WO2020184998A1 - Composition for preventing, alleviating or treating metabolic diseases - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases. A composition according to the present invention very effectively lowers blood glucose when administered to an individual afflicted with a metabolic disease, thereby being very suitably usable in the prevention, alleviation or treatment of metabolic diseases.

Description

Composition for preventing, improving or treating metabolic diseases

The present invention relates to a composition for preventing, improving or treating metabolic diseases.

Metabolic disorders are generally recognized as risk factors determining cardiovascular disease, obesity, diabetes, insulin resistance, abnormal lipid metabolism, hypertriglyceridemia, an increase in free fatty acids, and a decrease in high-density cholesterol. And diseases such as hypertension are included in metabolic diseases. The metabolic disorder is caused by a problem in the body's metabolic process due to a genetic defect. Most of the genetic defects of metabolic disorders are inherited from parents, and the types of genes responsible are very diverse. Metabolic processes refer to a series of processes that convert food consumed by the body into energy that can be used. In the process of metabolism, use enzymes present in the body to break down food into a simple form that can be digested and use another enzyme in the cell as an energy source that cannot be consumed from food. To produce. That is, genetic defects in metabolic disorders may occur when enzymes required for metabolism cannot function normally, or when the amount of enzymes the body produces is extremely reduced or disappears. Furthermore, due to genetic defects, ingested substances may not be decomposed and may become toxic in the body, resulting in the inability to supply substances necessary for the body through metabolic processes.

Meanwhile, in the modern society, obesity is caused by an increase in fat accumulation in the body due to various causes, and the importance of obesity has begun to be evaluated in the last century as obesity overcame malnutrition as a major problem. In addition, since obesity can develop into metabolic diseases such as hypertension, diabetes, heart disease, arteriosclerosis, and hyperlipidemia, its treatment and prevention are important. In recent years, non-alcoholic fatty hepatitis has been increasing due to an increase in obesity, diabetes, and hyperlipidemia, and some are known to progress to liver cirrhosis. Moreover, as fatty liver is regarded as an early symptom of metabolic disease rather than simple liver disease, the importance of early diagnosis and treatment of fatty liver due to obesity is increasing.

Despite such necessity, the effect on therapeutic agents for the prevention or treatment of metabolic diseases is insufficient.

One object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases.

Another object of the present invention is to provide a food composition for preventing or improving metabolic diseases.

Another object of the present invention is to provide a method for preventing or treating metabolic diseases.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned may be clearly understood by those of ordinary skill in the art from the following description.

One embodiment of the present invention provides a composition for preventing, improving or treating metabolic diseases.

The composition of the present invention comprises as an active ingredient a compound selected from a compound represented by the following Formula 1, a pharmaceutically acceptable salt, hydrate, and solvate thereof:

[Formula 1]

In Chemical Formula 1 of the present invention,

L ₁ and L ₂ are each independently selected from the group consisting of C ₃ to C ₄₀ cycloalkylene, C ₆ to C ₆₀ arylene, and heteroarylene having 5 to 60 nuclear atoms;

X and Y are each independently deuterium, halogen, cyano, nitro, sulfonyl, C ₁ ~ C ₁₀ alkylsulfonyl, azide, hydroxy, C ₁ ~ C ₄₀ alkyl, C ₂ ~ C ₄₀ Al Kenyl, C ₁ ~ C ₄₀ alkoxy, unsubstituted or substituted C ₆ ~ C ₆₀ aryloxy, unsubstituted or substituted C ₃ ~ C ₄₀ cycloalkyl, unsubstituted or substituted nuclear atoms of 3 to 20 Heterocycloalkyl, unsubstituted or substituted C ₆ ~C ₆₀ aryl, unsubstituted or substituted heteroaryl having 5 to 60 nuclear atoms, and -NR'R";

R'and R" are each independently hydrogen, C ₁ to C ₁₀ alkyl, C ₆ to C ₆₀ aryl, C ₃ to C ₄₀ cycloalkyl, C ₆ to C ₆₀ arylsulfonyl, 5 nuclear atoms It is selected from the group consisting of heteroaryl of to 60;

n And m is each independently selected from an integer of 0 to 5; N and m are not zero at the same time;

When the plurality of X or Y are each, the plurality of X or Y may be the same or different from each other;

The arylsulfonyl of R'and R" may be unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, and nitro.

The "aryl" of the present invention means a monovalent substituent derived from an aromatic hydrocarbon having 6 to 40 carbon atoms in which a single ring or two or more rings are combined. In addition, two or more rings may be simply attached to each other (Pendant) or condensed form may also be included. Examples of such aryl include phenyl, naphthyl, phenanthryl, and anthryl, but are not limited thereto.

The "arylene" of the present invention is an atomic group excluding one hydrogen atom from an aromatic hydrocarbon, and includes one having a condensed ring, an independent benzene ring or two or more condensed rings bonded directly or through a group such as vinylene. . The arylene group may have any substituent described in the present invention, such as alkoxy, and the number of carbon atoms excluding the substituent is usually about 6 to 60. In addition, the total number of carbon atoms including the arylene substituent is usually about 6 to 100. Examples of such arylene groups include phenylene group, naphthalenediyl group, dimethoxy benzyl group, anthracene-diyl group, biphenyl-diyl group, terphenyl-diyl group, condensed compound group, fluorene-diyl group, stilbene- It may be a diyl group, a distyrene diyl group, a benzofluorene-diyl group, a dibenzofluorene-diyl group, and the like, but is not limited thereto.

The "heteroarylene" of the present invention contains at least one aromatic ring, and at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N in the ring, divalent monocyclic It means an aromatic group or a divalent polycyclic aromatic group. Each ring of the heteroarylene group may contain one or two O atoms, one or two S atoms, and/or 1 to 4 N atoms, provided that the total number of heteroatoms in each ring is 4 or less. And each ring must contain at least one carbon atom. Examples of heteroarylene are not limited thereto, but benzofuranylene, benzimidazolylene, benzoisoxazolylene, benzopyranylene, benzothiadiazolylene, benzothiazolylene, benzothienylene, benzotriazolylene , Benzoxazolylene, furopyridylene, imidazopyridinylene, imidazothiazolylene, indolizinylene, indolylene, indazolylene, isobenzofuranylene, isobenzothienylene, isoindolylene, iso Quinolinylene, isothiazolylene, naphthyridinylene, oxazolopyridinylene, phthalazinylene, pteridinylene, furinylene, pyridopyridylene, pyrrolopyridylene, quinolinylene, quinoxalinylene, Quinazolinylene, thiadiazolopyrimidylene, and thienopyridylene. Examples of the tricyclic heteroarylene group are not limited thereto, but acridinylene, benzindolylene, carbazolylene, dibenzofuranylene, perimidinylene, phenanthrolinylene, phenanthridinylene, phenarsazinylene , Phenazinylene, phenothiazinylene, and phenoxazinylene.

The "alkyl" of the present invention means a linear or branched saturated monovalent hydrocarbon radical, and the alkyl may be optionally substituted with one or more substituents described in the present invention. Examples of alkyl are, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t -Butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms) may be included.

The "alkylsulfonyl group" of the present invention includes a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, and a t-butylsulfonyl group. The number of carbons constituting the alkylsulfonyl group is preferably 1 to 10, but is not limited thereto.

The "alkenyl" of the present invention means one or more, in one embodiment, 1 to 5, in another embodiment, a straight or branched chain monovalent hydrocarbon radical containing one, carbon-carbon double bond(s) do. Alkenyl may be optionally substituted with one or more substituents described herein. The term “alkenyl” includes radicals having “cis” or “trans” structures or mixtures thereof, or alternatively “Z” or “E” structures or mixtures thereof, as understood by one of skill in the art. The alkenyl may include, for example, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl, but is not limited thereto.

The "aryloxy" of the present invention is a monovalent substituent represented by RO-, and R means an aryl having 5 to 40 carbon atoms. Examples of such aryloxy include phenyloxy, naphthyloxy, and diphenyloxy, but are not limited thereto.

The "heterocycloalkyl" of the present invention refers to a monovalent monocyclic system containing 1 to 3 heteroatoms selected from N, O, P, or S, and having 3 to 20 ring atoms in which the remaining ring atoms are C. . One or more hydrogen atoms in the heterocycloalkyl group may be optionally substituted. Examples of the heterocycloalkyl group include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, or piperazine.

The "alkoxy" of the present invention is a monovalent substituent represented by R'O-, wherein R'means an alkyl having 1 to 40 carbon atoms, and has a linear, branched or cyclic structure It may include. Examples of the alkyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-propoxy, t-butoxy, n-butoxy, pentoxy, and the like.

The "arylamine" of the present invention means an amine substituted with an aryl having 6 to 40 carbon atoms.

The "cycloalkyl" of the present invention means a monovalent substituent derived from a monocyclic or polycyclic non-aromatic hydrocarbon having 3 to 40 carbon atoms. Examples of such cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantine, and the like.

The "halogen" of the present invention means fluorine, chlorine, bromine and/or iodine.

The above "substituted alkyl", "substituted alkylene", "substituted heteroalkylene", "substituted alkenyl", "substituted alkenylene", "substituted heteroalkenylene", "substituted Alkynyl", "substituted alkynylene", "substituted cycloalkyl", "substituted heterocycloalkyl", "substituted cycloalkylene", "substituted aryl", "substituted aryloxy", "substituted Arylene", "substituted aralkyl", "substituted heteroaryl", "substituted heteroarylene", "substituted heterocyclic", or "substituted heterocyclylene" refers to the above substituted alkyl, substituted Alkynyl, substituted alkynylene, substituted cycloalkyl, substituted heterocycloalkyl, substituted cycloalkylene, substituted aryl, substituted aryloxy, substituted arylene, substituted aralkyl, substituted heteroaryl, substituted It means that the substituted heteroarylene, substituted heterocyclic, or substituted heterocyclylene substituents may each independently be further substituted, for example, with one or more substituents independently selected from: C _{1- 6} alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl, and heterocyclyl , Hydroxy, oxo (=O), halo, cyano (-CN), nitro (-NO ₂ ), -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -C(NR _a )NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , -OC(O)NR _b R _c , -OC(=NR _a ) NR _b R _c , -OS(O)R _a , -OS(O) ₂ R _a , -OS(O)NR _b R _c , -OS(O) ₂ NR _b R _c , -NR _b R _c ,- NR _a C(O)R _d , -NR _a C(O)OR _d , -NR _a C(O)NR _b R _c , -NR _a C(=NR _d )NR _b R _c , -NR _a S( O)R _d , -NR _a S(O) ₂ R _d , -NR _a S(O)NR _b R _c , -NR _a S(O) ₂ NR _b R _c , -SR _a , -S(O) R _a , -S(O) ₂ R _a , -S(O)NR _b R _c , and -S(O) ₂ NR _b R _c; Wherein R _a , R _b , R _c , and R _d are each independently (1) hydrogen; (2) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-14 aryl, C _7-15 aralkyl, heteroaryl, or heterocyclyl Or; (3) R _b and Rc together with the N atom to which they are attached may form a substituted heterocyclyl.

The "pharmaceutically acceptable salt" of the present invention has low toxicity to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. The pharmaceutically acceptable salt may be an acid addition salt of a pharmaceutically acceptable free acid and a base compound of the compound represented by Formula 1, but is not limited thereto.

Preferred salt forms of the compounds of the present invention include salts with inorganic acids or organic acids. At this time, as the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, and the like may be used. In addition, organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like can be used. Organic bases that can be used to prepare an organic base addition salt are tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the preparation of amino acid addition salts are natural amino acids such as alanine and glycine. It will be apparent to those of ordinary skill in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.

The salt of the present invention can be prepared by a conventional method. For example, it can be prepared by dissolving the compound represented by Formula 1 above in a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, and then adding a free acid or a free base to crystallization. .

In addition to the above compound of the present invention, a hydrate or solvate form of the compound represented by Formula 1 may be included in the scope of the present invention.

In the present invention, the compound represented by Formula 1 may be a compound represented by Formula 2 below, a pharmaceutically acceptable salt, hydrate, and solvate thereof, but is not limited thereto:

[Formula 2]

In Formula 2 of the present invention,

N, Each of m, X and Y, and pharmaceutically acceptable salts, hydrates and solvates are as defined in Formula 1 above.

As a preferred example of the present invention, in Formula 2, the n And m may each independently be an integer of 1 or 2;

The X and Y are each independently sulfonyl, C ₁ ~ C ₁₀ alkylsulfonyl, C ₁ ~ C ₄₀ alkoxy, -NR'R", hydroxy, C ₆ ~ C ₆₀ aryloxy and unsubstituted or It may be selected from the group consisting of substituted heterocycloalkyl having 3 to 20 nuclear atoms;

The R'and R" may each independently be hydrogen or an aryl sulfone of C ₆ ~ C ₆₀ ,

The arylsulfonyl of R'and R" may be unsubstituted or substituted by one or more halogens.

As a preferred example of the present invention, in Formula 2,

n is 1;

X is -NR'R" or a substituent represented by the following formula (4);

Each of R'and R" may independently be hydrogen or a substituent represented by the following Formula 4:

[Formula 3]

[Formula 4]

In Formulas 3 and 4,

R ₁ may be selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C ₁ to C ₄₀ alkyl and C ₂ to C ₄₀ alkenyl, preferably, R ₁ may be hydrogen or hydroxy;

R ₂ may be selected from the group consisting of hydrogen, deuterium, halogen, and nitro, preferably halogen, more preferably chlorine, but is not limited thereto.

As a preferred example of the present invention, in Formula 2,

The Y may be hydroxy, C ₁ ~ C ₆ alkoxy, or a substituent represented by Formula 5 below, but is not limited thereto:

[Formula 5]

As a preferred example of the present invention, in Formula 2,

N is 1;

X is -NR'R";

Each of R'and R" is independently hydrogen or a substituent represented by Formula 5;

M is 2;

Y may be a substituent of C ₁ alkoxy, but is not limited thereto.

In the present invention, the compound represented by Formula 1 may be any one selected from the group consisting of the following compounds, but is not limited thereto:

In another embodiment of the present invention, the compound may be the following compound, but is not limited thereto:

In the case of including the compound of the present invention as an active ingredient, a remarkable effect on the prevention, improvement or treatment of metabolic diseases by controlling the degree to which PPARγ or NF-κB, a cell signaling protein related to metabolic diseases, is localized to the nucleus. Can be exercised.

The metabolic disease of the present invention refers to a disease originating from an abnormal metabolism such as glucose, fat, and protein, and refers to a disease mainly caused by abnormalities in glucose and fat metabolism.

The metabolic disease of the present invention is a disease that is highly related to PPARγ or NF-κB in cell signaling, for example, obesity, type 2 diabetes, dyslipidemia, insulin resistance, dyslipidemia, hepatic steatosis (Hepatic steatosis), arteriosclerosis and non-alcoholic fatty liver (Fatty liver), preferably at least one selected from the group consisting of obesity, type 2 diabetes, and arteriosclerosis, but , But is not limited thereto.

The PPARγ gene of the present invention encodes two proteins PPARγ1 and PPARγ2. The expression level of the PPARγ protein is highest in adipose tissue, and the protein plays a role in enhancing insulin activity of adipocytes in lipid metabolism of adipose tissue. When such a protein is present at a low level, metabolic diseases may be induced, such as elevated blood lipid levels, increased hepatic gluconeogenesis, and resistance to insulin (J. Clin. Invest., 116 (3), p. 581-9 (2006)., TRENDS in Pharmacological Sciences, 26 (5), p. 244-251 (2005).). For the purposes of the present invention, the compounds represented by Formulas 1 to 16 are used in the prevention or treatment of metabolic diseases by enhancing the function of the PPARγ protein as a transcription factor by allowing the PPARγ protein, which is highly related to lipid metabolism, to be located in the nucleus. It can be applied effectively.

The NF-κB of the present invention is a transcription factor that is activated by the κB kinase complex and localized to the nucleus, and induces an inflammatory response. Various metabolic diseases such as obesity, type 2 diabetes, and insulin resistance can be induced by the NF-κB pathway (Cell Metab., 13 (1) p. 11-22, (2011)., Aging Dis. , 2 (6), p. 449-65, (2011).). For the purposes of the present invention, the compound inhibits the localization of the NF-κB protein that induces the inflammatory response into the nucleus, and very effectively inhibits the inflammatory response induced by the NF-κB protein, thereby preventing or treating metabolic diseases. It can be applied very effectively to

The "prevention" of the present invention may include, without limitation, any action of blocking, suppressing or delaying the symptoms of a pigmented disease caused by metabolic diseases by using the pharmaceutical composition of the present invention.

The "treatment" or "improvement" of the present invention may include, without limitation, any action that improves or benefits the symptoms of metabolic diseases by using the pharmaceutical composition of the present invention.

The composition of the present invention can be used as a pharmaceutical composition or a food composition.

The pharmaceutical composition of the present invention may be characterized in that it is in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and the pharmaceutical composition may be characterized for human.

In the present invention, the pharmaceutical compositions are not limited thereto, but each formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. Can be used. The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be used as a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring agent, a flavoring agent, etc. for oral administration, and in the case of an injection, a buffering agent, a preservative, Painless agents, solubilizers, isotonic agents, stabilizers, and the like can be mixed and used. In the case of topical administration, base agents, excipients, lubricants, preservatives, and the like can be used.

The formulation of the pharmaceutical composition of the present invention may be variously prepared by mixing with a pharmaceutically acceptable carrier as described above. For example, when administered orally, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.In the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have. Others, solutions, suspensions, tablets, capsules, can be formulated as sustained-release preparations.

Examples of suitable carriers, excipients and diluents for the formulation of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate. , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, and the like may be used. In addition, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, and the like may additionally be included.

The route of administration of the pharmaceutical composition of the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Includes sublingual or rectal. Oral or parenteral administration is preferred. In the present invention, the "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. In addition, the pharmaceutical composition may be administered in the form of a suppository for rectal administration.

The pharmaceutical composition of the present invention depends on a number of factors including the activity of the specific compound used, age, weight, general health, sex, formulation, time of administration, route of administration, excretion rate, drug formulation and the severity of the specific disease to be prevented or treated. It may vary in various ways, and the dosage of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug form, route and duration of administration, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day It can be administered in kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be divided several times. The above dosage does not in any way limit the scope of the present invention. The pharmaceutical composition according to the present invention may be formulated as a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.

When the composition of the present invention is prepared as a food composition, it may be prepared in the form of foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, and bread.

When at least one compound selected from the group consisting of Formulas 1 to 15 of the present invention is included in the food composition as an active ingredient, the amount may be added in a proportion of 0.1 to 50% of the total weight, but is not limited thereto. .

When the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation other than including the food composition in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as an additional component like a normal beverage. . Specifically, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, and common sugars such as sucrose and polysaccharides, dextrins, cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol are used. Can include. The flavoring agent may be a natural flavoring agent (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and a synthetic flavoring agent (saccharin, aspartame, etc.).

The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjuster, a stabilizer, a preservative, a glycerin, an alcohol, a carbonation agent used in carbonated beverages, etc. may be further included.

The ingredients included in the food composition of the present invention may be used independently or in combination. Although the ratio of the additive does not correspond to the core element of the present invention, it may be selected from 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.

According to another embodiment of the present invention, prevention of metabolic diseases comprising administering to an individual a compound selected from a compound represented by the following Formula 1, a pharmaceutically acceptable salt, hydrate, and solvate thereof, in a pharmaceutically effective amount Or a treatment method.

In the present invention, the contents related to the compound represented by Formula 1, its pharmaceutically acceptable salts, hydrates, solvates, metabolic diseases, prevention and treatment, etc. are the same as described in the above composition, so as to avoid excessive complexity of the specification Omit it.

In the present invention, the "individual" refers to an individual in need of prevention or treatment of metabolic diseases, and includes not only primates such as humans, but also mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, cats, etc. It may include all, but is not limited thereto.

The "administration" of the present invention refers to a process of introducing the active ingredient of the present invention to an individual by any appropriate method, and the administration method in the treatment method of the present invention is through various routes such as oral or parenteral Can be administered.

For the purposes of the present invention, a specific pharmaceutically effective amount for a specific patient is a composition containing the specific active ingredient, including the type and degree of the reaction to be achieved, whether other agents are used in some cases, the patient's age, and weight , General health status, sex and diet, administration time, route of administration, and secretion rate of a composition containing the active ingredient, treatment period, a variety of factors including drugs used or concurrently used with a specific composition and similar well-known in the field of medicine It is desirable to apply differently depending on factors.

The method of preventing or treating metabolic diseases of the present invention may be a combination therapy further comprising administering a compound or substance having therapeutic activity against one or more diseases, but is not limited thereto.

In the present invention, the "combination" should be understood to represent simultaneous, individual or sequential administration. When the administrations are sequential or individual, the interval between administrations of the second component should be such that the beneficial effects of the combination are not lost.

When the composition according to the present invention is administered to an individual suffering from a metabolic disease, it very effectively lowers blood sugar and can be very appropriately used for the prevention, improvement or treatment of metabolic diseases.

1A and 1B show Western blot analysis results according to an embodiment of the present invention.

[Amendment under Rule 91 25.05.2020]
Figure 2 shows the results of immunocytochemistry analysis according to an embodiment of the present invention.

3A to 3D show the results of Western blot analysis (3a and 3c) and immunocytochemical analysis (3b) according to an embodiment of the present invention.

Figure 4 is a graph showing the results of confirming the blood sugar lowering effect according to an embodiment of the present invention

One embodiment of the present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases comprising the compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, and solvate thereof as an active ingredient.

Another embodiment of the present invention relates to a method for preventing or treating metabolic diseases comprising administering to an individual a pharmaceutically effective amount of a compound represented by Formula 1, a pharmaceutically acceptable salt, hydrate, and solvate thereof. will be.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example

[Preparation Examples 1 to 15] Synthesis of candidate substances

Preparation Examples 1 to 15 of Table 1 were prepared by the following [Method 1] or [Method 2].

Manufacturing example	compound
Manufacturing Example 1	(E)-1-(4-Aminophenyl)-3-(2,4-dimethoxyphenyl)prop-2-en-1-one (E)-1-(4-Aminophenyl)-3-( 2,4-dimethoxyphenyl)prop-2-en-1-one)
Manufacturing Example 2	(E)-1-(4-aminophenyl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one (E)-1-(4-Aminophenyl)-3-( 2,5-dimethoxyphenyl)prop-2-en-1-one)
Manufacturing Example 3	(E)-1-(3-aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (E)-1-(3-aminophenyl)-3-(4-methoxyphenyl )prop-2-en-1-one)
Manufacturing Example 4	(E)-1-(3-Aminophenyl)-3-(4-hydroxy-2-methoxyphenyl)prop-2-en-1-one (E)-1-(3-Aminophenyl)-3 -(4-hydroxy-2-methoxyphenyl)prop-2-en-1-one)
Manufacturing Example 5	(E)-1-(3-Aminophenyl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one (E)-1-(3-Aminophenyl)-3-( 2,5-dimethoxyphenyl)prop-2-en-1-one)
Manufacturing Example 6	(E)-4-chloro-N-(4-3(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfoamide (E)-4-Chloro-N-(4-(3- (2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfonamide)
Manufacturing Example 7	(E)-4-chloro-N-(3-(3-(4-methoxyphenyl)acryloyl)phenyl)benzenesulfoamide (E)-4-Chloro-N-(3-(3-( 4-methoxyphenyl)acryloyl)phenyl)benzenesulfonamide)
Manufacturing Example 8	(E)-4-chloro-N-(3-3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfoamide (E)-4-Chloro-N-(3-(3 -(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfonamide)
Manufacturing Example 9	(E)-4-chloro-N-((4-chlorophenyl)sulfonyl)-N-(3-(3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfoamide)( E)-4-Chloro-N-((4-chlorophenyl)sulfonyl)-N-(3-(3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfonamide)
Manufacturing Example 10	(E)-1-(4-aminophenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one (E)-1-(4-Aminophenyl) -3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one)
Manufacturing Example 11	(E)-1-(3-aminophenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one)(E)-1-(3-Aminophenyl )-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one)
Manufacturing Example 12	(E)-1-(4-hydroxyphenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one (E)-1-(4-Hydroxyphenyl )-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one)
Manufacturing Example 13	(E)-1-(2,4-dihydroxyphenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one (E)-1-( 2,4-Dihydroxyphenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one)
Manufacturing Example 14	(E)-3-(4-hydroxy-2-methoxyphenyl)-1-(4-(piperizin-1-yl)phenyl)prop-2-en-1-one (E)-3- (4-Hydroxy-2-methoxyphenyl)-1-(4-(piperazin-1-yl)phenyl)prop-2-en-1-one)
Manufacturing Example 15	(E)-3-(4-hydroxyphenyl)-1-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-en-1-one (E)-3-(4 -Hydroxyphenyl)-1-(4-(4-methylpiperazin-1-yl)phenyl)prop-2-en-1-one)

[Method 1]

Acetophenone derivative (1 equivalent), benzaldehyde derivative (1 equivalent) and NaOH (1 equivalent) were added to an ethanol solvent and stirred at room temperature. Adding water to the reaction mixture and extracting with ethyl acetate; And the organic solvent layer was collected, washed again with water, anhydrous MgSO ₄ was added and dehydrated, the solvent was distilled off under reduced pressure, and the remaining residue was purified by silica gel chromatography.

[Method 2]

Acetophenone derivative (1 equivalent), 4-((tetrahydro-2H-pyran-2-yl)oxy)) benzaldehyde (4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde) derivative (1 Equivalent) and NaOH (1 equivalent) into an ethanol solvent and stirred at room temperature; Adding 4M HCl to the reaction mixture, stirring for 20 minutes, adding water, and extracting with ethyl acetate; And washing the organic solvent layer with water again, adding anhydrous MgSO ₄ to dehydration, distilling off the solvent under reduced pressure, and purifying the remaining residue by silica gel chromatography.

[ Manufacturing example 1] (E)-1-(4- Aminophenyl )-3-(2,4- Dimethoxyphenyl ) Prof -2-en-1-one ((E)-1-(4-Aminophenyl)-3-(2,4-dimethoxyphenyl)prop-2-en-1-one))

According to [Method 1], 4-aminoacetophenone (0.30 g, 2.22mmol), 2,4-dimethoxybenzaldehyde (0.37 g, 2.22mmol) and NaOH (0.09 g, 2.22 mmol) was used and purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:2 → 1:1), and yellow Preparation Example 1 (0.15 g, 23.0%) was obtained. R _f 0.33 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400MHz, CDCl ₃ ) δ 3.85 (s, 3H), 3.89 (s, 3H), 6.47 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 8.4, 2.4 Hz, 1H) , 6.69 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 15.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 15.6 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 55.6, 55.7, 98.7, 105.5, 114.1, 117.8, 120.7, 129.4,130.8, 131.1, 139.0, 150.9, 160.4, 162.8, 189.1 ppm.

[ Manufacturing example 2] (E)-1-(4- Aminophenyl )-3-(2,5- Dimethoxyphenyl ) Prof -2-en-1-one ((E)-1-(4-Aminophenyl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one))

According to [Method 1], 4-aminoacetophenone (0.50 g, 3.70 mmol), 2,5-dimethoxybenzaldehyde (2,5-dimethoxybenzaldehyde) (0.62 g, 3.70 mmol) and NaOH (0.15 g, 3.70) mmol) was purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:2 → 1:1) to obtain a yellow Preparation Example 2 (0.66 g, 62.5%). R _f 0.36 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.81 (s, 3H), 3.85 (s, 3H), 4.19 (br s, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.8 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 15.6 Hz, 1H), 7.92 (d, J =8.8 Hz, 2H), 8.04 (d, J = 15.6 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 56.0, 56.3, 112.7, 113.9, 114.1, 116.8, 123.3, 125.2, 128.9, 131.3, 138.6, 151.2, 153.4, 153.7, 188.8 ppm.

[ Manufacturing example 3] (E)-1-(3- Aminophenyl )-3-(4- Methoxyphenyl ) Prof -2-en-1-one ((E)-1-(3-aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one))

According to [Method 1], 3-aminoacetophenone (1.00 g, 7.40 mmol), 4-dimethoxybenzaldehyde (1.00 g, 7.40 mmol) and NaOH (0.30 g, 7.40 mmol) was used and purified by silica gel chromatography (developing solvent: (ethyl acetate/n-hexane = 1:2 → 1:1) to obtain orange Preparation Example 3 (0.83g, 62.5%). R _f 0.40 (ethyl acetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.83 (br s, 2H), 3.85 (s, 3H), 6.88 (ddd, J = 8.0, 2.4, 0.8Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.27 (dd, J = 8.0, 7.6 Hz, 1H), 7.31 (dd, J = 2.0, 1.6 Hz, 1H), 7.36 (d, J = 15.6 Hz, 1H), 7.38 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 15.6 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 56.0, 56.3, 112.7, 113.9, 114.1, 116.8, 123.3,125.2, 128.9, 131.3, 138.6, 151.2, 153.4, 153.7, 188.8 ppm.

[ Manufacturing example 4] (E)-1-(3- Aminophenyl )-3-(4- Hydroxy -2- Methoxyphenyl ) Prof -2-en-1-one ((E)-1-(3-Aminophenyl)-3-(4-hydroxy-2-methoxyphenyl)prop-2-en-1-one))

3-aminoacetophenone (0.40 g, 2.96 mmol), 2-methoxy-4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (2-methoxy-4) according to [Method 2] -((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde) (0.70 g, 2.96 mmol) and NaOH (0.12 g, 2.96 mmol) were used and silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:1) to obtain an orange Preparation Example 4 (0.28 g, 35.1%). R _f 0.25 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.71 (s, 3H), 6.30 (d, J = 2.4 Hz, 1H), 6.34 (dd, J = 8.4, 2.0 Hz, 1H), 6.72 (ddd, J = 8.0, 2.4, 0.8 Hz, 1H), 7.08 (dd, J = 8.4, 8.0 Hz, 1H), 7.13 (d, J =2.4 Hz, 1H), 7.16 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H), 7.29 (d, J = 15.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 15.6 Hz, 1H), 9.35 (br s, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 55.3, 99.1, 108.2, 114.1,115.3, 118.1, 118.7,119.3, 129.1, 130.6, 139.8, 140.3, 147.0, 60.5, 161.4, 191.1 ppm.

[ Manufacturing example 5] (E)-1-(3- Aminophenyl )-3-(2,5- Dimethoxyphenyl ) Prof -2-en-1-one ((E)-1-(3-Aminophenyl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one))

According to [Method 1], 4-aminoacetophenone (0.50 g, 3.70 mmol), 2,5-dimethoxybenzaldehyde (0.62 g, 3.70 mmol) and NaOH (0.15 g, 3.70 mmol) were used, and silica gel Purified by chromatography (developing solvent: ethyl acetate/n-hexane = 1:3) to obtain Yellow Preparation Example 5 (0.27 g, 25.4%). R _f 0.62 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.81 (s, 3H), 3.86 (s,3H), 6.87 (d, J = 8.8 Hz, 1H), 6.88 (ddd, J = 8.4, 2.0, 0.8 Hz , 1H), 6.94 (dd, J = 8.8, 2.8 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 7.27 (dd, J = 8.0, 8.0 Hz, 1H), 7.31 (dd, J = 2.8, 2.8 Hz, 1H), 7.38 (ddd, J = 8.0, 2.0, 1.6 Hz, 1H), 7.53 (d, J = 15.6 Hz, 1H), 8.06 (d, J = 15.6 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 56.1, 56.3, 112.7, 113.9, 114.7, 117.4, 119.1,119.4, 123.6, 124.8, 129.6, 139.8, 140.0, 147.0, 153.5, 153.7, 191.4 ppm.

[ Manufacturing example 6] (E)-4-chloro-N-(4-3(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfoamide ((E)-4-Chloro-N-(4- (3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfonamide))

In a CH ₂ Cl ₂ solution in which Preparation Example 2 (0.67 g, 2.36 mmol) and triethylamine (TEA, 0.26 g, 2.60 mmol) are dissolved, 4-chlorobenzenesulfonyl chloride (4-chlorobenzenesulfonyl chloride) ( 0.75g, 3.54 mmol) was added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic solvent layer was collected, washed with saturated NaHCO ₃ , anhydrous MgSO ₄ was added and dehydrated, and the solvent was distilled off under reduced pressure, and the remaining residue was subjected to silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:2). Purified by to obtain a yellow Preparation Example 6 (0.55 g, 50.9%). R _f 0.18 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3H), 3.80 (s, 3H), 6.84 (d, J = 8.8 Hz, 1H), 6.88 (dd, J= 8.8, 2.4 Hz, 1H), 7.16 (d, J = 2.4Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 15.6 Hz, 1H) , 7.74 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 15.6 Hz, 1H), 10.58 (s, 1H); ¹³ C-NMR (100 MHz, DMSO-d6) 55.2, 55.6, 112.1, 112.7, 117.0, 118.0, 121.6,123.5, 128.0, 128.1, 128.7, 129.4, 132.9, 137.8, 138.3, 141.5, 152.5, 152.9,187.9 ppm .

[ Manufacturing example 7] (E)-4- Chloro -N-(3-(3-(4- Methoxyphenyl )Acryloyl)phenyl) Benzenesulfoamide ((E)-4- Chloro -N-(3-(3-(4-methoxyphenyl)acryloyl)phenyl)benzenesulfonamide)

N-(3-acetylphenyl)-4-chlorobenzenesulfonamide (N-(3-acetylphenyl)-4-chlorobenzenesulfonamide) (0.10 g, 0.32 mmol), 4-methoxybenzaldehyde (0.04 g, 0.32 mmol) and NaOH (0.03 g, 0.80 mmol) was added to an ethanol solvent and stirred at room temperature for 72 hours. Dilute aqueous hydrochloric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic solvent layer was collected, washed with water, anhydrous MgSO ₄ was added and dehydrated, the solvent was distilled off under reduced pressure, and the remaining residue was removed by silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:3 → 2:1) Purified with a yellow Preparation Example 7 (0.01 g, 6.5%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.84 (s, 3H), 6.92 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 15.6 Hz, 1H), 7.33 (dd, J = 8.0 , 7.6 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.41 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.68 (ddd , J = 7.6, 1.6, 1.2 Hz, 1H), 7.71-7.78 (m, 4H), 9.25 (s, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 55.6,114.6, 119.5, 121.1, 124.9, 125.0, 127.6, 128.8, 129.4, 129.7, 130.5, 137.

[ Manufacturing example 8] (E)-4-chloro-N-(3-3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfoamide ((E)-4-Chloro-N-(3 -(3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfonamide)

4-chlorobenzenesulfonyl chloride (0.09g, 0.43 mmol) was added to the CH ₂ Cl ₂ solution in which Preparation Example 5 (0.12 g, 0.43 mmol) and triethylamine (0.03 g, 2.60 mmol) were dissolved, and 24 at room temperature. Stir for hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic solvent layer was collected, washed with saturated NaHCO ₃ , anhydrous MgSO ₄ was added and dehydrated, the solvent was distilled off under reduced pressure, and the remaining residue was subjected to silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:3) Purified with yellow Preparation Example 8 (0.08 g, 37.3%) was obtained. R _f 0.33 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.82 (s, 3H), 3.88 (s, 3H), 6.88 (d, J = 8.8 Hz, 1H), 6.96 (dd, J= 8.4, 2.8 Hz, 1H ), 7.15 (d, J = 2.8Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.41 -7.43 (m, 2H), 7.55 (d, J = 16.0Hz, 1H), 7.73 (d , J = 8.8 Hz, 2H), 7.71-7.72 (m, 1H), 7.76-7.79 (m, 1H), 8.08 (d, J = 16.0 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 56.1, 56.3, 112.7, 114.5, 117.9, 121.6, 122.8, 124.4, 125.5, 125.8, 128.9,129.7, 130.0, 137.1,137.7, 139.9, 140.0, 141.6, 153.7, 153.8 , 190.3 ppm.

[ Manufacturing example 9] (E)-4-chloro-N-((4-chlorophenyl)sulfonyl)-N-(3-(3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfo Amide ((E)-4-Chloro-N-((4-chlorophenyl)sulfonyl)-N-(3-(3-(2,5-dimethoxyphenyl)acryloyl)phenyl)benzenesulfonamide))

To the CH ₂ Cl ₂ solution in which Preparation Example 5 (0.22 g, 0.78 mmol) and triethylamine (0.22 g, 2.12 mmol) were dissolved was added 4--chlorobenzenesulfonyl chloride (0.25 g, 1.17 mmol) at room temperature. It was stirred for 24 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic solvent layer was collected, washed with saturated NaHCO ₃ , and anhydrous MgSO ₄ was added thereto, followed by dehydration, and the solvent was distilled off under reduced pressure, and the remaining residue was subjected to silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:4). Purified with a yellow Preparation Example 8 (0.20 g, 39.8%) was obtained. R _f 0.77 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 3.86 (s, 3H), 6.89 (d, J = 9.2 Hz, 1H), 6.97 (dd, J= 9.2, 3.2 Hz, 1H) , 7.13 (d, J = 2.8Hz, 1H), 7.19 (dd, J = 8.4, 2.0 Hz,1H), 7.42 (d, J = 16.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H) , 7.54 (d, J = 8.8 Hz, 4H), 7.66 (dd, J = 1.6, 1.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 4H), 8.05 (d, J = 16.0 Hz, 1H) , 8.09 (d, J = 8.0 Hz, 1H),; ¹³ C-NMR (100 MHz, CDCl ₃ ) 56.1, 56.3, 112.7, 114.3, 117.9, 122.9, 124.3,129.8, 129.9, 130.3, 130.6, 131.6, 134.6, 135.2, 137.8, 140.2, 141.4, 141.8,153.7, 153.8 , 189.9 ppm.

[ Manufacturing example 10] (E)-1-(4- Aminophenyl )-3-(4-(piperidin-1-yl)phenyl) Prof -2-en-1-one ((E)-1-(4-Aminophenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one))

According to the above [Method 1] 4-aminoacetophenone (0.40 g, 2.96 mmol), 4-(piperidin-1-yl)benzaldehyde (4-(piperidin-1-yl)benzaldehyde) (0.56 g, 2.96 mmol) and NaOH (0.12 g, 2.96 mmol) were used and purified by silica gel chromatography (developing solvent: MeOH: CHCl3 = 1:19) to obtain an orange Preparation Example 10 (0.28 g, 30.9%). R _f 00.43 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.62-1.71 (m, 6H), 3.29 (t, J = 5.2 Hz, 4H), 4.10 (br s, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 15.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 15.6 Hz, 1H) , 7.95 (d, J = 8.8 Hz, 2H).

[ Manufacturing example 11] (E)-1-(3- Aminophenyl )-3-(4-(piperidin-1-yl)phenyl) Prof -2-en-1-one) ((E)-1-(3-Aminophenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one))

According to [Method 1], 3-aminoacetophenone (0.40 g, 2.96 mmol), 4-(piperidin-1-yl)benzaldehyde (0.56 g, 2.96 mmol) and NaOH (0.12 g, 2.96 mmol) were added. It was used and purified by silica gel chromatography (developing solvent: MeOH: CHCl ₃ = 1:19) to obtain an orange Preparation Example 11 (0.45 g, 49.6%). R _f 0.47 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.61-1.72 (m, 6H), 3.31 (t, J = 5.6 Hz, 4H), 3.80 (br s, 2H), 6.86 (ddd, J = 8.0, 2.4 , 0.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.28 (dd, J = 8.0, 8.0 Hz, 1H), 7.30 (d, J = 15.6 Hz, 1H), 7.31 (dd, J = 2.0, 2.0 Hz, 1H), 7.37 (ddd, J = 8.8, 1.2, 1.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 15.6 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 24.6, 25.7, 49.3, 114.7, 115.0, 118.4, 119.0,119.1, 124.7, 129.5, 130.4, 140.3, 145.4, 146.9, 153.4, 191.1 ppm.

[ Manufacturing example 12] (E)-1-(4- Hydroxyphenyl )-3-(4-(piperidin-1-yl)phenyl) Prof -2-en-1-one ((E)-1-(4- Hydroxyphenyl )-3-(4-( piperidin -One- yl )phenyl)prop-2-en-1-one))

1-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (1-(4-((tetrahydro-2H-pyran-2-)) according to the above [Method 2] yl)oxy)phenyl)ethan-1-one) (0.50g, 2.27 mmol), 4-(piperidin-1-yl)benzaldehyde (0.43 g, 2.27 mmol) and NaOH (0.09 g, 2.27 mmol) It was used and purified by silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:3 → 1:1) to obtain an orange Preparation 12 (0.24 g, 33.7%). R _f 0.17 (ethylacetate/n-hexane = 1:3); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.58-1.65 (m, 6H), 3.25 (t, J = 5.6 Hz, 4H), 6.84 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 15.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 15.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 9.34 (s, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 24.4, 25.5, 49.2, 114.9, 115.6, 117.8, 124.8,130.1, 130.6, 130.9, 144.2, 153.1, 161.7, 189.0 ppm.

[ Manufacturing example 13] (E)-1-(2,4-dihydroxyphenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one ((E)- 1-(2,4-Dihydroxyphenyl)-3-(4-(piperidin-1-yl)phenyl)prop-2-en-1-one))

1-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (0.50 g, 2.12 mmol), 4-(piperidine-1 according to [Method 2] above. -Yl) benzaldehyde (0.40 g, 2.12 mmol) and Ba(OH) ₂ 8H ₂ O (0.73 g, 2.33 mmol) using silica gel chromatography (developing solvent: ethyl acetate/n-hexane = 1:1) Purified with an orange color Preparation Example 13 (0.12 g, 16.8%) was obtained. R _f 0.66 (ethylacetate/n-hexane = 1:1); ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.58-1.65 (m, 6H), 3.27 (t, J = 5.6 Hz, 4H), 6.37-6.40 (m, 2H), 6.84 (d, J = 8.8 Hz , 2H), 7.34 (d, J = 15.2 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 15.2 Hz, 1H) ), 9.64 (s, 1H), 13.6 (s, 1H).

[ Manufacturing example 14] (E)-3-(4-hydroxy-2-methoxyphenyl)-1-(4-(piperizin-1-yl)phenyl)prop-2-en-1-one ((E) -3-(4-Hydroxy-2-methoxyphenyl)-1-(4-(piperazin-1-yl)phenyl)prop-2-en-1-one))

1-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (0.50 g, 2.45 mmol), 2-methoxy-4-( (Tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (0.58 g, 2.45 mmol) and NaOH (0.20 g, 4.90 mmol) were used, and the solid obtained after solvent removal was mixed with ethylacetate/n-hexane. Treated with. The resulting solid was filtered and dried under vacuum to obtain an orange Preparation 14 (0.28 g, 33.8%). ¹ H-NMR (400 MHz, DMSO-d6) δ 2.89 (dd, J= 7.2, 3.2 Hz, 4H), 3.26 (dd, J = 7.2,4.0 Hz, 4H), 3.82 (s, 3H), 6.40 ( dd, J =8.8, 2.0 Hz, 1H), 6.41 (d, J = 1.6Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H),7.51 (d, J = 15.6 Hz, 1H), 7.55 ( d, J = 8.8 Hz, 1H), 7.87 (d, J = 15.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H),; ¹³ C-NMR (100 MHz, DMSO-d6) 45.1, 47.5, 55.1, 98.7, 107.9, 112.9, 114.7,118.0, 127.7, 129.7, 129.8, 137.7, 153.7, 159.7, 161.2, 186.8 ppm.

[ Manufacturing example 15] (E)-3-(4- Hydroxyphenyl )-1-(4-(4- Methylpiperazine -1-yl)phenyl) Prof -2-en-1-one ((E)-3-(4- Hydroxyphenyl )-1-(4-(4- methylpiperazin -1-yl)phenyl)prop-2-en-1-one)

1-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (0.50 g, 2.29 mmol), 4-((tetrahydro-2H) according to the above [Method 2] -Pyran-2-yl)oxy)benzaldehyde (0.47 g, 2.29 mmol) and NaOH (0.09 g, 2.29 mmol) were used, and the solid obtained after removal of the solvent was treated with a mixed solvent of ethylacetate/n-hexane. The resulting solid was filtered and dried in vacuo to give an orange Preparation Example 15 (0.70 g, 94.8%). ¹ H-NMR (400 MHz,, CDCl ₃ ) δ 2.33 (s, 3H), 2.55 (t, J = 5.2 Hz, 4H), 3.37 (t, J= 5.2 Hz, 4H), 6.86 (d, J = 8.8 Hz,2H), 6.89 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 15.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 15.6 Hz , 1H), 7.95 (d, J = 8.8 Hz, 2H); ¹³ C-NMR (100 MHz, CDCl ₃ ) 46.2, 47.4, 54.8, 113.7, 116.2, 118.8, 126.8, 128.7,130.3, 130.6, 143.7, 154.0, 159.7, 188.4 ppm.

[ Example One] PPARγ ( Peroxisome proliferator -Check the effect on activated receptor γ)

[1-1] Western blot analysis

The effect of the compounds according to the present invention on PPARγ, which is highly related to metabolic diseases, was confirmed through Western blot analysis for localization of each of the nucleus and cytosol.

Specifically, HT22 and SH-SY5Y cells were treated with 0 or 5 μM of a compound corresponding to Preparation Example 6 (YE-06), respectively, and cultured for 24 hours. Then, a cell lysate was obtained from the nucleus or cytoplasm of the cells of the cells, and the amount of protein was quantified. The quantified protein was loaded on SDS-PAGE and subjected to electrophoresis. The protein present on the SDS-PAGE after electrophoresis was completed was transferred to a PVDF membrane. After washing the PVDF membrane, it was placed in a blocking buffer containing 5% skim milk in TBS-T buffer and incubated at room temperature. Then, the PPARγ-specific antibody and the PVDF membrane diluted at a certain ratio in TBS-T buffer containing 3% BSA were incubated at room temperature. Thereafter, the PVDF membrane was washed with TBS-T buffer, and incubated for 1 hour at room temperature with a dilution containing HRP-conjugated IgG. The PVDF membrane was washed 3 times using TBS-T buffer, and visualized using a detection reagent, and the results are shown in FIG. 1.

As shown in FIG. 1, when Preparation 6 (YE-06) was treated, it was confirmed that PPARγ was localized to the cell nucleus in both HT22 and SH-SY5Y cell lines.

From the above results, it can be seen that the compound according to the present invention can be used for the prevention or treatment of metabolic diseases that may occur when PPARγ is not localized to the cell nucleus.

[1-2] Immunocytochemistry analysis

In the same conditions as in [1-1], HT22 and SH-SY5Y cells were treated with 10 μM of Preparation Example 6 (YE-06), and cultured for 24 hours. Then, the cells were immobilized by treating the cells with 100% methanol and incubating for 5 minutes, followed by additional treatment with 0.1% Triton X-100 and incubated for 3 minutes. Then, it was treated with 5% BSA, incubated for 1 hour, and incubated with an antibody specific for PPARγ. Then, it was incubated with a secondary antibody to which fluorescence is bound, and after staining using 1 μg/ml DAPI, an image was taken through a confocal microscope (Zeiss LSM 510 Meta with LSM image examiner software, Germany), The results are shown in FIG. 2.

As shown in FIG. 2, PPARγ was scattered in the cytoplasm before Preparation Example 6 (YE-06) was treated, whereas when Preparation Example 6 (YE-06) was treated, it was confirmed that it was located in the cell nucleus. .

From the above results, it can be seen that the compound according to the present invention can be used for the prevention or treatment of metabolic diseases that may occur when PPARγ is not localized to the cell nucleus.

[ Example 2] NF - to κB Check the impact

In metabolic diseases, when NF-κB is located in the nucleus, it induces the expression of genes that cause inflammation. Thus, Western blot and immunocytochemical analysis were performed in the same manner as in [1-1] and [1-2] to determine how the compound of the present invention affects NF-κB, and the results are shown in FIGS. 3a to 3d. Done. However, in order to induce an inflammatory response, HT22 and SH-SY5Y cells were each treated with 1 μg/ml of LPS.

As shown in FIGS. 3A to 3D, when LPS was treated in both HT22 and SH-SY5Y cell lines, it was confirmed that the amount of NF-κB localized to the nucleus was increased. As described above, it was confirmed that the increase in the amount of NF-κB localized into the nucleus by LPS treatment was suppressed when Preparation Example 6 (YE-06) was treated.

From the above results, it can be seen that the compound according to the present invention very effectively induces the inflammatory response that may occur when NF-κB is localized into the nucleus.

[Example 3] Confirmation of the effect of lowering blood sugar in an animal model of metabolic disease

After purchase, 15-month-old male C57BL6/J mice were sufficiently stabilized in the breeding conditions provided by the provider. Thereafter, intraperitoneal glucose tolerance test (IPGTT) was performed in the following manner.

First, in order to maintain fasting for 16 hours before injecting glucose into the mice, fasting was performed from 7 pm the day before the experiment. Then, at the time of fasting for 16 hours, 2 g/kg of glucose diluted in saline and 2 μl/g of negative control (Dimethyl sulfoxide; DMSO) or 10 mg/kg diluted in DMSO was prepared in Preparation Example 6 ( After intraperitoneal injection of YE-06), blood glucose was measured from blood collected at 0, 15, 30, 60, 120 and 180 minutes, respectively, and the results are shown in FIG. 4. However, here, the experiment was performed in a total of 5 mice, and a cross-over analysis was performed.

As shown in Figure 4, compared to fasting blood glucose (0 minutes), the blood glucose of the mice administered with the negative control and Preparation Example 6 increased sharply at 15 minutes, but 30 minutes when Preparation Example 6 (YE-06) was injected. From 180 minutes, a remarkable blood sugar lowering effect was observed.

Through the above results, when the compound according to the present invention is administered to an individual, compared with the effect of naturally lowering blood sugar, it can exhibit a blood sugar lowering effect at a very rapid level, thereby preventing or treating metabolic diseases. It can be seen that it can be exerted.

As described above, specific parts of the present invention have been described in detail, and it is clear that these specific techniques are merely preferred embodiments, and the scope of the present invention is not limited thereto for those of ordinary skill in the art. Therefore, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

The present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases, wherein the composition according to the present invention, when administered to an individual suffering from a metabolic disease, very effectively lowers blood sugar, and is very suitable for preventing, improving or treating metabolic diseases. Can be used.

Claims (9)

1. A pharmaceutical composition for preventing or treating metabolic diseases comprising a compound represented by the following Formula 1, a pharmaceutically acceptable salt, hydrate, and solvate thereof as an active ingredient:

   [Formula 1]

   

   In Chemical Formula 1 of the present invention,

   L ₁ and L ₂ are each independently selected from the group consisting of C ₃ to C ₄₀ cycloalkylene, C ₆ to C ₆₀ arylene, and heteroarylene having 5 to 60 nuclear atoms;

   X and Y are each independently deuterium, halogen, cyano, nitro, sulfonyl, C ₁ ~ C ₁₀ alkylsulfonyl, azide, hydroxy, C ₁ ~ C ₄₀ alkyl, C ₂ ~ C ₄₀ Al Kenyl, C ₁ ~ C ₄₀ alkoxy, unsubstituted or substituted C ₆ ~ C ₆₀ aryloxy, unsubstituted or substituted C ₃ ~ C ₄₀ cycloalkyl, unsubstituted or substituted nuclear atoms of 3 to 20 Heterocycloalkyl, unsubstituted or substituted C ₆ ~C ₆₀ aryl, unsubstituted or substituted heteroaryl having 5 to 60 nuclear atoms, and -NR'R";

   The R'and R" are each independently hydrogen, C ₁ ~ C ₁₀ alkyl, C ₆ ~ C ₆₀ aryl, C ₃ ~ C ₄₀ cycloalkyl, C ₆ ~ C ₆₀ arylsulfonyl, the number of nuclear atoms Is selected from the group consisting of 5 to 60 heteroaryl;

   n And m is each independently selected from an integer of 0 to 5; N and m are not zero at the same time;

   When the X or Y is plural, each of the plurality of X or Y is the same or different from each other;

   The arylsulfonyl of R'and R'' is unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, and nitro.
2. The method of claim 1,

   L ₁ and L ₂ are phenylene;

   N and m are each independently an integer of 1 or 2;

   The X and Y are each independently sulfonyl, C ₁ ~ C ₁₀ alkylsulfonyl, C ₁ ~ C ₄₀ alkoxy, -NR'R", hydroxy, C ₆ ~ C ₆₀ aryloxy and unsubstituted or It is selected from the group consisting of substituted heterocycloalkyl having 3 to 20 nuclear atoms;

   The R'and R" are each independently hydrogen or C ₆ ~C ₆₀ arylsulfonyl;

   The aryl sulfonyl of R'and R" is unsubstituted or substituted by one or more halogens.
3. The method of claim 2,

   X is -NR'R" or a substituent represented by the following formula (3); And

   Wherein R'and R" are each independently hydrogen or a substituent represented by the following formula (4), a pharmaceutical composition:

   [Formula 3]

   

   [Formula 4]

   

   Here, R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C ₁ ~ C ₄₀ alkyl and C ₂ ~ C ₄₀ alkenyl;

   R ₂ is selected from the group consisting of hydrogen, deuterium, halogen, and nitro.
4. The method of claim 2,

   The Y is hydroxy, C ₁ ~ C ₆ alkoxy, or a substituent represented by the following formula 5, pharmaceutical composition:

   [Formula 5]

   
5. The method of claim 1,

   The composition comprises as an active ingredient at least one compound selected from the group consisting of the following compounds:

   
6. The method of claim 1,

   The metabolic disease is at least one selected from the group consisting of type 2 diabetes, dyslipidemia, insulin resistance, dyslipidemia, hepatic steatosis, arteriosclerosis and non-alcoholic fatty liver, Pharmaceutical composition.
7. A food composition for preventing or improving metabolic diseases comprising a compound represented by the following Formula 1, a pharmaceutically acceptable salt, hydrate, and solvate thereof as an active ingredient:

   [Formula 1]

   

   In Chemical Formula 1 of the present invention,

   L ₁ and L ₂ are each independently selected from the group consisting of C ₃ to C ₄₀ cycloalkylene, C ₆ to C ₆₀ arylene, and heteroarylene having 5 to 60 nuclear atoms;

   X and Y are each independently deuterium, halogen, cyano, nitro, sulfonyl, C ₁ ~ C ₁₀ alkylsulfonyl, azide, hydroxy, C ₁ ~ C ₄₀ alkyl, C ₂ ~ C ₄₀ Al Kenyl, C ₁ ~ C ₄₀ alkoxy, unsubstituted or substituted C ₆ ~ C ₆₀ aryloxy, unsubstituted or substituted C ₃ ~ C ₄₀ cycloalkyl, unsubstituted or substituted nuclear atoms of 3 to 20 Heterocycloalkyl, unsubstituted or substituted C ₆ ~C ₆₀ aryl, unsubstituted or substituted heteroaryl having 5 to 60 nuclear atoms, and -NR'R";

   The R'and R" are each independently hydrogen, C ₁ ~ C ₁₀ alkyl, C ₆ ~ C ₆₀ aryl, C ₃ ~ C ₄₀ cycloalkyl, C ₆ ~ C ₆₀ arylsulfonyl, the number of nuclear atoms Is selected from the group consisting of 5 to 60 heteroaryl;

   n And m is each independently selected from an integer of 0 to 5; N and m are not zero at the same time;

   When the X or Y is plural, each of the plurality of X or Y is the same or different from each other;

   The arylsulfonyl of R'and R" is unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, and nitro.
8. The metabolic disease is at least one selected from the group consisting of type 2 diabetes, dyslipidemia, insulin resistance, dyslipidemia, hepatic steatosis, arteriosclerosis and non-alcoholic fatty liver, Food composition.
9. A method for preventing or treating a metabolic disease comprising administering to an individual a compound represented by the following Formula 1, a pharmaceutically acceptable salt, hydrate, and solvate thereof in a pharmaceutically effective amount:

   [Formula 1]

   

   In Chemical Formula 1 of the present invention,

   L ₁ and L ₂ are each independently selected from the group consisting of C ₃ to C ₄₀ cycloalkylene, C ₆ to C ₆₀ arylene, and heteroarylene having 5 to 60 nuclear atoms;

   X and Y are each independently deuterium, halogen, cyano, nitro, sulfonyl, C ₁ ~ C ₁₀ alkylsulfonyl, azide, hydroxy, C ₁ ~ C ₄₀ alkyl, C ₂ ~ C ₄₀ Al Kenyl, C ₁ ~ C ₄₀ alkoxy, unsubstituted or substituted C ₆ ~ C ₆₀ aryloxy, unsubstituted or substituted C ₃ ~ C ₄₀ cycloalkyl, unsubstituted or substituted nuclear atoms of 3 to 20 Heterocycloalkyl, unsubstituted or substituted C ₆ ~C ₆₀ aryl, unsubstituted or substituted heteroaryl having 5 to 60 nuclear atoms, and -NR'R";

   The R'and R" are each independently hydrogen, C ₁ ~ C ₁₀ alkyl, C ₆ ~ C ₆₀ aryl, C ₃ ~ C ₄₀ cycloalkyl, C ₆ ~ C ₆₀ arylsulfonyl, the number of nuclear atoms Is selected from the group consisting of 5 to 60 heteroaryl;

   n And m is each independently selected from an integer of 0 to 5; N and m are not zero at the same time;

   When the X or Y is plural, each of the plurality of X or Y is the same or different from each other;

   The arylsulfonyl of R'and R" is unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, and nitro.

Images