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Ginkgolide B derivative and its salt, and their preparation methods and uses

A compound and unsubstituted technology, applied in the field of medicine, can solve problems affecting clinical application effects, poor water solubility, poor bioavailability, etc.

Active Publication Date: 2019-07-26
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, practice has shown that ginkgolide B has strong structural rigidity, poor water solubility, and poor bioavailability due to its hexacyclic cage-like diterpenoid structure, which limits its full efficacy and affects Clinical application effect

Method used

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  • Ginkgolide B derivative and its salt, and their preparation methods and uses
  • Ginkgolide B derivative and its salt, and their preparation methods and uses
  • Ginkgolide B derivative and its salt, and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Embodiment 1 prepares 10-O-(methoxyformylmethyl) ginkgolide B

[0139]

[0140] Take 212mg (0.5mmol) of ginkgolide B and dissolve it in 20mL THF, add 190mg (2.0mmol) of methyl chloroacetate, 166mg (1.0mmol) of KI, and 310mg (2.3mmol) of potassium carbonate in sequence, heat and reflux and stir for 2 hours, The plate traced until the substrate basically disappeared, and the post-reaction treatment was completed. Potassium carbonate was removed by filtration, the mother liquor was concentrated, and the residue was separated by column chromatography to obtain a pale yellow solid; filtered and dried to obtain 121 mg of the product, with a yield of 48%. 1 H-NMR (DMSO-d 6 ,400MHz):1.00(s,9H,t-Bu),1.09(d,3H,14-Me),1.74(dd,1H,8-H),1.87(ddd,1H,7α-H),2.13( dd,1H,7β-H),2.79(q,1H,14-H),3.71(s,1H,-OCH 3 ), 4.06(m, 1H, 1-H), 4.42(d, 1H, J=16Hz, 10-CH 2 -),4.63(d,1H,2-H),4.80(d,1H,J=16Hz,10-CH 2 -),5.15(d,1H,1-OH),5.29(s,1H,10-H),5.33(d,1H,6-H),6.19(s,1H,12-H),6.48(s ,1H,3-OH)...

Embodiment 2

[0141] Embodiment 2 prepares 10-O-(methoxyformyl allyl) ginkgolide B

[0142]

[0143] Take ginkgolide B 300mg (0.71mmol) and dissolve in 30mL THF, add 4-bromo-2-butenoic acid methyl ester 251mg (1.4mmol), KI 232mg (1.4mmol), potassium carbonate 434mg (3.1mmol), Heat to reflux and stir for 2 hours, track the plate layer until the substrate disappears, finish the post-reaction treatment, filter to remove potassium carbonate, concentrate the mother liquor, and conduct column chromatography on the residue to obtain a light yellow solid, which is filtered and dried to obtain 192mg of the product, with a yield of 52.5% . 1 H-NMR (DMSO-d 6 ,400MHz):1.01(s,9H,t-Bu),1.08(d,3H,14-Me),1.74(dd,1H,8-H),1.87(ddd,1H,7α-H),2.13( dd,1H,7β-H),2.79(q,1H,14-H),3.73(s,1H,-OCH 3 ), 4.06(m, 1H, 1-H), 4.42(d, 1H, J=16Hz, 10-CH 2 -),4.63(d,1H,2-H),4.80(d,1H,J=16Hz,10-CH 2 -),5.15(d,1H,1-OH),5.29(s,1H,10-H),5.33(d,1H,6-H),5.65(m,1H,-CH=),5.76(m ,1H,-CH=),6.19(s,1H,12-H),6.48(s,1H,3-OH).MS(m / z...

Embodiment 3

[0144] Embodiment 3 prepares 10-O-(tert-butoxyformylmethyl) ginkgolide B

[0145]

[0146] Take ginkgolide B 300mg (0.70mmol) and dissolve in 30mL THF, add bromoacetate tert-butyl alcohol 276mg (1.41mmol), KI 235mg (1.41mmol), potassium carbonate 434mg (3.2mmol), heat under reflux and stir for 2 After hours, the plate layer was tracked until the substrate basically disappeared, and the post-reaction treatment was completed. Potassium carbonate was removed by filtration, the mother liquor was concentrated, and the residue was column chromatographed to obtain light yellow needle crystals, which were filtered and dried to obtain 220 mg of the product, with a yield of 58%. 1 H-NMR (DMSO-d 6 ,400MHz):0.99(s,9H,t-Bu),1.09(d,3H,14-Me),1.42(s,9H,-O-t-Bu),1.70(dd,1H,8-H),1.86 (ddd,1H,7α-H),2.13(dd,1H,7β-H),2.79(q,1H,14-H),4.05(m,1H,1-H),4.28(d,1H,J = 16Hz, 10-CH 2 -),4.63(d,1H,2-H),4.65(d,1H,J=16Hz,10-CH 2 -),5.13(d,1H,1-OH),5.25(s,1H,10-H),5.31(d,1H,6-H),6.19(s,1H,12-H),6.50(s ...

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Abstract

The invention belongs to the technical field of medicine and relates to a derivative of ginkgolide B structure, shown as the formula 1 and formula 2, having a carboxylic group introduced to a hydroxylgroup 10, an ester derivative with the carboxylic group, and an organic or inorganic salt pharmaceutically acceptable. By applying chemical structural modifications to ginkgolide B as a matrix, so that solubility is improved, bioavailability is improved, and therapeutic effect is enhanced; the prepared compound and its carboxylate have evident antagonistic action upon the platelet activating factor, evident anticoagulant action and evident resistance to acute cerebral ischemia, and are applicable to the preparation of drugs to prevent and treat ischemic stroke, thrombosis, angina, cardiopulmonary infarct, inflammations, asthma, and other diseases associated with the platelet activating factor.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to ginkgolide B carboxylic acid derivatives and their esters, and the corresponding salts of ginkgolide B carboxylic acid derivatives, in particular to ginkgolide B carboxylic acid derivatives and their esters and their preparation methods and uses. The invention uses ginkgolide B as a matrix, and through chemical structure modification, produces ginkgolide B derivatives to achieve the purposes of changing the solubility, improving bioavailability and enhancing curative effect. Background technique [0002] There are records that Chinese folks used Ginkgo biloba to treat asthma and bronchitis around 1000 AD. In modern times, 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 extract (GBE) to treat diseases such as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22C07C227/18C07C229/26C07C209/00C07C211/05C07C211/07C07C213/08C07C215/10C07D295/023C07D295/037C07D233/64C07C257/14A61K31/365A61P9/10A61P7/02A61P9/04A61P29/00A61P11/06A61P11/00
CPCC07D493/22C07C229/26C07C211/05C07C211/07C07C215/10C07D233/64C07C257/14A61P9/10A61P7/02A61P11/06A61P11/00C07D295/027A61P9/04A61P29/00Y02P20/55
Inventor 张倩唐坚
Owner FUDAN UNIV
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