Glycoside derivatives of prostaglandin e1 and preparation method thereof

A prostaglandin and derivative technology, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of short half-life, rapid metabolic inactivation, poor water solubility of prostaglandin E1, etc.

Active Publication Date: 2012-02-01
北京中海康医药科技发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Among them, prostaglandin E1 (hereinafter referred to as PGE1) has the functions of dilating blood vessels, improving microcirculation disturbance, inhibiting platelet aggregation, preventing thrombosis and arteriosclerosis, but its application faces problems such as chemical instability and rapid metabolic inactivation
The chemical instability is due to the fact that the 11-position hydroxyl group in the molecule is easy to dehydrate under high temperature, acid or alkali catalysis to form inactive α, β-unsaturated ketones, which causes great inconvenience to production, storage, and transportation, while rapid metabolism. It refers to the short half-life caused by the 15th hydroxyl group in the molecule being easily oxidized by enzymes in the body. Therefore, the research and development of stable and long-acting PGE1 derivatives is the development direction of this field
Secondly, the water solubility of prostaglandin E1 is poor, and the products on the market need to be dissolved in alcohol solution or clarified by cyclodextrin to form a clear solution

Method used

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  • Glycoside derivatives of prostaglandin e1 and preparation method thereof
  • Glycoside derivatives of prostaglandin e1 and preparation method thereof
  • Glycoside derivatives of prostaglandin e1 and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Synthesis of 11,15-di-O-(2,3,4,6,-tetra-O-benzoyl-β-D-glucosyl)-PGE1 methyl ester (compound (IV))

[0024] (1) Take 0.50g (1.4mmol) PGE1, 4.7ml (0.12mol) methanol, 0.4ml (2.9mmol) triethylamine, add 10ml dichloromethane to dissolve. in N 2 After stirring for 5 minutes, 0.30 g (1.6 mmol) of p-toluenesulfonyl chloride was added. Stir at room temperature for 2.5 hours, wash with saturated ammonium chloride solution three times, and concentrate the organic phase to dryness. The residue was added to 50 ml of TRIS buffer solution of pH 8 and stirred for 15 minutes, then extracted with diethyl ether, the organic phase was washed with water until neutral, dried by adding anhydrous sodium sulfate, filtered, and concentrated. Pressurized column chromatography (chloroform-methanol=98:2) gave 0.24 g of PGE1 methyl ester as a white solid. ESI MS m / z: 391.4 (M+Na) + . 1 H NMR (CDCl 3 , 300MHz): δ0.89(t, 3H, J=6.9Hz), 1.12-1.83(m, 18H), 1.85-2.66(m, 7H), 2.73(dd, 1H, J=18.0, 7.6...

Embodiment 2

[0027] Synthesis of 11,15-di-O-(β-D-glucosyl)-PGE1 (compound (V))

[0028] Take 0.80g (0.52mmol) of 11,15-di-O-(2,3,4,6,-tetra-O-benzoyl-β-D-glucosyl)-PGE1 methyl ester obtained in Example 1, 0.21g (5.2mmol) sodium hydroxide, add 3ml dichloromethane, 10ml methanol, 2ml water to dissolve, stir at room temperature for 4 hours, add strong acidic cation exchange resin to neutralize to neutral, filter, concentrate the filtrate, wash with ether The residue. The residue was subjected to pressure column chromatography (chloroform-methanol-water=7:3:1) to obtain 0.31 g of the title compound. ESIMS m / z: 701.8 (M+Na) + . 1 H NMR (pyridine-d 5 , 300MHz): δ0.89(t, 3H, J=6.9Hz), 1.13-1.84(m, 18H), 1.87-2.67(m, 5H), 2.74(dd, 1H, J=18.0, 7.6Hz), 3.90-4.00(m, 2H), 4.03-4.07(m, 4H), 4.24-4.26(m, 4H), 4.39-4.45(m, 2H), 4.93(m, 2H), 5.63(m, 2H), 11.04(s, 1H).

Embodiment 3

[0030] Synthesis of 11,15-di-O-(β-D-glucosyl)-PGE1 methyl ester (compound (VI))

[0031] Take 0.80g (0.52mmol) of 11,15-di-O-(2,3,4,6,-tetra-O-benzoyl-β-D-glucosyl)-PGE1 methyl ester obtained in Example 1, Add 6ml of dichloromethane, dissolve in 6ml of methanol, add 0.52ml (0.52mmol) of 1M sodium methoxide methanol solution, stir at room temperature for 4 hours, add strong acid cation exchange resin to neutralize to neutral, filter, concentrate the filtrate, and diethyl ether Wash residue. The residue was subjected to pressure column chromatography (chloroform-methanol-water=7:3:1) to obtain 0.32 g of the title compound. ESI MS m / z: 715.2 (M+Na) + . 1 H NMR (pyridine-d 5 , 300MHz): δ0.89(t, 3H, J=6.9Hz), 1.13-1.84(m, 18H), 1.87-2.67(m, 5H), 2.74(dd, 1H, J=18.0, 7.6Hz), 3.68(s, 3H), 3.90-4.00(m, 2H), 4.03-4.07(m, 4H), 4.24-4.26(m, 4H), 4.39-4.45(m, 2H), 4.93(m, 2H), 5.63 (m, 2H), 11.04 (s, 1H).

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Abstract

The present invention is a prostaglandin derivative represented by formula (I), its pharmaceutically acceptable salt, and a preparation method thereof (wherein R1 is β-D-glucopyranosyl, β-D-galactopyranosyl, β-D-xylopyranosyl, α-L-rhamnopyranosyl, α-L-arabinopyranosyl, α-D-mannopyranosyl, α-D-fructofuranosyl, β -D-ribofuranosyl, β-L-fucopyranosyl, β-D-maltosyl, β-D-lactosyl, β-D-cellobiosyl, R2 is hydrogen or methyl). Provide a stable, long-acting prostaglandin E1 derivative to meet the needs of treatment.

Description

technical field [0001] The present invention relates to a novel prostaglandin E1 derivative, its pharmaceutically acceptable salt, and its preparation method. Background technique [0002] Prostaglandins (hereinafter referred to as PG) are a class of compounds that can exert various physiological activities in a trace amount. For the application in the field of medicine, the synthesis and biological activity of natural PG and its derivatives are constantly being studied, which have been reported in many literatures, such as review articles: [1] Synthesis of Therapeutically Useful Prostaglandin and Prostacyclln Analogs.Chemical Review , 1993, 93, 1533; [2] Recent Developments in the Synthesis of Prostaglandins and Analogues. Chemical Review, 2007, 107, 3286. [0003] The physiological actions of PG and its derivatives include vasodilator action, platelet aggregation inhibitory action, uterine contraction action, intestinal contraction action, intraocular pressure-lowering ac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/203C07H1/00
Inventor 徐庆春黄海
Owner 北京中海康医药科技发展有限公司
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