KR100886466B1 - New stigmasterol derivatives or pharmaceutically acceptable salts thereof, process for the preparation thereof and composition comprising the same for inhibiting obesity or for preventing and treating hyperlipidemia - Google Patents

Abstract

The present invention relates to a novel stigmasterol derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a composition for preventing and treating obesity or preventing hyperlipidemia comprising the same. The stigmasterol derivative according to the present invention is excellent in the effect of lowering the content of triglycerides, total cholesterol and LDL-cholesterol in the blood, increasing the content of HDL-cholesterol, and inhibiting weight gain. Therefore, the stigmasterol derivatives according to the present invention can be used as medicines and health foods useful for inhibiting obesity or preventing and treating hyperlipidemia.

Description

Novel stigmasterol derivatives or pharmaceutically acceptable salts thereof, preparation methods thereof, and compositions for preventing and treating obesity or hyperlipidemia including the same same for inhibiting obesity or for preventing and treating hyperlipidemia}

The present invention relates to a novel stigmasterol derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a composition for preventing and treating obesity or preventing hyperlipidemia comprising the same.

There are many changes in eating habits due to recent economic growth and lifestyle changes. In particular, busy modern people are gaining weight and obesity due to high calorie diets such as fast food and low exercise.

Overweight means a body mass index (BMI, an obesity measure of body weight divided by the square of height) of 25 or more and less than 30. Obesity is applicable when the body mass index is 30 or more.

Two-thirds of American adults are overweight or obese, and overweight increases blood pressure and cholesterol levels, increasing the incidence of various adult diseases, including heart disease, and obesity increasing the risk of heart disease, diabetes, arthritis and some cancers .

Overweight and obesity are one of the factors that increase the incidence of various adult diseases such as arteriosclerosis, hypertension, hyperlipidemia or heart disease not only in adults but also children and adolescents.

As such, obesity affects all age groups, but the incidence of older adults is high. It is known that obesity was not so much in the East because of vegetarian-oriented lifestyle, but in modern times, obesity was gradually increasing in Asian people as the dietary habits changed and the living environment changed due to the influence of western culture.

In addition, modern man has been reported that physical strength is reduced due to overwork, heavy drinking, stress, etc., about 30-40% have obesity, about 10% of them have severe or pathological obesity has been reported.

Obesity refers to a state in which fat is excessively accumulated in the body and a high proportion of fat in the body weight is classified into simple obesity and secondary obesity (symptomatic obesity).

The causes of simplicity obesity include overeating, lack of exercise, and decreased metabolism. The majority of cases that are clinically judged as obesity are simplicity obesity. If obesity manifests and the condition persists, it causes various health disorders.

Secondary obesity is obesity caused by any underlying disease, and may include endocrine obesity, hypothalamic obesity, hereditary obesity, or obesity due to drugs.

The main cause of obesity is overgrowth of fat cells, which is caused by a deficiency of a hormone called leptin, which is ordered and secreted by the brain. The deficiency of leptin hormone is reduced by overeating, weakening of metabolism in vivo due to aging, and excess animal cholesterol accumulated in the body, except when genetic deficiency occurs.

Cholesterol is present in the blood in the form of small round particles called lipoproteins. There are many types of lipoproteins.LDL (low density lipoprotein) which carries cholesterol from the liver to other tissues, and lipoprotein which brings cholesterol from other tissues to the liver are HDL (high density lipoprotein, high density lipoprotein). HDL-cholesterol, in particular, cleans blood vessels and lowers the risk of atherosclerosis. Therefore, low HDL-cholesterol levels increase the risk of atherosclerosis, as do many bad LDL-cholesterols.

Obesity itself is the cause of various diseases such as hyperlipidemia, hypertension, cardiovascular disease, pseudotumor cerebri, sleep apnea, cancer, pulmonary hypertension, cholecystitis and osteoarthritis Or cause problems such as deterioration of activity. In addition, obesity may be caused by various diseases and may appear as a complication.

The most common cause of obesity is that the energy consumed is consistently excessive compared to the energy consumed. Some obese patients are trying to reduce their weight and cholesterol levels through diet and exercise to avoid obesity. , Psychotherapy, drug therapy, or surgery (surgery, such as atrophy).

Diet is a treatment that controls the total energy intake, but weight loss as expected cannot be achieved because the metabolic rate at rest is lowered. There are many problems that cause physical and mental pain called malnutrition, fasting or stress.

Exercise therapy has been shown to increase energy consumption, improve metabolic rate at rest, correct insulin resistance, and reduce body fat, but at least three times a week of aerobic exercise at least three times a week It is difficult to carry out continuously because it is necessary to do it.

Behavioral or psychotherapy is an aid to maintain diet or exercise therapy, and it is generally difficult to achieve sufficient effects.

When the above treatment method is not effective or when urgent treatment for extreme obesity is necessary, pharmacotherapy or surgical therapy is performed, but the surgical therapy is very burdensome to the patient. The anti-obesity drugs used for drug therapy include appetite suppressants, digestive absorption inhibitors, obesity-inhibiting agents, or metabolic accelerators, but these anti-obesity drugs have a risk of causing side effects such as drug dependence. In addition, there is a problem in that resistance can be developed in a short period of time to a patient to be administered, so that it cannot be used continuously for a long time.

In addition, in the case of exercise therapy, if an obese person is forced to exercise violently, the risk of injuring the lower extremity joint increases, so it is generally preferable to perform light swimming. In this case, activating energy metabolism, increasing the muscles by combining light exercise such as drugs with little side effects and light swimming, and promoting energy consumption by increasing basic metabolism is considered as one preferable method for improving obesity.

On the other hand, stigmasterol is a plant sterol (phytosterol) contained in soymilk, which is similar in structure to animal cholesterol, but can be absorbed by competing with animal cholesterol in the intestine, thereby reducing cholesterol concentration in the body and inhibiting overgrowth of fat cells. Known as a substance. In addition, deficiency causes calcium phosphate accumulation and muscle atrophy in joints or muscles.

Glucosamine is one of the natural amino sugars that are components of joints and cartilage, and has a molecular formula of C ₆ H ₁₃ NO ₆ , and since it has 6 carbons, it is collectively referred to as hexamine with galactosamine. Glucosamine is a colorless needle crystal that decomposes at 110 ° C and is a strong base that dissolves in water. In nature, it is widely distributed as a component of polysaccharides such as chitin, bacterial cell walls, mucopolysaccharides that make up cartilage and skin of animals. In addition, glucosamine-binding proteins are contained in human blood or mucus, and glucosamine-bound glycolipids are present in the cell membranes of red blood cells, and can be prepared by hydrolyzing chitin. It also inhibits acetyl CoA formation by limiting the acetate supply in cells during biosynthesis, inhibiting fat and cholesterol synthesis. Glucosamine is known as a substance that helps to strengthen joints and cartilage, and is widely used in the treatment of degenerative arthritis, cosmetic compositions, and foods.

Recently, as the concern about obesity has emerged as a social problem, there is a demand for the development of a product that can suppress body cholesterol lowering and fat cell proliferation and promote weight loss more effectively than conventional stigmasterol or glucosamine.

Therefore, the present inventors have been studying a compound that can inhibit cholesterol lowering and proliferation of fat cells in the body, and produced a novel stigmasterol derivative, which is derived from triglyceride, total cholesterol and LDL- in the blood. Lowering the content of cholesterol, increasing the content of HDL-cholesterol, and confirmed that the effect of inhibiting weight gain was completed the present invention.

The present invention is to provide a novel stigmasterol derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a composition for preventing and treating obesity or hyperlipidemia comprising the same.

The present invention provides a novel stigmasterol derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be prepared as pharmaceutically acceptable salts and soluble compounds according to methods conventional in the art.

As the pharmaceutically acceptable salt, acid addition salts formed by free acid are useful. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered. In this case, an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacic acid, galactu Lonic acid, glutamic acid, glutaric acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, vanillic acid, hydroiodic acid, etc. may be used, but is not limited thereto.

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

Pharmaceutically acceptable salts of the compound represented by Formula 1 include salts of acidic or basic groups which may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate , Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts; It can be manufactured by a method or a manufacturing process.

In addition, the present invention provides an intermediate compound of the stigmasterol derivative represented by the following formula (3) or formula (4) or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method for preparing a stigmasterol derivative represented by the formula (1).

Method for producing a stigmasterol derivative of the present invention, as shown in Scheme 1 below,

1) preparing a compound of formula 3 by reacting stigmasterol with a compound of formula 2,

2) preparing a compound of formula 4 by reacting the compound of formula 3 prepared in step 1) with an aqueous ammonia solution, and

3) reacting the compound of formula 4 prepared in step 2) with palladium hydroxide [Pd (OH) ₂ ] to prepare a compound of formula (1).

In Scheme 1, the compound of Formula 2, which is a starting material, is represented by Chemical. Reviews 1993, Vol 93, No. 4, p1511 and the like or can be prepared and used in a similar manner.

In the step 1), after dissolving the stig masterol and the compound of formula 2 in an organic solvent, BF ₃ OEt ₂ was added to react for 10 to 20 hours at room temperature to prepare a compound of formula (3).

The organic solvent is preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methylene chloride, methanol, cyclohexene, acetonitrile, dimethylformamide and dimethyl sulfoxide, but is not limited thereto.

In step 2), the compound of Formula 3 prepared in step 1) is dissolved in an organic solvent, and reacted with an aqueous ammonia solution at 30 to 50 ° C. for 10 to 20 hours in a water bath to prepare a compound of Formula 4.

The organic solvent may be selected from among the organic solvents used in step 1). The base is preferably selected from the group consisting of sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU and ammonia water, It is not limited to this.

In step 3), the compound of Formula 4 prepared in step 2) is dissolved in an organic solvent and distilled water, and reacted with palladium hydroxide [Pd (OH) ₂ ] to prepare a compound of Formula 1. At this time, the organic solvent used may be selected from among the organic solvents used in step 1).

Another aspect of the present invention provides a composition for inhibiting obesity or preventing and treating hyperlipidemia, comprising a stigmasterol derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The stigmasterol derivative according to the present invention is excellent in the effect of lowering the content of triglycerides, total cholesterol and LDL-cholesterol in the blood, increasing the content of HDL-cholesterol, and inhibiting weight gain.

In addition, oral administration of the stigmasterol derivatives according to the present invention as a result of toxicity experiments, as a result, oral administration half dose (LD ₅₀ ) is determined to be a safe substance of more than 3000mg / kg.

Therefore, the stigmasterol derivatives according to the present invention can be used as medicines and health foods useful for inhibiting obesity or preventing and treating hyperlipidemia.

The composition of the present invention may contain one or more known active ingredients having the effect of inhibiting obesity or preventing and treating hyperlipidemia with the compound of Formula 1.

The composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary And other conventional additives such as bacteriostatic agents can be added. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dosage of the compound of Formula 1 is about 5-30 mg / kg, preferably about 10-25 mg / kg, and more preferably administered once to several times a day.

The composition of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, drug treatment and biological response modifiers for the purpose of inhibiting obesity or preventing and treating hyperlipidemia.

The composition of the present invention may be added to health foods for the purpose of improving diseases caused by obesity or hyperlipidemia. When the compound of Formula 1 of the present invention is used as a food additive, the compound of Formula 1 may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined depending on the purpose of use (prevention, health or therapeutic treatment). In general, in the preparation of food or beverages, the compound of formula 1 of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less based on the raw material. 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. .

There is no particular limitation on the kind of food. Examples of the food to which the substance may be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, beverages, tea, and drinks. Alcoholic beverages and vitamin complexes, and includes all of the health foods in the conventional sense.

The health beverage composition of the present invention may contain various flavors or natural carbohydrates, etc. as additional components, as in the general beverage. The above-mentioned natural carbohydrates are glucose, monosaccharides such as fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol. As the sweetening agent, natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonic acid. Carbonating agents and the like used in beverages. In addition, the composition of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage and vegetable beverage. These components can be used independently or in combination. The proportion of such additives is not critical but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example  One  : Stigmasterol  Preparation of Derivatives

1.Acetic acid 4- Acetoxy -2- Acetoxymethyl -5- Benzyloxycarbonylamino -6- [17- (4-ethyl-1,5-dimethyl-2- Hexenyl ) -10,13-dimethyl-2,3,4,7,8, 9,10,11,12,13,14,15,16,17-tetradecahydro-1H- Cyclopenta [a] phenanthrene -3- Iloxy ]-rim Trahadro Preparation of -pyran-3-yl ester (3)

Acetic acid 4-acetoxy-2-acetoxymethyl-5-benzyloxycarbonylamino-6- (2,2,2-trichloroacetimidoyloxy) -tetrahydro-pyran-3-yl ester (10 g, 0.0171 mol) and stigmasterol (7.0 g, 0.0171 mol) are dissolved in 250 ml of diethyl ether, and BF ₃ OEt ₂ 0.69 mL was added, followed by stirring for 16 hours at room temperature. After the reaction was terminated, the reaction solvent was removed, and a concentrate was obtained. The concentrate was dissolved in methylene chloride and separated by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (1: 3) to obtain compound (3).

Yield: 21%

Melting Point: 165-167 ℃

¹ H-NMR (500 MHz, CDCl ₃ ): 0.68-2.28 (43H, m), 1.97 (3H, s), 2.01 (3H, s), 2.07 (3H, s), 3.47 (2H, m), 3.61 ( 1H, m), 4.10 (1H, d), 4.25 (1H, m), 4.80 (1H, m), 5.02 (2H, t), 5.11 (3H, m), 5.30 (1H, s), 5.35 (1H , m), 7.33 (5H, s)

2. {2- [17- (4-ethyl-1,5-dimethyl-2- Hexenyl ) -10,13-dimethyl-2,3, 4,7,8,9,10,11,12,13,14,15,16,17, -tetratecahydro-1H- Cyclopenta [a] phenanthrene -3-yloxy] -4,5- Dehydro -6- Hydroxymethyl - Tetrahydro -Pyran-3-yl}- Carbamic acid  Preparation of Benzyl Ester 4

4-Acetoxy-2-acetoxymethyl-5-benzyloxycarbonylamino-6- [17- (4-methyl-1,5-dimethyl-2-hexenyl) -10,13 prepared in 1 above. -Dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-3-yloxy] Dissolve tetrahydro-pyran-3-yl ester (5.0 g, 0.006 mol) in 30 ml of methylene chloride, add 80 ml of methanol, add 25 ml of aqueous ammonia, and stop the reaction vessel with a stopper. Stirred for 16 h. The solid produced after the reaction was filtered, washed with water and dried to obtain the compound (4).

Yield: 85%

Melting Point: 193-195 ℃

¹ H-NMR (500 MHz, CDCl ₃ ): 0.68-2.26 (43H, m), 3.29 (2H, m), 3.42 (1H, m), 3.5-3.8 (3H, m), 4.58 (2H, m), 5.10 (3H, s), 5.28 (2H, s), 6.10 (1H, m), 7.30 (5H, s)

3. 5-Amino-6- [17- (4-ethyl-1,5-dimethyl-) Hexenyl ) -10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- Cyclopenta [a] phenanthrene -3-yloxy] -2- Hydromethyl - Tetrahydro -Pyran-3,4- Dior  Manufacture of (1)

{2- [17- (4-ethyl-1,5-dimethyl-hexenyl) -10,13-dimethyl-2,3,4,7,8,9,10,11,12, prepared in 2 above 13,14,15,16,17-tetratecahydro-1H-cyclopenta [a] phenanthrene-3-yloxyl] -4,5-dihydro-6-hydroxymethyl-tetrahydro-pyran-3- 220 ml of methanol, 110 ml of cyclohexene, and 20 ml of distilled water were added to the Japanese-carbamic acid benzyl ester (2.0 g, 0.0028 mol), followed by adding 5.0 g of palladium hydroxide [Pd (OH) ₂ ]. Was refluxed for a while. After the reaction was completed, Celite was placed, palladium was removed and the filtrate was concentrated. The concentrate was dissolved in a developing solvent (methylene chloride: methanol = 8: 1) and separated by silica gel column chromatography to obtain Compound (1).

Yield: 55%

Melting Point: 255 ℃

¹ H-NMR (500MHz, CDCl ₃ ): 0.68-2.17 (43H, m), 2.42 (2H, m), 3.11 (4H, m), 3.35 (2H, m), 3.69 (1H, m), 4.26 ( 2H, m), 4.48 (1H, t), 4.96 (1H, s), 5.08 (1H, m), 5.17 (1H, m), 5.37 (1H, s)

Experimental Example  One  : Anti-obesity , Anti-lipid  And Anti-cholesterol  Experiment

In order to confirm the anti-obesity, anti-lipid and anti-cholesterol effects of the compound of Formula 1 according to the present invention, the following experiment was performed.

Thirty three-week-old male SD rats were purchased from a central experimental animal company. The conditions of breeding were 23 ± 3 ℃, 55 ± 10% relative humidity, 10 ~ 20 times of ventilation times, 12 hours / day of fluorescent lighting, 8 am to 8 pm off, and 150 to 300 Lux. , The experimental animals were divided into five groups, and 6 animals per group were put in a polycarbonate breeding box (size: 220 W × 360 L × 200 H mm) and reared.

The feed was freely ingested for 4 weeks after a one-week acclimatization period of the experimental animals, and the water was microfiltered and UV sterilized with groundwater suitable for drinking water. After sterilization by using a sterilized water bottle freely fed.

While feeding the same feed for 6 weeks to the rats induced the obesity, distilled water in group 1 (negative control group), compound 1 400mg / kg prepared in Example 1 in group 2 (experimental group 1), group 3 (experimental group) 2) In the compound 1 prepared in Example 1 800mg / kg, Group 4 (positive control group 1) in the control drug stigmasterol 800mg / kg, Group 5 (positive control group 2) in the control drug glucosamine 800mg / kg, respectively Oral administration.

Rats fasted 16 hours before the end of the test were anesthetized with diethyl ether, and blood was drawn from the abdominal vein. The collected blood was centrifuged and serum was collected. The triglyceride, total cholesterol and HDL-cholesterol contents in serum were measured using a kit reagent (Asan Pharmaceutical) for quantification by enzyme colorimetry. , LDL-cholesterol was calculated by the Friedewald method as follows.

LDL-cholesterol = [total cholesterol-HDL-cholesterol-(triglyceride / 5)]

The experimental animals were separated and bred one by one, and the dietary intake and body weight were measured twice a week during the experimental period.

The blood triglyceride values are shown in Table 1, the blood total cholesterol values are shown in Table 2, the blood HDL-cholesterol values are shown in Table 3, and the blood LDL-cholesterol values are shown in Table 4. In addition, the weight change is shown in Table 5.

Blood triglyceride 6 weeks after sample administration (mg / dL) % Degradation Negative Control (Distilled Water) 80.19 ± 9.23 - Experimental group 1 (400 mg / kg) 55.71 ± 2.12 -30.52 Experimental group 2 (800 mg / kg) 53.63 ± 1.88 -33.12 Positive Control Group 1 (Stig Masterol) 74.29 ± 8.26 -7.30 Positive control group 2 (glucosamine) 71.54 ± 6.53 -10.70

Total cholesterol in the blood 6 weeks after sample administration (mg / dL) % Degradation Negative Control (Distilled Water) 82.09 ± 5.45 - Experimental group 1 (400 mg / kg) 73.27 ± 12.65 -10.70 Experimental group 2 (800 mg / kg) 71.75 ± 13.72 -12.59 Positive Control Group 1 (Stig Masterol) 78.05 ± 15.42 -4.90 Positive control group 2 (glucosamine) 80.48 ± 14.73 -1.90

HDL-cholesterol level in blood 6 weeks after sample administration (mg / dL) % Increase Negative Control (Distilled Water) 24.84 ± 2.33 - Experimental group 1 (400 mg / kg) 25.12 ± 1.92 +1.11 Experimental group 2 (800 mg / kg) 25.43 ± 2.12 +2.37 Positive Control Group 1 (Stig Masterol) 24.53 ± 3.12 - Positive control group 2 (glucosamine) 24.47 ± 1.86 -

LDL-cholesterol level in blood 6 weeks after sample administration (mg / dL) % Degradation Negative Control (Distilled Water) 42.21 ± 8.66 - Experimental group 1 (400 mg / kg) 37.01 ± 7.21 -10.19 Experimental group 2 (800 mg / kg) 35.59 ± 5.71 -13.64 Positive Control Group 1 (Stig Masterol) 38.66 ± 6.34 -6.20 Positive control group 2 (glucosamine) 41.70 ± 7.26 -1.19

As shown in Tables 1 to 4, the compounds according to the present invention have a blood triglyceride of 30-34%, blood total cholesterol of 10-13%, blood in comparison with the high-fat diet group (negative control group) in blood biochemical tests. LDL-cholesterol levels decreased by 10-14%, and blood HDL-cholesterol levels increased by 1-3%. Therefore, it can be seen that the compound according to the present invention is excellent in lipid improving effect.

In contrast, the positive control drugs stigmasterol and glucosamine were 7.30% and 10.70% in blood triglycerides, 4.90% and 1.90% in blood cholesterol, and 6.20 in LDL-cholesterol, respectively, compared to high-fat diet (negative control). % And 1.19% decreased, and blood HDL-cholesterol levels showed little increase, indicating very little lipid improvement effect.

Weight change Before sample administration (g) 6 weeks after sample administration (g) % Weight loss Negative Control (Distilled Water) 223.8 ± 6.3 386.0 ± 13.1 - Experimental group 1 (400 mg / kg) 221.0 ± 7.1 370.5 ± 14.9 -7.8 Experimental group 2 (800 mg / kg) 223.3 ± 6.9 365.4 ± 15.5 -12.4 Positive Control Group 1 (Stig Masterol) 223.4 ± 8.1 383.6 ± 16.6 -1.2 Positive control group 2 (glucosamine) 222.6 ± 5.6 379.3 ± 17.9 -3.4

As shown in Table 5, the compound according to the present invention showed an inhibitory effect of weight gain of 7.8 to 12.4% compared to the high fat diet group (negative control group), and the high fat diet group (negative ones for the positive control drugs stigmasterol and glucosamine). Compared with the control group, the weight gain inhibitory effect was 1.2% and 3.4%, respectively.

Experimental Example  2  : Acute Toxicity Test

In order to determine the acute toxicity of the stigmasterol derivative of the present invention, an acute toxicity test was performed by the Richfield-Wilcoxon method.

Six-week-old ICR mice were used as experimental animals, and solid feed and water were ingested freely at the conditions of 23 ± 1 ° C. and 60 ± 5% humidity before the experiment. Using 6 animals per group, Compound 1 prepared in Example 1 was suspended in 0.5% methylcellulose solution and administered orally at a dose of 1 g / kg / 15 ml. The appearance and live death of the mice were recorded for 14 days after administration of the test substance, and the mortal animals were examined by necropsy to observe gross lesions. LD ₅₀ value was calculated | required by the Richfield-Wilcoxon method.

As a result, all animals treated with the test substance had no clinical symptoms to be noted and no animals died.

As a result, all of the tested compounds did not show toxic changes up to 3000 mg / kg in mice, and the oral administration half dose (LD ₅₀ ) was determined to be a safe substance of 3000 mg / kg or more.

Examples of preparations for the compositions of the present invention are illustrated below.

Formulation example  One  : Preparation of Pharmaceutical Formulations

1. Preparation of powder

2 g of a compound of formula 1

1g lactose

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

2. Preparation of Tablets

100 mg of compound of Formula 1

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. Preparation of Capsule

100 mg of compound of Formula 1

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

Formulation example  2  : Manufacture of food

Food containing the compound of formula 1 of the present invention was prepared as follows.

1. Preparation of Cooking Seasonings

20 to 95% by weight of a compound of Formula 1 was prepared for cooking spices for health promotion.

2. Preparation of Tomato Ketchup and Sauce

Health care tomato ketchup or sauce was prepared by adding 0.2 to 1.0 wt% of the compound of Formula 1 to tomato ketchup or sauce.

3. Manufacturing of Flour Foods

0.5 to 5.0% by weight of the compound of Formula 1 was added to the flour, and the mixture was used to prepare bread, cake, cookies, crackers, and noodles to prepare health promoting food.

4. Preparation of soups and gravy

0.1 to 5.0% by weight of the compound of Formula 1 was added to soups and gravy to prepare health products, noodle soup and gravy.

5. Preparation of Ground Beef

10% by weight of the compound of Formula 1 was added to the ground beef to prepare a ground beef for health promotion.

6. Manufacture of Dairy Products

5 to 10% by weight of the compound of formula 1 was added to milk, and the milk was used to prepare various dairy products such as butter and ice cream.

Formulation example  3  : Preparation of Beverages

1. Preparation of carbonated drinks

5-10% of sugar, 0.05-0.3% citric acid, 0.005-0.02% caramel, 0.1-1% of vitamin C are mixed, and 79-94% purified water is mixed to make syrup, and the syrup is 85-98 Sterilizing at 20 ℃ for 180 seconds to mix with a cooling water 1: 1: ratio and then injected carbon dioxide 0.5 to 0.82% to prepare a carbonated beverage containing the compound of formula (1) of the present invention.

2. Manufacture of health drinks

Instant sterilization by homogeneously combining the compound of formula 1 with subsidiary materials such as liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%) and water (75%) Healthy drinks were prepared by packing them in small packaging containers such as bottles and plastic bottles.

3. Preparation of Vegetable Juice

5 g of the compound of Formula 1 was added to 1,000 ml of tomato or carrot juice to prepare vegetable juice for health promotion.

4. Preparation of Fruit Juice

1 g of the compound of Formula 1 was added to 1,000 ml of apple or grape juice to prepare fruit juice for health promotion.

The stigmasterol derivative according to the present invention is excellent in the effect of lowering the content of triglycerides, total cholesterol and LDL-cholesterol in the blood, increasing the content of HDL-cholesterol, and inhibiting weight gain. Therefore, the stigmasterol derivatives according to the present invention can be used as medicines and health foods useful for inhibiting obesity or preventing and treating hyperlipidemia.

Claims (6)

The stigmasterol derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. <Formula 1>

An intermediate compound of the stigmasterol derivative represented by the following formula (3) or a pharmaceutically acceptable salt thereof. <Formula 3>

An intermediate compound of the stigmasterol derivative represented by the following formula (4) or a pharmaceutically acceptable salt thereof.

1) preparing a compound of formula 3 by reacting stigmasterol with a compound of formula 2, 2) preparing a compound of formula 4 by reacting the compound of formula 3 prepared in step 1) with an aqueous ammonia solution, and 3) reacting the compound of Chemical Formula 4 prepared in step 2) with palladium hydroxide [Pd (OH) ₂ ] to prepare a compound of Chemical Formula 1, which is represented by Scheme 1 below. Process for the preparation of the compound. <Scheme 1>

A pharmaceutical composition for inhibiting obesity or preventing and treating hyperlipidemia comprising the compound of claim 1. A food composition useful for inhibiting obesity or preventing hyperlipidemia comprising the compound of claim 1.