KR20100044583A - Pharmaceutical and functional food composition for treating, preventing or improving respiratory diseases comprising amino acid-based derivatives - Google Patents

Abstract

PURPOSE: A pharmaceutical composition including an amino acid system derivative is provided to prevent and cure respiratory disease by effectively control an immune reaction inside lungs during asthma controlling effect using a mouse. CONSTITUTION: A pharmaceutical composition for preventing and curing respiratory disease contains an amino acid system derivative marked as the chemical formula 1, or its pharmaceutically acceptable salt as an active component. The respiratory disease includes asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and chronic obstructive pulmonary disease. A functional food composition also including the amino acid system derivative is in a form of a health food aiding agent, health beverage or a food additive.

Description

Pharmaceutical and functional food composition for treating, preventing or improving respiratory diseases comprising amino acid-based derivatives}

The present invention relates to a pharmaceutical composition and a functional food composition for preventing, ameliorating and treating a respiratory disease comprising an amino acid derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, It may have a formulation of a health food supplement, health beverage or food additive.

[Formula 1]

The composition containing the amino acid derivative represented by the formula (1) showed an effect of inhibiting the immune response in the lungs in the effect of inhibiting asthma using a mouse.

Inflammation is an important defense against cell and tissue damage and plays an important role in regenerating and restoring tissues that have been destroyed and removed from the defense. This unusual behavior in vivo leads to chronic inflammation and destruction in normal tissues. ROS (reactive oxygen species) is known as a representative substance for inducing many kinds of chronic immune diseases. Tissue damage is caused by the oxides that make up the lungs. The cells that make up the lungs induce immune responses induced by oxidants and nitrosative agents, as well as several cytokines and chemokines ( chemokines). Cytokines and chemokines activate the transcription factors that induce Neutrophil induction, immune factors such as nuclear factor-ĸB (NF-ĸB), and activator protein-1 (AP-1). Cause induction and tissue damage. As a result, the induction of chronic alveolar and bronchial immune responses can lead to chronic asthma, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). , acute respiratory distress syndrome (IPF), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF). There are many causes of the site of inflammation and inflammatory reactions, but in many cases it is known to be caused by the imbalance of oxidants and antioxidants in the lungs.

An object of the present invention to provide a pharmaceutical composition for the prevention and treatment of respiratory diseases comprising an amino acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention to provide a functional food composition for the prevention and improvement of respiratory diseases comprising an amino acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a pharmaceutical composition and a functional food composition for preventing, ameliorating and treating a respiratory disease comprising an amino acid derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, It may have a formulation of a health food supplement, health beverage or food additive.

[Formula 1]

[Wherein,

R ₁ is a C1-C7 alkyl group, benzyl, aromatic ring, or a conjugated polycyclic aromatic ring in which two or more aromatic rings are joined, wherein the alkyl group may be further substituted with halogen or hydroxy group, and the benzyl may be substituted or unsubstituted. Unsubstituted C 1 -C 5 alkoxy, wherein the aromatic group is C 1 -C 5 alkyl, nitro, halogen, carboxyl group, halogen substituted or unsubstituted C 1 -C 5 alkoxy or sulfonyl Can be further substituted.

R ₂ is a C1-C4 alkyl group or benzyl, and the alkyl group and benzyl may be substituted with a hydroxy group.

또는

이며, R₁₂는 C1-C3의 알킬, 방향족기 또는 방향족 헤테로 고리이며, 상기 방향족기는 모노 또는 디 C1-C3의 알킬아미노, 할로겐이 치환되거나 치환되지 않은 C1-C5의 알킬, 할로겐, 할로겐이 치환되거나 치환되지 않은 C1-C5의 알콕시, C1-C3의 알킬카르보닐, 니트로, C1-C5의 설포닐 또는 시아노로 더 치환될 수 있고, 상기 방향족 헤테로 고리는 할로겐으로 더 치환될 수 있다.]R ₃ is

or

R ₁₂ is C 1 -C 3 alkyl, aromatic group or aromatic hetero ring, wherein the aromatic group is mono or di C 1 -C 3 alkylamino, halogen substituted or unsubstituted C 1 -C 5 alkyl, halogen, halogen substituted Or unsubstituted C1-C5 alkoxy, C1-C3 alkylcarbonyl, nitro, C1-C5 sulfonyl or cyano, and the aromatic hetero ring may be further substituted with halogen.]

The amino acid derivative of Formula 1 includes a compound represented by the following Formula 2.

[Formula 2]

[Wherein, R ₁ to R ₃ are the same as defined above.]

The amino acid derivative of Formula 1 includes the compounds of Formulas 1-a and 1-b below.

[Formula 1-a]

[Formula 1-b]

이고, R₁₂는 니트로가 치환되거나 치환되지 않은 방향족기이다.][In Formulas 1-a and 1-b, R ₁ is phenyl or phenyl substituted with halogen, R ₂ is alkyl of C1-C4 with or without a hydroxy group substituted, and R ₃ is

And R ₁₂ is an aromatic group which is optionally substituted with nitro.]

Amino acid derivatives represented by the formula (1) is described in the 0675552 filed by the inventors and a method for producing the same. Specific examples of the compound represented by Chemical Formula 1 are as follows.

The amino acid derivative represented by Formula 1 showed an excellent asthma treatment effect in disease model animal experiments.

Amino acid derivatives represented by the formula (1) are bronchial asthma, emphysema (pulmonary fibrosis), chronic obstructive emphysema, lobular-centered emphysema (centrilobular emphysema), actinomycosis (panacinar pulmonary emphysema), acute bronchitis, chronic bronchitis, chronic obstructive bronchitis , Acute respiratory distress syndrome, reactive respiratory tract disease, cystic fibrosis, bronchiectasis, acquired bronchiectasis, Cartagener's syndrome, acute congenital armament, acute congenital armament, Pneumonia, essential thrombocytopenia, legionellosis, parrot disease, pneumoconiocis, diseases caused by organic dust, diseases caused by irritant gases and chemicals, Irritable, chronic obstructive pulmonary disease and idiopathic invasive lung di sorder), which is suitable for use as a pharmaceutical composition and a functional food composition for the prevention, amelioration and treatment of respiratory diseases selected from the group consisting of sorders. And those formed with both inorganic acids or bases. Pharmaceutically acceptable acid addition salts include hydrochloric acid, bromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, phenylacetic acid, substituted phenylacetic acid, for example methoxy Phenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acid (e.g. p-toluenesulfate) Phonic acid, benzenesulfonic acid, naphthalenesulfonic acid or naphthalenedisulfonic acid), salicylic acid, glutaric acid, gluconic acid, tricavalylic acid, mandelic acid, cinnamic acid, substituted cinnamic acid (e.g. 4-methyl and 4-methok) Methyl, methoxy, halo or phenyl substituted cinnamic acid, including cycinnamic acid and α-phenyl cinnamic acid), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (eg 1- or 3-hydroxy 2-naphthoic acid), naphthalate Acrylic acid (eg, naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2 or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (eg, 1,4- Benzenediacrylic acid) and isethionic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts and organic bases such as dicyclohexylamine and N-methyl-D -Salts with glucamine. However, in order to facilitate the escape of salts during manufacture, salts which are less soluble for the solvent selected depending on pharmaceutically acceptable may be preferred.

The amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof used to achieve the therapeutic effect according to the present invention will of course depend on the particular compound, the method of administration, the subject to be treated, and the disease to be treated, more preferably the formula (1) The effective dose of the compound of is administered in the range of 1 to 100 mg / kg (weight) / day. In addition, within a daily effective dosage range is divided into once a day or several times a day.

Oral administration of the pharmaceutical composition according to the present invention can be prepared in any of a variety of existing forms, for example tablets, powders, dry syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, It can exist in various forms, such as drink, sublingual tablet, and the like. Tablets according to the present invention may be administered to a patient in any form or manner in which an effective amount is bioavailable, ie, by oral route, depending on the nature of the disease state to be treated or prevented, the stage of the disease, and other relevant circumstances. Suitable dosage forms or modes can be readily selected and the compositions according to the invention can comprise one or more pharmaceutically acceptable excipients when the tablet is a tablet, the proportion and nature of such excipients being dependent on the solubility and chemical properties of the selected tablet. It may be determined by the route of administration chosen and standard pharmaceutical practice.

The amino acid derivative of Formula 1 according to the present invention may be added to health food supplements, health drinks or food additives for the purpose of preventing and improving the respiratory diseases. At this time, the amount of the compound in the food or beverage can be adjusted according to the purpose and purpose, and various flavors, such as vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and neutralizers (cheese) , Chocolate and the like), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.

Therefore, the amino acid derivative of Formula 1 contained as an active ingredient in the composition of the present invention reduces the induction of cells in the lungs in the respiratory disease, especially asthma-induced mice, inhibits mucous secretion, CD4, CD8, autoimmune cells, Since IL-17E positive cells inhibit the activity of interleukin-4 and exhibit excellent anti-asthmatic effects, the composition comprising the same may be usefully used as an effective medicine for the treatment of respiratory diseases caused by immune cells.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are merely to illustrate the present invention in more detail, the scope of the present invention is not limited to these examples and will be apparent to those of ordinary skill in the art.

Preparation Example 1 Synthesis of LX 300854

16 mL (228.7 mmol) of acetyl chloride was slowly added dropwise to 250 mL of methanol at 0 ° C., and then 10 g (76.2 mmol) of L-Leucine (111) was used as a starting material, and the mixture was refluxed for 60 minutes. .

After confirming that the starting compound 111 disappeared by TLC, the mixture was cooled to room temperature, distilled under reduced pressure to remove the solvent, and recrystallized with petroleum ether to obtain 12 g of compound 112 (yield 84%). Got as.

5 g (27.5 mmol) of Compound 112 was dissolved in 100 mL of methylene chloride, stirred at 0 ° C. for 10 minutes, and then maintained at 0 ° C. to 9.6 ml (69 mmol) of Compound 201 and 201. 7.3 g (32.9 mmol) of 2-nitrobenzenesulfonyl chloride was slowly added dropwise, followed by raising the temperature to room temperature. TLC confirmed the disappearance of compound 112 and the reaction was terminated. The above mixture was obtained by tube chromatography to obtain compound 113 in 7.3 g (yield 80%).

5 g (15.1 mmol) of Compound 113 was dissolved in 100 mL of ethanol, and 14.8 mL (151 mmol) of phenyl hydrazine of Compound 301 was added dropwise, followed by reflux for 60 minutes. After reflux, the mixture was cooled to room temperature and ethanol was distilled under reduced pressure, and then ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide, and concentrated to give the title compound (501). LX 300854) yielded 4.6 g (75% yield).

¹ H-NMR (300MHz, DMSO): δ 8.12 (m, 1H), 7.87 7.76 (m, 4H), 7.15 (m, 2H), 6.78 (m, 1H), 6.61 (m, 2H), 4.05 (m , 1H), 1.68 1.51 (m, 3H), 0.95 (m, 3H), 0.75 (m, 3H)

Preparation Example 2 Synthesis of LX 300902

18 mL (251.9 mmol) of acetyl chloride was slowly added dropwise to 250 mL of methanol at 0 ° C., and 10 g (83.9 mmol) of L-Allo threonine, a compound 114, was added as a starting material and the mixture was refluxed for 60 minutes. I was. After confirming the disappearance of the starting compound 114 by TLC, the mixture was cooled to room temperature, distilled under reduced pressure to remove the solvent, and recrystallized with petroleum ether to give 14 g of Compound 115 (yield 98%). Got as.

14 g (82.5 mmol) of Compound 115 was dissolved in 200 mL of dioxane / H ₂ O (volume ratio 1: 1), 8.4 g (210 mmol) of sodium hydroxide was added thereto, stirred at 0 ° C. for 10 minutes, and maintained at 0 ° C. While adding 18.1 g (83.0 mmol) of di-tert-butyldicarbonate of Compound 401, the temperature was raised to room temperature. TLC confirmed the disappearance of compound 115 and the reaction was terminated. After distillation under reduced pressure, ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide and concentrated to give 15 g (yield 78%) of compound 116 using column chromatography.

5 g (21.4 mmol) of Compound 116 was dissolved in 100 mL of ethanol, followed by dropwise addition of 21.1 mL (215 mmol) of phenyl hydrazine of Compound 301, followed by reflux for 60 minutes. After reflux, the mixture was cooled to room temperature and ethanol was distilled under reduced pressure, and then ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide and concentrated to give the title compound (502). LX 300902) yielded 4.7 g (71% yield).

¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.48 (s, 1H), 7.22 (m, 2H), 6.89 6.79 (m, 3H), 6.09 (s, 1H), 5.59 (m, 1H), 4.38 ( m, 1H), 4.10 (m, 1H), 3.42 (s, 1H), 1.48 (s, 9H), 1.21 (m, 3H)

Preparation Example 3 Synthesis of LX 519290

18 mL (251.9 mmol) of acetyl chloride was slowly added dropwise to 250 mL of methanol at 0 ° C., and 10 g (85.4 mmol) of L-Valine, a compound 117, was added as a starting material and the mixture was refluxed for 60 minutes. . After confirming the disappearance of the starting compound 117 by TLC, the mixture was cooled to room temperature, distilled under reduced pressure to remove the solvent, recrystallized with petroleum ether, and 14 g of compound 118 (yield 97%). Got as.

14 g (83.5 mmol) of Compound 118 was dissolved in 200 mL of dioxane / H ₂ O (volume ratio 1: 1), and 8.4 g (210 mmol) of sodium hydroxide was added thereto, stirred at 0 ° C. for 10 minutes, and maintained at 0 ° C. While 18.4 g (84.0 mmol) of di-tert-butyldicarbonate of Compound 401 was added, the temperature was raised to room temperature. TLC confirmed the disappearance of compound 118 and the reaction was terminated. After distillation under reduced pressure, ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide and concentrated to give 13.5 g (yield 70%) of compound 119 by column chromatography.

5 g (21.6 mmol) of Compound 119 was dissolved in 100 mL of ethanol, and 38.7 mL (216 mmol) of 4-chlorophenyl hydrazine hydrochloride of Compound 302 was added dropwise, followed by reflux for 60 minutes. After reflux, the mixture was cooled to room temperature and ethanol was distilled under reduced pressure, and then ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide, and concentrated to give the title compound (503). LX 519290) yielded 4.7 g (64% yield).

¹ H-NMR (300 MHz, DMSO): δ 7.17 (m, 2H), 6.79 (m, 2H), 3.85 (d, 2H, J = 4.7 Hz), 2.02 (m, 1H), 1.45 (s, 9H ), 0.99 (m, 6H)

Preparation Example 4 Synthesis of LX 300924

18 mL (251.9 mmol) of acetyl chloride was slowly added dropwise to 150 mL of methanol at 0 ° C., and 10 g (85.4 mmol) of L-Valine, a compound 117, was added as a starting material and the mixture was refluxed for 60 minutes. . After confirming the disappearance of the starting compound 117 by TLC, the mixture was cooled to room temperature, distilled under reduced pressure to remove the solvent, and recrystallized with petroleum ether to give 14 g of compound 118 (yield 97%). Got as.

9 g (53.7 mmol) of Compound 118 was dissolved in 100 mL of methylene chloride, stirred at 0 ° C. for 10 minutes, and then maintained at 0 ° C. to 18.7 mL (134.3 mmol) of Compound 202. 5 mL (64.4 mmol) of methanesulfonyl chloride was slowly added dropwise, followed by raising the temperature to room temperature. TLC confirmed the disappearance of compound 118 and the reaction was terminated. The above mixture was obtained by tube chromatography to obtain 9.4 g (yield 84%) of compound 120.

1.0 g (4.8 mmol) of Compound 120 was dissolved in 25 mL of ethanol, and then 4.8 mL (49 mmol) of phenyl hydrazine of Compound 301 was added dropwise, followed by reflux for 60 minutes. After reflux, the mixture was cooled to room temperature and ethanol was distilled under reduced pressure, and then ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide, and concentrated to give the title compound (504). LX 300924) yielded 1.1 g (80% yield).

¹ H-NMR (300 MHz, DMSO): δ 9.8 (d, 1H, J = 2.7 Hz), 7.95 (s, 1H), 7.38 (d, 1H, J = 9.1 Hz), 7.15 (m, 2H), 6.70 (m, 3H), 3.65 (m, 1H), 2.80 (s, 3H), 1.95 (m, 1H), 0.89 (m, 6H)

Preparation Example 5 Synthesis of LX 300932

16 mL (228.7 mmol) of acetyl chloride was slowly added dropwise to 250 mL of methanol at 0 ° C., and then 10 g (76.2 mmol) of L-Leucine (111) was used as a starting material, and the mixture was refluxed for 60 minutes. . After confirming the disappearance of the starting compound 111 by TLC, the mixture was cooled to room temperature, distilled under reduced pressure to remove the solvent, and recrystallized with petroleum ether to obtain 12 g of Compound 112 (yield 87%). Got as.

10 g (55 mmol) of Compound 112 was dissolved in 200 mL of dioxane / H ₂ O (volume ratio 1: 1), 5.5 g (138 mmol) of sodium hydroxide was added thereto, stirred at 0 ° C. for 10 minutes, and maintained at 0 ° C. While adding 12.1 g (55.5 mmol) of di-tert-butyldicarbonate of Compound 401, the temperature was raised to room temperature. TLC confirmed the disappearance of compound 112 and the reaction was terminated. After distillation under reduced pressure, ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide and concentrated to give 121 g (yield 70%).

After dissolving 5.0 g (20.4 mmol) of Compound 121 in 100 mL of ethanol, 20 mL (206 mmol) of phenyl hydrazine of Compound 301 was added dropwise, followed by reflux for 60 minutes. After reflux, the mixture was cooled to room temperature and ethanol was distilled under reduced pressure, and then ethyl acetate was added to dissolve the reaction mixture. The mixture was washed with distilled water, washed with saturated sodium hydroxide and concentrated to obtain the title compound (505). LX 300932) yielded 4.4 g (67% yield).

¹ H-NMR (300MHz, DMSO): δ 10.6 (s, 1H), 7.80 (s, 1H), 7.17 (m, 3H), 6.67 (m, 3H), 4.03 (m, 1H), 1.64 1.35 (m , 12H), 0.88 (m, 6H)

Example 1 Measurement of Cell Apoptosis by MTT

The MTT reaction was measured at 450 nm by the CCK-2 kit containing water-soluble tetrazolium salt at 450 nm for the reduction of mitochondrial dehydrogenase. Toxicity of montelukast and LX519290 compound (Preparation Example 3), which are currently used as a treatment for asthma, was evaluated using RAW 264.7 cell line.

As a result, as shown in Figure 1, the LX519290 compound (Preparation Example 3) according to the present invention was found to be less cytotoxic at the same concentration compared to the case of montelukast used as a control. From this result, it was found that the LX519290 compound according to the present invention is less cytotoxic than montelukast (FIG. 1).

Example 2 Animal Model Completion for Confirming Asthma Inhibitory Activity

An asthma model using a mouse was used to confirm the asthma inhibitory activity of the LX519290 compound (Preparation Example 3).

Using mouse (C57BL / 6, male, 6-8 weeks old), Ovalbumin (dissolved in physiological saline at 50 μg / mL) in the respiratory tract of the mouse was administered once daily for about 2 months to induce an immune response to the respiratory tract. It was. To determine the asthma-inhibiting effect of LX519290 compound (Preparation Example 3), 1 mg / mL (dissolved in physiological saline) was injected intraperitoneally to a final 1 mg / kg (Preparation Example 3), and the positive control Monteru The cast was also intraperitoneally administered three times. Since the lungs of the mouse was cut and fixed with formalin, paraffin blocks were made and sections were made to 5-10 μm.

Example 3 Confirmation of Cell Induction Inhibition Activity of Lung by LX519290 Compound (Preparation Example 3)

Tissue sections made from Example 2 were used to observe the increase in the number of cells due to induction of intrahepatic asthma using hematoxylin-eosin staining. As a result of the staining of FIG. 2, as the asthma-induced lung of the mouse showed an increase in the number of nuclei induced by hematoxylin than the mice that did not induce asthma, an increase in the number of cells occurred (FIG. 2). In contrast, asthma-induced mice, LX519290 compound (Preparation Example 3) and montelukast-treated groups showed an increase in intracellular lungs compared to asthma-induced mice (FIG. 2).

Example 4 Confirmation of Mucus Induction Inhibitory Activity in Lung by LX519290 Compound (Preparation Example 3)

The tissue sections made from Example 2 were used to observe the increase in mucus due to induction of asthma in the lungs by using the PAS (Periodic Acid Stain) staining. As a result of the staining of Figure 3, the lungs of asthma-induced mice showed an increase in mucus than mice that did not induce asthma, and it was confirmed that the secretion of mucus by an immune response was induced when asthma was induced (Figure 3 arrow). In contrast, mucus in lungs was not observed in asthma-induced mice, LX519290 compound (Preparation Example 3), and montelukast-treated groups (FIG. 3).

Example 5 Confirmation of CD4 Positive Cell Inhibitory Activity of Lungs by LX519290 Compound (Preparation Example 3)

Tissue sections made from Example 2 were used for immunostaining CD4 positive T-cells using CD4 antibodies. As a result of immunostaining in FIG. 4, asthma-induced lungs of mice were found to have a large number of T-cells stained brown by CD4 antibody (FIG. 4 asterisk) and LX519290 (physiology at a concentration of 1 mg / mL). CD4 positive T-cells were not seen in the lungs of mice that were dissolved in saline and intraperitoneally injected to the final 1 mg / kg) (FIG. 4).

Example 6 Confirmation of CD8 Positive Cell Inhibition Activity of Lung by LX519290 Compound

Tissue sections made from Example 2 were used for immunostaining CD8 positive T-cells using CD8 antibodies. As a result of the immunostaining of FIG. 5, asthma-induced lungs of mice were found to have observed a large number of T-cells stained brown by CD8 antibody (FIG. 5 asterisk), and LX519290 (physiology at a concentration of 1 mg / mL). CD8 positive T-cells were not seen in the lungs of mice that were dissolved in saline and intraperitoneally injected to a final 1 mg / kg) (FIG. 5).

Example 7 Confirmation of IEL 17E (IL-17E, IL-25) Positive Inhibitory Activity of Lung by LX519290 Compound

Tissue sections made from Example 2 were used to immunostain IL-17E positive cells using IL-17E antibodies. As a result of immunostaining in FIG. 6, asthma-induced lungs of mice were found to have a large number of cells stained brown by IL-17E antibody (FIG. 6 asterisk), and LX519290 (physiology at a concentration of 1 mg / mL). IL-17E positive cells were not seen in the lungs of mice that were dissolved in saline and intraperitoneally injected to a final 1 mg / kg (FIG. 6).

Example 8 Confirmation of IEL-4 (IL-4) Inhibitory Activity in Blood of Asthma Model by LX519290 Compound

Blood was collected using the animal model prepared in Example 2 to determine the expression level of serum IL-4. ELISA was intended to determine the level of IL-4 activity using this method to quantify proteins using immune responses. In the experimental method, the serum was added to the antibody-coated plate to bind the antibody, and then the HRP-labeled secondary antigen was added, and then the amount of IL-4 was measured using the HRP reaction. As a result, it was found that the amount of IL-4 was increased in asthma-induced mice, and as a result of the treatment of LX519290 compound, the amount of IL-4 in the blood was reduced like montelukast (FIG. 7). ).

1 is a result of cytotoxicity of LX519290 compounds according to the invention.

2 is the result of hematoxylin-eosin staining effect of asthma of LX519290 compound according to the present invention.

3 is a result of PAS staining the asthma inhibitory effect of the LX519290 compound according to the present invention.

4 is a result of CD4 positive staining effect on the asthma of the LX519290 compound according to the present invention.

5 is a result of CD8 positive staining effect of asthma inhibition of LX519290 compound according to the present invention.

6 is a result of IL-17E positive staining the asthma inhibitory effect of LX519290 compound according to the present invention.

7 is a result of the inhibitory effect of the expression of IL-4 asthma inhibitory effect of the LX519290 compound according to the present invention.

Claims (7)

A pharmaceutical composition for the prevention and treatment of respiratory diseases comprising an amino acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. [Formula 1]

[Wherein, R ₁ is a C1-C7 alkyl group, benzyl, an aromatic ring or a conjugated polycyclic aromatic ring in which two or more aromatic rings are bonded, wherein the alkyl group may be further substituted with a halogen or a hydroxy group, and the benzyl may be substituted or unsubstituted. Unsubstituted C 1 -C 5 alkoxy, wherein the aromatic group is C 1 -C 5 alkyl, nitro, halogen, carboxyl group, halogen substituted or unsubstituted C 1 -C 5 alkoxy or sulfonyl Can be further substituted. R ₂ is a C1-C4 alkyl group or benzyl, and the alkyl group and benzyl may be substituted with a hydroxy group. R ₃ is

or

R ₁₂ is C 1 -C 3 alkyl, aromatic group or aromatic hetero ring, wherein the aromatic group is mono or di C 1 -C 3 alkylamino, halogen substituted or unsubstituted C 1 -C 5 alkyl, halogen, halogen And optionally substituted or unsubstituted C1-C5 alkoxy, C1-C3 alkylcarbonyl, nitro, C1-C5 sulfonyl or cyano, and the aromatic hetero ring may be further substituted by halogen.] The method of claim 1, The amino acid derivative is a pharmaceutical composition for the prevention and treatment of a respiratory disease, characterized in that selected from the following compounds.

3. The method of claim 2, The respiratory diseases include bronchial asthma, emphysema (pulmonary fibrosis), chronic obstructive emphysema, centrilobular emphysema, panacinar pulmonary emphysema, acute bronchitis, chronic bronchitis, chronic obstructive bronchitis, acute respiratory distress syndrome ( Acute respiratory distress syndrome, reactive respiratory tract disease, cystic fibrosis, bronchiectasis, acquired bronchiectasis, Cartagener's syndrome, congenital armaments, acute congenital armaments, chronic congenital armaments, pneumonia, essential thrombocytopenia , Legionellosis, parrot disease, pneumoconiocis, diseases caused by organic dust, diseases caused by irritating gases and chemicals, irritability of the lungs, chronic obstructive Group consisting of lung disease and idiopathic invasive lung disorder Prevention and treatment of a pharmaceutical composition for the selection, characterized in that the respiratory disease. The method of claim 3, The respiratory disease is bronchial asthma, emphysema (pulmonary fibrosis), acute respiratory distress syndrome (Acute respiratory distress syndrome), cystic fibrosis or chronic obstructive pulmonary disease, characterized in that the pharmaceutical composition for the prevention and treatment of respiratory diseases. Functional food composition for the improvement and prevention of respiratory diseases comprising an amino acid derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. [Formula 1]

[Wherein, R ₁ is a C1-C7 alkyl group, benzyl, an aromatic ring or a conjugated polycyclic aromatic ring in which two or more aromatic rings are bonded, wherein the alkyl group may be further substituted with a halogen or a hydroxy group, and the benzyl may be substituted or unsubstituted. Unsubstituted C 1 -C 5 alkoxy, wherein the aromatic group is C 1 -C 5 alkyl, nitro, halogen, carboxyl group, halogen substituted or unsubstituted C 1 -C 5 alkoxy or sulfonyl Can be further substituted. R ₂ is a C1-C4 alkyl group or benzyl, and the alkyl group and benzyl may be substituted with a hydroxy group. R ₃ is

or

R ₁₂ is C 1 -C 3 alkyl, aromatic group or aromatic hetero ring, wherein the aromatic group is mono or di C 1 -C 3 alkylamino, halogen substituted or unsubstituted C 1 -C 5 alkyl, halogen, halogen substituted Or unsubstituted C1-C5 alkoxy, C1-C3 alkylcarbonyl, nitro, C1-C5 sulfonyl or cyano and the aromatic hetero ring may be further substituted with halogen.] The method of claim 5, The respiratory diseases include bronchial asthma, emphysema (pulmonary fibrosis), chronic obstructive emphysema, centrilobular emphysema, panacinar pulmonary emphysema, acute bronchitis, chronic bronchitis, chronic obstructive bronchitis, acute respiratory distress syndrome ( Acute respiratory distress syndrome, reactive respiratory tract disease, cystic fibrosis, bronchiectasis, acquired bronchiectasis, Cartagener's syndrome, congenital armaments, acute congenital armaments, chronic congenital armaments, pneumonia, essential thrombocytopenia , Legionellosis, parrot disease, pneumoconiocis, diseases caused by organic dust, diseases caused by irritating gases and chemicals, irritability of the lungs, chronic obstructive Group consisting of lung disease and idiopathic invasive lung disorder Improvement of being selected, characterized in preventing respiratory disease and functional food composition. The method of claim 6, The food composition is a functional food composition for the improvement and prevention of respiratory diseases, characterized in that the formulation of the health food supplements, health drinks or food additives.

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