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Preparation of 1,2-diaryl benzimidazole derivative and application thereof

A benzimidazole and diaryl technology, applied in the field of medicinal chemistry, can solve the problems of poor water solubility, poor structural stability, and low bioavailability

Active Publication Date: 2018-12-21
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, CA-4 is one of the most active compounds among known tubulin inhibitors. It has a simple structure, high efficiency and low toxicity, but it has poor water solubility, low bioavailability, and poor structural stability. Easy isomerization from cis-stilbene active structure to pharmacologically inactive relatively stable trans-structure

Method used

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  • Preparation of 1,2-diaryl benzimidazole derivative and application thereof
  • Preparation of 1,2-diaryl benzimidazole derivative and application thereof
  • Preparation of 1,2-diaryl benzimidazole derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Preparation of 1-phenyl-2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole (4a)

[0020]

[0021] Add o-fluoronitrobenzene (1.41g, 10mmol) and 3,4,5-trimethoxyaniline (1.692g, 12mmol) into water (20mL), stir and reflux for 6h. The reaction solution was cooled to room temperature and washed with NaHCO 3 (about 1.7g) neutralized, and extracted with ethyl acetate (3×100mL), the combined ethyl acetate extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to obtain the crude compound 2a, which was purified by silica gel column chromatography ( Eluent system: petroleum ether / ethyl acetate) to obtain compound 2a as orange powder. Under ice-bath conditions, a mixed solution containing compound 2a (6.37g, 20.0mmol) in tetrahydrofuran (100mL) and absolute ethanol (50mL) was added dropwise to a solution of sodium dithionite (55.7g, 320mmol) in water (125mL) , and then the mixed solution was stirred at room temperature for 1 h, a...

Embodiment 2

[0023] Preparation of 2-methoxy-5-(2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazol-1-yl)phenol (4b)

[0024]

[0025] The preparation method refers to Example 1. A white powder was obtained, yield: 65.6%, m.p.194-196°C. 1 H NMR (600MHz, DMSO-d6) δ7.83(s, 1H), 7.26(d, J=12.9Hz, 1H), 7.09(d, J=10.5Hz, 1H), 6.73(t, J=15.4Hz , 1H), 6.51-6.44(m, 2H), 6.37(d, J=5.5Hz, 2H), 6.29-6.22(m, 2H), 3.83(s, 3H), 3.71-3.64(m, 6H), 3.53(s, 3H).

Embodiment 3

[0027] Preparation of 1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole (4c)

[0028]

[0029] The preparation method refers to Example 1. A white powder was obtained, yield: 77.5%, m.p.171-173°C. 1 H NMR (600MHz, DMSO-d6) δ7.02(d, J=18.6Hz, 1H), 6.83(t, J=12.0Hz, 1H), 6.71-6.67(m, 3H), 6.52(s, 1H) , 6.28(m, 2H), 6.17(s, 2H), 3.91(s, 3H), 3.83(s, 3H), 3.75(s, 3H), 3.67(s, 3H).

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Abstract

The invention discloses a preparation method of a novel microtubular inhibitor 1,2-diaryl benzimidazole derivative and application thereof to the anti-tumor aspect. The 1,2-diaryl benzimidazole derivative has the structure shown in the formula I: the formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method, activity evaluation and antitumor application of a class of 1,2-diarylbenzimidazole derivatives. Background technique [0002] Tumor is a disease that seriously threatens human health at present, with a high lethality rate, and malignant proliferation of cells is its main feature. Inhibiting the malignant proliferation of cells can achieve the purpose of anti-tumor. Cell proliferation depends on the regulation of cell division by the spindle in the cell division phase. The formation of the spindle is closely related to the microtubules. To achieve the purpose of anti-tumor. According to different targets of action, microtubule inhibitors can be divided into two categories: the first category is microtubule stabilizers, such as paclitaxel; the second category is microtubule destabilizers, such as colchicine, vincristine, CA-4 Wait. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/18A61P35/00
CPCA61P35/00C07D235/18
Inventor 朱海亮杨蓉夏林颖张雅亮王保忠
Owner NANJING UNIV
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