Use of melanocortin-4 receptor agonists in prevention or treatment of rare hereditary obesity diseases

Abstract

The present invention relates to the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of a rare hereditary obesity disease associated with an impaired melanocortin-4 receptor (MC4R) pathway, in particular a rare hereditary obesity disease associated with a proaposmin (POMC) deficiency.

Description

Technical Field

[0001] The present invention relates to the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating rare genetic obesity diseases associated with the melanocortin-4 receptor (MC4R) pathway, particularly rare genetic obesity diseases associated with proopiomelanocortin (POMC) deficiency:

[0002] [Formula 1]

[0003]

[0004] In Formula 1, R1 is a C2-C5 alkyl group. Background Art

[0005] Melanocortin receptor (MCR) is a type of G protein coupled receptor (GPCR), and the main role of G protein is to activate second messengers, regulating the response of cells to many physiological stimuli through signal transduction. So far, five types of melanocortin receptors have been identified. MC1R is expressed in melanocytes and macrophages, and in melanocytes, it determines the color of skin and hair by regulating melanin. MC2R is expressed in the adrenal glands and adipose tissue, and its mediating function of regulating adrenal hormone secretion by adrenocorticotropic hormone in the adrenal glands is well known. MC3R, MC4R and MC5R are expressed in the brain and nerve endings, and are believed to mediate the central neuronal effects of melanocortin peptides, which are manifested as effects on behavior, learning, memory, appetite and neuronal development and regeneration. So far, MC3R is known to be associated with erectile dysfunction and inflammatory response, and MC4R is known to be associated with obesity and diabetes, and research on the specificity of each receptor is being actively conducted (MacNeil DJ et al., Eur J Pharmacol 2002, 450, 93). Therefore, genetic studies on humans with active obesity have shown that MC4R is closely related to this, and transgenic mice (knockout mice) in which MC4R is removed have been shown to become obese due to overeating, thereby proving that this receptor plays an important 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).

[0006] On the other hand, existing obesity treatments are mainly appetite suppressants that act on the central nervous system, and most of them are drugs that regulate the action of neurotransmitters (e.g., phentermine, mazindol, lorcaserin, fluoxetine and sibutramine). However, these neurotransmitter regulators play a wide range of roles in various physiological functions other than appetite suppression through many subtype receptors. Therefore, in the case of the above-mentioned drugs, the disadvantage is that they lack the selectivity to each subtype, so when applied in a long period of time, they can cause various side effects. On the other hand, melanocortin antagonists are neuropeptides rather than neurotransmitters, and their advantage is that they can induce weight loss by suppressing appetite without affecting other physiological functions, because in MC4R knockout (KO) mice, all other functions except energy metabolism are normal. DETAILED DESCRIPTION

[0007] Issues to be resolved

[0008] The present invention aims to provide a compound of formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating rare hereditary obesity diseases associated with the melanocortin-4 receptor (MC4R) pathway, in particular rare hereditary obesity diseases associated with proopiomelanocortin (POMC) deficiency:

[0009] [Formula 1]

[0010]

[0011] In Formula 1, R1 is a C2-C5 alkyl group.

[0012] Solutions to the problem

[0013] The present invention provides a drug for preventing or treating a rare genetic obesity disease associated with proopiomelanocortin (POMC) deficiency, comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof:

[0014] [Formula 1]

[0015]

[0016] In Formula 1, R1 is a C2-C5 alkyl group.

[0017] The present invention also provides a pharmaceutical composition for preventing or treating rare genetic obesity associated with pro-opiomelanocortin (POMC) deficiency, comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0018] In addition, the present invention provides a method for preventing or treating a rare genetic obesity disease associated with proopiomelanocortin (POMC) deficiency, comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0019] The present invention also provides a use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating a rare hereditary obesity disease associated with proopiomelanocortin (POMC) deficiency.

[0020] Hereinafter, the present invention will be described in more detail.

[0021] According to one aspect of the present invention, a drug for preventing or treating rare genetic obesity associated with proopiomelanocortin (POMC) deficiency is provided, comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0022] According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating rare genetic obesity associated with proopiomelanocortin (POMC) deficiency, comprising a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0023] In one embodiment of 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 the following Formula 2:

[0024] [Formula 2]

[0025] .

[0026] In another embodiment according to the present invention, pharmaceutically acceptable salts include but are not limited to acid addition salts formed by the following: 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, etc.; and sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, etc. In other embodiments according to the present invention, pharmaceutically acceptable salts can be selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid. In one embodiment according to the present invention, pharmaceutically acceptable salts are hydrochlorides.

[0027] In another embodiment according to the present invention, the hydrochloride of the compound of Formula 1 can be prepared according to the following 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.

[0028] [Solution 1]

[0029]

[0030] In the above scheme 1,

[0031] R2 is a C1-C5 alkyl group;

[0032] R3 is a C3-C8 cycloalkyl group which is unsubstituted or substituted with one or two C1-C5 alkyl groups; and

[0033] R4 and R5 are each independently hydrogen or halogen.

[0034] According to the present invention, the compound of formula 1 can effectively prevent or treat rare hereditary obesity diseases associated with proopiomelanocortin (POMC) deficiency. Proopiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues, which is synthesized in the anterior and middle lobes of the pituitary gland and acts as a precursor of several peptide hormones such as melanocyte stimulating hormone (MSH), endorphins and adrenocorticotropic hormone. As a ligand of melanocortin-4 receptor (MC4R), α-MSH acts upstream of MC4R, and if the Pomc gene encoding it is defective and not expressed normally, it can cause severe early-onset obesity.

[0035] In another embodiment according to the present invention, "therapeutically effective amount" for an individual subject means an amount sufficient to achieve the pharmacological effect (i.e., therapeutic effect) described above, and the amount of the compound will depend on the subject's condition and its severity, the method of administration and the age of the subject to be treated, but can be determined by ordinary technicians in the relevant field based on their own knowledge.

[0036] In another embodiment according to the present invention, the therapeutically effective dose of the compound of Formula 1, for example, the dose required for treating an adult, is generally in the range of about 0.1 to 500 mg per day, depending on the frequency and intensity of administration. For intramuscular or intravenous administration to adults, a total dose of about 0.1 to 300 mg per day, divided into single doses, is generally sufficient, but a higher daily dose may be required for some patients.

[0037] In the present invention, in addition to the active compound according to the present invention, the "pharmaceutical composition" may also include other chemical components, such as carriers, diluents, excipients, etc. Therefore, as required, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof. The pharmaceutical composition helps to administer the active compound to an organism. There are various techniques for administering compounds, including but not limited to oral, injection, aerosol, parenteral and topical administration.

[0038] As used herein, "carrier" means a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into cells or tissues of an organism.

[0039] As used herein, "diluent" is defined as a compound diluted in water that stabilizes the biologically active form of the compound of the invention as well as dissolving the compound. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which simulates the salt form of human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely change the biological activity of a compound.

[0040] As used herein, "pharmaceutically acceptable" means properties that do not impair the biological activity and physical properties of the compound.

[0041] In the present invention, the compound can be formulated into various pharmaceutical dosage forms according to the purpose. When preparing the pharmaceutical composition according to the present invention, the active ingredient, in particular the compound of Formula 1 or a pharmaceutically acceptable salt thereof, is mixed with various pharmaceutically acceptable carriers, which can be selected according to the preparation to be prepared. For example, the pharmaceutical composition according to the present invention can be formulated into an injectable preparation, an oral preparation, etc. according to the purpose.

[0042] The compounds of the present invention can be prepared by known methods using known pharmaceutical carriers and excipients, and can be introduced in unit dose form or in multi-dose containers. The form of the preparation can be in the form of a solution, suspension or emulsion in an oil or aqueous medium, and can contain conventional dispersants, suspending agents or stabilizers. It can also be in the form of a dry powder dissolved in sterile, pyrogen-free water, for example, before use. The compounds of the present invention can also be prepared in the form of suppositories using conventional suppository bases such as cocoa butter or other glycerides. Solid dosage forms for oral administration can be capsules, tablets, pills, granules and tablets, wherein capsules and tablets are particularly useful. 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, starch, etc. and carriers such as lubricants, disintegrants, binders, etc. such as magnesium stearate. It can also be prepared in a transdermal dosage form, for example, as a lotion, ointment, gel, cream, patch or spray. In another embodiment according to the present invention, the drug or pharmaceutical composition can be an oral preparation.

[0043] As used herein, "preventing" means reducing or eliminating the likelihood of contracting a disease.

[0044] As used herein, "treating" means halting, delaying or lessening the progression of a disease when applied to a subject exhibiting symptoms of the disease.

[0045] Effects of the Invention

[0046] The medicine or pharmaceutical composition according to the present invention can effectively prevent or treat rare genetic obesity diseases associated with the melanocortin-4 receptor (MC4R) pathway, especially rare genetic obesity diseases associated with proopiomelanocortin (POMC) deficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is a graph showing the results of anti-obesity efficacy in a high fat diet (HFD) POMC heterozygous deficient mouse model.

[0048] Figure 2 is a graph showing the results of anti-obesity efficacy in a high fat diet (HFD) POMC homozygous deficient mouse model.

[0049] Best Mode for Carrying Out the Invention

[0050] Hereinafter, the present invention will be described in more detail by working examples. However, these working examples are intended to illustrate one or more embodiments only by way of example, and the scope of the present invention is not limited thereto.

[0051] Preparation Example: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl Synthesis of ((1s,4R)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride

[0052]

[0053] The title compound was obtained by following steps A, B, C and D.

[0054] 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

[0055] (2S,4S)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (28.7 g, 82.73 mmol) obtained from Preparation Example 1, (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) from Preparation Example 2 were dissolved in N,N'-dimethylformamide (400 ml), and N,N'-diisopropylethylamine (72.0 ml, 413.66 mmol) was slowly added. At room temperature, stir for 16 hours and after the reaction solvent is concentrated under reduced pressure, 0.5 N sodium hydroxide aqueous solution is added and extracted twice with ethyl acetate. The organic layer is washed twice with sodium chloride aqueous solution and water, then filtered through anhydrous magnesium sulfate drying. The filtrate is concentrated under reduced pressure and purified by column chromatography to obtain the title compound (41.19 g, 87%).

[0056] MS [M+H] = 575 (M+1)

[0057] Step B: (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N- Preparation of ((1S,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid

[0058] 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 by step A above was dissolved in methanol (450 ml), followed by addition of 6N aqueous sodium hydroxide solution (57.2 ml, 343.09 mmol). 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 concentrate was dissolved in dichloromethane, and the insoluble solid was filtered through a paper filter. The filtrate was concentrated under reduced pressure to give a crude product (38.4 g, 99%), which was used in the next step without purification.

[0059] MS [M+H] = 561 (M+1)

[0060] Step C: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5- Preparation of (morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide

[0061] (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 obtained from step B above (13.0 g, 96.04 mmol) were dissolved in N,N'-dimethylformamide (200 ml), followed by the slow addition of morpholine (5.9 ml, 68.80 mmol) and N,N'-diisopropylethylamine (59.7 ml, 343.02 mmol). After stirring at room temperature for 16 h, the reaction solution was concentrated under reduced pressure; then 0.5 N sodium hydroxide aqueous solution was added and extracted twice with ethyl acetate. The organic layer was washed twice with sodium chloride aqueous solution and water, and then dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (37.05 g, 86%).

[0062] MS [M+H] = 630 (M+1)

[0063] Step D: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5- Preparation of (morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride

[0064] N-((3S, 5S)-1-((3S, 4R)-1-(tert-butyl)-4-(4-chlorophenyl) pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidine-3-yl)-N-((1s, 4R)-4-methylcyclohexyl) isobutyramide hydrochloride (5.0 g, 7.95 mmol) obtained by step C above 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 min, the reaction solvent was concentrated under reduced pressure. The obtained crude solid was purified by grinding with hexane and ether to obtain the title compound (5.23 g, 99%).

[0065] MS [M+H] = 630 (M+1)

[0066] 1H 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)

[0067] Working Example: Pomc knockout mouse model experiment

[0068] Proopiomelanocortin (POMC) is a precursor polypeptide of α-MSH, a ligand of melanocortin-4 receptor (MC4R), which acts upstream of the melanocortin-4 receptor; Pomc knockout mice, in which this proopiomelanocortin protein is not properly expressed, are a model of obesity that reflects the genetic obesity disease POMC deficiency, in which the mice exhibit abnormal metabolic disease-related phenotypes, such as excessive food intake and severe obesity.

[0069] Pomc heterozygous knockout mice in which the Pomc gene encoding proopiomelanocortin (POMC) is not normally expressed were fed a 60 kcal% high-fat diet (a diet containing 60 kcal% fat), and 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 obtained in Preparation Example (hereinafter referred to as "test compound") was administered at a dose of 10 mg / kg to 30 mg / kg for about 3 weeks to determine the anti-obesity efficacy, and the results were as follows. Figure 1 Shown in.

[0070] Pomc homozygous knockout mice in which the Pomc gene encoding proopiomelanocortin (POMC) is not expressed were administered the test compound at a dose of 10 mg / kg to 30 mg / kg for about 10 days while being fed a 45 kcal% high fat diet (diet containing 45 kcal% fat) to determine the anti-obesity efficacy, and the results were Figure 2 Shown in.

[0071] from Figure 1 and Figure 2 As can be seen, it could be confirmed that the test compound of the present invention exhibited an excellent anti-obesity effect.

Claims

1. A drug for preventing or treating a rare genetic obesity disease associated with pro-opiomelanocortin (POMC) deficiency, the drug comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] In Formula 1, R1 is a C2-C5 alkyl group.

2. The drug 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 below: [Formula 2] 。 3. The drug according to claim 1, characterized in that The pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid.

4. The drug according to claim 1, characterized in that The drug is in oral dosage form.

5. A pharmaceutical composition for preventing or treating a rare genetic obesity disease associated with pro-opiomelanocortin (POMC) deficiency, the pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier: [Formula 1] In Formula 1, R1 is a C2-C5 alkyl group.

6. The pharmaceutical composition 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 pharmaceutical composition according to claim 5, characterized in that The pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid.

8. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition is an oral preparation.

9. Use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating a rare hereditary obesity disease associated with proopiomelanocortin (POMC) deficiency: [Formula 1] In Formula 1, R1 is a C2-C5 alkyl group.

10. The use according to claim 9, 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] 。 11. The use according to claim 9, characterized in that The pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid.

12. The use according to claim 9, characterized in that The medicine is an oral preparation.

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