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Bilobalide K derivative and preparation method and application thereof

A technology of drugs and compounds, applied in the field of new ginkgolide K derivatives, can solve the problems of poor bioavailability, insoluble in water, and limitation of drug efficacy, and achieve simple preparation process, high activity, and water solubility Good results

Active Publication Date: 2015-09-09
CHENGDU BAIYU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since ginkgolide K is a diterpene compound with a six-ring cage structure, its structure is relatively rigid, it is difficult to dissolve in water, and its bioavailability is poor, so the full play of the drug effect is limited to a certain extent, which affects the clinical medicinal effect.

Method used

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  • Bilobalide K derivative and preparation method and application thereof
  • Bilobalide K derivative and preparation method and application thereof
  • Bilobalide K derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The preparation of embodiment 1 ginkgolide K

[0057] Dissolve 50 g of ginkgolide B in 100 mL of dry dichloromethane, stir and mix evenly, then cool down to -25°C under nitrogen protection. Add 200mL DAST dropwise (that is, the volume-to-weight ratio of ginkgolide B is 4mL / g), and keep it warm for 0.5h; Add 500mL of purified water to the reaction solution, quench the reaction and remove the organic solution by rotary evaporation, extract the water layer with ethyl acetate, wash the organic layer with saturated sodium bicarbonate solution and sodium chloride solution, and then dry it, then remove the organic solution by rotary evaporation to obtain Oil. Column chromatography purification (V 二氯甲烷 / V 甲醇 =20:1) to obtain white solid ginkgolide K altogether 12.5g, yield 26.15%, HPLC purity is 99.20%;

[0058] LC-MS: 407.2 [M+H + ], 835.3[2M+Na + ].

[0059] 1 H-NMR (DMSO, 400MHz): 1.04 (s, 9H, t-Bu), 2.16-2.20 (dd, 1H, 8-H), 1.86-1.88 (m, 5H, -CH3; 7-H), 3.82 -3.85(...

Embodiment 2

[0060] Example 2 Preparation of 10-O-(dimethylaminoethyl) ginkgolide K (GK-1)

[0061] 2.0g ginkgolide K was dissolved in 50mL acetonitrile, and 0.85g dimethylamino ethyl chloride hydrochloride (1.2eq), 6.81g potassium carbonate (10eq) and 0.82g KI catalyst (1.0eq) were added successively, in React at 30°C until the reaction of the raw material ginkgolide K is complete. Cool to room temperature, filter and remove the filtrate by rotary evaporation to obtain a pale yellow oil. Column chromatography purification (V 石油醚 :V 乙酸乙酯 =2:1) ​​After that, 0.67g of GK-1 was obtained as a white solid, with a yield of 28.51% and a purity of 99.40% by HPLC.

[0062] LC-MS: 478.2 [M+H + ].

[0063] 1 H-NMR (CDCl 3 , 400MHz): 1.11(s,9H,t-Bu),1.63-1.64(dd,1H,8-H),2.08-2.09(s,3H,14-CH 3 ),2.00(s,2H,7-H),2.30(s,6H,(CH 3 ) 2 N-),1.27,2.34-2.37,2.69-2.76,3.52-3.56(s,d,mx2,1Hx4,NCH 2 CH 2 O), 4.03-4.05(d, 1H, 1-H), 4.62-4.65(m, 1H, 1-OH), 4.67(s, 1H, 10-H), 4.74(dd, 1H, 6-H) , 5.57 (s, ...

Embodiment 3

[0064] Example 3 Preparation of 10-O-(aminoethyl) ginkgolide K (GK-2)

[0065] Dissolve 2.0g ginkgolide K in 50mL acetonitrile, add 0.68g 2-chloroethylamine hydrochloride (1.2eq), 6.81g sodium carbonate (10eq) and 0.82g KI catalyst in sequence, and react at 60°C until The reaction of raw material ginkgolide K is completed. Cool to room temperature, filter and remove the filtrate by rotary evaporation to obtain a light yellow solid. Column chromatography purification (V 石油醚 :V 乙酸乙酯 =1:1) to obtain 0.50 g of GK-2 as a white solid with a yield of 22.62%. HPLC purity 99.13%.

[0066] LC-MS: 450.20 [M+H + ].

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Abstract

The invention discloses a bilobalide K derivative and a preparation method and application thereof according to the formula I. Since structural modification is performed on bilobalide K, the bilobalide K derivative with higher water solubility and higher activity can be obtained and applied to prevention and treatment of cardiovascular and cerebrovascular diseases. Meanwhile, the bilobalide K derivative preparation process is facilitated and is adaptive to industrial production. (img file = 'DDA0000748217710000011.TIF' wi = '595' he = '515' / ).

Description

technical field [0001] The invention relates to a new class of ginkgolide K derivatives, in particular to the ginkgolide K derivatives and their preparation method and application. Background technique [0002] Ginkgolides are the main active ingredients in Ginkgo biloba, and they have been proved to have a wide range of pharmacological effects and pharmaceutical values. The ginkgolide compounds that have been discovered so far include ginkgolide A, ginkgolide B, ginkgolide C, bilobalide, ginkgolide J, ginkgolide M, ginkgolide L, ginkgolide K and the like. [0003] Among them, ginkgolide K has received widespread attention since Lou Fengchang et al. obtained trace samples by means of liquid preparation and carried out structural characterization by nuclear magnetic and infrared means. Literature "Chinese Journal of Pharmaceutical Sciences. 2011,46(13): 993-997", "Chinese Modern Applied Pharmacy. 2011, 28(10): 877-880" and other successive reports have reported that ginkgoli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22A61K31/365A61P9/12A61P9/10A61P9/04A61P9/00A61P7/02A61P3/06A61P9/06A61P25/28A61P13/12A61P3/00A61P3/10A61P19/06
CPCC07D493/22
Inventor 李大雄柯鸿樊小波孙毅
Owner CHENGDU BAIYU PHARMA CO LTD
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