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Tyrosine kinase inhibitor, preparation method and use thereof

A general formula compound and compound technology, applied in the field of chemical synthesis, can solve the problems of high toxicity and side effects, and achieve the effects of small toxicity and side effects, inhibition of tumor growth, and good targeting

Inactive Publication Date: 2004-11-03
黄文林 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the traditional methods of cancer treatment are radiotherapy and chemotherapy, and electrotherapy can be used for some local solid tumors. These traditional methods have certain curative effects, but their toxic and side effects are quite large. During the treatment process, they bring great harm to patients. pain

Method used

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  • Tyrosine kinase inhibitor, preparation method and use thereof
  • Tyrosine kinase inhibitor, preparation method and use thereof
  • Tyrosine kinase inhibitor, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Compound I preparation method:

[0027]

[0028] Compound I and its salts can be obtained by deprotecting Compound IX. Compound IX is an existing substance. During the implementation of this example, R 1 is trifluoromethane, m is 1, X 1 for N, R 4 stands for protected R 2 group, in this example R 2 The protecting group tert-butoxycarbonyl is reacted in a hydrochloric acid solution by heating in a water bath at 80°C, and the product is recovered after 30 minutes. The product is in the form of white powder, soluble in water, and has a pH of 6.4.

Embodiment 2

[0030] The dose dependence of the compound of the present invention was used to test the epiphyseal growth plate of rats.

[0031] Method: Alderley Park female young mice (4-8 weeks old, wostar-derived) were injected with the compound of the present invention (n=6) or excipients (n=5) at a dose of 0.25 mg / ml every day for 14 consecutive days. Epiphyseal joint tissue domains in experimental mice were stained with hematoxylin and eosin, and epiphyseal growth plate binding sites were measured using morphological impact analysis. The result is as figure 1 showed a dose-dependent increase in overgrown cartilage bands in the epiphyseal growth plate of growing mice. When the injection amount is 50 or 100 mg / ml / day, the ability of the compound of the present invention to inhibit VEGF signal is consistent with the anti-angiogenesis effect in vivo.

Embodiment 3

[0033] Experiment of the inhibitory effect of the compound of the present invention on human xenograft tumor in nude mice.

[0034] Method: 50 nude mice (male, 6 weeks old) were inoculated with PC-3 human prostate tumor until the tumor volume reached 0.2cm 2 At the same time, they were randomly divided into 5 groups, namely the control group, 100mg / kg / day dose group, 50mg / kg / day dose group, 25mg / kg / day dose group, and 12.5mg / kg / day dose group. Continuous administration for 7 days Day, intratumoral injection, observation for five weeks, the results are shown in Table 1.

[0035] Table 2 shows the inhibitory effect of oral administration of the compound of the present invention on human xenograft tumors in nude mice.

[0036] dosage

(mg / kg / kg /

sky)

Tumor volume (each observation day)

0

4

7

11

14

18

21

25

27

32

35

control

0.2

0.25

0.28

0.3 ...

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PUM

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Abstract

The present invention discloses one kind of quinazoline derivative as tyrosine kinase inhibitor and its preparation process and application as tumor treating medicine. As new tyrosine kinase inhibitor, the quinazoline derivative can inhibit endothelial cell VEGF signal factor and has obvious inhibition on anthropogenic naked mouse graft tumor.

Description

Technical field: [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a novel tyrosine kinase inhibitor with anti-tumor effect and a preparation method thereof. Specifically, the invention relates to quinazoline derivatives, a preparation method thereof and a drug for treating tumor diseases Applications. Background technique: [0002] VEGF is an angiogenic factor in the process of tumor angiogenesis and a hormone regulator of endothelial cell differentiation. The development of solid tumors is closely related to the expression of VEGF. The increased expression of VEGF is the result of stimulation by various factors, including primary carcinoma Gene activation and hypoxemia, because improper perfusion of tumor patients can cause hypoxemia in solid tumors, VEGF not only promotes the formation of new blood vessels, but also promotes the permeability of blood vessel walls, making tumors and The nutrient and metabolic exchange of adjacen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/498A61P35/00C07D239/94
Inventor 黄文林周晓虹
Owner 黄文林