Glycosides derivative of prostaglandin E1 and preparation method thereof

A technology for prostaglandins and derivatives, applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of poor water solubility, chemical instability, and inconvenient transportation.

Active Publication Date: 2010-03-17
北京中海康医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] of which prostaglandin E 1 (hereinafter referred to as PGE 1 ) has the effects of dilating blood vessels, improving microcirculation disorders, 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-un

Method used

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  • Glycosides derivative of prostaglandin E1 and preparation method thereof
  • Glycosides derivative of prostaglandin E1 and preparation method thereof
  • Glycosides derivative of prostaglandin E1 and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 11,15-Di-O-(2,3,4,6,-tetra-O-benzoyl-β-D-glucosyl)-PGE 1 Synthesis of methyl ester (compound (IV))

[0023] (1) Take 0.50g (1.4mmol) PGE 1 , 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 white solid PGE 1 Methyl ester 0.24g. 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, 7.6Hz...

Embodiment 2

[0026] 11,15-Di-O-(β-D-glucosyl)-PGE 1 (Compound (V)) Synthesis

[0027] Get 0.80g (0.52mmol) 11,15-di-O-(2,3,4,6,-tetra-O-benzoyl-β-D-glucosyl)-PGE obtained in Example 1 1 Methyl ester, 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, filter, and concentrate the filtrate, The residue was washed with ether. The residue was subjected to pressure column chromatography (chloroform-methanol-water=7:3:1) to obtain 0.31 g of the title compound. ESI MS 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

[0029] 11,15-Di-O-(β-D-glucosyl)-PGE 1 Synthesis of methyl ester (compound (VI))

[0030] Get 0.80g (0.52mmol) 11,15-di-O-(2,3,4,6,-tetra-O-benzoyl-β-D-glucosyl)-PGE obtained in Example 1 1 Add 6ml of dichloromethane and 6ml of methanol to dissolve methyl ester, add 0.52ml (0.52mmol) of 1M sodium methoxide methanol solution, stir at room temperature for 4 hours, add strong acidic cation exchange resin to neutralize, filter, and concentrate the filtrate , and the residue was washed with ether. 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 invention discloses a derivative of prostaglandin, represented by the formula (I), the pharmaceutically acceptable salt and a preparation method thereof. In the formula, R1 is beta-D-glucosylsorbitol, beta-D-pyrane galactosyl, beta-D-pyrane xylosyl, alpha-L-pyrane rhamnoside, alpha-L-pyrane arabinose, alpha-D-pyrane mannose, alpha-D-fructofurano, beta-D-fructo ribosyl, beta-L-pyrane fucosyl, beta-D-glucosyl, beta-D-lactosyl, beta-D-cellobiose diglycosyl, and R2 is hydrogen or methyl. The invention provides a stable and long-acting derivative of prostaglandin E1 so as to adapt to treating requirement.

Description

technical field [0001] The present invention relates to a novel prostaglandin E 1 Derivatives, pharmaceutically acceptable salts thereof, and preparation methods thereof. 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 Prostacyclin 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 pressur...

Claims

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Application Information

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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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