Use of melanocortin-4 receptor agonists

Abstract

To provide anti-obesity agents to overcome defects of currently used anti-obesity agents, that is, as main types of the previously developed anti-obesity drugs, appetite suppressants acting on the central nervous system are drugs that control the action of neurotransmitters (for example, phentermine, mazindol, lorcaserin, fluoxetine and sibutramine) were mostly used, but the neurotransmitter modulators exert a wide range of effects on various physiological actions in addition to appetite suppression by numerous subtype receptors, so that the modulators are lacking in selectivity for each subtype and have a large disadvantage in that various side effects are accompanied in a case of long-term administration.SOLUTION: The present invention relates to uses of a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof for the purpose of preventing or treating rare genetic obesity diseases, particularly rare genetic obesity diseases associated with a damaged melanocortin-4 receptor (MC4R) pathway.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to the use of a compound of the following formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of rare hereditary obesity, particularly rare hereditary obesity associated with disorders of the melanocortin-4 receptor (MC4R) pathway

Chemical Formula

Background Art

[0002] Melanocortin receptors (MCRs) are a type of G-protein coupled receptor (GPCR). The main role of G-proteins is to activate secondary messengers and control the cellular response to many physiological stimuli through signal transduction. To date, five subtypes of melanocortin receptors have been identified. MC1R is mainly expressed in melanocytes and macrophages and determines skin and hair color by regulating melanin pigment in melanocytes. MC2R is expressed in the adrenal gland and adipose tissue, and its function of mediating the regulation of adrenal hormone secretion by adrenocorticotropic hormone in the adrenal gland is well known. Since MC3R, MC4R, and MC5R are expressed not only at nerve endings but also in the brain, it has been found that they mediate the central nervous action of melanocortin peptides and affect behavior, learning, memory, appetite, nerve generation and regeneration, etc. So far, it has been known that MC3R is involved in erectile dysfunction and inflammatory responses, and MC4R is involved in obesity and diabetes, and research on the specificity of the action of each receptor has been actively conducted (Non-Patent Document 1). As a result, it has been found that MC4R is deeply involved in genetic studies of obese individuals, and it has been demonstrated that this receptor plays an important role in appetite regulation by showing that knockout mice lacking MC4R develop obesity due to overeating (Non-Patent Documents 2, 3, and 4).

[0003] On the one hand, among the anti-obesity drugs developed so far, appetite suppressants that act on the central nervous system are the mainstream. Among them, drugs that regulate the action of neurotransmitters (for example, phentermine, mazindol, lorcaserin, fluoxetine, and sibutramine) have been mainly used. However, in addition to suppressing appetite by a number of subtype receptors, the neurotransmitter regulators have a wide range of effects on various physiological functions. Therefore, the drugs have poor selectivity for each subtype and have a major drawback of being accompanied by various side effects in the case of long-term administration. On the other hand, melanocortin agonists are neuropeptides rather than neurotransmitters. Considering that in MC4R gene knockout (KO) mice, functions other than energy metabolism are normal, melanocortin agonists have advantages as an action point in that they can induce only weight loss by suppressing appetite without affecting other physiological functions.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present invention relates to the following formula (1)

Chemical Formula

[0006] The present invention provides a medicament for preventing or treating a rare genetic obesity disease, which comprises a therapeutically effective amount of a compound represented by the following formula (1)

Chemical formula

[0007] The present invention also provides a pharmaceutical composition for preventing or treating a rare genetic obesity disease, which comprises a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

[0008] Furthermore, the present invention provides a method for preventing or treating a rare genetic obesity disease, which comprises administering a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0009] The present invention also provides the use of the compound of formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of rare genetic obesity diseases.

[0010] Hereinafter, the present invention will be described in detail.

[0011] According to one aspect of the present invention, there is provided a medicament for preventing or treating rare genetic obesities, which comprises a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0012] According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a rare genetic obesity disorder, comprising a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

[0013] In one embodiment according to the present invention, the compound of formula (1) is the following formula (2)

Chemical formula

[0014] In another embodiment according to the present invention, the pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, 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, maleic acid; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid. In another embodiment according to the present invention, the pharmaceutically acceptable salt may be selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid. In another embodiment according to the present invention, the pharmaceutically acceptable salt is a hydrochloride salt.

[0015] In another embodiment according to the present invention, the hydrochloride salt 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) by various methods based on the structure of formula (1). <Reaction Scheme 1>

Chemical formula

[0016] In another embodiment according to the present invention, the rare genetic obesity disorder may be related to a damaged melanocortin-4 receptor (MC4R) pathway. In another embodiment according to the present invention, the rare genetic obesity disorder related to the damaged melanocortin-4 receptor (MC4R) pathway may be leptin receptor (LEPR) deficiency. Leptin is a hormone secreted from body fat cells (adipocytes), and the leptin hormone acts on the leptin receptor in the hypothalamus to maintain metabolism and appetite homeostasis upstream of the melanocortin-4 receptor (MC4R) pathway and plays an important role in body weight regulation. Therefore, leptin receptor deficiency may cause severe obesity.

[0017] In another embodiment according to the present invention, a "therapeutically effective amount" for an individual subject means an amount sufficient to achieve the above-described pharmacological effect, i.e., a therapeutic effect. The amount of the compound can vary depending on the condition and severity of the subject, the mode of administration, and the age of the subject to be treated, but can be determined based on the knowledge of those skilled in the art.

[0018] In another embodiment according to the present invention, the therapeutically effective amount of the compound of formula (1) is typically in the range of about 0.1 to 500 mg per day, for example, depending on the frequency and intensity of administration. The typical daily dose for intramuscular or intravenous administration to adults is in the range of about 0.1 to 300 mg per day, which can be administered in divided unit doses. In some patients, higher daily doses may be required.

[0019] In the present invention, the "pharmaceutical composition" can contain other components such as carriers, diluents, excipients, etc. in addition to the active ingredient according to the present invention. Therefore, the pharmaceutical composition may optionally contain a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. The pharmaceutical composition facilitates the administration of the compound into the body. Various methods for administering the compound include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration, etc.

[0020] As used herein, the "carrier" means a compound that facilitates the introduction of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a conventional carrier that facilitates the introduction of many organic compounds into the cells or tissues of an organism.

[0021] As used herein, the "diluent" means a compound that not only stabilizes the biologically active form but is also diluted in a solvent that dissolves the compound. In this field, salts dissolved in a buffer solution are used as diluents. A conventionally used buffer solution is phosphate buffered saline that mimics the form of salts in body fluids. Since the buffer solution can control the pH of the solution at a low concentration, the buffer diluent hardly changes the biological activity of the compound.

[0022] As used herein, "pharmaceutically acceptable" means a property that does not impair the biological activity or physical properties of the compound.

[0023] The compound according to the present invention can be formulated into various pharmaceutically administered dosage forms. In the preparation of the pharmaceutical composition of the present invention, the active ingredient, specifically the compound of formula (1) or a pharmaceutically acceptable salt thereof, is mixed with a pharmaceutically acceptable carrier selected in consideration of the dosage form to be prepared. For example, the pharmaceutical composition according to the present invention can be formulated into an injection, an oral preparation, etc. as required.

[0024] The compounds of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients and inserted into single or multiple unit containers. The formulation may be a solution, suspension or emulsion in an oil or aqueous solvent and contains conventional dispersants, suspending agents or stabilizers. Further, the compound may be in the form of a dry powder which is dissolved, for example, in sterile, pyrogen-free water before use. The compounds of the present invention can be formulated into suppositories using conventional suppository bases such as cocoa butter and other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are particularly preferred. Tablets and pills are preferably enteric-coated. The solid form can be prepared by mixing the compound of the present invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrants, binders and the like. Further, it can also be formulated into a transdermal administration form, for example, a lotion, an ointment, a gel, a cream, a patch or a spray. In another embodiment according to the present invention, the drug or pharmaceutical composition may be an oral preparation.

[0025] As used herein, the term "prevention" means reducing or eliminating the possibility of contracting a disease.

[0026] As used herein, the term "treatment" means arresting, delaying or improving the progression of a disease in a subject exhibiting symptoms of the disease.

Advantages of the Invention

[0027] The drug or pharmaceutical composition according to the present invention can efficiently prevent or treat rare genetic obesity diseases, particularly rare genetic obesity diseases associated with a damaged melanocortin-4 receptor (MC4R) pathway.

Brief Description of the Drawings

[0028]

Figure 1

Mode for Carrying Out the Invention

[0029] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, it should be understood that the protection scope of the present invention is not limited to these examples.

[0030] Production Example: Synthesis of 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)isobutylamide hydrochloride

Chemical formula

[0031] Step A: Preparation of methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutylamide)pyrrolidine-2-carboxylate Methyl (2S,4S)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutylamide)pyrrolidine-2-carboxylate hydrochloride (28.7 g, 82.73 mmol), (3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (24.5 g, 86.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.2 g, 115.83 mmol) and 1-hydroxybenzotriazole hydrate (15.7 g, 115.83 mmol) were dissolved in N,N'-dimethylformamide (400 mL), and N,N'-diisopropylethylamine (72.0 mL, 413.66 mmol) was slowly added. After stirring at room temperature for 16 hours, the reaction solvent was concentrated under reduced pressure, 0.5N aqueous sodium hydroxide solution was added, and extraction was performed twice with ethyl acetate. The organic layer was washed twice with aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (41.19 g, 87%). MS [M+H] = 575 (M+1)

[0032] Step B: Preparation of (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutylamide)pyrrolidine-2-carboxylic acid Methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutylamide)pyrrolidine-2-carboxylate (39.4 g, 68.62 mmol) obtained in the above Step A was dissolved in methanol (450 mL), and 6N aqueous sodium hydroxide solution (57.2 mL, 343.09 mmol) was added. After stirring at room temperature for 16 hours and adjusting the pH to about 5 with 6N aqueous hydrochloric acid solution, the reaction solution was concentrated under reduced pressure. The concentrated solution was dissolved in dichloromethane, and the insoluble solid was filtered off with filter paper. The filtrate was concentrated under reduced pressure to obtain a crude product (38.4 g, 99%), which was used in the next step without purification. MS [M+H] = 561 (M+1)

[0033] Step C: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramide)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 the above Step B were dissolved in N,N'-dimethylformamide (200 mL), and morpholine (5.9 mL, 68.80 mmol) and N,N'-diisopropylethylamine (59.7 mL, 343.02 mmol) were slowly added thereto in sequence. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, 0.5 N aqueous sodium hydroxide solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (37.05 g, 86%). MS [M+H] = 630 (M+1)

[0034] Step D: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride 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)isobutylamide (5.0 g, 7.95 mmol) obtained in the above step C was dissolved in ethyl acetate (50 mL), and 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 obtained crude solid was purified by trituration with hexane and diethyl ether to obtain the title compound (5.23 g, 99%). MS [M+H] = 630 (M+1) 1 H NMR (500 MHz, CD3OD) δ 7.49-7.44 (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)

[0035] Example: db / db mouse model experiment Db / db mice with a mutation in the leptin receptor gene that acts upstream of the melanocortin-4 receptor (MC4R) are a model that reflects receptor-deficient obesity, and these mice exhibit abnormal phenotypes related to metabolic diseases such as hyperphagia and severe obesity. To confirm the anti-obesity effect, while feeding db / db mice, a genetic obesity mouse model with a mutation in the leptin receptor related to the MC4R pathway, a 45 kcal% high-fat diet (diet with 45 kcal% fat), the N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutylamide hydrochloride (hereinafter referred to as 'test compound') obtained in the preparation example was repeatedly administered for 4 weeks. The body weight gain inhibitory effect was measured by measuring the body weight during the administration period, and the body fat mass reduction effect was confirmed by measuring the total body fat mass after 4 weeks of repeated administration. As a result, the body weight was significantly decreased and the body weight gain rate was also significantly decreased compared with the negative control group. As a result of body fat analysis, the fat-free mass was not different from that of the negative control group, whereas the body fat mass was significantly decreased compared with the negative control group. The above results are shown in Figure 1.

[0036] As can be seen from Figure 1, it was confirmed that the test compound of the present invention exhibits a significant weight loss effect.

Claims

1. A therapeutically effective amount of the following formula (1) 【Chemical 1】 (In the formula, R1 is C 2 -C 5 alkyl.) A medicament for preventing or treating a rare genetic obesity disorder, comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof.

2. The compound of formula (1) is the following formula (2) [Chemical 2] N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide, characterized in that the medicament according to claim 1.

3. The pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid, characterized in that the medicament according to claim 1.

4. The rare genetic obesity disorder is associated with a damaged melanocortin-4 receptor (MC4R) pathway, characterized in that the medicament according to claim 1.

5. The rare genetic obesity disorder associated with the damaged melanocortin-4 receptor (MC4R) pathway is leptin receptor (LEPR) deficiency, characterized in that the medicament according to claim 4.

6. An oral preparation, characterized in that the medicament according to claim 1.

7. A therapeutically effective amount of the following formula (1) [Chemical Formula 3] (wherein, R1 is C 2 -C 5 alkyl). A pharmaceutical composition for preventing or treating a rare genetic obesity disorder, comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

8. The compound of formula (1) is the following formula (2) 【Chemical Formula 4】 N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide, characterized in that the pharmaceutical composition according to claim 7.

9. The pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid, characterized in that the pharmaceutical composition according to claim 7.

10. The rare genetic obesity disorder is associated with a damaged melanocortin-4 receptor (MC4R) pathway, characterized in that the pharmaceutical composition according to claim 7.

11. The rare genetic obesity disorder associated with the damaged melanocortin-4 receptor (MC4R) pathway is leptin receptor (LEPR) deficiency, characterized in that the pharmaceutical composition according to claim 10.

12. An oral preparation, characterized in that the pharmaceutical composition according to claim 7.

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