JPS63135395A - Phospholipid derivative and production thereof - Google Patents
Phospholipid derivative and production thereofInfo
- Publication number
- JPS63135395A JPS63135395A JP28168686A JP28168686A JPS63135395A JP S63135395 A JPS63135395 A JP S63135395A JP 28168686 A JP28168686 A JP 28168686A JP 28168686 A JP28168686 A JP 28168686A JP S63135395 A JPS63135395 A JP S63135395A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- glycerophosphorylcholine
- acid
- reaction
- expressed
- 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
- 150000003904 phospholipids Chemical class 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 239000008777 Glycerylphosphorylcholine Substances 0.000 claims abstract description 20
- 229960004956 glycerylphosphorylcholine Drugs 0.000 claims abstract description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 13
- 239000000194 fatty acid Substances 0.000 claims abstract description 13
- 229930195729 fatty acid Natural products 0.000 claims abstract description 13
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 abstract description 10
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 abstract description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000012190 activator Substances 0.000 abstract 1
- 230000001900 immune effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000003998 snake venom Substances 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229940057303 naja naja venom Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 2
- 102000015439 Phospholipases Human genes 0.000 description 2
- 108010064785 Phospholipases Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- TVIDDXQYHWJXFK-UHFFFAOYSA-N dodecanedioic acid Chemical compound OC(=O)CCCCCCCCCCC(O)=O TVIDDXQYHWJXFK-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BNJOQKFENDDGSC-UHFFFAOYSA-N octadecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCC(O)=O BNJOQKFENDDGSC-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- -1 phospholipid compounds Chemical class 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- XETRHNFRKCNWAJ-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate Chemical compound FC(F)(F)C(F)(F)C(=O)OC(=O)C(F)(F)C(F)(F)F XETRHNFRKCNWAJ-UHFFFAOYSA-N 0.000 description 1
- UDSFAEKRVUSQDD-UHFFFAOYSA-N Dimethyl adipate Chemical compound COC(=O)CCCCC(=O)OC UDSFAEKRVUSQDD-UHFFFAOYSA-N 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000002390 cell membrane structure Anatomy 0.000 description 1
- SUHOQUVVVLNYQR-MRVPVSSYSA-N choline alfoscerate Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC[C@H](O)CO SUHOQUVVVLNYQR-MRVPVSSYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- ZOXMHKCFDXHCJX-UHFFFAOYSA-N dimethyl octadecanedioate Chemical compound COC(=O)CCCCCCCCCCCCCCCCC(=O)OC ZOXMHKCFDXHCJX-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、薬理学的に有効な新規なリン脂質誘導体及び
その製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel pharmacologically effective phospholipid derivative and a method for producing the same.
（従来の技術とその問題点）
細胞膜構造の脂質中には下記の構造式で表されるリン脂
質化合物が多く存在しており、生体内酸化反応により式
中の２位の不飽和炭化水素ＭＲ３が種々の官能基に置換
され、薬理学的に有効である化合物が生成する。(Prior art and its problems) There are many phospholipid compounds represented by the following structural formula in the lipids of the cell membrane structure. is substituted with various functional groups to produce compounds that are pharmacologically effective.
ｔｈｅ−ＯＣＲｚ ＨＣ−ＯＣＲ。the-OCRz HC-OCR.
（式中、Ｒ２はアルキル基を示し、Ｒ：ｌは不飽和炭化
水素基を示す。）
しかしながら、これまでに式中２位に官能基を有するリ
ン脂質化合物の製造に成功した報告はなされていない。(In the formula, R2 represents an alkyl group, and R:l represents an unsaturated hydrocarbon group.) However, to date, there have been no reports of successful production of phospholipid compounds having a functional group at the 2-position in the formula. do not have.
本発明の目的は、式中２位に官能基を有する薬理学的に
有効な新規なリン脂質誘導体及びその製造方法を提供す
ることにある。An object of the present invention is to provide a novel pharmacologically effective phospholipid derivative having a functional group at the 2-position in the formula, and a method for producing the same.
（問題点を解決するための手段）
本発明の薬理学的に有効な新規なリン脂質３′ｊ、導体
は次の構造式（１）で表されるような２位にカルボキシ
ル基を有する化合物である。(Means for Solving the Problems) In the pharmacologically effective novel phospholipid 3'j of the present invention, the conductor is a compound having a carboxyl group at the 2-position as represented by the following structural formula (1). It is.
１１２Ｃ−ＯＣＲ＋ （式中、Ｒ，は炭素数３〜２１のアルキル基である。112C-OCR+ (In the formula, R is an alkyl group having 3 to 21 carbon atoms.
また、ｎは２〜２０である。）
」二記式中、Ｒ１は炭素数３〜２１のアルキル基を表す
が、この範囲外では薬理学的な有効性に乏しい。Moreover, n is 2-20. ) In the formula, R1 represents an alkyl group having 3 to 21 carbon atoms, but outside this range, pharmacological effectiveness is poor.
また、ｎは２〜２０であるが、この範囲外では同様に薬
理学的な有効性に乏しい。Further, n is 2 to 20, but if it is outside this range, pharmacological effectiveness is similarly poor.
本発明のリン脂質誘導体（１）は、以下に記載する方法
によって製造することができる。The phospholipid derivative (1) of the present invention can be produced by the method described below.
すなわち、次の一般式
％式％
（式中、Ｒ，は炭素数３〜２１のアルキル基を示す。）
で表される１−モノアシル−３−グリセロホス、Ｉ；リ
ルコリンと、次の一般式：
（式中、ｎは２〜２０である。）
で表される二塩基酸を、・次の一般式：％式％（）
（式中、ｍは０〜２である。）
で表される無水フッ素置換脂肪酸の存在下で反応させる
。That is, the following general formula % formula % (In the formula, R represents an alkyl group having 3 to 21 carbon atoms.)
1-monoacyl-3-glycerophos, I; lylcholine, represented by the following general formula: (wherein, n is 2 to 20), and a dibasic acid represented by the following general formula: The reaction is carried out in the presence of an anhydrous fluorine-substituted fatty acid represented by the formula % (in the formula, m is 0 to 2).
反応は、１−モノアシル−３−グリセロホス；トリルコ
リン（ＩＩ）を二塩基酸（Ｉ［［）と無水フッ累置換脂
肪酸（ＩＶ）の存在下で行われるが、この３種の化合物
を同時に反応させるか、または、まず二塩基酸（ＩＴＳ
）と無水フン素置換脂肪酸（ＴＶ）とを反応させて反応
中間体（Ｖ）を生成し、次いでこれと１−モノアシル−
３−グリセロボスボリルコリン（ＩＩ）とを反応させる
ことにより行われる。The reaction is carried out with 1-monoacyl-3-glycerophos; tolylcholine (II) in the presence of a dibasic acid (I[[) and anhydrous fluorosubstituted fatty acid (IV), but these three compounds are reacted simultaneously. Or, first dibasic acid (ITS
) and a fluorine-substituted fatty acid anhydride (TV) to produce a reaction intermediate (V), which is then reacted with 1-monoacyl-
This is carried out by reacting with 3-glycerobosborylcholine (II).
後者の方法は、反応の中間体を一旦取り出して精製する
ため最終生成物の収量が上がるので一層好ましい。反応
温度及び反応時間は特に限定はないが、通常は０〜９０
℃で、５〜４８時間である。後者の場合には例えば次の
方法によって製造することができる。The latter method is more preferable because the yield of the final product is increased because the reaction intermediate is once removed and purified. The reaction temperature and reaction time are not particularly limited, but are usually 0 to 90
℃ for 5 to 48 hours. In the latter case, it can be produced, for example, by the following method.
（ＩＩＩ ） （ｒＶ ）（Ｖ）
（Ｖｌ）１１２Ｃ−ＯＣＩ’ｌ１
１１、Ｃ−０−Ｐ−０−（ＣＩ＋２） ｚ−Ｎ（Ｃｌ１
３） ３！
（ｎ）
π
１１□Ｃ−０Ｃｒ！。(III) (rV) (V)
(Vl) 112C-OCI'l1 11, C-0-P-0-(CI+2) z-N(Cl1
3) 3! (n) π 11□C-0Cr! .
ＨＣ−ＱＣ（ＣＩＩ２）、１ＣＯＨ（＋ ）（式中、Ｒ
１は炭素数３〜２１のアルキル基を示し、ｎは２〜２０
で、「ｎは０〜２である。）なお、この反応で副生ずる
フン素置換脂肪酸（■）は減圧に縮によって留去できる
。HC-QC (CII2), 1COH(+) (in the formula, R
1 represents an alkyl group having 3 to 21 carbon atoms, and n is 2 to 20
"n is 0 to 2." Note that the fluorine-substituted fatty acid (■) produced as a by-product in this reaction can be distilled off by condensation under reduced pressure.
（＋７１）と（ｒＶ）との反応における反応温度及び反
応時間は特に限定はないが、通常は０〜４０℃で、５〜
２４時間である。ピリジン存在下での（Ｖ）と１）との
反応についても反応温度及び反応時間は°［、νに限定
はないが、通常は４０〜９０℃で、１０〜４８時間であ
る。The reaction temperature and reaction time in the reaction between (+71) and (rV) are not particularly limited, but are usually 0-40°C and 5-40°C.
It is 24 hours. Regarding the reaction of (V) with 1) in the presence of pyridine, the reaction temperature and reaction time are not limited to °[, ν, but are usually 40 to 90°C and 10 to 48 hours.
１−４ノアシル−３−グリセロホスホリルコリン（［［
）としては、（列えば、■−）゛チリルシー３−グリセ
ロホスホリルコリン、１−オクタノイル−３−グリセロ
ホスホリルコリン、１−ラウロイル−３−グリセロホス
ホリルコリン、■−パルミ；・イル−３−グリセロホス
ホリルコリン、■−ステアロイルー３−グリセロホスホ
リルコリン、１−エイコサノイル−３−グリセロホスホ
リルコリンが挙げられる。1-4 noacyl-3-glycerophosphorylcholine ([[
), (for example, ■-) tyrylic-3-glycerophosphorylcholine, 1-octanoyl-3-glycerophosphorylcholine, 1-lauroyl-3-glycerophosphorylcholine, ■-palmy;-yl-3-glycerophosphorylcholine, ■- Examples include stearoyl-3-glycerophosphorylcholine and 1-eicosanoyl-3-glycerophosphorylcholine.
二塩基酸（ＩＩＩ）としては、コハク酸、グルタル酸、
アジピン酸、ピメリン酸、スペリン酸、アゼライン酸、
セバシン酸、１，１０−デカンジカルボン酸、１．１２
−ドデカンジカルボン酸、１゜１４−テトラデカンジカ
ルボン酸、■、１６−へキナデカンジカルボン酸などが
あげられる。As dibasic acid (III), succinic acid, glutaric acid,
Adipic acid, pimelic acid, speric acid, azelaic acid,
Sebacic acid, 1,10-decanedicarboxylic acid, 1.12
Examples include -dodecanedicarboxylic acid, 1°14-tetradecanedicarboxylic acid, and 1,16-hequinadecanedicarboxylic acid.
また、無水フッ素置換脂肪酸（ＩＶ）としては、無水Ｉ
・リフルオロ酢酸、無水ペンタフルオロプロピオン酸、
無水へブタフルオロｎ８ｈ’Ｚがあげら１する。In addition, as the anhydrous fluorinated fatty acid (IV), anhydrous I
・Lifluoroacetic acid, pentafluoropropionic anhydride,
Anhydrous hebutafluoro n8h'Z is used.
次にピリジン存在下での（Ｖ）と（汀）との反応につい
ても反応温度及び反応時間は特に限定はないが、＋１１
常は４０〜９０℃で、１０〜．１８時間である。Next, regarding the reaction of (V) and (bean) in the presence of pyridine, the reaction temperature and reaction time are not particularly limited, but +11
Usually the temperature is 40~90℃, 10~. It is 18 hours.
反応終了後、反応混合物を）濃縮し、残留物をシリカゲ
ルクロマトグラフィー等の分、■手段により精製して、
目的化合物（［）の純品をｉコ、ることかできる。After the reaction is completed, the reaction mixture is concentrated, and the residue is purified by means such as silica gel chromatography.
It is possible to obtain a pure product of the target compound ([).
（発明の効果）
本発明のリン脂質誘導体は新規な物質であり、免疫賦活
剤としての効力を有すると考えられ、薬理学的に極めて
有用な化合物である。(Effects of the Invention) The phospholipid derivative of the present invention is a novel substance, is thought to have efficacy as an immunostimulant, and is a pharmacologically extremely useful compound.
また、本発明の新規なリン脂質誘導体の製造方法は、薬
理学的に極めて有用な化合物であるリン脂質誘導体を少
ない工程数で、しかも容易に入手できる原料を使用して
、高収率・高純度で得ることができ、工業的に極めて有
用な製法である。In addition, the novel method for producing phospholipid derivatives of the present invention can produce phospholipid derivatives, which are pharmacologically extremely useful compounds, in a small number of steps and using easily available raw materials in high yields and high yields. It can be obtained with high purity and is an extremely useful production method industrially.
（実施例）
以下、実施例及び比較例をあげて本発明をさらに具体的
に説明する。(Examples) Hereinafter, the present invention will be explained in more detail by giving Examples and Comparative Examples.
実施例１
攪拌子の入った１００ｍ１活栓付ナス形フラスコに、ア
ゼライン酸（純度９９％） １０００■及び無水トリフ
ルオロ酢酸（純度９９％）７４０■を導入し、室温で１
６時間反応させた。反応終了後、副生ずるトリフルオロ
酢酸を減圧下で留去した。次いで、１−バルミトイル−
３−グリセロホスホリルコリン６００■をピリジン（純
度９９％）８ｍｌに；フ濁し、この）脈濁液を先の反応
容器に加え、８０℃で１６時間反応させた。Example 1 1000 μ of azelaic acid (purity 99%) and 740 μ of trifluoroacetic anhydride (purity 99%) were introduced into a 100 ml eggplant-shaped flask with a stopper containing a stirring bar, and the mixture was heated at room temperature for 1
The reaction was allowed to proceed for 6 hours. After the reaction was completed, by-produced trifluoroacetic acid was distilled off under reduced pressure. Then, 1-valmitoyl-
600 μl of 3-glycerophosphorylcholine was added to 8 ml of pyridine (purity 99%) to make it cloudy, and this turbid liquid was added to the reaction vessel and reacted at 80° C. for 16 hours.
反応終了後、反応混合物を濃縮し、残留物をり１１１コ
ボルムにン８角了し、シリカゲルＦＪＢクロマトグラフ
ィー（展開ン夜；クロロホルム：メタノール二吊、酸；
水−５０：２５：８二４ （容積比））で分離した。そ
してＲ２値０．５１のスポットを分取し、メタノールで
抽出した。抽出液を濃縮後、酢酸を除去するためにｎ−
へキサンを力■えてン農１宿した。残留物をクロロホル
ムに溶屑し、不溶物を濾過で除去した後、再度濃縮した
。さらに残留物を水に熔解させて凍結乾燥を行い、パウ
ダー状の１−バルミトイル−２−（８−カルボキシル）
オクタノイル−３−グリセロホスホリルコリン２１０ｎ
ｗ （収率２６．１％）を得た。After the reaction was completed, the reaction mixture was concentrated, the residue was diluted with 111 cobalt, and subjected to silica gel FJB chromatography (eluent; chloroform: methanol, acid;
Water - 50:25:824 (volume ratio)). Then, a spot with an R2 value of 0.51 was collected and extracted with methanol. After concentrating the extract, n-
I went to Hexan and stayed there for one night. The residue was dissolved in chloroform, insoluble matter was removed by filtration, and then concentrated again. Furthermore, the residue was dissolved in water and freeze-dried to obtain powdered 1-valmitoyl-2-(8-carboxyl).
Octanoyl-3-glycerophosphorylcholine 210n
w (yield 26.1%) was obtained.
マススペクトル、赤外スペクトル及び元素分析の結果は
次の通りであった。The results of mass spectrum, infrared spectrum and elemental analysis were as follows.
マススペクトル（ｍ／Ｚ） ： ６６Ｇ （Ｍ”＋Ｈ
）赤外スペクトル： ２９００ｃｍ−’ （カルボキシ
ル０１１伸縮振動）
元素分析： Ｃ３：＋ｔｌｂ４ＮＯ＋。Ｐとして（計
算値） ： Ｃ５９，５５％、 １１９．６２％。Mass spectrum (m/Z): 66G (M”+H
) Infrared spectrum: 2900 cm-' (carboxyl 011 stretching vibration) Elemental analysis: C3:+tlb4NO+. As P (calculated value): C59.55%, 119.62%.
Ｎ ２．１１％、 Ｐ ４．６６％ （実測値）： Ｃ５９，０５％、 Ｈ９，５１％。N 2.11%, P 4.66% (Actual measurements): C59.05%, H9.51%.
Ｎ ２．１５％、 Ｐ ４．６９％
なお、リン脂質の２位の炭素のエステル結合を特異的に
分解する酵素を用いて、２位の炭素に結合した基を確認
した。N 2.15%, P 4.69% The group bonded to the 2nd carbon position of the phospholipid was confirmed using an enzyme that specifically decomposes the ester bond at the 2nd carbon position.
実施例１で合成した化合物１００１■を、へび毒ホスホ
リパーゼＡｚ（ｎａｊａ ｎａｊａ ｖｅｎｏｍ ；
ＳＩＧＭＡ Ｃｈｅｍ。Compound 1001■ synthesized in Example 1 was treated with snake venom phospholipase Az (naja naja venom;
SIGMA Chem.
Ｃｏｒｐ、） ０．３＋ｗ、５％（ａｃｌｚ水？容；夜
０．１ｍ１ｌ及びエチルエーテル１０ ｍｌの混合液に
加え、室温で１晩攪拌して反応さ−Ｕた。反応後、シリ
カゲル薄層クロマトクラフィー（展開液；クロロホルム
：メタノール： ｒＩｌ：水−５０；２５： ８ ；
４ （容積比））で分ｊｕｌｌ ＋、た。Ｒ１値０．９
０付近の脂肪酸成分のスポットを分取してメタノールで
抽出した。この脂肪酸成分、お常法によりメチルエステ
ル化した後ガスクロマトグラフィーで分析した結果、標
品のアゼラインこクジメチルエステルと同じピークが９
５．３％の純度で得られた。Corp.) 0.3+w, 5% (aclz water?volume) was added to a mixture of 0.1 ml of water and 10 ml of ethyl ether, and reacted by stirring overnight at room temperature. After the reaction, silica gel thin layer chromatography Claffy (Developing solution; Chloroform: Methanol: rIl: Water-50; 25: 8;
4 (volume ratio)) for minutes jull +. R1 value 0.9
A spot containing fatty acid components near 0 was fractionated and extracted with methanol. This fatty acid component was methyl esterified by a conventional method and then analyzed by gas chromatography. As a result, the same peak as the standard azelain kokudimethyl ester was found at 9.
Obtained with a purity of 5.3%.
以上の分析結果より、１−バルミトイル−２＝（８−カ
ルボキシル）オクタノイル−３−グリセロホスホリルコ
リンが合成されていることが確かめられた。From the above analysis results, it was confirmed that 1-balmitoyl-2=(8-carboxyl)octanoyl-3-glycerophosphorylcholine was synthesized.
実施例２
アゼライン酸のかわりに１．１６−ヘキサデカンジカル
ボン酸（′４屯度９９％） １６７０．■を、またｌ−
バルミトイル−３−グリセロホスホリルコリンのかわり
に１−ステアＩフィルー３−グリセロホスホリルコリン
６３５■を用いた以外は、実施例１に述べた方法と同様
の条件で反応させ、シリカゲル薄層クロマトグラフィー
で分離した。そしてＲ２値０．５５のスポットを分取し
、メタノールで抽出した。Example 2 1,16-hexadecanedicarboxylic acid ('4 toughness 99%) 1670. instead of azelaic acid. ■, again l-
The reaction was carried out under the same conditions as described in Example 1, except that 1-Stear I fill-3-glycerophosphorylcholine 635.mu. was used in place of valmitoyl-3-glycerophosphorylcholine, and the mixture was separated by silica gel thin layer chromatography. Then, a spot with an R2 value of 0.55 was collected and extracted with methanol.
以下、実施例１に述べた方法と同様の方法で操作して、
パウダー状の１−ステアロイル−２−（１７−カルボキ
シル）ヘプタデカノイル−３−グリセロホスホリルコリ
ン２２０■（収率２２．２％′６）を得た。Hereinafter, by operating in the same manner as described in Example 1,
220 μg of 1-stearoyl-2-(17-carboxyl)heptadecanoyl-3-glycerophosphorylcholine (yield 22.2%'6) was obtained in the form of a powder.
マススペクトル、赤外スペクトル及び元素分析の結果は
次の通りであった。The results of mass spectrum, infrared spectrum and elemental analysis were as follows.
マススペクトル（ｍ／Ｚ） ： ８２０ （Ｍ”
＋ ＩＩ）赤外スペクトル： ２９００ｃｍ−’ （
カルボキシル０１１伸縮振動）
元素分析： Ｃ４４１１１１６ＮＯＩＯＰとして（計
算値） ： Ｃ６４，４７％、 ８１０．５０％。Mass spectrum (m/Z): 820 (M”
+ II) Infrared spectrum: 2900 cm-' (
Carboxyl 011 stretching vibration) Elemental analysis: As C4411116 NOIOP (calculated value): C64,47%, 810.50%.
Ｎ １．７１％、 Ｐ ３．７９％
（実測値） ： Ｃ６４，７７％、 Ｈ１０，６１
％。N 1.71%, P 3.79% (actual measurements): C64,77%, H10,61
%.
Ｎ １．６８％、 Ｐ ３．７５％
なお、リン脂質の２位の炭素のエステル結合を特異的に
分解する酵素を用いて、２位の炭素に結合した基を実施
例１と同様に確認した。N 1.68%, P 3.75% In addition, using an enzyme that specifically decomposes the ester bond at the carbon position 2 of phospholipids, the group bonded to the carbon position 2 was confirmed in the same manner as in Example 1. did.
実施例２で合成した化合物１００＋ｎｇを、へび毒ホス
ホリパーゼΔ、（ｎａｊａ ｎａｊａ ｖｅｎｏｍ ；
ＳＩＧＭＡ Ｃｈｅｍ。100+ng of the compound synthesized in Example 2 was added to snake venom phospholipase Δ, (naja naja venom;
SIGMA Chem.
Ｃｏｒｐ、） ０．３ｍｇ、５％ＣａＣ１ｚ水溶液Ｑ、
１ｍｊ！及びエチルエーテルｌＱｍｊ！の混合液に加え
、室温で１晩撹拌して反応させた。反応後、シリカゲル
薄層クロマトグラフィー（展開液；クロロホルム：メタ
ノール：酢酸：水＝５０：２５： ８ ： ４ （容積
比））で分離した。Ｒ２値０．９０付近の脂肪酸成分の
スポットを分取してメタノールで抽出した。この脂肪酸
成分を常法によりメチルエステル化した後ガスクロマト
グラフィーで分析した結果、標品の１，１６−ヘキサデ
カンジカルボン酸ジメチルエステル同じピークが９７．
１％の純度で得られた。Corp, ) 0.3 mg, 5% CaC1z aqueous solution Q,
1mj! and ethyl ether lQmj! was added to the mixed solution, and the mixture was stirred at room temperature overnight to react. After the reaction, the mixture was separated by silica gel thin layer chromatography (developing solution: chloroform:methanol:acetic acid:water=50:25:8:4 (volume ratio)). A spot containing fatty acid components with an R2 value of around 0.90 was fractionated and extracted with methanol. This fatty acid component was methyl esterified by a conventional method and then analyzed by gas chromatography. As a result, the same peak of 1,16-hexadecanedicarboxylic acid dimethyl ester of the standard sample was found at 97.
Obtained with a purity of 1%.
以上の分析結果より、■ーステアロイルー２−（１７−
カルボキシル）ヘプタデカノイル−３−グリセロホスホ
リルコリンが合成されていることが確かめられた。From the above analysis results, ■-stearoyroux 2-(17-
It was confirmed that (carboxyl)heptadecanoyl-3-glycerophosphorylcholine was synthesized.
実施例３
アゼライン酸のかわりにアジピンｆｆ１５（１°屯度９
９％）７８０ｍｇを、また１−バルミトイル−３−グリ
セロホスホリルコリンのかわりに１−ラウロイル−３−
グリセロホスホリルコリン５３０＋ｎｇを用いた以外は
、実施例１に述べた方法と同様の条件で反応させ、シリ
カゲル薄層クロマトグラフィーで分離した。そしてＲｒ
値０．４８のスポットを分取し、メタノールで抽出した
。Example 3 Adipine ff15 (1° toughness 9
9%) 780 mg and also 1-lauroyl-3-in place of 1-valmitoyl-3-glycerophosphorylcholine.
The reaction was carried out under the same conditions as in Example 1, except that 530+ ng of glycerophosphorylcholine was used, and the mixture was separated by silica gel thin layer chromatography. And Rr
A spot with a value of 0.48 was collected and extracted with methanol.
以下、実施例１に述べた方法と同Ｉｎの方法で１ｅ作し
て、パウダー状の１−ラウロイル−２−（５−カルボキ
シル）ペンタノイル−３−グリセ１１ホスホリルコリン
１９５■（収￥−２８．４％）を１７た。Hereinafter, 1e was prepared using the same method as described in Example 1, and powdered 1-lauroyl-2-(5-carboxyl)pentanoyl-3-glyceride 11phosphorylcholine 195■ (yield: ¥28.4 %) was 17.
マススペクトル、赤外スペクトル及び元素分間の結果は
次の通りであった。The results of mass spectrum, infrared spectrum, and elemental analysis were as follows.
マススペクトル（ｍ／７，） ： ５６８ （Ｍ”
←Ｉ＋）赤外スペクトル： ２’ｌＯＯｃｍ− ’
（カルボキシル叶伸縮振動）
元素分析： Ｃｚ６１１ｓｏＮＯ＋ ｏＰとして（計
算値） ： Ｃ ５５．０３％， ）ｌ ８．８２
％。Mass spectrum (m/7,): 568 (M”
←I+) Infrared spectrum: 2'lOOcm-'
(Carboxyl leaf expansion and contraction vibration) Elemental analysis: Cz611soNO+ as oP (calculated value): C 55.03%, )l 8.82
%.
Ｎ ２．４７％， Ｐ ５．４７％
（実ンＲす（ｉ） ： Ｃ ５５．８５ ％＋
）１ Ｂ−６５ ％。N 2.47%, P 5.47% (Actual R(i): C 55.85%+
)1 B-65%.
Ｎ ２．４５％， Ｐ ５．５０％なお、リン脂質
の２位の炭素のエステル結合を特異的に分解する酵素を
用いて、２位の炭素に結合したＶをＩｉ′ｒｆｊ．こし
た。N 2.45%, P 5.50% By using an enzyme that specifically decomposes the ester bond at the 2nd carbon position of the phospholipid, the V bonded to the 2nd carbon position was converted to Ii′rfj. I strained it.
実施例３で合成した化合物１００■を、へび毒ポスボリ
バーゼＡ．（ｎａｊａ ｎａｊａ ｖｅｎｏｍ ； Ｓ
ＩＧＭＡ Ｃｈｅｍ。The compound 100cm synthesized in Example 3 was treated with snake venom postbolivase A. (naja naja venom; S
IGMA Chem.
Ｃｏｒｐ．） ０．３ｗ、５％ＣａＣｌ□水？８ ？ａ
Ｏ 、 ｔ ｍｉ及びエチルエーテル１ ０ ｍｌの
混合液に加え、室温で１晩攪拌巳て反応させた。反応後
、シリカゲル薄層クロマトグラフィー（展開液；クロロ
ホルム：メタノール：酢酸：水＝５０：２５： ８ ：
４ （容積比））で分Ｚｌｆ した。Ｒ，値０，９０
付近の脂肪酸成分のスボ・ノドを分取してメタノールで
抽出した。この脂肪酸成分を常法によりメチルエステル
化した後ガスクロマトグラフィーで分析した結果、標品
のアジピン酸ジメチルエステルと同じピークが９３．８
％の純度で得られた。Corp. ) 0.3w, 5% CaCl□water? 8? a
The mixture was added to a mixture of O2, tmi, and 10 ml of ethyl ether, and the mixture was stirred at room temperature overnight to react. After the reaction, silica gel thin layer chromatography (developing solution; chloroform: methanol: acetic acid: water = 50:25: 8:
4 (volume ratio)) for minutes. R, value 0,90
Nearby fatty acid components such as subo-nod were collected and extracted with methanol. This fatty acid component was methyl esterified by a conventional method and analyzed by gas chromatography. As a result, the same peak as the standard adipic acid dimethyl ester was found at 93.8.
% purity.
以上の分析結果より、１−ラウロイル−２−（５−カル
ボキシル）ペンタノイル−３−グリセロホスボリルコリ
ンが合成されていることが誼かめられた。From the above analysis results, it was confirmed that 1-lauroyl-2-(5-carboxyl)pentanoyl-3-glycerophosphoborylcholine was synthesized.
比１校例１
無水トリフルオロ酢酸を用いなかった外は実施例１に述
べた方法と同様に操作したが、ｌ−パルミ１ーイル〜２
−（８−カルボキシル）オクタノイル−３−グリセロホ
スホリルコリンは得られなかった。Ratio 1 Example 1 The procedure was the same as that described in Example 1 except that trifluoroacetic anhydride was not used, but l-palmyl-2
-(8-carboxyl)octanoyl-3-glycerophosphorylcholine was not obtained.
Claims (2)
ｎは２〜２０である。） で表されるリン脂質誘導体。(1) The following general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents an alkyl group having 3 to 21 carbon atoms,
n is 2-20. ) is a phospholipid derivative represented by
ｎは２〜２０である。） で表されるリン脂質誘導体を製造するにあたり、次の一
般式 ▲数式、化学式、表等があります▼（II） （式中、Ｒ＿１は炭素数３〜２１のアルキル基を示す。 ）で表される１−モノアシル−３−グリセロホスホリル
コリンと、次の一般式： ▲数式、化学式、表等があります▼（III） （式中、ｎは２〜２０である。） で表される二塩基酸を、次の一般式： ▲数式、化学式、表等があります▼（IV） （式中、ｍは０〜２である。） で表される無水フッ素置換脂肪酸の存在下で反応させる
ことを特徴とする製造方法。(2) The following general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents an alkyl group having 3 to 21 carbon atoms,
n is 2-20. ) To produce the phospholipid derivative represented by the following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) 1-monoacyl-3-glycerophosphorylcholine and the dibasic acid represented by the following general formula: ▲Mathematical formula, chemical formula, table, etc.▼(III) (In the formula, n is 2 to 20.) is reacted in the presence of an anhydrous fluorine-substituted fatty acid represented by the following general formula: ▲Mathematical formula, chemical formula, table, etc.▼(IV) (In the formula, m is 0 to 2.) manufacturing method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28168686A JPS63135395A (en) | 1986-11-28 | 1986-11-28 | Phospholipid derivative and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28168686A JPS63135395A (en) | 1986-11-28 | 1986-11-28 | Phospholipid derivative and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63135395A true JPS63135395A (en) | 1988-06-07 |
Family
ID=17642572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28168686A Pending JPS63135395A (en) | 1986-11-28 | 1986-11-28 | Phospholipid derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63135395A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5310958A (en) * | 1989-07-06 | 1994-05-10 | Yutaka Mizushima | Lysolecithin derivatives |
| EP1626728A4 (en) * | 2003-05-27 | 2009-09-02 | Vascular Biogenics Ltd | Oxidized lipids and uses thereof in the treatment of inflammatory diseases and disorders |
| US8569529B2 (en) | 2007-01-09 | 2013-10-29 | Vascular Biogenics Ltd. | High-purity phospholipids |
| US8759557B2 (en) | 2004-07-09 | 2014-06-24 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
| US9006217B2 (en) | 2007-01-09 | 2015-04-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
| US9206206B2 (en) | 2008-11-06 | 2015-12-08 | Vascular Biogenics Ltd. | Oxidized lipid compounds and uses thereof |
| US9771385B2 (en) | 2014-11-26 | 2017-09-26 | Vascular Biogenics Ltd. | Oxidized lipids |
| US10022388B2 (en) | 2014-11-26 | 2018-07-17 | Vascular Biogenics Ltd. | Oxidized lipids and treatment or prevention of fibrosis |
-
1986
- 1986-11-28 JP JP28168686A patent/JPS63135395A/en active Pending
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5310958A (en) * | 1989-07-06 | 1994-05-10 | Yutaka Mizushima | Lysolecithin derivatives |
| US7893291B2 (en) | 2000-11-24 | 2011-02-22 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
| US8563534B2 (en) | 2000-11-24 | 2013-10-22 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
| EP1626728A4 (en) * | 2003-05-27 | 2009-09-02 | Vascular Biogenics Ltd | Oxidized lipids and uses thereof in the treatment of inflammatory diseases and disorders |
| US7902176B2 (en) | 2003-05-27 | 2011-03-08 | Vascular Biogenics Ltd. | Oxidized lipids and uses thereof in the treatment of inflammatory diseases and disorders |
| US7973023B2 (en) | 2003-05-27 | 2011-07-05 | Vascular Biogenics Ltd. | Oxidized lipids and uses thereof in the treatment of inflammatory diseases and disorders |
| US8802875B2 (en) | 2004-07-09 | 2014-08-12 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
| US8759557B2 (en) | 2004-07-09 | 2014-06-24 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
| US8569529B2 (en) | 2007-01-09 | 2013-10-29 | Vascular Biogenics Ltd. | High-purity phospholipids |
| US9006217B2 (en) | 2007-01-09 | 2015-04-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
| US9566288B2 (en) | 2007-01-09 | 2017-02-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
| US9206206B2 (en) | 2008-11-06 | 2015-12-08 | Vascular Biogenics Ltd. | Oxidized lipid compounds and uses thereof |
| US9771385B2 (en) | 2014-11-26 | 2017-09-26 | Vascular Biogenics Ltd. | Oxidized lipids |
| US10022388B2 (en) | 2014-11-26 | 2018-07-17 | Vascular Biogenics Ltd. | Oxidized lipids and treatment or prevention of fibrosis |
| US10206936B2 (en) | 2014-11-26 | 2019-02-19 | Vascular Biogenics Ltd. | Oxidized lipids and treatment or prevention of fibrosis |
| US10464957B2 (en) | 2014-11-26 | 2019-11-05 | Vascular Biogenics Ltd. | Oxidized lipids and methods of use thereof |
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