JP2006249057A - Dna synthase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a DNA synthase inhibitor by using 3-acylated flavan-3-ols. <P>SOLUTION: The 3-acylated flavan-3-ols having the DNA synthase inhibitory effects inhibit the DNA synthase derived from mammalian animals selectively, and have the more potent activity by having the longer carbon chain length of the acyl group (except for galloyl group). Therefore the 3-acylated flavan-3-ols are able to be utilizable for foods, medicines, etc., as the DNA synthase inhibitor. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to the use of a compound having a DNA synthase inhibitory action.

  As for eukaryotic DNA synthase (DNA polymerase), 13 kinds of DNA synthases of α, β, γ, δ, ε, ζ, η, θ, ι, κ, λ, μ and σ are known so far. ing. These DNA synthase groups are involved in cell growth, division, differentiation, etc., but α-type is DNA replication, β-type is repair and recombination, λ-type is repair, δ-type and ε-type are replication. It is known to have different functions depending on the type, such as being responsible for both repairs.

  Thus, since DNA synthase is involved in cell growth and the like, a DNA synthase inhibitor that inhibits the enzyme activity, for example, 1) shows cancer cell growth inhibitory action against cancer, 2 It is considered that it exhibits an inhibitory action against HIV-derived reverse transcriptase against AIDS and 3) an immunosuppressive action against immune diseases that suppresses specific antibody production against antigens. For this reason, development of pharmaceuticals effective for prevention and treatment of cancer diseases, viral diseases such as AIDS, and immune diseases using a DNA synthase inhibitor is expected.

  Currently, dideoxy TTP (ddTTP), N-methylmaleimide, butylphenyl-dGTP, and the like are known as DNA synthetase inhibitors (see Non-Patent Document 1 below). In addition, sulfosynovosyl acylglycerides, which are plant-derived glycolipids, have been found to have a DNA synthase inhibitory effect (see Patent Document 1 below).

  As for flavan-3-ols contained in tea, etc., (2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-gallate {(3R) modified with gallic acid {( -)-Epicatechin gallate, ECg}, (2R, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-gallate {(−)-epigallocatechin gallate, EGCg}, etc. It is known to have an inhibitory activity on DNA synthetases α, β, and γ. In contrast, a compound in which gallic acid is not bonded to the 3-position, (2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−)-epicatechin, EC} and ( Since 2R, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(−)-epigallocatechin, EGC} has no inhibitory activity, gallic acid at position 3 It has been suggested that the presence or absence of is greatly contributing to the activity (see Non-Patent Document 2 below).

  Thus, flavan-3-ols (epigallocatechin gallate) having a DNA synthase inhibitory activity reported so far are naturally-derived components originally contained in tea, and are highly safe. However, the effect of the DNA synthase activity inhibitor is still not sufficient.

Annual Review of Biochemistry, 1991, 60, 513-552.   JP 2000-143516 A Food Phytochemicals for Cancer Prevention II, Teas, Spices, and Herbs, pages 56-64. (ACS Symposium Series No. 547)

  Accordingly, an object of the present invention is to provide a novel DNA synthase activity inhibitor by finding a substance that is highly safe and superior in DNA synthase activity inhibitory activity compared to conventional ones.

  In order to search for a component having a potency superior to that of the prior art, the present inventors conducted extensive studies using a naturally derived tea component as a raw material. As a result, an acyl group (galloyl group) was located at the 3-position of the flavan-3-ols. For the first time that 3-acylated flavan-3-ols introduced with the above-mentioned compounds have a strong inhibitory action on DNA synthase activity and that the longer the carbon chain length of the acyl group, the stronger the activity. The invention has been completed.

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_５、Ｒ_６はそれぞれ独立して水素原子、もしくは、水酸基であることを表し、Ｒ_４は、直鎖もしくは分岐状のアルキル基であることを表し（３位のアシル基のうちガロイル基は除く）、ベンゾピラン環の２位と３位の立体配置はそれぞれＲ配置またはＳ配置のいずれであってもよい。）で表される３−アシル化フラバン−３−オール類。
請求項２記載の本発明は、下記の式（２）により表される化合物を有効成分とするＤＮＡ合成酵素活性阻害剤である。

（式中、Ｒ_１、Ｒ_２、Ｒ_３はそれぞれ独立して水素原子、もしくは、水酸基であることを表し、Ｒ_４は、直鎖もしくは分岐状のアルキル基で表し（３位のアシル基のうちガロイル基は除く）、ベンゾピラン環の２位と３位の立体配置はそれぞれＲ配置またはＳ配置のいずれであってもよい）で表される３−アシル化フラバン−３−オール類。
請求項３記載の本発明は、下記の式（３）により表される化合物を有効成分とするＤＮＡ合成酵素活性阻害剤である。

（式中、Ｒ_１、Ｒ_２、Ｒ_３はそれぞれ独立して水素原子、もしくは、水酸基であることを表し、ベンゾピラン環の２位と３位の立体配置はそれぞれＲ配置またはＳ配置のいずれであってもよい。）で表される３−アシル化フラバン−３−オール類。
請求項４記載の本発明は、ＤＮＡ合成酵素が哺乳類由来のＤＮＡ合成酵素γである請求項１乃至３記載のＤＮＡ合成酵素阻害剤である。That is, the present invention described in claim 1 is a DNA synthase activity inhibitor comprising a compound represented by the following formula (1) as an active ingredient.

(In the formula, R ₁ , R ₂ , R ₃ , R ₅ and R ₆ each independently represent a hydrogen atom or a hydroxyl group, and R ₄ is a linear or branched alkyl group. (Excluding the galloyl group among the acyl groups at the 3-position), and the steric configurations at the 2-position and the 3-position of the benzopyran ring may be either R-configuration or S-configuration, respectively. Flavan-3-ols.
The present invention according to claim 2 is a DNA synthase activity inhibitor comprising a compound represented by the following formula (2) as an active ingredient.

(In the formula, R ₁ , R ₂ and R ₃ each independently represents a hydrogen atom or a hydroxyl group, and R ₄ represents a linear or branched alkyl group (the acyl group at the 3-position) Among them, the steric configurations at the 2-position and 3-position of the benzopyran ring may be either the R configuration or the S configuration), and 3-acylated flavan-3-ols.
The present invention according to claim 3 is a DNA synthase activity inhibitor comprising a compound represented by the following formula (3) as an active ingredient.

(In the formula, R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom or a hydroxyl group, and the steric configurations at the 2- and 3-positions of the benzopyran ring are either R configuration or S configuration, respectively. 3-acylated flavan-3-ols represented by:
The present invention according to claim 4 is the DNA synthase inhibitor according to claims 1 to 3, wherein the DNA synthase is a mammal-derived DNA synthase γ.

  The DNA synthase inhibitor of the present invention strongly inhibits a DNA synthase derived from a mammal in particular, and can be suitably used for the prevention / treatment of viral diseases such as cancer and AIDS and immune diseases. In addition, since the DNA synthase activity inhibitor of the present invention has no problem in safety, it can be used in various ways such as adding to foods, cosmetics, etc. as well as its use as pharmaceuticals.

Hereinafter, specific embodiments and technical scope of the present invention will be described in detail.
The present invention is based on the fact that 3-acylated flavan-3-ols can inhibit the activity of DNA synthase, and is particularly effective for DNA synthases derived from mammals such as humans.

Flavan-3-ols are a general term for compounds generally represented by the formula (4).

（式中、Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_５、Ｒ_６はそれぞれ独立して水素原子、もしくは、水酸基であることを表し、Ｒ_４は、直鎖もしくは分岐状のアルキル基であることを表し（３位のアシル基のうちガロイル基は除く）、ベンゾピラン環の２位と３位の立体配置はそれぞれＲ配置またはＳ配置のいずれであってもよい。）で表される３−アシル化フラバン−３−オール類。The 3-acylated flavan-3-ols, which are active ingredients of the DNA synthase activity inhibitor of the present invention, are compounds in which the hydroxyl group at the 3-position of the flavan-3-ols is acylated. It has the chemical structure shown in 1).

(In the formula, R ₁ , R ₂ , R ₃ , R ₅ and R ₆ each independently represent a hydrogen atom or a hydroxyl group, and R ₄ is a linear or branched alkyl group. (Excluding the galloyl group among the acyl groups at the 3-position), and the steric configurations at the 2-position and the 3-position of the benzopyran ring may be either R-configuration or S-configuration, respectively. Flavan-3-ols.

Specific examples of 3-acylated flavan-3-ols of the present invention include (2R, 3S) -5,7-dihydroxyflavan-3-ol {in the formula (5), R ₁ , R ₂ , R ₃ are A hydrogen atom is shown, and the configuration at the 2nd and 3rd positions represents 2R and 3S. } 3-Acylated-5,7-dihydroxyflavan-3-ol, acylated at the 3-position hydroxyl group of (2S, 3R) -5,7-dihydroxyflavan-3-ol {R ₁ in formula (5) , R ₂ and R ₃ represent a hydrogen atom, and the configuration at the 2nd and 3rd positions represents 2S and 3R. } 3-Acylated-5,7-dihydroxyflavan-3-ol, (2S, 3S) -5,7-dihydroxyflavan-3-ol {R ₁ in formula (5) , R ₂ and R ₃ represent a hydrogen atom, and the configuration at the 2nd and 3rd positions represents 2S and 3S. } 3-Acylated-5,7-dihydroxyflavan-3-ol, (2R, 3R) -5,7-dihydroxyflavan-3-ol {R ₁ in formula (5) , R ₂ and R ₃ represent a hydrogen atom, and the configuration at the 2nd and 3rd positions represents 2R and 3R. } 3-Acylated-5,7-dihydroxyflavan-3-ol, acylated at the 3-position hydroxyl group of (2R, 3S) -4 ′, 5,7-trihydroxyflavan-3-ol {(+) -Aphzelekin: In formula (5), R ₁ and R ₃ represent a hydrogen atom, R ₂ represents a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2R and 3S. } 3-acylated aphzelequinyl acylated at the 3-position hydroxyl group of (2S, 3R) -4 ′, 5,7-trihydroxyflavan-3-ol {(−)-afzelekin: R ₁ in formula (5) , R ₃ represents a hydrogen atom, R ₂ represents a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2S and 3R. } 3-acylated aphzelequinyl acylated at the 3-position hydroxyl group of (2S, 3S) -4 ′, 5,7-trihydroxyflavan-3-ol {(+)-epiafuzelekin: R ₁ in formula (5) , R ₃ represents a hydrogen atom, R ₂ represents a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2S and 3S. } 3-Acylated Epiafzelekine acylated at the 3-position hydroxyl group of (2R, 3R) -4 ′, 5,7-trihydroxyflavan-3-ol {(−)-Epiafzerequin: R ₁ in Formula (5) , R ₃ represents a hydrogen atom, R ₂ represents a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2R and 3R. } 3-Acylated Epiafzelequine acylated at the 3-position hydroxyl group of (2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-catechin: Formula (5) In the formula, R ₃ represents a hydrogen atom, R ₁ and R ₂ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2R and 3S. } 3-acylated catechin acylated at the 3-position hydroxyl group of (2S, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−)-catechin: Formula (5) R ₃ represents a hydrogen atom, R ₁ and R ₂ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2S and 3R. } 3-Acylated catechin acylated at the 3-position hydroxyl group of (2S, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-epicatechin: Formula (5) ), R ₃ represents a hydrogen atom, R ₁ and R ₂ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2S and 3S. } 3-Acylated epicatechin acylated at the 3-position hydroxyl group of (2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−)-epicatechin: In 5), R ₃ represents a hydrogen atom, R ₁ and R ₂ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2R and 3R. } 3-Acylated epicatechin acylated at the 3-position hydroxyl group of (2R, 3S) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(+)-gallocatechin: In the formula (5), R ₁ , R ₂ and R ₃ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2R and 3S. } 3-Acylated gallocatechin acylated at the 3-position hydroxyl group of (2S, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(−)-gallocatechin: formula In (5), R ₁ , R ₂ and R ₃ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2S and 3R. } 3-acylated gallocatechin acylated at the 3-position hydroxyl group of (2S, 3S) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(+)-epigallocatechin In formula (5), R ₁ , R ₂ and R ₃ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2S and 3S. } 3-Acylated epigallocatechin obtained by acylating the hydroxyl group at position 3, (2R, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(−)-epi Gallocatechin: In formula (5), R ₁ , R ₂ and R ₃ represent a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2R and 3R. } 3-acylated epigallocatechin obtained by acylating the hydroxyl group at the 3-position.
In the present invention, these components may be used alone or in combination of two or more at a desired mixing ratio.

In addition, although only the compound group in which the 5th position and 7th position in Formula (5) show a hydroxyl group is mentioned in the said specific example, this invention is not limited to this, For example, Formula (6) As shown, a compound group in which the 5-position represents a hydrogen atom and a 7-position represents a hydroxyl group, and a compound group in which the 7-position represents a hydrogen atom and the 5-position represents a hydroxyl group, as represented by formula (7), or R in formula (8) ₅ and the compound group etc. in which R ₆ represents a hydrogen atom can also be included.

  The 3-acylated flavan-3-ols used as an active ingredient in the present invention are preferably 3-acylated aphzelechin, 3-acylated epiafzerekin, 3-acylated catechin, 3-acylated epicatechin, 3-acylated Gallocatechin and 3-acylated epigallocatechin, more preferably 3-acylated catechin and 3-acylated epicatechin.

（式中、Ｒ_１、Ｒ_２、Ｒ_３はそれぞれ独立して水素原子、もしくは、水酸基であることを表し、ベンゾピラン環の２位と３位の立体配置はそれぞれＲ配置またはＳ配置のいずれであってもよい。）で表される３−アシル化フラバン−３−オール類。Examples of the acyl group of 3-acylated flavan-3-ols in the present invention include, for example, an acetyl group, a propionyl group, a butyryl group, a valeryl group, a hexanoyl group, a heptanoyl group, an octanoyl group, a decanoyl group, a lauroyl group, and a myristoyl group. , Palmitoyl group, stearoyl group and the like, and galloyl group is excluded. These acyl groups may be linear or branched. Since the DNA synthase activity inhibitor of the present invention becomes stronger as the carbon chain length of the acyl group becomes longer, the hexanoyl group, heptanoyl group, octanoyl having 6 to 18 carbon atoms (n = 4 to 16 in the formula (3)). Group, decanoyl group, lauroyl group, myristoyl group, palmitoyl group, stearoyl group, preferably lauroyl group, myristoyl group, palmitoyl group having 12 to 18 carbon atoms (n = 10 to 16 in formula (3)) More preferably, a stearoyl group is used.

(In the formula, R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom or a hydroxyl group, and the steric configurations at the 2- and 3-positions of the benzopyran ring are either R configuration or S configuration, respectively. 3-acylated flavan-3-ols represented by:

  Next, a method for producing the DNA synthase inhibitor of the present invention will be described.

  First, catechins, which are representative compounds of flavan-3-ols that are raw materials, are mainly leaves, stems, xylem, bark, roots, and fruits obtained from tea tree (Camellia sinensis) belonging to Camellia family. It is obtained by extracting from one of seeds, a mixture of two or more of these, or a pulverized product thereof with water, hot water, an organic solvent, a water-containing organic solvent, or a mixture thereof. In particular, the extract itself obtained by extracting from fresh tea leaves or dried products thereof with water, hot water, organic solvent, hydrous organic solvent, a mixture thereof, or the like, or a purified product obtained by purification as necessary. It is preferable to obtain as. Regarding purified products of catechins, JP-B-1-44232, JP-A-2-12474, JP-A-2-22755, JP-A-4-20589, JP-A-5-260907, and JP-A-8-09178. For example, an extract obtained by extracting tea leaves with the above-mentioned solvent can be purified to a desired level using an organic solvent fraction or an adsorption resin. it can. Extraction from plants other than tea may be carried out by the same method as that for tea. The catechins used in the present invention may be commercially available products. Examples of such commercially available products include “Polyphenone” manufactured by Mitsui Norin Co., Ltd., “Sunphenon” manufactured by Taiyo Kagaku Co., Ltd. An example is ITO EN's “Theafranc”.

  The method for acylating the thus obtained flavan-3-ols is not particularly limited, and a generally well-known method may be used. For example, the readily available (2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-catechin} and (2R, 3R) shown in formula (10) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−)-epicatechin} is used as a raw material, and 3-acylated catechins and 3-acylated catechins shown in Table 1 are represented by the formula It can be synthesized as in (9).

（式（１０）において、Ｒ_１がＯＨ、Ｒ_２がＨである化合物が、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オール｛（＋）−カテキン｝、Ｒ_１がＨ、Ｒ_２がＯＨである化合物が（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オール｛（−）−エピカテキン｝である。）

(In the formula (10), the compound in which R ₁ is OH and R ₂ is H is (2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-catechin }, The compound in which R ₁ is H and R ₂ is OH is (2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−)-epicatechin}.

［第一行程］

ジル−フラバン−３−オール（木材学会誌、１９９１，３７，４８８−４９３頁）の３位の水酸基にアシル基を導入し、一般式［ＩＩ］表される３−アシル化３’，４’，

ピリジンやトリエチルアミンなど、通常のアシル化反応に用いることができる塩基であれば如何なる塩基も使用できる。また、この行程に用いられる溶媒としては、反応に関与しないものであれば如何なるものも使用できるが、好適には塩素系溶媒、特にジクロロメタンが用いられる。
［第二行程］

−ベンジル−フラバンの保護基であるベンジル基を脱保護して、一般式［ＩＩＩ］で表される３−アシル化３’，４’，５，７−テトラヒドロキシフラバン−３−オールを製造するものである。水素雰囲気化、パラジウムなどの触媒を加えベンジル基を脱保護するが、この行程に用いられる触媒としては、ベンジル基以外の部位に影響を及ぼさないものであれば、如何なる触媒でも使用できるが、公知の方法（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９９９，１２１，１２０７３−１２０８１頁）、Ｐｄ（ＯＨ）_２／Ｃを用いる方法が良い。また、この行程に用いられる溶媒としては、反応に関与しないものであれば如何なるものも使用できるが、公知の方法（文献）であるＰｄ（ＯＨ）_２／Ｃとの組み合わせで用いられるテトラヒドロフラン−メタノール−水の混合溶媒が良い。

[First step]

An acyl group is introduced into the hydroxyl group at the 3-position of zil-flavan-3-ol (Journal of the Wood Society, pages 991, 37, 488-493), and 3-acylated 3 ′, 4 ′ represented by the general formula [II] ,

Any base such as pyridine or triethylamine can be used as long as it can be used in a usual acylation reaction. As the solvent used in this step, any solvent can be used as long as it does not participate in the reaction, but a chlorinated solvent, particularly dichloromethane, is preferably used.
[Second step]

-The benzyl group which is a protecting group of benzyl-flavan is deprotected to produce 3-acylated 3 ', 4', 5,7-tetrahydroxyflavan-3-ol represented by the general formula [III] Is. Benzyl group is deprotected by adding a catalyst such as hydrogen atmosphere and palladium. As the catalyst used in this process, any catalyst can be used as long as it does not affect sites other than benzyl group. (J. Am. Chem. Soc., 1999, 121, 12073-12081) and a method using Pd (OH) ₂ / C are preferable. As the solvent used in this step, any solvent can be used as long as it does not participate in the reaction. Tetrahydrofuran-methanol used in combination with Pd (OH) ₂ / C which is a known method (document) -A mixed solvent of water is good.

  In addition, for example, a method for synthesizing a catechin derivative using a boron compound (Japanese Patent Laid-Open Nos. 57-118580 and 57-12058), a method using trifluoroacetic acid and an acid chloride (Bioorganic & Medicinal Chemistry Letters, 2000, 10, pp. 1673-1675), a method using lipase (Journal of Molecular Catalysis B: Enzymatic, 2000, 10, pp. 577-582) and the like.

  The DNA synthase inhibitor of the present invention is active against any DNA synthase such as a DNA synthase derived from mammals such as humans, rats and calves, a plant-derived DNA synthase and a prokaryotic DNA synthase. The inhibitory action can be sufficiently exerted. In particular, the DNA synthase inhibitor of the present invention is preferably directed to a DNA synthase derived from a mammal, and particularly exhibits an effect on a DNA synthase derived from a higher animal such as a human.

Moreover, the DNA synthase inhibitor of the present invention is any of α, β, γ, δ, ε, ζ, η, θ, ι, κ, λ, μ, and σ types known so far. An inhibitory action can also be exerted on these DNA synthases, among which α, β, δ, ε type and λ type DNA synthases are preferred, and λ type DNA synthase is most preferred.
It is known that there are 13 kinds of molecular species of DNA synthase, α, β, γ, δ, ε, ζ, η, θ, ι, κ, λ, μ, and σ types, Are thought to work slightly differently. For example, since the DNA synthase α is a replication-type DNA synthase, the enzyme activity is high only for cells and tissues such as cancer cells where cell division is active. On the other hand, DNA synthase β is said to play a role in the diversity of antibodies due to mutations, as well as being involved in the origin of antibodies or receptor molecules that react antigen-specifically in the DNA reconstitution of immune reactions. It is closely involved in the reaction. Therefore, suppressing DNA synthase α leads to suppression of cancer cell growth, and acts as an anticancer agent, and suppressing DNA synthase β leads to suppression of immune reaction, immunity Expected to act as an inhibitor. The DNA synthase λ is a repair-type DNA synthase, which removes DNA base mutations and abnormalities and then performs repair DNA synthesis. Even in daily life, when DNA damage or modification to DNA occurs due to ultraviolet rays or X-rays, a repair-type DNA synthase acts to restore the normal state. The same applies to cancer cells, and in the radiotherapy of cancer, after irradiation with X-rays or γ-rays, repair-type DNA synthase works actively and tries to restore damaged DNA. If the damage to the cancer cell DNA due to irradiation is sufficient, the repair by the repair-type DNA synthase is not in time, and the cancer cells die by self-cell death (apoptosis). However, if the damage is insufficient and does not reach apoptosis, incomplete repair by the DNA synthase occurs, causing a risk of further canceration. Therefore, in combination with acylated flavan-3-ols having a repair type DNA synthase inhibitory activity during radiotherapy, the function of the repair type DNA synthase of cancer cells is stopped, and all cancer cells are removed. It is thought that it can lead to apoptosis.

  As a use of the DNA synthetase inhibitor of this invention, it can be used as food-drinks, a pharmaceutical, a quasi-drug, cosmetics, etc.

  The DNA synthase inhibitor of the present invention may be ingested in a form blended with foods and drinks or pharmaceuticals, but can also be ingested as it is. The intake varies depending on the intake form, age, weight, etc., and is not particularly limited, but is preferably 0.1 mg to 100 mg / kg of body weight per 1 kg of body weight, more preferably 0.5 mg to 50 mg / dose. preferable. At this time, the number of intakes per day is once or several times. For example, in the case of an injectable preparation, in adults, 1 to 60 mg per day as a weight of the compound of the present invention, intravenous drip, subcutaneous injection and intramuscular injection are suitable.

  The administration method of the DNA synthase inhibitor of the present invention is not particularly limited, and can be administered by various methods.

  In the case where the DNA synthase inhibitor of the present invention is formulated alone, the formulation form is any form as long as it comprises the aforementioned 3-acylated flavan-3-ols as an active ingredient. For example, it may be solid such as powder, granule, tablet, etc., and may be liquid or semi-solid.

  Further, the DNA synthase inhibitor of the present invention does not cause any problems even when used in combination with other DNA synthase inhibitors. When used in combination with other DNA synthase inhibitors, a more excellent inhibitory effect of DNA synthase can be expected.

  When the DNA synthase inhibitor of the present invention is formulated alone, or used by blending in foods and drinks, pharmaceuticals, etc., it may be used in combination with various additives as necessary. For example, binders, disintegrants, extenders, antioxidants, colorants, fragrances, flavoring agents, surfactants, lubricants, fluidity promoters, solubilizers, preservatives, sugars, sweeteners, acidulants Various known additives such as vitamins can be used in appropriate combination. Examples of the binder include starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, sodium methylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol and the like. Examples of the disintegrant include starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted hydroxypropylcellulose. Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester and the like. Examples of lubricants include talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol and the like. Examples of the fluidity promoter include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like. In addition, when used as an injectable preparation, generally used are distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol and the like as diluents. . Furthermore, you may add a disinfectant, antiseptic | preservative, and a stabilizer as needed. In addition, from the viewpoint of stability, it can be frozen after filling into a vial or the like, the water can be removed by ordinary freeze-drying treatment, and the liquid preparation can be re-prepared from the freeze-dried product immediately before use. Furthermore, you may add an isotonic agent, a stabilizer, an antiseptic | preservative, and a soothing agent as needed.

  The food / beverage products and pharmaceuticals, etc., which are the subject of blending of the DNA synthase inhibitor of the present invention, can be blended with 3-acylated flavan-3-ols which are active ingredients of DNA synthase inhibitors. For example, any form may be used, for example, a liquid form such as an aqueous solution, a turbid substance, an emulsion, a semi-solid form such as a gel or a paste, a powder, a granule, a capsule, It may be a solid form such as a tablet.

  Examples of foods and drinks include instant foods (immediate noodles, cup noodles, retort / cooked food, canned food, microwave food, instant miso soup, soup, freeze-dried food, etc.), carbonated drinks, citrus fruits (grapefruit, orange , Lemon, etc.) fruit juices, fruit juice drinks, soft drinks with fruit juices, fruit drinks with citrus fruits and fruit drinks, vegetable drinks containing vegetables such as tomatoes, peppers, celery, cucumbers, carrots, potatoes, asparagus, soy milk・ Soy milk beverages, coffee beverages, tea beverages, powdered beverages, concentrated beverages, sports beverages, nutritional beverages, alcoholic beverages and other favorite beverages such as tobacco, bread, macaroni and spaghetti, noodles, cake mix, deep-fried flour, bread crumbs , Flour products such as gyoza peel, caramel candy, chewing gum, Chocolate, cookies / biscuits, cakes / pies, snacks / crackers, sweets such as Japanese confectionery / rice confectionery / bean confectionery, dessert confectionery, soy sauce, miso, sauces, tomato processing seasonings, mirins, vinegars, sweeteners, etc. Basic seasonings, flavor seasonings, cooking mixes, curry ingredients, sauces, dressings, noodle soups, spices and other complex seasonings and foods, butter, margarines, mayonnaise, vegetable oils and other fats and oils , Milk and processed milk, milk drinks, yogurts, lactic acid bacteria drinks, cheese, ice cream, prepared milk powder, milk and other dairy products such as cream, frozen foods, semi-cooked frozen foods, frozen frozen foods such as cooked frozen foods Fish processing such as canned fish, canned fruits and pastes, fish ham and sausage, fish paste products, fish delicacy, dried fish and boiled fish , Livestock canning / pastes, canned meat, fruit canning, jams / marmalades, pickles / boiled beans, dried agricultural products, cereals (cereal processed products), and other processed foods, baby foods, sprinkles, and green tea paste Etc. Further, it may be animal feed such as livestock blended feed (cattle feed, pig feed, poultry feed, etc.) and pet food.

  Examples of the form of the pharmaceutical composition include oral preparations such as tablets, pills, drinking liquids, suspensions, emulsions, capsules, granules, fine granules, powders, injections, liquids for external use, patches. And parenterals such as ointments, creams, suppositories for rectal administration, inhalants, nasal drops, sprays and the like.

  The method of blending the DNA synthase inhibitor of the present invention into foods and beverages and pharmaceuticals is not particularly limited, and conventional methods commonly known in this field are used in the preparation stage of foods and beverages and pharmaceuticals. Can be blended. Further, the amount of the DNA synthase inhibitor of the present invention for foods and drinks and pharmaceuticals is not particularly limited, but it is preferable to appropriately set the amount depending on the article to be blended. Generally, it may be 0.0001 to 50% by weight in the final product, but is preferably 0.001 to 20% by weight, and more preferably 0.01 to 10% by weight. In the case of food and drink, it may be 0.0001 to 5% by weight in the final product, but is preferably 0.001 to 1% by weight, more preferably 0.01 to 0.5% by weight, Particularly preferred is 0.05 to 0.5% by weight.

  Hereinafter, the present invention will be described in more detail with reference to production examples and test examples. However, the present invention is not limited to this.

−３−オールの製造方法
（＋）−カテキン｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オール｝（２０．０ｇ，０．０６９ｍｏｌ）を蒸留して脱水したＤＭＦ５００ｍＬに溶かし、氷冷しながら炭酸カリウム（５２．４ｇ，０．３８ｍｏｌ）を少しずつ加えた。１０分間０度で攪拌した後、ベンジルブロミド（５８．９ｇ、０．３４ｍｏｌ）を滴下し、４８時間室温で攪拌した。反応終了後、反応液を氷水に注ぎ、生じた沈殿を濾過して祖生成物を得た。この組成生物を酢酸エチルに溶解させ、水、及び、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで有機層を乾燥した。濾過・濃縮後、シリカゲルカラムクロマトグラフィーで精製し、白色粉末

ール（２３．８ｇ，０．０３７ｍｏｌ，５３％収率）を得た。

-3-Ole Production Method (+)-Catechin {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol} (20.0 g, 0.069 mol) was distilled. Dissolved in 500 mL of dehydrated DMF, potassium carbonate (52.4 g, 0.38 mol) was added little by little while cooling with ice. After stirring at 0 degree for 10 minutes, benzyl bromide (58.9 g, 0.34 mol) was added dropwise, and the mixture was stirred at room temperature for 48 hours. After completion of the reaction, the reaction solution was poured into ice water, and the resulting precipitate was filtered to obtain a parent product. This composition organism was dissolved in ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration, purify by silica gel column chromatography to obtain white powder

(23.8 g, 0.037 mol, 53% yield) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) 7.45-7.29 (20H, m), 7.03 (1H, s), 6.95 (2H, s), 6.27 (1H, d, J = 2.2 Hz), 6.20 (1H, d, J = 2.2 Hz), 5.20-5.13 (2H, m), 5.18 (2H, s), 5.03 (2H, s) ), 4.99 (2H, s), 4.64 (1H, d, J = 8.3 Hz), 4.06-3.98 (1H, m), 3.11 (1H, dd, J = 5) .6, 16.3 Hz), 2.65 (1H, dd, J = 9.0, 16.3 Hz), 1.61 (1H, d, J = 3.9 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 158.8, 157.8, 155.3, 149.3, 149.1, 137.1, 137.0, 136.9, 136.8, 130.8, 128.6, 120.51 (x2), 128.48, 128.44, 128.0, 127.9, 127.8 (x2), 127.52, 127.47, 127.2, 127.1, 120.6, 115.0, 113.8, 102.3, 94.3, 93.8, 81.6, 71.3, 71.2, 71.1, 69.9, 69.2, 27. 6;

３−オールの製造方法
（−）−エピカテキン｛（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オール｝（１０．０ｇ，０．０３５ｍｏｌ）を蒸留して脱水したＤＭＦ５００ｍＬに溶かし、氷冷しながら炭酸カリウム（２６．２ｇ，０．１９ｍｏｌ）を少しずつ加えた。１０分間０度で攪拌した後、ベンジルブロミド（２９．５ｇ、０．１７ｍｏｌ）を滴下し、４８時間室温で攪拌した。反応終了後、反応液を氷水に注ぎ、生じた沈殿を濾過して祖生成物を得た。この組成生物を酢酸エチルに溶解させ、水、及び、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで有機層を乾燥した。濾過・濃縮後、シリカゲルカラムクロマトグラフィーで精製し、白

−オール（１０．２ｇ，０．０１６ｍｏｌ，４５％収率）を得た。

Method for producing 3-ol (-)-epicatechin {(2R, 3R) -3 ', 4', 5,7-tetrahydroxyflavan-3-ol} (10.0 g, 0.035 mol) was distilled. It was dissolved in 500 mL of dehydrated DMF, and potassium carbonate (26.2 g, 0.19 mol) was added little by little while cooling with ice. After stirring at 0 ° C. for 10 minutes, benzyl bromide (29.5 g, 0.17 mol) was added dropwise and stirred at room temperature for 48 hours. After completion of the reaction, the reaction solution was poured into ice water, and the resulting precipitate was filtered to obtain a parent product. This composition organism was dissolved in ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration, purify by silica gel column chromatography.

-All (10.2 g, 0.016 mol, 45% yield) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) 7.46-7.26 (20 H, m), 7.14 (1 H, d, J = 1.7 Hz), 6.99 (1 H, dd, J = 1. 7, 8.3 Hz), 6.95 (1 H, d, J = 8.3 Hz), 6.27 (1 H, d, J = 2.2 Hz), 6.26 (1 H, d, J = 2.2 Hz) ), 5.18 (2H, s), 5.16 (2H, s), 5.13-4.98 (2H, m), 5.00 (2H, s), 4.89 (1H, br s) ), 4.24-4.23 (1H, m), 2.99 (1H, dd, J = 2.0, 17.4 Hz), 2.91 (1H, dd, J = 4.4, 17. 4 Hz), 1.68 (1H, d, J = 5.6 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 158.8, 158.3, 155.2, 149.0, 148.8, 137.2, 137.1, 137.0, 136.9, 131.4, 128.6, 128.50, 128.47, 128.45, 128.0, 127.9, 127.83, 127.79, 127.52, 127.48, 127.24, 127.19, 119. 5, 115.1, 113.5, 100.9, 94.7, 94.0, 78.3, 71.4, 71.3, 70.1, 69.9, 66.3, 28.2;

フラバン−３−オール（５００ｍｇ，０．７７ｍｍｏｌ）を蒸留して脱水したジクロロメタン３０ｍｌに溶かし、氷冷しながらトリエチルアミン（０．３２ｍＬ，２．３１ｍｍｏｌ）、オクタノイルクロライド（０．２０ｍＬ，１．１６ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え、１２時間室温で攪拌した。水で反応を止め、クロロホルムで抽出し、有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過・濃縮後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ８：１）で精製し、淡黄色油状物の（２Ｒ，３Ｓ）

８８ｍｇ、０．５０ｍｍｏｌ，６５％収率）を得た。Production Example 3: Production Method of Compound 1 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-octanoate}

Flavan-3-ol (500 mg, 0.77 mmol) was dissolved in 30 ml of dehydrated dichloromethane, and triethylamine (0.32 mL, 2.31 mmol) and octanoyl chloride (0.20 mL, 1.16 mmol) were cooled with ice. And N, N-dimethylaminopyridine (5 mg) was added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with water, extracted with chloroform, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, purification by silica gel column chromatography (n-hexane: ethyl acetate 8: 1) gave (2R, 3S) as a pale yellow oil.

88 mg, 0.50 mmol, 65% yield).

[Α] _D ²⁴ = + 8.0 (c1.64, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.28 (20 H, m), 6.98 (1 H, br s), 6.88 (2 H, br s), 6.26 (1 H, d , J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.20-5.35 (1H, m), 5.13 (2H, s), 5.10 (2H , S), 5.00 (4H, s), 5.00-4.90 (1H, m), 2.89 (1H, dd, J = 5.2, 16.9 Hz), 2.70 (1H , Dd, J = 6.6, 16.9 Hz), 2.26 (2H, m), 1.48-1.41 (2H, m), 1.28-1.14 (8H, m), 0 .88 (3H, t, J = 6.8 Hz);
¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.28 (20 H, m), 6.98 (1 H, br s), 6.88 (2 H, br s), 6.26 (1 H, d , J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.20-5.35 (1H, m), 5.13 (2H, s), 5.10 (2H , S), 5.00 (4H, s), 5.00-4.90 (1H, m), 2.89 (1H, dd, J = 5.2, 16.9 Hz), 2.70 (1H , Dd, J = 6.6, 16.9 Hz), 2.26 (2H, m), 1.48-1.41 (2H, m), 1.28-1.14 (8H, m), 0 .88 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 127.9, 158.9, 157.6, 154.9, 148.9, 148.8, 137.2, 137.1, 136.8, 131.1, 128.6, 128.52, 128.45, 128.42 (x2), 128.0, 127.9, 127.8 (x2), 127.6, 127.4, 127.22, 127.19, 119.9, 114.8, 113.4, 101.4, 94.3, 93.7, 78.3, 71.23, 71.18, 70.1, 69.9, 68.7, 34. 3, 31.6, 28.7 (x2), 24.8, 24.0, 22.6, 14.0; IR (neat, cm ⁻¹ ) 3065 (w), 3032 (m), 2928 (s ), 2859 (m), 1734 (s), 1618 (s), 1593 ( ), 1516 (s), 1377 (s), 1265 (s), 1145 (s), 1028 (s), 910 (w), 852 (w), 812 (w), 754 (s);
FAB-MS (m / z) 800 (3.1), 799 ([M + Na] ⁺ , 6.1), 778 (15), 777 ([M + H] ⁺ , 27), 776 (6.0), 633 (72), 632 (100), 631 (17);
FAB-HRMS calcd ^{_{C 51 H 53 O 7 [M}} + H] +, 777.3791; Found: 777.3787.

オクタノエート（２１８ｍｇ，０．２８ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，２２ｍＬ）に溶解し、触媒として２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。触媒を濾過して除き、濾液を濃縮し、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、無色油状物の化合物１｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オクタノエート｝（１１１ｍｇ，０．２７ｍｍｏｌ，９６％収率）を得た。

Dissolve octanoate (218 mg, 0.28 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL), add 20% Pd (OH) ₂ / C (5 mg) as a catalyst, and stir for 12 hours in a hydrogen atmosphere. The benzyl group was deprotected. The catalyst was removed by filtration, the filtrate was concentrated and purified by Cosmosil 75C-18OPN column chromatography (methanol-water) to give a colorless oily compound 1 {(2R, 3S) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-octanoate} (111 mg, 0.27 mmol, 96% yield).

[Α] _D ²⁵ = + 7.9 (c 0.34, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 6.83 (1H, d, J = 1.7 Hz), 6.76 (1H, d, J = 8.3 Hz) 6.65 (1H, dd, J = 1.7, 8.3 Hz), 6.01 (1H, d, J = 2.2 Hz), 5.89 (1H, d, J = 2.2 Hz), 5.19 (1H, ddd, J = 5.4, 6.6, 6.8 Hz), 4.87 (1H, d, J = 6.6 Hz), 2.77 (1H, dd, J = 5. 4, 16.4 Hz), 2.56 (1 H, dd, J = 6.8, 16.4 Hz), 2.20-2.12 (2 H, m), 1.45-1.38 (2 H, m ), 1.30-1.10 (8H, m), 0.82 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 173.5, 158.0, 157.2, 156.1, 145.9, 145.8, 130.7, 119 0.0, 115.8, 114.5, 98.9, 96.3, 95.2, 78.8, 70.1, 34.8, 32.3, 30.6-29.4 (Cx2), 25.6, 24.7, 23.2, 14.3;
FAB-MS (m / z) 440 (10), 439 ([M + Na] ⁺ , 28), 438 (6.7), 418 (11), 417 ([M + H] ⁺ , 31), 275 (14), 274 (57), 273 (100), 272 (27);
FAB-HRMS calcd ^{_{C 23 H 28 O 7 [M}} + Na] +, 439.1733; Found: 439.1747

．７７ｍｍｏｌ）のジクロロメタン溶液（３０ｍＬ）に、氷冷しながらトリエチルアミン（０．３２ｍＬ，２．３１ｍｍｏｌ）、ドデカノイルクロライド（０．２４ｍＬ，１．１６ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ８：１）で精製し、淡黄色油状物の（２Ｒ，３Ｓ）−３’，４’，５

ｍｏｌ，７６％収率）を得た。Production Example 4: Production Method of Compound 2 {(2R, 3S) -3 ′, 4 ′, 5,7-Tetrahydroxyflavan-3-dodecanoate} Production in the same manner as the synthesis of Compound 1 described in Production Example 3. Obtained in Example 1 (2R, 3S

. 77 mmol) in dichloromethane (30 mL), ice-cooled triethylamine (0.32 mL, 2.31 mmol), dodecanoyl chloride (0.24 mL, 1.16 mmol), and N, N-dimethylaminopyridine (5 mg) The reaction was followed by post-treatment, and purified by silica gel column chromatography (n-hexane: ethyl acetate 8: 1) to give (2R, 3S) -3 ′, 4 ′, 5 as a pale yellow oil.

mol, 76% yield).

[Α] _D ²³ = + 8.5 (C1.32, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.25 (20 H, m), 6.98 (1 H, br s), 6.88 (2 H, br s), 6.26 (1 H, d , J = 2.2 Hz), 6.24 (1H, d, J = 2.2 Hz), 5.32 (1H, ddd, J = 5.3, 6.6, 9.5 Hz), 5.13 ( 2H, s), 5.10 (2H, s), 4.99 (4H, s), 4.98 (1H, d, J = 9.5 Hz), 2.90 (1H, dd, J = 5. 3, 16.8 Hz), 2.70 (1H, dd, J = 6.6, 16.8 Hz), 2.22-2.09 (2H, m), 11.48-1.41 (2H, m ), 1.28-1.10 (12H, m), 0.86 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 172.9, 158.9, 157.6, 154.8, 148.9, 148.8, 137.2, 137.0, 136.8, 131.0, 128.6, 128.49, 128.43, 128.40 (x2), 128.0, 127.9, 127.7, 127.5, 127.4, 127.19 (x2), 127.17, 119.9, 114.7, 113.3, 101.4, 94.3, 93.7, 78.3, 71.21, 71.15, 70.1, 69.9, 68.7, 34. 3, 31.8, 29.3, 29.24, 29.21, 28.9, 24.8, 24.0, 22.6, 14.1;
IR (neat, cm ⁻¹ ) 3065 (w), 3032 (w), 2926 (s), 2855 (s), 1950 (w), 1871 (w), 1811 (w), 1734 (s), 1620 ( s), 1593 (s), 1498 (s), 1379 (s), 1265 (s), 1180 (s), 1147 (s), 1028 (s), 910 (w), 850 (w), 812 ( m), 754 (m);
FAB-MS (m / z) 828 (5.6), 827 ([M + Na] ⁺ , 7.7), 807 (5.5), 806 (17), 805 ([M + H] ⁺ , 29), 804 (6.9), 634 (22), 633 (69), 632 (100), 631 (22);
FAB-HRMS calcd ^{_{C 53 H 57 O 7 [M}} + H] +, 805.4104; Found: 805.4135.

ラバン−３−ドデカノエート（４００ｍｇ，０．５０ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，２２ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、無色油状物の化合物２｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ドデカノエート｝（１９０ｍｇ，０．４３ｍｍｏｌ，８６％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-dodecanoate (400 mg, 0.50 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. After the workup, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water), and colorless oily compound 2 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-dodecanoate } (190 mg, 0.43 mmol, 86% yield).

[Α] _D ²⁵ = + 6.5 (C0.34, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 6.83 (1H, d, J = 1.7 Hz), 6.76 (1H, d, J = 8.3 Hz) 6.66 (1H, dd, J = 1.7, 8.3 Hz), 6.01 (1H, d, J = 2.2 Hz), 5.89 (1H, d, J = 2.2 Hz), 5.19 (1H, ddd, J = 5.3, 6.8, 6.8 Hz), 4.87 (1H, d, J = 6.8 Hz), 2.77 (1H, dd, J = 5. 3, 16.3 Hz), 2.56 (1H, dd, J = 6.8, 16.3 Hz), 2.18-2.14 (2H, m), 1.45-1.35 (2H, m ), 1.25-1.10 (12H, m), 0.82 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 173.3, 157.8, 157.1, 155.9, 145.71, 145.66, 130.56, 118 , 115.6, 114.3, 98.8, 96.1, 95.0, 78.7, 69.9, 34.6, 32.3, 30.4-29.2 (Cx4), 25.4, 24.5, 23.1, 14.2;
FAB-MS (m / z) 468 (11), 467 ([M + Na] ⁺ , 29), 466 (6.7), 446 (8.8), 445 ([M + H] ⁺ , 21), 275 (16 ), 274 (59), 273 (100), 272 (30);
FAB-HRMS calcd ^{_{C 25 H 33 O 7 [M}} + H] +, 445.2226; Found: 445.2213.

．１４ｍｍｏｌ）のジクロロメタン溶液（５０ｍＬ）に、氷冷しながらトリエチルアミン（０．３２ｍＬ，２．２８ｍｍｏｌ）、ラウロイルクロライド（０．３９ｍＬ，１．７０ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ６：１）で精製し、白色粉末の（２Ｒ，３Ｓ）−３’，４’，５，７−テ

７６％収率）を得た。Production Example 5: Production method of Compound 3 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-lauroate} Production in the same manner as the synthesis of Compound 1 described in Production Example 3. Obtained in Example 1 (2R, 3S

. 14 mmol) in dichloromethane (50 mL) with ice cooling, triethylamine (0.32 mL, 2.28 mmol), lauroyl chloride (0.39 mL, 1.70 mmol), and N, N-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 6: 1) to give (2R, 3S) -3 ′, 4 ′, 5,7-te of white powder.

76% yield).

[Α] _D ²⁵ = + 8.7 (c 2.78, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.42-7.24 (20H, m), 6.98 (1H, s), 6.87 (2H, s), 6.25 (1H, br s) , 6.24 (1H, br s), 5.32 (1H, dt, J = 5.1, 6.8 Hz), 5.12 (2H, s), 5.09 (2H, s), 4. 98 (4H, s), 4.97 (1H, d, J = 6.8 Hz), 2.90 (1H, dd, J = 5.1, 16.9 Hz), 2.70 (1H, dd, J = 6.8, 16.9 Hz), 2.21-2.10 (2H, m), 1.47-1.10 (21 H, m); ¹³ C-NMR (100 MHz, CDCl ₃ ) 172.9, 158.9, 157.7, 154.9, 148.93, 148.88, 137.2, 137.1, 136.7, 131.1, 128 6, 128.53, 128.49, 128.46, 128.0, 127.9, 127.8 (x2), 127.6, 127.4, 127.23, 127.22, 120.0, 114 8, 113.4, 101.5, 94.4, 93.7, 78.3, 71.24, 71.18, 70.1, 69.9, 68.7, 60.4, 34.3 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.0, 24.8, 22.7, 14.2, 14.1;
IR (neat, cm ⁻¹ ) 3065 (w), 3032 (m), 2926 (s), 2855 (s), 2361 (w), 1950 (w), 1869 (w), 1809 (w), 1736 ( s), 1680 (s), 1593 (s), 1514 (s), 1454 (s), 1377 (s), 1263 (s), 1219 (s), 1180 (s), 1147 (s), 1028 ( s), 910 (w), 851 (w), 810 (m), 735 (s);
FAB-MS (m / z) 856 (4.6), 855 ([M + Na] ⁺ , 6.0), 835 (6, 5), 834 (17), 833 ([M + H] ⁺ , 29), 832 (7.1), 831 (8.8), 634 (24), 633 (69), 632 (100), 631 (21);
FAB-HRMS calculated C ₅₅ H ₆₁ O ₇ [M + H] ⁺ , found; found: 833.4401.

ラバン−３−ラウロエート（９１ｍｇ，０．１１ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，１１ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、無色アモルファスの化合物３｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ラウロエート｝（３４ｍｇ，０．０７２ｍｍｏｌ，６５％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-lauroate (91 mg, 0.11 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 11 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water) and colorless amorphous compound 3 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-lauroate} (34 mg, 0.072 mmol, 65% yield) was obtained.

[Α] _D ²³ = + 3.5 (c 0.68, EtOH);
¹ H-NMR (400 MHz, CD ₃ OD) 6.78 (1H, d, J = 2.0 Hz), 6.72 (1H, d, J = 8.3 Hz), 6.67 (1H, dd, J = 2.0, 8.3 Hz), 5.94 (1H, d, J = 2.4 Hz), 5.88 (1H, d, J = 2, 4 Hz), 5.19 (1H, ddd, J = 5.4, 6.8, 7.1 Hz), 4.85 (1H, d, J = 6.8 Hz), 2.80 (1H, dd, J = 5.4, 16.4 Hz), 2.59 (1H, dd, J = 7.1, 16.4 Hz), 2.19 (2H, m), 1.48-1.39 (2H, m), 1.35-1.13 (6H, m) , 0.88 (3H, t, J = 7.1 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 174.7, 158.1, 157.6, 156.6, 146.4, 146.3, 131.1, 119.5, 116.1, 114.8, 96.7, 96.5, 95.5, 79.6, 70.9, 35.2, 33.1, 30.7 (x2), 30.51, 30.48, 30.3, 30.0 , 26.0, 25.1, 23.7, 14.5;
FAB-MS (m / z) 496 (3.4), 495 ([M + Na] ⁺ , 9.9), 474 (3.8), 473 ([M + H] ⁺ , 11), 392 (7.9) , 391 (27), 330 (27), 329 (100);
FAB-HRMS calcd ^{_{C 27 H 37 O 7 [M}} + H] +, 473.2539; Found: 473.2571.

．３６ｍｍｏｌ）のジクロロメタン溶液（５０ｍＬ）に、氷冷しながらトリエチルアミン（０．５７ｍＬ，４．０８ｍｍｏｌ）、ミリストイルクロライド（０．５６ｍＬ，２．０４ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ８：１）で精製し、白色粉末の（２Ｒ，３Ｓ）−３’，４’，５，７−

ｌ，７２％収率）を得た。Production Example 6: Production method of compound 4 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-myristate} Production in the same manner as the synthesis of compound 1 described in Production Example 3. Obtained in Example 1 (2R, 3S

. 36 mmol) in dichloromethane (50 mL) with ice cooling, triethylamine (0.57 mL, 4.08 mmol), myristoyl chloride (0.56 mL, 2.04 mmol), and N, N-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 8: 1) to give (2R, 3S) -3 ′, 4 ′, 5,7-

l, 72% yield).

[Α] _D ²³ = + 8.6 (c 0.72, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.24 (20 H, m), 6.97 (1 H, br s), 6.88 (1 H, br s), 6.25 (1 H, d , J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.31 (1H, ddd, J = 5.3, 6.6, 6.8 Hz), 5.13 ( 2H, s), 5.10 (2H, s), 5.00 (4H, s), 4.97 (1H, d, J = 6.6 Hz), 2.89 (1H, dd, J = 5. 3, 16.8 Hz), 2.70 (1H, dd, J = 6.8, 16.8 Hz), 2.22-2.09 (2H, m), 1.47-1.42 (2H, m ^{), 1.35-1.10 (20H, m)} , 0.87 (3H, t, J = 6.8Hz); 13 C-NMR (100MHz, CDCl 3) 172.9,158 9, 157.6, 154.8, 148.9, 148.8, 137.2, 137.0, 136.8, 131.0, 128.6, 128.5, 128.44, 128.40, 128.0, 127.9, 127.7 (x2), 127.5, 127.4 (x2), 127.20, 127.17, 119.9, 114.7, 113.4, 101.4, 94.3, 93.7, 78.3, 71.22, 71.15, 70.1, 69.9, 68.7, 34.3, 31.9 (x2), 29.7, 29.6 (X2), 29.4, 29.3, 29.2, 28.9, 24.8, 24.0, 22.7, 14.1;
IR (neat, cm ⁻¹ ) 3065 (w), 3032 (w), 2926 (s), 2855 (s), 1736 (s), 1620 (s), 1593 (s), 1376 (m), 1265 ( m), 1146 (s), 1028 (m), 910 (w), 850 (w), 810 (w), 735 (m);
FAB-MS (m / z) 884 ([M + Na] ⁺ , 8.1), 883 (13.1), 862 (16), 861 ([M + H] ⁺ , 28), 860 (7.6), 634 (25), 633 (69), 632 (100), 631 (20);
FAB-HRMS calcd ^{_{C 57 H 65 O 7 [M}} + H] +, 861.4730; Found: 861.4737.

ラバン−３−ミリストエート（５００ｍｇ，０．５８ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，２２ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、無色アモルファスの化合物４｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ミリストエート｝（２１２ｍｇ，０．４２ｍｍｏｌ，７２％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-myristate (500 mg, 0.58 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water) and colorless amorphous compound 4 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-myristate} (212 mg, 0.42 mmol, 72% yield) was obtained.

[Α] _D ²⁵ = + 6.3 (c1.46, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 6.80 (1H, d, J = 1.7 Hz), 6.74 (1H, d, J = 8.3 Hz) , 6.63 (1H, dd, J = 1.7, 8.3 Hz), 5.99 (1H, d, J = 2.2 Hz), 5.87 (1H, d, J = 2.2 Hz), 5.18 (1H, ddd, J = 5.4, 6.4, 6.6 Hz), 4.86 (1H, d, J = 6.4 Hz), 2.73 (1H, dd, J = 5. 4, 16.4 Hz), 2.54 (1H, dd, J = 6.6, 16.4 Hz), 2.19-2.12 (2H, m), 1.43-1.37 (2H, m ), 1.25-1.15 (20H, m), 0.79 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 173.5, 157.4, 156.8, 155.7, 145.5, 130.4, 118.7, 115 6, 114.2, 98.7, 96.0, 95.0, 78.4, 69.7, 34.5, 32.2, 30.4-29.2 (Cx9), 25.2. 24.2, 22.9, 14.1;
FAB-MS (m / z) 524 (17), 523 ([M + Na] ⁺ , 34), 522 (7.4), 502 (8.7), 501 ([M + H] ⁺ , 18), 275 (21 ), 274 (72), 273 (100). 171 (29);
FAB-HRMS calculated C ₂₉ H ₄₁ O ₇ [M + H] ⁺ , 501.2852; f found: 501.2879.

．０７ｍｍｏｌ）のジクロロメタン溶液（５０ｍＬ）に、氷冷しながらトリエチルアミン（０．４５ｍＬ，３．２１ｍｍｏｌ）、パルミトイルクロライド（０．４９ｍＬ，１．６０ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ８：１）で精製し、白色粉末の（２Ｒ，３Ｓ）−３’，４’，５，７−

ｌ，７２％収率）を得た。Production Example 7: Production method of Compound 5 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-palmitoate} Production in the same manner as the synthesis of Compound 1 described in Production Example 3. Obtained in Example 1 (2R, 3S

. 07 mmol) in dichloromethane (50 mL) with ice cooling, triethylamine (0.45 mL, 3.21 mmol), palmitoyl chloride (0.49 mL, 1.60 mmol) and N, N-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 8: 1) to give (2R, 3S) -3 ′, 4 ′, 5,7-

l, 72% yield).

[Α] _D ²⁴ = + 7.4 (c0.74, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.51-7.25 (20H, m), 6.97 (1H, brs), 6.88 (2H, brs), 6.26 (1H, d , J = 1H, d, J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.32 (1H, dt, J = 5.4, 6.8 Hz), 5. 13 (2H, s), 5.10 (2H, s), 5.00 (4H, s), 4.98 (1H, d, J = 6.8 Hz), 2.89 (1H, dd, J = 5.4, 16.8 Hz), 2.70 (1H, dd, J = 6.8, 16.8 Hz), 2.22-2.09 (2H, m), 1.48-1.42 (2H , M), 1.35-1.10 (24H, m), 0.88 (3H, t, J = 6.8Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 172.9, 158.9, 157.6, 154.8, 148.9, 148.8, 137.2, 137.0, 136.8, 131.0, 128.6, 128.5, 128.42, 128.40, 128.0, 127.9, 127.7 (x2), 127.5, 127.4 (x2), 127.20, 127.18, 119.9, 114.7, 113.3, 101.4, 94.3, 93.7, 78.3, 71.21, 71.15, 70.1, 69.9, 68.7, 34. 3, 31.9, 29.3 (x3), 29.6 (x3), 29.4, 29.3, 29.2, 28.9, 24.8, 24.0, 22.7, 14. 1;
IR (neat, cm ⁻¹ ) 3065 (w), 3032 (w), 2924 (s), 2853 (s), 1736 (m), 1618 (m), 1593 (m), 1514 (m FAB-MS ( m / z) 912 (7.9), 911 ([M + Na] ⁺ , 11), 891 (12), 890 ([M + H] ⁺ , 19), 634 (18), 633 (58), 632 (75) , 631 (23), 321 (27), 319 (100);), 1377 (m), 1265 (m), 1146 (s), 1028 (m), 910 (w), 850 (w), 810 ( w), 735 (m);
FAB-HRMS calculated C ₅₉ H ₆₉ O ₇ [M + H] ⁺ , 889.55043; found: 889.5082.

ラバン−３−パルミトエート（４００ｍｇ，０．４５ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，２２ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、白色粉末の化合物５｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−パルミトエート｝（１８８ｍｇ，０．３６ｍｍｏｌ，７９％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-palmitoate (400 mg, 0.45 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water) and white powdered compound 5 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-palmiate} (188 mg, 0.36 mmol, 79% yield) was obtained.

[Α] _D ²⁵ = + 6.1 (c1.14, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 6.81 (1H, d, J = 1.7 Hz), 6.74 (1H, d, J = 8.3 Hz) 6.64 (1H, dd, J = 1.7, 8.3 Hz), 6.00 (1H, d, J = 2.2 Hz), 5.88 (1H, d, J = 2.2 Hz), 5.18 (1H, ddd, J = 5.4, 6.5, 6.6 Hz), 4.86 (1H, d, J = 6.6 Hz), 2.75 (1H, dd, J = 5. 4, 16.4 Hz), 2.55 (1 H, dd, J = 6.5, 16.4 Hz), 2.21-2.13 (2 H, m), 1.44-1.37 (2 H, m ), 1.30-1.10 (24H, m), 0.81 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 173.4, 157.5, 156.9, 155.7, 145.6, 145.5, 130.4, 118 7, 115.6, 114.2, 98.7, 96.1, 95.0, 78.5, 69.8, 34.5, 32.3, 30.4-29.2 (Cx10), 25.3, 24.3, 23.0, 14.1;
FAB-MS (m / z) 552 (10), 551 ([M + Na] ⁺ , 30), 550 (6.3), 530 (3.8), 529 ([M + H] ⁺ , 11), 275 (12 ), 274 (62), 273 (100);
FAB-HRMS calculated C ₃₁ H ₄₅ O ₇ [M + H] ⁺ , 59.3165; found: 529.3143.

．７７ｍｍｏｌ）のジクロロメタン溶液（５０ｍＬ）に、氷冷しながらトリエチルアミン（０．３２ｍＬ，２．３１ｍｍｏｌ）、ステアロイルクロライド（０．３９ｍＬ，１．１６ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ７：１）で精製し、白色粉末の（２Ｒ，３Ｓ）−３’，４’，５，７−

ｌ，１００％収率）を得た。Production Example 8: Production method of compound 6 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-stearate} Production in the same manner as the synthesis of compound 1 described in Production Example 3. Obtained in Example 1 (2R, 3S

. 77 mmol) in dichloromethane (50 mL) with ice cooling, triethylamine (0.32 mL, 2.31 mmol), stearoyl chloride (0.39 mL, 1.16 mmol) and N, N-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 7: 1) to give (2R, 3S) -3 ′, 4 ′, 5,7-

l, 100% yield).

[Α] _D ²⁵ = + 6.7 (c2.70, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.25 (20H, m), 6.97 (1H, br s), 6.88 (2H, br s), 6.26 (1H, d , J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.32 (1H, ddd, J = 5.4, 6.6, 6.8 Hz), 5.13 ( 2H, s), 5.10 (2H, s), 5.00 (4H, s), 4.98 (1H, d, J = 6.6 Hz), 2.89 (1H, dd, J = 5. 4, 16.9 Hz), 2.70 (1H, dd, J = 6.8, 16.9 Hz), 2.22-2.09 (2H, m), 1.48-1.42 (2H, m ^{), 1.30-1.10 (28H, m)} , 0.88 (3H, t, J = 6.8Hz); 13 C-NMR (100MHz, CDCl 3) 172.9,158 9, 158.6, 154.8, 148.9, 148.8, 137.2, 137.0, 136.8, 130.0, 128.54, 128.48, 128.41, 128.40 ( x2), 127.94, 127.85, 127.7 (x2), 127.5, 127.4, 127.2 (x2), 119.9, 114.7, 113.3, 101.3, 94 3, 93.7, 78.3, 71.2, 71.1, 70.0, 69.9, 68.7, 34.2, 31.9, 29.7 (x8), 29.4 29.3, 29.2, 28.9, 24.8, 24.0, 22.7, 14.1;
IR (neat, cm ⁻¹ ) 3065 (w), 3032 (w), 2924 (s), 2853 (s), 2363 (w), 1736 (m), 1618 (m), 1593 (m), 1500 ( m), 1379 (m), 1265 (m), 1145 (s), 1028 (m), 910 (w), 850 (w), 810 (w), 735 (m);
FAB-MS (m / z) 941 (1.2), 940 ([M + Na] ⁺ , 1.5), 919 (4.4), 918 ([M + H] ⁺ , 7.0), 634 (22) 633 (51), 632 (50), 631 (23), 543 (19), 542 (32), 541 (62), 540 (18), 321 (24), 320 (100);
FAB-HRMS calcd ^{_{C 61 H 73 O 7 [M}} + H] +, 917.5356; Found: 917.5388.

ラバン−３−ステアロエート（３８５ｍｇ，０．４２ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，２２ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、白色粉末の化合物６｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ステアロエート｝（２１４ｍｇ，０．３８ｍｍｏｌ，９０％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-stearoate (385 mg, 0.42 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water) and white powdered compound 6 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-stearoate} (214 mg, 0.38 mmol, 90% yield) was obtained.

[Α] _D ²⁴ = + 4.0 (c1.18, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 6.82 (1H, d, J = 1.7 Hz), 6.75 (1H, d, J = 8.3 Hz) 6.65 (1H, dd, J = 1.7, 8.3 Hz), 6.01 (1H, d, J = 2.2 Hz), 5.89 (1H, d, J = 2.2 Hz), 5.19 (1H, ddd, J = 5.3, 6.5, 6.8 Hz), 4.87 (1H, d, J = 6.8 Hz), 2.76 (1H, dd, J = 5. 3, 16.3 Hz), 2.56 (1H, dd, J = 6.5, 16.3 Hz), 2.21-2.13 (2H, m), 1.45-1.38 (2H, m ), 1.30-1.10 (28H, m), 0.82 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 173.3, 157.7, 157.0, 155.8, 145.65, 145.61, 130.5, 118 8, 115.6, 114.3, 98.8, 96.1, 95.0, 78.6, 69.8, 34.6, 32.3, 30.4-29.2 (Cx12), 25.3, 24.4, 23.1, 14.2;
FAB-MS (m / z) 580 (15), 579 ([M + Na] ⁺ , 36), 578 (8.4), 558 (4.3), 557 ([M + H] ⁺ , 11), 275 (15 ), 274 (66), 273 (100), 272 (41);
FAB-HRMS calcd ^{_{C 33 H 49 O 7 [M}} + H] +, 557.3478; Found: 557.3441.

．０６ｍｍｏｌ）のジクロロメタン溶液（５０ｍＬ）に、氷冷しながらトリエチルアミン（０．３０ｍＬ，２．１２ｍｍｏｌ）、ラウロイルクロライド（０．３７ｍＬ，１．６０ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル６：１）で精製し、白色粉末の（２Ｒ，３Ｒ）−３’，４’，５，

ｌ，７６％収率）を得た。Production Example 9: Production method of Compound 7 {(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-lauroate} Production in the same manner as the synthesis of Compound 1 described in Production Example 3. Obtained in Example 2 (2R, 3R

. (06 mmol) in dichloromethane (50 mL) with ice cooling, triethylamine (0.30 mL, 2.12 mmol), lauroyl chloride (0.37 mL, 1.60 mmol), and N, N-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 6: 1) to give (2R, 3R) -3 ′, 4 ′, 5,

1, 76% yield).

[Α] _D ²³ = −19.5 (c0.94, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.47-7.28 (20H, m), 7.11 (1H, d, J = 1.7 Hz), 6.96 (1H, dd, J = 1. 7, 8.3 Hz), 6.92 (1 H, d, J = 8.3 Hz), 6.28 (1 H, d, J = 2.2 Hz), 6.27 (1 H, d, J = 2.2 Hz) ), 5.45-5.41 (1H, m), 5.17 (1H, d, J = 12.0 Hz), 5.15 (2H, s), 5.14 (1H, d, J = 12) .0Hz), 5.02 (4H, s), 4.99 (1H, br s), 3.02 (1H, dd, J = 4.6, 18.1 Hz), 2.95 (1H, dd, J = 2.0, 18.1 Hz), 2.19-2.07 (2H, m), 1.45-1.37 (2H, m), 1.32-1.10 (16H, m), 0.86 ( 3H, t, J = 5.6 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 173.1, 158.7, 157.9, 155.5, 148.9, 148.7, 137.2, 136.9, 131.1, 128.6 127.1 (Cx14), 119.7, 114.7, 113.6, 100.8, 94.6, 93.8, 77.2, 71, 4, 71.3, 70.1, 69.9 67.5, 34.2, 31.9, 29.62, 29.60, 29.4, 29.3, 29.26, 28.98, 26.0, 24.8, 22.7, 14 .1;
IR (neat, cm ⁻¹ ) 3065 (m), 3034 (m), 2924 (s), 2855 (s), 2361 (w), 2338 (w), 1950 (w), 1871 (w), 1819 ( w), 1782 (s), 1618 (s), 1593 (s), 1518 (s), 1454 (s), 1379 (s), 1269 (s), 1217 (s), 1184 (s), 1152 ( s), 1115 (s), 1020 (s), 945 (w), 810 (m), 735 (s);
FAB-MS (m / z) 856 (11), 855 ([M + Na] ⁺ , 17), 834 (3.6), 833 ([M + H] ⁺ , 7.5), 633 (21), 632 (28 ), 610 (54), 609 (100);
FAB-HRMS calcd ^{_{C 55 H 61 O 7 [M}} + H] +, 833.4417; Found: 833.4448.

ラバン−３−ラウロエート（１２０ｍｇ，０．１４ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，１１ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、無色アモルファスの化合物７｛（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ラウロエート｝（４１ｍｇ，０．０８７ｍｍｏｌ，６２％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-lauroate (120 mg, 0.14 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 11 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water) and colorless amorphous compound 7 {(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-lauroate} (41 mg, 0.087 mmol, 62% yield) was obtained.

[Α] _D ²⁴ = −54.0 (c0.58, EtOH);
¹ H-NMR (400 MHz, CDCl ₃ ) 6.91 (1H, br s), 6.73 (2H, br s), 5.94 (1H, d, J = 2.4 Hz), 5.91 (1H , D, J = 2.4 Hz), 5.33-5.32 (1H, m), 4.93 (1H, brs), 2.90 (1H, dd, J = 4.7, 17.6 Hz). ), 2.78 (1H, d, J = 17.6 Hz), 2.19-2.14 (2H, m), 1.44-1.39 (2H, m), 1.30-1.09. (16H, m), 0.88 (3H, t, J = 6.6 Hz); ¹³ C-NMR (100 MHz, CDCl ₃ ) 175.0, 157.83, 157.79, 157.1, 145.99 , 145.96, 131.3, 119.0, 115.9, 114.9, 99.1, 96.5, 95.8, 78.2. 69.9, 35.2, 33.1, 30.72, 30.70, 30.51, 30.47, 30.3, 29.9, 26.6, 26.0, 23.7, 14 .4;
FAB-MS (m / z) 496 (5.5), 495 ([M + Na] ⁺ , 17), 494 (5.8), 474 (6.3), 473 ([M + H] ⁺ , 20), 275 (13), 274 (55), 273 (100), 272 (22);
FAB-HRMS calculated C ₂₇ H ₃₇ O ₇ [M + H] ⁺ , 473.2539; found: 473.2542.

．７７ｍｍｏｌ）のジクロロメタン溶液（４０ｍＬ）に、氷冷しながらトリエチルアミン（０．３２ｍＬ，２．３１ｍｍｏｌ）、ミリストイルクロライド（０．３１ｍＬ，１．１６ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ７：１）で精製し、白色粉末の（２Ｒ，３Ｒ）−３’，４’，５，７−

ｌ，５４％収率）を得た。Production Example 10: Production method of compound 8 {(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-myristoate} Obtained in Example 2 (2R, 3R

. 77 mmol) in dichloromethane (40 mL) with ice cooling, triethylamine (0.32 mL, 2.31 mmol), myristoyl chloride (0.31 mL, 1.16 mmol) and N, N-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 7: 1) to give (2R, 3R) -3 ′, 4 ′, 5,7-

l, 54% yield).

[Α] _D ²³ = −20.4 (c 0.72, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.47-7.30 (20H, m), 7.11 (1H, d, J = 1.7 Hz), 6.96 (1H, dd, J = 1. 7, 8.3 Hz), 6.92 (1 H, d, J = 8.3 Hz), 5.46-5.41 (1 H, m), 5.17 (1 H, d, J = 11.9 Hz), 5.15 (2H, s), 5.13 (1H, d, J = 11.9 Hz), 5.12 (4H, s), 4.99 (1H, br s), 3.02 (1H, dd) , J = 4.6, 16.1 Hz), 2.94 (1H, d, J = 16.1 Hz), 2.19-2.05 (2H, m), 1.42-1.38 (2H, m), 1.29-1.10 (20H, m), 0.88 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 173.1, 158.7, 157.9, 155.4, 148.8, 148.7, 137.2 (x2), 136.9, 136.8, 131 1,128.6,128.5,128.4 (x2), 128.0,127.9,127.8,127.7,127.5,127.4,127.2,127.1 119.7, 114.7, 113.6, 100.8, 94.6, 93.8, 77.2, 71.4, 71.2, 70.1, 69.9, 67.5, 34. 2, 31.9, 29.7, 29.63, 29.61 (x2), 29.4, 29.3, 29.2, 29.0, 25.9, 24.8, 22.7, 14 .1;
IR (neat, cm ⁻¹ ) 2924 (s), 2853 (s), 1732 (s), 1653 (s), 1558 (s), 1456 (s), 1385 (s), 1339 (m), 1151 ( s), 1115 (s), 1078 (m), 1028 (m), 902 (w), 810 (w), 733 (m);
FAB-MS (m / z) 885 (9.4), 884 (24), 883 ([M + Na] ⁺ , 36), 862 (14), 861 ([M + H] ⁺ , 29), 860 (7.9) ), 695 (12), 694 (44), 693 (100);
FAB-HRMS calcd ^{_{C 57 H 65 O 7 [M}} + H] +, 861.4730; Found: 861.4730.

ラバン−３−ミリストエート（３１２ｍｇ，０．３６ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，２２ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、無色アモルファスの化合物８｛（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ミリストエート｝（１５３ｍｇ，０．３１ｍｍｏｌ，８５％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-myristoate (312 mg, 0.36 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL), and the mixture was charged with hydrogen for 12 hours. Stir to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water) and colorless amorphous compound 8 {(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-myristate} (153 mg, 0.31 mmol, 85% yield) was obtained.

[Α] _D ²⁵ = −38.3 (c 0.38, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 6.94 (1H, brs), 6.76 (2H, brs), 6.02 (1H, d, J = 2.2 Hz), 5.91 (1 H, d, J = 2.2 Hz), 5.33 (1 H, br s), 4.96 (1 H, br s), 2.92 (1 H, dd, J = 4.3, 17.3 Hz), 2.73 (1H, d, J = 17.3 Hz), 2.13-2.10 (2H, m), 1.40-1.36 (2H, m) , 1.25-1.08 (20H, m), 0.82 (3H, t, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 173.5, 157.4, 157.3, 156.5, 145.3 (x2), 130.7, 118.6, 115.3, 114.5, 8.4, 96.2, 95.3, 77.5, 68.9, 34.5, 32.3, 30.4-29.1 (Cx8), 26.2, 25.3, 23.0 , 14.2;
FAB-MS (m / z) 524 (15), 523 ([M + Na] ⁺ , 30), 522 (6.8), 502 (6.0), 501 ([M + H] ⁺ , 14), 275 (28 ), 274 (90), 273 (100), 272 (43);
FAB-HRMS calculated C ₂₉ H ₄₁ O ₇ [M + H] ⁺ , 501.2852; found: 501.2861.

．７７ｍｍｏｌ）のジクロロメタン溶液（４０ｍＬ）に、氷冷しながらトリエチルアミン（０．３２ｍＬ，２．３１ｍｍｏｌ）、パルミトイルクロライド（０．３５ｍＬ，１．１６ｍｍｏｌ）、及び、Ｎ，７−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ６：１）で精製し、白色粉末の（２Ｒ，３Ｒ）−３’，４’，５，７−

ｌ，７１％収率）を得た。Production Example 11 Production Method of Compound 9 {(2R, 3R) -3 ′, 4 ′, 5,7-Tetrahydroxyflavan-3-palmitoate} Production in the same manner as the synthesis of Compound 1 described in Production Example 3. Obtained in Example 2 (2R, 3R

. 77 mmol) in dichloromethane (40 mL) with ice cooling, triethylamine (0.32 mL, 2.31 mmol), palmitoyl chloride (0.35 mL, 1.16 mmol), and N, 7-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 6: 1) to give (2R, 3R) -3 ′, 4 ′, 5,7-

l, 71% yield).

[Α] _D ²⁵ = −16.1 (c1.34, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.46-7.27 (20 H, m), 7.12 (1 H, d, J = 1.7 Hz), 6.95 (1 H, dd, J = 1. 7, 8.3 Hz), 6.91 (1 H, d, J = 8.3 Hz), 6.29 (1 H, d, J = 2.2 Hz), 6.27 (1 H, d, J = 2.2 Hz) ), 5.48-5.41 (1H, m), 5.17 (1H, d, J = 12.2 Hz), 5.14 (2H, s), 5.13 (1H, d, J = 12) .2 Hz), 5.01 (4 H, s), 4.98 (1 H, br s), 3.01 (1 H, dd, J = 4.4, 17.8 Hz), 2.95 (1 H, dd, J = 2.2, 17.8 Hz), 2.19-2.06 (2H, m), 1.45-1.37 (2H, m), 1.35-1.05 (24H, m), 0.88 ( 3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 171.1, 158.7, 157.9, 155.4, 148.8, 148.7, 137.2, 136.84, 136.82, 131.1, 128.54 (x2), 128.48, 128.39 (x2), 127.9, 127.8, 127.74, 127.70, 127.5, 127.3, 127.2, 127.1, 119.6, 114.6, 113.5, 100.8, 94.6, 93.8, 77.1, 71.4, 71.2, 70.0, 69.8, 67.5, 34. 2, 31.9, 29.64 (x2), 29.60 (x2), 29.6, 29.4, 29.3, 29.2, 28.9, 25.9, 24.8, 22. 7, 21.0, 14.1;
IR (neat, cm ⁻¹ ) 3063 (w), 3034 (w), 2923 (s), 2853 (s), 1948 (w), 1809 (w), 1782 (s), 1618 (s), 1593 ( s), 1520 (s), 1379 (s), 1184 (s), 1151 (s), 1028 (s), 943 (w), 810 (m), 733 (m);
FAB-MS (m / z) 912 (12), 911 ([M + Na] ⁺ , 19), 891 (15), 890 ([M + H] ⁺ , 21), 889 (7.2), 634 (19), 633 (59), 632 (78), 631 (19), 320 (22), 319 (100);
FAB-HRMS calcd ^{_{C 59 H 69 O 7 [M}} + H] +, 889.5043; Found: 889.5089.

ラバン−３−パルミトエート（４２０ｍｇ，０．４７ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，２２ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理

ー水）で精製し、無色アモルファスの化合物９｛（２Ｒ，３Ｒ）−３’、４’、５，７−テトラヒドロキシフラバン−３−パルミトエート｝（１６５ｍｇ，０．３１ｍｍｏｌ，６６％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-palmitoate (420 mg, 0.47 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. Post-processing

-Water) to give colorless amorphous compound 9 {(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-palmitoate} (165 mg, 0.31 mmol, 66% yield). Obtained.

[Α] _D ²⁵ = −42.0 (c1.22, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 6.94 (1H, brs), 6.76 (2H, brs), 6.01 (1H, d, J = 2.2 Hz), 5.91 (1H, d, J = 2.2 Hz), 5.32-5.31 (1H, m), 4.95 (1H, br s), 2.91 (1H, dd, J = 4.9, 17.5 Hz), 2.72 (1H, dd, J = 2.0, 17.5 Hz), 2.16-2.10 (2H, m), 1.41-1 .34 (2H, m), 1.26-1.10 (24H, m), 0.82 (3H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CD ₃ CO CD ₃ -D ₂ O, 10: 1) 173.4, 157.4, 157.2, 156.5, 145.3 (x2), 130.7, 118. 6, 115.3, 114.5, 98.4, 96.2, 95.3, 77.5, 68.9, 34.5, 32.3, 30.4-29.2 (Cx10), 26. .2, 25.3, 23.0, 14.2;
FAB-MS (m / z) 552 (11), 551 ([M + Na] ⁺ , 29), 550 (6.1), 530 (4.4), 529 ([M + H] ⁺ , 11), 275 (15 ), 274 (77), 273 (100), 272 (44);
FAB-HRMS calculated C ₃₁ H ₄₅ O ₇ [M + H] ⁺ , 59.3165; found: 539.3167.

．７７ｍｍｏｌ）のジクロロメタン溶液（４０ｍＬ）に、氷冷しながらトリエチルアミン（０．３２ｍＬ，２．３１ｍｍｏｌ）、ステアロイルクロライド（０．３９ｍＬ，１．１６ｍｍｏｌ）、及び、Ｎ，Ｎ−ジメチルアミノピリジン（５ｍｇ）を加え反応させ、後処理した後、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル ６：１）で精製し、白色粉末の（２Ｒ，３Ｒ）−３’，４’，５，７−

ｌ，８０％収率）を得た。Production Example 12: Production method of compound 10 {(2R, 3R) -3 ', 4', 5,7-tetrahydroxyflavan-3-stearate} Production in the same manner as the synthesis of compound 1 described in Production Example 3. Obtained in Example 2 (2R, 3R

. (77 mmol) in dichloromethane (40 mL) with ice cooling, triethylamine (0.32 mL, 2.31 mmol), stearoyl chloride (0.39 mL, 1.16 mmol), and N, N-dimethylaminopyridine (5 mg). After addition, reaction, and post-treatment, the product was purified by silica gel column chromatography (n-hexane: ethyl acetate 6: 1) to give (2R, 3R) -3 ′, 4 ′, 5,7-

l, 80% yield).

[Α] _D ²⁴ = −19.8 (C1.76, CHCl ₃ );
¹ H-NMR (400 MHz, CDCl ₃ ) 7.46-7.29 (20H, m), 7.11 (1H, d, J = 1.7 Hz), 6.95 (1H, dd, J = 1. 7, 8.3 Hz), 6.91 (1 H, d, J = 8.3 Hz), 6.28 (1 H, d, J = 2.2 Hz), 6.27 (1 H, d, J = 2.2 Hz) ), 5.45-5.41 (1H, m), 5.17 (1H, d, J = 11.9 Hz), 5.14 (2H, s), 5.12 (1H, d, J = 11) .9 Hz), 5.00 (4 H, s), 4.98 (1 H, br s), 3.01 (1 H, dd, J = 4.4, 17.3 Hz), 2.94 (1 H, d, J = 4.4, 17.3 Hz), 2.17-2.04 (2H, m), 1.42-1.39 (2H, m), 1.35-1.10 (28H, m), 0.88 (3 H, t, J = 6.8 Hz);
¹³ C-NMR (100 MHz, CDCl ₃ ) 173.1, 158.7, 157.9, 155.4, 148.8, 148.7, 137.2, 136.9, 136.8, 131.1, 128.6, 128.5, 128.4 (x3), 128.0, 127.9, 127.8, 127.7, 127.5, 127.4, 127.2, 127.1, 119.6 114.7,113.6,100.8,94.6,93.8,77.1,71.4,71.2,70.1,69.9,67.5,34.2,31 .9, 29.7-29.6 (Cx8), 29.4, 29.3, 29.2, 29.0, 25.9, 24.8, 22.7, 14.1;
IR (neat, cm ⁻¹ ) 3090 (w), 3065 (w), 3034 (w), 2923 (s), 2853 (m), 1950 (w), 1732 (s), 1620 (s), 1593 ( s), 1500 (s), 1379 (s), 1271 (m), 1151 (s), 1115 (s), 1028 (m), 947 (w), 903 (w), 810 (m);
FAB-MS (m / z) 941 (3.2), 940 ([M + Na] ⁺ , 5.3), 919 (12), 918 ([M + H] ⁺ , 17), 917 (7.8), 633 (85), 632 (100):
FAB-HRMS calcd ^{_{C 61 H 73 O 7 [M}} + H] +, 917.5356; Found: 917.5403.

ラバン−３−ステアロエート（１３０ｍｇ，０．１４ｍｍｏｌ）のテトラヒドロフラン−メタノール−水（２０：１：１，１１ｍＬ）溶液に、２０％Ｐｄ（ＯＨ）_２／Ｃ（５ｍｇ）を加え、水素雰囲気下１２時間攪拌しベンジル基を脱保護した。後処理後、Ｃｏｓｍｏｓｉｌ ７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、白色粉末の化合物１０｛（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ステアロエート｝（５０ｍｇ，０．０９０ｍｍｏｌ，６４％収率）を得た。

20% Pd (OH) ₂ / C (5 mg) was added to a solution of Laban-3-stearoate (130 mg, 0.14 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 11 mL), and the mixture was added under a hydrogen atmosphere for 12 hours. Stir to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil 75C-18OPN column chromatography (methanol-water) and white powdered compound 10 {(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-stearate} (50 mg, 0.090 mmol, 64% yield) was obtained.

[Α] _D ²⁵ = −xx (c1.22, CH ₃ CO CH ₃ );
¹ H-NMR (400 MHz, CD ₃ OD) 6.92 (1H, s), 6.74 (2H, s), 5.94 (1H, d, J = 2.2 Hz), 5.91 (1H, d, J = 2.2 Hz), 5.33 (1H, dd, J = 2.0, 4.6 Hz), 4.83 (1H, br s), 2.91 (1H, dd, J = 4. 6,17.5 Hz), 2.78 (1H, dd, J = 2.0, 17.5 Hz), 2.19-2.16 (2H, m), 1.45-1.38 (2H, m ), 1.33-1.10 (28H, m), 0.89 (3H, t, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CD ₃ OD) 175.1, 157.9, 157 8, 157.1, 146.02, 145.99, 131.4, 119.0, 115.9, 114.9, 99.1, 96.5, 95 8, 78.2, 69.9, 35.2, 33.1, 30.8-30.74 (Cx7), 30.72, 30.52, 30.46, 30.3, 29.9, 26 .6, 26.0, 23.7, 14.4;
FAB-MS (m / z) 580 (38), 579 ([M + Na] ⁺ , 100), 578 (23), 558 (12), 557 ([M + H] ⁺ , 29);
FAB-HRMS calcd ^{_{C 33 H 49 O 7 [M}} + H] +, 557.3478; Found: 557.3445.

Test Example 1: DNA synthetase inhibitory activity test with 3-acylated catechins and 3-acylated epicatechins As compounds 1 to 10 obtained in Production Examples 3 to 12 and a control compound (11) The compounds 11 and 12 (see Table 2) obtained by acetylating the 3 ′, 4 ′, 5 and 7 position phenolic hydroxyl groups shown in FIG. Evaluated.

(Test method)
The activity of the compounds 1 to 12 on the DNA synthase group was measured by the following method. Tests were conducted on mammalian DNA synthases α, β and λ as DNA synthases. DNA synthase α is a sample extracted and purified from bovine thymus by a conventional method, DNA synthase β is a rat-derived gene, DNA synthase λ is a human-derived gene, and a conventional gene recombination method is used. The preparations incorporated into Escherichia coli and produced were used.
For the measurement of the inhibitory action of compounds 1 to 12 on these DNA synthases, a general DNA synthase reaction system (edited by the Japanese Biochemical Society, Shinsei Chemistry Laboratory 2, Nucleic Acid IV, Tokyo Kagaku Dojin, pages 63-66) ) Was used. That is, a DNA synthesis reaction is carried out in a system containing [ ³ H] -TTP labeled with a radioisotope, and the radioactivity is used as an index of the amount of product (synthetic DNA chain).

The inhibition rate is as follows: (a) amount of synthetic DNA in the control, (b) amount of synthetic DNA in the presence of the test substance.
(Ab) / a × 100 = inhibition rate (%)
As evaluated. The results obtained are shown in Table 3 as 50% inhibitory concentration (μM).

（結果）
表３に示したように、化合物１〜１２が哺乳類由来のＤＮＡ合成酵素α、βおよびλを阻害し、その中でも、λを最も強く阻害した。また、その阻害活性は、脂肪酸の炭素鎖が長くなるほど強くなり、その傾向は、３−アシル化カテキン類でも、３−アシル化エピカテキン類でも同様であった。化合物１〜１２のうち、アシル基の炭素鎖が１８である化合物６が最も活性が強かった。一方、アセチル基で水酸基を保護した化合物１１，１２は、ＤＮＡ合成酵素を阻害しなかったことから、フェノール性水酸基はＤＮＡ合成酵素阻害活性に必須であることが確認された。また、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバンー３−オール｛（＋）−カテキン｝及び、（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オール｛（−）−エピカテキン｝には阻害活性が見られないことから（データ示さず）、３位に導入した脂肪酸も阻害活性に必須であることがわかる。

(result)
As shown in Table 3, compounds 1 to 12 inhibited mammal-derived DNA synthases α, β and λ, and among them, λ was most strongly inhibited. Moreover, the inhibitory activity became stronger as the carbon chain of the fatty acid became longer, and the tendency was the same for 3-acylated catechins and 3-acylated epicatechins. Among the compounds 1 to 12, the compound 6 in which the carbon chain of the acyl group was 18 had the strongest activity. On the other hand, since the compounds 11 and 12 in which the hydroxyl group was protected with an acetyl group did not inhibit the DNA synthase, it was confirmed that the phenolic hydroxyl group is essential for the DNA synthase inhibitory activity. In addition, (2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-catechin} and (2R, 3R) -3 ′, 4 ′, 5,7- Since tetrahydroxyflavan-3-ol {(−)-epicatechin} has no inhibitory activity (data not shown), it is understood that the fatty acid introduced at the 3-position is also essential for the inhibitory activity.

Test Example 2: DNA synthetase inhibitory activity test with compound 6 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-stearate} (test method)
For the compound 6 into which an acyl group having a carbon chain length of 18 was introduced, the six types of DNA synthases (calf DNA synthase α, rat DNA synthase β, human DNA synthase δ, human DNA synthase ε, The activities of human DNA synthase λ (full length) and human DNA synthase λ (β-like core) were measured by the same method as in Test Example 1.
FIG. 1 shows the inhibitory activity of compound 6 on six types of DNA synthase.

(result)
As shown in FIG. 1, compound 6 comprises six types of DNA synthases (calf DNA synthase α, rat DNA synthase β, human DNA synthase δ, human DNA synthase ε, human DNA synthase λ (full length ) And human DNA synthase λ (β-like core)), and showed the strongest inhibition particularly on human-derived λ type.

Test Example 3: DNA Synthetase Inhibitory Activity Test with Compound 6 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-stearate} (Test Method)
In the test method of Test Example 1, 0 μM, 0.2 μM, 0.4 μM, 0.6 μM, 0.8 μM, and 1 μM of Compound 6 into which an acyl group having a carbon chain length of 18 was introduced were added. The concentration-dependent inhibitory effect on λ (full length) was examined.
The results are shown in FIG.

(result)
From these results, compound 6 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-stearate} into which an acyl group having a carbon chain length of 18 was introduced was dependent on the concentration of DNA synthase λ. It was found to inhibit.

  It is a figure which shows the result of having investigated the inhibitory effect with respect to the mammalian DNA synthetase of the compound 6. FIG.   It is a graph which shows the result of having investigated the concentration-dependent inhibitory action with respect to DNA synthetase (lambda) (full length) of the compound 6. FIG.

Claims (4)

A DNA synthase inhibitor comprising a compound represented by the following formula (1) as an active ingredient.

(In the formula, R ₁ , R ₂ , R ₃ , R ₅ and R ₆ each independently represent a hydrogen atom or a hydroxyl group, and R ₄ is a linear or branched alkyl group. (Excluding the galloyl group among the acyl groups at the 3-position), and the steric configurations at the 2-position and the 3-position of the benzopyran ring may be either R-configuration or S-configuration, respectively. Flavan-3-ols. A DNA synthase inhibitor comprising a compound represented by the following formula (2) as an active ingredient.

(In the formula, R ₁ , R ₂ and R ₃ each independently represents a hydrogen atom or a hydroxyl group, and R ₄ represents a linear or branched alkyl group (the acyl group at the 3-position) Among them, the steric configurations at the 2-position and 3-position of the benzopyran ring may be either the R configuration or the S configuration), and 3-acylated flavan-3-ols. A DNA synthase inhibitor comprising a compound represented by the following formula (3) as an active ingredient.

(In the formula, R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom or a hydroxyl group, and the steric configurations at the 2- and 3-positions of the benzopyran ring are either R configuration or S configuration, respectively. 3-acylated flavan-3-ols represented by:   4. The DNA synthase inhibitor according to claim 1, wherein the DNA synthase is a mammal-derived DNA synthase γ.

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