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Crystal form of 7, 8-dihydroxy flavone derivative and preparation method and application thereof

A technology of dihydroxyflavonoids and derivatives is applied in the directions of organic chemical methods, medical preparations containing active ingredients, and drug combinations, which can solve the problems of affecting the bioavailability of drugs and affecting the absorption of drugs, and achieve low hygroscopicity and preparation. Simple method and good stability

Active Publication Date: 2019-04-05
上海博芮健制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For drugs, this polymorphic phenomenon may affect the absorption of drugs, and then affect the bioavailability of drugs, thus showing different clinical efficacy and side effects

Method used

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  • Crystal form of 7, 8-dihydroxy flavone derivative and preparation method and application thereof
  • Crystal form of 7, 8-dihydroxy flavone derivative and preparation method and application thereof
  • Crystal form of 7, 8-dihydroxy flavone derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1 Preparation of crystalline form D of 7,8-dihydroxyflavone derivatives as shown in formula I

[0068] Refer to 4-oxo-2phenyl-4H-chromene-7,8-diyl bis(dimethylcarbamate) compound R in patent CN201380062367.X 7 In the preparation of the raw material, dimethylcarbamoyl chloride is replaced by methylcarbamoyl chloride to obtain 7,8-dihydroxyflavone derivatives as shown in formula I.

[0069]

[0070] After XRPD detection, its X-ray powder diffraction pattern represented by 2θ angle is at 6.745±0.2°, 7.896±0.2°, 8.212±0.2°, 8.839±0.2°, 9.433±0.2°, 10.201±0.2°, 10.890± 0.2°, 13.300±0.2°, 13.500±0.2°, 14.432±0.2°, 15.961±0.2°, 16.814±0.2°, 17.742±0.2°, 18.472±0.2°, 19.224±0.2°, 19.692±0.2°, 20.484± 0.2°, 21.078±0.2°, 22.319±0.2°, 22.873±0.2°, 23.542±0.2°, 24.545±0.2°, 25.613±0.2°, 26.146±0.2°, 26.760±0.2°, 28.653±0.2°, 30.654± There are characteristic diffraction peaks at 0.2° and 31.061±0.2°; its XRPD pattern is as follows figure 1 shown.

Embodiment 2

[0071] Example 2 Preparation of crystalline form A of 7,8-dihydroxyflavone derivatives as shown in formula I

[0072] Weigh 200 mg of the 7,8-dihydroxyflavone derivative represented by formula I into an 8 mL glass bottle, add 4 mL of methanol, and shake for 2 minutes until the mixture is uniform. After stirring at 50°C for 1 day, the solution was in a suspension state, centrifuged and dried to obtain 182 mg of solid.

[0073] After XRPD detection, its X-ray powder diffraction pattern represented by 2θ angle is at 6.710±0.2°, 8.821±0.2°, 10.203±0.2°, 13.537±0.2°, 16.814±0.2°, 18.511±0.2°, 20.424± 0.2°, 22.910±0.2°, 25.631±0.2°, 26.857±0.2°, 31.064±0.2°, 33.229±0.2°, 35.260±0.2°, 36.131±0.2°, 37.594±0.2°, 38.678±0.2° and 39.470± There is a characteristic diffraction peak at 0.2°, and its XRPD pattern is as follows figure 2 shown.

[0074] It is detected by TGA that the weight loss at 100±3°C accounts for 0.45% of the weight before weight loss. It is an ansolvate, and the wei...

Embodiment 3

[0077] Example 3 Preparation of Form A of 7,8-dihydroxyflavone derivatives as shown in Formula I

[0078] Weigh 500 mg of 7,8-dihydroxyflavone derivative shown in formula I into a 40 mL glass bottle, add 10 mL of ethanol, and mix well. After stirring at 50°C for 1 day, the solution was in a suspension state, centrifuged and dried to obtain 465 mg of solid. Its identification data are the same as in Example 2.

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Abstract

The invention discloses a crystal form of a 7, 8-dihydroxy flavone derivative and a preparation method and application thereof. The crystal form A of the 7, 8-dihydroxy flavone derivative shown as a formula I has high solubility in water, high stability in a high-humidity condition, extremely low hygroscopicity and high bioavailability, and the preparation method is simple. The crystal form A is of important value in optimization and development of drug.

Description

technical field [0001] The invention relates to a crystal form of a 7,8-dihydroxyflavone derivative and a preparation method and application thereof. Background technique [0002] 7,8-Dihydroxyflavone (7,8-Dihydroxyflavon, 7,8-DHF for short) is a specific agonist of tyrosine kinase B (TrkB) receptor, which can activate TrkB receptor. Experiments in vivo and in vitro have proved that 7,8-DHF has effects on neurodegenerative diseases Parkinson's disease, Alzheimer's disease, depression, psychiatric disorders, post-traumatic stress disorder, autism spectrum disorder, stroke, Rett syndrome It has curative effect and plays an important biological role. However, 7,8-DHF is easily metabolized into two-phase metabolites in the body to be eliminated from the body, with a relatively short half-life in the body, low bioavailability, and poor druggability. CN201380062367.X discloses that 7,8-dihydroxyflavone is modified to obtain 7,8-dihydroxyflavone derivatives, the structural formul...

Claims

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Application Information

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IPC IPC(8): C07D311/30A61P25/16A61P25/28A61P25/24A61P25/18A61P9/10A61P25/00A61K31/352
CPCA61P9/10A61P25/00A61P25/16A61P25/18A61P25/24A61P25/28C07D311/30C07B2200/13Y02A50/30
Inventor 章志宏陈建丽
Owner 上海博芮健制药有限公司
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