Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof

A technology of heterocyclic amide and diaryl urea, which is applied in the field of biomedicine, can solve the problems that chemical drugs cannot achieve therapeutic effects, hair loss, etc., achieve good application prospects and scientific research value, inhibit proliferation and migration, and achieve the effect of cheap reagents

Inactive 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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  • Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof
  • Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof
  • Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] In the structural formula of the compound, Ar is a pyridine heterocycle containing a pivalylamino group, R 1 is trifluoromethyl, R 2 For bromine, prepared by the following steps (see figure 1 ):

[0042] 1) Preparation of N-(5-bromopyridin-2-yl)-2,2-dimethylpropionamide (compound 2) from 5-bromo-2-aminopyridine (compound 1)

[0043]Dissolve 8.6g of 5-bromo-2-aminopyridine (compound 1) in anhydrous dichloromethane, add 25ml of anhydrous triethylamine, stir in ice bath for 30min, then slowly add 12ml of pivaloyl chloride in anhydrous Dichloromethane solution, after the dropwise addition, react at room temperature overnight. Extract the reaction solution with dichloromethane for 2 to 3 times, then wash the extract with water for 2 times, and finally wash with saturated sodium bicarbonate solution and saturated brine successively, dry over anhydrous sodium sulfate, spin dry to obtain a residue, and use chromatography Column separation obtained 7.3 g of solid N-(5-bromop...

Embodiment 2

[0055] In the structural formula of the compound, Ar is a pyridine heterocycle containing a pivalylamino group, R 1 is trifluoromethoxy, R 2 for bromine.

[0056] Steps 1) to 2) are the same as steps 1) to 2) in Example 1, that is, N-(5-bromopyridin-2-yl)-2 is prepared from 5-bromo-2-aminopyridine (compound 1), 2-Dimethylpropanamide (compound 2), and then prepared N-[5-(4-aminophenyl)pyridin-2-yl] by Suzuki coupling reaction with p-aminophenyl borate hydrochloride (compound 11) -2,2-Dimethylpropanamide (compound 12).

[0057] 3) From N-[5-(4-aminophenyl)pyridin-2-yl]-2,2-dimethylpropionamide (compound 12) and 4-bromo-2-trifluoromethoxyaniline (compound 15) N-(5-(4-(3-(4-bromo-2-(trifluoromethoxy) phenyl) ureido) phenyl) pyridin-2-yl) pivalamide ( Compound 16), the specific operation steps are:

[0058] Under ice bath conditions, dissolve 0.13g (0.44mmol) bis(trichloromethyl)carbonate (BTC) with 15mL redistilled dichloromethane and stir for 5min, then slowly add 0.28g (1.1...

Embodiment 3

[0064] In the structural formula of the compound, Ar is a pyridine heterocycle containing a pivalylamino group, R 1 , R 2 for chlorine.

[0065] Steps 1) to 2) are the same as steps 1) to 2) in Example 1, that is, N-(5-bromopyridin-2-yl)-2 is prepared from 5-bromo-2-aminopyridine (compound 1), 2-Dimethylpropanamide (compound 2), and then prepared N-[5-(4-aminophenyl)pyridin-2-yl] by Suzuki coupling reaction with p-aminophenyl borate hydrochloride (compound 11) -2,2-Dimethylpropanamide (compound 12).

[0066] 3) By condensation reaction of N-[5-(4-aminophenyl)pyridin-2-yl]-2,2-dimethylpropionamide (compound 12) and 3,4-dichloroaniline (compound 15) To prepare N-(5-(4-(3-(3,4-dichlorophenyl)ureido)phenyl)pyridin-2-yl)pivalamide (compound 16), the specific operation steps are:

[0067] Under ice-bath conditions, dissolve 0.18g (0.6mmol) of bis(trichloromethyl)carbonate (BTC) with 15mL of redistilled dichloromethane and stir for 5min, then slowly add 0.24g (1.5mmol) of 3,4 -T...

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Abstract

The invention provides an aromatic heterocyclic amide substituted diarylurea compound, a preparation method and application thereof. The structural formula of the compound is shown as the specification, wherein Ar is a pyridine heterocycle containing pivaloyl amino or methylamine carbonyl, R1 and R2 are trifluoromethyl, trifluoromethoxy or halogen, R2 can also be alkoxy with a tertiary amine group substituted end and a carbon atom number of 2-3, and the alkoxy is connected to the para-position of urea through the O atom. The compound can be prepared by three-step organic synthesis reaction, and the method has the advantages of easy operation of the reaction process, easily available raw materials, mild reaction conditions, cheap reagents and the like, and is suitable for large-scale production by pharmaceutical enterprises. The compound has good inhibitory activity on VEGFR-2 kinase, also can inhibit the proliferation activity of tumor cells, and can be used for preparation of antitumor drugs and VEGFR-2 kinase activity inhibition drugs, thus having good application prospects and scientific research value.

Description

technical field [0001] The invention relates to the technical field of biomedicine, relates to an anti-tumor compound, in particular to a diaryl urea compound substituted by an aromatic heterocyclic amide, 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. [0003] 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 suppre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75C07D213/81A61P35/00A61P35/02
CPCC07D213/75C07D213/81
Inventor 张杰卢闻贺怀贞苏萍王嗣岑潘晓艳张涛贺浪冲
Owner XI AN JIAOTONG UNIV
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