Water-soluble amino-acid ester derivative of ginkgolide B

A technology of ginkgolide and amino acid ester is applied in the directions of drug combination, organic active ingredients, medical preparations containing active ingredients, etc., and can solve the problems of poor water solubility of ginkgolide B, limited clinical application, etc.

Inactive Publication Date: 2010-11-10
BEIJING MEIBEITA DRUG RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the poor water solubility of ginkgolide B limits its clinical application.

Method used

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  • Water-soluble amino-acid ester derivative of ginkgolide B
  • Water-soluble amino-acid ester derivative of ginkgolide B
  • Water-soluble amino-acid ester derivative of ginkgolide B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 110-0

[0020] Embodiment 110-O-L-glycyl-ginkgolide B hydrochloride (I 1a ) and 1-O-L-glycyl-ginkgolide B hydrochloride (I 2a ) preparation

[0021] Dissolve 4.3g of ginkgolide B and 1.8g of N-Boc-glycine in 50ml of dimethylformamide, then add 0.1ml of dimethylaminopyridine and 2.1g of dicyclohexylcarbodiimide, stir at room temperature overnight, filter, The filtrate was evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography, eluted with a mixed solvent of ethyl acetate:petroleum ether (1:4), and the desired components were collected and evaporated to dryness under reduced pressure to obtain 10-O-(N-Boc-L- Glycyl)-Ginkgolide B(II 1a ) 2.4g, 1-O-(N-Boc-L-glycyl)-ginkgolide B (II 1a ) 0.8 g.

[0022] 2.4 g of 10-O-(N-Boc-L-glycyl)-ginkgolide B (II 1a ) was dissolved in 10ml of dry 1,4-dioxane, cooled to 0°C with an ice-salt bath under the protection of nitrogen, slowly added dropwise 8ml of 1,4-dioxane solution containing 15% hy...

Embodiment 21-O

[0024] Embodiment 21-O, 10-O-(two-L-glycyl)-ginkgolide B hydrochloride (I 3a ) preparation

[0025] Dissolve 4.3g of ginkgolide B and 5.4g of N-Boc-glycine in 80ml of dimethylformamide, then add 0.3ml of dimethylaminopyridine and 6.2g of dicyclohexylcarbodiimide, stir at room temperature overnight, filter, The filtrate was evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate:petroleum ether (1:4), the desired components were collected, and evaporated to dryness under reduced pressure to obtain 1-O,10-O-(di- N-Boc-L-glycyl)-ginkgolide B(II 3a ) 1.9 g.

[0026] 1.9 g of 1-O, 10-O-(di-N-Boc-L-glycyl)-ginkgolide B (II 3a ) was dissolved in 10ml of dry 1,4-dioxane, cooled to 0°C with an ice-salt bath under the protection of nitrogen, slowly added dropwise 8ml of 1,4-dioxane solution containing 15% hydrogen chloride, and stirred at 0°C The reaction was carried out for 1 hour...

Embodiment 310

[0027] Embodiment 310-O-L-alanyl-ginkgolide B hydrochloride (I 1b ) and 1-O-L-alanyl-ginkgolide B hydrochloride (I 2b ) preparation

[0028] Dissolve 4.3g of ginkgolide B and 1.9g of N-Boc-alanine in 50ml of dimethylformamide, then add 0.1ml of dimethylaminopyridine and 2.1g of dicyclohexylcarbodiimide, and stir at room temperature overnight. Filter, and evaporate the filtrate to dryness under reduced pressure. The residue was separated by silica gel column chromatography, eluted with a mixed solvent of ethyl acetate:petroleum ether (1:4), and the desired components were collected and evaporated to dryness under reduced pressure to obtain 10-O-(N-Boc-L- Alanyl)-Ginkgolide B(II 1b ) 2.5g, 1-O-(N-Boc-L-alanyl)-ginkgolide B (II 1b ) 0.7 g.

[0029]2.5 g of 10-O-(N-Boc-L-alanyl)-ginkgolide B (II 1b ) was dissolved in 10ml of dry 1,4-dioxane, cooled to 0°C with an ice-salt bath under the protection of nitrogen, slowly added dropwise 8ml of 1,4-dioxane solution containing 15% ...

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Abstract

The invention relates to an amino-acid ester derivative of ginkgolide B shown as a formula I and pharmaceutical salts thereof, a medicinal composition taking the compounds as active ingredients, and application of the compounds and the medicinal composition in serving as medicaments for treating cardiovascular and cerebrovascular diseases. In the formula I, A1 and A2 is residues of H, glycyl, L-alanyl, L-leucyl, L-valyl, L-isoleucyl, or L-phenylaminoacyl and other amino acids; A1 is the same as or different from A2; and A1 and A2 cannot be H at the same time.

Description

technical field [0001] The present invention relates to novel derivatives of amino acid esters of ginkgolide B and their non-toxic pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds as active ingredients, and the compounds and pharmaceutical compositions as cardiovascular and cerebrovascular agents. Use of medicines for disease treatment. Background technique [0002] Ginkgolide B is one of the strongest platelet activating factor antagonists discovered so far, it can be used clinically to treat thrombosis, acute pancreatitis and cardiovascular diseases, it also has protective effect on damaged neurons, and it has anti-oxidation, delays aging effect. However, the poor water solubility of ginkgolide B limits its clinical application. [0003] [0004] Ginkgolide B Contents of the invention [0005] The present invention relates to derivatives of amino acid esters of ginkgolide B represented by structural formula I and ...

Claims

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Application Information

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IPC IPC(8): C07D493/22A61K31/365A61P9/00A61P7/02A61P25/00A61P1/18A61P17/18
Inventor 杨振强徐明
Owner BEIJING MEIBEITA DRUG RES
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