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A class of hdacs and mdm2 dual target inhibitors and its preparation method and application

A MDM2 and dual-target technology, applied in the field of medicine, can solve the problems that have not been reported, and achieve the effect of delaying tumor growth, good HDACs and MDM2 enzyme inhibitory activity, and broad-spectrum anti-tumor activity in vitro

Active Publication Date: 2021-11-09
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But about a class of histone deacetylases (HDACs) and MDM2 dual-target inhibitors of the present invention and their preparation methods and applications have not yet been reported

Method used

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  • A class of hdacs and mdm2 dual target inhibitors and its preparation method and application
  • A class of hdacs and mdm2 dual target inhibitors and its preparation method and application
  • A class of hdacs and mdm2 dual target inhibitors and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Preparation (1) of embodiment 1 compound (1)

[0079] Compound (1) N-(5-((2-aminophenyl)amino)-5-oxopentyl)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis (4-Chlorophenyl)-4,5-dihydro- 1 The preparation method of H-imidazole-1-carboxamide:

[0080] (1) Methyl-5-(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro- 1 Synthesis of H-imidazole-1-carboxamide) pentanoate:

[0081] Methyl 5-aminovalerate (0.18g, 1.35mmol) was dissolved in CH 2 Cl 2 (10mL), sequentially added 2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-1 -carbonyl chloride (0.60g, 1.14mmol) and Et 3 N (0.32 mL, 2.28 mmol). After stirring at room temperature for 1.5 hours, the reaction solution was washed with 2N HCl (5 mL), 10% NaHCO 3 (5mL), washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent, dichloromethane / methanol=100 / 1) to obtain ...

Embodiment 2

[0084] Preparation (two) of embodiment 2 compound (2)

[0085] Compound (2) N-(6-((2-aminophenyl)amino)-6-oxohexyl)-2(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4 The preparation method of -chlorophenyl)-4,5-dihydro-1H-imidazole-1-carboxamide:

[0086] (1) Methyl-6-(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro- 1 Synthesis of H-imidazole-1-carboxamide) hexanoate.

[0087] Operation and feeding are the same as in Example 1 step (1).

[0088] (2) N-(6-((2-aminophenyl)amino)-6-oxohexyl)-2(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4- Synthesis of chlorophenyl)-4,5-dihydro-1H-imidazole-1-carboxamide:

[0089] The operation and feeding were the same as in step (2) of Example 1, and 0.13 g of white solid was obtained by column chromatography, with a yield of 69%.

Embodiment 3

[0090] The preparation (three) of embodiment 3 compound (3)

[0091] Compound (3) N-(7-((2-aminophenyl)amino)-7-oxoheptyl)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5- Bis(4-chlorophenyl)-4,5-dihydro- 1 The preparation method of H-imidazole-1-carboxamide:

[0092] (1) Methyl-7-(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H - Synthesis of imidazole-1-carboxamide) heptanoate:

[0093] Operation and feeding are the same as in Example 1 step (1).

[0094](2) N-(7-((2-aminophenyl)amino)-7-oxoheptyl)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis (4-Chlorophenyl)-4,5-dihydro- 1 Synthesis of H-imidazole-1-carboxamide:

[0095] The operation and feeding were the same as in step (2) of Example 1, and 0.10 g of white solid was obtained by column chromatography with a yield of 70%.

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Abstract

The present invention relates to a class of histone deacetylases (HDACs) and MDM2 dual-target inhibitors and their preparation methods and applications. 3, spliced ​​from functional groups of RG7112). Its advantages are as follows: (1) The present invention not only exhibits good HDACs and MDM2 enzyme inhibitory activity, but also has a certain broad-spectrum anti-tumor activity in vitro, can obviously delay tumor growth, and can be applied to HDACs and MDM2-mediated diseases Physiologically characterized neoplastic disease. (2) As the first reported dual-target antitumor drug based on HDACs and MDM2, this kind of compound has further development and research value.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of dual-target inhibitors of HDACs and MDM2 and its preparation method and application. Background technique [0002] The p53 protein is a key tumor suppressor protein in the prevention of cancer. In normal cells, p53 and MDM2 proteins maintain a fine balance of the two through negative feedback regulation (Vogelstein, B. et al., Nature 408, 307-310 ( 2000)). After tumorigenesis, the overexpression of MDM2 protein reduces the concentration of p53 protein in tumor cells and significantly reduces the effect of inhibiting tumors. Aiming at the regulatory mechanism between the tumor suppressor protein p53 and MDM2, it was found that by interfering with the interaction between the two, the activity of tumor cells will be significantly weakened (Hainaut, P. et al., Adv. CancerRes, 77, 81-137 (2000)) . Therefore, inhibiting p53-MDM2 protein interaction can be used as a new m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/38C07D403/14C07D401/14C07D401/06A61K31/4164A61K31/496A61K31/506A61K31/454A61P35/00
CPCA61P35/00C07D233/38C07D401/06C07D401/14C07D403/14
Inventor 盛春泉王卫何世鹏张永强董国强武善超
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY