[(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt

A technology for aminophenyl and derivatives, applied in the field of preparation of [pyrimidin-2-yl]aminophenylprop-2-enamide derivatives and their salts, capable of solving adverse metabolism, short half-life, high dosage, etc. question

Active Publication Date: 2015-12-16
河南英诺唯医药科技有限公司
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  • Summary
  • Abstract
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AI Technical Summary

Problems solved by technology

However, the half-life of AZD9291 is short, and the dosage is high, resulting in adverse metabolism, such as a higher incidence of diarrhea, rash and naus

Method used

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  • [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt
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  • [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt

Examples

Experimental program
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preparation example Construction

[0053] The present invention provides a preparation method of the derivative described in the above technical scheme, comprising the following steps:

[0054] reacting the compound having the structure of formula III with the compound having the structure of formula IV to obtain the compound having the structure of formula V;

[0055] The compound having the structure of formula V is sequentially reduced and amidated to obtain a derivative having the structure of formula I;

[0056]

[0057] The R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 independently selected from hydrogen or deuterium;

[0058] In formula III, the M is F, Cl, Br or I.

[0059] In the present invention, the compound having the structure of formula VI is reacted with the compound having the structure of formula VII to obtain the compound having the structure of formula V.

[0060] In the present invention, the compound ...

Embodiment 1

[0118] See figure 1 The reaction scheme shown, figure 1 Be the reaction route diagram of the embodiment of the present invention 1:

[0119] Step 1: Preparation of 3-(2-chloropyrimidin-4-yl)-1H-indole

[0120] N 2 Under the atmosphere, to compound 1 (21g, 0.14mol) dichloromethane (500mL) solution was added AlCl 3 (22.5g, 0.17mol), the addition was completed in 10 minutes. After the obtained suspension was stirred at room temperature for 10 minutes, the reaction system was basically clear. At room temperature, compound 2 (16.5 g, 0.14 mol) was added in batches to the above reaction solution, and the addition was completed within 10 minutes. The resulting brown suspension was stirred overnight at room temperature; the reaction was monitored by TLC. When compound 1 was completely consumed, the reaction solution was poured into ice water (500 mL) with stirring, and the system was extracted 3 times with EtOAc (300 mL). The organic phases were combined, washed twice with brine...

Embodiment 2

[0177] Preparation of N-(2-{2-[bis(trideuteromethyl)amino]ethyl-(methyl)amino}-4-methoxy-5-{[4-(1-trideuteromethyl) -2,4,5,6,7-Pentadeuterioindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate (AZD9291-D14 methanesulfonate )

[0178] Example 2 was prepared according to the method described in Example 1, except that 1H-indole was replaced with 1H-indole-2,3,4,5,6,7-d6 to obtain the target product.

[0179] Tested: chemical purity >98%, deuterated purity >98%; LCMS (ESI+): m / z 514 (M-OMs).

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Abstract

The invention provides a [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, a preparation method of the derivative, and application of the derivative and the salt. The [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative has a structure shown in the formula I below. Deuterium-carbon bonds in the derivative enable the derivative to decompose slowly in a human body, a medicament of the derivative has a longer half-life period and a higher concentration in blood, the dosage of the medicament is finally reduced, and toxic and side effects of the medicament are decreased. Experiments show that compared with AZD 9291 mesylates, AZD 929-D9 mesylate of the deuterium-substituted derivative has Cmax which is 1.32 times as high as that of AZD 9291, exposed dose 1.41 times as high as that of AZD 9291, and elimination half-life 1.31 times as long as that of AZD 9291.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to [(indol-3-yl)pyrimidin-2-yl]aminophenylprop-2-enamide derivatives and salts thereof, preparation methods and applications thereof. Background technique [0002] Lung cancer is the malignant tumor with the highest morbidity and mortality rate in the world, the most common of which is non-small cell lung cancer. Epidermal growth factor receptor-1 (epidermal growth factor receptor, EGFR) is usually expressed on the surface of non-small cell lung cancer tumor cells; after binding to its ligand or forming a heterodimer with other epidermal growth factor receptors (HER2, EGFR3), it can Activate the downstream signal transduction pathway of cells, leading to abnormal proliferation of cells. It can be seen that EGFR is a very important therapeutic target for non-small cell lung cancer. In particular, in some non-small cell lung cancers, such as non-squamous cell carcinoma, ...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61P35/00A61P35/02A61P35/04
CPCC07D403/04
Inventor 彭快郑飞鸣傅勇
Owner 河南英诺唯医药科技有限公司
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