WO2021034111A1 - Novel sesquiterpene derivative and use thereof - Google Patents

Abstract

The present invention relates to a novel sesquiterpene derivative and use thereof and, more particularly, to a novel sesquiterpene derivative or optical isomer thereof, a pharmaceutical composition, food composition and feed composition, comprising same, and use thereof for the prevention or treatment of obesity or metabolic disease.

Description

Novel sesquiterpene derivatives and uses thereof

The present invention relates to novel sesquiterpene derivatives and uses thereof, and more particularly to novel sesquiterpene derivatives or optical isomers thereof; Pharmaceutical compositions, food compositions, and feed compositions comprising them; And it relates to the use of the prevention or treatment of obesity or metabolic disease.

Obesity is one of the diseases that are difficult to avoid in the modern living environment. As visceral fat-type obesity increases in modern people due to changes in living conditions different from the past, the onset of metabolic syndrome, which is accompanied by diabetes, hypertension, lipid abnormality syndrome, and insulin-resistant diabetes (type 2 diabetes), is rapidly increasing. These diseases increase the risk of occurrence of each other, and are common diseases related to various metabolic changes in living organisms such as aging, stress, and immune function decline. According to the 2015 National Health and Nutrition Survey, more than 32% of Korean adults over the age of 20 were obese (35.2% of adult males and 28.3% of female adults). The incidence of childhood obesity in Koreans has also recently increased, 11.3% of elementary school students, 10.7% of middle school students, and 16% of high school students were classified as obese (standard: BMI> 25kgm ² ), and overweight (standard: BMI> 23kg/m ² ) And 17% of obese adolescents have metabolic syndrome (as of 2015). As described above, the increase in overweight and obese population leads to an increase in the prevalence of chronic diseases, for example, hypertension (male 30.2%, female 25.6%), diabetes (male 9.0%, female 7.2%), for Koreans aged 30 or older. The prevalence of high cholesterol (7.5% for men and 8.8% for women) is higher than that of other countries (as of 2015). The socioeconomic loss due to obesity is estimated to be 2.2 trillion won per year in 2018, and accordingly, the government has set lowering the adult obesity rate to less than 20% and the juvenile obesity rate to less than 15% as major indicators of national health promotion A system is being developed to manage this nationally. Obesity can be treated only when diet and exercise therapy are combined, but this method requires a lot of time, effort, and cost, and it is difficult to implement due to various restrictions, making it difficult to sufficiently achieve the intended purpose. Recently, health supplements and diet products that are effective in treating obesity are being used, but it is also difficult to quantitatively prove their effectiveness.

In the case of orlistat, a drug currently used as a treatment for obesity, its use is very limited because it is known to inhibit the absorption of vitamin D in the body and side effects such as unbearable urgency, fat stool, intestinal gas bloating, and abdominal bloating. . In addition, drugs that inhibit fat absorption in the body are not desirable drugs for Koreans, who have relatively less meat intake than Westerners. In the case of sibutramine, another drug used as a treatment for obesity, side effects such as headache, dry mouth, loss of appetite, insomnia, constipation, increased heart rate, palpitations, and dizziness appear. It is not a topical drug but is known to act on the cerebral central nerve system and its use is extremely limited.

Main ingredients extracted from the woody part of cedar ( Cupressus funebris ) or juniper ( Juniperus chinensis ) include (+)-sedrol, alpha-sedrene, beta-sedrene, alpha-funebrin, beta-funebrin, etc. Cedrol and cedrene derivatives are known, and these are sesquiterpene-like compounds composed of three isoprene units. Cedrol and its derivatives are used in various pharmaceutical applications such as psoriasis, atopy, eczema, seborrheic skin composition, scleroderma, skin immune hypersensitivity treatment (Korean Patent No. 10-1828557), hair growth promotion and hair loss prevention (Chinese Patent Publication 107260710). Is known. Cedrol and its derivatives isolated and purified from the woody part of natural cedar or juniper have low solubility in water (21.88mg/L, reference; Int.J of Nanomedicine, 2017) despite showing pharmacological effects in vitro. , 12, pp4850), so there is little absorption in the body, so there is a pharmaceutical barrier that is too large to be developed for practical pharmaceutical use. That is, there is a disadvantage that this cannot be achieved due to low solubility in water when the dose is increased to reach the medicinal capacity.

The present invention provides novel sesquiterpene derivatives or optical isomers thereof.

The present invention provides a pharmaceutical composition comprising the novel sesquiterpene derivative or optical isomer thereof as an active ingredient.

The present invention provides a pharmaceutical composition for preventing or treating obesity or metabolic diseases comprising the novel sesquiterpene derivative or an optical isomer thereof as an active ingredient.

The present invention provides a food composition for preventing or improving obesity or metabolic diseases comprising the novel sesquiterpene derivative or optical isomer thereof as an active ingredient.

The present invention provides a feed composition for preventing or improving obesity or metabolic diseases comprising the novel sesquiterpene derivative or an optical isomer thereof as an active ingredient.

The present invention provides a method for preventing or treating obesity or metabolic diseases comprising administering the pharmaceutical composition to an individual.

The present invention provides the use of the novel sesquiterpene derivative or optical isomer thereof for the prevention or treatment of obesity or metabolic diseases.

The present invention provides the use of the novel sesquiterpene derivative or optical isomer thereof for the manufacture of a medicament for the prevention or treatment of obesity or metabolic disease.

As a result of research efforts to overcome the side effects of the existing synthetic anti-obesity drugs and to solve the problem of low solubility in water, new sesquiterpene derivatives or optical isomers thereof show high solubility in water, and weight and visceral fat mass In addition to reducing the plasma total cholesterol, triglycerides, blood sugar, insulin concentration, and confirmed the excellent effect of reducing the concentration of triglycerides in liver tissue, and completed the present invention.

Novel sesquiterpene derivatives

The present invention provides a novel sesquiterpene derivative, that is, a compound represented by the following Chemical Formulas 1 to 12, or an optical isomer thereof.

1) (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-4-hydroxy-3-methoxy Benzoate;

2) (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-4-acetoxy-3-methoxy Benzoate;

3) (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-3-methoxy-4-pivalo Monooxybenzoate;

4) (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-5-methyl-2-oxo-1 ,3-dioxole-4-carboxylate;

5) (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-2-(((cyclohexyloxy )Carbonyl)oxy)propanate;

6) (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-4-(pivaloyloxy)benzo Nate;

7) (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-3-(4- Hydroxyphenyl)acrylate;

8) (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-3-(4- Hydroxy-3-methoxyphenyl)acrylate;

9) (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-3-(3, 4-dihydroxyphenyl)acrylate;

10) (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl cinnamate;

11) (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-3-(4- (2-hydroxyethoxy)phenyl)acrylate;

12) (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-3-(4- (2-(dimethylamino)ethoxy)phenyl)acrylate.

The present invention provides a compound represented by Formula 3, Formula 4, Formula 6 to Formula 8, or an optical isomer thereof.

The compounds represented by Chemical Formulas 1 to 12 of the present invention or optical isomers thereof may reduce body weight, visceral fat mass, plasma total cholesterol, triglyceride, blood sugar, and insulin concentration, and triglyceride concentration in liver tissue. Accordingly, the compounds represented by Chemical Formulas 1 to 12 of the present invention or optical isomers thereof may be usefully used in the prevention or treatment of obesity or metabolic diseases.

In a specific experimental example of the present invention, the compounds represented by Chemical Formulas 1 to 12 of the present invention or optical isomers thereof reduce the fat content of the nematode nematode (Figs. 1 and 2), and reduce the weight and visceral fat mass of the mouse. In addition to reducing (Table 2), it was confirmed that plasma total cholesterol, triglyceride, blood sugar and insulin concentrations and hepatic triglyceride concentrations were reduced in mice (Table 3).

Composition comprising novel sesquiterpene derivative or optical isomer thereof, use thereof, and treatment method using the same

The present invention provides a pharmaceutical composition comprising any one or more of the compounds represented by the following Chemical Formulas 1 to 12 or optical isomers thereof as an active ingredient.

The present invention provides a pharmaceutical composition for the prevention or treatment of obesity or metabolic diseases comprising any one or more of a compound represented by the following Chemical Formulas 1 to 12 or optical isomers thereof as an active ingredient.

In the present invention, the pharmaceutical composition may include a compound represented by Formula 3, Formula 4, Formula 6 to Formula 8, or any one or more of optical isomers thereof as an active ingredient.

The term "obesity" of the present invention refers to a state in which an excessive amount of fat is accumulated in the body, which causes various types of metabolic diseases such as diabetes, hyperlipidemia, fatty liver, arteriosclerosis, and the like.

The term "metabolic disease" of the present invention refers to a disease caused by metabolic disorders in vivo, and in the present invention, the metabolic disease may be selected from the group consisting of diabetes, hyperlipidemia, fatty liver, but is limited thereto. no.

The term "diabetic disease" refers to a chronic disease characterized by a relative or absolute lack of insulin resulting in glucose-intolerance. In the present invention, the diabetes includes all types of diabetes, for example, type 1 diabetes, type 2 diabetes, and inherited diabetes. Type 1 diabetes is insulin dependent diabetic disease, which is mainly caused by the destruction of beta cells. Type 2 diabetes is insulin nondependent diabetic disease, which is caused by insufficient insulin secretion after a meal or by insulin resistance. A composition comprising as an active ingredient any one or more of the compounds represented by Chemical Formulas 1 to 12 of the present invention or optical isomers thereof, prevents or treats type 1 diabetes, more preferably, type 2 diabetes caused by insulin resistance. It can have an effect.

The term "hyperlipidemia" refers to a disease caused by a high level of fat in the blood due to inadequate lipid metabolism such as triglycerides and cholesterol. Specifically, it refers to a state in which lipid components such as neutral fat acid, LDL (low density lipid), cholesterol, phospholipids, and fatty acids in the blood are increased, and the frequency of occurrence thereof is increased. It may refer to, but is not limited to, hyper-cholesterol disease.

The term "fatty liver" refers to a condition in which an excessive amount of fat is accumulated in hepatocytes due to liver metabolism disorder, which is various such as angina pectoris, myocardial infarction, stroke, arteriosclerosis, and pancreatic composition. It causes disease.

A composition comprising as an active ingredient any one or more of the compounds represented by Chemical Formulas 1 to 12 or optical isomers thereof of the present invention is weight, visceral fat mass, plasma total cholesterol, triglyceride, blood sugar, and insulin concentration, and liver tissue neutrality. It can reduce fat concentration. Accordingly, a composition comprising as an active ingredient any one or more of the compounds represented by Chemical Formulas 1 to 12 or optical isomers thereof of the present invention may be usefully used in the prevention or treatment of obesity or metabolic diseases.

In a specific experimental example of the present invention, a composition comprising as an active ingredient any one or more of the compounds represented by Chemical Formulas 1 to 12 or optical isomers thereof of the present invention reduces the fat content of the nematode (Fig. 1 and Figure 2), as well as reducing the body weight and visceral fat mass of the mouse (Table 2), it was confirmed that the plasma total cholesterol, triglyceride, blood glucose and insulin concentrations and liver triglyceride concentration of the mouse were reduced (Table 3).

The term "prevention" of the present invention means any action that inhibits or delays the onset of a disease by administration of a compound or composition.

As used herein, the term "treatment" refers to any action in which symptoms of an individual suspected of and onset of a disease are improved or beneficially altered by administration of a compound or composition.

The pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers in addition to any one or more of the compounds represented by Chemical Formulas 1 to 12 or optical isomers thereof. Pharmaceutically acceptable carriers are commonly used in the art, and specifically lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidine, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral, or oil may be, but is not limited thereto. The pharmaceutical compositions of the present invention may further include lubricants, wetting agents, sweetening agents, flavoring agents, emulsifying agents, suspending agents, preservatives, dispersing agents, stabilizers, and the like in addition to the above components. In addition, the pharmaceutical composition of the present invention uses pharmaceutically acceptable carriers and excipients for oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, solutions, emulsions, syrups, external preparations, suppositories, etc. Alternatively, it may be formulated in the form of a sterile injectable solution and prepared in a unit dosage form, or may be prepared by being placed in a multi-dose container. The formulation may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (19 ^th ed., 1995), and may be formulated into various formulations according to each disease or ingredient.

The pharmaceutical composition of the present invention may be administered orally or parenterally administered according to a desired method, and may preferably be administered orally, but is not limited thereto.

The dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration mode, patient's age, weight, sex, pathological condition, dietary intake type, administration route, excretion rate, and response sensitivity. can do. A preferred dosage of the pharmaceutical composition of the present invention is 1 mg/kg to 1000 mg/kg on an adult basis, and may be administered once to several times a day.

The present invention provides a method for preventing or treating obesity or metabolic diseases comprising administering the pharmaceutical composition to an individual.

The term "administration" of the present invention means introducing a given substance to an individual in an appropriate manner.

The term "individual" of the present invention refers to all animals such as mice, mice, livestock, etc., including humans that have or may develop disease, and may specifically be mammals including humans, but is not limited thereto. .

The method of preventing or treating obesity or metabolic disease of the present invention may be administering the pharmaceutical composition in a pharmaceutically effective amount.

As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not cause side effects, which is the sex, age, and weight of the patient. , Health condition, type of disease, severity, drug activity, sensitivity to drugs, method of administration, time of administration, route of administration, and rate of excretion, duration of treatment, factors including drugs used in combination or simultaneously, and other medical fields. It can be determined by a person skilled in the art according to known factors.

The present invention provides a food composition for preventing or improving obesity or metabolic diseases comprising any one or more of a compound represented by the following Chemical Formulas 1 to 12 or optical isomers thereof as an active ingredient.

The meanings of the terms "obesity", "metabolic disease", "prevention" and the like are as described above.

The term "improvement" of the present invention refers to any action in which a disease is improved or beneficially altered by administration of the composition.

As used herein, the term "food" refers to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages , Vitamin complexes, health functional foods, health foods, and health supplements, and all foods in the usual sense are included.

The term "functional food" is the same term as food for special health use (FoSHU). In addition to supplying nutrients, the processed medicine and medical effects are effective so that the biological control function is effectively displayed. Means high food. Here, the term'function (sex)' means to control nutrients for the structure and function of the human body or to obtain useful effects for health purposes such as physiological actions.

The "health food" refers to a food having an active health maintenance or enhancement effect compared to general food, and "health supplement food" refers to a food for the purpose of health supplementation. In some cases, the terms health functional food, health food, and health supplement food are used interchangeably.

The food of the present invention can be prepared by a method commonly used in the art, and during the production, raw materials and ingredients commonly added in the art may be added to prepare the food product. Specifically, proteins, carbohydrates, fats, nutrients, flavoring agents, and flavoring agents may be included, and examples of the carbohydrates are glucose, fructose, maltose, sucrose, oligosaccharide, dextrin, cyclodextrin, xylitol, sorbitol, ery Troll, saccharin, or synthetic flavoring agents, but are not limited thereto. The food composition of the present invention may be prepared in various forms without limitation, provided that it is a formulation recognized as a food.

The present invention provides a feed composition for preventing or improving obesity or metabolic diseases comprising any one or more of a compound represented by the following Chemical Formulas 1 to 12 or optical isomers thereof as an active ingredient.

The meanings of the terms "obesity", "metabolic disease", "prevention", "improvement" and the like are as described above.

The term "feed" of the present invention means any natural or artificial diet, one meal meal, etc., or a component of the one meal meal for consumption and digestion by livestock. The feed may contain feed additives or auxiliary feeds.

The kind of feed is not particularly limited, and feed commonly used in the art may be used. Non-limiting examples of the feed include vegetable feeds such as grains, root fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, meals or grain by-products; Animal feeds such as proteins, inorganic logistics, oils and fats, minerals, oils and fats, single-cell proteins, zooplanktons or foods. These may be used alone or in combination of two or more.

The present invention provides a use of a compound represented by the following Formulas 1 to 12 or an optical isomer thereof for the prevention or treatment of obesity or metabolic diseases.

The present invention provides the use of a compound represented by the following Formulas 1 to 12 or an optical isomer thereof for the manufacture of a medicament for preventing or treating obesity or metabolic diseases.

The meanings of the terms "obesity", "metabolic disease", "prevention", "treatment" and the like are as described above.

The novel sesqueterpene derivatives or optical isomers thereof of the present invention not only reduce body weight and visceral fat mass, but also have the effect of reducing plasma total cholesterol, triglyceride, blood sugar, insulin concentration, and triglyceride concentration in hepatic tissue. It can be usefully used in the prevention or treatment of metabolic diseases.

1 is an image showing the fat content of the nematode after treatment of the novel sesquiterpene derivative of the present invention by concentration. The numerical value in the image indicates the fat content colored in the composition and the lower the value (+1) the fat content The lower the number and the higher the value (+4), the higher the fat content.

Figure 2 is a graph showing the fat content of nematodes after treatment of the novel sesquiterpene derivative of the present invention by concentration, the X-axis of the graph is the sample concentration (μg/ml) and the Y-axis is the fat content (+1 to +4). Means).

Hereinafter, the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not construed as being limited by these examples.

Example 1: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-4-hydroxy-3- Preparation of methoxybenzoate [Compound 1]

[Formula 1]

(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-ol 13.3g (1.2equiv.) and 4-hydroxy 8.4 g (0.05 mol, 1equiv.) of -3-methoxybenzoic acid was added to 250 mL of dimethylacetamide and stirred to dissolve. Potassium carbonate 103.6g (1.5equiv.), 4-toluenesulfonyl chloride 9.5g (1.2equiv.) and 4-dimethylaminopyridine 0.9g (15mol%) were sequentially added to the solution and stirred at room temperature for 2 hours. A mixture of 550 mL of ethyl acetate, 53.6 g of ammonium chloride and 600 mL of purified water was added, followed by stirring for 30 minutes. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the labeled compound (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoa 13.4 g (72%) of julen-6-yl-4-hydroxy-3-methoxybenzoate were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 1H), 1.66 ( m, 3H), 1.72(m, 1H), 1.95(m, 2H), 3.83(s, 3H), 5.35(s, 1H), 7.15(d, 1H, J=7.5), 7.45(s, 1H) , 7.46 (d, 1H, J=7.5). IR(KBr) 3440, 2995, 1710, 1645, 1420, 1391, 1250, 1165, 760cm ^-1 . MS (ESI) m/z (M+1), 372.23 (100.0%), 373.23 (25.0%), 374.24 (3.1%).

Example 2: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-4-acetoxy-3- Preparation of methoxybenzoate [Compound 2]

[Formula 2]

(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-4- prepared in Example 1 in 250 mL of dichloromethane Hydroxy-3-methoxybenzoate 18.6g (0.05mol, 1equiv.) was added and stirred. To the solution, 0.9 g (15 mol%) of 4-dimethylaminopyridine, 4.71 g (1.2equiv.) of acetyl chloride, and 10.5 mL (1.5equiv.) of triethylamine were sequentially added, followed by stirring at room temperature for 2 hours. Upon completion of the reaction, 600 mL of purified water was added and stirred for 30 minutes. Stirring was stopped, the layers were separated, the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of dichloromethane. The organic layer was washed with water, brine, and saturated sodium hydrogencarbonate solution, respectively, and then dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude compound. The crude crystal compound was recrystallized by adding hexane and the labeled compound (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl 17.6 g (85%) of -4-acetoxy-3-methoxybenzoate was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 1H), 1.66 ( m, 3H), 1.72 (m, 1H), 1.95 (m, 2H), 2.28 (s, 3H), 3.83 (s, 3H), 7.29 (d, 1H, J=7.5), 7.59 (s, 1H) , 7.62 (d, 1H, J=7.5). IR(KBr) 3000, 1690, 1650, 1510, 1410, 1381, 1251, 1165, 761cm ^-1 . MS (ESI) m/z (M+1) 414.24 (100.0%), 415.24 (27.2%), 416.25 (3.7%), 416.24 (1.0%).

Example 3: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-3-methoxy-4- Preparation of pivaloyloxybenzoate [Compound 3]

[Formula 3]

(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-4- prepared in Example 1 in 250 mL of dichloromethane Hydroxybenzoate 17.1g (0.05mol, 1equiv.) was added and stirred. To the solution, 0.9g (15mol%) of 4-dimethylaminopyridine, 7.2g (1.2equiv.) of pivaloyl chloride, and 10.5mL (1.5equiv.) of triethylamine were sequentially added and stirred at room temperature for 4 hours. After the reaction was over, 600 mL of cold purified water was added and stirred for 30 minutes. Stirring was stopped, the layers were separated, the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of dichloromethane. The organic layer was washed with water, brine, and saturated sodium hydrogencarbonate solution, respectively, and then dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude compound. The crude crystal compound was recrystallized by adding hexane and the labeled compound (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl 16.4 g (72%) of -3-methoxy-4-pivaloyloxybenzoate was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.23 (s, 9H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 ( m, 1H), 1.66 (m, 3H), 1.72 (m, 1H), 1.95 (m, 2H), 3.83 (s, 3H), 7.29 (d, 1H, J=7.5), 7.59 (s, 1H) , 7.62 (d, 1H, J=7.5). IR(KBr) 2928, 2875, 1695, 1640, 1466, 1379, 1251, 1165, 726cm ^-1 . MS (ESI) m/z (M+1) 456.29 (100.0%), 457.29 (30.9%), 458.29 (5.4%).

Example 4: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-5-methyl-2-oxo Preparation of -1,3-dioxole-4-carboxylate [Compound 4]

[Formula 4]

(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-ol 13.3g (1.2euiqv.) and 5-methyl- 7.2 g (0.05 mol, 1equiv.) of 2-oxo-1,3-dioxol-4-carboxylic acid was added to 250 mL of dimethylacetamide and stirred to dissolve. N,N'-dicyclohexylcarbodiimide 12.4g (1.2equiv.) and 4-dimethylaminopyridine 0.9g (15mol%) were sequentially added to the solution and stirred at room temperature for 5 hours. After filtration under reduced pressure with a membrane filter (25 μm membrane filter), 550 mL of ethyl acetate, 53.6 g of ammonium chloride, and 600 mL of purified water were added to the filtrate, followed by stirring for 30 minutes. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the labeled compound (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoa Julen-6-yl-5-methyl-2-oxo-1,3-dioxol-4-carboxylate 9.75 g (56%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2 (m, 1H), 1.35 (m, 3H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 2H), 1.66 (m, 3H), 1.76 (m, 1H), 1.99 (m, 1H), 2.51 (s, 3H). IR(KBr) 2985, 1712, 1690, 1647, 1468，1379, 1225, 1050, 755cm ^-1 . MS (ESI) m/z (M+1) 348.19 (100.0%), 349.20 (22.1%), 350.20 (3.4%).

Example 5: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-2-(((cyclohex Preparation of siloxy)carbonyl)oxy)propanate [Compound 5]

[Formula 5]

(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-ol 13.3g (1.2equiv.) and (((cyclocyclone) Hexyloxy)carbonyl)oxy)propionic acid 10.8 g (0.05 mol, 1equiv.) was added to 250 mL of dimethylacetamide and stirred to dissolve. N,N'-dicyclohexylcarbodiimide 12.4g (1.2equiv.) and 4-dimethylaminopyridine 0.9g (15mol%) were sequentially added to the solution and stirred at room temperature for 10 hours. After filtration under reduced pressure with a membrane filter, 550 mL of ethyl acetate, 53.6 g of ammonium chloride, and 600 mL of purified water were added to the filtrate, followed by stirring for 30 minutes. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the labeled compound (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoa Julen-6-yl-2-(((cyclohexyloxy)carbonyl)oxy)propanate 12.6g (60%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.8 (m, 28H), 1.99 (m, 1H), 3.91 (m, 1H), 4.98 (m, 1H). IR(KBr) 2992, 2887, 1710, 1692, 1640, 1478, 1388, 1222, 1053, 765cm ^-1 . MS (ESI) m/z (M+1) 420.29 (100.0%), 421.29 (27.7%), 422.29 (4.5%).

Example 6: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-4-(pivaloyloxy ) Preparation of benzoate [Compound 6]

Example 6-1: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-4-hydroxybenzo Preparation of Nate

(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-ol 13.3g (1.2equiv.) and 4-hydroxy 6.9 g (0.05 mol, 1equiv.) of benzoic acid was added to 250 mL of dimethylacetamide and stirred to dissolve. Potassium carbonate 103.6g (1.5equiv.), 4-toluenesulfonyl chloride 9.5g (1.2equiv.) and 4-dimethylaminopyridine 0.9g (15mol%) were sequentially added to the solution and stirred at room temperature for 2 hours. A mixture of 550 mL of ethyl acetate, 53.6 g of ammonium chloride and 600 mL of purified water was added, followed by stirring for 30 minutes. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the labeled compound (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoa 10.8 g (63%) of julen-6-yl-4-hydroxybenzoate were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.23 (s, 9H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 ( m, 1H), 1.66 (m, 3H), 1.72 (m, 1H), 1.95 (m, 2H), 5.35 (s, 1H), 6.81 (d, 2H, J=7.5), 7.90 (d, 2H, J=7.5). IR(KBr) 3560, 2983, 1647, 1519, 1468, 1221, 767cm ^-1 . MS (ESI) m/z (M+1) 342.22 (100.0%), 343.22 (23.9%), 344.23 (2.8%).

Example 6-2: (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-4-(pivalo Preparation of monooxy)benzoate

[Formula 6]

(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl- prepared in Example 6-1 in 250 mL of dichloromethane 4-hydroxy-3-methoxybenzoate 18.6g (0.05mol, 1equiv.) was added and stirred. To the solution, 0.9g (15mol%) of 4-dimethylaminopyridine, 7.2g (1.2equiv.) of pivaloyl chloride, and 10.5mL (1.5equiv.) of triethylamine were sequentially added and stirred at room temperature for 4 hours. Upon completion of the reaction, 600 mL of cold purified water was added and stirred for 30 minutes. Stirring was stopped, the layers were separated, the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of dichloromethane. The organic layer was washed with water, brine, and saturated sodium hydrogencarbonate solution, respectively, and then dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude compound. The crude crystal compound was recrystallized by adding hexane and the labeled compound (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl 16.2 (76%) of -4-(pivaloyloxy)benzoate was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.23 (s, 9H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 ( m, 1H), 1.66 (m, 3H), 1.72 (m, 1H), 1.95 (m, 2H), 7.40 (d, 2H, J=7.5), 8.04 (d, 2H, J=7.5). IR(KBr) 2959, 2928, 1692, 1640, 1463，1378, 1225, 1048, 760cm ^-1 . MS (ESI) m/z (M+1) 426.28 (100.0%), 427.28 (29.8%), 428.28 (5.0%).

Example 7: (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-3-( Preparation of 4-hydroxyphenyl)acrylate [Compound 7]

[Formula 7]

(E)-3-(4-hydroxyphenyl)acrylic acid 16.4 g (0.1 mol, 1.2equiv.) and (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro- 26.7 g (1.2equiv.) of 1H-3a,7-methanoazulene-6-ol was added to 500 ml of tetrahydrofuran and stirred to dissolve. 4 mL of sulfuric acid was added to the solution, stirred for 30 minutes, 30 g of magnesium sulfate was added, and the reaction solution was heated to reflux for 4 hours. When the reaction was completed, the mixture was concentrated under reduced pressure to remove tetrahydrofuran, and 550 mL of ethyl acetate and 600 mL of saturated sodium hydrogencarbonate solution were added, followed by stirring for 30 minutes. Stirring was stopped, the layers were separated, and the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of ethyl acetate. The organic layer was washed with water and brine, respectively, then dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude (Crude) compound. The crude compound was purified by column chromatography (ethyl acetate:hexane = 1:5), and the labeled compound (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethylocta Hydro-1H-3a,7-methanoazulen-6-yl-3-(4-hydroxyphenyl)acrylate 23.6g (64%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 2H), 1.66 ( m, 3H), 1.72(m, 1H), 1.99(m, 1H), 5.35(s, 1H), 6.30(d, 1H, J=15.1), 6.65(d, 2H, J=7.5), 7.48( d, 1H, J=15.1), 7.56 (d, 2H, J=7.5). IR(KBr) 3560, 2959, 1692, 1640, 1520, 1463, 1225, 760cm ^-1 . MS (ESI) m/z (M+1) 368.24 (100.0%), 369.24 (26.4%), 370.24 (4.0%).

Example 8: (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-3-( Preparation of 4-hydroxy-3-methoxyphenyl)acrylate [Compound 8]

[Formula 8]

(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid 9.7 g (0.05 mol, 1equiv.) and (3R,3aS,6R,7R,8aS)-3,6,8,8-tetra Methyloctahydro-1H-3a,7-methanoazulene-6-ol 13.3g (1.2equiv.) was added to 250ml of tetrahydrofuran and stirred to dissolve. 2 mL of sulfuric acid was added to the solution, stirred for 30 minutes, 15 g of magnesium sulfate was added, and the reaction solution was heated to reflux for 6 hours. When the reaction was completed, the mixture was concentrated under reduced pressure to remove tetrahydrofuran, and 550 mL of ethyl acetate and 600 mL of saturated sodium hydrogencarbonate solution were added, followed by stirring for 30 minutes. Stirring was stopped, the layers were separated, and the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of ethyl acetate. The organic layer was washed with water and brine, respectively, dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude compound (Crude). The crude compound was purified by column chromatography (ethyl acetate:hexane = 1:10), and the labeled compound (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethylocta Hydro-1H-3a,7-methanoazulen-6-yl-3-(4-hydroxy-3-methoxyphenyl)acrylate 13.4 g (67%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 2H), 1.66 ( m, 3H), 1.72 (m, 1H), 1.99 (m, 1H), 3.82 (s, 3H), 5.35 (s, 1H), 6.30 (d, 1H, J=15.1), 6.79 (d, 1H, J=7.5), 6.99 (d, 1H, J=7.5), 7.16 (s, 1H), 7.48 (d, 1H, J=15.1). IR(KBr) 3550, 2979, 1640, 1522, 1466, 1223, 760cm ^-1 . MS (ESI) m/z (M+1) 398.25 (100.0%), 399.25 (27.6%), 400.25 (4.4%).

Example 9: (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-3-( Preparation of 3,4-dihydroxyphenyl)acrylate [Compound 9]

[Formula 9]

(E)-3-(3,4-dihydroxyphenyl)acrylic acid 9.0 g (0.05 mol) and (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H 13.3 g (1.2equiv.) of -3a,7-methanoazulene-6-ol was added to 250 ml of tetrahydrofuran and stirred to dissolve. 2 mL of sulfuric acid was added to the solution, stirred for 30 minutes, 15 g of magnesium sulfate was added, and the reaction solution was heated to reflux for 2.5 hours. When the reaction was completed, the mixture was concentrated under reduced pressure to remove tetrahydrofuran, and 550 mL of ethyl acetate and 600 mL of saturated sodium hydrogencarbonate solution were added, followed by stirring for 30 minutes. Stirring was stopped, the layers were separated, and the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of ethyl acetate. The organic layer was washed with water and brine, respectively, then dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude (Crude) compound. The crude compound was purified by column chromatography (ethyl acetate:hexane = 1:3) and labeled compound (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethylocta Hydro-1H-3a,7-methanoazulen-6-yl-3-(3,4-dihydroxyphenyl)acrylate 13.8g (72%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 2H), 1.66 ( m, 3H), 1.72 (m, 1H), 1.99 (m, 1H), 5.35 (s, 2H), 6.31 (d, 1H, J=15.1), 6.79 (d, 1H, J=7.5), 6.92 ( d, 1H, J=7.5), 7.17 (s, 1H), 7.48 (d, 1H, J=15.1). IR(KBr) 3552, 2989, 1640, 1523, 1466, 1225, 767cm ^-1 . MS (ESI) m/z (M+1) 384.23 (100.0%), 385.23 (26.1%), 386.24 (3.4%).

Example 10: Preparation of (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl cinnamate [Compound 10]

[Formula 10]

7.4 g (0.05 mol, 1equiv.) of cinnamic acid and (3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-ol 13.3 g (1.2equiv.) was added to 250 ml of tetrahydrofuran, and 0.4 g (5 mol%) of iron chloride was added and stirred. The reaction solution was heated to reflux and reacted for 24 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent, and 500 mL of ethyl acetate and 600 mL of purified water were added thereto, followed by layer separation. The organic layer was collected, washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by column chromatography (ethyl acetate:hexane = 1:10), and the labeled compound (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethylocta 13.1 g (74%) of hydro-1H-3a,7-methanoazulen-6-yl cinnamate was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 2H), 1.66 ( m, 3H), 1.72 (m, 1H), 1.99 (m, 1H), 6.31 (d, 1H, J=15.1), 7.33-7.40 (m, 3H), 7.48 (d, 1H, J=15.1) 7.60 (d, 2H, J=7.5). IR(KBr) 2985, 1642, 1519, 1468, 1225, 767cm ^-1 . MS (ESI) m/z (M+1) 352.24 (100.0%), 353.24 (26.0%), 354.25 (3.3%).

Example 11: (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulen-6-yl-3-( Preparation of 4-(2-hydroxyethoxy)phenyl)acrylate [Compound 11]

[Formula 11]

(E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6- prepared in Example 7 in 250 mL of dichloromethane Il-3-(4-hydroxyphenyl)acrylate 18.4g (0.05mol, 1equiv.) was added and stirred. To the solution, 0.9g (15mol%) of 4-dimethylaminopyridine, 4.8g (1.2equiv.) of 2-chloroethanol, and 10.5mL (1.5equiv.) of triethylamine were sequentially added and stirred at room temperature for 2 hours. After the reaction was over, 600 mL of cold purified water was added and stirred for 30 minutes. Stirring was stopped, the layers were separated, the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of dichloromethane. The organic layer was washed with water, brine, and saturated sodium hydrogencarbonate solution, respectively, and then dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude compound. The crude crystal compound was recrystallized by adding hexane and the labeled compound (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene -6-yl-3-(4-(2-hydroxyethoxy)phenyl)acrylate 13.6g (66%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 2H), 1.66 ( m, 3H), 1.72(m, 1H), 1.99(m, 1H), 3.67(m, 3H), 4.33(t, 2H, J=7.1), 6.31(d, 1H, J=15.1), 6.94( d,2H,J=7.5), 7.48 (d, 1H, J=15.1) 7.60 (d, 2H, J=7.5). IR(KBr) 3600, 2995, 1645, 1525, 1467, 1225, 757cm ^-1 . MS (ESI) m/z (M+1) 412.26 (100.0%), 413.26 (28.1%), 414.27 (4.8%).

Example 12: (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6-yl-3-( Preparation of 4-(2-(dimethylamino)ethoxy)phenyl)acrylate [Compound 12]

[Formula 12]

(E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene-6- prepared in Example 7 in 250 mL of dichloromethane Il-3-(4-hydroxyphenyl)acrylate 18.4g (0.05mol, 1equiv.) was added and stirred. To the above solution, 0.9 g (15 mol%) of 4-dimethylaminopyridine, 6.5 g (1.2equiv.) of 2-chloro-N,N-dimethylethenamine, and 10.5 mL (1.5equiv.) of triethylamine were sequentially added to the solution at room temperature. The mixture was stirred for 3 hours. Upon completion of the reaction, 600 mL of cold purified water was added and stirred for 30 minutes. Stirring was stopped, the layers were separated, the organic layer was collected, and the aqueous layer was extracted twice with 500 mL of dichloromethane. The organic layer was washed with water, brine, and saturated sodium hydrogencarbonate solution, respectively, and then dried over sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude compound. The crude crystal compound was recrystallized by adding hexane and the labeled compound (E)-(3R,3aS,6R,7R,8aS)-3,6,8,8-tetramethyloctahydro-1H-3a,7-methanoazulene -6-yl-3-(4-(2-(dimethylamino)ethoxy)phenyl)acrylate 16.7g (76%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.99 (m 9H), 1.2-1.3 (m, 4H), 1.46 (m, 2H), 1.48 (s, 3H), 1.56 (m, 2H), 1.66 ( m, 3H), 1.72(m, 1H), 1.99(m, 1H), 2.76(t, 2H, J=7.1), 2.82(s, 6H) 4.11(t, 2H, J=7.1), 6.31(d , 1H, J=15.1), 6.94 (d, 2H, J=7.5), 7.48 (d, 1H, J=15.1) 7.62 (d, 2H, J=7.5). IR(KBr) 2993, 1647, 1521, 1468, 1221, 767cm ^-1 . MS (ESI) m/z (M+1) 439.31 (100.0%), 440.31 (31.2%), 441.32 (4.6%).

<Experimental Example 1> Anti-obesity effect; Analysis of changes in fat content of pretty little nematodes

In order to measure the anti-obesity efficacy of the novel sesquiterpene derivatives prepared in the above example, changes in fat content of Caenorhabditis elegans were analyzed. In this experiment, an adult (L4 stage; C. elegans), which was just before laying eggs, was used. Therefore, the eggs hatched after the sample treatment, and from the third day after the sample treatment, the adult almost died and the fat content of the nematode was observed. Using a dissecting microscope (magnification 50 times), 7 pretty little nematodes were transferred to 3 ml of S medium to which cholesterol was added, and 100 _{μl of E. coli OP50 (OD 600} = 0.2) cultured in the solution the day before was added. A rosewood fraction sample was added to the liquid medium containing the nematode nematode and incubated by rotating at 100 rpm in a dark room at a room temperature of 15 °C to 20 °C. The sample was dissolved in DMSO and added to the culture medium, and the final concentration of DMSO was 1% or less. 1% DMSO had no effect on the lipid synthesis and growth of the nematode. After 24 hours of processing the sample on the nematode, 10 ug/ml of Nile Red reagent 30 µl was added to adjust the final concentration of Nile Red to 100 µg/ml, and rotation culture was continued for 2 days.

_{The movement was stopped by dropwise adding 20 μl of 0.3% NaN 3} to a slide glass, adding Nile Red to it, and adding 100 μl of a nematode solution cultured for 2 days. Adipocytes of the nematode nematode that emit red fluorescence in a dark room were photographed using a luminescent microscope, and the fat content was measured. The lowest fat content was expressed as +1 (high activity), and the fat content was expressed as +4 (low activity).

As shown in Figs. 1 and 2, it was confirmed that all of the novel sesquiterpene derivatives prepared in the above example reduced the fat content of the nematode.

Accordingly, the compounds of the present invention exhibit excellent anti-obesity efficacy, from which it was found that the novel sesquiterpene derivative of the present invention can be usefully used as a treatment for obesity.

<Experimental Example 2> Effect of preventing or treating obesity or metabolic disease

<Experimental Example 2-1> Preparation of experimental diet and breeding of experimental animals

The obesity-induced diet used in this experiment was a high fat diet; HFD, 40% fat calorie: 17g pig oil lard + 3% corn oil/100g diet], and the diet containing the novel sesquiterpene derivative of the present invention is prepared in the same composition as HFD, but the compound is 0.5% It was prepared to contain at the level. The composition of the experimental diet is as shown in Table 1 below.

[Table 1]

6-week-old male (male) C57BL/6J mice were adapted to the experimental environment for 1 week with solid feed (after acclimatization), followed by a high fat diet control group and a novel sesquiterpene derivative of the present invention according to the randomized block method. It was randomly placed as a dietary experimental group including and reared for a total of 6 weeks. Diet was supplied with water between 10 and 11 am every day, and dietary intake was measured daily and once every 3 days.

<Experimental Example 2-2> Effect of preventing or treating obesity; Checking changes in weight and visceral fat mass

In order to prevent sudden weight change due to feed intake, the feed container was removed and the body weight was measured 2 hours later. Dietary efficiency was calculated from the date of supply of the test diet to the day of sacrifice as the total test period, and the cumulative weight gain during the test period was calculated as the total. It was calculated by dividing by dietary intake. After fasting for 12 hours or longer, blood, liver, and visceral adipose tissue (epididymal fat, peri-renal fat, mesenteric fat and retroperitoneal fat) were collected under anesthesia with diethyl ether and 0.1M phosphate buffer solution After washing with (0.1M phosphate buffer solution, pH 7.4), the weight was measured. Blood collected from the abdominal aorta was centrifuged (1000 rpm) for 15 minutes to separate plasma.

Table 2 shows the change in body weight of mice after feeding the experimental diet for 8 weeks. As shown in Table 2, the weight of the diet experiment group containing the novel sesquiterpene derivative of the present invention was about 40% to 80% compared to the weight of the high fat diet (HFD) control group, all of which were significantly reduced. (P<0.05).

After supplying the experimental diet for 8 weeks, the total visceral fat weight of the mouse epididymis fat, kidney peripheral fat, mesenteric fat, and posterior abdominal fat was measured. As shown in Table 2, a novel sesquiterpene derivative of the present invention was obtained. The visceral fat mass of the included diet experiment group was about 25% to 60% compared to the visceral fat mass of the high fat diet (HFD) control group, and all were significantly reduced (P<0.05).

[Table 2]

(Significantly different from the value for group by student's t-test at P<0.05)

<Experimental Example 2-3> Effect of preventing or treating metabolic diseases; Analysis of obesity-related indicators in mouse blood and liver tissue

Plasma total cholesterol, triglyceride, and glucose concentrations were measured twice each using a commercially available measurement kit (Bio-clinical system), and insulin concentration was measured by ELISA using a mouse insulin kit (Shibayaki Japan). . The lipid component of liver tissue was extracted according to the method of Folch et al. After adding 1 ml of distilled water to 0.25 g of liver tissue, it was homogenized using a polytron homogenizer (IKA-WERKE GmH & Co., Germany). Dichloromethane: methanol solution (2:1 v/v) 5 mL was added to the homogenate, mixed well, centrifuged for 10 minutes (1000 rpm) to separate the lower layer solution, and then added to the upper layer solution. After adding 2 mL of dichloromethane:methanol solution (2:1 v/v) again, the same procedure was repeated to completely separate the lipid component of the liver. To the obtained low layer solution, _{3 mL of dichloromethane: methanol: 0.05% CaCl 2} solution (3:48:47, v/v/v) was added, mixed for 1 minute, and then centrifuged (1000 rpm) for 10 minutes, and the final After taking a low layer solution _{and completely drying it with nitrogen (N 2} ) gas, the dried lipid was dissolved in 1 mL methanol and used for lipid component analysis. The concentration of neutral fatty in the liver organ section lipid extract was measured using the same commercial lipid assay kit (Bio-clinical system) used for plasma analysis.

Table 3 shows the changes in plasma total cholesterol, triglyceride, glucose and insulin concentrations, IRI (insulin resistance index), and the content of triglyceride in the liver after feeding the experimental diet for 8 weeks.

[Table 3]

*) Significantly different from the value for high fat diet(HFD) group by student's t-test at P<0.05

1) IRI (insulin resistance index) = 10 ^-3 pmol insulin x mmol glucose x L ^-2

As can be seen in Table 3, the plasma total cholesterol concentration of the diet experiment group containing the novel sesquiterpene derivative of the present invention was significantly reduced compared to the plasma total cholesterol concentration of the high fat diet (HFD) control group.

As can be seen in Table 3, the plasma triglyceride concentration of the dietary experimental group containing the novel sesquiterpene derivative of the present invention was significantly reduced compared to the plasma triglyceride concentration of the high fat diet (HFD) control group.

From this, it was found that the novel sesquiterpene derivative of the present invention can be usefully used in the prevention, alleviation, amelioration or treatment of hyperlipidemia.

As can be seen in Table 3, the concentration of triglycerides in liver tissues of the dietary experimental group containing the novel sesquiterpene derivatives of the present invention was significantly reduced compared to the concentrations of hepatic triglycerides in the high fat diet (HFD) control group. .

From this, it was found that the novel sesquiterpene derivatives of the present invention can be usefully used in the prevention, alleviation, improvement or treatment of fatty liver.

As can be seen in Table 3, the fasting blood glucose of the dietary experimental group containing the novel sesquiterpene derivative of the present invention was significantly decreased compared to the fasting blood glucose of the high fat diet (HFD) control group.

As can be seen in Table 3, the insulin concentration of the dietary experimental group containing the novel sesquiterpene derivative of the present invention was significantly decreased compared to the insulin concentration of the high fat diet (HFD) control group.

In addition, the insulin resistance index (IRI) of the diet experiment group containing the novel sesquiterpene derivative of the present invention was significantly reduced compared to the insulin resistance index of the control group on a high fat diet.

From this, it was found that the novel sesquiterpene derivatives of the present invention can be usefully used in preventing, alleviating, improving or treating diabetes, and improving insulin resistance.

<Experimental Example 3> Analysis of physicochemical properties

In order to analyze the physicochemical properties of the novel sesquiterpene derivatives prepared in the above examples, appearance, solubility for water, hygroscopicity for humidity, deliquesce for new material, acceleration 6 months The stability (accelerated chemical stabilities for 6 months) and the behavior of thermal stability were compared and evaluated.

As shown in Table 4, all of the novel sesquiterpene derivatives prepared in the above examples showed excellent physicochemical stability. In particular, in terms of solubility in water, which is a significant factor for new drug profile, both showed superior results compared to Cedrol, and 6 months accelerated condition [relative humidity (RH) 75%, temperature (temp. ) Long-term storage conditions compared to 40°C; Relative humidity 60%, temperature 25°C] has significantly less impurities than cedrol, so it has excellent chemical stability for new drug, another important factor determining the shelf life and shelf life of the drug. Showed the results. In addition, habitability, deliquescent property, and thermal stability all showed excellent results compared to Cedrol.

[Table 4]

As described above, a specific part of the present invention has been described in detail, and for those of ordinary skill in the art, it will be apparent that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. will be. Accordingly, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

1. A compound represented by the following Chemical Formulas 1 to 12 or an optical isomer thereof.

   
2. A compound represented by Formula 3, Formula 4, Formula 6 to Formula 8, or an optical isomer thereof.

   
3. A pharmaceutical composition comprising any one or more of the compounds represented by Chemical Formulas 1 to 12 of claim 1 or optical isomers thereof as an active ingredient.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is for the prevention or treatment of obesity or metabolic diseases.
5. The pharmaceutical composition according to claim 3, wherein the metabolic disease is selected from the group consisting of diabetes, hyperlipidemia, and fatty liver.
6. A food composition for preventing or improving obesity or metabolic diseases, comprising as an active ingredient any one or more of the compounds represented by Chemical Formulas 1 to 12 of claim 1 or optical isomers thereof.
7. A feed composition for preventing or improving obesity or metabolic diseases, comprising as an active ingredient any one or more of the compounds represented by Chemical Formulas 1 to 12 of claim 1 or optical isomers thereof.
8. A method for preventing or treating obesity or metabolic disease, comprising administering the pharmaceutical composition of claim 3 to an individual.
9. The use of a compound represented by Chemical Formulas 1 to 12 or optical isomers thereof for the prevention or treatment of obesity or metabolic diseases.
10. The use of a compound represented by Formulas 1 to 12 of claim 1 or an optical isomer thereof for the manufacture of a medicament for preventing or treating obesity or metabolic diseases.

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