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5-arylphenol-2 alkyl substituted urea benzimidazole compounds and their applications

A technology of benzimidazole and arylphenol, which is applied in the field of chemical medicine, can solve the problems of complex chemical structure and poor solubility, and achieve the effects of wide source of raw materials, low cost and drug resistance

Inactive Publication Date: 2018-04-27
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs all have complex chemical structures, poor solubility, and drug resistance issues

Method used

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  • 5-arylphenol-2 alkyl substituted urea benzimidazole compounds and their applications
  • 5-arylphenol-2 alkyl substituted urea benzimidazole compounds and their applications
  • 5-arylphenol-2 alkyl substituted urea benzimidazole compounds and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Synthesis of 1-(5-phenoxy-1H-benzimidazole-2)-3-methylurea

[0073] Step 12 - Synthesis of nitro-5-phenoxyaniline

[0074]

[0075] Dissolve 0.9mL (10mmol) of phenol in 10mL of N,N-dimethylformamide, add 1.4g (10mmol) of anhydrous potassium carbonate, and stir at 100°C for 1h. Subsequently, 0.8 g (5 mmol) of 5-fluoro-2-nitroaniline was added and reacted at 100° C. for about 6 h. The reaction was tracked by TLC, and it was found that the raw material had reacted completely. After being cooled to room temperature, it was poured into ice water, and a precipitate was precipitated. It was suction-filtered with a Buchner funnel to obtain 1.1 g of crude product 2-nitro-5-phenoxyaniline, and the yield was 98.5%. The crude product was directly used for Next reaction.

[0076] Step 24 - Synthesis of phenoxy-1,2-phenylenediamine

[0077]

[0078] Dissolve 1.1g (4.9mmol) of 2-nitro-5-phenoxyaniline synthesized in the previous step in 10mL of ethanol, add 0.03g (0.24mmol) o...

Embodiment 2

[0086] Synthesis of 1-(5-phenoxy-1H-benzimidazole-2)-3-ethylurea

[0087]

[0088] Weigh 0.6g (2.1mmol) of methyl-5-benzyloxy-1H-benzimidazole-2-carbamate into 5mL acetonitrile, 0.54mL (4.2mmol) 70% ethylamine aqueous solution, microwave 140 After reacting at ℃ for 2 hours, it was poured into ice water, and a precipitate was precipitated. It was filtered under reduced pressure to obtain 0.32 g of the product 1-(5-phenoxy-1H-benzimidazole-2)-3-ethylurea, with a yield of 51.0%. 1 HNMR (400MHz, DMSO-d6) δ11.53(s,1H),9.85(s,1H),7.36-7.31(m,3H),7.20(s,1H),7.06-7.03(m,2H),6.91 (d, J=8.4Hz, 2H), 6.75(d, J=8.4Hz, 1H), 3.22-3.18(m, 2H), 1.10(t, J=7.2Hz, 3H). HRMS (ESI), [M+H] + : 297.1347.

Embodiment 3

[0090] Synthesis of 1-(5-(2-chlorophenoxy)-1H-benzimidazole-2)-3-methylurea

[0091]

[0092] Using 2-chlorophenol as the starting material, the procedure is the same as that of 1-(5-phenoxy-1H-benzimidazole-2)-3-methylurea, and the total yield is 8.5%. Among them, the method of nitro reduction is iron powder reduction, and the specific operation is as follows: add 1.4g (24.6mmol) iron powder to 2mL water, drop into concentrated hydrochloric acid 0.5mL, and reflux at 100°C for 1h. Add 1.3 g (4.9 mmol) of 2-nitro-5-(2-chlorophenoxy)aniline dissolved in 6 mL of ethanol, and react overnight. Suction filtration while hot, adjust the pH of the filtrate to neutral with a saturated solution of sodium bicarbonate, there is precipitation, suction filtration under reduced pressure, spin the filtrate to dry the solvent, and column chromatography to obtain 1.0g of the product 1-(5-(2-chlorophenoxy Base)-1H-benzimidazole-2)-3-methylurea, the yield was 87.2%. 1 HNMR (400MHz, DMSO-d6) δ...

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Abstract

The present invention discloses a 5-aryl phenol-2 alkyl substituted urea benzimidazole compound and applications thereof, wherein the compound has a structure represented by a formula (I). According to the present invention, the 5-aryl phenol-2 alkyl substituted urea benzimidazole compound can significantly inhibit proliferation of a variety of tumor cells in vitro, presents a dose-dependent manner for tumor cell microtubule formation and cell cycle G2 / M phase blocking, and provides a new drug selection for clinical tumor treatment. The formula I is defined in the instruction.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a 5-arylphenol-2 alkyl substituted urea benzimidazole compound and its application. Background technique [0002] Tumors, especially malignant tumors, are major diseases that seriously threaten human health and life safety. According to statistics, malignant tumors caused 8.2 million deaths worldwide in 2012; and it is predicted that in the next 20 years, the annual number of cancer cases worldwide will rise from 14 million in 2012 to 22 million (Globocan 2012, IARC). In China, cancer is also one of the most important causes of death. Therefore, discovering and searching for new and effective antineoplastic drugs is an important topic in the world at present. [0003] Microtubule inhibitors are important antitumor drugs, including microtubule stabilizers and microtubule destabilizers. Microtubule inhibitor drugs are mainly of plant origin, such as vinblastine analogs and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D235/30A61K31/4184A61P35/00A61P35/02
CPCC07D235/30
Inventor 丁克程辉敏李迎君谈理王雪聪张章庄晓曦龙活尤
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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