JP2729201B2 - Sialic acid derivatives with amide bonds - Google Patents
Sialic acid derivatives with amide bondsInfo
- Publication number
- JP2729201B2 JP2729201B2 JP1156888A JP1156888A JP2729201B2 JP 2729201 B2 JP2729201 B2 JP 2729201B2 JP 1156888 A JP1156888 A JP 1156888A JP 1156888 A JP1156888 A JP 1156888A JP 2729201 B2 JP2729201 B2 JP 2729201B2
- Authority
- JP
- Japan
- Prior art keywords
- sialic acid
- formula
- methanol
- acid derivative
- acid derivatives
- 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.)
- Expired - Lifetime
Links
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、シアル酸とアミノ酸、蛋白質などの各種ア
ミノ化合物とが結合した新規シアル酸誘導体に関する。Description: TECHNICAL FIELD The present invention relates to a novel sialic acid derivative in which sialic acid is bound to various amino compounds such as amino acids and proteins.
シアル酸とアミノ化合物とが結合したシアル酸誘導体
については、下記の一般式〔II〕 （式中、Ｒ1は水素またはアセチル基、Ｒ2は水素、ナト
リウムまたは低級アルキル基、Acはアセチル基、Ｘはア
ミノ化合物からｍ個のアミノ基を除いた残部をそれぞれ
表す）で示されるシアル酸誘導体が本発明者らによって
合成されている（特願昭62-295641号（特開昭63-264493
号）。For a sialic acid derivative in which sialic acid and an amino compound are bonded, the following general formula (II) (Wherein, R 1 is hydrogen or an acetyl group, R 2 is hydrogen, sodium or a lower alkyl group, Ac is an acetyl group, and X is a residue obtained by removing m amino groups from an amino compound). An acid derivative has been synthesized by the present inventors (Japanese Patent Application No. 62-295641 (Japanese Patent Application Laid-Open No. 63-264493).
issue).
本発明者は、シアル酸と各種アミノ化合物とが結合し
たシアル酸誘導体の生体内での生理活性作用について鋭
意研究を重ね、新たなシアル酸誘導体を見出すに到っ
た。The present inventors have conducted intensive studies on the in vivo biological activity of a sialic acid derivative in which sialic acid and various amino compounds are bonded, and have come to find a new sialic acid derivative.
本発明の目的は、シアル酸と各種アミノ化合物とが結
合したシアル酸誘導体を提供することにある。An object of the present invention is to provide a sialic acid derivative in which sialic acid and various amino compounds are bonded.
本発明は、式〔Ia〕 （式中、Acはアセチル基を表す）で示されるアミド結合
を持ったシアル酸誘導体、式〔Ib〕 （式中、Acはアセチル基を表す）で示されるアミド結合
を持ったシアル酸誘導、式〔Ic〕 （式中、Acはアセチル基を表す）で示されるアミド結合
を持ったシアル酸誘導である。The present invention has the formula (Ia) (Wherein Ac represents an acetyl group), a sialic acid derivative having an amide bond represented by the formula [Ib] (Where Ac represents an acetyl group), a sialic acid derivative having an amide bond represented by the formula [Ic] (Wherein, Ac represents an acetyl group).
アミノ酸、ペプチド、蛋白質、あるいは蛋白質と補欠
分子族とが結合した複合蛋白質などの各種アミノ化合物
をシアル酸との複合体として生体内に投与すると、シア
ル酸の存在によって、上記生理活性物質が本来有する生
物学的反応が阻害ないし遅緩されるものと予測される。When various amino compounds such as amino acids, peptides, proteins, or complex proteins in which a protein and a prosthetic group are bound are administered to a living body as a complex with sialic acid, the presence of sialic acid causes the physiologically active substance to originally possess It is expected that the biological response will be inhibited or slowed.
すなわち、ここでシアル酸は、これら生理活性物質の
生物学的半減期を延長する作用を示す。That is, here, sialic acid has the effect of extending the biological half-life of these physiologically active substances.
そこで、例えば、アミノ酸を栄養剤として動物や人体
に投与する場合、あるいは、インシュリン、成長ホルモ
ン、インターフェロン、免疫原などを医薬として投与す
る場合、これらを本発明のシアル酸誘導体のかたちで投
与することにより、これら生理活性物質の体内での持続
性が高まる、少量の投与で有効な薬効を呈するなどの効
果が得られる。Therefore, for example, when amino acids are administered to animals or human bodies as nutritional supplements, or when insulin, growth hormone, interferon, immunogen, etc. are administered as pharmaceuticals, these should be administered in the form of the sialic acid derivative of the present invention. Thereby, effects such as enhancement of the persistence of these physiologically active substances in the body, and exhibiting effective medicinal effects with a small amount of administration can be obtained.
以下、本発明を実施例により、詳述する。 Hereinafter, the present invention will be described in detail with reference to examples.
〔実施例１〕 Ｎ−〔カルボキシメチル ５−アセタミド−3,5−ジ
デオキシ−α−Ｄ−グリセロ−Ｄ−ガラクト−２−ノニ
ュロピラノシド）オノイル〕−Ｌ−アラニンの二ナトリ
ウム塩の合成 製法−１ 特願昭62-295641号（特開昭63-264493号）記載の製法
で得たＮ−〔（メチル ５−アセタミド−4,7,8,9−テ
トラ−Ｏ−アセチル−3,5−ジデオキシ−α−Ｄ−グリ
セロ−Ｄ−ガラクト−２−ノニュロピラノシルオネー
ト）オキシアセチル〕−Ｌ−アラニン メチルエステル
150mg（204μmol）をテトラヒドロフラン5ml/メタノー
ル2mlの混合溶媒に溶解し、1N−NaOH水溶液1.23ml（1.2
3mmol）を加え、室温で一夜撹拌した。反応液をダウエ
ックス50W−×８で中和し、溶媒を留去して残滓101mgを
得た。[Example 1] Synthesis of disodium salt of N- [carboxymethyl 5-acetamido-3,5-dideoxy-α-D-glycero-D-galact-2-nonulopyranoside) -onyl] -L-alanine Production method-1 N-[(methyl 5-acetamide-4,7,8,9-tetra-O-acetyl-3, 5-Dideoxy-α-D-glycero-D-galact-2-nonulopyranosylonate) oxyacetyl] -L-alanine methyl ester
150 mg (204 μmol) was dissolved in a mixed solvent of 5 ml of tetrahydrofuran / 2 ml of methanol, and 1.23 ml of a 1N-NaOH aqueous solution (1.23 ml) was added.
3 mmol) and stirred at room temperature overnight. The reaction solution was neutralized with Dowex 50W-x8, and the solvent was distilled off to obtain 101 mg of a residue.
本品は、TLC分析法によりＮ−〔（ナトリウム ５−
アセタミド−3,5−ジデオキシ−α−Ｄ−グリセロ−Ｄ
−ガラクト−２−ノニュロピラノシルオネート）オキシ
アセチル〕−Ｌ−アラニン−ナトリウム塩と1:1の混合
物として得られた。This product was analyzed by N-[(sodium 5-
Acetamide-3,5-dideoxy-α-D-glycero-D
-Galact-2-nonulopyranosylonate) oxyacetyl] -L-alanine-sodium salt in a 1: 1 mixture.
製法−２ 上記製法−１で用いたＮ−〔（メチル ５−アセタミ
ド−4,7,8,9−テトラ−Ｏ−アセチル−3,5−ジデオキシ
−α−Ｄ−グリセロ−Ｄ−ガラクト−２−ノニュロピラ
ノシルオネート）オキシアセチル〕−Ｌ−アラニン メ
チルエステル200mgをテトラヒドロフラン5mlに溶解し、
1N-NaOHを水溶液1.4mlを加えて室温で一時間撹拌し、水
2mlを加えてさらに30分撹拌した。反応液をセファデッ
クスLH-20カラムクロマトグラフィに付し、メタノール
で溶出して261mgの精製物を得た。Production method-2 The N-[(methyl 5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-α-D-glycero-D-galacto-2 used in the above production method-1 was used. -Nonuropyranosylonate) oxyacetyl] -L-alanine methyl ester 200 mg was dissolved in tetrahydrofuran 5 ml,
1.4N aqueous solution of 1N-NaOH was added and stirred at room temperature for 1 hour.
2 ml was added and the mixture was further stirred for 30 minutes. The reaction solution was subjected to Sephadex LH-20 column chromatography, and eluted with methanol to obtain 261 mg of a purified product.
本品は、上記製法−１のTLC分析法により、目的物質
と、Ｎ−〔（ナトリウム ５−アセタミド−3,5−ジデ
オキシ−α−Ｄ−グリセロ−Ｄ−ガラクト−２−ノニュ
ロピラノシルオネート）オキシアセチル〕−Ｌ−アラニ
ン−ナトリウム塩の1:10混合物として得られた。According to the TLC analysis method of the above-mentioned production method-1, the product was analyzed for N-[(sodium 5-acetamide-3,5-dideoxy-α-D-glycero-D-galacto-2-nonulopyranosyloxy) Nate) oxyacetyl] -L-alanine-sodium salt.
〔実施例２〕 Ｎ−〔（メトキシカルボニルメチル ５−アセタミド
−3,5−ジデオキシ−α−Ｄ−グリセロ−Ｄ−ガラクト
−２−ノニュロピラノシド）オノイル〕−Ｌ−アラニン
メチルエステルの合成 製法−１ 前記実施例１で用いたＮ−〔（メチル ５−アセタミ
ド−4,7,8,9−テトラ−Ｏ−アセチル−3,5−ジデオキシ
−α−Ｄ−グリセロ−Ｄ−ガラクト−２−ノニュロピラ
ノシルオネート）オキシアセチル〕−Ｌ−アラニン メ
チルエステル30mg（0.473mmol）をメタノール5mlに溶解
し、1N−ナトリウムメトキシド0.5mlを加え、室温で一
夜撹拌した。反応液をダウエックス50W−×８で中和
し、濾過後、濾液を留去した。残滓をシリカゲル（メル
ク社製、キーゼルゲル60,20g）カラムクロマトグラフィ
に付し、クロロホルム：メタノール＝10:1混合溶媒で溶
出して22mg（収率＝79.5％）の精製物を得た。 Example 2 Synthesis of N-[(methoxycarbonylmethyl 5-acetamide-3,5-dideoxy-α-D-glycero-D-galact-2-nonulopyranoside) -onyl] -L-alanine methyl ester Production method-1 N-[(methyl 5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-α-D-glycero-D-galacto-2 used in Example 1 described above. -Nonulopyranosylonate) oxyacetyl] -L-alanine methyl ester (30 mg, 0.473 mmol) was dissolved in methanol (5 ml), 1N-sodium methoxide (0.5 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with Dowex 50W-x8, filtered, and the filtrate was distilled off. The residue was subjected to column chromatography on silica gel (manufactured by Merck, Kieselgel 60, 20 g) and eluted with a mixed solvent of chloroform: methanol = 10: 1 to obtain 22 mg (yield = 79.5%) of a purified product.
TLC:Rf値＝0.84（シリカゲル、クロロホルム：メタノー
ル＝5:1） 製法−２ 特願昭62-295641号記載の製法で得たＮ−〔（メチル
５−アセタミド−3,5−ジデオキシ−α−Ｄ−グリセ
ロ−Ｄ−ガラクト−２−ノニュロピラノシルオネート）
オキシアセチル〕−Ｌ−アラニン メチルエステル5mg
（10.7μmol）をメタノール0.5mlに溶解し、1N−ナトリ
ウムメトキシド１滴を加えて室温で６時間撹拌した。得
られた生成物をTLC分析法で固定した。TLC: Rf value = 0.84 (silica gel, chloroform: methanol = 5: 1) Production method-2 N-[(methyl 5-acetamide-3,5-dideoxy-α-) obtained by the production method described in Japanese Patent Application No. 62-295641. D-glycero-D-galact-2-nonulopyranosylonate)
[Oxyacetyl] -L-alanine methyl ester 5 mg
(10.7 μmol) was dissolved in 0.5 ml of methanol, 1 drop of 1N-sodium methoxide was added, and the mixture was stirred at room temperature for 6 hours. The resulting product was fixed by TLC analysis.
TLC:Rf値＝0.35（シリカゲル、クロロホルム：メタノー
ル＝5:1） 製法−３ 前記実施例１の製法−１で得た生成物50mg（1.1mmo
l）をジメチルスルホキシド0.5mlに溶解し、過剰のヨウ
化メチルを加えて室温で１時間30分撹拌した。反応液を
そのままシリカゲル（Ｃ−300,10g）カラムクロマトグ
ラフィに付し、クロロホルム：メタノール＝5:1混合溶
媒で溶出し、TLC分析法（シリカゲル，クロロホルム：
メタノール＝5:1）により、Rf値＝0.27および0.17のう
ち、Rf値＝0.27の分画部から目的物質を得た。TLC: Rf value = 0.35 (silica gel, chloroform: methanol = 5: 1) Production method-3 50 mg (1.1 mmol) of the product obtained in Production method-1 of Example 1 above.
l) was dissolved in 0.5 ml of dimethyl sulfoxide, excess methyl iodide was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction solution was directly subjected to silica gel (C-300, 10 g) column chromatography, eluted with a mixed solvent of chloroform: methanol = 5: 1, and analyzed by TLC (silica gel, chloroform:
Methanol = 5: 1) to obtain the target substance from the fractionation part having an Rf value of 0.27 among Rf values of 0.27 and 0.17.
NMR測定により、上記生成物は、上記製法−１および
２で得られた生成物と一致した。なお、Rf値＝0.17の分
画部から得られた生成物は、Ｎ−〔（メチル ５−アセ
タミド−3,5−ジデオキシ−α−Ｄ−グリセロ−Ｄ−ガ
ラクト−２−ノニュロピラノシルオネート）オキシアセ
チル〕−Ｌ−アラニン メチルエステルのNMR測定値と
一致した。By NMR measurement, the product was consistent with the products obtained in Production Methods 1 and 2. The product obtained from the fractionation part having an Rf value of 0.17 was N-[(methyl 5-acetamide-3,5-dideoxy-α-D-glycero-D-galact-2-nonulopyranosylthiol. Nate) oxyacetyl] -L-alanine methyl ester.
〔実施例３〕 Ｎ−〔（メトキシカルボニルメチル ５−アセタミド
−4,7,8,9−テトラ−Ｏ−アセチル−3,5−ジデオキシ−
α−Ｄ−グリセロ−Ｄ−ガラクト−２−ノニュロピラノ
シド）オノイル〕−Ｌ−アラニン メチルエステルの合
成 前記実施例２で得た生成物20mg（42.8μmol）をピリ
ジン0.5ml/無水酢酸0.5ml混合溶媒に溶解し、室温で１
夜撹拌した。反応液を留去し、残滓をシリカゲルカラム
クロマトグラフィ（Ｃ−300,10mg,クロロホルム：メタ
ノール＝20:1）に付して18.3mg（収率＝67.3％）の精製
物を得た。 Example 3 N-[(methoxycarbonylmethyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
Synthesis of α-D-glycero-D-galact-2-nonulopyranoside) onoyl] -L-alanine methyl ester 20 mg (42.8 μmol) of the product obtained in the above Example 2 was obtained by adding 0.5 ml of pyridine / 0.5 of acetic anhydride. Dissolve in a mixed solvent and mix at room temperature.
Stirred at night. The reaction solution was distilled off, and the residue was subjected to silica gel column chromatography (C-300, 10 mg, chloroform: methanol = 20: 1) to obtain 18.3 mg (yield = 67.3%) of a purified product.
TLC:Rf＝0.738（シリカゲル、クロロホルム：メタノー
ル＝10:1） 〔生成物の物性値〕 TLC: Rf = 0.738 (silica gel, chloroform: methanol = 10: 1) [Physical properties of the product]
Claims (3)
を持ったシアル酸誘導体。1. The formula [Ia] (In the formula, Ac represents an acetyl group) A sialic acid derivative having an amide bond represented by the following formula:
を持ったシアル酸誘導体。2. The formula [Ib] (In the formula, Ac represents an acetyl group) A sialic acid derivative having an amide bond represented by the following formula:
を持ったシアル酸誘導体。3. The formula [Ic] (In the formula, Ac represents an acetyl group) A sialic acid derivative having an amide bond represented by the following formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1156888A JP2729201B2 (en) | 1988-01-21 | 1988-01-21 | Sialic acid derivatives with amide bonds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1156888A JP2729201B2 (en) | 1988-01-21 | 1988-01-21 | Sialic acid derivatives with amide bonds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01190693A JPH01190693A (en) | 1989-07-31 |
| JP2729201B2 true JP2729201B2 (en) | 1998-03-18 |
Family
ID=11781535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1156888A Expired - Lifetime JP2729201B2 (en) | 1988-01-21 | 1988-01-21 | Sialic acid derivatives with amide bonds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2729201B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4427900B2 (en) | 1998-04-10 | 2010-03-10 | 三菱化学株式会社 | Solid dispersion containing sialic acid derivatives |
-
1988
- 1988-01-21 JP JP1156888A patent/JP2729201B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01190693A (en) | 1989-07-31 |
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