Derivatives of fucosylated chondroitin sulfate oligosaccharides, methods of making and uses thereof

Abstract

The application provides a fucosylated chondroitin sulfate oligosaccharide derivative, a preparation method and application thereof, and belongs to the field of marine biotechnology. The fucosylated chondroitin sulfate from the class Holothuroidea of echinoderms is used as raw material, is subjected to degradation, chemical modification and derivation, a series of derivatives of the fucosylated chondroitin sulfate oligosaccharide is obtained, and the anti-coagulation activity of the derivatives is detected. The detection result shows that, compared with dFCS, S-dFCS can significantly improve the anti-coagulation activity, especially the sulfated derivatives of the fucosylated chondroitin sulfate hexasaccharide and the sulfated derivatives of the fucosylated chondroitin sulfate nonasaccharide, the anti-coagulation activity is improved by more than 100 times, has great potential and can be used for preparation of anti-coagulation activity drugs, and has a huge application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a derivative of fucoidan-modified chondroitin sulfate oligosaccharide, its preparation method, and its application. Background Technology

[0002] Currently, non-communicable diseases (NCDs) pose a significantly increased threat to global mortality, with cardiovascular disease being a leading cause of the NCD burden. This primarily includes ischemic heart disease, stroke, and venous thromboembolism (VTE). Thrombosis is the most common cause. There are two main types of thrombi: arterial thrombosis and venous thrombosis. Changes in blood composition, reduced blood flow, or alterations in the vessel wall that promote thrombus formation induce venous thrombosis (VTE), including deep vein thrombosis and pulmonary embolism, which is the third leading cause of cardiovascular-related death after myocardial infarction and stroke. Anticoagulants for treating VTE are divided into four main classes: heparin, direct inhibitors, vitamin K antagonists (VKAs), and others.

[0003] However, due to the varying degrees of bleeding side effects and high prices associated with the aforementioned drugs, there is an urgent need for novel anticoagulants with superior efficacy for clinical use.

[0004] Fucosylated chondroitin sulfate (FCS) is a glycosaminoglycan (GAG) obtained from the body wall of sea cucumbers. It possesses a chondroitin sulfate backbone, consisting of disaccharide repeating units linked by glucuronic acid (GlcA) and acetylgalactosamine (GalNAc) via β-1,3 / β-1,4 glycosidic bonds, with fucose (Fuc) attached to the O-3 position of GlcA as its side chain. As a highly sulfated polysaccharide with fucose branches, FCS exhibits significant anticoagulant and antithrombotic activities. However, due to its potential to activate factor XII (FXII) and induce platelet aggregation, natural FCS has not been directly developed into an anticoagulant drug, leaving room for further research. Summary of the Invention

[0005] The purpose of this invention is to provide a sulfated derivative of fucoidan-containing chondroitin sulfate oligosaccharide, and to provide a method for preparing the derivative and its application, so as to overcome the shortcomings of the prior art.

[0006] A derivative of fucoidan sulfate oligosaccharide, the derivative being a sulfated derivative (S-dFCS) obtained by sulfation modification of fucoidan sulfate oligosaccharide (dFCS).

[0007] Further, the monosaccharide composition of the sulfated derivative (S-dFCS) of the fucosylated chondroitin sulfate oligosaccharide includes glucuronic acid or sulfate, acetylglucosamine sulfate, fucose sulfate; the weight average molecular weight of the sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide ranges from 500 to 20,000 Da; and the polydispersity index of the sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide is between 1.0 and 1.8.

[0008] Further, the specific structure of the sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide is as follows:

[0009]

[0010] wherein n is a natural integer from 0 to 4, and R1, R2, R3 are optionally and independently -H or -SO3H.

[0011] Further, n is 0 or 1, respectively obtaining a sulfated derivative of fucosylated chondroitin sulfate hexaose or a sulfated derivative of fucosylated chondroitin sulfate nonaose.

[0012] The preparation method of the S-dFCS includes:

[0013] (1) taking FCS derived from the body wall of animals in the class Holothuroidea of the phylum Echinozoa as raw material, first performing hydrazine treatment to cause partial deacetylation of the FCS to obtain a partial deacetylation product of the FCS, and then performing nitrous acid treatment to cause depolymerization of the product, followed by reduction treatment to obtain a fucosylated chondroitin sulfate oligosaccharide mixture with a terminal 2,5-anhydrotalose group (dFCS);

[0014] (2) taking the dFCS as raw material, performing sulfation modification on it under anhydrous conditions using a sulfating agent to obtain a sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide (S-dFCS).

[0015] Further, the sulfating agent is any one or a mixture of two or more of sulfur trioxide·triethylamine, sulfur trioxide·pyridine or chlorosulfonic acid·pyridine.

[0016] Further, the dFCS and S-dFCS are subjected to purification treatment, specifically:

[0017] The dFCS and S-dFCS are first subjected to dialysis to remove small molecular salts and other impurities, and then subjected to further purification by gel chromatography or ion exchange chromatography to obtain purified fucosylated chondroitin sulfate oligosaccharide compounds (dFCS) 1-5 and sulfated derivatives of purified fucosylated chondroitin sulfate oligosaccharide (S-dFCS) 6-10 having the structure of formula (II);

[0018] The dFCS 1-5 and S-dFCS 6-10 refer to "purified oligosaccharide compounds, each with a purity of not less than 95%; the detection method is HPGPC analysis, and the area normalization method is used for calculation.

[0019] Further, the animals of the class Holothuroidea of the phylum Echinodermata include, but are not limited to:

[0020] Apostichpus japonicus, Actinopyga mauritiana, Actinopyga miliaris, Acaudina molpadioides, Bohadschia argus, Holothuria edulis, Cucumaria frondose,

[0021] Holothuria fuscopunctata, Holothuria Mexicana, Holothuria nobilis, Holothuria leucospilota, Holothuria polii, Holothuria sinica, Holothuria scabraJaege, Holohutria tubulosa, Holothuria vagabunda, Isostichopus badionotus, Ludwigothurea grisea, Stichopuschloronotus, Thelenota ananas, and Thelenota anax.

[0022] Further, the animals of the class Holothuroidea of the phylum Echinodermata include Holohutria tubulosa, Isostichopus badionotus, and Holothuria polii.

[0023] The sulfated derivative (S-dFCS) of the fucosylated sulfated chondroitin oligosaccharide in the preparation of an anticoagulant drug.

[0024] The sulfated derivative (S-dFCS) of the fucosylated sulfated chondroitin oligosaccharide in the preparation of an anticoagulant drug.

[0025] Use of the sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide or its pharmaceutically acceptable salt in the preparation of a drug for the treatment and / or prevention of thrombotic diseases, including but not limited to venous thrombosis, arterial thrombosis, ischemic heart disease, ischemic cerebrovascular disease.

[0026] Further, the sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide (S-dFCS) or its pharmaceutically acceptable salt is used in the preparation of a drug for inhibiting the activity of endogenous factor X enzyme complex (Xase).

[0027] Further, the sulfated derivative of the fucosylated chondroitin sulfate hexasaccharide (S-dFCS) or its pharmaceutically acceptable salt is used in the preparation of an anticoagulant or antithrombotic drug.

[0028] Further, the sulfated derivative of the fucosylated chondroitin sulfate nonasaccharide (S-dFCS) or its pharmaceutically acceptable salt is used in the preparation of an anticoagulant or antithrombotic drug.

[0029] A pharmaceutical composition comprising the sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide (S-dFCS) or the sulfated derivative of the fucosylated chondroitin sulfate oligosaccharide (S-dFCS) in a pharmaceutically acceptable salt.

[0030] Further, the dosage form of the pharmaceutical composition is an aqueous injection solution or a freeze-dried powder injection; the pharmaceutical composition further comprises a pharmaceutical excipient, which is a pharmaceutically acceptable sodium chloride, a phosphate buffer salt.

[0031] Advantages and beneficial effects of the present application:

[0032] The present application uses fucosylated chondroitin sulfate derived from the class of sea cucumber of echinoderm as raw material, through degradation, chemical modification and derivation, a series of derivatives of fucosylated chondroitin sulfate oligosaccharide are obtained, and the anticoagulant activity of the derivatives is detected. The detection results show that, compared with dFCS, S-dFCS can significantly improve the anticoagulant activity, especially the sulfated derivative of fucosylated chondroitin sulfate hexasaccharide and the sulfated derivative of fucosylated chondroitin sulfate nonasaccharide, the anticoagulant activity is increased by more than 100 times, which has great potential to be used in the preparation of anticoagulant activity drugs, and has great application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 HPGPC analysis spectrum of dFCS.

[0034] Figure 2 FCS oligosaccharide and its sulfated derivative 1 H-NMR spectrum.

[0035] Figure 3Preparation of FCS oligosaccharides and sulfated derivatives thereof 13 C-NMR spectra.

[0036] Figure 4 HPGPC chart of compounds 1-5.

[0037] Figure 5 HPGPC chart of compounds 6-10.

[0038] Figure 6 ESI-CID-MS spectra of compounds 1 and 2 and assignment; wherein A: compound 1; B: compound 2.

[0039] Figure 7 ESI-CID-MS spectra of compounds 6 and 7 and assignment; wherein A: compound 6; B: compound 7. DETAILED DESCRIPTION

[0040] The present application is further illustrated by the following description with reference to the accompanying drawings and specific examples, which are not intended to limit the scope of the present application. Unless otherwise specified, the reagents, methods and devices employed in the present application are of a kind commonly used in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0041] Example 1 Preparation of fucosylated chondroitin sulfate oligosaccharide mixture (dFCS)

[0042] This example is the preparation of dFCS of the present application, which comprises the following steps:

[0043] Step 1. Preparation of polysaccharide deacetylation intermediate

[0044] About 1.0 g of polysaccharide FCS from the body wall of animals of the class Holothurioidea of the phylum Echinozoa was weighed into a reaction bottle, dissolved with 25 mL of hydrazine hydrate, and 250 mg of hydrazine sulfate was added. The reaction was stirred at 250 rpm under N2 protection at 90°C for 27 h. After the reaction was completed, the reaction solution was cooled to room temperature, and 200 mL of anhydrous ethanol was added to precipitate, and the supernatant was removed by centrifugation. The obtained precipitate was dissolved with 25 mL of water, and 200 mL of anhydrous ethanol was added for precipitation. The alcohol precipitation was repeated 4 times, and then the precipitate was dissolved with water and dialyzed with a dialysis bag with a molecular weight cut-off of 1000 Da. The dialysis cut-off liquid was concentrated and lyophilized to obtain a sample of polysaccharide deacetylation intermediate (daFCS).

[0045] Step 2. Preparation of dFCS

[0046] Take 100 mg daFCS in a reaction bottle, add 5 mL H2O to dissolve at 0°C, add 10 mL 5.5M nitrous acid solution (5.5M NaNO2 solution mixed with 0.5M H2SO4 at a ratio of 3:5), stir the reaction at 0°C for 3h, after the reaction is completed, add 1.0M sodium hydroxide solution to adjust pH 8-9 to terminate the reaction, add 300mg / mL NaBH40.6mL to heat the reaction at 50°C for 2h, after the reaction, cool to room temperature, add 0.5M H2SO4 to the reaction solution to adjust pH≈4 to remove excess sodium borohydride, finally use 1.0M sodium hydroxide solution to adjust pH≈7, 1000Da dialysis bag dialysis, collect the dialysate in the dialysis bag, freeze-drying. HPGPC method is used to detect the degradation of the sample, and the analysis conditions are as follows: Agilent technologies 1260 series high performance liquid chromatograph, SuperdexPeptide 10 / 300GL (10mm×300mm) column, temperature 30°C, mobile phase is 0.2M NaCl, flow rate 0.4mL / min, sample injection amount: 50μL, detector is differential refractive index detector (G1362A), record the chromatogram of 0-60min after sample injection.

[0047] Results:

[0048] As Figure 1 shown, the FCS oligosaccharide mixture of hexaose, nonasaccharide, dodecaose, pentadecasaccharide and octadecasaccharide with relatively uniform structure is obtained by degradation.

[0049] Example 2 Preparation of sulfated FCS oligosaccharide derivative (S-dFCS)

[0050] Take 200mg dFCS and dissolve in 20mL anhydrous DMF, add 2.0g sulfur trioxide triethylamine, under N2 atmosphere, heat and stir at 70°C for 24h, after the reaction is completed, place the reaction bottle in an ice bath, slowly add saturated sodium bicarbonate solution to adjust pH to pH≈8, continue to react for 30min, then dialyze and freeze-dry to obtain S-dFCS.

[0051] Example 3 NMR analysis of FCS oligosaccharide and its sulfated derivative

[0052] Respectively take about 5mg sample, after heavy water exchange, perform one-dimensional 1 H NMR, 13 C NMR analysis on JEOL JNM-ECP600 600-MHz superconducting nuclear magnetic resonance spectrometer at 298K.

[0053] As Figure 2 , Figure 3As shown, after sulfation modification, the H signals and C signals of S-dFCS as a whole move to low field except the anomeric carbon region and the methyl peak signals; among them, the signal type of the anomeric hydrogen region of Fuc (δ5.20-5.70 ppm) is obviously reduced, which is presumably caused by the overlapping of the Fuc signals at the reducing end and the non-reducing end after sulfation modification. In addition, although the Fuc anomeric hydrogen signals overlap, they do not continue to move to low field, indicating that the -OH of Fuc is not completely sulfated, which also avoids the toxic side effects that may be caused by excessive sulfation.

[0054] Preparation of purified oligosaccharides of dFCS and S-dFCS

[0055] Take 200 mg of dFCS and S-dFCS respectively, dissolve in about 3 mL of 0.3M NH4HCO3, filter with a 0.22 μm filter membrane, and separate with equilibrated Bio-Gel P10 (1.6 cm x 150 cm). The eluent is 0.3M NH4HCO3, the flow rate is 200 μl / min, and the eluent is collected in 10 min / tube. The total sugar content of each tube is detected by the sulfuric acid phenol method, the elution curve is drawn, each component is collected according to the elution curve, the purity of each component is analyzed by HPGPC, and the molecular weight of each component is analyzed by collision-induced tandem mass spectrometry (ESI-CID-MS). The mass spectrometry conditions are ion source temperature 80℃, capillary voltage -3kV, collision voltage 15-30eV, flow rate 400L / h, temperature 200℃, and the data is analyzed by Xcalibur 4.1 (LTQ-Orbitrap XL mass spectrometer) software.

[0056] Results:

[0057] The purity of each component is detected by HPGPC, and the HPGC charts of FCS oligosaccharide compounds 1-5 are shown in Figure 4 The HPGC of sulfated FCS oligosaccharide derivative compounds 6-10 is shown in Figure 5 The ESI-CID-MS mass spectra and assignments of compounds 1 and 2 are shown in Figure 6 The ESI-CID-MS mass spectra and assignments of compounds 6 and 7 are shown in Figure 7

[0058] Based on the analysis of the ESI-CID-MS mass spectra, the structural formulas of compounds 1-5 are:

[0059]

[0060] The structural formulas of compounds 6-10 are:

[0061]

[0062] ​wherein n is a natural integer from 0 to 4, R1, R2are optionally -H or -SO3H, independently from each other, R3is H or -SO3H; in 1 and 6, n = 0; in 2 and 7, n = 1; in 3 and 8, n = 2; in 4 and 9, n = 3; in 5 and 10, n = 4.

[0063] Example 5 Determination of molecular weight of FCS series oligosaccharide derivatives

[0064] The weight average molecular weight of the sample was determined by high performance gel permeation chromatography (HPGPC) combined with multi-angle laser light scattering (MALLS). The chromatographic conditions were as follows: chromatographic column: Shodex Ohpak SB-803HQ (8.0 μm x 300 mm) and Shodex Ohpak SB-802.5HQ (8.0 μm x 300 mm) chromatographic column in series; mobile phase: 0.1 M Na2SO4solution; detector: differential detector combined with multi-angle laser light scattering detector. The Astra software was used for data processing to calculate the molecular weight and polydispersity index of the sample.

[0065] It was calculated that the weight average molecular weight of the fucosylated chondroitin sulfate oligosaccharide sulfated derivatives ranged from 500 to 20,000 Da; the polydispersity index of the fucosylated chondroitin sulfate oligosaccharide sulfated derivatives was between 1.0 and 1.8.

[0066] Example 6 Evaluation of the coagulation factor inhibitory activity of FCS series oligosaccharide derivatives

[0067] Inhibition of FXase activity detection: the coagulation factor VIII and factor VIII detection kit were combined, and the detection was carried out according to the kit instructions and literature method. Specifically, 30 μL of gradient concentration of oligosaccharide sample diluted in 20 mM Tris-HCl (Tris-HCl buffer was added to the control well) was added to a 96-well plate, followed by sequentially adding 30 μL of 2 IU / mL FVIII solution, 30 μL of 60 nM FIXa solution, 30 μL of a solution containing 47 nM FIIa, 0.32 mg / mL phospholipid, 20 mM Tris-HCl and 12 mM CaCl2, mixed well, incubated at 37°C for 2 min, then added 30 μL of 50 nM FX in 20 mM Tris-HCl solution (pH 7.5, containing 0.3% fibrin polymerization inhibitor and 0.1% PEG-8000), mixed well and incubated at 37°C for 1 min; 30 μL of preheated 8.4 mM FXa specific chromogenic substrate S-2765 was added, and the OD value (405 nm) was detected by a microplate reader within 10 min.

[0068] AT-dependent Anti-FIIa activity assay: Assay using Heparin Anti-FIIa kit. Gradient concentrations of oligosaccharide samples diluted in 20 mM Tris-HCl 30 μL (Tris-HCl buffer for control wells) were added to 96-well plates, followed by 30 μL of 1 IU / mL AT solution, mixed and incubated at 37°C for 2 min; 30 μL of 24 IU / mL FIIa solution was added, mixed and incubated for 2 min, followed by 30 μL of pre-warmed 1.25 mM FIIa-specific chromogenic substrate CS-01 (38), mixed and OD values (405 nm) were measured in a microplate reader for 10 min.

[0069] AT-dependent Anti-FXa activity assay: Assay using Heparin Anti-FXa kit. Gradient concentrations of oligosaccharide samples diluted in 20 mM Tris-HCl 30 μL (Tris-HCl buffer for control wells) were added to 96-well plates, followed by 30 μL of 1 IU / mL AT solution, mixed and incubated at 37°C for 2 min; 30 μL of 24 IU / mL FIIa solution was added, mixed and incubated for 2 min, followed by 30 μL of pre-warmed 1.25 mM FIIa-specific chromogenic substrate CS-01 (38), mixed and OD values (405 nm) were measured in a microplate reader for 10 min.

[0070] Data processing: OD 405-time curves were plotted and linearly fitted to express the enzyme activity of coagulation factors as the slope (change in absorbance, ΔOD rate). The enzyme activity of coagulation factors in the presence of test samples was calculated as a percentage of the enzyme activity in the presence of solvent control (100%), which was plotted against the concentration of test samples and fitted according to the equation B = (IC 50 ) n / {(IC 50 n +[I] n} to calculate the IC 50 value. In the equation, B is the enzyme activity of coagulation factors in the presence of test samples (percentage), [I] is the concentration of test samples, IC 50 is the half-inhibitory concentration (concentration of test samples required to inhibit 50% of enzyme activity), and n is the Hill coefficient.

[0071] Table 1 Coagulation factor inhibitory activity of FCS oligosaccharide compounds and their derivatives

[0072]

[0073] Results:

[0074] The in vitro coagulation factor inhibitory activity showed that S-dFCS had the strongest anti-coagulation activity compared to dFCS, indicating that the increase in the content of sulfate groups can enhance the anti-coagulation activity. ​

[0075] The coagulation factor inhibition activity research of 10 compounds shows that the compounds 2-10 all have significant FXase inhibition activity, and the activity of the compounds 1-5 is enhanced with the increase of the polymerization degree, but the activity of the compounds 6-10 does not have the regularity, which shows that after the sulfation modification, the size of the polymerization degree does not have a decisive effect on the anticoagulation activity, and the compound 2 (nonasaccharide) and the sulfated modified compound 6 (hexasaccharide) are the smallest structural units with the strong factor Xase inhibition activity in the two types of compounds.

[0076] The above experiment shows that the S-dFCS prepared by the application has great application potential in the anticoagulation direction.

[0077] On the basis of the above embodiment, the technical features involved in the embodiment and the functions and roles of the technical features in the application are described in detail to help the skilled in the art fully understand the technical solutions of the application and reproduce the technical solutions.

[0078] Finally, although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the specification is described in this way only for the sake of clarity, and the skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can be combined appropriately to form other embodiments that can be understood by the skilled in the art.

Claims

1. A derivative of fucoidan-modified chondroitin sulfate oligosaccharide, characterized in that, This derivative is a sulfated derivative S-dFCS obtained by sulfation modification of fucosylated chondroitin sulfate oligosaccharide dFCS; the monosaccharide composition of S-dFCS includes glucuronic acid or sulfate ester, acetylgalactosyl sulfate, and fucose sulfate; the weight-average molecular weight range of S-dFCS is 500-20000 Da; the polydispersity index of S-dFCS is between 1.0 and 1.8; the specific structure of the sulfated derivative of fucosylated chondroitin sulfate oligosaccharide is as follows: ； Where n is a natural integer from 0 to 4, and R1, R2, and R3 are arbitrarily chosen to be either -H or -SO3H, which are independent of each other.

2. The derivative of fucosylated chondroitin sulfate oligosaccharide as claimed in claim 1, characterized in that, The S-dFCS is a sulfated derivative of fucosylated chondroitin sulfate hexasaccharide or a sulfated derivative of fucosylated chondroitin sulfate nonasaccharide.

3. The method for preparing the derivative of fucosylated chondroitin sulfate oligosaccharide according to claim 1, characterized in that, include: (1) Using FCS derived from the body wall of sea cucumbers in the phylum Echinodermata as raw material, the FCS was first treated with hydrazine to partially deacetylate the FCS, and the partially deacetylated FCS product was obtained. The product was then treated with nitrite to depolymerize it, and then reduced to obtain a mixture of fucosylated chondroitin sulfate oligosaccharides dFCS with terminal 2,5-dehydrated taroyl groups. (2) Using dFCS as raw material, under anhydrous conditions, it is modified by sulfation with a sulfation reagent to obtain the sulfated derivative S-dFCS of fucoidan sulfate oligosaccharide.

4. The preparation method according to claim 3, characterized in that, The phylum Echinodermata, class Holothuroidea, includes: sea cucumber (similar to sea cucumber), white-based radiated sea cucumber, black-wrinkled radiated sea cucumber, sea cucumber, snake-eyed white sea cucumber, red-bellied sea cucumber, Arctic sea cucumber, ivory sea cucumber, Mexican sea cucumber, black-breasted sea cucumber, jade-footed sea cucumber, Aegean sea cucumber, Chinese sea cucumber, bald sea cucumber, Turkish sea cucumber, drooping-skin sea cucumber, American sea cucumber, Brazilian sea cucumber, green sea cucumber, plum blossom sea cucumber, and giant plum blossom sea cucumber.

5. The preparation method according to claim 3, characterized in that, S-dFCS was further purified by first removing impurities by dialysis, and then by gel chromatography or ion exchange chromatography to obtain sulfated derivatives of chondroitin sulfate hexasaccharide, chondroitin sulfate nonasaccharide, chondroitin sulfate dodecanose, chondroitin sulfate pentadecose, and chondroitin sulfate octadecose.

6. The use of the derivative of the fucosylated chondroitin sulfate oligosaccharide of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anticoagulant.

7. The use of a derivative of the fucosylated chondroitin sulfate oligosaccharide of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment and / or prevention of thrombotic diseases.

8. The use of the derivative of fucosylated chondroitin sulfate hexasaccharide as described in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of anticoagulant or antithrombotic drugs.

9. The use of the derivative of fucosylated chondroitin sulfate nonose as described in claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of anticoagulant or antithrombotic drugs.

10. A pharmaceutical composition, characterized in that, The derivatives of fucosylated chondroitin sulfate oligosaccharide as described in claim 1 and / or pharmaceutically acceptable salts of fucosylated chondroitin sulfate oligosaccharide derivatives are included.

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