JP2012021021A - Anti-inflammatory agent or food or drink having anti-inflammatory action - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a food or drink or a medicine which uses a tea compound and has a COX-2 inhibiting and/or PGE2 biosynthesis-inhibiting action.SOLUTION: Tea compounds of 40 kinds separated from green tea, oolong tea and black tea have been offered, and researches targeting an enzyme COX-2 causing chronic inflammation and its product, PGE2, have zealously been performed. Consequently, it have been found that 18 kinds of tea compounds inhibit the expression of the COX-2 and/or the production of the PGE2.

Description

The present invention relates to anti-inflammatory activity, in particular cyclooxygenase-2 (cyclooxygena).
se-2; hereinafter referred to as COX-2) inhibitory action and / or prostaglandin E2 (hereinafter referred to as PG)
E2) It relates to a polyphenol derivative having a biosynthesis inhibitory action.

Prostaglandins are physiologically active substances that cause inflammation in organs and tissues of human living body parts. In particular, PGE2 is known to be a substance that induces lung cancer, breast cancer, colon cancer, prostate cancer and the like. Prostaglandins have cyclooxygenase (arachidonic acid) as a precursor.
Cyclooxygenase (COX) is biosynthesized.

It is known that there are three types of COX. One of these exists in various organs,
Cyclooxygenase-1 that works constantly, such as digestive juice secretion, diuresis, and aggregation of platelets
(Cyclooxygenase-1; COX-1). One is COX-2, which is induced by stimulation with inflammatory cytokines and active oxygen.

COX-2 is a prostaglandin H ₂ synthase and is known as an enzyme finally involved in the biosynthesis of PGE2 in the arachidonic acid cascade. For example, tumor necrosis factor α (TNFα), an inflammatory cytokine
) -Induced transcription factor NF-κB (necrosis factor κB;
NFκB) is activated, and COX-2 is expressed by this activation. The expression of COX-2 enhances the biosynthesis of PGE2, and the cancer cells proliferate and become resistant to anticancer agents and the like. It has been shown that which part of this biosynthetic cascade in the human body can be suppressed is a goal in developing cancer treatment and prevention drugs.

Those having the effect of suppressing the expression of COX-2 are called COX-2 inhibitors. CO
As an example of the X-2 inhibitor, there is a description of Celebrex. There is a description that “it exhibits the strongest activity among COX inhibitors in suppressing the growth of hematological tumors and epithelial tumors” (Non-Patent Document 1, Waskewich, C. et al .: Cancer).
Res. 62: 2029-2033).

Polyphenol is a general term for polyhydric phenols that bind to proteins, alkaloids, etc., and show a tendency to become poorly soluble (Non-Patent Document 2, Toshio Kawasaki, et al .: Natural Drug Chemistry, Yodogawa Shoten, 19
April 1986: 124). Among them, polyphenols contained in tea leaves (commonly called tea polyphenols)
Has been reported to have many biological activities. For example, an antioxidant effect (Non-patent Document 3, H
asimoto, F.A. et al. : Biosci. Biotechnol. Bioc
hem. 67: 396-401, 2003), anti-HIV action (Non-Patent Document 4, Hash)
imoto, F.M. et al. : Bioorg. Med. Chem. Lett. 6: 6
95-700, 1996), antiallergic action (Non-Patent Document 5, Yamada, K. et.
al. : Food Sci. Technol. Res. 5: 1-8, 1999), anti-topoisomerase I and II action (non-patent document 6, Suzuki, K. et al .: B
iol. Pharm. Bull. 24: 1088-1090, 2001), anticancer action (
Non-Patent Document 7, Yoshishi Nakamura: Antimutagenic and anticancer action of tea, Asakura Shoten, September 1997: 13
1-143), lipase activity inhibitory action (Non-patent Document 8, Nakai, M. et al .:
J. et al. Agri. Food Chem. 53: 4593-4598, 2005).

Tea polyphenols are isolated from green tea, black tea, oolong tea, and black tea, and are known to contain over 70 types of polyphenols (Non-Patent Document 9, Yutaka Hashi: Polyphenols of various teas) , 1988 February: 68-72, 147-
151, 162-164; Non-Patent Document 10, Hashimoto, F .; et al. : C
hem. Pharm. Bull. 35: 611-616, 1987;
Hashimoto, F.H. et al. : Chem. Pharm. Bull. 36: 1
676-1684, 1988; Non-Patent Document 12, Hashimoto, F .; et al.
: Chem. Pharm. Bull. 37: 77-85, 1989;
Hashimoto, F.H. et al. : Chem. Pharm. Bull. , 37: 3
255-3263, 1989; Non-Patent Document 14, Hashimoto, F .; et al.
: Chem. Pharm. Bull. 40: 1383-1389, 1992).

Tea polyphenols are classified into two types depending on the biosynthetic mechanism. That is, it is roughly classified into primary polyphenols originally contained in fresh leaves and secondary polyphenols converted from flavan-3-ols in the production process (wilt, fermentation) of black tea, oolong tea, and the like. The Primary polyphenols include flavan-3-ol.
), Proanthocyanidins, hydrolyzable tannins, charcan-flavan dimers (c)
halcan-flavan dimers), oolong homobisflavans (oolon)
gomobisflavans). On the other hand, as secondary polyphenols, theasinensins, theaflagallins
in) and theaflavins (Non-Patent Document 9).

Epigallocatechin 3-gallate, the main polyphenol called so-called tea catechins
(−)-Epigallocatechin 3-O-galte, EGCG), epigallocatechin ((−)-epigallocatechin, EGC), epicatechin 3
-Galate ((-)-epicatechin 3-O-gallate, ECG), Epicatechin ((-)-epicatechin, EC), Gallocatechin ((+)-gal
except locchin, GC), catechin ((+)-catechin, CA),
Various polyphenols have a problem that it was difficult to conduct various biological activity tests because they were not easily isolated from tea leaves.

In recent years, the expression suppression of COX-2 gene of five types of theasinens isolated from fermented tea has been reported. When the protein produced by the expression of COX-2 was analyzed, it was reported that theasinensins A and D strongly suppressed the production, and consequently suppressed the expression of COX-2 (Non-patent Document 15, Tomoko Masasaki, Four others: 2003 Japan Agricultural Chemistry Society West Japan Branch, Chugoku / Shikoku Branch, Japan Nutrition and Food Society West Japan Branch,
Japan Food Science and Technology Society West Japan Branch Kagoshima Joint Conference and Symposium, September 2003: 3
7).

JP 2002-220340 (hereinafter referred to as Patent Document 1) describes a pharmacological composition derived from tea (paragraphs 0033 to 0056 of Patent Document 1). “We examined various pharmacological actions for components obtained at each production stage after extraction, such as hot water extract extracted from tea, polyphenols, catechins, EGCg, etc., and completed the present invention based on the findings obtained as a result. "At this time, the pharmacological action of catechin enhanced is at least cyclooxygenase-2 activity inhibitory action, interferon-γ-production inhibitory action, tumor necrosis factor-alpha-
Production inhibitory effect, fibronectin-mediated cell adhesion inhibitory effect, vascular endothelial growth factor (VGE)
F) can suppress defective endothelial cell proliferation inhibitory effect and breast cancer cell proliferation inhibitory action ”,“ the present invention is also effective for “mixture X” containing the above-mentioned “warm water extraction non-catechin component” and catechins. It is contained as a component, and preferably (-)-epigallocatechin gallate (EGCg), (-)-epicatechin gallate (ECg), (-)-epigallocatechin (EGC), ( -)-Epicatechin (EC), (-)-gallocatechin gallate (GCg), (-)-catechin gallate (Cg), (±) -gallocatechin (GC) and (
±) -catechin (C) total amount (hereinafter, this total amount is referred to as “catechin total amount”, and these eight types of catechins are referred to as “total catechin”).
There is a description that "a pharmacological composition containing ~ 40% by weight is proposed".
33, 0038, 0039 paragraphs).

WO 2004052873 (hereinafter referred to as Patent Document 2) describes a chemotherapeutic or chemopreventive agent for polyphenols of green tea and related derivatives. “This is a method for preparing a novel compound useful as a chemotherapeutic agent or chemopreventive agent and contained in green tea such as epigallocatechin 3
Related compounds of —O-gallate (EGCG), including those represented by the functional groups from R ₁ to R _{11 in} the chemical formula (I) [C ₆ -C ₃ -C ₆ skeleton] are shown here. ”,“ The functional group of R ₄ is preferably a functional group of O, S, NH ₂ , CH ₂ , ”“ Is provided "(the gist of the patent document).

In addition, JP-A 2000-226329 (hereinafter referred to as Patent Document 3) describes MMP inhibitors (paragraphs 0001 to 0014 of Patent Document 3). “As a result of investigating the biological activity such as antioxidant activity and antiviral activity of catechin compounds, catechin compounds may have an inhibitory effect on MMPs, and investigating the MMPs inhibitory activity of catechins, Show MMP inhibitory action in combination with various biological activities, and as a result, MMPs
It has been found that the usefulness for treatment and prevention of intractable diseases caused by dysregulation of activity can be expected (paragraph 0013 of Patent Document 3).

Japanese Unexamined Patent Publication No. 2000-344672 (hereinafter referred to as Patent Document 4) describes a matrix metalloproteinase inhibitor (paragraphs 0001 to 0014 of Patent Document 4). “As a result of examining MMPs inhibitory activity of tannin compounds which are polyphenols, the compound showed excellent MMP inhibitory activity, and as a result, the treatment and prevention of refractory diseases caused by dysregulation of MMPs activity. The present invention has been completed by finding that it can be expected to be useful. ''
(Paragraph 0013 of Patent Document 4).

Japanese Patent Application Laid-Open No. 2004-359576 (hereinafter referred to as Patent Document 5) describes an apoptosis inducer (paragraphs 0015 and 0016 of Patent Document 5). “As a result of examining the induction of apoptosis in human acute promyelocytic leukemia disease cells (HL-60 cells) by purpurogallin derivatives extracted from black tea and the synthesized purprogarin derivatives, purpurogallin (pu
It was found that rpurogallin) induces apoptosis in a concentration-dependent manner and over time, and that theaflavins also induce apoptosis in HL-60 cells, and as a result, in normal cells It has been found that apoptosis can be induced only to cancer cells without inducing apoptosis. "" Purpurogallin activates caspase 8 on HL-60 cells, activates caspase 3 by direct action of caspase 8, and subsequently DNA is fragmented to induce apoptosis. " In addition, the bid (Bid) is not cleaved from caspase 8, and cytochrome c is not released from the mitochondria to the cytoplasm,
We have found that caspase 9 is not activated as a result. This cell death mechanism is HL-6
It was found that apoptosis was induced without an increase in active oxygen in the 0 cells, and the present invention was completed. Is described.

Japanese Patent Application Laid-Open No. 2005-075790 (hereinafter referred to as Patent Document 6) discloses Apoptosis.
Inducing agents (paragraphs 0019 and 0020 of Patent Document 6) are described. "As a result of investigating the induction of apoptosis of polyphenol derivatives extracted from black tea and the synthesized polyphenol derivatives in human acute promyelocytic leukemia disease cells (HL-60 cells) and human colon cancer cells (LoVo cells), prodelphinidin B- 2 (prodelphindin B-2
) In combination with concentration-dependent and time-dependent induction of apoptosis,
Polyphenol) was also found to induce apoptosis of HL-60 cells and LoVo cells and to induce apoptosis of cancer cells. ", Prodelphinidin B-2 activates caspase 8 on HL-60 cells and activates caspase 3 by direct action of caspase 8,
It was subsequently found that DNA was fragmented and apoptosis was induced. It was also found that caspase 9 is also activated. This cell death mechanism was found to induce apoptosis accompanied by an increase in active oxygen in HL-60 cells, and completed the present invention. Is described.

JP 2002-220340 A International Publication WO20044052873 Pamphlet JP 2000-226329 A JP 2000-344672 A JP 2004-359576 A Japanese Patent Laying-Open No. 2005-075790

Washoewich, C.I. , And five others, “Celecoxib Exhibits the Greatest Potency Amongst Cycloxygenase (COX) Inhibitors for Growth Inhibit of CX-2-Negative Helmet. 2002, vol. 62, p. 2029-2033 Toshio Kawasaki and 10 others, “Tannin”, Natural Drug Chemistry, Yodogawa Shoten, April 1986, P.A. 124 Hashimoto, F.H. , And nine others, “Evaluation of the Anti-oxidative Effect (in vitro) of Tea Polyphenols”, Biosci. Biotechnol. Biochem. 2003, vol. 67, p. 396-401 Hashimoto, F.H. , 6 others, “Evaluation of Tea Polyphenols as Anti-HIV Agents”, Bioorg. Med. Chem. Lett. 1996, Vol. 6, p. 695-700 Yamada, K .; , And four others, “Structure-activity Relationship of Immunoregulatory Factors in Foodstuffs”, Food Sci. Technol. Res. 1999, Vol. 5, p. 1-8 Suzuki, K .; , And three others, “Inhibitory Activities of (−)-Epigallocatechin-3-O-gallate Against Topoisomerase I and II”, Biol. Pharm. Bull. 2001, Vol. 24, p. 1088-1090 Nishioka Goo, “Polyphenols of Tea”, Tea Science, Asakura Shoten, September 1997, p. 115-123 Nakai, M .; , 8 others, “Inhibitory Effects of Tea Polyphenols on Pancreatic Lipase in Vitro”, J. et al. Agric. Food Chem. 2005, volume 53, p. 4593-4598 Fumio Hashi, “Chemical Study on Polyphenols in Various Teas”, Ph.D. Thesis, February 1988, p. 68-72, 147-151, 162-164 Hashimoto, F.H. , And two others, "Tannins and Related Compounds. LVI. Isolation of four New Attached Flavan-3-ols from Oolong Tea. (I)", Chem. Pharm. Bull. 1987, vol. 35, p. 611-616 Hashimoto, F.H. , And two others, "Tannins and Related Compounds. LXIX. Isolation and Structure Elucidation of B, B'-linked Bisflavonoids, Theasinsins D-G and OlongoT. Pharm. Bull. 1988, Vol. 36, p. 1676-1684 Hashimoto, F.H. , And two others, "Tannins and Related Compounds.LXXVII.Novel Chalcan-flavan Dimers, Assamicains A, B andC, and a New Flavan-3-ol and Proanthocyanidins from the Fresh Leaves of Camellia sinensis L. var. Assamica Kitamura", Chem. Pharm. Bull. 1989, vol. 37, p. 77-85 Hashimoto, F.H. , And two others, “Tannins and Related Compounds. XC.8-C-Ascorbyl (−) — Epigallocatechin 3-O-gallate and Novel Dimeric Flavan-3-ols, Olonghomobolflavon Chem. Pharm. Bull. 1989, vol. 37, p. 3255-3263 Hashimoto, F.H. , And two others, "Tannins and Related Compounds.CXIV.Structures of Novel Fermentation Products, Theogallinin, Theaflavonin and Desgalloyl Theaflavonin from Black Tea, and Changes of Tea Polyphenols during Fermentation", Chem. Pharm. Bull. 1992, vol. 40, p. 1383-1389 Ms. Tomoko Saki and 4 others, “Regulation of COX-2 gene expression by Theasinens”, 2003 Agricultural Chemistry Society West Japan Branch, China-Shikoku Branch, Japanese Society of Nutrition and Food Science West Japan Branch, Japanese Food Science and Technology The West Japan Branch Kagoshima Joint Conference and Symposium, September 2003, p. 37

In the above-mentioned patent documents, although it has been clarified that eight types of tea catechins have COX-2 inhibitory activity, other compounds excluding theacinensins contained in tea leaves are COX-
2 was not known to have inhibitory activity. If these tea compounds can confirm the effect of COX-2 inhibitory activity, various tea compounds other than the eight tea catechins can be used as COX-2 inhibitors and / or PGE2 biosynthesis inhibitors, so-called anti-inflammatory agents. It can be used for the prevention or treatment of cancer diseases.

Further, in the above non-patent documents, it has been clarified that theacinensins have COX-2 inhibitory activity, but it has not been known whether or not PGE2 biosynthesis is inhibited. If the effect of the PGE2 biosynthesis inhibitory activity of theasinensins can be confirmed, theasinensins can be converted to PGE.
It is considered that 2 biosynthesis inhibitors can be used as so-called anti-inflammatory agents for the prevention or treatment of various cancer diseases.

The object of the present invention is to find a compound having an anti-inflammatory action, more specifically a COX-2 inhibitory action and / or a PGE2 biosynthesis inhibitory action, from among tea-derived compounds. And this invention aims at providing the food-drinks which have the anti-inflammatory agent and anti-inflammatory action which contain this compound as an active ingredient.

In order to solve the above-mentioned problems, the present inventors tested tea compounds isolated from green tea, oolong tea, and black tea, and conducted earnest research targeting the enzyme COX-2 that causes chronic inflammation and its product PGE2. As a result, 18 types of tea compounds were found to express COX-2 and / or PGE.
As a result, the present invention was completed.

  The present invention includes the following inventions.

(1) Formula (I):
[Where:
R ₁₁ and R ₁₂ are independently —H or —OH;
R ₁₃ is —H or a galloyl group,
R ₁₄ is
(R ₁₅ is —H or —OH, R ₁₆ is —H or a galloyl group, and * represents a bonding position),
The 2- and 3-positions of formula (I) are independently R-configuration or S-configuration,
When the 3-position of formula (I) is in the R configuration, the group R ₁₄ is bonded to the 4-position by a β bond, and when the 3-position of formula (I) is in the S-configuration, the group R ₁₄ is bonded to the 4-position by an α bond. Connect by. ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

(2) Prodelphinidin B-2 3,3′-di-O— wherein the compound is shown in Tables 1 and 2
Galate (Compound 1), Prodelphinidin B-2 3′-O-gallate (Compound 2),
Epigallocatechin-3-O-gallate- (4β-8) -epicatechin-3-O-gallate (compound 3), epigallocatechin- (4β-8) -epicatechin-3-O-gallate (compound 4) ), Prodelphinidin B-4-3′-O-gallate (compound 5), prodelphinidin B-4 (compound 6), gallocatechin- (4α-8) -epicatechin (compound 7),
Or the anti-inflammatory agent of (1) description which is catechin- (4 (alpha) -8) -epigallocatechin (compound 8).

(3) Formula (II):
[Where:
R ₂₁ and R ₂₂ are independently —H or —OH;
R ₂₃ is —H or a galloyl group,
R ₂₄ and R ₂₅ are independently —H or
(R ₂₆ is —H or —OH, preferably —OH, R ₂₇ is —H or a galloyl group, and * represents a bonding position),
The 2nd and 3rd positions of the formula (II) are independently R configuration or S configuration. ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

(4) The anti-inflammatory agent according to (3), wherein the compound is oolong homobisflavan A (compound 9) or monodesgaloyl oolong homobisflavan A (compound 10) shown in Table 3.

(5) Formula (III):
[Where:
R ₃₁ is —H or —OH;
R ₃₂ and R ₃₃ are independently -H or
(R ₃₄ represents —H or a galloyl group, and * represents a bonding position). ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

(6) Theaflavin 3′-O-gallate (compound 11), theaflavin 3,3′-di-O-gallate (compound 12), epitheaflavalin 3-O-gallate (compound 13) shown in Table 4 Or an anti-inflammatory agent according to (5), which is purpurogallin (compound 14).

(7) Formula (IV):
[Where:
R ₄₁ and R ₄₂ are independently —H or —OH;
R ₄₃ is —H or a galloyl group,
R ₄₄ is
Wherein R ₄₅ is —H or —OH, preferably —OH, R ₄₆ is —H or a galloyl group, and * represents a bonding position;
2nd and 3rd positions of formula (IV) are independently R configuration or S configuration,
The configuration generated between the flavan skeleton of formula (IV) and the group R ₄₄ may be the R configuration or the S configuration. ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

(8) Theacinensin A (compound 15), theacinensin B (compound 16), theacinensin D (compound 17), or theacinensin E (compound 18) shown in Table 5
The anti-inflammatory agent according to (7).

(9) The anti-inflammatory agent according to any one of (1) to (8), which is a prostaglandin biosynthesis inhibitor.
(10) The anti-inflammatory agent according to any one of (1) to (6), which is a cyclooxygenase-2 (COX-2) inhibitor.
(11) The compound represented by the formula (I), the compound represented by the formula (II), the formula (I)
II) and at least one compound selected from the group consisting of the compounds represented by formula (IV) or a salt or solvate acceptable as a food or drink is artificially added. Food and drink having anti-inflammatory action.
(12) The compound represented by the formula (I), the compound represented by the formula (II), the formula (I)
II) and at least one compound selected from the group consisting of the compounds represented by formula (IV), or a salt or solvate acceptable as a food or drink, and anti-inflammatory A food and drink having an anti-inflammatory effect, which is labeled as having an effect.
(13) The food or drink according to (11) or (12), which is non-fermented tea, semi-fermented tea, strong fermented tea or post-fermented tea.

The compounds listed in Tables 1-4 are all green tea (non-fermented tea), oolong tea (semi-fermented tea), black tea (
It is a compound extracted from so-called tea leaves such as strong fermented tea) and black tea (post-fermented tea). As a result of intensive studies by the present inventors, it has been found that they have a cyclooxygenase (COX-2) inhibitory action and a prostaglandin biosynthesis inhibitory action. On the other hand, the compounds listed in Table 5 are compounds extracted from so-called fermented tea leaves such as oolong tea (semi-fermented tea), black tea (strongly fermented tea), and black (pu-er) tea (post-fermented tea). As a result of intensive studies by the present inventors, it has been found to have a prostaglandin biosynthesis inhibitory action.

The compounds used in the present invention can exist as pharmacologically acceptable salts. Such salts include pharmacologically acceptable non-toxic salts such as sodium salts,
Alkali metal salt such as potassium salt or calcium salt, or alkaline earth metal salt, hydrohalide salt such as hydrochloride, inorganic acid salt such as nitrate, sulfate or phosphate, methanesulfonic acid, benzenesulfonic acid, etc. Examples thereof include organic acid salts such as sulfonate, fumaric acid, succinic acid, citric acid, oxalic acid and maleic acid, and amino acid salts such as glutamic acid and aspartic acid.

The compounds used in the present invention can also exist as solvates. Preferred solvates include hydrates and ethanol solvates.

ADVANTAGE OF THE INVENTION By this invention, the food-drinks which have the anti-inflammatory agent and anti-inflammatory action which contain the compound derived from tea as an active ingredient are provided. The anti-inflammatory agent of the present invention has a COX-2 inhibitory action and / or PGE.
2. It has a biosynthesis inhibitory action.

FIG. 6 is an electrophoresis diagram of Experiment 4. FIG. 6 is an electrophoresis diagram of Experiment 4. FIG. 6 is an electrophoresis diagram of Experiment 4. FIG. 6 is an electrophoresis diagram of Experiment 4. FIG. 6 is an electrophoresis diagram of Experiment 4. FIG. 10 is an electrophoresis diagram of Experiment 5. It is the figure which compared the amount of prostaglandin E2 production of Experiment 5. It is the figure which showed the polyphenol concentration change of the prostaglandin E2 production amount of Experiment 5. FIG. 11 is an electrophoresis diagram of Experiment 6. It is the figure which showed the concentration change of the polyphenol about the expression of COX-2. It is the figure which showed the polyphenol concentration change of the prostaglandin E2 production amount of Experiment 6. FIG. 10 is an electrophoresis diagram of Experiment 7. FIG. 10 is an electrophoresis diagram of Experiment 8. FIG. 10 is an electrophoresis diagram of Experiment 8. It is the figure which showed the concentration change of the polyphenol about the expression of COX-2. It is the figure which compared the amount of prostaglandin E2 production of Experiment 8. It is the figure which showed the polyphenol density | concentration change of the prostaglandin E2 production amount of the experiment 8.

  Hereinafter, the present invention will be described in detail.

The compound used as an active ingredient in the present invention is any fresh tea leaf, or non-fermented tea (eg, green tea), semi-fermented tea (eg, oolong tea), strong fermented tea (eg, black tea), post-fermented tea (eg, black) It can be isolated by extraction from so-called tea leaves such as tea) using conventional methods. The extraction method is not particularly limited, but can be extracted from fresh tea leaves or the above tea leaves according to a conventional method using water, a water-soluble organic solvent such as lower alcohol or acetone, or a mixed solvent of an aqueous organic solvent and water. . The compound used as an active ingredient in the present invention is also
It may be synthesized by a chemical synthesis method.

The compound used as an active ingredient in the present invention is, for example, Japanese Patent Application Laid-Open No.
4-359576 (patent document 4) and JP-A-2005-075790 (patent document 5).
It can be prepared by the method described in 1.

In the following Examples, compounds isolated using literature-described methods were used (Non-patent Document 9).
). Moreover, the compound synthesize | combined by the method of patent document was used for purpurogallin, theasinensins, and oolong homobisflavans (patent document 5). In addition, epitheaflavalin 3-O-gallate was synthesized and used by the method described in the literature (Nonaka, G., et.a
l. : Chem. Pharm. Bull. 34, 61-65: 1986).

The anti-inflammatory agent of the present invention is formulated for, for example, oral administration or parenteral administration (intravenous, intraarterial, intraperitoneal, intrarectal, subcutaneous, intramuscular, sublingual, intranasal, intravaginal, etc.) Can be done. Such preparations can be administered to animals such as humans and mammals as anti-inflammatory agents, for example. The anti-inflammatory agent of the present invention is characterized by having a COX-2 inhibitory action and / or a PGE2 biosynthesis inhibitory action. The anti-inflammatory agent of the present invention is expected to be useful for the prevention or treatment of cancer. The form of the preparation is not particularly limited, and examples thereof include solutions, tablets, powders, granules, capsules, suppositories, sprays, controlled release agents, suspensions, and drinks.

In formulating the anti-inflammatory agent of the present invention, a pharmaceutically acceptable carrier (excipient or diluent), a binder, a filler, a lubricant, a disintegrant, a wetting agent, an emulsifier, a buffer, Suspending agent,
Additives appropriately selected from preservatives, coloring agents, flavoring agents, sweetening agents and the like can be included. Carriers and additives that are commonly used for formulation can be used in the production of the anti-inflammatory agent of the present invention. Examples of the binder include starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and the like. Examples of the bulking agent include lactose and microcrystalline cellulose. Examples of lubricants include talc, silica, magnesium stearate and the like. Examples of disintegrants include starch and sodium starch glycolate. Examples of the wetting agent include sodium lauric sulfate. Examples of emulsifiers include cellulose derivatives and sorbitol. Examples of preservatives include methyl-p-hydroxybenzoate and sorbic acid. However, it is not limited to the above specific example.

The dosage of the tea compound of the present invention can vary depending on the age, weight, sex, condition, severity, etc. of the patient. The daily dose administered to the patient is, for example, 0.1 to 200 m / kg of the patient's body weight.
g, preferably in the range of 1 to 100 mg, but not limited to this range. If necessary, the dose may be divided and administered in several divided doses, for example, 2-3 times. The anti-inflammatory agent of the present invention can also be administered to a patient in combination with other cyclooxygenase-2 (COX-2) inhibitors or prostaglandin biosynthesis inhibitors having the same or different therapeutic uses.

The compound of the present invention can also be added to foods and drinks such as solid foods, semi-solid foods and beverages according to conventional methods. Specific examples include confectionery, retort food, juices, teas, dairy products, soft drinks, alcoholic drinks and the like, but are not limited thereto. These foods and drinks are preferably so-called specific health foods and health supplements. Such food has an anti-inflammatory action (specifically, a COX-2 inhibitory action and / or a PGE2 biosynthesis inhibitory action).

The food / beverage products of the present invention can be obtained by adding or encapsulating an effective amount of the tea compound to any form such as tablets, capsules, granules, drinks, PET bottles, etc., or adding it to any food.

Sweeteners, seasonings, emulsifiers, suspending agents, preservatives and the like may be added to the food and drink of the present invention as necessary, or vitamins, nutrients, immune enhancers (for example, propolis, Mushroom extract etc.) may be added.

The amount of tea compound added to the food or drink is an amount in the range corresponding to 0.1 to 200 mg per kg of adult body weight, for example, 50 mg to 1 g per product, but is not limited to this range.

The food and drink of the present invention is not only the above-mentioned food and drink prepared by artificially adding a predetermined tea compound, but also a conventional non-fermented tea, semi-fermented tea, strong fermented tea or post-fermented tea and has an anti-inflammatory effect. Also included are those containing a tea compound in an amount effective for performance.

The food / beverage product of the present invention has an indication of its effectiveness on its main body, packaging, instructions, promotional material or promotional electronic information, for example, an indication that it has an anti-inflammatory action, more specifically, cyclooxygenase-
2 (COX-2) It is preferable that the indication of having an inhibitory action and the indication of having a prostaglandin biosynthesis inhibitory action are given.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples. However, the technical scope of the present invention is not limited to these examples.

The tea compound (compounds 1-18) used for a present Example was prepared by the method of a nonpatent literature 9 (P.166-218 of a nonpatent literature 9). As a tea leaf of the material, commercially available Oolong tea "Shiraori",
Fresh Assam tea leaves (large leaf varieties, Camellia sinensis)
var. assamica), a commercially available black tea “Nitto: blended tea of Indian and Ceylon tea” was used. These tea leaves were immersed in 80% aqueous acetone solution and extracted (the operation was repeated three times). The extract was distilled off acetone under reduced pressure, and the precipitated chlorophyll was filtered off.
Alternatively, it was partitioned with a solvent such as ether and removed. The filtrate or partition solution (both in the form of an aqueous solution) was directly used as MC eye gel CHP-20P (MCI gel CHP-20P, Mitsubishi Chemical Corporation, Mitsubishi Chemical Corporation).
And Sephadex LH-20 (Sephadex LH-20, Pharmacia Fine Chemical Co., Ltd.) open column chromatography. Chromatography was performed by increasing the content of B liquid from A liquid using water (H ₂ O) as A liquid and methanol (MeOH) as B liquid in the moving bed. In this method, chromatography can also be performed by using liquid A (H ₂ O) for the moving bed, using acetone (Me ₂ CO) as liquid C, and increasing the content of liquid A from liquid C. Bonder pack C18 (Bond
ApakC18 ODS, using a Waters Co.), using a solution A _(H 2 O) and B solution (MeOH) in mobile phase, was chromatographed by increasing the content of the liquid B from A solution. By repeating these chromatography, the tea compounds (compounds 1 to 18) used in this example can be extracted and isolated.

Further, oolong homobisflavans can be synthesized by the method described in Non-Patent Document 13. (
When-)-epigallocatechin 3-O-gallate is treated with formalin at room temperature in an acidic solvent such as hydrochloric acid, oolong homobisflavans are synthesized as main components.

Theasinensins can be synthesized by the method described in Non-Patent Document 11. Theacinensins can be synthesized by oxidizing (−)-epigallocatechin 3-O-gallate with potassium ferricyanide K ₃ Fe (CN) ₆ at room temperature under weakly alkaline conditions such as sodium bicarbonate NaHCO ₃ .

[Experiment 1] Cell culture method (1) Cell types Mouse macrophage-like cells (Cel) obtained from RIKEN CELL BANK
l No. RCB0535, hereinafter referred to as RAW264) was used.

(2) Medium preparation D-MEM (Dulbecco's Modified Eagle Medium)
“Nissui”) (9.5 g) was dissolved in 1 L of water (H ₂ O), and autoclaved in an autoclave. After cooling, 15 ml of 10% NaHCO ₃ solution was added and mixed with antibiotics (PSG
[Penicillin, streptomycin, glutamine]: Gibco
100 mL Lot No. 10858) was added. FBS (Fetal
Bovine Serum: Equitech-Bio 500 mL Lot No.
The SFB30-1463) solution was added to the prepared solution at a rate of 10% to prepare a medium.

(3) Cell Passage RAW264 cells previously stored in a freezer (−80 ° C.) were thawed, and 10 mL of the adjusted medium (hereinafter referred to as medium) was added and mixed with the cells. Mix gently and centrifuge (1
000 rpm, 5 min), the supernatant was discarded, and this operation was repeated twice. The supernatant was removed, and 1 mL of trypsin (Trypsin-EDTA: Gibco 100 mL) was added.
After 9 mL of medium was added and stirred, the mixture was centrifuged (1000 rpm, 5 min), the supernatant medium was removed, and 10 mL of medium was added. The medium containing the cells was placed in a 10 cm petri dish. The concentration of RAW264 cells in each dish was adjusted to be about the number 1～3X10 ⁵ cells. The cell is an incubator (hereinafter referred to as “incubator”) in which 5% carbon dioxide (CO ₂ ) is mixed in the airflow at 37 ° C.
The cells were cultured in a CO ₂ incubator).

[Experiment 2] Induction method of COX-2 in cells (1) Culture of control cells In a petri dish (6 mL size), the concentration of RAW264 cells was adjusted to 1 × 10 ⁶ cells. This was previously cultured at 37 ° C. for 21 hours in a CO ₂ incubator. After incubation
The cells were placed in a petri dish (3 mL size). At this time, no FBS solution was added to the medium. Subsequently, the cells were cultured in a CO ₂ incubator at 37 ° C. for 3 hours. After culture, lipopolysaccharide adjusted to 5 ng / μL (hereinafter referred to as LPS) is added to 24 μL medium, and 3
The cells were cultured in a CO ₂ incubator at 7 ° C. for 12 hours. By this method, in addition to COX-2, the induction of COX-1 and iNOS was also investigated.

(2) Preparation of test compound A predetermined tea compound was dissolved at a concentration of 40 to 100 µM. Water (H ₂ O) and dimethyl sulfoxide (hereinafter referred to as DMSO) were used as the solvent. Hereinafter, the sample adjusted to this concentration is referred to as a test compound.

(3) Culture of test cells In a petri dish (6 mL size), the concentration of RAW264 cells was adjusted to 1 × 10 ⁶ cells. This was previously cultured at 37 ° C. for 21 hours in a CO ₂ incubator. After incubation
The cells were placed in a petri dish (3 mL size). At this time, no FBS solution was added to the medium. Subsequently, the cells were cultured in a CO ₂ incubator at 37 ° C. for 2.5 hours. After culturing, the prepared test compound was added and cultured in a CO ₂ incubator at 37 ° C. for 30 minutes. To this, a lipopolysaccharide adjusted to 5 ng / μL (hereinafter referred to as LPS) was added to a 24 μL medium and cultured in a CO ₂ incubator at 37 ° C. for 12 hours. In this way, CO
In addition to X-2, the induction of COX-1 and iNOS was also investigated.

[Experiment 3] Recovery and detection method of COX-2 expressed protein in cells (1) Recovery of COX-2 expressed protein The cells cultured in Experiment 2 (1) and (3) were recovered. Collected cells were 37 ° C, PB
S (KCl: 0.02%, KH ₂ PO ₄ : 0.02%, NaHPO ₄ · 12H ₂ O: 0.29%
, NaCl: 0.8% aqueous solution), then SDS reagent (1M Tris-HCl, pH
6.8 mL of 6.8; 0.4 g of SDS (2% w / v); Glycerol (10%) 2
1 mL of 1M DTT (50 mM); bromophenol blue (0.1%
20 mL of a mixture of 0.02 g) was added and boiled and heated at 100 ° C. for 5 minutes to recover proteins in the cells.

(2) Detection of COX-2 expressed protein The protein solution collected in (1) above is 10 μL for examining COX-2 expressed protein, 30 μL for examining COX-1 expressed protein, iNOS In order to examine the expressed protein, 37 μL was adsorbed to each electrophoresis well. Electrophoresis was performed at a constant current. After activating the membrane and washing it well, it was immersed in a transfer buffer, and the gel plate and filter paper were mounted together and transferred at a constant current. The recovered membrane was subjected to Western blot, the antibody reaction was repeated, and the protein was detected with a chemiluminescence detector. For the detected protein, Lumi Vision A
The electrophoresis image was preserve | saved using nalyzer 140. FIG.

[Experiment 4] Screening of anti-inflammatory function of tea compound (1) COX-2 inhibitory effect of proanthocyanidins having 4β-8 bond Prodelphinidin B-2, prodelphinidin B-2 3,3′-di-O— Galate (1), prodelphinidin B-2 3′-O-gallate (2), epigallocatechin-3
About -O-gallate- (4β-8) -epicatechin-3-O-gallate (3), epigallocatechin- (4β-8) -epicatechin-3-O-gallate (4) (Table 1), COX
-2 Expression was screened for inhibitory effect. The result is shown in FIG. In the figure, the numbers indicate compound numbers. In addition, LPS marked with “−” indicates that LPS was not added, and COX-2 expression was not observed. LPS marked with “+” is added with LPS, indicating that COX-2 is expressed. “PDB2” is prodelphinidin B-2 isolated from tea leaves. Prodelphinidin B-2 is LP
It turns out that COX-2 expression by S induction is not suppressed. Prodelphinidin B-2 3
, 3′-di-O-gallate (1) is the strongest, followed by epigallocatechin-3-O-gallate- (4β-8) -epicatechin-3-O-gallate (3) in this order, COX -2 is suppressed. All five proanthocyanidins are COX-1.
It turns out that the expression of is not suppressed (FIG. 1).

(2) COX-2 inhibitory effect of proanthocyanidins having 4α-8 bond Procyanidin B-4, prodelphinidin B-4-3′-O-gallate (5), prodelphinidin B-4 (6), gallocatechin- (4α-8) -Epicatechin (7) and catechin- (4α-8) -epigallocatechin (8) (Table 2) were screened for the inhibitory effect on COX-2 expression. The result is shown in FIG. In the figure, the numbers indicate compound numbers. In addition, LPS marked with “-” is the one without LPS added,
The expression of COX-2 is not observed. LPS marked with “+” is added with LPS, indicating that COX-2 is expressed. “PCB4” is procyanidin B-4 isolated from tea leaves. Procyanidin B-4 is an LPS-induced COX-2
It turns out that expression is not suppressed. Prodelphinidin B-4-3′-O-gallate (5)
Prodelphinidin B-4 (6) is the strongest, and gallocatechin- (4α-8) -epicatechin (7) and catechin- (4α-8) -epigallocatechin (8) are similarly COX-
2 is suppressed (FIG. 2).

(3) COX-2 inhibitory effect of oolong homobisflavans Oulon homobisflavans A (9), monodesgaloyl oolong homobisflavans A (
10) (Table 3) was screened for the inhibitory effect of COX-2 expression. The results are shown in FIGS. In the figure, the numbers indicate compound numbers. In addition, LPS marked with “−” indicates that LPS was not added, and COX-2 expression was not observed. LPS marked with “+” is added with LPS, indicating that COX-2 is expressed. In FIG. 4, “ST” is strictinin isolated from tea leaves. “TriG” is 1,4,6-tri-O-galloyl-β-D-glucose isolated from tea leaves. “PCQA” is p-coumaroyl-quinic acid isolated from tea leaves. "T
“G” is theogarin isolated from tea leaves. [ST], [TriG], “pCQA”,
It can be seen that “TG” does not suppress LPS-induced COX-2 expression. Oolong homobisflavan A (9), monodesgaloyl oolong homobisflavan A (10), both CO
It turns out that the expression of X-2 is suppressed (FIGS. 3 and 4).

(4) COX-2 inhibitory effect of purpurogallin Purpurogallin (14) (Table 4) was screened for the inhibitory effect of COX-2 expression. The result is shown in FIG. In the figure, the numbers indicate compound numbers. In addition, LPS
Those marked with “−” are those to which LPS has not been added, and the expression of COX-2 is not observed. LPS marked with “+” is added with LPS,
It can be seen that X-2 is expressed. In FIG. 4, “AsEC” is ascorbic acid (−)-epigallocatechin isolated from tea leaves. “Caf” is caffeine isolated from tea leaves. “GA” is gallic acid isolated from tea leaves. [AsEC], [Caf], “
It can be seen that “GA” does not suppress LPS-induced COX-2 expression. Purpurogallin (
14) suppresses the expression of COX-2 (FIG. 5).

(5) COX-2 inhibitory effect of other tea polyphenol monomers (-)-epigallocatechin 3-O-gallate, (-)-epigallocatechin, (-)-epicatechin 3-O-gallate, (- ) -Epicatechin, (+)-catechin, (±) -gallocatechin, (−)-epicatechin 3-O— (3′-O-methyl) -gallate, (−)-epigallocatechin 3,5-di -O-gallate was screened for the inhibitory effect on COX-2 expression. As a result, it was found that none of the polyphenols suppressed the expression of COX-2, or the effect was considerably weak.

[Experiment 5] Anti-inflammatory function of proanthocyanidins having 4β-8 bond (1) Inhibitory effect of intracellular iNOS production induced by LPS Prodelphinidin B-2, Prodelphinidin B-2 3,3′-di-O— Galate (1), prodelphinidin B-2 3′-O-gallate (2), epigallocatechin-3
-O-gallate- (4β-8) -epicatechin-3-O-gallate (3), epigallocatechin- (4β-8) -epicatechin-3-O-gallate (4) (Table 1) About iNOS production, the inhibitory effect test of iNOS production was done. The result is shown in FIG. In the figure, the numbers indicate compound numbers. In addition, LPS marked with “−” indicates that LPS is not added, and iNOS production is not observed. LPS marked “+” is LP
It can be seen that iNOS is produced with the addition of S. “PDB2” is prodelphinidin B-2 isolated from tea leaves. It can be seen that prodelphinidin B-2 does not suppress LPS-induced iNOS production. Prodelphinidin B-2 3,3′-di-O-gallate (1) and epigallocatechin-3-O-gallate- (4β-8) -epicatechin-3-O-gallate (3) produce iNOS (Fig. 6)
.

(2) Inhibitory effect of LPS-induced intracellular prostaglandin E2 (PGE2) production Prodelphinidin B-2, prodelphinidin B-2 3,3′-di-O-gallate (1), prodelphinidin B-2 3 '-O-gallate (2), epigallocatechin-3
-O-gallate- (4β-8) -epicatechin-3-O-gallate (3), epigallocatechin- (4β-8) -epicatechin-3-O-gallate (4) (Table 1) About, the inhibitory effect test of PGE2 production was done. The result is shown in FIG. In the figure, the numbers indicate compound numbers. In addition, LPS marked with “−” indicates that LPS is not added, and production of PGE2 is not observed. LPS marked “+” is LP
It is understood that PGE2 is produced with the addition of S. “PDB2” is prodelphinidin B-2 isolated from tea leaves. It can be seen that prodelphinidin B-2 does not suppress LPS-induced PGE2 production. Prodelphinidin B-2 3,3′-di-O-gallate (1), prodelphinidin B-2 3′-O-gallate (2), epigallocatechin-3-O-gallate- (4β-8)- Epicatechin-3-O-gallate (3)
, Epigallocatechin- (4β-8) -epicatechin-3-O-gallate (4) are all P
It can be seen that GE2 production is suppressed (FIG. 7).

(3) Concentration change of PGE2 production inhibitory effect of prodelphinidin B-2 3,3′-di-O-gallate (1) PGE2 of prodelphinidin B-2 3,3′-di-O-gallate (1) Concentration change was investigated about the production inhibitory effect. The result is shown in FIG. In the figure, LPS marked with “-” indicates that LPS is not added, and production of PGE2 is not observed. LPS marked with “+” is added with LPS, indicating that PGE2 is produced. It can be seen that treatment with prodelphinidin B-2 3,3′-di-O-gallate (1) at concentrations of 12.5, 25, and 50 μM strongly suppresses the production of PGE2 (FIG. 8).

[Experiment 6] Anti-inflammatory function of proanthocyanidins having 4α-8 bond (1) CO induced by LPS induction of prodelphinidin B-4 3′-O-gallate (5)
Inhibition of X-2 expression and concentration-dependent changes in intracellular iNOS production inhibition Prodelphinidin B-4 3′-O-gallate (5) suppresses COX-2 expression and i
Concentration change was investigated about the NOS production suppression effect. The result is shown in FIG. In the figure, L
PS marked with “-” is not added with LPS, and COX-2
Expression and iNOS production are not observed. LPS marked with “+” is L
It is understood that COX-2 is expressed and iNOS is produced with the addition of PS. To this, 25, 50, 75 of prodelphinidin B-4 3′-O-gallate (5)
, 100 μM, the COX-2 expression and iNOS production are suppressed in a concentration-dependent manner. Prodelphinidin B-4 3′-O-gallate (5)
It can also be seen that does not suppress the expression of COX-1 (FIG. 9).

(2) PG induced by LPS of prodelphinidin B-4 3′-O-gallate (5)
Concentration change of E2 production inhibitory effect About the PGE2 production inhibitory effect of prodelphinidin B-4 3'-O-gallate (5), the concentration change was investigated. The result is shown in FIG. In the figure, it can be seen that LPS was added with LPS and PGE2 was produced. When this LPS-added medium was treated with prodelphinidin B-4 3′-O-gallate (5) at concentrations of 25, 50, 75, and 100 μM, it was found that the production of PGE2 was suppressed in a concentration-dependent manner (FIG. 10).

[Experiment 7] Anti-inflammatory function of purpurogallin derivative Theaflavin 3′-O-gallate (11), theaflavin 3,3′-di-O-gallate (12), epitheaflavalin 3-O-gallate (13), purpurogallin (14) About the compound of (Table 4), the inhibitory effect test of COX-2 expression and iNOS production was done. The result is shown in FIG. In the figure, the numbers indicate compound numbers. In addition, LPS marked with “−” indicates that LPS is not added, and COX-2 expression and iNOS production are not observed. LPS marked with “+” is added with LPS,
It can be seen that COX-2 is expressed and iNOS is produced. “PGC” is purpurogallin galbonic acid. It can be seen that prodelphinidin B-2 does not suppress LPS-induced COX-2 expression. Theaflavin 3′-O-gallate (11), theaflavin 3,
It can be seen that 3′-di-O-gallate (12), epitheaflagalin 3-O-gallate (13), and purpurogallin (14) suppress the expression of COX-2 and the production of iNOS (FIG. 11).

[Experiment 8] Anti-inflammatory function of theacinensins (1) COX-2, COX-1 expression suppression and iNOS production suppression of theacinensins Theacinensin A (15), Theacinensin B (16), Theacinensin D (17),
The effect of inhibiting the expression of COX-2 and iNOS production by theacinensin E (18) (Table 5) was investigated. The result is shown in FIG. In the figure, LPS marked with “-” indicates that LPS has not been added, and COX-2 expression and iNOS production are not observed. LPS marked with “+” is added with LPS, COX-2
It can be seen that iNOS is produced. Also, in the figure, “TSS” is theasinensins, and the symbols A to E are theasinensin A (15), theasinensin B (16), theosinensin C, theasinensin D (17), and theasinensin E (1), respectively.
8). As a result, it can be seen that theacinensin A (15) and theacinensin D (17) strongly suppress the expression of COX-2 and the production of iNOS. All compounds are COX-
1 is not suppressed (FIG. 12).

(2) Concentration changes in COX-2 expression suppression and intracellular iNOS production suppression effect by theacinensin A (15) induced by LPS induction Theasinensin A (15) The change was investigated. The result is shown in FIG. In the figure, LPS marked with “-” indicates that LPS has not been added, and COX-2 expression and iNOS production are not observed. LPS marked with “+” is added with LPS, C
It can be seen that OX-2 is expressed and iNOS is produced. When treated with 25, 50, 75, and 100 μM concentrations of theacinensin A (15), the concentration-dependent CO
It can be seen that the expression of X-2 and the production of iNOS are suppressed. Theacinensin A (1
It can also be seen that 5) does not suppress the expression of COX-1 (FIG. 13).

(3) PGS2 production suppression by LPS induction Theasinensin A (15), Theasinensin B (16), Theasinensin D (17),
For theacinensin E (18) (Table 5), a PGE2 production inhibitory effect test was performed. The result is shown in FIG. In the figure, the numbers indicate compound numbers. Further, in the figure, it can be seen that LPS was added with LPS and PGE2 was produced. As a result of adding each theacinensin to this LPS-added medium, theacinensin A (15), theacinensin B (16),
It can be seen that theacinensin D (17) and theacinensin E (18) suppress the production of PGE2. “TSC” is theasinensin C isolated from tea leaves. It can be seen that theacinensin C does not suppress LPS-induced PGE2 production (FIG. 14).

(4) Concentration change of the PGE2 production inhibitory effect of theacinensin A (15) by LPS induction The concentration change was investigated about the PGE2 production inhibitory effect of theasinensin A (15).
The result is shown in FIG. In the figure, it can be seen that LPS was added with LPS and PGE2 was produced. To this LPS-added medium, 25,50 of theacinensin A (15)
, 75, and 100 μM, the production of PGE2 is suppressed in a concentration-dependent manner (FIG. 13).

According to the present invention, 18 kinds of tea compounds separated from green tea, oolong tea and black tea have the action of suppressing the expression of COX-2 and / or the production of PGE2, so that the COX-2 inhibitor, PGE
2 It can be used as an inhibitor.

Claims (13)

Formula (I):
[Where:
R ₁₁ and R ₁₂ are independently —H or —OH;
R ₁₃ is —H or a galloyl group,
R ₁₄ is
(R ₁₅ is —H or —OH, R ₁₆ is —H or a galloyl group, and * represents a bonding position),
The 2- and 3-positions of formula (I) are independently R-configuration or S-configuration,
When the 3-position of formula (I) is in the R configuration, the group R ₁₄ is bonded to the 4-position by a β bond, and when the 3-position of formula (I) is in the S-configuration, the group R ₁₄ is bonded to the 4-position by an α bond. Connect by. ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The compound is prodelphinidin B-2 3,3′-di-O-gallate, prodelphinidin B-2 3′-O-gallate, epigallocatechin-3-O-gallate- (4β-8
) -Epicatechin-3-O-gallate, epigallocatechin- (4β-8) -epicatechin-3-O-gallate, prodelphinidin B-4-3′-O-gallate, prodelphinidin B-4, gallocatechin -(4α-8) -epicatechin or catechin- (4α-8
The anti-inflammatory agent according to claim 1, which is) -epigallocatechin. Formula (II):
[Where:
R ₂₁ and R ₂₂ are independently —H or —OH;
R ₂₃ is —H or a galloyl group,
R ₂₄ and R ₂₅ are independently —H or
Wherein R ₂₆ is —H or —OH, R ₂₇ is —H or a galloyl group, and * represents a bonding position;
The 2nd and 3rd positions of the formula (II) are independently R configuration or S configuration. ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The anti-inflammatory agent according to claim 3, wherein the compound is oolong homobisflavan A or monodesgaloyl oolong homobisflavan A. Formula (III):
[Where:
R ₃₁ is —H or —OH;
R ₃₂ and R ₃₃ are independently -H or
(R ₃₄ represents —H or a galloyl group, and * represents a bonding position). ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. 6. The anti-inflammatory agent according to claim 5, wherein the compound is theaflavin 3′-O-gallate, theaflavin 3,3′-di-O-gallate, epitheaflavalin 3-O-gallate, or purpurogallin. Formula (IV):
[Where:
R ₄₁ and R ₄₂ are independently —H or —OH;
R ₄₃ is —H or a galloyl group,
R ₄₄ is
(R ₄₅ is —H or —OH, R ₄₆ is —H or a galloyl group, and * represents a bonding position),
2nd and 3rd positions of formula (IV) are independently R configuration or S configuration,
The configuration generated between the flavan skeleton of formula (IV) and the group R ₄₄ may be the R configuration or the S configuration. ]
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The anti-inflammatory agent according to claim 7, wherein the compound is theacinensin A, theasinensin B, theasinensin D, or theasinensin E.   The anti-inflammatory agent according to any one of claims 1 to 8, which is a prostaglandin biosynthesis inhibitor. The anti-inflammatory agent according to any one of claims 1 to 6, which is a cyclooxygenase-2 (COX-2) inhibitor. The compound represented by the formula (I), the compound represented by the formula (II), the formula (III)
And at least one compound selected from the group consisting of the compound represented by formula (IV), or a salt or solvate acceptable as a food or drink, was artificially added. Food and drink having anti-inflammatory action. The compound represented by the formula (I), the compound represented by the formula (II), the formula (III)
And at least one compound selected from the group consisting of the compound represented by formula (IV) or a salt or solvate acceptable as a food or drink,
A food or drink product having an anti-inflammatory action, which is labeled as having an anti-inflammatory action. The food or drink according to claim 11 or 12, which is non-fermented tea, semi-fermented tea, strong fermented tea or post-fermented tea.