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Ginkgolide B derivative as well as preparation method and application thereof

A ginkgolide and ester-based technology, which is applied to ginkgolide B derivatives and the fields of preparation and application thereof, can solve the problem of harsh and complex synthesis process, low yield, lack of test data for improvement of water solubility and pharmacodynamic activity, etc. question

Active Publication Date: 2017-06-27
CHENGDU BAIYU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Document CN1139435A reported that the structure of ginkgolide B was modified, and the water solubility and anti-PAF activity of some derivative compounds were improved, but the synthesis process was harsh and complicated, and the yield was low, which brought great difficulties to the actual production operation.
Patent CN1837212A also reported the structural modification of the 10-O position of ginkgolide B, and obtained a series of carboxylic acid and nitrogen-containing derivative compounds, but the improvement of water solubility and pharmacodynamic activity lacks detection data

Method used

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  • Ginkgolide B derivative as well as preparation method and application thereof
  • Ginkgolide B derivative as well as preparation method and application thereof
  • Ginkgolide B derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1, the preparation of compound BZ

[0077]

[0078] Weigh 5.0 g (11.78 mmol) of GB and 2.55 g (15.32 mmol) of 3,5,6-trimethylpyrazine-2-carboxylic acid, dissolve them in acetonitrile, and stir and mix them in an ice bath. Then add 0.29g (2.36mmol) 4-dimethylaminopyridine (DMAP) and 3.17g (16.49mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl), after stirring for 1 hour under ice-bath conditions, the mixture was reacted at 20 ° C for 6 h, the solvent was removed by rotary evaporation, the crude product was dissolved with ethyl acetate, and 5% NaHCO 3 Wash twice, and wash once with saturated sodium chloride solution. The organic phase was collected, dried, filtered and concentrated. After separation and purification, a total of 2.80 g of white solid BZ was obtained, with a yield of 41.48% and an HPLC purity of 99.80%.

[0079] LC-MS: 573.2 [M+H + ], 595.2 [M+Na + ].

[0080] 1 H-NMR (DMSO, 400MHz): 1.02(s, 9H, t-Bu), 1.13-1.1...

Embodiment 2

[0081] Embodiment 2, the preparation of compound BA

[0082]

[0083] Weigh 5.0g (11.78mmol) GB and 2.76g (15.32mmol) acetylsalicylic acid dissolved in acetonitrile, stir and mix in an ice bath. Then add 0.29g (2.36mmol) 4-dimethylaminopyridine (DMAP) and 3.17g (16.49mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl), after stirring for 1 hour under ice-bath conditions, the mixture was reacted at 30 ° C for 4 h, the solvent was removed by rotary evaporation, the crude product was dissolved with ethyl acetate, and the mixture was washed with 5% NaHCO 3 Wash twice and once with saturated NaCl. The organic phase was collected, dried, filtered and concentrated. After separation and purification, a total of 2.52 g of white solid BA was obtained, with a yield of 36.52% and an HPLC purity of 99.13%.

[0084] MS: 609.16 [M+Na + ], C 29 h 30 NaO 13 .

[0085] 1 H-NMR (CDCl 3 , 400MHz): 1.08(s,9H,t-Bu),1.24-1.26(d,3H,14-Me)1.99-2.03(dd,1H,8-H),2.16(s,...

Embodiment 3

[0086] Embodiment 3, the preparation of compound BL

[0087]

[0088] Weigh 5.0g (11.78mmol) GB and 4.70g (15.32mmol) S(+)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothiophene[3,2- c] Pyridine-5) acetic acid was dissolved in acetonitrile and stirred in an ice bath to mix. Then add 0.29g (2.36mmol) 4-dimethylaminopyridine (DMAP) and 3.17g (16.49mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl), after stirring for 1 hour under ice-bath condition, the mixture was reacted at 25° C. for 5 h. The solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate, and washed with 5% NaHCO 3 Wash twice and once with saturated NaCl. The organic phase was collected, dried, filtered and concentrated. After separation and purification, a total of 3.46 g of white solid BL was obtained, with a yield of 41.09% and an HPLC purity of 99.58%.

[0089] LC-MS: 714.3 [M+H + ], 736.0 [M+Na + ].

[0090] 1 H-NMR (CDCl 3 , 400MHz): 1.05(s,9...

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Abstract

The invention discloses a compound shown as a formula I or a formula II or pharmaceutically acceptable salts thereof. In the formula, R1 is selected from pyrazinyl or substituted pyrazinyl; and R2 is selected from pyrazinyl or substituted pyrazinyl, phenyl or substituted phenyl and alkyl or substituted alkyl. The structural formula is as shown in the specification.

Description

technical field [0001] The invention relates to a ginkgolide B derivative, a preparation method and application thereof. Background technique [0002] Ginkgolide B (Ginkgolide B, GB) is one of the main active ingredients extracted from Ginkgo biloba, and it is also the strongest platelet activating factor (PAF) antagonist found so far, which can inhibit platelet aggregation, anti-inflammation, anti-shock, Protecting cardiovascular and cerebrovascular and treating acute pancreatitis, etc., is an effective drug for treating acute and chronic cerebral ischemic diseases. However, ginkgolide B is a diterpene compound with a six-ring cage structure, which has a rigid structure, poor water solubility, and low bioavailability, which limits the full use of the drug effect and affects its clinical application. [0003] In recent years, the research on the structural modification of ginkgolide B has become a hot topic. Document WO9306107 modified the structure of ginkgolide B for the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22A61K31/497A61K31/365A61K31/4365A61P9/12A61P9/00A61P9/04A61P9/06A61P3/06A61P13/12A61P9/10A61P7/02A61P35/00A61P25/28A61P3/10A61P19/06
CPCC07D493/22A61K31/365A61P9/12C07D519/00A61P9/00
Inventor 李大雄李慧琴柯鸿樊小波孙毅
Owner CHENGDU BAIYU PHARMA CO LTD
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