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Multi-target compound with anticoagulant and antiplatelet activity, preparation method and application

A multi-target and compound technology, applied in the field of biomedicine, can solve the problems of dose matching, affecting clinical antithrombotic effect, bleeding, etc., and achieve the effect of avoiding dose matching and reducing bleeding risk.

Active Publication Date: 2021-07-13
SHAANXI MICOT TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently problems such as dose matching, bleeding, and coordination of effects in combination therapy, which greatly affects the clinical antithrombotic effect.

Method used

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  • Multi-target compound with anticoagulant and antiplatelet activity, preparation method and application
  • Multi-target compound with anticoagulant and antiplatelet activity, preparation method and application
  • Multi-target compound with anticoagulant and antiplatelet activity, preparation method and application

Examples

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preparation example Construction

[0078] One aspect of the present invention provides a preparation method of the antithrombin and platelet GPⅡb / Ⅲa receptor multi-target antagonistic compound, the method comprising the following steps: (1) adopting solid-phase synthesis method to start from the carboxyl terminal according to the polypeptide sequence Beginning to insert the corresponding protected amino acids or fragments in sequence to obtain the side chain fully protected amino acid polypeptide-Wang resin; (2) acid hydrolyzing the side chain fully protected amino acid polypeptide-Wang resin with an acid hydrolysis reagent to obtain a linear polypeptide crude product; ( 3) Cyclize the crude linear polypeptide to form a disulfide bond, and then purify it using high-pressure preparative liquid phase to obtain a polypeptide sequence.

[0079] One aspect of the present invention also provides a pharmaceutical composition, the active ingredients of which include the antithrombin and the multi-target antagonistic com...

Embodiment 1

[0091] Example 1 is used to illustrate the compound and its preparation process according to one embodiment of the present invention.

[0092] 1. Preparation of Fragment I Fmoc-Gly-Gly-Gly-Gly-OH: Weigh Fmoc-Gly-2-Cl-Trt-resin (23.5g, 16.5mmol) with a degree of substitution of 0.7mmol / g and use 2.5L 25% PIP / DMF solution to remove Fmoc protection for 25 minutes, and after filtration, the resin was washed alternately with DMF and DCM for 3 times, each time not less than 1 minute. Fmoc-Gly-OH (14.8g, 50mmol) was added, stirred and reacted at 30°C for 4 hours, and the reaction endpoint was detected by the ninhydrin method. After the reaction was completed, the resin was filtered and washed alternately with DMF and DCM three times respectively.

[0093] Repeat the above steps 2 times to connect another 2 Gly to finally obtain Fmoc-Gly-Gly-Gly-Gly-2-Cl-Trt-resin. The obtained resin was dissolved in 5 L of 30% hexafluoroisopropanol / DCM solution, stirred and reacted for 2 hours, the...

Embodiment 2

[0101] The polypeptide compound 2 was prepared according to the same method as in Example 1, except that the L' fragment was GluAlaAlaAlaLys to obtain polypeptide 2, and the product quality was 1.2 g. The mass spectrometry detection results of polypeptide 2 are as follows: figure 2shown.

[0102] The structural formula of polypeptide 2 is as follows (peptide sequence shown in SEQ ID No.5): D-Phe ProArg Pro GlyGly Gly GlyAsn GlyAsp Phe Glu Glu Ile Pro Glu Glu Tyr Leu GluAlaAlaAla LysCys Har GlyAsp Trp Pro Cys

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Abstract

Provided is an anticoagulant and platelet GPⅡb / Ⅲa receptor multi-target compound, its general formula is as follows: A-L-B-L'-C, wherein A and B are binding sites for thrombin, and C is For the platelet GPⅡb / Ⅲa receptor binding site, L is the first linking group, and L' is the second linking group. Preparation methods and uses of the above compounds are also provided. The compound has in vitro human thrombin inhibitory activity, in vitro platelet GPIIb / IIIa receptor inhibitory activity, in vitro / in vivo antiplatelet aggregation, in vivo anticoagulant and antithrombotic effects.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a multi-target compound for anticoagulation and antagonizing platelet GPIIb / IIIa receptors, a preparation method and application thereof. Background technique [0002] Thrombosis is an early event in the occurrence of thrombotic diseases and runs through the beginning and end of the disease development. Platelet activation and coagulation system activation play an important role in the process of thrombus formation, and they are closely related in vivo. Thrombin, which is produced after the activation of the coagulation system, is a powerful platelet activating factor, and the activation of platelets will promote the coagulation process. The principle of preventing and treating thrombotic diseases is to improve the hypercoagulable state, prevent thrombus expansion and new thrombus formation, dissolve thrombus, and then dredge or rebuild the blood flow path to prevent tissue ischemia a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K9/00A61P7/02A61P9/10A61K38/16
CPCA61K38/16C07K9/00A61P7/02C07K14/001
Inventor 丁伟范蔷薇尹博付国琴
Owner SHAANXI MICOT TECH LTD
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