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Anticoagulant pentasaccharide compound, preparation method and medical use thereof

A compound and composition technology, applied in the field of pentasaccharide compounds, can solve problems such as increased bleeding risk, and achieve the effects of prolonging the half-life in vivo, strong anticoagulant factor Xa activity, and less side effects

Active Publication Date: 2021-09-28
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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  • Anticoagulant pentasaccharide compound, preparation method and medical use thereof
  • Anticoagulant pentasaccharide compound, preparation method and medical use thereof
  • Anticoagulant pentasaccharide compound, preparation method and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0069] 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 liquid, spin-dried to obtain D1 (804g, yield 100%).

[0070] Preparation of compound D2: Add D1 (804g) to acetic acid: water: sulfuric acid = 2000g:400g:98g, reflux reaction for 1h, add ethyl acetate and water for extraction, and evaporate the organic phase to dryness to obtain D2 (690g, yield 89%) .

[0071] Preparation of compound D3: D2 (388g) was dissolved in anhydrous dichloromethane, added with 288g of trichloroacetonitrile and 15g of DBU to react for 1h, and then spin-dried to obtain D3 (489g, yield 92%) by column chromatography.

[0072] The second part preparation of monosaccharide E ring

[0073] synthetic route:

[0074]

[0075] a) dimethyl sulfate, KOH, tetrahydrofu...

Embodiment 1 5

[0158] The preparation of embodiment 1 pentasaccharide III-1 (sodium salt)

[0159] synthetic route:

[0160]

[0161] a) TMSOTf, dichloromethane, b) palladium on carbon, hydrogen, c) sulfur trioxide triethylamine salt, DMF, sodium bicarbonate, dowex-50x4, d) 4N NaOH, sephadex g25

[0162] Preparation of compound DEFGH10: Dissolve DE5 (29g) and FGH6 (45g) in anhydrous dichloromethane, add 1g of TMSOTf dropwise at 0°C, add triethylamine to quench after reacting for 1h, and obtain DEFGH10 (59g, Yield 87%). 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),4.49-4.19(m,5H),4.00(m,2H),3.80-3.77(m,8H),3.70(s,6H),3.61(d,2H),3.50(d ,3H),3.41-3.40(m,15H),3.36(m,2H),2.02(s,3H).MS(ESI):1843.8[M+Na] +

[0163] Preparation of compound DEFGH11: Dissolve DEFGH10 (59 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....

Embodiment 2 5

[0167] The preparation of embodiment 2 pentasaccharide III-2 (sodium salt)

[0168] synthetic route:

[0169]

[0170] Referring to the method of Example 1, DE9 and FGH6 were used as raw materials to react, and then the target compound was obtained through hydrogenolysis reaction to remove benzyl group, sulfation reaction and hydrolysis reaction.

[0171] Compound DEFGH20:

[0172] 1 H NMR (300MHz, CDCl 3 )δ8.05-7.55(m,5H),7.34-7.29(m,45H),5.60(m,5H),4.64–4.62(m,20H),4.49-4.19(m,3H),4.00(m, 2H),3.80-3.77(m,10H),3.70(s,6H),3.61(d,2H),3.50(d,3H),3.41-3.40(m,15H),3.36(m,2H),2.02 (s,3H).MS(ESI):1891.8[M+Na] +

[0173] Compound DEFGH21:

[0174] 1 H NMR (300MHz, CDCl 3 )δ8.05-7.55(m,5H),5.40(m,5H),4.77(d,5H),4.71(d,2H),4.64–4.62(m,2H),4.49-4.19(m,5H) ,4.10(m,3H),3.94-3.80(m,8H),3.70(d,6H),3.60-3.50(m,8H),3.41-3.40(m,15H),3.30(m,2H).MS (ESI):1081.4[M+Na] +

[0175] Compound DEFGH22:

[0176] 1 H NMR (300MHz, CDCl 3 )δ8.05-7.55(m,5H),5.54(m,5H),5.30-5.24(m,7H),,4.64–...

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Abstract

The invention relates to anticoagulant drugs, in particular to a class of synthetic pentasaccharide compounds and their salts, their preparation methods and their pharmaceutical use. The present invention synthesizes a class of pentasaccharide compounds in ionic form represented by formula III or its acid form or its salt form, which has stronger anticoagulant factor Xa activity and longer elimination half-life than fondaparinux sodium. The pentasaccharide compound of the present invention can be used in the preparation of medicines for the prevention and treatment of diseases related to blood coagulation disorders, such as deep vein thrombosis, thrombophlebitis, arterial blockage caused by thrombosis or embolism, postoperative venous thrombosis Or embolism and other diseases.

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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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/04C07H15/18C07H1/00A61K31/7028A61P7/02A61P29/00A61P9/10A61P11/00
CPCC07H1/00C07H15/04C07H15/18
Inventor 吴舰张林林宋洁梅冯海威王华萍徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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