KR20080014365A - Novel chalcone derivatives which inhibit the il-5 activity - Google Patents

Abstract

A novel chalcone derivative having an effect of inhibiting interleukin-5 is provided to inhibit introduction of eosinophils into the airway and to improve airway sensitivity so as to obtain an agent for controlling asthma and inflammatory conditions and an antiallergic agent having no non-specific response to protein. A novel chalcone derivative having an effect of inhibiting interleukin-5 is represented by the following formula 1. In formula 1, R1 is a benzyl, cyclohexyl, hydrogen, methyl or ethyl; R2 is benzyl, cyclohexyl, hydrogen, methyl or ethyl; R3 is methoxy or H; and R4 is Cl, -NHCOCH3, -COOCH3, CH2OH, -CHO, -SO2NH2, -NO2 or -COOH.

Description

Novel Chalcone Derivatives which Inhibit the IL-5 Activity}

The present invention relates to a novel chalcone derivative, a method for preparing the same, and use as an interleukin-5 (IL-5) inhibitor. The present invention relates to a novel chalcone derivative and a preparation method thereof.

Allergic diseases are known as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria. Allergic diseases with very high incidences do not have appropriate treatments, and most of them have a chronic course, and thus suffer from pain and economic loss. Therefore, NIH is regarded as one of the five diseases to be overcome in the 21st century.

Allergies may cause symptoms such as itching due to early reactions, and epithelial cells of the target organs are deprived through late reactions, resulting in irritable local inflammation. The drugs used in the past are mainly used cromoglycate, antihistamine, steroids, etc., developed as a membrane stabilizing agent for mast cells, and in case of asthma, adrenergic β ₂ agonist (salmetrol, etc.) and anticholinergic drugs (ipratropium) Etc.) and xanthine derivatives (theophylline, etc.) are used, but they alleviate the symptoms and cannot provide fundamental treatment.

Allergy is an irritable disease and is accompanied by an inflammatory response. Inflammatory responses that occur after repeated exposure to antigens are associated with inflammation-related cells such as mast cells, eosinophils, and Th2 cells, and structures such as vascular endothelial cells, fibroblasts, and epithelial cells. It is caused by complex interactions between sex cells.

Antigens are captured by antigen-presenting cells, such as macrophages, processed, and then released onto the surface of APC (Antigen-presenting cells). T-cells presented with antigens from APC secrete cytokines such as interleukin-4 (IL-4) to activate B cells, which in turn produce Ig E as antibodies. This Ig E is mixed with mast cells having an Ig E receptor on its surface. When combined with antigens, mast cells are activated, releasing chemicals such as histamine, prostaglandin (PG) and leukotriene (LT) to cause pathological symptoms. This leads to acute allergic inflammation.

Th2 cells exposed to antigens release cytokine such as IL-5, IL-3 and GM-CSF. In particular, IL-5 increases the differentiation of bone marrow cells into eosinophils and increases the adhesion of eosinophils to vascular endothelial cells, thereby increasing the migration of eosinophils to target organs, inhibiting apoptosis and activating eosinophils. It plays an important role in allergic reactions. Activated eosinophils release toxic proteins of major basic protein (MBP) and eosinophil cationic protein (ECP). These toxic proteins induce lipid mediators, cytokines, and chemokines, depriving allergic target organ epithelial cells of hypersensitivity. This causes chronic allergic inflammation such as bronchial asthma, which is a pathological symptom. Common inflammation is dominated by neutrophils, while allergic hypersensitivity is dominated by eosinophils. Therefore, it is well known that by inhibiting IL-5, it is possible to treat chronic allergic inflammation.

To develop a drug aimed at inhibiting eosinophils and IL-5, Schering-Plough is conducting a clinical trial to develop a single antibody of human IL-5 as an allergic agent, and Roche isothiazolone to inhibit IL-5. Although derivatives (Devos et. Al., Europ. J. Biochem., 1994, 225, 635) have been synthesized, they are facing limitations in the development of pharmaceuticals by non-specific reactions to other proteins.

Therefore, it is necessary to develop a substance that can be orally administered as a substance having low selectivity and inhibitory activity against IL-5 as a non-peptide-based allergy therapeutic agent that can regulate the physiological activity of IL-5. Accordingly, the present inventors have disclosed in Korean Patent No. 541222 a novel chalcone derivative having a low molecular weight and non-peptide-based substance, which has an IL-5 inhibitory effect, and a preparation method thereof. As a result of further research in order to obtain a more effective compound, a novel chalcone derivative and a method of preparing the derivative are more effective as an IL-5 inhibitor.

The present invention is to solve the problems of the prior art as described above, and an object of the present invention is to provide a novel compound and a method for producing the same, which is a non-peptide-based low molecule and has selectivity and inhibitory activity against IL-5.

Another object of the present invention is to provide an IL-5 inhibitor using the compound.

The present invention for achieving the above object relates to a novel chalcone-based derivative represented by the following formula (1), a method for preparing the same and its use as an IL-5 inhibitor.

(화학식 1)

(Formula 1)

[Where R ₁ = benzyl, benzyl, cyclohexylmethyl, optionally substituted cyclohexylmethyl, hydrogen, methyl, or ethyl optionally substituted

R ₂ = benzyl, optionally substituted benzyl, cyclohexylmethyl, optionally substituted cyclohexylmethyl, hydrogen, methyl, or ethyl

R ₃ = methoxy or H

R ₄ = Cl, -NHCOCH ₃ , -COOCH ₃ , CH ₂ OH, -CHO, -SO ₂ NH ₂ , -NO ₂ , or -COOH]

Hereinafter, the present invention will be described in detail for the preparation method of each derivative and the measurement of IL-5 inhibitory effect.

(1) Preparation of New Chalcone Derivatives

The compound of formula 1 may be prepared by condensation reaction of compound (A) and compound (B) using alcohol as a solvent in the presence of a base. Scheme 1 is a scheme for preparing a compound of Formula 1. R ₁ , R ₂ , R ₃ and R ₄ in compound (A) and compound (B) are the same as defined in formula (1).

Scheme 1

Here, the alcohol solvent represents C1-C5 lower alcohols, and it is preferable to use sodium hydroxide and potassium hydroxide as a base.

(2) Examination of inhibitory effect of IL-5

It was confirmed the inhibitory effect on the IL-5 of the compounds obtained through the above process.

The inhibitory effect of mIL-5 in the sample was measured by using absorbance as an indicator of the proliferation of mIL-5-dependent Y16 using mouse Y16 cells and IL-5 (%) and IC at 50 μM concentration. ₅₀ values are shown in Table 1.

As can be seen in Table 1, the new chalcone-based compound showed an inhibitory effect of more than 80% of all compounds at 50 μM concentration, most of the compounds showed a high inhibitory effect of more than 99%. Compared to the chalcone-based compound of Patent No. 541222 having an IC ₅₀ value of 10 μM or more, the chalcone-based compound of the present invention was found to have a higher inhibitory effect of IL-5 at most 5 μM or less.

As can be seen from the above results, the chalcone-based compound of the present invention can be used as an IL-inhibitor. In order to use the chalcone-based compound of the present invention as a therapeutic agent, the chalcone-based compound may be prepared by a known method in the pharmaceutical field, and may be mixed with itself or a pharmaceutically acceptable carrier, forming agent, diluent, and the like. It can be prepared and used in the form of powders, granules, tablets, capsules or injections. In addition, they can be formulated into unit dosage forms or multiple dose formulations, such as oral or parenteral formulations, to be used as therapeutic agents having an IL-5 inhibitory effect.

The present invention will be described in more detail with reference to the following Examples. The following examples are merely examples for clearly describing the production method of the present invention, and the scope of the present invention is not limited or changed by the examples. In addition, it is easy for those skilled in the art to change and apply various conditions of the following examples within a reasonable range, and such modifications will be included in the technical scope of the present invention.

Example

1) Preparation of Chalcone Derivatives

Example 1 Preparation of (E) -1- (2-cyclohexylmethoxy-6-hydroxyphenyl) -3-phenylpropenone (1 in Table 1)

0.116 g (0.47 mmol) of 2-cyclohexylmethoxy-6-hydroxyacetophenone was dissolved in 10 mL of a solvent in which sodium hydroxide was dissolved in 90% ethyl alcohol to 8.7%. 0.050 g (0.47 mmol) of benzaldehyde was added thereto and stirred at 40-50 ° C. for 12 hours. The solvent was removed by concentration under reduced pressure, 30 mL of distilled water was added thereto, acidified with 10 mL of 2N hydrochloric acid, and then dissolved in dichloromethane. The dichloromethane layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. This crude product was purified by column chromatography to give 0.091 g of compound 1 (Table 1).

Yield 58%; Orange solid; mp = 94-96 ° C .; Rf = 0.29 (hexanes: ethyl acetate = 10: 1), IR (KBr) 3400, 3100, 2950, 1640 cm ^-1 ; NMR (CDCl ₃ ) δ 1.01 to 1.89 (m, 11H), 3.84 (d, 2H, J = 6.0 Hz), 6.39 (d, 1H, J = 8.0 Hz), 6,59 (d, 1H, J = 8.4 I), 7.32 (t, 1H, J = 8.4 μs), 7.39 to 7.41 (m, 3H), 7.59 to 7.61 (m, 2H), 7.79 (d, 1H, J = 15.6 μs), 7.94 (d, 1H , J = 15.6 Hz), 13.07 (s, 1 H).

Example 2 Preparation of Methyl (E) -4- [3- (2-cyclohexylmethoxy-6-hydroxyphenyl) -3-oxopropen-1-yl] benzoate (2 in Table 1)

0.5 g (1.3 mmol) of (E) -4- [3- (2-cyclohexylmethoxy-6-hydroxyphenyl) -3-oxoprop-1-enyl] benzoic acid was dissolved in MeOH (250 mL) with heating to 60 ° C. , Sulfuric acid (2 mL) was slowly added dropwise and stirred for 1 hour. MeOH was removed by distillation under reduced pressure, diluted with dichloromethane (50 mL), and washed with water several times. The organic layer was separated, dehydrated with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the remaining residue was separated and purified through flash column chromatography to obtain 0.2 g of Compound 2 (Table 1).

Yield 40%; Dark yellow solid; mp = 118-119 ° C .; Rf = 0.22 (hexanes: ethylacetate = 8: 1), IR (KBr) 3450, 3100, 2950, 1720, 1610 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.04-1.88 (m, 11H), 3.86 (d, 2H, J = 5.6 Hz), 3.95 (s, 3H), 6.40 (d, 1H, J = 8.4 Hz), 6.60 (d, 1H, J = 6.4 μs), 7.34 (t, 1H, J = 8.4 μs), 7.65 (d, 2H, J = 8.4 μs), 7.77 (d, 1H, J = 15.6 μs), 7.98 (d, 1H, J = 15.6 Hz), 8.07 (d, 2H, J = 8.4 Hz), 13.07 (s, 1H).

Example 3: Preparation of (E) -3- (4-chlorophenyl) -1- (2-cyclohexylmethoxy-6-hydroxyphenyl) propenone (3 in Table 1)

Condensation reaction of 2-cyclohexylmethoxy-6-hydroxyacetophenone (1 g, 4 mmol) and 4-chlorobenzaldehyde (1.14 g, 8 mmol) under the same conditions as in Example 1 Compound 3 (Table 1) 0.8 g was prepared.

Yield 53.7%; mp = 120-122 ° C .; Dark orange solid; Rf = 0.29 (hexanes: ethyl acetate = 10: 1); IR (KBr) 3400, 3100, 2950, 1640 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.01 to 1.88 (m, 11H), 3.85 (d, 2H, J = 6.0 Hz), 6.39 (d, 1H, J = 8.4 Hz), 6.59 (d, 1H, J = 8.4 Hz) , 7.33 (t, 1H, J = 8.4 μs), 7.37 (d, 2H, J = 8.4 μs), 7.52 (d, 2H, J = 8.4 μs), 7.72 (d, 1H, J = 15.6 μs), 7.09 (d, 1H, J = 15.6 Hz), 13.05 (s, 1H).

Example 4 of N- (E) -4- [3- (2-cyclohexylmethoxy-6-hydroxyphenyl) -3-oxopropen-1-yl] phenyl acetamide (4 in Table 1) Produce

Condensation of 2-cyclohexylmethoxy-6-hydroxyacetophenone (3 g, 4 mmol) with 4-acetamidobenzaldehyde (2 g, 12 mmol) under the same conditions as in Example 1 Compound 4 (Table 1) 3.0 g was prepared.

Yield 64%; Yellow solid; mp = 203-205 ° C .; Rf = 0.21 (hexanes: ethyl acetate = 6: 1); IR (KBr) 3300, 3100, 2950, 1680 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.05-1.89 (m, 11H), 2.21 (s, 3H), 3.85 (d, 2H, J = 6.0 Hz), 6.39 (d, 1H, J = 8.4 Hz), 6.58 (d, 1H, J = 8.4 Hz), 7.32 (t, 1H, J = 8.4 Hz), 7.44 (s, 1H), 7.56 (m, 4H), 7.75 (d, 1H, J = 15.6 Hz), 7.88 (d, 1H, 15.6 Hz), 13.07 (s, 1H).

Example 5: Preparation of (E) -1- (2-cyclohexylmethoxy-6-hydroxyphenyl) -3- (4-ethylphenyl) propenone (5 in Table 1)

Condensation of 4-cyclohexylmethoxy-6-hydroxyacetophenone (2 g, 8.1 mmol) and 4-ethylbenzaldehyde (0.87 g, 8.2 mmol) under the same conditions as in Example 1 Compound 5 (Table 1) 2 g was prepared.

Yield 69%; Orange solid; mp = 81-83 ° C .; Rf = 0.29 (hexanes: ethyl acetate = 10: 1); IR (KBr) 3100, 2950, 1640 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.03 to 1.27 (m, 8H), 1.66 (t, 3H, J = 7.6 kPa), 1.88 (m, 3H), 2.68 (q, 2H, J = 7.6 kPa), 3.85 (d, 2H, J = 5.6 Hz), 6.39 (d, 1H, J = 8.4 Hz), 6.58 (d, 1H, J = 8.4 Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.31 (t, 1H, J = 8.4 kPa), 7.52 (d, 2H, J = 8.0 kPa), 7.79 (d, 1H, J = 15.6 kPa), 7.91 (d, 1H, J = 15.6 kPa), 13.07 (s, 1H).

Example 6: Preparation of (E) -1- (2-cyclohexylmethoxy-6-hydroxyphenyl) -3- [4- (hydroxymethyl) phenyl] propenone (6 in Table 1)

Condensation of 4-cyclohexylmethoxy-6-hydroxyacetophenone (0.2 g, 0.81 mmol) and 4-hydroxymethylbenzaldehyde (0.136 g, 2.42 mmol) under the same conditions as in Example 1 Compound 6 (Table 1) 0.2 g was prepared.

Yield 66%; Orange solid; mp = 93 ° C .; Rf = 0.45 (hexanes: ethyl acetate = 2: 1), IR (KBr) 3300, 3100, 2930, 2850, 1640 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.08-1.89 (m, 11H), 3.87 (d, 2H, J = 6.0 Hz), 4.75 (s, 2H), 6.39 (d, 1H, J = 8.4 Hz), 6.59 (d, 1H, J = 8.4 Hz), 7.33 (t, 1H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.79 (d, 1H, J = 15.6 Hz), 7.95 (d, 1 H, J = 15.6 Hz), 13.20 (s, 1 H).

Example 7 Preparation of (E) -4- [3- (2-cyclohexylmethoxy-6-hydrocyphenyl) -3-oxopropen-1-yl] benzaldehyde (7 in Table 1)

Condensation reaction of 4-cyclohexylmethoxy-6-hydroxyacetophenone (0.126 g, 0.5 mmol) with terephthalaldehyde (0.068 g, 0.5 mmol) under the same conditions as in Example 1 gave 0.11 g of Compound 7 (Table 1). Prepared.

Yield 60%; Red solid; mp = 116-118 ° C .; Rf = 0.19 (hexanes: ethyl acetate = 8: 1), IR (KBr) 3450, 3100, 2950, 1700, 1640 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.00-1.87 (m, 11H), 3.86 (d, 2H, J = 6.0 Hz), 6.40 (d, 1H, J = 8.4 Hz), 6.60 (d, 1H, J = 8.4 Hz) , 7.36 (t, 1H, J = 8.4 μs), 7.74 (d, 2H, J = 8.4 μs), 7.77 (d, 1H, J = 15.6 μs), 7.92 (d, 2H, J = 8.4 μs), 8.01 (d, 1H, J = 15.6 Hz), 10.04 (s, 1H), 13.05 (s, 1H).

Example 8 Preparation of (E) -4- [3- (2-cyclohexylmethoxy-6-hydroxyphenyl) -3-oxopropen-1-yl] benzenesulfonamide (8 in Table 1)

Condensation of 4-cyclohexylmethoxy-6-hydroxyacetophenone (0.10 g, 0.4 mmol) and 4-plymylbenzenesulfonamide (0.075 g, 0.41 mmol) under the same conditions as in Example 1 Compound 8 (Table 1 ) 0.092 g was prepared.

Yield 56%; Dark yellow solid; mp = 130 ° C .; Rf = 0.33 (hexanes: ethyl acetate = 23: 1); IR (KBr) 3400, 3330, 3100, 2950, 1640 cm ⁻¹ ; NMR (DMSO-d ₆ ) δ 1.03-1.87 (m, 11H), 3.79 (d, 2H, J = 5.6 Hz), 6.53 (d, 1H, J = 8.0 Hz), 6.56 (d, 1H, J = 8.4 Iii), 7.26 (t, 1H, J = 8.4 μs) 7.39 (d, 2H, J = 6.4 μs), 7.45 (s, 2H), 7.82-7.88 (m, 4H), 10.63 (s, 1H).

Example 9 Preparation of (E) -4- [3- (2-benzyloxy-6-hydroxyphenyll) -3-oxopropen-1-yl] benzenesulfonamide (9 in Table 1)

Compound 9 (Table 1) using 4-benzyloxy-6-hydroxyacetophenone (0.10 g, 0.41 mmol) and 4-phamylbenzenesulfonamide (0.076 g, 0.41 mmol) as starting materials under the same conditions as in Example 1. 0.087 g was prepared.

Yield 52%; Dark yellow solid; mp = 182-183 ° C .; Rf = 0.33 (hexanes: ethyl acetate = 2: 1); IR (KBr) 3400, 3330, 3100, 1640 cm ⁻¹ ; NMR (DMSO-d ₆ ) δ 5.13 (s, 2H), 6.57 (d, 1H, J = 8.4 Hz), 6.68 (d, 1H, J = 8.4 Hz), 7.26 (t, 1H, J = 8.4 Hz) , 7.36 (d, 2H, J = 8.4 μs), 7.44-7.72 (m, 7H), 7.78 (d, 1H, J = 15.6 μs), 7.82 (d, 1H, J = 15.6 μs), 10.65 (s, 1H).

Example 10 Preparation of N- (E) -4- [3- (2,6-dimethoxyphenyl) -3-oxopropen-1-yl] phenyl acetamide (10 in Table 1)

1.20 g of Compound 10 (Table 1) was prepared by condensing 2,6-dimethoxyacetophenone (1 g, 5.54 mmol) and 4-acetamidobenzaldehyde (1.08 g, 6.65 mmol) under the same conditions as in Example 1. It was.

Yield 67%; Ocher solid; mp = 221-222 ° C .; Rf = 0.15 (hexanes: ethyl acetate = 1: 1); IR (KBr) 3390, 3050. 2950, 1700, 1650 cm ⁻¹ ; NMR (Acetone-d ₆ ) δ 2.09 (s, 3H), 3.77 (s, 6H), 6.74 (d, 2H, J = 8.4 μs), 6.85 (d, 1H, J = 16.4 μs), 7.20 (d, 1H, J = 16.4 μs), 7.38 (t, 1H, J = 8.4 μs), 7.58 (d, 2H, J = 8.8 μs), 7.71 (d, 2H, J = 8.8 μs).

Example 11 Preparation of (E) -1- (2,6-dimethoxyphenyl) -3- (4-ethylphenyl) propenone (11 in Table 1)

Condensation of 2,6-dimethoxyacetophenone (0.5 g, 2.77 mmol) and 4-ethylbenzaldehyde (0.45 g, 3.32 mmol) under the same conditions as in Example 1 gave 0.62 g of compound 11 (Table 1). .

Yield 75%; Light yellow solid; mp = 55-57 ° C .; Rf = 0.10 (hexanes: ethyl acetate = 10: 1); IR (KBr) 3050, 2950, 1650 cm ⁻¹ ; NMR (Acetone-d ₆ ) δ 1.20 (t, 3H, J = 7.6 μs), 2.64 (q, 2H, J = 7.6 μs), 3.74 (s, 6H), 6.72 (d, 2H, J = 8.4 μs) , 6.90 (d, 1H, J = 16.4 μs), 7.24 (d, 1H, J = 16.4 μs), 7.25 (d, 2H, J = 8.0 μs), 7.26 (t, 1H, J = 8.4 μs), 7.52 (d, 2H, J = 8.0 μs).

Example 12 Preparation of (E) -1- (2,6-dimethoxyphenyl) -3- [4- (hydroxymethyl) phenyl] propenone (12 in Table 1)

Condensation of 2,6-dimethoxyacetophenone (0.26 g, 1.44 mmol) and 4-hydromethylmethylbenzaldehyde (0.2 g, 1.41 mmol) under the same conditions as in Example 1 gave 0.30 g of Compound 12 (Table 1). Prepared.

Yield 70%; Yellow liquid; Rf = 0.14 (hexanes: ethyl acetate = 1: 1); IR (film) 3450 (OH), 3150 (Alkene), 2950 (Alkane), 1630 (C = O), 1600 (Ar), 1240 (CO), NMR (CDCl3) = 2.57 (s, 1H), 3.76 ( s, 6H), 4.68 (s, 2H), 6.60 (d, 2H, J = 8.0 μs), 6.91 (d, 1H, J = 16.4 μs), 7.29 (d, 2H, J = 8.0 μs), 7.33 ( t, 1H, J = 8.0 Hz, 7.34 (d, 2H, J = 8.0 Hz), 7.47 (d, 2H, J = 8.0 Hz).

Example 13: Preparation of (E) -4- [3- (2,6-dimethoxyphenyl) -3-oxopropen-1-yl] benzenesulfonamide (13 in Table 1)

Condensation of 2,6-dimethoxyacetophenone (0.1 g, 0.56 mmol) and 4-plymylbenzenesulfonamide (0.095 g, 1.70 mmol) under the same conditions as in Example 1 to prepare 0.12 g of compound 13 (Table 1) It was.

Yield 62%; Yellow solid; mp = 180-181 ° C .; Rf = 0.33 (hexanes: ethyl acetate = 3: 1); IR (KBr) 3420, 3200, 2950, 1650 cm ⁻¹ ; NMR (CDCl ₃ ) δ 3.78 (s, 6H), 6.63 (d, 2H, J = 8.4 μs), 7.01 (d, 1H, J = 16.4 μs), 7.34 (d, 1H, J = 16.4 μs), 7.36 (t, 1H, J = 8.4 mm 3), 7.64 (d, 2H, J = 8.4 mm 3), 7.92 (d, 2H, J = 8.4 mm 3).

Example 14 Preparation of (E) -1- (2,6-dimethoxyphenyl) -3- (4-nitrophenyl) propenone (14 in Table 1)

Condensation of 2,6-dimethoxyacetophenone (3 g, 17 mmol) and 4-nitrobenzaldehyde (2.5 g, 17 mmol) under the same conditions as in Example 1 to prepare 4.03 g of compound 14 (Table 1) It was.

Yield 77%; Yellow solid; mp = 164-166 ° C .; Rf = 0.18 (hexanes: ethyl acetate = 3: 1); IR (KBr) 3100, 2950, 1690 cm ^-1 ; NMR (CDCl ₃ ) δ 3.80 (s, 6H), 6.63 (d, 2H, J = 8.4 μs), 7.05 (d, 1H, J = 16.0 μs), 7.36 (t, 1H, J = 8.4 μs), 7.38 (d, 1H, J = 16.0 mm 3), 7.67 (d, 2H, J = 8.8 mm 3), 8.22 (d, 2H, J = 8.8 mm 3).

Example 15 Preparation of (E) -3- (4-chlorophenyl) -1- (2,6-diethoxyphenyl) propenone (15 in Table 1)

Condensation reaction of 2,6-diethoxyacetophenone (0.1 g, 0.56 mmol) with 4-chlorobenzaldehyde (0.072 g, 0.56 mmol) under the same conditions as in Example 1 gave 0.089 g of compound 15 (Table 1). .

Yield 48%; Light yellow solid; mp = 92 ° C .; Rf = 0.35 (hexanes: ethyl acetate = 6: 1), IR (KBr) 3100, 2950, 1690 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.33 (t, 6H, J = 8.4 Hz), 4.04 (q, 4H, J = 8.4 Hz), 6.57 (d, 2H, J = 8.4 Hz), 6.92 (d, 1H, J = 16.0 Hz), 7.26 (d, 1H, J = 16.0 Hz), 7.28 (t, 1H, J = 8.6 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.45 (d, 2H, J = 8.4 Hz) ).

Example 16 Preparation of N- (E) -4- [3- (2,6-diethoxyphenyl) -3-oxopropen-1-yl] phenyl acetamide (16 in Table 1)

Condensation of 2,6-diethoxyacetophenone (0.5 g, 2.57 mmol) and 4-acetamidobenzaldehyde (0.42 g, 8.02 mmol) under the same conditions as in Example 1 gave 0.535 g of compound 16 (Table 1). Prepared.

Yield 59%; Dark yellow solid; mp = 175 ° C .; Rf = 0.23 (hexanes: ethyl acetate = 1: 1); IR (KBr) 3390, 3050. 2950, 1700 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.33 (t, 6H, J = 8.4 Hz), 2.19 (s, 3H), 4.04 (q, 4H, J = 8.4 Hz), 6.57 (d, 2H, J = 8.4 Hz), 6.88 (d, 1H, J = 16.0 μs), 7.25 (d, 1H, J = 16.0 μs), 7.27 (t, 1H, J = 8.4 μs), 7.41 (s, 1H), 7.47 (d, 2H, J = 8.8 Hz), 7.54 (d, 2H, J = 8.8 Hz).

Example 17 Preparation of (E) -4- [3- (2,6-diethoxyphenyl) -3-oxopropen-1-yl) benzenesulfonamide (17 in Table 1)

Condensation reaction of 2,6-diethoxyacetophenone (0.1 g, 0.56 mmol) and 4-phamylbenzenesulfonamide (0.095 g, 1.70 mmol) under the same conditions as in Example 1 to prepare 0.13 g of compound 17 (Table 1) It was.

Yield 62%; Yellow solid; mp = 62 ° C .; Rf = 0.33 (hexanes: ethyl acetate = 3: 1); IR (KBr) 3420, 3200, 2950, 1650 cm ⁻¹ ; NMR (CDCl ₃ ) δ 1.33 (t, 6H, J = 8.4 μs), 4.04 (q, 4H, J = 8.4 μs), 4.91 (s, 2H), 6.59 (d, 2H, J = 8.4 μs), 7.02 (d, 1H, J = 16.0 μs), 7.29 (t, 1H, J = 8.4 μs), 7.34 (d, 1H, J = 16.0 μs), 7.65 (d, 2H, J = 8.4 μs), 7.93 (d , 2H, J = 8.4 μs).

Example 18 Preparation of (E) -1- (2,6-diethoxyphenyl) -3- (4-nitrophenyl) propenone (18 in Table 1)

Condensation of 2,6-diethoxyacetophenone (0.1 g, 0.56 mmol) and 4-nitrobenzaldehyde (0.095 g, 0.56 mmol) under the same conditions as in Example 1 to prepare 0.126 g of compound 18 (Table 1) It was.

Yield 66%; Yellow solid; mp = 108 ° C .; Rf = 0.44 (hexanes: ethyl acetate = 6: 1); IR (KBr) 3100, 2950, 1690 cm ^-1 ; NMR (CDCl ₃ ) δ 1.33 (t, 6H, J = 8.4 μs), 4.04 (q, 4H, J = 8.4 μs), 6.59 (d, 2H, J = 8.4 μs), 7.05 (d, 1H, J = 16.0 kPa), 7.30 (t, 1H, J = 8.4 kPa), 7.37 (d, 1H, J = 16.0 kPa), 7.67 (d, 2H, J = 8.8 kPa), 8.23 (d, 2H, J = 8.8 kPa ).

Example 19 Preparation of (E) -1- (2,6-diethoxyphenyl) -3-phenylpropenone (19 in Table 1)

0.129 g of Compound 19 (Table 1) was prepared by condensation of 2,6-diethoxyacetophenone (0.1 g, 0.56 mmol) and benzaldehyde (0.080 g, 1.43 mmol) under the same conditions as in Example 1.

Yield 78%; Light yellow solid; mp = 71-72 ° C .; Rf = 0.32 (hexanes: ethyl acetate = 7: 1); IR (KBr) 3100, 2970, 1650 cm ^-1 ; NMR (CDCl ₃ ) δ 1.33 (t, 6H, J = 8.4 Hz), 4.04 (q, 4H, J = 8.4 Hz), 6.56 (d, 2H, J = 8.4 Hz), 6.96 (d, 1H, J = 16.0 Hz), 7.28 (t, 1H, J = 8.3 Hz), 7.31 (d, 1H, J = 16.0 Hz), 7.37 (m, 3H), 7.52 (m, 2H).

Example 20 Preparation of (E) -4- [3- (2,4,6-trimethoxyphenyl) -3-oxopropen-1-yl] benzenesulfonamide (20 in Table 1)

Condensation of 2,4,6-trimethoxyacetophenone (0.1 g, 0.48 mmol) and 4-plymylbenzenesulfonamide (0.088 g, 0.48 mmol) under the same conditions as in Example 1 Compound 20 (Table 1) 0.144 g was prepared.

Yield 80%; Light yellow solid; mp = 65 ° C .; Rf = 0.18 (hexanes: ethyl acetate = 2: 1); IR (KBr) 3420, 3100, 2950, 1650 cm ⁻¹ ; NMR (CDCl ₃ ) δ 3.78 (s, 6H), 3.87 (s, 3H), 6.16 (s, 2H), 7.01 (d, 1H, J = 16.0 Hz), 7.37 (d, 1H, J = 16.0 Hz) , 7.61 (d, 2H, J = 8.4 mm 3), 7.89 (d, 2H, J = 8.4 mm 3).

Example 21 Preparation of (E) -1- (2,4,6-trimethoxyphenyl) -3- (4-nitrophenyl) propenone (21 in Table 1)

Condensation of 2,4,6-trimethoxyacetophenone (0.1 g, 0.48 mmol) and 4-nitrobenzaldehyde (0.072 g, 0.48 mmol) under the same conditions as in Example 1 Compound 21 (Table 1) 0.131 g was prepared.

Yield 80%; Light yellow solid; mp = 163-164 ° C .; Rf = 0.35 (hexanes: ethyl acetate = 4: 1); IR (KBr) 3100, 2950, 1690 cm ^-1 ; NMR (CDCl ₃ ) δ 3.78 (s, 6H), 3.87 (s, 3H), 6.17 (s 2H), 7.07 (d, 1H, J = 16.0 Hz), 7.44 (d, 1H, J = 16.0 Hz), 7.67 (d, 2H, J = 8.8 μs), 8.23 (d, 2H, J = 8.8 μs).

Example 22 Preparation of (E) -1- (2,6-dichlorophenyl) -3- (4-nitrophenyl) propenone (22 in Table 1)

0.131 g of Compound 22 (Table 1) was prepared by condensation of 2,6-dichloroacetophenone (0.2 g, 1.05 mmol) and 4-nitrobenzaldehyde (0.19 g, 1.2 mmol) under the same conditions as in Example 1. .

Yield 38%; Light yellow solid; mp = 145-146 ° C .; Rf = 0.18 (hexanes: ethyl acetate = 8: 1); IR (KBr) 3100, 2950, 1690 cm ^-1 ; NMR (CDCl ₃ ) δ 7.04 (d, 1H, J = 16.0 Hz), 7.29 (d, 1H, J = 16.0 Hz), 7.35 to 7.41 (m, 3H), 7.70 (d, 2H, J = 8.0 Hz) , 8.26 (d, 2H, J = 8.0 μs).

Example 23; Preparation of (E) -4- [3- (2,6-dichlorophenyl) -3-oxopropen-1-yl] benzenesulfonamide (23 in Table 1)

Condensation reaction between 2,6-dichloroacetophenone (0.1 g, 0.56 mmol) and 4-phamylbenzenesulfonamide (0.103 g, 0.56 mmol) under the same conditions as in Example 1 gave 0.078 g of compound 23 (Table 1). .

Yield 42%; Light yellow solid; mp = 141-142 ° C .; Rf = 0.33 (hexanes: ethyl acetate = 3: 1); IR (KBr) 3420, 3100, 2950, 1650 cm ⁻¹ ; NMR (CDCl ₃ ) δ 7.22 (d, 1H, J = 16.0 Hz), 7.39 (d, 1H, J = 16.0 Hz), 7.54-7.62 (m, 3H), 7.86 (d, 2H, J = 8.0 Hz) , 7.92 (d, 2H, J = 8.0 μs).

2) Measurement of IL-5 Inhibitory Effect

(1) Sample dissolution and dilution

The samples of the chalcone-based compounds prepared in Examples 1 to 23 were dissolved and used in 100% DMSO so as to have a concentration of 100 mg / ml.

(2) Passage culture of cell line Y16

The Y16 cell used in the experiment was a floating cell that floated in a medium and diluted to 1 × 10 ⁵ cells / ml with RPMI-8% FBS medium, and then dispensed in 1 ml in a petri dish and 9 ml RPMI-8%. FBS medium and final concentration of 5 U / ㎖ mIL-5 was added and then incubated for 48 hours at 5% CO ₂ , 37 ℃. Cells were precipitated by centrifugation at 1500 rpm and 4 ° C, suspended in 1 ml of medium, stained with trypan blue, and counted by counting the number of cells.

(3) Measurement of proliferation of Y16 cells dependent on mIL-5

Dispense 1 × 10 ⁵ cells / ml of Y16 cells into 100 μl per well of a 96 well microplate, dilute mIL-5 from 100 units to 0.003 units in 1/3 series, add 100 μl per well, and then add 5% CO ₂ , Incubated for 48 hours at 37 ℃. After 48 hours, 20 μl of WST-1 solution was added to the above plate and allowed to stand at 5% CO ₂ , 37 ° C. for 3-4 hours, and then the absorbance was measured at 450 nm with a wavelength of 690 nm as a control using a microplate reader.

(4) Measurement of mIL-5 bioassay inhibition by sample

The inhibitory effect of mIL-5 on the samples was evaluated using the proliferation of Y16 dependent on mIL-5.

100 μl / well of 1 × 10 ⁵ cells / ml of Y16 cells were dispensed, and 50 μl of mIL-5 and 50 μl of sample were added. At this time, mIL-5 and the sample solution were diluted with RPMI-8% FBS medium, and the control group was added to the medium instead of the sample, and the control was added to the medium instead of the IL-5 and sample. Thus absorbance was measured after incubation under the same conditions as 3) above.

The inhibitory effect (%) of IL-5 by the sample at 50 μM concentration was calculated by the following formula and is shown in Table 1 together with the IC ₅₀ value.

As described above, the novel chalcone-based derivative represented by Formula 1 inhibits the influx of eosinophils, which are the main inflammatory cells of the asthma reaction, and improves airway hyperresponsiveness as an asthma symptom regulator and inflammatory response inhibitor. It works.

In addition, since the novel chalcone derivatives according to the present invention are low molecular non-peptide-based substances, unlike the conventionally known allergic inflammatory agents, they may be useful as allergic inhibitors because they do not have a non-specific response to proteins.

Claims (3)

Chalcone derivatives of the general formula (1).

(Formula 1) [Where R ₁ = benzyl, cyclohexylmethyl, hydrogen, methyl, or ethyl R ₂ = benzyl, cyclohexylmethyl, hydrogen, methyl, or ethyl R ₃ = methoxy or H R ₄ = Cl, -NHCOCH ₃ , -COOCH ₃ , CH ₂ OH, -CHO, -SO ₂ NH ₂ , -NO ₂ , or -COOH] A method for preparing a chalcone derivative of formula 1 according to claim 1 by condensing an alcohol with a solvent in the presence of a base according to the route of Scheme 1 below.

Scheme 1 Use of a chalcone derivative of formula 1 according to claim 1 as an interleukin-5 (IL-5) inhibitor.