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Diaryl-beta-lactam compounds, and preparation method and application thereof in drug preparation

A technology of lactams and compounds, applied in the field of chemical pharmacy, can solve the problems of few compounds and toxicity, and achieve the effect of good tumor growth

Active Publication Date: 2017-10-10
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] According to reports, the research on tubulin aggregation inhibitors, especially the research on the structural modification of compridine, has made important progress; some of the inhibitors of the drugs have entered clinical trials, although they have been shown to be effective in inhibiting tumor growth , but there is a certain degree of toxicity, resulting in fewer compounds that are finally approved for marketing

Method used

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  • Diaryl-beta-lactam compounds, and preparation method and application thereof in drug preparation
  • Diaryl-beta-lactam compounds, and preparation method and application thereof in drug preparation
  • Diaryl-beta-lactam compounds, and preparation method and application thereof in drug preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 Compound (S)-1-(3,4,5-trimethoxyphenyl)-4-(3-hydroxy-4-methoxyphenyl)-3-methyleneazetidine Synthesis of -2-one (1)

[0066] References (Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y.-J.; Liu, L.; Wang, Z.; Ding, K. Angewandte Chemie Int. Ed. 2012,124,9410-9416.) method, the present invention synthesizes target compound 1 according to the following route:

[0067]

[0068] 1.1 Synthesis of 3-tert-butyldimethylsilyloxy-4-methoxybenzaldehyde (1b)

[0069] Add 3-hydroxy-4-methoxybenzaldehyde (1a) (1.58g, 10.4mmol), DMAP (25mg, 0.2mmol), anhydrous DCM (50mL) and anhydrous triethylamine (2mL, 14.5mmol), cooled to an ice bath, TBSCl (1.88g, 12.5mmol) was dissolved in anhydrous DCM (10mL), and added slowly from the dropping funnel. Remove the ice bath after dropping, stir at room temperature for two hours, add saturated aqueous sodium bicarbonate solution to quench the reaction, separate the organic phase, extract the aqueous phase with DCM three times, combine...

Embodiment 2

[0080] Example 2 (S)-1-(3,4,5-trimethoxyphenyl)-4-(3-methoxy-4-methoxyphenyl)-3-methyleneazetidine Synthesis of alkan-2-ones (2)

[0081]

[0082] Add anhydrous DMF (1mL), compound 1 (22mg, 0.059mmol) and potassium carbonate (15mg, 0.108mmol) into a 20mL eggplant-shaped bottle, stir at room temperature for 10min, the solution is yellow at this time, add iodomethane (17mg, 0.12mmol) , after stirring and reacting for 3h, TLC (developing solvent: petroleum ether / ethyl acetate=1:1) showed that raw material 1 (R f =0.3) disappear completely, and new points are generated (R f = 0.5). To stop the reaction, 10 mL of ethyl acetate was added, washed with water (2 x 10 mL), washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Mixed with silica gel column chromatography for separation and purification, the corresponding eluent was collected, and the solvent was evaporated to dryness to obtain 23 mg of white solid (2), with a yield of 97%. Mp 138-139°C; [α] ...

Embodiment 3

[0083] Example 3 (S)-1-(3,4,5-trimethoxyphenyl)-4-(3-ethoxy-4-methoxyphenyl)-3-methyleneazetidine Synthesis of alkan-2-ones (3)

[0084]

[0085] Add 1mL of anhydrous DMF, compound 1 (22mg, 0.059mmol) and potassium carbonate (15mg, 0.108mmol) into a 20mL eggplant-shaped bottle, stir at room temperature for 10min, the solution is yellow at this time, add bromoethane (12mg, 0.12mmol) , overnight reaction, TLC (developing solvent: sherwood oil / ethyl acetate=1:1) shows raw material 1 (R f =0.3) disappear completely, and new points are generated (R f =0.5), stop the reaction, add 10 mL of ethyl acetate, wash with water (3 x 10 mL), and dry over anhydrous sodium sulfate. It was directly mixed with silica gel column chromatography for separation and purification, the corresponding eluent was collected, and the solvent was evaporated to dryness to obtain 23 mg of white solid (3) with a yield of 97%. Mp 92-93°C; [α] D 20 =+34.0(c 0.27, CHCl 3 ). 1 HNMR (400MHz, CDCl 3 )δ6.98...

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PUM

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Abstract

The invention belongs to the field of synthetic pharmaceutical chemistry, and relates to diaryl-beta-lactam compounds having a structure in a general formula below and having remarkable antitumor activity and application thereof in drug preparation. The invention also comprises application of the compounds, pharmaceutical salts thereof and pharmaceutical compositions thereof in preparation of drugs for preventing or treating tumor-related diseases. The compounds or pharmaceutically acceptable salts thereof provided by the invention can effectively inhibit the growth of nude mouse transplanted tumors in vitro and in vivo through an in-vitro regulation and control mechanism capable of inhibiting the growth of tumor cells by inhibiting tubulin aggregation, and can be used in preparation of drugs for preventing or treating the tumor-related diseases, wherein the tumor-related diseases comprise benign and malignant tumors and other diseases caused by the tumors. The general formula is shown in the specification.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy and relates to diaryl-β-lactam compounds, in particular to diaryl-β-lactam compounds with significant antitumor activity, preparation method and in vitro and in vivo antitumor activity, and The application of the compounds and their pharmaceutical salts or compound drugs containing them in the preparation of drugs for the prevention and treatment of tumor-related diseases. Background technique [0002] The prior art discloses that cancer is one of the main diseases that currently threaten human health, and its mortality rate is second only to cardiovascular and cerebrovascular diseases, ranking second; it is estimated that by 2020 there will be 15 million new cases, and the death toll will reach 10 million; current cancer treatment methods include surgery, radiation therapy, chemotherapy (drug therapy) and biological therapy, among which chemotherapy is the most common means, that is, the use of o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/10C07D205/08C07D205/12C07D403/04C07D205/085C07D491/113C07D401/12C07D403/12C07F9/568C07F7/18C07F7/10A61K31/397A61K31/4192A61K31/5377A61K31/4427A61K31/4035A61K31/675A61K31/695A61P35/00
CPCC07D205/08C07D205/085C07D205/10C07D205/12C07D401/12C07D403/04C07D403/12C07D491/113C07F7/10C07F7/1804C07F9/568A61K31/397A61K31/4192A61K31/4427A61K31/5377A61K31/695A61K45/06A61K31/357A61K31/4035A61P35/00C07D413/12
Inventor 王洋刘明明周鹏飞冯克昌丁奎岭王晓明
Owner FUDAN UNIV
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