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Novel pyrimidine compound, preparation method thereof, pharmaceutical composition containing novel pyrimidine compound and application of novel pyrimidine compound

A compound and hydrate technology, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problem of low correlation of tumor incidence

Active Publication Date: 2013-03-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Various Met germline and somatic mutations are less associated with tumor incidence

Method used

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  • Novel pyrimidine compound, preparation method thereof, pharmaceutical composition containing novel pyrimidine compound and application of novel pyrimidine compound
  • Novel pyrimidine compound, preparation method thereof, pharmaceutical composition containing novel pyrimidine compound and application of novel pyrimidine compound
  • Novel pyrimidine compound, preparation method thereof, pharmaceutical composition containing novel pyrimidine compound and application of novel pyrimidine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] 4,6-Dichloropyrimidine-5-carbaldehyde (a)

[0124]

[0125] 4.8ml of DMF was added dropwise into 15ml of POCl3 which had been cooled in advance, and the internal temperature was controlled to be less than 10°C. After the dropwise addition was completed, it was stirred in an ice-water bath for 30 minutes. Add 3.75g of 4,6-dihydroxypyrimidine, transfer to an oil bath and heat to 100°C to react for 6h. After the reaction, the reaction solution was poured into crushed ice, extracted with ethyl acetate, and the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated to obtain 2.75 g of an orange solid, with a yield of 69.6%.

[0126] 1 H NMR (300MHz, CDCl 3 )δ: 10.46 (S, 1H, -C H O), 8.90(s, 1H).

[0127]MS(ESI): 175.9[M+H] + .

Embodiment 2

[0129] 4-Amino-6-chloropyrimidine-5-carbaldehyde (b)

[0130]

[0131] Dissolve 15g of compound a in 300ml of toluene, slowly add 45ml of ammonia in methanol solution (4M) dropwise, and react at room temperature for about 20h. After the reaction, add water, extract with ethyl acetate (150ml×4), combine the organic phases, wash with water and saturated brine respectively, and dry over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated to obtain an orange solid, which was recrystallized by adding 100 ml of methanol to obtain 6.47 g of a light yellow solid with a yield of 48.5%.

[0132] 1 H NMR (300MHz, DMSO-d6) δ: 10.24 (S, 1H, -C H O), 8.74 (S, 1H, -N H ), 8.57 (S, 1H, -N H ), 8.40(s, 1H).

[0133] MS(ESI): 157.0[M+H] + .

Embodiment 3

[0135] N-[4-(6-amino-5-formylpyrimidine-4-oxygen)-3-fluorophenyl]-N-(4-fluorophenyl)cyclopropyl-1,1-dicarboxamide (c )

[0136]

[0137] 3.2g compound b was dissolved in 60ml DMF, added 7.61g K 2 CO 3 And 6.13g of N-(3-fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dicarboxamide, stirred at room temperature for 2h. After the reaction, add water, extract with ethyl acetate (50ml×4), combine the organic phases, wash with water and saturated brine respectively, and dry over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated to obtain a yellow-white solid, and 50 ml of methanol was added, stirred and filtered to obtain 5.88 g of off-white solid, with a yield of 70.2%.

[0138] 1 H NMR (300MHz, DMSO-d6) δ: 10.37(s, 1H, -C H O), 10.32(s, 1H, -CON H -), 10.03(s, 1H, -CON H -), 8.53(s, -N H 2 , 2H), 8.18(s, 1H), 7.81-7.76(dd, J 1 =1.89,J 2 =12.84, 1H), 7.65-7.61 (m, 2H), 7.43-7.40 (m, 1H), 7.36-7.30 (t, J=8.71, 1H), 7.18-7.12 (t,...

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PUM

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Abstract

The invention relates to pyrimidine derivate as shown in a formula I, and pharmaceutically acceptable salt, hydrate, solvate and prodrug of the pyrimidine derivate. The invention also relates to a compound which is shown in the formula 1 and has high inhibitive capability to c-Met kinase, and relates to a compound and pharmaceutically acceptable salt and hydrate thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a pyrimidine compound as a receptor tyrosine kinase MET inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound and use thereof. Background technique [0002] Targeted therapy has undoubtedly had a major impact on cancer treatment. Tumor occurrence, evolution, spread and tumor angiogenesis depend on various signal transduction pathways. Significant progress has been made in the treatment of tumors by targeting these signaling pathways, and many drugs have been successfully marketed. For example, the anticancer drug imatinib developed based on ABL tyrosine kinase has a good curative effect on chronic myelogenous leukemia (CML). In recent years, members of the Met proto-oncogene family have received extensive attention. The Met family includes the Met (also known as c-Met) and Ron receptors. Tyrosine prot...

Claims

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Application Information

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IPC IPC(8): C07D239/47A61K31/505A61K31/506A61K31/5377A61P35/00
Inventor 黄文龙钱海黄丹丹邓欣杨宝卫邱波
Owner CHINA PHARM UNIV
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