N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof

A formamide compound, methyl phenyl technology, applied in the field of drug synthesis

Inactive Publication Date: 2014-11-19
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Although the above two BCR-ABL kinase inhibitors have shown good curative effect, due to the increasing drug resistance and the differences between individuals in the treatment population, researchers in the industry are required to continuously research and develop new safe and effective small molecules Compounds to inhibit ABL kinase

Method used

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  • N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof
  • N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof
  • N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: synthetic compound 1 , N-(2-chloro-6-methylphenyl)-2-[[2-methyl-6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyrimidine- 4-yl]amino]thiazole-5-carboxamide

[0044] Under stirring at room temperature, 2-((6-chloro-2-methylpyrimidin-4-yl)amino )-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (0.3 g, 0.76 mmol) and N,N-diisopropylethylamine (0.56 mL, 1.6 mmol) In 4-dioxane (10 mL) solution, the temperature was raised to reflux, and the reaction was carried out overnight, and the disappearance of the starting material was monitored by TLC. The reaction was stopped and cooled down to room temperature, and the solvent was removed. The obtained solid was washed twice with methanol and diethyl ether, respectively, and subjected to column chromatography to obtain a white solid (20 mg, yield 6%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.47 (br s, 1H), 9.88 (s, 1H), 8.22 (s, 1H), 7.40 (dd, J = 7.5, 1.6 Hz, 1H), 7.35 – 7.20 (m, 2H), 5.69 (s, 1H), 4.72 (s, 4H), 4.15 (s, 4H)...

Embodiment 2

[0046] Embodiment 2: synthetic compound 2 , N-(2-chloro-6-methylphenyl)-2-[[2-methyl-6-(2-thia-6-azaspiro[3.3]heptane-6-yl)pyrimidine- 4-yl]amino]thiazole-5-carboxamide

[0047] Under stirring at room temperature, 2-thio-6azaspiro[3,3]heptane oxalate (128 mg, 0.4 mmol) was added to 2-((6-chloro-2-methylpyrimidin-4-yl)amino) 1,4- In dioxane (5 mL) solution, the temperature was raised to reflux, and the reaction was carried out overnight, and the disappearance of the starting material was monitored by TLC. The reaction was stopped and cooled to room temperature, and the solvent was removed. The obtained solid was washed twice with methanol and diethyl ether, respectively, and subjected to column chromatography to obtain a white solid (10 mg, yield 5%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.49 (s, 1H), 9.89 (s, 1H), 8.22 (s, 1H), 7.40 (dd, J = 7.2, 1.2 Hz, 1H), 7.34 – 7.19 (m, 2H), 5.69 (s, 1H), 4.04 (s, 4H), 3.40 (s, 4H), 2.40 (s, 3H), 2.24 (s, 3H).

[0048]

Embodiment 3

[0049] Example 3: Synthetic compound 3, N-(2-chloro-6-methylphenyl)-2-[[2-methyl-6-(2-oxo-2-thia-6-azaspiro[ 3.3] Heptane-6-yl)pyrimidin-4-yl]amino]thiazole-5-carboxamide

[0050] Under stirring at room temperature, 2-oxa-6-thiaspiro[3.3]heptane-6-oxide oxalate (55, 359 mg, 1.02 mmol) was added to 2-((6-chloro-2-methyl Pyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (52, 200 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.356 mL, 2.04 mmol) in a solution of 1,4-dioxane (5 mL), heated to reflux, reacted overnight, and TLC monitored the disappearance of the starting material. The reaction was stopped and cooled to room temperature, the solvent was removed, and the obtained solid was washed twice with methanol and diethyl ether, and separated and prepared by high performance liquid chromatography to obtain a light yellow solid (10 mg, yield 4%). 1 H NMR (400 MHz, DMSO- d 6) δ 11.50 (s, 1H), 9.89 (s, 1H), 8.23 ​​(s, 1H), 7.40 (dd, J = 7.6, 1.6 Hz, 1H)...

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Abstract

The invention belongs to the field of medicament synthesis, relates to an N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound shown in a general formula (b), and in particular relates to a pyrimidine 6-bit four-membered heterocyclic ring or spiro ring substituted N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound, a preparation method of the pyrimidine 6-bit four-membered heterocyclic ring or spiro ring substituted N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound, and an application of the pyrimidine 6-bit four-membered heterocyclic ring or spiro ring substituted N-(2-chloro-6-methylphenyl)-2[(2-methylpyrimidine-4-group) amino] thiazole-5-formamide compound in medical science. The compound disclosed by the invention is subjected to in-vitro ABL kinase inhibitory activity and anti-tumor activity tests, and results show that the compound has good ABL kinase inhibitory activity and anti-tumor activity and can be further used for preparing a new anti-tumor medicament.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to a new N -(2-Chloro-6-methylphenyl)-2[(2-methylpyrimidin-4-yl)amino]thiazole-5-carboxamide compound, preparation method and application. It specifically relates to a pyrimidine 6-position four-membered heterocycle or a spiro ring substituted N -(2-Chloro-6-methylphenyl)-2[(2-methylpyrimidin-4-yl)amino]thiazole-5-carboxamide compound, its preparation method and its application in medicine. Background technique [0002] The prior art discloses that chronic myelogenous leukemia (CML) is a malignant clonal proliferative disease of the blood system that occurs in hematopoietic stem cells, and is also one of the four most common leukemias, accounting for about 15%-20% of leukemia cases , with an incidence rate of 1.6 / 100,000, which can occur in all age groups, and is most common in middle-aged and elderly cases. According to reports, in the United States, there are about 5,000 new cases of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107C07D495/10C07D417/14C07D487/10A61K31/506A61P35/00A61P35/02
CPCC07D417/14C07D487/10C07D491/107C07D495/10
Inventor 董肖椿赵伟利赵逸超林赵虎陆秀宏王雯董潜
Owner FUDAN UNIV
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