KR100653948B1 - Ikappa;B KINASE INHIBITOR AND Ikappa;B KINASE INHIBITING COMPOSITION COMPRISING THEREOF - Google Patents

Abstract

The present invention relates to an IκB kinase inhibitor and a composition for inhibitors of IκB kinase comprising the same, and more particularly, to the activation of NF-κB, which is the cause of the immune, inflammatory response, cell proliferation inhibition, apoptosis-related gene transcription, Fruit of mangosteen (Garcinia mangostana L.) as an IκB kinase inhibitor that inhibits IκB kinase, which has properties such as intracellular information interference and IRS-1 deterioration (phosphorylation), which causes intracellular glucose influx. Or it relates to an IκB kinase containing at least one selected from extracts extracted from the skin with a water-containing organic solvent or an organic solvent, α- mangosteen, γ- mangosteen as an active ingredient, and a composition for IκB kinase inhibitor comprising the same.

IκB kinase, mangosteen

Description

IκＢ kinase inhibitors and compositions for IκＢ kinase inhibitors comprising the same

The present invention relates to an IκB kinase inhibitor and a composition for inhibitors of IκB kinase comprising the same, and more particularly, to the activation of NF-κB, which is the cause of the immune, inflammatory response, cell proliferation inhibition, apoptosis-related gene transcription, The fruit of mangosteen ( Garcinia mangostana L. ) as an IκB kinase inhibitor that inhibits IκB kinase, which has properties such as intracellular information interference and IRS-1 deterioration (phosphorylation), which causes intracellular glucose influx. Or it relates to an IκB kinase containing at least one selected from extracts extracted from the skin with a water-containing organic solvent or an organic solvent, α- mangosteen, γ- mangosteen as an active ingredient, and a composition for IκB kinase inhibitor comprising the same.

IκB kinase is a protein recently identified as an important kinase on the NF-κB pathway and is an essential component of the basic immune response in mammals. NF-κB is also known to cause a variety of gene transcriptional control as a cell transcription factor.

In general, NF-κB binds to IκB and stays in the cytoplasm, but cells induce inflammatory cytokines such as lipopolysaccharide (LPS), TNF-α, IL-1, T cell activation signals, growth factors, and stress induction. When stimulated by a factor or the like, IκB kinase is activated to phosphorylate IκB. Phosphorylated IκB is released from NF-κB, which activates and migrates into the nucleus. Active NF-κB, which has migrated into the nucleus, binds to a specific gene sequence and promotes transcription of genes involved in immunity, inflammatory response, cell proliferation control and apoptosis.

Thus, activation of NF-κB may be associated with rheumatism, asthma, thyroid dysfunction and fluids, atherosclerosis, HIV, EB virus, apoptosis, cell death in ischemic / reperfusion stroke models, Alzheimer's disease, stroke, microbial infection, virus carcinogenesis, It is associated with the occurrence of various diseases such as kidney hardening and diabetes.

Since IκB kinase inhibitors inhibit the activity of IκB kinase and inhibit the development of these diseases, the search has been made, but there has been no success in developing safe and effective inhibitors. It has also been reported that IκB kinase inhibits insulin influx into cells by insulin and is involved in insulin resistance and type II diabetes.

On the other hand, mangosteen ( Garcinia Mangostana L. ) is a preservative for food (for example, see Japanese Patent Application Laid-Open No. 6-98738, Japanese Patent Application Laid-Open No. 7-147951), 5α-reductase inhibitor ( For example, see Japanese Patent Application Laid-Open No. Hei 5-17365), an antibacterial agent (see Japanese Patent Application Laid-Open No. Hei 7-250658 for example), an anti-helicobacter pylori drug (see, for example, Japanese Patent Application Laid-Open No. Hei 8-208501), Ultraviolet absorbers (for example, see Japanese Patent Application Laid-open No. Hei 9-87155) and serine protease inhibitors (see, for example, Japanese Patent Laid-Open No. Hei 10-120586).

In addition, the water-soluble extracts of the mangosteen ( Garcinia Mangostana L. ) rinds are whitening, anti-inflammatory action (for example, see Japanese Patent Application Laid-Open No. 4-244004) and mangosteen ( Garcinia ) by histamine release from mast cells. Mangostana L. ) Anti-allergic action by antagonistic action against histamine and serotonin against polar solvent extracts of skin and its components α-mangosteen and γ-mangosteen (see, for example, Japanese Patent Application Laid-Open No. 10-72357). Is known.

Mangosteen extracts are also known to inhibit the production of prostaglandins (see, for example, Japanese Patent Application Laid-Open No. 2002-47180). However, the fact that inhibiting IκB kinase as in the present invention, nothing is known about inhibiting gene expression mediating NF-κB activation.

Thus, the inventors of the present invention, as a result of research efforts to solve the above problems, the extract of the extract from the fruit, the fruit of the mangosteen ( Garcinia mangostana L. ) edible as a red pepper, various solvents, Several components contained in the extract were isolated, and the extract and the components of the species were studied. As a result, a mangosteen extract, α-mangosteen, and γ obtained by extraction with an organic solvent or an organic solvent The present invention was completed by discovering that mangosteen has IκB kinase inhibitory activity and gene expression inhibitory action mediating NF-κB activation.

Accordingly, the present invention causes the activation of NF-κB, which promotes immune, inflammatory response, cell proliferation, and transcription of apoptosis-related genes, and inhibits intracellular communication of insulin and IRS-, which inhibits intracellular glucose influx. It is an object of the present invention to provide an IκB kinase inhibitor and a composition comprising the same, which inhibits IκB kinase having such properties as causing a decrease in function (phosphorylation).

That is, the present invention is safe and potent IκB kinase inhibitors and IκB kinase inhibitors containing the same by using a plant extract obtained from the fruit or fruit of Garcinia mangostana L. as an organic organic or organic solvent as a medicinal ingredient To provide a composition.

The present invention is effective to extract one or more mixtures selected from the extract, α-mangosteen and γ-mangosteen obtained by extracting the fruit or skin of mangosteen ( Garcinia mangostana L. ) with a water-containing organic or organic solvent It comprises a component and is characterized by an IκB kinase inhibitor for the treatment and prevention of diseases caused by IκB kinase activity and gene expression by NF-κB.

In addition, the present invention includes a composition for an IκB kinase inhibitor comprising the IκB kinase inhibitor as an active ingredient.

In addition, the present invention is one or more selected from the extract, α- mangosteen and γ- mangosteen, the extract obtained by extracting the fruit or skin of the mangosteen ( Garcinia mangostana L. ) with a functional organic solvent or organic solvent It includes a mixture as an active ingredient, food additives having an IκB kinase inhibitory activity and a food comprising the same.

Hereinafter, the present invention will be described in detail.

The present invention causes the activation of NF-κB, which is the cause of immunity, inflammatory response, cell proliferation, apoptosis-related gene transcription, and impairs the function of IRS-1, which causes intracellular communication of insulin and inhibition of intracellular glucose influx. As an IκB kinase inhibitor that inhibits IκB kinase having properties such as (phosphorylation), an extract obtained by extraction with a water-containing organic or organic solvent from the fruit or peel of Garcinia mangostana L. , α-mangosteen, It relates to an IκB kinase containing at least one selected from γ-mangosteen as an active ingredient, and a composition for an IκB kinase inhibitor comprising the same.

The present invention extracts the extracts from various fruits and fruit of red pepper, Garcinia mangostana L. , whose fruit is edible, and isolates the components of several species contained in the extract, the extract and species As a result of the study on the components of, the mangosteen extract, α-mangosteen and γ-mangosteen obtained by extracting with a water-containing organic solvent or organic solvents inhibited IκB kinase inhibition and gene expression inhibition mediating NF-κB activation. It is the invention proposed by discovering the fact that it has.

That is, the present inventors confirmed the effect as an IκB kinase inhibitor, the extract obtained by extracting from the mangosteen fruit, fruit with organic solvents or organic solvents, α- mangosteen represented by the following formula (1), and represented by the following formula (2) The paper has found that γ-manganese has excellent IκB kinase inhibitory activity, gene expression inhibition mediating NF-κB activation, and completed the present invention.

Accordingly, the present invention is effective to extract one or more mixtures selected from the fruit of mangosteen ( Garcinia mangostana L. ), the extract obtained from the extract with a water-based organic solvent or an organic solvent, α- mangosteen and γ- mangosteen IκB kinase inhibitor comprising as a component and a composition comprising the same.

Extracts obtained by the extraction of the organic and organic solvents from the fruits and skins of the mangosteen of the present invention, the IκB kinase inhibitors comprising α-mangosteen and / or γ-mangostine as an active ingredient have excellent IκB kinase inhibitory activity and NF It has a gene transcription inhibitory effect by -κB. In addition, the extract obtained by extracting the organic organic solvent or a water-containing organic solvent from the fruit, the rind of the mangosteen of the present invention is safe from side effects because it can be prepared from natural products. In addition, since the IκB kinase inhibitor of the present invention is excellent in taste, it is possible to provide a composition for inhibiting IκB kinase having excellent taste by incorporating it into medicines and food and drink.

The extract obtained by extracting from the fruit and skin of mangosteen, the active ingredient of the IκB kinase inhibitor of the present invention, with an organic or organic solvent is extracted from the fruit and skin of the red pepper, Garcinia mangostana L. In addition, although the fruit and skin of mangosteen may be used as it is, it is preferable to use dry and crushed powder, since extraction efficiency becomes good. Moreover, before extracting the fruit and skin of mangosteen with a water-containing organic solvent or an organic solvent, you may degrease with a nonpolar solvent, such as n-hexane and a petroleum ether.

As the extraction solvent, organic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, ethyl acetate, diethyl ether, chloroform, glycerin, ethyl glycol and propyl glycol, preferably polar solvents, especially ethanol and It is good to use the same alcohol or the thing which mixed water with the organic solvent. In addition, in consideration of the case where the inhibitor and the composition of the present invention are used as oral administration or food and drink, it is preferable to use only ethanol or a mixture of water and ethanol from the viewpoint of safety. The mixing ratio with water is not particularly limited, but the ratio of water is preferably 70% (v / v) or less, and more preferably 60% (v / v) or less. Regarding the extraction temperature, considering the extraction efficiency, the reflux temperature of the solvent is preferable from room temperature. The extraction time depends on the type of the extraction solvent, the crushed state of the fruit and skin, and the extraction temperature, but 0.5 hours to 2 hours are preferable.

The extract obtained by extracting with the extracting solvent may be concentrated or removed by an evaporator if necessary. In addition, the extract may be purified by solvent fractionation and chromatography, if necessary.

In addition, α- mangosteen and γ- mangosteen, the active ingredients of the IκB kinase inhibitor of the present invention can be prepared by extracting and purifying, for example, from the fruit of mangosteen ( Garcinia mangostana L. ) according to a known method. It is also possible to use the synthesized thing.

In addition, agents that currently suggest treatment and prevention of diseases by inhibiting IκB kinase include aspirin and sodium sarylate [Yin MJ, Yamamoto Y. and Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB-b, Nature 396: 77-80. Meanwhile, the IκB kinase inhibitor of the present invention is a naturally occurring IκB kinase inhibitor.

Therefore, the inhibitory effect of IκB kinase and the inhibition of gene expression by NF-κB can be safely used for the treatment and prevention of diseases effective. Diseases effective in inhibiting the activity of IκB kinase and diseases in which transcriptional inhibition by NF-κB are effective include, for example, asthma, allergic rhinitis, atopic dermatitis, gall margin, conjunctivitis, spring catarrh, Psoriasis, Ulcerative Colitis, Systemic Inflammatory Syndrome, Sepsis, Multiple Myositis, Dermatitis, Nodular Polyarthritis, Mixed Combined Tissue Syndrome, Sjogren's Syndrome, Gout, Alzheimer's Dementia, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Chronic Arthritis , Type I diabetes, multiple sclerosis, Crohn's disease, chronic thyroiditis (Hashimoto's disease), ceriac disease, myasthenia gravis, vulgaris ulcer, systemic erythematodes, viral diseases (HIV, herpes, Sendai rotavirus, Influenza virus, rabies virus, bullous stomatitis virus, rhinovirus, hepatitis A virus, hepatitis B virus, rubella virus, etc.), bacterial disease, radiation Due to a failure, atherosclerosis, reperfusion injury, cardiac hypertrophy, and cancer.

Moreover, IκB kinase is known to directly phosphorylate IRS-1, and this action lowers the function of IRS-1, and may inhibit the intracellular information transfer of insulin and the influx of sugar into cells. The present invention can be used for the treatment and prevention of insulin resistance, type II diabetes.

The IκB kinase inhibitor of the present invention can be used alone or in admixture with other medicines, carriers for arbitrary preparations, diluents, and the like, in any dosage form as a medicine. For example, tablets, granules, powders, fine granules, aerosols, light capsules, soft capsules, oral liquid preparations, injections and the like can be exemplified as the formulation.

In addition, examples of the composition for inhibiting IκB kinase of the present invention include food and beverages such as beverages, sweets, frozen desserts, dairy products, alcoholic beverages, and meats. These IκB kinase inhibitory compositions are obtained by blending at least one kind of fruit of mangosteen ( Garcinia mangostana L. ), an organic or organic solvent extract of the peel, α-mangosteen and γ-mangosteen into various foods and beverages. .

The effective contents of mangosteen extract, α-mangosteen and γ-mangosteen in this IκB kinase inhibitory composition vary depending on the administration method and necessary treatment, so it is difficult to define collectively, but as the dosage of the mangosteen extract In the calculation, the dry weight per kg of human and animal weight is 0.5 mg to 5 g, preferably 5 mg to 5 g, more preferably 10 mg to 1 g, and 1 mg / L to 100 mg / for cultured cells. L, α-mangosteen and γ-mangosteen, the dosage of 0.1 mg to 1 g per kg of human and animal body weight, preferably 1 mg to 1 g, more preferably 2 mg to 200 mg, cultured cells About 1 micrometerol / L-30 micrometersol / L about the thing.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the following Examples.

Test Example

This test was designed to inhibit the IκB kinase inhibitory activity of α-mangosteen and γ-mangosteen, inhibit the phosphorylation of IκB, and inhibit NF-κB activation. To find out.

(1) Preparation of Sample

The following samples were used for this test.

1) Sample 1

1 kg of undried peel of mangosteen ( Garcinia Mangostana L. ) was immersed in 10 L of methanol and extracted at room temperature for 24 hours. After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 80 g of an extract.

2) Sample 2

500 g of dried and peeled powder of mangosteen ( Garcinia Mangostana L. ) were immersed in 5 L of 40% ethanol and extracted at room temperature for 24 hours. After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 104 g of an extract.

3) Sample 3

480 g of dried and peeled powder of mangosteen ( Garcinia Mangostana L. ) were immersed in 5 L of 70% ethanol and extracted by stirring for 4 hours (60 ° C). After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 128 g of extract.

4) Sample 4

1.1 kg of dried and peeled powder of mangosteen ( Garcinia Mangostana L. ) was immersed in 11 L of ethanol, and extracted with stirring for 4 hours (60 ° C). After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 128 g of extract.

5) Sample 5

1.1 kg of fruit of Mangosteen ( Garcinia Mangostana L. ) was pulverized and stirred for 5 hours (70 ° C.) with 5 L of ethanol. After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 88 g of an extract.

6) Samples 6 and 7

80 g of the extract of Sample 1 was dissolved in 350 ml of ethyl acetate, and then washed twice with 200 ml of water. The ethyl acetate fraction was removed with the evaporator to obtain 20 g of dried product. This dried product was purified by silica gel column chromatography. Elution was gradually carried out by eluting with ethyl hexane acetate to elevate the polar gradient to obtain three fractions. The first obtained fraction (5 g) was purified again by silica gel column chromatography (ethyl hexane acetate, 10: 90 → 30: 70 → 50: 50, then ethyl acetate only, finally ethyl acetate, 50:50). , 500 mg of yellow amorphous sample 7 (γ-mangosteen) was obtained.

(2) Test method

1) LPS-induced IκB phosphorylation test

C6 cells were incubated with test samples for 1 hour, 10 μg / ml LPS was added, incubated for 30 minutes and stimulated. Cells were lysed with sample buffer for SDS-PAGE, SDS-PAGE was performed, and transcribed onto a polyvinylidene fluoride membrane. Rabbit antiphosphorylated IκB antibody (0.2 μg / ml) was added and incubated at 25 ° C. for 2 hours. After washing, it was incubated with horseradish peroxidase-binding anti-rabbit IgG antibody. Phosphorylated IκB was measured according to the chemiluminescence method, and the relative values when phosphorylated IκB amount of C6 cells without LPS were set to 1 are shown in Table 1 below.

Sample Sample concentration Phosphorylated IκB Control - 5.37 Α-mangosteen of sample 6 3 μM 3.56 Α-mangosteen of sample 6 10 μM 1.60 Γ-mangosteen of sample 6 1 μM 5.20 Γ-mangosteen of sample 6 3 μM 3.49 Γ-mangosteen of sample 6 10 μM 1.56 Γ-mangosteen of sample 6 30 μM 0.96 IκB Kinase Inhibitor of Sample 1 1 µg / ml 4.56 IκB Kinase Inhibitor of Sample 1 10g / ml 3.07 IκB Kinase Inhibitor of Sample 1 100g / ml 1.00 Inhibitor of IκB Kinase of Sample 2 10g / ml 2.82 IκB Kinase Inhibitor of Sample 3 10g / ml 2.52 IκB Kinase Inhibitor of Sample 4 10g / ml 3.13 Inhibition of IκB Kinase by Sample 5 10g / ml 3.34

2) In vitro IκB Kinase Test

C6 cells were stimulated with LPS (10 μg / ml) for 10 minutes and washed with PBS, followed by lysis buffer (2 mM EGTA, 150 mM NaCl, 2 mM DTT, 1 mM APMSF, 10 μg / ml Leupeptin, 10 μg). / ml aprotinin 1 mM Na ₃ VO ₄ , 10 mM Tris-HCl, pH 7.5) was added to prepare a cell extract. 6 μg anti IKKα / β antibody was added and the immunocomplex was recovered with proteinA-Sepharose 4B beads. IKK protein binding beads were washed three times with lysis buffer, 10 mM MgCl ₂ .6H ₂ O, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 5 mM β-glycerophosphate, [γ-32P] -ATP, 25 μL of 25 mM Tris-HCl, pH 7.5 kinase reaction solution was added. The test sample was added, incubated at 30 ° C. for 10 minutes, and then 1 μg of IκBα was added and incubated for 30 minutes. SDS-PAGE sample buffer was added to stop the reaction, the protein was divided by SDS-PAGE electrophoresis, phosphorylated IκBα was quantified using Molecular Imager (GS363, Bio-Rad), and phosphorylation when no substrate IκB was added. Relative values for the amount of IκBα are shown in Table 2 below.

Sample Sample concentration Phosphorylated IκBα Control - 6.90 Α-mangosteen of sample 6 3 μM 6.52 Α-mangosteen of sample 6 10 μM 4.35 Γ-mangosteen of sample 6 3 μM 6.13 Γ-mangosteen of sample 6 10 μM 4.17 Γ-mangosteen of sample 6 30 μM 2.61 IκB Kinase Inhibitor of Sample 1 10 µg / ml 3.07 Inhibitor of IκB Kinase of Sample 2 10 µg / ml 2.82 IκB Kinase Inhibitor of Sample 3 10 µg / ml 2.52 IκB Kinase Inhibitor of Sample 4 10 µg / ml 3.13 IκB Kinase Inhibitor of Sample 5 10 µg / ml 3.34

2) NFκB signal transduction activation test by dual luciferase measurement

C6 cells were seeded in 24-well plates and 2 days later, 0.475 μg / well of pNFκB-Luc (firefly luciferase reporter plasmid containing repeated NFκB response sequences) or dN-Luc (pNFκB-Luc). Reporter Prasmid, Hirai, 1994), which lacked the NFκB sequence, was transfected. In addition, C6 cells were simultaneously transfected with 0.025 μg control factor Renilla luciferase. After transfection, the cells were incubated for 13 hours and incubated with the test samples for 3 hours. 1 μg / ml LPS was added to the cells, the cells were incubated for 8 hours, and the cells were collected. Firefly luciferase and Renilla luciferase activity was measured by MiniLumat LB9506. The results of the test samples in Table 3 are shown as relative values of firefly luciferase activity to Renilla luciferase activity.

Sample Sample concentration Relative Luciferase Activity Control - 0.73 Α-mangosteen of sample 6 10 μM 0.50 Γ-mangosteen of sample 6 10 μM 0.50 IκB Kinase Inhibitor of Sample 1 10 µg / ml 0.50 Inhibitor of IκB Kinase of Sample 2 10 µg / ml 0.56 IκB Kinase Inhibitor of Sample 3 10 µg / ml 0.49 IκB Kinase Inhibitor of Sample 4 10 µg / ml 0.51 IκB Kinase Inhibitor of Sample 5 10 µg / ml 0.47

(3) Test result

From the results of this experimental example, the extract obtained by extracting with organic or organic solvents from the fruits or skins of Garcinia mangostana L. , α-mangosteen and γ-mangosteen, had IκB kinase inhibitory activity and NF It has been clarified to inhibit gene expression that mediates -κB activation.

Therefore, the present invention is useful as an IκB kinase inhibitor, and may be useful for the treatment and prevention of diseases involving IκB kinase in mammals and diseases involving NF-κB.

Next, the optimum form for implementing this invention in an Example is demonstrated in detail.

Example 1

1 kg of undried peel of mangosteen ( Garcinia mangostana L. ) was immersed in 10 L of methanol and extracted at room temperature for 24 hours. After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 80 g of IκB kinase inhibitor.

Example 2

500 g of dry rind powder of mangosteen ( Garcinia mangostana L. ) were immersed in 5 L of 40% ethanol and extracted at room temperature for 24 hours. After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 104 g of IκB kinase inhibitor.

Example 3

480 g of dry skin powder of mangosteen ( Garcinia mangostana L. ) was extracted with 5 L of 70% ethanol for 4 hours (60 ° C.). After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 128 g of IκB kinase inhibitor.

Example 4

1.1 kg of dried skin peel of mangosteen ( Garcinia mangostana L. ) was extracted with 11 L of ethanol for 4 hours (60 ° C.). After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 128 g of IκB kinase inhibitor.

Example 5

1.1 kg of fruit of Mangosteen ( Garcinia mangostana L. ) was pulverized and stirred for 4 hours (60 ° C.) with 5 L of 70% ethanol. After filtration, the filtrate was dried under reduced pressure with an evaporator to obtain 128 g of IκB kinase inhibitor.

Example 6

Example 1 80 g of the base extract was dissolved in 350 ml of ethyl acetate and then washed twice with 200 ml of water. The ethyl acetate fraction was removed with solvent by an evaporator to obtain 20 g of dried product. This dried product was purified by silica gel column chromatography. Elution was gradually carried out with hexane-ethyl acetate, and eluted with gradient of higher polarity to obtain three fractions. The first obtained fraction (5 g) was further purified by silica gel column chromatography (hexane-ethyl acetate, 10:90-> 30:70-> 50:50) to give 2 g of yellow crystalline α-mangosteen. The second fraction (2 g) was purified again by silica gel column chromatography (hexane-ethyl acetate, 30: 70 → 50: 50, then ethyl acetate only, finally ethyl acetate 50:50) to give a yellow amorphous phase. 500 mg of γ-mangosteen was obtained.

Example 7

The IκB kinase inhibitor obtained in Example 1 was combined with the following composition, and the powder containing an IκB kinase inhibitor was prepared.

Lactose 25 parts by weight

Potato starch 10 parts by weight

5 parts by weight of IκB kinase inhibitor obtained in Example 1

Example 8

The IκB kinase inhibitor obtained in Example 2 was combined with the following composition, and the powder containing an IκB kinase inhibitor was prepared.

Lactose 25 parts by weight

Potato starch 10 parts by weight

5 parts by weight of IκB kinase inhibitor obtained in Example 2

Example 9

The IκB kinase inhibitor obtained in Example 3 was combined with the following composition, and the powder containing an IκB kinase inhibitor was prepared.

Lactose 25 parts by weight

Potato starch 10 parts by weight

5 parts by weight of IκB kinase inhibitor obtained in Example 1

Example 10

The IκB kinase inhibitor obtained in Example 4 was combined with the following composition, and the powder containing the IκB kinase inhibitor was prepared.

Lactose 25 parts by weight

Potato starch 10 parts by weight

5 parts by weight of IκB kinase inhibitor obtained in Example 4

Example 11

The IκB kinase inhibitor obtained in Example 5 was combined with the following composition, and the powder containing an IκB kinase inhibitor was prepared.

Lactose 25 parts by weight

Potato starch 10 parts by weight

5 parts by weight of IκB kinase inhibitor obtained in Example 5

Example 12

The α-mangosteen obtained in Example 6 was combined with the following composition, and the tablet containing an IκB kinase inhibitor was produced.

10 parts by weight of D-mannitol

10 parts by weight of lactose

2 parts by weight of crystalline cellulose

1 part by weight of hydroxypropyl cellulose

α-mangosteen 4 parts by weight

Example 13

A γ-B kinase inhibitor-containing syrup was prepared by combining γ-mangosteen obtained in Example 6 with the following composition.

10 parts by weight of sweet syrup

1 part by weight of carboxymethyl cellulose

0.3 parts by weight of γ-mangosteen

Example 14

The IκB kinase inhibitor obtained in Example 2 was combined with the following composition, and the injection containing an IκB kinase inhibitor was prepared.

0.5 part by weight of chlorobutanol

0.9 parts by weight of sodium chloride

80 parts by weight of water for injection

20 parts by weight of IκB kinase inhibitor obtained in Example 2

Example 15

The IκB kinase inhibitor obtained in Example 5 was combined with the following composition, and the IκB kinase inhibitor containing ointment was prepared.

3 parts by weight of beeswax

Hydrogenated lanolin 8 parts by weight

34 weight parts of squalene

2 parts by weight of solid paraffin

Microcrystalline Wax 9 parts by weight

White Vaseline 5 parts by weight

Hexyldecyl adipic acid 13 parts by weight

Sesquioleic acid sorbitan 1 part by weight

Polyoxyethylene (50) Cured Castor Oil 1 part by weight

10 parts by weight of glycerin

1 part by weight of ethanol

10 parts by weight of water

30 parts by weight of the IκB kinase inhibitor obtained in Example 5

Example 16

Γ-mangosteen obtained in Example 6 was combined with the following composition to prepare an IκB kinase-containing candy.

45 parts by weight per granule

50 parts by weight of starch syrup (D. E. 42)

20 parts by weight of water

γ-mangosteen 0.5 parts by weight

Lemon Flavor 1 part by weight

Example 17

IκB kinase obtained in Example 2 was combined with the following composition, and the IκB kinase containing chocolate was manufactured.

20 parts by weight of cacao butter

Kakaover 17 parts by weight

43 parts by weight of sugar

20 parts by weight of whole milk powder

1 part by weight of IκB kinase obtained in Example 2

Vanilla Flavor 0.1 part by weight

Example 18

The IκB kinase obtained in Example 3 was combined with the following composition, and the IκB kinase containing chewing gum was produced.

20 parts by weight of gum base

56 parts by weight of sugar

13 parts by weight of starch syrup

10 parts by weight of glucose

1 part by weight of softener

0.5 part by weight of IκB kinase obtained in Example 3

Mint Flavor 0.5

Example 19

The IκB kinase obtained in Example 4 was combined with the following composition, and the IκB kinase inhibitor containing fruit was prepared.

75 parts by weight of sugar

19 parts by weight of glucose

0.2 parts by weight of sucrose fatty acid ester

0.5 parts by weight of IκB kinase obtained in Example 4

4 parts by weight of water

As described above, the extract obtained by the extraction of the organic or organic solvents, α-mangosteen and γ-mangosteen from the fruit or skin of the mangosteen ( Garcinia mangostana L. ) has an IκB kinase inhibitory activity and NF- It was clear to inhibit gene expression that mediates κB activation.

Therefore, the IκB kinase inhibitor of the present invention and the composition comprising the same are useful as IκB kinase inhibitors, and can be expected to be useful in the treatment and prevention of diseases involving IκB kinase in mammals and diseases involving NF-κB.

Claims (4)

It contains as an active ingredient an extract obtained by extracting the fruit or skin of mangosteen ( Garcinia mangostana L. ) with an organic or organic solvent, α-mangosteen and γ-mangosteen. And asthma, allergic rhinitis, atopic dermatitis, gallbladder, conjunctivitis, spring catarrh, psoriasis, ulcerative colitis, systemic inflammatory plaque syndrome, sepsis, caused by IκB kinase activity and gene expression by NF-κB Multiple myositis, dermatitis, nodular polyarthritis, mixed connective histosis, Sjogren's syndrome, gout, Alzheimer's dementia, Parkinson's disease, muscular dystrophy, chronic arthritis, type I diabetes, multiple sclerosis, Crohn's disease, chronic thyroiditis ( Hashimoto disease), Ceria disease, myasthenia gravis, vulgaris vulgaris, systemic erythematodes, viral diseases (HIV, herpes, Sendai rotavirus, Fluenza virus, rabies virus, bullous stomatitis virus, rhinovirus, hepatitis A virus, hepatitis B virus, rubella virus, etc.), bacterial disease, radiation disorders, arteriosclerosis, reperfusion disorders, cardiac hypertrophy, cancer and IκB kinase inhibitors for the treatment and prevention of type II diabetes. As an active ingredient comprising the IκB kinase inhibitor of claim 1, asthma, allergic rhinitis, atopic dermatitis caused by IκB kinase activity and gene expression by NF-κB, gall margin, conjunctivitis, spring catarrh, psoriasis, Ulcerative colitis, systemic inflammatory symptom syndrome, sepsis, polymyositis, dermatitis, nodular polyarthritis, mixed connective histosis, Sjogren's syndrome, gout, Alzheimer's dementia, Parkinson's disease, muscular dystrophy, sclerosis, chronic arthritis, type I Diabetes mellitus, multiple sclerosis, Crohn's disease, chronic thyroiditis (Hashimoto's disease), ceriac disease, myasthenia gravis, vulgaris vulgaris, systemic erythematodes, viral diseases (HIV, herpes, Sendai rotavirus, influenza virus, Rabies virus, bullous stomatitis virus, rhinovirus, hepatitis A virus, hepatitis B virus, rubella virus, etc.), bacterial diseases, A composition for inhibiting IκB kinase for the treatment and prevention of radiation-induced disorders, arteriosclerosis, reperfusion disorders, cardiac hypertrophy, cancer, and type II diabetes. delete delete