WO2022039523A1 - Use of composition comprising amodiaquine and artesunate-based drug as active ingredient for prevention, alleviation, or treatment of type 2 diabetes mellitus - Google Patents

Abstract

The present invention relates to a use of a composition comprising amodiaquine activating both PPAR-γ and PPAR-α and an artesunate-based drug activating SIRT-1 as active ingredients for prevention, alleviation, or treatment of type 2 diabetes mellitus. More specifically, the present invention provides: a pharmaceutical composition comprising a combination of amodiaquine and an artesunate-based drug for prevention, alleviation, or treatment of type 2 diabetes mellitus or a metabolic syndrome-related disease; a pharmaceutical composition comprising a combination of amodiaquine and an artesunate-based drug for alleviation of insulin tolerance; a method for prevention, alleviation, or treatment of type 2 diabetes mellitus or a metabolic syndrome-related disease by using a combination of amodiaquine and an artesunate-based drug; and a method for alleviation of insulin tolerance by using a combination of amodiaquine and an artesunate-based drug.

Description

Use of a composition containing amodiaquine and artesunate-based drugs as active ingredients for the prevention, improvement or treatment of type 2 diabetes

The present invention provides a composition containing amodiaquine, which activates both PPAR-γ and PPAR-α, and an artesunate-based drug (altesunate-based drug) that activates SIRT-1, as active ingredients for the prevention of type 2 diabetes , It relates to an improvement or therapeutic use, and more particularly, a pharmaceutical composition for preventing, improving or treating type 2 diabetes or metabolic syndrome-related diseases containing a combination of amodiaquine and artesunate-based drugs; A pharmaceutical composition for improving insulin resistance containing a combination of amodiaquine and artesunate drugs; a method for preventing, improving, or treating type 2 diabetes or metabolic syndrome-related diseases using a combination of amodiaquine and an artesunate drug; And it provides a method for improving insulin resistance using a combination of amodiaquine and artesunate-based drugs.

Due to the westernization of dietary life over the past 30 years, the incidence of chronic degenerative diseases such as diabetes, arteriosclerosis, and cancer, and the resulting deaths, have increased significantly due to environmental changes and aging due to an increase in the intake of processed and animal foods and a decrease in the intake of plant foods. . As for glucose metabolic diseases, imbalance of energy metabolism in the body caused by high-fat and high-carbohydrate meals leads to obesity and induces insulin resistance and metabolic inflammation, leading to degenerative diseases such as abnormal lipid metabolism and type 2 diabetes. Diabetes mellitus is when the body does not produce the required amount of insulin, a hormone that regulates glucose, secreted by beta cells of the pancreas, or the insulin does not work properly on the cells, so the glucose in the blood is not used as energy and accumulates in the blood for high blood sugar It is a symptom in which sugar is detected in the urine. In general, diabetes is divided into insulin-dependent diabetes mellitus (type 1 diabetes) and non-insulin-dependent diabetes mellitus (type 2 diabetes) depending on whether or not insulin is essential for treatment. Type 2 diabetes is non-insulin-dependent diabetes mellitus, which occurs due to insufficient insulin action or relatively insufficient insulin due to insulin resistance. It is also referred to as adult-type diabetes mellitus.

If diabetes continues for a long time, glucose absorption in the body does not occur normally, causing abnormalities in carbohydrate metabolism, lipid metabolism, and protein metabolism, leading to hyperinsulinemia, neurological complications, and diabetic retinopathy (non-proliferative retinopathy, proliferative retinopathy, diabetic cataract). , kidney failure, sexual dysfunction, skin disease (allergy), high blood pressure, arteriosclerosis, stroke (stroke), heart disease (myocardial infarction, angina pectoris, heart attack), gangrene and other complications of diabetes occur. Therefore, in order to understand the various causes and etiology of type 2 diabetes and to come up with improvement measures, studies on glucose transport and metabolic processes, insulin signaling system, etc. are being actively conducted at home and abroad, but there are still Drugs have not been developed.

Currently known treatment for type 2 diabetes can be divided into four major categories: sulfonylureas-based drugs that induce insulin secretion, and acetabular drugs that move sugar to muscle cells and inhibit sugar synthesis in the liver Biguanides, α-glucosidase inhibitors that inhibit the enzyme that makes glucose in the small intestine, thiazolidions that activate PPAR (Peroxisome proliferator-activated receptors)-γ, which are involved in adipocyte differentiation (TZD, thiazolidinedione) drugs, etc. However, these oral hypoglycemic agents have many side effects, such as hypoglycemia (sulfonylurea drug), nephrotoxicity (biguanide drug), lactic acidosis (biguanide drug), diarrhea and upset stomach (alpha-glucosidase inhibitor). accompanying

On the other hand, peroxisome is one of the intracellular organelles that cause these target function abnormalities, and plays an important role in the metabolism of oxygen, glucose, lipids, and hormones, and regulates cell proliferation and differentiation, and inflammatory mediators. It also has a wide effect on regulation. In addition, peroxisomes play an important role in aging and tumor development by influencing the formation of cell membranes and mast cells as well as insulin sensitivity through lipid metabolism and glucose metabolism, and influencing oxidative stress. Peroxisome proliferator-activated receptors (PPAR) are one of nuclear receptors that regulate gene expression by ligand binding, and various fatty acids act as endogenous ligands. Presently identified PPARs are peroxisome proliferator activated receptor alpha (PPAR-α), peroxisome proliferator activated receptor beta/delta (PPAR-β/δ), and peroxisome proliferator activated receptor gamma (PPAR-γ). there is

PPAR-γ is found most often in adipose tissue, and is also found in vascular endothelium, macrophages, and pancreatic β cells, regulates adipocyte differentiation and plays a crucial role in systemic lipid homeostasis. Compounds that fully or partially activate PPAR-γ are particularly effective in the treatment of type 2 diabetes. However, obesity, dyslipidemia, cardiovascular disease, fatty liver, etc. that occur as side effects when PPAR-γ is activated are problematic.

PPAR-α is mainly found in blood vessel walls, liver, heart, muscle, kidney, and brown adipose tissue. It prevents or delays the onset of arteriosclerosis together with the agonist fibrate, and anti-obesity through promotion of fat oxidation. it works

Therefore, there is a need for discovering new compounds capable of more effectively regulating the activity of PPAR for the prevention, improvement, or treatment of various diseases regulated by the action of PPAR.

In addition, SIRT1 is a mammalian homologue of Sirtuins protein known to induce lifespan extension effects in yeast, and belongs to a class of histone deacetylases that require NAD ⁺ as a cofactor. There are a total of 7 types of sirtuins, including SIRT1-7, which have been discovered in animals so far, and they differ from each other in the location and function of their action. It regulates the activity of various substrates related to When SIRT1 expression and activity are increased in various tissues such as liver, fat, and pancreas, transcription factors such as PPARγ and FOXO1 and UCP1-3 proteins related to mitochondrial energy metabolism are directly deacetylated or co-regulated by p300, NcoR, and PGC1α. Indirect activity regulation by deacetylation of factor (coregulatory) prevents glycolysis in the liver, reduces fat accumulation in adipose tissue, increases insulin sensitivity in pancreas, and enhances energy metabolism in muscle tissue, resulting in heat dissipation will cause weight loss. When a mouse overexpressing the SIRT1 gene was fed a high-fat diet, the study showed that it reduced inflammation due to fat, increased glucose tolerance, and prevented fatty liver formation compared to normal mice. It has been reported that this is due to the activation of PGC1α and inhibition of inflammation-inducing cytokines.

[Prior art literature]

[Patent Literature]

(Patent Document 1) Domestic Registered Patent Publication No. 10-1934328 (2018.12.26)

The present invention is (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; And (b) artesunate (artesunate) for the purpose of providing a pharmaceutical composition for preventing, improving or treating type 2 diabetes containing a drug or a pharmaceutically acceptable salt thereof as an active ingredient.

In this regard, another object of the present invention is (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; And (b) to provide a method for preventing, improving or treating type 2 diabetes, comprising administering an artesunate-based drug or a pharmaceutically acceptable salt thereof to an individual in need thereof in an effective amount.

Another object of the present invention is when preparing a medicament for use in the prevention, improvement or treatment of type 2 diabetes, (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; And (b) to provide the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; and (b) an artesunate-based drug or a pharmaceutically acceptable salt thereof as an active ingredient. An object of the present invention is to provide a pharmaceutical composition for improving insulin resistance.

In this regard, another object of the present invention is (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; And (b) to provide a method for improving insulin resistance, comprising administering to an individual in need thereof an effective amount of an artesunate-based drug or a pharmaceutically acceptable salt thereof.

Another object of the present invention is when preparing a medicament for use in improving insulin resistance, (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; And (b) to provide the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; and (b) an artesunate-based drug or a pharmaceutically acceptable salt thereof, as an active ingredient, for preventing, improving, or treating a metabolic syndrome-related disease.

In this regard, another object of the present invention is (a) amodiaquine (amodiaquine) or a pharmaceutically acceptable salt thereof; And (b) to provide a method for preventing, improving or treating metabolic syndrome-related diseases, comprising administering an artesunate-based drug or a pharmaceutically acceptable salt thereof to an individual in need thereof in an effective amount.

Another object of the present invention is to prepare a medicament for use in the prevention, improvement or treatment of metabolic syndrome-related diseases, (a) amodiaquine or a pharmaceutically acceptable salt thereof; And (b) to provide the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

The present invention relates to (a) amodiaquine represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And (b) provides a pharmaceutical composition for preventing or treating type 2 diabetes containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by the following formula (2) as an active ingredient:

[Formula 1]

,

,

[Formula 2]

,

,

이다.In Formula 2, R is a ketone group, a hydroxyl group, a C1 to C6 alkoxy group, or

am.

In addition, the present invention is amodiaquine (amodiaquine) represented by the formula (1) or a pharmaceutically acceptable salt thereof; and (b) preventing, improving or treating type 2 diabetes, comprising administering to an individual in need thereof an effective amount of an artesunate-based drug represented by Formula 2 or a pharmaceutically acceptable salt thereof provide a way

Additionally, the present invention relates to a preparation of a medicament for use in the prevention, improvement or treatment of type 2 diabetes mellitus, (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) it provides the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by Formula 2 above.

The artesunate-based drug is artesunate represented by Formula 3 below, artemisinin represented by Formula 4 below, and dihydroartemisinin represented by Formula 5 below. , may be an artemeter represented by the following formula (6) or an artemotil represented by the following formula (7):

[Formula 3]

,

,

[Formula 4]

,

,

[Formula 5]

,

,

[Formula 6]

,

,

[Formula 7]

.

.

The concentration ratio of the amodiaquine and the artesunate-based drug may be 10:1 to 1:10.

The prevention or treatment of type 2 diabetes may be through improvement of insulin resistance and promotion of glucose absorption.

In another aspect, the present invention provides (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) it provides a pharmaceutical composition for improving insulin resistance containing an artesunate-based drug represented by Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention is (a) amodiaquine (amodiaquine) represented by the formula (1) or a pharmaceutically acceptable salt thereof; And (b) provides a method for improving insulin resistance, comprising administering to an individual in need thereof an effective amount of an artesunate-based drug represented by Formula 2 or a pharmaceutically acceptable salt thereof.

In addition, the present invention relates to a preparation of a medicament for use in improving insulin resistance, comprising: (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) it provides the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by Formula 2 above.

The artesunate-based drug is artesunate represented by Formula 3, artemisinin represented by Formula 4, and dihydroartemisinin represented by Formula 5. , may be an artemeter represented by Formula 6 or Artemotil represented by Formula 7 above.

The concentration ratio of the amodiaquine and the artesunate-based drug may be 10:1 to 1:10.

The amodiaquine and the artesunate-based drug may be administered to a patient suffering from a metabolic syndrome-related disease.

The metabolic syndrome-related diseases are obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, non-alcoholic fatty liver, alcoholic fatty liver, non-viral chronic hepatitis, cirrhosis, chronic liver disease And it may be at least one selected from the group consisting of liver cancer.

In another aspect, the present invention provides (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) provides a pharmaceutical composition for preventing, improving, or treating metabolic syndrome-related diseases, comprising an artesunate-based drug represented by Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention is (a) amodiaquine (amodiaquine) represented by the formula (1) or a pharmaceutically acceptable salt thereof; and (b) preventing, improving or treating metabolic syndrome-related diseases, comprising administering to an individual in need thereof an effective amount of an artesunate-based drug represented by Formula 2 or a pharmaceutically acceptable salt thereof provide a way

In addition, the present invention relates to the preparation of a medicament for use in the prevention, improvement or treatment of metabolic syndrome-related diseases, (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) it provides the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by Formula 2 above.

The artesunate-based drug is artesunate represented by Formula 3, artemisinin represented by Formula 4, and dihydroartemisinin represented by Formula 5. , may be an artemeter represented by Formula 6 or Artemotil represented by Formula 7 above.

The concentration ratio of the amodiaquine and the artesunate-based drug may be 10:1 to 1:10.

The metabolic syndrome-related diseases are obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, non-alcoholic fatty liver, alcoholic fatty liver, non-viral chronic hepatitis, cirrhosis, chronic liver disease And it may be at least one selected from the group consisting of liver cancer.

The pharmaceutical composition according to the present invention comprises (a) amodiaquine or a pharmaceutically acceptable salt thereof; and (b) an artesunate-based drug or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the amodiaquine can activate both PPAR-γ and PPAR-α, and the artesunate Nate-based drugs can activate SIRT-1. Therefore, when using the amodiaquine and artesunate-based drug as a combination formulation, compared to the case of a single formulation, it shows a great synergistic effect in improving insulin resistance and promoting glucose absorption, so it is useful for preventing, improving or treating type 2 diabetes. It is expected to be useful. In addition, through the effect of improving insulin resistance, it can be effectively used in the prevention, improvement or treatment of metabolic syndrome-related diseases such as obesity, hyperlipidemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, and liver disease.

1A and 1B are graphs confirming whether cytotoxicity to amodiaquine and artesunate in a mouse-derived muscle cell C2C12 myotube cell line, respectively.

2 is a graph confirming whether a combination formulation of amodiaquine and artesunate has an effect on improving insulin resistance in a C2C12 myotube cell line, which is a mouse-derived muscle cell in an insulin resistance state induced by palmitic acid. .

Figure 3a shows the glucose uptake promoting effect when the concentration ratio of amodiaquine and artesunate in a C2C12 myotube cell line, a mouse-derived muscle cell induced by palmitic acid, is 1:1. It is a graph that confirms whether or not

Figure 3b shows the glucose uptake promoting effect when the concentration ratio of amodiaquine and artesunate is 2:1 in the C2C12 myotube cell line, which is a mouse-derived muscle cell in an insulin-resistant state induced by palmitic acid. It is a graph that confirms whether or not

4 shows a group treated with amodiaquine and artesunate in various concentration ratios and amodiaquine and rosiglitazone in a C2C12 myotube cell line, which is a mouse-derived muscle cell in an insulin-resistant state induced by palmitic acid. It is a graph comparing the insulin resistance improvement effect of the group treated with the concentration ratio.

The present inventors have prepared amodiaquine or a pharmaceutically acceptable salt thereof capable of activating both PPAR-α and PPAR-γ, an artesunate-based drug capable of activating SIRT-1 or a pharmaceutically acceptable salt thereof. In the case of the mixed formulation, compared to the case of the single formulation, it showed a great synergistic effect in improving insulin resistance and promoting glucose absorption, confirming that it can effectively prevent or treat type 2 diabetes, and completed the present invention.

Specifically, in the Example of the present invention, it was confirmed that there was no cytotoxicity to amodiaquine and artesunate in muscle cells (see Example 1), and in muscle cells in insulin resistance induced by palmitic acid It was confirmed that the combination formulation of amodiaquine and artesunate had an effect on improving insulin resistance (refer to Example 2), and the combination formulation of amodiaquine and artesunate in muscle cells in a state of insulin resistance induced by palmitic acid It was confirmed that I had an effect on promoting glucose absorption (see Example 3).

As a result, it was confirmed that when the combination formulation of amodiaquine and artesunate was treated, it showed a great synergistic effect in improving insulin resistance and promoting glucose absorption, compared to the case where the single formulation was treated.

Accordingly, the present invention is (a) amodiaquine (amodiaquine) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And (b) provides a pharmaceutical composition for preventing or treating type 2 diabetes containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by the following formula (2) as an active ingredient:

[Formula 1]

,

,

[Formula 2]

,

,

이다. In Formula 2, R is a ketone group, a hydroxyl group, a C1 to C6 alkoxy group, or

am.

At the same time, as a side effect according to PPAR-γ activation, preventing or treating at least one selected from the group consisting of obesity, dyslipidemia, cardiovascular disease and fatty liver in response to PPAR-α (Peroxisome proliferator-activated receptor-alpha) activation it may be for In this case, the dyslipidemia may be at least one selected from the group consisting of hyperlipidemia, hypertriglyceridemia, and hypercholesterolemia.

First, the amodiaquine or a pharmaceutically acceptable salt thereof is capable of activating both PPAR-α and PPAR-γ, and even when used as a single agent, it responds to PPAR-γ (Peroxisome proliferator-activated receptor-gamma) activation. can prevent or treat type 2 diabetes, and at the same time, as a side effect of PPAR-γ activation, obesity, dyslipidemia, cardiovascular disease and fatty liver in response to PPAR-α (Peroxisome proliferator-activated receptor-alpha) activation One or more selected from the group consisting of can be prevented or treated.

Next, the artesunate-based drug or a pharmaceutically acceptable salt thereof is capable of activating SIRT-1. Specifically, the artesunate-based drug is artesunate represented by the following Chemical Formula 3 , artemisinin represented by the following formula 4, dihydroartemisinin represented by the following formula 5, artemeter represented by the following formula 6, or artemotyl represented by the following formula 7 artemotil), preferably, but not limited to, artesunate:

[Formula 3]

,

,

[Formula 4]

,

,

[Formula 5]

,

,

[Formula 6]

,

,

[Formula 7]

.

.

However, when amodiaquine or a pharmaceutically acceptable salt thereof is used as a single agent, or when an artesunate-based drug or a pharmaceutically acceptable salt thereof is used as a single agent, the effects of improving insulin resistance and promoting glucose absorption are insignificant. just a level However, in the case of a combination formulation for these, it shows a great synergistic effect in improving insulin resistance and promoting glucose absorption.

The concentration ratio of the amodiaquine and the artesunate-based drug may be 10:1 to 1:10, preferably 2:1 to 1:2, but is not limited thereto. At this time, when the concentration ratio of amodiaquine becomes too small, there is a problem in that PPAR-γ and PPAR-α cannot be sufficiently activated, and therefore there is a problem of generating side effects according to PPAR-γ activation, and the artesunate drug When the concentration ratio becomes too small, there is a problem in that SIRT-1 cannot be sufficiently activated.

In addition, the concentration of amodiaquine and artesunate drug in the composition may be 1 μM to 25 μM, respectively, the concentration of amodiaquine in the composition is 1 μM to 25 μM, and artesunate-based drug in the composition The concentration of the drug is preferably 1 μM to 12.5 μM, but is not limited thereto. At this time, when the concentration of amodiaquine and artesunate-based drug in the composition is too high, a problem occurs due to cytotoxicity.

As used herein, the term “treatment” refers to any action in which the symptoms of diabetes are improved or changed to advantage by administration of the pharmaceutical composition according to the present invention.

Accordingly, it may further include suitable carriers, excipients, and diluents commonly used for preparing the pharmaceutical composition. In addition, according to a conventional method, it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions.

Carriers, excipients, and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. When formulating the composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.

The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like. In addition, it may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. As other pharmaceutically acceptable carriers, reference may be made to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The pharmaceutical composition of the present invention may be administered to mammals including humans by any method. For example, it may be administered orally or parenterally, and parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal. , intranasal, enteral, topical, sublingual or rectal administration.

The pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the administration route as described above. When formulated, one or more buffers (eg, saline or PBS), carbohydrates (eg, glucose, mannose, sucrose, or dextran, etc.), antioxidants, bacteriostats, chelating agents (eg, EDTA) or glutathione), fillers, bulking agents, binders, adjuvants (eg aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrating or surfactants, diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, liquids, gels, syrups, slurries, suspensions or capsules, etc., and these solid preparations include at least one excipient in the pharmaceutical composition of the present invention, for example , Starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose , methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropylmethyl-cellulose or gelatin may be mixed and prepared. For example, tablets or dragees can be obtained by blending the active ingredient with solid excipients, grinding them, adding suitable adjuvants, and processing them into a mixture of granules.

In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, or syrups. In addition to water or liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, flavoring agents, or preservatives may be included. .

In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, and an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, and a preservative may be additionally included. .

When administered parenterally, the pharmaceutical composition of the present invention may be formulated according to methods known in the art in the form of injections, transdermal administrations and nasal inhalants together with suitable parenteral carriers. In the case of the injection, it must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. For injection, examples of suitable carriers include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof, and/or a solvent or dispersion medium containing vegetable oil. can More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc. can be used. In order to protect the injection from microbial contamination, it may further include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, in most cases, the injection may further contain an isotonic agent such as sugar or sodium chloride.

In the case of transdermal administration, forms such as ointment, cream, lotion, gel, external solution, pasta, liniment, and air are included. In the above, 'transdermal administration' means that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin by topically administering the pharmaceutical composition to the skin.

In the case of administration by inhalation, the compounds for use according to the invention may be administered in pressurized packs or using a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from the nebulizer. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. For example, gelatin capsules and cartridges for use in inhalers or insufflators may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a recipe commonly known to all pharmaceutical chemistry.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to drug, administration time, administration route and excretion rate, duration of treatment, factors including concurrent drugs, and other factors well known in the medical field.

The pharmaceutical composition according to the present invention may be administered simultaneously (simultaneous), separately (separate), or sequentially (sequential), preferably single or multiple administration, in order to enhance the therapeutic effect. . In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art. Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, inactivation rate and excretion rate, disease type, and drugs used in combination.

The pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration can be envisaged, for example, by oral administration, intranasal administration, bronchial administration, arterial injection, intravenous injection, subcutaneous injection, intramuscular injection, or intraperitoneal injection. The daily dose is about 0.0001 mg/kg to 100 mg/kg, preferably 8 mg/kg to 20 mg/kg, and it is preferable to administer it once or several times a day, but is not limited thereto. When the daily dose of the pharmaceutical composition is maintained at 8 mg/kg to 20 mg/kg, both PPAR-γ and PPAR-α and SIRT-1 can be activated, and problems due to cytotoxicity can be minimized. have an advantage

The dosage of the pharmaceutical composition of the present invention is determined according to the type of drug as the active ingredient, together with several related factors such as the disease to be treated, the route of administration, the patient's age, sex, weight, and the severity of the disease. Considering this point, those of ordinary skill in the art will be able to determine an appropriate effective dosage for the pharmaceutical composition of the present invention according to a specific use for preventing, improving or treating type 2 diabetes. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited.

The total effective amount of the pharmaceutical composition of the present invention may be administered to a patient as a single dose, or may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time.

On the other hand, the present invention is (a) amodiaquine (amodiaquine) represented by the formula (1) or a pharmaceutically acceptable salt thereof; and (b) preventing or improving type 2 diabetes, comprising administering an effective amount of an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by Formula 2 to an individual in need thereof in an effective amount or a method of treatment.

At the same time, as a side effect of PPAR-γ activation, one or more selected from the group consisting of obesity, dyslipidemia, cardiovascular disease and fatty liver in response to PPAR-α (Peroxisome proliferator-activated receptor-alpha) activation is prevented and improved Or it can be treated.

In the present invention, "individual" means a subject in need of treatment for a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses, cattle, etc. means the mammals of

In the method for preventing, improving or treating type 2 diabetes of the present invention, amodiaquine and artesunate-based drugs provide a desirable prevention, improvement or treatment effect for type 2 diabetes when administered in an effective amount can do. As used herein, the term “effective amount” refers to an amount that exhibits a higher response than a negative control, and preferably has the same meaning as the aforementioned “pharmaceutically effective amount”. For a desirable effect, the pharmaceutical composition of the present invention may be administered once or repeatedly several times at regular time intervals. In this case, the amodiaquine and the artesunate-based drug may be administered simultaneously (simultaneous), separately (separate), or sequentially (sequential). In addition, it may be used in combination with other methods for preventing, improving or treating type 2 diabetes.

Furthermore, the present invention relates to a preparation of a medicament for preventing, improving or treating type 2 diabetes mellitus, (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) it provides the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by Formula 2 above. At the same time, as a side effect of PPAR-γ activation, one or more selected from the group consisting of obesity, dyslipidemia, cardiovascular disease and fatty liver in response to PPAR-α (Peroxisome proliferator-activated receptor-alpha) activation is prevented and improved or for use in the manufacture of a medicament for treatment.

In another aspect, the present invention is (a) amodiaquine (amodiaquine) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And (b) provides a pharmaceutical composition for improving insulin resistance containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by the following formula (2) as an active ingredient:

[Formula 1]

,

,

[Formula 2]

,

,

이다.In Formula 2, R is a ketone group, a hydroxyl group, a C1 to C6 alkoxy group, or

am.

In addition, the present invention provides (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) provides a method for improving insulin resistance, comprising administering to an individual in need thereof an effective amount of an artesunate-based drug represented by Formula 2 or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention relates to a preparation of a medicament for use in improving insulin resistance, comprising: (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) provides the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by Formula 2 above.

The artesunate-based drug is artesunate represented by the formula 3, artemisinin represented by the formula 4, dihydroartemisinin represented by the formula 5, and the formula It may be an artemeter represented by 6 or an artemotil represented by Formula 7, preferably artesunate, but is not limited thereto.

In diabetes mellitus related to obesity and high-fat diet, which accounts for most of type 2 diabetes, insulin resistance is generally considered to be the primary cause. In addition, insulin resistance is the most important antecedent of type 2 diabetes because it suppresses the rise of blood sugar and increases the risk of other cardiovascular diseases by suppressing the rise of blood sugar even in a state of impaired glucose tolerance in which insulin secretion is compensated for insulin resistance. It is thought to be a factor and a key factor in the occurrence of metabolic syndrome. Metabolic syndrome is a concept that does not think of each disease as a single disease, but as a group of diseases that can be caused by a common cause. It is not easy to explain the etiology of the syndrome with one factor. However, insulin resistance is most commonly found among the components of metabolic syndrome, and has a close mechanistic correlation with the occurrence of most other factors, suggesting that it is a fundamental cause of metabolic syndrome along with obesity.

In an example of the present invention, it was confirmed that a combination formulation of amodiaquine and artesunate in muscle cells in a state of insulin resistance induced by palmitic acid had an effect on improving insulin resistance (refer to Example 2), particularly Amodia In the case of treatment with the combination formulation of quin and artesunate, it was confirmed that a large synergistic effect was shown in the improvement of insulin resistance, compared to the case of treatment with the single agent. For the purpose of improving the pharmaceutical composition of the present invention can be used.

The metabolic syndrome-related disease may be any one or more selected from the group consisting of obesity, dyslipidemia, cardiovascular disease, and liver disease. For example, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, nonalcoholic fatty liver, alcoholic fatty liver, nonviral chronic hepatitis, cirrhosis, chronic liver disease, liver cancer and the like, but is not limited thereto.

In the pharmaceutical composition, method and use related to the improvement of insulin resistance of the present invention, the description of the composition and effect of the amodiaquine and the artesunate-based drug is the same as described above, so the description omit

In the pharmaceutical composition, method and use related to the improvement of insulin resistance of the present invention, the pharmaceutical composition or its active ingredient amodiaquine and artesunate-based drug concentration, ratio, dosage, The description of various embodiments for carrying out the present invention, including the route of administration, administration method, etc., is the same as that described in the prevention, improvement or treatment of type 2 diabetes, and thus description thereof will be omitted.

In another aspect, the present invention is (a) amodiaquine (amodiaquine) represented by the following formula (1) or a pharmaceutically acceptable salt thereof; And (b) provides a pharmaceutical composition for preventing, improving, or treating metabolic syndrome-related diseases containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by the following formula (2) as an active ingredient:

[Formula 1]

,

,

[Formula 2]

,

,

이다.In Formula 2, R is a ketone group, a hydroxyl group, a C1 to C6 alkoxy group, or

am.

In addition, the present invention provides (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; and (b) preventing, improving or treating metabolic syndrome-related diseases, comprising administering to an individual in need thereof an effective amount of an artesunate-based drug represented by Formula 2 or a pharmaceutically acceptable salt thereof provide a way

Furthermore, the present invention relates to the preparation of a medicament for use in the prevention, improvement or treatment of metabolic syndrome-related diseases, (a) amodiaquine represented by Formula 1 or a pharmaceutically acceptable salt thereof; And (b) it provides the use of a composition containing an artesunate-based drug or a pharmaceutically acceptable salt thereof represented by Formula 2 above.

The artesunate-based drug is artesunate represented by the formula 3, artemisinin represented by the formula 4, dihydroartemisinin represented by the formula 5, and the formula It may be an artemeter represented by 6 or an artemotil represented by Formula 7, preferably artesunate, but is not limited thereto.

The metabolic syndrome-related disease may be any one or more selected from the group consisting of obesity, dyslipidemia, cardiovascular disease, and liver disease. For example, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, nonalcoholic fatty liver, alcoholic fatty liver, nonviral chronic hepatitis, cirrhosis, chronic liver disease, liver cancer and the like, but is not limited thereto.

In the pharmaceutical composition, method and use for the prevention, improvement or treatment of metabolic syndrome-related diseases of the present invention, the description of the composition and effect of the amodiaquine and the artesunate-based drug is described above. Since it is the same as described above, the description thereof is omitted.

In the pharmaceutical composition, method and use for the prevention, improvement or treatment of metabolic syndrome-related diseases of the present invention, the pharmaceutical composition or its active ingredient, amodiaquine and artesunate-based drug The description of various embodiments for carrying out the present invention, including concentration, ratio, dosage, administration route, administration method, etc., is the same as that described in the prevention, improvement or treatment of type 2 diabetes, and thus description thereof will be omitted. .

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Amodiaquine, artesunate, insulin, and palmitic acid (PA) for inducing insulin resistance of the C2C12 myotube cell line used in the Examples below were purchased from Sigma Aldrich.

Meanwhile, the C2C12 myoblast cell line was cultured in DMEM medium (Hyclone) containing 10% fetal bovine serum (FBS) (Hyclone). When the cell density reached about 80-90%, the C2C12 myoblast cell line was replaced with DMEM medium (Hyclone) containing 2% horse serum (Gibco) once every 48 hours for 6 days. Complete differentiation was achieved by inducing cell differentiation into a myotube cell line.

Example 1. Confirmation of cytotoxicity to artesunate and amodiaquine in muscle cells

In order to confirm the concentration exhibiting cytotoxicity to artesunate and amodiaquine in the C2C12 myoblast cell line, a cell activity experiment using the Cell Count Kit-8 (CCK8) kit (Dojindo) was performed. Incubated in DMEM medium containing 10% FBS in 96-well plates. When the cell density reached about 80-90%, it was substituted with DMEM medium containing no serum and treated with artesunate and amodiaquine by concentration.

As a result, as shown in FIG. 1a , amodiaquine exhibited about 80% activity up to 25 μM, and as shown in FIG. 1b , artesunate exhibited about 80% activity up to 12.5 μM. Therefore, it can be seen that the optimal concentration of amodiaquine in the composition is 25 μM or less, and the optimal concentration of artesunate is 12.5 μM.

Example 2. Confirmation of whether a combination formulation of artesunate and amodiaquine has an effect on improving insulin resistance in muscle cells in a state of insulin resistance induced by palmitic acid (measurement of Akt phosphorylation)

A fully differentiated C2C12 myotube cell line was treated with DMEM medium containing 250 mM palmitic acid, amodiaquine at a concentration of 5 and 10 μM, and artesunate at a concentration of 5 and 10 μM individually or in combination for 16 hours. did. Thereafter, 100 nM insulin was treated for 15 minutes, and the degree of Akt phosphorylation was confirmed by western blotting. In this case, the antibody was purchased from Cell signaling.

As a result, as shown in FIG. 2 , compared to the group treated with amodiaquine and artesunate, the degree of Akt phosphorylation was significantly increased in the group treated with amodiaquine and artesunate in combination. Therefore, it can be seen that the combined formulation of amodiaquine and artesunate has the effect of significantly improving insulin resistance in muscle cells.

Example 3. Confirmation of whether a combination drug of artesunate and amodiaquine has an effect on promoting glucose absorption in muscle cells in a state of insulin resistance induced by palmitic acid

A fully differentiated C2C12 myotube cell line was treated with DMEM medium containing 250 mM palmitic acid, amodiaquine at a concentration of 10 μM and artesunate at a concentration of 5 and 10 μM each or in combination for 16 hours. Thereafter, it was substituted with a DMEM medium without glucose and treated with amodiaquine at a concentration of 10 μM and artesunate at a concentration of 5 and 10 μM for 4 hours. After that, 100nM insulin and 200μg/mL 2-NBDG were treated together for 30 minutes, washed twice with PBS, and then 100μL of the assay buffer provided by the glucose uptake cell-based assay kit (Cayman) was added and 485/535nm ( exitation/emission).

As a result, as shown in FIGS. 3A and 3B , the glucose absorption level was significantly increased in the group treated with amodiaquine and artesunate at the same concentration as compared to the group treated with amodiaquine and artesunate, respectively. . Therefore, it can be seen that the combined treatment of amodiaquine and artesunate has the effect of promoting glucose absorption into the muscle cells.

Example 4. Comparative confirmation of whether the combination of amodiaquine and artesunate has an effect on improving insulin resistance compared to the combination of amodiaquine and rosiglitazone (measurement of Akt phosphorylation)

Fully differentiated C2C12 myotube cells were treated with amodiaquine (5 and 10 μM, respectively) and artesunate (5 and 10 μM, respectively) or rosiglitazone (5 and 10 μM, respectively) with DMEM medium containing 500 mM palmitic acid. were treated in combination for hours. Thereafter, 100 nM insulin was treated for 10 minutes, and the phosphorylation level of Akt was confirmed by western blotting.

As a result, as shown in FIG. 4 , the group treated with amodiaquine 5 μM and artesunate 10 μM had a higher degree of phosphorylation of Akt compared to the group treated with amodiaquin 5 μM and rosiglitazone (5 μM and 10 μM, respectively). increased. In addition, the group treated with amodiaquine 10 μM and artesunate (5 and 10 μM, respectively) further increased the phosphorylation of Akt compared to the group treated with amodiaquin 10 μM and rosiglitazone (5 μM and 10 μM, respectively). Therefore, it can be seen that the combination of amodiaquine and artesunate is more effective in improving insulin resistance than the combination of amodiaquine and rosiglitazone.

The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (13)

(a) amodiaquine represented by the following formula (1) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutical composition for preventing, improving or treating type 2 diabetes containing an artesunate-based drug represented by the following formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

, [Formula 2]

, In Formula 2, R is a ketone group, a hydroxyl group, a C1 to C6 alkoxy group, or

am. According to claim 1, The artesunate-based drug is artesunate represented by Formula 3 below, artemisinin represented by Formula 4 below, and dihydroartemisinin represented by Formula 5 below. , A pharmaceutical composition for preventing, improving or treating type 2 diabetes, which is an artemeter represented by Formula 6 or an artemotil represented by Formula 7: [Formula 3]

, [Formula 4]

, [Formula 5]

, [Formula 6]

, [Formula 7]

. According to claim 1, A pharmaceutical composition for preventing, improving or treating type 2 diabetes, wherein the concentration ratio of the amodiaquine and the artesunate-based drug is 10:1 to 1:10. According to claim 1, The prevention or treatment of type 2 diabetes is through improvement of insulin resistance and promotion of glucose absorption, a pharmaceutical composition for preventing, improving or treating type 2 diabetes. (a) amodiaquine represented by the following formula (1) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutical composition for improving insulin resistance containing an artesunate-based drug represented by the following formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

, [Formula 2]

, In Formula 2, R is a ketone group, a hydroxyl group, a C1 to C6 alkoxy group, or

am. 6. The method of claim 5, The artesunate-based drug is artesunate represented by Formula 3 below, artemisinin represented by Formula 4 below, and dihydroartemisinin represented by Formula 5 below. , which is an artemeter represented by Formula 6 or Artemotil represented by Formula 7, a pharmaceutical composition for improving insulin resistance: [Formula 3]

, [Formula 4]

, [Formula 5]

, [Formula 6]

, [Formula 7]

. 6. The method of claim 5, A pharmaceutical composition for improving insulin resistance, wherein the concentration ratio of the amodiaquine and the artesunate-based drug is 10:1 to 1:10. 6. The method of claim 5, A pharmaceutical composition for improving insulin resistance, which is administered to a patient suffering from a metabolic syndrome-related disease. 9. The method of claim 8, The metabolic syndrome-related diseases are obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, nonalcoholic fatty liver, alcoholic fatty liver, nonviral chronic hepatitis, cirrhosis, chronic liver disease And at least one selected from the group consisting of liver cancer, a pharmaceutical composition for improving insulin resistance. (a) amodiaquine represented by the following formula (1) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutical composition for preventing, improving or treating metabolic syndrome-related diseases containing an artesunate-based drug represented by the following Chemical Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

, [Formula 2]

, In Formula 2, R is a ketone group, a hydroxyl group, a C1 to C6 alkoxy group, or

am. 11. The method of claim 10, The artesunate-based drug is artesunate represented by Formula 3 below, artemisinin represented by Formula 4 below, and dihydroartemisinin represented by Formula 5 below. , A pharmaceutical composition for preventing, improving or treating metabolic syndrome-related diseases, which is an artemeter represented by Formula 6 or an artemotil represented by Formula 7: [Formula 3]

, [Formula 4]

, [Formula 5]

, [Formula 6]

, [Formula 7]

. 11. The method of claim 10, The concentration ratio of the amodiaquine and the artesunate-based drug is 10:1 to 1:10, a pharmaceutical composition for preventing, improving or treating metabolic syndrome-related diseases. 11. The method of claim 10, The metabolic syndrome-related diseases are obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, hyperinsulinemia, diabetes, nonalcoholic fatty liver, alcoholic fatty liver, nonviral chronic hepatitis, cirrhosis, chronic liver disease And one or more selected from the group consisting of liver cancer, metabolic syndrome-related disease prevention, improvement or treatment pharmaceutical composition.

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