KR20070044198A - Anti-metabolic syndrome treatment with fumaric acid and fumaric acid derivatives - Google Patents

Abstract

The present invention relates to a composition for preventing and treating metabolic syndrome containing fumaric acid and fumaric acid derivatives as an active ingredient. And it relates to a metabolic syndrome prevention and treatment composition containing the fumaric acid derivatives (fumaric acid derivatives) as an active ingredient.

Fumaric acid and fumaric acid derivatives, metabolic syndrome, obesity. Diabetes

Description

Anti-metabolic syndrome treatment with fumaric acid and fumaric acid derivatives}

Figure 1 is a result of measuring the effect on weight change with time after treatment with dimethyl fumarate in DIO (diet-induced obesity), an obese model animal.

Figure 2 is the result of measuring the effect on weight change with time after treatment with dimethyl fumarate in C57BL / 6JL Lep ob / Lep ob obese model animals.

3 is a graph comparing the degree of fat accumulation by staining the distribution of adipose tissue over time after treatment of dimethyl fumarate to C57BL / 6JL Lep ob / Lep ob , an obese model animal.

Figure 4 is a graph comparing the change in the size of adipocytes in adipose tissue after treatment with dimethyl fumarate in C57BL / 6JL Lep ob / Lep ob obese model animals.

Figure 5 is a table comparing the change in blood glucose, antioxidant index, cholesterol and triglycerides in blood after treatment with dimethyl fumarate in obese model animal C57BL / 6JL Lep ob / Lep ob .

The present invention relates to a composition for preventing and treating metabolic syndrome, which comprises fumaric acid and fumaric acid derivatives as active ingredients.

Metabolic Syndrome refers to a syndrome that is accompanied by risk factors such as hypertriglyceridemia, hypertension, abnormal glucose metabolism, abnormal blood coagulation, and obesity. The symptom itself is not fatal, but because it has a predisposition to develop serious diseases such as diabetes and ischemic cardiovascular disease, it is the most threatening condition for modern people. At one time it was not known for its cause, but it was named by various names including Syndrome X, but it was recently established by the World Health Organization and the National Institute of Health's Heart, Lung, and Blood Research Institute. ATP III) is officially referred to as metabolic syndrome or insulin resistance syndrome.

According to the ATP III of the National Cholesterol Education Program (NCEP) published in 2001, ① Abdominal obesity with waist circumference of 40 inches (102 cm) for men and 35 inches (88 cm) for women, ② Triglycerides 150 mg / One of five risk factors: dL or higher, ③ HDL cholesterol in men 40mg / dL, female 50mg / dL or less, ④ blood pressure 130 / 85mmHg or higher, ⑤ fasting glucose in 110mg / dL or higher. If more than three are indicated metabolic syndrome. In Asians, when waist circumference is more than 90cm for males and 80cm for females, abdominal obesity is somewhat adjusted. have. Insulin resistance refers to a phenomenon in which insulin does not function properly in the body, even though insulin is normally secreted in the body, and glucose in the blood does not enter the cell, resulting in hyperglycemia. Cells do not function properly because of the lack of glucose in the cell as a result of the symptoms of metabolic syndrome.

Until now, the drug for the treatment of metabolic syndrome has not been developed and attempts to treat the metabolic syndrome using only drugs for treating diabetes, hyperlipidemia and hypertension, but has limitations as a drug. Currently available drugs are metformin, TZD (thiazolidinediones), glucosidase inhibitors, dual PPARγ / α agonist and DDP (Dipeptidyl peptidase) IV inhibitors, which are used as antidiabetic drugs. ApoA-I isoforms, related peptides, and CTP (Cholesterol ester transport protein) inhibitors are also attracting attention.

Fumaric acid and fumaric acid derivatives are metabolites of the citric acid cycle and have been used as additives in food and agriculture. Fumaric acid and fumaric acid derivatives are used in the pharmaceutical field as a therapeutic for psoriasis. Recently, dimethylfumarate, a derivative of fumaric acid, is known to be a glutathione-dependent detoxification inducer (Investigative ophthalmology & visual science 1999, 40, 1927-1935). The mechanism of action of dimethylfumarate so far 1) Inhibits the action of phosphorylase sensitive to redox by increasing glutathione content in cells. 2) It inhibits the phosphorylation and ubiquitination of IkB, which inhibits the translocation of NFkB. This mechanism regulates the expression of NFkB-dependent inflammation-related cytokine and adhesion molecules. It is understood that such a mechanism is effective for psoriasis. US Pat. No. 6,858,750 B2 describes that fumarate derivatives are effective in treating mitochondrial diseases such as Parkinson's disease, Alzheimer's disease, Chorea Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy.

Thus, in the present invention, fumaric acid (fumaric acid) and fumaric acid derivatives (fumaric acid derivatives) obesity model animals that cause obesity, obesity diabetes model db / db mice and diabetes-derived DIO (diet- Induced obesity resulted in the prevention and treatment of metabolic syndrome including obesity and diabetes. Therefore, fumaric acid (fumaric acid) and fumaric acid derivatives (fumaric acid derivatives) was confirmed that the effect of preventing and treating metabolic syndrome and completed the present invention.

Therefore, an object of the present invention is to provide a metabolic syndrome prevention and treatment composition containing fumaric acid (fumaric acid) and fumaric acid derivatives (fumaric acid derivatives) as an active ingredient that has the effect of preventing and treating metabolic syndrome.

The present invention is characterized by the composition for preventing and treating metabolic syndrome comprising a pharmaceutically acceptable carrier of fumaric acid and fumaric acid derivatives represented by the following formula.

The present invention will be described in more detail as follows.

The present invention relates to a composition for preventing and treating metabolic syndrome, which comprises fumaric acid and fumaric acid derivatives represented by the above formulas as active ingredients.

Fumaric acid (fumaric acid) and fumaric acid derivatives represented by the above formula used as an active ingredient of the present invention is fumaric acid, fumaric acid metal salt, fumaric acid dialkyl esters, fumaric acid monoalkylesters, etc. It can be used to treat metabolic diseases.

Fumaric acid dialkyl esters have the following structural formula:

In the above formula, R1 and R2 may be composed of the same or different independent straight, branched, saturated, unsaturated C1-24 alkyl radical or C5-50 aryl radical, and these radicals are halogen ( Optionally substituted with F, Cl, Br, I), hydroxy, C1-4 alkoxy, nitro or cyano.

R1 and R2 radicals are methyi, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2 -hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-methoxyethyl, methoxymethyl, 2-or 30methoxypropyl and the like.

Fumaric acid monoalkyl esters are represented by the following structural formula.

R corresponds to the radical described above. A may be made of hydrogen or a salt or a cationic metal, and specifically, may be made of Li, Na, K, Mg, Ca, Zn, Fe, Mn, and the like. n means 1 or 2.

In the present invention, one or more of fumaric acid and fumaric acid derivatives may be used alone or in combination. The group of fumaric acid and fumaric acid derivatives is fumaric aicd dimethyl ester, fumaric aicd diethyl ester, fumaric aicd methyl ethyl ester, methyl hydrogen fumarate, ethyl hydrogen fumarate, magnesium methyl fumarate, ethyl hydrogen fumarate, magnesium methyl These may be fumarate, magnesium ethyl fumarate, zinc methyl fumarate, zinc ethyl fumarate, iron methyl fumarate, iron ethyl fumarate, calcium methyl fumarate, calcium ethyl fumarate, etc.

Fumaric acid and fumaric acid derivatives represented by the above formulas promote metabolism by inhibiting fat accumulation in the body by promoting energy metabolism in the body. In the present invention, physiologically conferred fumaric acid and fumaric acid derivatives are ob / ob mice, which are obese model animals, db / db mice, which are obese diabetes models, and high-fat diet-induced DIO In vivo experiments related to the prevention and treatment of metabolic syndrome in mice showed very good effects.

Therefore, the metabolic syndrome prevention and treatment composition containing the fumaric acid and fumaric acid derivatives represented by the above formula as an active ingredient can prevent and treat metabolic syndrome through activation of energy metabolism. It is possible to develop various medicines for various diseases related to metabolic syndrome. Metabolic syndrome prevention and treatment composition according to the present invention contains the fumaric acid (fumaric acid) and fumaric acid derivatives (fumaric acid derivatives) represented by the above formula as an active ingredient, and metabolized as needed with a pharmaceutically acceptable carrier It can be prepared as an agent for preventing and treating syndrome.

Pharmaceutical Properties

The compounds are useful for the prevention and / or treatment of clinical diseases associated with metabolic syndrome. These clinical diseases may include, but are not limited to, general obesity, abdominal obesity, hypertension, arteriosclerosis, hyperinsulinemia, hyperglycemia, type 2 diabetes and dyslipidemia characterized by insulin resistance. Dyslipidemia, also known as atheroliposomal lipoproteins, includes a significant increase in non-esterified fatty acids, an increase in ultra low density lipoprotein (VLDL) triglyceride rich particles, high ApoB levels, small, dense low density lipoprotein (LDL) particles, and the presence of phenotype B. Characterized by low high density lipoprotein (HDL) levels associated with high ApoB levels and low apoAI particle levels.

The compounds of the present invention are expected to be useful in the treatment of patients with varying degrees of hypertriglyceridemia and postprandial dyslipidemia with or without complex hyperlipidemia or other signs of metabolic syndrome.

Treatment with the present compounds is expected to lower cardiovascular morbidity and mortality associated with atherosclerosis due to their anti-inflammatory as well as anti-dyslipidemia. Cardiovascular diseases include macrovascular disease, heart failure, cerebrovascular disease, and terminal peripheral artery failure of various internal organs that cause myocardial infarction. Due to the insulin sensitivity effect, the compound is also expected to prevent or delay the development of type 2 diabetes in metabolic syndrome and diabetes during pregnancy. It is therefore expected to delay the development of long-term complications associated with clinical hyperglycemia in diabetes, such as the development of microangiopathy resulting in renal disease, retinal disorders and terminal peripheral vascular disease. Moreover, the compounds may be associated with various diseases other than the cardiovascular system such as polycystic ovary syndrome, obesity, cancer, and inflammatory diseases such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease and multiple sclerosis, regardless of whether they are linked to insulin resistance It will be useful to

The compound not only has an inhibitory effect on the development of fatty liver condition in the liver, but also may play a role in lowering triglycerol concentrations by activating β-oxidation, resulting in fatty liver, hepatitis and It is expected to be useful for cirrhosis.

The compounds of the present invention change the composition of lipids in various tissues. It has also been found that the compounds of the present invention can not only change fat content but also change fat distribution.

Compounds of the invention reduce plasma cholesterol and triacylglycerol levels. Therefore, it can be seen that such compounds of the present invention will reduce the levels of triglycerides and cholesterol in plasma.

The treatment of this compound is known to be effective for NO production in endothelial cells and is expected to be useful for cardiac disease, vascular disease hypertension and erectile dysfunction. Diseases that contribute to high blood pressure include heart failure, myocardial infarction, cerebrovascular rupture and blood clots, and kidney damage.

The treatment of the compound is expected to be useful for the removal of local fats such as subcutaneous and abdominal fat as well as general obesity as a material that promotes fatty acidization and energy consumption. Therefore, if you want to remove the fat from certain areas such as subcutaneous fat, abdominal fat and abdominal fat and cellulite, where local fat is gathered, ointment, patch, cream, and paste can be used. It is expected to be useful by conveying.

In addition, the compounds of the present invention can be used as antidiabetic drugs by reducing blood sugar levels. In addition, the inventors of the present invention have confirmed that the compounds of the present invention reduce the plasma insulin concentration in hyperinsulinic animals. In animals with reduced sensitivity to insulin, the compounds of the invention have been found to enhance the effects of insulin.

The compound promotes the production of mitochondria (biogenesis) to increase the active capacity of mitochondria and at the same time induces the conversion of muscle tissue into exercise tissues to improve athletic performance, endurance, energy production capacity, fatigue recovery, vitality, It is expected to be effective in the treatment of related diseases through reduction of oxidative stress caused by reactive oxygen species. Diseases that can be caused by free radicals (ROS) include: Arteriosclerosis, diabetes, neurological diseases, kidney disease, cirrhosis, arthritis, prematurity retinopathy, ocular uveitis, senile cataract, side effects of radiation therapy, smoking bronchial damage, anticancer side effects, brain edema, pulmonary edema, foot edema, cerebral infarction, Many diseases have been reported, including hemolytic anemia, premature ejaculation, epilepsy, Alzheimer's disease, Down's syndrome, Crohn's disease, and collagen disease.

As mentioned above, the compounds of the present invention have been found to provide beneficial effects on all of these conditions by modulating glucose and lipid homeostasis. Thus, it can be seen that the compound of the present invention is a suitable substance for controlling the metabolic syndrome (sometimes referred to as syndrome X).

 In the present invention, "metabolic syndrome" is particularly characterized by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, type 2 diabetes, dyslipidemia, cardiovascular disease or high blood pressure. It relates to the use of a compound for the manufacture of a pharmaceutical composition for the treatment and / or prevention of multiple metabolic syndrome (metabolic syndrome).

Pharmaceutical preparations

Therefore, metabolic syndrome prevention and treatment composition containing the fumaric acid and fumaric acid derivatives represented by the above formula as an active ingredient can prevent and treat metabolic syndrome through activation of energy metabolism. It may be possible to develop various medicines for various diseases related to the disease. Metabolic syndrome prevention and treatment composition according to the present invention contains the fumaric acid (fumaric acid) and fumaric acid derivatives (fumaric acid derivatives) represented by the above formula as an active ingredient, and metabolized as needed with a pharmaceutically acceptable carrier It can be prepared as an agent for preventing and treating syndrome.

Suitable dosages of the pharmaceutical compositions of the present invention may vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be. The pharmaceutical composition of the present invention for preventing and treating metabolic syndrome contains the fumaric acid and fumaric acid derivatives as active ingredients. The fumaric acid and fumaric acid derivatives may be administered orally or parenterally during clinical administration and may be used in the form of general pharmaceutical preparations. That is, the fumaric acid and fumaric acid derivatives of the present invention may be administered in various oral and parenteral dosage forms during actual clinical administration, and when formulated, commonly used fillers, extenders, binders, It is prepared using diluents or excipients such as wetting agents, disintegrating agents and surfactants. Solid form preparations for oral administration include tablets, pills, powders, granules and capsules, and the like form at least one excipient such as starch in fumaric acid and fumaric acid derivatives. , Calcium carbonate, sucrose, lactose and gelatin are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol and gelatin may be used.

Concentrations of fumaric acid and fumaric acid derivatives for the treatment of metabolic syndrome can range from 100 mg to 10,000 mg based on 60 kg of adult, preferably 200 mg-5,000 in terms of fumaric acid. It may be made between mg and more preferably between 300mg-3,000mg. It may be administered 1-6 times a day.

In addition, the present invention provides a health and functional food composition for the prevention and treatment of metabolic syndrome containing fumaric acid and fumaric acid derivatives as an active ingredient.

In the present specification, the health and functional food is a food that improves the function of the general food by adding fumaric acid and fumaric acid derivatives to the general food, and fumaric acid and fumaric acid derivatives. derivatives) can be added to general foods, or can be prepared by encapsulation, powdering, suspensions, and the like. When ingested, it brings a specific effect on health, and unlike the general medicine because it is made of food as a raw material has the advantage that there is no side effect that can occur when taking long-term use of the drug.

When the fumaric acid and fumaric acid derivatives of the present invention are used as food additives, the fumaric acid and fumaric acid derivatives are added as they are or used together with other food or food ingredients, It can be suitably used according to a conventional method. The blending amount of the active ingredient can be suitably determined according to the purpose of its use (prevention, health or therapeutic treatment). In general, fumaric acid and fumaric acid derivatives may be added in amounts of 0.0001 to 10% by weight, preferably 0.1 to 5% by weight, based on the raw materials in the manufacture of food or beverage. However, in the case of prolonged ingestion for health and hygiene purposes or for health control purposes, the amount may be adjusted below the above range. In addition, when the health food of the present invention is used in the pharmaceutical composition, it is preferable to contain fumaric acid and fumaric acid derivatives within the measured toxicity range.

There is no particular limitation on the kind of food. Examples of foods to which the fumaric acid and fumaric acid derivatives may be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, powdered milk, wire , Raw foods, lactobacillus fermented milk, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes. Specifically, health foods containing fumaric acid and fumaric acid derivatives include health such as juice, tea, jelly, juice, etc., which are made of fumaric acid and fumaric acid derivatives. Foods and favorite foods; folk remedies for the purpose of edema, nephritis, urethritis, and the like.

When fumaric acid and fumaric acid derivatives of the present invention are used as cosmetic raw materials, fumaric acid and fumaric acid derivatives are added as they are or used together with other cosmetic ingredients, and used in conventional methods. Can be used accordingly. The mixed amount of the active ingredient can be suitably determined according to the purpose of use thereof. In general, in the preparation of cosmetics using fumaric acid and fumaric acid derivatives may be added in an amount of 0.0001 to 10% by weight, preferably 0.1 to 5% by weight relative to the raw material. Cosmetics can be applied to skins, lotions, creams, packs and cosmetics.

Hereinafter, the present invention will be described in more detail based on the following examples, but the scope of the present invention is not limited to the following examples.

Example  1: obese model animal DIO (diet induced obesity)  Obesity Prevention and Treatment in Mice

Diet- induced obesity ( DIO ) mice were fed Diet Diet D12451, 45% kcal fat feed at 4 weeks of age after C57BL / 6 male animals.

As a result, fat accumulates excessively in the body, which causes the body to maintain more than 31 to 32 g, which is 1.4 times the weight of a normal mouse at about 3 months after birth. Therefore, we investigated 16 DIO mice, weighing 31-32g or more, to investigate the effects of fumaric acid and fumaric acid derivatives on fat metabolism. Dimethylfumarate (150 mg / kg) was administered to the eight experimental groups, and the same amount of distilled water was administered to the eight control groups. As a result of measuring the body weight of the test group and the control group 30 days after the administration, as shown in FIG. ) Showed a low level.

Example  2 : Dimethyl fumarate ( Dimethylfumarate Obesity by administration rat (ob / ob At)  effect

The male C57BL / 6JL Lep ob / Lep ob mice, which have the characteristics of obesity, were purchased from the Korea Experimental Animal Center. Breeding was conducted in a kennel with a temperature of 23 degrees, a humidity of 55%, a roughness of 300-500 lux, a light and dark cycle of 12 hours, and an exhaust environment of 10-18 cycles / hr. The feed was purchased freely by Purina Rodent Laboratory Chow 5001, Purina Mills, USA, and the drinking water was freely ingested. After the purification process, two weeks of the dimethyl fumarate (Dimethylfumarate) was administered for 30 days to 200mg / kg. Changes in body weight, blood glucose, and dietary intake were measured and the changes in fat distribution, changes in adipocyte size, blood glucose, lipids, and enzymes were determined in tissues of each organ after administration.

Result, the change in weight with time of the administration of dimethyl fumarate (Dimethylfumarate) C57BL / 6JL Lep ob / Lep ob mice to a figure compared to the control By the administration of dimethylfumarate (Dimethylfumarate) it was found that the weight loss is significantly reduced compared to the control (Fig. 2).

Further, the dimethyl fumarate (Dimethylfumarate) Histological analysis of livers of administered C57BL / 6JL Lep ob / Lep ob mice was performed to determine the changes in fat distribution in liver before and after 10 days, 20 days and 30 days. It was confirmed using. As shown in the figure, when dimethylfumarate was administered, the accumulation of fat in the liver was significantly reduced over time compared to before administration through staining of adipose tissue (FIG. 2).

As well as, Separating dimethyl fumarate fat cells (Dimethylfumarate) a C57BL / 6JL Lep ob / Lep ob mice by the administration were compared to the size of fat cells and the control group. As you see in the picture There is a local cell size of the test group administered with dimethyl fumarate (Dimethylfumarate) can see the small so that the size of the adipocytes significantly than the control group (Fig. 2).

In addition, changes in lipids and blood glucose in the blood of C57BL / 6JL Lep ob / Lep ob mice to which dimethylfumarate was administered were observed. As shown in the table, triglyceride, cholesterol, GOT, GPT and blood glucose in the blood of the dimethylfumarate-administered group showed a significant decrease compared to the control group (Fig. 2).

Example   12: Preparation of the Tablet

Dimethyl fumarate 300 g

Whey Protein 540 g

140 g of crystalline cellulose

10 g of magnesium stearate

10 g of hydroxypropyl methyl cellulose

Example  13: Preparation of powder

10 g of dimethyl fumarate

50 g soybean isolate

40 g of carboxy cellulose

Total amount 100 g

A powder was prepared by crushing and mixing the ingredients listed above. 500 mg of powder was put in a hard capsule made of gelatin to prepare a capsule.

Example   14: Dimethyl fumarate  Application to milk

99.9% milk

Dimethylfumarate 0.1%

Example   15 :. Of dimethyl fumarate Of orange juice  apply

Liquid fructose -------------------- 5%

Polydextrose --------------- 1%

Citric Acid ---------------------- 5%

Vitamin C --------------------- 0.02%

Dimethylfumarate -------------- 0.1%

Orange Juice Concentrate ------------- 25%

Sucrose Fatty Acid Ester ----------- 0.2%

Water ------------------------ 63%

Example  16: manufacture of beverages

Calcium lactate 50 mg

Citric acid 5 mg

Nicotinamide 10 mg

Riboflavin Sodium Hydrochloride 3 mg

Pyridoxine hydrochloride 2 mg

Arginine 10 mg

Sucrose fatty acid ester 10 mg

Dimethyl fumarate 10 mg

200 ml of water

Example  17: Application to cosmetic lotion

1,3-butylene glycol ---------------------- 5%

glycerine -------------------------------- 5%

EDTA-2Na --------------------------------- 0.02%

trimethylglycine ------------------------- 2.0%

cetanol ---------------------------------- 1.0%

glyceryl monostearate emulsifier --------- 1.0%

polysorbate 60 --------------------------- 1.2%

sorbitan sesquioleate -------------------- 0.3%

cetyl 2-ethyl-hexaoate ------------------- 4.0%

squalane --------------------------------- 5.0%

dimethicone ------------------------------ 0.3%

glyceryl stearate ------------------------ 0.5%

carbomer --------------------------------- 0.15%

triethanoamine --------------------------- 0.5%

imidazolidinyl urea ---------------------- 0.2%

Dimethylfumarate -------------------------- 1%

Purified Water ----------------------------------- 71.8%

Example  18: Application to cosmetic skin

1,3-butylene glycol ---------------------- 4.0%

dipropylene glycol ----------------------- 5.0%

EDTA-2Na --------------------------------- 0.02%

octyldodeceth-16 ------------------------- 0.3%

PEG60 hydrogenate castor oil ------------- 0.2%

Dimethyl fumarate ------------------------ 0.1%

Purified water ----------------------------------- 90%

As described above, the fumaric acid and fumaric acid derivatives of the present invention are The activation of energy metabolism effectively reduces body weight, prevents the accumulation of fat in the body, lowers blood sugar, and effectively inhibits the amount of cholesterol and triglycerides. ) Are useful for the prevention and treatment of metabolic syndrome.

In addition, fumaric acid and fumaric acid derivatives not only prevent fat accumulation in the body but also regulate blood sugar, which can prevent or treat diseases related to metabolic syndrome caused by abnormal fat and glucose metabolism. It can be developed into food, cosmetic and pharmaceutical compositions.

Claims (34)

Metabolic syndrome prevention and / or composition comprising at least one active ingredient in the group consisting of fumaric acid (fumaric acid) or fumaric acid derivatives (Formula 1)

The composition of claim 1, wherein the fumaric acid and the fumaric acid derivative are at least one selected from the group consisting of fumaric acid, fumaric acid metal salt, fumaric acid dialkyl esters, and fumaric acid monoalkylesters in the form of acids or salts.  According to claim 2, wherein the composition comprising the fumaric acid dialkyl esters having a structure of formula (2) as an active ingredient

 Where  R1 and R2 represent the same or different independent straight, branched, saturated, unsaturated C1-24 alkyl radicals or C5-50 aryl radicals, The radical may be optionally substituted with halogen (F, Cl, Br, I), hydroxy, C1-4 alkoxy, nitro or cyano.  The method of claim 3, wherein the R1 and R2 radical is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-methoxyethyl, methoxymethyl, 2-or 3-methoxypropyl composition, characterized in that any one selected from the group consisting of. According to claim 2, wherein the composition comprising the fumaric acid monoalkyl esters having the structure of formula (3) as an active ingredient

Where R represents a straight, branched, saturated, unsaturated C1-24 alkyl radical or C5-50 aryl radical, The radical may be optionally substituted with halogen (F, Cl, Br, I), hydroxy, C1-4 alkoxy, nitro or cyano.  The method of claim 5, wherein the R radical is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, and vinyl, allyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-methoxyethyl, methoxymethyl, or 2-or 3-methoxypropyl. The composition according to claim 5 or 6, wherein A (???) represents hydrogen or a salt or a cationic metal, and n represents 1 or 2. 8. The composition of claim 7, wherein the salt or cation is selected from the group consisting of Li, Na, K, Mg, Ca, Zn, Fe, Mn. According to claim 1, wherein the fumaric acid and fumaric acid derivatives are fumaric aicd dimethyl ester, fumaric aicd diethyl ester, fumaric aicd methyl ethyl ester, methyl hydrogen fumarate, ethyl hydrogen fumarate, magnesium methyl fumarate, ethyl hydrogen fumarate, magnesium methyl fumarate, magnesium ethyl at least one selected from the group consisting of fumarate, zinc methyl fumarate, zinc ethyl fumarate, iron methyl fumarate, iron ethyl fumarate, calcium methyl fumarate, calcium ethyl fumarate  The composition of claim 1, wherein the composition enhances the activity of energy metabolism. 10. The composition of claim 1, wherein the composition has activity to increase the biogenesis of mitochondria or the active dose of mitochondria. The composition of claim 1, wherein the composition has an activity of inducing conversion of muscle tissue to motor tissue. 10. Prevention and / or metabolic syndrome disease, characterized in that it contains a compound as defined in claims 1 to 9, a pharmaceutically acceptable salt, prodrug, hydrate, solvate or (stereochemical) isomer as an active ingredient. Therapeutic Composition The composition according to claim 13, wherein the content of the active ingredient is administered in the range of 0.1 to 1,000 mg / day, preferably 0.2 to 500 mg / day, more preferably 0.3 to 300 mg / day, per 1 Kg of adult body weight. 15. The method of claim 13, wherein the composition further comprises a pharmaceutically acceptable excipient in the form of a drug, drug additive, beverage, beverage additive or food, food additive or cosmetic, cosmetic additive. And / or therapeutic compositions Obesity, abdominal obesity, hypertension, arteriosclerosis, hyperlipidemia, liver disease, hyperinsulinemia, hyperglycemia, type 1 and 2 diabetes, dyslipidemia, erectile dysfunction, cardiovascular disease comprising the composition of claim 13 Or agents for treating ischemic disease The agent of claim 16, wherein the cardiovascular disease comprises macrovascular disease, heart failure, myocardial infarction, cerebrovascular disease, and terminal peripheral artery insufficiency of various internal organs that cause myocardial infarction. Preparation for the treatment of microangiopathy resulting in kidney disease, retinal disorders and terminal peripheral vascular disease as a prolonged hyperglycemia or diabetic complication comprising the composition of claim 13 14. An agent for treating polycystic ovary syndrome, obesity, cancer, inflammatory diseases and neurodegenerative diseases comprising the composition of claim 13. 20. The agent of claim 19, wherein the inflammatory disease is mild cognitive impairment, Alzheimer's disease, or Parkinson's disease. 20. The agent of claim 19, wherein the neurodegenerative disease is multiple sclerosis. 17. The agent according to claim 16, wherein the liver disease is fatty liver, hepatitis and cirrhosis due to lipid metabolism abnormality between alcoholic and non-alcoholic. Formulation for improving athletic performance, endurance, energy production capacity, fatigue recovery or vitality comprising the composition of claim 13 The formulation of claim 13, wherein the formulation comprises at least one pharmaceutically acceptable carrier or excipient. The formulation of claim 24 is an oral or parenteral formulation. The method of claim 25, wherein the oral formulation is a solid formulation such as tablets, pills, powders, granules and capsules, and one or more excipients consisting of starch, calcium carbonate, sucrose, lactose and gelatin, and magnesium styrate talc, etc. Formulations comprising a lubricant 27. The method of claim 25, wherein the oral preparation is a liquid preparation such as suspensions, solvents, emulsions and syrups, and includes one or more excipients consisting of wetting agents, sweeteners, fragrances and preservatives, and diluents such as water and liquid paraffin. Characterized formulation  26. The method of claim 25, wherein the parenteral preparation is a suspension sterilized aqueous solution, non-aqueous solvent, suspending agent, emulsion, lyophilized preparation and suppository, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, ethyl as a non-aqueous solvent and suspension Formulations comprising injectable esters such as oleate and comprising supwitsol, macrogol, tween 61, cacao butter, laurin butter, glycerol and gelatin as the basis for suppositories The formulation of claim 25, wherein the parenteral formulation is in the form of an ointment, a patch, a cream or a paste. 25. The formulation according to claim 24, wherein the carrier or excipient is a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant and surfactant. Functional food or beverage composition comprising the composition of claim 13 Food additive composition containing the composition of claim 13 Cosmetic composition containing the composition of claim 13 34. A composition according to claim 31, wherein the active compound comprises 0.0001 to 10% by weight, preferably 0.1 to 5% by weight.

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