Unlock instant, AI-driven research and patent intelligence for your innovation.

Tyrosine kinase inhibitor and pharmaceutical application thereof

A technology of tyrosine kinases and inhibitors, which can be used in drug combinations, antineoplastic drugs, organic chemistry, etc., and can solve the problems that gefitinib cannot be combined with it, the selectivity is not good enough, and it is easy to cause drug resistance.

Pending Publication Date: 2022-04-26
JIANGSU CONCORD BIOTECHNOLOGY CO LTD
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a "gatekeeper group", threonine is located outside the core of the tyrosine kinase contact reaction, and forms a hydrogen bond with a high affinity with the aniline group of gefitinib, thus ensuring the tight combination of the drug and the tyrosine kinase without Play an anti-tumor effect; once a mutation occurs, threonine is replaced by methionine, which introduces a larger amino acid side chain at this site to form a steric hindrance, thus affecting the relationship between tyrosine kinase and gefitinib The formation of hydrogen bonds between them eventually leads to the inability of Gefitinib to combine
[0007] The first generation of tyrosine kinase inhibitors all function in the form of reversible inhibition (hydrogen bond formation), so generally speaking, the selectivity is not good enough, the drug effect is not strong and long-lasting, and it is easy to cause drug resistance

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Tyrosine kinase inhibitor and pharmaceutical application thereof
  • Tyrosine kinase inhibitor and pharmaceutical application thereof
  • Tyrosine kinase inhibitor and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of 4-(4-fluoro-3-chloroanilino)-7-methoxy-6-(N-bromoacetyl)aminoquinazoline, the steps are as follows:

[0027] (1) Preparation of 4-chloro-7-fluoro-6-nitroquinazoline.

[0028] 8.5 g of 4-hydroxy-7-fluoro-6-nitroquinazoline and 150 ml of phosphorus oxychloride were added to a 250 ml round bottom bottle, and the mixture was heated to reflux for 6 hours with stirring. Rotary evaporation removes excess phosphorus oxychloride, then washes with 10:1 petroleum ether / ethyl acetate to obtain 8 grams of solid 4-chloro-7-fluoro-6 nitroquinazoline, MS (m / z) :227.78(M+1) + .

[0029] (2) Preparation of 4-(4-fluoro-3-chloroanilino)-7-fluoro-6-nitroquinazoline.

[0030] 2.3 grams of 4-chloro-7-fluoro-6-nitroquinazoline, 1.6 grams of 4-fluoro-3-chloroaniline, and 1.73 grams of potassium carbonate were added to 30 ml of N, N dimethylformamide, and the mixture was stirred and heated to 50 degrees After 10 hours, the solvent was removed under reduced pressure distillatio...

Embodiment 2

[0042] Preparation of 4-(4-fluoro-3-chloroanilino)-7-methoxy-6-(N-chloroacetyl) aminoquinazoline, the steps are as follows:

[0043] 160 mg of 4-(4-fluoro-3-chloroanilino)-7-methoxy-6-aminoquinazoline and 129 mg of triethylamine were dissolved in 50 ml of dichloromethane, then cooled to 0 degrees, slowly Add 68 mg of chloroacetyl chloride dropwise, stir for 5 hours, add 10 ml of water, separate the dichloromethane and dry it with anhydrous magnesium sulfate, filter and concentrate to obtain a crude product, and further column purification to obtain 120 mg of the product, MS (m / z): 394.68(M+1) + .

Embodiment 3

[0045] Preparation of 4-(4-fluoro-3-chloroanilino)-7-methoxy-6-(N-3'-chloropropionyl) aminoquinazoline, the steps are as follows:

[0046] 160 mg of 4-(4-fluoro-3-chloroanilino)-7-methoxy-6-aminoquinazoline and 60 mg of p-dimethylaminopyridine were dissolved in 10 ml of N,N-dimethylformamide, Add 125 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, 70 mg of 3-chloropropionic acid and 129 mg of N,N-diisopropylethylamine, and stir After 15 hours, 20 ml of water was added, extracted with 100 ml of ethyl acetate, and the ethyl acetate was separated and dried over magnesium sulfate. Concentrate by filtration, and the residue is separated by column separation with dichloromethane / methanol to obtain the product 4-(4-fluoro-3-chloroanilino)-7-methoxy-6-(N-3'-chloropropionyl)amino Quinazoline 55 mg, MS (m / z): 408.68 (M+1) + .

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a tyrosine kinase inhibitor and a drug application thereof.The tyrosine kinase inhibitor is a quinazoline derivative, the structural formula of the tyrosine kinase inhibitor is as follows: a functional group containing XCH2 (CH2) nC = O is introduced on the basis of a quinazoline structure, and the functional group is easily combined with cysteine sulfydryl through nucleophilic reaction to form a covalent bond, so that the tyrosine kinase inhibitor can be used for preparing a medicine. Therefore, the tyrosine kinase activity is irreversibly inhibited.

Description

technical field [0001] The invention relates to a tyrosine kinase inhibitor and its application in therapeutic drugs for inhibiting and treating diseases caused by overexpression of tyrosine kinase. Background technique [0002] There are many signaling pathway systems in cells, which interact to control cell proliferation, growth, metastasis and apoptosis. Tyrosine kinase plays a key role in signal transduction, and the combination of human epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) can activate the activity of tyrosine kinase, leading to the expression of epidermal growth factor in various human solid tumors. Overexpression can cause uncontrollable cell division, and Tyrosine Kinase Inhibitors (TKI) can prevent and control the activity of tyrosine kinase and control cell proliferation. Its mechanism of action is to compete with adenosine triphosphate (ATP) for the ATP binding site of the kinase. Compared with traditional cytotoxic anticancer...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/93C07D239/94C07D239/86C07D239/88A61P35/00
CPCC07D239/93C07D239/94C07D239/86C07D239/88A61P35/00
Inventor 陈华标龙正宇李涛
Owner JIANGSU CONCORD BIOTECHNOLOGY CO LTD