KR102034310B1 - Pharmaceutical composition for prevention or treatment of inflammatory diseases containing integrin inhibitor as an active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention and treatment of inflammatory diseases, including an integrin inhibitor, specifically the experiment to evaluate the inhibitory activity against the integrin α5β1 inhibitor of the compound represented by the formula (1) of the present invention As a result, Compounds 1 to 123 according to the present invention have an excellent effect of blocking integrin activity by inhibiting the conversion of α5β1 into the active form through binding of α5β1 to an inhibitor prior to the binding of α5β1 to fibronectin. By confirming that the pharmaceutical composition containing the low molecular weight compound and its derivative which inhibits the binding of the integrin α5β1 and the extracellular matrix protein fibronectin of the present invention as an active ingredient can be usefully used for the prevention and treatment of inflammatory diseases. .

Description

Pharmaceutical composition for prevention or treatment of inflammatory diseases containing integrin inhibitor as an active ingredient

The present invention relates to a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing an integrin α5β1 and an extracellular matrix protein fibronectin, a low molecular compound and its derivatives as an active ingredient.

Rheumatoid arthritis, which is the target of the present invention, is a chronic inflammatory disease, which is a disease that occurs when tissues or cells are damaged or when the body is infected by an external infectious agent such as bacteria. When inflammation occurs, immune-related cells in blood vessels and fluids in the body are activated, resulting in complex physiological reactions such as secretion of enzymes and inflammatory mediators, fluid infiltration, migration of cells into inflammatory tissues, and tissue destruction, erythema, edema, fever, Appears as external symptoms such as pain. In addition, depending on the nature of the inflammatory process, it appears as acute and chronic inflammation (J clin Immunol, 1989; 9: 295-314).

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints and the whole body. The cause of the disease has not been clearly identified to date, but it is believed to be caused by genetic and environmental factors. Many studies are being conducted to find out. Genetic factors play an important role in susceptibility and prognostic diagnosis of rheumatoid arthritis, and an imbalance in epigenetic control over the overall immune response has been reported to cause autoimmune diseases including rheumatoid arthritis. Clin Immuno, 2003; 109: 72-79).

In rheumatoid arthritis, inflammation progresses mainly in the synovial membrane and is diagnosed as arthritis, especially if the inflammation persists for more than six weeks. As arthritis progresses, a large amount of blood vessels are generated in the synovial tissue, which causes various inflammatory cells to migrate into the tissue, forming a mass called pannus. As Pannus settles in the joint tissue, the activated inflammatory cells that make up destroy cartilage, deform the joints, and weaken the surrounding bone tissue. If the inflammation of the joint persists, the swelling of the joint becomes visible, pain is felt, the range of motion of the joint is narrowed, and the fever phenomenon due to the inflammation can be felt.

Rheumatoid arthritis is a disease caused by abnormal immune function in the body and is a disease caused by attacking one's body for an unknown reason in which the immune system, which should act as a defense mechanism against external infectious agents such as bacteria in the body, is unknown. This ?? autoimmune ?? It is called a condition and destroys joints by autoimmunity, and in severe cases, it attacks not only the joints but also various organs such as the lungs, heart, eyes, blood vessels and nerves. In addition, rheumatoid arthritis is known to occur during the active phase of life, causing physical dysfunction, resulting in a loss of quality of life and disruption of normal life, leading to enormous social and economic losses.

Although a number of basic and clinical researchers have studied rheumatoid arthritis and many studies have been reported on the progression and mechanism of action of arthritis, it is not yet clear the cause of arthritis. However, various clinical treatments for rheumatoid arthritis have been developed, and can be divided into general conservative therapy, drug therapy, and surgical therapy. The goal of the treatment of rheumatoid arthritis is to minimize joint pain and deformation caused by arthritis, and to reduce the function of the joint. The typical method used to achieve this is drug therapy, which is used according to the severity or nature of the symptoms. Aspirin and nonsteroidal anti-inflammatory drugs, low-dose oral steroids, antimalarial drugs, sulfasalazines, gold compounds, penicilamines, etc. can be used to suppress pain and inflammation. Mesotrexate, known as anti-rheumatic agents (DMARDs), (MTX), Imuran (Immuran), etc. can be used, etc. Recently, as the mechanism of inflammation progress is known, many biological agents have been developed. Tumor necrosis factor blockers (etanercept, infliximab, adalimumab) developed for the purpose of blocking are commercially available, and other interleukin-1 receptor antagonists (anikinra) for blocking IL-1β, and anti-B cell activity blocking. CD20 antibodies (rituximab), etc. These drugs are effective in suppressing inflammation and treating rheumatoid arthritis, but at the same time gastrointestinal, liver and kidney functions. Cliff, it has the disadvantage of side effects such as infection requires additional therapeutic agents that can control the side effects ever had inflammation, swelling, abnormal new blood vessels generated, bone and cartilage erosion developed in order to improve it.

A key mechanism in the inflammatory process is invasion of tissues by inflammatory cells. Extracellular matrix proteins serve as a guideline when inflammatory cells stimulated by inflammatory mediators move through blood vessels into tissues. Extracellular matrix proteins play an important role in constituting the skeletal structure of tissues, and many studies have shown that they play a key role in maintaining and regulating not only tissue morphology but also function. Inflammatory processes such as T lymphocytes in arthritis and inflammatory processes have mechanisms that increase adhesion and migration or cell activation through binding to extracellular matrix proteins as they move into inflammatory tissues.

Integrin is a representative substance that binds to extracellular matrix proteins in cell membrane receptors. Integrins are cell membrane proteins composed of heterodimers of the αβ type, which act as receptors for recognizing extracellular matrix proteins or other membrane proteins. Integrins contain various types of subunits such as α5β1, αIIbβ3, αVβ3, and αVβ5 by a combination of 24 types of αβ subunits. After incorporation with extracellular proteins, intracellular signaling pathways result in cell attachment and migration, proliferation or differentiation. Induce. This function increases the influx of inflammation-related cells, including T cells, in inflammatory tissues, thereby intensifying diseases such as rheumatoid arthritis.

In particular, α5β1 in the integrin family serves as a representative receptor for fibronectin in the extracellular matrix protein, which induces invasion and cellular activation of inflammation-related cells in tissues. Although integrin α5β1 is not expressed much before or on the condition of disease, it is known that the expression of integrin α5β1 is increased in tissues and is predominantly distributed than other integrin subunits, especially in invasive processes. Integrin α5β1 is overexpressed in T-cells and endothelial cells involved in the process of migrating to inflammatory tissues through cells, and integrin α5β1 expression is also increased in inflammatory tissues and panus formation (Rheumatol). Int, 1996; 16: 53-60).

Therefore, blocking the tissue-invasive action of inflammation-related cells inhibits the core mechanism in the development of arthritis, and thus the therapeutic effect will be high, thereby increasing the selectivity of inflammation treatment due to the increase of inflammation-specific expression of integrin α5β1. Integrin α5β1 is also suitable as a target that can reduce side effects caused by blocking integrin subunits (α4β1, αLβ2, etc.), which play a physiological role.

Accordingly, the present inventors are working to develop a pharmaceutical composition for preventing and treating arthritis which minimizes side effects, and by identifying compounds and derivatives having an effect of inhibiting integrin α5β1, the pharmaceutical composition comprising the integrin inhibitor of the present invention is The present invention has been completed by revealing that it can be usefully used for the prevention and treatment of inflammatory diseases.

It is an object of the present invention to provide a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing an integrin α5β1 and an extracellular matrix protein fibronectin, a low molecular compound and its derivatives as an active ingredient. .

In order to achieve the above object,

The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;

[Formula 1]

The present invention also provides a functional food for preventing or improving an inflammatory disease containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing a low molecular compound and its derivatives as an active ingredient that inhibits the binding of integrin α5β1 and the extracellular matrix protein fibronectin (fibronectin), specifically Since the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has an excellent effect of inhibiting integrin α5β1, it may be usefully used as a pharmaceutical composition for preventing or treating inflammatory diseases related thereto.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;

[Formula 1]

Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.

The inflammatory disease is characterized in that it is caused by integrin α5β1 overactivity, the inflammatory disease is characterized in that rheumatoid arthritis.

In general, in order to develop inhibitors targeting integrin α5β1, a mechanism of action that inhibits the adhesion and migration of inflammatory cells by inhibiting the binding of α5β1 to the extracellular matrix protein fibronectin was used. Looking at the binding model of integrin α5β1 and fibronectin, α5β1 binds to the Arg-Gly-Asp (RGD) motif in fibronectin, and there is a ligand binding pocket between the α and β subunits and a metal ion-dependent Binding sites such as adhesion site (MIDAS), ligand-associated metal binding site (LIMBS), and adjacent to MIDAS (ADMIDAS) play a role in regulating binding affinity with RGD. Coordinating rearrangement of MIDAS in integrin α5β1 occurs after incorporation with the RGD motif, resulting in structural transformation of integrins from inactive to activated forms. Thus, by combining α5β1 with an inhibitor prior to the binding of α5β1 to fibronectin, it is possible to induce the effect of blocking integrin activity by inhibiting the conversion of α5β1 into the active form.

In a specific embodiment of the present invention, as a result of experiments to evaluate the inhibitory activity of the compound represented by the formula (1) according to the present invention to the integrin α5β1 inhibitor, Compounds 1 to 123 according to the present invention is α5β1 and fibronectin (fibronectin Integrin α5β1 and the extracellular matrix protein of the present invention were confirmed to have an excellent effect of blocking integrin activity by inhibiting the conversion of α5β1 to the active form through the combination of α5β1 and an inhibitor before binding to Pharmaceutical compositions containing low molecular weight compounds and derivatives thereof that inhibit the binding of infibronectin may be usefully used for the prevention and treatment of inflammatory diseases.

The present invention includes not only the compound represented by Formula 1, but also pharmaceutically acceptable salts thereof, and possible solvates, hydrates, racemates, or stereoisomers which can be prepared therefrom.

The compound represented by Formula 1 of the present invention may 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. 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. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, Xylene Sulfonate, Phenyl Acetate, Phenylpropionate, Phenyl Butyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate , Naphthalene-2-sulfonate or mandelate.

The acid addition salts according to the present invention can be dissolved in conventional methods, for example, by dissolving a compound represented by the formula (1) in an excess of an aqueous solution of an acid, which salt is a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using. The mixture may also be prepared by evaporation of a solvent or excess acid to evaporate or by precipitation filtration of the precipitated salt.

Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali metal or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

The compound represented by the formula (1) according to the present invention can be administered in various oral and parenteral dosage forms during clinical administration, and when formulated, the commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. Prepared using diluents or excipients.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-1000 mg / kg / day, preferably Preferably it is 0.01-100 mg / kg / day, and may be divided once to several times a day at regular intervals according to the judgment of the doctor or pharmacist.

The present invention also provides a health functional food for preventing or improving an inflammatory disease containing a compound represented by the following Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;

[Formula 1]

Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.

The inflammatory disease is characterized in that it is caused by integrin α5β1 overactivity, the inflammatory disease is characterized in that rheumatoid arthritis.

The health functional food of the present invention may be added as it is, the compound represented by the formula (1), the optical isomer thereof, or a pharmaceutically acceptable salt thereof as it is, or used with other food or food ingredients, and may be appropriately used according to a conventional method. have.

There is no particular limitation on the formulation of the health food, and includes all of the health functional foods in the conventional sense.

The health functional food of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, Carbonating agent and the like. These components can be used independently or in combination. The proportion of such additives is not critical but is generally selected in the range of 0.001 to 10 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

< EXAMPLE  1> Preparation of Derivative of Formula 1

Derivatives of Formula 1 used in the present invention are ChemBridge Corporation (16981169Via Tazon, Suite G, San Diego, CA, 92127, USA)

The compound was purchased from and used. Table 1 summarizes the chemical structural formulas for the derivatives of Chemical Formula 1.

number Chemical structure number Chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

< Experimental Example  1> Evaluation of inhibitory effect of adhesion and migration

Integrin α5β1 inhibitory activity against the derivatives 1 to 123 represented by Formula 1 according to the present invention was evaluated by the following method.

Specifically, 1 μg / ml of human fibronectin was put into 100 μl / well in a 96 well plate and coated at 4 ° C. for 24 hours. In a 100 μl volume of RPMI + 1% FBS (Fetal Bovine Serum) medium, 200,000 Jurkat T cells (peripheral blood-derived T cell lines of human acute lymphoblastic leukemia patients) and 20 uM of integrin-targeted small molecule inhibitors were mixed at 37 ° C. After incubation for 30 minutes, the cells were divided into fibronectin-coated wells. After incubation for 1 hour and washed with phosphate buffered saline (PBS) to remove the unattached cells, the substrate (4--N-acetyl glucosaminidase activated by the substrate (4-N-acetyl glucosaminidase) Nitrophenyl N-acetyl-β-D-glucosaminide, Sigma, USA) was added at 60 μl / well and incubated at 37 ° C. for 3 hours. Thereafter, 90 μl / well of glycine EDTA solution (0.5 M EDTA, 50 mM glycine, pH 10.4) was added to block enzymatic activity, and the degree of color development according to the number of attached cells was measured by absorbance (405 nm). The degree of adhesion (%) of the relative T cells compared to the control is shown in Table 2 below.

As shown in Table 2, Derivatives 1 to 123 of Formula 1 according to the present invention was shown to excellently inhibit the adhesion and migration of inflammation-related cells.

number % T cell adhesion at 20 uM number % T cell adhesion at 20 uM One 101.44 ± 8.81 2 90.38 ± 7.68 3 107.80 ± 13.09 4 117.32 ± 9.20 5 48.79 ± 5.21 6  87.42 ± 6.10 7 45.87 ± 2.13 8 86.68 ± 7.06 9 100.10 ± 0.92 10 114.67 ± 6.30 11 105.73 ± 1.96 12 69.56 ± 5.94 13 115.77 ± 14.37 14 100.64 ± 6.79 15 103.95 ± 5.37 16 111.02 ± 19.90 17 115.65 ± 11.02 18 101.21 ± 7.05 19 117.07 ± 4.12 20 114.72 ± 7.29 21  128.89 ± 13.40 22 117.56 ± 6.35 23 72.17 ± 2.46 24 124.14 ± 6.69 25 98.92 ± 6.08 26 101.02 ± 5.87 27 82.91 ± 6.13 28 96.31 ± 9.47 29 140.18 ± 14.11 30 115.44 ± 15.24 31 66.30 ± 8.31 32 117.88 ± 9.17 33 96.00 ± 1.54 34 104.54 ± 9.37 35 81.73 ± 6.77 36 95.21 ± 10.16 37  141.19 ± 20.49 38 117.98 ± 17.70 39 120.27 ± 18.70 40  97.48 ± 18.70 41 66.83 ± 4.20 42  89.86 ± 4.66 43 99.04 ± 2.28 44 86.27 ± 5.36 45 42.88 ± 10.55 46 81.54 ± 6.97 47 73.23 ± 6.02 48 79.06 ± 11.35 49 51.45 ± 8.71 50 89.30 ± 13.44 51 97.06 ± 12.40 52 82.51 ± 7.74 53 62.97 ± 4.41 54 22.01 ± 2.86 55 98.90 ± 7.33 56 102.19 ± 6.48 57 - 58 88.53 ± 7.65 59 100.30 ± 7.35 60 76.78 ± 4.15 61 91.83 ± 6.10 62 105.35 ± 6.80 63 65.70 ± 3.27 64 99.29 ± 2.55 65 90.55 ± 2.35 66 60.00 ± 10.74 67  114.98 ± 4.42 68 71.76 ± 11.10 69 95.01 ± 3.30 70  101.89 ± 13.81 71 11.68 ± 3.62 72 110.23 ± 10.04 73  89.20 ± 3.90 74 84.08 ± 8.70 75 90.26 ± 21.33 76 70.34 ± 15.35 77 106.70 ± 6.65 78 108.30 ± 8.60 79 115.85 ± 9.37 80 91.90 ± 6.18 81 84.05 ± 9.63 82 28.01 ± 5.68 83 68.57 ± 8.00 84 37.14 ± 5.96 85 86.21 ± 9.92 86 19.43 ± 2.64 87 68.24 ± 5.08 88 81.53 ± 7.64 89 84.35 ± 9.87 90 79.05 ± 7.78 91 92.33 ± 7.66 92 61.51 ± 9.93 93 23.48 ± 3.62 94 61.31 ± 3.87 95 52.75 ± 3.75 96 68.43 ± 8.43 97 67.13 ± 8.59 98 61.70 ± 4.83 99 97.61 ± 4.96 100 80.45 ± 5.73 101 82.01 ± 4.54 102 80.49 ± 2.76 103 60.90 ± 15.66 104 27.75 ± 7.84 105 115.29 ± 14.91 106 95.95 ± 14.61 107 105.88 ± 4.03 108 91.50 ± 4.36 109 54.17 ± 9.35 110 86.38 ± 14.07 111 83.03 ± 5.41 112 82.92 ± 8.49 113 94.08 ± 7.68 114 92.00 ± 10.29 115 104.04 ± 4.08 116 89.98 ± 4.82 117 83.14 ± 8.69 118 92.93 ± 6.18 119 83.89 ± 16.39 120 - 121 48.17 ± 21.32 122 77.10 ± 6.42 123 120.69 ± 18.10

Among the 123 compounds, compounds 54, 71, 86, and 93 having excellent effects were selected, and the effects were evaluated in the same manner as in the above experimental method, but each material was treated with 10 uM to 100 uM to determine the IC50 value. Calculated.

The results are shown in Table 3 below.

number Molecular Weight IC50 (uM) 54 487 12.2 ± 0.9 71 485 5.2 ± 1.1 86 520 33.1 ± 1.6 93 491 6.7 ± 0.3

Therefore, the derivative (compound 1 to 123), the optical isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention has an excellent effect of inhibiting the activity of integrin α5β1, thus preventing or treating inflammatory diseases related thereto. It can be usefully used as a composition.

The present invention relates to a pharmaceutical composition for the prevention and treatment of inflammatory diseases containing a low molecular compound and its derivative as an active ingredient that inhibits the binding of integrin α5β1 and the extracellular matrix protein fibronectin (fibronectin), specifically Compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has an excellent effect of inhibiting integrin α5β1 and thus can be usefully used as a pharmaceutical composition for the prevention or treatment of inflammatory diseases related thereto, and thus has excellent industrial applicability. Do.

Claims (8)

A pharmaceutical composition for preventing or treating an inflammatory disease comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Chemical Formula 1,
R 1 is selected from the group consisting of H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
R2 and R3 are the same as or different from each other, and are each independently selected from the group consisting of H, C1-C5 alkyl and C1-C5 alcohol, and R2 and R3 may be connected to adjacent atoms to form a heterocyclic ring There is,
The heterocyclic ring may be substituted with O, and may have one or more substituted or unsubstituted alkyl residues of H, OH, O, or C1-C4;
R4 and R5 are the same as or different from each other, and are each independently selected from the group consisting of H, C1-C5 alkoxy, OF ₂ Cl, CONH ₂ , OCH ₂ CONH (R8), and halogen,
R8 is C1-C4 alkyl;
R 6 and R 7 may be H, or R 6 and R 7 may be linked to atoms adjacent to each other to form an aromatic ring;
X and Y are the same as or different from each other, and are each independently H or alkoxy of C1-C3.
The pharmaceutical composition according to claim 1, wherein the compound represented by Chemical Formula 1 is one selected from the group consisting of Chemical Formulas 5, 7, 45, 54, 71, 82, 84, 86, 93, and 104.
[Formula 5]

[Formula 7]

[Formula 45]

[Formula 54]

[Formula 71]

[Formula 82]

[Formula 84]

[Formula 86]

[Formula 93]

[Formula 104]

The composition of claim 1, wherein the inflammatory disease is rheumatoid arthritis.
The composition of claim 1, wherein the compound is an integrin α5β1 inhibitor.
Health functional food for the prevention or improvement of inflammatory diseases comprising a compound represented by the following formula (1) or a salt thereof as an active ingredient:

[Formula 1]

In Chemical Formula 1,
R 1 is selected from the group consisting of H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
R2 and R3 are the same as or different from each other, and are each independently selected from the group consisting of H, C1-C5 alkyl and C1-C5 alcohol, and R2 and R3 may be connected to adjacent atoms to form a heterocyclic ring There is,
The heterocyclic ring may be substituted with O, and may have one or more substituted or unsubstituted alkyl residues of H, OH, O, or C1-C4;
R4 and R5 are the same as or different from each other, and are each independently selected from the group consisting of H, C1-C5 alkoxy, OF ₂ Cl, CONH ₂ , OCH ₂ CONH (R8), and halogen,
R8 is C1-C4 alkyl;
R 6 and R 7 may be H, or R 6 and R 7 may be linked to atoms adjacent to each other to form an aromatic ring;
X and Y are the same as or different from each other, and are each independently H or alkoxy of C1-C3.
The health functional food according to claim 5, wherein the compound represented by Chemical Formula 1 is one selected from the group consisting of Chemical Formulas 5, 7, 45, 54, 71, 82, 84, 86, 93 and 104.
[Formula 5]

[Formula 7]

[Formula 45]

[Formula 54]

[Formula 71]

[Formula 82]

[Formula 84]

[Formula 86]

[Formula 93]

[Formula 104]

The health functional food according to claim 5, wherein the inflammatory disease is rheumatoid arthritis.
The dietary supplement according to claim 5, wherein the compound is an integrin α5β1 inhibitor.