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Anti-coagulation pentasaccharide compound and preparing method and medical application thereof

A technology of compound and sulfation reaction, which is applied in the direction of sugar derivatives, pharmaceutical formulas, and medical preparations containing active ingredients, etc., can solve the problems of increased bleeding risk, achieve the effects of simplified preparation methods, small dosages, and reduced raw materials

Active Publication Date: 2019-01-04
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the case of bleeding, it is necessary to turn off the anticoagulant effect as soon as possible, and the half-life is too long, which will increase the risk of bleeding

Method used

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  • Anti-coagulation pentasaccharide compound and preparing method and medical application thereof
  • Anti-coagulation pentasaccharide compound and preparing method and medical application thereof
  • Anti-coagulation pentasaccharide compound and preparing method and medical application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0083] Preparation of compound D1: Dissolve D0 (748g) in tetrahydrofuran, use excess potassium hydroxide as a base, add dimethyl sulfate dropwise at 0°C for 2 hours, add potassium hydroxide aqueous solution to quench for 4 hours after the reaction, and then extract the fraction with ethyl acetate solution, spin-dried to obtain D1 (804g), yield 100%.

[0084] The preparation of compound D2: Add D1 (804g) to the solution of acetic acid: water: sulfuric acid = 2000g:400g:98g, add ethyl acetate and water after reflux reaction for 1h, and evaporate the organic phase to dryness to obtain D2 (690g). 89%.

[0085] Preparation of compound D3: Dissolve D2 (388g) in anhydrous dichloromethane, add 288g of trichloroacetonitrile and 15g of DBU to react for 1h, then spin to dry column chromatography to obtain D3 (490g) with a yield of 92%.

[0086] The second part preparation of monosaccharide E ring

[0087] synthetic route:

[0088]

[0089] a) dimethyl sulfate, KOH, tetrahydrofuran,...

Embodiment 1 5

[0159] Embodiment 1 pentasaccharide II-1 (R 1 for the preparation of methyl, sodium salt)

[0160] synthetic route:

[0161]

[0162] Preparation of compound DEFGH10: Dissolve DE16 (32g) and FGH5 (50g) in anhydrous dichloromethane, add TMSOTf 1g dropwise at 0°C, add triethylamine to quench after reacting for 1h, and obtain DEFGH10 (61g, Yield 81%). 1 H NMR (300MHz, CDCl 3 )δ8.05-7.55(m,5H),7.34-7.29(m,40H),5.99(d,1H),5.60(m,4H),5.17(dd,J=9.0,3.4Hz,1H),4.64 –4.62(m,18H),4.23-4.19(m,3H),4.00(m,3H),3.80-3.77(m,8H),3.70(s,6H),3.61(d,3H),3.50(d ,3H),3.41-3.40(m,18H),3.36(m,3H).MS(ESI):1815.8[M+Na] +

[0163] Preparation of compound DEFGH11: Dissolve DEFGH10 (60 g) in anhydrous methanol, add 10% palladium carbon, reduce with hydrogen under normal pressure for 24 h, filter and spin dry to obtain DEFGH11 (34 g, yield 95%). 1 H NMR (300MHz, CDCl 3 )δ8.05-7.55 (m, 5H), 5.99 (d, J = 3.6Hz, 1H), 5.60 (d, J = 8Hz, 1H), 5.40 (m, 3H), 5.17 (dd, J = 9.0, 3.4Hz, 1H), 4.77(d, 3H), 4...

Embodiment 2 5

[0166] The preparation of embodiment 2 pentasaccharide II-2 (sodium salt)

[0167] synthetic route:

[0168]

[0169] Referring to the preparation method of Example 1, DE15 and FGH5 were used as raw materials to react, and then the pentasaccharide II-2 (sodium salt) was obtained through hydrogenolysis reaction to remove benzyl group, sulfation reaction and hydrolysis reaction.

[0170] Compound DEFGH20: 1 H NMR (300MHz, CDCl 3 )δ8.05-7.55(m,5H),7.34-7.29(m,40H),5.99(d,1H),5.97(d,J=3.4Hz,,1H),5.60(m,3H),5.17( dd,J=9.0,3.4Hz,2H),4.64–4.62(m,18H),4.23-4.19(m,4H),4.00(m,3H),3.80-3.77(m,6H),3.70(s, 6H),3.61(d,3H),3.50(d,3H),3.41-3.40(m,18H),3.36(m,2H),2.02(s,3H).MS(ESI):1843.8[M+Na ] +

[0171] Compound DEFGH21: 1 H NMR (300MHz, CDCl 3 )δ8.05-7.55 (m, 5H), 5.99 (d, J = 3.6Hz, 2H), 5.40 (m, 3H), 5.17 (dd, J = 9.0, 3.4Hz, 2H), 4.77 (d, 3H ),4.71(d,2H),4.64–4.62(m,2H),4.23-4.19(m,4H),4.10(m,1H),3.94-3.80(m,10H),3.70(d,6H), 3.57-3.50(m,8H),3.41-3.40(m,15H),3.30(m,2H),2.02(...

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Abstract

The invention relates to an anti-coagulation medicine, in particular to a synthesized pentasaccharide compound, salt thereof, and a preparing method and medical application of the pentasaccharide compound. The pentasaccharide compound or acid or salt thereof in the ion form shown in the formula II (the formula can be seen in the description) is synthesized and has stronger anti-coagulation factorXa activity and a longer elimination half life compared with sodium sulfonate. The pentasaccharide compound can be used for preparing medicines for preventing and treating blood coagulation disorder related diseases such as deep venous thrombosis, thrombophlebitis, artery blockage caused by thrombosis or embolism and postoperative vein thrombosis or embolism.

Description

technical field [0001] The invention relates to a pentasaccharide compound used as an anticoagulant, its preparation method and its medical application in anticoagulation. Background technique [0002] Thrombotic disease is a class of diseases that seriously endanger human health, and its incidence rate ranks first among various diseases, and it has gradually increased in recent years. It is mainly divided into arterial thrombosis and venous thrombosis. Venous thrombosis is common in deep veins, clinically manifested as local pain and swelling due to thrombus formation, distal blood reflux disorder, and embolism caused by thrombus dislodgment leading to organ dysfunction. Arterial thrombosis begins with atherosclerotic lesions on the arterial wall and activation of platelets, which can lead to serious cardiovascular diseases such as acute myocardial infarction and stroke. Treatment methods include anticoagulant therapy, antiplatelet therapy, and thrombolytic therapy, and a...

Claims

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Application Information

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IPC IPC(8): C07H15/04C07H15/18A61K31/7028A61P7/02A61P9/10
CPCC07H15/04C07H15/18
Inventor 宋洁梅张林林吴舰赵建良王华萍徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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