Composition for prevention, alleviation, or treatment of diabetes and related diseases

Abstract

A compound provided in the present invention, when administered, even solely by oral administration, may enable prevention, alleviation, or treatment of diabetes or various diseases related to diabetes.

Description

Composition for preventing, improving or treating diabetes and related diseases

[0001] The present invention relates to a composition for various uses that can prevent, improve or treat diabetes and related diseases.

[0002] Diabetes is a condition in which the body does not produce the amount of insulin, a hormone that regulates sugar (glucose) secreted by the beta cells of the pancreas, required by the body, or the insulin does not work properly in the cells, so that the glucose in the blood is not used for energy but builds up in the blood, causing high blood sugar levels and sugar to be detected in the urine. In general, diabetes is divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes) depending on whether insulin is essential for treatment. Type 2 diabetes is non-insulin-dependent diabetes, and it develops when insulin action is insufficient due to insulin resistance or when there is a relative shortage of insulin. 90% of all diabetes patients are type 2 diabetes, and it is also called adult-onset diabetes because it mainly develops in people in their 30s or older.

[0003] Although type 2 diabetes is most commonly associated with hyperglycemia and insulin resistance, other diseases, conditions, symptoms, and complications associated with type 2 diabetes include diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and increased cancer risk.

[0004] Due to the progressive nature of type 2 diabetes, many patients ultimately require oral hypoglycemic agents in addition to insulin and / or exenatide injections. Currently known oral treatments for type 2 diabetes can be broadly categorized into four groups: sulfonylureas, which induce insulin secretion; biguanides, which promote the transport of sugar into muscle cells and inhibit glucose synthesis in the liver; alpha-glucosidase inhibitors, which inhibit the enzyme that produces glucose in the small intestine; and thiazolidinediones (TZDs), which activate peroxisome proliferator-activated receptors (PPAR-γ), which are involved in adipocyte differentiation. However, these oral hypoglycemic drugs carry numerous side effects, including nephrotoxicity (biguanides), lactic acidosis (biguanides), and diarrhea and stomach upset (alpha-glucosidase inhibitors). Long-term use also significantly reduces their effectiveness. Therefore, alternative and improved medications are urgently needed to treat diabetes and related conditions.

[0005] One object of the present invention is to provide a composition for preventing, improving or treating diabetes and related diseases caused by it, which comprises a compound according to the present invention as an active ingredient.

[0006] Another object of the present invention is to provide a composition for preventing, improving or treating obesity or overweight, comprising the compound according to the present invention as an active ingredient.

[0007] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0008] Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, various specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and configurations. In other instances, well-known processes and manufacturing techniques have not been described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0009] Unless otherwise specifically defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0010]

[0011] According to one embodiment of the present invention, the present invention relates to a composition for preventing, improving or treating diabetes or a related disease, comprising as an active ingredient a compound selected from the group consisting of a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof:

[0012] [Chemical Formula 1]

[0013]

[0014] In the above chemical formula 1,

[0015] At least one of R1 and R2 is -C(=O)R9, and the others are H or C1~C6 alkyl groups;

[0016] R3 to R6 are each independently H or a C1~C6 alkyl group;

[0017] At least one of R7 and R8 is -C(=O)R 10 and the remainder is H or C1~C6 alkyl group;

[0018] R9 and R 10 are each independently a C1~C6 alkyl group.

[0019] In the present invention, unless otherwise specified, the term 'C1~C6 alkyl' means a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, etc.

[0020] In one example of the present invention, the compound may be a compound represented by the following chemical formula 2, but is not limited thereto:

[0021] [Chemical Formula 2]

[0022]

[0023] In the above chemical formula 2,

[0024] The definitions of R1, R2, R7 and R8 are as defined in the chemical formula 1 above.

[0025] In one example of the present invention, the compound may be a compound represented by the following chemical formula 3, but is not limited thereto:

[0026] [Chemical Formula 3]

[0027]

[0028] In the present invention, the pharmaceutically acceptable salt is a salt generally considered by those skilled in the art to be suitable for medical applications (e.g., because such salt is not harmful to a subject to be treated with said salt), or a salt that causes acceptable side effects within the respective treatment. Typically, the pharmaceutically acceptable salt is a salt considered acceptable by a regulatory authority such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Ministry of Health, Labour and Welfare of Japan. However, the present invention also includes salts of the compounds of the present invention that are not pharmaceutically acceptable in themselves, for example, as intermediates in the preparation of the compounds of the present invention or physiologically functional derivatives thereof, or as intermediates in the preparation of pharmaceutically acceptable salts of the compounds of the present invention or physiologically functional derivatives thereof. The salts include water-insoluble salts, and in particular, water-soluble salts.

[0029] In each case, a person skilled in the art can readily determine whether a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming a salt, i.e. whether the compound according to the invention or a physiologically functional derivative thereof has a group capable of carrying a charge, such as, for example, an amino group, a carboxylic acid group, etc.

[0030] Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmacy, which are water-insoluble or particularly water-soluble acid addition salts. Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable. Acid addition salts can be formed, for example, by mixing a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Similarly, pharmaceutically acceptable base addition salts include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates).Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide, Including but not limited to 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, valerate, etc.

[0031] Salts which are not pharmaceutically acceptable in the present invention and which can be obtained, for example, as process products during the production of the compounds according to the present invention on an industrial scale, are also included in the present invention and, if desired, can be converted into pharmaceutically acceptable salts by methods known to those skilled in the art.

[0032] Meanwhile, the compounds according to the present invention may have an asymmetric carbon center and thus may exist as R or S isomers or racemic compounds, and all of these optical isomers and mixtures may be included in the scope of the present invention.

[0033] Specifically, in one example of the present invention, the compound may be an optical isomeric compound represented by the following chemical formula 4 or 5 or a racemic mixture thereof, but is not limited thereto:

[0034] [Chemical Formula 4]

[0035]

[0036] [Chemical Formula 5]

[0037]

[0038] In addition, the compounds of the present invention, as well as their salts, may contain varying amounts of solvent, for example when isolated in crystalline form. Accordingly, solvates, particularly hydrates, of the compounds of the present invention, as well as solvates, particularly hydrates, of salts of the compounds of the present invention, may be included within the scope of the present invention. More particularly, the present invention may include hydrates of the compounds, salts, and / or physiologically functional derivatives according to the present invention, which contain one, two, or half water molecules with respect to the stoichiometry.

[0039] In the present invention, the above "diabetes" is a symptom in which insulin, a glucose-regulating hormone secreted from beta cells of the pancreas, is not produced in the amount required by the body or insulin does not function properly in cells, so that glucose in the blood is not used as energy but accumulates in the blood, causing hyperglycemia and sugar being detected in the urine, and may include all of type 1 diabetes, type 2 diabetes, and gestational diabetes, but may preferably be type 2 diabetes.

[0040] In the present invention, the "prevention, improvement or treatment of diabetes" includes reducing, improving or eliminating all or part of the clinical symptoms and related diseases associated with diabetes, or preventing, improving or treating the disease. In the present invention, the "diabetes-related disease" may include all diseases that can be caused by diabetes, but includes, for example, insulin resistance, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, obesity, hyperinsulinemia, Bardet-Biedl syndrome, dyslipidemia, hypertension, non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease.

[0041]

[0042] According to another embodiment of the present invention, there is provided a composition for preventing, improving or treating obesity or overweight, comprising as an active ingredient a compound selected from the group consisting of a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof:

[0043] [Chemical Formula 1]

[0044]

[0045] In the above chemical formula 1,

[0046] At least one of R1 and R2 is -C(=O)R9, and the others are H or C1~C6 alkyl groups;

[0047] R3 to R6 are each independently H or a C1~C6 alkyl group;

[0048] At least one of R7 and R8 is -C(=O)R 10 and the remainder is H or C1~C6 alkyl group;

[0049] R9 and R 10 are each independently a C1~C6 alkyl group.

[0050] In one example of the present invention, the compound may be a compound represented by the following chemical formula 2, but is not limited thereto:

[0051] [Chemical Formula 2]

[0052]

[0053] In the above chemical formula 2,

[0054] The definitions of R1, R2, R7 and R8 are as defined in the chemical formula 1 above.

[0055] In one example of the present invention, the compound may be a compound represented by the following chemical formula 3, but is not limited thereto:

[0056] [Chemical Formula 3]

[0057]

[0058] In one example of the present invention, the compound may be an optical isomeric compound represented by the following chemical formula 4 or 5 or a racemic mixture thereof, but is not limited thereto:

[0059] [Chemical Formula 4]

[0060]

[0061] [Chemical Formula 5]

[0062]

[0063] In the present invention, the term "obesity" refers to a state in which there is an excess of adipose tissue in the body, and obesity is caused by an energy imbalance when nutrients are consumed in excess of energy consumption over a long period of time. It can be caused by genetic mutations in specific genes that cause problems with the function of the appetite control center, endocrine diseases such as Cushing's syndrome, or various drugs that increase appetite, but it is generally caused by energy intake exceeding energy expenditure. In general, obesity is caused by a complex interaction of genetic and environmental influences. In particular, the modern lifestyle, which is abundant in high-calorie foods and allows people to live comfortably even with less physical activity, is causing an explosive increase in obesity.

[0064] In the composition for preventing, improving or treating obesity or overweight of the present invention, the definition of the alkyl group or the definition of salt, optical isomer, hydrate and solvate overlaps with that described above, and thus, to avoid excessive complexity of the specification, the description thereof is omitted below.

[0065] The above composition of the present invention can be used as a pharmaceutical composition or a food composition.

[0066] In the present invention, the term "prevention" may include, without limitation, any act that can block, suppress or delay symptoms caused by diabetes or diseases related thereto by using the composition of the present invention.

[0067] In the present invention, the term "treatment" may include, without limitation, any act that can improve or benefit symptoms caused by diabetes or diseases related thereto by using the composition of the present invention.

[0068] In the present invention, the term "improvement" may include, without limitation, any act in which symptoms caused by diabetes or diseases related thereto are improved or beneficially changed by using the composition of the present invention.

[0069] The pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injection solutions, according to conventional methods, but is not limited thereto. Preferably, the pharmaceutical composition may be formulated for intravenous administration or inhalation; or for use as an injection, but is not limited thereto.

[0070] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a fragrance, etc. for oral administration. In the case of injections, a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc. may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative, etc. may be used. The dosage form of the pharmaceutical composition of the present invention may be prepared in various ways by mixing it with the pharmaceutically acceptable carrier described above. For example, the composition may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. for oral administration. In the case of injections, the composition may be prepared in the form of unit dose ampoules or multiple doses. In addition, the composition may be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, etc.

[0071] Examples of carriers, excipients, and diluents suitable for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0072] The routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal. It can be administered orally or parenterally, and is preferably administered orally, but is not limited thereto.

[0073] The parenteral route of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0074] The pharmaceutical composition of the present invention may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, sex, dosage form, administration time, administration route, excretion rate, drug combination, and severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, form of medicine, administration route, and period, but may be appropriately selected by those skilled in the art, and may be administered at 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several times. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, a sugar-coated tablet, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.

[0075] When the food composition of the present invention is manufactured in the form of a beverage, there are no special limitations other than including the food composition in the indicated ratio, and various flavoring agents or natural carbohydrates, etc. may be contained as additional ingredients like a typical beverage. Specifically, the natural carbohydrates may include monosaccharides such as glucose, disaccharides such as fructose, sucrose, and other polysaccharides, dextrin, cyclodextrin, and other typical sugars, and sugar alcohols such as xylitol, sorbitol, and erythritol. The flavoring agents may include natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.).

[0076] The food composition of the present invention may further include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0077] The ingredients included in the food composition of the present invention may be used independently or in combination. The proportion of the additives is not a key element of the present invention, but may be selected within the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

[0078]

[0079] According to another embodiment of the present invention, there is provided a method for preventing, improving or treating diabetes or a related disease thereof, comprising administering a pharmaceutically effective amount of a composition of the present invention to a subject in need of administration.

[0080] In the present invention, the subject is an individual who has developed diabetes or a related disease thereof or is suspected of developing the same, and the subject suspected of developing the disease means all animals including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs that have developed or can develop the disease, but an individual that can be treated with the effective substance provided in the present invention is included without limitation.

[0081]

[0082] According to another embodiment of the present invention, there is provided a method for preventing, improving or treating obesity or overweight, comprising administering a pharmaceutically effective amount of a composition of the present invention to a subject in need of administration.

[0083] In the present invention, the subject is an subject that has developed or is suspected of developing obesity or overweight, and the subject suspected of developing the disease means all animals including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs that have developed or may develop the disease, but subjects that can be treated with the effective substance provided in the present invention are included without limitation.

[0084] In the present invention, the term "pharmaceutically effective amount" is an amount sufficient to stop or alleviate the physiological effects of a subject or patient caused by the disease. An appropriate effective amount may be determined by a treating physician within the scope of sound medical judgment, and may be administered once or in several divided doses. However, for the purpose of the present invention, it is preferable to apply a specific therapeutically effective amount for a specific patient differently depending on various factors such as the type and degree of the response to be achieved, whether other agents are used in some cases, the composition containing the specific effective ingredient, the patient's age, weight, general health condition, sex, and diet, the time of administration, route of administration, number of administrations, and secretion rate of the composition containing the effective ingredient, the treatment period, drugs used together or concurrently with the specific composition, and similar factors well known in the medical field.

[0085] The total effective amount of the composition of the present invention can be administered to a patient as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The composition of the present invention may vary in the content of the active ingredient depending on the severity of the disease. Specifically, a preferred total dose of the composition of the present invention may be about 0.0001 mg to 500 mg per kg of patient body weight per day. However, since the dosage of the composition is determined by taking into consideration various factors such as the route of administration of the pharmaceutical composition and the number of treatments, as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate, a person having ordinary skill in the art will be able to determine an appropriate effective dosage for a specific use of the composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, route of administration, or method of administration, as long as it exhibits the effects of the present invention.

[0086] In addition, the method for preventing, improving or treating diabetes or a related disease thereof, or obesity or overweight in the present invention may be a combination therapy further comprising administering a compound or substance having therapeutic activity against one or more diseases.

[0087] In the present invention, the term "combination" should be understood to refer to simultaneous, separate, or sequential administration. If the administration is sequential or separate, the interval between administrations of the secondary components should be such that the beneficial effects of the combination are not lost.

[0088] When administering a composition according to the present invention, diabetes can be effectively prevented, improved or treated, and further, diseases related to diabetes, including obesity and overweight, can also be prevented, improved or treated.

[0089] Figure 1 is a graph showing the results of confirming changes in blood sugar levels after orally administering a compound (α,δ-NAG) according to the present invention to a type 2 diabetes-induced mouse model for 12 weeks in Experimental Example 1.

[0090] Figure 2 is a graph showing the results of confirming the change in the content of glycated hemoglobin after orally administering the compound (α,δ-NAG) according to the present invention to a type 2 diabetes-induced mouse model for 12 weeks in Experimental Example 2.

[0091] Figure 3 is a graph showing the results of confirming the change in body weight after orally administering the compound (α,δ-NAG) according to the present invention to a type 2 diabetes-induced mouse model for 12 weeks in Experimental Example 3.

[0092] According to one embodiment of the present invention, the present invention relates to a composition for preventing, improving or treating diabetes or a related disease, comprising as an active ingredient a compound selected from the group consisting of a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof:

[0093] [Chemical Formula 1]

[0094]

[0095] In the above chemical formula 1,

[0096] At least one of R1 and R2 is -C(=O)R9, and the others are H or C1~C6 alkyl groups;

[0097] R3 to R6 are each independently H or a C1~C6 alkyl group;

[0098] At least one of R7 and R8 is -C(=O)R 10 and the remainder is H or C1~C6 alkyl group;

[0099] R9 and R 10 are each independently a C1~C6 alkyl group.

[0100] The above compound may be a compound represented by the following chemical formula 2:

[0101] [Chemical Formula 2]

[0102]

[0103] In the above chemical formula 2, the definitions of R1, R2, R7 and R8 are as defined in the above chemical formula 1.

[0104] The above compound may be a compound represented by the following chemical formula 3:

[0105] [Chemical Formula 3]

[0106]

[0107] The above diabetes may include type 1 diabetes, type 2 diabetes, and gestational diabetes, but preferably type 2 diabetes. The diabetes-related disease may include all diseases that can be caused by diabetes, and includes, for example, insulin resistance, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, obesity, hyperinsulinemia, Bardet-Biedl syndrome, dyslipidemia, hypertension, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease.

[0108] According to another embodiment of the present invention, the present invention relates to a composition for preventing, improving or treating obesity or overweight, comprising as an active ingredient a compound selected from the compound represented by the above chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof.

[0109] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0110]

[0111] Example

[0112]

[0113] [Preparation Example 1] Synthesis of 2,5-diacetamido-5-oxopentanoic acid ('α,δ-NAG')

[0114] According to the following reaction scheme 1, a compound of 2,5-diacetamido-5-oxopentanoic acid, which is α,δ-N-acetyl glucosamine, was synthesized, and is referred to herein as “α,δ-NAG.”

[0115] [Reaction Formula 1]

[0116]

[0117] 1. Synthesis of Benzyl 2-acetamido-5-amino-5-oxopentanoate (a)

[0118] 2-acetamido-5-amino-5-oxopentanoic acid (26.6 mmol) and benzyl bromide (1.5 eq) were added to 100 ml of dimethylformamide (DMF) and stirred at room temperature. Then, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU (1.2 eq)) was added, and after completion of the dropwise addition, the mixture was stirred at room temperature for 24 hours. When the reaction was complete, the reaction was quenched using water, and dichloromethane was additionally added to extract the organic layer. After washing the organic layer with brine, the moisture was removed with sodium sulfite, and the solvent was distilled under reduced pressure. The resulting residue was recrystallized using hexane and ethyl acetate to obtain intermediate 1 (1), which is benzyl 2-acetamido-5-amino-5-oxopentanoate.

[0119] 1H NMR (400 MHz, MeOD) δ 7.43 - 7.27 (m, 5H), 5.19 (s, 2H), 4.46 (dd, J = 9.1, 5.1 Hz, 1H), 2.36 - 2.24 (m, 2H), 2.26 - 2.12 (m, 1H), 2.00 (s, 3H), 1.99 - 1.85 (m, 1H)

[0120] 2. Synthesis of benzyl 2,5-diacetamido-5-oxopentanoate (b)

[0121] The intermediate 1 (23.0 mmol), acetaldehyde (3.0 eq), and hydrochloric acid (0.001 eq) were placed in a microwave tube and stirred for 30 minutes at 50 W and 120°C. Then, the organic layer was extracted using ethyl acetate and water, washed with brine, and moisture was removed using sodium sulfite. Thereafter, the remaining solvent was distilled under reduced pressure, and the resulting residue was separated and purified using MPLC to obtain intermediate 2 (2), which is benzyl 2,5-diacetamido-5-oxopentanoate.

[0122] 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.30 (d,J= 7.5 Hz, 1H), 7.47 - 7.23 (m, 5H), 5.17 - 5.06 (m, 2H), 4.27 (ddd,J= 9.3, 7.5, 5.4 Hz, 1H), 2.70 - 2.38 (m, 2H), 2.12 (s, 3H), 2.07 - 1.91 (m, 1H), 1.85 (s, 3H), 1.83 - 1.73 (m, 1H)

[0123] 3. Synthesis of 2,5-diacetamido-5-oxopentanoic acid (c) (DN204360)

[0124] After dissolving the intermediate 2 (4.06 mmol) in 5 ml of methanol, 0.2 g of Pd / C (palladium adsorbed on activated carbon) was additionally added, and the mixture was stirred under hydrogen for 24 hours. After the reaction was completed, the reaction solution was filtered through Celite and then distilled under reduced pressure to obtain the target compound, (S)-2,5-diacetamido-5-oxopentanoic acid (DN204360).

[0125] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.13 (d,J= 7.8 Hz, 1H), 4.15 (td,J= 8.9, 5.1 Hz, 1H), 2.56 - 2.46 (m, 2H), 2.13 (s, 3H), 2.06 - 1.89 (m, 1H), 1.84 (s, 3H), 1.80 - 1.64 (m, 1H)

[0126]

[0127] [Preparation Example 2] Preparation of an animal model

[0128] Specific pathogen-free, 6- to 7-week-old female C57BL / 6 mice were purchased from Orient Bio Korea Inc. (Gapyeong, Gyeonggi-do, South Korea) and housed in an airflow-type sterile laboratory bench, fed standard solid food ad libitum. All experimental animals used in this study were cared for in accordance with protocols approved by the Institutional Animal Care and Use Committee of the Chonbuk National University Medical School.

[0129] It has been reported that high-fat diet-fed C57BL / 6 mice develop early-stage type 2 diabetes (Diabetologia 47:1541-1549, 2004). Accordingly, in this experiment, to establish a type 2 diabetes animal model, 8-week-old mice were fed a high-fat diet (HFD) containing 60% fat (D12492, (Research Diets, Inc., New Brunswick, NJ) for 12 weeks (3 months). As a control group, a normal pellet diet (NFD) containing 5% fat (Purina, Cargil, Inc., Seongnam, Korea) was fed.

[0130]

[0131] [Experimental Example 1] Confirmation of blood sugar lowering effect

[0132] In order to confirm the blood sugar lowering effect of 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention, as in Preparation Example 2, a drug solution in the form of 8 μg / ml of 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) synthesized in Preparation Example 1 was dissolved in water together with a high-fat diet, and administered orally for a total of 12 weeks to type 2 diabetic mice. At this time, the daily dose of 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) was set to 40 μg. At weeks 0, 8, and 12 after the start of the experiment, mice were fasted for 12 h. Whole blood was collected from the tail vein, and blood glucose levels were measured using the Accu-Chek Active kit (F. Hoffmann-La Roche Ltd, Basel, Switzerland). All experiments were performed at least three times, and seven mice were used per group. Statistical analysis data were expressed as the mean standard deviation, and statistical comparisons were performed using one-way ANOVA and Fisher's test. Significant differences between groups were determined using the unpaired Student's t-test. The results of the experiment are shown in Figure 1.

[0133] As shown in Fig. 1, in the case of type 2 diabetic mice fed a high-fat diet, blood sugar levels increased over time compared to mice fed a normal diet. However, when 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention was administered together with a high-fat diet, a blood sugar reduction effect of 60% was observed at 12 weeks compared to the control group administered only a high-fat diet, and a statistically significant difference was also observed (**p ≤ 0.001 vs. normal control group, #p ≤ 0.05 vs. 60% Kcal high-fat diet administration group, ##p ≤ 0.001 vs. 60% Kcal high-fat diet administration group).

[0134]

[0135] [Experimental Example 2] Confirmation of the inhibitory effect on the production of glycated hemoglobin.

[0136] Glycosylated hemoglobin (HbA1c) refers to a state in which glucose is bound to hemoglobin in red blood cells. Since glucose remains bound to red blood cells for three months, the lifespan of red blood cells, testing the glycated hemoglobin level can determine the average blood sugar level over the past three months. Therefore, compared to a one-time blood sugar test that only indicates blood sugar at the moment of measurement, the glycated hemoglobin test is used to diagnose diabetes, determine whether blood sugar levels are well controlled in diabetic patients, and determine long-term hyperglycemia. As the importance of the glycated hemoglobin test in diabetes diagnosis has increased, the World Health Organization (WHO) also included the glycated hemoglobin level check item in its diabetes diagnosis criteria in 2009.

[0137] In order to confirm the inhibitory effect of 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) on the production of glycated hemoglobin (HbA1C) in the present invention, an experiment was performed using the same method as Experimental Example 1, but the content of glycated hemoglobin in whole blood was measured using an A1C EZ 2.0 kit (Wuxi BioHermes Biomedical Technology Co., Jiangsu, China), and the results are shown in Fig. 2.

[0138] As shown in Fig. 2, in the case of type 2 diabetic mice fed a high-fat diet, the content of glycated hemoglobin increased over time compared to mice fed a normal diet, and more specifically, the content of glycated hemoglobin increased by 38% (4.7% vs 6.5%) and 57% (4.7% vs 7.4%) at 8 and 12 weeks after the start of the experiment, respectively (all p<0.01). However, when 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention was administered to mice along with a high-fat diet, the effect of inhibiting the production of glycated hemoglobin was observed to be 44% at 12 weeks compared to the control group administered only a high-fat diet, and a statistically significant difference was also observed (**p ≤ 0.001 vs. normal control group, ##p ≤ 0.001 vs. 60% Kcal high-fat diet administered group).

[0139]

[0140] [Experimental Example 3] Confirmation of the weight gain suppression effect

[0141] In order to confirm the weight gain inhibitory effect of 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention, an experiment was conducted in the same manner as Experimental Example 1, but the body weights of the mice were measured using an electronic scale (Dragon 204 / S, Mettler Toledo, USA) for 21 weeks at 10:00 AM at 0, 8, and 12 weeks after the start of the experiment. The experiment was performed at least 3 times, and the average body weight was calculated by adding up the body weights of 7 mice per group and dividing by the number of mice. Statistical analysis data were expressed as the mean standard deviation, and statistical comparisons were performed using one-way ANOVA and Fisher's test. Significant differences between groups were determined using unpaired Student's t-test. The results of the experiment are shown in Fig. 3.

[0142] As shown in Fig. 3, in the case of type 2 diabetic mice fed a high-fat diet, the body weight increased significantly over time compared to mice fed a normal diet. However, when 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention was administered together with a high-fat diet, a body weight reduction effect of 82% was observed at week 8 and 53% was observed at week 12 compared to the control group fed only a high-fat diet, and a statistically significant difference was observed (*p ≤ 0.05 vs. normal control group, **p ≤ 0.001 vs. normal control group, #p ≤ 0.05 vs. 60% Kcal high-fat diet group).

[0143] In summary of the above results, it can be seen that the 2,5-diacetamido-5-oxopentanoic acid (α,δ-NAG) according to the present invention has excellent effects in preventing, improving, and treating diabetes even when administered orally, and also has a weight control effect, so it can be used as an agent for preventing, improving, and treating obesity or overweight.

[0144]

[0145] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred implementation examples and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0146] The present invention relates to a composition for pharmaceutical use that can prevent, improve or treat diabetes and related diseases.

Claims

1. A pharmaceutical composition for preventing or treating diabetes or a related disease, comprising as an active ingredient a compound selected from a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof, A pharmaceutical composition wherein the above diabetes-related diseases are selected from the group consisting of insulin resistance due to diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, hyperinsulinemia, Bardet Biedl syndrome, dyslipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 At least one of them is -C(=O)R 9 and the rest are H or C 1 ~C 6 is an alkyl group; R 3 Inland R 6 are each independently H or C 1 ~C 6 is an alkyl group; R 7 and R 8 At least one of them is -C(=O)R 10 and the rest are H or C 1 ~C 6 is an alkyl group; R 9 and R 10 are each independently C 1 ~C 6 It is an alkyl group.

2. In paragraph 1, The above compound is a pharmaceutical composition represented by the following chemical formula 2: [Chemical formula 2] In the above chemical formula 2, R 1 , R 2 , R 7 and R 8 Each definition is as defined in Article 1.

3. In paragraph 1, The above compound is a pharmaceutical composition represented by the following chemical formula 3: [Chemical Formula 3] 4. A food composition for preventing or improving diabetes or a related disease, comprising as an active ingredient a compound selected from a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof, A food composition wherein the above diabetes-related diseases are selected from the group consisting of insulin resistance due to diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, hyperinsulinemia, Bardet Biedl syndrome, dyslipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 At least one of them is -C(=O)R 9 and the rest are H or C 1 ~C 6 is an alkyl group; R 3 Inland R 6 are each independently H or C 1 ~C 6 is an alkyl group; R 7 and R 8 At least one of them is -C(=O)R 10 and the rest are H or C 1 ~C 6 is an alkyl group; R 9 and R 10 are each independently C 1 ~C 6 It is an alkyl group.

5. In paragraph 4, The compound is a food composition represented by the following chemical formula 2: [Chemical formula 2] In the above chemical formula 2, R 1 , R 2 , R 7 and R 8 The definition of each is as defined in Article 4.

6. In paragraph 4, The compound is a food composition represented by the following chemical formula 3: [Chemical Formula 3] 7. A pharmaceutical composition for preventing or treating obesity or overweight, comprising as an active ingredient a compound selected from a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 At least one of them is -C(=O)R 9 and the rest are H or C 1 ~C 6 is an alkyl group; R 3 Inland R 6 are each independently H or C 1 ~C 6 is an alkyl group; R 7 and R 8 At least one of them is -C(=O)R 10 and the rest are H or C 1 ~C 6 is an alkyl group; R 9 and R 10 are each independently C 1 ~C 6 It is an alkyl group.

8. A food composition for preventing or improving obesity or overweight, comprising as an active ingredient a compound selected from a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 At least one of them is -C(=O)R 9 and the rest are H or C 1 ~C 6 is an alkyl group; R 3 Inland R 6 are each independently H or C 1 ~C 6 is an alkyl group; R 7 and R 8 At least one of them is -C(=O)R 10 and the rest are H or C 1 ~C 6 is an alkyl group; R 9 and R 10 are each independently C 1 ~C 6 It is an alkyl group.

9. A method for preventing or treating diabetes or a related disease thereof, comprising administering to a subject in need of administration a pharmaceutically effective amount of a composition comprising a compound selected from the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof as an active ingredient, A method for preventing or treating diabetes or a disease related thereto, wherein the disease related to the above diabetes is selected from the group consisting of insulin resistance due to diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, hyperinsulinemia, Bardet Biedl syndrome, dyslipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 At least one of them is -C(=O)R 9 and the rest are H or C 1 ~C 6 is an alkyl group; R 3 Inland R 6 are each independently H or C 1 ~C 6 is an alkyl group; R 7 and R 8 At least one of them is -C(=O)R 10 and the rest are H or C 1 ~C 6 is an alkyl group; R 9 and R 10 are each independently C 1 ~C 6 It is an alkyl group.

10. A method for preventing or treating obesity or overweight, comprising administering to a subject in need of administration a composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof as an active ingredient, in a pharmaceutically effective amount: [Chemical Formula 1] In the above chemical formula 1, R 1 and R 2 At least one of them is -C(=O)R 9 and the rest are H or C 1 ~C 6 is an alkyl group; R 3 Inland R 6 are each independently H or C 1 ~C 6 is an alkyl group; R 7 and R 8 At least one of them is -C(=O)R 10 and the rest are H or C 1 ~C 6 is an alkyl group; R 9 and R 10 are each independently C 1 ~C 6 It is an alkyl group.

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