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Epimerized derivatives of K5 polysaccharide with a very high degree of sulfation

A technology of sulfation and derivatives, which is applied to the derivative pharmaceutical composition of K5 polysaccharide, the beginning field of K5 polysaccharide, can solve the problems of undetectable and other problems

Inactive Publication Date: 2005-09-28
GLYCORES 2000 SRL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] - K5-amine means at least 95% N-deacetylated K5, but wherein the N-acetyl group is not detectable with conventional NMR equipment;

Method used

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  • Epimerized derivatives of K5 polysaccharide with a very high degree of sulfation
  • Epimerized derivatives of K5 polysaccharide with a very high degree of sulfation
  • Epimerized derivatives of K5 polysaccharide with a very high degree of sulfation

Examples

Experimental program
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Effect test

preparation example Construction

[0184] Preparation of K5-N-sulfate

[0185] (i) N-Deacetylation

[0186] 10 g of pure K5 polysaccharide prepared according to Preparation II was dissolved in 1000 ml of 2N sodium hydroxide and the solution was left at 60°C for 24 hours. The solution was brought to room temperature, and then the pH was made neutral (pH 7) with 6N hydrochloric acid.

[0187] (ii) N-sulfation

[0188] Add 16 g of sodium carbonate to the solution containing deacetylated K5 maintained at 40 °C, followed by 16 g of pyridine.SO after 4 h 3 - . At the end of the reaction, that is, after 24 hours, the solution was returned to room temperature, and then the pH was adjusted to 6.5-7 with 5% hydrochloric acid solution. The product was purified from the salt by diafiltration using a 1,000D helically wound membrane (purchased from cartridge-Millipore). Diafiltration is terminated when the conductivity of the permeate is less than 1000 μS, preferably less than 100 μS. Use the same concentration of dia...

Embodiment 1

[0193] LMW-epiK5-N-sulfate, sequence (i)→(ii)

[0194] (i) Epimerization of epiK5-N-sulfate

[0195] 10 grams of K5-N-sulfate obtained according to WO 02 / 068477 embodiment 1, steps (i) and (ii) 1 No relevant acetyl or NH groups were found in the H-RMN spectrum 2 signal) dissolved in 600ml 25mM HEPES buffer (pH7, containing 50mM CaCl 2 ), the resulting solution was recirculated through a 50 ml column packed with Sepharose 4B resin containing 5 g of immobilized C5-epimerase recombinant (WO 96 / 14425) as described in Example 1 of WO 01 / 72848 stated. The reaction was carried out at 30° C., pH 7, and a flow rate of 200 ml / h for 24 hours. The resulting product was purified by ultrafiltration and precipitated with ethanol. This gave epiK5-N-sulfate with an iduronic acid content of 54%.

[0196] (ii) Depolymerization of epiK5-N-sulfate

[0197] 1 g of the product thus obtained was dissolved in 25 ml of distilled water, and 230 mg of sodium nitrite dissolved in 115 ml of distille...

Embodiment 2

[0199] LMW-epiK5-N-sulfate, sequence (ii) → (i)

[0200] (ii) Depolymerization of K5-N-sulfate

[0201] As described in preparation method I, 2 g of K5-N-sulfate obtained according to WO02 / 068477 Example 1, steps (i) and (ii) were depolymerized with 100 mg sodium nitrite and 300 mg sodium borohydride. 1.8 g of LMW-K5-N-sulfate having an average molecular weight of 5,000 was obtained.

[0202] (i) Epimerization of LMW-K5-N-sulfate

[0203] 1 g of LMW-K5 N-sulfate obtained from step (ii) above was treated as described in Example 1, step (i). The epimeric product was obtained with an iduronic acid / glucuronic acid ratio of 44 / 56, which is different from the 0 / 100 ratio of the starting material, and its molecular weight distribution was from 2,000-10,000, with an average molecular weight of 5,000D. The yield measured by measuring the content of uronic acid relative to the standard substance was 90% by the carbazole method (Bitter and Muir, Anal. Biochem. 1971, 39, 88-92).

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Abstract

A new method is described for the oversulfation of epiK5-N-sulfate to obtain an epiK5-amine-O-oversulfate with very high sulfation degree which, by subsequent N-sulfation, provides new epiK5-N,O-oversulfate-derivatives with a sulfation degree of at least 4, basically free of activity on the coagulation parameters and useful in the cosmetic or pharmaceutical field. Also described are new low molecular weight epiK5-N-sulfates useful as intermediates in the preparation of the corresponding LMW-epiK5-N,O-oversulfate-derivatives.

Description

[0001] purpose of invention [0002] The present invention relates to novel derivatives of very highly sulfated K5 polysaccharides, a process for their preparation, novel highly O-sulfated intermediates for their synthesis, and compounds containing The active ingredient is a pharmaceutical composition of derivatives of the K5 polysaccharide. [0003] In particular, the present invention relates to a polysaccharide starting from at least 20% of the K5 polysaccharide previously N-deacetylated, N-sulfated and C5-epimerized by O-persulfating under suitable conditions and subsequent N-sulfation to prepare epiK5-N, a method for O-persulfate, relating to said epiK5-N, O-persulfate having angiogenesis inhibitory activity and antiviral activity, and relating to said epi Low molecular weight intermediate of -K5-N-sulfate. Background of the invention [0004] Aminodextran, such as heparin, heparan sulfate, dermatan sulfate, chondroitin sulfate, and hyaluronic acid, are biopolymers extr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K8/60A61K8/72A61K8/73A61K31/726A61K31/727A61K31/737A61P3/06A61P3/10A61P7/02A61P9/00A61P17/06A61P17/16A61P19/02A61P27/02A61P27/06A61P31/12A61P35/00A61P35/04A61P39/06A61P43/00C07H1/00C08B37/00C08B37/10
CPCA61K31/737C08B37/0078A61K31/727C08B37/0075C07H1/00A61K31/726C08B37/006A61P17/06A61P17/16A61P19/02A61P27/02A61P27/06A61P31/12A61P35/00A61P3/06A61P35/04A61P39/06A61P43/00A61P7/02A61P9/00A61P3/10
Inventor 帕斯夸·安娜·奥雷斯特乔治·佐派蒂
Owner GLYCORES 2000 SRL
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