Imidazobenzimidazole derivative and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are an imidazobenzimidazole derivative and a preparation method therefor and the use thereof. The imidazobenzimidazole derivative is a compound as shown in formula 3, and the compound is prepared by means of reacting a compound as shown in formula 1 with a compound as shown in formula 2. The imidazobenzimidazole derivative has the effect of inhibiting tumor activity.

Description

Imidazole benzimidazole derivative and its preparation method and application Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to an imidazole benzimidazole derivative and a preparation method and application thereof. Background Art

[0002] Nitrogen-containing heterocyclic compounds are ubiquitous in natural products and pharmaceuticals. Functionalized benzimidazoles with a bicyclic core structure and their derivatives exhibit a wide range of biological activities. Among them, functionalized dihydroimidazole benzimidazole derivatives with a tricyclic core structure have demonstrated promising biological activity. For example, compound CCT031374 is a potent inhibitor of β-catenin / transcription factor (TCF) complex signaling and exhibits anti-tumor activity. Consequently, this class of compounds has attracted widespread attention from synthetic and medicinal chemists. However, few synthetic methods for this class of compounds have been reported, and those that have been reported often utilize copper catalysts. Therefore, the development of new imidazole benzimidazole derivatives, novel preparation methods, and investigation of their biological activities are crucial for medicinal chemistry. Summary of the Invention

[0003] The purpose of the present invention is to provide an imidazole benzimidazole derivative and a preparation method and application thereof.

[0004] To achieve the purpose of the present invention, the following embodiments are provided.

[0005] In one embodiment, an imidazole benzimidazole derivative of the present invention is a compound represented by Formula 3,

[0006] In the formula, R is selected from hydrogen, halogen, alkyl and alkoxy.

[0007] In some embodiments, in the imidazole benzimidazole derivative of the present invention, the halogen is F, Cl or Br.

[0008] In some embodiments, in the imidazole benzimidazole derivatives of the present invention, the alkyl group is a C1-C4 alkyl group, preferably a methyl group or a tert-butyl group.

[0009] In some embodiments, in the imidazole benzimidazole derivatives of the present invention, the alkoxy group is -OC1-C4 alkoxy, preferably methoxy.

[0010] In one embodiment, the imidazole benzimidazole derivative of the present invention is selected from the following compounds:

[0011] In another embodiment, the present invention provides a method for preparing a compound of formula 3, wherein the reaction formula is as follows:

[0012] The method comprises reacting a compound of formula 1 with a compound of formula 2 in an organic solvent in the presence of potassium carbonate to obtain a compound. In formulas 2 and 3, R is selected from hydrogen, halogen, alkyl, and alkoxy. Preferably, the halogen is F, Cl, or Br, the alkyl is a C1-C4 alkyl, more preferably a methyl or tert-butyl group, and the alkoxy is an -OC1-C4 alkoxy, preferably a methoxy group.

[0013] In some embodiments, in the above method of the present invention, preferably, the organic solvent is acetonitrile.

[0014] In some embodiments, the present invention provides a pharmaceutical composition comprising the compound represented by the aforementioned formula 3 and pharmaceutical excipients.

[0015] In some embodiments, the compound represented by the aforementioned formula 3 is used in the preparation of anti-tumor drugs.

[0016] Preferably, the compound represented by the aforementioned formula 3 is selected from any one of compounds represented by 3-1 to 3-12.

[0017] In some embodiments, the tumor is selected from the group consisting of colon cancer cells, prostate cancer, breast cancer, and lung cancer.

[0018] The imidazole benzimidazole derivative provided by the present invention has the effect of inhibiting tumor activity. DETAILED DESCRIPTION

[0019] The following examples are provided to describe the present invention in more detail. However, the following examples are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art will appreciate that any equivalent substitutions made to the present invention, or corresponding improvements, still fall within the scope of protection of the present invention.

[0020] The reaction formulas of the preparation methods of the following examples are as follows:

[0021] Example 1 Synthesis of Compound 3-1

[0022] The experimental procedure was as follows: In a 20 mL reaction tube, a magnetic stirrer was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 4-fluorophenylsulfonium tetraphenylborate (502 mg, 1.0 mmol) were then added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 hours. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-1 in a 76% yield.

[0023] 1 H NMR(400MHz, CDCl3)δ7.62(d,J=7.8Hz,1H),7.24-7.16(m,2H),7.16-7.01(m,3H),6.94(t,J=8.6Hz ,2H),5.70(dd,J=9.1,3.5Hz,1H),4.47(t,J=9.5Hz,1H),3.94(dd,J=9.8,3.6Hz,1H),3.80(s,3H). 13 C NMR (101MHz, CDCl3) δ163.97,161.51,152.45,151.50,147.45,135.77,131.16,127 .78,127.70122.24,121.97,119.49,116.27,116.06,108.52,64.61,54.12,48.57.

[0024] Example 2 Synthesis of Compound 3-2

[0025] The experimental procedure was as follows: In a 20 mL reaction tube, a magnetic stirrer was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 3-methylphenylsulfonium tetraphenylborate (498 mg, 1.0 mmol) were then added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then separated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-2 in an 88% yield.

[0026] 1 H NMR(400MHz, CDCl3)δ7.66(d,J=7.7Hz,1H),7.22-7.00(m,7H),5.75(dd,J=9.1,3.5H z,1H),4.52(t,J=9.4Hz,1H),4.00(dd,J=9.7,3.5Hz,1H),3.85(s,3H),2.24(s,3H). 13 C NMR (101MHz, CDCl3) δ152.73,151.64,147.56,139.89,139.12,131.28,129.61,129 .10,126.12,122.85,122.17,121.88,119.59,108.47,65.26,54.18,48.72,21.44.

[0027] Example 3 Synthesis of Compound 3-3

[0028] The experimental procedure was as follows: In a 20 mL reaction tube, a magnetic stirrer was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 2-bromostyrylsulfonium tetraphenylborate (563 mg, 1.0 mmol) were then added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-3 in a yield of 78%.

[0029] 1 H NMR(400MHz, CDCl3)δ7.65(d,J=7.8Hz,1H),7.57(d,J=7.8Hz,1H),7.18-7.02(m,6H) ,6.19(dd,J=9.0,3.2Hz,1H),4.64(t,J=9.5Hz,1H),3.97-3.93(m,1H),3.88(s,3H). 13C NMR (101MHz, CDCl3) δ152.59,151.45,147.42,138.69,133.45,131.23,130.00, 128.24,125.83,122.21,121.99,121.64,119.59,108.49,64.68,54.30,47.92.

[0030] Example 4 Synthesis of Compound 3-4

[0031] The experimental procedure was as follows: In a 20 mL reaction tube, a stirring magnet was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 3-bromostyrylsulfonium tetraphenylborate (563 mg, 1.0 mmol) 2-4 were then added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-4 in an 82% yield.

[0032] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=7.9Hz,1H),7.37(dd,J=5.4,2.1Hz,2H),7.13(dt,J=4.0,2.8Hz,3H),7.06(dt,J =16.1,4.2Hz,2H),5.68(dd,J=9.2,3.6Hz,1H),4.47(t,J=9.5Hz,1H),3.94(dd,J=9.8,3.6Hz,1H),3.83(s,3H). 13 C NMR (101MHz, CDCl3) δ152.42,151.45,147.53,142.11,131.95,131.18,130.84, 128.85,124.35,123.22,122.27,122.01,119.59,108.55,64.59,54.26,48.43.

[0033] Example 5 Synthesis of Compound 3-5

[0034] The experimental procedure was as follows: In a 20 mL reaction tube, a stirring magnet was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 2-naphthylenesulfonium tetraphenylborate (534 mg, 1.0 mmol) 2-5 were added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then separated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-5 in an 86% yield.

[0035] 1 H NMR (400MHz, CDCl3) δ7.77-7.64(m,5H),7.37(dd,J=5.6,3.8Hz,2H),7.26(dd,J=8.5,1.3Hz,1H),7.13(dd,J=11.8,4.7 Hz,1H),7.10-7.00(m,2H),5.87(dd,J=9.1,3.4Hz,1H),4.49(t,J=9.5Hz,1H),4.01(dd,J=9.8,3.6Hz,1H),3.79(s,3H). 13 C NMR (101MHz, CDCl3) δ152.74,151.62,147.58,137.06,133.33,133.19,131.27,129.53,128.09, 127.78,126.76,126.63,125.12,122.98,122.23,121.95,119.59,108.54,65.45,54.18,48.55.

[0036] Example 6 Synthesis of Compound 3-6

[0037] The experimental procedure was as follows: In a 20 mL reaction tube, a stirring magnet was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 4-methylphenylsulfonium tetraphenylborate (498 mg, 1.0 mmol) 2-6 were added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-6 in an 87% yield.

[0038] 1 H NMR(400MHz, CDCl3)δ7.64(d,J=7.8Hz,1H),7.17-7.01(m,7H),5.72(dd,J=9.1,3.6H z,1H),4.48(t,J=9.4Hz,1H),3.97(dd,J=9.7,3.6Hz,1H),3.82(s,3H),2.24(s,3H). 13 C NMR (101MHz, CDCl3) δ152.69,151.62,147.56,138.69,136.98,131.27,129 .85,125.73,122.13,121.85,119.56,108.45,65.13,54.12,48.71,21.18.

[0039] Example 7 Synthesis of Compound 3-7

[0040] The experimental procedure was as follows: In a 20 mL reaction tube, a magnetic stirrer was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 4-tert-butylphenylsulfonium tetraphenylborate (540 mg, 1.0 mmol) 2-7 were added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-7 in an 86% yield.

[0041] 1H NMR (400MHz, CDCl3) δ7.63(d,J=8.0Hz,1H),7.25(d,J=8.3Hz,2H),7.14-6.95(m,5H),5.69(dd, J=9.0,3.3Hz,1H),4.41(t,J=9.4Hz,1H),3.92(dd,J=9.7,3.4Hz,1H),3.80(s,3H),1.19(s,9H). 13 C NMR (101MHz, CDCl3) δ152.68,151.69,147.55,136.87,131.27,126.28,126.08,12 6.01,125.40,122.05,121.79,119.47,108.45,64.97,54.07,48.64,34.61,31.27.

[0042] Example 8 Synthesis of Compound 3-8

[0043] The experimental procedure was as follows: In a 20 mL reaction tube, a magnetic stirrer was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and styrylsulfonium tetraphenylborate (518 mg, 1.0 mmol) 2-8 were then added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-8 in an 83% yield.

[0044] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=7.9Hz,1H),7.31(d,J=8.5Hz,2H),7.26-7.07(m,5H),5.7 5(dd,J=9.1,3.5Hz,1H),4.54(t,J=9.5Hz,1H),4.00(dd,J=9.8,3.6Hz,1H),3.88(s,3H). 13 C NMR (101MHz, CDCl3) δ152.43,151.44,147.50,138.41,134.62,131.16,129.39,127.28,122.23,121.97,119.53,108.52,64.63,54.16,48.43.

[0045] Example 9 Synthesis of Compound 3-9

[0046] The experimental procedure was as follows: In a 20 mL reaction tube, a magnetic stirrer was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 4-methoxyphenylsulfonium tetraphenylborate (514 mg, 1.0 mmol) 2-9 were added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-9 in a 91% yield.

[0047] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=7.8Hz,1H),7.18-7.04(m,5H),6.79(d,J=8.7Hz,2H),5.72(dd, J=9.1,3.5Hz,1H),4.49(t,J=9.4Hz,1H),3.99(dd,J=9.8,3.6Hz,1H),3.83(s,3H),3.70(s,3H). 13 C NMR (101MHz, CDCl3) δ159.86,152.62,151.63,147.55,131.95,131.26,127.76,127 .26,122.13,121.85,119.56,114.75,114.49,108.45,64.91,55.33,54.11,48.70.

[0048] Example 10 Synthesis of Compound 3-10

[0049] The experimental procedure was as follows: In a 20 mL reaction tube, a stirring magnet was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 3-chlorostyrylsulfonium tetraphenylborate (518 mg, 1.0 mmol) 2-10 were added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-10 in an 86% yield.

[0050] 1 H NMR (400MHz, CDCl3) δ7.64 (d, J=8.0Hz, 1H), 7.25-7.17 (m, 3H), 7.09 (dddd, J=26.7, 24.0, 12.3, 4.5H z,4H),5.68(dd,J=9.1,3.4Hz,1H),4.46(t,J=9.5Hz,1H),3.92(dd,J=9.8,3.6Hz,1H),3.82(s,3H). 13 C NMR (101MHz, CDCl3) δ152.42,151.45,147.52,141.88,135.09,131.17,130.59, 129.00,125.97,123.87,122.25,122.00,119.58,108.54,64.65,54.24,48.41.

[0051] Example 11 Synthesis of Compound 3-11

[0052] The experimental procedure was as follows: In a 20 mL reaction tube, a stirring magnet was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and styrylsulfonium tetraphenylborate (484 mg, 1.0 mmol) 2-11 were added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-11 in an 85% yield.

[0053] 1 H NMR (400MHz, CDCl3) δ7.65 (d, J = 7.8Hz, 1H), 7.32-7.21 (m, 5H), 7.17-7.03 (m, 3H), 5.77 (dd,J=9.1,3.4Hz,1H),4.52(t,J=9.4Hz,1H),4.00(dd,J=9.7,3.5Hz,1H),3.83(s,3H). 13 C NMR (101MHz, CDCl3) δ152.65,151.59,147.51,139.89,131.24,129.23,128.81,125.74,122.19,121.91,119.58,108.47,65.28,54.16,48.67.

[0054] Example 12 Synthesis of Compound 3-12

[0055] The experimental procedure was as follows: In a 20 mL reaction tube, a magnetic stirrer was first added. Compound 1 (191 mg, 1.0 mmol) was then dissolved in 10 mL of acetonitrile. Potassium carbonate (138 mg, 1.0 mmol) and 4-bromostyrylsulfonium tetraphenylborate (562 mg, 1.0 mmol) 2-12 were then added sequentially with stirring at room temperature. The reaction was stirred under air at room temperature for 6 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction was complete when TLC indicated complete conversion of the starting material and the appearance of a new fluorescent spot. The reaction mixture was washed, dried, filtered, and concentrated by rotary evaporation. It was then isolated and purified by flash column chromatography. Finally, the organic solvent was removed by vacuum distillation on a rotary evaporator to obtain the target product 3-12 in an 83% yield.

[0056] 1 H NMR(400MHz, CDCl3) δ7.64(d,J=7.8Hz,1H),7.39(d,J=8.3Hz,2H),7.17-7.00(m,5H),5.6 9(dd,J=9.1,3.5Hz,1H),4.49(t,J=9.5Hz,1H),3.94(dd,J=9.8,3.6Hz,1H),3.82(s,3H). 13C NMR (101MHz, CDCl3) δ152.43,151.47,147.52,138.91,132.37,131.17,127.57,122.80,122.27,122.00,119.58,108.51,64.70,54.21,48.39.

[0057] Anticancer activity test

[0058] The cells used in the anti-tumor test of this example are LoVo, 22RV1 and MDA-MB-231, which correspond to human colon cancer cells, human prostate cancer epithelial cells and human breast cancer cells, respectively.

[0059] The cells were cultured in DMEM containing fetal bovine serum and penicillin-streptomycin solution in a constant temperature incubator at 37°C and 5% CO2. The specific steps are as follows:

[0060] (1) Count the cells using a hemocytometer and dilute them to 5×10 4 / mL;

[0061] (2) Add 100 μL of cell suspension to each well of a 96-well plate, pipette and mix thoroughly, and incubate at 37°C in an incubator for 24 h;

[0062] (3) Dilute the test compound to a concentration of 10 μM, add the compound (i.e., the compounds prepared in Examples 1-12) in sequence according to the concentration, and incubate in an incubator at 37°C for 48 h;

[0063] (4) Add MTT at a concentration of 5 mg / mL and incubate at 37°C for 4 h;

[0064] (5) Add DMSO to dissolve the cells and measure the OD values ​​at 490 nm and 630 nm using a microplate reader;

[0065] (6) Data were processed and the inhibition rate was calculated based on the OD value. The results are shown in Table 1.

[0066] Table 1. Inhibitory effect of compounds on tumor cells

Claims

1. An imidazole benzimidazole derivative, a compound represented by formula 3, In the formula, R is selected from hydrogen, halogen, alkyl and alkoxy.

2. The imidazole benzimidazole derivative according to claim 1, wherein the halogen is F, Cl or Br.

3. The imidazole benzimidazole derivative according to claim 1, wherein the alkyl group is a C1-C4 alkyl group. The imidazole benzimidazole derivative according to claim 1 , wherein the alkoxy group is an —OC1-C4 alkoxy group.

5. The imidazole benzimidazole derivative according to claim 1, selected from the following compounds:

6. A method for preparing the compound of formula 3, wherein the reaction formula is as follows: include: The compound of formula 1 is reacted with the compound of formula 2 in an organic solvent in the presence of potassium carbonate to obtain the product, wherein R is selected from hydrogen, halogen, alkyl and alkoxy.

7. The method of claim 6, wherein the organic solvent is acetonitrile.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 and a pharmaceutical excipient.

9. Use of the compound according to any one of claims 1 to 5 in the preparation of antitumor drugs.

10. The use according to claim 9, wherein the tumor is selected from colon cancer, prostate cancer, breast cancer and lung cancer.