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Anticoagulant pentasaccharide compound and its preparation method and medical application

A compound and composition technology, applied in the field of pentasaccharide compounds, can solve the problems of increased bleeding risk and achieve the effects of simplified preparation method, long half-life in vivo, and small 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 and its preparation method and medical application
  • Anticoagulant pentasaccharide compound and its preparation method and medical application
  • Anticoagulant pentasaccharide compound and its preparation method and medical application

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0076] Preparation of Compounds D1-D6:

[0077] Refer to Bioorganic & Medicinal Chemistry Letters, 2009, 19(14), 3875-3879.

[0078] The second part preparation of monosaccharide E ring

[0079] synthetic route:

[0080]

[0081] a) dimethyl sulfate, KOH, tetrahydrofuran, b) trifluoroacetic acid, water, c) pyridinium p-toluenesulfonate, benzaldehyde dimethyl acetal, d) ethyl acetate, acetic anhydride, triethylamine, DMAP, e) boron trifluoride ether, p-methoxyphenol, f) sodium methoxide, methanol, g) preparation E7: potassium hydroxide, benzyl bromide, preparation E8: potassium hydroxide, dimethyl sulfate, h) acetic acid, water , i) TEMPO, BAIB, dichloromethane, water, j) iodomethane, potassium bicarbonate, acetonitrile

[0082] Preparation of Compounds E1-E4:

[0083] Reference Tetrahedron, 2012, 68(36), 7386-7399.

[0084] Preparation of Compound E5:

[0085] Dissolve E4 (366g) and 130g of p-methoxyphenol in 366ml of anhydrous dichloromethane, inject 280g of boron tr...

Embodiment 1

[0201] Example 1 Preparation of Pentasaccharide I-1

[0202] synthetic route:

[0203]

[0204] Preparation of compound DEFGH10:

[0205] Dissolve DE7 (29g) and FGH3 (47g) in anhydrous dichloromethane, add 1g of TMSOTf dropwise at 0°C, add triethylamine to quench after reacting for 1h, and perform column chromatography to obtain DEFGH10 (59g, yield 85%) . 1 H NMR (300MHz, CDCl 3 )δ7.34-7.29(m,35H),5.99(d,J=8Hz,,1H),5.60(m,3H),5.17(dd,J=9.0,3.4Hz,2H),4.64–4.62(m ,16H),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(d,15H),3.36(m,3H),2.02(s,3H).MS(ESI):1705.7[M+Na] +

[0206] Preparation of Compound DEFGH11:

[0207] Dissolve DEFGH10 (59 g) in anhydrous methanol, add 10% palladium carbon, reduce under hydrogen pressure for 24 h, filter and spin dry to obtain DEFGH11 (36.9 g, yield 100%). 1 H NMR (300MHz, CDCl 3)δ5.99(d,J=3.6Hz,1H),5.60(d,1H),5.40(m,2H),5.17(dd,J=9.0,3.4Hz,2H),4.77(d,2H), 4.71(d,2H),4.64–4.62(m,2H),4.23-4.19(m,4H),3....

Embodiment 2

[0212] Example 2 Preparation of Pentasaccharide I-2

[0213] synthetic route:

[0214]

[0215] Preparation:

[0216] Referring to the method of Example 1, DE8 and FGH3 were used as raw materials to react, and then the pentasaccharide I-2 was prepared after hydrogenolysis reaction to remove benzyl group, sulfation reaction and hydrolysis reaction.

[0217] Compound DEFGH40: 1 H NMR (300MHz, CDCl 3 )δ7.34-7.29(m,35H),5.99(d,J=8Hz,,1H),5.60(m,3H),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(d,15H),3.36(m,3H),2.02(s,3H).MS(ESI):1705.7[M+Na] +

[0218] Compound DEFGH41: 1 H NMR (300MHz, CDCl 3 )δ5.99(d,J=3.6Hz,1H),5.60(d,1H),5.40(m,3H),5.17(dd,J=9.0,3.4Hz,1H),4.77(d,3H), 4.71(d,2H),4.64–4.62(m,2H),4.23-4.19(m,3H),4.10(m,1H),3.94(m,3H),3.90(m,4H),3.80-3.76( m,5H),3.70(d,6H),3.60-3.50(m,8H),3.41-3.40(m,18H),3.30(m,2H),2.02(s,3H).MS(ESI):1033.4 [M+Na] +

[0219] Compound DEFGH42: 1 H NMR (...

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Abstract

The present invention relates to the anticoagulant compound represented by formula I and its salt, its preparation method and its use in the preparation of medicines for preventing and / or treating diseases related to blood coagulation disorders.

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] Thromboembolic disease is a kind of disease that seriously endangers human health, and its incidence rate ranks first among all kinds of 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 therap...

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 张林林宋洁梅吴舰王超群王华萍徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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