Agent for promoting energy consumption

Abstract

The present invention addresses the problem of providing: an excellent drug which has an energy consumption promoting effect, suppresses an increase in body weight and body fat rate, and / or contributes to the prevention or amelioration of obesity; and a pharmaceutical composition, a food composition, or the like, which contains the drug. The problem can be solved by using a compound represented by formula (A). [Chemical Formula 1]

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480037771.X (22) Application Date 2024.06.14 (30) Priority Data 2023-099429 2023.06.16 JP (85) PCT International Application Entering National Phase Date 2025.12.05 (86) PCT International Application Application Data PCT / JP2024 / 021602 2024.06.14 (87) PCT International Application Publication Data WO2024 / 257845 JA 2024.12.19 (71) Applicant: Otsuka Pharmaceutical Co., Ltd., Address: Tokushima Prefecture, Japan (72) Inventors: Ippei Yamaoka, Tomohiro Kagawa, Yukari Miki (74) Patent Agency: Beijing Jinzhirui Intellectual Property Agency (General Partnership) 11379 Patent Attorney: Minjun Cai (51) Int.Cl. A61K 31 / 4015 (2006.01) A23L 33 / 10 (2006.01) A61P 3 / 00 (2006.01) A61P 3 / 04 (2006.01) A61P 3 / 06 (2006.01) A61P 21 / 00 (2006.01) (54) Title of Invention: Energy Consumption Promoter (57) Abstract: The subject of this invention is to provide an excellent pharmaceutical agent that has the effect of promoting energy consumption, inhibiting the increase of body weight and body fat percentage, and / or can help prevent or improve obesity, as well as a pharmaceutical composition or food composition containing the pharmaceutical agent. The above-mentioned subject matter can be solved by using a compound represented by the following formula (A). [Chemical 1] Claims 3 pages Description 21 pages Drawings 11 pages CN 121285373 A 2026.01.06 CN 1 21 28 53 73 A 1. An energy consumption promoter, characterized in that it contains a compound represented by the following formula (A) or a salt thereof as an active ingredient. [Chemical 1] 2. The energy consumption promoter according to claim 1, characterized in that it promotes energy consumption by increasing oxygen consumption. 3. A lipid burning promoter, characterized in that it contains a compound represented by the following formula (A) or a salt thereof as an active ingredient. [Chemical 2] 4. The lipid burning promoter of claim 3, characterized in that it is used to promote fat burning. 5. A thermicidal promoter, characterized in that it contains a compound represented by formula (A) or a salt thereof as an active ingredient. [Chemical 3] 6. The thermicidal promoter of claim 5, characterized in that it is used to raise body temperature. 7. A weight gain inhibitor, characterized in that it contains a compound represented by formula (A) or a salt thereof as an active ingredient.[Chemical 4] Claims 1 / 3 page 2 CN 121285373 A. 8. An inhibitor or reducer of increased body fat percentage, characterized in that it contains a compound represented by the following formula (A) or a salt thereof as an active ingredient. [Chemical 5] 9. The inhibitor or reducer of increased body fat percentage according to claim 8, characterized in that it is used to inhibit the increase of body fat mass. 10. The inhibitor or reducer of increased body fat percentage according to claim 8, characterized in that it is used to inhibit the accumulation of body fat. 11. A muscle enhancer, characterized in that it contains a compound represented by the following formula (A) or a salt thereof as an active ingredient. [Chemical 6] 12. The muscle enhancer according to claim 11, characterized in that it is used to promote the increase of muscle mass. 13. An agent for the prevention or improvement of obesity, characterized in that it contains a compound represented by the following formula (A) or a salt thereof as an active ingredient. [Chemical 7] Claims 2 / 3 page 3 CN 121285373 A. 14. An inhibitor or reducer of total cholesterol, characterized in that it contains a compound represented by formula (A) or a salt thereof as an active ingredient. [Chemical 8]. 15. A pharmaceutical composition or food composition, characterized in that it contains the agent according to any one of claims 1 to 14. Claims 3 / 3 pages 4 CN 121285373 A Energy Expenditure Promoter Technical Field

[0001] This invention relates to energy expenditure promoters, lipid burning promoters, thermogenesis promoters, weight gain inhibitors, inhibitors or reducers of increased body fat percentage, muscle enhancers, obesity prevention or improvement agents, inhibitors or reducers of increased total cholesterol, etc. Background Art

[0002] Obesity is a state in which energy from carbohydrates, lipids, etc., is excessively stored as fat under the skin and around internal organs, resulting in a weight increase compared to normal. In addition, the concept of metabolic syndrome has received attention in recent years. It is a state of predisposition to arteriosclerosis, which is based on excessive accumulation of visceral fat (obesity) and complicated by impaired glucose tolerance (hyperglycemia), hypertriglyceridemia (hyperlipidemia), and hypertension. It is a state in which the risk of developing lifestyle-related diseases is increased.

[0003] In recent years, against the backdrop of overnutrition and insufficient exercise, the number of patients with obesity and metabolic syndrome has been increasing. The increase in patients with obesity and metabolic syndrome has also led to an increase in medical expenses. Obesity and metabolic syndrome are not limited to Japan and have become a major problem worldwide.

[0004] Since obesity is caused by energy intake exceeding energy expenditure, in order to improve obesity, it is possible to consider reducing the intake of energy such as lipids, or to increase energy expenditure by promoting the metabolism of the organism through some method.

[0005] As substances that promote energy expenditure, it has been reported that, for example, there are substances derived from natural products such as rice bran extract (Patent Document 1) and licorice extract (Patent Document 2).While substances derived from natural products are preferred in terms of long-term safety, they also have issues such as unstable quality and susceptibility to problems caused by impurities. Therefore, chemically synthesized compounds are readily used as active ingredients. However, in the case of compounds, considering their industrial application, it is required that they can be synthesized inexpensively and in large quantities. Furthermore, there are safety concerns regarding substances in synthetic compounds that have no prior experience of consumption.

[0006] On the other hand, compounds represented by the following formula (A) are known, and it is also known that these compounds have the effect of inhibiting liver damage such as non-alcoholic steatohepatitis (NASH) (Patent Document 3). Since this compound is a substance contained in the neutralized extract of plum pulp, it has extensive experience of consumption, and a technology for its inexpensive large-scale synthesis, separation, and refining has been established (Patent Document 4). Therefore, it is suitable for industrial use as an ingredient in food, pharmaceuticals, etc.

[0007] [Chemical 1]

[0008]

[0009] However, other effects of this compound are not yet clear.

[0010] [Prior Art Documents]

[0011] [Patent Documents]

[0012] [Patent Document 1] Japanese Patent Application Publication No. 2012-020941, specification 1 / 21 pages, CN 121285373 A

[0013] [Patent Document 2] Japanese Patent Application Publication No. 2018-58832

[0014] [Patent Document 3] WO2017 / 077707

[0015] [Patent Document 4] WO2018 / 199040 Summary of the Invention

[0016] [Problems to be Solved by the Invention]

[0017] The problem of the present invention is to provide an excellent pharmaceutical agent that has the effect of promoting energy consumption, inhibiting the increase of body weight or body fat percentage, and / or can help prevent or improve obesity, as well as a pharmaceutical composition or food composition containing the pharmaceutical agent.

[0018] [Means for Solving the Problem]

[0019] The inventors discovered that a compound represented by the following formula (A) (hereinafter also referred to as "Compound A") has an energy consumption promoting effect, inhibits the increase of body weight or body fat percentage, and can help prevent or improve obesity, etc., thereby completing the present invention.

[0020] [Chemical 2]

[0021]

[0022] That is, the present invention relates to a solution specified by the following.

[0023] [1] An energy consumption promoter containing a compound represented by the following formula (A) or a salt thereof as an active ingredient.

[0024] [Chemical 3]

[0025]

[0026] [2] The energy consumption promoter as described in [1] above promotes energy consumption by increasing oxygen consumption.

[0027] [3] A lipid burning promoter containing a compound represented by the following formula (A) or a salt thereof as an active ingredient.

[0028] [Chemical 4] Specification 2 / 21 pages 6 CN 121285373 A

[0029]

[0030] [4] The lipid burning promoter as described in [3] above, used to promote fat burning.

[0031] [5] A thermogenating promoter containing a compound represented by the following formula (A) or a salt thereof as an active ingredient.

[0032] [Chemical 5]

[0033]

[0034] [6] The thermogenating promoter as described in [5] above, used to raise body temperature.

[0035] [7] A weight gain inhibitor containing a compound represented by the following formula (A) or a salt thereof as an active ingredient.

[0036] [Chemical 6]

[0037]

[0038] [8] An inhibitor or reducer of body fat percentage, containing a compound represented by the following formula (A) or a salt thereof as an active ingredient.

[0039] [Chemical 7]

[0040]

[0041] [9] An inhibitor or reducer of body fat percentage as described in [8] above, used to inhibit the increase of body fat mass.

[0042]

[10] An inhibitor or reducer of body fat percentage as described in [8] above, used to inhibit the accumulation of body fat.

[0043]

[11] A muscle enhancer containing a compound represented by the following formula (A) or a salt thereof as an active ingredient. Specification 3 / 21 pages 7 CN 121285373 A

[0044] [Chemical 8]

[0045]

[0046]

[12] A muscle enhancer as described in

[11] above, used to promote the increase of muscle mass.

[0047]

[13] An agent for the prevention or improvement of obesity, containing a compound represented by the following formula (A) or a salt thereof as an active ingredient.

[0048] [Chemical 9]

[0049]

[0050]

[14] An inhibitor or reducer of total cholesterol, comprising a compound or a salt thereof represented by the following formula (A) as an active ingredient.

[0051] [Chemical 10]

[0052]

[0053]

[15] A pharmaceutical composition or food composition comprising any one of the above [1] to

[14] .

[0054] In addition, as other embodiments of the present invention, the following can be cited.

[0055] (1) A method of using a compound A or a salt thereof for manufacturing an energy consumption promoter, an oxygen consumption increaser, a lipid burning promoter, a fat burning promoter, a heat production promoter, a body temperature riser, a weight gain inhibitor, an inhibitor or reducer of body fat percentage increase, an inhibitor of body fat mass increase, an inhibitor of body fat accumulation, a muscle enhancer, a muscle mass increase promoter, an obesity prevention or improvement agent, or an inhibitor or reducer of total cholesterol, etc.

[0056] (2-1) A compound A or a salt thereof, used for promoting energy expenditure, increasing oxygen consumption, promoting lipid burning, promoting fat burning, promoting thermogenesis, increasing body temperature, inhibiting weight gain, inhibiting or reducing the increase in body fat percentage, inhibiting the increase in body fat mass, inhibiting the accumulation of body fat, strengthening muscles, promoting the increase in muscle mass, preventing or improving obesity, or inhibiting or reducing the increase in total cholesterol.

[0057] (2-2) A compound A or a salt thereof, used for the prevention or treatment of hypothermia or chills. Specification 4 / 21 pages 8 CN 121285373 A

[0058] (2-3) A compound A or a salt thereof, used for the prevention or treatment of obesity or metabolic syndrome.

[0059] (2-4) A compound A or a salt thereof, used for the prevention or treatment of symptoms or diseases caused by obesity or metabolic syndrome.

[0060] (2-5) A compound A or a salt thereof for use in the prevention or treatment of dyslipidemia.

[0061] (2-6) A compound A or a salt thereof for use in the prevention or treatment of symptoms or diseases caused by an increase in total cholesterol.

[0062] (3-1) A method comprising applying an effective amount of compound A or a salt thereof to a desired subject to promote energy expenditure, increase oxygen consumption, promote lipid burning, promote fat burning, promote heat production, increase body temperature, inhibit weight gain, inhibit or reduce increase in body fat percentage, inhibit increase in body fat mass, inhibit body fat accumulation, enhance muscle, promote increase in muscle mass, prevent or improve obesity, or inhibit or reduce increase in total cholesterol.

[0063] (3-2) A method or treatment comprising applying an effective amount of compound A or a salt thereof to a subject requiring the prevention or treatment of hypothermia or chills to prevent or treat hypothermia or chills.

[0064] (3-3) A method or treatment method comprising administering an effective amount of compound A or a salt thereof to a subject requiring prevention or treatment of obesity or metabolic syndrome.

[0065] (3-4) A method or treatment method comprising administering an effective amount of compound A or a salt thereof to a subject requiring prevention or treatment of symptoms or diseases caused by obesity or metabolic syndrome.

[0066] (3-5) A method or treatment method comprising administering an effective amount of compound A or a salt thereof to a subject requiring prevention or treatment of dyslipidemia.

[0067] (3-6) A method or treatment method comprising administering an effective amount of compound A or a salt thereof to a subject requiring prevention or treatment of symptoms or diseases caused by increased total cholesterol.

[0068] [Effects of the Invention]

[0069] According to the present invention, it is possible to provide pharmaceutical agents, food compositions, and pharmaceutical compositions that are useful for promoting energy consumption, promoting lipid burning, promoting thermogenesis, inhibiting weight gain, inhibiting or reducing the increase in body fat percentage, enhancing muscle mass, preventing or improving obesity, and / or inhibiting or reducing the increase in total cholesterol. Brief Description of the Drawings

[0070] Figure 1 is a graph showing the daily calorie intake during the test period. In the figure, “CON” represents the “CON group (control group)” described in the examples, and “Compound A” represents the “Compound A application group” described in the examples. The same applies to the following figures.

[0071] Figure 2 is a graph showing the cumulative oxygen consumption 24 hours after application on the morning of the 82nd day of the test.

[0072] Figure 3 is a graph showing the cumulative carbon dioxide production 24 hours after application on the morning of the 82nd day of the test.

[0073] Figure 4 is a graph showing the cumulative energy consumption 24 hours after application on the morning of the 82nd day of the test.

[0074] Figure 5 is a graph showing the cumulative lipid burning over 24 hours after administration on the morning of the 82nd day of the experiment.

[0075] Figure 6 is a graph showing the rectal temperature before necropsy.

[0076] Figure 7 is a graph showing the weight change during the administration of the experimental diet.

[0077] Figure 8 is a graph showing the body fat percentage and lean body mass percentage after 6 weeks, 9 weeks, and 12 weeks of experimental diet administration.

[0078] Figure 9 is a graph showing the weight of white fat per unit body weight (perididious fat, mesenteric fat, perirenal fat, and interscapular fat) at necropsy.

[0079] Figure 10 is a graph showing the weight of the plantar muscles, tibialis anterior, and extensor digitorum longus muscles per unit body weight at necropsy, and the total weight of these three muscles.

[0080] Figure 11 is a graph showing the total cholesterol level in plasma at the time of necropsy. Detailed Description

[0081] The energy expenditure promoter, lipid burning promoter, heat production promoter, weight gain inhibitor, body fat percentage increase inhibitor or reducer, muscle enhancer, obesity prevention or improvement agent, and total cholesterol increase inhibitor or reducer (hereinafter, these may also be collectively referred to as "the agents of the present invention") of the present invention contain compound A or a salt thereof as an active ingredient.

[0082] Here, "containing...as an active ingredient" means containing an effective amount. An effective amount means an amount sufficient to exert the desired effect in a living organism. Furthermore, in the present invention, "as an active ingredient" also means that other components besides compound A or a salt thereof may be included to a limit that does not impair the effects of the present invention. The effective amount may vary depending on the condition, symptom or disease severity of the subject, the animal species, age (months), sex, or weight of the subject.

[0083] (Compound A)

[0084] Compound A used in this invention is a compound represented by the following formula (A).

[0085] [Chemical 11]

[0086]

[0087] Since compound A has two asymmetric carbons, there are four stereoisomers (i.e., compounds A whose stereostructure is represented by RS notation as SS configuration, SR configuration, RS configuration, or RR configuration), but in this invention, there is no particular limitation on which stereoisomer is used. That is, in this invention, a certain stereoisomer can be used alone, or a mixture of any two, three, or four of them in any proportion can be used. However, compounds A with stereostructures represented by RS notation as SS and RR configurations are easier to process due to their crystallinity (WO2018 / 199040). Therefore, in this invention, it is preferable to use compounds A with stereostructures represented by RS notation as SS or RR configurations, or a mixture of compounds A with SS and RR configurations.

[0088] Compound A is known to exist in plums, plum extracts, neutralized plum extracts, etc. Therefore, it can be used by isolating and refining compound A from these substances by any method, by chemical synthesis, or by purchasing commercially available products. However, the amount of compound A contained in plums, plum extracts, neutralized plum extracts, etc. is limited, so its effectiveness as an active ingredient in the pharmaceutical preparation of this invention is low. If it is derived from a natural product, there is a problem of unstable quality and impurities. Therefore, it is preferable to use chemically synthesized compound A or its salt. That is, the pharmaceutical preparation of this invention may also be in a form that does not contain, or substantially does not contain, plums, plum extracts, neutralized plum extracts, etc. Furthermore, the pharmaceutical agent of the present invention may be in the form of not containing, or substantially not containing, other natural products (e.g., Rosaceae plants), natural product extracts (e.g., Rosaceae plant extracts), neutralized extracts of natural products (e.g., neutralized extracts of Rosaceae plants), etc. Here, "substantially not containing" means not containing an effective amount, and / or may contain an amount that does not reach an effective amount.

[0089] The method of chemically synthesizing, separating, or refining compound A or its salt is not particularly limited. For example, compound A can be obtained by reacting citric acid with L-aspartic acid. In the case of chemically synthesizing, separating, or refining compound A or its salt, for example, if the methods described in WO2017 / 07707 or WO2018 / 19940 are used, refined (highly purified) compound A or its salt can be obtained cheaply and in large quantities, and is therefore preferred.

[0090] (Salt of Compound A)

[0091] As the salt of Compound A used in this invention, examples include metal salts or amino acid salts of Compound A.

[0092] As a metal salt, examples include metal salts selected from the group consisting of sodium salts, potassium salts, magnesium salts, and calcium salts, and preferably calcium salts.

[0093] As an amino acid salt, examples include amino acid salts selected from the group consisting of arginine salts, citrulline salts, ornithine salts, and histidine salts. The amino acid salt is preferably an L-type amino acid salt.

[0094] (Energy Consumption Promoter and Oxygen Consumption Increaser)

[0095] Compound A or its salts are preferably used as an effective component of an energy consumption promoter because they have an energy consumption promoting effect.

[0096] In this invention, "energy consumption" refers to the metabolism of nutrients (energy sources) such as lipids, proteins, and carbohydrates in various tissues of an organism, converting them into chemical energy or thermal energy. "Metabolism" includes "combustion" or "oxidation".

[0097] "Energy consumption promotion" refers to increasing energy consumption, for example, increasing the cumulative energy consumption over a certain period of time after the application of compound A. For example, the cumulative energy consumption over 24 hours can be calculated based on the average oxygen consumption and average carbon dioxide production over approximately 24 hours (e.g., 24 hours ± 1 hour) using the formula shown below.

[0098] Cumulative energy consumption (kcal / kg / day) = [{3.816 × average VO2 (mL / min) over approximately 24 hours + 1.231 × average VCO2 (mL / min) over approximately 24 hours} / body weight (kg) × 60 (min / h) × 24 (h)] / 1000 (cal / kcal)

[0099] (VO2: oxygen consumption; VCO2: carbon dioxide production)

[0100] When compound A or its salt is applied, the cumulative energy consumption over a certain period of time (e.g., 24 hours) can be increased compared to when it is not applied. Examples of increases include an increase of 3% or more, more preferably 5% or more, even more preferably 7% or more, and particularly preferably 10% or more. Additionally, examples of increases include an increase of 20% or less, more preferably 18% or less, and particularly preferably 15% or less. Therefore, examples of increases include 3%–20%, 5%–20%, 7%–20%, 10%–20%, 3%–18%, 5%–18%, 7%–18%, 10%–18%, 3%–15%, 5%–15%, 7%–15%, and 10%–15%.

[0101] Furthermore, since oxygen is required in the process of consuming energy, the energy consumption promoter of the present invention can also be used as an energy consumption promoter that increases oxygen consumption (an energy consumption promoter that promotes energy consumption by increasing oxygen consumption). That is, compound A or its salt can also preferably be used as an effective component of an oxygen consumption increaser or an oxygen consumption promoter.There are no particular limitations on the method of calculating oxygen consumption; for example, it can be measured using a commercially available device capable of measuring exhaled gases. Furthermore, oxygen consumption can also be evaluated as a cumulative oxygen consumption over a certain period of time. For example, the cumulative oxygen consumption over 24 hours can be calculated based on the average oxygen consumption over approximately 24 hours (e.g., 24 hours ± 1 hour) using the formula shown below.

[0102] Cumulative oxygen consumption (mL / kg / day) = Average VO2 (mL / min) over approximately 24 hours / body weight (kg) × 60 (min / h) × 24 (h)

[0103] (VO2: oxygen consumption) Specification 7 / 21 pages 11 CN 121285373 A

[0104] "Increased oxygen consumption" or "promoted oxygen consumption" refers to an increase in oxygen consumption. With the application of compound A or its salt, oxygen consumption over a certain period of time (e.g., 24 hours) can be increased compared to the absence of application. Examples of increases include an increase of 3% or more, more preferably 5% or more, even more preferably 7% or more, and particularly preferably 10% or more. Furthermore, examples of increases include an increase of 20% or less, more preferably 18% or less, and particularly preferably 15% or less. Therefore, examples of increases include 3% to 20%, 5% to 20%, 7% to 20%, 10% to 20%, 3% to 18%, 5% to 18%, 7% to 18%, 10% to 18%, 3% to 15%, 5% to 15%, 7% to 15%, and 10% to 15%.

[0105] (Lipid Burning Promoter)

[0106] Compound A or its salts are preferred as active ingredients in lipid burning promoters because they have lipid burning promoting effects.

[0107] In this invention, "lipid burning" refers to the metabolism and conversion of lipids, particularly fatty acids, derived from diet or fat accumulated in the body into chemical or thermal energy in various tissues of the organism.

[0108] "Promoting lipid burning" means increasing the amount of lipid burned, for example, increasing the cumulative amount of lipid burned over a certain period of time after the application of compound A. For example, the cumulative amount of lipid burned over 24 hours can be calculated based on the average oxygen consumption and average carbon dioxide production over approximately 24 hours (e.g., 24 hours ± 1 hour) using the formula shown below.

[0109] Cumulative amount of lipid burned (mg / kg / day) = 1.67 × [average VO2 (mL / min) over approximately 24 hours - average VCO2 (mL / min) over approximately 24 hours] / body weight (kg) × 60 (min / h) × 24 (h)

[0110] (VO2: oxygen consumption; VCO2: carbon dioxide production)

[0111] When compound A or its salt is applied, the cumulative amount of fat burned over a certain period of time (e.g., 24 hours) can be increased compared to when it is not applied.Examples of increases include an increase of 1% or more, more preferably 2% or more, and even more preferably 3% or more. Furthermore, examples of increases include an increase of 10% or less, more preferably 8% or less, and even more preferably 5% or less. Therefore, examples of increases include 1%–10%, 2%–10%, 3%–10%, 1%–8%, 2%–8%, 3%–8%, 1%–5%, 2%–5%, and 3%–5%.

[0112] Furthermore, the lipid burning promoter of the present invention can also preferably be used to promote the burning of fat (especially white fat) accumulated in the body. That is, compound A or its salt can also be appropriately used as an effective component of a fat burning promoter.

[0113] (Heat-generating promoter)

[0114] As described above, compound A or its salt has an energy consumption promoting effect; if energy consumption is promoted in the body, heat production is also promoted. Therefore, compound A or its salt has a heat-generating promoting effect and can be appropriately used as an effective component of a heat-generating promoter.

[0115] In this invention, "thermogenesis" refers to the generation of heat, i.e., energy, by the body through more active metabolism than usual.

[0116] The method for evaluating thermoogenesis is not particularly limited; for example, it can be evaluated by measuring body temperature. Furthermore, body temperature can be the temperature of any part of the body, such as the rectum, armpit, mouth, ear, etc.

[0117] In addition, since body temperature may rise if thermoogenesis is promoted in the body, the thermogenic promoter of this invention can also be used to raise body temperature. That is, compound A or its salt can also be used appropriately as an effective ingredient in a body temperature-raising agent. The thermogenic promoter or body temperature-raising agent of this invention can also be used for the prevention or improvement of hypothermia or chills (e.g., cold intolerance).

[0118] For example, when compound A or its salt is applied, rectal temperature can be raised after a certain period (e.g., twice daily for 12 weeks) compared to when it is not applied. Examples of such an increase include preferably 1% or more, more preferably 2% or more, and even more preferably 3% or more. Furthermore, the increase can be preferably 10% or less, more preferably 9% or less, and even more preferably 7% or less. Therefore, the increase can be 1% to 10%, 2% to 10%, 3% to 10%, 1% to 9%, 2% to 9%, 3% to 9%, 1% to 7%, 2% to 7%, 3% to 7%, etc.

[0119] Furthermore, the increase can be preferably 0.1°C or more, more preferably 0.2°C or more, and even more preferably 0.3°C or more. Furthermore, the increase can be preferably 3°C or less, more preferably 2.8°C or less, and even more preferably 2.5°C or less.Therefore, increases can be exemplified by 0.1–3°C, 0.2–3°C, 0.3–3°C, 0.1–2.8°C, 0.2–2.8°C, 0.3–2.8°C, 0.1–2.5°C, 0.2–2.5°C, 0.3–2.5°C, etc.

[0120] (Weight gain inhibitor)

[0121] Compound A or its salt has an inhibitory effect on weight gain, so it can be appropriately used as an effective ingredient for weight gain inhibitor. In addition, the weight gain inhibitor of the present invention can also be used as a weight reduction agent.

[0122] The method of calculating weight is not particularly limited, for example, it can be calculated by commercially available scales or body composition analyzers.

[0123] For example, when the weight gain during a certain period (e.g., 12 weeks) is 100% without the application of compound A or its salt, the weight gain can be 10%–90%, 20%–90%, 30%–90%, 10%–80%, 20%–80%, 30%–80%, 10%–70%, 20%–70%, 30%–70%, etc. with the application of compound A or its salt.

[0124] (Inhibitor or reducer of body fat percentage)

[0125] Since compound A or its salt has an inhibitory effect on the increase of body fat percentage or body fat mass (e.g., body fat weight per unit body weight, especially white fat weight), it can be used appropriately as an active ingredient of body fat percentage increase inhibitor or body fat percentage reducer, or body fat mass increase inhibitor or body fat mass reducer. Furthermore, if body fat percentage or body fat mass decreases, lean body mass percentage or lean body weight increases, and vice versa. Therefore, the body fat percentage increase inhibitor or reducer of the present invention, or the body fat mass increase inhibitor or reducer, can also be appropriately used as a lean body mass decrease inhibitor or increaser, or a lean body weight decrease inhibitor or increaser. In addition, since the body fat percentage increase inhibitor or reducer of the present invention inhibits the increase of body fat mass as described above, it can also be appropriately used to inhibit the accumulation of body fat. That is, compound A or its salt can also be appropriately used as an effective ingredient of body fat accumulation inhibitor.

[0126] "Body fat" refers to fat accumulated in the body, of which neutral fat accounts for the majority and is mainly accumulated in fat cells. Fat cells are roughly divided into two types: white fat cells, such as subcutaneous fat and visceral fat, and brown fat cells. White fat cells have unilocular fat droplets and have the function of storing excess energy as neutral fat in the fat droplets and decomposing it into glycerol and free fatty acids as an energy source to supply the whole body as needed. Therefore, in an obese state where energy supply consistently exceeds energy expenditure, fat droplets accumulated in white adipocytes will enlarge. Most of the adipose tissue in adults is white adipose tissue. There are no specific limitations on the types of white adipose tissue composed of white adipocytes; examples include perididymal fat, mesenteric fat, perirenal fat, and interscapular fat.

[0127] In this invention, the method for calculating body fat mass (e.g., white fat weight) is not particularly limited. For example, it can be calculated using commercially available body composition analysis devices, computed tomography (CT) scans, magnetic resonance imaging (MRI), etc. Furthermore, the method for calculating body fat percentage is not particularly limited. For example, it can be calculated using the same method as body fat mass, or as the proportion of body fat mass to body weight. In addition, when using laboratory animals, body fat mass can also be calculated by removing individual fat cells (e.g., white fat) and directly measuring their weight.

[0128] (Muscle Enhancer and Muscle Mass Increase Promoter)

[0129] Compound A or its salt can be appropriately used as an active ingredient in a muscle enhancer. In this invention, "muscle enhancement" refers to increased muscle strength and / or increased muscle mass. Compound A or its salt can also be used to promote muscle mass increase because it particularly promotes the increase of muscle mass (e.g., muscle weight per unit body weight, especially skeletal muscle weight). That is, Compound A or its salt can also be appropriately used as an active ingredient in a muscle mass increase promoter.

[0130] Muscles are not particularly limited; for example, skeletal muscles can be cited, particularly the plantar muscles, tibialis anterior, and extensor digitorum longus muscles, which are described in the manual for the skeletal muscles of the left and right lower limbs (page 9 / 21, CN 121285373 A).

[0131] The method for calculating muscle mass (e.g., skeletal muscle weight) is not particularly limited; for example, it can be calculated using commercially available body composition analysis devices, computed tomography (CT) scans, magnetic resonance imaging (MRI), etc. Furthermore, in the case of experimental animals, muscle mass can also be calculated by removing each muscle (e.g., skeletal muscle) from the body and directly measuring its weight. Additionally, muscle mass can be evaluated, for example, by each muscle as illustrated above, or by summing the weights of these multiple muscles. The proportion of muscle in body weight can also be referred to as muscle percentage or muscle mass percentage. That is, compound A or its salts can also be used as an effective ingredient in a muscle percentage or muscle mass percentage increase promoter. Furthermore, if muscle mass or muscle (mass) percentage increases, muscle strength also increases (enhances), therefore compound A or its salt can also be used as an effective ingredient of a muscle strength enhancer or muscle strength agent.

[0132] (Obesity prevention or improvement agent)

[0133] Compound A or its salt, as described above, has the effects of promoting energy consumption, promoting fat burning, inhibiting the increase of body fat percentage, and inhibiting weight gain, so it can be appropriately used as an effective ingredient of an obesity prevention agent or obesity improvement agent.

[0134] "Obesity" refers not only to a large body weight, but also to a state of excessive accumulation of body fat. In the determination of obesity, the international standard indicator BMI (Body Mass Index) is used = [weight (kg)] ÷ [height (m)2].For both men and women, the standard BMI is set at 22.0. Obesity is defined as "a body mass index (BMI) of 25 or higher in a state of excessive fat accumulation in adipose tissue".

[0135] In addition, compound A or its salt can also be used as an effective ingredient for the prevention or improvement of metabolic syndrome. Metabolic syndrome is a complex syndrome of obesity, hypertension, lipid dyslipidemia, hyperglycemia (diabetes), etc., which refers to a state in which cardiovascular diseases are prone to occur. Therefore, compound A or its salt can also be used as a preventive or therapeutic agent for symptoms or diseases caused by obesity or metabolic syndrome. There are no particular limitations on diseases caused by obesity or metabolic syndrome, such as arteriosclerosis, heart disease (angina, myocardial infarction, etc.), stroke, cerebral infarction, etc.

[0136] (Total cholesterol increase inhibitor or reducer)

[0137] Since compound A or its salt has the effect of inhibiting the increase of total cholesterol, it can be used as an effective ingredient for the inhibitor of the increase of total cholesterol or the reducer of total cholesterol.

[0138] "Total cholesterol" refers to the total amount of cholesterol contained in the blood. If the total cholesterol level is high, it is considered a lipid dyslipidemia, such as arteriosclerosis, which may be the cause of various diseases such as myocardial infarction and cerebral infarction.

[0139] The method of calculating total cholesterol is not particularly limited; for example, it can be calculated by collecting blood and measuring the total cholesterol level in the blood.

[0140] In addition, compound A or its salt can also be used appropriately as a preventive or therapeutic agent for symptoms or diseases caused by increased total cholesterol. Diseases caused by increased total cholesterol are not particularly limited; for example, arteriosclerosis, heart disease (angina, myocardial infarction, etc.), stroke, cerebral infarction, etc. can be mentioned.

[0141] (Composition)

[0142] Compound A or its salt can also be used as is, but can also be used appropriately in combination with other ingredients as a composition without impairing the effects of the present invention. That is, compositions containing the energy expenditure promoter, lipid burning promoter, thermogenesis promoter, weight gain inhibitor, body fat percentage increase inhibitor or reducer, muscle mass increase promoter, muscle strengthening agent, obesity prevention or improvement agent, and total cholesterol increase inhibitor or reducer of the present invention can be provided. In other words, the compositions of the present invention can be appropriately used as compositions for promoting energy expenditure, promoting lipid burning, promoting thermogenesis, inhibiting weight gain, inhibiting or reducing body fat percentage increase, promoting muscle mass increase, strengthening muscles, preventing or improving obesity, and inhibiting or reducing total cholesterol increase. Food compositions or pharmaceutical compositions are preferred examples of such compositions. In particular, from the viewpoint of daily intake, food compositions are preferred.

[0143] (Food Composition)

[0144] In this invention, food includes beverages. The form of the food composition in this invention is not particularly limited, as long as it is a form that can be ingested and is suitable for consumption by mammals or similar organisms. Examples include solid, liquid, semi-liquid, granular, powder, capsule, paste, and porridge forms.

[0145] In the food composition of this invention, other ingredients corresponding to the form of each food can be added. Here, these other ingredients are not particularly limited, as long as they do not impair the effects of this invention. Examples include various proteins, carbohydrates, fats, trace elements, nourishing and strengthening ingredients, vitamins, organic acid salts such as citric acid and acetic acid. Furthermore, depending on its type, the food in this invention may appropriately contain or not contain additives that are permitted and commonly used in food, such as sweeteners like aspartame and stevia, acidulants like citric acid, malic acid, and tartaric acid, excipients like dextrin and starch, as well as colorants, flavorings, bittering agents, buffers, thickeners and stabilizers, gelling agents, stabilizers, gum bases, binders, diluents, emulsifiers, dispersants, suspending agents, antioxidants, preservatives, antifungal agents, colorants, bleaching agents, gloss agents, enzymes, seasonings, and spice extracts.

[0146] In this invention, "food" is used in the sense of including health foods, functional foods, foods for specific health purposes, nutritional supplements, and foods for patients. Preferably, it is provided as a food suitable for consumers who wish to prevent or improve obesity, i.e., a food for specific health purposes. The term "foods for specific health purposes" as used here refers to foods that are sometimes subject to certain regulatory restrictions from a health perspective when they are manufactured or sold for the purpose of preventing or improving obesity.

[0147] The aforementioned health foods may also be in the form of ordinary food, but are preferably in the form of beverages or supplements (tablets, granules, fine granules, pills, chewable tablets, capsules (soft capsules, hard capsules), etc.).

[0148] In this invention, examples of foods that are the objects of compound A or its salt complex include beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit juice drinks, and dairy drinks (including concentrated stock solutions and powders for preparation of these beverages); carbohydrate-containing diets such as rice, noodles, bread, and pasta; Western-style confectionery such as biscuits and cakes; Japanese-style confectionery such as steamed buns and yokan; confectionery such as candy, chewing gum, and various types of cold desserts or ice cream such as yogurt, pudding, and jelly; processed aquatic / livestock products such as fish cakes, chikuwa, hamburgers, ham, and sausages; dairy products such as processed milk, fermented milk, yogurt, butter, and cheese; oils and oil-processed foods such as margarine, mayonnaise, shortening, whipped cream, and sauces; and seasonings such as sauces and condiments; but not limited to these.

[0149] (Pharmaceutical Composition)

[0150] In this invention, pharmaceuticals include quasi-drugs (referred to as "quasi-drugs" in Japan). The pharmaceutical compositions of this invention may contain or not contain appropriate additives that are permitted in pharmaceuticals and are appropriately selected according to the dosage form (e.g., carriers, excipients, diluents, binders, lubricants, disintegrants or disintegration aids, solubilizers, stabilizers, preservatives, preservatives, thickeners, emulsifiers, dispersants, suspending agents, buffers, etc.), and may be provided in various formulations that can be prepared by various known methods for oral or non-oral systemic or local administration.

[0151] The pharmaceutical compositions of this invention can be administered orally or non-orally. In the case of oral administration of the pharmaceuticals of this invention, they may also be formulated into tablets (including sugar-coated tablets), capsules, granules, powders, pills, oral aqueous solutions, suspensions, emulsions, syrups, etc., or prepared as a dried product that is redissolved upon use. Furthermore, in the case of non-oral administration of the pharmaceutical products of the present invention, they can be formulated as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), drops, suppositories (e.g., rectal suppositories, vaginal suppositories), etc., and in the case of injectable formulations, they are provided in the form of single-dose ampoules or multi-dose containers.

[0152] Here, the formulation can be manufactured, for example, as follows. Oral dosage forms can be manufactured by adding excipients (e.g., lactose, sugar, starch, mannitol), disintegrants (e.g., calcium carbonate, calcium carboxymethyl cellulose), binders (e.g., pregelatinized starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose), and lubricants (e.g., talc, magnesium stearate, polyethylene glycol 6000) to the active ingredient and then compressing it. Subsequently, as needed, for purposes such as flavor masking, enteric solubility, and persistence, the dosage form can be coated using known methods. Examples of coating agents include ethyl cellulose, hydroxymethyl cellulose, polyethylene glycol, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and Eudragit (manufactured by ROHM AG, Germany, a methacrylic acid-acrylic acid copolymer).

[0153] (Content in the composition)

[0154] In the above-described food composition or pharmaceutical composition, the content of compound A or its salt may be, for example, 0.01% by mass or more, 0.1% by mass or more, 1.0% by mass or more, 95% by mass or less, 80% by mass or less, 60% by mass or less, etc., of the total mass of the composition. Furthermore, it may be 0.01 to 95% by mass, 0.1 to 80% by mass, 1.0% to 60% by mass, etc.

[0155] (Dosage)

[0156] In this invention, the dosage of compound A or its salt as an active ingredient is not particularly limited as long as it does not impair the effect of the invention. For example, it is in the range of 0.6 mg to 36,000 mg / day, preferably 30 mg to 720 mg / day (adult), and most preferably 60 to 360 mg / day (adult). However, it can be appropriately determined according to the age (months), weight, sex, symptoms, and sensitivity to compound A or its salt of the recipient.

[0157] (Method of Application)

[0158] The method of application of the agent or composition of the present invention containing compound A or its salt is not particularly limited as long as it does not impair the effect of the invention. Examples include a period of 1 day or more, 3 days or more, 5 days or more, 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or more, 7 weeks or more, preferably 8 weeks or more, 9 weeks or more, more preferably 10 weeks or more, 11 weeks or more, and even more preferably 12 weeks or more. Better results can be obtained through long-term continuous use. Furthermore, there is no particular limitation on the number of daily applications; for example, it can be applied once daily, or multiple times daily, two or three times or more.

[0159] (Target of Application)

[0160] The target of application of the pharmaceutical agent or composition of the present invention containing compound A or its salt is any animal that needs or desires it, and is not particularly limited. Examples include mammals such as humans, pigs, cattle, horses, goats, sheep, wild boars, rabbits, mice, rats, hamsters, guinea pigs, monkeys, macaques, cynomolgus monkeys, marmosets, orangutans, chimpanzees, dogs, and cats, preferably humans.

[0161] (Combined Use)

[0162] The pharmaceutical agent or composition of the present invention may also contain one or more active ingredients other than compound A or its salt. Furthermore, when applying the composition of the present invention, it may be combined with one or more active ingredients other than compound A or its salt, or with a pharmaceutical agent containing them.

[0163] (Uses)

[0164] The agents or compositions of the present invention can be used to promote energy consumption, increase oxygen consumption, promote lipid burning, promote fat burning, promote thermogenesis, increase body temperature, inhibit weight gain, inhibit or reduce the increase in body fat percentage, inhibit or reduce the increase in body fat mass, inhibit body fat accumulation, promote the increase in muscle mass, enhance muscle strength, prevent or improve obesity, and / or inhibit or reduce the increase in total cholesterol. Here, the use can be either therapeutic or non-therapeutic. Specification 12 / 21 pages 16 CN 121285373 A Non-therapeutic means excluding the concept of medical acts, that is, excluding the concept of methods of performing surgery, treatment or diagnosis on humans, and more specifically, excluding the concept of methods of performing surgery, treatment or diagnosis on humans by physicians or persons under the instruction of physicians.

[0165] Hereinafter, the present invention will be described in more detail by way of examples, but the technical scope of the present invention is not limited by these examples.

[0166] [Examples]

[0167] 1. Test materials and experimental methods

[0168] 1-1. Test materials

[0169] (1) Test substance

[0170] Name: Compound A (a compound represented by the following formula (A)).

[0171] [Chemical 12]

[0172]

[0173] Manufacturing method: According to the method described in paragraphs

[0048] -

[0049] of WO2018 / 199040, crystalline compound A (a mixture of SS and RR configurations in stereostructure using RS notation) was manufactured.

[0174] Appearance: Powder, white

[0175] Storage conditions: refrigerated

[0176] Usage method: Weigh the specified weight and disperse it in a 0.5% carboxymethyl cellulose (CMC) solution in a solvent to prepare an oral administration solution.

[0177] (2) Control substance

[0178] Name: CMC

[0179] Manufacturer: Nacalai Tesque Co., Ltd., Japan

[0180] Container: 500mL plastic bottle

[0181] Batch number: MOA9874

[0182] Appearance: Powder, white

[0183] Storage conditions: refrigerated

[0184] Usage: Weigh the specified weight, dissolve in Otsuka distilled water to make 0.5%, and prepare an oral administration solution.

[0185] 1-2. Animals used

[0186] (1) Species, strain and sex

[0187] Mice, C57BL / 6J, male

[0188] (2) Reasons for selection of species and strain

[0189] Mice are widely used in safety tests and pharmacological tests of pharmaceuticals and medical devices, etc. The strain of mice used in this test was selected because its characteristics are well known.

[0190] (3) Microbial Control Instructions, Page 13 / 21, CN 121285373 A

[0191] SPF (Specific Pathogen Free)

[0192] (4) Manufacturer

[0193] Jackson Laboratories Japan

[0194] (5) Number of animals admitted

[0195] 48

[0196] (6) Age at admission

[0197] 7-8 weeks

[0198] (7) Weight at admission

[0199] 21-28g

[0200] (8) Individual identification method

[0201] Identification was performed by marking the tail with an oil-based marker. In this experiment, each animal was assigned a number from 1 to 40.

[0202] (9) Quarantine and adaptation

[0203] No quarantine was performed. After being placed in storage, an acclimatization period was set up. During this period, the animals were fed a high-fat solid diet (D12492) in the rearing room, and their health status was monitored at all times.

[0204] 1-3. Husbandry Environment

[0205] Temperature: 23±3°C

[0206] Humidity: 55±15%

[0207] Air exchange rate: 13-16 times / hour

[0208] Lighting time: 12 hours (7:00-19:00)

[0209] 1-4. Feed

[0210] During the experiment, the experimental animals were allowed free access to D12492 (EP Trading Co., Ltd., Japan, batch number: 22041308) as an ultra-high fat feed. After the experiment, all experimental food fed to the animals was discarded.

[0211] Name: D12492 (ultra-high fat feed, 60kcal% fat, blue)

[0212] Manufacturer: EP Trading Co., Ltd., Japan

[0213] Batch number: 22041308

[0214] Usage: Take it out of the refrigerator when feeding.

[0215] Composition: As shown in Table 1.

[0216] [Table 1] Instruction manual 14 / 21 pages 18 CN 121285373 A

[0217]

[0218] 1-5. Drinking water

[0219] Dedicated tap water is freely obtained from the water bottle. Instruction manual 15 / 21 pages 19 CN 121285373 A

[0220] 1-6. Group composition

[0221] As shown in Table 2. On the grouping day, the weight of animals with no visible abnormalities was measured, and grouping was performed using the statistical analysis system EXSUS version 10 (EP Cross Corporation, Japan) through stratified randomization based on weight.

[0222] [Table 2]

[0223]

[0224] 1-7. Preparation and administration of test substances

[0225] (1) Preparation method of test substances

[0226] Weigh compound A, add a small amount of 0.5% CMC in a magnetic mortar, and grind until uniform. Add another 0.5% CMC to the ground compound A to adjust the concentration to 720mg / 10mL. Store in cold storage after preparation.

[0227] (2) Administration method of test substances

[0228] During the 12-week period, administer the test substances orally (10mL / kg) twice a day, once in the morning and once in the afternoon. Restraint was performed manually during oral administration.

[0229] 1-8. Observation

[0230] (1) Observation of general condition

[0231] Observe the general condition of the animals in detail during the administration of the test substances.

[0232] (2) Calculation of calorie intake

[0233] From the grouping date to the time of necropsy, the food intake (g) was measured more than once a week. The calorie intake was calculated by multiplying the food intake of each individual by the calories per unit weight (kcal).

[0234] (3) Exhaled gas analysis

[0235] Exhaled gases were measured using a 32-channel small animal energy metabolism measurement system (ARCO-2000-RAT, ARCO Systems Ltd.). The air flow rate was set to 0.3 L / min, and the oxygen consumption (mL / min) and carbon dioxide production (mL / min) of the animals were measured at 10-minute intervals. Measurements were taken approximately 24 hours after oral administration on the morning before necropsy, and the cumulative oxygen consumption (mL / kg / day), energy expenditure (kcal / kg / day), and lipid burning (mg / kg / day) for 24 hours were calculated using the following formulas.

[0236] Calculation formula:

[0237] Cumulative oxygen consumption (mL / kg / day) = Average VO2 (mL / min) over approximately 24 hours / Body weight (kg) × 60 (min / h) × 24 (h)

[0238] Cumulative energy consumption (kcal / kg / day) = [{3.816 × Average VO2 (mL / min) over approximately 24 hours + 1.231 × Average VCO2 (mL / min) over approximately 24 hours} / Body weight (kg) × 60 (min / h) × 24 (h)] / 1000 (cal / kcal)

[0239] Cumulative lipid burning (mg / kg / day) = 1.67 × [Average VO2 (mL / min) over approximately 24 hours - Average VCO2 (mL / min) over approximately 24 hours] / Body weight (kg) × 60 (min / h) × 24 (h)

[0240] (VO2: oxygen consumption, VCO2: carbon dioxide production)

[0241] (4) Rectal temperature

[0242] Before necropsy, a small animal body temperature maintenance device (NS-TC10 temperature controller, Neuroscience, Japan) connected to a rectal temperature measurement probe was inserted into the rectum to measure the rectal temperature.

[0243] (5) Weight measurement instructions 16 / 21 pages 20 CN 121285373 A

[0244] It was performed weekly from the time of entry into the warehouse and from the grouping date to the time of necropsy. It was also performed on the day of body composition measurement, just before the necropsy.

[0245] (6) Body composition

[0246] At 6, 9 and 12 weeks of the experimental diet intake, body fat mass and lean body mass were measured using a body composition analysis device (EchoMRI-700, Hitachi, Japan), and the body fat percentage and lean body mass percentage were calculated by dividing by the body weight.

[0247] 1-9. Experimental Methods

[0248] Animals were allowed free access to a solid diet (D12492) containing extremely high-fat food from the time of entry into the facility. After the acclimatization period, the animals were grouped based on their body weight. Then, the animals were allowed free access to the extremely high-fat food in individual feeding.All groups were administered the test substance orally twice daily (once in the morning and once in the afternoon) (CON group: oral administration of 0.5% CMC; Compound A administration group: oral administration of Compound A). The first administration day was designated as day 0 of the experiment. For the animals, five were designated as the first half of the experiment, and the rest as the second half. Feeding and administration to the second half began on day 2 of the experiment for the first half (day 0 of the experiment for the second half). To acclimatize the animals to the environment of the exhalation gas analyzer, after oral administration at 9:00 AM on days 7, 21, and 49 of the experiment, they were individually housed in the exhalation gas analyzer for 5.5 hours (10:00 AM–3:30 PM) with free access to water and fasting. On days 28 and 65, after oral administration at 11:00 AM, all corresponding animals were quickly individually housed in the exhalation gas analyzer and allowed to acclimatize for approximately 24 hours with free access to water and food. Oral administration was administered on the afternoon of the day (3:30 PM) and the following morning (8:30 AM), and the animals were quickly brought back to the expiratory gas measurement room after administration. After acclimatization, the animals were returned to their cages. On day 82, all animals were quickly brought back to the expiratory gas measurement room before the morning oral administration (10:00 AM). Oral administration was administered on the morning of the day (11:00 AM) and the afternoon of the day (3:30 PM), and expiratory gas was measured after the oral administration the following morning (8:30 AM) until necropsy. On the afternoon of day 83 (1:00 PM), the animals were presented for necropsy. During necropsy, the abdomen was opened under isoflurane anesthesia, and blood was drawn from the posterior vena cava. After blood collection, euthanasia was performed by exsanguination from the blood collection site, and internal organs (fat and skeletal muscle) were harvested.

[0249] 1-10. Sample Collection

[0250] (1) White adipose tissue 1: periepididymal fat

[0251] During the necropsy, after removing the fat surrounding the left and right epididymis, the epididymis were removed. The tissue was gently rinsed with physiological saline (0.9% sodium chloride aqueous solution, manufactured by Otsuka Pharmaceutical Co., Ltd.), and after wiping off the water, the weight of the left and right sides was measured together using a precision balance. The tissue on the right side was frozen in liquid nitrogen and then frozen and stored in a freezer set at -80°C until it was provided for analysis. The visceral organs on the left side were stored in 10% neutral buffered formalin until they were provided for analysis.

[0252] (2) White adipose tissue 2: mesenteric fat

[0253] During the necropsy, the fat from the stomach to the rectum was removed. The tissue was gently rinsed with physiological saline (0.9% sodium chloride aqueous solution, manufactured by Otsuka Pharmaceutical Co., Ltd., Japan), and after wiping off the water, the weight was measured using a precision balance. After freezing in liquid nitrogen until ready for analysis, it is frozen and stored in a freezer set at -80°C.

[0254] (3) White adipose tissue 3: perirenal fat

[0255] During dissection, after removing the fat surrounding the left and right kidneys, it was gently rinsed with physiological saline (0.9% sodium chloride aqueous solution, manufactured by Otsuka Pharmaceutical Co., Ltd., Japan), and after wiping off the moisture, the weight of the left and right kidneys was measured together using a precision balance. After freezing in liquid nitrogen, it was frozen and stored in a freezer set at -80°C until it was provided for analysis.

[0256] (4) White adipose tissue 4: white fat between the scapulae

[0257] During dissection, after removing the white fat between the scapulae and the brown fat, it was gently rinsed with physiological saline (0.9% sodium chloride aqueous solution, manufactured by Otsuka Pharmaceutical Co., Ltd., Japan), and after wiping off the moisture, the weight was measured using a precision balance. After freezing in liquid nitrogen, it was frozen and stored in a freezer set at -80°C until it was provided for analysis. Instructions 17 / 21 pages 21 CN 121285373 A

[0258] (5) Skeletal muscle

[0259] During the necropsy, the plantar muscles, tibialis anterior muscles and extensor digitorum longus muscles of the lower limbs were removed from both sides, and the total weight of both sides was measured with a precision balance. After being frozen in liquid nitrogen, they were frozen and stored in a freezer set at -80°C until they were provided for analysis.

[0260] (6) Blood

[0261] During the necropsy, the abdomen was opened under isoflurane anesthesia, and about 0.5 mL of blood was collected from the posterior vena cava and collected in a plasma separation tube containing heparin (BD micro plasma separation tube PST™365985 (yellow-green) containing lithium heparin anticoagulant; BD Corporation, Japan) and temporarily stored under ice. Centrifugation was performed (3000 rpm, 10 min, 4 °C), and the plasma supernatant was transferred to 1.5 mL microtubes (1.5 mL ultramicrotubes, round bottom hard cap type, 131-715C, manufactured by Watson Corporation, Japan), and frozen in a freezer set at -80 °C until provided for analysis. Total cholesterol in plasma was measured by the Nagahama Life Science Laboratory of the Nagahama Plant of Oriental Yeast Industries, Ltd., Japan.

[0262] 1-11. Data Summary and Statistical Analysis

[0263] Data are expressed as mean ± standard deviation. For statistical processing, a two-sample t-test of equal variance (two-tailed test) was performed, and inter-group comparisons were performed with the CON group as the control. The significance level was set at 5%. Excel (2013 version, Microsoft) was used in these analyses.

[0264] 2. Results

[0265] 2-1. Caloric Intake

[0266] There were no differences in the average daily caloric intake between groups during the experiment (Table 3, Figure 1). Since there were missing data in Group CON due to incomplete measurements, the corresponding portions (food intake on days 4 and 5) were removed and the data were quantified.

[0267] [Table 3]

[0268]

[0269] 2-2. Oxygen Consumption, Energy Consumption, and Lipid Burning

[0270] Compared with the CON group, the cumulative values ​​of oxygen consumption, energy consumption, and lipid burning in the compound A application group were significantly higher during the 24 hours (11:32-11:32) from the start of application to the end of measurement (Table 4, Figures 2-5). This result indicates that compound A has the effect of increasing oxygen consumption, energy consumption, and lipid burning.

[0271] [Table 4] Specification 18 / 21 pages 22 CN 121285373 A

[0272]

[0273] 2-3. Rectal Temperature

[0274] Regarding rectal temperature, it was confirmed that the compound A application group was significantly higher than the CON group (Table 5, Figure 6). This result indicates that the intake of compound A promotes thermogenesis in mice, resulting in an increase in body temperature. That is, it indicates that compound A has the effect of promoting thermogenesis and raising body temperature.

[0275] [Table 5]

[0276]

[0277] 2-4. Body weight

[0278] Regarding the weight shift during the administration of the experimental diet, compared with the CON group, the weight of the compound A administration group showed a low trend at weeks 7, 8 and 9 at the beginning of the experiment; the low value was significantly confirmed at weeks 10, 11 and 12 (Table 6, Figure 7). This result indicates that compound A has the effect of inhibiting weight gain.

[0279] For example, during the 12-week administration, the CON group gained an average of 7.2g of body weight, while the compound A administration group gained an average of 3.8g. That is, if the weight gain of the CON group is 100%, the weight gain of the compound A administration group is 52.8 ((3.8 ÷ 7.2) × 100)%.

[0280] [Table 6] Specification 19 / 21 pages 23 CN 121285373 A

[0281]

[0282] 2-5. Body fat percentage and lean body mass percentage

[0283] Regarding body fat percentage and lean body mass percentage, at 6 weeks of the experimental diet intake, the body fat percentage of the compound A treatment group tended to be lower than that of the CON group, while the lean body mass percentage tended to be higher; at 9 and 12 weeks, the body fat percentage of the compound A treatment group was significantly lower and the lean body mass percentage was higher (Table 7, Figure 8). This result indicates that compound A has the effect of inhibiting the increase of body fat percentage (i.e., inhibiting the decrease of lean body mass percentage).

[0284] [Table 7]

[0285]

[0286] 2-6. White fat weight

[0287] Regarding the white fat weight per unit body weight, compared with the CON group, the periepididymal fat, mesenteric fat, perirenal fat, and interscapular fat in the compound A treatment group were significantly lower (Table 8, Figure 9). This result indicates that compound A has the effect of inhibiting the increase of white fat weight per unit body weight.

[0288] [Table 8] Instruction manual 20 / 21 pages 24 CN 121285373 A

[0289]

[0290] 2-7. Muscle weight

[0291] Regarding the weight per unit body weight, the weight of the plantar muscles, tibialis anterior, and extensor digitorum longus, as well as the total weight of these three muscles, were significantly higher in the compound A treatment group (Table 9, Figure 10). This result indicates that compound A has the effect of promoting an increase in muscle weight per unit body weight.

[0292] [Table 9]

[0293]

[0294] 2-8. Total cholesterol

[0295] Compared with the CON group, the total cholesterol in the plasma of the compound A treatment group was significantly lower (Table 10, Figure 11). This result indicates that compound A has the effect of inhibiting an increase in total cholesterol.

[0296] [Table 10]

[0297]

[0298] [Industrial Applicability]

[0299] The present invention can be used particularly effectively in the manufacturing of food and pharmaceutical products. Instruction manual page 21 / 21, 25 CN 121285373 A, Figure 1; Instruction manual figure 1 / 11 page, 26 CN 121285373 A, Figure 2; Instruction manual figure 2 / 11 page, 27 CN 121285373 A, Figure 3; Instruction manual figure 3 / 11 page, 28 CN 121285373 A, Figure 4; Instruction manual figure 4 / 11 page, 29 CN 121285373 A, Figure 5; Instruction manual figure 5 / 11 page, 30 CN 121285373 A, Figure 6; Instruction manual figure 6 / 11 page, 31 CN 121285373 A, Figure 7; Instruction manual figure 7 / 11 page, 32 CN 121285373 A, Figure 8; Instruction manual figure 8 / 11 page, 33 CN 121285373 A, Figure 9; Instruction manual figure 9 / 11 page, 34 CN 121285373 A, Figure 10 Figure 11, page 35, illustration 10 / 11, CN 121285373 A; Figure 11, page 36, illustration 11 / 11, CN 121285373 A.

Claims

1. An energy consumption promoter, characterized by, A compound represented by the following formula (A) or a salt thereof. [Chem. 1] 。 2. The energy consumption promoter according to claim 1, wherein Promoting energy consumption by increasing oxygen consumption.

3. A lipid combustion accelerator characterized by, A compound represented by the following formula (A) or a salt thereof. [Chem. 2] 。 4. The lipid combustion accelerant of claim 3, wherein, For promoting the combustion of fat.

5. A heat production accelerator characterized by comprising: A compound represented by the following formula (A) or a salt thereof. [Chem. 3] 。 6. The heat production accelerator according to claim 5, wherein For raising body temperature.

7. A body weight gain inhibitor, characterized by, A compound represented by the following formula (A) or a salt thereof. [Chem. 4] 。 8. An inhibitor or reducer of increased body fat percentage, characterized in that, A compound represented by the following formula (A) or a salt thereof. [Chem. 5] 。 9. The agent for inhibiting or reducing increase in body fat ratio according to Claim 8, wherein For inhibiting the increase in the amount of body fat.

10. The agent for inhibiting or reducing increase in body fat ratio according to Claim 8, wherein For inhibiting the accumulation of body fat.

11. A muscle enhancing agent, characterized by, A compound represented by the following formula (A) or a salt thereof. [Chem. 6] 。 12. The muscle strengthening agent according to claim 11, wherein For promoting the increase in the amount of muscle.

13. A prophylactic or improving agent for obesity, characterized by comprising the compound or salt of claim 1. A compound represented by the following formula (A) or a salt thereof. [Chem. 7] 。 14. An inhibitor or reducer of an increase in the total cholesterol amount, characterized by, A compound represented by the following formula (A) or a salt thereof. [Chem. 8] 。 15. A pharmaceutical composition or a food composition, characterized by comprising the compound according to any one of claims 1 to 14. A medicament according to any one of claims 1 to 14.

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