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Preparation and medicinal use of ginkgolide B N-heterocycle derivatives and salts thereof
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A technology of ginkgolide and nitrogen heterocycle, applied in the field of medicine, can solve problems such as influence on clinical application effect, poor water solubility and bioavailability, limitation and the like
Active Publication Date: 2019-11-01
FUDAN UNIV
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Embodiment 1、1
[0025] Embodiment 1, 10-O-(cyanomethyl) ginkgolide B
[0026]
[0027] Ginkgolide B 424mg (1.0mmol) was dissolved in 30mL chloroform, bromoacetonitrile 240mg (2.0mmol), KI 332mg (2.0mmol), triethylamine 1mL were added successively, and the reaction was terminated after heating to reflux for 2 hours. After post-processing, the mother liquor was concentrated, and the residue was subjected to column chromatography to obtain 240 mg of a light yellow solid with a yield of 52%. 1 H-NMR (DMSO-d 6 ,400MHz):1.03(s,9H,t-Bu),1.11(d,J=8Hz,3H,14-Me),1.70(dd,1H,8-H),1.81(ddd,1H,7α-H ),2.12(dd,1H,7β-H),2.81(q,J=8Hz,1H,14-H),4.02(m,1H,1-H),4.57(d,1H,2-H), 4.82(d,1H,J=16Hz,10-CH 2 -),4.91(d,1H,J=16Hz,10-CH 2 -),5.28(s,1H,10-H),5.31(d,1H,1-OH),5.77(d,1H,6-H),6.15(s,1H,12-H),6.43(s ,1H,3-OH).LCMS(m / z):464(M+H + ).
Embodiment 2、1
[0028] Embodiment 2, 10-O-(1-cyanoethyl) ginkgolide B
[0029]
[0030] Ginkgolide B 424mg (1.0mmol) was dissolved in 30mL chloroform, 1-bromopropionitrile 266mg (2.0mmol), KI 332mg (2.0mmol), triethylamine 1mL were added successively, and heated to reflux to complete the reaction. After post-processing, the mother liquor was concentrated, and the residue was subjected to column chromatography to obtain 340 mg of a yellow solid with a yield of 71%. 1 H-NMR (DMSO-d 6 ,400MHz):1.05(s,9H,t-Bu),1.13(d,J=8Hz,3H,14-Me),1.72(dd,1H,8-H),1.81(ddd,1H,7α-H ), 1.91 (d, 3H, J=5Hz, 10-CHCH 3 ),2.10(dd,1H,7β-H),2.82(q,J=8Hz,1H,14-H),4.04(m,1H,1-H),4.58(d,1H,2-H), 4.83(q,1H,J=5Hz,10-CH-),5.29(s,1H,10-H),5.30(d,1H,1-OH),5.77(d,1H,6-H),6.15 (s,1H,12-H),6.43(s,1H,3-OH).LC-MS(m / z):478(M+H + ).
Embodiment 3、1
[0031] Embodiment 3, 10-O-(3-cyanoallyl) ginkgolide B
[0032]
[0033] Ginkgolide B 424mg (1.0mmol) was dissolved in 30mL chloroform, 4-bromo-2-butenenitrile 290mg (2.0mmol), KI 332mg (2.0mmol), triethylamine 1mL were added successively, and heated to reflux to complete the reaction . After post-processing, the mother liquor was concentrated, and the residue was subjected to column chromatography to obtain 368 mg of a light yellow solid with a yield of 75%. 1 H-NMR (DMSO-d 6 ,400MHz):1.04(s,9H,t-Bu),1.11(d,J=8Hz,3H,14-Me),1.70(dd,1H,8-H),1.81(ddd,1H,7α-H ),2.12(dd,1H,7β-H),2.81(q,J=8Hz,1H,14-H),4.02(m,1H,1-H),4.57(d,1H,2-H), 4.78(m,2H,10-CH 2 -),5.28(s,1H,10-H),5.31(d,1H,1-OH),5.51(d,J=16Hz,1H,10-CH=),5.77(d,1H,6-H ),6.15(s,1H,12-H),6.43(s,1H,3-OH),6.64(d,J=16Hz,1H,10-CH=).LC-MS(m / z):490 (M+H + ).
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Abstract
The invention belongs to the technical field of medicine, and relates to ginkgolide B N-heterocycle derivatives and salts thereof, and a preparation method and medicinal use thereof. In the method, derivatives and salts thereof, which are obtained by structurally modifying ginkgolide B adopted as a matrix to introduce an N-heterocycle structure, particularly to introduce an N-heterocycle to the No.10-site hydroxy of the ginkgolide B, are the ginkgolide B N-heterocycle derivatives shown as a formula 1 and salts thereof. Experiments prove that the compounds of the formula 1 and salts thereof have significant platelet activating factor (PAF) antagonism effect, can be used for preparing medicines for prevention and clinical treatment of ischemic stroke, stenocardia, cardiopulmonary infarction,cerebral thrombosis, inflammation, asthma, and other diseases related to the platelet activating factor, and can achieve the purpose of improving water solubility and enhancing curative effect.
Description
technical field [0001] The invention belongs to the technical field of medicine, and relates to a ginkgolide Bnitrogen heterocyclic derivative and a salt thereof, a preparation method and a medicinal use thereof. The present invention uses ginkgolide B as the matrix, introduces a nitrogen-containing heterocyclic structure through structural modification, and prepares ginkgolide B nitrogen-heterocycle derivatives and corresponding salts of ginkgolide B nitrogen-heterocycle derivatives to improve water solubility. Sex, the purpose of enhancing the curative effect. Background technique [0002] Ginkgo biloba has been used as a medicinal plant for a long time. As early as around 1000 AD, Chinese people 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 extra...
Claims
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Application Information
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