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Novel substituted benzamide compounds and pharmaceutically-acceptable salts, and preparation method and application thereof

A benzamide and compound technology, applied in the field of new substituted benzamide compounds, can solve the problems of steric hindrance, death, adverse reactions of patients, etc., and achieve a wide therapeutic window, wide anti-cancer spectrum, excellent anti-tumor activity and safety effect

Inactive Publication Date: 2019-10-25
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is because the T315I mutation produces steric hindrance, which prevents the 3-hydroxy-phenylethyl group at the N-9 position of the purine in the inhibitor structure from binding to the hydrophobic pocket of ABL, but the FDA has currently terminated the use of Ponatinib, mainly because Ponatinib produces significant coagulation effects, leading to serious adverse reactions or death of patients

Method used

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  • Novel substituted benzamide compounds and pharmaceutically-acceptable salts, and preparation method and application thereof
  • Novel substituted benzamide compounds and pharmaceutically-acceptable salts, and preparation method and application thereof
  • Novel substituted benzamide compounds and pharmaceutically-acceptable salts, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 Synthesis of compound M1

[0049]

[0050] 1. Synthesis of intermediate a1

[0051] The 3-bromoimidazo[1,2-b]pyridazine (36.64g, 0.186mol), Pd(pph 3 ) 4 (10.73g, 9.29mmol), CuI (5.30g, 0.028mmol) and DIPEA (32.4mL, 0.279mol) were added to N,N dimethylformamide (150mL), under nitrogen protection, added trimethylsilylacetylene ( 21.89g, 0.223mol), react at room temperature for 1h, pour the reaction solution into 200mL water, extract with ethyl acetate (100mL×3) to separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate, and separate the product by column chromatography on silica gel 28.22g, yield 71%, MS (ESI) m / z (%): 216.3[M+H] + .

[0052] 2. Synthesis of intermediate b1

[0053] The intermediate a1 (28.38g, 0.132mol) and K 2 CO 3 (36.43g, 0.264mol) was added to MeOH (150mL), reacted at room temperature for 0.5h, the reaction solution was concentrated, the crude product was separated by column chromatography on silica gel to obtain 16.88g,...

Embodiment 2

[0066] Example 2 Synthesis of Compound M2

[0067]

[0068] 1. Synthesis of intermediate g2

[0069] Add formaldehyde (0.07g, 2.25mmol), R 1 (Tetrahydropyrrole) (0.16g, 2.25mmol) was added to glacial acetic acid (10mL), reacted at room temperature for 0.5h, intermediate f 1 (0.6g, 1.5mmol) was added, reacted at 35℃ for 4h, and glacial acetic acid was evaporated under reduced pressure , Add saturated Na 2 CO 3 The solution adjusted the pH of the reaction night to 8-9, extracted with dichloromethane (50mL×3), separated the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography on silica gel to obtain a white solid 0.44g with a yield of 61.7% ,MS(ESI)m / z(%):486.2[M+H] + .

[0070] 2. Synthesis of compound M2

[0071] Intermediate g2 (0.24g, 0.5mmol), intermediate b1 (0.093g, 0.65mmol), Pd(ph 3 ) 4 (0.029g, 0.025mmol), CuI (0.007g, 0.038mmol), DIPEA (0.19g, 1.5mmol), DMF (15mL), under nitrogen protection, react at 55℃ for 4.5h, ...

Embodiment 3

[0072] Example 3 Synthesis of Compound M3

[0073]

[0074] 1. Synthesis of intermediate g3

[0075] Add formaldehyde (0.07g, 2.25mmol), R 1 (Morpholine) (0.20g, 2.25mmol) was added to glacial acetic acid (10mL) and reacted at room temperature for 0.5h. Intermediate f1 (0.6g, 1.5mmol) was added and reacted at 35℃ for 4h. The glacial acetic acid was evaporated under reduced pressure and saturated Na 2 CO 3 The solution adjusts the pH of the reaction night to 8-9, extracts with dichloromethane (50mL×3) and separates the organic phase, then dried with anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography on silica gel to obtain a white solid 0.45

[0076] g, yield 61.5%, MS (ESI) m / z (%): 502.2[M+H] + .

[0077] 2. Synthesis of compound M3

[0078] Intermediate g3 (0.25g, 0.5mmol), intermediate b1 (0.093g, 0.65mmol), Pd(pph 3 ) 4 (0.029g, 0.025mmol), CuI (0.007g, 0.038mmol), DIPEA (0.19g, 1.5mmol), DMF (15mL), under nitrogen protection, react at 55℃ for ...

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Abstract

The invention relates to novel substituted benzamide compounds and pharmaceutically-acceptable salts, and a preparation method and application thereof of the general formula (1). The invention also provides a pharmaceutical composition comprising the novel substituted benzamide compounds and the pharmaceutically-acceptable salts thereof, a result of antitumor effects in vitro and in vivo and an acute toxicity research. The novel substituted benzamide compounds for antitumor drugshas a better anti-tumor activity and safety, can be applied in the treatment of leukemia, lung cancer, colon cancer,ovarian cancer, kidney cancer, and the like, therefore, the windowing can be treated, and the novel substituted benzamide compounds are very valuable in the field of medicine as antineoplastic agents.

Description

Technical field [0001] The invention belongs to the field of medicine, and particularly relates to a novel substituted benzamide compound that inhibits tumor cell growth and exerts an anti-tumor effect, and a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. Background technique [0002] Imatinib competitively inhibits the binding site of adenosine triphosphate (ATP) and thymidine kinase (TK) receptors such as KIT, blocks TK phosphorylation, thereby inhibiting signal transduction, and can inhibit KIT mutations related to kinase activity (causing KIT receptor activation) and wild-type KIT. There are three main targets: Abelson (ABL) protein, KIT protein, and platelet-derived growth factor (PDGF) receptor. Imatinib can reduce the kinase phosphorylation of GIST-derived cell line (GIST882) through gain-of-function KIT mutations that cause stem cell factor-independent activation. When the concentration reaches 1μmol / L, it can completely inhib...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D471/04A61P35/00A61P35/02A61K31/5377A61K31/5025A61K31/437A61K31/4545A61K31/496
CPCA61P35/00A61P35/02C07D471/04C07D487/04
Inventor 陈烨刘举丁实李军刘雨彤史建涛李杰周子筠张娇娇宫益林
Owner LIAONING UNIVERSITY
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