WO1999028351A1 - Sulfates de chondroitine persulfatee, procede de production de ces derniers et anticoagulants contenant ces derniers comme ingredient actif - Google Patents

Sulfates de chondroitine persulfatee, procede de production de ces derniers et anticoagulants contenant ces derniers comme ingredient actif Download PDF

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Publication number
WO1999028351A1
WO1999028351A1 PCT/JP1998/000023 JP9800023W WO9928351A1 WO 1999028351 A1 WO1999028351 A1 WO 1999028351A1 JP 9800023 W JP9800023 W JP 9800023W WO 9928351 A1 WO9928351 A1 WO 9928351A1
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WIPO (PCT)
Prior art keywords
chondroitin sulfate
persulfated
sulfate
sulfur trioxide
same
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PCT/JP1998/000023
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English (en)
Japanese (ja)
Inventor
Toshio Imanari
Toshihiko Toida
Robert J. Linhardt
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Shin Nippon Yakugyo Co., Ltd.
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Application filed by Shin Nippon Yakugyo Co., Ltd. filed Critical Shin Nippon Yakugyo Co., Ltd.
Publication of WO1999028351A1 publication Critical patent/WO1999028351A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to persulfated chondroitin sulfate, a method for producing the same, and an anticoagulant containing the same as an active ingredient.
  • Heparin is a drug widely used in clinical settings as a preoperative and postoperative thrombosis preventive agent.
  • serious side effects such as bleeding tendency and thrombocytopenia have been observed in long-term use of heparin, and it is urgently necessary to develop alternative medicines.
  • the anticoagulant activity of various natural polysaccharides and their chemical derivatives has been investigated, and their potential as pharmaceuticals has been explored.
  • chondroitin sulfate is a kind of complex carbohydrate called glycosaminoglycan, and N-acetylgalactosamine and glucuronic acid are linear chains that form a repeating unit of 3GalNAc; 81 ⁇ 4GlcA ⁇ 1 ⁇ It is an acidic polysaccharide. On average, there is one sulfate per disaccharide, and usually the 4- or 6-position hydroxyl group of ⁇ -acetylgalactosamine is sulfated.
  • This polysaccharide is usually found as a proteoglycan as a proteoglycan linked to a serine or threonine residue in a protein via a bridging structure (GlcA-Gato Gato Xy SerVThr). It is assumed to be one of the molecules existing on the extracellular matrix or on the cell surface and responsible for intercellular communication. It is thought that chondroitin sulfate plays a part in the hemostasis mechanism in vivo, but its anticoagulant activity is weaker than that of heparin or the like, so there are few opportunities to use it as a drug.
  • an object of the present invention is to provide a novel compound having high anticoagulant activity, which is different from heparin, and a method for producing the same.
  • the present inventor has developed a new method for producing chondroitin sulfate in which the number of sulfate groups per repeating unit is greater than that of conventional persulfated chondroitin sulfate.
  • the present invention has been completed by providing chondroitin sulfate for the first time, and finding that the persulfated chondroitin sulfate has a high anticoagulant activity, which is comparable to that of heparin / phosphorus.
  • the present invention provides persulfated chondroitin sulfate or pharmacologically acceptable salts thereof having an average of 3.5 or more O-sulfate groups in the disaccharide repeating unit. Further, the present invention relates to a method for forming a salt between chondroitin sulfate and sulfur trioxide in a non-protic solvent at a temperature of 30 ° C. to 50 ° C. Provided is a method for producing persulfated chondroitin sulfate, wherein the reaction is carried out at a molar ratio of 1:10 to 1:20.
  • the present invention provides an anticoagulant comprising the above-mentioned persulfated chondroitin sulfate of the present invention as an active ingredient. Further, the present invention provides a method for preventing blood coagulation, which comprises adding the above-mentioned persulfated chondroitin sulfate of the present invention to blood. Furthermore, the present invention provides the use of the above-mentioned persulfated chondroitin sulfate of the present invention as an anticoagulant.
  • a novel persulfated chondroitin sulfate having a higher sulfation rate of free hydroxyl groups than before.
  • the persulfated chondroitin sulfate of the present invention has excellent anticoagulant activity, particularly excellent Ila factor inhibitory activity, and is useful as a substitute for heparin having strong side effects.
  • Figure 1 shows the raw material chondroitin sulfate (a), persulfate reacted with sulfur trioxide at 0 ° C.
  • FIG. 4 shows the results of gradient PAGE of persulfated chondroitin sulfate (b) and persulfated chondroitin sulfate (c) of the present invention reacted with sulfur trioxide at 40 ° C.
  • FIG. 2 shows IR spectra of the raw material chondroitin sulfate (A) and the completely O-sulfated chondroitin sulfate (B) of the present invention prepared in Example 1.
  • Figure 3 shows raw chondroitin sulfate (A), persulfated chondroitin sulfate (B) reacted with sulfur trioxide at 0 ° C, and persulfated chondroitin of the present invention reacted with sulfur trioxide at 40 ° C.
  • 1 shows the results of one-dimensional 1 HNMR of sulfuric acid (C).
  • FIG. 4 shows the results of two-dimensional DOF-GOSY (A) and NOESY (B) spectra of fully O-sulfated chondroitin sulfate.
  • FIG. 5 shows the equilibrium state of the three-dimensional structures of the conventional persulfated chondroitin sulfate (A) and the completely O-persulfated oxidized chondroitin sulfate (B) of the present invention.
  • FIG. 6 shows the relationship between the number of sulfate groups in the disaccharide unit of chondroitin sulfate and anticoagulant activity.
  • chondroitin sulfate is a linear acidic polysaccharide in which N-acetylgalactosamine and glucuronic acid constitute a repeating unit of —3Ga I NAc ⁇ l- ⁇ 4G I cA 1—.
  • an average of one of these four hydroxyl groups is a sulfate ester.
  • the chondroitin sulfate of the present invention has an average of 3.5 or more, preferably ⁇ 3.8 or more, and most preferably 4 of the four hydroxyl groups in the disaccharide repeating unit. Has become an ester.
  • the average number of sulfate groups in the disaccharide repeating unit is 3.5 or more, preferably 3.8 or more, and most preferably 4, the number of sulfate groups is significantly higher than that of conventional persulfated chondroitin sulfate. Increases anticoagulant activity.
  • the number of repetitions of the disaccharide repeating unit is not particularly limited, but is preferably about 10 to 50, and more preferably 20 to 30.
  • the persulfated chondroitin sulfate of the present invention may be in the form of a pharmacologically acceptable salt.
  • a pharmacologically acceptable salt examples include, but are not limited to, alkali metal salts such as sodium salts and potassium salts, calcium salts, aluminum salts and the like.
  • the persulfated chondroitin sulfate of the present invention is obtained by reacting a salt of chondroitin sulfate and sulfur trioxide in an aprotic solvent at a temperature of 30 ° C. to 50 ° C. with free hydroxyl groups in chondroitin sulfate. It can be produced by reacting with sulfur oxide at a molar ratio of 1:10 to 1:20.
  • the chondroitin sulfate used as a starting material is preferably an organic amine salt, particularly preferably a trialkyl (particularly lower alkyl having 1 to 6 carbon atoms) amine salt, and particularly preferably a triptylamine salt.
  • Organic amine salts of chondroitin sulfate include, for example, chondroitin sulfate sodium salt (a commercially available product) prepared from cartilage of sea urchin is applied to a cation exchange resin, and then the organic amine is added and concentrated by freeze-drying. Thus, it can be easily prepared.
  • the cation exchange resin that can be used here is not limited at all.
  • the amount of the organic amine added to chondroitin sulfate after cation exchange is preferably about 1 to 1.2 mol per 1 mol of acidic group (carboxyl group or sulfate group) contained in chondroitin sulfate.
  • the obtained salt of chondroitin sulfate and sulfur trioxide are mixed in an aprotic solvent. Then, at a temperature of 30 ° C. to 50 ° C., the reaction is carried out at a molar ratio of free hydroxyl groups in chondroitin sulfate to sulfur trioxide of 1:10 to 1:20.
  • preferred aprotic solvents include, but are not limited to, N, N-dimethylformamide, dimethylsulfoxide and the like.
  • the reaction temperature is from 30 to 50 ° C, preferably from 37 to 43 ° C, most preferably about 40 ° C.
  • the molar ratio of free hydroxyl groups to sulfur trioxide in chondroitin sulfate is from 1:10 to 1:20, preferably from 1:13 to 1:17, and most preferably about 1: One is five.
  • the reaction time is about 30 minutes or more, preferably 30 minutes to 2 hours, and more preferably 45 to 90 minutes.
  • Sulfur trioxide may be reacted alone with chondroitin sulfate.
  • a cyclic amine such as pyridine is reacted with sulfur trioxide in advance to form a complex, which is then reacted with chondroitin sulfate. May be.
  • the reaction conditions between the cyclic amine and sulfur trioxide are, for example, as follows. In other words, the fuming sulfuric acid is distilled and the outflow so 3 gas is cooled. To so 3 that exhibited asbestos-like, under cooling, was added dropwise a cyclic amine, after becoming liquid, returning to room temperature, continue dropping until the such no longer observed smoke.
  • the above method produces the persulfated chondroitin sulfate of the present invention.
  • the reaction can be stopped by adding distilled water.
  • the obtained crude product can be precipitated with cold ethanol saturated with sodium acetate and recovered by centrifugation.
  • the product can be purified by dissolving the recovered product in distilled water, dialyzing against water, and freeze-drying.
  • the persulfated chondroitin sulfate of the present invention can be used as an anticoagulant similarly to heparin.
  • the dose is appropriately selected according to the symptoms and the mode of use.
  • 100 to 300 units of heparin international unit may be used. It can be administered intermittently at 500 to 1500 units per hour after administration.
  • physiological saline or distilled water for injection can be added and dissolved at the time of use so as to be 10000 units per 1 ml.
  • the persulfated chondroitin sulfate of the present invention is derived from chondroitin sulfate, which is a constituent of living organisms, and has no toxicity because the sulfate group is also non-toxic.
  • chondroitin sulfate triptylamine 100 100 mg of sodium chondroitin sulfate derived from tracheal cartilage was applied to cation exchange resin (Dowex 50W X8). At this time, a column with a column size of 1 cm (inner diameter) x 15 cm (length) was eluted with water at a flow rate of 1. OmIZ. Then, Tribylamine 100 I was added, and the mixture was concentrated by freeze-drying to obtain chondroitin sulfate triptylamine. 1 Omg of the obtained chondroitin sulfate triptylamine salt was dissolved in 0.8 ml of N, N-dimethylformamide (DMF).
  • DMF N, N-dimethylformamide
  • the fuming sulfuric acid was distilled, the outgoing so 3 gas was cooled, and cyclic amine was dropped into the asbestos-like so 3 under cooling, and after cooling to a liquid state, the temperature was returned to room temperature, and the fuming no longer occurred.
  • the pyridine 'sulfur trioxide complex obtained by continuing dropping until no longer observed was added to the chondroitin sulfate triptylamine salt DMF solution in an amount such that sulfur trioxide became 15 times the moles of free hydroxyl groups of chondroitin sulfate. . After reacting at 40 ° C for 1 hour, 1.6 ml of distilled water was added to stop the reaction.
  • the crude product was precipitated with cold ethanol (3 volumes) saturated with sodium acetate and collected by centrifugation.
  • the obtained complete O-sulfated chondroitin sulfate was dissolved in double-distilled water, and the salts were removed by dialysis, and then recovered by freeze-drying.
  • lane a shows the results for chondroitin sulfate used as a raw material (no sulfation treatment)
  • lane b shows the results for partially sulfated chondroitin sulfate reacted with sulfur trioxide at 0 ° C.
  • Lane c shows the results for the persulfated chondroitin sulfate of the present invention reacted with sulfur trioxide at 40 ° C.
  • Lane d shows the oligosaccharide molecular weight marker (4 g). Sulfation of chondroitin sulfate hardly changed the molecular weight, but a slight increase in molecular weight was observed.
  • Chondroitin sulfate for quantification of sulfate groups was thoroughly dialyzed against distilled water in a dialysis tube having a molecular weight cutoff of 12,000, freeze-dried, and dried in a desiccator in the presence of diphosphorus pentoxide for 2 days. After oxidization, the sulfate group was measured by HPLC using a CM-8 conductivity detector manufactured by Tosouichi Co., Ltd.
  • the number of sulfate groups in the disaccharide repeating unit was such that the raw material chondroitin sulfate was sulfated at 1,0 ° C, and that the persulfated chondroitin sulfate was 2.5-3.3, and the sulfated at 40 ° C.
  • the persulfated chondroitin sulfate of the present invention was 4, and it was confirmed that all of the free hydroxyl groups in chondroitin sulfate were sulfated by the method of the present invention described above. Was.
  • the infrared absorption spectrum of the solid sample was measured using FT / 1R-230 manufactured by JASCO Corporation. 100 g of glycosaminoglycan was mixed with 500 g of dried potassium bromide to prepare a tablet having a diameter of 3 mm, which was set in a spectrometer.
  • FIG. 2 shows the obtained IR spectrum.
  • A shows the IR spectrum of the raw material chondroitin sulfate
  • B shows the IR spectrum of the complete O-sulfated chondroitin sulfate of the present invention prepared in Example 1.
  • Figure 2 shows that the hydroxyl groups in all chondroitin sulfates have been converted to axial sulfates.
  • the signals assigned to the C-0-H bending vibrations at 2900, 1440, 1380, and 1100 Kaiser are reduced in the spectrum of completely 0-sulfated chondroitin sulfate.
  • a portion of the dried sample was weighed and dissolved in distilled water to a concentration of 5 mg / ml, and the optical rotation was measured. The measurement was performed with sodium D line using DIP-140 manufactured by JASCO Corporation.
  • the optical rotation was 130 degrees for the raw material chondroitin sulfate, while it was 18 degrees for the completely O-sulfated chondroitin sulfate. This indicates that the three-dimensional structure of completely O-sulfated chondroitin sulfate has changed compared to that of the raw material chondroitin sulfate.
  • One-dimensional and two-dimensional NMR measurements were performed using a JSX GSX50 OA spectrum meter equipped with a tunable 5 mm field gradient probe and standard JE0L software. At 303K, other measurements were taken at 333K. The HOD signal was eliminated by pre-saturation for 3 s in the one-dimensional spectrum and 1.5 s in the two-dimensional spectrum. In the two-dimensional spectrum, with an observation width of 2,000 Hz, 512 integrations were performed to obtain 1024 sampling data points, and the time domain data was shifted after zero filling (data matrix size, 1K x 1K). Using sine-bell window function, we amplified for two-dimensional double quantum fi Itered (DQF) -COSY, N0ESY and T0CSY. In the measurement of two-dimensional TOC SY and N0ESY, the mixing time was set to 150, 250, and 500 ms, and as a result, the MLEV-17 mixing sequence of 100 ms was used.
  • DQF double quantum fi
  • Figure 3 shows the results of the HN MR spectrum.
  • A is the result for the raw material chondroitin sulfate
  • B is the persulfated chondroitin sulfate prepared by reacting with sulfur trioxide at 0 ° C (average number of sulfate groups in the disaccharide repeating unit: 3.2)
  • C shows the results for the fully O-sulfated chondroitin sulfate of the present invention.
  • the raw material chondroitin sulfate spectrum shows a slight heterogeneity in the degree of sulfation. In other words, it is clear that this is a mixture of partial structures in which either the 4-position or the 6-position of N-acetylgalactosamine is sulfated.
  • the persulfated chondroitin sulfate prepared at 0 ° C. was as expected (see aarouf i, RM et a, Thromb. Res., 59, 174-758 (1995); Bartolucci, C. et a I., Carbohydr. Res., 276, 401-408 (1995))
  • the structural heterogeneity was increased compared to the raw material chondroitin sulfate. This increase in structural heterogeneity suggests not only sulfation at positions 4 and 6 of N-acetylgalactosamine but also incomplete sulfonation of glucuronic acid residues at positions 2 and 3.
  • FIG. 4 shows the two-dimensional 1 H NMR spectrum, DQF-COSY and N0ESY spectrum of completely 0-sulfated chondroitin sulfate. Each cross peak in the upper panel in FIG. 4 indicates the following.
  • Normal human plasma was collected from healthy volunteers. Anti-factor Xa activity was measured using Coatest and hepar in / hepar in kit (Chromogen ix, olndal, Sweden; Chondroitin sulfate, persulfated chondroitin sulfate derivative and low molecular weight heparin standard were diluted) Dissolved in normal human plasma 2.9 mM Chromogen ic Xa substrate S-2732 (50 mM Tr is, containing Sue-1 IeG Iu ( ⁇ iPeridyI) -GI y-Ar -pNA) ⁇ .5 ⁇ EDTA buffer (pH 8.4) 200 ⁇ l of Bacillus factor Xa (1.25 / ml) was added, incubated at 37 ° C for 8 minutes, and then 200 ⁇ l of 20% acetic acid was added. Factor Xa activity was measured by absorbance at 405 nm.
  • the anti-Ila factor activity was determined by mixing 50 ⁇ l of an aqueous solution of chondroitin sulfate or a persulfated derivative, 850 ⁇ l of Tris buffer ( ⁇ 8.3), 30 ⁇ l of normal human plasma, and human thrombin (1.2 NIH units / ml). 1.9mM after incubating at 37 ° C for 30 seconds
  • Chromogenic TH ⁇ ethyImaIonyI-Pro-Arg-p-nitroaniide hydrochloride was caloried, and Ila factor activity was measured by absorbance at 405 nm.
  • AGL 300 plus purchased from instrument at ion (Lexington, MA) was used for measurement, and USP Heparin reference Standard of U.S. Ph armacopeial Convention (ROCK I Ile, MD) was used as a control.
  • Fig. 6 shows the results.
  • squares indicate anti-Ila factor activity
  • circles indicate anti-factor Xa activity.
  • complete 0-sulfation dramatically increased the Ila factor inhibitory activity.
  • the anti-factor Xa activity increased slightly with sulfation, but was not as high as that of the Ila factor. This result suggests that the increase in the inhibitory activity against factor Xa is simply due to the nonspecific increase in the negative charge due to the introduction of the sulfate group.

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Abstract

L'invention concerne de nouveaux composés différents de l'héparine, présentant une activité anticoagulante importante. Ces composés sont des sulfates de chondroïtine persulfatée comprenant en moyenne au moins 3,5 de groupes O-sulfate par unité disaccharidique répétée ou des sels pharmacologiquement acceptables de ces derniers. On peut produire ces composés en faisant réagir un sel de sulfate de chondroïtine avec du trioxyde de soufre dans un solvant aprotique à une température comprise entre 30 et 50 °C, le rapport molaire des groupes hydroxyle libres dans le sel de sulfate de chondroïtine et le trioxyde de soufre étant réglé entre 1:10 et 1:20.
PCT/JP1998/000023 1997-12-02 1998-01-08 Sulfates de chondroitine persulfatee, procede de production de ces derniers et anticoagulants contenant ces derniers comme ingredient actif WO1999028351A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9347071A JPH11166001A (ja) 1997-12-02 1997-12-02 過硫酸化コンドロイチン硫酸、その製造方法及びそれを有効成分として含有する抗血液凝固剤
JP9/347071 1997-12-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104198635A (zh) * 2014-08-13 2014-12-10 南京健友生化制药股份有限公司 一种应用快速分离蛋白纯化仪检测肝素钠中多硫酸软骨素的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4636818B2 (ja) * 2004-06-07 2011-02-23 マルホ株式会社 多硫酸化コンドロイチン硫酸の製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6147701A (ja) * 1984-08-14 1986-03-08 Seikagaku Kogyo Co Ltd 合成コンドロイチン多硫酸の製造法
JPH08301771A (ja) * 1995-03-08 1996-11-19 Shiseido Co Ltd 腎疾患の予防または治療用製剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6147701A (ja) * 1984-08-14 1986-03-08 Seikagaku Kogyo Co Ltd 合成コンドロイチン多硫酸の製造法
JPH08301771A (ja) * 1995-03-08 1996-11-19 Shiseido Co Ltd 腎疾患の予防または治療用製剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104198635A (zh) * 2014-08-13 2014-12-10 南京健友生化制药股份有限公司 一种应用快速分离蛋白纯化仪检测肝素钠中多硫酸软骨素的方法

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