WO2020139001A1 - Pharmaceutical composition for promotion of intracellular atp production - Google Patents

Abstract

The present invention provides a novel aryl-substituted aminomethyloxetenyl amino alcohol derivative or a pharmaceutically acceptable salt thereof. More specifically, the derivative has an effect of promoting ATP production and as such, can be advantageously used for preventing or treating a disease requiring an increased level of ATP for therapy thereof.

Description

Pharmaceutical composition for promoting ATP production in cells

The present invention relates to a pharmaceutical composition for promoting ATP production in cells.

Metabolic Disease (Metabolic Disease, Metabolic Syndrome) refers to diseases originating from metabolic abnormalities such as glucose, fat, and protein. Cancer, diabetes, bone metabolism, fatty liver, obesity, and cardiovascular diseases, which are mainly caused by glucose and fat metabolism abnormalities, etc. Collectively.

Midadorine, an alpha sympathetic stimulator, is a relatively safe drug with few side effects currently prescribed to patients in clinical trials.It has been shown to activate hypertension, hyperlipidemia, obesity, arteriosclerosis, and fatty liver failure by activating catabolic metabolism in cells and tissues in previous studies. We have found a similar exercise effect to improve back. Therefore, analogs that partially modify the chemical structure of this midodrine are likely to be developed as new drugs that can work better for cardiovascular, metabolic and inflammatory diseases while maintaining the safety of the existing drugs.

Prior Art Literature: Korean Patent Registration No. 10-1845952

It is an object of the present invention to provide an aryl-substituted aminomethyloxetenyl amino alcohol derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

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

The present invention provides an aryl substituted aminomethyloxetenyl amino alcohol derivative represented by Formula 1 below or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Chemical Formula 1,

A represents a C ₆ -C ₁₅ aryl group, or a 5 to 14 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms,

R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group comprising one or more selected from the group consisting of N, O, and S.

In one embodiment of the present invention, the aryl-substituted aminomethyloxetenyl amino alcohol derivative is selected from the group consisting of the following compounds: aryl-substituted aminomethyloxetenyl amino alcohol derivative or a pharmaceutically acceptable salt thereof. to provide:

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol (Formula 1-1, 2-((3-( aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethanol, Chemical Formula: C ₁₄ H ₂₂ N ₂ O ₄ ),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2-methoxyphenyl)ethan-1-ol (Formula 1-2, 2-((3-(aminomethyl)oxetan -3-yl)amino)-1-(2-methoxyphenyl)ethanol, Chemical Formula: C ₁₃ H ₂₀ N ₂ O ₃ )

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethan-1-ol (Formula 1-3, 2-((3-( aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethanol, Chemical Formula: C ₁₄ H ₂₂ N ₂ O ₄ ),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(3,5-dimethoxyphenyl)ethan-1-ol (Formula 1-4, 2-((3-( aminomethyl)oxetan-3-yl)amino)-1-(3,5-dimethoxyphenyl)ethanol, Chemical Formula: C ₁₄ H ₂₂ N ₂ O ₄ ),

;

;2-(2-((3-(aminomethyl)oxetan-3-yl)amino)-1-hydroxyethyl)-4-methoxyphenol (Formula 1-5, 2-(2-((3- (aminomethyl)oxetan-3-yl)amino)-1-hydroxyethyl)-4-methoxyphenol, Chemical Formula: C ₁₃ H ₂₀ N ₂ O ₄ ),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(4-aminophenyl)ethan-1-ol (Formula 1-6, 2-((3-(aminomethyl)oxetan- 3-yl)amino)-1-(4-aminophenyl)ethanol, Chemical Formula: C ₁₂ H ₁₉ N ₃ O ₂ ),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4,6-trimethoxyphenyl)ethan-1-ol (Formula 1-7, 2-((3 -(aminomethyl)oxetan-3-yl)amino)-1-(2,4,6-trimethoxyphenyl)ethanol, Chemical Formula: C ₁₅ H ₂₄ N ₂ O ₅ ),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(pyridin-3-yl)ethan-1-ol(Formula 1-8, 2-((3-(aminomethyl)oxetan -3-yl)amino)-1-(pyridin-3-yl)ethanol, Chemical Formula: C ₁₁ H ₁₇ N ₃ O ₂ ),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(5-bromothiophen-2-yl)ethan-1-ol (Formula 1-9, 2-((3- (aminomethyl)oxetan-3-yl)amino)-1-(5-bromothiophen-2-yl)ethanol, Chemical Formula: C ₁₀ H ₁₅ BrN ₂ O ₂ S),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(1-methyl-1H-pyrrole-3-yl)ethan-1-ol (Formula 1-10, 2-(( 3-(aminomethyl)oxetan-3-yl)amino)-1-(1-methyl-1H-pyrrol-3-yl)ethanol, Chemical Formula: C ₁₁ H ₁₉ N ₃ O ₂ ),

;

;2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(furan-2-yl)ethan-1-ol(Formula 1-11, 2-((3-(aminomethyl)oxetan -3-yl)amino)-1-(furan-2-yl)ethanol, Chemical Formula: C ₁₀ H ₁₆ N ₂ O ₃ ),

;

; 및2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(cyazole-5-yl)ethan-1-ol(Formula 1-12, 2-((3-(aminomethyl) oxetan-3-yl)amino)-1-(thiazol-5-yl)ethanol, Chemical Formula: C ₉ H ₁₅ N ₃ O ₂ S),

; And

.2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(benzofuran-2-yl)ethan-1-ol(Formula 1-13, 2-((3-(aminomethyl) oxetan-3-yl)amino)-1-(benzofuran-2-yl)ethanol, Chemical Formula: C ₁₄ H ₁₈ N ₂ O ₃ ),

.

In another embodiment of the present invention, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be a middrine analog or a pharmaceutically acceptable salt thereof, characterized in that it promotes ATP production.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof may have a weight control and/or weight loss use with reduced drug resistance and drug side effects.

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of a disease requiring an ATP increase comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the ATP increase is characterized by an increase in ATP in skeletal muscle, an increase in ATP in myocardium, an increase in ATP in leukocytes, or an increase in mitochondrial oxidative function.

As another embodiment of the present invention, the disease requiring an increase in ATP is metabolic syndrome, obesity, diabetes, hypertension, dyslipidemia, chronic fatigue syndrome, alcoholic liver disease, non-alcoholic liver disease, non-alcoholic steatohepatitis (NASH), Atherosclerotic vascular disease, aging, degenerative neurological disease, myasthenia, metabolic diseases related to hypothyroidism, heart failure, cardiomyopathy, left ventricular hypertrophy, hypoxia reperfusion injury, cardiac amyloidosis, chronic obstructive pulmonary disease, pulmonary fibrosis, atherosclerotic vascular disease, It may be one or more selected from the group consisting of myocardial infarction, angina pectoris, cerebral infarction, chronic inflammatory disease, malignant tumor, mitochondrial dysfunction disease and aging-related disease.

In addition, the present invention provides a pharmaceutical composition for weight control and/or weight loss with reduced drug resistance and drug side effects, including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention can provide a pharmaceutical composition for preventing or treating skin inflammatory diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition is provided in the form of an external preparation. It may be, but is not limited thereto.

As one embodiment of the present invention, the prevention or treatment of the skin inflammatory disease may be achieved to suppress the increase in the expression of IL-17A in skin cells, and the skin inflammatory disease is psoriasis, atopic dermatitis, and contact It may be one or more chronic dermatitis selected from the group consisting of dermatitis.

On the other hand, the present invention provides a method for preventing or treating a disease requiring an increase in ATP, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual.

In addition, the present invention provides a method for weight control and/or weight loss comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method for preventing or treating skin inflammatory diseases, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to an individual.

In addition, the present invention provides a cosmetic composition for protecting the skin barrier comprising the compound represented by Formula 1 or a salt thereof as an active ingredient, wherein the skin barrier protection is to protect the skin keratinocytes from external harmful substances and cause inflammation. It may be achieved by inhibiting an increase in cytokine expression.

The novel compounds of the present invention, by promoting the production of adenosine triphosphate (Adenosine Tri-Phosphate, ATP) can be useful for the prevention and treatment of metabolic diseases, cardiovascular diseases, inflammatory diseases, and the like. In addition, the compounds of the present invention may be used as a composition for weight control and/or weight loss with reduced side effects of drug-resistant drugs. In addition, the compounds of the present invention can reduce the increase in the expression of inflammatory cytokines in skin keratinocytes, and thus can be used as a composition for the prevention, treatment, and/or improvement of skin inflammatory diseases.

1 is a comparison of vasoconstrictor action of midodorin (MIDO) and desglymidodrine (ST1059).

Figure 2 shows the effect of middorine and desglymidodrine on the energy metabolism protein molecules PPARδ, AMPK, PGC1α.

Figure 3 shows the effect of middrine and desglymidodrine on the activity of succinate deydrogenase reflecting the function of the TCA cycle and ETC of the midchondria.

Figure 4 shows the effect of middrine and desglymidodrine on the oxygen consumption rate (OCR) reflecting the state of the oxidative function of the midchondria.

5 shows the results of NMR analysis of the compound of Formula 1-1.

6 shows the results of NMR analysis of the compound of Formula 1-2.

Figure 7 shows the results of NMR analysis of the compound 1-3.

8 shows the results of NMR analysis of the compound of Formula 1-4.

9 shows the results of NMR analysis of the compound of Formula 1-6.

Figure 10 shows the change in cell viability during treatment by concentration of new drug (sanmido-0571001, Formula 1-1) in C2C12 cells.

Figure 11 shows the change in the oxygen consumption rate (oxidative phosphorylation in cells) when 30 uM treatment of new drug (sanmido-0571001) middoline on C2C12 cells.

Figure 12 shows the change in the ATP concentration (intracellular energy state) in cells after treatment with middoline drug (NM) in C2C12 cells at concentrations of 10, 30, and 50 uM.

Figure 13 shows the change in cell viability during treatment by concentration of new drug in the middrine H9C2 cells.

FIG. 14 shows changes in the expression levels of PPARδ, AMPK, and PGC-1α proteins when H9C2 cells were treated with 10, 30, and 50 uM of mididoline new drug (sanmido-0571001).

Figure 15 shows the change in the oxygen consumption rate (oxidative phosphorylation in the cell) when treated with 30 uM of new drug (sanmido-0571001) in H9C2 cells.

Figure 16 shows the change in the ATP concentration (intracellular energy state) in cells after treatment with new drug (sanmido-0571001) midodrine in H9C2 cells at a concentration of 10, 30, 50 uM.

Figure 17 shows the immunocytochemical staining (immunocytochemistry: ICC) of CCR2 and mannose receptor protein expression in a state where 10, 30, 50 uM of new drug was given to Raw264.7 cells.

FIG. 18 shows p-eNOS ICC after treatment with middoline new drug (sanmido-0571001) at a concentration of 30M in the state of 50 uM treatment of cholesterol and palmitic acid in HUVECs.

19 shows AT1R (Angiotensin II type-1 receptor) ICC in the state of 10, 30, 50 uM treatment with sanmido-0571001 in HUVECs.

FIG. 20 shows sanmido-0571001[CVT1: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethane-1 in an in vitro arterial experiment in mice. -Ol], CVT2[2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethan-1-ol], CVT3[2-( (3-(aminomethyl)oxetan-3-yl)amino)-1-(2-methoxyphenyl)ethan-1-ol], CVT4[2-((3-(aminomethyl)oxetane-3- 1)amino)-1-(3,5-dimethoxyphenyl)ethan-1-ol], CVT5[2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(4 -Aminophenyl) ethane-1-ol], etc., respectively, 0.1, 1, 10, 30, 50 uM treated in the state of 15 minutes for blood vessel contraction.

FIG. 21 shows Western blot results showing changes in IL-17A expression following administration of a new drug (sanmido-0571001) for increased IL-17A expression by SDS or DNCB in HaCaT cells.

Alpha sympathetic stimulator, middoline compound known to improve hypertension, hyperlipidemia, obesity, arteriosclerosis, fatty liver heart failure, etc. is sold under the trade names of amatine, proamatine, gutron, etc. And the IUPAC name is (RS)-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]glycinamide ((RS)-N-[2-(2,5-dimethoxyphenyl)- 2-hydroxyethyl]glycinamide), which is represented by Formula 2 below.

[Formula 2]

Existing middrine compounds, as shown below, showed a half-life in the prodrug state of 25 minutes, and when metabolized to desglymidodrine (ST1059), an active drug by blood amidase or peptidase, the half-life increased to 3-4 hours.

Vasoconstriction is rare in prodrugs, but 10-15 times stronger in active drugs (Thulesius O et al. Eur J Clin Pharmcol 1979; 16:423-24 and Figure 1). On the other hand, in the case of energy metabolism, the present inventors measured using cell experiments, and prodrug, midodrine, was found to be stronger than desglymidodrine, an active drug (FIG. 2).

In addition, the effect of middrine and desglymidodrine on the activity of succinate deydrogenase reflecting the function of the TCA cycle and ETC, which represents the energy generation function of mitochondria, showed that midodrine appeared stronger than desglymidodrine (Figure 3).

In addition, in the test for measuring the degree of oxidative action in mitochondria, it was confirmed that more oxidative action occurred than desglymidodrine when administration of midodrine (FIG. 4).

Therefore, it can be seen that middrine, a prodrug, has a stronger metabolism of mitochondria, which is more metabolically stronger than desglymidorine, an active drug.

Accordingly, in the present invention, in the prodrug state, middrine [DMAE-glycine: (1-(2',5'-dimethoxyphenyl)-2-aminoethanol)-glycine is an active drug, desglymidodrine [DMAE: (1-(2', To maintain the metabolized state with 5'-dimethoxyphenyl)-2-aminoethanol), the peptide bond connecting DMAE and glycine is not hydrolyzed by peptidase or aminase in the blood, and replaced with a new bond that maintains the connection. A new substance remaining in DMAE-glycine was synthesized to confirm its metabolism.

As a result, the aryl-substituted aminomethyloxetenyl amino alcohol derivative represented by the following Chemical Formula 1 synthesized in the present invention or a pharmaceutically acceptable salt thereof, together with the effect of increasing ATP in skeletal muscle, myocardium, and white blood cells, and the effect of increasing mitochondrial oxidation function The effect of suppressing the increase in inflammatory cytokine expression by external stimulation in skin keratinocytes was confirmed, thereby completing the present invention.

Accordingly, the present invention aims to provide an aryl-substituted aminomethyloxetenyl amino alcohol derivative represented by Formula 1 below or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Chemical Formula 1,

A represents a C ₆ -C ₁₅ aryl group, or a 5 to 14 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms,

R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group including one or more selected from the group consisting of N, O, and S.

Therefore, the novel compound of the present invention has no vasoconstriction function, which is a characteristic of a typical alpha-1 adrenergic receptor activating agent, but can provide a new kind of activating agent mainly exhibiting energy metabolic activation function.

On the other hand, the novel compounds synthesized in the present invention may be used interchangeably with the terms "new drug of mididorin" and "midodorin analog", and "new drug" herein refers to the new drug of mididorin.

In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of a disease in need of ATP increase comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The increase in ATP may be an increase in ATP in skeletal muscle, an increase in ATP in myocardium, an increase in ATP in white blood cells, or an increase in mitochondrial oxidative function.

In another aspect, the present invention provides a composition for weight control and/or weight loss comprising the compound represented by Formula 1 or a salt thereof as an active ingredient, which is a drug for the purpose of weight control and/or weight loss, or It can be added to food.

In another aspect, the present invention provides a composition for the prevention, treatment, and/or improvement of skin inflammatory diseases comprising the compound represented by Formula 1 or a salt thereof as an active ingredient, which is an inflammatory cytokine in skin keratinocytes. It can suppress a decrease in expression or an increase in its expression, and can be added to drugs or cosmetics for the purpose of preventing, treating, and/or improving skin inflammatory diseases.

The effects of the new compounds of the present invention are as follows:

end). ATP increase in skeletal muscle

-Intermediate metabolic markers: PPARδ (Peroxisome Proliferator activated Receptor-δ), AMPK (AMP-activated protein kinase), PGC-1α (Peroxisome proliferator-activated receptor Gamma Coactivator-1α), mitochondrial oxidative phosphorylation (oxygen consumption rate: OCR ), Succinate dehydrogenase activity

-Direct effect: Improvement of systolic and diastolic functions

-Target diseases: metabolic syndrome, obesity, diabetes, high blood pressure, dyslipidemia, chronic fatigue syndrome, alcoholic liver disease, non-alcoholic liver disease, non-alcoholic fatty hepatitis (NASH), arteriosclerotic vascular disease, aging, degenerative neurological disease ( AD, PD, MS, hypoxic brain damage, etc.), work history, metabolic diseases related to hypothyroidism, etc.

I). Increased myocardial ATP

-Intermediate metabolic markers: PPARδ, AMPK, PGC-1α, mitochondrial oxidative phosphorylation (oxygen consumption rate: OCR), succinic dehydrogenase activity

-Direct effect: increase skeletal muscle strength and improve exercise ability and endurance

-Target diseases: heart failure (systolic heart failure: Heart failure with reduced Ejection Fraction: HFrEF, diastolic heart failure: preserved Ejection Fraction: HFpEF), hypertrophic cardiomyopathy, left ventricular heart failure, hypoxia reperfusion Hypoxia-reperfusion injury, amyloid heart, doxorubicin-induced cardiomyopathy, septic cardiomyopathy

All). Increased phosphorylated eNOS expression in vascular endothelial cells and decreased AT1R expression in Angiotensin II

-Intermediate metabolic markers: PPARδ, AMPK, PGC-1α, mitochondrial oxidative phosphorylation (oxygen consumption rate: OCR), succinic acid dehydrogenase activity

-Direct effect: inhibition and relaxation of vasoconstrictor action

-Target diseases: hypertension and hypertensive heart disease, heart failure with low blood pressure, coronary spasm and variant angina, atherosclerotic vascular disease-myocardial infarction, angina, cerebral infarction, peripheral arterial occlusive disease, Buerger's disease

la). ATP increase in white blood cells

-Intermediate metabolic markers: PPARδ, AMPK, PGC-1α, mitochondrial oxidative phosphorylation (oxygen consumption rate: OCR), succinic dehydrogenase activity, decreased CCR, and increased Mannose receptor expression

-Direct effect: anti-inflammatory action

-Target diseases: chronic obstructive pulmonary disease, pulmonary fibrosis, atherosclerotic vascular disease-myocardial infarction, angina, cerebral infarction, chronic inflammatory disease, malignant tumor

hemp). Increased mitochondrial oxidation

-Intermediate metabolic markers: mitochondrial oxidative phosphorylation (oxygen consumption rate: OCR), increased succinic acid dehydrogenase activity,

-Direct effect: cell energy charging

-Target disease: Mitochondrial dysfunction disease

bar). Reduction of IL-17A expression in cutaneous keratinocytes (HaCaT)

-Intermediate metabolic markers: PPARδ, AMPK, PGC-1α, mitochondrial oxidative phosphorylation (oxygen consumption rate: OCR), succinic acid dehydrogenase activity

-Direct effect: anti-inflammatory effect due to reduction of skin inflammation-induced cytokine expression

-Target diseases: chronic dermatitis such as psoriasis, atopic dermatitis, contact dermatitis, etc.

In another aspect, the present invention provides a pharmaceutical composition for weight control and/or weight loss with reduced drug resistance and drug side effects, including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The following describes the terms and definitions of various substituents according to the present invention.

The term “C ₆ -C ₁₅ aryl group” used in the present invention means an unsaturated aromatic cyclic compound having 6 to 15 carbon atoms having a single ring (eg phenyl) or a plurality of condensed rings (eg naphthyl). do. The aryl includes phenyl, naphthyl and the like.

The heteroaryl group means a ring compound in which 1 to 4 different atoms of the ring constituent atoms are present, and the different atoms may be nitrogen, oxygen, or sulfur, for example, furan, benzofuran, pyrrole, cyazole, etc. The same functional group is exemplified.

The term "C ₁ -C ₇ alkyl" used in the present invention means a monovalent alkyl group having 1 to 7 carbon atoms. The term is exemplified by functional groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-hexyl, and the like. Alkyl described in the present invention, and other substituents comprising an alkyl moiety includes both straight-chain or pulverized forms.

The term "C ₁ -C ₇ alkoxy" used in the present invention means the -OR group, where R means "C ₁ -C ₇ alkyl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like. Substituents comprising the alkyl, alkoxy and other alkyl moieties described in the present invention include both straight-chain or ground forms.

The term "C ₇ -C ₁₃ arylalkyl" used in the present invention means an alkyl group having an aryl substituent including benzyl, phenylethyl, and the like.

The compound of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.

The term "salt" used in the present invention is useful an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol Rate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention is dissolved in a conventional method, for example, by dissolving the compound in an excess of an aqueous acid solution, and the salt is precipitated using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by ordering. It can also be prepared by evaporating a solvent or excess acid from this mixture, then drying it or suction-filtering the precipitated salt.

It is also possible to make pharmaceutically acceptable metal salts using bases. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the inexpensive compound salt, and evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

In addition, the compounds of the present invention include all salts, isomers, hydrates and solvates that can be prepared by conventional methods, as well as pharmaceutically acceptable salts.

In the present invention, "prevention" refers to all actions that inhibit ATP reduction by administration of the composition according to the present invention or delay a disease in which ATP increase is necessary, and "treatment" means ATP by administration of the composition according to the present invention. Refers to all actions that improve or beneficially change the symptoms of a disease that requires increased production or increased ATP.

The present invention provides a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as a new drug, and a method for preventing or treating diseases and/or skin inflammatory diseases that require ATP increase by administering the new drug to an individual Gives

In addition, the present invention provides a method for weight control and/or weight loss comprising the step of administering the new drug to an individual, and the method for weight control and/or weight loss of the present invention comprises each cell constituting an individual (especially skeletal muscle cells). , Myocardial cells, and leukocyte cells) to improve the metabolic ability and function (mitochondrial function and ATP production amount) to suppress the body weight gain or induce the reduction of the drug resistance and side effects.

Accordingly, the present invention may provide a food composition comprising the new drug, that is, the compound represented by Formula 1 or a salt thereof as an active ingredient, and the compound represented by Formula 1 or a salt thereof may control weight and/or weight It can be added to foods for the purpose of relief. Food in the present invention is meant to include functional foods and health functional foods. When the compound represented by Formula 1 of the present invention or a salt thereof is used as a food additive, the compound represented by Formula 1 or a salt thereof may be added as it is or used with other food or food ingredients, and appropriately used according to a conventional method. Can be used. The mixing amount of the active ingredient can be appropriately determined according to the purpose of use (prevention, health, or therapeutic situation).

In addition, the present invention was confirmed that the expression of IL-17A in HaCaT cells is increased by treating DNCB or SDS on skin keratinocytes (HaCaT) through specific examples, and when DNCB or SDS is used in combination with the new drug of the present invention It has been confirmed that the increase in expression of IL-17A is remarkably low. The new drug of the present invention protects the skin barrier from harmful substances that cause skin inflammation and damage to the skin barrier, such as SDS and DNCB, or prevents inflammatory skin diseases. It was found that treatment is possible.

In addition, SDS and DNCB are surfactants and organic solvents that can be easily contacted in everyday life, and the new drug of the present invention may be included in a cosmetic composition for the purpose of preventing or improving skin inflammatory diseases along with skin barrier protection. In this case, "prevention" means any action that delays the increase in the expression of inflammatory cytokines in skin keratinocytes by administration of the composition according to the invention, and "treatment" is inflammation of the skin by administration of the composition according to the invention Refers to all actions in which disease symptoms are improved or beneficially altered, and "improvement" is an inflammatory cytokine (IL-17A) of keratinocytes (including keratinocytes, etc.) forming the physical barrier of the skin by administration of the composition according to the present invention. All the actions to suppress the increase in expression or decrease the severity of symptoms associated with skin inflammatory diseases, including symptoms.

On the other hand, "individual" in the present invention is not limited if it is a mammal, but preferably refers to a human who needs an increase in ATP, needs weight control and/or alleviation, or needs to prevent or treat skin inflammatory diseases.

The formulation of the cosmetic composition according to the present invention is a skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, foundation, essence, nutrition essence, It may be in the form of a pack, soap, cleansing foam, cleansing lotion, cleansing cream, body lotion or body cleanser.

The pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, but is not limited thereto. In addition, lubricants, wetting agents, sweetening agents, flavoring agents, emulsifying agents, suspending agents, preservatives, etc. may be further included in addition to the above components.

The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage may be adjusted according to the patient's condition, weight, and disease. It depends on the degree, drug type, route of administration, and time, but can be appropriately selected by those skilled in the art.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "a pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, Sensitivity to the drug, time of administration, route of administration and discharge rate, duration of treatment, factors including co-drugs, and other factors well established in the medical field can be determined. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered in single or multiple doses. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption of active ingredients in the body, inactivation rate and excretion rate, disease type, and drugs used in combination. 0.001 to 150 mg per kg body weight, preferably 0.01 to 100 mg can be administered daily or every other day, or divided into 1 to 3 times a day. However, since the dosage may be increased or decreased depending on the route of administration, the severity of obesity, gender, weight, and age, the dosage is not limited to the scope of the present invention in any way.

In another aspect of the present invention, the present invention provides a method of treating a disease in need of increased ATP, comprising administering the pharmaceutical composition to a subject. In the present invention, "individual" means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, a mammal such as a mouse (mouse, dog, cat, horse, and cow).

In Examples 4 to 6 of the present invention, the effect of increasing ATP production was confirmed, and the effect of lowering blood pressure in blood vessels was confirmed. As a result, the derivatives of the present invention may be useful for the treatment and prevention of diseases requiring an increase in ATP. Is judged.

Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

[Example]

Example 1: Compound Synthesis

1-1: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol synthesis [sanmido-0571001]

[Formula 1-1]

Step 1: tert -Butyl((3-(dibenzylamino)oxetan-3-yl)methyl)carbamate

[Formula 1-1-1]

In a round bottom flask, 3-(aminomethyl)-N,N-dibenzyloxetane-3-amine (1.0 g, 3.54 mmol) was added, and tetrohydrofuran (20 mL) was added to dissolve. Sodium carbonate (1.05 g, 10.6 mmo) is dissolved in distilled water (6 mL) and added at 0°C. After stirring at 0° C. for 10 minutes, di-tert-butyl dicarbonate (864 mg, 4.25 mmol) is added. After stirring at room temperature for 4 hours, the reaction solution was extracted with ethyl acetate and water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column column chromatography (20% ethyl acetate/hexane) to obtain the target compound (1.0 g, 72%). LCMS (ESI) m/z 383 [M + H]<+>.

Step 2: tert -Butyl((3-aminooxetan-3-yl)methyl)carbamate

[Formula 1-1-2]

In a round bottom flask, tert-butyl((3-(dibenzylamino)oxetan-3-yl)methyl)carbamate (1.0 g, 2.61 mmol) was added, and methanol (10 mL) was added and dissolved. Then, Pd/C (100 mg) was added, and hydrogen gas was pressurized using a hydrogen balloon. After stirring for 6 hours, it was filtered through a pad of celite and concentrated. Then, dichloromethane and ethyl ether were used to wash the target compound (400 mg, 76%). LCMS (ESI) m/z 203 [M + H]<+>.

Step 3: 2-Bromo-1-(2,5-dimethoxyphenyl)ethan-1-one

[Formula 1-1-3]

In a round bottom flask, 2,5-dimethoxy acetophenone (1.0 g, 5.55 mmol) was added, and ethanol (25 mL) was added and dissolved. After adding cooper(II) bromide (2.0 g, 1.61 mmol) at room temperature, the mixture was stirred at 60 oC for 24 hours. After filtering through a pad of celite, it was extracted using dichloromethane and sodium thiosulfate solution. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column column chromatography (10% ethyl acetate/hexane) to obtain the target compound (850 mg, 60%). LCMS (ESI) m/z 259 [M + H]<+>.

Step 4: tert -Butyl ((3-((2-(2,5-dimethoxyphenyl)-2-oxoethyl)amino)oxetan-3-yl)methyl)carbamate

[Formula 1-1-4]

In a round bottom flask, tert-butyl((3-aminooxetan-3-yl)methyl)carbamate (100 mg, 0.49 mmol) was added and acetonitrile (5 mL) was added and dissolved. 2-Bromo-1-(2,5-dimethoxyphenyl)ethan-1-one (125 mg, 0.5 mmol) was dissolved in acetonitrile (2 mL) and slowly added at 0 oC, diisopropylethyl Amine (0.14 mL, 1 mmol) was performed. After stirring at room temperature for 3 hours, the reaction solution was extracted with ethyl acetate and water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column column chromatography (50% ethyl acetate/hexane) to obtain the target compound (760 mg, 40%). LCMS (ESI) m/z 381 [M + H]<+>.

Step 5: tert -Butyl((3-((2-(2,5-dimethoxyphenyl)-2-hydroxyethyl)amino)oxetan-3-yl)methyl)carbamate

[Formula 1-1-5]

Tert-butyl((3-((2-(2,5-dimethoxyphenyl)-2-oxoethyl)amino)oxetan-3-yl)methyl)carbamate (50 mg, 0.13 mmol) in a round bottom flask ) Was added, and metalol (5 mL) was added and dissolved. Sodium borohydride (12 mg, 0.3 mmol) was slowly added at 0° C., followed by stirring at room temperature for 20 minutes, and then saturated aqueous ammonium chloride solution (2 mL) was added to terminate the reaction. The reaction solution was extracted with ethyl acetate and water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column column chromatography (50% ethyl acetate/hexane) to obtain the target compound (35 mg, 78%). LCMS (ESI) m/z 383 [M + H]<+>.

Step 6: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol

[Formula 1-1]

Tert-butyl((3-((2-(2,5-dimethoxyphenyl)-2-hydroxyethyl)amino)oxetan-3-yl)methyl)carbamate (20 mg, 0.05 in a round bottom flask mmol) was added and 1 mL of dichloromethane was added and dissolved. 4 N HCl-1,4-dioxane solution (1 mL) was added, followed by stirring at room temperature for 30 minutes. After the reaction solution was concentrated, it was washed with metalol and ethyl ether to obtain the target compound (11 g, 66%). LCMS (ESI) m/z 283 [M + H]<+>.

The results of NMR analysis of the prepared compounds are shown below (FIG. 5).

1- 2: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2-methoxyphenyl)ethan-1-ol

[Formula 1-2]

The synthesis method is the same as in Example 1, except that 1-(2,5-dimethoxyphenyl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 253 [M + H]<+>.

The results of NMR analysis of the prepared compounds are shown below (FIG. 6).

1-3: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethan-1-ol

[Formula 1-3]

The synthesis method is the same as in Example 1, except that 1-(2,4-dimethoxyphenyl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 283 [M + H]<+>.

The results of NMR analysis of the prepared compounds are shown below (FIG. 7).

1-4: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(3,5-dimethoxyphenyl)ethan-1-ol

[Formula 1-4]

The synthesis method is the same as in Example 1, except that 1-(3,5-dimethoxyphenyl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 283 [M + H]<+>.

1-5: 2-(2-((3-(aminomethyl)oxetan-3-yl)amino)-1-hydroxyethyl)-4-methoxyphenol

[Formula 1-5]

The synthesis method is the same as in Example 1, except that 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 269 [M + H]<+>.

1-6: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(4-aminophenyl)ethan-1-ol

[Formula 1-6]

The synthesis method is the same as in Example 1, except that 1-(4-aminophenyl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 238 [M + H]+.

The results of NMR analysis of the prepared compounds are shown below (FIG. 8).

1-7: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4,6-trimethoxyphenyl)ethan-1-ol

[Formula 1-7]

The synthesis method is the same as in Example 1, except that 1-(2,4,6-trimethoxyphenyl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 313 [M + H]<+>.

1-8: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(pyridin-3-yl)ethan-1-ol

[Formula 1-8]

The synthesis method is the same as in Example 1, except that 1-(pyridin-3-yl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 224 [M + H] ⁺ .

1-9: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(5-bromothiophen-2-yl)ethan-1-ol

[Formula 1-9]

The synthesis method is the same as in Example 1, except that 1-(5-bromothiophen-2-yl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 308 [M + H] ⁺ .

1-10: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(1-methyl-1 H -Pyrrole-3-yl)ethan-1-ol

[Formula 1-10]

The synthesis method is the same as in Example 1, except that in step 3, 1-(1-methyl- 1H -pyrrole-3-yl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone. LCMS (ESI) m/z 226 [M + H] ⁺ .

1-11: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(furan-2-yl)ethan-1-ol

[Formula 1-11]

The synthesis method is the same as in Example 1, except that 1-(furan-2-yl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 213 [M + H] ⁺ .

1-12: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(cyazole-5-yl)ethan-1-ol

[Formula 1-12]

The synthesis method is the same as in Example 1, except that 1-(cyazole-5-yl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 230 [M + H] ⁺ .

1-13: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(benzofuran-2-yl)ethan-1-ol

[Formula 1-13]

The synthesis method is the same as in Example 1, except that 1-(benzofuran-2-yl)ethan-1-one was used instead of 2,5-dimethoxy acetophenone in Step 3. LCMS (ESI) m/z 263 [M + H] ⁺ .

Example 2: Experimental method

2-1) C2C12, H9C2, HUVEC, Raw264.7 cell culture method

C2C12 (mouse skeletal cell line), H9C2 (rat cardiac muscle cell line), and Raw264.7 (mouse macrophage cell line) cells are 10% fetal bovine serum (FBS) and 1% in a 37°C, 5% CO ₂ incubator. Cultured in high glucose Dulbecco's modified eagle's medium (DMEM) containing antibiotic antimycotic solution (AA). HUVEC (human umbilical vein endothelial cells) were cultured with a dedicated medium for vascular endothelial cell culture (manufactured by Therma). All other cell culture-related reagents were purchased from Weljin (Gyeongsangbuk-do, Korea).

C2C12, H9C2, and Raw264.7 cells were dispensed in 6-well plates and 96-well plates at 2.0×10 ⁵ cells and 1.0×10 ⁴ cells per well, respectively. In the state of adding high glucose DMEM medium, the new drug was treated with concentrations of 10, 30, and 50 uM, followed by incubation for 24 hours.

When HUVEC cells are grown to 80% by dispensing 1.0×10 ⁴ cells per well in a 96 well plate, the medium drug is treated with 10, 30, 50 uM concentration in the state of adding HUVEC-specific medium, and then cultured for 24 hours Experimented.

2-2) Cell viability test

Cell viability was measured using a cell counting kit-8 (CCK-8, Dojindo laboratories, Kumamoto, Japan). Cells were aliquoted into 96 well culture plates at 1.0×10 ⁴ cells per well, and cultured for 24 hours in an incubator at 37° C. and 5% CO ₂ conditions. Middrine new drug (samido-0571001) was treated for each concentration and incubated for 24 hours, followed by incubation for 3 hours by adding 10 μl of CCK-8 solution per well.

After incubation, absorbance was measured at 450 nm using a SpectraMax Plus 384 Microplate Reader (Molecular Devices LLC. Sunnyvale, CA, USA).

2-3) Western blot analysis

After the drug treatment, the cells cultured for 24 hours were collected by scraping with a scraper, and then left to stand in a protein extraction solution for 20 minutes to extract the protein and quantified using Bradford reagent. Mix the extracted protein with sample buffer, boil it at 95℃ for 5 minutes, then electrophore it on 10% polyacrylamide gel, transfer the protein to the Nitrocellulose membrane (blotting), membrane blocking -> sequential binding of primary and secondary antibodies -> chemiluminescent reagent After adding (chemiluminescent reagents), protein expression was confirmed through the process of photosensitive -> development on the x-ray film.

2-4) Immunocytochemistry staining method (Immunocytochemistry, ICC)

Cells dispensed on a 96 well plate were fixed at minus 20°C in methanol for 15 minutes and 4% formaldehyde (Biosesang) for 5 minutes. After reacting with 0.3% H ₂ O ₂ solution for 5 minutes, it was washed with PBS. After reacting with 0.5% SDS for 10 minutes, washing with PBS 3 times, blocking with blocking solution for 1 hour. The CCR2 (Abcam), phosphorylated-eNOS (Invitrogen), AT1R (Novus), and mannose receptor (Abcam) primary antibodies were reacted at room temperature for 1 hour, and then washed 3 times with PBS. VECTASTAIN ABC kit was purchased from Vector Laboratories (Burlingame, CA, USA). After treating the secondary antibody for 30 minutes, and then washing with PBS, VECTASTAIN ABC reagent was treated for 30 minutes, followed by washing with PBS, reacting with DAB solution until desired color development, and then washing with running water. After staining the nucleus with Hematoxylin (Sigma-Aldrich), it was observed under a microscope.

2-5) Measurement of oxygen consumption rate

1. Remove the'Cell Culture Microplate' (blue package) from the clean bench and seed the cells to be tested in each well. (It is recommended for one group to seed more than the minimum triplicate.) Then, 8 moat chambers around the well were filled with 3,200 μL of D.W., 400 μL each.

2. 80 μL of CO ₂ culture media/cell was added to the well, and CO _{2 was} incubated until the day of XF assay. (On the day of the experiment, seeding is performed so that up to about one-third of the cell number corresponding to 80%-90% confluence can be cultured based on a typical 96 well.

3. The well (background well) that was not seeded was filled with the same amount of culture media (XFp; 80μL).

4. Drug handling

5. Take the'Sensor Cartridge+Utility Plate' (green package) from the clean bench, put 200μL/well of XF calibrant buffer into the well in the'Utility Plate', fill the entire moat with 400 μL of 400 μL each in the moat, and fill a total of 3.2mL DW. Cartridge+Spacer' was re-covered and overnight in a non-CO ₂ incubator (37℃).

6. After confirming the carbon source composition of the media used for CO ₂ culture, D-glucose, sodium pyruvate and L-glutamine of the same concentration were added to'XF Base Media'.

-After preheating to 37℃, the pH was adjusted to 7.4 (NaOH is recommended).

7. The'Cell Culture Microplate' incubated in the CO ₂ incubator was taken out and carefully rinsed twice with the prepared'XF Running Media', and then filled with the same media to a final 180 μL/well. (Residual pressure during suction during rinse or'PIPETTING')

; During rinse, media was replaced while leaving 20μL for each well (to prevent the cells in each well from drying out).

8. As above,'XF Running Media' was filled and non-CO ₂ incubation was performed for 1 hour.

9. The drug compound to be put in the drug port was prepared. (Resuspend and dilute using'XF base media'.)

10. Take out the'Sensor Cartridge+Utility Plate' contained in the Non-CO ₂ Incubator and carefully insert the prepared drug into each drug port as much as it is.

11. Non-CO ₂ incubation of'Sensor Cartridge+Utility Plate' filled with the drug for about 5-10 minutes.

2-6) ATP concentration measurement

1. The desired number of coated wells were fixed and added to the holder.

100 μL of standard sample solution and sample solutions were added to each well. Add 10 μL of Balance Solution to the wells containing the sample. 100 μL of PBS (pH 7.0-7.2) is added to the blank control well.

2. 50 μL of Conjugate solution was added to each well (not into a blank control well) and incubated at 37° C. for 1 hour.

3. After discarding the reaction solution, add 200 μL of 1× wash solution and wash. This process was repeated five times.

4. 50 μL of Substrate A and B solutions were added to each well and reacted at 37° C. for 10-15 minutes.

5. After adding 50 μL of the reaction stopper, absorbance was measured after setting the UV wavelength to 450 nm in a micro plate reader.

Example 3: Confirmation of cell viability after concentration-dependent treatment of the new drug in C2C12 cells

Up to a concentration of 50 uM, cell viability was increased in a concentration-dependent manner, and there was no change in cell viability until a high concentration of 150 uM (FIG. 10). Therefore, it was confirmed that the drug side effects would not appear even when the new drug of the middrine of the present invention was used.

Example 4: Improvement of mitochondrial function of skeletal muscle cells and increased ATP production

Oxygen consumption was measured after 30 uM treatment of new drug (sanmido-0571001) on C2C12 cells. Oxygen consumption was slightly increased compared to the control group after treatment with 30 uM of middrine for 24 hours (FIG. 11).

C2C12 cells were treated with new drug middoline at concentrations of 10, 30, and 50 uM, and then ATP concentration was measured. In the experimental group treated with 30 uM of new drug, the intracellular ATP concentration increased compared to the control group (FIG. 12).

Through the above results, it was confirmed that the middrine drug of the present invention can be utilized for the treatment and prevention of diseases requiring increased ATP in skeletal muscle cells.

Example 5: Improvement of mitochondrial function of cardiomyocytes and increase of ATP production

The cell viability was measured after treatment with new concentration of middrine drug in H9C2 cells. Middrine new drug had no change in cell viability until 50 uM and the highest cell viability at 30 uM (FIG. 13 ).

After treatment with middrine new drug (sanmido-0571001) in H9C2 cells at concentrations of 10, 30, and 50 uM, changes in expression levels of PPARδ, AMPK, and PGC-1α were compared with midodrine (30uM). Western blot results are shown in FIG. 14. The expression of PPARδ, AMPK, and PGC-1α proteins in the 30 uM treatment group of middrine new drug (sanmido-0571001) was increased compared to the control group.

Oxygen consumption was measured after treatment with 30 uM of a new drug (sanmido-0571001) in middoline on H9C2 cells (FIG. 15). After 24 hours of treatment with 30 uM sanmido-0571001, the oxygen consumption rate increased significantly compared to the control group.

ATP concentration was measured after treatment with new drugs (sanmido-0571001) of mididoline in H9C2 cells at concentrations of 10, 30, and 50 uM (FIG. 16). Compared to the control group, ATP concentration tended to increase when the new drug was given.

Through the above results, it was confirmed that the middrine new drug of the present invention can be used for the treatment and prevention of diseases requiring increased ATP in myocardial cells.

Example 6: Improvement of mitochondrial function of white blood cells and increased ATP production

CMD2 (inflammatory effect) and mannose receptor (anti-inflammatory labeling factor) Immunocytochemistry are shown in FIG. 17 after treatment with a new drug (sanmido-0571001) in raw264.7 cells at a concentration of 10, 30, 50 uM. When treated with new drug, the CCR2 decreased and the mannose receptor increased compared to the control group.

Through the above results, it was confirmed that the middrine new drug of the present invention can be used for the treatment and prevention of diseases requiring an increase in ATP in leukocytes.

Example 7: Effect of vascular endothelial cell eNOS and angiotensin II on AT1 receptor

Immunocytochemistry of p-eNOS (blood pressure lowering through vascular relaxation) after treatment with 30 uM of mididoline drug (sanmido-0571001) in the treatment of 50 uM of Cholesterol and 50 uM of palmitic acid in HUVECs is shown in FIG. 18.

As a result, when cholesterol and palmitic acid were treated, the protein expression of p-eNOS was decreased compared to the normal control group, but when the new drug (sanmido-0571001) was treated, it was increased compared to the cholesterol and palmitic acid treated groups. It can be seen that new drugs have the effect of relaxing blood vessels.

Immunocytochemistry of AT1R (hypertensive action of blood pressure through vasoconstriction) after treatment of HUVECs with a new drug (sanmido-0571001) at a concentration of 10, 30, 50 uM is shown in FIG. 19. In the 30 μM and 50 uM treatment groups of middrine, AT1R protein expression was significantly decreased compared to the control group.

Through the above results, it can be confirmed that the new drug of the present invention has an effect of lowering blood pressure.

Example 8: Effect on arterial vasoconstriction

Immediately after extracting the thoracic aorta from a 4-week-old experimental C57BL/6 mouse, it was divided into 3 mm sections after removal of surrounding connective tissue without damage to vascular endothelial cells. Each section was immersed in a chamber containing Kreb's solution and then connected to a muscle contraction transducer (Mechano-transducer 620M, Denmark). During the experiment, the chamber was maintained at a temperature of 37°C, oxygen 95%, and carbon dioxide 5%. After stabilization for one hour by setting the initial tension to 0.7 to 0.9 g, each new drug was treated with concentrations (0.1 μM, 1 μM, 10 μM, 30 μM, and 100 μM) and the contraction reaction was observed for 15 minutes (FIG. 20 ). ).

Through the above results, it can be confirmed that the new drug of the present invention has an effect of not contracting normal blood vessels.

Example 9: Effect of a new drug (sanmido-0571001) on IL-17A expression after SDS and DNCB treatment in skin cells (HaCaT)

After dispensing the cells in a 96-well culture dish, grow to 80% cell confluence with 10% FBS and 1% antibiotic-containing medium (DMEM), and change the medium with 1% FBS-containing medium. The experiment was conducted 24 hours after treatment with the drug (SDS, DNCB, and/or sanmido-0571001,). All the culturing procedures were performed in a sterile laboratory table (clean bench), and the cells were cultured in a CO ₂ incubator at 37°C.

To determine the appropriate concentrations of SDS (sodium dodecyl sulfate) and DNCB (2,4-Dinitrochlorobenzene) treated in the HaCaT cell line, 5,000 cells were dispensed per well in a 96-well culture dish, and after 24 hours, SDS and DNCB were 5 to 2000 μM, respectively. , And then treated with concentrations of 0.5 to 400 μM, and after 24 hours, 10 μl of CCk-8 reagent was added to each well, and after 2 hours, absorbance at a wavelength of 450 nm was measured using an ELISA reader, and cell viability was 50%. The concentration to be reduced was determined as the appropriate treatment concentration, and the concentration was 50 μM for SDS and 10 μM for DNCB. In addition, in the case of midodrine, the appropriate treatment concentration was determined to be 30 μM. For reference, SDS (sodium dodecyl sulfate) is a surfactant that can damage the skin barrier by prolonged contact with the skin, roughening the skin and causing dermatitis if severe. DNCB (2,4-dinitrochlorobenzene) is an organic solvent commonly known to cause contact dermatitis and atopic dermatitis.

After treating 30 μM of new drug (sanmido-0571001) with skin cells (HaCaT) treated with 10 μM of DNCB or 50 μM of SDS for 24 hours, the protein was extracted and tested after measuring the protein using the Bradford method. 10 ug of the extracted protein was subjected to 10% SDS-PAGE (sodium dodecyl sulfate polyacrylamide) electrophoresis and then blotted on a nitrocellulose membrane, followed by 5% skim milk solution (dissolved in TBS (TBS-T) containing 0.05% tween20) at room temperature 2 After blocking for 12 hours or more at 4° C. or longer, the IL-17A primary antibody was bound for 2 hours at room temperature. After washing with TBS-T, the secondary antibody was bound for 1 hour at room temperature, then washed with TBS-T, treated with chemiluminescent substrate and enhancer solutions, photosensitive to x-ray film in the dark, and developed. solution), and soaked in a fixing solution for a suitable time to check the protein expression level.

Figure 21 shows the Western blot results showing the expression level of IL-17A according to the new drug (sanmido-0571001) treatment in turn. When sanmido-0571001 was combined with SDS or DNCB compared to SDS or DNCB alone, the expression level of IL-17A protein was decreased in both cases (FIG. 20 ).

The result is that when the skin is exposed to harmful substances such as SDS and DNCB, the skin barrier is protected by using drugs containing a new drug (sanmido-0571001) as an active ingredient, and skin protection or skin inflammation through reduction of cell metabolism and inflammation It means that it can be effective in prevention and treatment.

The above description of the present invention is for illustration only, and a person having ordinary knowledge in the technical field 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.

The novel compounds of the present invention, by promoting the production of adenosine triphosphate (Adenosine Tri-Phosphate, ATP) can be usefully used in the field of treatment, such as metabolic diseases, cardiovascular diseases, inflammatory diseases. In addition, the compounds of the present invention may be used for weight control and/or weight reduction purposes in which drug-resistant drug side effects are reduced, and at the same time, it is possible to reduce the increase in the expression of inflammatory cytokines in skin keratinocytes. Can be used in the field.

Claims (17)

An aryl-substituted aminomethyloxetenyl amino alcohol derivative represented by Formula 1 below or a pharmaceutically acceptable salt thereof: [Formula 1]

In Chemical Formula 1, A represents a C ₆ -C ₁₅ aryl group, or a 5 to 14 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms, R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group including one or more selected from the group consisting of N, O, and S. According to claim 1, The derivative represented by Formula 1 is selected from the group consisting of the following compounds, an aryl substituted aminomethyloxetenyl amino alcohol derivative or a pharmaceutically acceptable salt thereof: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2-methoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(3,5-dimethoxyphenyl)ethan-1-ol; 2-(2-((3-(aminomethyl)oxetan-3-yl)amino)-1-hydroxyethyl)-4-methoxyphenol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(4-aminophenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4,6-trimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(pyridin-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(5-bromothiophen-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(1-methyl-1H-pyrrole-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(furan-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(cyazole-5-yl)ethan-1-ol; And 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(benzofuran-2-yl)ethan-1-ol. According to claim 1, The derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is characterized in that it promotes ATP production, an aryl substituted aminomethyloxetenyl amino alcohol derivative or a pharmaceutically acceptable salt thereof. According to claim 1, The derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof is an amino alcohol derivative or a pharmaceutically acceptable salt thereof having a weight control and/or weight loss use with reduced drug resistance and drug side effects. A pharmaceutical composition for the prevention or treatment of diseases in which ATP increase is required, which includes the compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

In Chemical Formula 1, A represents a C ₆ -C ₁₅ aryl group, or a 5 to 14 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms, R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group comprising one or more selected from the group consisting of N, O, and S. The method of claim 5, The compound represented by Formula 1 is selected from the group consisting of the following compounds, pharmaceutical composition: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2-methoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(3,5-dimethoxyphenyl)ethan-1-ol; 2-(2-((3-(aminomethyl)oxetan-3-yl)amino)-1-hydroxyethyl)-4-methoxyphenol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(4-aminophenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4,6-trimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(pyridin-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(5-bromothiophen-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(1-methyl-1H-pyrrole-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(furan-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(cyazole-5-yl)ethan-1-ol; And 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(benzofuran-2-yl)ethan-1-ol. The method of claim 5, The ATP increase, ATP increase in skeletal muscle, ATP increase in myocardium, ATP increase in white blood cells, or mitochondrial oxidative function is characterized in that the pharmaceutical composition. The method of claim 5, The diseases requiring increased ATP include metabolic syndrome, obesity, diabetes, hypertension, dyslipidemia, chronic fatigue syndrome, alcoholic liver disease, non-alcoholic liver disease, non-alcoholic fatty hepatitis (NASH), atherosclerotic vascular disease, aging, degenerative diseases Neurological diseases, myasthenia, metabolic diseases related to hypothyroidism, heart failure, cardiomyopathy, left ventricular hypertrophy, hypoxia reperfusion injury, cardiac amyloidosis, hypertension and hypertensive heart disease, heart failure with hypotension, coronary artery spasm and variant angina, atherosclerosis Atherosclerotic vascular disease-myocardial infarction, angina, cerebral infarction, peripheral arterial obstructive disease, Buerger's disease, chronic obstructive pulmonary disease, pulmonary fibrosis, atherosclerotic vascular disease, myocardial infarction, angina, cerebral infarction, psoriasis, atopy, chronic inflammatory disease , One or more pharmaceutical compositions selected from the group consisting of malignant tumors, mitochondrial dysfunctional diseases and aging-related diseases. A pharmaceutical composition for weight control and/or weight loss with reduced drug resistance and drug side effects comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

In Chemical Formula 1, A represents a C ₆ -C ₁₅ aryl group, or a 5- to 14-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms, respectively, R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group including one or more selected from the group consisting of N, O, and S. The method of claim 9, The compound represented by Formula 1 is selected from the group consisting of the following compounds, pharmaceutical composition: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2-methoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(3,5-dimethoxyphenyl)ethan-1-ol; 2-(2-((3-(aminomethyl)oxetan-3-yl)amino)-1-hydroxyethyl)-4-methoxyphenol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(4-aminophenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4,6-trimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(pyridin-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(5-bromothiophen-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(1-methyl-1H-pyrrole-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(furan-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(cyazole-5-yl)ethan-1-ol; And 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(benzofuran-2-yl)ethan-1-ol. A pharmaceutical composition for preventing or treating skin inflammatory diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

In Chemical Formula 1, A represents a C ₆ -C ₁₅ aryl group, or a 5- to 14-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms, respectively, R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group comprising one or more selected from the group consisting of N, O, and S. The method of claim 11, The compound represented by Formula 1 is selected from the group consisting of the following compounds, pharmaceutical composition: 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,5-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2-methoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4-dimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(3,5-dimethoxyphenyl)ethan-1-ol; 2-(2-((3-(aminomethyl)oxetan-3-yl)amino)-1-hydroxyethyl)-4-methoxyphenol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(4-aminophenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(2,4,6-trimethoxyphenyl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(pyridin-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(5-bromothiophen-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(1-methyl-1H-pyrrole-3-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(furan-2-yl)ethan-1-ol; 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(cyazole-5-yl)ethan-1-ol; And 2-((3-(aminomethyl)oxetan-3-yl)amino)-1-(benzofuran-2-yl)ethan-1-ol. The method of claim 11, The skin inflammatory disease is a pharmaceutical composition characterized in that at least one selected from the group consisting of atopic dermatitis, contact dermatitis and psoriasis. The method of claim 11, The prevention or treatment of the skin inflammatory disease is characterized by being achieved by inhibiting the increase in the expression of IL-17A in skin cells, pharmaceutical composition. A method for preventing or treating a disease requiring an ATP increase, comprising administering to a subject a pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

In Chemical Formula 1, A represents a C ₆ -C ₁₅ aryl group, or a 5 to 14 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms, R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group including one or more selected from the group consisting of N, O, and S. A method for weight control and/or weight loss in which drug resistance and drug side effects are reduced, comprising administering to a subject a pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

In Chemical Formula 1, A represents a C ₆ -C ₁₅ aryl group, or a 5- to 14-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms, respectively, R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group comprising one or more selected from the group consisting of N, O, and S. A method for preventing or treating skin inflammatory diseases, comprising administering to a subject a pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

In Chemical Formula 1, A represents a C ₆ -C ₁₅ aryl group, or a 5- to 14-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O), and sulfur (S) atoms, respectively, R _1, R ₂ and R ₃ are each independently H; OH; Halogen group; C ₁ -C ₇ alkyl group; C ₁ -C ₇ alkoxy group; C ₁ -C ₇ amino group; A substituted or unsubstituted C ₃ -C ₁₀ aryl group; And a C ₃ -C ₁₀ heteroaryl group or heterocyclyl group including one or more selected from the group consisting of N, O, and S.

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