KR102010520B1 - Novel bisabolol derivatives and use thereof - Google Patents

Abstract

The present invention relates to a novel bisabolol derivative or a pharmaceutically acceptable salt thereof, and an anti-obesity composition comprising them as an active ingredient. Specifically, the bisabolol derivatives of the present invention not only inhibit the proliferation of adipocytes into adipocytes, but also do not exhibit toxicity, and thus may be useful for the prevention or treatment of obesity or various diseases that may be caused thereby. .

Description

Novel bisabolol derivatives and uses thereof

The present invention relates to a novel bisabolol derivative or a pharmaceutically acceptable salt thereof, and an anti-obesity composition comprising them as an active ingredient.

Obesity or obesity is a term used to refer to the overweight of a person. Pathologically refers to a case in which the so-called body mass index (BMI) set by the World Health Organization (WHO) is over 30, but Korea In Esau over 25 is diagnosed as obesity. Most of them mean that your weight is higher than normal, but even if you don't weigh too much, your body is said to be obese if you have a high percentage of fat. Obesity may not be an issue on its own, but the social complications caused and the secondary complications caused by excess fat are severe. For example, obesity can significantly increase the incidence of hyperlipidemia, hypertension, arteriosclerosis, diabetes, fatty liver, joint abnormalities, and the like.

Thus obesity is the cause of various adult diseases. Increasing your weight can reduce your blood sugar and make you more likely to develop diabetes and high blood pressure. If your weight is 20% higher than your normal weight, your chances of developing diabetes are 10 times higher than normal. It can also shorten heart and lung function, leading to a shortened lifespan. Complex factors, such as high blood pressure, diabetes, hypercholesterolemia, and atherosclerosis, can put pressure on heart function, lead to heart failure, and cause sudden death. In addition to women, the incidence of endometrial cancer increases and the likelihood of developing gallstones. In men, the incidence of colorectal and prostate cancer increases. In addition, if you gain weight, you will have to be conscious of how others look at you, and if you become more obsessive about it, you will avoid people and stay alone. Inferiority from the body also loses confidence in one's life and affects self.

In order to prevent such obesity and maintain a healthy weight, a balanced diet and regular exercise should be managed consistently throughout life. In particular, once the fat cells are made, they can be reduced in size, but they are impossible to remove naturally, so they remain permanently in the human body. Therefore, weight loss can be achieved primarily by reducing the amount of calories consumed and by increasing the amount of activity and exercise.

However, as described above, once formed fat cells can not be removed, there is a case of taking a drug such as reducing fat absorption with the intake of a diet. However, these diet pills can cause side effects such as cardiovascular disease and stroke, such as high blood pressure, and if you stop taking them, you will often gain weight again. Surgical therapy can be performed for severe obesity, and surgery is performed to remove fat, gastric plastic surgery or band insertion to limit the amount of food the body can digest.

Accordingly, the present inventors have diligently researched to find small molecule compounds having low anti-obesity effect and low toxicity. As a result, a series of newly synthesized bisabolol derivatives show the effect of inhibiting differentiation into adipocytes, thus preventing or treating obesity. It was confirmed that the present invention can be used to complete the present invention.

[Prior literature]

[Patent Documents]

1. Korea Patent Registration No. 10-0823537 (2008.04.21)

[Non-Patent Documents]

1. Journal of Advances in Chemistry, 2014, 10 (2): pp. 2305-2316 (2014.06.30.)

2. Current Pharmaceutical Biotechnology, 2014, 15 (2): pp. 173-181

One object of the present invention is to provide novel bisabolol derivatives or pharmaceutically acceptable salts thereof.

It is another object of the present invention to provide a pharmaceutical composition for preventing or treating obesity comprising the bisabolol derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide an external skin preparation for preventing or treating obesity, including the bisabolol derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a food composition for preventing or improving obesity, comprising the bisabolol derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a feed composition for preventing or improving obesity, comprising the bisabolol derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a method for treating obesity, comprising administering the pharmaceutical composition for preventing or treating obesity in a pharmaceutically effective amount to a subject having or possibly developing obesity.

Detailed description for carrying out the present invention is as follows. Meanwhile, each description and embodiment disclosed herein may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein are within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific description described below.

As one aspect for achieving the above object, the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Chemical Formula 1,

R ₁ is hydrogen,

R ₂ is straight or branched C _1-6 hydroxyalkyl, or straight or branched C _1-6 carboxyalkyl.

Specifically, the compound represented by Formula 1 may be a compound in which R ₁ is hydrogen, R ₂ is hydroxypropyl, or carboxyethyl.

Specifically, the compound

(S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol (bisadiol; BisaD), or (S) -4-hydroxy-4-((S ) -4-methylcyclohex-3-enyl) pentanoic acid (bisaacid; BasaA), but is not limited thereto.

The compound represented by Formula 1 of the present invention may exist in the form of a pharmaceutically acceptable salt. As salts are acid addition salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention is any concentration of the compound which is relatively nontoxic and innocuous to the patient, and the adverse effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (1). Means any organic or inorganic addition salt.

Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

The acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by Chemical Formula 1 in an excess of aqueous acid solution, and the salt is water-miscible organic solvent such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile.

In addition, the compound represented by Formula 1 of the present invention can be used to make a pharmaceutically acceptable metal salt using a base. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt. Corresponding silver salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

In another embodiment, the present invention includes a first step of dihydroxylation of a double bond located at carbon 5 of a hydrocarbon chain of (-)-α-bisabolol to convert to a adjacent diol, Provided is a method for preparing a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In the above formula,

R ₁ is hydrogen,

R ₂ is straight or branched C _1-6 hydroxyalkyl, straight or branched C _1-6 dihydroxyalkyl, or straight or branched C _1-6 carboxyalkyl, or

R ₁ and R ₂ together form an C _3-7 cycloheteroalkyl which is unsubstituted or substituted with oxo, including oxygen and carbon atoms bonded thereto.

The salt of the compound represented by Chemical Formula 1 is as described above.

For example, the compound represented by Formula 1 may be a compound in which R ₁ is hydrogen, R ₂ is hydroxypropyl, 2-methyl-2,3-dihydroxypentyl, or carboxyethyl.

Alternatively, the compound represented by Formula 1 may be a compound in which R ₁ and R ₂ together form tetrahydrofuranyl substituted with oxo, including oxygen and carbon atoms bonded thereto.

Specifically, the compound

1) (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol,

2) (S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol,

3) (S) -5-methyl-5-((S) -4-methylcyclohex-3-enyl) dihydrofuran-2 (3H) -one, or

4) (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid, but is not limited thereto.

The (-)-α-bisabolol is IUPAC name (S) -6-methyl-2-((S) -4-methylcyclohex-3-enyl) hept-5-en-2-ol ((S ) -6-methyl-2-((S) -4-methylcyclohex-3-enyl) hept-5-en-2-ol), also known as levomenol. It is a natural monocyclic sesquiterpene alcohol and is the main component of essential oils such as chamomile. Structurally, in addition to the double bond present on the cyclohexenyl ring, a heptenyl group substituted therein further includes a double bond, and in the method for preparing a compound represented by Chemical Formula 1 of the present invention, the dihydrate is obtained through the first step. The double bond to be oxylated is not a double bond of the cyclohexenyl ring but a double bond of heptenyl substituted thereon.

For example, the first step may be carried out in the presence of a compound containing a high-oxidation state transition metal and optionally a chiral ligand. For example, the high oxidation water transition metal may be osmium or manganese, but is not limited thereto.

For example, the compound represented by the formula (1) according to the present invention after the reaction of the first step, the compound obtained from the first step is 5 to 20 at 10 to 35 ℃ in the presence of sodium periodate salt (NaIO ₄ ) Maintaining the time to form a cyclic intermediate; And a step 3-1 of reducing the intermediate formed from the second step to induce ring opening, or step 3-2 of oxidizing and carbonizing an alcohol of the intermediate formed from the second step. It may be, but is not limited thereto. In steps 3-1 and 3-2, one of the two steps may be selectively performed after the second step depending on the type of the compound to be obtained.

For example, steps 3-1 and 3-2 may be performed in the presence of sodium porohydride (NaBH ₄ ) and pyridinium chlorochromate (PCC) as catalysts, respectively, but induce reduction and oxidation reactions, respectively. So long as it can provide the desired product.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating obesity, comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a method for treating obesity, comprising administering the pharmaceutical composition for preventing or treating obesity to a subject having, or possibly developing, obesity in a pharmaceutically effective amount.

[Formula 1]

In the above formula,

R ₁ is hydrogen,

R ₂ may be straight or branched C _1-6 hydroxyalkyl, straight or branched C _1-6 dihydroxyalkyl, or straight or branched C _1-6 carboxyalkyl.

The compound represented by Formula 1 and salts thereof are as described above.

For example, the compound represented by Formula 1 may be a compound in which R ₁ is hydrogen, R ₂ is hydroxypropyl, 2-methyl-2,3-dihydroxypentyl, or carboxyethyl.

Specifically, the pharmaceutical composition of the present invention as a compound of Formula 1

1) (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol,

2) (S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol, or

3) (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid, but is not limited thereto.

The term "obesity" of the present invention refers to an excessive state of body fat, and clinically means a body mass index of 25 or more in Korea and 30 or more according to the World Health Organization (WHO). The body mass index (BMI) is calculated as the body weight (kg / m ² ) of the height squared. In general, the weight is higher than the normal value, but even if the body weight does not go much, if the proportion of body fat of the body components is high, diagnosed as obesity, a disease that occurs in both adults and children. Obesity can shorten your life and put you at risk for diseases such as high blood pressure, diabetes, heart disease and some cancers. Obesity is a high risk of health problems, and as the degree of obesity increases, the risk increases. There are many reasons why obesity can occur, and many different causes often work in combination. The most frequent of these are genetic effects, physiological effects, food and eating disorders, lifestyle, weight, pregnancy or drugs. The first signs of obesity are above average weight and symptoms include: sleep problems, sleep apnea, shortness of breath, varicose veins, skin problems, osteoarthritis due to gallstones or weight bearing. Obesity is also associated with diseases such as hyperglycemia (diabetes), hypercholesterolemia, hypertriglyceridemia, including hypertension. Once you're overweight, it's easy to get out of it, so most obesity will last a lifetime. However, diseases and problems caused by obesity can improve with weight loss.

Hereinafter, in the present invention, the term "anti-obesity" is used to mean all of the prevention, treatment or improvement of obesity. Accordingly, the term "anti-obesity composition" used in the present invention means the pharmaceutical composition for preventing or treating obesity.

In the present invention, the term "prevention" means any action that inhibits or delays the development of obesity by administration of the pharmaceutical composition according to the present invention, and "treatment" means suspicion and onset of obesity by administration of the pharmaceutical composition. It means any action that improves or beneficially changes the symptoms.

Obesity prevention or treatment by the pharmaceutical composition of the present invention can be achieved by inhibiting the differentiation of adipocytes into adipocytes.

For example, the pharmaceutical composition of the present invention may be a peroxisome proliferator-activated receptor (PPARγ), fatty acid binding protein 4 (FABP4), stearoyl-coenzyme A desaturase 1 (SCD1), stearoyl-coenzyme A desaturase 2 (SCD2) or fatty (FAS). It can be used for the prevention or treatment of obesity because it inhibits the activity of acid synthase) to inhibit the differentiation of fat precursor cells into fat cells.

For example, the pharmaceutical compositions of the present invention may exhibit the effects of weight loss, body fat loss, and triglyceride accumulation.

In addition, the anti-obesity composition of the present invention may exhibit the effect of preventing or treating fatty liver or lipid-related cardiovascular diseases related directly or indirectly to obesity as well as obesity by inhibiting fat production.

The term "fatty liver" is a disease in which fat, especially triglyceride, accumulates in hepatocytes and accounts for 5% or more of liver weight. Fats that are ingested through foods, etc. may not be processed smoothly, but a major cause of fatty liver is alcohol. Alcohol reduces liver metabolism, in particular fatty acid oxidative degradation, thereby accumulating fat in the liver. Fatty liver often occurs in obese people, and can also be caused by endocrine diseases such as diabetes mellitus, hyperthyroidism, overuse of steroid hormones or severe malnutrition. Because there are no special symptoms, symptoms can not be diagnosed alone, fatigue, anorexia, and lethargy, which are common symptoms of liver disease, may appear, and you may feel discomfort or dull pain under the right rib.

The term "lipid related cardiovascular disease" of the present invention is a disease caused by accumulation due to excessive intake of fatty acids or cholesterol or metabolic disorders. In particular, hypertriglyceridemia with abnormally high levels of triglycerides in the blood is defined as a risk factor for cardiovascular disease by the American Heart Association. Plasma triglycerides increase rapidly after meals and return to pre-meal levels after about 8 hours. Triglycerides increase in diabetics, obesity, and drinkers, and also in people who consume high amounts of sugar. In addition, hypothyroidism, nephrotic syndrome, kidney failure, birth control pills, and large amounts of diuretics and beta-blockers can increase triglycerides. As the triglyceride increases, the low density lipoprotein (LDL) -cholesterol increases, which promotes atherosclerosis. The lipid-related cardiovascular disease includes, but is not limited to, hyperlipidemia, heart disease, hypertension, arteriosclerosis, and the like.

For example, the pharmaceutical composition may be provided by formulating tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, lyophilized preparations or suppositories.

In this case, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" in the present invention means to exhibit properties that are not toxic to cells or humans exposed to the composition. The carrier can be used without limitation so long as it is known in the art such as buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, bases, excipients, lubricants. In addition, the pharmaceutical compositions of the present invention may be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and the like, oral formulations, suppositories, and sterile injectable solutions, respectively, according to a conventional method. have. Furthermore, it may be used in the form of an external preparation for skin in the form of an ointment, lotion, spray, patch, cream, powder, suspension, gel or gel. Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose ( It is prepared by mixing sucrose or lactose and gelatin. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Liquid preparations for oral use may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, 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, glycerogelatin and the like can be used.

On the other hand, the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "administration" of the present invention means introducing a predetermined substance into an individual in an appropriate manner and the route of administration of the composition can be administered via any general route as long as it can reach the target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto.

The term "individual" refers to all animals, including rats, mice, livestock, and the like, including humans who may or may have developed obesity. Preferably, it may be a mammal including a human. By administering the pharmaceutical composition of the present invention to an individual, the obesity can be effectively prevented or treated, and the pharmaceutical composition of the present invention can be used alone or for surgery, hormonal therapy, drug treatment, and biological response modifier for the prevention or treatment of obesity. It can be used in combination with the methods used.

The term “pharmaceutically effective amount” means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment and not causing side effects, wherein the effective dose level is the sex, age and weight of the patient. Well-known factors such as health status, type of disease, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration, and rate of release, duration of treatment, combination or drug used, and other medical fields. It can be easily determined by those skilled in the art according to known factors. For example, the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 100 mg / kg body weight per day, specifically, at 0.001 to 100 mg / kg body weight based on solids. The administration may be administered once a day, or divided into several times, but is not limited thereto.

Furthermore, the present invention may be provided in the form of an external preparation for skin containing the pharmaceutical composition for preventing or treating obesity.

The term "skin external preparation" of the present invention is a general concept encompassing a substance generally used for external application of the skin. Non-limiting examples of formulations containing the pharmaceutical composition include PLASTERS, lotion, and LPTIONS. , LINIMENTS, LIQUIDS AND SOLUTIONS, AEROSOLS, EXTRACTS, Ointments, FLUIDEXTRACTS, Emulsions, Suspensions CAPSULES, CREAMS, soft or hard gelatin capsules, patches, sustained release agents.

The external preparation for skin according to the present invention may be a parenteral dosage form formulated in the form of a solid, semisolid or liquid by adding a commercially available inorganic or organic carrier, excipient and diluent. For parenteral administration, the preparation may be a transdermal dosage form selected from the group consisting of drops, ointments, lotions, gels, creams, patches, sprays, suspensions and emulsions, but is not limited thereto.

Carriers, excipients and diluents that may be included in the external preparation include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In the external composition for skin according to each formulation, other ingredients other than the composition of the present invention described above may be appropriately selected and blended by those skilled in the art according to the formulation or use purpose of the external skin preparation, and in this case, simultaneously applied with other raw materials. If you do, synergistic effects may occur.

In addition, when the composition according to the present invention is used as a pharmaceutical composition, it may further contain pharmaceutical supplements and other therapeutically useful substances such as preservatives, stabilizers, hydrating or emulsifiers, salts or buffers for controlling osmotic pressure. And may be formulated in parenteral dosage forms according to conventional methods.

It is to be understood that the actual dosage of the active ingredient should be determined in light of several relevant factors such as the severity of the symptom, the route of administration chosen, the age, sex, weight and health of the subject.

Generally, the dosage of the active ingredient ranges from 0.001 μg / kg / day to approximately 2000 μg / kg / day. More preferred dosages are from 0.5 μg / kg / day to 2.5 μg / kg / day. Topical administration may be administered once a day or may be divided several times.

In another aspect, the present invention provides a food composition for preventing or improving obesity comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In the above formula,

R ₁ is hydrogen,

R ₂ may be straight or branched C _1-6 hydroxyalkyl, straight or branched C _1-6 dihydroxyalkyl, or straight or branched C _1-6 carboxyalkyl.

The compound represented by Formula 1 and salts thereof are as described above.

For example, the compound represented by Formula 1 may be a compound in which R ₁ is hydrogen, R ₂ is hydroxypropyl, 2-methyl-2,3-dihydroxypentyl, or carboxyethyl.

Specifically, the food composition of the present invention as a compound of Formula 1

1) (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol,

2) (S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol, or

3) (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid, but is not limited thereto.

For example, the anti-obesity composition comprising the compound represented by Formula 1 of the present invention may be added to a food composition for preventing or improving obesity. When using an anti-obesity composition comprising a compound represented by the formula (1) of the present invention as a food additive, the composition may be added as it is, or used with other foods or food ingredients, and may be appropriately used according to conventional methods. . 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 manufacture of food or beverage, the composition of the present invention is added in an amount of 0.01 to 10% by weight, specifically 0.05 to 1% by weight, based on the raw materials. However, in the case of prolonged ingestion for health and hygiene purposes or for health control purposes, the amount may be used below the above range.

There is no particular limitation on the kind of food. Examples of foods to which the substance may be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, dairy products including ice cream, soups, beverages, teas, drinks, alcoholic beverages and vitamins. Combinations and the like, and include 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 usual 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 a sweetener, natural sweeteners such as tautin and stevia extract, or synthetic sweeteners such as saccharin or aspartame may be used. The proportion 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, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, And carbonating agents used in carbonated drinks. In addition, the composition of the present invention may contain a pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components can be used independently or in combination. The proportion of such additives is not critical but is usually 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. These components can be used independently or in combination.

In another aspect, the present invention provides a feed composition for preventing or improving obesity comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In the above formula,

R ₁ is hydrogen,

R ₂ may be straight or branched C _1-6 hydroxyalkyl, straight or branched C _1-6 dihydroxyalkyl, or straight or branched C _1-6 carboxyalkyl.

The compound represented by Formula 1 and salts thereof are as described above.

For example, the compound represented by Formula 1 may be a compound in which R ₁ is hydrogen, R ₂ is hydroxypropyl, 2-methyl-2,3-dihydroxypentyl, or carboxyethyl.

Specifically, the feed composition of the present invention as the compound of Formula 1

1) (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol,

2) (S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol, or

3) (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid, but is not limited thereto.

For example, the anti-obesity composition comprising the compound represented by Formula 1 of the present invention may be added to the feed composition for the prevention or improvement of obesity.

As used herein, the term "feed" refers to a food ingested by an animal, and specifically, may mean a material supplying organic or inorganic nutrients necessary for maintaining the life of the animal or producing meat, milk, and the like. . The feed may include the bisabolol derivative of the present invention in the form of a feed additive to prevent or improve obesity in the subject animal, and may be prepared in various forms known in the art.

The kind of the feed is not particularly limited, and may be used a feed commonly used in the art. Non-limiting examples of the feed include, but are not limited to, vegetable feeds such as cereals, fruits, food processing by-products, algae, fibres, oils, starches, gourds or grain by-products; And animal feeds such as proteins, minerals, fats and oils, minerals, fats and oils, single cell proteins, zooplankton or foods. These may be used alone or in combination of two or more thereof.

The feed may further be used by mixing one or more components of organic acids such as citric acid, fumaric acid, adipic acid, lactic acid or natural antioxidants such as polyphenols, catechin, tocopherol, vitamin C, green tea extract, chitosan, tannic acid, If necessary, other conventional additives such as buffers and bacteriostatic agents can be added. It may also be formulated into liquids, capsules, granules or tablets as needed.

Feed composition of the present invention can be fed to a number of animals, including mammals, poultry. Commercially important animals, such as pigs, cows, goats, mammals, dogs, cats, etc. can be used, but is not limited to these.

For example, bisabolol, a natural-derived compound having a structure similar to the compounds of the present invention, is formulated as a compound itself or in various forms, and is used in the form of a pharmaceutical composition as well as a tee, for example, to promote skin penetration. In order to make the formulation on the nanocarrier has been reported. Therefore, the compounds of the present invention, which share the nucleus structure represented by Formula 1 compared to the bisabolol, may be formulated in a similar manner to be used as pharmaceutical compositions, specifically as external skin preparations, as well as food or feed. It is apparent to those skilled in the art that it can be used.

Since the bisabolol derivatives of the present invention not only inhibit the proliferation of adipocytes into adipocytes but also do not exhibit toxicity, they can be usefully used for the prevention or treatment of various diseases that can be caused by obesity.

1 is a diagram showing the differentiation-related mRNA levels in 3T3L cells treated with nonsabolol derivatives (BisaA, BisaD, BisaL and BisaT) at 100 μM concentration according to the present invention as a result of real-time PCR.
Figure 2 is a diagram showing the effect on weight loss and blood sugar drop in the animal model administered with the bisabolol derivative BisaT according to the present invention.
Figure 3 is a diagram showing the expression of mRNA involved in adipose tissue differentiation in the animal model administered with the bisabolol derivative BisaT according to the present invention.
Figure 4 is a diagram showing the effect on the liver accumulation of free fatty acids and triglycerides in the animal model administered the non-saborol derivative BisaT according to the present invention.
Figure 5 is a diagram showing the fatty liver-associated mRNA expression in real time PCR results in the animal model to which the non-saborol derivative BisaT according to the present invention.
Figure 6 is a diagram showing the cytotoxicity of the bisabolol derivatives of the present invention. A is a result of microscopic observation of AML cells cultured by treatment with a non-treated group as a negative control group, a BisaB treated group as a positive control group and a bisabolol derivative according to the present invention at a concentration of 200 μM, and B and C are RAW cells, respectively. And HeLa cells are graphs showing cytotoxicity measured by treating the compounds by concentration.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention more specifically, but the scope of the present invention is not limited by these examples.

Example  1: (-)-α- Bisabolol - Of diols (bissatriols, BisaT; 2)  synthesis

AD-mix β (40.0) to a solution of (-)-α-bisabolol ( 1 : 20.0 g, 90.0 mmol) in ^t BuOH / H ₂ O (v / v, 2: 1, 400 mL) at room temperature g) and methanesulfoneamide (8.52 g, 90.0 mmol) were added. The resulting orange suspension was stirred at rt for 72 h. Na ₂ S0 ₃ (40 g) was added to the reaction mixture and stirred for 3 hours. The resulting mixture was extracted with EtOAc (3 × 100 mL) and washed with 1 M KOH solution and brine. The combined extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue obtained was purified by flash column chromatography (SiO ₂ , hexanes: EtOAc = 1: 1 to 1: 2) to give (-)-α-bisabolol-diol ( 2 ) as pale yellow oil. 13.5 g (58%) of BisaT, (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol) were obtained.

R _f = 0.2 (hexanes: EtOAc = 1: 1).

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.36 (m, 1H), 3.35 (dd, J = 7.2, 1.5 Hz, 1 H), 2.0-1.82 (m, 3H), 1.75 (m, 1H), 1.68 (m, 2H), 1.65 (s, 3H), 1.65-1.58 (m, 3H), 1.42 (m, 1H), 1.30 (dd, J = 8.7, 4.0 Hz, 1H), 1.24 (s, 3H), 1.16 (s, 3 H), 1.11 (s, 3 H).

Example  2: (-)-α- Bisabolol - Of lactol (3)  synthesis

(-)-Α-bisabolol-diol ( 2 ; 12.2 g, 47.5 mmol) obtained from Example 1 was added to Me ₂ CO / H ₂ O (v / v, 10: 1, 200 mL) at 0 ° C. Sodium periodate, in a stirred solution 15.3 g, 71.4 mmol) was added. The resulting white suspension was warmed to room temperature and then stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc (3 × 100 mL). The combined extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting yellow crude residue was eluted with ether (300 mL) and filtered through a pad of silica gel. The filtrate was concentrated to give 6.70 g of crude (-)-α-bisabolol-lactol ( 3 ) which was used immediately in the next step without further purification.

Example  3: (-)-α- Bisabolol -Alcohol( Visaadiol , BisaD ; 4)  synthesis

To a solution of (-)-α-bisabolol-lactol ( 3 ; 5.00 g, 25.5 mmol) obtained in Example 2 in MeOH (100 mL) at room temperature, sodium borohydride, 1.06 g, 28.0 mmol) was added. The resulting mixture was stirred at rt for 4 h. The reaction mixture was concentrated and diluted with EtOAc. The mixture was washed with water and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue obtained was purified by flash column chromatography (SiO ₂ , hexanes: EtOAc = 3: 1 to 1: 1) to give (-)-α-bisadiol ( 4 , BisaD, 4.9 g (95%) of (S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol) was obtained.

R _f = 0.2 (hexanes: EtOAc = 2: 1).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.36 (m, 1H), 3.65 (t, J = 6.0 Hz, 2H), 2.04-1.92 (m, 3H), 1.91 (m, 1H), 1.78 (m, 1H), 1.70-1.66 (m, 2H), 1.67 (s, 3H), 1.64-1.53 (m, 3H), 1.29 (m, 1H), 1.02 (s, 3H).

Example  4: (-)-α- Bisabolol -Lactone ( Bisalactone , BisaL ; 5)  synthesis

Pyridinium chlorochlomate in a solution of (-)-α-bisabolol-lactol ( 3 ; 5.00 g, 25.5 mmol) obtained from Example 2 in CH ₂ Cl ₂ (300 mL) at room temperature. , 14.8 g, 68.8 mmol) was added. The resulting brown slurry was stirred at room temperature for 3 hours. The reaction mixture was filtered through a pad of celite, washed with CH ₂ Cl ₂ , and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by flash column chromatography (SiO ₂ , hexanes: EtOAc = 4: 1) to give (-)-α-bisabolol-lactone ( 5 , BisaL, ( 8.2 g (79%) of S) -5-methyl-5-((S) -4-methylcyclohex-3-enyl) dihydrofuran-2 (3H) -one) was obtained.

R _f = 0.4 (hexanes: EtOAc = 2: 1).

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.36 (m, 1H), 2.63 (ddd, J = 18.0, 9.5, 9.0 Hz, 1H), 2.53 (ddd, J = 18.0, 10.0, 4.5 Hz, 1H), 2.13 (m, 1H), 2.05-1.98 (m, 3H), 1.93-1.90 (m, 2H), 1.88-1.75 (m, 2H), 1.65 (s, 3H), 1.35 (m, 1H), 1.33 ( s, 3H).

Example  5: (-)-α- Bisabolol - Acid ( Visasaid , BisaA ; 6) Synthesis of Sodium Salt

To the (-)-α-bisabolol-lactone ( 5 ; 6.41 g, 32.9 mmol) obtained from Example 4 in MeOH (100 mL) at room temperature was added NaOH (1.32 g, 32.9 mmol). The resulting white suspension was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ and stirred for 1 hour. The resulting precipitate was filtered off and washed with a small amount of cold MeOH. The white horse was dried in a vacuum oven to obtain (-)-α-bisabolol-acid ( 6 , BisaA, (S) -4-hydroxy-4-((S) -4-methylcyclohex-) as a white powder. 5.2 g (74%) of 3-enyl) pentanoic acid were obtained in the form of a sodium salt.

R _f = 0.1 (EtOAc).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.32 (m, 1H), 2.07 (t, J = 8.0 Hz, 2H), 1.90 (m, 4H), 1.71-1.56 (m, 2H), 1.59 (s , 3H), 1.48 (m, 1H), 1.35 (m, 1H), 1.10 (m, 1H), 0.89 (s, 3H).

Example  6: on the regulation of fat differentiation Bisabolol  Effect of Derivatives

In order to confirm the adipose differentiation control ability of the bisabolol derivatives of the present invention synthesized according to Examples 1 to 5, the mouse fibroblasts 3T3L cell line insulin (10 μg / mL), dexamethasone (dexamethasone, 1 μM), 3 After treatment with isobutyl-1-methylxanthine (3-isobutyl-1-methylxanthine, IBMX, 500 μM) for 3 days to induce differentiation into adipocytes, the bisabolol derivative and positive control group of the present invention (- ) -α-bisabolol (BisaB) was incubated in two-day intervals with insulin (10 μg / mL) in mouse fibroblast 3T3L cell line, which is a progenitor cell, at 100 μM concentration to induce fat differentiation. MRNA levels of the genes involved in the synthesis were confirmed by real-time PCR, and the results are shown in FIG. 1. As a negative control group, a non-treated group (Con) was used.

As shown in FIG. 1, BisaA, BisaD, Bisa L, and BisaT, although to varying degrees, reduced mRNA levels of one or more of PPARγ, FABP4, SCD1, and SCD2, which are genes related to liposynthesis. In particular, BisaT significantly reduced FABP4 and SCD1 levels.

Example  7: HFD  About Weight and Glucose Control in Model Mice Bisabolol  Effect of Derivatives

The BisaT showing the best effect on the in vitro mRNA expression was administered to the experimental animals to confirm the effect of weight and blood glucose control. The experimental animal was a high-fat diet-mouse (HFD) model of type 2 diabetes. Each result is shown in FIGS. 2A and 2B with values for negative control and positive control.

As shown in FIG. 2, weight loss was confirmed in mice administered BisaT, but the effect of improving blood glucose was insignificant.

Example  8: Related to adipose tissue differentiation in vivo mRNA  About manifestation Bisabolol  Effect of Derivatives

In order to confirm the in vivo fat differentiation regulating ability of the bisabolol derivatives according to the present invention based on the results of in vitro adipose differentiation-related mRNA expression in Example 6, fat in mice administered BisaT as in Example 7 Expression of mRNA involved in tissue differentiation was confirmed. FAS and ACL were further confirmed in addition to the four factors, and the obtained results are shown in FIG. 3.

As shown in Figure 3, BisaT according to the present invention significantly reduced FAS and SCD2.

Example  9: HFD  About Fatty Liver Generation in Model Mice Bisabolol  Effect of Derivatives

Using the HFD model used in Example 7 was confirmed the effect on the fatty liver production of BisaT according to the present invention. Specifically, the amount of free fatty acid (FFA) and triglyceride (TG) accumulated in liver tissue was measured, and the results are shown in FIG. 4.

As shown in Figure 4, the administration of BisaT according to the present invention significantly reduced the accumulation of triglycerides in the liver.

In addition, fatty liver-associated mRNA expression in the HFD model was confirmed by real-time PCR, and the results are shown in FIG. 5. Specifically, fatty liver-related mRNA expression levels in liver tissue of the HFD model were confirmed by a similar method as in Example 8. As a result, unlike the mRNA expression pattern in Example 8, BisaT according to the present invention significantly reduced the mRNA expression of all six genes measured in liver tissue. This indicates that the bisabolol derivative according to the present invention is particularly useful for inhibiting fatty liver formation because it effectively inhibits fat formation in the liver.

Example  10: Bisabolol  Cytotoxicity of Derivatives

In order to confirm the cytotoxicity of the bisabolol derivatives according to the present invention, by treating bisabolol (BisaB) as a positive control group with four kinds of bisabolol derivatives according to the present invention at 200 μM concentration to AML cells that are mouse liver cells Incubation was performed for 24 hours and morphology was observed under a microscope. The results are shown in FIG. 6A. In addition, in order to confirm the toxicity according to the concentration, the compounds were treated for 24 hours while increasing to 400 μM each of RAW cells (mouse macrophages) and HeLa cells (human cervical canal immortalized cells), which exist only in cells By measuring the activity of lactate dehydrogenase (LDH), cytotoxicity was confirmed by measuring the degree of leakage of the enzyme into the cell culture due to cytotoxicity, and the results are shown in FIGS. 6B and 6C, respectively. Indicated.

As shown in FIG. 6, BisaB, i.e., (-)-α-bisabolol, used as a positive control began to show cytotoxicity from a concentration of 50 μM in all three cell lines. However, the bisabolol derivatives according to the present invention showed no toxicity at concentrations of 100 μM or less, and some compounds showed cytotoxicity at concentrations of 200 to 400 μM, but the ratio was at most 20%. This indicates that the bisabolol derivatives according to the present invention can be usefully used as pharmaceutical compositions or food compositions because they have anti-obesity effects and do not exhibit toxicity.

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, it should be understood that the embodiments described above are exemplary in all respects and not limiting. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (20)

A compound represented by Formula 1, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Chemical Formula 1,
R ₁ is hydrogen,
R ₂ is hydroxypropyl, or carboxyethyl,
The compound is (S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol, or (S) -4-hydroxy-4-((S) -4 -Methylcyclohex-3-enyl) pentanoic acid, or a pharmaceutically acceptable salt thereof.
delete delete comprising a first step of dihydroxylation of a double bond of (-)-α-bisabolol to an adjacent diol,
To prepare a compound represented by the formula (1), or a pharmaceutically acceptable salt thereof:
[Formula 1]

In the above formula,
R ₁ is hydrogen,
R ₂ is straight or branched C _1-6 hydroxyalkyl, straight or branched C _1-6 dihydroxyalkyl, or straight or branched C _1-6 carboxyalkyl, or
R ₁ and R ₂ together form an C _3-7 cycloheteroalkyl which is unsubstituted or substituted with oxo, including oxygen and carbon atoms bonded thereto.
The method of claim 4, wherein
R ₁ is hydrogen,
R ₂ is hydroxypropyl, 2-methyl-2,3-dihydroxypentyl, or carboxyethyl.
The method of claim 4, wherein
R ₁ and R ₂ together form oxygen and carbon atoms bonded thereto to form tetrahydrofuranyl substituted with oxo.
The method of claim 4, wherein
Compound represented by Formula 1 is
1) (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol,
2) (S) -4-((S) -4-methylcyclohex-3-enyl) pentane-1,4-diol,
3) (S) -5-methyl-5-((S) -4-methylcyclohex-3-enyl) dihydrofuran-2 (3H) -one, or
4) (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid.
The method of claim 4, wherein
The first step is carried out in the presence of a compound containing a transition metal of a high-oxidation state (high-oxidation state) as a catalyst.
The method of claim 4, wherein
The first step is performed in the presence of a chiral ligand.
The method of claim 4, wherein
A second step of forming the cyclic intermediate by maintaining the compound obtained from the first step at 5 to 20 hours at 10 to 35 ° C. in the presence of sodium periodate (NaIO ₄ ); And
Step 3-1 to induce ring opening by reducing the intermediate formed from the second step, or
3-2 to oxidize and carbonylate the alcohol of the intermediate formed from the second step.
The method of claim 10,
Steps 3-1 and 3-2 are carried out in the presence of sodium borohydride (NaBH ₄ ) and pyridinium chlorochromate (PCC) as catalysts, respectively.
A pharmaceutical composition for preventing or treating obesity comprising the compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In the above formula,
R ₁ is hydrogen,
R ₂ is 3,4-dihydroxy-4-methyl-pentyl, hydroxypropyl, or carboxyethyl,
The compound is (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol, (S) -4-((S)- 4-methylcyclohex-3-enyl) pentane-1,4-diol or (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid Pharmaceutical composition for preventing or treating obesity.
delete The method of claim 12,
The pharmaceutical composition has any one formulation selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, lyophilized preparations and suppositories. Pharmaceutical composition.
An external skin preparation comprising the pharmaceutical composition for preventing or treating obesity according to any one of claims 12 and 14.
A food composition for preventing or improving obesity comprising a compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In the above formula,
R ₁ is hydrogen,
R ₂ is 3,4-dihydroxy-4-methyl-pentyl, hydroxypropyl, or carboxyethyl,
The compound is (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol, (S) -4-((S)- 4-methylcyclohex-3-enyl) pentane-1,4-diol or (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid , Food composition for preventing or improving obesity.
delete Feed composition for preventing or improving obesity comprising a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In the above formula,
R ₁ is hydrogen,
R ₂ is 3,4-dihydroxy-4-methyl-pentyl, hydroxypropyl, or carboxyethyl,
The compound is (6S) -2-methyl-6-((S) -4-methylcyclohex-3-enyl) heptan-2,3,6-triol, (S) -4-((S)- 4-methylcyclohex-3-enyl) pentane-1,4-diol or (S) -4-hydroxy-4-((S) -4-methylcyclohex-3-enyl) pentanoic acid Feed composition for preventing or improving obesity.
delete The method for preventing or treating obesity comprising administering the pharmaceutical composition for preventing or treating obesity according to any one of claims 12 and 14 to an individual except for a human having the onset or possibility of developing obesity in a pharmaceutically effective amount. Way.

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