阅读说明：本技术 抗炎用组合物 (Anti-inflammatory composition ) 是由 川崎健吾 花房知夏 青柳守纮 田冈幸一 于 2018-05-11 设计创作，主要内容包括：本发明的目的在于提供一种具有抗炎作用的组合物。本发明的抗炎用组合物含有式1表示的化合物作为有效成分。式1中,R<Sub>1</Sub>为氢或羟基,A为可被羟基或甲基取代的苯基或者被羟基及甲叉基取代的环己烯基,<Image he="340" wi="357" file="DDA0002267874540000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention aims to provide a composition with anti-inflammatory effect. The anti-inflammatory composition of the present invention contains a compound represented by formula 1 as an active ingredient. In the formula 1, R 1 Is hydrogen or hydroxy, A is phenyl which may be substituted by hydroxy or methyl or cyclohexenyl which may be substituted by hydroxy and methylene,)

1. An anti-inflammatory composition comprising a compound represented by formula 1 or a salt thereof as an active ingredient,

formula 1

[ solution 1]

In the formula 1, R₁Is hydrogen or hydroxy, A is a group represented by formula 2 or formula 3,

formula 2

[ solution 2]

Formula 3

[ solution 3]

R₂Is hydrogen or a hydroxyl group, and the compound is,

R₃is hydrogen or a hydroxyl group, and the compound is,

R₄is a methyl group, a hydrogen group or a hydroxyl group,

R₂、R₃and R₄At least one of (a) is a hydroxyl group.

2. A composition for inhibiting production of prostaglandin E2, comprising a compound represented by formula 1 or a salt thereof as an active ingredient,

formula 1

[ solution 4]

In the formula 1, the reaction mixture is,

R₁is hydrogen or a hydroxyl group, and the compound is,

a is a group represented by formula 2 or formula 3,

formula 2

[ solution 5]

Formula 3

[ solution 6]

R₂Is hydrogen or a hydroxyl group, and the compound is,

R₃is hydrogen or a hydroxyl group, and the compound is,

R₄is a methyl group, a hydrogen group or a hydroxyl group,

R₂、R₃and R₄At least one of (a) is a hydroxyl group.

3. A composition for inhibiting nitric oxide production, comprising a compound represented by formula 1 or a salt thereof as an active ingredient,

formula 1

[ solution 7]

In the formula 1, the reaction mixture is,

R₁is hydrogen or a hydroxyl group, and the compound is,

a is a group represented by formula 2 or formula 3,

formula 2

[ solution 8]

Formula 3

[ solution 9]

R₂Is hydrogen or a hydroxyl group, and the compound is,

R₃is hydrogen or a hydroxyl group, and the compound is,

R₄is a methyl group, a hydrogen group or a hydroxyl group,

R₂、R₃and R₄At least one of (a) is a hydroxyl group.

4. A compound represented by the formula 4 or a salt thereof,

formula 4

[ solution 10]

Technical Field

The present invention relates to an anti-inflammatory composition that can be used as a food, drink, or drug, a composition for inhibiting the production of prostaglandin E2, and a composition for inhibiting the production of nitric oxide.

The present invention also relates to a novel compound having prostaglandin E2 production inhibitory activity and nitric oxide production inhibitory activity.

Background

Prostaglandin E2(PGE2) is produced in leukocytes (macrophages), mast cells, endothelial cells, platelets, and the like. Arachidonic acid present as a constituent of cell membrane phospholipids is cleaved by phospholipase and synthesized into PGE2 through the cyclooxygenase pathway. During inflammation this pathway is activated and the production of PGE2 is increased.

PGE2 released from a particular cell acts on nearby target cells and induces an inflammatory response in the target cell. PGE2 is one of the chemical mediators used to amplify the inflammatory response at the site of inflammation, which activates the inflammatory response at the site of inflammation.

Nitric Oxide (NO) is produced by type II nitric oxide synthase (iNOS) of leukocytes (macrophages) induced by inflammatory cytokines or bacterial endotoxins in the process of inflammation (non-patent document 1). Since excessive NO is converted into peroxynitrous acid and then shows a cell-damaging effect such as DNA damage and LDL oxidation (non-patent document 2), it is important to suppress excessive NO generated in inflammation. In addition, NO activates intracellular signaling pathways that promote inflammation, such as the NF- κ B pathway (non-patent document 3), and therefore, inhibition of NO production is also important in exerting an anti-inflammatory effect (patent document 1).

Inflammation is a defense reaction that is initiated by a stimulus such as infection, trauma, or foreign matter, and that eliminates self cells and tissues necrotic by the stimulus together with the stimulus itself. The inflammatory response helps to eliminate the harmful stimuli that predominate in infections. On the other hand, inflammation also damages normal tissues, and therefore may adversely damage the body, and it is necessary to suppress excessive inflammatory reactions.

Examples of PGE2 production inhibitors and anti-inflammatory agents containing natural compounds as active ingredients include those described in patent document 2. Patent document 1 describes that a mixture of soybean seeds or an extract thereof and chlorophyll, which is activated by light treatment and/or heat treatment, has NO production inhibitory activity and can be used as an anti-inflammatory agent.

On the other hand, turmeric (Curcuma longa) contains many sesquiterpene compounds, and many bisabolane (bisabolane) compounds such as curcumol a (turmeronol a) and curcumol b (turmeronol b) are known as sesquiterpene compounds derived from turmeric (Curcuma longa) (non-patent document 4).

Disclosure of Invention

Problems to be solved by the invention

The object of the present invention is to provide an anti-inflammatory composition, a composition for inhibiting the production of PGE2, or a composition for inhibiting the production of NO.

Means for solving the problems

The present invention includes the following inventions.

(1) An anti-inflammatory composition comprising a compound represented by formula 1 or a salt thereof as an active ingredient,

formula 1

[ solution 1]

In the formula 1, R₁Is hydrogen or hydroxy, A is a group represented by formula 2 or formula 3,

formula 2

[ solution 2]

Formula 3

[ solution 3]

R₂Is hydrogen or a hydroxyl group, and the compound is,

R₃is hydrogen or a hydroxyl group, and the compound is,

R₄is a methyl group, a hydrogen group or a hydroxyl group,

R₂、R₃and R₄At least one of (a) is a hydroxyl group.

(2) A composition for inhibiting production of prostaglandin E2, comprising the compound represented by the formula 1 or a salt thereof as an active ingredient.

(3) A composition for inhibiting nitric oxide production, comprising the compound represented by the formula 1 or a salt thereof as an active ingredient.

(4) A compound represented by the formula 4 or a salt thereof,

formula 4

[ solution 4]

(5) A method of treating or preventing inflammation, comprising:

administering the compound represented by the formula 1 or a salt thereof to a subject or the like.

(6) A compound represented by the formula 1 or a salt thereof for use in the treatment or prevention of inflammation in a subject such as a human.

(7) Use of the compound represented by the formula 1 or a salt thereof for manufacturing a pharmaceutical composition for treating or preventing inflammation in a subject such as a human.

(8) A non-medical use of the compound represented by the formula 1 or a salt thereof in a food or drink composition for treating or preventing inflammation.

(9) A method of inhibiting production of prostaglandin E2, comprising:

administering the compound represented by the formula 1 or a salt thereof to a subject or the like.

(10) A compound represented by the above formula 1 or a salt thereof for use in inhibiting prostaglandin E2 production in a subject such as a human.

(11) Use of the compound represented by formula 1 or a salt thereof for producing a pharmaceutical composition for inhibiting production of prostaglandin E2 in a human or the like.

(12) A non-medical use of the compound represented by formula 1 or a salt thereof in a food or beverage composition for inhibiting production of prostaglandin E2.

(13) A method of treating or preventing a disease ameliorated or prevented by the inhibition of the production of prostaglandin E2, comprising:

administering the compound represented by the formula 1 or a salt thereof to a subject or the like.

(14) A compound represented by the above formula 1 or a salt thereof for use in treating or preventing a disease in a subject such as a human, which is improved or prevented by inhibiting the production of prostaglandin E2.

(15) Use of the compound represented by the formula 1 or a salt thereof for the manufacture of a pharmaceutical composition for treating or preventing a disease in a subject such as a human, which is ameliorated or prevented by inhibiting the production of prostaglandin E2.

(16) A non-medical use of the compound represented by formula 1 or a salt thereof in a food or beverage composition for the treatment or prevention of a disease which is ameliorated or prevented by inhibiting the production of prostaglandin E2.

(17) A method of inhibiting the production of nitric oxide, comprising:

administering the compound represented by the formula 1 or a salt thereof to a subject or the like.

(18) A compound represented by the formula 1 or a salt thereof is used for inhibiting nitric oxide production in a human or the like.

(19) Use of the compound represented by the formula 1 or a salt thereof for manufacturing a pharmaceutical composition for inhibiting nitric oxide production in a subject such as a human.

(20) A non-medical use of the compound represented by formula 1 or a salt thereof in a food or beverage composition for inhibiting the production of nitric oxide.

(21) A method of treating or preventing a disease, comprising:

administering the compound represented by the formula 1 or a salt thereof to a subject or the like,

the disease is ameliorated or prevented by inhibiting the production of nitric oxide.

(22) A compound represented by the formula 1 or a salt thereof for use in treating or preventing a disease in a subject such as a human, which is ameliorated or prevented by inhibiting the production of nitric oxide.

(23) Use of the compound represented by the formula 1 or a salt thereof for the manufacture of a pharmaceutical composition for treating or preventing a disease in a subject such as a human, which is ameliorated or prevented by inhibiting the production of nitric oxide.

(24) A non-medical use of the compound represented by the formula 1 or a salt thereof in a food or beverage composition for the treatment or prevention of a disease which is ameliorated or prevented by inhibiting the production of nitric oxide.

(25) A food or drink composition comprising the compound represented by formula 4 or a salt thereof and other ingredients acceptable as food or drink. The content of the compound represented by formula 4 or a salt thereof is preferably an effective amount that exerts one or more of an anti-inflammatory effect, an effect of inhibiting prostaglandin E2 production, and an effect of inhibiting nitric oxide production in a human body when the food or beverage composition is orally ingested by a human, and more preferably 0.0001 wt% or more, 0.001 wt% or more, 0.01 wt% or more, 0.1 wt% or more, or 1 wt% or more, relative to the total amount of the food or beverage composition.

(26) A pharmaceutical composition comprising the compound represented by formula 4 or a salt thereof and other ingredients acceptable as a pharmaceutical product. The content of the compound represented by formula 4 or a salt thereof is preferably an effective amount that produces at least one of an anti-inflammatory effect, an effect of inhibiting prostaglandin E2 production, and an effect of inhibiting nitric oxide production in the body of a subject when the pharmaceutical composition is administered to the subject such as a human, and more preferably 0.0001 wt% or more, 0.001 wt% or more, 0.01 wt% or more, 0.1 wt% or more, or 1 wt% or more, relative to the total amount of the food or beverage composition.

The present specification includes the disclosure of japanese patent application No. 2017-095713 as a basis for priority of the present application.

ADVANTAGEOUS EFFECTS OF INVENTION

The compositions of the present invention can be used as anti-inflammatory agents, inhibitors of PGE2 production, or inhibitors of NO production.

The compound of the present invention has an anti-inflammatory activity, a PGE2 production inhibitory activity or a NO production inhibitory activity.

Drawings

Figure 1 shows PGE2 concentration in the culture supernatant of RAW264.7 after treatment with curcumol a.

FIG. 2 shows the PGE2 concentration in the culture supernatant of RAW264.7 after treatment with 2-methyl-6- (4-hydroxyphenyl) -2-hepten-4-one.

FIG. 3 shows the PGE2 concentration in the culture supernatant of RAW264.7 after treatment with 4-methylidene-5-hydroxybisabol-2, 10-dien-9-one.

FIG. 4 shows the PGE2 concentration in the culture supernatant of RAW264.7 after treatment with component D-b.

Figure 5 shows PGE2 concentration in the culture supernatant of RAW264.7 after treatment with curcumol B.

FIG. 6 shows NO in the culture supernatant of RAW264.7 after treatment with curcumol A₂ ^－And (4) concentration.

FIG. 7 shows NO in the culture supernatant of RAW264.7 after treatment with 2-methyl-6- (4-hydroxyphenyl) -2-hepten-4-one₂ ^－And (4) concentration.

FIG. 8 shows NO in the culture supernatant of RAW264.7 after treatment with 4-methylidene-5-hydroxybisabol-2, 10-dien-9-one₂ ^－And (4) concentration.

FIG. 9 shows NO in the culture supernatant of RAW264.7 after treatment with component D-b₂ ^－And (4) concentration.

FIG. 10 shows NO in the culture supernatant of RAW264.7 after treatment with curcumol B₂ ^－And (4) concentration.

Detailed Description

Active compound

The composition of the present invention contains the compound represented by the formula 1 or a salt thereof as an active ingredient having an anti-inflammatory activity, a PGE2 production inhibitory activity and a NO production inhibitory activity. In the following description, the compound represented by formula 1 or a salt thereof is sometimes referred to as "active compound".

The compound represented by formula 1 is not particularly limited as long as it has a planar structure represented by formula 1, and may be a mixture of compounds having a plurality of steric configurations. Note that in formulas 2 and 3, the bond interrupted by a wavy line represents a bond toward the carbon to which a is bonded in formula 1.

Next, a more preferred form of the compound of formula 1 when a is a group represented by formula 2 will be described.

In the formula 2, R is preferred₄Is methyl or hydroxy. In the formula 2, R is preferred₂、R₃And R₄Only one of them is hydroxy, more preferably R₂、R₃And R₄Only one of which is hydroxy and R₄Is methyl or hydroxy.

When a is a group represented by formula 2, the compound of formula 1 is more preferably a compound having any one of the following planar structures.

[ solution 5]

[ solution 6]

[ solution 7]

[ solution 8]

Wherein the component D-b is a novel compound isolated and identified from a turmeric extract by the present inventors. The component D-b can be named as 2-methyl-5-hydroxy-6- (3-hydroxy-4-methylphenyl) -2-hepten-4-one.

It is known that, in a natural product isolated from a turmeric extract, the steric configuration of the 6-carbon in the partial structure of 2-methyl-2-hepten-4-one among curcumol a, curcumol B and 2-methyl-6- (4-hydroxyphenyl) -2-hepten-4-one is an S-isomer. However, in the above-described more preferred examples of the compound of formula 1, the steric structure is not particularly limited as long as it has the above-described planar structure.

Next, a more preferred form of the compound of formula 1 in which a is a group represented by formula 3 will be described.

The group represented by formula 3 is more preferably represented by the following formula 3-1

[ solution 9]

The group shown. The group represented by formula 3 or formula 3-1 is not particularly limited as long as it has a planar structure represented by formula 3 or formula 3-1, and may include groups of various steric configurations.

The compound of formula 1 in which a is a group represented by formula 3 is more preferably a compound having the following planar structure.

[ solution 10]

The salt of the compound represented by formula 1 is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include: sodium salt (sodium salt of phenolic hydroxyl group).

Process for producing active compound

The active compound used in the present invention may be a plant-derived compound or a compound artificially synthesized. For example, (+) -curcumol A, which is optically active, can be obtained by Biosci Biotechnol biochem.1993; 57(7): 1137-40 by the methods described herein.

The active compound used in the present invention is more preferably a compound derived from a plant material, and still more preferably a compound derived from a plant belonging to the genus curcuma of the family zingiberaceae. Examples of plants belonging to the genus Curcuma of the family Zingiberaceae include: curcuma longa (Curcuma longa), Curcumaaromatica (Curcuma aromatica), Curcuma zedoaria (Curcuma zedoaria), Curcuma phaeocaulis (Curcuma zedoaria), Curcumakwangsiensis (Curcuma kwangsiensis), Curcuma wenyujin (Curcuma wenyu), and Curcuma xanthorrhiza (Curcuma xanthorrhiza), with Curcuma longa (Curcuma longa) being particularly preferred. The active compound can be obtained from the rhizome of plant of Curcuma of Zingiberaceae. The rhizome may be used as it is, or may be used after cutting it into a suitable size or shape, or may be used in the form of a ground product. The plant material may be suitably dried.

The active compound can be extracted from a plant material containing the active compound. As the extraction solvent, a polar organic solvent (methanol, ethanol, etc.), water, a nonpolar organic solvent (ethyl acetate, etc.) can be used. In particular, a water extract obtained by water extraction from a plant material, a methanol/water extract obtained by further subjecting the water extract to methanol/water mixed solvent extraction and/or the methanol/water extract is preferable as the plant extract containing an active compound. As the water, hot water of 95 ℃ or higher is preferably used. The plant extract is used after removing the extraction solvent by volatilization as required. Plant extracts containing the active compounds may also be incorporated in the compositions of the invention in their native form.

In addition, a fraction obtained by highly purifying an active compound from a plant extract containing the active compound may be blended in the composition of the present invention. For example, plant extracts containing active compounds can be used for ethyl acetate/water liquid partitioning to achieve high purity of the active compounds into the ethyl acetate fraction. In addition, the plant extract or a part of the plant extract containing the active compound can be subjected to a purification treatment by chromatography to obtain the active compound having a high purity. As the chromatography, reverse phase column chromatography, normal phase thin layer chromatography, or the like can be used.

The plant extract containing the active compound or the retentate thereof may be a substance obtained by processing by a usual method such as drying, powdering, granulating, solubilizing or the like.

The active compound is preferably purified.

Composition of the invention and its use

The composition of the invention may be the active compound itself or a composition comprising the active compound and at least one other ingredient. When the composition of the present invention contains an active compound and at least one other ingredient, the composition may be a composition in which the active compound and at least one other ingredient are mixed, a composition in which the active compound and at least one other ingredient are formulated by an appropriate method, or a composition in which a formulated composition of the active compound and at least one other ingredient is further mixed with other ingredients. The active compounds can also be in the form of plant extracts or parts of plant extracts which comprise the active compounds. The shape of the composition containing an active compound in the present invention is not particularly limited, and may be any shape such as a liquid, a fluid, a gel, a semi-solid, or a solid.

The at least one other component is not particularly limited, but is preferably an acceptable component in the final form of foods, drinks, medicines, etc., and more preferably an orally ingestible component.

Examples of such other components include: sweetening agent, sour agent, vitamins, minerals, tackifier, emulsifier, antioxidant, water, etc. Further, if necessary, pigments, perfumes, preservatives (additives for inhibiting bacterial growth and preventing deterioration and putrefaction), preservatives, antifungal agents, additional physiologically active substances, and the like may be added.

Examples of the sweetener include: monosaccharides or disaccharides such as glucose, fructose, sucrose, lactose, maltose, palatinose, trehalose, and xylose, isomerized sugars (such as fructose syrup, high fructose syrup, and granulated sugar-mixed isomerized sugar), sugar alcohols (such as erythritol, xylitol, lactitol, isomalt, sorbitol, and reducing syrup), honey, and high-sweetness sweeteners (such as sucralose, acesulfame potassium, thaumatin, stevioside, and aspartame).

The sour seasoning includes citric acid, malic acid, gluconic acid, tartaric acid, lactic acid, phosphoric acid, or a salt thereof, and one or two or more of these can be used.

Examples of vitamins include: vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin E, nicotinic acid, inositol, etc.

Examples of the minerals include: calcium, magnesium, zinc, iron, etc.

Examples of the tackifier include: carrageenan, gellan gum, xanthan gum, gum arabic, tamarind gum, guar gum, locust bean gum, karaya gum, agar, gelatin, pectin, soybean polysaccharides, carboxymethylcellulose (CMC), etc.

Examples of emulsifiers include: glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, lecithin, phytosterol, saponin, etc.

As the antioxidant, there may be mentioned: vitamin C, tocopherol (vitamin E), enzyme-treated rutin, catechin, etc.

The other components can be appropriately blended in amounts within the ranges generally used in compositions such as foods, drinks, medicines and the like by those skilled in the art.

The composition in which the active compound and at least one other ingredient are formulated by an appropriate method may be in the form of a solid composition such as a powder, a granule, a capsule, a tablet (including a coated tablet such as a sugar-coated tablet, a multilayer tablet, an orally disintegrating agent, a chewable tablet, etc.), or a liquid composition such as a solution.

The composition of the present invention is preferably a food or drink or a pharmaceutical product, and more preferably a food or drink. Here, the food and drink also includes food additives and forms of food and drink raw materials used in combination with other food materials for producing food and drink. When the composition containing the active compound as an active ingredient is a food or drink or a food or drink raw material used for producing a food or drink in combination with other food materials, the "food or drink" is preferably in the form of a functional food, a specific health food, a nutritional supplement for supplying nutrition, or the like.

By administering the compound represented by the formula 1 or a salt thereof to a subject such as a human, inflammation can be treated or prevented in the subject. Herein, the compound represented by the formula 1 or a salt thereof is administered in an effective amount for treating or preventing inflammation. Oral or nasal administration is preferred as the route of administration, and oral administration is particularly preferred. Therefore, the composition of the present invention comprising the compound represented by said formula 1 or a salt thereof can be used as an anti-inflammatory composition. The anti-inflammatory composition may be a pharmaceutical composition or a composition for non-medical use such as a food or beverage composition.

By administering the compound represented by the formula 1 or a salt thereof to a subject such as a human, production of prostaglandin E2 can be inhibited in the subject. Here, the compound represented by formula 1 or a salt thereof is administered in an effective amount for inhibiting the production of prostaglandin E2. Oral or nasal administration is preferred as the route of administration, and oral administration is particularly preferred. In a subject to which the compound represented by the above formula 1 or a salt thereof is administered, production of prostaglandin E2 in cells such as leukocytes (macrophages), mast cells, endothelial cells, platelets, and the like is inhibited. Therefore, the composition of the present invention comprising the compound represented by said formula 1 or a salt thereof can be used as a composition for inhibiting the production of prostaglandin E2. The composition for inhibiting the production of prostaglandin E2 may be a pharmaceutical composition or a composition for non-medical use such as a food or beverage composition.

By administering the compound represented by the formula 1 or a salt thereof to a subject such as a human, a disease which is improved or prevented by inhibiting the production of prostaglandin E2 can be treated or prevented in the subject. Herein, the compound represented by the formula 1 or a salt thereof is administered in an effective amount for treating or preventing the diseases. Oral or nasal administration is preferred as the route of administration, and oral administration is particularly preferred. In a subject to which the compound represented by the above formula 1 or a salt thereof is administered, the production of prostaglandin E2 in cells such as leukocytes (macrophages), mast cells, endothelial cells, platelets and the like is inhibited, whereby the disease can be treated or prevented.

By administering the compound represented by the formula 1 or a salt thereof to a subject such as a human, the production of nitric oxide can be inhibited in the subject. Here, the compound represented by the formula 1 or a salt thereof is administered in an effective amount for inhibiting the production of nitric oxide. Oral or nasal administration is preferred as the route of administration, and oral administration is particularly preferred. In a subject to which the compound represented by the above formula 1 or a salt thereof is administered, production of nitric oxide in cells such as leukocytes (macrophages) is suppressed. Therefore, the composition of the present invention comprising the compound represented by said formula 1 or a salt thereof can be used as a composition for inhibiting nitric oxide production. The composition for inhibiting the production of nitric oxide may be a pharmaceutical composition, or a composition for non-medical use such as a food or beverage composition.

By administering the compound represented by the formula 1 or a salt thereof to a subject such as a human, a disease that is improved or prevented by inhibiting the production of nitric oxide can be treated or prevented in the subject. Herein, the compound represented by the formula 1 or a salt thereof is administered in an effective amount for treating or preventing the diseases. Oral or nasal administration is preferred as the route of administration, and oral administration is particularly preferred. In a subject to which the compound represented by the above formula 1 or a salt thereof is administered, the production of nitric oxide in cells such as leukocytes (macrophages) is suppressed, and thus the disease can be treated or prevented.