KR102348322B1 - Novel enamide compound and composition for preventing or treating diabetes comprising the same - Google Patents

Abstract

The present invention relates to a novel enamide compound and a composition for preventing or treating diabetes comprising the same.

Description

A novel enamide compound and a composition for preventing or treating diabetes comprising the same

The present invention relates to a novel enamide compound and a composition for preventing or treating diabetes comprising the same.

Diabetes is a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia resulting from defective insulin secretion or insulin action. Various complications occur due to disability and chronic vascular damage.

Diabetes is a representative adult metabolic disease, affecting about 5% of the world's population, and the resulting human and economic loss is enormous. Most of the diabetic patients are taking oral therapeutics, but a safe therapeutic agent has not been developed so far. Although insulin resistance is known as the most important mechanistic cause, the exact mechanism is not yet clear, but it has been found that a complex cause of genetic predisposition and environment is acting.

Existing diabetes drugs are mainly insulin preparations, sulfonurea drugs, thiazolidinedione (TZD) drugs, biguanide drugs, α-glucosidase inhibitors, miglitinides, incretin mimetics, DPP-IV It can be classified as an inhibitor. In the case of oral antidiabetic drugs currently used in clinical practice, long-term administration causes various side effects such as hypoglycemia, diarrhea, abdominal bloating, weight gain, lactic acidemia, cardiotoxicity, and hepatotoxicity, as well as beta cells of the pancreas that eventually secrete insulin. Since it is irreversibly damaged and destroyed and insulin resistance develops, there is a problem that the drug efficacy is reduced and a vicious cycle of insulin injection occurs. In particular, in the case of insulin preparations, there is a large problem of discomfort and rejection to injection, and the possibility of hypoglycemia is very high.

Accordingly, there is a demand for the development of a new target therapeutic agent to fundamentally improve the problems with the existing diabetes drug.

Nature Communications volume 6, Article number: 7079 (2015), 「FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization 」 Korean Diabetes J 33:375~381, 2009 「Role of hypothalamic FoxO1 on hyperphagia in a model of streptozotocin-induced diabetes」

It is an object of the present invention to provide a compound having a novel enamide skeleton.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetes comprising the compound of the enamide skeleton.

Another object of the present invention is to provide a food composition for improving diabetes comprising the compound of the enamide skeleton.

One aspect of the present invention for achieving the above object provides a compound comprising an enamide skeleton represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In the above formula, R is a substituent bonded to any one or more positions of 5 carbons of the phenyl group bonded to the enamide skeleton, hydrogen, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 30 carbon atoms, allyl having 3 to 20 carbon atoms It is at least one selected from the group consisting of a group, an arylalkyl group having 6 to 30 carbon atoms or an acyl group having 1 to 20 carbon atoms, a nitro group, an amino group, an aminoalkyl group, an aminoaryl group, an epoxy group, an acryl group, and a carboxyl group.

Specifically, the compound of Formula 1 is methyl-4-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)benzoate, methyl-2-(3-(benzo[ d][1,3]dioxo-5-yl)acrylamido)benzoate or dimethyl-5-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido) It may be isophthalate, but is not limited thereto.

In addition, specifically, the compound represented by Formula 1 may be used for preventing or treating diabetes.

Another aspect of the present invention provides a compound comprising an enamide skeleton represented by the following Chemical Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 2]

In the above formula, R is a substituent bonded to any one or more positions of 5 carbons of the phenyl group bonded to the enamide skeleton, hydrogen, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 30 carbon atoms, allyl having 3 to 20 carbon atoms It is at least one selected from the group consisting of a group, an arylalkyl group having 6 to 30 carbon atoms or an acyl group having 1 to 20 carbon atoms, a nitro group, an amino group, an aminoalkyl group, an aminoaryl group, an epoxy group, an acryl group, and a carboxyl group.

Specifically, the compound of Formula 2 is dimethyl-5-(3-(3,4-dimethoxyphenyl)acrylamido)isophthalate, methyl-4-(3-(3,4-dimethoxyphenyl) ) acrylamido)benzoate or methyl-2-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate, but is not limited thereto.

Specifically, the compound represented by Formula 2 may be used for preventing or treating diabetes.

The novel compound of the present invention includes an enamide skeleton, and the enamide compound generates carbon-carbon and carbon-nitrogen bonds such as Aza-ene reaction, Michael reaction, Friedel-Craft reaction, Cycloaddition reaction, and Arylation reaction. It is a useful compound used in the reaction. In particular, the enamide compound may be used as a synthetic starting material useful in various fields such as medicine, material, biochemistry, and the like, and may include the following structure.

R1 and R2 represent a substituent, and the type of the substituent is not limited.

In one embodiment of the present invention, it was confirmed that the compounds represented by Chemical Formulas 1 and 2 of the present invention inhibit the activity of FoxO-1, which can be utilized as a new target for the prevention, treatment and improvement of diabetes. confirmed that there is.

The 'FoxO-1' is known to play various roles in the liver, muscle, fat, pancreas, etc., which are insulin-responsive organs.

In the liver, the expression of enzymes such as Phosphoenolpyruvate Carboxykinase (PEPCK) and Glucose-6-Phosphatase (G6Pase) related to gluconeogenesis increases, resulting in gluconeogenesis. It has been reported that it inhibits the differentiation of skeletal muscle and adipocytes and reduces the differentiation of pancreatic beta cells. It has been reported that FoxO-1, a key transcription factor for gluconeogenesis, acts on insulin-responsive tissues and shows insulin resistance, and that insulin resistance is improved by inhibiting FoxO-1 (Nature Communications volume 6, Article number) : 7079 (2015), 「FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization」). Since the novel compounds of the present invention inhibit the activity of FoxO-1, they can be utilized for prevention and treatment of new diabetes, and for improvement of diabetes.

Furthermore, in one embodiment of the present invention, it was confirmed that the compounds represented by Formulas 1 and 2 also exhibit inhibitory effects on FoxO-3a and FoxO-4, FoxO family that is affected by excessive sugar production causing diabetes It was confirmed that through the inhibitory effect of

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).

In addition, another aspect of the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising the compound represented by Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).

The pharmaceutical composition according to the present invention may be prepared into a pharmaceutical formulation using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In the preparation of the formulation, the pharmaceutical composition according to the present invention may additionally include a pharmaceutically acceptable carrier within a range that does not inhibit the activity of the compound of the present invention.

The pharmaceutically acceptable carriers include those commonly used, such as 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, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, the pharmaceutical composition of the present invention may include a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and other pharmaceutically acceptable additives.

Administration of the pharmaceutical composition according to the present invention may be administered in a pharmaceutically effective amount. "Pharmaceutically effective amount" means an amount sufficient to prevent or treat a disease with a reasonable benefit/risk ratio applicable to medical treatment. The effective dose level may be variously selected by those skilled in the art according to factors such as formulation method, patient's condition and weight, patient's sex, age, disease severity, drug form, administration route and duration, excretion rate, reaction sensitivity, etc. have. An effective amount will vary depending on the route of treatment, the use of excipients, and the potential for use with other agents, as will be appreciated by those skilled in the art. However, for desirable effects, in the case of oral administration, the composition of the present invention is generally administered to adults at an amount of 0.0001 to 100 mg/kg, preferably 0.001 to 100 mg/kg of the composition of the present invention per kg of body weight per day to adults. However, the dosage does not limit the scope of the present invention in any way.

The pharmaceutical composition of the present invention may be administered to mammals such as mice, livestock, and humans through various routes. Specifically, the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, application or intravenous, subcutaneous, or intraperitoneal injection), but oral administration is preferred. For the prevention and treatment of vaginitis, it may be administered intravaginally. Solid preparations for oral administration may include powders, granules, tablets, capsules, soft capsules, pills, and the like. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, aerosols, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are included. can Formulations for parenteral administration include sterile aqueous solutions, solutions, non-aqueous solutions, suspensions, emulsions, eye drops, eye ointments, syrups, suppositories, aerosols, etc. can be used, preferably, a pharmaceutical composition of cream, gel, patch, spray, ointment, warning agent, lotion, liniment, eye ointment, eye drop, pasta, or cataplasma can be prepared and used. , but is not limited thereto. Formulations for topical administration may be anhydrous or aqueous, depending on the clinical prescription. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

Another aspect of the present invention provides a method for preventing or treating diabetes, comprising administering to a subject the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).

In addition, another aspect of the present invention provides a method for preventing or treating diabetes, comprising administering to a subject the compound represented by Formula 2, a stereoisomer or a pharmaceutically acceptable salt thereof.

Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).

In the present invention, terms such as 'a compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof', a compound represented by Formula 2, a stereoisomer or a pharmaceutically acceptable salt thereof, etc. same as bar

The subject refers to an animal, and may typically be a mammal capable of exhibiting a beneficial effect by treatment with the compound of the present invention. Preferred examples of such subjects may include primates such as humans. Also, such subjects may include all subjects having symptoms of diabetic disease or a risk of having such symptoms.

Another aspect of the present invention provides a food composition for improving diabetes, comprising the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).

In addition, another aspect of the present invention provides a food composition for improving diabetes, comprising the compound represented by Formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Specifically, the compound may inhibit the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a), or Fox-4 (FoxO-4).

More specifically, the food composition may be a health functional food.

In the present invention, health functional food refers to food manufactured and processed using raw materials or ingredients useful for the human body in accordance with Health Functional Food Act No. 6727, and controls nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes, such as physiological action or the like. The health functional food of the present invention may contain normal food additives, and whether or not it is suitable as a food additive is evaluated on the item according to the general rules and general test methods of food additives approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the relevant standards and standards.

The health functional food is a food that emphasizes the bioregulatory function of food, and is a food with added value to act and express for a specific purpose using a physical, biochemical, and bioengineering method. The ingredients of these health functional foods are designed and processed to sufficiently exert the body control functions related to the body defense, regulation of body rhythm, prevention and recovery of diseases, and are food supplementary additives, sweeteners or functionalities that are acceptable as food. It may contain raw materials.

Health function comprising the 'compound represented by the formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof', and a 'compound represented by the formula 2, a stereoisomer or a pharmaceutically acceptable salt thereof' of the present invention When used in food or health functional beverage, the compound may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. In addition, the mixing amount may be appropriately determined depending on the intended use thereof (prevention, health or improvement, therapeutic treatment).

There is no particular limitation on the kind of food to which the present invention can be applied. Examples of foods to which the compound of the present invention and its stereoisomer can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, and various soups. , beverages, teas, drinks, alcoholic beverages, vitamin complexes, etc. may be included, and may include all foods in a conventional sense.

In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol , a carbonation agent used in carbonated beverages, and the like. In addition, it may contain the pulp for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination. In addition, the food can be prepared in the form of tablets, granules, powders, capsules, liquid solutions and pills according to known manufacturing methods. In addition, various conventional flavoring agents or natural carbohydrates may be included as additional ingredients.

The novel compound of the enamide skeleton of the present invention can be utilized as a new target for the prevention and treatment of diabetes by reducing insulin resistance by inhibiting the activity of the FoxO family.

It should be understood that the effects of the present invention are not limited to the above-described effects, and include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples only illustrate the present invention, and the present invention is not limited by the following examples.

Preparation Example 1. Synthesis of a novel enamide (enamide) skeleton compound

The compounds of Formulas 3 and 4 below are reacted with a compound of Formula 6 in the presence of Castro's reagent (BOP) of Formula 5 and an organic solvent to obtain a compound of a novel enamide skeleton having structures of Formulas 1 and 2 synthesized.

The reaction formula of the above process is as follows.

[Scheme 1]

[Scheme 2]

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

1-1. methyl 　 (E) -4- (3- (benzo [d] [1,3] dioxo-5-yl) acrylamido) benzoate (methyl 　 (E) -4- (3- (benzo [d] [ 1,3]dioxol-5-yl)acrylamido)benzoate)

After stirring 5 mmol of the compound of formula 3 and 5.5 mmol of methyl 4-aminobenzoate in dichloromethane (30 mL), 6 mmol of benzotriazolyl oxytris (dimethyl amino) phosphonium hexafluorophosphate (BOP) and tri 20 mmol of ethylamine (TEA) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then washed with 10% citric acid (2×20 mL), water (20 mL) and saturated NaHCO ₃ solution (2×20 mL) or NaOH (2×20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

Thereafter, the product was purified by column chromatography or crystallized from an appropriate solvent. The synthesized compound was ^{confirmed using 1} H NMR.

^₁ H-NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 12 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.52 ( t, J = 16 Hz, 1H), 7.48 (d, J = 12 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.64 (d, J = 12 Hz, 1H), 6.09 (s, 2H), 3.87 (s, 3H).

1-2. methyl 　 (E) -2- (3- (benzo [d] [1,3] dioxo-5-yl) acrylamido) benzoate (methyl 　 (E) -2- (3- (benzo [d] [ 1,3]dioxol-5-yl)acrylamido)benzoate)

The same preparation method as in 1-1 was used, and the compound of Formula 3 and methyl 2-aminobenzoate were added and reacted for synthesis. Thereafter, it was confirmed using ^{1 H NMR.}

^₁ H-NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 12 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.52 ( t, J = 16 Hz, 1H), 7.48 (d, J = 12 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 1H), 6.64 (d, J = 12 Hz, 1H), 6.09 (s, 2H), 3.93 (s, 3H).

1-3. Dimethyl　(E)-5-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)isophthalate (dimethyl　(E)-5-(3-(benzo[d] [1,3]dioxol-5-yl)acrylamido)isophthalate)

The same preparation method as in 1-1 was used, and the compound of Formula 3 and dimethyl 5-aminoisophthalate were added and reacted for synthesis. Thereafter, it was confirmed using ^{1 H NMR.}

^₁ H-NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 8.59 (s, 2H), 8.17 (s, 1H), 7.22 (s, 1H), 6.14 (s, 1H), 6.10-6.06 (m) , 3H), 5.75 (s, 2H), 3.90 (s, 6H).

1-4. Dimethyl　(E)-5-(3-(3,4-dimethoxyphenyl)acrylamido)isophthalate (dimethyl　(E)-5-(3-(3,4-dimethoxyphenyl)acrylamido)isophthalate)

The same preparation method as in 1-1 was used, and the compound of Formula 4 and dimethyl 5-aminoisophthalate were added and reacted for synthesis. Thereafter, it was confirmed using ^{1 H NMR.}

^₁ H-NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 8 Hz, 2H), 8.07 (t, J = 8 Hz, 1H), 7.67 (t, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.83 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 3.83 (s, 6H), 3.65 (s, 6H).

1-5. methyl　(E)-4-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate (methyl　(E)-4-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate)

The same preparation method as in 1-1 was used, and the compound of Formula 4 and methyl 4-aminobenzoate were added and reacted for synthesis. Thereafter, it was confirmed using ^{1 H NMR.}

^₁ H-NMR (400 MHz, CDCl₃) δ 8.13 (d, J = 8 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 7.67 (t, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.83 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 6H).

1-6. methyl　(E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate ((methyl　(E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate)

The same preparation method as in 1-1 was used, and the compound of Formula 4 and methyl 2-aminobenzoate were added and reacted for synthesis. Thereafter, it was confirmed using ^{1 H NMR.}

^₁ H-NMR (400 MHz, CDCl₃) δ 8.55 (d, J = 8 Hz, 1H), 8.04 (s, 2H), 7.87 (d, J = 8 Hz, 1H), 7.81 (t, J = 8 Hz, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 6.93 (d, J = 8 Hz, 1H), 6.60 (d, J = 8 Hz, 1H), 4.00 (s, 3H), 3.96 ( s, 3H), 3.83 (s, 3H).

Experimental Example 1. Confirmation of FoxO-1 activity inhibitory effect of novel derivatives having an enamide skeleton

The inhibitory effect on FoxO-1 activity of the derivative having an enamide skeleton synthesized in Preparation Example 1 was confirmed. pcDNA3-Flag-FoxO-1, a vector expressing FoxO-1 protein, and Pgl3-IRE-Luc, a vector expressing insulin response element (IRE) and luciferase in HepG2 cells (a human-derived liver cancer cell line) The change in luciferase activity shown by FoxO-1 and IRE binding was measured by transfection and treatment with each synthesized derivative.

Specifically, the HepG2 cell line ^{was aliquoted in a 96-well plate at 1×10 4} cell/100 ul and cultured for 24 hours, followed by exchange with a serum-free, antibiotic-free medium. Thereafter, X-tream, FoxO-1 vector and IRE vector were mixed so as to be 50 ng/ul per well, left at room temperature for 15 minutes, and then transfection was carried out by dispensing 100 ul into each well. After culturing for 24 hours, the luciferase promoter activity was measured by analyzing the promoter activity using the Dual Luciferase Reporter Assay Kit (Promega).

After evaluating the inhibitory activity against FoxO-1 by adding 50 uM of each of the derivatives synthesized in the above preparation example, the derivatives exhibiting 50% or more of FoxO-1 inhibitory activity were treated again by concentration to measure the inhibitory activity, and the inhibitory activity was measured. was quantified as IC _{50 .} In this result, a _{lower IC 50} value indicates that the inhibitory activity is exhibited at a lower concentration, and a _{lower IC 50} value indicates better inhibitory activity.

The inhibitory activity of each derivative on FoxO-1 is shown in Table 1 below.

production example Inhibition (%)
@50μM IC ₅₀ (μM) 1-1 76 14 1-2 45 - 1-3 82 19 1-4 75 20 1-5 46 - 1-6 NA -

Experimental Example 2. Confirmation of the inhibitory effect of FoxO-3a and FoxO-4 activity of novel derivatives having an enamide skeleton

The inhibitory effect on FoxO-3a and FoxO-4 was confirmed using the same experimental method as in Experimental Example 1. However, instead of the FoxO-1 vector, FoxO-3a and FoxO-4 inserted vectors were used, respectively.

production example FoxO-3a FoxO-4 Inhibition (%) @50μM Inhibition (%) @50μM 1-1 55 30 1-4 30 45

As described above, it was confirmed that the novel compound containing the enamide skeleton of the present invention exhibits inhibitory activity against FoxO-1, FoxO-3a and FoxO-4, which act on insulin-responsive tissues to show resistance to insulin. , confirmed that it can be used for new treatment and improvement of diabetes.

The above description of the present invention 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. For example, each component described as a single type may be implemented in a dispersed form, and likewise components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present invention.

Claims (10)

delete delete delete delete delete delete methyl-4-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)benzoate, methyl-2-(3-(benzo[d][1,3]dioxo -5-Nyl)acrylamido)benzoate, dimethyl-5-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)isophthalate, dimethyl-5-( 3-(3,4-dimethoxyphenyl)acrylamido)isophthalate or methyl-4-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate compound, stereoisomer thereof, or pharmaceutical thereof A pharmaceutical composition for preventing or treating diabetes, comprising an acceptable salt. The pharmaceutical for preventing or treating diabetes according to claim 7, wherein the compound inhibits the activity of oxo-1 (FoxO-1), oxo-3a (FoxO-3a) or oxo-4 (FoxO-4). composition. methyl-4-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)benzoate, methyl-2-(3-(benzo[d][1,3]dioxo -5-Nyl)acrylamido)benzoate, dimethyl-5-(3-(benzo[d][1,3]dioxo-5-yl)acrylamido)isophthalate, dimethyl-5-( 3-(3,4-dimethoxyphenyl)acrylamido)isophthalate or methyl-4-(3-(3,4-dimethoxyphenyl)acrylamido)benzoate compound, stereoisomer thereof, or pharmaceutical thereof A food composition for improving diabetes, comprising an acceptable salt. The food composition for improving diabetes according to claim 9, wherein the compound inhibits the activity of Fox-1 (FoxO-1), Fox-3a (FoxO-3a) or Fox-4 (FoxO-4).