosphate buffer (PBS) of a certain concentration was added according to the wet weight of the lens. After separating the hybridized lens at 4 ° C, the supernatant was saturated with ammonium sulfate to 40%, and the supernatant obtained by centrifugation was again taken. Stirring was continued for 1 hour by addition of ammonium sulfate to 70% rk, The resulting pellet was suspended in a minimum amount of buffer solution, dialyzed for 1 day, and used as an enzyme source.

An enzyme solution was added to the reaction mixture prepared by mixing 100 μl of enzyme source and 100 μl of NADPH (1.6 mM) as a coenzyme and 100 μl of DL-glyceraldehyde (0.1 M) as a substrate, and then the rate of decrease of NADPH absorbance at 340 nm was measured with a spectrophotometer . Quercetin, an aldose reductase inhibitor, was used as a control. The aldose reductase inhibitory activity of the above compounds 1 to 3 was converted into the IC ₅₀ value at the time when the activity of aldose reductase was inhibited by 50%.

As shown in Table 3, it was confirmed that the compound 1 and the compound 3 isolated from the undiluted extract had an IC ₅₀ value of 9.81 μg / ml and 6.31 μg / ml, respectively.

Concentration (μg / ml) Aldose reductase inhibitory activity (%) IC ₅₀ (μg / ml) Compound 1 10 55.43 + - 12.24 9.81 ± 2.24 5 27.09 + - 5.01 One -7.43 ± 0.59 Compound 2 10 29.94 + 2.39 Compound 3 10 62.97 + - 4.81 6.31 ± 0.08 5 39.42 + - 4.30 One 16.91 + - 13.16 Control group 10 90.87 ± 1.20 0.57 + 0.24 One 58.35 ± 9.88 0.1 25.77 + - 5.43

Claims (11)

A cinnamoyl derivative compound having a structure represented by the following formula (1).
≪ Formula 1 >

here,
R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cycloalkyl, A C ₆ to C ₆₀ aryl group,
R ₂ to R ₄ are each independently selected from the group consisting of H, halogen, -COOR ', and -OR'
R 'is hydrogen or a C ₁ to C ₅ alkyl group. A cinnamoyl derivative compound having a structure represented by the following formula (2).
(2)

here,
R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cycloalkyl, A C ₆ to C ₆₀ aryl group,
R ₂ to R ₄ are each independently selected from the group consisting of H, halogen, -COOR ', and -OR'
R 'is hydrogen or a C ₁ to C ₅ alkyl group. The method according to claim 1,
Wherein the stereoisomer of the compound of Formula 1 has the structure of Formula 3 below.
(3)

here,
R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cycloalkyl, A C ₆ to C ₆₀ aryl group,
R ₂ to R ₄ are each independently selected from the group consisting of H, halogen, -COOR ', and -OR'
R 'is hydrogen or a C ₁ to C ₅ alkyl group. 3. The method of claim 2,
Wherein the stereoisomer of the compound of Formula 2 has the structure of Formula 4 below.
≪ Formula 4 >

here,
R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, C ₁ to C ₄₀ alkyl, C ₂ to C ₄₀ alkenyl, C ₂ to C ₄₀ alkynyl, C ₃ to C ₄₀ cycloalkyl, A C ₆ to C ₆₀ aryl group,
R ₂ to R ₄ are each independently selected from the group consisting of H, halogen, -COOR ', and -OR'
R 'is hydrogen or a C ₁ to C ₅ alkyl group. 3. The method according to any one of claims 1 to 2,
The compounds are compounds in which the R _1, wherein an aryl group of C ₆ ~ C _60. 3. The method according to any one of claims 1 to 2,
Said compound being characterized in that said R ₄ is -COOR 'and R' is hydrogen or a C ₁ -C ₅ alkyl group. 3. The method according to any one of claims 1 to 2,
Wherein R < _{1 >} is phenyl. A pharmaceutical composition for treating and preventing diabetes, cataract, colon cancer, asthma, or COPD comprising a compound according to any one of claims 1 to 2 as an active ingredient. 9. The method of claim 8,
Wherein said composition comprises a pharmaceutical agent. 10. The method of claim 9,
Wherein said pharmaceutical preparation is in the form of a tablet, pill, powder, capsule, syrup or emulsion. 10. The method of claim 9,
Wherein the pharmaceutical preparation further comprises at least one selected from the group consisting of a pharmaceutically acceptable carrier, a reinforcing agent and an excipient.

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