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Aminopyrimidine compound, composition containing same and application thereof

一种氨基嘧啶、化合物的技术，应用在氨基嘧啶类化合物及包含该化合物的组合物领域，能够解决限制应用范围、病人依从性差、副作用治疗成本等问题

Active Publication Date: 2018-12-07
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Poor absorption, distribution, metabolism and / or excretion (ADME) properties are known to be a major reason for failure of many drug candidates in clinical trials
Many currently marketed drugs also limit their application range due to poor ADME properties
The rapid metabolism of drugs will cause many drugs that can treat diseases with high efficiency to be eliminated from the body too quickly, making it difficult to become a drug
Although frequent or high-dose medication may solve the problem of rapid drug clearance, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and increased treatment costs
In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites

Method used

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  • Aminopyrimidine compound, composition containing same and application thereof
  • Aminopyrimidine compound, composition containing same and application thereof
  • Aminopyrimidine compound, composition containing same and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Embodiment 1N-(5-((4-(4-((dimethylamino)methyl-d 2 )-3-phenyl-1H-pyrazol-1-yl-5-d)pyrim Preparation of pyridin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (compound T-1).

[0123]

[0124] Concrete synthetic steps are as follows:

[0125]

[0126]

[0127] Step 1 Synthesis of compound 2.

[0128] Add 4-chloro-2-methylthiopyrimidine (compound 1) (7.25mL, 62.3mmol) and 95% ethanol (100mL) to a 250mL single-necked flask equipped with magnetic stirring in sequence, stir to dissolve, cool to 0°C, Ammonium molybdate tetrahydrate (2.18g, 1.87mmol) in hydrogen peroxide (30%, 14.4mL, 187mmol) was slowly added dropwise, and after the drop was completed, the temperature was raised to room temperature, and the reaction was stirred overnight under nitrogen.

[0129] Evaporate most of the organic solvents under reduced pressure, add water (200mL), extract with dichloromethane (70mLx3), combine the organic phases, wash with saturated brine, dry over anhydrous sod...

Embodiment 2

[0162] Example 2N-(5-((4-(4-((dimethylamino)methyl)-3-(phenyl-d 5 )-1H-pyrazol-1-yl)pyrimidine- Preparation of 2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (compound T-2).

[0163]

[0164] Concrete synthetic steps are as follows:

[0165]

[0166]

[0167] Step 1 Synthesis of Compound 18.

[0168] Add benzene-d to a 50mL three-necked flask equipped with magnetic stirring and condenser 6 (Compound 17, 3.0g, 35.65mmol) and carbon disulfide (15mL), stir well, add AlCl at room temperature 3 (10.46g, 78.43mmol), slowly heated to a slight boil (47°C) under nitrogen, slowly added acetic anhydride (2.91g, 28.52mmol) dropwise, and kept stirring for 1h.

[0169] Cool to room temperature, pour concentrated hydrochloric acid (3.5mL) into ice water (50g), stir for 10 minutes, separate the water phase, extract with ethyl acetate (30mLx3), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate , filtered, concentrated, and passed t...

Embodiment 3

[0191] Example 3N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)ammonia Base)-4-(methoxy-d 3 )-2-Morpholinophenyl)acrylamide (Compound T-3).

[0192]

[0193] Concrete synthetic steps are as follows:

[0194]

[0195]

[0196] Step 1 Synthesis of compound 27.

[0197] Add acetonitrile (30mL) and 2-hydroxy-4-fluoronitrobenzene (compound 26) (3.1g, 20mmol) to a 100mL single-necked flask equipped with a magnetic stirrer, stir to completely dissolve, add TsOMe-d 3 (4.0 g, 21.2 mmol), stirred overnight at room temperature under nitrogen. The insoluble solid was filtered off, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and passed through a silica gel column to obtain 3.2 g of a white solid, with a yield of 92.0%. LC-MS(APCI):m / z=175.1(M+1) + .

[0198] Step 2 Synthesis of compound 28.

[0199] Add ethanol (30mL) and compound 27 (3.2g, 18.4mmol) to a 100mL single-necked flask equipped with a magnetic sti...

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PUM

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Abstract

The invention discloses an aminopyrimidine compound as shown in a formula (I), preparation and application thereof, and particularly discloses an aminopyrimidine compound as shown in the formula (I),or polymorphism, pharmaceutically acceptable salt, prodrug, stereoisomer, isotope variant, hydrate or solvate thereof, as well as medicinal compositions and application thereof. The aminopyrimidine compound and composition containing the compound have excellent inhibitive property for protein kinase, better pharmacokinetic parameter characteristics, and can be used for improving the medicinal concentration of the compound in an animal body to improve the curative effect and safety of medicines.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an aminopyrimidine compound, a composition containing the compound and an application thereof. More specifically, the present invention relates to certain deuterium-substituted N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide, these deuterium-substituted compounds and compositions thereof are useful in the treatment of certain mutant forms of EGFR-mediated diseases, and have better pharmacokinetic properties. Background technique [0002] EGFR tyrosine kinase inhibitor (EGFR-TKI) is a molecularly targeted drug against EGFR, mainly by binding with ATP to the binding site of the catalytic domain of EGFR tyrosine kinase on the cell surface, blocking the signal to the intracellular Further delivery, inhibition of tumor cell growth and induction of apoptosis. At present, EGFR-TKIs such as gefiti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07B59/00A61P35/00A61P35/02A61P9/00A61P29/00A61P31/00A61P37/06A61P31/12A61P3/00A61K31/5377
CPCA61P3/00A61P9/00A61P29/00A61P31/00A61P31/12A61P35/00A61P37/06C07D403/04C07B2200/05A61P37/00A61P19/02A61P19/06A61P11/06A61P11/00A61P11/02A61P11/08A61P35/02C07B59/002C07D413/14
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC
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