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Bilobalide B derivatives and pharmaceutical application thereof

A technology of ginkgolides and derivatives, which is applied in the field of medicine, can solve the problems of affecting the clinical application effect, poor bioavailability, and limitation of full drug effect, and achieve bioavailability and curative effect enhancement, improve water solubility, and improve bioavailability. The effect of utilization

Active Publication Date: 2006-09-27
JIANGSU CAREFREE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, ginkgolide B is a diterpene compound with a hexacyclic cage structure. It has a rigid structure, is insoluble in water, and has poor bioavailability, which limits the full use of the drug effect and affects the clinical application effect.

Method used

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  • Bilobalide B derivatives and pharmaceutical application thereof
  • Bilobalide B derivatives and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1. Synthesis and structure confirmation of 10-((sodium formate) methoxy)-ginkgolide B

[0043] Add 1.47g of bromoacetic acid, 20g of potassium carbonate, and 300mg of ginkgolide B in sequence to 40mL of acetonitrile, pass inert gas, stir, and heat to reflux for 2 hours. The mixture is treated with acid solution, concentrated under reduced pressure, dissolved in chloroform, filtered, and the filtrate is concentrated. The resulting product was separated by column chromatography (eluent: chloroform / methanol=20 / 1) to obtain 142 mg of product (yield 42%), which was then dissolved in an appropriate amount of saturated sodium bicarbonate solution, adjusted to pH 9.0, and filtered to remove insoluble and the filtrate was dried to obtain the desired compound.

[0044] 1 H-NMR (DMSO-d6) δ6.22(brs, 1H), 6.05(s, 1H), 5.24(d, 1H), 4.96(s, 1H), 4.81(brs, 2H), 4.50(d, 1H ), 4.04(d, 1H), 2.81(q, 1H), 2.30(d, 2H), 2.05~1.64(m, 3H), 1.10(d, 3H), 0.96(s, 9H).

Embodiment 2

[0045] Example 2. Synthesis and structure confirmation of 10-((3'-sodium formate) propoxy) ginkgolide B

[0046] Add 1.77g of bromobutyric acid, 2.0g of potassium carbonate, and 300mg of ginkgolide B in sequence to 40mL of acetonitrile, pass inert gas, stir, and heat to reflux for 2 hours. The mixture is treated with acid solution, concentrated under reduced pressure, dissolved in chloroform, filtered, and the filtrate concentrate. The resulting product was separated by column chromatography (eluent: chloroform / methanol=20 / 1) to obtain 132 mg of the product (yield 35%), which was then dissolved in an appropriate amount of saturated sodium bicarbonate solution, adjusted to pH 9.0, and filtered to remove insoluble The filtrate was dried to obtain the expected compound.

[0047] 1 H-NMR (CDCl 3 )δ5.95(brs, 1H), 5.59(s, 1H), 5.43(d, 1H), 4.78(s, 1H), 4.70(brs, 1H), 4.46(d, 1H), 3.86(d, 1H ), 2.67(q, 1H), 2.42(d, 2H), 2.23(d, 2H), 2.01~1.55(m, 3H), 1.05(d, 3H), 0.97(s, 9H).

Embodiment 3

[0048] Example 3. Synthesis and structure confirmation of 10-((sodium formate) chloromethoxy)-ginkgolide B

[0049] Dichloroacetic acid 1.45g, potassium carbonate 2.0g, potassium iodide 400g, ginkgolide B 300mg, followed by

[0050] Add 40 mL of acetonitrile, pass inert gas, stir, and heat to reflux for 2 hours. The mixture is treated with acid solution, concentrated under reduced pressure, dissolved in chloroform, filtered, and the filtrate is concentrated. The resulting product was separated by column chromatography (eluent: chloroform / methanol=20 / 1) to obtain 161 mg of the product (yield 45%), which was then dissolved in an appropriate amount of saturated sodium bicarbonate solution, adjusted to pH 9.0, and filtered to remove insoluble The filtrate was dried to obtain the expected compound.

[0051] 1 H-NMR (DMSO-d6) δ6.42(brs, 1H), 6.15(s, 1H), 5.38(d, 1H), 5.05(ABq, 2H), 4.80(brs, 1H), 4.60(d, 1H ), 4.19 (d, 1H), 2.88 (q, 1H), 2.61 (d, H), 2.15-1.71 (m, 3H), 1.12 (d, 3H)...

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PUM

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Abstract

The invention provides a bilobalide B derivative having the structural formula described in the specification, wherein when R2 represents -COOH, R1 represents -X-, X represents C1-C18 alkylidene, the alkylidene is unsubstituted or substituted by C1-C5 straight chain or branch chain alkane. When R2 represents -NR3R4, R1 represents -XCO-, X represents C1-C5 alkylidene, the alkylidene is unsubstituted or substituted by C1-C5 straight chain or branch chain alkane, R3 and R4 are identical or different, and both are H, C1-C8 alkyl or C3-C10 cycloalkyl.

Description

technical field [0001] The present invention relates to a compound derivative and its preparation method, and its application in pharmacy, especially relates to ginkgolide B derivative, its preparation method, and its application in pharmacy, and belongs to the field of medical technology. Background technique [0002] Ginkgo biloba has been used as a medicinal plant for a long time. Around 1000 AD, Chinese folks used ginkgo leaves to treat asthma and bronchitis. With the standardization of drug extraction process and the in-depth study of pharmacological activity, countries all over the world, especially European countries such as Germany and France, have widely used Ginkgo biloba extract (GBE) to treat respiratory system, cardiovascular and cerebrovascular system and other diseases. Ginkgolides are a series of diterpenoid compounds present in Ginkgo biloba leaves and rhizomes, and their chemical properties are quite stable. Ginkgolide is a strong antagonist of platelet-ac...

Claims

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Application Information

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IPC IPC(8): C07D493/22A61K31/365A61K9/08A61K9/14A61K9/20A61K9/48A61P31/00A61P11/06A61P9/10
Inventor 秦引林
Owner JIANGSU CAREFREE PHARM CO LTD
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