JPH10218902A5 - - Google Patents

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Publication number
JPH10218902A5
JPH10218902A5 JP1997031489A JP3148997A JPH10218902A5 JP H10218902 A5 JPH10218902 A5 JP H10218902A5 JP 1997031489 A JP1997031489 A JP 1997031489A JP 3148997 A JP3148997 A JP 3148997A JP H10218902 A5 JPH10218902 A5 JP H10218902A5
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sulfated polysaccharide
low
uronic acid
polysaccharide according
molecular
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JP1997031489A
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JPH10218902A (en
JP4051099B2 (en
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Claims (19)

グリコサミノグリカン分解酵素による分解と高速液体クロマトグラフィーによる分析を組み合わせた二糖分析により得られる下記構造式で表される二糖体組成において（Ａ）の規定を充たし、且つ（Ｂ）及び（Ｃ）に規定する物性を有することを特徴とするヘキソサミンとウロン酸の繰り返し構造を基本骨格とする低分子化硫酸化多糖。
（Ａ）ΔＤｉ−ｔｒｉ（Ｕ，６，Ｎ）Ｓのモル％が６５％以上
（但し、ΔＤｉ−ｔｒｉ（Ｕ，６，Ｎ）Ｓは、式中において、Ｒ１、Ｒ２、Ｒ３がＳＯ３ −であることを意味する。）。
（Ｂ）ＡＰＴＴ活性及び抗トロンビン活性の少なくとも一方が標準ヘパリンに比して２％以下
（Ｃ）平均分子量が１，０００〜８，０００Ｄａ（ダルトン）
A low molecular weight sulfated polysaccharide having a repeating structure of hexosamine and uronic acid as a basic skeleton, characterized in that the disaccharide composition represented by the following structural formula, obtained by disaccharide analysis combining digestion with a glycosaminoglycan-degrading enzyme and analysis by high-performance liquid chromatography, satisfies the requirement (A) and has the physical properties specified in (B) and (C).
(A) The mole percentage of ΔDi-tri(U,6,N)S is 65% or more (wherein ΔDi-tri(U,6,N)S means that R 1 , R 2 and R 3 are SO 3 — ).
(B) At least one of the APTT activity and antithrombin activity is 2% or less compared to standard heparin. (C) The average molecular weight is 1,000 to 8,000 Da (Daltons).
請求項１に記載の二糖体組成において、ΔＤｉ−ＵＳを実質的に含有しないことを特徴とする請求項１に記載の低分子化硫酸化多糖
（但し、ΔＤｉ−ＵＳは、上記構造式中においてＲ１がＨ、Ｒ２が−ＣＯＣＨ３、Ｒ３がＳＯ３ −であることを意味する。）。2. The low molecular weight sulfated polysaccharide according to claim 1, characterized in that it is substantially free of ΔDi-US in the disaccharide composition described in claim 1 (wherein ΔDi-US means that in the above structural formula, R1 is H, R2 is —COCH3 , and R3 is SO3— ) . 平均分子量が３，５００〜６，０００Ｄａであることを特徴とする請求項１又は２のいずれか一項に記載の低分子化硫酸化多糖。3. The low-molecular-weight sulfated polysaccharide according to claim 1, wherein the average molecular weight is 3,500 to 6,000 Da. 平均分子量が１，０００〜３，５００Ｄａであることを特徴とする請求項１又は２のいずれか一項に記載の低分子化硫酸化多糖。3. The low-molecular-weight sulfated polysaccharide according to claim 1, wherein the average molecular weight is 1,000 to 3,500 Da. 塩基性繊維芽細胞増殖因子の細胞増殖活性に対する促進効果及び抑制効果の少なくともいずれかの効果が、標準ヘパリンに比して５０％以上であることを特徴とする請求項１〜４のいずれか一項に記載の低分子化硫酸化多糖。A low molecular weight sulfated polysaccharide according to any one of claims 1 to 4, characterized in that at least one of the promoting and inhibiting effects on the cell proliferation activity of basic fibroblast growth factor is 50% or more compared to standard heparin. 標準ヘパリンに対する抗トロンビン活性及びＡＰＴＴ活性が、０≦抗トロンビン活性／ＡＰＴＴ活性≦０．５であることを特徴とする請求項１〜５のいずれか一項に記載の低分子化硫酸化多糖。The low-molecular-weight sulfated polysaccharide according to any one of claims 1 to 5, characterized in that the antithrombin activity and APTT activity against standard heparin are 0 ≤ antithrombin activity/APTT activity ≤ 0.5. 塩基性繊維芽細胞増殖因子の細胞増殖活性に対する促進効果が標準ヘパリンに比して実質的に０％であり、かつ抑制効果が６０％以上であることを特徴とする請求項１、２又は４〜６のいずれか一項に記載の低分子化硫酸化多糖。A low molecular weight sulfated polysaccharide described in any one of claims 1, 2 or 4 to 6, characterized in that the promoting effect on the cell proliferation activity of basic fibroblast growth factor is essentially 0% compared to standard heparin, and the inhibitory effect is 60% or more. 抗トロンビン活性及びＡＰＴＴ活性が標準ヘパリンに比して、１％以下であることを特徴とする請求項１、２又は４〜７のいずれか一項に記載の低分子化硫酸化多糖。8. The low molecular weight sulfated polysaccharide according to claim 1, 2, or 4 to 7, characterized in that its antithrombin activity and APTT activity are 1% or less compared to standard heparin. 下記の工程を含む方法により得られる請求項１〜８に記載の低分子化硫酸化多糖。
(a)ヘキソサミンとウロン酸の繰り返し構造を基本骨格とする硫酸化多糖の構成ウロン酸の２位の硫酸基を部分的脱硫酸化し、
(b)次いで酸化剤により２位の硫酸基を有しないウロン酸を２位と３位の炭素原子間で開裂した後、
(c)上記開裂された糖残基において硫酸化多糖の切断処理を行うこと。The low molecular weight sulfated polysaccharide according to claims 1 to 8, which is obtained by a method comprising the steps of:
(a) Partially desulfating the sulfate group at the 2-position of the constituent uronic acid of a sulfated polysaccharide having a basic skeleton of a repeating structure of hexosamine and uronic acid,
(b) Then, the uronic acid without the sulfate group at the 2-position is cleaved between the 2- and 3-carbon atoms with an oxidizing agent,
(c) cleaving the sulfated polysaccharide at the cleaved sugar residues; ヘキソサミンとウロン酸の繰り返し構造を基本骨格とする硫酸化多糖がヘパリンであることを特徴とする請求項９に記載の低分子化硫酸化多糖。10. The low molecular weight sulfated polysaccharide according to claim 9, wherein the sulfated polysaccharide having a basic skeleton of a repeating structure of hexosamine and uronic acid is heparin. 構成ヘキソサミンがＤ−グルコサミンであることを特徴とする請求項１〜１０のいずれか一項に記載の低分子化硫酸化多糖。11. The low-molecular-weight sulfated polysaccharide according to any one of claims 1 to 10, wherein the constituent hexosamine is D-glucosamine. 構成ウロン酸がＤ−グルクロン酸又はＬ−イズロン酸であることを特徴とする請求項１〜１１のいずれか一項に記載の低分子化硫酸化多糖。12. The low-molecular-weight sulfated polysaccharide according to claim 1, wherein the constituent uronic acid is D-glucuronic acid or L-iduronic acid. 下記工程を含むことよりなるヘキソサミンとウロン酸の繰り返し構造を基本骨格とする低分子化硫酸化多糖の製造法。
工程：
(a)ヘキソサミンとウロン酸の繰り返し構造を基本骨格とする硫酸化多糖の構成ウロン酸の２位の硫酸基を２〜８５％部分的脱硫酸化し、
(b)次いで酸化剤により２位に硫酸基を有しないウロン酸を２位と３位の炭素原子間で開裂した後、
(c)上記開裂された糖残基において、硫酸化多糖の切断処理を行うこと。A method for producing a low molecular weight sulfated polysaccharide having a basic skeleton consisting of a repeating structure of hexosamine and uronic acid, comprising the steps of:
Process:
(a) A sulfated polysaccharide having a basic skeleton of a repeating structure of hexosamine and uronic acid, in which 2 to 85% of the sulfate group at the 2-position of the constituent uronic acid is partially desulfated;
(b) Then, after cleaving the uronic acid that does not have a sulfate group at the 2-position with an oxidizing agent between the 2- and 3-carbon atoms,
(c) performing a cleavage treatment of the sulfated polysaccharide at the cleaved sugar residues. ヘキソサミンとウロン酸の繰り返し構造を基本骨格とする硫酸化多糖がヘパリンである請求項１３に記載の低分子化硫酸化多糖の製造法。14. The method for producing a low-molecular-weight sulfated polysaccharide according to claim 13, wherein the sulfated polysaccharide having a basic skeleton consisting of repeating units of hexosamine and uronic acid is heparin. 工程（ｂ）において、２位に硫酸基を有しないウロン酸の２位と３位の炭素原子間で開裂した後、さらに開裂した硫酸化多糖の末端に生じたアルデヒド基を還元処理することを特徴とする請求項１３又は１４に記載の低分子化硫酸化多糖の製造法。15. The method for producing a low-molecular-weight sulfated polysaccharide according to claim 13 or 14, wherein in step (b), after cleavage between the carbon atoms at the 2- and 3-positions of the uronic acid that does not have a sulfate group at the 2-position, the aldehyde group generated at the terminal of the cleaved sulfated polysaccharide is further reduced. 工程（ｃ）の切断処理が、酸又はアルカリによる処理である請求項１３〜１５のいずれか１項に記載の低分子化硫酸化多糖の製造法。16. The method for producing a low-molecular-weight sulfated polysaccharide according to claim 13, wherein the cleavage treatment in step (c) is a treatment with an acid or an alkali. 請求項１３に記載の製造法において、工程(a)の部分的脱硫酸化反応はアルカリの存在下行われ、該アルカリ濃度を調整することにより硫酸化多糖の分子量を制御することを特徴とする請求項１３〜１６のいずれか１項に記載の低分子化硫酸化多糖の製造法。17. The method for producing a low-molecular-weight sulfated polysaccharide according to any one of claims 13 to 16, wherein the partial desulfation reaction in step (a) is carried out in the presence of an alkali, and the molecular weight of the sulfated polysaccharide is controlled by adjusting the alkali concentration. 部分的脱硫酸化反応はアルカリ存在下、凍結乾燥処理によって行われ、該アルカリ濃度が０．０１〜０．２Ｎであることを特徴とする請求項１７に記載の低分子化硫酸化多糖の製造法。18. The method for producing a low-molecular-weight sulfated polysaccharide according to claim 17 , wherein the partial desulfation reaction is carried out by freeze-drying in the presence of an alkali, the alkali concentration being 0.01 to 0.2N. 請求項１〜１２のいずれか一項に記載の低分子化硫酸化多糖を有効成分として含有することを特徴とする医薬組成物。A pharmaceutical composition comprising the low-molecular-weight sulfated polysaccharide according to any one of claims 1 to 12 as an active ingredient.
JP03148997A 1997-01-31 1997-01-31 Low molecular weight heparin, process for producing the same, and pharmaceutical composition Expired - Fee Related JP4051099B2 (en)

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JPH10218902A JPH10218902A (en) 1998-08-18
JPH10218902A5 true JPH10218902A5 (en) 2004-12-24
JP4051099B2 JP4051099B2 (en) 2008-02-20

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JP4633223B2 (en) * 1999-03-31 2011-02-16 生化学工業株式会社 Inhibitors of vascular endothelial growth factor-dependent vascular endothelial cell proliferation
IT1316986B1 (en) 2000-01-25 2003-05-26 Sigma Tau Ind Farmaceuti GLYCOSAMINOGLICAN DERIVATIVES PARTIALLY DESULPHATED NONANTICOAGULANTS WITH ANTIANGIOGENIC ACTIVITY.
JP4633233B2 (en) * 2000-06-29 2011-02-16 生化学工業株式会社 Chlamydia infection treatment
CZ307433B6 (en) * 2001-09-12 2018-08-22 Leadiant Biosciences Sa Derivatives of partially desulphated glycosaminoglycans as heparanase inhibitors having antiangiogenic effects and preventing anticoagulant activity
JPWO2005092348A1 (en) * 2004-03-29 2008-02-07 敏一 中村 Heparin-like oligosaccharide-containing HGF production promoter
FR2871379B1 (en) 2004-06-14 2006-09-29 Ifremer USE OF HIGHLY SULFATED POLYSACCHARIDE DERIVATIVES WITH LOW MOLECULE MASS TO MODULATE ANGIOGENESIS
FR2871476B1 (en) * 2004-06-14 2011-04-01 Ifremer EXOPOLYSACCHARIDE (EPS) SULFATE DEPOLYMERIZED DERIVATIVES FROM MESOPHILIC MARINE BACTERIA, PROCESS FOR THEIR PREPARATION AND THEIR USE IN TISSUE REGENERATION
FR2956322A1 (en) * 2010-02-17 2011-08-19 Urgo Lab USE OF SYNTHETIC POLYSULFATE OLIGOSACCHARIDES AS DETERSION AGENTS OF A WOUND.
CN103145878B (en) * 2012-12-08 2016-04-13 青岛九龙生物医药有限公司 A kind of ultralow point of heparin sodium technical study
CN104280490B (en) * 2013-07-02 2016-03-02 南通中国科学院海洋研究所海洋科学与技术研究发展中心 A kind of mass analysis method of algal polysaccharide sulfate
CN117180525A (en) * 2023-08-03 2023-12-08 天津大学温州安全(应急)研究院 A new anti-coagulant and anti-inflammatory coating and its preparation method and application

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