RU2850792C1 - Use of a melanocortin-4 receptor agonist - Google Patents

Abstract

FIELD: chemistry; pharmaceuticals.

SUBSTANCE: the proposed composition contains a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein R1 is C₂-C₅alkyl.

EFFECT: treatment of a genetic form of obesity associated with a disruption of the melanocortin-4 receptor (MC4R) signalling pathway.

6 cl, 1 dwg, 2 ex

Description

AREA OF TECHNOLOGY

The present invention relates to the use of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of rare genetic forms of obesity, in particular a rare genetic form of obesity associated with a disorder of the melanocortin-4 receptor (MC4R) pathway:

[Formula 1]

where R1 is C ₂ -C ₅ alkyl.

LEVEL OF TECHNOLOGY

The melanocortin receptor (MCR) is a type of G protein-coupled receptor (GPCR), whose primary role is to activate second messengers and regulate cellular responses to a variety of physiological stimuli through signal transduction. Five subtypes of the melanocortin receptor have been identified to date. MC1R is primarily expressed in melanocytes and macrophages and determines skin and hair color by regulating the melanin pigment in melanocytes. MC2R is expressed in the adrenal glands and adipose tissue, and the role of adrenocorticotropic hormone in regulating adrenal hormone secretion in the adrenal glands is well established. MC3R, MC4R, and MC5R are expressed not only in nerve terminals but also in the brain, and thus, it is understood that they mediate central nervous system function through melanocortin peptides, which manifests itself through effects on behavior, learning, memory, appetite, and nerve formation and regeneration. MC3R is currently known to be involved in erectile dysfunction and the inflammatory response, while MC4R is implicated in obesity and diabetes, and research into the specificity of each receptor's action is actively underway (MacNeil DJ et al., Eur J Pharmacol 2002, 450, 93). As a result, MC4R has been found to be deeply involved in genetic studies in obese humans, and it has been demonstrated that this receptor plays an important role in appetite regulation by demonstrating that knockout mice in which MC4R has been deleted develop obesity following overeating (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).

Meanwhile, the main types of previously developed anti-obesity drugs are appetite suppressants that act on the central nervous system. Among these, the most widely used are drugs that control the action of neurotransmitters (e.g., phentermine, mazindol, lorcaserin, fluoxetine, and sibutamine). However, beyond appetite suppression, neurotransmitter modulators exhibit a wide range of effects on various physiological functions through several receptor subtypes. Therefore, modulators lack selectivity for each receptor subtype and have the major drawback of causing various side effects with long-term administration. On the other hand, melanocortin agonists are neuropeptides, not neurotransmitters, and given that all other functions other than energy metabolism are normal in MC4R gene knockout (KO) mice, melanocortin agonists have an advantage as a target because only weight loss can be induced through appetite suppression without affecting other physiological functions.

DESCRIPTION OF THE INVENTION

TECHNICAL PROBLEM

The present invention provides for the use of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of rare genetic forms of obesity, in particular a rare genetic form of obesity associated with a disorder of the melanocortin-4 receptor (MC4R) pathway:

[Formula 1]

where R1 is C ₂ -C ₅ alkyl.

SOLUTION TO THE PROBLEM

The present invention relates to a medicinal product for the prevention or treatment of a rare genetic form of obesity, which comprises a therapeutically effective amount of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

where R1 is C ₂ -C ₅ alkyl.

Furthermore, the present invention relates to a pharmaceutical composition for the prevention or treatment of a rare genetic form of obesity, which comprises a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

Furthermore, the present invention relates to a method for preventing or treating a rare genetic form of obesity, which comprises administering a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

Furthermore, 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 genetic form of obesity.

The present invention is described in more detail below.

According to one aspect of the present invention, there is provided a medicament for the prevention or treatment of a rare genetic form of obesity, which comprises a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of a rare genetic form of obesity, which comprises a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

In one embodiment 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 below:

[Formula 2]

In another embodiment according to the present invention, examples of the pharmaceutically acceptable salt include, but are not limited to, acid addition salts formed with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; an organic carboxylic acid 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 a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 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.

In another embodiment according to the present invention, the hydrochloride of the compound of formula 1 can be prepared according to the following reaction scheme 1. However, one skilled in the art can prepare the compound of formula 1 in various ways based on the structure of formula 1.

[Reaction scheme 1]

In the reaction scheme 1

R2 is C ₁ -C ₅ alkyl;

R3 is _C3 - _C8 cycloalkyl, which is unsubstituted or substituted with 1 or 2 _C1 - _C5 alkyls; and

each of R4 and R5 independently represents hydrogen or halogen.

In another embodiment of the present invention, a rare genetic form of obesity may be associated with a defect in the melanocortin-4 receptor (MC4R) pathway. In another embodiment of the present invention, a rare genetic form of obesity associated with a defect in the melanocortin-4 receptor (MC4R) pathway may be a deficiency of the leptin receptor (LEPR). Leptin is a hormone secreted by the body's fat cells (adipocytes). The hormone leptin acts on leptin receptors in the hypothalamus, maintaining metabolic and appetite homeostasis upstream of the MC4R pathway, and plays an important role in body weight regulation. Thus, leptin receptor deficiency can lead to severe obesity.

In another embodiment, according to the present invention, a "therapeutically effective amount" for a particular individual refers to an amount sufficient to achieve the aforementioned pharmacological effect—i.e., the therapeutic effect as described above. The amount of the compound may vary depending on the condition and its severity in the individual, the route of administration, and the age of the subject being treated, but can be determined by those skilled in the art, taking into account their knowledge.

In another embodiment according to the present invention, a therapeutically effective dosage of a compound of Formula 1 typically ranges from, for example, approximately 0.1 to 500 mg per day, depending on the frequency and intensity of administration. A typical daily dose for intramuscular or intravenous administration in adults ranges from approximately 0.1 to 300 mg per day, which can be administered in divided single doses. Some patients may require a higher daily dose.

As used herein, a "pharmaceutical composition" may include other components, such as carriers, diluents, excipients, etc., in addition to the active ingredient of the present invention. Thus, a pharmaceutical composition may optionally include pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. A pharmaceutical composition facilitates the administration of compounds to the body. Various routes of administration of the compounds include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration.

As used herein, "carrier" refers to a compound that facilitates the incorporation of compounds into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the incorporation of many organic compounds into living cells or tissues.

In this description, "diluent" refers to a compound that not only stabilizes the biologically active form but is also diluted in a solvent that dissolves the compound. In this field, a dissolved salt in a buffer is used as a diluent. A commonly used buffer is phosphate-buffered saline, which mimics the salt form in bodily fluids. Because the buffer can control the pH of the solution at low concentrations, the buffered diluent has virtually no effect on the biological activity of the compounds.

As used herein, "pharmaceutically acceptable" means a property that does not interfere with the biological activity and physical property of the compounds.

The compounds of the present invention can be formulated into various pharmaceutically administrable dosage forms. To prepare a pharmaceutical composition according to the present invention, the active ingredient, in particular a compound of Formula 1 or a pharmaceutically acceptable salt thereof, is mixed with selected pharmaceutically acceptable carriers, taking into account the dosage form to be obtained. For example, the pharmaceutical composition of the present invention can be formulated, if necessary, as injection forms, oral preparations, etc.

The compound of the present invention can be formulated by conventional methods using known pharmaceutical carriers and excipients and placed in single- or multiple-dose containers. The compositions can be a solution, suspension, or emulsion in an oily or aqueous vehicle and include conventional dispersing agents, suspending agents, or stabilizers. In addition, the compound can be, for example, in the form of a dry powder, which is dissolved in sterilized, pyrogen-free water before use. The compound of the present invention can be formulated as suppositories using a conventional suppository base, such as cocoa butter or other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders, and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric-coated. Solid forms are prepared by mixing the compounds 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, etc. In addition, they can be formulated as a transdermal dosage form, for example, as a lotion, ointment, gel, cream, patch or spray.

As used herein, the term "prevention" refers to reducing or eliminating the likelihood of acquiring a disease.

As used herein, the term "treatment" is used to mean stopping, slowing, or reducing the progression of a disease in an individual who has symptoms of the disease.

EFFECTS OF THE INVENTION

The medicinal product or pharmaceutical composition according to the present invention can effectively prevent or treat rare genetic forms of obesity, in particular rare genetic forms of obesity associated with a disorder of the melanocortin-4 receptor (MC4R) pathway.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows graphs showing the results of measuring the effect of body weight loss in a mouse model with leptin receptor deficiency (db/db mouse model).

METHOD FOR CARRYING OUT THE INVENTION

The present invention is further explained in more detail using the following examples. However, it should be understood that the scope of protection of the present invention is not limited by the examples.

Example of production: synthesis of hydrochloride N -((3 S ,5 S )-1-((3 S ,4 R )-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramide

The title compound was prepared via steps A, B, C, and D.

Step A: Production of methyl (2 S ,4 S )-1-((3 S ,4 R )-1-(tert-

butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-( N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate

Methyl ( 2S , 4S )-4-( N -(( 1S , 4R )-4-methylcyclohexyl)isobutyramido)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 was slowly added (72.0 mL, 413.66 mmol). After stirring at room temperature for 16 h, the reaction solvent was concentrated under reduced pressure, then 0.5 N 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 give the title compound (41.19 g, 87%).

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

Stage B: Receiving (2 S ,4 S )-1-((3 S ,4 R )-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-( N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramido)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)isobutyramido)pyrrolidine-2-carboxylate (39.4 g, 68.62 mmol) obtained in step A was dissolved in methanol (450 mL), and 6 N 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 approximately 5 with 6 N aqueous hydrochloric acid, the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane, and then the insoluble solid was filtered off through filter paper. The filtrate was concentrated under reduced pressure to give a crude material (38.4 g, 99%), which was used in the next step without purification.

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

Stage C: Receipt N -((3 S ,5 S )-1-((3 S ,4 R )-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-

carbonyl)pyrrolidin-3-yl)- N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramide

(2 S ,4 S )-1-((3 S ,4 R )-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-( N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid (38.4 g, 68.60 mmol) obtained in step B, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.4 g, 96.04 mmol) and 1-hydroxybenzotriazole hydrate (13.0 g, 96.04 mmol) 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). After stirring at room temperature for 16 h, the reaction solution was concentrated under reduced pressure, 0.5 N 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 give the title compound (37.05 g, 86%).

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

Step D: Obtaining the hydrochloride N -((3 S ,5 S )-1-((3 S ,4 R )-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramide

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 2N hydrochloric acid in ethyl acetate (3.97 mL, 15.89 mmol) was slowly added thereto. After stirring at room temperature for 30 min, the reaction solvent was concentrated under reduced pressure. The resulting crude solid was purified by trituration with hexane and diethyl ether to give the title compound (5.23 g, 99%).

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

¹ H-NMR (500 MHz, CD ₃ OD) 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).

Example: Experiment with the db/db mouse model

The db/db mouse, which has a mutation in the leptin receptor gene that acts upstream of the melanocortin-4 receptor (MC4R), is a model that reflects leptin receptor-deficient obesity, and this mouse exhibits abnormal metabolic disease-associated phenotypes such as hyperphagia and severe obesity. In order to confirm the anti-obesity efficacy, 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 "test compound") obtained according to the Production Example was administered repeatedly for 4 weeks while simultaneously feeding a 45 kcal% high-fat diet (45 kcal% fat diet) to db/db mice, which are a mouse model of genetic obesity in which a mutation in the leptin receptor associated with the MC4R pathway is present. The weight gain inhibition effect was confirmed by measuring body weight during the administration period, and the weight-reducing effect was confirmed by measuring total body fat mass after repeated administration for 4 weeks. As a result, body weight decreased significantly compared to the negative control group, and the rate of weight gain also significantly decreased. Body fat analysis showed no difference in lean mass compared to the negative control group, while fat mass decreased significantly compared to the negative control group. The results are presented in Fig. 1.

As can be seen from Fig. 1, it was confirmed that the test compound according to the present invention exhibits a significant body weight reducing effect.

Claims (11)

1. A composition for the treatment of a genetic form of obesity associated with a disorder of the melanocortin-4 receptor (MC4R) pathway, wherein the composition comprises a therapeutically effective amount of a compound of formula 1 below or a pharmaceutically acceptable salt thereof. [Formula 1] where R1 is C ₂ -C ₅ alkyl. 2. The composition according to claim 1, wherein 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 [Formula 2] 3. The composition according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of salts based on hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid. 4. The composition of claim 1, wherein the rare genetic form of obesity associated with a disorder of the melanocortin-4 receptor (MC4R) pathway is leptin receptor deficiency (LEPR). 5. The composition according to claim 1, which is an oral formulation. 6. The composition according to claim 1, which is formulated as a pharmaceutical composition together with a pharmaceutically acceptable carrier.