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Ginkgolide B derivative based on double target spots of PAF (Platelet Activating Factor)/ROS (Reactive Oxygen Species), and preparation method of derivative

A technology of ginkgolide and derivatives, applied in the directions of drug combination, antidote, blood diseases, etc., to achieve the effect of excellent inhibition of lipid peroxidation, avoid drug quality control difficulties, and inhibit oxidative stress damage

Inactive Publication Date: 2015-04-22
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the reports on the structural modification of GB mainly focus on the modification of the 10-position hydroxyl group, and there are few reports on the modification of the 1-position or 7-position.

Method used

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  • Ginkgolide B derivative based on double target spots of PAF (Platelet Activating Factor)/ROS (Reactive Oxygen Species), and preparation method of derivative
  • Ginkgolide B derivative based on double target spots of PAF (Platelet Activating Factor)/ROS (Reactive Oxygen Species), and preparation method of derivative
  • Ginkgolide B derivative based on double target spots of PAF (Platelet Activating Factor)/ROS (Reactive Oxygen Species), and preparation method of derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Synthesis of Intermediate A - 1-phenyl-3-methyl-4-(2`-bromoacetyl)-5-pyrazolone

[0055]

[0056] Weigh 4.5 g 1-phenyl-3-methyl-5-pyrazolone and 3.8 g Ca(OH) 2 In the reaction flask, add 70 ml of 1,4-dioxane as the reaction medium. Then 2 ml of bromoacetyl chloride was added dropwise to the reaction system, the drop was completed within 15 min, and the reaction was heated under reflux for 1 h. After the reaction, filter to remove insoluble Ca(OH) 2 , and add 30 ml of 1 mol / L hydrochloric acid aqueous solution to the reaction system, collect the generated crystals, MeOH-H 2 O recrystallized to obtain product 4.95g, yield 65%.

[0057] 1 H NMR (CDCl 3 , 500MHz): 7.58-7.64 (m, 2H), 7.18-7.26 (m, 2H), 6.98-7.02 (m, 1H), 4.32(s, 2H), 3.27 (s, 1H), 0.87 (s, 3H ).

Embodiment 2

[0058] Example 2: Synthesis of Intermediate A—1-methyl-3-trifluoromethyl-4-(4`-bromobutyryl)-5-pyrazolone

[0059]

[0060] The synthesis process is as in Example 1, except that 1-phenyl-3-methyl-5-pyrazolone in Example 1 is replaced by 1-methyl-3-trifluoromethyl-5-pyrazoline ketone. Yield 57%.

[0061] 1 H NMR (CDCl 3 , 500MHz): 3.45 (t, 2H), 3.31 (s, 1H), 2.64 (s, 3H), 2.45 (t, 2H), 2.11(m, 2H).

Embodiment 3

[0062] Embodiment 3: the synthesis of target product (I-1)

[0063]

[0064] Target product I-1

[0065] Weigh 0.85g GB and 0.83g anhydrous K 2 CO 3 In the reaction flask, add 30 ml CH 3 CN as the reaction solvent, followed by dropwise addition of 0.885 g of 1-phenyl-3-methyl-4-(2`-bromoacetyl)-5-pyrazolone 3 The CN solution was dropped within 30 min, and the reaction was continued at room temperature for 20 h. After the reaction, remove the insoluble matter by filtration, concentrate the filtrate under reduced pressure, add 20 ml of 2 mol / L hydrochloric acid aqueous solution and wash with CH 2 Cl 2 or CHCl 3 Extracted three times, combined extracts, washed with water, anhydrous MgSO 4 dry. The crude product was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography, petroleum ether / acetone = 2:1 as the eluent, and 0.918 g of a colorless solid was finally obtained with a yield of 72%.

[0066] 1 H N...

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Abstract

The invention discloses a ginkgolide B derivative based on double target spots of PAF(Platelet Activating Factor) / ROS (Reactive Oxygen Species), and a preparation method of the derivative, wherein the general structure formulas of the ginkgolide B derivative are shown as general formulas (I) and (II). The ginkgolide B derivative, which takes a platelet activating factor receptor antagonist ginkgolide B as a parent nucleus and combines a functional group of an edaravone or lipoic acid for scavenging active oxygen, has multiple functions of inhibiting platelet aggregation induced by the PAF, scavenging free radicals, inhibiting oxidative stress injury and the like; and due to low toxicity, the ginkgolide B derivative can be used for preventing and treating cerebrovascular diseases such as cerebral ischemia and cerebral infarction.

Description

1. Technical field [0001] The invention relates to a ginkgolide B derivative and a preparation method thereof, specifically a ginkgolide B derivative based on PAF / ROS dual targets and a preparation method thereof, which have the functions of inhibiting platelet aggregation, scavenging free radicals, and inhibiting oxidation. Multiple activities such as stress injury can be applied to the prevention and treatment of cerebral ischemia, cerebral infarction and other cerebrovascular diseases. 2. Background technology [0002] Cerebrovascular disease, also known as cerebral apoplexy and cerebral apoplexy, greatly endangers human life and health because of its "high morbidity, high mortality, high disability, and high recurrence rate". With the continuous increase of the elderly population and the improvement of living standards, the incidence of cerebrovascular disease is on the rise. Clinically, ischemic cerebrovascular disease is more common, accounting for about 60-70% of the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/22A61P7/02A61P39/06A61P9/10
Inventor 惠爱玲袁传勋潘见张文成
Owner HEFEI UNIV OF TECH
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