WO2003020735A1 - Saccharide sulfation methods - Google Patents
Saccharide sulfation methods Download PDFInfo
- Publication number
- WO2003020735A1 WO2003020735A1 PCT/US2002/027614 US0227614W WO03020735A1 WO 2003020735 A1 WO2003020735 A1 WO 2003020735A1 US 0227614 W US0227614 W US 0227614W WO 03020735 A1 WO03020735 A1 WO 03020735A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- saccharide
- pyridine
- salt
- starting
- disaccharide
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
-
- 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
-
- 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
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- 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
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
- C08B37/0078—Degradation products
Definitions
- This invention relates to methods for the sulfation of saccharides.
- the invention relates to methods for the sulfation of low molecular weight oligosaccharides.
- Sulfated polysaccharides exhibit a variety of important biological activities.
- Guezennec et al. Carbohydrate Polymers, 37: 19 (1998), discloses that dextran sulfate has anticoagulant and antilipemic properties.
- Baba et al, Antimicrob. Agents Chemother., 32, 1742 (1988) discloses that sulfated polysaccharides are potent and selective inhibitors of various enveloped viruses.
- Glycosaminoglycans are polysaccharides composed of alternating hexosamine and aldouronic acid residues.
- Naturally occurring biologically active glycosaminoglycans include heparin, heparan sulfate, dermatan sulfate, chondroitins, chondroitin sulfates, keratin sulfate, and hyaluronic acid.
- Low molecular weight fragments of glycosaminoglycans and synthetic sulfated oligosaccharides also exhibit biological activity. Petitou and Choay, U.S. Patent No.
- the invention provides methods for ' the sulfation of low molecular weight oligosaccharides. These methods offer advantages in yield and efficiency when compared to prior art methods.
- the invention provides a process for the sulfation of a sodium or ammonium saccharide salt.
- the starting saccharide preferably comprises a heterogeneous or homogeneous collection of mono-, di-, and/or oligosaccharides in sodium or ammonium salt form. In certain preferred embodiments, more than 85% of the saccharides in the starting saccharide are composed maximally of eight sugar residues.
- the starting saccharide comprises a glucuronic acid or iduronic acid residue.
- the disaccharides in the starting saccharide have no more than seven sulfation sites. In some embodiments, the disaccharides in the starting saccharide have no more than six sulfation sites.
- the starting saccharide salt is dissolved in a dipolar aprotic solvent, preferably selected from the group consisting of pyridine, pyridine-dimethyl formamide (DMF), and pyridine-dimethylsulfoxide (DMSO), and is treated with a sulfating agent.
- a dipolar aprotic solvent preferably selected from the group consisting of pyridine, pyridine-dimethyl formamide (DMF), and pyridine-dimethylsulfoxide (DMSO)
- the invention provides a process for the sulfation of a saccharide derived from a glycosammoglycan.
- the glycosammoglycan is first depolymerized under conditions suitable to produce a starting saccharide comprising a mixture of mono-, di-, and oligosaccharides.
- more than 85% of the saccharides in the starting saccharide are composed maximally of eight sugar residues.
- the starting saccharide comprises a glucuronic acid or iduronic acid residue.
- the disaccharides in the starting saccharide have no more than seven sulfation sites, hi some embodiments, the disaccharides in the starting saccharide have no more than six sulfation sites.
- the starting saccharide in sodium or ammonium salt form, is then dissolved in a dipolar aprotic solvent and treated with a sulfating agent, as described for the first aspect of the invention, hi one embodiment, the dipolar aprotic solvent is selected from the group consisting of pyridine, pyridine-DMF, and pyridine-DMSO.
- the invention provides a process F ⁇ he 11 s ⁇ l r ⁇ OT disaceh ⁇ dfr derived from a glycosammoglycan.
- the glycosammoglycan is first depolymerized under conditions suitable to produce a mixture of mono-, di-, and oligosaccharides, and the saccharide mixture is separated to afford a disaccharide fraction, preferably wherein the disaccharides are in sodium or ammonium salt form.
- the disaccharides comprise a glucuronic acid or iduronic acid residue. In some embodiments, the disaccharides have no more than seven sulfation sites. In some embodiments, the disaccharides have no more than six sulfation sites. [014]
- the disaccharide fraction is then dissolved in a dipolar aprotic solvent and treated with a sulfating agent as described for the first and second aspects of the invention.
- the dipolar aprotic solvent is selected from the group consisting of pyridine, pyridine-DMF, and pyridine-DMSO.
- This invention relates to methods for the sulfation of saccharides.
- the invention provides methods for the sulfation of low molecular weight oligosaccharides.
- the invention provides methods for the sulfation of low molecular weight oligosaccharides derived from glycosaminoglycans.
- GAG glycosammoglycan
- GAG includes any polysaccharide essentially composed of alternating hexosamine and aldouronic acid residues, as well as fractions, fragments, and salts thereof. Thus, “GAG” is not limited to naturally occurring GAGs.
- degree of sulfation refers to the number of sulfate groups -OSO 3 per disaccharide unit.
- sulfation site refers to a functional group that can be sulfated.
- the functional group is a hydroxy or amino group.
- sulfation site includes both free functional groups that can be sulfated and functional groups that already bear a sulfate group.
- heparin and heparan sulfate refer generally to any preparation isolated from a mammalian tissue in a manner conventional for the preparation of heparin as an anticoagulant, or to any preparation otherwise obtained or synthesized and corresponding to that obtained from tissue. Such preparations are composed of repeating units of D- glucosamine and either L-iduronic or D-glucuronic acids. The size and precise nature of the polymeric chains and the degree of sulfation in heparin varies from preparation to preparation, and the terms “heparin” and “heparin sulfate” are intended to cover all such preparations.
- ammonium salt refers ⁇ N ⁇ 4 +,' salTs , M , a 'e pr 'S ' Sly excludes salts derived from organic amines, e.g., tetrabutylammom ' um salts.
- the terms “comprise(s)” and “comprising” are to be interpreted as having an open- ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
- the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
- the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
- the invention provides a process for the sulfation of a saccharide sodium or ammonium salt.
- the starting saccharide preferably comprises a heterogeneous or homogeneous collection of mono-, di-, and/or oligosaccharides in sodium or ammonium salt form.
- the starting saccharide salt is dissolved in a dipolar aprotic solvent, preferably selected from the group consisting of pyridine, pyridine-DMF, and pyridine-DMSO, and is treated with a sulfating agent.
- the starting saccharide is obtained by chemical synthesis, utilizing art-recognized procedures for carbohydrate synthesis.
- the starting saccharide is obtained by depolymerization of a polysaccharide. Methods for depolymerization of polysaccharides are known in the art, and are further described below.
- the polysaccharide is a glycosaminoglycan, more preferably a naturally occurring biologically active glycosaminoglycan.
- Non-limiting examples of such naturally occurring biologically active glycosaminoglycans include heparin, heparan sulfate, dermatan sulfate, chondroitins, chondroitin sulfates, keratin sulfate, and hyaluronic acid.
- the polysaccharide is heparin or heparan sulfate.
- the starting saccharide comprises a glucuronic acid or iduronic acid residue
- the disaccharides in the starting saccharide have no more than seven sulfation sites
- the dis cc i h * arid ⁇ s rit i ⁇ "sferting , 'sa'cchted , e have no more than six sulfation sites.
- more than 85%, 90%, or 95% of the saccharides in the starting saccharide are composed maximally of eight sugar residues.
- less than about 25%, more preferably about 20%, still more preferably about 15% of the saccharides in the starting saccharide have more than four (4) sugar residues.
- at least about 20%, preferably about 25%, more preferably about 30%, still more preferably about 35%) of the saccharides in the starting saccharide are disaccharides.
- the sulfation of the starting saccharide salt can be carried out using known methods for the sulfation of hydroxy groups.
- suitable sulfating agents include complexes of sulfur trioxide, such as, for example, SO 3 • pyridine, SO 3 • trimethylamine, SO 3 • triethylamine, SO 3 • dioxane, and SO • dimethyl formamide.
- suitable sulfating agents include, without limitation, chlorosulfonic acid, mixtures of chlorosulfonic acid and sulfuric acid, and piperidine N-sulfate.
- the sulfation reaction is preferably performed in a dipolar aprotic solvent. Pyridine enhances solubility of the saccharide sodium or ammom ' um salt, and is preferably included in the solvent mixture.
- Preferred solvents include, without limitation, pyridine, pyridine-DMF, and pyridine-DMSO.
- the reaction can be performed at room temperature or at an elevated temperature, for example at 15-100 °C.
- the reaction temperature is at least about 20 °C, more preferably about 25 °C, still more preferably about 30 °C.
- the reaction temperature does not exceed about 90 °C, preferably about 80 °C, still more preferably about 70 °C.
- the reaction mixture is heated at about 50-60 °C.
- the invention provides a process ' for the s ' tiifa ⁇ ib ⁇ i'Ofa sa'cch'ar ⁇ d derived from a glycosaminoglycan.
- the glycosaminoglycan is first depolymerized under conditions suitable to produce a starting saccharide comprising a mixture of mono-, di-, and oligosaccharides.
- the depolymerization step can be performed using any of the procedures known in the art.
- Non-limiting examples of reagents suitable for effecting depolymerization of polysaccharides, including glycosaminoglycans such as heparin, include nitrous acid, periodate, and heparinase.
- nitrous acid is prepared in situ by acidification of solutions containing sodium nitrite. By adjusting the reaction conditions, it is possible to alter the extent of depolymerization.
- more than 85%, 90%, or 95% of the saccharides present in the reaction mixture after depolymerization are composed maximally of eight sugar residues.
- less than about 25%, more preferably about 20%, still more preferably about 15% of the saccharides in the mixture have more than four (4) sugar residues.
- at least about 20%, preferably about 25%, more preferably about 30%, still more preferably about 35% of the saccharides in the mixture are disaccharides.
- nitrous acid is employed in large excess, at a concentration from about 0.2 M to about 0.5 M.
- the pH of the reaction mixture is preferably maintained from about 1 to about 4, more preferably from about 1 to about 3, and most preferably from about 1.5 to about 2.
- a reaction temperature near ambient temperature is preferred, but somewhat lower or somewhat higher temperatures may be tolerated.
- the term "ambient temperature" refers to the customary indoor temperature in the place and at the time that the reaction is carried out. Typically, ambient temperatures range from about 15 °C to about 30 °C.
- the depolymerization step further comprises treating the reaction mixture with a reducing agent.
- the reaction mixture is preferably made basic by the addition of an alkali base, preferably sodium hydroxide, and treated with a reducing agent, preferably sodium borohydride.
- the starting saccharide is preferably isolated by lyophilization of the neutralized reaction mixture.
- sodium hydroxide is used to adjust the pH of the reaction mixture, and the starting saccharide is obtained in sodium salt form.
- the starting saccharide comprises a " gmcmrorfc"acid ; Of id ⁇ ir ⁇ lr ⁇ c acid residue, hi some embodiments, the disaccharides in the starting saccharide have no more than seven sulfation sites, hi some embodiments, the disaccharides in the starting saccharide have no more than six sulfation sites.
- the starting saccharide, in sodium or ammonium salt form is then dissolved in a dipolar aprotic solvent and treated with a sulfating agent, as described for the first aspect of the invention.
- the dipolar aprotic solvent is selected from the group consisting of pyridine, pyridine-DMF, and pyridine-DMSO.
- the invention provides a process for the sulfation of a disaccharide derived from a glycosaminoglycan.
- the glycosaminoglycan is first depolymerized under conditions suitable to produce a mixture of mono-, di-, and oligosaccharides, and the saccharide mixture is separated to afford a disaccharide fraction. Separation is preferably accomplished by a chromatographic procedure, preferably size exclusion chromatography.
- Fractions preferably are eluted with ammonium bicarbonate solutions, and the fractions containing disaccharides are combined and lyophilized to obtain a disaccharide fraction, wherein the disaccharides are in ammonium salt form.
- the disaccharide fractions are then sulfated followed by a subsequent separation step, preferably accomplished by a chromatographic procedure, preferably size exclusion chromatography.
- Fractions preferably are eluted with ammonium bicarbonate solutions
- the salt form can be changed, for example to the sodium salt, by exposure to a cation exchange resin prior to lyophilization of the solid..
- the disaccharides comprise a glucuronic acid or iduronic acid residue. In some embodiments, the disaccharides have no more than seven sulfation sites. In some embodiments, the disaccharides have no more than six sulfation sites. [031]
- the disaccharide fraction is then dissolved in a dipolar aprotic solvent and treated with a sulfating agent as described for the first and second aspects of the invention.
- the dipolar aprotic solvent is selected from the group consisting of pyridine, pyridine-DMF, and pyridine-DMSO. The supersulfated disaccharides thus produced are recovered and again separated.
- Separation is preferably accomplished by a chromatographic procedure, preferably size exclusion chromatography.
- Fractions preferably are eluted with ammonium bicarbonate solutions, and the fractions containing disaccharides are combined and lyophilized to obtain a disaccharide fraction, wherein the disaccharides are in ammonium salt form.
- the salt form can be changed, for ex irip'le i, td tfM s druhr salt -by exposure to a cation exchange resin.
- Step 1 Preparation of oligomix
- Heparin sodium USP 25 g (Pharmacia-Upjohn, Franklin, OH, USA) was gradually added to a glass beaker containing purified water (125 ml) at room temperature. The mixture was stirred with a mechanical stirrer for 50 minutes until it was completely dissolved. Concentrated HCl was added dropwise to the solution to a pH of approximately 1.5. NaNO 2 (2.6 g) ( J. T. Baker, Phillipsburg, NJ, USA) was added over 5 minutes to the acidified solution and the solution was stirred for 1 hour. The pH of the reaction mixture was maintained at 1.5 by addition of concentrated HCl.
- Step 2 Supersulfation of oligomix sodium salt [035] Anhydrous DMF (10 ml) was added to a stirred suspension of heparin-derived oligomix sodium salt (5 g) and pyridine-sulfur trioxide complex [Aldrich Chemical Co., (14.05 g)] in anhydrous pyridine (50 ml) under an argon atmosphere. The reaction mixture was heated to 60 °C in an oil bath and stirred at this temperature for 18 hours.
- reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure to produce a solid residue.
- the solid residue was dissolved in purified water, and the pH of the solution was adjusted to' ⁇ .S ⁇ f , 0 l) 1, im , bdi ⁇ y i; &yMiii ⁇ , e' ' solution.
- Step 3 Separation of supersulfated disaccharide by size exclusion chromatography
- the crude supersulfated oligomix was purified by size exclusion chromatography of the solid on a 1.5 m x 90 cm column containing BioRad P4 BioGel (10 L) (BioRad Labs, Hercules, CA., USA) and eluted with 0.2 M NH 4 HCO 3 .
- the ammonium salt of the supersulfated disaccharide (2.3 g) was obtained after lyophilization of the appropriate fractions.
- ammonium salt of the supersulfated disaccharide was exchanged for the sodium salt by passing an aqueous solution of the ammonium salt through a column containing Amberlite LR120PLUS Cation Exchange Resin (150 g) (Sigma Chemical Co., St. Louis, MO., USA). The filtrate from the ion exchange column was freeze-dried to afford the product as a white to off-white solid (2.3 g).
- Oligomix sodium salt (40 g), obtained as described in Example 1, was purified by size exclusion chromatography on a 1.5 m x 90 cm column containing BioRad P4 BioGel (10 L) and eluting with 0.2 M NH 4 HCO .
- the disaccharide ammonium salt (10 g) was obtained after lyophilization of the appropriate fractions.
- the ammonium salt was either directly subjected to the supersulfation conditions, or was first converted to the sodium salt by ion exchange chromatography, as described above in Example 1, step 3.
- Step 2 Supersulfation of disaccharide salt [041] Anhydrous DMF (10 ml) was added to a stirred suspension of heparin-derived disaccharide sodium salt (4 g) and pyridine-sulfur trioxide complex [Aldrich Chemical Co., (6.8 g)] in anhydrous pyridine (40 ml) under an argon atmosphere': Tne ⁇ eadl ⁇ oh mixture was heated to 65 °C in an oil bath and stirred at .this temperature for 18 hours.
- reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure to produce a solid residue.
- the solid residue was dissolved in purified water, and the solution pH was adjusted to 6.95 (+ 0.1) with sodium hydroxide solution.
- the ammonium salt of the supersulfated disaccharide was exchanged for the sodium salt by passing an aqueous solution of the ammonium salt through a column containing Amberlite IR120PLUS Cation Exchange Resin [Sigma Chemical Co., (150 g)].
- the filtrate from the ion exchange column was freeze-dried to afford the product as a white to off-white solid (3.95 g).
- Step 1 Preparation ofDisacchari.de salt: [046] Heparin Sodium USP (25 g) (Pharmacia-Upjohn) was gradually added to a glass beaker containing purified water (125 ml) at room temperature. The mixture was stirred with a mechanical stirrer for 50 minutes until it was completely dissolved. NaNO 2 (2.6 g) (J. T. Baker) was added and the solution stirred until the salt dissolved. Concentrated HCl was then added dropwise to the solution to a pH of approximately 1.5 and the resulting acidified solution stirred for approximately 1 hour. Step 2: Reduction of aldehyde with NaBHi.
- Step 3 Separation ofDisacchari.de fraction by SEC (provides the NH + salt).
- Step 4 Reaction of Disaccharide Na + (or NFL "1" ) salt with Pyridine.SO ⁇ in anhydrous
- Step 5 Extraction of supersulfated disaccharide.
- Step 6 SEC of aqueous solution of solid residue to give Super-Di NH 4 + salt.
- the ammonium salt of the supersulfated disaccharide was exchanged for the sodium salt by passing an aqueous solution of the ammonium salt through a column containing Amberlite IR120PLUS Cation Exchange Resin [Sigma Chemical Co., (150 g)].
- the filtrate from the ion exchange column may again be decolorized with activated carbon and then freeze-dried to afford the product as a white to off-white solid (2.3 g).
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Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/487,464 US20050119469A1 (en) | 2001-08-31 | 2002-08-30 | Saccharide sulfation methods |
JP2003525005A JP2005504067A (en) | 2001-08-31 | 2002-08-30 | Saccharide sulfation method |
EP02763576A EP1421091A4 (en) | 2001-08-31 | 2002-08-30 | Saccharide sulfation methods |
AU2002327578A AU2002327578B2 (en) | 2001-08-31 | 2002-08-30 | Saccharide sulfation methods |
CA2458651A CA2458651C (en) | 2001-08-31 | 2002-08-30 | Saccharide sulfation methods |
KR10-2004-7002850A KR20040066090A (en) | 2001-08-31 | 2002-08-30 | Saccharide sulfation methods |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US31633701P | 2001-08-31 | 2001-08-31 | |
US60/316,337 | 2001-08-31 |
Publications (1)
Publication Number | Publication Date |
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WO2003020735A1 true WO2003020735A1 (en) | 2003-03-13 |
Family
ID=23228623
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/027614 WO2003020735A1 (en) | 2001-08-31 | 2002-08-30 | Saccharide sulfation methods |
Country Status (7)
Country | Link |
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US (1) | US20050119469A1 (en) |
EP (1) | EP1421091A4 (en) |
JP (1) | JP2005504067A (en) |
KR (1) | KR20040066090A (en) |
AU (1) | AU2002327578B2 (en) |
CA (1) | CA2458651C (en) |
WO (1) | WO2003020735A1 (en) |
Cited By (4)
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US8586637B2 (en) | 2007-06-26 | 2013-11-19 | Dais Analytic Corporation | Stable and compatible polymer blends |
EP2851362A1 (en) | 2013-09-18 | 2015-03-25 | Ulusal Bor Arastirma Enstitusu | A method for the production of sulfate or sulfonate esters |
CN110470750A (en) * | 2019-05-27 | 2019-11-19 | 南京健友生化制药股份有限公司 | A kind of method of chondroitin polysulfate in measurement crude heparin sodium |
WO2022015902A1 (en) | 2020-07-14 | 2022-01-20 | Massachusetts Institute Of Technology | Synthetic heparin mimetics and uses thereof |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040171819A1 (en) | 2002-10-10 | 2004-09-02 | Aventis Pharma S.A. | Mixtures of polysaccharides derived from heparin, their preparation and pharmaceutical compositions containing them |
JP4636818B2 (en) * | 2004-06-07 | 2011-02-23 | マルホ株式会社 | Method for producing polysulfated chondroitin sulfate |
CN104558250B (en) * | 2015-02-03 | 2017-06-20 | 华北制药华坤河北生物技术有限公司 | A kind of method that Nadroparin Calcium is produced by heparin sodium crude |
EP3398971A4 (en) * | 2015-12-30 | 2019-09-25 | Shenzhen Hepalink Pharmaceutical Group Co., Ltd. | Sulfated heparin oligosaccharide and preparation method and application thereof |
EP3672603A1 (en) | 2017-08-23 | 2020-07-01 | Cell Receptor AG | Combination of a mapk/erk pathway inhibitor and a glycosaminoglycan for the treatment of cancer |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5874548A (en) * | 1994-07-27 | 1999-02-23 | Genzyme Corporation | Regioselective sulfation |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3585184A (en) * | 1967-12-29 | 1971-06-15 | Univ Ohio State | 2-amino - 2 - deoxy-d-glucopyrano-d-glucopyranans having the alpha-d-glucose configuration,method,and use |
IL61201A (en) * | 1979-10-05 | 1984-09-30 | Choay Sa | Oligosaccharides having no more than 8 saccharide moieties,their obtention from heparin and pharmaceutical compositions containing them |
US4948881A (en) * | 1982-12-28 | 1990-08-14 | Sanofi | Process for the depolymerization and sulfation of polysaccharides |
FR2538404B1 (en) * | 1982-12-28 | 1985-08-23 | Anic Spa | |
FR2584728B1 (en) * | 1985-07-12 | 1987-11-20 | Choay Sa | PROCESS FOR THE SULFATION OF GLYCOSAMINOGLYCANS AND THEIR FRAGMENTS |
SE8702254D0 (en) * | 1987-05-29 | 1987-05-29 | Kabivitrum Ab | NOVEL HEPARIN DERIVATIVES |
US5254556A (en) * | 1988-11-07 | 1993-10-19 | Janssen Pharmaceutica N.V. | 3-piperidinyl-1,2-benzisoxazoles |
US6017901A (en) * | 1995-05-10 | 2000-01-25 | Fidia Advanced Bioplymers S.R.L. | Heavy metal salts of succinic acid hemiesters with hyaluronic acid or hyaluronic acid esters, a process for their preparation and relative pharmaceutical compositions |
IT1289613B1 (en) * | 1997-02-07 | 1998-10-15 | Inalco Spa | O-SULPHATED BACTERIAL POLYSACCHARIDES |
JP3163359B2 (en) * | 1997-02-28 | 2001-05-08 | 経済産業省産業技術総合研究所長 | Sulfated oligosaccharide compounds |
-
2002
- 2002-08-30 JP JP2003525005A patent/JP2005504067A/en active Pending
- 2002-08-30 AU AU2002327578A patent/AU2002327578B2/en not_active Ceased
- 2002-08-30 KR KR10-2004-7002850A patent/KR20040066090A/en not_active Application Discontinuation
- 2002-08-30 US US10/487,464 patent/US20050119469A1/en not_active Abandoned
- 2002-08-30 CA CA2458651A patent/CA2458651C/en not_active Expired - Fee Related
- 2002-08-30 EP EP02763576A patent/EP1421091A4/en not_active Withdrawn
- 2002-08-30 WO PCT/US2002/027614 patent/WO2003020735A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5874548A (en) * | 1994-07-27 | 1999-02-23 | Genzyme Corporation | Regioselective sulfation |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8586637B2 (en) | 2007-06-26 | 2013-11-19 | Dais Analytic Corporation | Stable and compatible polymer blends |
EP2851362A1 (en) | 2013-09-18 | 2015-03-25 | Ulusal Bor Arastirma Enstitusu | A method for the production of sulfate or sulfonate esters |
CN110470750A (en) * | 2019-05-27 | 2019-11-19 | 南京健友生化制药股份有限公司 | A kind of method of chondroitin polysulfate in measurement crude heparin sodium |
WO2022015902A1 (en) | 2020-07-14 | 2022-01-20 | Massachusetts Institute Of Technology | Synthetic heparin mimetics and uses thereof |
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EP1421091A1 (en) | 2004-05-26 |
AU2002327578B2 (en) | 2009-01-08 |
KR20040066090A (en) | 2004-07-23 |
CA2458651C (en) | 2011-11-29 |
US20050119469A1 (en) | 2005-06-02 |
JP2005504067A (en) | 2005-02-10 |
CA2458651A1 (en) | 2003-03-13 |
EP1421091A4 (en) | 2008-02-20 |
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