Medicine for preventing and treating disease attributable to obese condition

Abstract

Provided is a pharmaceutical composition for treating and / or preventing a disease attributable to an obese condition, particularly an obesity disease, which has an excellent MGAT2-inhibiting activity and is at least not accompanied by at least one side effect selected from digestive tract disorders, chleystitis, heart beat increase, hypoglycemia, acute pancreatitis, abnormal hemostasis, hepatic disorders, renal disorders and embryonic lethality.　Also provided is a pharmaceutical composition which is very useful for body weight management in obesity, i.e., body weight reduction and body weight maintenance after body weight reduction.　This pharmaceutical composition for treating and / or preventing a disease attributable to an obese condition contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

Drugs for preventing and treating diseases caused by obesity

[0001] The present invention relates to a pharmaceutical agent for preventing and treating diseases caused by obesity.

[0002] Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as a major risk factor for health problems. Body mass index (BMI) is a simple index of weight-to-height ratio commonly used to classify adult (age 15 and over) populations or individuals as overweight or obese. It is calculated as weight in kilograms divided by the square of height in meters (kg / m 2 The World Health Organization defines a BMI of 25 kg / m 2 Overweight: 30 kg / m 2 On the other hand, the Japan Society for the Study of Obesity defines a BMI of 25 kg / m 2 The above is considered "obesity" because the number of obesity-related diseases, including diabetes and dyslipidemia, increases with BMI, and the average number of these diseases is 25 kg / m 2This is because the RI is greater than 1.0. According to a 2022 survey by the World Health Organization, approximately 2.5 billion people worldwide are overweight and at least 890 million are obese (Non-Patent Document 1). Obesity is primarily caused by an increase in the ratio of calorie intake to expenditure in physical activity and daily life. The number of obese people has increased in recent years due to increased consumption of high-fat and high-sugar foods. According to the World Obesity Federation's World Obesity Atlas 2023, by 2035, more than 4 billion people, more than half of the world's population, will be classified as overweight or obese. Furthermore, unless preventive and therapeutic measures are improved, the global economic impact of overweight and obesity is predicted to reach 4.32 trillion US dollars per year by 2035. Treatments for these conditions include dietary therapy, exercise therapy, and drug therapy. Drug therapies such as semaglutide, tirzepatide, liraglutide, Saxenda, Contrave, and phentermine are used, but none of them are satisfactory in terms of efficacy, side effects, or medical costs. In particular, clinical trials have shown that GLP-1 receptor agonists, such as semaglutide and tirzepatide, recently approved by the FDA, can reduce body weight by approximately 15-20% per year with weekly subcutaneous injections. However, these drugs have side effects such as gastrointestinal disorders, require gradually increasing administration over several months, and are very expensive, raising concerns about medical expenses. Rapid weight loss is also known to result in a decrease in muscle mass along with fat mass, leading to wrinkles and sagging in the face, neck, and buttocks. Administration of these drugs to patients with sarcopenia or elderly patients who are prone to muscle loss is also a concern (Non-Patent Documents 2 and 3). Furthermore, clinical trials have shown that discontinuing treatment with GLP-1 receptor agonists can lead to rapid weight rebound. Generally, weight rebound following short-term weight loss due to dietary restriction or obesity treatment is accompanied by an increase in fat mass in place of the lost muscle mass, and this fluctuation is known to be extremely harmful to metabolic health.

[0003] In monoacylglycerol acyltransferase 2 (hereinafter also referred to as MGAT2) knockout mice, it has been confirmed that they suppress high-fat diet-induced weight gain, the onset of insulin resistance, elevated blood cholesterol levels, and fatty liver formation, as well as increased energy consumption (Non-Patent Document 4). Based on these findings, MGAT2 inhibitors are expected to be promising therapeutic agents for diseases caused by obesity, but no drugs that are effective in humans have yet been developed.

[0004] Patent documents 1 to 3 disclose compounds of the formula: It is described that dihydropyridinone derivatives represented by the following formula (I) have an MGAT2 inhibitory activity and are useful for treating and / or preventing diseases involving MGAT2. Furthermore, in the examples of Patent Documents 1 to 3, the following compounds are described: Patent Document 4 discloses a compound of the formula: Patent Document 5 describes a pharmaceutical for preventing and treating diseases involving anti-obesity effects, which is characterized by combining a compound represented by the formula (I): or a pharmaceutically acceptable salt thereof with at least one drug selected from the group consisting of drugs having anti-obesity effects, drugs for controlling blood glucose levels, drugs for controlling cholesterol and / or triglycerides in the blood, and drugs for controlling blood pressure. and / or a hydrate crystal of the compound represented by the formula (I): Patent Document 7, which has not been published as of June 2025, describes a pharmaceutical composition for treating and / or preventing fatty liver disease, particularly non-alcoholic fatty liver disease, comprising a compound represented by formula (I): Patent Document 8 describes a pharmaceutical composition containing a compound represented by formula (VIII): or a pharmaceutically acceptable salt thereof. Furthermore, a deuterated version of compound 13 is also described.

[0005] International Publication No. 2019013311 International Publication No. 2019013312 Japanese Patent Application Laid-Open No. 2020-111571 (Patent Application No. 2020-02515) International Publication No. 2023038039 International Publication No. 2023243616 International Patent Application JP2024 / 043962 (Patent Application No. 2023-210184) International Patent Application JP2025 / 003013 (Patent Application No. 2024-013082) Japanese Patent Application Laid-Open No. 2024-105489

[0006] "Obesity and overweight", World Health Organization, 1 March 2024.Elizabeth S. O'Neill et al., "Injectable Weight Loss Medications in Plastic Surgery: What We Know, Perioperative Considerations, and Recommendations for the Future", Plast Reconstr Surg Glob Open. 2024 Jan; 12(1): e5516.Muellertz et al., "Potent incretin-based therapy for obesity: A systematic review and meta-analysis of the efficacy of semaglutide and tirzepatide on body weight and waist circumference, and safety", Obesity Reviews, Volume 25, Issue 5, May 2024, p1-19.Nature Medicine volume 15, pages442-446 (2009)

[0007] The present invention addresses the need for a pharmaceutical composition for the treatment and / or prevention of diseases caused by obesity, particularly obesity-related diseases, which has excellent MGAT2 inhibitory activity and is free of at least one or more side effects, such as gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality. The present invention also provides a pharmaceutical composition that is highly useful for weight management in obesity, i.e., weight loss and weight maintenance after weight loss. The present invention also provides a pharmaceutical composition that can reduce weight and / or fat mass without causing a rapid loss of muscle mass, and is particularly effective in patients with low muscle mass and elderly patients. The present invention also provides a pharmaceutical composition that, when combined with a GLP-1 receptor agonist, is effective for enhancing the efficacy of the GLP-1 receptor agonist during treatment and for maintaining weight.

[0008] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that, among the compounds having MGAT2 inhibitory activity described in Patent Documents 1 to 3, certain compounds are effective in treating and / or preventing obesity-related diseases, and are free from at least one or more side effects, such as gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality. Furthermore, they have found that these compounds are sufficiently safe for use as pharmaceutical compositions for weight management, and have thus completed the present invention. The present invention relates to the following:

[0009] [1] Formula (I): [2] A pharmaceutical composition for treating and / or preventing a disease caused by an obese state, comprising a compound represented by formula (I): or a pharmaceutically acceptable salt thereof. [3] The pharmaceutical composition according to [1], wherein the disease caused by an obese state is obesity. [4] A compound represented by formula (I): or a pharmaceutically acceptable salt thereof. [4] The pharmaceutical composition according to any one of [1] to [3], wherein administration of the pharmaceutical composition does not result in a rapid decrease in muscle mass. [4'] The pharmaceutical composition according to any one of [1] to [3], wherein administration of the pharmaceutical composition does not result in a decrease in muscle mass relative to a decrease in fat mass. [5] The pharmaceutical composition according to any one of [1] to [4] and [4'], for subjects with low muscle mass or elderly people. [6] The pharmaceutical composition according to any one of [1] to [5] and [4'], wherein administration of the pharmaceutical composition does not result in at least one side effect of gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality. [7] The pharmaceutical composition according to any one of [1] to [5] and [4'], wherein administration of the pharmaceutical composition does not result in at least one side effect of gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality. [8] The pharmaceutical composition according to any one of [1] to [5] and [4'], wherein administration of the pharmaceutical composition does not result in at least one side effect of gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality. ２ [8] The pharmaceutical composition according to any one of [1] to [6] and [4'], for a subject having a body mass index (BMI) of 30 kg / m or more. ２ [9] The pharmaceutical composition according to [7], for a subject having a body mass index (BMI) of 25 kg / m or more. ２ The pharmaceutical composition according to any one of [1] to [6] and [4'], for a subject receiving treatment with a GLP-1 receptor agonist, wherein the compound is administered in an effective amount to the subject.

[12] The pharmaceutical composition according to

[11] , wherein the effective amount of the compound is in the range of 0.5 mg to 100 mg per day.

[13] The pharmaceutical composition according to

[12] , wherein the effective amount of the compound is in the range of 1 mg to 50 mg per day.

[14] The pharmaceutical composition according to

[13] , wherein the effective amount of the compound is in the range of 3 mg to 50 mg per day.

[15] The pharmaceutical composition according to

[14] , wherein the effective amount of the compound is in the range of 3 mg to 30 mg per day.

[16] The pharmaceutical composition according to

[14] , wherein the effective amount of the compound is 3 mg, 10 mg, 30 mg, or 50 mg per day.

[17] The pharmaceutical composition according to

[15] , wherein the effective amount of the compound is 3 mg, 10 mg, or 30 mg per day.

[0010]

[20] A method for treating and / or preventing a disease caused by obesity, comprising administering to a subject of the present invention a compound of formula (I):

[21] A method for treating and / or preventing a disease caused by obesity, comprising a step of administering an effective amount of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof to an individual in need of such treatment and / or prevention.

[22] Use of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof for treating and / or preventing a disease caused by obesity. or a pharmaceutically acceptable salt thereof.

[0011]

[30] (A) Formula (I): or a pharmaceutically acceptable salt thereof, and (B) at least one drug selected from GLP-1 receptor agonists.

[31] (B) is danugliplon, PF07081532, LY-3502970, RGT-075, liraglutide, lixisenatide, exenatide, semaglutide, dulaglutide, efpeglenatide, exenatide, neuglutide, GMA105, HM-15136, noriglycopeptide, SHR-20004, tirzepatide, BI-456906, GSBR-1290, ECC5004, CT-996, survodutide, retatorutide, CT-868, VK2735, mazdutide, malidebat

[31] The pharmaceutical composition according to

[30] , wherein the active ingredient is at least one selected from the group consisting of benzodiazepine, benzocaine, ...

[32] The medicine according to

[31] , wherein (B) is at least one selected from liraglutide, semaglutide, tirzepatide, BI-456906, danugliplon, PF07081532, LY-3502970, RGT-075, GSBR-1290, ECC5004, CT-996, survodutide, retatorutide, CT-868, VK2735, mazdutide, and maridebart cafraglutide.

[33] The medicine according to any of

[30] to

[32] , wherein (A) and (B) are administered in combination.

[34] The medicament according to any one of

[30] to

[33] , which is a combination drug.

[35] The medicament according to any one of

[30] to

[34] , for treating and / or preventing diseases caused by obesity.

[36] The pharmaceutical composition according to any one of

[30] to

[34] , for weight management.

[37] The pharmaceutical composition according to any one of

[30] to

[36] , which does not cause a rapid decrease in muscle mass upon administration of the pharmaceutical composition. [37'] The pharmaceutical composition according to any one of

[30] to

[36] , which does not cause a decrease in muscle mass relative to a decrease in fat mass upon administration of the pharmaceutical composition.

[38] The pharmaceutical composition according to any one of

[30] to

[37] and [37'], for subjects with low muscle mass or elderly people.

[39] The pharmaceutical composition according to any one of

[30] to

[38] and [37'], wherein administration of the pharmaceutical composition does not result in at least one side effect of gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality.

[40] A body mass index (BMI) of 25 kg / m. ２

[41] The pharmaceutical composition according to any one of

[30] to

[39] and [37'], for a subject having a body mass index (BMI) of 30 kg / m or more. ２ The pharmaceutical composition according to

[40] , for a subject having the above symptoms.

[42] The pharmaceutical composition according to any one of

[30] to

[41] and [37'], for a subject undergoing treatment with a GLP-1 receptor agonist.

[43] An action enhancer of (B) of

[30] , containing (A) of

[30] .

[44] A pharmaceutical for use in combination with (B) of

[30] , containing (A) of

[30] as an active ingredient.

[45] A pharmaceutical composition for enhancing efficacy or maintaining weight during treatment with (B) of

[30] , containing (A) of

[30] .

[46] A pharmaceutical composition comprising (A) of

[30] , for maintaining weight by completely switching the therapeutic agent to (A) of

[30] during treatment with (B) of

[30] .

[47] A pharmaceutical composition comprising (A) of

[30] , for weight management during treatment with (B) of

[30] , by further administering (A) of

[30] in combination.

[0012] The pharmaceutical composition of the present invention is effective in treating and / or preventing diseases caused by obesity, particularly obesity-related diseases, and is highly safe without at least one side effect such as gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality, and is therefore very useful for weight management, weight loss, and weight maintenance after weight loss in obesity.

[0013] 1 shows the weight change in Test Example 6. 2 shows the weight change in Test Example 7. 3 shows the weight change in Test Example 8. 4 shows the weight change in Test Example 9.

[0014] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprise" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0015] "Diseases caused by obesity" refers to all diseases that improve with weight loss. Examples include eating disorders, obesity, impaired glucose tolerance (such as type 2 diabetes and impaired glucose tolerance), dyslipidemia (abnormal blood cholesterol and triglyceride levels), hypertension, hyperuricemia, gout, coronary artery disease (myocardial infarction and angina pectoris), cerebral infarction (cerebral thrombosis and transient ischemic attack), non-alcoholic fatty liver disease, menstrual disorders and infertility, obstructive sleep apnea syndrome and obesity-hypoventilation syndrome, musculoskeletal diseases (osteoarthritis (knee and hip arthritis, etc.) and spondylosis), and obesity-related kidney disease.

[0016] "Weight management" means maintaining or reducing weight. "Weight maintenance" means maintaining weight after weight loss. For example, it also includes alleviating weight gain after discontinuing administration of (B) by administering (A).

[0017] "Not causing a rapid loss of muscle mass" means not causing a rapid loss of muscle mass (e.g., skeletal muscle) and preserving or maintaining muscle function while controlling weight and / or reducing fat mass (e.g., visceral fat mass). This also includes alleviating further muscle mass loss caused by administration of a GLP-1 receptor agonist compared to weight loss and / or fat mass loss during weight management.

[0018] "Enhancing the efficacy of GLP-1 receptor agonists during treatment" means administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the compound of formula (I) during treatment with a GLP-1 receptor agonist, thereby enhancing the efficacy of the GLP-1 receptor agonist against diseases caused by obesity. Drugs other than the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered. "Maintaining body weight during treatment with a GLP-1 receptor agonist" means completely switching the therapeutic agent to the compound of formula (I) or a pharmaceutically acceptable salt thereof and administering it, or administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one drug selected from GLP-1 receptor agonists, thereby maintaining body weight during treatment with a GLP-1 receptor agonist.

[0019] In this specification, Body Mass Index (BMI) means a simple index of weight-to-height ratio commonly used to classify adult (age 15 and over) populations or individuals as overweight or obese, and is defined as weight in kilograms divided by the square of height in meters (kg / m ２ ) In particular, BMI is 25 kg / m ２ It is effective for subjects with a BMI of 25 kg / m or more. ２ In one embodiment, the present invention is also effective for subjects with a BMI of less than 30 kg / m ２ It is administered to subjects who meet the above criteria.

[0020] The "GLP-1 receptor agonist" may be any drug that has a GLP-1 agonist effect. Examples of the "GLP-1 receptor agonist" include, but are not limited to, the peptides, low molecular weight compounds, and salts thereof described below. Danuglipron (formerly PF06882961); PF07081532 (Lotiglipron); LY-3502970 (Orforglipron); RGT-075; Liraglutide; Lixisenatide; Exenatide; Semaglutide; Dulaglutide; Efpeglenatide; Exenatide; Noiiglutide; GMA105; HM-15136; Noliglycopeptide (SHR-20004); Tirzepatide; BI-456906; GSBR-1290; ECC5004; CT-996; Survodutide; Retatrutide, CT-868, VK2735, Mazdutide, Maridebart cafraglutide. Further examples include, but are not limited to, compounds and salts thereof described in the following patent documents:WO2018109607; WO2019239319; WO2019239371; WO2021081207; WO2021154796; US20110160198; WO2021096284; WO2021096304; WO2018056453; WO2020263695; JP2020200308A; JP2020511411A; WO2020103815; WO2020207474; WO2021018023; WO2021155841; WO2019103060; WO2022031994; WO2021112538; WO2021160127; WO2021187886; WO2021197464; WO2021219019; WO2021242817; WO2021244645; WO2021249492; WO2021259309; WO2021254470; WO2022028572; WO2022040600; WO2022042691; WO2022078380; WO2022078152; WO2022078407; WO2022109182; WO2022111624; WO2022111693; Chinese Patent Application Publication No. 113493447; Chinese Patent Application Publication No. 113480534; Chinese Patent Application Publication No. 113773310; Chinese Patent Application Publication No. 113816948; Chinese Patent Application Publication No. 113801136.

[0021] One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced by an isotope of the hydrogen, carbon and / or other atom, respectively. Examples of such isotopes include, but are not limited to, ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. 123 I and ３６The isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of the present invention also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals and include all isotopes and radiolabeled compounds of the compounds of the present invention. The present invention also includes a "radiolabeling method" for producing the "radiolabeled compounds," and the "radiolabeled compounds" are useful as research and / or diagnostic tools in metabolism pharmacokinetic studies and binding assays.

[0022] Radiolabeled compounds of the present invention can be prepared by methods known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) via catalytic dehalogenation using tritium. This method involves reacting a precursor of a compound of formula (I) in which the appropriate halogen is substituted with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0023] Pharmaceutically acceptable salts of the compounds according to the present invention include salts of the compounds according to the present invention with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

[0024] The compounds according to the present invention or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates, etc.), co-crystals, and / or crystalline polymorphs, and the present invention also encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with the compound according to the present invention with any number of solvent molecules (e.g., water molecules, etc.). When the compound according to the present invention or a pharmaceutically acceptable salt thereof is left in the atmosphere, it may absorb moisture, resulting in the adsorbed water adsorbing, or may form a hydrate. Furthermore, the compound according to the present invention or a pharmaceutically acceptable salt thereof may form a crystalline polymorph by recrystallization. A "co-crystal" means that the compound according to the present invention or a salt thereof and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.

[0025] The compound represented by formula (I) has excellent MGAT2 inhibitory activity and is therefore useful as a therapeutic and / or preventive agent for diseases caused by obesity, particularly obesity-related diseases. It is also useful as a therapeutic and / or preventive agent for MGAT2-related diseases, such as metabolic diseases, cardiovascular diseases (angina pectoris, acute / congestive heart failure, myocardial infarction, etc.), central and peripheral nervous system diseases (bulimia, affective disorders, depression, etc.), reproductive system diseases (infertility, premature birth, sexual dysfunction, etc.), cognitive function-related diseases (Alzheimer's disease, dementia, mild cognitive impairment, memory impairment, etc.), and other diseases such as digestive diseases (hepatic fibrosis), respiratory diseases, renal fibrosis, cancer, and pigmentation. Furthermore, the compound represented by formula (I) is useful as a pharmaceutical and preferably has one or more of the following excellent characteristics: a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits good pharmacokinetics, such as high bioavailability and moderate clearance. c) It has high metabolic stability. d) It does not exhibit irreversible inhibitory effect on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described in this specification. e) It is not mutagenic. f) It has low cardiovascular risk. g) It has high solubility. h) It is not associated with at least one side effect of gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality. i) It can be administered orally, making it highly convenient. j) It can be used for weight management during treatment with a GLP-1 receptor agonist.

[0026] (Method for producing the compound according to the present invention) A general method for producing the compound according to the present invention is exemplified below. Furthermore, extraction, purification, etc. may be carried out by the same processes as those performed in ordinary organic chemistry experiments. The synthesis of the compound according to the present invention can be carried out by taking into consideration methods known in the art. As the raw material compounds, commercially available compounds, those described in this specification, those described in the literature cited in this specification, and other known compounds can be used.

[0027] When it is desired to obtain a salt of the compound according to the present invention, if the compound according to the present invention is obtained in the form of a salt, it may be purified as is, or if it is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0028] The compound (A) according to the present invention can be prepared by the methods described in, for example, Patent Documents 1 to 3.

[0029] The compound represented by (B) according to the present invention may be a commercially available compound, or may be prepared by a method described in a known document such as a patent document.

[0030] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0031] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0032] In the case of parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0033] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0034] The dosage of the compound represented by formula (I) is desirably determined taking into consideration the patient's age, body weight, type and severity of disease, route of administration, etc., but typically, in the case of oral administration, the dosage for an adult is about 0.5 mg to 100 mg per day, preferably about 1 mg to 50 mg, and more preferably about 3 mg to 50 mg. In another embodiment, the dosage for an adult is about 3 mg to 30 mg per day. In one embodiment, about 3 mg, 10 mg, 30 mg, or 50 mg is orally administered per day to an adult. In one embodiment, about 3 mg is orally administered per day to an adult. In one embodiment, about 10 mg is orally administered per day to an adult. In one embodiment, about 30 mg is orally administered per day to an adult. In one embodiment, about 50 mg is orally administered per day to an adult. In addition, for children, the dosage is about 1 to 50 mg or 0.04 to 1 mg / kg per day depending on body weight. In the case of parenteral administration, the daily dose for an adult is about 0.1 mg to 100 mg, preferably about 0.5 mg to 50 mg, or about 1 mg to 30 mg. This dose may be administered all at once or in divided doses. For example, the above dose may be administered once a day. For example, the above dose may be administered twice a day.

[0035] In one aspect, the present invention provides a pharmaceutical comprising: (A) a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and (B) at least one agent selected from GLP-1 receptor agonists. In another embodiment, the present invention provides a pharmaceutical for preventing and / or treating obesity or obesity-related diseases, comprising (A) and (B).

[0036] In another aspect, the present invention provides an effect enhancer that combines (A) and (B). In another embodiment, the present invention provides a pharmaceutical for weight maintenance that combines (A) and (B).

[0037] Here, "a pharmaceutical characterized by a combination" includes a pharmaceutical containing each compound, a mode in which each compound is used as a combination drug, a mode in which each compound is used as a kit, a mode in which they are administered simultaneously, a mode in which they are administered at an interval, and a mode in which a drug is used in combination with another drug, and although it is sometimes abbreviated to "combined", these are synonymous.

[0038] The compound represented by (A) or a pharmaceutically acceptable salt thereof can enhance the weight-reducing effect by further adding (B) at least one drug selected from GLP-1 receptor agonists during treatment.

[0039] The compound represented by (A) or a pharmaceutically acceptable salt thereof can be used in combination with a reduced dose of (B) a GLP-1 receptor agonist during treatment with at least one drug selected from the group consisting of GLP-1 receptor agonists, thereby enabling weight maintenance, thereby reducing side effects caused by the GLP-1 receptor agonist.

[0040] The dosage of the pharmaceutical of the present invention can be appropriately selected based on the clinically used dosage. Furthermore, the blending ratio of the compound represented by (A) and the concomitant drug (B) can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug (B) may be used per part by weight of the compound represented by (A). In one embodiment, about 1 mg to 50 mg per day of the compound represented by (A) and a GLP-1 receptor agonist (B) at a dose described in the package insert or a dose whose efficacy has been confirmed in clinical trials can be used. In one embodiment, about 1 mg to 50 mg per day of the compound represented by (A) and a GLP-1 receptor agonist (B) at a dose that is 1 to 90% by weight of the dose described in the package insert or a dose whose efficacy has been confirmed in clinical trials can be used. In one embodiment, about 1 mg to 50 mg of the compound represented by (A) and about 10 to 70% by weight of the dose described in the package insert or the dose whose efficacy has been confirmed in clinical trials can be used per day. In one embodiment, about 1 mg to 50 mg of the compound represented by (A) and about 10 to 50% by weight of the GLP-1 receptor agonist (B) can be used per day.

[0041] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be used in combination with at least one drug selected from the group consisting of drugs having anti-obesity effects, drugs for controlling blood glucose levels, drugs for controlling cholesterol and / or triglycerides in the blood, and drugs for controlling blood pressure, for the purpose of enhancing the effect of the compound or reducing the dose of the compound, etc.

[0042] The "at least one drug selected from the group consisting of drugs having anti-obesity effects, drugs for controlling blood glucose levels, drugs for controlling blood cholesterol and / or triglycerides, and drugs for controlling blood pressure" is not limited to drugs on the market or under development, but examples of drugs on the market or under development include orlistat, cetilistat, phentermine, mazindol, benzphetamine, amfepramone, methamphetamine, phentermine hydrochloride / topiramate, naltrexone hydrochloride / bupropion hydrochloride, liraglutide, semaglutide, setomelanotide (s etmelanotide, RM-493), metreleptin, topiramate, naltrexone, bupropion, acarbose, voglibose, miglitol, ipragliflozin, dapagliflozin, remogliflozin, KGT-1075, luseogliflozin, tofogliflozin, canagliflozin, empagliflozin, ertugliflozin, bexagliflozin, enavogliflozin, henagliflozin, janagliflozin, sotagliflozin, insulin Aspart, insulin lispro, insulin glulisine, biosynthetic human neutral insulin, human insulin, biosynthetic human isophane insulin, human isophane insulin, intermediate-acting insulin lispro, insulin detemir, insulin glargine, insulin degludec, glibenclamide, gliclazide, glimepiride, glipizide, gliquidone, nateglinide, mitiglinide calcium hydrate, repaglinide, metformin hydrochloride, buformin hydrochloride, pioglitazone hydrochloride, rosiglitazone, lobeglitazone ne), sitagliptin phosphate, vildagliptin, alogliptin benzoate, linagliptin, teneligliptin hydrobromide, anagliptin, saxagliptin, trelagliptin succinate, omarigliptin, gemigliptin, evogliptin, lixisenatide, exenatide, dulaglutide, tirzepatide, imeglimin,Sitagliptin phosphate / ipragliflozin, pioglitazone hydrochloride / metformin, pioglitazone hydrochloride / glimepiride, teneligliptin hydrobromide / canagliflozin, alogliptin benzoate / pioglitazone hydrochloride, alogliptin benzoate / metformin hydrochloride, vildagliptin / metformin hydrochloride, mitiglinide calcium / voglibose, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, lovastatin, clinofibrate, clofibrate fibrate, bezafibrate, fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, colestimide, cholestyramine, colesevelam hydrochloride, colestipol, ezetimibe, brobucol, nicomol, tocopherol nicotinate, niceritrol, ethyl icosapentate, omega-3 fatty acid ethyl ester, evolocumab, alirocumab, nifedipine, amlodipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nilvadipine, Barnidipine, felodipine, benzipine, manidipine, azelnidipine, aranidipine, diltiazem, tolchlormethiazide, benzylhydrochlorothiazide, hydrochlorothiazide, meicran, invadamide, tripamide, mefruside, furosemide, triamterene, spinololactone, eplerenone, tolvaptan, torasemide, hydrochlorothiazide, bumetanide, chlorthalidone, isosorbide, metolazone, losartan, cande Sartan, valsartan, telmisartan, olmesartan, irbesartan, azilsartan, captopril, enalapril, alacepril, delapril, cilazapril, lisinopril, benazepril, imidapril, temocapril, quinapril, trandolapril, perindopril erbumine, urapidil, terazosin, brazosin, doxazosin, bunazosin, atenolol, bisobrolol, metoprolol, acebutolol, celiprolol, propranolol, nadolol, nipradilol, carteolol, pindolol, nebivolol,Carvedilol, labetalol, sotalol, landiolol, arotinolol, amosulalol, arotinolol, carvedilol, labetalol, bevantolol, clonidine, guanabenz, methyldopa, reserpine, hydralazine, nitroprusside, aliskiren, kallidinogenase, alprostadil alfadex, dihydroergotoxine, doxazosin, urapidil, hydralazine, prazosin, moxonidine, guanfacine, rilmenidine, amlo Dipine / atorvastatin, losartan / hydrochlorothiazide, valsartan / hydrochlorothiazide, candesartan / hydrochlorothiazide, telmisartan / hydrochlorothiazide, irbesartan / trichlorthiazide, valsartan / amlodipine, olmesartan / azelnidipine, candesartan / amlodipine, telmisartan / amlodipine, irbesartan / amlodipine, valsartan / cilnidipine, azilsartan / amlodipine, tirzepatide, SCO-094, efinopegdutide (HM12525A), BI -456906, DD01, NN-9423, LY-3437943, danuglipron, PF07081532, LY-3502970, RGT-075, efpeglenatide, exenatide, noiglutide, GMA105, HM-15136, noliglycopeptide (SHR-20004), carbetocin (LV-101), PYY-1562 (NNC0165-1562), PYY-1875 (NNC0165-187 5), cotadutide / AM833 (NN9838, NNC-01740833), cotadutide (cotadutide, MEDI0382), LY3305677, pegapamodutide (pegapamodutide, LY2944876, OPK88003), NGM395, YH34160, CT-388, CT-868, SCO-267, SCO-792, diazoxide, tesofensine, namodenoson, ERX1000, AMG133, ASC41, Xla1,HDV Biotin, EMP16, metoprolol / tesofensine, RZL-012, CB4211, BI1356225, AMG171, NO-13065, bardoxolone methyl, HSG4112, YHC2129, YHC2134, KTX-0200, obeticholic acid, cilofexor (GS-9674), tropifexor (LJN452), EDP-305, EYP-001, resmetirom ( resmetirom), VK-2809, cenicriviroc, saroglitazar, lanifibranor, selonsertib, PF-06835919, pegbelfermin, efrugxifermin, aldafermin, aramcol, MK-3655, MSDC- 0602K, belapectin, firsocostat (GS-0976), PF-05221304, erbogastat, ION-224, AXA-1125, HU-6, MET-409, MET-642, TERN-101, TERN-501, LPCN-1144, denifanstate, fluxifermin, leronlimab, Examples include pegozafermin, rencofilstat, retatorutide, tipelukast, S-237648, S-723595, GSBR-1290, ECC5004, CT-996, survodutide, retatorutide, CT-868, VK2735, mazdutide, Maridebart cafraglutide, etc. Furthermore, when these drugs do not form a salt, their pharmaceutically acceptable salts are also included, and when they form a salt, they may form other pharmaceutically acceptable salts. Preferably, orlistat, cetilistat, phentermine, mazindol,Benzphetamine, amfepramone, methamphetamine, phentermine hydrochloride / topiramate, naltrexone hydrochloride / bupropion hydrochloride, liraglutide, semaglutide, setmelanotide (RM-493), metreleptin, topiramate, naltrexone, bupropion, tirzepatide, SCO-094, efinopegdutide (H M12525A), BI-456906, DD01, NN-9423, LY-3437943, danuglipron, PF07081532, LY-3502970, RGT-075, efpeglenatide, exenatide, neuglutide, GMA105, HM-15136, noriglycopeptide ( noliglycopeptide, SHR-20004), carbetocin (LV-101), PYY-1562 (NNC0165-1562), PYY-1875 (NNC0165-1875), cotadutide / AM833 (NN9838, NNC-01740833), cotadutide (MEDI0382), LY33 05677, pegapamodutide (LY2944876, OPK88003), NGM395, YH34160, CT-388, CT-868, SCO-267, SCO-792, diazoxide, tesofensine, namodenoson, ERX1000, AMG133, ASC41, Xla1, HDV Biotin, EMP16, metoprolol / tesofensine, RZL-012, CB4211, BI1356225, AMG171, NO-13065, bardoxolone methyl, HSG4112, YHC2129, YHC2134, KTX-0200, S-237648, S-723595, GSBR-1290, ECC5004, CT-996, survodutide, retatorutide, CT-868, VK2735, mazdutide, Maridebart More preferably,Examples include liraglutide, semaglutide, tirzepatide, BI-456906, danugliplon, PF07081532, LY-3502970, RGT-075, S-237648, S-723595, GSBR-1290, ECC5004, CT-996, survodutide, retatorutide, CT-868, VK2735, mazdutide, and maridebart cafraglutide.

[0043] The administration timing of the compound of formula (I) and the concomitant drug used in combination is not limited, and they may be administered to a subject simultaneously or sequentially, or may be administered at staggered times. Furthermore, the compound of formula (I) and the concomitant drug may be administered as two or more preparations containing the respective active ingredients, or as a single preparation containing the active ingredients.

[0044] The dosage of the compound of formula (I) and the concomitant drug used in combination can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of formula (I) and the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the target disease, symptoms, combination, etc. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0045] The present invention will be explained in more detail below with reference to examples and test examples of the present invention, but the present invention is not limited thereto. Furthermore, changes may be made within the scope of the present invention. The names of compounds shown in the following examples and comparative examples do not necessarily conform to the IUPAC nomenclature.

[0046] (Synthesis Example 1) The above compound was synthesized from a commercially available compound according to the method described in Patent Document 1. 1H-NMR (CDCl3) δ: 2.19-2.26(m, 1H), 2.32-2.40(m, 4H), 2.99(d, J=16.2 Hz, 1H), 3.22(s, 3H), 3.81(d, J=16.2 Hz, 1H), 4.15-4.20(m, 4H), 5.77(s, 1H), 6.47-6.52(m, 2H), 7.69-7.71(m, 1H), 7.81(d, J=8.3 Hz, 1H), 8.30(br-s, 1H).

[0047] Study Example 1: Clinical Trial (Phase 1 Study) A randomized, double-blind, placebo-controlled study was conducted to evaluate safety, tolerability, food effects, drug-drug interactions (DDIs), pharmacokinetics (PK), and biomarkers in healthy adult and obese but otherwise healthy adult subjects. Part 1: Healthy subjects received a single dose of 1, 3, 10, 30, 100, or 300 mg of the study drug or placebo in the fasted state. The 30 mg group received an additional dose of study drug or placebo in the fed state on Day 15. Part 2: Healthy adult subjects received 50 mg of the study drug or placebo once daily in the fed state for 15 days, including Day 1 of the midazolam DDI study. Healthy obese participants received 50 mg of the study drug or placebo once daily in the fed state for 14 days. (Results) In all studies conducted, no significant risks were identified, no serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) were associated with discontinuation of the study intervention. Plasma concentrations of the compound of the present invention were measured over time in each subject at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after a single dose of the study drug. The geometric mean half-life (t1 / 2) of the study drug was 21.8 to 25.8 hours (estimated t1 / 2 for individual subjects ranged from 17.5 to 36.5 hours), and no clinically meaningful food effects on the PK of the study drug were observed. Overall plasma study drug exposure (area under the plasma concentration-time curve [AUC]) following a single oral dose in the fasted state is shown below. In particular, within the dose range of 3 to 100 mg, the increase was almost proportional to the dose. 24-hour AUC (AUC 0-τ ) value (114200ng.hr / mL) and the AUC at steady state estimated by accumulating the concentration transition after a single 30mg dose 0-τ Since the 50 mg dose-proportional values ​​are similar, the AUC is dose-proportional even with repeated administration up to at least 50 mg.

[0048] Test Example 2: Measurement of human MGAT2 inhibitory activity

[0049] 10 μL of enzyme solution prepared in assay buffer (100 mmol / L phosphate buffer (pH 7.4) containing 2 mmol / L DTT), 5 μL of substrate solution (100 mmol / L phosphate buffer (pH 7.4), 80 μmol / L 2-oleoylglycerol, 26 μmol / L oleoyl-CoA), and 5 μL of a DMSO solution of the compound of formula (I) were mixed and incubated at room temperature for 1 hour. After the enzymatic reaction, 50 μL of a stop solution (containing 0.2 μmol / L Diolein-d5, 0.4% formic acid, and 50% isopropanol) containing an internal standard (IS) was added to terminate the reaction, and the activity was measured using an Agilent RapidFire 360 ​​and 6550 Q-TOF mass spectrometer. The reaction products (P) Diolein and IS of the substrate 2-oleoylglycerol were detected, and the peak intensity ratio P / IS was calculated using the peak area to evaluate inhibitory activity. The cases with and without enzyme addition were designated Control(+) / Control(-), respectively, and the respective inhibition rates were designated 0% and 100%. The peak intensity ratio P / IS when the compound according to the present invention was added was designated Sample, and the inhibitory activity was calculated using Excel XLfit software according to the following formula: Inhibitory activity (%) = [1 - {Sample - Control(-)} / {Control(+) - Control(-)}] * 100. The concentration of the compound according to the present invention that exhibits 50% enzyme inhibition (IC 50 ) and the concentration at which 80% of the enzyme is inhibited (IC 80 ) (Results) IC 50 : 3.7 nmol / L IC 80Based on the prediction of PK data from the Phase 1 study of the compound of formula (I), the minimum effective daily dose that partially exceeds the human IC50 value was set at 3 mg. 50 The effective daily dose to maintain the IC80 level above the trough plasma concentration in humans was set at 10 mg. The maximum effective daily dose to maintain the IC80 level above the trough plasma concentration in humans was set at 30 mg.

[0049] Study Example 3: Clinical Trial (Phase 2) A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of an investigational drug (active ingredient: a compound of formula (I): 3, 10, or 30 mg once daily) administered orally to obese adult subjects. The study population consisted of obese male and female participants aged 18 years or older (BMI ≥ 30 kg / m²). In accordance with the Guidelines for Anti-Obesity Drug Development, subjects adhered to a dietary restriction regimen during the study period, limiting their daily calorie intake to 500 kcal less than their total energy expenditure (calculated based on their age and gender). They also completed daily questionnaires regarding their eating behavior. The primary endpoint was the percent change in body weight from baseline at week 24, as assessed for efficacy compared with placebo. Secondary endpoints included safety and tolerability of the investigational drug and changes in body composition from baseline at week 24. In addition, an evaluation was also conducted using a questionnaire regarding eating behavior. Subjects were selected if they met all of the following criteria: BMI of 30 or higher (regardless of whether they had complications) Stable weight for 90 days prior to the start of the screening period Have undergone dietary therapy at least once to lose weight

[0050] (Clinical trial design) The study subjects were randomly assigned to one of the following groups in a 1:1:1:1 ratio: 3 mg, 10 mg, 30 mg of the study drug (compound represented by formula (I)), or a placebo group, using sex at birth as a stratification factor. The study drug (3, 10, or 30 mg) or placebo was orally administered once daily for 24 weeks.

[0051] Test Example 4: Toxicity Evaluation in Rats by Repeated Doses for 4 Days Toxicity evaluation of the compound of formula (I) and / or drugs was investigated in Crl:CD(SD) rats. Six-week-old male Crl:CD(SD) rats were administered the compound of formula (I) or BMS-963272 by gavage once daily for 4 days, followed by general observation, body weight and food intake measurements, hematology and blood chemistry tests, and pathology examinations. (Results) No toxicity was observed in the group administered the compound of formula (I) up to the maximum dose of 500 mg / kg / day. On the other hand, in the BMS-963272 group, prolongation of blood clotting time and elevation of hepatobiliary damage markers were observed at doses of 500 and 1000 mg / kg / day, while liver damage, kidney damage, deterioration of general condition, and decreases in body weight and food intake were observed at the 1000 mg / kg / day dose.

[0052] Test Example 5: Reproductive and Developmental Toxicity Test The embryo-fetal developmental toxicity of the compound of formula (I) was evaluated in Crl:CD(SD) rats. Female Crl:CD(SD) rats aged 10 to 14 weeks were given the compound of formula (I) by gavage once daily for 12 days from days 6 to 17 of gestation, and then underwent cesarean section on day 21 of gestation. The maternal general condition was observed, and weight and food intake were measured, followed by necropsy and corpus luteum count. In addition, the viability and sex of the embryos and fetuses were confirmed, and weight and placental weight were measured, and external and placental macroscopic examinations were performed, as well as internal organ and skeletal examinations. (Results) No toxicity was observed in the group administered with the compound of formula (I) up to a dose of 1,000 mg / kg / day.

[0053] Test Example 6: Anti-obesity effect test (enhancement of weight loss effect during treatment with GLP-1 receptor agonist) Six-week-old male C57BL / 6J mice were fed a high-fat diet (TestDiet; 58Y1) for 25 weeks to create high-fat diet-fed obese mice. Starting 10 days before compound administration, mice were administered a vehicle (0.5% HPMC and PBS) once daily. Randomization was performed based on the weight change, food intake, and body weight on the day of group assignment during this acclimation period, and the mice were assigned to groups. Vehicle or a GLP-1 receptor agonist (semaglutide, 25 μg / kg or 625 μg / kg, SC) was administered once daily for 21 days. Subsequently, each administration group was divided into a group that continued to receive vehicle or semaglutide alone, and a group that additionally received the compound of formula (I) (10 mg / kg, PO) in combination, and these groups were administered once daily for an additional 21 days. Semaglutide (25 μg / kg or 625 μg / kg, SC) was administered in a gradually increasing dose regimen at 5 to 25 μg / kg or 5 to 625 μg / kg once daily for 2 to 4 days up to the maximum dose. Body weight was measured daily during the administration period. The compound of formula (I) (10 mg / kg, PO) is equivalent to 3 mg / man when extrapolated to humans. (Results) Body weight changes are shown in Figure 1. The weight loss rate after the final administration compared to the vehicle-administered group was as follows: These results showed that the group receiving additional co-administration of the compound of formula (I) from 21 days after semaglutide administration had a synergistic weight-reducing effect compared to the groups receiving either compound alone. Furthermore, because co-administration of semaglutide (25 μg / kg) and the compound of formula (I) produced a weight-reducing effect equivalent to that of semaglutide (625 μg / kg) alone, the compound of formula (I) is expected to enable lower doses of semaglutide.

[0054] Test Example 7: Anti-obesity effect test (effect on body weight and body composition) Six-week-old male C57BL / 6J mice were fed a high-fat diet (TestDiet; 58Y1) for 30 weeks to create high-fat diet-fed obese mice. Starting 10 days before compound administration, the mice were administered a vehicle (0.5% HPMC and PBS) once daily. Randomization was performed based on the weight change, food intake, and body weight on the day of group assignment during this acclimation period, and the mice were divided into groups. The vehicle or a GLP-1 receptor agonist (tirzepatide, 50 μg / kg, SC) was administered once daily for 21 days. Subsequently, each treatment group was divided into a group that continued to receive vehicle or tirzepatide alone and a group that additionally received the compound of formula (I) (10 mg / kg, PO) in combination with the vehicle or tirzepatide, and these groups were administered once daily for an additional 21 days. Body weights were measured daily during the treatment period, and visceral fat mass and skeletal muscle mass were measured the day after the final treatment. (Results) The changes in body weight are shown in Figure 2. The weight loss rate after the final administration compared to the vehicle-administered group, and the weights of visceral fat and skeletal muscle measured the day after the final administration were as follows. From the above results, unlike tirzepatide, the compound represented by formula (I) reduced visceral fat weight without affecting skeletal muscle weight. Therefore, it is expected that the compound represented by formula (I) will reduce body weight without causing a rapid decrease in muscle mass. Furthermore, in the group that was additionally administered with the compound represented by formula (I) starting 21 days after tirzepatide administration, a synergistic weight-reducing effect was observed compared to the groups that received either compound alone.

[0055] Test Example 8: Anti-obesity effect test (effect on switching and weight maintenance) Six-week-old male C57BL / 6J mice were fed a high-fat diet (TestDiet; 58Y1) for 31 weeks to create high-fat diet-loaded obese mice. Starting 10 days before compound administration, the mice were administered a vehicle (0.5% HPMC and PBS) once daily. Randomization was performed based on the weight change, food intake, and body weight on the day of group allocation during this acclimation period, and the mice were divided into groups. The vehicle or a GLP-1 analog (semaglutide, 25 μg / kg, SC) was administered once daily for 21 days. The semaglutide group was then divided into three groups: a group switched to the vehicle or the compound of formula (I) (10 mg / kg, PO), and a group continued to receive semaglutide alone, and the group received semaglutide once daily for another 21 days. Semaglutide was administered in a gradually increasing dose of 5-25 μg / kg once daily for two days up to the maximum dose. Body weight was measured daily during the administration period. (Results) Body weight changes are shown in Figure 3. The weight loss rate after the final administration compared to the vehicle-administered group was as follows: These results demonstrate that the group switched to the compound of formula (I) 21 days after semaglutide administration exhibited a rebound-suppressing effect compared with the group switched to the vehicle during the drug withdrawal period. These results suggest that the compound of formula (I) is beneficial for maintaining weight after treatment with a GLP1 agonist.

[0056] Test Example 9: Anti-obesity effect test (effect on switching and weight maintenance) Six-week-old male C57BL / 6J mice were fed a high-fat diet (TestDiet; 58Y1) for 31 weeks to create high-fat diet-loaded obese mice. Starting 10 days before compound administration, a vehicle (0.5% HPMC and PBS) was administered once daily. Randomization was performed based on the weight change, food intake, and weight on the day of group allocation during this acclimation period, and group allocation was performed. The vehicle or a GLP-1 analog (semaglutide, 25 μg / kg, SC) was administered alone once daily for 21 days. The semaglutide group was then divided into three groups: one group switched to low-dose semaglutide (25 μg / kg, SC) alone or low-dose semaglutide (5 μg / kg, SC) in combination with the compound of formula (I) (10 mg / kg, PO), and one group continued to receive semaglutide alone, and these groups received semaglutide once daily for an additional 21 days. Semaglutide was administered in a gradually increasing dose of 5 to 25 μg / kg once daily for two days up to the maximum dose. Body weight was measured daily during the administration period. (Results) Body weight changes are shown in Figure 4. The weight loss rate after the final administration compared to the vehicle-administered group was as follows: These results show that reducing the dose of semaglutide to one-fifth from 21 days after administration results in weight rebound, but combining reduced-dose semaglutide with the compound of formula (I) (10 mg / kg, PO) was shown to be effective in preventing weight rebound. Therefore, the compound of formula (I) is expected to enable the use of lower doses of semaglutide.

[0057] The following formulation examples are illustrative only and are not intended to limit the scope of the invention. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments, or creams, or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0058] The method for treating and / or preventing a disease caused by an obese state of the present invention, and the therapeutic pharmaceutical composition used therein, are believed to exhibit excellent therapeutic effects when a predetermined amount of the active ingredient, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, is administered to a patient suffering from a disease caused by an obese state. Furthermore, the administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof does not cause at least one side effect, such as gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality, and can be applied extremely safely and is suitable for long-term administration, making the therapeutic and / or preventive method and therapeutic pharmaceutical composition of the present invention extremely excellent.

Claims

1. Formula (I): or a pharmaceutically acceptable salt thereof, for treating and / or preventing a disease caused by an obese state.

2. The pharmaceutical composition according to claim 1, wherein the disease caused by an obese state is obesity.

3. Formula (I): A pharmaceutical composition for weight management comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein administration of said pharmaceutical composition does not cause a rapid loss of muscle mass.

5. A pharmaceutical composition according to any one of claims 1 to 4 for subjects with low muscle mass or elderly people.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein administration of the pharmaceutical composition does not cause at least one side effect of gastrointestinal disorders, cholecystitis, increased heart rate, hypoglycemia, acute pancreatitis, hemostatic disorders, liver damage, kidney damage, or embryonic lethality.

7. Body mass index (BMI) is 25 kg / m ２ The pharmaceutical composition according to any one of claims 1 to 6, for treating and / or preventing a disease associated with anti-obesity effects in the above subjects.

8. A pharmaceutical composition according to any one of claims 3 to 7 for a subject undergoing treatment with a GLP-1 receptor agonist.

9. A pharmaceutical composition according to any one of claims 1 to 8, wherein an effective amount of said compound is administered to a subject.

10. The pharmaceutical composition of claim 9, wherein the effective amount of said compound ranges from 0.5 mg to 100 mg per day.

11. The pharmaceutical composition of claim 10, wherein the effective amount of said compound ranges from 1 mg to 50 mg per day.

12. The pharmaceutical composition of claim 11, wherein the effective amount of the compound is 3 mg, 10 mg, or 30 mg per day.

13. (A) Formula (I): or a pharmaceutically acceptable salt thereof, and (B) at least one drug selected from GLP-1 receptor agonists.

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