A biphenylurea compound containing an oxime group and its preparation method and application

A compound, the technology of bifenurea, applied in the field of bifenurea compound and its preparation, and anti-tumor compound, can solve the problems that chemical drugs cannot achieve therapeutic effect, hair loss, etc., achieve inhibition of tumor growth and migration, and enhance inhibitory activity , good inhibitory effect

Active Publication Date: 2015-08-05
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, antineoplastic drugs also have many adverse reactions, such as hair loss, vomiting, myelosuppression, rapid drug resistance, etc., which lead to the inability of chemical drugs to achieve the expected therapeutic effect

Method used

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  • A biphenylurea compound containing an oxime group and its preparation method and application
  • A biphenylurea compound containing an oxime group and its preparation method and application
  • A biphenylurea compound containing an oxime group and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] In the structural formula of this compound, R 1 for hydrogen, R 2 It is an alkoxy group with 2 carbon atoms, and the end is substituted by diethylamino, prepared by the following steps (see figure 1 ):

[0053] 1) 3-methoxyl-4-hydroxybenzaldehyde (1) is prepared by bromination reaction compound 3-methoxyl-4-hydroxyl-5-bromobenzaldehyde (2)

[0054] 20.0g (132mmol) of 3-methoxy-4-hydroxybenzaldehyde (1), 21.59g (263mmol) of sodium acetate and 0.68g (12mmol) of iron powder were placed in a 500mL three-necked flask, and 120mL of glacial acetic acid was added, Stir at room temperature for 30 minutes; after the stirring is completed, control the temperature at 23-25°C, add dropwise a solution prepared by mixing 7.0mL (140mmol) liquid bromine and 30mL glacial acetic acid in advance, and then control the temperature at 23-25°C to continue Stir for 3h;

[0055] Then add 250 mL of ice water, stir for 1 h; filter, dry the solid, and recrystallize from ethanol to obtain 24.70 ...

Embodiment 2

[0102] where R 1 is methyl, R 2 It is an alkoxy group with 3 carbon atoms, the terminal is substituted by dimethylamino, and it is located at the para position of urea.

[0103] Steps 1 to 8 are the same as those in Example 1, that is, compound 1-(4'-acetyl-5,6-dimethoxy- 3'-Hydroxy-[1,1'-biphenyl]-3-yl)-3-(4-(2-(dimethylamino)propyl)phenyl)urea followed by conversion of acetyl group to oxime group, The specific operation steps are:

[0104] 0.51g (1mmol) 1-(4'-acetyl-5,6-dimethoxy-3'-hydroxy-[1,1'-biphenyl]-3-yl)-3 -(4-(2-(Dimethylamino)propyl)phenyl)urea dissolved, heated to 50°C, added 2mL of 0.72g (10mmol) hydroxylamine hydrochloride aqueous solution, reacted for 1h, cooled the reaction solution to room temperature, and Saturated sodium carbonate solution was added to the reaction solution to adjust the reaction solution to pH=8, extracted with chloroform (20mL×3), the organic phases were combined, and dried over anhydrous sodium sulfate to obtain 0.47g of crude produc...

Embodiment 3

[0110] where R 1is methyl, R 2 The compound whose tertiary amino group is morpholino, n=3, is located at the meta-position of urea.

[0111] Steps 1 to 8 are the same as those in Example 1, that is, compound 1-(4'-acetyl-5,6-dimethoxy- 3'-Hydroxy-[1,1'-biphenyl]-3-yl)-3-(2-methyl-5-(2-morpholinopropyl)phenyl)urea followed by conversion of the acetyl group to oxime base, the specific operation steps are:

[0112] 0.56g (1mmol) 1-(4'-acetyl-5,6-dimethoxy-3'-hydroxyl-[1,1'-biphenyl]-3-yl)-3 -(2-Methyl-5-(2-morpholinopropyl)phenyl)urea dissolved, heated to 50°C, added 0.72g (10mmol) of hydroxylamine hydrochloride aqueous solution 2mL, reacted for 1h, and cooled the reaction solution to room temperature , adding saturated sodium carbonate solution to the reaction solution to adjust the reaction solution to pH=8, extracting with chloroform (20mL×3), combining the organic phases and drying with anhydrous sodium sulfate to obtain 0.50g of crude product with a yield of 87.3%. The ...

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Abstract

The invention discloses an oximido diphenyl urea compound as well as a preparation method and an application thereof. The oximido diphenyl urea compound is a novel compound with the antitumor activity, which has the good inhibitory activity to VEGFR-2 (Vascular Endothelial Growth Factor Receptor 2) kinases and can be used for preparing antitumor medicines. According to the oximido diphenyl urea compound, each oximido and each hydroxyl are adjacent so as to form an intramolecular hydrogen bond, so that the affinity and the inhibitory activity of the compound and the VEGFR-2 are enhanced; and meanwhile, the physicochemical properties such as the water solubility and the like of the compound are improved by leading the hydroxyls into the compound, so that the medicine likeness of the compound is improved.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to an antitumor compound, in particular to a biphenylurea compound containing an oxime group and a preparation method and application thereof. Background technique [0002] Malignant tumors, as one of the largest public health problems in the world, have greatly endangered human health and will become the number one killer of human beings in the new century. Malignant tumors are no longer just a serious disease in developed industrial countries, and developing countries are facing a greater burden of disease. Chemotherapy, as one of the important means of treating tumors, has undergone tremendous development and progress in the past three decades, and a large number of clinical antitumor drugs with different mechanisms of action have been obtained. However, antineoplastic drugs also have many adverse reactions, such as hair loss, vomiting, bone marrow suppression, rapid drug resis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C275/40C07C273/18C07D295/088A61P35/00A61P35/02
Inventor 张杰贺浪冲张彦民高洪平王琛潘晓艳
Owner XI AN JIAOTONG UNIV
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