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Pyrimidine ring-containing compound, EGFR inhibitor and application thereof

A compound, pyrimidine ring technology, applied in the field of medicine, can solve the problems of poor curative effect of drug-resistant patients, serious side effects of skin rash of patients, etc.

Active Publication Date: 2018-03-27
TETRANOV PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the second-generation inhibitors also have strong wild-type EGFR inhibitory activity, and the inhibitory activity to wild-type EGFR is significantly higher than that of the drug-resistant T790M mutation. Some first-generation EGFR inhibitor-resistant patients respond to these drugs

Method used

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  • Pyrimidine ring-containing compound, EGFR inhibitor and application thereof
  • Pyrimidine ring-containing compound, EGFR inhibitor and application thereof
  • Pyrimidine ring-containing compound, EGFR inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] The compound containing pyrimidine ring in this embodiment has a structural formula as shown in formula (P-1):

[0157]

[0158]

[0159] The synthetic process of this compound is as follows:

[0160]

[0161] The synthetic method of this compound is: get the single mouth bottle of 100ml, add the raw material amine of 60mg (compound SM 2 -1), add 1.2eq of p-toluenesulfonic acid monohydrate crystals, add 1.2eq raw material pyrimidine compound (SM 1 -1) and 15ml of 2-pentanol, heated to 110°C overnight under stirring; the next day, distilled off the 2-pentanol, added 50ml of saturated aqueous sodium carbonate and 50ml of dichloromethane, dichloromethane extracted two Once, the organic phases were combined, dried, concentrated, and passed through the column to obtain 15 mg of the product. The analytical data of this compound are as follows: 1 H NMR (CDCl 3 )δ10.20(br,1H),8.75(m,2H),7.53(s,1H),7.10(m,3H),6.72(s,1H),6.36(m,3H),5.74(m,1H ),3.82(s,3H),2.84(br,2H)...

Embodiment 2

[0163] The compound containing pyrimidine ring of the present embodiment has a structural formula as shown in formula (P-2'):

[0164]

[0165] The synthetic process of this compound is as follows:

[0166]

[0167]Wherein, the synthesis method of compound (P-2) is the same as that of Example 1. The preparation method of compound P-2' (hydrochloride) in this example is: add 200 mg of compound P-2 into a 50 ml one-mouth bottle, add 10 ml of acetone and 1 ml of water, and slowly add it under stirring after the addition 140mg of hydrochloric acid with a mass concentration of 10%, reacted at room temperature for 3 hours after adding, evaporated the reaction solution to dryness, added 6ml of acetonitrile and raised the temperature to 70°C and stirred for 30 minutes, cooled slowly to precipitate the solid, filtered the solid, and used acetonitrile After washing and drying, 160 mg of white solid was obtained, which was the hydrochloride of compound P-2.

[0168] The analytica...

Embodiment 3

[0170] The compound containing pyrimidine ring of the present embodiment has a structural formula as shown in formula (P-3):

[0171]

[0172] The synthetic process of this compound is as follows:

[0173]

[0174] The synthetic method of this compound is with embodiment 1. The analytical data of this compound are as follows: 1 H NMR (CDCl 3 )δ10.10(br,1H),8.73(m,2H),7.56(s,1H),7.23(m,2H),7.10(m,2H),6.68(s,1H),6.43(m,3H ),5.74(m,1H),3.79(s,3H),2.85(m,2H),2.64(s,3H),2.44(s,3H),2.30(br,8H); MS m / z(ESI ):546.2[M+H] + .

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Abstract

The invention relates to a pyrimidine ring-containing compound, an EGFR inhibitor and an application thereof and belongs to the technical field of medicines. The pyrimidine ring-containing compound comprises a compound shown in the formula (I) or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug. The EGFR inhibitor comprises the pyrimidine ring-containing compound. The compound can inhibit activation or resistance mutation of one or more EGFR, can be used for preparing drugs for adjusting and controlling EGFR tyrosine kinase activity or treating EGFR-related diseases suchas cancers, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases and is particularly suitable for preparation of drugs for treating non-small cell lung cancers caused by EGFR mutation comprising sensitive mutation (such as L858R mutation or exon 19 deletion) and drug resistance mutation (such as EGFR T790M mutation).

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a compound containing a pyrimidine ring, and also relates to an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, especially non-small cell lung cancer Pharmaceutical applications. Background technique [0002] Epidermal Growth Factor Receptor EGFR (Epidermal Growth Factor Receptor) is a transmembrane protein tyrosine kinase of the erbB receptor family. When bound to a growth factor ligand such as epidermal growth factor (EGF), the receptor can homodimerize with an additional EGFR molecule, or with another family member such as erbB2 (HER2), erbB3 (HER3), Or erbB4 (HER4)) undergoes heterodimerization. Homodimerization and / or heterodimerization of the erbB receptor leads to phosphorylation of key tyrosine residues in the intracellular domain and to stimulation of many intracellular signaling pathways in...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61K45/06A61P35/00A61P37/02A61P25/00A61P9/00A61P3/10
CPCC07D471/04A61K31/519A61K45/06A61P3/10A61P9/00A61P25/00A61P35/00A61P37/02
Inventor 吴豫生牛成山耿阳梁阿鹏郭中伟刘建涛杨俊亮霍云峰韩兴旺孟庆国李敬亚郭瑞云邹大鹏
Owner TETRANOV PHARMA CO LTD
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