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Multi-target compound with anticoagulation and antiplatelet activity as well as preparation method and application of multi-target compound

一种化合物、血小板的技术，应用在生物医药领域，能够解决剂量匹配、出血、影响临床抗栓效果等问题，达到降低出血风险、避免剂量匹配的效果

Active Publication Date: 2021-12-10
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 anticoagulation and antiplatelet activity as well as preparation method and application of multi-target compound
  • Multi-target compound with anticoagulation and antiplatelet activity as well as preparation method and application of multi-target compound
  • Multi-target compound with anticoagulation and antiplatelet activity as well as preparation method and application of multi-target compound

Examples

Experimental program
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Effect test

preparation example Construction

[0079] 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.

[0080] 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

[0092] Example 1 is used to illustrate the compound and its preparation process according to one embodiment of the present invention.

[0093] 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% The PIP / DMF solution was deprotected by Fmoc for 25 minutes. After filtering, 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.

[0094] 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 fil...

Embodiment 2

[0102] The polypeptide compound 2 was prepared according to the same method as in Example 1, except that the L' fragment was Glu Ala AlaAla Lys to obtain polypeptide 2, and the product quality was 1.2 g. The mass spectrometry detection results of polypeptide 2 are as follows: figure 2 shown.

[0103] The structural formula of polypeptide 2 is as follows (peptide sequence shown in SEQ ID No.5): D-Phe Pro Arg Pro GlyGly Gly Gly Asn Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Glu Ala Ala AlaLys Cys Har Gly Asp Trp Pro Cys

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Abstract

The invention relates to a general formula and physiologically acceptable salts thereof: A-L-B-L'-C, wherein A and B are binding sites with thrombin, C is a binding site with a platelet GPIIb / IIIa receptor, L is a first linking group, and L' is a second linking group. The invention also relates to a preparation method and application of the compound. The invention provides an anticoagulant and antiplatelet GPIIb / IIIa receptor multi-target compound, which has good in-vitro human thrombin inhibition activity, in-vitro platelet GPIIb / IIIa receptor inhibition effect, in-vitro / in-vivo anti-platelet aggregation, in-vivo anticoagulant and antithrombotic effects; and the multi-target compound can be clinically used for preventing and treating peripheral artery thrombosis and arteriovenous bypass thrombosis, treating thrombosis in acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI), and preventing and treating cerebral arterial thrombosis.

Description

[0001] This application has an international filing date of August 5, 2015, a date of entering the Chinese national phase: February 2, 2018, and the title of the invention is "Multi-target compounds with anticoagulant and antiplatelet activities and their preparation methods and uses" , The international application number is: PCT / CN2015 / 086173, and the national application number is 201580082185.8 The divisional application of the invention. technical field [0002] 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 [0003] 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C07K1/16C07K1/06C07K1/04A61K38/16A61P7/02
CPCA61K38/16C07K9/00A61P7/02C07K14/001
Inventor 付国琴
Owner SHAANXI MICOT TECH LTD
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