Combination therapy for preventing or treating obesity

Abstract

The present invention relates to a combination therapy for effective prevention or treatment of obesity. More specifically, an object of the present invention is to effectively prevent or treat obesity through a synergistic effect obtained when a melanocortin-4 receptor (MC4R) agonist and a glucagon-like peptide-1 (GLP-1) agonist are administered in combination.

Description

Technical Field

[0001] The present invention relates to a combination therapy for effectively preventing or treating obesity, and more particularly, to effectively preventing or treating obesity by a synergistic effect obtained by co-administering a melanocortin-4 receptor (MC4R) agonist and a glucagon-like peptide-1 (GLP-1) receptor agonist. Background Art

[0002] Melanocortin receptors (MCRs) are a class of G protein-coupled receptors (GPCRs) in which the main role of G proteins is to activate second messengers, thereby regulating the response of cells to a variety of physiological stimuli through signal transduction. To date, 5 types of melanocortin receptors have been identified. MC1R is expressed in melanocytes and macrophages, where it regulates the production of melanin, thereby determining the color of skin and hair. MC2R is expressed in the adrenal glands and adipose tissue, and it is well known that it plays a role in mediating the secretion of adrenal hormones in the adrenal glands in response to adrenocorticotropic hormone. MC3R, MC4R and MC5R are expressed not only in nerve endings, but also in the brain, and are believed to mediate the effects of melanocortin peptides in the central nervous system, where they affect behavior, learning, memory, appetite, and the formation and regeneration of neurons. To date, MC3R has been associated with erectile dysfunction and inflammatory responses, while MC4R has been associated with obesity and diabetes, and receptor-specific effects have been extensively studied (MacNeil DJ et al., Eur J Pharmacol 2002, 450, 93). Genetic studies of individuals with advanced obesity have shown that MC4R is strongly involved in the disease, and MC4R knockout mice have been shown to develop obesity due to excessive food intake, demonstrating that this receptor has a key role in appetite regulation (Lu D, Willard D et al., Nature 1994, 371 (6500), 799; Huszar D et al., Cell 1997, 88 (1), 131; Hinney A et al., J Clin Endocrinol Metab 1990, 84 (4), 1483).

[0003] Most of the anti-obesity drugs currently under development are appetite suppressants that act on the central nervous system, especially those that modulate neurotransmitter activity (e.g., phentermine, mazindol, lorcaserin, fluoxetine, and sibutramine). However, these neurotransmitter modulators exert a wide range of effects on various physiological functions beyond appetite suppression through many subtype receptors. Therefore, these drugs lack selectivity for specific subtypes, and thus have the disadvantage of causing various side effects when administered for a long time. In contrast, melanocortin agonists are neuropeptides rather than neurotransmitters, which may have advantages in terms of target sites, as evidenced by the fact that after administration in MC4R knockout (KO) mice, all functions except energy metabolism remain normal, indicating that melanocortin agonists can induce weight loss by suppressing appetite without affecting other physiological functions.

[0004] Meanwhile, glucagon-like peptide-1 (GLP-1) is an incretin that plays a role in promoting insulin secretion from β cells, increasing glucose utilization in peripheral tissues, inhibiting glucagon secretion from α cells, and increasing glucose production in the liver. However, endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) within a few minutes and loses its activity. GLP-1 receptor agonists are GLP-1 analogs that are not hydrolyzed by DPP-4.

[0005] Description of the invention

[0006] Technical issues

[0007] The present invention aims to provide a combined therapy that can effectively prevent or treat obesity and has excellent physical fitness improvement effect and safety.

[0008] Solutions to the problem

[0009] In order to solve the aforementioned problems, the present invention provides a pharmaceutical composition for preventing or treating obesity, which comprises a melanocortin-4 receptor (MC4R) agonist or a pharmaceutically acceptable salt thereof, in combination with a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0010] In addition, the present invention provides a kit for combined prevention or treatment of obesity, comprising the following combinations (i) and (ii):

[0011] (i) a preparation containing a glucagon-like peptide-1 (GLP-1) receptor agonist, and

[0012] (ii) A preparation containing a melanocortin-4 receptor (MC4R) agonist or a pharmaceutically acceptable salt thereof.

[0013] In addition, the present invention provides a method for preventing or treating obesity, which comprises co-administering a glucagon-like peptide-1 (GLP-1) receptor agonist and a melanocortin-4 receptor (MC4R) agonist or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount to a subject in need thereof.

[0014] Hereinafter, the present invention will be described in detail.

[0015] The present invention has demonstrated that co-administration of a MC4R agonist and a GLP-1 receptor agonist can show excellent preventive or therapeutic efficacy for obesity through a synergistic effect.

[0016] According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating obesity, the pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, used in combination with a glucagon-like peptide-1 (GLP-1) receptor agonist:

[0017] [Formula 1]

[0018]

[0019] In formula 1, R1 is C 2 -C 5 alkyl.

[0020] In one example according to the present invention, the compound of formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1S,4R)-4-methylcyclohexyl)isobutyramide of formula 2:

[0021] [Formula 2]

[0022]

[0023] In another example according to the present invention, pharmaceutically acceptable salts may include, but are not limited to, for example: inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid and maleic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid. In another example according to the present invention, pharmaceutically acceptable salts may be selected from the group consisting of hydrochloride, sulfate, nitrate, phosphate, hydrobromide and hydroiodide. In another example according to the present invention, pharmaceutically acceptable salts may be hydrochloride.

[0024] In another example according to the present invention, the hydrochloride of the compound of Formula 1 can be prepared according to the following reaction scheme 1. However, those skilled in the art can prepare the compound of Formula 1 based on the structure of Formula 1 by various methods.

[0025] [Reaction Scheme 1]

[0026]

[0027] In the above reaction scheme 1,

[0028] R2 is C 1 -C 5 alkyl;

[0029] R3 is unsubstituted or substituted with one or two C 1 -C 5 Alkyl substituted C 3 -C 8 cycloalkyl; and

[0030] R4 and R5 are each independently hydrogen or halogen.

[0031] In another example of the present invention, the GLP-1 receptor agonist can be a peptide drug or a small molecule. As generally understood in the art, a small molecule refers to an organic compound having a molecular weight of approximately less than 900 Daltons, which is not a peptide drug composed of amino acids. In another example according to the present invention, a peptide drug can be selected from a group consisting of, for example, semaglutide, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, benaglutide, PEG-loxenatide, efenatide and voronatide, but is not limited thereto. In another example according to the present invention, a small molecule can be dangglitazone (PF-06882961) or LY-3502970, but is not limited thereto. In another example according to the present invention, a GLP-1 receptor agonist can be selected from a group consisting of semaglutide, exenatide, liraglutide, lixisenatide, albiglutide and dulaglutide. In another example according to the present invention, the GLP-1 receptor agonist may be semaglutide or danglitazone (PF-06882961).

[0032] In another example according to the present invention, for individual subjects, the term "therapeutically effective amount" refers to an amount sufficient to achieve the aforementioned pharmacological effect (i.e., therapeutic effect). The amount of the compound can vary according to the subject's condition, condition severity, mode of administration, and age of the subject to be treated. However, those skilled in the art can determine a suitable amount based on their own knowledge.

[0033] In another example according to the present invention, the therapeutically effective dose of the compound of Formula 1 (e.g., the dose required for treating an adult) is generally within the range of about 0.1 to 500 mg per day, depending on the frequency and intensity of administration. When administered intramuscularly or intravenously to an adult, a total daily dose of about 0.1 to 300 mg (divided into multiple single doses) is generally sufficient, although in some cases, a higher daily dose may be required for some patients.

[0034] In the present invention, the term "pharmaceutical composition" may include other chemical components, such as carriers, diluents, excipients, etc., in addition to the active compound of the present invention. Therefore, the pharmaceutical composition may optionally include a pharmaceutically acceptable carrier, diluent, excipient, or a combination of these. The pharmaceutical composition helps to administer the active compound to an organism. There are various techniques for administering the compound, including but not limited to oral, injection, spray, parenteral, and topical administration.

[0035] In this specification, the term "carrier" refers to a compound that facilitates the delivery of an active compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that helps deliver many organic compounds into cells or tissues of an organism.

[0036] In this specification, the term "diluent" is defined as a compound that not only stabilizes the biologically active form of the target compound, but also dilutes the water in which the target compound is dissolved. In the related art, salts dissolved in buffer solutions are used as diluents. Commonly used buffers include phosphate buffered saline, which simulates the salt form of body fluids. Because buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely change the biological activity of the compound.

[0037] In the present specification, the term "pharmaceutically acceptable" refers to properties that do not impair the biological activity and physical properties of the compound.

[0038] According to the intended purpose, the compounds of the present invention can be formulated into various pharmaceutical dosage forms. When preparing the pharmaceutical composition according to the present invention, the active ingredient, specifically the compound of formula 1 or its pharmaceutically acceptable salt, is mixed with various pharmaceutically acceptable carriers selected according to the desired dosage form. For example, the pharmaceutical composition according to the present invention can be formulated into an injectable preparation, an oral preparation or other forms according to the intended purpose.

[0039] The compounds of the present invention can be formulated into unit dosage forms or incorporated into multi-dose containers by known methods, which involve known pharmaceutically acceptable carriers and excipients. These preparations can be in the form of solutions, suspensions or emulsions in oily or aqueous media, and can contain conventional dispersants, suspending agents or stabilizers. In addition, for example, these preparations can be in the form of dry powders, which are reconstituted with sterile, pyrogen-free water before use. The compounds of the present invention can also be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. Solid oral dosage forms can include capsules, tablets, pills, powders and granules, and capsules and tablets are particularly preferred. Tablets and pills are preferably prepared with enteric coatings. Solid dosage forms can be prepared by mixing the compounds of the present invention with one or more inert diluents (such as sucrose, lactose or starch) and carriers such as lubricants (for example, magnesium stearate), disintegrants and adhesives. In addition, the compound can be formulated for transdermal administration and can be prepared in the form of lotions, ointments, gels, creams, patches or sprays. In another embodiment of the present invention, the pharmaceutical agent or pharmaceutical composition may be an oral dosage form.

[0040] In this specification, the term "prevention" means reducing or eliminating the possibility of disease progression.

[0041] In this specification, the term "treatment" means to stop, delay or alleviate the progression of a disease when applied to a subject showing symptoms of the disease.

[0042] According to another aspect of the present invention, there is provided a kit for combined prevention or treatment of obesity, comprising the following combinations (i) and (ii):

[0043] (i) a preparation containing a glucagon-like peptide-1 (GLP-1) receptor agonist, and

[0044] (ii) a preparation containing the compound of formula 1 or a pharmaceutically acceptable salt thereof.

[0045] In another example according to the present invention, the kit allows for simultaneous, sequential or separate administration of a preparation containing a GLP-1 receptor agonist and a preparation containing a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0046] In another example according to the present invention, the preparation containing each active ingredient may further include a pharmaceutically acceptable excipient.

[0047] In another example according to the present invention, the kit may include, in addition to the preparation containing the active ingredient, a packaging container, an operating manual, accompanying documents, etc. The packaging container, operating manual, and accompanying documents may disclose the combination used in combination with the substance. In addition, the combined use form when the additional substance is applied, or the form as a mixture, or the usage, dosage, etc. may be disclosed.

[0048] Advantages of the present invention

[0049] According to the present invention, due to the synergistic effect obtained by combining the melanocortin-4 receptor (MC4R) agonist of the above-mentioned formula 1 or its pharmaceutically acceptable salt and the glucagon-like peptide-1 (GLP-1) receptor agonist, excellent physical improvement effect and safety can be obtained, and obesity can be effectively prevented or treated. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 is a graph showing the results of measuring the weight loss effect over 18 days after co-administration of the compound prepared according to Preparation Example (hereinafter referred to as “test compound”) and semaglutide in a diet-induced obesity (DIO) mouse model.

[0051] Figure 2 is a graph showing the results of measuring the weight loss effect after 18 days of co-administration of a test compound and semaglutide in a diet-induced obesity (DIO) mouse model.

[0052] Figure 3 is a graph showing the results of measuring the liver and fat weight reduction effects after 3 weeks of co-administration of a test compound and semaglutide in a diet-induced obesity (DIO) mouse model.

[0053] Figure 4 is a graph showing the results of measuring the weight loss effect after 18 days of co-administration of a test compound and semaglutide in a diet-induced obesity (DIO) mouse model.

[0054] Figure 5 is a graph showing the results of measuring the food intake reducing effect over 28 days following co-administration of a test compound and PF-06882961 in a diet-induced obesity (DIO) mouse model.

[0055] Figure 6 is a graph showing the results of measuring the weight loss effect over 28 days after co-administration of a test compound and PF-06882961 in a diet-induced obesity (DIO) mouse model.

[0056] Figure 7is a graph showing the results of measuring the body fat mass reducing effect after 28 days of co-administration of a test compound and PF-06882961 in a diet-induced obesity (DIO) mouse model.

[0057] Figure 8 is a graph showing the results of measuring the glucose tolerance improving effect after 28 days of co-administration of a test compound and PF-06882961 in a diet-induced obesity (DIO) mouse model. DETAILED DESCRIPTION

[0058] Hereinafter, the present invention will be described in more detail with reference to embodiments of the present invention. However, these embodiments are provided only for illustrative purposes to help understand the present invention, and the scope of the present invention is not limited thereto.

[0059] Preparation Example: Synthesis of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-yl)- carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)

[0060] Isobutyramide hydrochloride

[0061]

[0062] The title compound was obtained by following steps A, B, C, and D.

[0063] Step A: (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N- Preparation of methyl ((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate

[0064] (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid methyl ester (28.7 g, 82.73 mmol), (3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (24.5 g, 86.87mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.2g, 115.83mmol) and 1-hydroxybenzotriazole hydrate (15.7g, 115.83mmol) were dissolved in N,N'-dimethylformamide (400ml), and then N,N'-diisopropylethylamine (72.0ml, 413.66mmol) was slowly added. After stirring at room temperature for 16 hours and concentrating the reaction solvent under reduced pressure, 0.5N sodium hydroxide aqueous solution was added and extracted twice with ethyl acetate. After washing the organic layer twice with sodium chloride aqueous solution and water respectively, dry filtration was performed with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (41.19g, 87%).

[0065] MS [M+H] = 575 (M+1)

[0066] Step B: Preparation of (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4- (N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid

[0067] The (2S, 4S)-1-((3S, 4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1S, 4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid methyl ester (39.4 g, 68.62 mmol) obtained in step A was dissolved in methanol (450 ml), and then a 6N aqueous sodium hydroxide solution (57.2 ml, 343.09 mmol) was added. After stirring at room temperature for 16 hours, the pH was adjusted to about 5 with a 6N aqueous hydrochloric acid solution, and the reaction solution was concentrated under reduced pressure. After the concentrated solution was dissolved with dichloromethane, the undissolved solid was filtered with a paper filter. The filtrate was concentrated under reduced pressure to obtain a crude product (38.4 g, 99%), which was used in the subsequent step without purification.

[0068] MS[M+H]=561(M+1)

[0069] Step C: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl (1S,4R)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1S,4R)-4-methylcyclohexyl)isobutyramide

[0070] The (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid (38.4 g, 68.60 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.4 g, 96.04 mmol) and 1-hydroxybenzotriazole hydrate (13.0 g, 96.04 mmol) obtained in step B were dissolved in N,N'-dimethylformamide (200 ml), and then morpholine (5.9 ml, 68.80 mmol) and N,N'-diisopropylethylamine (59.7 ml, 343.02 mmol) were slowly added in sequence. After stirring at room temperature for 16 hours and concentrating the reaction solution under reduced pressure, 0.5N sodium hydroxide aqueous solution was added and extracted twice with ethyl acetate. After washing the organic layer twice with sodium chloride aqueous solution and water respectively, dry filtration was performed with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (37.05 g, 86%).

[0071] MS[M+H]=630(M+1)

[0072] Step D: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl ((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride

[0073] N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1S,4R)-4-methylcyclohexyl)isobutyramide (5.0 g, 7.95 mmol) obtained in step C was dissolved in ethyl acetate (50 ml), and then 2N hydrochloric acid ethyl acetate solution (3.97 ml, 15.89 mmol) was slowly added. After stirring at room temperature for 30 minutes, the reaction solvent was concentrated under reduced pressure. The resulting crude solid was purified by trituration with hexane and diethyl ether to obtain the title compound (5.23 g, 99%).

[0074] MS[M+H]=630(M+1)

[0075] 1 H NMR (500MHz, CD 3 OD)δ7.49-7.44(m,4H),4.83(m,1H),4.23-4.20(m,1H),3.95-3.91(m,2H),3.79-3.47(m,14H),3.03-3.00(m,1H),2.86-2.82( m,1H),2.73-2.67(m,1H),2.20-2.14(m,1H),1.97(m,1H),1.80-1.62(m,5H),1.50(s,9H),1.44-1.27(m,3H),1.06-1.04(m,9H)

[0076] Example 1: Measuring weight loss effect

[0077] In a diet-induced obesity (DIO) mouse model in which obesity is induced using a high-fat diet, the weight loss effect was measured over 18 days after repeated co-administration of semaglutide (a GLP-1 receptor agonist, trade name: Ozempic) and the MC4R agonist N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1S,4R)-4-methylcyclohexyl)isobutyramide hydrochloride (hereinafter referred to as the "test compound") obtained in the Preparation Example. Before administration of the test substance, body weight was measured once a day, and the change in body weight compared to the body weight before administration of the test substance (D1) was calculated, and the results are presented in Figure 1 and Figure 2 The effect of co-administration of a GLP-1 receptor agonist and a test compound was evaluated by comparing the weight loss effect in the co-administration group with the weight loss effect in the single administration group. Figure 1 and Figure 2As shown, co-administration of semaglutide, a GLP-1 receptor agonist, and the test compound demonstrated a synergistic weight loss effect.

[0078] Example 2: Measuring Liver / Fat Weight Loss Effect

[0079] In the diet-induced obesity (DIO) mouse model using a high-fat diet to induce obesity, liver and fat weight reduction effects were measured after repeated co-administration of semaglutide (a GLP-1 receptor agonist, trade name: Ozempic) and the test compound (a MC4R agonist) for 3 weeks. Figure 3 From Figure 3 As can be seen in Figure 3, co-administration of semaglutide (a GLP-1 receptor agonist) and the test compound demonstrated a synergistic effect in reducing liver and fat weight.

[0080] Comparative Examples

[0081] In the diet-induced obesity (DIO) mouse model using a high-fat diet to induce obesity, the weight loss effect was compared after repeated co-administration of semaglutide (a GLP-1 receptor agonist, trade name: Ozempic) with a test compound (a MC4R agonist) or semaglutide (RM-493) (a peptide MC4R agonist) (hereinafter referred to as "comparative compound") for 18 days. The doses of the test compound and the comparative compound were selected based on the effective doses observed in the single administration study (test compound: 15 mg / kg / day, comparative compound: 3 mg / kg / day). Before the administration of the test substance, body weight was measured once a day, and the change in body weight after 18 days relative to the body weight before the administration of the test substance (D1) was calculated, and the results are presented in Figure 4 In terms of the effect of co-administration with a GLP-1 receptor agonist, Figure 4 As shown, the test compound demonstrated a significant synergistic weight loss effect in the co-administration group, whereas such a synergistic weight loss effect was not observed in the co-administration group with the comparator compound.

[0082] Example 3: Combination study with PF-06882961 (Danglitazone)

[0083] In a diet-induced obesity (DIO) mouse model using a high-fat diet to induce obesity, changes in food intake and body weight were measured over 4 weeks of repeated co-administration of PF-06882961 (danglitazone), an oral GLP-1 receptor agonist, and a test compound, an MC4R agonist. Food intake and body weight were measured once daily before test substance administration, and changes in body weight relative to the body weight before test substance administration (D1) were calculated and the results are presented in Figure 5 and Figure 6 In addition, on the 28th day after administration of the test substance, body fat mass and oral glucose tolerance test (OGTT) were measured, and the results are shown in Figure 7 and Figure 8 Use 1 Body fat mass was measured using the H-Mini-spec system (LF-90II, Bruker Optics GmbH, Germany), blood glucose was measured using GM9 (Analox Instruments Ltd., UK), and blood samples were collected from the tail vein.

[0084] from Figure 5 and Figure 6 As can be seen in Figure 2, co-administration of the GLP-1 receptor agonist PF-06882961 and the test compound demonstrated a synergistic weight loss effect proportional to a significant reduction in food intake compared to their respective single administration. Figure 7 and Figure 8 As shown, it has been demonstrated that combination therapy induces a greater reduction in body fat mass and improvement in glucose tolerance than either administration alone.

Claims

1. A pharmaceutical composition for preventing or treating obesity, which is used in combination with a glucagon-like peptide-1 (GLP-1) receptor agonist, the pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] Wherein in Formula 1, R1 is a C2-C5 alkyl group.

2. The pharmaceutical composition for preventing or treating obesity according to claim 1, characterized in that: The compound of formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide of formula 2: [Formula 2] 3. The pharmaceutical composition for preventing or treating obesity according to claim 1, characterized in that: The pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, nitrate, phosphate, hydrobromide and hydroiodide.

4. The pharmaceutical composition for preventing or treating obesity according to claim 1, characterized in that: The GLP-1 receptor agonist is a peptide drug or a small molecule.

5. A kit for combined prevention or treatment of obesity, comprising the following combinations (i) and (ii): (i) a preparation containing a glucagon-like peptide-1 (GLP-1) receptor agonist, and (ii) a preparation containing a compound of formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] Wherein in Formula 1, R1 is a C2-C5 alkyl group.

6. The kit for combined prevention or treatment of obesity according to claim 5, characterized in that: The compound of formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide of formula 2: [Formula 2] 7. The kit for combined prevention or treatment of obesity according to claim 5, characterized in that: The pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, nitrate, phosphate, hydrobromide and hydroiodide.

8. The kit for combined prevention or treatment of obesity according to claim 5, characterized in that: The GLP-1 receptor agonist is a peptide drug or a small molecule.

9. The kit for combined prevention or treatment of obesity according to claim 5, characterized in that: The preparation containing the GLP-1 receptor agonist and the preparation containing the compound of formula 1 or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or separately.

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