Cyclomalonamide compound with antitumor activity, and preparation method and application thereof

A cyclomalonamide, anti-tumor activity technology, applied in the field of biomedicine, can solve the problems of chemical drugs failing to achieve therapeutic effect, hair loss, etc., and achieve the effect of inhibiting growth and migration, inhibiting proliferation and migration, and good inhibiting activity.

Active Publication Date: 2016-09-07
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, antineoplastic drugs also have many adverse reactions, such as hair loss, vomiting, myelosuppression, rap

Method used

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  • Cyclomalonamide compound with antitumor activity, and preparation method and application thereof
  • Cyclomalonamide compound with antitumor activity, and preparation method and application thereof
  • Cyclomalonamide compound with antitumor activity, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] In the structural formula of the cyclomalonamide compound with anti-tumor activity, R 1 for CF 3 , R 2 is Br, prepared by the following steps (see figure 1 ):

[0035] 1) Preparation of 7-bromoquinazolin-2-amine (compound 2) from 2-fluoro-5-bromobenzaldehyde (compound 1)

[0036] Dissolve 10g (49.2mmol) of 2-fluoro-5-bromobenzaldehyde and 13.3g (74mmol) of guanidine carbonate in N,N-dimethylacetamide solution, and react at reflux at 140°C for 5h. After the reaction, the reaction solution Cool to room temperature, add 120mL of water, a large amount of solids are precipitated, filter with suction, and the obtained filter cake is 7-bromoquinazolin-2-amine, about 5g, yield 60%;

[0037] 2) Preparation of 7-(4-aminophenyl)quinazoline-2 from 7-bromoquinazolin-2-amine (compound 2) and p-aminophenyl borate hydrochloride (compound 3) by Suzuki coupling reaction -amine (compound 4)

[0038] 2g (8.9mmol) 7-bromoquinazolin-2-amine, 1.54g (8.9mmol) p-aminophenyl borate hydroch...

Embodiment 2

[0048] In the structural formula of the cyclomalonamide compound with anti-tumor activity, R 1 , R 2 for chlorine.

[0049] Step 1) to step 2) are the same as steps 1) to 2) of Example 1, that is, preparing 7-bromoquinazolin-2-amine (compound 2) from 2-fluoro-5-bromobenzaldehyde (compound 1) , and then prepared 7-(4-aminophenyl)quinazoline-2 by Suzuki coupling reaction from 7-bromoquinazolin-2-amine (compound 2) and p-aminophenyl borate hydrochloride (compound 3) - Amines (Compound 4).

[0050] 3) Preparation of 1-({3,4-dichloroanilineamino}carbonyl)cyclopropanecarboxylic acid by condensation reaction of 1,1-cyclopropanedicarboxylic acid (compound 5) and 3,4-dichloroaniline (compound 6) (compound 7)

[0051] Under nitrogen protection conditions, 12.9 mL of anhydrous triethylamine was added dropwise to 4 g (30.8 mmol) of 1,1-cyclopropanedicarboxylic acid in dichloromethane solution, stirred for 30 min under ice bath conditions, and then slowly added dropwise 2.3 mL SOCl 2...

Embodiment 3

[0059] In the structural formula of the cyclomalonamide compound with anti-tumor activity, R 1 , R 2 for chlorine.

[0060] Step 1) to step 2) are the same as steps 1) to 2) of Example 1, that is, preparing 7-bromoquinazolin-2-amine (compound 2) from 2-fluoro-5-bromobenzaldehyde (compound 1) , and then prepared 7-(4-aminophenyl)quinazoline-2 by Suzuki coupling reaction from 7-bromoquinazolin-2-amine (compound 2) and p-aminophenyl borate hydrochloride (compound 3) - Amines (Compound 4).

[0061] 3) Preparation of 1-({2,4-dichloroanilineamino}carbonyl)cyclopropanecarboxylic acid by condensation reaction of 1,1-cyclopropanedicarboxylic acid (compound 5) and 2,4-dichloroaniline (compound 6) (Compound 7)

[0062] Under nitrogen protection conditions, 12.9 mL of anhydrous triethylamine was added dropwise to 4 g (30.8 mmol) of 1,1-cyclopropanedicarboxylic acid in dichloromethane solution, stirred for 30 min under ice bath conditions, and then slowly added dropwise 2.3 mL SOCl 2...

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PUM

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Abstract

The invention provides a cyclomalonamide compound with antitumor activity, and a preparation method and application thereof. The compound has a structural formula as described in the specification. In the structural formula, R1 is a halogen group; and R2 is a halogen group or a group as described in the specification, or a group formed by R1 and R2 together. The compound provided by the invention has good inhibitory activity to VEGFR-2 kinase, so a signal channel induced by the VEGFR-2 kinase can be blocked through inhibition of the activity of the VEGFR-2 kinase, and proliferation and migration of tumor cells are inhibited; thus, the compound can be applied in preparation of antitumor drugs. Meanwhile, the preparation method for the compound has the following advantages: raw materials are easily available; reaction conditions are mild; the process of reaction is simple to operate; and used reagents are cheap.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to an antitumor compound, in particular to a cyclomalonamide compound with antitumor activity 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 resi...

Claims

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Application Information

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IPC IPC(8): C07D239/84C07D405/12C07D413/12A61P35/00
CPCC07D239/84C07D405/12C07D413/12
Inventor 张杰卢闻苏萍王金凤潘晓艳贺浪冲王嗣岑贺怀贞
Owner XI AN JIAOTONG UNIV
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