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Abietane diterpenoid compound, preparation method thereof, pharmaceutical composition with antiplatelet activity and application thereof

A compound and diterpenoid technology, applied in the field of pharmaceutical compositions with antiplatelet activity, rosinane-type diterpenoids and their preparation fields, can solve the problem of platelet hyperreactivity, pharmacokinetics and pharmacodynamics Large differences, individual differences in drug efficacy, etc., to achieve significant in vivo antithrombotic activity, potent in vivo antithrombotic activity, and potent antiplatelet activity.

Active Publication Date: 2020-03-27
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the large individual differences in the efficacy of drugs and the tendency to bleed at high doses, the existing antiplatelet and antithrombotic drugs have the disadvantages of a narrow safety window and may cause drug resistance (McFadyen JD, Schaff M and Peter K. Current and futureantiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol. 2018; 15, 181-191)
For example, the use of aspirin still cannot completely avoid ischemic events, and its thrombus inhibitory effect is poor in an inflammatory state with a large amount of COX-2 expression, and side effects such as aspirin resistance, allergies, and gastrointestinal bleeding may occur when using this drug
Thienopyridine P2Y 12 Receptor antagonists such as clopidogrel and prasugrel need to be metabolized in vivo to produce active molecules, and their pharmacokinetics and pharmacodynamics vary greatly among individuals, and may lead to therapeutic platelet hyperresponsiveness

Method used

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  • Abietane diterpenoid compound, preparation method thereof, pharmaceutical composition with antiplatelet activity and application thereof
  • Abietane diterpenoid compound, preparation method thereof, pharmaceutical composition with antiplatelet activity and application thereof
  • Abietane diterpenoid compound, preparation method thereof, pharmaceutical composition with antiplatelet activity and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0056] The present invention provides the preparation method of abietane-type diterpenoids described in the above technical scheme, comprising the following steps:

[0057] Sage Kangding is extracted with acetone, and the obtained extract is distilled under reduced pressure to obtain an extract;

[0058] The extract is subjected to silica gel column chromatography, and the eluent used is chloroform, and then the obtained chloroform part is subjected to silica gel column chromatography under gradient elution conditions, and the eluent used is a mixed solution of petroleum ether / chloroform / ethyl acetate , collected in turn to obtain 7 fractions, recorded as A~G fractions;

[0059] Mix the sample of component B with polyamide, pass it through the MCI column under gradient elution conditions, the mobile phase used is methanol / water mixture, and collect 8 components sequentially, which are recorded as components B1 to B8;

[0060] Under gradient elution conditions, the B5 componen...

Embodiment 1

[0080] The preparation method of compound 1~7, comprises the following steps:

[0081] Take the dried whole herb of Kangding Sage, pulverize it, extract it by cold soaking with acetone at room temperature for 3 times (48h / time), combine the obtained extracts, and distill under reduced pressure to obtain the extract;

[0082] Extraction extract was subjected to silica gel column chromatography, and eluted with chloroform; Gained chloroform fraction (667g) was carried out silica gel column chromatography, and gradient elution with petroleum ether / chloroform / ethyl acetate mixed solution (petroleum ether, chloroform and ethyl acetate The volume ratio is 50:1:1, 20:1:1, 10:1:1, 5:1:1, 1:1:1), and 7 components are collected by thin-layer chromatography. Recorded as A ~ G components;

[0083] Among them, component B (223g) was mixed with polyamide, passed through MCI column, and used methanol / water mixture as mobile phase gradient elution (the volume ratio of methanol and water was ...

Embodiment 2

[0119] The compound described in embodiment 1 is to the effect of rabbit platelet aggregation induced by arachidonic acid (AA):

[0120] 1. Solution preparation

[0121] AA solution: add the marked volume of pure water according to the instructions, fully dissolve the prepared AA solution with a concentration of 15mM, subpackage and refrigerate (-20°C) for later use;

[0122] Test sample (compound described in Example 1) solution or reference substance (aspirin) solution: use dimethyl sulfoxide (DMSO) preparation concentration to be the test sample mother solution or reference substance mother solution of 10mg / mL, then use DMSO was used to dilute and prepare the test sample solution or reference solution of the required concentration;

[0123] Ca-free 2+ Tyrode's solution (Ca 2+ free Tyrode's buffer): containing NaCl 137mM, KCl 2.68mM, MgSO 4 ·7H 2 O 0.2mM, NaH 2 PO 4 2H 2 O 0.42mM, NaHCO 3 11.9mM, glucose 5.05mM, EGTA 0.2mM, pH 6.5;

[0124] Tyrode's buffer (0.25%...

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Abstract

The invention provides an abietane diterpenoid compound, a preparation method thereof, a pharmaceutical composition with antiplatelet activity and application thereof and belongs to the technical field of medicines. The abietane diterpenoid compound provided by the invention has remarkable inhibitory activity on arachidonic acid induced rabbit platelet aggregation and obvious in-vivo antithrombotic activity, and the pharmaceutical composition taking an antiplatelet compound as an effective component can be used for preparing a medicine for preventing and / or treating thrombotic diseases and hasa potential clinical application value.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to an abietane type diterpenoid compound and a preparation method thereof, a pharmaceutical composition with antiplatelet activity and an application thereof. Background technique [0002] Salvia (Salvia) is one of the famous medicinal plant groups. There are 82 species in my country, among which Hengduan Mountain is one of the three major distribution centers in the world, and its resources are extremely rich. In addition to Salvia (S.miltiorhiza), which is listed as the top grade in "Shen Nong's Materia Medica", there are more than 20 kinds of plants of this genus, such as Yunnan sage, red root grass, and purple salvia, which are used as medicines in various places. Blood stasis, cooling blood and hemostasis. Plants of the genus Salvia mainly contain diterpenoids and polyphenols, among which diterpenoids have variable structures and significant activities, and have always been ...

Claims

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Application Information

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IPC IPC(8): C07D311/92C07D307/88C07D307/93C07C49/513C07C49/517C07C45/78A61K31/352A61K31/343A61K31/122A61P9/10A61P9/00
CPCA61P9/00A61P9/10C07C49/513C07C49/517C07D307/88C07D307/93C07D311/92
Inventor 许刚赵金华夏凡林丽莎
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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