JP7124145B2 - Composition for Tie2 activation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a composition for Tie2 activation and the like. More specifically, the present invention contains one or more ingredients selected from the group consisting of novel iridoid compounds (Compound A and Compound B), oleanoside A, and Kaempferol as active ingredients, The present invention relates to a composition for activating Tie2, a composition for inhibiting vascular permeability, a composition for maturing blood vessels, a composition for normalizing blood vessels, a composition for stabilizing blood vessels, and a composition for stabilizing lymphatic vessels. The invention also relates to novel iridoid compounds (Compound A and Compound B) and compositions containing said compounds.

Olive (Olea europaea) is a plant belonging to the genus Olive of the family Oleaceae, and is widely cultivated in the Mediterranean region and elsewhere, and its fruits are widely used for extraction of olive oil and for food throughout the world.

Olive fruits are rich in polyphenols such as hydroxytyrosol, acteoside, and oleuropein (Non-Patent Documents 1 and 2), and olive extracts and their polyphenol components have antiarteriosclerosis effects (Non-Patent Document 3). ), hypertension inhibitory action (Patent Document 1), bone weight loss inhibitory action (Non-Patent Document 4), and the like.

In recent years, it has been found that aging and functional deterioration of blood vessels affect skin properties such as wrinkles and rough skin, and it is known that the normality of blood vessels is an effective index for judging skin properties. These blood vessels not only deliver oxygen and nutrients to the organs of the whole body through the blood, but also carry waste products from the tissues and excrete them outside the body. . In general, aging and functional breakdown of blood vessels have a significant impact on the health of the human body, as typified by arteriosclerosis, and also lead to appearance findings such as wrinkles and swelling. In recent years, the activation of receptor tyrosine kinase Tie2 (Tyrosine kinase with Ig and ECF homology domain 2) has attracted attention for this vascular aging. It is known that when Tie2 is activated by angiopoietin-1 from vascular wall cells, adhesion between vascular endothelial cells is induced and contributes to stabilization of vascular endothelial cells. In recent years, ingredients and foods that have this Tie2 activating action have been found, and are used in supplements, beverages, etc., for beauty, prevention of swelling, prevention of sensitivity to cold, etc. (Patent Documents 2 to 4).

JP 2005-334022 A JP 2014-097977 A JP 2013-241356 A JP 2011-102272 A

J. Agric. Food Chem., vol.52, pp479-484, 2004 J. Agric. Food Chem., vol.53, pp8963-8969, 2005, Atherosclerosis, vol.188, No.1, pp35-42, 2006 Clin Nutr., vol.25, No.5, 859-868, 2006

An object of the present invention is to provide a composition having a Tie2 activating effect, a vascular permeability suppressing effect, a vascular maturation effect, a vascular normalizing effect, a vascular stabilizing effect, a lymphatic vessel stabilizing effect, and the like. for the purpose.

In order to solve the above problems, the present inventors conducted extensive research and found that among the components isolated from the olive fruit extract, oleanoside A and kaempferol have Tie2 activating action, vascular permeability suppressing action, and vascular It has been newly found that it has a maturation action, a blood vessel normalization action, a blood vessel stabilization action, a lymphatic vessel stabilization action, and the like. Furthermore, in addition to discovering novel iridoid compounds (Compound A and Compound B) from the olive fruit extract, the novel compounds also have Tie2 activating action, vascular permeability inhibitory action, vascular maturation action, vascular normalizing action, and vascular regulating action. They have clarified that it has a stabilizing action, a lymphatic vessel stabilizing action, and the like, and have completed the present invention.

（２）前記（Ｉ）で表される化合物、前記（ＩＩ）で表される化合物、前記（ＩＩＩ）で表される化合物（Oleanoside A）、前記（ＩＶ）で表される化合物（Kaempferol）、及びそれらの塩からなる群から選択される１以上の成分を含有する、血管透過性抑制用組成物。
（３）前記（Ｉ）で表される化合物、前記（ＩＩ）で表される化合物、前記（ＩＩＩ）で表される化合物（Oleanoside A）、前記（ＩＶ）で表される化合物（Kaempferol）、及びそれらの塩からなる群から選択される１以上の成分を含有する、血管の成熟化用組成物。
（４）前記（Ｉ）で表される化合物、前記（ＩＩ）で表される化合物、前記（ＩＩＩ）で表される化合物（Oleanoside A）、前記（ＩＶ）で表される化合物（Kaempferol）、及びそれらの塩からなる群から選択される１以上の成分を含有する、血管の正常化用組成物。
（５）前記（Ｉ）で表される化合物、前記（ＩＩ）で表される化合物、前記（ＩＩＩ）で表される化合物（Oleanoside A）、前記（ＩＶ）で表される化合物（Kaempferol）、及びそれらの塩からなる群から選択される１以上の成分を含有する、血管の安定化用組成物。
（６）前記（Ｉ）で表される化合物、前記（ＩＩ）で表される化合物、前記（ＩＩＩ）で表される化合物（Oleanoside A）、前記（ＩＶ）で表される化合物（Kaempferol）、及びそれらの塩からなる群から選択される１以上の成分を含有する、リンパ管の安定化用組成物。
（７）血管透過性抑制作用、血管の成熟化作用、血管の正常化作用、血管の安定化作用、又はリンパ管の安定化作用が、Ｔｉｅ２活性化作用に起因するものである、（２）～（６）のいずれかに記載の組成物。
（８）食品組成物である、（１）～（７）のいずれかに記載の組成物。
（９）飲料組成物である、（１）～（７）のいずれかに記載の組成物。
（１０）Ｔｉｅ２を活性化することにより発揮される機能、血管透過性抑制により発揮される機能、血管の成熟化により発揮される機能、血管の正常化により発揮される機能、血管の安定化により発揮される機能、及びリンパ管安定化により発揮される機能からなる群から選択される１以上の機能の表示を付した、（１）～（９）のいずれかに記載の組成物。
（１１）機能表示が、「血管透過性亢進を抑制する」、「血管内因子の血管外への漏出を抑制する」、「血管を正常な状態に改善する」、「血管を正常な状態に維持する」、「血管内皮細胞同士の乖離を抑制する」、「血管内皮細胞の細胞死を抑制する」、及び「組織間液の速やかな回収機能を保持する」からなる群から選択される１以上である、（１０）に記載の組成物。
（１２）Ｔｉｅ２活性化のための、前記（Ｉ）で表される化合物、前記（ＩＩ）で表される化合物、前記（ＩＩＩ）で表される化合物（Oleanoside A）、前記（ＩＶ）で表される化合物（Kaempferol）、及びそれらの塩からなる群から選択される１以上の使用。
（１３）前記（Ｉ）で表される化合物、前記（ＩＩ）で表される化合物、前記（ＩＩＩ）で表される化合物（Oleanoside A）、前記（ＩＶ）で表される化合物（Kaempferol）、及びそれらの塩からなる群から選択される１以上を有効成分として使用する、Ｔｉｅ２を活性化する方法。
（１４）下記式（Ｉ）

で表される化合物。
（１５）下記式（ＩＩ）

で表される化合物。
（１６）（１４）又は（１５）に記載の化合物を含有する組成物。
（１７）（１４）及び（１５）に記載の化合物を含有する組成物。
（１８）食品組成物である、（１６）又は（１７）に記載の組成物。
（１９）飲料組成物である、（１６）又は（１７）に記載の組成物。 That is, aspects of the present invention include, but are not limited to, the following inventions.
(1) a compound represented by (I) below, a compound represented by (II) below, a compound (Oleanoside A) represented by (III) below, a compound (Kaempferol) represented by (IV) below, and salts thereof, a Tie2 activating composition containing one or more components selected from the group consisting of:

(2) the compound represented by (I), the compound represented by (II), the compound (Oleanoside A) represented by (III), the compound (Kaempferol) represented by (IV), and a composition for inhibiting vascular permeability, containing one or more components selected from the group consisting of salts thereof.
(3) the compound represented by (I), the compound represented by (II), the compound (Oleanoside A) represented by (III), the compound (Kaempferol) represented by (IV), A composition for maturation of blood vessels containing one or more components selected from the group consisting of and salts thereof.
(4) the compound represented by (I), the compound represented by (II), the compound (Oleanoside A) represented by (III), the compound (Kaempferol) represented by (IV), A composition for normalizing blood vessels, comprising one or more ingredients selected from the group consisting of and salts thereof.
(5) the compound represented by (I), the compound represented by (II), the compound (Oleanoside A) represented by (III), the compound represented by (IV) (Kaempferol), A composition for stabilizing blood vessels, comprising one or more ingredients selected from the group consisting of and salts thereof.
(6) the compound represented by (I), the compound represented by (II), the compound (Oleanoside A) represented by (III), the compound represented by (IV) (Kaempferol), and salts thereof, a composition for stabilizing lymphatic vessels.
(7) the vascular permeability inhibitory action, vascular maturation action, vascular normalization action, vascular stabilizing action, or lymphatic vessel stabilizing action is attributed to the Tie2 activating action; (2) The composition according to any one of (6).
(8) The composition according to any one of (1) to (7), which is a food composition.
(9) The composition according to any one of (1) to (7), which is a beverage composition.
(10) Functions exhibited by activating Tie2, functions exhibited by inhibition of vascular permeability, functions exhibited by maturation of blood vessels, functions exhibited by normalization of blood vessels, and stabilization of blood vessels The composition according to any one of (1) to (9), labeled with one or more functions selected from the group consisting of functions exerted and functions exerted by stabilizing lymphatic vessels.
(11) The function indication is "suppress vascular hyperpermeability", "suppress extravasation of intravascular factors", "improve blood vessels to normal state", "restore blood vessels to normal state" 1 selected from the group consisting of "maintains", "suppresses dissociation between vascular endothelial cells", "suppresses cell death of vascular endothelial cells", and "preserves rapid collection function of interstitial fluid" The composition according to (10) above.
(12) for Tie2 activation, the compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV) (Kaempferol), and salts thereof.
(13) the compound represented by (I), the compound represented by (II), the compound (Oleanoside A) represented by (III), the compound represented by (IV) (Kaempferol), and a method for activating Tie2, using one or more selected from the group consisting of salts thereof as an active ingredient.
(14) Formula (I) below

A compound represented by
(15) Formula (II) below

A compound represented by
(16) A composition containing the compound according to (14) or (15).
(17) A composition containing the compound described in (14) and (15).
(18) The composition according to (16) or (17), which is a food composition.
(19) The composition according to (16) or (17), which is a beverage composition.

According to the present invention, a composition containing as an active ingredient one or more ingredients selected from the group consisting of novel iridoid compounds (Compound A and Compound B), oleanoside A, kaempferol, and salts thereof has a Tie2 activating action , vascular permeability inhibitory action, vascular maturation action, vascular normalization action, vascular stabilization action, and lymphatic vessel stabilization action. In addition, the connection between vascular endothelial cells is strengthened by the normalization of blood vessels according to the present invention, so that nutrients are distributed to the skin through the blood vessels, and cosmetic effects such as improvement of skin firmness and texture and prevention of wrinkles can be obtained. be done. In addition, by closing the gaps between the endothelial cells of blood vessels and lymphatic vessels, blood flow is improved, and water and waste products are collected from the tissue, which has the effect of improving various symptoms such as coldness, stiff shoulders, swelling, and dark circles. and preventive effects.

FIG. 1 shows the chemical structures of novel iridoid compounds (Compound A and Compound B), oleanoside A, and kaempferol. FIG. 2 shows the purification flow of olive fruit extract. FIG. 3 shows ¹ H-NMR and ¹³ C-NMR signals of a novel iridoid compound (Compound A) and megaritolactonol. FIG. 4 shows the two-dimensional NMR analysis results of the novel iridoid compound (Compound A). Specifically, as the shift correlation spectrum analysis, ¹ H- ¹ H shift correlation two-dimensional NMR ( ¹ H- ¹ H correlation spectroscopy (COSY)) analysis and ¹ H- ¹³ C long range shift correlation two-dimensional NMR ( ¹ H -detected heteronuclear multiple bond connectivity (HMBC) analysis results. FIG. 5 shows ¹ H-NMR and ¹³ C-NMR signals of a novel iridoid compound (Compound B) and oleanoside A (Oleanoside A). FIG. 6 shows the two-dimensional NMR analysis results of the novel iridoid compound (Compound B). Specifically, results of ¹ H- ¹³ C long range shift correlation two-dimensional NMR ( ¹ H-detected heteronuclear multiple bond connectivity (HMBC)) analysis as shift correlation spectrum analysis are shown. FIG. 7 shows the results of comparing the Tie2 activation effects of novel iridoid compounds (Compound A and Compound B), oleanoside A, kaempferol, hydroxytyrosol, and tyrosol with those of a control group (DMSO). Figure 8 shows the results of evaluating the inhibitory effect of novel iridoid compounds (Compound A and Compound B) on the enhancement of vascular permeability caused by vascular endothelial growth factor (VEGF), which is a vascular permeability factor. show.

1. Composition
1-1. Composition One aspect of the present invention is a composition containing, as an active ingredient, one or more ingredients selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof. Active ingredients contained in the composition of the present invention are compounds represented by the following formulas (I) to (IV).

The compounds represented by formulas (I) and (II) are novel iridoid compounds. The compound of formula (I) has the IUPAC name 2-(3,4-dihydroxyphenyl)ethyl (E)-2-(5-ethylidene-2-oxotetrahydropyran-4-yl)acetate (2-(3 ,4-dihydroxyphenyl)ethyl (E)-2-(5-ethylidene-2-oxotetrahydropyran-4-yl)acetate) and may be referred to as “Compound A” in this specification. The compound of formula (II) has the IUPAC name of 2-(3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl)acetic acid (2-( 3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl)acetic acid) and may be described as "Compound B" in this specification. Further, the compound represented by the formula (III) is oleanoside A, and the compound represented by the formula (IV) is Kaempferol.

The compound in the present invention may be in the form of any pharmacologically acceptable salt (including inorganic salts and organic salts). As used herein, "salt" refers to any pharmacologically acceptable salt (including inorganic salts and organic salts), for example, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, hydrochloric acid Salts, sulfates, nitrates, phosphates, organic acid salts (acetates, citrates, maleates, malate, oxalates, lactates, succinates, fumarates, propionates, formates , benzoates, picrates, benzenesulfonates, trifluoroacetates, etc.), but are not limited thereto. Salts of the compounds of the present invention can be readily prepared by those skilled in the art by any method known in the art.

1-2. Isolation and Synthesis of Active Ingredients Contained in the Composition of the Present Invention It may be produced by extraction and isolation, or may be produced by a chemical synthesis method, and is not particularly limited. When the active ingredients contained in the composition of the present invention are produced from natural products, the natural products used as raw materials are not particularly limited, but olives, for example, are preferably used. Olive is a plant of the Oleaceae family, and olive fruits can be used as the main raw material, but leaves, seeds, stems, and the like may be mixed. When olive fruit is used as a raw material, it may be used as it is, or may be used after being dried by freeze-drying or the like. Also, the residue left after oil has been squeezed from the olive fruit can be used as it is or in a dried state. It is preferable to use only olive juice, which is a water layer obtained by separating a liquid phase obtained from olive fruits into an oil layer and a water layer, as a raw material.

In addition, although the variety of olives is not particularly limited, for example, varieties such as Manzanillo, Lucca, Nevadillo Blanco, Mission, Picual, Arbequina, Hojiblanca, Cornicabra, Gordal, Moroiolo, Frantoio, Colatina, and Leccino can be preferably used. can.

As used herein, the term "olive juice" refers to an extract obtained from a water layer obtained by separating a liquid phase obtained from an olive fruit extract into an oil layer and a water layer. Olive fruit extracts can also be extracted, for example, from olives using an aqueous solvent. Aqueous solvents include water and alcohols (eg, ethanol). As the olive fruit extract, olive juice or aqueous solvent extract may be used as it is, or an extract obtained by filtering these, concentrating polyphenols in an adsorption column, and spray-drying may be used. Olive fruit extract can be obtained through a process of separating and purifying olive fruit. In the olive fruit separation step, the raw material olive fruit is pressed and separated into oil and juice by centrifugation to obtain olive juice. can be done. In the purification step, an extract obtained by filtering and concentrating the olive juice obtained in the separation step can be used as the olive fruit extract in the present invention. In addition, the filtrate obtained by filtering olive juice is added to a column filled with an adsorption resin, and after removing components that are not adsorbed to the adsorption resin such as sugars, minerals, and organic acids, or a mixture thereof) may be used as an olive fruit extract. A person skilled in the art can appropriately set the conditions for the type of adsorption resin and the elution solvent for the column according to the variety, form, etc. of olives to be used.

Extraction of the active ingredient contained in the composition of the present invention from raw materials derived from natural products can be performed using a solvent, but is not limited to this. Any solvent may be used as long as the active ingredient contained in the composition of the present invention can be extracted, and water, an aqueous solution such as a buffer solution, an organic solvent, or a combination thereof can be used. Any commonly used organic solvent may be used, and for example, alcohols and ketones can be used. Examples of alcohols include lower alcohols (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, etc.) and liquid polyhydric alcohols (1,3-butylene alcohol, propylene glycol, glycerin, etc.). Hydrous lower alcohols or lower alcohols are preferably used. Examples of ketones include acetone and butanone. The amount of the solvent to be used can be appropriately set according to the amount of raw material to be treated and the content of the target compound in the raw material. 0-500 mL, more preferably 5.0-100 mL of solvent may be used.

The active ingredient contained in the composition of the present invention can be further purified to increase its purity after extraction from the raw material, if necessary. Purification may be performed by any technique, for example, by chromatography. Examples of chromatography include, but are not limited to, ion exchange chromatography, hydrophobic chromatography, hydrophilic chromatography, gel filtration chromatography, and the like. The purity of the sample can be confirmed by high-performance liquid chromatography or LC-MS, which is a combination of high-performance liquid chromatography and mass spectrometry, but is not limited to this. Furthermore, the chemical structure of the active ingredient contained in the composition of the present invention can be analyzed by nuclear magnetic resonance (NMR), mass spectrum, or the like. The composition of the present invention does not include naturally occurring animals and plants that have not been processed at all.

When chemically synthesizing the active ingredient contained in the composition of the present invention, the compounds of the present invention are produced by appropriately selecting generally known organic chemistry techniques using available compounds as starting materials. can do.

1-3. One aspect of the present invention, such as a Tie2 activating composition, is a Tie2 activating composition containing, as an active ingredient, one or more components selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof. It is a composition for

In the present invention, the “composition for activating Tie2” refers to a composition having the ability to convert Tie2 into its active form (phosphorylated Tie2) by phosphorylating Tie2. Activation of a receptor called Tie2 present in vascular endothelial cells plays an important role in stabilizing the structure of capillaries. This Tie2 has been shown to exist not only in vascular endothelial cells but also in lymphatic endothelial cells, and is activated by angiopoietin-1 released from parietal cells. involved in stabilization. For example, it has been reported that the activity of Tie2 decreases with age, and it has been clarified that blood vessels and lymphatic vessels also age accordingly. Therefore, the Tie2-activating composition of the present invention can prevent and improve the aging of blood vessels and lymphatic vessels through Tie2-activating action.

In addition, when the vascular structure becomes unstable due to aging of the blood vessels, nutritional components such as plasma components leak out of the blood vessels, and necessary components cannot be transported to required locations. As a result, it is conceivable that various troubles such as deterioration of the skin condition may occur. Therefore, the Tie2-activating composition of the present invention can stabilize vascular endothelial cells by Tie2-activating action and exhibit vascular permeability-inhibiting action. The endothelial cells of the blood vessels are tightly bound together, so that nutrients are distributed to the skin, and cosmetic effects such as improved skin firmness and texture, and prevention of wrinkles can be obtained. In addition, by closing the gaps between the endothelial cells of blood vessels and lymphatic vessels, blood flow is improved, water and waste products are collected from the tissue, and various symptoms such as coldness, stiff shoulders, swelling, dark circles, etc. are improved. , has a preventive effect. Accordingly, the present invention provides a composition for activating Tie2 containing as an active ingredient one or more ingredients selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof, The composition may have a permeability suppressing effect, a vascular maturation effect, a vascular normalizing effect, a vascular stabilizing effect, or a lymphatic vessel stabilizing effect.

Another aspect of the present invention includes a composition for suppressing vascular permeability, a composition for maturing blood vessels, a composition for normalizing blood vessels, a composition for stabilizing blood vessels, a composition for stabilizing lymphatic vessels, and the like. be done. These compositions preferably contain, as active ingredients, one or more ingredients selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof.

In the present invention, “suppression of vascular permeability” refers to suppression of increased vascular permeability caused by VEGF (vascular endothelial growth factor) and the like. “Maturation of blood vessels” refers to the formation of focal adhesions between vascular endothelial cells that induce adhesion between vascular endothelial cells and vascular wall cells to prevent intravascular environmental factors from easily leaking out of the blood vessels. Say. “Normalization of blood vessels” refers to enhancing the adhesion between vascular endothelial cells and promoting the lining of vascular wall cells to vascular endothelial cells, leading to blood vessels with impaired vascular permeability and disordered proliferation of blood vessels. It means to normalize abnormal blood vessels. The term "stabilization of blood vessels" refers to the action of inhibiting injury to existing blood vessels, dissociation between vascular endothelial cells, dissociation between vascular endothelial cells and vascular wall cells, and inhibition of cell death of vascular endothelial cells. . The term “lymphatic vessel stabilization” refers to stabilizing lymphatic vessels so that lymphatic endothelial cells are appropriately arranged and lined, and maintaining the function of rapid collection of interstitial fluid.

1-4. Content of Active Ingredients in Composition The amount is not particularly limited as long as the desired effect is obtained. For example, when Compound A is used as an active ingredient, the content of Compound A in the composition of the present invention is 0.01 wt% to 99 wt%, preferably 0.1 wt% to 50% by weight, more preferably 1% to 30% by weight, even more preferably 10% to 30% by weight. When Compound B is used as an active ingredient, the content of Compound B in the composition of the present invention is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, relative to the total amount of the composition. %, more preferably 1 wt % to 30 wt %, even more preferably 10 wt % to 30 wt %. When oleanoside A is used as an active ingredient, the content of oleanoside A in the composition of the present invention is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, relative to the total amount of the composition. %, more preferably 1 wt % to 30 wt %, even more preferably 10 wt % to 30 wt %. When kaempferol is used as an active ingredient, the content of kaempferol in the composition of the present invention is 0.001% by weight to 99% by weight, preferably 0.01% by weight to 50% by weight, based on the total weight of the composition. %, more preferably 0.1 wt % to 30 wt %, even more preferably 1 wt % to 30 wt %. As used herein, "wt%" means weight percent weight/weight (w/w), unless otherwise specified. In addition, when various active ingredients are in the form of salts, hydrates, etc., the above-mentioned content shall be calculated after converting this to the free form (free form).

The content of Compound A, Compound B, oleanoside A, kaempferol and salts thereof can be measured according to methods known to those skilled in the art. For example, using LC-MS/MS, HPLC, etc., measurement can be performed by appropriately setting conditions according to the type of the active ingredient.

1-5. Other Ingredients The composition of the present invention may contain optional additives and ingredients in addition to the active ingredient, depending on its form. Although these additives and/or components are not particularly limited, for example, excipients, binders, disintegrants, lubricants, antioxidants, preservatives, flavoring agents, flavoring agents, coloring agents, additives such as perfumes can be used. For example, L-ascorbic acid, catechin, dextrin, cyclodextrin, calcium carbonate, trehalose and the like can be used. In addition, the composition may contain known ingredients, and may contain ingredients known to be effective in anti-aging of blood vessels and beauty. For example, Tie2 activating activity has been reported for quillaya, yellow lily, ginkgo nut, oyster, turmeric, chrysanthemum, jujube, wolfberry, chamomile, butcher bloom, hawthorn, star fruit, Alpinia purpurea, lotus, rooibos, Indian dates, Chinese quince, and sijuum. Guava, hihatsu, Siberian carrot, mango ginger, Korean ginseng, autumn gummy, hijiki hijiki, harigiri, ryobu, licorice, juniper, honeywort, Japanese horsetail, mbe, salamander, konara oak, sawtooth oak, poppy, juniper, plantain, nobir, bayberry, Extracts of cinnamon, pine bark, pine bark, peanut seed coat, lychee seed coat, etc., L-citrulline, L-arginine, etc. of amino acids can be used.

1-6. Uses The compositions of the present invention may exhibit various physiological effects as described above. For example, by applying the composition of the present invention, vascular permeability suppressing effect, vascular maturation effect, vascular normalizing effect, vascular stabilizing effect, lymphatic vessel stabilizing effect, Tie2 activating effect, etc. are exerted. As a result, it is possible to obtain cosmetic effects such as improving the firmness and texture of the skin and preventing wrinkles, as well as improving and preventing effects such as coldness, stiff shoulders, swelling, dark circles, etc.

The compositions of the present invention can be applied for either therapeutic use (medical use) or non-therapeutic use (non-medical use). Examples of such compositions include pharmaceuticals (pharmaceutical compositions), food and drink (including foods, beverages, food and drink compositions, food compositions, and beverage compositions), cosmetics (cosmetic compositions), and the like. is not limited to

The composition of the present invention can be prepared according to known methods as solid formulations such as tablets (including coated tablets), granules, powders, powders, or capsules, oral solutions, suspensions, emulsions, syrups, or It can be provided as a drug formulation such as a liquid drug such as a drink. These agents can be taken as they are or together with water or the like. In addition, after being prepared in a form that can be easily blended (for example, powder form or granule form), it can be used, for example, as a raw material for pharmaceuticals and food and drink, but is not limited to this form. The formulation of the composition of the present invention as a cosmetic (cosmetic composition) can be arbitrarily selected according to the purpose. It can be in the form of forms, packs, lotions, powders and sticks. The formulation form is also a wide range of forms such as aqueous solution system, solubilization system, emulsion system, powder system, oil system, gel system, ointment system, aerosol system, water-oil two-layer system and water-oil-powder three-layer system. can do. In other words, if it is basic cosmetics, facial cleanser, lotion, lotion, milky lotion, cream, gel, essence (beauty liquid), pack, mask, massage agent, foundation, lipstick, bath powder, shampoo, hair conditioner, hair tonic , ointments, pastes, and sheet-like products (absorbent articles such as sanitary products, baby wipes, wet tissues, etc.). And it is not limited to the dosage forms and forms of the present invention. In addition, various oils, surfactants, gelling agents, preservatives, antioxidants, solvents, alcohols, water, chelating agents, thickeners, ultraviolet absorbers, emulsion stabilizers, pH Adjusting agents, dyes, perfumes, and the like can be added as appropriate.

Specific examples of the beverages of the present invention include oolong tea beverages, black tea beverages, green tea beverages, fruit juice beverages, vegetable juices, sports drinks, isotonic beverages, enhanced water, mineral water, near water, energy drinks, beauty drinks, and various beverages. Alcoholic beverages and the like can be mentioned.

In addition, the beverage of the present invention is made into a packaged beverage after undergoing a process such as sterilization as necessary. For example, a sterilized container-packed beverage can be produced by a method of performing heat sterilization after filling the beverage in a container, or a method of sterilizing the beverage and then filling the container in an aseptic environment.

The type of container used for packaged beverages is not particularly limited, and examples include resin containers such as PET bottles, paper containers such as paper packs, glass containers such as glass bottles, metal containers such as aluminum and steel cans, and aluminum pouches. Any container that is usually used for beverages can be used.

The food and drink of the present invention are not particularly limited, but for example, health food, functional food (including specified health food, conditionally specified health food, nutrient functional food, food with function claims), food for special use, or Examples include health supplements. The content of the active ingredient in the food or drink of the present invention is as described above for the composition.

The food and drink of the present invention may be prepared, for example, by mixing a predetermined amount of the active ingredient with the raw material when preparing a known food and drink according to a known food and drink manufacturing method. You may prepare by adding the said active ingredient to well-known food-drinks so that it may become the said predetermined amount. Incidentally, known food and drink may originally contain the above-mentioned active ingredient, and if the above-mentioned active ingredient is in the above-mentioned predetermined amount, it can be prepared by blending as appropriate.

The composition of the present invention can be applied by a suitable method depending on its form. The application method is not particularly limited as long as the active ingredient according to the present invention can be transferred into the circulating blood. For example, it can be in the form of oral solid preparations, oral liquid preparations such as oral liquid preparations or syrups, or parenteral preparations such as injections, external preparations, suppositories or percutaneous absorbable preparations. is not limited to In this specification, the term "application" is used to include all aspects such as ingestion, dosing, drinking, and percutaneous absorption. The dosage of the composition of the present invention is appropriately set according to its form, administration method, purpose of use, and age, body weight, and symptoms of a patient or animal to be administered, and is not constant. The effective human intake of the composition of the present invention is also not constant and is not particularly limited. The effective human intake of the composition of the present invention is, for example, 0.1 mg to 400 mg (0.002 mg/kg to 8 mg/kg), preferably 1 mg to 300 mg (0.02 mg/kg) per day for a human weighing 50 kg. ~6 mg/kg), more preferably 10 mg to 200 mg (0.2 mg/kg to 4 mg/kg). The composition of the present invention may be applied once or several times within a day within the desired intake range. The application period is also arbitrary. The effective human intake of the composition of the present invention is the intake of the composition of the present invention that exhibits effective effects in humans, and the type of active ingredient contained in the composition is not particularly limited.

The subject of application of the composition of the present invention is preferably human, but also domestic animals such as cows, horses and goats, pet animals such as dogs, cats and rabbits, and laboratory animals such as mice, rats, guinea pigs and monkeys. may be When applied to animals other than humans, the daily dosage per mouse (about 20 g) depends on conditions such as the content of the active ingredient in the composition, the condition of the subject, body weight, sex and age. Depending on the dosage, it is, for example, 0.002 mg/kg to 8 mg/kg, preferably 0.02 mg/kg to 6 mg/kg, more preferably 0.2 mg/kg to 4 mg/kg. In another aspect of the present invention, the above It relates to a composition containing the agent of the present invention. Such indications or functional indications are not particularly limited, but examples include "suppressing vascular hyperpermeability", "suppressing extravascular leakage of intravascular factors", and "improving blood vessels to a normal state". , "maintaining blood vessels in a normal state", "suppressing dissociation between vascular endothelial cells", "suppressing cell death of vascular endothelial cells", or "preserving the rapid collection function of interstitial fluid" etc., or indications or functional indications that can be equated with these. In the present specification, indications such as the indication and function indication may be attached to the composition itself, or may be attached to the container or packaging of the composition.

2. Use for activating Tie2 One aspect of the present invention is to use one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof to inhibit vascular permeability, reduce vascular The use for maturation, vascular normalization, vascular stabilization, lymphatic stabilization, or Tie2 activation, preferably for Tie2 activation.

In addition, by using the present invention, Tie2 is activated to obtain a vascular permeability suppressing effect, a vascular maturation effect, a vascular normalizing effect, a vascular stabilizing effect, a lymphatic vessel stabilizing effect, and the like. can also The use may be in humans or non-human animals and may be therapeutic or non-therapeutic. Here, "non-therapeutic" is a concept that does not include medical treatment, ie treatment of the human body by treatment.

3. Method for activating Tie2 One aspect of the present invention is a method for activating Tie2, using as an active ingredient one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof. be. Specifically, one aspect of the present invention provides a method of activating Tie2, comprising administering a therapeutically effective amount of the active ingredient to a subject in need of Tie2 activation. The subject requiring Tie2 activation is as described above regarding the composition.

In addition, one aspect of the present invention provides vascular permeability suppression and vascular maturation using one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof as an active ingredient. , vascular normalization, vascular stabilization, or lymphatic stabilization.

In the present specification, the term “therapeutically effective amount” means that when the subject ingests one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof, It is the amount that results in Tie2 activation compared to a control without. A specific effective amount is set as appropriate depending on the form of administration, administration method, purpose of use, age, body weight, symptoms, etc. of the subject and is not constant.

In the method of the present invention, the active ingredient may be administered as it is or as a composition containing the active ingredient so as to achieve the therapeutically effective amount.

4. Novel Iridoid Compound One aspect of the present invention is a novel iridoid compound represented by the following formula (I) or (II).

The compound of formula (I) has the IUPAC name of 2-(3,4-dihydroxyphenyl)ethyl (E)-2-(5-ethylidene-2-oxotetrahydropyran-4-yl)acetate (2- (3,4-dihydroxyphenyl)ethyl (E)-2-(5-ethylidene-2-oxotetrahydropyran-4-yl)acetate) and may be referred to as “Compound A” in this specification. The compound of formula (II) has the IUPAC name of 2-(3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl)acetic acid (2-( 3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl)acetic acid) and may be described as "Compound B" in this specification.

The compound in the present invention may be in the form of any pharmacologically acceptable salt (including inorganic salts and organic salts). As used herein, the term "salt" is not particularly limited as long as it is any pharmacologically acceptable salt (including inorganic salts and organic salts), as described above. salts, magnesium salts, ammonium salts, hydrochlorides, sulfates, nitrates, phosphates, organic acid salts (acetates, citrates, maleates, malate, oxalates, lactates, succinates, fumarates acid salts, propionates, formates, benzoates, picrates, benzenesulfonates, trifluoroacetates, etc.). Salts of the compounds of the present invention can be readily prepared by those skilled in the art by any method known in the art.

4-1. Method for Producing Novel Iridoid Compounds The novel iridoid compounds (Compound A, Compound B) of the present invention may be produced by extracting and isolating from natural products, or may be produced by a chemical synthesis method, and are not particularly limited. When producing from a natural product, the natural product used as a raw material is not particularly limited, but it is particularly preferable to use olives. Olive is a plant of the Oleaceae family, and olive fruits can be used as the main raw material, but leaves, seeds, stems, and the like may be mixed. When olive fruit is used as a raw material, it may be used as it is, or may be used after being dried by freeze-drying or the like. Also, the residue left after oil has been squeezed from the olive fruit can be used as it is or in a dried state. It is preferable to use only olive juice, which is a water layer obtained by separating a liquid phase obtained from olive fruits into an oil layer and a water layer, as a raw material. "Olive" and "olive juice" are as described above with respect to the composition.

Extraction of the novel iridoid compound of the present invention from raw materials derived from natural products (eg, olive fruit extract, etc.) can be performed using a solvent, but is not limited to this. Any solvent may be used as long as the active ingredient contained in the composition of the present invention can be extracted, and water, an aqueous solution such as a buffer solution, an organic solvent, or a combination thereof can be used. Any commonly used organic solvent may be used, and for example, alcohols and acetone can be used. Examples of alcohols include lower alcohols (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, etc.) and liquid polyhydric alcohols (1,3-butylene alcohol, propylene glycol, glycerin, etc.). Hydrous lower alcohols or lower alcohols are preferably used. The amount of the solvent to be used can be appropriately set according to the amount of raw material to be treated and the content of the target compound in the raw material. 0-500 mL, more preferably 5.0-100 mL of solvent may be used.

The novel iridoid compounds of the present invention can be further purified after extraction from the starting material to increase purity, if desired. Purification may be performed by any technique, for example, by chromatography. Examples of chromatography include, but are not limited to, ion exchange chromatography, hydrophobic chromatography, hydrophilic chromatography, gel filtration chromatography, and the like. The purity of the sample can be confirmed by high-performance liquid chromatography or LC-MS, which is a combination of high-performance liquid chromatography and mass spectrometry, but is not limited to this. Furthermore, the chemical structure of the novel iridoid compound of the present invention can be analyzed by nuclear magnetic resonance (NMR), mass spectrum, or the like.

When chemically synthesizing the novel iridoid compound of the present invention, the desired compound can be produced by using an available compound as a starting material and appropriately selecting generally known organic chemistry techniques.

4-2. Compositions One aspect of the present invention is compositions containing Compound A and/or Compound B. As described above, Compound A and Compound B, which are novel iridoid compounds of the present invention, have various physiological actions, such as Tie2 activation action, vascular permeability suppression action, vascular maturation action, and vascular normalization action. , blood vessel stabilizing action, and lymphatic vessel stabilizing action. Therefore, in one aspect, the composition of the present invention exhibits Tie2 activating action, vascular permeability suppressing action, vascular maturation action, vascular normalizing action, vascular stabilizing action, or lymphatic vessel stabilizing action. have. In addition, aspects of the composition include pharmaceuticals (pharmaceutical compositions), food and drink (including foods, beverages, food and drink compositions, food compositions, and beverage compositions), cosmetics (cosmetic compositions), and the like. , but not limited to.

As described above, Compound A and/or Compound B contained in the composition of the present invention may be produced by extracting and isolating from natural products, or may be produced by chemical synthesis, and is not particularly limited. When the active ingredients contained in the composition of the present invention are produced from natural products, the natural products used as raw materials are not particularly limited, but olives, for example, are preferably used. Also, the methods for isolating and synthesizing Compound A and/or Compound B are as described above. The composition of the present invention does not include naturally-occurring animals and plants that have not been processed at all, or extracts thereof that are not mixed with other ingredients.

The content of Compound A and / or Compound B in the composition of the present invention is not particularly limited, for example, the content of Compound A in the composition of the present invention is 0.01% by weight with respect to the total amount of the composition ~99% by weight, preferably 0.1% to 50% by weight, more preferably 1% to 30% by weight, even more preferably 10% to 30% by weight, Compound B in the composition of the present invention The content of is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, more preferably 1% to 30% by weight, still more preferably 10% to 30% by weight. Other components that can be blended in the composition are as described above.

EXAMPLES The present invention will be described in more detail below based on examples. However, the present invention is not limited to these examples.

Example 1: Structure determination of Compound A and Compound B
1-1. Preparation of Olive Fruit Extract Olive fruits are pressed, centrifuged and separated into oil and juice. After filtering the olive juice obtained here, components that are not adsorbed to the adsorption resin, such as sugars, minerals, and organic acids, are removed in an adsorption column. Used as an extract. Next, this fruit extract (500 g) was subjected to column chromatography using Dia ion HP20 (resin volume: 10 L, elution solvent: ethanol:water (0:100→70:30)) to fractionate the olive fruit extract. , each fraction was obtained as follows (Fr.1: 179 g, Fr.2: 120 g, Fr.3: 85 g, Fr.4: 71 g, Fr.5: 26 g). Among the fractions in which Tie2 activity was observed in Fr.1 to Fr.5, Fr.4 (50% ethanol elution, 20 g) was subjected to column chromatography using Toyopearl HW-40C (resin volume: 500 mL, elution Solvent: methanol:water (10:90→70:30)→acetone:water (70:30)) to fractionate Fr.4 into 19 fractions (Fr.4a to Fr.4s). Fraction Fr.4k, in which Tie2 activity was observed in Fr.4a to Fr.4s, was subjected to preparative HPLC under the following analysis conditions 1, and further divided into six fractions (Fr.4ka to 4kf). Among the fractions in which the highest Tie2 activity was observed in Fr.4ka to Fr.4kf, Fr.4kb and Fr.4kd were purified using preparative HPLC under the following analytical conditions 2 and 3. , Compound A (46.2 mg), Compound B (19.5 mg) and Oleanoside A (98.1 mg) were isolated. Note that Fr.4r, in which Tie2 activity was observed, was also subjected to preparative HPLC (Preparative HPLC) under analytical conditions 4 to isolate Kaempferol (3.7 mg). In addition, FIG. 2 shows the purification flow of the olive fruit extract.

<Analysis condition 1>
Detection: 220nm
Flow rate: 15 mL/min
Column: Capcell Pack C18 TYPE AQ φ3.0×25.0 cm (SHISEIDO)
Mobile phase: _CH3CN : _H2O (32:68)
Column temperature: Room temperature 25℃
<Analysis condition 2>
Detection: 220 nm
Flow rate: 10 mL/min
Column: TSK-Gel Amide-80 φ2.15×30.0 cm (TOSOH)
Mobile phase: _CH3CN : _H2O (0 min, 100:0→15 min, 100:0→20 min, 80:20→ 35 min, 80:20)
Column temperature: Room temperature 25℃
<Analysis condition 3>
Detection: 220 nm
Flow rate: 10 mL/min
Column: COSMOSIL Cholester φ2.0×25.0 cm (nacalai tesque)
Mobile phase: _CH3CN : _H2O (20:80)
Column temperature: Room temperature 25℃
<Analysis condition 4>
Detection: 280 nm
Flow rate: 15 mL/min
Column: Capcell Pack C18 TYPE AQφ3.0×25.0 cm (SHISEIDO)
Mobile phase: _CH3CN : _H2O (27:73)
Column temperature: Room temperature 25℃

1-2. Structural analysis of Compound A
Compound A was obtained as a colorless oily substance, and the results of high-resolution electrospray-ionization mass spectrometry (HRESI-MS) revealed that it had a molecular formula of C ₁₇ H ₂₀ O ₆ . Also, from its UV spectrum pattern (λmax 282), it was presumed that this compound has a benzene ring in the molecule. Next, in ¹ H-nuclear magnetic resonance ( ¹ H-NMR), one set of ABX signals [δ _H : 6.62 (1H, dd, J=2.0, 8.0 Hz), 6.74 (1H, d, J=2.0 Hz ), 6.82 (1H, d, J = 8.0 Hz)] and the eight peak patterns observed in ¹³ C-NMR ( _δc : 34.6, 66.0, 115.5, 116.4, 121.3, 130.7, 143.5, 143.6) suggested the presence of hydroxytyrosol. Furthermore, ¹ H-NMR confirmed 1 methyl-derived signal, 3 methylene-derived signals, 1 methine-derived signal, and 1 olefinic proton. When the units other than hydroxytyrosol were confirmed in ¹³ C-NMR, 1 methyl-derived signal, 3 methylene-derived signals, 2 methine-derived signals, and 3 quaternary carbon-derived signals were confirmed. Subsequently, ¹ H- ¹ H correlation spectroscopy ( ¹ H- ¹ H COSY), ¹ H-detected multiple quantum coherence (HMQC), ¹ H-detected multiple-bond connectivity ( HMBC) were measured and detailed analysis revealed that the structure of this unit is a compound characterized by an iridoid. With reference to reports on the isolation of iridoids derived from olives, detailed analysis of spectral data centered on two-dimensional NMR revealed that the structure of the iridoid unit clarified this time is that the hydroxyl group at the 3-position of megaritractonol is a carboxyl group. revealed a transformed structure.

Subsequently, when HMBC was analyzed to examine the binding mode of each unit, a correlation was confirmed from the 8'-position proton of the hydroxytyrosol unit to the 3-position carbonyl carbon of megalitractonol, so both units It was revealed that the 8'-position of hydroxytyrosol and the 3-position of megalitractonol are ester-bonded. The structure of Compound A was determined from the above spectral data. ¹ H-NMR and ¹³ C-NMR signals of Compound A and megaritractonol are shown in FIG. FIG. 4 shows the results of two-dimensional NMR analysis ( ¹ H- ¹ H correlation spectroscopy (COSY) analysis and ¹ H-detected heteronuclear multiple bond connectivity (HMBC) analysis) of Compound A.

1-3. Structural analysis of Compound B
Compound B was obtained as a colorless oil. In ¹ H-NMR, one methyl group-derived signal, two methylene group-derived signals, three methine group-derived signals, one methoxy group-derived signal, and one olefin-derived signal were confirmed. In ¹³ C-NMR, two methyl groups ( _δc : 19.4, 51.5), two methylene groups ( _δc : 38.2, 62.3), four methine groups ( _δc : 29.6, 45.0, 74.1, 156.2 ) and three quaternary carbons (δ _c : 108.5, 169.3, 174.3), a total of 11 carbon signals were confirmed. Based on the above ¹ H-NMR and ¹³ C-NMR results and the fact that UV absorption could not be confirmed, this compound was presumed to be an iridoid. Next, two-dimensional NMR ( ¹ H- ¹ H COSY, HMQC, HMBC) was analyzed for the purpose of confirming these binding modes, and the structure of this compound was clarified. The structure clarified by the above analysis is similar to the oleanosides reported as one of the components of olive fruit. It was confirmed that there was a good correlation except for In addition to the above results, the structure of Compound B was determined based on the fact that the HMBC correlation from methylene at position 8 to carbonyl carbon at position 7 could not be confirmed in this compound and the molecular weight results obtained by MS. . ¹ H-NMR and ¹³ C-NMR signals of Compound B and Oleanoside A are shown in FIG. FIG. 6 shows the results of two-dimensional NMR analysis ( ¹ H- ¹ H correlation spectroscopy (COSY) analysis and ¹ H detected heteronuclear multiple bond connectivity (HMBC) analysis) of Compound B. In addition, oleanoside A and Keampferol were identified after comparison with literature values described in the paper.

Example 2: Evaluation of Tie2 activation effect
Compound A and Compound B were dissolved in a serum vascular endothelial cell growth medium (manufactured by Kurashiki Boseki Co., Ltd., Humedia-EG2) to a final concentration of 10 μg/mL to prepare a test sample. In addition, a test sample was prepared by dissolving angiopoietin-1 in Humedia-EG2 at a concentration of 500 ng/mL and used as a positive control.

Next, normal human umbilical vein endothelial cells (HUVEC) cultured to confluence were seeded in a 96-well plate at 2.0×10 ⁴ cells/0.1 mL/well and cultured overnight using Humedia-EG2. HUVEC after overnight culture was replaced with 0.1 mL of vascular endothelial cell basal medium (manufactured by Kurashiki Boseki Co., Ltd., Humedia-EB2) 3 hours before cell stimulation (addition of test sample), and cultured again. After that, 0.1 mL of the test sample was added into the wells and incubated for 20 minutes. After incubation, an immunoassay kit (manufactured by R&D Systems, Human Phospho-Tie2 (Y992) Immunoassay) was used according to the protocol to measure the amount of intracellular phosphorylated Tie2. As a negative control, phosphorylated Tie2 was similarly measured in dimethyl sulfoxide (DMSO) used for dissolving the test sample. Then, the Tie2 activation rate was calculated according to the following formula to evaluate the phosphorylation action.

Tie2 activation rate (%) = measured value of phosphorylated Tie2 upon addition of test sample/measured value of phosphorylated Tie2 in negative control) × 100

The results are shown in Table 1 and FIG. As shown in Table 1 and FIG. 7, Tie2 activating action was confirmed in Compound A, Compound B, oleanoside A and kaempferol.

Example 3: Vascular Permeability Suppressing Effect of Compound A and Compound B Miles assay was used to evaluate the inhibition of vascular permeability induced by endothelial growth factor (VEGF). This animal experiment was conducted in compliance with the Animal Welfare Management Act and other related laws and regulations, and was conducted based on a plan approved by the director of the institution after review by the in-house animal experimentation committee.

3-1. Test method
After preliminarily breeding 8-week-old Balb/c female mice for more than 1 week, 8 administration compartments were set per mouse (4 on each side of the back midline), and evaluated with n = 6. did.

100 μL of 1% Evans blue dye prepared in physiological saline was administered intravenously under anesthesia 15 minutes later, equal volumes of VEGF (final concentration 300 ng/mL) and each test sample were mixed, and 15 μL of this was applied to the dorsal skin. administered inside. After 40 minutes of intradermal administration, the dye that leaked into the skin was extracted with 500 µL of formamide, and the amount of dye was quantified by absorbance at 620 nm. A section to which neither VEGF nor the test sample was administered and a section to which only VEGF was administered were also provided at the same time. Dunnett's multiple comparison test was used for the test of significance.

3-2. FIG. 8 shows the amount of leaked Evans blue dye. The vascular permeability inhibition rates of the test samples were 89% for Compound A and 139% for Compound B. From the above, both Compound A and Compound B were confirmed to have an effect of suppressing permeability from blood vessels.

The present invention provides a composition having Tie2 activating effect, vascular permeability suppressing effect, vascular maturation effect, vascular normalizing effect, vascular stabilizing effect, lymphatic vessel stabilizing effect, and the like. is. Thus, the present invention provides novel compositions and the like having favorable physiological activity, and can be used for foods and drinks.

Claims (16)

Formula (II) below

A compound represented by A composition for activating Tie2 containing, as an active ingredient, one or more components selected from the group consisting of a compound represented by (I) below, a compound represented by (II) below, and salts thereof:

A composition for suppressing vascular permeability containing, as an active ingredient, one or more ingredients selected from the group consisting of a compound represented by (I) below, a compound represented by (II) below, and salts thereof:

A composition for vascular maturation containing, as an active ingredient, one or more ingredients selected from the group consisting of a compound represented by (I) below, a compound represented by (II) below, and salts thereof:

A composition for normalizing blood vessels containing, as an active ingredient, one or more ingredients selected from the group consisting of compounds represented by the following (II) and salts thereof:

A composition for stabilizing blood vessels containing, as an active ingredient, one or more ingredients selected from the group consisting of compounds represented by the following (II) and salts thereof:

A composition for stabilizing lymph vessels containing, as an active ingredient, one or more ingredients selected from the group consisting of a compound represented by (I) below, a compound represented by (II) below, and salts thereof. :

According to claims 3 to 7, the vascular permeability inhibitory action, vascular maturation action, vascular normalization action, vascular stabilizing action, or lymphatic vessel stabilizing action is caused by the Tie2 activating action. A composition according to any one of the preceding claims. A composition according to any one of claims 2 to 8, which is a food composition. A composition according to any one of claims 2 to 8, which is a beverage composition. 3. The composition according to claim 2, labeled with a function exhibited by activating Tie2. 4. The composition according to claim 3, labeled with a function exerted by vascular permeability inhibition. 5. The composition according to claim 4, labeled with a function exhibited by maturation of blood vessels. 6. The composition according to claim 5, labeled with a function exerted by normalization of blood vessels. 7. The composition according to claim 6, labeled with a function exerted by stabilizing blood vessels. 8. The composition according to claim 7, labeled with a function exerted by stabilizing lymphatic vessels.

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