JPH0543524A - Choline ester of highly unsaturated fatty acid - Google Patents
Choline ester of highly unsaturated fatty acidInfo
- Publication number
- JPH0543524A JPH0543524A JP3226337A JP22633791A JPH0543524A JP H0543524 A JPH0543524 A JP H0543524A JP 3226337 A JP3226337 A JP 3226337A JP 22633791 A JP22633791 A JP 22633791A JP H0543524 A JPH0543524 A JP H0543524A
- Authority
- JP
- Japan
- Prior art keywords
- fatty acid
- highly unsaturated
- unsaturated fatty
- acid
- choline ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】高度不飽和脂肪酸は様々な生理活
性を持っていることが知られている。例えばリノレン
酸、アラキドン酸はプロスタグランジン類の前駆体であ
り、イコサペンタエン酸は血栓溶解作用、抗動脈硬化作
用、血圧降下作用を持つ。またドコサヘキサエン酸は記
憶、学習能の改善、視力低下抑制、抗腫瘍作用、免疫抑
制作用などの薬理効果があるとして最近、注目を集めて
いる高度不飽和脂肪酸である。これらの脂肪酸は医薬品
として用いられることが期待される重要な脂肪酸である
が本発明はそれらの高度不飽和脂肪酸に水溶性を賦与す
ることを目的とした高度不飽和脂肪酸のコリンエステル
誘導体に関するものであり、医薬品、食品、化成品、化
粧品等として利用されることが期待される。[Industrial application] Polyunsaturated fatty acids are known to have various physiological activities. For example, linolenic acid and arachidonic acid are precursors of prostaglandins, and icosapentaenoic acid has thrombolytic action, anti-atherogenic action, and hypotensive action. Docosahexaenoic acid is a polyunsaturated fatty acid that has recently been attracting attention as it has pharmacological effects such as memory, learning ability improvement, suppression of visual acuity deterioration, antitumor effect and immunosuppressive effect. Although these fatty acids are important fatty acids expected to be used as pharmaceuticals, the present invention relates to choline ester derivatives of highly unsaturated fatty acids for the purpose of imparting water solubility to these highly unsaturated fatty acids. Yes, it is expected to be used as medicines, foods, chemical products, cosmetics, etc.
【０００２】[0002]
【従来の技術】高度不飽和脂肪酸は現在、主として医薬
用としてはエチルエステルの形で、また食品用としては
各種の脂肪酸との混合型グリセリドの形で供給されてい
る。しかし一般的にこれらの高度不飽和脂肪酸誘導体は
全く水に溶解せず、医薬品、食品、化成品、化粧品等と
しての応用には限界がある。さらに、医薬品として用い
られているエチルエステルは経口投与する方法が提唱さ
れているものの、吸収効率が極めて悪いことが報告され
ている。（Lipids, 22, 711 (1987)）一方水溶性を賦与
した誘導体を作成する試みも報告されている（特開昭63
-230663）が今だに水溶性が十分でなく実用化には至っ
ていない。BACKGROUND OF THE INVENTION Polyunsaturated fatty acids are currently supplied mainly in the form of ethyl esters for pharmaceutical use and in the form of mixed glycerides with various fatty acids for food use. However, generally, these highly unsaturated fatty acid derivatives are not dissolved in water at all, and there is a limit in their application as pharmaceuticals, foods, chemical products, cosmetics and the like. Furthermore, although an oral administration method has been proposed for ethyl ester used as a drug, it has been reported that the absorption efficiency is extremely poor. (Lipids, 22, 711 (1987)) On the other hand, an attempt to prepare a derivative endowed with water solubility has been reported (JP-A-63).
-230663) is still insufficient in water solubility and has not yet been put to practical use.
【０００３】[0003]
【発明が解決しようとする課題】高度不飽和脂肪酸のエ
チルエステル、例えばイコサペンタエン酸エチルは医薬
として上市されているが経口投与による吸収性は高くな
い。これは主としてエチルエステルが非水溶性であるこ
とに起因する。そこで水溶性を賦与するために高度不飽
和脂肪酸の各種誘導体を作成し、水溶性の有無を検討し
た。すなわち本発明の目的は水溶性を賦与することによ
り吸収効率を高め、医薬品、食品、化成品、化粧品等へ
の幅広い応用を目指すものである。一方、水溶性を賦与
することにより化学修飾が好ましくない生理作用を持ち
込む可能性もある。これを避けるために、元来生体内に
大量に存在するものもしくは、日常生活において食品と
して摂取しているものと結合させた誘導体を作製し、水
溶性の賦与を試みた。上記の課題を解決すべく鋭意検討
の結果、高度不飽和脂肪酸のコリンエステル体が目的に
合致するものであり、かつ以下のごとく容易に作製し得
る事を見いだし、本発明を完成するに至った。The ethyl ester of polyunsaturated fatty acid, for example, ethyl icosapentaenoate, is marketed as a medicine, but its absorbability by oral administration is not high. This is mainly due to the water insolubility of the ethyl ester. Therefore, in order to impart water solubility, various derivatives of polyunsaturated fatty acids were prepared and examined for water solubility. That is, the object of the present invention is to enhance the absorption efficiency by imparting water-solubility, and aim for a wide range of applications to medicines, foods, chemical products, cosmetics and the like. On the other hand, by imparting water solubility, chemical modification may bring about an unfavorable physiological action. In order to avoid this, we tried to impart water-solubility by preparing a derivative that was bound to a substance that originally exists in a large amount in the living body or a substance that is ingested as food in daily life. As a result of diligent studies to solve the above problems, it was found that a choline ester form of a polyunsaturated fatty acid is suitable for the purpose, and that it can be easily produced as follows, and completed the present invention. ..
【０００４】[0004]
【課題を解決するための手段】本発明は一般式ＲＣＯ2
（ＣＨ2）2Ｎ+（ＣＨ3）3・Ｘ-、（式中Ｒは高度不飽和
脂肪酸残基、Ｘ-は塩形成陰イオンを表す。）で表わさ
れる、高度不飽和脂肪酸のコリンエステル体である。The present invention has the general formula RCO 2
A choline ester of a highly unsaturated fatty acid represented by (CH 2 ) 2 N + (CH 3 ) 3 · X − , (wherein R is a highly unsaturated fatty acid residue and X − is a salt-forming anion). It is the body.
【０００５】本発明の高度不飽和脂肪酸のコリンエステ
ル体の式中、Ｒの高度不飽和脂肪酸残基としてはドコサ
ヘキサエン酸、ドコサペンタエン酸、イコサペンタエン
酸、アラキドン酸、リノレン酸等の脂肪酸残基が例示で
き、又Ｘ-の塩形成陰イオンとしては、ハロゲン、硫
酸、酢酸、乳酸等の陰イオンが例示できる。In the formula of the choline ester form of the polyunsaturated fatty acid of the present invention, examples of the polyunsaturated fatty acid residue of R include fatty acid residues such as docosahexaenoic acid, docosapentaenoic acid, icosapentaenoic acid, arachidonic acid and linolenic acid. Examples of the salt-forming anion of X − include anions such as halogen, sulfuric acid, acetic acid, and lactic acid.
【０００６】本発明の高度不飽和脂肪酸のコリンエステ
ルは以下のいずれかの方法により合成することが出来
る。The choline ester of a polyunsaturated fatty acid of the present invention can be synthesized by any of the following methods.
【０００７】高度不飽和脂肪酸またはそのエステルに、
常法に従って、Ｎ、Ｎ−ジメチル−２−アミノエタノー
ルを作用させてＮ、Ｎ−ジメチル−２−アミノエタノー
ルの脂肪酸エステルを作製し、ついでメチル化剤、例え
ばハロゲン化メチルや硫酸ジメチル等を用いてメチル化
してコリンエステル体とすることができる。For highly unsaturated fatty acids or their esters,
According to a conventional method, N, N-dimethyl-2-aminoethanol is allowed to act to produce a fatty acid ester of N, N-dimethyl-2-aminoethanol, and then a methylating agent such as methyl halide or dimethyl sulfate is used. It can be methylated to a choline ester form.
【０００８】高度不飽和脂肪酸の２−ハロエタノールエ
ステルを作製し、このものにトリメチルアミンを作用さ
せてコリンエステル体とすることができる。A 2-haloethanol ester of a polyunsaturated fatty acid can be prepared, and trimethylamine can be allowed to act on it to give a choline ester form.
【０００９】高度不飽和脂肪酸とコリン塩を直接または
酸クロリド等を経由して縮合せしめコリンエステル体と
することができる。The polyunsaturated fatty acid and choline salt can be condensed directly or via an acid chloride to form a choline ester form.
【００１０】[0010]
【発明の効果】すなわち、本発明によって提供される高
度不飽和脂肪酸のコリンエステル体はクロロホルム、各
種アルコール等の有機溶媒に易溶であると同時に水に対
しても非常によく溶ける。さらに凍結乾燥することによ
ってフレーク状にすることも可能であり、医薬品、食
品、化成品、化粧品等の各分野での幅広い応用が期待で
きる。That is, the choline ester form of highly unsaturated fatty acid provided by the present invention is readily soluble in organic solvents such as chloroform and various alcohols, and at the same time, is very soluble in water. Further, it can be freeze-dried to form flakes, which can be expected to have a wide range of applications in various fields such as pharmaceuticals, foods, chemical products, and cosmetics.
【００１１】以下、実施例及び試験例に基づき本発明を
更に具体的に説明する。Hereinafter, the present invention will be described more specifically based on Examples and Test Examples.
実施例１ 高度不飽和脂肪酸としてドコサヘキサエン酸エチルエス
テル１０．０ｇを用い、このものとＮ、Ｎ−ジメチル−
２−アミノエタノール２４．９ｇの混合物にナトリウム
少量を加え遮光、アルゴン雰囲気下で密栓、室温で攪拌
する。反応の進行状況は薄層クロマトグラフィーでトレ
ースする。反応終了後は、まず液量が全体の１／４程度
になるまで過剰に存在するアミノエタノールを留去し、
次いで酢酸エチルを加えて希釈する。この溶液を蒸留水
で繰り返し洗浄し、残存アミノエタノールを完全に除去
する。その後、酢酸エチル層を無水硫酸マグネシウムで
乾燥し、酢酸エチルを留去して１０．３ｇの粗成ドコサ
ヘキサエン酸Ｎ、Ｎ−ジメチル−２−アミノエチルを得
た。これをシリカゲル２００ｇを用い酢酸エチルで展開
してカラムクロマト精製すると純品７．３ｇがオレンジ
からやや褐色の油状物質として得られた。Example 1 10.0 g of docosahexaenoic acid ethyl ester was used as the polyunsaturated fatty acid, and this was mixed with N, N-dimethyl-
A small amount of sodium is added to a mixture of 24.9 g of 2-aminoethanol, and the mixture is protected from light, sealed under an argon atmosphere, and stirred at room temperature. The progress of the reaction is traced by thin layer chromatography. After completion of the reaction, first, excess aminoethanol present is distilled off until the liquid volume becomes about 1/4 of the total volume,
Then ethyl acetate is added to dilute. This solution is washed repeatedly with distilled water to completely remove the residual aminoethanol. Then, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off to obtain 10.3 g of crude N, N-dimethyl-2-aminoethyl docosahexaenoate. When this was developed using 200 g of silica gel with ethyl acetate and purified by column chromatography, 7.3 g of a pure product was obtained as an orange to slightly brown oily substance.
【００１２】このドコサヘキサエン酸Ｎ、Ｎ−ジメチル
−２−アミノエチル７．３ｇをイソプロピルアルコール
１１０ｍｌに溶解し、よう化メチル５．２ｇを加えて、
室温で密栓、遮光して攪拌し反応させる。約１２時間反
応させた後、反応が終了していることを薄層クロマトで
確認してからイソプロピルアルコールを留去すると、ド
コサヘキサエノイルコリンイオダイド１０．７ｇが得ら
れた。本生成物は褐色の吸湿性のある固体で、水および
クロロホルム、メタノール、エタノール及びイソプロパ
ノール等に易溶性であった。元素分析の結果を第１表に
示す。なお、元素分析用サンプルは純水に溶解した後、
凍結乾燥して得られるフレーク状固体を用いた。 7.3 g of this N, N-dimethyl-2-aminoethyl docosahexaenoate was dissolved in 110 ml of isopropyl alcohol, and 5.2 g of methyl iodide was added.
Seal at room temperature, stir and shield from light to react. After reacting for about 12 hours, it was confirmed by thin layer chromatography that the reaction was completed, and then isopropyl alcohol was distilled off to obtain 10.7 g of docosahexaenoylcholine iodide. This product was a brown hygroscopic solid, and was easily soluble in water and chloroform, methanol, ethanol, isopropanol and the like. The results of elemental analysis are shown in Table 1. After the elemental analysis sample was dissolved in pure water,
The flaky solid obtained by freeze-drying was used.
【００１３】本生成物のＮＭＲ分析値は以下の通りであ
った。 0.98(3H,t,J=7.5), 2.09(2H,m), 2.4(2H,br.t,J=7), 2.
5(2H,m), 2.8-2.9(10H,m), 3.5(9H,s), 4.1(2H,m), 4.6
(2H,m), 5.3-5.4(12H,m) また質量分析の結果、ヨウ素イオンがとれた形の４１４
のピークが得られた。The NMR analysis values of this product were as follows. 0.98 (3H, t, J = 7.5), 2.09 (2H, m), 2.4 (2H, br.t, J = 7), 2.
5 (2H, m), 2.8-2.9 (10H, m), 3.5 (9H, s), 4.1 (2H, m), 4.6
(2H, m), 5.3-5.4 (12H, m) In addition, as a result of mass spectrometry, 414 in a form with iodine ions removed
Was obtained.
【００１４】実施例２ イコサペンタエン酸エチルエステル１．００ｇとＮ、Ｎ
−ジメチル−２−アミノエタノール２．７０ｇの混合物
にナトリウム少量を加え遮光、アルゴン雰囲気下で密
栓、室温で攪拌する。反応の進行状況は薄層クロマトグ
ラフィーでトレースする。反応終了後はまず、液量が全
体の１／４程度になるまで過剰に存在するアミノエタノ
ールを留去し、次いで酢酸エチルを加えて希釈する。こ
の溶液を蒸留水で繰り返し洗浄し、残存アミノエタノー
ルを完全に除去する。その後、酢酸エチル層を無水硫酸
マグネシウムで乾燥し、酢酸エチルを留去して０．７５
ｇの粗成イコサペンタエン酸Ｎ、Ｎ−ジメチル−２−ア
ミノエチルを得た。これをシリカゲル３５ｇを用い、酢
酸エチルで展開してカラムクロマト精製すると純品０．
３５ｇが淡黄色の油状物質として得られた。Example 2 1.00 g of icosapentaenoic acid ethyl ester and N, N
-A small amount of sodium is added to a mixture of 2.70 g of dimethyl-2-aminoethanol, and the mixture is protected from light, sealed under an argon atmosphere, and stirred at room temperature. The progress of the reaction is traced by thin layer chromatography. After the completion of the reaction, first, excess aminoethanol present is distilled off until the liquid volume becomes about 1/4 of the total volume, and then ethyl acetate is added to dilute. This solution is washed repeatedly with distilled water to completely remove the residual aminoethanol. Then, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off to obtain 0.75.
g of crude N, N-dimethyl-2-aminoethyl icosapentaenoate was obtained. This was purified by column chromatography using 35 g of silica gel and developed with ethyl acetate to give a pure product of 0.
35 g was obtained as a pale yellow oil.
【００１５】このイコサペンタエン酸Ｎ、Ｎ−ジメチル
−２−アミノエチル０．３５ｇをイソプロピルアルコー
ル５．３７ｍｌに溶解し、ヨウ化メチル０．３６ｇを加
えて、室温で密栓、遮光して攪拌し反応させる。約１２
時間反応させた後、反応が終了していることを薄層クロ
マトで確認してからイソプロピルアルコールを留去する
とイコサペンタエノイルコリンイオダイド０．４８ｇを
得た。これは褐色の吸湿性のある固体で、水、クロロホ
ルム、メタノール、エタノール及びイソプロパノールに
易溶性であった。本生成物のＮＭＲ分析値は以下の通り
であった。0.35 g of this N, N-dimethyl-2-aminoethyl icosapentaenoate is dissolved in 5.37 ml of isopropyl alcohol, 0.36 g of methyl iodide is added, and the mixture is stirred at room temperature, sealed and shielded from light to react. .. About 12
After reacting for a period of time, it was confirmed by thin layer chromatography that the reaction was completed, and then isopropyl alcohol was distilled off to obtain 0.48 g of icosapentaenoylcholine iodide. It was a brown, hygroscopic solid which was readily soluble in water, chloroform, methanol, ethanol and isopropanol. The NMR analysis value of this product was as follows.
【００１６】0.98(3H,t,J=7.5), 17(2H,m), 2.05-2.15
(4H,m), 2.4(2H,t,J=7.7),2.8(8H,m), 3.6(9H,s), 4.15
(2H,m), 4.6(2H,br.s), 5.3-5.4(10H,m) また質量分析の結果、ヨウ素イオンの取れた形の３７３
のピークが得られた。0.98 (3H, t, J = 7.5), 17 (2H, m), 2.05-2.15
(4H, m), 2.4 (2H, t, J = 7.7), 2.8 (8H, m), 3.6 (9H, s), 4.15
(2H, m), 4.6 (2H, br.s), 5.3-5.4 (10H, m) In addition, as a result of mass spectrometry, 373 in the form without iodine ion
Was obtained.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/23 ＡＢＬ 8413−4Ｃ ＡＢＵ 8413−4Ｃ ＡＢＸ 8413−4Ｃ ＡＣＢ 8413−4Ｃ ＡＤＵ 8413−4Ｃ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification number Office reference number FI Technical display location A61K 31/23 ABL 8413-4C ABU 8413-4C ABX 8413-4C ACB 8413-4C ADU 8413-4C
Claims (3)
Ｘ-、（式中Ｒは高度不飽和脂肪酸残基、Ｘ-は塩形成陰
イオンを表す。）で表わされる、高度不飽和脂肪酸のコ
リンエステル体。1. The general formula RCO 2 (CH 2 ) 2 N + (CH 3 ) 3
A choline ester of a polyunsaturated fatty acid represented by X − , (wherein R represents a polyunsaturated fatty acid residue, and X − represents a salt-forming anion).
和結合数３以上を有する脂肪酸である請求項１記載の高
度不飽和脂肪酸のコリンエステル体。2. The choline ester of highly unsaturated fatty acid according to claim 1, wherein the highly unsaturated fatty acid is a fatty acid having 18 or more carbon atoms and 3 or more unsaturated bonds.
ン酸、イコサペンタエン酸、ドコサペンタエン酸又はド
コサヘキサエン酸である請求項２記載の高度不飽和脂肪
酸のコリンエステル体。3. The choline ester of highly unsaturated fatty acid according to claim 2, wherein the highly unsaturated fatty acid is linolenic acid, arachidonic acid, icosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3226337A JPH0543524A (en) | 1991-08-13 | 1991-08-13 | Choline ester of highly unsaturated fatty acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3226337A JPH0543524A (en) | 1991-08-13 | 1991-08-13 | Choline ester of highly unsaturated fatty acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0543524A true JPH0543524A (en) | 1993-02-23 |
Family
ID=16843589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3226337A Pending JPH0543524A (en) | 1991-08-13 | 1991-08-13 | Choline ester of highly unsaturated fatty acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0543524A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1334869B1 (en) | 2002-02-07 | 2017-01-11 | Toyota Jidosha Kabushiki Kaisha | Vehicle operation supporting device and vehicle operation supporting system |
-
1991
- 1991-08-13 JP JP3226337A patent/JPH0543524A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1334869B1 (en) | 2002-02-07 | 2017-01-11 | Toyota Jidosha Kabushiki Kaisha | Vehicle operation supporting device and vehicle operation supporting system |
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