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4-methoxyphenyl-1, 3-diamine derivative containing 1-methyl-1H-indole structure and application of 4-methoxyphenyl-1, 3-diamine derivative

A technology of methoxyphenyl and diamine derivatives, which can be used in medical preparations containing active ingredients, drug combinations, organic chemistry, etc., and can solve problems such as drug resistance

Pending Publication Date: 2022-07-29
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The second-generation and third-generation EGFR inhibitors currently on the market are irreversible kinase inhibitors, and there is a risk of drug resistance due to the C797S mutation of the Cys797 residue of the kinase

Method used

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  • 4-methoxyphenyl-1, 3-diamine derivative containing 1-methyl-1H-indole structure and application of 4-methoxyphenyl-1, 3-diamine derivative
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  • 4-methoxyphenyl-1, 3-diamine derivative containing 1-methyl-1H-indole structure and application of 4-methoxyphenyl-1, 3-diamine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of Example 1 Compound 1

[0035]

[0036] Step 1: Preparation of Intermediate c

[0037] 2,4-Dichloropyrimidine (5.00 g, 1 eq), anhydrous AlCl 3 (5.40g, 1.2eq) was added to the reaction flask, 1,4-dioxane (30mL) was added to dissolve, and the mixture was stirred in an oil bath at 60°C under nitrogen protection until it was completely dissolved. After complete dissolution, N-methyl indole (5.30 g, 1.2 eq) was added by injection and stirred for about 15 min. After the reaction was detected by TLC, the reaction solution was added to 10 times the amount of ice water, and an orange-yellow solid was precipitated, which was washed with suction and dried in a vacuum oven at 50°C. The dried solid was separated and purified by silica gel column chromatography to obtain 6.69 g of off-white solid, namely intermediate c, with a yield of 81.8%. This solid can be used directly in the next reaction.

[0038] Step 2: Preparation of Intermediate d

[0039] Take the in...

Embodiment 10

[0049] Example 10 Preparation of Compound 10

[0050]

[0051] Wherein, intermediate c and intermediate d can be prepared by referring to the method in Example 1.

[0052] Step 1: Synthesis of Intermediate f

[0053] Get intermediate d (3.50g, 1eq), K in above-mentioned embodiment 1 2 CO 3 The solid (2.58g, 2eq) was placed in a 50mL round-bottom flask, DMF (20.0mL) was added to dissolve it, transferred to an oil bath at 90°C, and then dimethylamine hydrate (0.633g, 1.5eq) was added dropwise with stirring. The reaction was continued for about 6 h, and the reaction was completed after TLC dot plate detection. The reaction solution was cooled to room temperature, extracted three times with DCM, the organic phases were combined, washed three times with saturated aqueous NaCl solution, and anhydrous Na 2 SO 4 Dewatering and drying. Spin-dried under reduced pressure to obtain 3.304 g of a red solid product, namely intermediate f, with a yield of 88.8%. This solid can be us...

Embodiment 20

[0063] Example 20 Preparation of Compound 20

[0064]

[0065] Among them, intermediate c and intermediate d can be synthesized according to the method in Example 1.

[0066] Step 1: Synthesis of Intermediate h

[0067] Take the intermediate d (3.00g, 1eq) in the above example 1 and place it in a 50mL round bottom flask, add DMF (30mL) to dissolve it, add K 2 CO 3 The solid (2.10g, 2eq) was transferred to an oil bath at 90°C, and N,N,N-trimethylethylenediamine liquid (1.16g, 1.5eq) was added dropwise to start the reaction. After 6h, the reaction was complete by TLC dot plate detection. The reaction solution was cooled to room temperature, extracted three times with DCM, the organic phases were combined, washed three times with saturated aqueous NaCl solution, and anhydrous Na 2 SO 4 Dewatering and drying. Spin-dried under reduced pressure to obtain 3.23 g of a red solid product, namely intermediate h, with a yield of 90.2%. This solid can be used directly in the next...

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Abstract

The invention discloses a 4-methoxyphenyl-1, 3-diamine derivative containing a 1-methyl-1H-indole structure and an application of the 4-methoxyphenyl-1, 3-diamine derivative containing the 1-methyl-1H-indole structure. The compound has a structural general formula as shown in (I). The 4-methoxyphenyl-1, 3-diamine derivative containing the 1-methyl-1H-indole structure and the pharmaceutically acceptable salt of the 4-methoxyphenyl-1, 3-diamine derivative are reversible inhibitors of EGFR (epidermal growth factor receptor) kinases, are compounds with inhibition effects on tumor cells with mutational EGFR tyrosine kinases, and can be used for treatment, combined treatment or prevention of various cancers.

Description

technical field [0001] The present invention discloses a class of 4-methoxyphenyl-1,3-diamine derivatives containing 1-methyl-1H-indole structure and a pharmaceutically acceptable salt thereof, a preparation method and a medicine The invention is a compound having an inhibitory effect on tumor cells with mutated EGFR tyrosine kinase, which can be used for the treatment, combined treatment or prevention of various cancers. Background technique [0002] Cancer is the biggest public health problem in the world and seriously threatens human health. Among them, EGFR is a tyrosine kinase that regulates the homeostasis of the intracellular environment, and its signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. It is widely present on the surface of mammalian epithelial cells, fibroblasts, glial cells, and keratinocytes, and is overexpressed in various human malignant tumors, especially in lung cancer, gastri...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/14C07D471/04A61P35/00A61K31/506A61K31/519
CPCC07D401/14C07D403/14C07D471/04A61P35/00
Inventor 陈烨丁实刘举董晓勇吴爽高子晔刘放郑湘山胡自强祁瑞何梓煊张荠方
Owner LIAONING UNIVERSITY
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