CN111004221B - Pyrimidine/benzimidazole heterozygote, preparation method and medical application - Google Patents
Pyrimidine/benzimidazole heterozygote, preparation method and medical application Download PDFInfo
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Abstract
本发明公开了一种嘧啶/苯并咪唑杂合物、制备方法及医药用途，其具有如下的化学结构：其中，R选自下列结构：
本发明提供的嘧啶/苯并咪唑杂合物对非小细胞肺癌细胞H1975、A549、HCC827有显著的增殖抑制作用，且抑制作用强于阳性药吉非替尼，但对人结肠癌细胞HCT116的增殖抑制能力较弱。该嘧啶/苯并咪唑杂合物具有开发成抗非小细胞肺癌药物的前景。The invention discloses a pyrimidine/benzimidazole hybrid compound, a preparation method and medical application, and the compound has the following chemical structure: 
where R is selected from the following structures: The pyrimidine/benzimidazole hybrid provided by the present invention has significant inhibitory effect on the proliferation of non-small cell lung cancer cells H1975, A549 and HCC827, and the inhibitory effect is stronger than that of the positive drug gefitinib, but has a significant inhibitory effect on the proliferation of human colon cancer cells HCT116. Proliferation inhibitory ability is weak. The pyrimidine/benzimidazole hybrid has the prospect of being developed as an anti-non-small cell lung cancer drug.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a pyrimidine/benzimidazole heterozygote, a preparation method and a medical application thereof.
Background
Lung cancer is one of the most common malignant tumors in the world, and has become the 1 st cause of death of malignant tumors in urban population in China. Non-small cell lung cancer (NSCLC) includes squamous cell carcinoma (squamous carcinoma), adenocarcinoma, large cell carcinoma, which has slower growth and division of cancer cells and relatively late metastatic spread as compared to small cell carcinoma. Non-small cell lung cancer accounts for about 80% of all lung cancers, with about 75% of patients finding a middle-to-late stage, very low 5-year survival rate, with the majority of advanced patients, and about 50% of lung cancer patients aged >65 years.
The non-small cell lung cancer is still one of the malignant tumors with the highest human mortality, so the research and development of small molecule drugs for treating the non-small cell lung cancer have extremely important practical significance.
Disclosure of Invention
The invention aims to provide a pyrimidine/benzimidazole heterozygote, a preparation method and medical application thereof.
The above purpose of the invention is realized by the following technical scheme:
a pyrimidine/benzimidazole hybrid having the chemical structure:
wherein R is selected from the following structures:
the preparation method of the pyrimidine/benzimidazole hybrid comprises the following steps: adding 20mL of 95% ethanol and 0.02mol of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone into a 50mL round-bottom flask, stirring for about 15min to completely dissolve solids, adding 8mL of 10% sodium hydroxide aqueous solution, adding 0.02mol of benzaldehyde or 2-chlorobenzaldehyde or 3-chlorobenzaldehyde or 4-chlorobenzaldehyde or 2-methylbenzaldehyde or 3-methylbenzaldehyde or 4-methylbenzaldehyde or 2-methoxybenzaldehyde or 3-methoxybenzaldehyde or 4-methoxybenzaldehyde after 15min, tracking the reaction process by TLC, after reacting for 10H, dropwise adding 3mol/L of HCl solution into the reaction solution to separate out grey solids, performing suction filtration, repeatedly leaching filter cakes by using HCl solution, and drying to obtain solid A; adding 2mmol of solid A, 3.5mmol of potassium carbonate and 3.01mmol of 2,4, 5-trichloropyrimidine into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate solid, filtering, drying and weighing to obtain solid B; adding 0.2mmol of solid B, 0.2mmol of 2-methoxy-4- (4-methylpiperidine-1-yl) aniline and 100mmol of TFA into 25mL of sec-butyl alcohol, reacting at 105 ℃ for 5-7h, concentrating under reduced pressure after the reaction is finished, and carrying out column chromatography to obtain the compound.
The application of the pyrimidine/benzimidazole heterozygote in preparing a non-small cell lung cancer resistant medicament.
Has the advantages that:
the compound provided by the invention has obvious proliferation inhibition effect on non-small cell lung cancer cells H1975, A549 and HCC827, the inhibition effect is stronger than that of a positive drug gefitinib, but the proliferation inhibition capability on human colon cancer cells HCT116 is weaker. The pyrimidine/benzimidazole heterozygote has the prospect of being developed into a non-small cell lung cancer resistant medicament.
Detailed Description
The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.
Example 1: preparation and structure confirmation of compounds
Compound 1: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3-phenylprop-2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, after 15min, 2.12g (0.02mol) of benzaldehyde is added, TLC tracks the reaction progress, after 10H of reaction, 3mol/L of HCl solution is dripped into the reaction liquid, gray solid is separated out, suction filtration is carried out, the filter cake is repeatedly rinsed by HCl solution, and drying is carried out to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3-phenylpropyl-2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3-phenylpropyl-2-alkene-1-ketone (0.528g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate solid, filtering, drying and weighing to obtain milky solid. Mixing (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzimidazole-2-ethyl) -3-phenylpropyl-2-en-1-one (0.082g, 0.2mmol) and 2-methoxy-4- (4-methylpiperidin-1-yl)) Aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol and reacted at 105 ℃ for 5h, concentrated under reduced pressure, and column chromatography (dichloromethane: methanol ═ 15:1) afforded a pale yellow solid with melting point 118.1-119.4 ℃ and overall yield 23.0%.1H NMR(500MHz,Chloroform)δ8.15(t,J＝46.5Hz,3H),8.04(s,1H),8.04(s,1H),7.83–7.73(m,2H),7.57–7.48(m,4H),7.40(s,1H),7.27(s,1H),6.88(d,J＝10.3Hz,2H),6.71(s,1H),6.33(d,J＝4.1Hz,2H),3.91(s,3H),3.66–3.62(m,2H),3.53–3.49(m,2H),2.65–2.61(m,2H),2.45–2.41(m,2H),2.29(s,3H).
Compound 2: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (2-chlorophenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, 2.80g (0.02mol) of 2-chlorobenzaldehyde is added after 15min, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L of HCl solution is dripped into the reaction solution to precipitate gray solid, the filtration is carried out, the filter cake is repeatedly rinsed by HCl solution and dried to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (2-chlorphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (2-chlorphenyl propyl) -2-alkene-1-ketone (0.596g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate solid, filtering, drying, weighing to obtain yellow solid. (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (2-chlorophenylpropyl) -2-en-1-one (0.089g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 5H, concentrated under reduced pressure, and column chromatographed (dichloromethane: methyl methane: methanol)Alcohol 15:1) gave a yellowish-brown solid with a melting point of 173.5-175.1 ℃ in an overall yield of 27.3%.1H NMR(500MHz,Chloroform)δ8.41(s,1H),8.28(s,1H),8.16(s,1H),7.55(d,J＝2.6Hz,2H),7.41(d,J＝4.1Hz,2H),7.33(d,J＝12.8Hz,2H),7.23(s,1H),6.92(d,J＝18.9Hz,2H),6.82(s,1H),6.52(d,J＝26.0Hz,2H),3.89(s,3H),3.67–3.63(m,2H),3.49–3.45(m,2H),2.63–2.59(m,2H),2.48–2.44(m,2H),2.26(s,3H).
Compound 3: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (3-chlorophenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, 2.80g (0.02mol) of 3-chlorobenzaldehyde is added after 15min, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L HCl solution is dripped into the reaction solution to precipitate gray solid, the filtration is carried out, the filter cake is repeatedly rinsed by HCl solution and dried to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (3-chlorphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (3-chlorphenyl propyl) -2-alkene-1-ketone (0.596g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate solid, filtering, drying, weighing to obtain yellow solid. (E) -1- (6- ((2, 5-dichloropyrimidine-4-ethyl) oxy) -1H-benzimidazole-2-ethyl) -3- (3-chlorophenylpropyl) -2-en-1-one (0.089g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL of sec-butanol, reacted at 105 ℃ for 5H, concentrated under reduced pressure, and column chromatography (dichloromethane: methanol ═ 15:1) gave an earth yellow solid, melting point 179.7-181.3 ℃, total yield 31.2%.1HNMR(500MHz,Chloroform)δ8.25(d,J＝74.2Hz,2H),7.91(s,1H),7.74–7.58(m,3H),7.51(d,J＝17.3Hz,2H),7.44(s,1H),7.25(s,1H),6.92(d,J＝30.0Hz,2H),6.74(s,1H),6.32(d,J＝2.9Hz,2H),3.90(s,3H),3.61–3.57(m,2H),3.54–3.50(m,2H),2.49–2.45(m,2H),2.38–2.34(m,2H),2.26(s,3H).
Compound 4: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (4-chlorophenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, after 15min, 2.80g (0.02mol) of 4-chlorobenzaldehyde is added, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L of HCl solution is dripped into the reaction solution to precipitate gray solid, the filtration is carried out, the filter cake is repeatedly rinsed by HCl solution and dried to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (4-chlorphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (4-chlorphenyl propyl) -2-alkene-1-ketone (0.596g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL DMF, reacting at normal temperature, pouring the reaction liquid into cold water to precipitate solid, filtering, drying, weighing to obtain yellow solid. (E) -1- (6- ((2, 5-dichloropyrimidine-4-ethyl) oxy) -1H-benzimidazole-2-ethyl) -3- (4-chlorophenylpropyl) -2-en-1-one (0.089g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 5H, concentrated under reduced pressure, and column chromatography (dichloromethane: methanol ═ 15:1) gave a bright yellow solid, melting point 199.6-201.9 ℃, overall yield 21.6%.1H NMR(500MHz,Chloroform)δ8.26(s,2H),8.18(s,2H),7.99(s,2H),7.91–7.79(m,4H),7.79–7.65(m,4H),7.61(s,2H),7.44(s,2H),7.28(s,2H),6.95(s,3H),6.86(s,1H),6.78(s,2H),6.32(d,J＝3.2Hz,4H),3.90(s,6H),3.61–3.57(m,4H),3.49–3.45(m,4H),2.61–2.57(m,4H),2.40–2.36(m,4H),2.16(s,6H).
Compound 5: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (2-methylphenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, 2.40g (0.02mol) of 2-methylbenzaldehyde is added after 15min, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L of HCl solution is dropwise added into the reaction solution to precipitate gray solid, suction filtration is carried out, the filter cake is repeatedly rinsed by HCl solution, and drying is carried out to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (2-methylphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (2-methylphenyl propyl) -2-alkene-1-ketone (0.556g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate a solid, filtering, drying and weighing to obtain a white solid. (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzoimidazol-2-ethyl) -3- (2-methylphenylpropyl) -2-en-1-one (0.085g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 6H, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 25:1) to give a white solid with a melting point of 217.5 to 219.1 ℃ and overall yield of 26.1%.1H NMR(500MHz,Chloroform)δ8.27(s,2H),8.23(d,J＝15.0Hz,2H),7.64(s,2H),7.62–7.46(m,3H),7.44(d,J＝13.0Hz,1H),7.40(s,2H),7.28–7.16(m,6H),7.14(s,2H),6.94(s,1H),6.89(d,J＝40.8Hz,5H),6.53(s,2H),6.45(s,2H),3.84(s,6H),3.68–3.64(m,4H),3.48–3.44(m,4H),2.64–2.60(m,4H),2.50–2.43(m,10H),2.26(s,6H).
Compound 6: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (3-methylphenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, 2.40g (0.02mol) of 3-methylbenzaldehyde is added after 15min, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L HCl solution is dropwise added into the reaction solution to precipitate gray solid, suction filtration is carried out, the filter cake is repeatedly rinsed by HCl solution, and drying is carried out to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (3-methylphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (3-methylphenyl propyl) -2-alkene-1-ketone (0.556g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate a solid, filtering, drying and weighing to obtain a white solid. (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzoimidazol-2-ethyl) -3- (3-methylphenylpropyl) -2-en-1-one (0.085g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 6H, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 25:1) to give a white solid with a melting point of 241.6-243.3 ℃ and overall yield of 22.9%.1H NMR(500MHz,Chloroform)δ8.29(s,1H),8.20(d,J＝84.4Hz,21H),7.78(s,11H),7.67(s,11H),7.52(d,J＝16.1Hz,22H),7.43(s,11H),7.33(s,10H),7.19(d,J＝10.6Hz,22H),7.03(d,J＝59.8Hz,22H),6.73(s,11H),6.38(d,J＝2.8Hz,22H),3.90(s,32H),3.65–3.61(m,21H),3.48–3.44(m,21H),2.64–2.60(m,21H),2.46(s,32H),2.43–2.39(m,21H),2.22(s,32H).
Compound 7: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (4-methylphenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, after 15min, 2.40g (0.02mol) of 4-methylbenzaldehyde is added, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L of HCl solution is dropwise added into the reaction solution to precipitate gray solid, suction filtration is carried out, the filter cake is repeatedly rinsed by HCl solution, and drying is carried out to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (4-methylphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (4-methylphenyl propyl) -2-alkene-1-ketone (0.556g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate a solid, filtering, drying and weighing to obtain a white solid. (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzoimidazol-2-ethyl) -3- (4-methylphenylpropyl) -2-en-1-one (0.085g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 6.5H, concentrated under reduced pressure, and column chromatography (dichloromethane: methanol ═ 25:1) gave a white solid with a melting point of 233.2-235.6 ℃ and a total yield of 28.6%.1H NMR(500MHz,Chloroform)δ8.30(s,1H),8.10(s,1H),7.85–7.71(m,2H),7.60(s,1H),7.53–7.47(m,4H),7.12(s,1H),7.14–6.84(m,3H),6.75(s,1H),6.38(d,J＝19.0Hz,2H),3.93(s,3H),3.63–3.59(m,2H),3.51–3.47(m,2H),2.64–2.60(m,2H),2.48–2.41(m,5H),2.28(s,3H).
Compound 8: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (2-methoxyphenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, 2.72g (0.02mol) of 2-methoxybenzaldehyde is added after 15min, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L HCl solution is dripped into the reaction liquid to precipitate gray solid, the filtration is carried out, the filter cake is repeatedly rinsed by HCl solution and dried to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (2-methoxyphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (2-methoxyphenylpropyl) -2-en-1-one (0.588g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate a solid, filtering, drying and weighing to obtain a white solid. (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzoimidazol-2-ethyl) -3- (2-methoxyphenylpropyl) -2-en-1-one (0.088g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 7H, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 35:1) to give a white solid with a melting point of 206.3 to 207.9 ℃ and overall yield of 21.2%.1H NMR(500MHz,Chloroform)δ8.22(s,1H),8.17(s,1H),8.02(s,1H),7.87(s,1H),7.62(s,1H),7.51(s,1H),7.41(s,1H),7.29(s,1H),7.18(d,J＝3.6Hz,2H),6.89(d,J＝16.1Hz,2H),6.67(s,1H),6.34(d,J＝9.4Hz,2H),3.95(s,3H),3.90(s,3H),3.72–3.68(m,2H),3.53–3.49(m,2H),2.67–2.63(m,2H),2.48–2.44(m,2H),2.33(s,3H).
Compound 9: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (3-methoxyphenyl) -2-en-1-one
20ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are added into a 50ml round bottom flask, the mixture is stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, after 15min, 2.72g (0.02mol) of 3-methoxybenzaldehyde is added, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L HCl solution is dropwise added into the reaction solution to precipitate gray solid, the filtration is carried out, the filter cake is repeatedly rinsed by HCl solution, and the white solid is obtained after drying. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (3-methoxyphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (3-methoxyphenylpropyl) -2-en-1-one (0.588g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate a solid, filtering, drying and weighing to obtain a white solid. (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzoimidazol-2-ethyl) -3- (3-methoxyphenylpropyl) -2-en-1-one (0.088g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 7H, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 35:1) to give a white solid with a melting point of 212.4 to 214.8 ℃ and overall yield of 26.5%.1H NMR(500MHz,Chloroform)δ8.24(d,J＝55.8Hz,2H),7.93(s,1H),7.59(d,J＝16.4Hz,2H),7.52–7.37(m,2H),7.32(s,1H),7.24(s,1H),7.03(s,1H),6.94(s,1H),6.83(d,J＝66.5Hz,2H),6.32(d,J＝3.0Hz,2H),3.90(s,3H),3.84(s,3H),3.62–3.58(m,2H),3.48–3.44(m,2H),2.54–2.50(m,2H),2.44–2.40(m,2H),2.26(s,3H).
Compound 10: (E) -1- (6- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-ethyl) phenyl) amino) pyrimidin-4-ethyl) oxy) -1H-benzimidazol-2-ethyl) -3- (4-methoxyphenyl) -2-en-1-one
Adding 2 into a 50ml round-bottom flask0ml of 95% ethanol and 3.52g (0.02mol) of 1- (6-hydroxy-1H-benzimidazole-2-ethyl) -ketone are stirred for about 15min to completely dissolve the solid, 8ml of 10% sodium hydroxide aqueous solution is added, 2.72g (0.02mol) of 4-methoxybenzaldehyde is added after 15min, the TLC tracks the reaction progress, after 10H of reaction, 3mol/L HCl solution is dropwise added into the reaction solution to precipitate gray solid, suction filtration is carried out, the filter cake is repeatedly rinsed by HCl solution, and drying is carried out to obtain white solid. Recrystallizing to obtain (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (4-methoxyphenyl propyl) -2-alkene-1-ketone. Adding (E) -1- (6-hydroxy-1H-benzimidazole-2-ethyl) -3- (4-methoxyphenylpropyl) -2-en-1-one (0.588g, 2mmol), potassium carbonate (0.483g, 3.5mmol) and 2,4, 5-trichloropyrimidine (0.345mL, 3.01mmol) into 40mL of DMF, reacting at normal temperature, pouring the reaction solution into cold water to precipitate a solid, filtering, drying and weighing to obtain a white solid. (E) -1- (6- ((2, 5-dichloropyrimidin-4-ethyl) oxy) -1H-benzoimidazol-2-ethyl) -3- (4-methoxyphenylpropyl) -2-en-1-one (0.088g, 0.2mmol), 2-methoxy-4- (4-methylpiperidin-1-yl) aniline (0.044g, 0.2mmol), TFA (6.5mL, 100mmol) were added to 25mL sec-butanol, reacted at 105 ℃ for 7H, concentrated under reduced pressure, and column chromatographed (dichloromethane: methanol ═ 35:1) to give a white solid with a melting point of 220.7-222.0 ℃ and a total yield of 24.3%.1H NMR(500MHz,Chloroform)δ8.28(s,1H),7.90(s,1H),7.84(t,J＝5.1Hz,3H),7.52(d,J＝13.1Hz,2H),7.23–7.16(m,3H),6.96(s,1H),6.77(d,J＝30.8Hz,2H),6.39(d,J＝7.5Hz,2H),3.91(s,3H),3.87(s,3H),3.64–3.60(m,2H),3.51–3.47(m,2H),2.67–2.63(m,2H),2.43–2.39(m,2H),2.29(s,3H).
Example 2: MTT method for determining proliferation inhibition effect of compounds 1-10 on different tumor cell strains
1. Cell line
Non-small cell lung cancer A549, H1975 and HCC827, human colon cancer cell HCT116 were purchased from the institute of basic medicine of Chinese academy of medical sciences, and were stored and subcultured in the laboratory according to the culture data. The cells were routinely inoculated into 50mL cell culture flasks using DMEM/RPI-1640 medium containing 10% fetal bovine serum at 37 deg.C with 5% CO2And culturing under 100% humidity, and changing the culture solution every day. When it grows to 80-90%, it is usedDigesting by pancreatin EDTA mixed liquor, and carrying out 1:3 passage.
2. Experimental methods
In vitro cell activity proliferation inhibition experiments, the MTT method is adopted to investigate the influence of a target compound on the survival activity of each cell. Taking cells in logarithmic growth phase at 5X 103Each cell (100. mu.l) was inoculated in a 96-well plate and cultured. Adding compounds (100 μ l) with different concentrations prepared in advance after 24h, wherein each concentration is provided with at least 3 parallel holes, and a solvent control group without the compound and a blank control group without cells are arranged; the marginal wells were filled with 200. mu.l of sterile water. After 48h of contact of the compound with the cells, 20. mu.l MTT (5mg/ml, formulated in PBS, filtered and aliquoted at-20 ℃ for storage) was added to each well at 37 ℃ with 5% CO2Culturing for 4h under the condition, carefully sucking out the liquid in the wells, adding 150 μ l DMSO in each well, gently shaking on a micro-oscillator for 10min to fully dissolve the purple crystals, and then measuring the absorbance value at 570nm by using an enzyme-labeling instrument. Using the cell viability of the solvent control group without the compound as 100%, calculating the cell viability (absorbance value of the compound-blank control group)/(absorbance value of the control-blank control group) × 100%, calculating the half Inhibitory Concentration (IC) of the compound on the cells by using Graphpad Prism 5 software50)。
3. Results of the experiment
IC of compound-10 and positive drug for inhibiting tumor cell proliferation50The values are given in Table 1.
TABLE 1 IC of Compounds 1-10 and Positive drugs for tumor cell proliferation inhibition50Value of
The results show that: the compounds 1-10 have obvious proliferation inhibition capacity on tumor cells H1975, A549 and HCC827, and have weak proliferation inhibition capacity on human colon cancer cells HCT 116. The proliferation inhibition ability of the compounds 1-10 on non-small cell lung cancer H1975, A549 and HCC827 is generally stronger than that of a positive drug gefitinib, and the pyrimidine/benzimidazole hybrid has a prospect of being developed into a non-small cell lung cancer resistant drug.
The above-described embodiments are intended to be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.
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