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An oligosaccharide compound and its pharmaceutical composition for inhibiting endogenous factor X enzyme activity

A technology for compounds and carbohydrates, which is applied to the invention and belongs to the field of medical technology, can solve the problems of complex chemical structure of FG, limited quality controllability, and lack of in-depth research and sufficient understanding of the basic chemical structure.

Active Publication Date: 2017-12-01
JIUZHITANG +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these mixtures can be used for the treatment and / or prevention of thrombotic diseases, they are limited to the nature of the mixture, and their quality controllability is relatively limited. The difference in pharmacological and pharmacodynamic activity caused by the difference in the chemical structure of the different components contained in the mixture and the side effects and Safety concerns are unavoidable, for example, a certain proportion of large molecular weight components contained in these mixtures may have XII activating activity and platelet activating activity
[0005] Due to the complex chemical structure of FG, especially because FG is a highly sulfated product and the sulfation forms of its structural units are complex and changeable, it is very difficult to prepare and purify FG compounds with pure chemical structure. , there is no research report on FG compounds with pure chemical structure
It is precisely because there are no reports of compounds with pure chemical structures that the exact structure of FG compounds is still in doubt, for example, the existence form of side chain fucose (L-Fuc) (may be monosaccharide side chain or disaccharide side chain) and The connection position (possibly the C3 position of D-GlcUA, the C4 or C6 position of D-GalNAc, etc.); related to this, the basic chemical structure required for FG compounds to inhibit endogenous Xase has not been studied in depth and fully know

Method used

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  • An oligosaccharide compound and its pharmaceutical composition for inhibiting endogenous factor X enzyme activity
  • An oligosaccharide compound and its pharmaceutical composition for inhibiting endogenous factor X enzyme activity
  • An oligosaccharide compound and its pharmaceutical composition for inhibiting endogenous factor X enzyme activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Preparation of compound a and compound b: L-2,4-disulfated fucosyl-(α1,3)-D-glucuronyl-(β1,3)-2,5-anhydrotalitol (trisaccharide); L-2,4-disulfated fucosyl-(α1,3)-D-glucuronyl-(β1,3)-D-N-acetyl-2-deoxy-2-amino -4,6-disulfated galactosyl-(β1,4)-[L-2,4-disulfated fucosyl-(α1,3)-]D-glucuronyl-(β1, 3) -2,5-anhydrotalitol (hexasaccharide)

[0075] 1.1 Materials

[0076] Fucosylated glycosaminoglycan (FG, sodium salt) derived from the body wall of Stichopus Variegatus Semper was extracted and purified according to the literature method (Marine Drugs, 2013, 11, 399–417), with a weight average molecular weight of about 70kDa. Hydrazine hydrate, hydrazine sulfate, sodium chloride, sodium nitrite, concentrated sulfuric acid, sodium borohydride, absolute ethanol, sodium hydroxide and other reagents are commercially available analytical reagents.

[0077] 1.2 Method

[0078] Step 1. Preparation of partially deacetylated FG: Weigh 2.0 g of FG raw material from Stichopus Variegatu...

Embodiment 2

[0097] Preparation of compounds c~f: L-2,4-disulfated fucosyl-(α1,3)-D-glucuronyl-(β1,3)-{D-N-acetyl-2-deoxy- 2-amino-4,6-disulfated galactosyl-(β1,4)-[L-2,4-disulfated fucosyl-(α1,3)-]D-glucuronyl- (β1,3)-} n -2,5-Anhydrotalitol. In compound c, n=2; in compound d, n=3; in compound e, n=4; in compound f, n=5.

[0098] 2.1 Materials

[0099] With embodiment 1.

[0100] 2.2 Method

[0101] Step 1. Preparation of partially deacetylated FG: Weigh 2.0 g of FG (sodium salt) derived from Stichopus Variegatus, and treat it with the deacetylation reaction and post-treatment method described in Example 1, but the hydrazinolysis reaction time is about 18 hours. About 1.93 g of the deacetylated intermediate product sample was obtained through the reaction, and the yield was about 96.5%. 1 The deacetylation rate of the obtained product detected by H NMR was 40%.

[0102] Step 2. Deamination and depolymerization product preparation: Take 1.50 g of the partially deacetylated intermedi...

Embodiment 3

[0122] Preparation of compounds g~m: L-2,4-disulfated fucosyl-(α1,3)-D-glucuronyl-(β1,3)-{D-N-acetyl-2-deoxy- 2-amino-4,6-disulfated galactosyl-(β1,4)-[L-2,4-disulfated fucosyl-(α1,3)-]D-glucuronyl- (β1,3)-} n -2,5-anhydrotalose diol. In compound g, n=0; in compound h, n=1; in compound i, n=2; in compound j, n=3; in compound k, n=4; in compound l, n=5, compound In m, n=6.

[0123] 3.1 Materials

[0124] The fucosylated glycosaminoglycan (FG, sodium salt) derived from the body wall of Stichopus monotuberculatus was extracted and purified according to the literature method (Marine Drugs, 2013, 11, 399–417), with a weight average molecular weight of about 68kDa. Other reagents and materials are the same as in Example 1.

[0125] 3.2 Method

[0126] Step 1. Preparation of partially deacetylated FG: Take 2.0 g of FG raw material from Stichopus monotuberculatus, and use the same deacetylation reaction and post-treatment method as described in Example 1 with slight changes. Wh...

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Abstract

The invention discloses an oligosaccharide compound with a pure chemical structure that inhibits endogenous blood coagulation factor X enzyme, its preparation method, a pharmaceutical composition containing the oligosaccharide compound and its use in preventing and / or treating thrombotic diseases Applications. The oligosaccharide compound is composed of L-2,4-disulfate group fucose, D-glucuronic acid, D-2-deoxy-2-acetylamino-4,6-disulfate group-galactose , 2,5-anhydrotalose or its sugar alcohol, the oligosaccharide with the structure shown in formula (I) composed of sugar amine, wherein in formula (I), n is 0,1,2,3,4, 5 or 6; R is optionally -CH=O, -CH(OH)2, -CH2OH, -CH2NH2, -CH2NHR' or -CH2N(R')2, wherein R' is substituted or unsubstituted C1-C6 Straight chain or branched chain alkyl, substituted or unsubstituted C7-C12 aryl.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a compound consisting of L-2,4-disulfate-based fucose, D-glucuronic acid, D-2-deoxy-2-acetylamino-4,6-disulfate The oligosaccharide compound with pure chemical structure composed of galactose, 2,5-anhydrotalose or its sugar alcohol and sugar amine, the preparation method of the oligosaccharide compound, and the medicine containing the oligosaccharide compound Compositions and their use as endogenous factor X enzyme inhibitors and / or heparin-coenzyme II-dependent thrombin inhibitors in the prevention and / or treatment of thrombotic diseases. Background technique [0002] Cardiovascular and cerebrovascular diseases seriously endanger human health, and pathological thrombosis is one of the main causes of cardiovascular and cerebrovascular diseases. Antithrombotic drugs, including anticoagulant drugs, are widely used in the clinical treatment of cardiovascular diseases....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H11/00C07H1/00C08B37/00A61K31/737A61K31/7024A61P7/02A61P9/10
Inventor 赵金华何金星吴明一赵龙岩刘峙汶杨莲李姿高娜肖创徐丽陈钧周路坦
Owner JIUZHITANG