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Arylphthalazine compound and its preparation method and use

A compound, aryl technology, applied in the field of drug synthesis, can solve the problems of anti-tumor drug resistance, reduce CML cells, reduce the growth of imatinib-resistant CML cells, etc.

Inactive Publication Date: 2016-10-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Studies have reported that Hedgehog signaling pathway inhibitors can not only reduce the number of CML cells but also reduce the number of NSCLC patients in the treatment of non-small cell lung cancer (CML) patients who are resistant to the tyrosine kinase inhibitor imatinib. Growth of matinib CML cells; however, the problem of drug resistance to existing anticancer drugs is still an important problem in the clinical treatment of cancer

Method used

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  • Arylphthalazine compound and its preparation method and use
  • Arylphthalazine compound and its preparation method and use
  • Arylphthalazine compound and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of compound 1, N-(1-(4-(1-methyl-pyrazol-5-yl)-phthalazin-1-yl)piperidin-3-yl)-4-fluoro-2 -Trifluoromethylbenzamide

[0029] 1) Synthesis of N-(1-benzyl-piperidin-3-yl)-4-fluoro-2-trifluoromethylbenzamide

[0030] In a 50mL eggplant-shaped bottle, add 2-trifluoromethyl-4-fluorobenzoic acid (546mg, 2.63mmol), ultra-dry THF (10mL), EDC . HCl (1.0g, 5.26mmol), stirred at room temperature for 0.5h, added DMAP (65mg, 0.53mmol), replaced the air in the reaction system with argon, and added dropwise the compound N-benzyl-3-aminopiperidine (500mg, 2.63 mmol) in ultra-dry THF (5 mL). After the dropwise addition was completed, stir at room temperature for 16 h under argon atmosphere, TLC (PE:EA=1:1) detected that the reaction was complete, added saturated sodium bicarbonate solution (150 mL), extracted with DCM (50 mL×3), combined the organic layers, and saturated salt Wash with water (50mL×1), dry over anhydrous sodium sulfate, evaporate the solvent und...

Embodiment 2

[0037] Example 2: Preparation of compound 2, N-methyl-N-(1-(4-(1-methyl-pyrazol-5-yl)-phthalazin-1-yl)piperidin-3-yl)- 4-Fluoro-2-trifluoromethylbenzamide

[0038] 1) Synthesis of N-methyl-N-(1-tert-butoxycarbonyl-piperidin-3-yl)-4-fluoro-2-trifluoromethylbenzamide

[0039] In a 50mL eggplant-shaped bottle, add 2-trifluoromethyl-4-fluorobenzoic acid (1.5g, 7.1mmol), ultra-dry THF (25mL), EDC . HCl (1.8g, 9.3mmol), stirred at room temperature for 0.5h, added DMAP (120mg, 0.93mmol), replaced the air in the reaction system with argon, and added dropwise the compound N-tert-butoxycarbonyl-3-aminomethylpiperidine ( 1.0 g, 4.7 mmol) in ultra-dry THF (5 mL). After the dropwise addition was completed, stir at room temperature for 16 h under argon atmosphere, TLC (PE:EA=1:1) detected that the reaction was complete, added saturated sodium bicarbonate solution (50 mL), extracted with DCM (50 mL×3), combined the organic layers, and saturated salt Washed with water (50mL×1), dried over ...

Embodiment 3

[0046] Example 3: Preparation of compound 3, 2-(4-(1-methylpyrazol-5-yl)phthalazin-1-yl)-6-(2-trifluoromethyl-4-fluoro-benzoyl )-2,6-diazaspiro[3,3]heptane

[0047] 1) Synthesis of 2-tert-butoxycarbonyl-6-(2-trifluoromethyl-4-fluoro-benzoyl)-2,6-diazaspiro[3,3]heptane

[0048] In a 50mL eggplant-shaped bottle, add 2-trifluoromethyl-4-fluorobenzoic acid (1.5g, 7.1mmol), ultra-dry THF (25mL), EDC . HCl (1.8g, 9.3mmol), stirred at room temperature for 0.5h, added DMAP (120mg, 0.93mmol), replaced the air in the reaction system with argon, and added compound 11 (1.0g, 7.4mmol) in ultra-dry THF (5mL) dropwise solution. After the dropwise addition was completed, stir at room temperature for 16 h under argon atmosphere, TLC (PE:EA=1:3) detected that the reaction was complete, added saturated sodium bicarbonate solution (50 mL), extracted with DCM (50 mL×3), combined the organic layers, and saturated salt Wash with water (50mL×1), dry over anhydrous sodium sulfate, evaporate the sol...

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Abstract

The invention belongs to the field of drug synthesis, relates to an arylphthalazine compound with a structure shown in a general formula (I) and its pharmaceutically acceptable salt and especially relates to an arylphthalazine compound containing piperazine, pyrrolidine or azetidine and its preparation method and use in medical science. An in-vitro Hedgehog signal path target gene Gli inhibition activity test proves that the compound has good Hedgehog signal path inhibition activity. The compound can be used for preparation of a novel anti-tumor drug.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a novel arylphthalazine compound, a preparation method and application. It specifically relates to an arylphthalazine compound containing piperazine, pyrrolidine or azetidine, its preparation method and its application in medicine. Background technique [0002] Studies have reported that malignant tumors have become a common disease that seriously endangers people's lives and health. According to incomplete statistics, there are about 20 million new cases in the world every year; in my country, there are about 1.6-2 million new cases and 1.3 million deaths each year. Because the tumor has the ability to metastasize in the early stage, about 50% of the patients in the clinical diagnosis of the primary tumor have developed distant metastasis, and the tumor cells grow rapidly and easily mutate, resulting in multidrug resistance, leading to the failure of chemotherapy. According to relev...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D487/10C07D403/14C07D403/04A61K31/502A61P35/00
Inventor 董肖椿陆秀宏王娟谭文福赵伟利鲍小龙彭元求杨君刘原
Owner FUDAN UNIV
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