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Chalcone-benzimidazole salt compounds and preparation thereof

A technology of benzimidazole and chalcone, applied in the field of chalcone-benzimidazole salt compound and its preparation, can solve the problems of acquired drug resistance and complex chemical structure

Active Publication Date: 2018-05-18
YUNNAN MINZU UNIV
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Problems solved by technology

[0004] Therefore, using benzimidazole compounds as lead compounds, designing and synthesizing novel chalcone-benzimidazole salt compounds, it is expected to obtain tubulin inhibitors with novel mechanism of action, simple chemical structure, and significant antitumor activity. Provide new ideas on the complex chemical structure of tubulin inhibitors and easy to produce acquired drug resistance

Method used

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  • Chalcone-benzimidazole salt compounds and preparation thereof
  • Chalcone-benzimidazole salt compounds and preparation thereof
  • Chalcone-benzimidazole salt compounds and preparation thereof

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preparation example Construction

[0021] The preparation method specifically includes:

[0022] A, the preparation of chalcone structure intermediate 1:

[0023] In a 100 mL round bottom flask, dissolve 3,4,5-trimethoxybenzaldehyde (7.00 mmol) in ethanol: water = 4:1 (35 mL) solvent at room temperature, add sodium hydroxide (14 mmol), stirred for 15 minutes, added 4-hydroxyacetophenone (8.4 mmol), stirred at room temperature for 24 hours, TLC thin-layer chromatography detected the reaction until the reaction was complete, extracted with ethyl acetate, washed with saturated brine, combined organic layers, Drying over anhydrous magnesium sulfate, the organic layer was evaporated to dryness under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 1 as a yellow solid (yield: 94%).

[0024] B, the preparation of bromoalkane chalcone intermediate 2:

[0025] In a 100 mL round-bottom flask, dissolve compound 1 (...

Embodiment 1

[0032] Preparation of compound 6: see the above preparation methods A, B, C, D:

[0033]

[0034] Compound 6: Formula C 37 h 38 Br 2 N 2 o 5。 Yield 79%, yellow solid, melting point: 122.4-123.3 ℃; IR(KBr) ν max (cm -1 ): 3450, 2361, 2341, 2027, 1655, 1603, 1460, 1160, 1068, 952,861, 547. 1 H NMR (400 MHz, DMSO), δ (ppm): 9.76 (1H, s), 8.16 (2H, d, J = 8.7Hz), 7.90 (2H, d, J = 15.2 Hz), 7.73 (2H, d, J = 5.8 Hz), 7.67 (1H, d, J =15.5 Hz), 7.40 (2H, t, J = 8.3 Hz), 7.23 (2H, s), 6.97 (2H, d, J = 8.9 Hz),5.77 (2H, s), 4.72 (2H, t, J = 13.3 Hz), 4.20 (2H, t, J = 11.2 Hz), 3.88 (6H, s), 3.72 (3H, s), 2.51 (6H, d, J = 1.7 Hz), 2.35 (3H, d, J =6.2 Hz). 13C NMR(100 MHz, DMSO), δ (ppm): 187.74, 162.45, 153.58, 144.20, 142.99, 142.36,140.11,, 137.47, 137.06, 133.74, 133.25, 133.17, 131.39, 131.37, 131.15,130.93, 130.81, 130.66 , 130.27, 130.19, 130.10, 128.91, 124.34, 124.35,123.34, 121.61, 114.79, 113.60, 106.97, 65.43, 60.62, 56.65, 50.89,50.74, 28.63, ...

Embodiment 2

[0036] Preparation of compound 7: see the above preparation methods A, B, C, D:

[0037]

[0038] Compound 7: Formula C 41 h 41 BrN 2 o 5, Yield 89%, yellow solid, melting point: 166.2-166.9 ℃; IR(KBr) ν max (cm -1 ): 3450, 2344, 2027, 1657, 1605, 1564, 1461, 1313, 1272, 1218, 1160, 1068, 952, 861, 548. 1 H NMR (400 MHz, DMSO), δ (ppm): 9.93 (1H, s), 8.14 (1H, d, J = 8.2Hz), 8.06 (1H, s), 7.89 (5H,m), 7.68 (1H, d, J = 15.4Hz), 7.56 (3H, s), 7.23 (2H, s), 6.95 (2H, d, J = 8.2 Hz), 5.89 (2H, s), 4.71(2H, s), 4.71 (2H, s), 4.22 (2H, s), 3.88 (6H, s), 3.73 (3H, s), 2.51 (3H ,s), 2.34 (6H, d, J = 9.5 Hz). 13 C NMR (100 MHz, DMSO), δ (ppm): 187.74,162.45, 153.59, 144.19, 141.98, 140.14, 136.90, 133.17, 131.96, 131.35,131.37, 130.81, 130.42, 129.99, 129.99, 129.24, 128.33, 128.14, HRMS (ESI-TOF) m / z Calcd for C 41 h 41 BrN 2 o 5 [M-Br] + 641.3015, found 641.3008.

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Abstract

The invention relates to a series of chalcone-benzimidazole salt compounds with a general structural formula (as shown in a figure I which is described in the specification). According to the invention, 3,4,5-trimethoxybenzaldehyde and hydroxyacetophenone are used as raw materials and subjected to an aldol condensation reaction in a solvent consisting of ethanol and water in ratio of 4: 1 under the catalysis of the catalyst NaOH so as to produce a compound with a chalcone structure; then the compound reacts with 1,3-dibromopropane in ultra-dry DMF at room temperature to produce a brominated chalcone intermediate; and the brominated chalcone intermediate separately reacts with benzimidazole, 2-methylbenzimidazole and 5,6-dimethylbenzimidazole in a toluene solvent under the catalysis of thecatalyst Et3N to produce benzimidazole compositions, and the benzimidazole compositions react with brominated substances in an acetone solvent to synthesize the novel chalcone-benzimidazole salt compounds. Good in-vitro antitumor activity is obtained when a substituent, located at the position 3, of 5,6-dimethylbenzimidazole is a menaphthyl group.

Description

technical field [0001] The invention relates to a novel chalcone-benzimidazolium salt compound and a preparation method thereof, and the anti-tumor application of a pharmaceutical composition using the compound as an active ingredient. Background technique [0002] Malignant tumors are currently the main killer of human health and one of the most important diseases that seriously threaten human life. The comprehensive treatment of tumor mainly consists of surgery, radiotherapy and chemotherapy. Drugs play an important role in the chemotherapy of malignant tumors, and play an important role in prolonging the survival time and improving the quality of life of cancer patients. The recently developed anti-tumor drugs that act on microtubules—tubulin inhibitors have opened up a new world in the search for non-cytotoxic drug-directed therapy, and play a very important role in the clinical treatment of malignant tumors. However, currently clinically used tubulin inhibitors genera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/08C07D235/06A61P35/00
CPCC07D235/06C07D235/08
Inventor 杨丽娟李燕华陈文黄超钏永明杨云汉
Owner YUNNAN MINZU UNIV
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