JP2008115079A

JP2008115079A - Anti-inflammatory agent

Info

Publication number: JP2008115079A
Application number: JP2005069038A
Authority: JP
Inventors: Noriyuki Nakajima; 範行中島; Yoshiyuki Mizushina; 善之水品; Akiko Saito; 安貴子齊藤
Original assignee: Mitsui Norin Co Ltd
Current assignee: Mitsui Norin Co Ltd
Priority date: 2005-03-11
Filing date: 2005-03-11
Publication date: 2008-05-22
Also published as: WO2006095864A1

Abstract

<P>PROBLEM TO BE SOLVED: To provide an anti-inflammatory agent comprising a 3-acylated flavan-3-ol compound or a pharmaceutically acceptable salt thereof as an active ingredient. <P>SOLUTION: The 3-acylated flavan-3-ol compound is newly provided as a substance having an anti-inflammatory action. It is found that the 3-acylated flavan-3-ol compound has its stronger activity as the carbon chain length of an acyl group increases, and accordingly, is applicable to foods and medicines as an anti-inflammatory agent. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は、３−アシル化フラバン−３−オール化合物の新規な医薬用途に関する。 The present invention relates to a novel pharmaceutical use of 3-acylated flavan-3-ol compounds.

近年、アトピー性皮膚炎、化学物質過敏症、花粉症など、炎症性疾患の患者数が増大し、社会問題になっている。従来、皮膚炎などの炎症性疾患にはステロイド系の薬剤が多用され、一定の治療効果が認められてきた。しかし、最近ではむしろ、ステロイド剤の過剰使用による副作用が問題とされるようになってきている。また、非ステロイド系の抗炎症剤であるアスピリンや、インドメタシンは、多量に服用することにより、急性の胃潰瘍を発症するなど深刻な副作用を有している。
一方、フラバン−３−オール化合物は、植物中に広く存在し、その中には有用な特性を有する化合物が数多く含まれている。例えば、３位の水酸基にアシル基を導入したフラバン−３−オール化合物の生物活性、及び、その利用に関しては、例えば、下記の非特許文献１において、３位の水酸基に炭素鎖長３〜１８のアシル基を導入した（２Ｒ，３Ｒ）−３’，４’，５’，５，７−ペンタヒドロキシフラバン−３−オール｛（−）−エピガロカテキン、ＥＧＣ｝の抗腫瘍活性が評価され、炭素鎖長８〜１０のアシル基を導入した誘導体が、（２Ｒ，３Ｒ）−３’，４’，５’，５，７−ペンタヒドロキシフラバン−３−ガレート｛（−）−エピガロカテキンガレート、ＥＧＣｇ｝よりも強い活性を持つことが見出されている。また、３位の水酸基にアシル基を導入したフラバン−３−オール化合物の、免疫調節特性を有する化合物としての用途についての特許文献が存在する（下記特許文献１参照）。さらに、３位の水酸基にアシル基を導入したカテキン類が油脂類に対して優れた抗酸化性を有することが知られている（下記特許文献２参照）。しかしながら、３位の水酸基にアシル基を導入したフラバン−３−オール化合物についての抗炎症作用に関する開示は、これまでなされていない。
特開昭５６−１５４４１５号公報特開平６−２７９４３０公報 Bioorganic & Medicinal Chemistry Letters, 2000, 10, 1673-1675頁 In recent years, the number of patients with inflammatory diseases such as atopic dermatitis, chemical hypersensitivity, and hay fever has increased and has become a social problem. Conventionally, steroidal drugs have been frequently used for inflammatory diseases such as dermatitis, and a certain therapeutic effect has been recognized. Recently, however, side effects caused by excessive use of steroids have become a problem. Aspirin and indomethacin, which are non-steroidal anti-inflammatory agents, have serious side effects such as acute gastric ulcers when taken in large amounts.
On the other hand, flavan-3-ol compounds are widely present in plants, and many of them have useful properties. For example, regarding the biological activity of a flavan-3-ol compound in which an acyl group is introduced into the hydroxyl group at the 3-position and the use thereof, for example, in the following Non-Patent Document 1, the carbon chain length of 3-18 is added to the hydroxyl group at the 3-position. Anti-tumor activity of (2R, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(−)-epigallocatechin, EGC} introduced with And a derivative into which an acyl group having a carbon chain length of 8 to 10 is introduced is (2R, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-gallate {(−)-epigallocatechin It has been found to have stronger activity than gallate, EGCg}. Further, there is a patent document regarding the use of a flavan-3-ol compound having an acyl group introduced into the hydroxyl group at the 3-position as a compound having immunomodulatory properties (see Patent Document 1 below). Furthermore, it is known that catechins in which an acyl group is introduced into the hydroxyl group at the 3-position have excellent antioxidant properties against fats and oils (see Patent Document 2 below). However, there has been no disclosure regarding anti-inflammatory action of flavan-3-ol compounds in which an acyl group is introduced into the hydroxyl group at the 3-position.
JP-A-56-154415 JP-A-6-279430 Bioorganic & Medicinal Chemistry Letters, 2000, 10, 1673-1675

本発明の目的は、安全性が高く、かつ、抗炎症作用において優れている物質を見出し、新規な抗炎症剤を提供することにある。 An object of the present invention is to find a substance having high safety and excellent anti-inflammatory action, and to provide a novel anti-inflammatory agent.

本発明者らは上記目的を達成すべく鋭意検討を重ねた結果、３位の水酸基にアシル基を導入したフラバン−３−オール化合物が強い抗炎症作用を有することを初めて見出し、本発明を完成するに至った。 As a result of intensive studies to achieve the above object, the present inventors have found for the first time that a flavan-3-ol compound in which an acyl group is introduced into the hydroxyl group at the 3-position has a strong anti-inflammatory action, thereby completing the present invention. It came to do.

すなわち、請求項１記載の本発明は、下記の一般式（１）により表される３−アシル化フラバン−３−オール化合物またはその薬学的に許容される塩を有効成分とする抗炎症剤である。 That is, the present invention according to claim 1 is an anti-inflammatory agent comprising a 3-acylated flavan-3-ol compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. is there.

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁵、Ｒ⁶は、それぞれ独立して、水素原子、水酸基、低級アルコキシ基、低級アシルオキシ基を表し、Ｒ⁴は、直鎖もしくは分岐状のアルキル基を表す） (Wherein R ¹ , R ² , R ³ , R ⁵ and R ⁶ each independently represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower acyloxy group, and R ⁴ represents a linear or branched group. Represents an alkyl group)

請求項２記載の本発明は、請求項１記載の抗炎症剤において、有効成分が下記の一般式（２）により表される３−アシル化フラバン−３−オール化合物またはその薬学的に許容される塩である。 The present invention according to claim 2 is the anti-inflammatory agent according to claim 1, wherein the active ingredient is a 3-acylated flavan-3-ol compound represented by the following general formula (2) or a pharmaceutically acceptable product thereof. Salt.

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴は前記の通り） (Wherein R ¹ , R ² , R ³ and R ⁴ are as described above)

請求項３記載の本発明は、請求項１または２記載の抗炎症剤において、有効成分が下記の一般式（３）により表される３−アシル化フラバン−３−オール化合物またはその薬学的に許容される塩である。 The present invention according to claim 3 is the anti-inflammatory agent according to claim 1 or 2, wherein the active ingredient is a 3-acylated flavan-3-ol compound represented by the following general formula (3) or a pharmaceutically acceptable salt thereof. It is an acceptable salt.

（式中、Ｒ¹、Ｒ²、Ｒ³は前記の通り。ｎは４〜１６の整数を表す） (In the formula, R ¹ , R ² and R ³ are as described above. N represents an integer of 4 to 16)

本発明の抗炎症剤は、抗炎症作用において優れているだけでなく、安全性においても問題が無い。したがって、医薬品としての使用はもとより、食品、化粧品などに添加するなど、多様な利用が可能である。 The anti-inflammatory agent of the present invention is not only excellent in anti-inflammatory action, but also has no problem in safety. Therefore, various uses such as addition to foods, cosmetics and the like as well as use as pharmaceuticals are possible.

以下、本発明の具体的態様、技術的範囲等について詳しく説明する。 Hereinafter, specific embodiments and technical scope of the present invention will be described in detail.

本発明は、３−アシル化フラバン−３−オール化合物が炎症を抑制しうることに基づくものであり、特に、12-O-tetradecanoylphorbol-13-acetate（ＴＰＡ）によって誘発される慢性炎症に対して好適に効果を奏する。 The present invention is based on the fact that 3-acylated flavan-3-ol compounds can suppress inflammation, and in particular against chronic inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). An effect is suitably produced.

フラバン−３−オール化合物とは、一般的に、式（４）により表される骨格を有する化合物の総称である。 The flavan-3-ol compound is a general term for compounds having a skeleton represented by the formula (4).

本発明の抗炎症剤の有効成分である３−アシル化フラバン−３−オール化合物とは、フラバン−３−オール化合物の３位の水酸基をアシル化した化合物であり、下記の一般式（１）により表される化学構造を有するものである。 The 3-acylated flavan-3-ol compound which is an active ingredient of the anti-inflammatory agent of the present invention is a compound obtained by acylating the hydroxyl group at the 3-position of the flavan-3-ol compound, and is represented by the following general formula (1) It has a chemical structure represented by

ここで、３位の水酸基に導入されるアシル基としては、例えば、アセチル基、プロピオニル基、ブチリル基、バレリル基、ヘキサノイル基、ヘプタノイル基、オクタノイル基、デカノイル基、ラウロイル基、ミリストイル基、パルミトイル基、ステアロイル基などの炭素数が２〜２０のものが挙げられる。これらアシル基は直鎖状であっても分岐状であってもどちらでもよい。本発明の抗炎症活性はアシル基の炭素鎖長が長くなるほど強くなる傾向があるため、炭素数が６〜１８であるヘキサノイル基、ヘプタノイル基、オクタノイル基、デカノイル基、ラウロイル基、ミリストイル基、パルミトイル基、ステアロイル基などを用いることが好ましく、炭素数が１２〜１８であるラウロイル基、ミリストイル基、パルミトイル基、ステアロイル基などを用いることがさらに好ましい。 Here, examples of the acyl group introduced into the hydroxyl group at the 3-position include 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, a myristoyl group, and a palmitoyl group. And those having 2 to 20 carbon atoms such as a stearoyl group. These acyl groups may be linear or branched. Since the anti-inflammatory activity of the present invention tends to increase as the carbon chain length of the acyl group increases, the hexanoyl group, heptanoyl group, octanoyl group, decanoyl group, lauroyl group, myristoyl group, palmitoyl having 6 to 18 carbon atoms It is preferable to use a group, a stearoyl group, or the like, and it is more preferable to use a lauroyl group, myristoyl group, palmitoyl group, stearoyl group or the like having 12 to 18 carbon atoms.

低級アルコキシ基としては、メトキシ基、エトキシ基、１−メチルエトキシ基、１，１−ジメチルエトキシ基、プロポキシ基、２−メチルプロポキシ基等の直鎖もしくは分岐した炭素数が１〜６のものが挙げられる。低級アシルオキシ基としては、アセトキシ基、プロピオニルオキシ基、２，２−ジメチルプロピオニルオキシ基等の直鎖もしくは分岐した炭素数が２〜６のものが挙げられる。 As the lower alkoxy group, linear or branched ones having 1 to 6 carbon atoms such as methoxy group, ethoxy group, 1-methylethoxy group, 1,1-dimethylethoxy group, propoxy group, 2-methylpropoxy group, etc. Can be mentioned. Examples of the lower acyloxy group include those having 2 to 6 straight or branched carbon atoms such as an acetoxy group, a propionyloxy group, and a 2,2-dimethylpropionyloxy group.

一般式（１）で表される３−アシル化フラバン−３−オール化合物は、２位と３位に不斉炭素を有するので、種々の立体異性体や光学異性体が存在し得るが、本発明の抗炎症剤の有効成分としては、そのいずれであってもよい。 Since the 3-acylated flavan-3-ol compound represented by the general formula (1) has asymmetric carbons at the 2-position and the 3-position, various stereoisomers and optical isomers may exist. Any of the active ingredients of the anti-inflammatory agent of the invention may be used.

３位の水酸基がアシル化されるフラバン−３−オール化合物の具体例としては、下記の一般式（５）により表される化学構造を有するものが挙げられる。 Specific examples of the flavan-3-ol compound in which the hydroxyl group at the 3-position is acylated include those having a chemical structure represented by the following general formula (5).

（式中、Ｒ¹、Ｒ²、Ｒ³は前記の通り） (Wherein R ¹ , R ² and R ³ are as described above)

一般式（５）により表される化学構造を有するフラバン−３−オール化合物から合成される３−アシル化フラバン−３−オール化合物の具体例としては、以下のような化合物が挙げられる。 Specific examples of the 3-acylated flavan-3-ol compound synthesized from the flavan-3-ol compound having the chemical structure represented by the general formula (5) include the following compounds.

（２Ｒ，３Ｓ）−５，７−ジヒドロキシフラバン−３−オール｛一般式（５）においてＲ¹、Ｒ²、Ｒ³は水素原子を表し、２位および３位の立体配置は２Ｒ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化−５，７−ジヒドロキシフラバン−３−オール。
（２Ｓ，３Ｒ）−５，７−ジヒドロキシフラバン−３−オール｛一般式（５）においてＲ¹、Ｒ²、Ｒ³は水素原子を表し、２位および３位の立体配置は２Ｓ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化−５，７−ジヒドロキシフラバン−３−オール。
（２Ｓ，３Ｓ）−５，７−ジヒドロキシフラバン−３−オール｛一般式（５）においてＲ¹、Ｒ²、Ｒ³は水素原子を表し、２位および３位の立体配置は２Ｓ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化−５，７−ジヒドロキシフラバン−３−オール。
（２Ｒ，３Ｒ）−５，７−ジヒドロキシフラバン−３−オール｛一般式（５）においてＲ¹、Ｒ²、Ｒ³は水素原子を表し、２位および３位の立体配置は２Ｒ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化−５，７−ジヒドロキシフラバン−３−オール。 (2R, 3S) -5,7-dihydroxyflavan-3-ol {in the general formula (5), R ¹ , R ² and R ³ represent a hydrogen atom, and the configuration at the 2nd and 3rd positions is 2R and 3S. 3-acylated-5,7-dihydroxyflavan-3-ol obtained by acylating the hydroxyl group at the 3-position of
(2S, 3R) -5,7-dihydroxyflavan-3-ol {in the general formula (5), R ¹ , R ² and R ³ represent a hydrogen atom, and the configuration at the 2nd and 3rd positions is 2S and 3R. 3-acylated-5,7-dihydroxyflavan-3-ol obtained by acylating the hydroxyl group at the 3-position of
(2S, 3S) -5,7-dihydroxyflavan-3-ol {in the general formula (5), R ¹ , R ² and R ³ represent a hydrogen atom, and the configuration at the 2nd and 3rd positions is 2S and 3S. 3-acylated-5,7-dihydroxyflavan-3-ol obtained by acylating the hydroxyl group at the 3-position of
(2R, 3R) -5,7-dihydroxyflavan-3-ol {in the general formula (5), R ¹ , R ² and R ³ represent a hydrogen atom, and the configuration at the 2nd and 3rd positions is 2R and 3R. 3-acylated-5,7-dihydroxyflavan-3-ol obtained by acylating the hydroxyl group at the 3-position of

（２Ｒ，３Ｓ）−４’，５，７−トリヒドロキシフラバン−３−オール｛（＋）−アフゼレキン：一般式（５）においてＲ¹、Ｒ³は水素原子を表し、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｒ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化アフゼレキン。
（２Ｓ，３Ｒ）−４’，５，７−トリヒドロキシフラバン−３−オール｛（−）−アフゼレキン：一般式（５）においてＲ¹、Ｒ³は水素原子を表し、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｓ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化アフゼレキン。
（２Ｓ，３Ｓ）−４’，５，７−トリヒドロキシフラバン−３−オール｛（＋）−エピアフゼレキン：一般式（５）においてＲ¹、Ｒ³は水素原子を表し、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｓ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化エピアフゼレキン。
（２Ｒ，３Ｒ）−４’，５，７−トリヒドロキシフラバン−３−オール｛（−）−エピアフゼレキン：一般式（５）においてＲ¹、Ｒ³は水素原子を表し、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｒ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化エピアフゼレキン。 (2R, 3S) -4 ′, 5,7-trihydroxyflavan-3-ol {(+)-afzerequin: In general formula (5), R ¹ and R ³ represent a hydrogen atom, and R ² represents a hydroxyl group. A 3-acylated aphzelekin obtained by acylating the hydroxyl group at the 3-position of the 2- and 3-positions represents 2R and 3S.
(2S, 3R) -4 ′, 5,7-trihydroxyflavan-3-ol {(−)-afzerequin: In general formula (5), R ¹ and R ³ represent a hydrogen atom, and R ² represents a hydroxyl group. A 3-acylated aphzelequinyl obtained by acylating the hydroxyl group at the 3-position of the 2- and 3-positions represents 2S and 3R.
(2S, 3S) -4 ′, 5,7-Trihydroxyflavan-3-ol {(+)-Epiafzerequin: In general formula (5), R ¹ and R ³ represent a hydrogen atom, and R ² represents a hydroxyl group. A 3-acylated epiafzerekin obtained by acylating the hydroxyl group at the 3-position of the 2- and 3-positions represents 2S and 3S.
(2R, 3R) -4 ′, 5,7-Trihydroxyflavan-3-ol {(−)-epiafuzerequin: In general formula (5), R ¹ and R ³ represent a hydrogen atom, and R ² represents a hydroxyl group. A 3-acylated epiafzerekin obtained by acylating the hydroxyl group at the 3-position of the 2- and 3-positions represents 2R and 3R.

（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：一般式（５）においてＲ³は水素原子を表し、Ｒ¹、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｒ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化カテキン。
（２Ｓ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オール｛（−）−カテキン：一般式（５）においてＲ³は水素原子を表し、Ｒ¹、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｓ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化カテキン。
（２Ｓ，３Ｓ）−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：一般式（５）においてＲ³は水素原子を表し、Ｒ¹、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｓ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化エピカテキン。
（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−オール｛（−）−エピカテキン：一般式（５）においてＲ³は水素原子を表し、Ｒ¹、Ｒ²は水酸基を表し、２位および３位の立体配置は２Ｒ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化エピカテキン。 (2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-catechin: In the general formula (5), R ³ represents a hydrogen atom, R ¹ and R ² are 3-acylated catechin in which the hydroxyl group at the 3-position of the 3-position is represented by the hydroxyl group and the configuration at the 2- and 3-positions represents 2R and 3S}.
(2S, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−)-catechin: In the general formula (5), R ³ represents a hydrogen atom, and R ¹ and R ² are 3-acylated catechins in which the hydroxyl group at the 3-position of the hydroxyl group is represented, and the configuration at the 2- and 3-positions represents 2S and 3R}.
(2S, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-epicatechin: In the general formula (5), R ³ represents a hydrogen atom, R ¹ , R ² Represents a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2S and 3S}. 3-Acylated epicatechin obtained by acylating the 3rd hydroxyl group.
(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−)-epicatechin: In the general formula (5), R ³ represents a hydrogen atom, R ¹ , R ² Represents a hydroxyl group, and the configuration at the 2nd and 3rd positions represents 2R and 3R}. 3-Acylated epicatechin obtained by acylating the hydroxyl group at the 3rd position.

（２Ｒ，３Ｓ）−３’，４’，５’，５，７−ペンタヒドロキシフラバン−３−オール｛（＋）−ガロカテキン：一般式（５）においてＲ¹、Ｒ²、Ｒ³は水酸基を表し、２位および３位の立体配置は２Ｒ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化ガロカテキン。
（２Ｓ，３Ｒ）−３’，４’，５’，５，７−ペンタヒドロキシフラバン−３−オール｛（−）−ガロカテキン：一般式（５）においてＲ¹、Ｒ²、Ｒ³は水酸基を示し、２位および３位の立体配置は２Ｓ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化ガロカテキン。
（２Ｓ，３Ｓ）−３’，４’，５’，５，７−ペンタヒドロキシフラバン−３−オール｛（＋）−エピガロカテキン：一般式（５）においてＲ¹、Ｒ²、Ｒ³は水酸基を表し、２位および３位の立体配置は２Ｓ、３Ｓを表す｝の３位の水酸基をアシル化した３−アシル化エピガロカテキン。
（２Ｒ，３Ｒ）−３’，４’，５’，５，７−ペンタヒドロキシフラバン−３−オール｛（−）−エピガロカテキン：一般式（５）においてＲ¹、Ｒ²、Ｒ³は水酸基を表し、２位および３位の立体配置は２Ｒ、３Ｒを表す｝の３位の水酸基をアシル化した３−アシル化エピガロカテキン。 (2R, 3S) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(+)-gallocatechin: In the general formula (5), R ¹ , R ² and R ³ are hydroxyl groups. And the steric configuration at the 2nd and 3rd positions represents 2R and 3S}. 3-Acylated gallocatechin obtained by acylating the hydroxyl group at the 3rd position.
(2S, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(−)-gallocatechin: In the general formula (5), R ¹ , R ² and R ³ represent a hydroxyl group. 3 -acylated gallocatechin obtained by acylating the hydroxyl group at the 3-position of the 2-position and 3-position configuration represents 2S, 3R.
(2S, 3S) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(+)-epigallocatechin: In the general formula (5), R ¹ , R ² and R ³ are A 3-acylated epigallocatechin obtained by acylating the hydroxyl group at the 3-position of the hydroxyl group, the 2- and 3-positions representing 2S and 3S.
(2R, 3R) -3 ′, 4 ′, 5 ′, 5,7-pentahydroxyflavan-3-ol {(−)-epigallocatechin: In the general formula (5), R ¹ , R ² and R ³ are A 3-acylated epigallocatechin obtained by acylating the hydroxyl group at the 3-position of the hydroxyl group, wherein the configuration at the 2- and 3-positions represents 2R and 3R}.

なお、前記の具体例には、一般式（５）により表されるフラバン−３−オール化合物において、５位（Ｒ⁵）と７位（Ｒ⁶）がいずれも水酸基である化合物群しか挙げていないが、本発明はこれに限定されるものではなく、例えば、下記の一般式（６）により表されるフラバン−３−オール化合物のように、５位が水素原子、７位が水酸基である化合物群や、下記の一般式（７）により表されるフラバン−３−オール化合物のように、５位が水酸基、７位が水素原子である化合物群や、下記の一般式（８）により表されるフラバン−３−オール化合物のように、５位と７位がいずれも水素原子である化合物群も含むことができる。 In the above specific examples, in the flavan-3-ol compound represented by the general formula (5), only the compound group in which the 5-position (R ⁵ ) and the 7-position (R ⁶ ) are both hydroxyl groups is listed. However, the present invention is not limited to this. For example, as in the flavan-3-ol compound represented by the following general formula (6), the 5-position is a hydrogen atom and the 7-position is a hydroxyl group. Like the compound group or the flavan-3-ol compound represented by the following general formula (7), the compound group in which the 5-position is a hydroxyl group and the 7-position is a hydrogen atom, or the following general formula (8) A compound group in which both the 5-position and the 7-position are hydrogen atoms can also be included, such as the flavan-3-ol compound.

本発明で有効成分として用いる３−アシル化フラバン−３−オール化合物は、特に、天然に存在する化合物であることが好ましく、例えば、３−アシル化アフゼレキン、３−アシル化エピアフゼレキン、３−アシル化カテキン、３−アシル化エピカテキン、３−アシル化ガロカテキン、３−アシル化エピガロカテキンが挙げられる。さらに好ましくは、３−アシル化カテキン、３−アシル化エピカテキンである。 The 3-acylated flavan-3-ol compound used as an active ingredient in the present invention is particularly preferably a naturally occurring compound, such as 3-acylated aphzelekin, 3-acylated epiafzerekin, 3-acylated. Examples include catechin, 3-acylated epicatechin, 3-acylated gallocatechin, and 3-acylated epigallocatechin. More preferred are 3-acylated catechins and 3-acylated epicatechins.

次に、本発明の抗炎症剤の有効成分である３−アシル化フラバン−３−オール化合物の製造方法について説明する。
まず、原料となるフラバン−３−オール化合物について、その代表的な化合物であるカテキン類は、主にツバキ科に属する茶樹（Ｃａｍｅｌｌｉａｓｉｎｅｎｓｉｓ）から得られる葉、茎、木部、樹皮、根、実、種子のいずれか、あるいはこれらの２種類以上の混合物もしくはそれらの粉砕物から水、熱水、有機溶媒、含水有機溶媒あるいはこれらの混合物などにより抽出することにより得られる。特に、茶生葉あるいはその乾燥物から水、熱水、有機溶媒、含水有機溶媒、これらの混合物などを用いて抽出することにより得られる抽出物自体、或い必要に応じて精製して得られる精製物として得ることが好ましい。カテキン類の精製物に関しては、特公平１−４４２３２号公報、同２−１２４７４号公報、同２−２２７５５号公報、特開平４−２０５８９号公報、同５−２６０９０７号公報、同８−０９１７８号公報などに記載された方法により製造することができ、例えば茶葉を上記の溶媒で抽出して得られた抽出物を、有機溶媒分画や吸着樹脂などを用いて所望の程度に精製することができる。茶以外の植物から抽出する場合も、茶の場合と同様の方法により実施すればよい。また、本発明で使用するカテキン類は市販品を用いてもよく、このような市販品としては、例えば三井農林（株）製「ポリフェノン」、太陽化学（株）製「サンフェノン」、（株）伊藤園製「テアフラン」などを例示することができる。 Next, the manufacturing method of the 3-acylated flavan-3-ol compound which is an active ingredient of the anti-inflammatory agent of this invention is demonstrated.
First, about the flavan-3-ol compound used as a raw material, catechins, which are representative compounds thereof, are leaves, stems, xylem, bark, roots, fruits, mainly obtained from tea trees belonging to the camellia family (Camellia sinensis). 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 its dried product using water, hot water, organic solvent, water-containing organic solvent, a mixture thereof, or the like, or a purification obtained by purification if necessary. It is preferable to obtain as a product. 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”.

このようにして得られたフラバン−３−オール化合物の３位をアシル化する方法は、特に限定されるものではなく、一般的によく知られている方法を用いればよい。例えば、下記の一般式（９）により表される容易に入手可能な（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：一般式（９）においてＲ⁷は水酸基を表し、Ｒ⁸は水素原子を表す｝、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：一般式（９）においてＲ⁷は水素原子を表し、Ｒ⁸は水酸基を表す｝を原料として用い、各種の３−アシル化カテキン及び３−アシル化エピカテキンを以下の方法によって合成することができる。 The method for acylating the 3-position of the thus obtained flavan-3-ol compound is not particularly limited, and a generally well-known method may be used. For example, a readily available (2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(+)-catechin: represented by the following general formula (9): In (9), R ⁷ represents a hydroxyl group, R ⁸ represents a hydrogen atom}, and (2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol {(−) — Epicatechin: In the general formula (9), R ⁷ represents a hydrogen atom and R ⁸ represents a hydroxyl group} as raw materials, and various 3-acylated catechins and 3-acylated epicatechins are synthesized by the following methods. be able to.

（式中、Ｒ⁷とＲ⁸の組み合わせは、Ｒ⁷が水酸基でＲ⁸が水素原子であるか、Ｒ⁷が水素原子でＲ⁸が水酸基であるかのいずれかである） (In the formula, the combination of R ⁷ and R ⁸ is either R ⁷ is a hydroxyl group and R ⁸ is a hydrogen atom, or R ⁷ is a hydrogen atom and R ⁸ is a hydroxyl group)

（式中、ＲはＲ⁴と同義） (Wherein R is synonymous with R ⁴ )

［第一行程］
本行程は、一般式［Ｉ］で表される公知の３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール化合物（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］で表される３−アシル化３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン化合物を製造するものである。使用する塩基は、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。 [First step]
This process is carried out by using a known 3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol compound represented by the general formula [I] (Journal of the Wood Society of Japan, pages 1991, 37, 488-493). ) Is introduced into the hydroxyl group at the 3-position to produce a 3-acylated 3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan compound represented by the general formula [II]. . As the base to be used, any base such as pyridine or triethylamine can be used as long as it can be used for ordinary acylation reactions. 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.

［第二行程］
本行程は、一般式［ＩＩ］で表される３−アシル化３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン化合物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−オール化合物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。 [Second step]
In this step, the benzyl group, which is a protecting group of the 3-acylated 3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan compound represented by the general formula [II], is deprotected, and the general formula A 3-acylated 3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol compound represented by [III] is produced. 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.

この他にも、例えば、ホウ素化合物を用いたカテキン誘導体の合成法（特開昭５７−１１８５８０号公報、特開昭５７−１２０５８４号公報）、トリフルオロ酢酸と酸塩化物を用いる方法（Bioorganic & Medicinal Chemistry Letters, 2000, 10, 1673-1675頁）、リパーゼを用いる方法（Journal of Molecular Catalysis B: Enzymatic, 2000, 10, 577-582頁）等の方法を用いることができる。 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, pages 1673-1675), a method using lipase (Journal of Molecular Catalysis B: Enzymatic, 2000, 10, pages 577-582) and the like can be used.

本発明の抗炎症剤の用途としては、一般的な炎症による痛みやかゆみの改善を目的とした飲食品、医薬品、医薬部外品及び化粧品等の他に、アトピー性皮膚炎の皮膚の炎症に伴うかゆみや炎症及び花粉症に伴う炎症の軽減を目的とした飲食品、医薬品、医薬部外品及び化粧品等としても使用することが出来る。また、汎用化粧品成分による炎症予防を目的とした成分としても用いることが出来る。更に、紙おむつを構成するセンターシートや吸収体等の吸収性物品、お尻ふきやウエットティッシュ等のシート状製品に適当な方法で含浸させることにより、おむつかぶれの予防・改善等の抗炎症機能を付加した製品を得ることも出来る。 The anti-inflammatory agent of the present invention can be used for skin inflammation caused by atopic dermatitis in addition to foods and drinks, pharmaceuticals, quasi drugs and cosmetics for the purpose of improving pain and itching due to general inflammation. It can also be used as foods and drinks, pharmaceuticals, quasi-drugs, cosmetics and the like for the purpose of reducing accompanying itching, inflammation and inflammation associated with hay fever. It can also be used as a component for the purpose of preventing inflammation with general-purpose cosmetic ingredients. Furthermore, by impregnating absorbent articles such as center sheets and absorbent bodies that make up disposable diapers, and sheet-like products such as wipes and wet tissues, anti-inflammatory functions such as prevention and improvement of diaper rash are added. You can also get the product you want.

本発明の抗炎症剤は、飲食品や医薬品等へ配合した形態で摂取してもよいが、そのまま単独で摂取することもできる。その摂取量は、摂取形態、年齢、体重などにより異なり、特に制限されるものではないが、体重１ｋｇあたり０．１ｍｇ〜１００ｍｇ／回の摂取が好ましく、０．５ｍｇ〜５０ｍｇ／回の摂取がより好ましい。このとき、１日当たりの摂取回数は１回若しくは数回とする。例えば、注射用製剤の場合、成人で本発明の化合物の重量として１日あたり１ｍｇ〜６０ｍｇの静注、点滴静注、皮下注射、筋肉注射が適当である。なお、本発明においては、有効成分となる一般式（１）により表される３−アシル化フラバン−３−オール化合物またはその薬学的に許容される塩を単独で用いてもよいし、２種以上を所望とする混合比で組み合わせて用いてもよい。ここで、３−アシル化フラバン−３−オール化合物の薬学的に許容される塩としては、例えば、ナトリウム塩やカリウム塩などのアルカリ金属塩や、マグネシウム塩やカルシウム塩などのアルカリ土類金属塩などが挙げられる。 Although the anti-inflammatory agent of this invention may be ingested with the form mix | blended with food-drinks, a pharmaceutical, etc., it 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, intravenous, intravenous, subcutaneous, and intramuscular injections of 1 mg to 60 mg per day as the weight of the compound of the present invention are appropriate for adults. In the present invention, the 3-acylated flavan-3-ol compound represented by the general formula (1) serving as an active ingredient or a pharmaceutically acceptable salt thereof may be used alone or in combination of two kinds. The above may be used in combination at a desired mixing ratio. Here, examples of the pharmaceutically acceptable salt of the 3-acylated flavan-3-ol compound include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium salt and calcium salt. Etc.

本発明の抗炎症剤の投与方法は特に限定されるものではなく種々の方法で投与することができる。 The administration method of the anti-inflammatory agent of this invention is not specifically limited, It can administer by various methods.

本発明の抗炎症剤を単独で製剤化する場合における製剤形態は、有効成分として前述の３−アシル化フラバン−３−オール化合物を含んでなるものであればどのような形態であってもよく、例えば粉末状、顆粒状、錠剤などの固形状であってもよいし、液状や半固形状などであってもよい。 The preparation form in the case of formulating the anti-inflammatory agent of the present invention alone may be any form as long as it contains the aforementioned 3-acylated flavan-3-ol compound as an active ingredient. For example, it may be in a solid form such as powder, granule, or tablet, and may be liquid or semi-solid.

また、本発明の抗炎症剤は、他の抗炎症剤と併用して用いても何ら問題は生じない。他の抗炎症剤と併用した場合には、より優れた抗炎症効果を期待することができる。 Further, the anti-inflammatory agent of the present invention does not cause any problems even when used in combination with other anti-inflammatory agents. When used in combination with other anti-inflammatory agents, a better anti-inflammatory effect can be expected.

本発明の抗炎症剤を単独で製剤化する場合、あるいは飲食品や医薬品等に配合して利用する場合には、必要に応じて、各種添加剤と適宜組み合わせて用いてもよい。例えば、結合剤、崩壊剤、増量剤、酸化防止剤、着色剤、香料、矯味剤、界面活性剤、滑沢剤、流動性促進剤、溶解補助剤、保存剤、糖類、甘味料、酸味料、ビタミン類などの公知の各種添加剤等を適宜に組み合わせて使用することができる。ここに、結合剤としてデンプン、デキストリン、アラビアゴム末、ゼラチン、ヒドロキシプロピルスターチ、メチルセルロースナトリウム、ヒドロキシプロピルセルロース、結晶セルロース、エチルセルロース、ポリビニルピロリドン、マクロゴール等を例示できる。崩壊剤としてはデンプン、ヒドロキシプロピルスターチ、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロース、低置換ヒドロキシプロピルセルロース等を例として挙げることができる。界面活性剤の例としてラウリル硫酸ナトリウム、大豆レシチン、蔗糖脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル等を挙げることができる。滑沢剤では、タルク、ロウ類、水素添加植物油、蔗糖脂肪酸エステル、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸アルミニウム、ポリエチレングリコール等を例示できる。流動性促進剤では、軽質無水ケイ酸、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、ケイ酸マグネシウム等を例として挙げることができる。また、注射用製剤として利用する場合は、希釈剤として一般に注射用蒸留水、生理食塩水、ブドウ糖水溶液、注射用植物油、ゴマ油、ラッカセイ油、大豆油、トウモロコシ油、プロピレングリコール等を用いることができる。さらに必要に応じて、殺菌剤、防腐剤、安定剤を加えてもよい。また、安定性の点から、バイアル等に充填後冷凍し、通常の凍結乾燥処理により水分を除き、使用直前に凍結乾燥物から液剤を再調製することもできる。さらに必要に応じて、等張化剤、安定剤、防腐剤、無痛化剤を加えてもよい。 When formulating the anti-inflammatory agent of the present invention alone, or when blending and using it 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.

本発明の抗炎症剤の配合対象物である飲食品や医薬品等は、抗炎症剤の有効成分である３−アシル化フラバン−３−オール化合物を配合することができるものであれば、どのような形態であってもよく、例えば水溶液や混濁物や乳化物などの液状形態であっても、ゲル状やペースト状の半固形状形態であっても、粉末や顆粒やカプセルやタブレットなどの固形状形態であってもよい。 Any food, beverage, medicine, or the like, which is a compounded object of the anti-inflammatory agent of the present invention, can be used as long as it can compound a 3-acylated flavan-3-ol compound that is an active ingredient of the anti-inflammatory agent. For example, it may be a liquid form such as an aqueous solution, turbidity or emulsion, a semi-solid form such as a gel or paste, a solid such as a powder, granule, capsule or tablet. A shape form may be sufficient.

飲食品としては、例えば、即席食品類（即席めん、カップめん、レトルト・調理食品、調理缶詰め、電子レンジ食品、即席味噌汁・吸い物、スープ缶詰め、フリーズドライ食品など）、炭酸飲料、柑橘類（グレープフルーツ、オレンジ、レモンなど）の果汁や果汁飲料や果汁入り清涼飲料、柑橘類の果肉飲料や果粒入り果実飲料、トマト、ピーマン、セロリ、ウリ、ニンジン、ジャガイモ、アスパラガスなどの野菜を含む野菜系飲料、豆乳・豆乳飲料、コーヒー飲料、お茶飲料、粉末飲料、濃縮飲料、スポーツ飲料、栄養飲料、アルコール飲料やタバコなどの嗜好飲料・嗜好品類、パン、マカロニ・スパゲッティ、麺類、ケーキミックス、唐揚げ粉、パン粉、ギョーザの皮などの小麦粉製品、キャラメル・キャンディー、チューイングガム、チョコレート、クッキー・ビスケット、ケーキ・パイ、スナック・クラッカー、和菓子・米菓子・豆菓子、デザート菓子などの菓子類、しょうゆ、みそ、ソース類、トマト加工調味料、みりん類、食酢類、甘味料などの基礎調味料、風味調味料、調理ミックス、カレーの素類、たれ類、ドレッシング類、めんつゆ類、スパイス類などの複合調味料・食品類、バター、マーガリン類、マヨネーズ類、植物油などの油脂類、牛乳・加工乳、乳飲料、ヨーグルト類、乳酸菌飲料、チーズ、アイスクリーム類、調製粉乳類、クリームなどの乳・乳製品、素材冷凍食品、半調理冷凍食品、調理済み冷凍食品などの冷凍食品、水産缶詰め、果実缶詰め・ペースト類、魚肉ハム・ソーセージ、水産練り製品、水産珍味類、水産乾物類、佃煮類などの水産加工品、畜産缶詰め・ペースト類、畜肉缶詰め、果実缶詰め、ジャム・マーマレード類、漬物・煮豆類、農産乾物類、シリアル（穀物加工品）などの農産加工品、ベビーフード、ふりかけ・お茶漬けのりなどの市販食品などが挙げられる。また、家畜用配合飼料（養牛用飼料、養豚用飼料、養鶏用飼料など）やペットフードなどの動物用飼料であってもよい。 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 beverages, yogurts, lactic acid bacteria beverages, cheese, ice cream, prepared milk powder, milk and other dairy products such as creams, frozen foods, semi-cooked frozen foods, frozen frozen foods such as cooked frozen foods , Marine canning, fruit canning and paste, fish ham and sausage, marine products, marine delicacies, marine dry matter, 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.

医薬用組成物の形態としては、例えば、錠剤、丸剤、飲用液剤、懸濁剤、乳剤、カプセル剤、顆粒剤、細粒剤、散剤等の経口剤や、注射剤、外用液剤、貼付剤、軟膏剤、クリーム剤、直腸内投与のための坐剤、吸入剤、点鼻剤、スプレー剤等の非経口剤が挙げられる。 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.

飲食品や医薬品等への本発明の抗炎症剤の配合方法は特に制限されるものではなく、飲食品や医薬品等の調製段階において、この分野で通常知られた慣用的な方法を用いて配合することができる。また、飲食品や医薬品などに対する本発明の抗炎症剤の配合量については特に制限されないが、配合対象となる物品により配合量を適宜設定することが好ましい。一般的には、最終製品中で０．０００１〜５０重量％であればよいが、０．００１〜２０重量％であることが好ましく、さらに０．０１〜１０重量％がより好ましい。飲食品の場合は、最終製品中で０．０００１〜５重量％であればよいが、０．００１〜１重量％であることが好ましく、さらに０．０１〜０．５重量％がより好ましく、特に好ましくは０．０５〜０．５重量％である。 The method of blending the anti-inflammatory agent of the present invention into foods and beverages and pharmaceuticals is not particularly limited, and blended using conventional methods usually known in this field in the preparation stage of foods and beverages and pharmaceuticals. can do. Moreover, although there is no restriction | limiting in particular about the compounding quantity of the anti-inflammatory agent of this invention with respect to food-drinks, a pharmaceutical, etc., It is preferable to set a compounding quantity suitably with the articles | goods used as a compounding object. 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.

以下に製造例、試験例を挙げ、本発明をさらに詳しく説明する。ただし、本発明はこれに限定されるものではない。 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.

製造例１：化合物１｛（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ヘキサノエート｝の製造
工程１：（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オールの製造
（＋）−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、白色粉末の（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（２３．８ｇ，０．０３７ｍｏｌ，５３％）を得た。 Production Example 1: Production of Compound 1 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-hexanoate} Step 1: (2R, 3S) -3 ′, 4 ′, 5 Preparation of 7-tetra-O-benzyl-flavan-3-ol (+)-catechin {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-ol} (20.0 g, 0.069 mol) was dissolved in 500 mL of dehydrated DMF, and 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, the residue was purified by silica gel column chromatography, and (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (23.8 g, 0. 037 mol, 53%).

¹H-NMR (400 MHz, CDCl₃) 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); ¹³C-NMR (100 MHz, CDCl₃) 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. 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.

工程２：（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−ヘキサノエートの製造
工程１で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−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）、ヘキサノイルクロライド（０．１６ｍＬ，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＝６：１）で精製し、無色油状物の（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−ヘキサノエート（４９５ｍｇ、０．６６ｍｍｏｌ，８６％収率）を得た。 Step 2: Production of (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-hexanoate (2R, 3S) -3 ′, 4 ′, obtained in Step 1 5,7-Tetra-O-benzyl-flavan-3-ol (500 mg, 0.77 mmol) was dissolved in 30 mL of dehydrated dichloromethane, triethylamine (0.32 mL, 2.31 mmol), hexanoyl while cooling with ice. Chloride (0.16 mL, 1.16 mmol) and N, N-dimethylaminopyridine (5 mg) were 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, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to give (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl as a colorless oil. -Flavan-3-hexanoate (495 mg, 0.66 mmol, 86% yield) was obtained.

[α]_D ²⁵= +8.8 (c 1.92, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 7.43-7.25 (20H, m), 6.98 (1H, br s), 6.88 (2H, br s), 6.25 (1H, d, J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.35-5.29 (1H, m), 5.16 (2H, s), 5.13 (2H, s), 5.00 (4H, s), 5.00-4.95 (1H, m), 2.90 (1H, dd, J = 5.6, 16.8 Hz), 2.70 (1H, dd, J = 6.5, 16.8 Hz), 2.20-2.10 (2H, m), 1.47-1.39 (2H, m), 1.28-1.05 (4H, m), 0.83 (3H, t, J = 6.8 Hz); ¹³C-NMR (100 MHz, CDCl₃) 172.8, 158.8, 157.7, 154.8, 148.83, 148.75, 137.1, 137.0, 136.8, 131.0, 128.5, 128.44, 128.37, 128.35, 127.9, 127.8, 127.7 (x2), 127.5, 127.3, 127.1 (x3), 119.9, 114.6, 113.3, 101.3, 94.3, 93.6, 78.3, 71.14, 71.05, 69.99, 69.8, 68.6, 34.2, 30.9, 24.4, 24.0, 22.2, 13.8; IR (neat, cm^-1) 3065 (m), 3032 (m), 2955 (s), 2932 (s), 2870 (s), 1952 (w), 1871 (w), 1809 (w), 1736 (s), 1630 (s), 1593 (s), 1515 (s), 1379 (m), 1265 (m), 1145 (s), 1028 (m), 910 (w), 850 (w), 812 (m), 754 (s); FAB-MS (m/z) 722 (3.2), 771 ([M+Na]⁺, 5.1), 750 (13), 749 ([M+H]⁺, 24), 748 (5.5), 723 (12), 722 (12), 634 (24), 633 (70), 632 (100), 631 (20); FAB-HRMS 計算値 C₄₉H₄₉O₇[M+H]⁺, 749.3478; 実測値: 749.3480. [α] _D ²⁵ = +8.8 (c 1.92, CHCl ₃ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.25 (20H, m), 6.98 (1H, br s), 6.88 (2H, br s ), 6.25 (1H, d, J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.35-5.29 (1H, m), 5.16 (2H, s), 5.13 (2H, s), 5.00 (4H, s), 5.00-4.95 (1H, m), 2.90 (1H, dd, J = 5.6, 16.8 Hz), 2.70 (1H, dd, J = 6.5, 16.8 Hz), 2.20-2.10 (2H, m ), 1.47-1.39 (2H, m), 1.28-1.05 (4H, m), 0.83 (3H, t, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CDCl ₃ ) 172.8, 158.8, 157.7, 154.8 , 148.83, 148.75, 137.1, 137.0, 136.8, 131.0, 128.5, 128.44, 128.37, 128.35, 127.9, 127.8, 127.7 (x2), 127.5, 127.3, 127.1 (x3), 119.9, 114.6, 113.3, 101.3, 94.3, 93.6 , 78.3, 71.14, 71.05, 69.99, 69.8, 68.6, 34.2, 30.9, 24.4, 24.0, 22.2, 13.8; IR (neat, cm ^-1 ) 3065 (m), 3032 (m), 2955 (s), 2932 ( s), 2870 (s), 1952 (w), 1871 (w), 1809 (w), 1736 (s), 1630 (s), 1593 (s), 1515 (s), 1379 (m), 1265 ( m), 1145 (s), 1028 (m), 910 (w), 850 (w), 812 (m), 754 (s); FAB-MS (m / z) 722 (3.2), 771 ([M + Na] ⁺ , 5.1), 750 (13), 749 ([M + H] ⁺ , 24), 748 (5.5), 723 (12), 722 (12), 634 (24), 633 (70), 632 (100), 631 (20); FAB-HRMS calculated C ₄₉ H ₄₉ O ₇ [M + H] ⁺ , 749.3478; Value: 749.3480.

工程３：（２Ｒ，３Ｓ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ヘキサノエートの製造
工程２で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−ヘキサノエート（３８２ｍｇ，０．５１ｍｍｏｌ）を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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、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−ヘキサノエート｝（１３１ｍｇ，０．３４ｍｍｏｌ，６７％）を得た。 Step 3: Production of (2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-hexanoate (2R, 3S) -3 ′, 4 ′, 5,7- obtained in Step 2 Tetra-O-benzyl-flavan-3-hexanoate (382 mg, 0.51 mmol) was dissolved in tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) and 20% Pd (OH) ₂ / C (5 mg as a catalyst). ) And stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. The catalyst was removed by filtration, the filtrate was concentrated, purified by Cosmosil® 75C-18OPN column chromatography (methanol-water), and the target compound, colorless oily compound 1 {(2R, 3S)- 3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-hexanoate} (131 mg, 0.34 mmol, 67%) was obtained.

[α]_D ²⁴= +8.7 (c 1.06, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃COCD₃-D₂O, 10 : 1) 6.78 (1H, d, J = 1.7, 6.71 (1H, d, J = 8.3 Hz), 6.61 (1H, dd, J = 1.7, 8.3 Hz), 5.97 (1H, d, J = 2.2 Hz), 5.84 (1H, d, J = 2.2 Hz), 5.14 (1H, ddd, J = 5.4, 6.8, 6.8 Hz), 4.82 (1H, d, J = 6.8 Hz), 2.73 (1H, dd, J = 5.4, 16.4 Hz), 2.52 (1H, dd, J = 6.8, 16.4 Hz), 2.12-2.08 (2H, m), 1.39-1.30 (2H, m), 1.18-1.00 (4H, m), 0.74 (3H, t, J = 6.8 Hz); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 10 : 1) 173.3, 157.8, 157.0, 155.9, 145.7, 145.6, 130.5, 118.9, 115.6, 114.3, 98.8, 96.1, 95.0, 78.7, 69.9, 34.6, 31.5, 25.1, 24.6, 22.7, 14.0; FAB-MS (m/z) 412 (8.2), 411([M+Na]⁺, 27), 410 (8.7), 391 (15), 390 (17), 389 ([M+H]⁺, 59), 388 (9.3), 274 (17), 273 (71), 272 (100), 271 (28); FAB-HRMS 計算値 C₂₁H₂₅O₇[M+H]⁺, 389.1600; 実測値: 389.1568. [α] _D ²⁴ = +8.7 (c 1.06, CH ₃ COCH ₃ ); ¹ H-NMR (400 MHz, CD ₃ COCD ₃ -D ₂ O, 10: 1) 6.78 (1H, d, J = 1.7, 6.71 (1H, d, J = 8.3 Hz), 6.61 (1H, dd, J = 1.7, 8.3 Hz), 5.97 (1H, d, J = 2.2 Hz), 5.84 (1H, d, J = 2.2 Hz), 5.14 (1H, ddd, J = 5.4, 6.8, 6.8 Hz), 4.82 (1H, d, J = 6.8 Hz), 2.73 (1H, dd, J = 5.4, 16.4 Hz), 2.52 (1H, dd, J = 6.8 , 16.4 Hz), 2.12-2.08 (2H, m), 1.39-1.30 (2H, m), 1.18-1.00 (4H, m), 0.74 (3H, t, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CD ₃ COCD ₃ -D ₂ O, 10: 1) 173.3, 157.8, 157.0, 155.9, 145.7, 145.6, 130.5, 118.9, 115.6, 114.3, 98.8, 96.1, 95.0, 78.7, 69.9, 34.6, 31.5, 25.1 , 24.6, 22.7, 14.0; FAB-MS (m / z) 412 (8.2), 411 ([M + Na] ⁺ , 27), 410 (8.7), 391 (15), 390 (17), 389 ([[ M + H] ⁺ , 59), 388 (9.3), 274 (17), 273 (71), 272 (100), 271 (28); FAB-HRMS calculated C ₂₁ H ₂₅ O ₇ [M + H] ⁺ , 389.1600; found: 389.1568.

製造例２：化合物２｛（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｝の製造
製造例１に記載の化合物１の合成と同様にして、製造例１の工程１で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（５００ｍｇ，０．７７ｍｍｏｌ）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）、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’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オクタノエート（３８８ｍｇ、０．５０ｍｍｏｌ，６５％収率）を得た。 Production Example 2: Production of Compound 2 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-octanoate} A production example was carried out in the same manner as the synthesis of Compound 1 described in Production Example 1. To a dichloromethane solution (30 mL) of (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (500 mg, 0.77 mmol) obtained in step 1 of 1, Triethylamine (0.32 mL, 2.31 mmol), octanoyl chloride (0.20 mL, 1.16 mmol), and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, and after-treatment, Purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1), (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl- Flavane-3-octanoate (388 mg, 0.50 mmol, 65% yield) was obtained.

[α]_D ²⁴= +8.0 (c 1.64, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 7.43-7.28 (20H, m), 6.98 (1H, br s), 6.88 (2H, br s), 6.26 (1H, d, J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.20-5.35 (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); ¹³C-NMR (100 MHz, CDCl₃) 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 (s), 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 計算値 C₅₁H₅₃O₇[M+H]⁺, 777.3791; 実測値: 777.3787. [α] _D ²⁴ = +8.0 (c 1.64, CHCl ₃ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.28 (20H, m), 6.98 (1H, br s), 6.88 (2H, br s ), 6.26 (1H, d, J = 2.2 Hz), 6.23 (1H, d, J = 2.2 Hz), 5.20-5.35 (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 (s), 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); F AB-HRMS calculated C ₅₁ H ₅₃ O ₇ [M + H] ⁺ , 777.3791; found: 777.3787.

製造例１に記載の化合物１の合成と同様にして、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−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）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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、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−オクタノエート｝（１１１ｍｇ，０．２７ｍｍｏｌ，９６％）を得た。 In the same manner as in the synthesis of Compound 1 described in Preparation Example 1, (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-octanoate (218 mg, 0.28 mmol) To a tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) solution, 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target compound 2 {(2R, 3S) -3 ′, 4 ′, 5, 7-tetrahydroxyflavan-3-octanoate} (111 mg, 0.27 mmol, 96%) was obtained.

[α]_D ²⁵= +7.9 (c 0.34, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃COCD₃-D₂O, 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 (1H, dd, J = 6.8, 16.4 Hz), 2.20-2.12 (2H, m), 1.45-1.38 (2H, m), 1.30-1.10 (8H, m), 0.82 (3H, t, J = 6.8 Hz); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 10 : 1) 173.5, 158.0, 157.2, 156.1, 145.9, 145.8, 130.7, 119.0, 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 計算値 C₂₃H₂₈O₇[M+Na]⁺, 439.1733; 実測値: 439.1747. [α] _D ²⁵ = +7.9 (c 0.34, CH ₃ COCH ₃ ); ¹ H-NMR (400 MHz, CD ₃ COCD 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 (1H, dd, J = 6.8, 16.4 Hz), 2.20-2.12 (2H, m), 1.45-1.38 (2H, m), 1.30-1.10 (8H, m), 0.82 (3H, t, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CD ₃ COCD ₃ -D ₂ O, 10: 1) 173.5, 158.0, 157.2, 156.1, 145.9, 145.8, 130.7, 119.0, 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 calculated C ₂₃ H ₂₈ O ₇ [M + Na] ⁺ , 439.1733; Found: 439.1747.

製造例３：化合物３｛（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｝の製造
製造例１に記載の化合物１の合成と同様にして、製造例１の工程１で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（５００ｍｇ，０．７７ｍｍｏｌ）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’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−ドデカノエート（４６８ｍｇ、０．５８ｍｍｏｌ，７６％収率）を得た。 Production Example 3: Production of Compound 3 {(2R, 3S) -3 ′, 4 ′, 5,7-Tetrahydroxyflavan-3-dodecanoate} In the same manner as in the synthesis of Compound 1 described in Production Example 1, Production Example 3 To a dichloromethane solution (30 mL) of (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (500 mg, 0.77 mmol) obtained in step 1 of 1, Triethylamine (0.32 mL, 2.31 mmol), dodecanoyl chloride (0.24 mL, 1.16 mmol), and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by post-treatment. Purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1), (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl- Flavane-3-dodecanoate (468 mg, 0.58 mmol, 76% yield) was obtained.

[α]_D ²³= +8.5 (c 1.32, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 7.43-7.25 (20H, m), 6.98 (1H, br s), 6.88 (2H, br s), 6.26 (1H, 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); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₅₃H₅₇O₇[M+H]⁺, 805.4104; 実測値: 805.4135. [α] _D ²³ = +8.5 (c 1.32, CHCl ₃ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.25 (20H, m), 6.98 (1H, br s), 6.88 (2H, br s ), 6.26 (1H, 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 calculated C ₅₃ H ₅₇ O ₇ [M + H] ⁺ , 805.4104; Found: 805.4135.

製造例１に記載の化合物１の合成と同様にして、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、無色油状物の化合物３｛（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％）を得た。 In the same manner as in the synthesis of Compound 1 described in Production Example 1, (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-dodecanoate (400 mg, 0.50 mmol) To a tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) solution, 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target compound 3 {(2R, 3S) -3 ′, 4 ′, 5, 7-tetrahydroxyflavan-3-dodecanoate} (190 mg, 0.43 mmol, 86%).

[α]_D ²⁵= +6.5 (c 0.34, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃COCD₃-D₂O, 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); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 10 : 1) 173.3, 157.8, 157.1, 155.9, 145.71, 145.66, 130.56, 118.8, 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 計算値 C₂₅H₃₃O₇[M+H]⁺, 445.2226; 実測値: 445.2213. [α] _D ²⁵ = +6.5 (c 0.34, CH ₃ COCH ₃ ); ¹ H-NMR (400 MHz, CD ₃ COCD 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 COCD ₃ -D ₂ O, 10: 1) 173.3, 157.8, 157.1, 155.9, 145.71, 145.66, 130.56, 118.8, 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 calculated C ₂₅ H ₃₃ O ₇ [M + H] ⁺ , 445.2226; Found: 445.2213.

製造例４：化合物４｛（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｝の製造
製造例１に記載の化合物１の合成と同様にして、製造例１の工程１で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（７３９ｍｇ，１．１４ｍｍｏｌ）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−テトラ−Ｏ−ベンジル−フラバン−３−ラウロエート（７１９ｍｇ、０．８６ｍｍｏｌ，７６％収率）を得た。 Production Example 4: Production of Compound 4 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-lauroate} A production example was carried out in the same manner as the synthesis of Compound 1 described in Production Example 1. To a dichloromethane solution (50 mL) of (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (739 mg, 1.14 mmol) obtained in Step 1 of Triethylamine (0.32 mL, 2.28 mmol), lauroyl chloride (0.39 mL, 1.70 mmol) and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by silica gel treatment. Purification by column chromatography (n-hexane: ethyl acetate = 6: 1) and white powder of (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan -3-Lauroate (719 mg, 0.86 mmol, 76% yield) was obtained.

[α]_D ²⁵= +8.7 (c 2.78, CHCl₃);¹H-NMR (400 MHz, CDCl₃) 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 (21H, m); 13C-NMR (100 MHz, CDCl₃) 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 計算値 C₅₅H₆₁O₇[M+H]⁺, 実測値; found: 833.4401. [α]_D ^{twenty five}= +8.7 (c 2.78, CHCl_Three);¹H-NMR (400 MHz, CDCl_Three) 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 (21H, m); 13C-NMR (100 MHz, CDCl_Three) 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 C₅₅H₆₁O₇[M + H]⁺, Measured; found: 833.4401.

製造例１に記載の化合物１の合成と同様にして、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、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−ラウロエート｝（３４ｍｇ，０．０７２ｍｍｏｌ，６５％）を得た。 In the same manner as in the synthesis of Compound 1 described in Production Example 1, (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-lauroate (91 mg, 0.11 mmol) 20% Pd (OH) ₂ / C (5 mg) was added to a tetrahydrofuran-methanol-water (20: 1: 1, 11 mL) solution, and the mixture was stirred for 12 hours under a hydrogen atmosphere to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target product, colorless amorphous compound 4 {(2R, 3S) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-lauroate} (34 mg, 0.072 mmol, 65%) was obtained.

[α]_D ²³= +3.5 (c 0.68, EtOH); ¹H-NMR (400 MHz, CD₃OD) 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); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₂₇H₃₇O₇[M+H]⁺, 473.2539; 実測値: 473.2571. [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); Calculated FAB-HRMS C ₂₇ H ₃₇ O ₇ [M + H] ⁺ , 473.2539; Found: 473.2571.

製造例５：化合物５｛（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｝の製造
製造例１に記載の化合物１の合成と同様にして、製造例１の工程１で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（８８６ｍｇ，１．３６ｍｍｏｌ）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−テトラ−Ｏ−ベンジル−フラバン−３−ミリストエート（８４６ｍｇ、０．９８ｍｍｏｌ，７２％収率）を得た。 Production Example 5: Production of Compound 5 {(2R, 3S) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-myristate} Production Example 1 was carried out in the same manner as the synthesis of Compound 1 described in Production Example 1. 1 to (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (886 mg, 1.36 mmol) in dichloromethane (50 mL) obtained in Step 1 of Triethylamine (0.57 mL, 4.08 mmol), myristoyl chloride (0.56 mL, 2.04 mmol) and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by silica gel treatment. Purified by column chromatography (n-hexane: ethyl acetate = 8: 1), (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-fura of white powder Van-3-myristate (846 mg, 0.98 mmol, 72% yield) was obtained.

[α]_D ²³= +8.6 (c 0.72, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 7.43-7.24 (20H, m), 6.97 (1H, br s), 6.88 (1H, br s), 6.25 (1H, 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 = 6.8 Hz); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₅₇H₆₅O₇[M+H]⁺, 861.4730; 実測値: 861.4737. [α] _D ²³ = +8.6 (c 0.72, CHCl ₃ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 7.43-7.24 (20H, m), 6.97 (1H, br s), 6.88 (1H, br s ), 6.25 (1H, 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 = 6.8 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, 128.5, 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 calculated C ₅₇ H ₆₅ O ₇ [M + H ] ⁺ , 861.4730; Found: 861.4737.

製造例１に記載の化合物１の合成と同様にして、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、無色アモルファスの化合物５｛（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％）を得た。 In the same manner as in the synthesis of Compound 1 described in Preparation Example 1, (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-myristate (500 mg, 0.58 mmol) To a tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) solution, 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target product, colorless amorphous compound 5 {(2R, 3S) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-myristoate} (212 mg, 0.42 mmol, 72%).

[α]_D ²⁵= +6.3 (c 1.46, CH₃COCH₃); 1H-NMR (400 MHz, CD₃COCD₃-D₂O, 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); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 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 計算値 C₂₉H₄₁O₇[M+H]⁺, 501.2852; 実測値: 501.2879. [α] _D ²⁵ = +6.3 (c 1.46, CH ₃ COCH ₃ ); 1H-NMR (400 MHz, CD ₃ COCD 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 COCD 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; Actual value: 501.2879.

製造例６：化合物６｛（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｝の製造
製造例１に記載の化合物１の合成と同様にして、製造例１の工程１で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（６９６ｍｇ，１．０７ｍｍｏｌ）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−テトラ−Ｏ−ベンジル−フラバン−３−パルミトエート（６８２ｍｇ、０．７７ｍｍｏｌ，７２％収率）を得た。 Production Example 6: Production of Compound 6 {(2R, 3S) -3 ′, 4 ′, 5,7-Tetrahydroxyflavan-3-palmitoate} In the same manner as in the synthesis of Compound 1 described in Production Example 1, Production Example 6 To a dichloromethane solution (50 mL) of (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (696 mg, 1.07 mmol) obtained in Step 1 of Triethylamine (0.45 mL, 3.21 mmol), palmitoyl chloride (0.49 mL, 1.60 mmol), and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by silica gel treatment. Purified by column chromatography (n-hexane: ethyl acetate = 8: 1), (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-fura of white powder Van-3-palmitoate (682 mg, 0.77 mmol, 72% yield) was obtained.

[α]_D ²⁴= +7.4 (c 0.74, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 7.51-7.25 (20H, m), 6.97 (1H, br s), 6.88 (2H, br s), 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 = 6.8 Hz); ¹³C-NMR (100 MHz, CDCl₃) 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), 1377 (m), 1265 (m), 1146 (s), 1028 (m), 910 (w), 850 (w), 810 (w), 735 (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); FAB-HRMS 計算値 C₅₉H₆₉O₇[M+H]⁺, 889.5043; 実測値: 889.5082. [α] _D ²⁴ = +7.4 (c 0.74, CHCl ₃ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 7.51-7.25 (20H, m), 6.97 (1H, br s), 6.88 (2H, br s ), 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 = 6.8 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, 128.5, 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), 1377 (m), 1265 (m), 1146 (s), 1028 (m), 910 (w), 850 (w), 810 (w), 735 (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); FAB-HRMS calculation Value C ₅₉ H ₆₉ O ₇ [M + H] ⁺ , 889.5043; found: 889.5082.

製造例１に記載の化合物１の合成と同様にして、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、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−パルミトエート｝（１８８ｍｇ，０．３６ｍｍｏｌ，７９％）を得た。 In the same manner as in the synthesis of Compound 1 described in Production Example 1, (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-palmiate (400 mg, 0.45 mmol) To a tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) solution, 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target product, white powder compound 6 {(2R, 3S) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-palmitoate} (188 mg, 0.36 mmol, 79%).

[α]_D ²⁵= +6.1 (c 1.14, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃COCD₃-D₂O, 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 (1H, dd, J = 6.5, 16.4 Hz), 2.21-2.13 (2H, m), 1.44-1.37 (2H, m), 1.30-1.10 (24H, m), 0.81 (3H, t, J = 6.8 Hz); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 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 計算値 C₃₁H₄₅O₇[M+H]⁺, 529.3165; 実測値: 529.3143. [α] _D ²⁵ = +6.1 (c 1.14, CH ₃ COCH ₃ ); ¹ H-NMR (400 MHz, CD ₃ COCD 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 (1H, dd, J = 6.5, 16.4 Hz), 2.21-2.13 (2H, m), 1.44-1.37 (2H, m), 1.30-1.10 (24H, m), 0.81 (3H, t, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CD ₃ COCD 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] ⁺ , 529.3165; measured : 529.3143.

製造例７：化合物７｛（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｝の製造
製造例１に記載の化合物１の合成と同様にして、製造例１の工程１で得られた（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（５００ｍｇ，０．７７ｍｍｏｌ）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−テトラ−Ｏ−ベンジル−フラバン−３−ステアロエート（７０６ｍｇ、０．７７ｍｍｏｌ，１００％収率）を得た。 Production Example 7: Production of Compound 7 {(2R, 3S) -3 ', 4', 5,7-tetrahydroxyflavan-3-stearate} Production Example 1 was carried out in the same manner as the synthesis of Compound 1 described in Production Example 1. To a dichloromethane solution (50 mL) of (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (500 mg, 0.77 mmol) obtained in Step 1 of Triethylamine (0.32 mL, 2.31 mmol), stearoyl chloride (0.39 mL, 1.16 mmol), and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by silica gel treatment. Purified by column chromatography (n-hexane: ethyl acetate = 7: 1), (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-fura of white powder Van-3-stearoate (706 mg, 0.77 mmol, 100% yield) was obtained.

[α]_D ²⁵= + 6.7 (c 2.70, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 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 = 6.8 Hz); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₆₁H₇₃O₇[M+H]⁺, 917.5356; 実測値: 917.5388. [α] _D ²⁵ = + 6.7 (c 2.70, 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 = 6.8 Hz); ¹³ C-NMR (100 MHz, 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 calculated C ₆₁ H ₇₃ O ₇ [M + H] ⁺ , 917.5356; Found: 917.5388.

製造例１に記載の化合物１の合成と同様にして、（２Ｒ，３Ｓ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、白色粉末の化合物７｛（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％）を得た。 In the same manner as in the synthesis of Compound 1 described in Production Example 1, (2R, 3S) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-stearate (385 mg, 0.42 mmol) To a tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) solution, 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target compound, white powder compound 7 {(2R, 3S) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-stearoate} (214 mg, 0.38 mmol, 90%) was obtained.

[α]_D ²⁴= +4.0 (c 1.18, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃COCD₃-D₂O, 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); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 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 計算値 C₃₃H₄₉O₇[M+H]⁺, 557.3478; 実測値: 557.3441. [α] _D ²⁴ = +4.0 (c 1.18, CH ₃ COCH ₃ ); ¹ H-NMR (400 MHz, CD ₃ COCD 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 COCD 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 calculated C ₃₃ H ₄₉ O ₇ [M + H] ⁺ , 557.3478; Found: 557.3441.

製造例８：化合物８｛（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｝の製造
工程１：（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オールの製造
製造例１の工程１と同様にして、（−）−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、白色粉末の（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（１０．２ｇ，０．０１６ｍｏｌ，４５％）を得た。 Production Example 8 Production of Compound 8 {(2R, 3R) -3 ′, 4 ′, 5,7-Tetrahydroxyflavan-3-lauroate} 1: (2R, 3R) -3 ′, 4 ′, 5 Production of 7-tetra-O-benzyl-flavan-3-ol In the same manner as in Production Example 1, Step 1, (-)-epicatechin {(2R, 3R) -3 ', 4', 5,7-tetra Hydroxyflavan-3-ol} (10.0 g, 0.035 mol) 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, the residue was purified by silica gel column chromatography, and (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (10.2 g, 0. 016 mol, 45%).

¹H-NMR (400 MHz, CDCl₃) 7.46-7.26 (20H, m), 7.14 (1H, d, J = 1.7 Hz), 6.99 (1H, dd, J = 1.7, 8.3 Hz), 6.95 (1H, d, J = 8.3 Hz), 6.27 (1H, d, J = 2.2 Hz), 6.26 (1H, 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); ¹³C-NMR (100 MHz, CDCl₃) 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. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.46-7.26 (20H, m), 7.14 (1H, d, J = 1.7 Hz), 6.99 (1H, dd, J = 1.7, 8.3 Hz), 6.95 (1H, d, J = 8.3 Hz), 6.27 (1H, d, J = 2.2 Hz), 6.26 (1H, 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.

工程２：（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−ラウロエートの製造
製造例１の工程１と同様にして、工程１で得られた（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（６９２ｍｇ，１．０６ｍｍｏｌ）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’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−ラウロエート（６６８ｍｇ、０．８０ｍｍｏｌ，７６％収率）を得た。 Step 2: Production of (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-lauroate In the same manner as in Step 1 of Production Example 1, it was obtained in Step 1 ( 2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (692 mg, 1.06 mmol) in dichloromethane solution (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) were reacted, followed by post-treatment and silica gel column chromatography (n-hexane: acetic acid). (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-lauroate (668 mg, 0.80 mmol, 76% yield).

[α]_D ²³= -19.5 (c 0.94, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 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 (1H, d, J = 8.3 Hz), 6.28 (1H, d, J = 2.2 Hz), 6.27 (1H, 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 = 12.0 Hz), 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); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₅₅H₆₁O₇[M+H]⁺, 833.4417; 実測値: 833.4448. [α] _D ²³ = -19.5 (c 0.94, 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 (1H, d, J = 8.3 Hz), 6.28 (1H, d, J = 2.2 Hz), 6.27 (1H, 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 = 12.0 Hz), 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 calculated C ₅₅ H ₆₁ O ₇ [M + H] ⁺ , 833.4417; Found: 833.4448.

工程３：（２Ｒ，３Ｒ）−３’，４’，５，７−テトラヒドロキシフラバン−３−ラウロエートの製造
製造例１の工程１と同様にして、工程２で得られた（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、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−ラウロエート｝（４１ｍｇ，０．０８７ｍｍｏｌ，６２％）を得た。 Step 3: Production of (2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-lauroate In the same manner as in Production Example 1, Step 1 (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-lauroate (120 mg, 0.14 mmol) in tetrahydrofuran-methanol-water (20: 1: 1, 11 mL) solution with 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target product, colorless amorphous compound 8 {(2R, 3R) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-lauroate} (41 mg, 0.087 mmol, 62%) was obtained.

[α]_D ²⁴= -54.0 (c 0.58, EtOH); ¹H-NMR (400 MHz, CDCl₃) 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, br s), 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); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₂₇H₃₇O₇[M+H]⁺, 473.2539; 実測値: 473.2542. [α] _D ²⁴ = -54.0 (c 0.58, 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, br s), 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; Actual value: 473.2542.

製造例９：化合物９｛（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｝の製造
製造例８に記載の化合物８の合成と同様にして、製造例８の工程１で得られた（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（５００ｍｇ，０．７７ｍｍｏｌ）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−テトラ−Ｏ−ベンジル−フラバン−３−ミリストエート（３６０ｍｇ、０．４２ｍｍｏｌ，５４％収率）を得た。 Production Example 9: Production of Compound 9 {(2R, 3R) -3 ′, 4 ′, 5,7-tetrahydroxyflavan-3-myristate} Production Example 9 was carried out in the same manner as the synthesis of Compound 8 described in Production Example 8. 8 (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (500 mg, 0.77 mmol) in dichloromethane (40 mL) obtained in Step 1 of Triethylamine (0.32 mL, 2.31 mmol), myristoyl chloride (0.31 mL, 1.16 mmol), and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by silica gel treatment. Purified by column chromatography (n-hexane: ethyl acetate = 7: 1), (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-fura of white powder Van-3-myristate (360 mg, 0.42 mmol, 54% yield) was obtained.

[α]_D ²³= -20.4 (c 0.72, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 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 (1H, d, J = 8.3 Hz), 5.46-5.41 (1H, m), 5.17 (1H, 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); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₅₇H₆₅O₇[M+H]⁺, 861.4730; 実測値: 861.4730. [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 (1H, d, J = 8.3 Hz), 5.46-5.41 (1H, m), 5.17 (1H, 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 calculated C ₅₇ H ₆₅ O ₇ [M + H] ⁺ , 861.4730; found: 861.4730.

製造例８に記載の化合物８の合成と同様にして、（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、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−ミリストエート｝（１５３ｍｇ，０．３１ｍｍｏｌ，８５％）を得た。 In the same manner as in the synthesis of Compound 8 described in Production Example 8, (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-myristate (312 mg, 0.36 mmol) To a tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) solution, 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target product, colorless amorphous compound 9 {(2R, 3R) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-myristoate} (153 mg, 0.31 mmol, 85%).

[α]_D ²⁵= -38.3 (c 0.38, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃COCD₃-D₂O, 10 : 1) 6.94 (1H, br s), 6.76 (2H, br s), 6.02 (1H, d, J = 2.2 Hz), 5.91 (1H, d, J = 2.2 Hz), 5.33 (1H, br s), 4.96 (1H, br s), 2.92 (1H, 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); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 10 : 1) 173.5, 157.4, 157.3, 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, 30.4-29.1 (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 計算値 C₂₉H₄₁O₇[M+H]⁺, 501.2852; 実測値: 501.2861. [α] _D ²⁵ = -38.3 (c 0.38, CH ₃ COCH ₃ ); ¹ H-NMR (400 MHz, CD ₃ COCD ₃ -D ₂ O, 10: 1) 6.94 (1H, br s), 6.76 (2H , br s), 6.02 (1H, d, J = 2.2 Hz), 5.91 (1H, d, J = 2.2 Hz), 5.33 (1H, br s), 4.96 (1H, br s), 2.92 (1H, 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 COCD 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, 98.4, 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.

製造例１０：化合物１０｛（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｝の製造
製造例８に記載の化合物８の合成と同様にして、製造例８の工程１で得られた（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（５００ｍｇ，０．７７ｍｍｏｌ）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，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−テトラ−Ｏ−ベンジル−フラバン−３−パルミトエート（４８７ｍｇ、０．５５ｍｍｏｌ，７１％収率）を得た。 Production Example 10: Production of Compound 10 {(2R, 3R) -3 ′, 4 ′, 5,7-Tetrahydroxyflavan-3-palmitoate} A production example was carried out in the same manner as the synthesis of Compound 8 described in Production Example 8. 8 (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (500 mg, 0.77 mmol) in dichloromethane (40 mL) obtained in Step 1 of Triethylamine (0.32 mL, 2.31 mmol), palmitoyl chloride (0.35 mL, 1.16 mmol) and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by silica gel treatment. Purified by column chromatography (n-hexane: ethyl acetate = 6: 1), (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl- Flavane-3-palmitoate (487 mg, 0.55 mmol, 71% yield) was obtained.

[α]_D ²⁵= -16.1 (c 1.34, CHCl₃);¹H-NMR (400 MHz, CDCl₃) 7.46-7.27 (20H, m), 7.12 (1H, d, J = 1.7 Hz), 6.95 (1H, dd, J = 1.7, 8.3 Hz), 6.91 (1H, d, J = 8.3 Hz), 6.29 (1H, d, J = 2.2 Hz), 6.27 (1H, 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 (4H, s), 4.98 (1H, br s), 3.01 (1H, dd, J = 4.4, 17.8 Hz), 2.95 (1H, 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); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₅₉H₆₉O₇[M+H]⁺, 889.5043; 実測値: 889.5089. [α] _D ²⁵ = -16.1 (c 1.34, CHCl ₃ ); ¹ H-NMR (400 MHz, CDCl ₃ ) 7.46-7.27 (20H, m), 7.12 (1H, d, J = 1.7 Hz), 6.95 ( 1H, dd, J = 1.7, 8.3 Hz), 6.91 (1H, d, J = 8.3 Hz), 6.29 (1H, d, J = 2.2 Hz), 6.27 (1H, 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 (4H, s), 4.98 (1H, br s), 3.01 (1H, dd, J = 4.4, 17.8 Hz), 2.95 (1H, 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 Calculated C ₅₉ H ₆₉ O ₇ [M + H] ⁺ , 889.5043; Found: 889.5089.

製造例８に記載の化合物８の合成と同様にして、（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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。後処理後、Ｃｏｓｍｏｓｉｌ（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、無色アモルファスの化合物１０｛（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％）を得た。 In the same manner as in the synthesis of Compound 8 described in Production Example 8, (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-palmiate (420 mg, 0.47 mmol) To a tetrahydrofuran-methanol-water (20: 1: 1, 22 mL) solution, 20% Pd (OH) ₂ / C (5 mg) was added and stirred under a hydrogen atmosphere for 12 hours to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target product, colorless amorphous compound 10 {(2R, 3R) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-palmitoate} (165 mg, 0.31 mmol, 66%) was obtained.

[α]_D ²⁵= -42.0 (c 1.22, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃COCD₃-D₂O, 10 : 1) 6.94 (1H, br s), 6.76 (2H, br s), 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); ¹³C-NMR (100 MHz, CD₃COCD₃-D₂O, 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 計算値 C₃₁H₄₅O₇[M+H]⁺, 529.3165; 実測値: 529.3167. [α] _D ²⁵ = -42.0 (c 1.22, CH ₃ COCH ₃ ); ¹ H-NMR (400 MHz, CD ₃ COCD ₃ -D ₂ O, 10: 1) 6.94 (1H, br s), 6.76 (2H , br s), 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 COCD 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] ⁺ , 529.3165; Found: 529.3167.

製造例１１：化合物１１｛（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｝の製造
製造例８に記載の化合物８の合成と同様にして、製造例８の工程１で得られた（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−３−オール（５００ｍｇ，０．７７ｍｍｏｌ）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−テトラ−Ｏ−ベンジル−フラバン−３−ステアロエート（５６５ｍｇ、０．６２ｍｍｏｌ，８０％収率）を得た。 Production Example 11 Production of Compound 11 {(2R, 3R) -3 ′, 4 ′, 5,7-Tetrahydroxyflavan-3-stearate} Production Example 1 was conducted in the same manner as the synthesis of Compound 8 described in Production Example 8. 8 (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-ol (500 mg, 0.77 mmol) in dichloromethane (40 mL) obtained in Step 1 of Triethylamine (0.32 mL, 2.31 mmol), stearoyl chloride (0.39 mL, 1.16 mmol), and N, N-dimethylaminopyridine (5 mg) were added and reacted while cooling with ice, followed by silica gel treatment. Purified by column chromatography (n-hexane: ethyl acetate = 6: 1), (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl- Flavane-3-stearoate (565 mg, 0.62 mmol, 80% yield) was obtained.

[α]_D ²⁴= -19.8 (c 1.76, CHCl₃); ¹H-NMR (400 MHz, CDCl₃) 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 (1H, d, J = 8.3 Hz), 6.28 (1H, d, J = 2.2 Hz), 6.27 (1H, 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 (4H, s), 4.98 (1H, br s), 3.01 (1H, dd, J = 4.4, 17.3 Hz), 2.94 (1H, 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 (3H, t, J = 6.8 Hz); ¹³C-NMR (100 MHz, CDCl₃) 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 計算値 C₆₁H₇₃O₇[M+H]⁺, 917.5356; 実測値: 917.5403. [α] _D ²⁴ = -19.8 (c 1.76, 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 (1H, d, J = 8.3 Hz), 6.28 (1H, d, J = 2.2 Hz), 6.27 (1H, 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 (4H, s), 4.98 (1H, br s), 3.01 (1H, dd, J = 4.4, 17.3 Hz), 2.94 (1H, 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 (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, 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): Calculated FAB-HRMS C ₆₁ H ₇₃ O ₇ [M + H] ⁺ , 917.5356; Found: 917.5403.

製造例８に記載の化合物８の合成と同様にして、（２Ｒ，３Ｒ）−３’，４’，５，７−テトラ−Ｏ−ベンジル−フラバン−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（登録商標）７５Ｃ−１８ＯＰＮカラムクロマトグラフィー（メタノール−水）で精製し、目的物である、白色粉末の化合物１１｛（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％）を得た。 In the same manner as in the synthesis of Compound 8 described in Production Example 8, (2R, 3R) -3 ′, 4 ′, 5,7-tetra-O-benzyl-flavan-3-stearate (130 mg, 0.14 mmol) 20% Pd (OH) ₂ / C (5 mg) was added to a tetrahydrofuran-methanol-water (20: 1: 1, 11 mL) solution, and the mixture was stirred for 12 hours under a hydrogen atmosphere to deprotect the benzyl group. After the post-treatment, the product was purified by Cosmosil (registered trademark) 75C-18OPN column chromatography (methanol-water), and the target compound, white powder compound 11 {(2R, 3R) -3 ′, 4 ′, 5,7 -Tetrahydroxyflavan-3-stearoate} (50 mg, 0.090 mmol, 64%) was obtained.

[α]_D ²⁵= -19.4 (c 0.32, CH₃COCH₃); ¹H-NMR (400 MHz, CD₃OD) 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); ¹³C-NMR (100 MHz, CD₃OD) 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 計算値 C₃₃H₄₉O₇[M+H]⁺, 557.3478; 実測値: 557.3445. [α] _D ²⁵ = -19.4 (c 0.32, CH ₃ COCH 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 calculated C ₃₃ H ₄₉ O ₇ [M + H] ⁺ , 557.3478; Found: 557.3445.

製造例１〜製造例１１において製造した化合物１〜化合物１１の化学構造を、以下の表１にまとめて示す。 The chemical structures of Compounds 1 to 11 produced in Production Examples 1 to 11 are summarized in Table 1 below.

試験例１：各種の３−アシル化カテキン、及び、３−アシル化エピカテキンの抗炎症活性の評価
（試験方法）
実験では、マウス耳に予め所定量の化合物１〜化合物１１を塗布後、ＴＰＡ（12-O-tetradecanoylphorbol-13-acetate）によって誘発される炎症性浮腫の重量を測定することで各阻害効果を算出した。
試験は、基本的にCancer Lett. 1984, 25, 177-85頁記載の方法にしたがって行った。詳細に説明すると、ＩＣＲ系マウス（４週令・メスを５匹で実施）の一方の耳に、アセトンに溶かした化合物１〜化合物１１を２５０μｇ塗布して、もう片方の耳にアセトンのみ（コントロール）を塗布する。３０分後、両方の耳にアセトンに溶解したＴＰＡを０．５μｇ塗布する。そして７時間後、両方の耳をパンチで穴を空けて、両方の耳片のＴＰＡによって誘発される炎症性浮腫の重量を測定した。そして以下の計算式を用いて、抗炎症活性を算出した。 Test Example 1: Evaluation of anti-inflammatory activity of various 3-acylated catechins and 3-acylated epicatechins (test method)
In the experiment, each inhibitory effect was calculated by measuring the weight of inflammatory edema induced by TPA (12-O-tetradecanoylphorbol-13-acetate) after applying a predetermined amount of compound 1 to compound 11 to the mouse ear in advance. did.
The test was basically performed according to the method described in Cancer Lett. 1984, 25, pages 177-85. Specifically, 250 μg of compound 1 to compound 11 dissolved in acetone was applied to one ear of an ICR mouse (five-week-old females were performed with 5 females), and acetone alone (control) was applied to the other ear. ) Is applied. After 30 minutes, 0.5 μg of TPA dissolved in acetone is applied to both ears. And after 7 hours, both ears were punched and the weight of inflammatory edema induced by TPA in both ear pieces was measured. And the anti-inflammatory activity was computed using the following formulas.

（試験結果）
塗布量を２５０μｇ／耳とした場合の、化合物１〜化合物１１の抗炎症活性を図１に示す。図１から明らかなように、各化合物はそれぞれ、塗布量２５０μｇで炎症を効果的に抑制した。これらの結果より、アシル基の炭素鎖長が長くなるほど抑制活性が強くなることが確認された。なお、化合物４と化合物８の３’，４’，５，７位のフェノール性水酸基をアセチル化した化合物についても同様の評価を行ったところ、フェノール性水酸基をアセチル化することで抗炎症活性は低下する傾向にあることがわかった（データは省略）。 (Test results)
FIG. 1 shows the anti-inflammatory activity of Compound 1 to Compound 11 when the coating amount is 250 μg / ear. As apparent from FIG. 1, each compound effectively suppressed inflammation at a coating amount of 250 μg. From these results, it was confirmed that the inhibitory activity became stronger as the carbon chain length of the acyl group became longer. In addition, when the same evaluation was performed on the compounds obtained by acetylating the phenolic hydroxyl groups at the 3 ′, 4 ′, 5 and 7 positions of Compound 4 and Compound 8, the anti-inflammatory activity was confirmed by acetylating the phenolic hydroxyl group. It turned out to be decreasing (data not shown).

試験例２：化合物７の抗炎症活性の濃度依存性の評価
（試験方法）
マウスの一方の耳に製造例７で得られた化合物７を３１．２５μｇ、６２．５μｇ、１２５μｇ、２５０μｇそれぞれ塗布し、これ以外は試験例１と同様な実験を行った。 Test Example 2: Evaluation of concentration dependency of anti-inflammatory activity of compound 7 (test method)
31.25 μg, 62.5 μg, 125 μg, and 250 μg of Compound 7 obtained in Production Example 7 were applied to one ear of a mouse, respectively, and the same experiment as in Test Example 1 was performed except that.

（試験結果）
図２に示す。図２から明らかなように、化合物７は、濃度依存的に炎症を抑制していることが明らかとなった。これらの実験結果から、化合物１〜化合物１１は抗炎症作用を有するものと認められた。 (Test results)
As shown in FIG. As is clear from FIG. 2, it was revealed that Compound 7 suppressed inflammation in a concentration-dependent manner. From these experimental results, it was recognized that Compounds 1 to 11 have an anti-inflammatory effect.

製剤例１：錠剤
化合物５を３ｇ、乳糖を８０ｇ、ステアリン酸マグネシウムを１７ｇ、合計１００ｇを均一に混合し、常法に従って錠剤とした。 Formulation Example 1: Tablet 3 g of Compound 5, 80 g of lactose, 17 g of magnesium stearate, and a total of 100 g were uniformly mixed to obtain tablets according to a conventional method.

製剤例２：顆粒剤
化合物７を５ｇ、澱粉を３７ｇ、乳糖を５８ｇ、合計１００ｇを均一に混合し、常法に従って顆粒剤とした。 Formulation Example 2: Granules Compound 7 (5 g), starch (37 g), lactose (58 g), and a total of 100 g were uniformly mixed to obtain granules according to a conventional method.

製剤例３：ビスケット
化合物１０を１ｇ、薄力粉を３３ｇ、全卵を１５ｇ、バターを１６ｇ、砂糖を２４ｇ、水を１０ｇ、ベーキングパウダーを１ｇ、合計１００ｇを用い、常法に従ってビスケットとした。 Formulation Example 3: Biscuits 1 g of compound 10, 33 g of flour, 15 g of whole egg, 16 g of butter, 24 g of sugar, 10 g of water, 1 g of baking powder, and a total of 100 g were used to make biscuits according to a conventional method.

本発明は、３−アシル化フラバン−３−オール化合物またはその薬学的に許容される塩を有効成分とするこれまでにない抗炎症剤を提供することができる点において産業上の利用可能性を有する。 The present invention has industrial applicability in that it can provide an unprecedented anti-inflammatory agent comprising a 3-acylated flavan-3-ol compound or a pharmaceutically acceptable salt thereof as an active ingredient. Have.

実施例における、各種の３−アシル化カテキン、及び、３−アシル化エピカテキンのマウス耳に対する抗炎症活性を調べた結果を示すグラフである。It is a graph which shows the result of having investigated the anti-inflammatory activity with respect to the mouse | mouth ear of various 3-acylated catechin and 3-acylated epicatechin in an Example. 化合物７のマウス耳に対する抗炎症活性の濃度依存的な作用を調べた結果を示すグラフである。It is a graph which shows the result of having investigated the concentration-dependent effect | action of the anti-inflammatory activity with respect to the mouse | mouth ear of the compound 7. FIG.

Claims

An anti-inflammatory agent comprising a 3-acylated flavan-3-ol compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

(Wherein R ¹ , R ² , R ³ , R ⁵ and R ⁶ each independently represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower acyloxy group, and R ⁴ represents a linear or branched group. Represents an alkyl group)

The anti-inflammatory agent according to claim 1, wherein the active ingredient is a 3-acylated flavan-3-ol compound represented by the following general formula (2) or a pharmaceutically acceptable salt thereof.

(Wherein R ¹ , R ² , R ³ and R ⁴ are as described above)

The anti-inflammatory agent according to claim 1 or 2, wherein the active ingredient is a 3-acylated flavan-3-ol compound represented by the following general formula (3) or a pharmaceutically acceptable salt thereof.

(Wherein R ¹ , R ² and R ³ are as described above, n represents an integer of 4 to 16)