CN114671858B - Benzimidazole compound, and preparation method and application thereof - Google Patents
Benzimidazole compound, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to a benzimidazole compound and a preparation method and application thereof, and more particularly relates to a compound shown in formula I, a derivative and a preparation method thereof, a pharmaceutical composition and application of the compound shown in formula I in preparing medicines for treating cancers and preventing and treating plant pathogenic fungi. The compound is a compound shown in a formula L or an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt, a crystalline hydrate, a keto-enol tautomeric compound or a solvate of the compound shown in the formula L, wherein R 1 Is H, halogen, alkyl or alkoxy; r is R 2 Is alkyl; n is 0 or 1. The compound shown in the formula L provided by the invention has excellent inhibitory activity on cancer cells and plant pathogenic fungi.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a benzimidazole compound and a preparation method and application thereof, and more particularly relates to a compound shown in a formula L, a derivative and a preparation method thereof, a pharmaceutical composition and application of the compound shown in the formula L in preparation of medicines for treating cancers and preventing and treating plant pathogenic fungi.
Background
Tumors are abnormal lesions formed by the fact that under the action of various cancerogenic factors, a certain cell of local tissues loses the normal regulation of the growth of the cells at the gene level, and the cells cause the clonality abnormal hyperplasia of the cells. The academia generally classifies neoplasms into benign and malignant categories. However, the existing treatments for tumors remain to be improved.
Plant diseases caused by pathogenic fungi can lead to a great reduction in crop yield, however, the existing treatment means for the plant pathogenic fungi still need to be improved.
Disclosure of Invention
The object of the present invention is to solve at least one of the technical problems in the related art to some extent. To this end, the present invention proposes a benzimidazole compound which can be used for preparing a medicament for treating cancer and preventing plant pathogenic fungi.
In order to achieve the above object, the present invention provides a benzimidazole compound, which is a compound represented by formula L or an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, keto-enol tautomer compound or solvate of the compound represented by formula L,
wherein R is 1 Is H, halogen, alkyl or alkoxy; r is R 2 Is alkyl; n is 0 or 1.
Preferably, R 1 The halogen is F, cl or Br.
Preferably, R 1 The alkyl groups represented contain 1 to 10 carbon atoms.
Preferably, R 1 The alkoxy groups represented contain 1 to 10 carbon atoms.
Preferably, R 2 The alkyl groups represented contain 1 to 10 carbon atoms.
Preferably, the compound is the following compound or an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, keto-enol tautomer or solvate of the following compound:
in a second aspect, the present invention provides a process for preparing the benzimidazole compound described above, which comprises the steps of:
(1) Contacting a compound represented by formula a with propynyl alcohol to obtain a compound represented by formula B;
(2) Contacting a compound represented by formula B with manganese dioxide to obtain a compound represented by formula C;
(3) Contacting a compound represented by formula D with glycolic acid to obtain a compound represented by formula E;
(4) Contacting a compound represented by formula E with a bromoalkane to obtain a compound represented by formula F;
(5) Contacting a compound represented by formula F with manganese dioxide to obtain a compound represented by formula G;
(6) Contacting a compound represented by formula G with a compound represented by formula H to obtain a compound represented by formula I;
(7) Contacting a compound represented by formula C with a compound represented by formula I to obtain a compound represented by formula L;
wherein R is 1 、R 2 The same definition as described above.
In a third aspect, the present invention provides a pharmaceutical composition comprising a benzimidazole compound as described above.
In a fourth aspect, the present invention provides the use of a benzimidazole compound as described hereinbefore or a pharmaceutical composition as described hereinbefore in the manufacture of a medicament for the treatment of cancer.
Preferably, the cancer cells are human large cell lung cancer cell H460, human osteosarcoma cancer cell MG63, human cavity floor cancer cell KB, and human lung cancer cell PC9.
In a fifth aspect, the present invention provides the use of a benzimidazole compound as described above or a pharmaceutical composition as described above for controlling phytopathogenic fungi.
Preferably, the fungus is Aphis citrina, rhizoctonia cerealis, rhizoctonia solani, alternaria cerealis, pyricularia oryzae, phytophthora capsici, sclerotinia sclerotiorum and Rhizoctonia cerealis.
The antitumor activity test and the antifungal activity test in the examples show that the compound shown in the formula L provided by the invention has excellent inhibition activity on cancer cells and plant pathogenic fungi.
Detailed Description
The following describes specific embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating and illustrating the invention, are not intended to limit the invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The first aspect of the invention provides a benzimidazole compound, which is a compound shown in a formula L or an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt, a crystalline hydrate, a keto-enol tautomeric compound or a solvate of the compound shown in the formula L,
wherein R is 1 Is H, halogen, alkyl or alkoxy; r is R 2 Is alkyl; n is 0 or 1.
The inventors have surprisingly found that the compounds of formula L and their derivatives have potent antitumor and anti-plant fungal activity. In particular, for cancers, such as cancer cells are human large cell lung cancer cell H460, human osteosarcoma cancer cell MG63, human bottom cavity cancer cell KB, and human lung cancer cell PC9; for fungi, such as apple ring rot, wheat sheath blight, tomato early blight, wheat scab, rice blast, phytophthora capsici, rape sclerotium and sheath blight of rice.
In one embodiment, R 1 The halogen is F, cl or Br.
In another embodiment, R 1 The alkyl groups being represented by radicals containing 1 to 10 carbon atoms, e.g. R 1 Methyl, ethyl, propyl, butyl, etc. In a preferred embodiment, R 1 Is methyl (-CH) 3 )。
R 1 And R is 2 May be the same or different.
In a third embodiment, R 1 The alkoxy groups represented contain 1 to 10 carbon atoms.
In a specific embodiment, R 2 The alkyl group represented contains 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, etc. R is R 1 And R is 2 May be the same or different. In a preferred embodiment, R 2 is-CH 2 CH 3 。
In particular embodiments, the compound may be the following compound or an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate, keto-enol tautomer or solvate of the following compound:
in a second aspect, the present invention provides a process for preparing the benzimidazole compound described above, which comprises the steps of:
(1) Contacting a compound represented by formula a with propynyl alcohol to obtain a compound represented by formula B;
(2) Contacting a compound represented by formula B with manganese dioxide to obtain a compound represented by formula C;
(3) Contacting a compound represented by formula D with glycolic acid to obtain a compound represented by formula E;
(4) Contacting a compound represented by formula E with a bromoalkane to obtain a compound represented by formula F;
(5) Contacting a compound represented by formula F with manganese dioxide to obtain a compound represented by formula G;
(6) Contacting a compound represented by formula G with a compound represented by formula H to obtain a compound represented by formula I;
(7) Contacting a compound represented by formula C with a compound represented by formula I to obtain a compound represented by formula L;
wherein R is 1 、R 2 The same definition as described above.
The compounds of formula L prepared according to the process of the present invention are effective against cancer cells and phytopathogenic fungi.
The synthetic route of the compounds of formula L of the present invention is shown below:
in the specific preparation process, the mol ratio of the compound A to propynyl alcohol is 1:1-1:3, the mixed solvent of solvents such as tertiary butanol, tetrahydrofuran and DMF and water is directly adopted as the solvent, sodium ascorbate/cupric sulfate, cuprous iodide (chloride) or other cuprous compounds are used as the catalyst, the compound B is obtained through reaction, the compound B is oxidized by using oxidants such as manganese dioxide, chromium trioxide and PCC to obtain a compound C, the mol ratio of the compound D to glycollic acid is 1:1-1:3, 4N hydrochloric acid is adopted as the solvent, the compound E is obtained through reaction, the mol ratio of the compound E to bromoalkane is 1:1-1:3, the alkali such as triethylamine, sodium carbonate and potassium carbonate is adopted as the catalyst, acetonitrile, THF and DMF are adopted as the solvent, the F is obtained through reaction, the mol ratio of the compound F is obtained through oxidation by using oxidants such as manganese dioxide, chromium trioxide and PCC, the alkali such as triethylamine, sodium carbonate and the like as the catalyst, the alkali such as the solvent THF, the DCM and the alcohol are adopted as the catalyst, the mol ratio of the compound H is 1:1-1:3, the mol ratio of the compound I to the compound C is obtained through reaction by using the alkali such as triethylamine, the sodium carbonate and the alkali such as potassium carbonate as the triethylamine, the alkali such as the carbonate and the alkali such as the solvent is the solvent, the solvent is directly adopted as the solvent, the solvent is obtained through reaction with the solvent such as the solvent.
In a third aspect, the present invention provides a pharmaceutical composition comprising a benzimidazole compound as described above. The pharmaceutical composition has the characteristics and advantages of the compounds described above. The pharmaceutical composition may also contain pharmaceutically acceptable excipients.
In a fourth aspect, the present invention provides the use of a benzimidazole compound as described hereinbefore or a pharmaceutical composition as described hereinbefore in the manufacture of a medicament for the treatment of cancer.
In specific embodiments, the cancer cells are human large cell lung cancer cell H460, human osteosarcoma cancer cell MG63, human basal cavity cancer cell KB, and human lung cancer cell PC9.
In a fifth aspect, the present invention provides the use of a compound as hereinbefore described or a pharmaceutical composition as hereinbefore described for the control of phytopathogenic fungi.
In specific embodiments, the fungus is cucumber wilt, peanut brown spot, apple ring spot, wheat sheath blight, corn small spot, watermelon anthracnose, tomato early blight, wheat gibberella, rice blast, phytophthora capsici, rape sclerotium, cucumber gray mold, and rice sheath blight germ. In a preferred embodiment, the fungus is April, rhizoctonia cerealis, rhizoctonia solani, alternaria wheat, pyricularia oryzae, phytophthora capsici, sclerotinia sclerotiorum and Rhizoctonia cerealis.
The present invention will be described in detail by way of examples, but the scope of the present invention is not limited thereto.
Example 1 is used to illustrate the preparation of compound 1, compounds 2-22 were prepared according to a similar method to compound 1. The specific preparation process is as the synthetic route of the compound shown in the formula L.
Compound 1
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-phenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
In a100 mL three-necked flask, phenyl azide (50 mmol) and propynyl alcohol (3.36 g,60 mmol) were added, THF was dissolved in 30mL, 1mmol of cuprous iodide was added to react at 25-100deg.C, TLC monitored the reaction, 100mL of water was added, ethyl acetate extraction (20 mL. Times.3) was performed, the organic phases were combined, dried over anhydrous sodium sulfate for 12h, and the tan solid was obtained by filtration. Purifying by silica gel column chromatography to obtain intermediate B, and obtaining the yield: 82, melting point 108-110 ℃.
In a 50mL single-necked flask was added intermediate B (5 mmol), DCM (20 mL) was added for dissolution, manganese dioxide (5.22 g,60 mmol) was added under stirring, TLC was used to monitor the reaction progress, after the reaction was complete, suction filtration was performed, and intermediate C was obtained after desolventizing, yield: 82%, melting point 94-96 ℃.
In a 250mL three-necked flask, adding phenylenediamine (6.5 g,60 mmol), glycollic acid (6.8 g,90 mmol) and hydrochloric acid solution (4N 120 mL), heating and refluxing, monitoring the reaction progress by TLC, stopping heating after the reaction is complete, cooling, adjusting pH to 7-8 by NaOH, filtering, washing with water, washing with a small amount of ethanol, and drying to obtain a white solid intermediate E, wherein the yield is 71%, and the melting point is 85-87 ℃.
In a 50mL single-necked flask was added intermediate E (2.96 g,20 mmol), dissolved in acetonitrile (20 mL), and after adding TEA100mmol, bromoalkane (40 mmol) was added with stirring. Stirring at room temperature, monitoring reaction progress by TLC, and performing desolventizing silica gel column chromatography to obtain an intermediate F, wherein the yield is 51%, and the melting point is 105-107 ℃.
In a 50mL single-necked flask, add intermediate F (2 mmol), add DCM (20 mmol) to dissolve, add manganese dioxide (2.1G, 24 mmol) with stirring, stir at room temperature, TLC monitor the progress of the reaction, after the reaction is complete, suction filtration, desolventize to obtain intermediate G, yield 80%, melting point 117-120 ℃.
In a 50mL single-necked flask was added compound H phosphate substituted acetone (3.30G, 10 mmol), ethanol (10 mL), and a solution of 10mL of water-soluble potassium carbonate (1.38G, 10 mmol) was added dropwise with stirring, and stirring was performed at room temperature for 30min, and a solution of 5mL of ethanol-soluble compound G (5 mmol) was added dropwise. Stirring at room temperature after dripping, TLC monitoring reaction progress, suction filtering after reaction is completed, adding dilute hydrochloric acid (1N, 10 mL), extracting with dichloromethane (10 mL×3), retaining water phase, and extracting with saturated NaHCO 3 Neutralizing with water solution, extracting with dichloromethane (10 mL×3), mixing organic phases, drying with anhydrous sodium sulfate for 12 hr, desolventizing to obtain yellow solid, and column-chromatography to obtain intermediate I with yield of 51% and melting point of 121-123 ℃.
To a 50mL flask were added intermediate C (2 mmol) and intermediate I (2 mmol), ethanol (10 mL), after dissolution, a solution of 2mL of water-soluble potassium carbonate (0.28 g,2 mmol) was added dropwise, stirring was performed at room temperature, TLC monitored the progress of the reaction, after completion of the reaction, 20mL of water was added, stirring was continued for 30min, and the solution was extracted with dichloromethane (10 mL. Times.3). The organic phases are combined, dried over anhydrous sodium sulfate for 12h to remove solvent, and subjected to column chromatography to obtain the target compound 1, wherein the yield is 52%, and the melting point is 241-243 ℃.
The molecular formula: c (C) 22 H 19 N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):9.28(s,1H,trLzol-H),7.96(d,J＝7.8Hz,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.89(dd,J＝15.6Hz,2H,ArH),7.81(d,J＝15.4Hz,1H,ArH),7.75(d,J＝7.8Hz,1H,ArH),7.69(dd,J＝7.9Hz,3H,ArH),7.63–7.51(m,2H,ArH),7.40–7.27(m,2H,＝CH-CO),4.58(q,J＝7.0Hz,2H,- 2 CHCH 3 ),1.39(t,J＝7.0Hz,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.93,147.63,136.49,131.55,130.25,129.92,129.84,129.25,128.05,127.00,124.04,123.43,121.93,120.59,120.36,109.79,38.57,15.93.
HRMS(ESL):caICd.for C 22 H 19 N 5 O 369.16696,found:[M+H] + 370.16652.
Compound 2
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methylphenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 60 percent, and the melting point is 237-239 ℃.
The molecular formula: c (C) 23 H 2 1N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):9.20(s,1H,trLzol-H),7.88(d,J＝3.0Hz,1H,LmLdazol-CH＝),7.85(d,J＝2.1Hz,1H,trLzol-CH＝),7.80(d,J＝8.2Hz,3H,ArH),7.72(d,J＝7.5Hz,1H,ArH),7.68(d,J＝8.0Hz,1H,ArH),7.52(d,J＝16.0Hz,1H,ArH),7.46(s,1H,ArH),7.44(s,1H,ArH),7.36–7.26(m,2H,＝CH-CO),4.55(q,J＝7.4Hz,2H,- 2 CHCH 3 ),2.41(s,3H,Ar- 3 CH),1.36(t,J＝7.1Hz,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.94,147.60,144.06,143.25,139.42,135.28,134.15,131.70,130.35,130.29,127.85,126.89,124.01,123.40,121.95,120.43,120.29,109.78,108.58,38.54,20.59,15.94.
HRMS(ESL):caICd.for C 23 H 2 1N 5 O 383.18261,found:[M+H] + 384.18208.
Compound 3
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-o-methylphenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid with a yield of 55% and a melting point of 244-246 ℃.
The molecular formula: c (C) 23 H 21 N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):9.22(s,1H,trLzol-H),7.88(d,J＝3.0Hz,1H,LmLdazol-CH＝),7.85(d,J＝2.1Hz,1H,trLzol-CH＝),7.80(d,J＝8.2Hz,3H,ArH),7.72(d,J＝7.5Hz,1H,ArH),7.68(d,J＝8.0Hz,1H,ArH),7.52(d,J＝16.0Hz,1H,ArH),7.46(s,1H,ArH),7.44(s,1H,ArH),7.36–7.26(m,2H,＝CH-CO),4.55(q,J＝7.4Hz,2H,- 2 CHCH 3 ),2.40(s,3H,Ar- 3 CH),1.35(t,J＝7.1Hz,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.94,147.57,143.40,143.21,135.83,135.25,133.54,131.70,131.59,130.26,130.20,127.77,126.95,126.88,125.79,125.56,123.99,123.39,120.24,109.77,38.51,17.40,15.91.
HRMS(ESL):caICd.for C 23 H 21 N 5 O 383.18161,found:[M+H] + 384.18145.
Compound 4
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methoxyphenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid with a yield of 45% and a melting point of 227-229 ℃.
The molecular formula: c (C) 23 H 21 N 5 O 2
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.10(s,1H,trLzol-H),7.93(d,J＝14.6Hz,1H,LmLdazol-CH＝),7.87(d,J＝15.7Hz,1H,trLzol-CH＝),7.83(d,J＝4.1Hz,1H,ArH),7.77(d,J＝14.4Hz,1H,ArH),7.66(d,J＝6.9Hz,2H,ArH),7.41(s,1H,ArH),7.36(d,J＝16.1Hz,3H,ArH),7.05(d,J＝6.1Hz,2H,＝CH-CO),4.40(s,2H,- 2 CHCH 3 ),3.89(s,3H,OCH 3 ),1.49(s,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.56,159.72,147.27,143.67,142.95,134.95,131.39,129.90,129.49,127.44,126.55,123.65,123.04,121.84,121.71,119.96,114.50,109.42,55.29,38.19,15.54.
HRMS(ESL):caICd.for C 23 H 21 N 5 O 2 399.17652,found:[M+H] + 400.17642.
Compound 5
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-chlorophenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 62 percent, and the melting point is 250-252 ℃.
The molecular formula: c (C) 22 H 18 ClN 5 O
1 H NMR(400MHz,DMSO)δ(ppm):9.29(s,1H,trLzol-H),8.01(s,1H,LmLdazol-CH＝),7.99(s,1H,trLzol-CH＝,1H,ArH),7.90(d,J＝14.0Hz,1H,ArH),7.86(d,J＝13.7Hz,1H,ArH),7.80(d,J＝15.8Hz,1H,ArH),7.77(s,1H,ArH),7.74(d,J＝5.4Hz,2H,ArH),7.71(d,J＝8.0Hz,1H,ArH),7.54(t,J＝14.7Hz,1H,ArH),7.40–7.27(m,2H,＝CH-CO),4.57(q,J＝7.0Hz,2H,- 2 CHCH 3 ),1.38(t,J＝7.1Hz,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.50,147.19,144.06,142.90,134.94,134.67,134.56,130.88,129.82,129.72,127.93,126.67,123.71,123.09,121.39,121.32,119.95,109.45,38.20,15.55.
HRMS(ESL):caICd.for C 22 H 18 ClN 5 O 403.12799,found:[M+H] + 404.12717.
Compound 6
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-bromophenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The obtained pure product is yellow solid, the yield is 60 percent, and the melting point is 260-262 ℃.
The molecular formula: c (C) 22 H 18 BrN 5 O
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.16(s,1H,trLzol-H),7.94(d,J＝14.6Hz,1H,LmLdazol-CH＝),7.86(d,J＝16.6Hz,1H,trLzol-CH＝),7.84–7.81(m,1H,ArH),7.78(d,J＝15.1Hz,1H,ArH),7.69(s,2H,ArH),7.68(s,2H,ArH),7.39(d,J＝21.4Hz,2H,ArH),7.35(s,2H,＝CH-CO),4.41(s,2H,- 2 CHCH 3 ),1.49(s,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.78,147.51,144.39,143.24,143.22,135.35,135.26,133.00,131.14,130.09,128.26,127.00,124.01,123.39,122.87,121.84,121.59,120.28,109.74,38.51,15.86.
HRMS(ESL):caICd.for C 22 H 18 BrN 5 O 447.07547,found:[M+H] + 448.07573.
Compound 7
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-phenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The obtained pure product is yellow solid, the yield is 55%, and the melting point is 245-247 ℃.
The molecular formula: c (C) 24 H 23 N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):9.28(s,1H,trLzol-H),7.97(s,1H,LmLdazol-CH＝),7.95(s,1H,trLzol-CH＝),7.89(s,1H,ArH),7.88–7.82(m,2H,ArH),7.74(d,J＝7.9Hz,1H,ArH),7.69(dd,J＝13.1,7.0Hz,2H,ArH),7.56(dd,J＝19.5,12.0Hz,2H,ArH),7.38–7.27(m,2H,＝CH-CO),4.53(t,J＝6.5Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),1.79–1.70(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.91(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.55,147.65,143.87,142.84,136.12,135.42,131.16,129.75,129.54,128.87,127.76,126.80,123.61,123.02,121.54,120.21,119.93,109.65,43.24,32.34,19.81,13.34.
HRMS(ESL):caICd.for C 24 H 23 N 5 O 397.19726,found:[M+H] + 398.19710.
Compound 8
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methylphenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 63%, and the melting point is 250-252 ℃.
The molecular formula: c (C) 25 H 25 N 5 O
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.15(s,1H,trLzol-H),7.94(d,J＝15.1Hz,1H,LmLdazol-CH＝),7.87(d,J＝16.0Hz,1H,trLzol-CH＝),7.82(d,J＝5.1Hz,1H,ArH),7.76(d,J＝15.1Hz,1H,ArH),7.63(d,J＝8.1Hz,2H),ArH,7.38(d,J＝8.9Hz,2H,ArH),7.35(s,1H,ArH),7.34(s,1H,ArH；1H,＝CH-CO),7.33–7.31(m,1H,＝CH-CO),4.32(t,J＝6.9Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),2.44(s,3H,Ar- 3 CH),1.87–1.79(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.38(d,J＝7.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.96(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.89,147.93,144.02,143.07,139.37,135.69,134.10,131.64,130.31,130.11,127.89,127.01,123.91,123.32,121.88,120.37,120.17,109.96,43.53,32.62,21.09,20.10,13.64.
HRMS(ESL):caICd.for C 25 H 25 N 5 O 411.21291,found:[M+H] + 412.21264.
Compound 9
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-o-methylphenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid with a yield of 57% and a melting point of 254-256 ℃.
The molecular formula: c (C) 25 H 25 N 5 O
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.16(s,1H,trLzol-H),7.96(d,J＝15.1Hz,1H,LmLdazol-CH＝),7.85(d,J＝16.0Hz,1H,trLzol-CH＝),7.80(d,J＝5.1Hz,1H,ArH),7.76(d,J＝15.1Hz,1H,ArH),7.63(d,J＝8.1Hz,2H),ArH,7.38(d,J＝8.9Hz,2H,ArH),7.35(s,1H,ArH),7.34(s,1H,ArH；1H,＝CH-CO),7.33–7.31(m,1H,＝CH-CO),4.32(t,J＝6.9Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),2.44(s,3H,Ar- 3 CH),1.87–1.79(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.38(d,J＝7.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.96(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.61,147.27,144.15,143.09,135.53,134.95,133.25,131.35,131.27,131.17,130.10,129.91,129.88,127.48,126.58,125.49,125.18,123.67,123.06,119.97,109.42,38.20,17.94,17.57,15.55,14.68,10.42.
HRMS(ESL):caICd.for C 25 H 25 N 5 O 410.20591,found:[M+H] + 411.20575.
Compound 10
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methoxyphenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid with a yield of 50% and a melting point of 236-237 ℃.
The molecular formula: c (C) 25 H 25 N 5 O 2
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.10(s,1H,trLzol-H),7.92(s,1H,LmLdazol-CH＝),7.85(s,1H,trLzol-CH＝),7.82(s,1H,ArH),7.77(s,1H,ArH),7.66(s,2H,ArH),7.39(s,1H,ArH),7.33(s,3H,ArH),7.04(s,2H,＝CH-CO),4.31(s,2H,- 2 CHCH 2 CH 2 CH 3 ),3.87(s,3H,O 3 CH),1.83(s,2H,-CH 2 2 CHCH 2 CH 3 ),1.38(s,2H,-CH 2 CH 2 2 CHCH 3 ),0.95(s,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.55,159.71,147.65,143.68,142.80,135.40,131.39,129.79,129.48,127.52,126.70,123.59,123.00,121.82,121.72,119.88,114.49,109.65,55.28,43.22,32.31,19.80,13.33.
HRMS(ESL):caICd.for C 25 H 25 N 5 O 2 427.20761,found:[M+H] + 428.20783.
Compound 11
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-chlorophenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 65%, and the melting point is 257-260 ℃.
The molecular formula: c (C) 24 H 22 ClN 5 O
1 H NMR(400MHz,DMSO)δ(ppm):9.29(s,1H,trLzol-H),8.01(s,1H,LmLdazol-CH＝),7.99(s,1H,trLzol-CH＝,1H,ArH),7.90(d,J＝14.0Hz,1H,ArH),7.86(d,J＝13.7Hz,1H,ArH),7.80(d,J＝15.8Hz,1H,ArH),7.77(s,1H,ArH),7.74(d,J＝5.4Hz,2H,ArH),7.71(d,J＝8.0Hz,1H,ArH),7.54(t,J＝14.7Hz,1H,ArH),7.40–7.27(m,2H,＝CH-CO),4.53(t,J＝6.5Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),1.79–1.70(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.91(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.70,147.85,144.21,143.01,135.62,135.34,131.51,131.12,129.95,128.13,127.01,123.95,123.21,122.51,121.83,121.43,120.02,109.96,43.34,32.43,20.07,13.54.
HRMS(ESL):caICd.for C 24 H 22 ClN 5 O 431.15829,found:[M+H] + 432.15864.
Compound 12
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-bromophenyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 60%, and the melting point is 261-262 ℃.
The molecular formula: c (C) 24 H 22 BrN 5 O
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.16(s,1H,trLzol-H),7.94(d,J＝14.6Hz,1H,LmLdazol-CH＝),7.86(d,J＝16.6Hz,1H,trLzol-CH＝),7.84–7.81(m,1H,ArH),7.78(d,J＝15.1Hz,1H,ArH),7.69(s,2H,ArH),7.68(s,2H,ArH),7.39(d,J＝21.4Hz,2H,ArH),7.35(s,2H,＝CH-CO),4.53(t,J＝6.5Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),1.79–1.70(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.91(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.75,147.89,144.39,143.13,135.72,135.34,132.99,131.12,129.95,128.33,127.18,123.95,123.34,122.86,121.83,121.57,120.22,109.97,43.54,32.63,20.11,13.64.
HRMS(ESL):caICd.for C 24 H 22 BrN 5 O 475.10776,found:[M+H] + 476.10768.
Compound 13
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-benzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The yellow powdery solid was obtained in a yield of 45% and a melting point of 227-229 ℃.
The molecular formula: c (C) 23 H 21 N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.61(s,1H,trLzol-H),7.81(t,J＝14.8Hz,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.76–7.69(m,2H,ArH),7.67(d,J＝8.1Hz,1H,ArH),7.47–7.42(m,1H,ArH),7.41(d,J＝5.7Hz,1H,ArH),7.39(d,J＝5.1Hz,1H,ArH),7.37(d,J＝5.3Hz,2H,ArH),7.34(s,1H,ArH),7.32(d,J＝8.5Hz,1H,＝CH-CO),7.30–7.25(m,1H,＝CH-CO),5.68(d,J＝10.5Hz,2H,Ar- 2 CH-trLzol),4.53(q,J＝7.0Hz,2H,- 2 CHCH 3 ),1.34(t,J＝7.1Hz,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.61,147.23,143.62,142.86,134.90,133.67,131.60,129.95,128.88,128.64,127.74,127.13,126.45,123.65,123.64,123.03,119.89,109.43,53.94,38.17,15.51.
HRMS(ESL):caICd.for C 23 H 21 N 5 O 383.18231,found:[M+H] + 384.18218.
Compound 14
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methylbenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 52%, and the melting point is 231-233 ℃.
The molecular formula: c (C) 24 H 23 N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.57(s,1H,trLzol-H),7.80(t,J＝16.4Hz,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.73(d,J＝13.2Hz,1H,ArH),7.71–7.65(m,2H,ArH),7.42(d,J＝16.0Hz,1H,ArH),7.35–7.30(m,1H,ArH),7.29(d,J＝7.6Hz,1H,ArH),7.25(d,J＝8.0Hz,2H,ArH),7.21(d,J＝7.9Hz,2H,＝CH-CO),5.68–5.59(m,2H,Ar- 2 CH-trLzol),4.53(q,J＝7.1Hz,2H,- 2 CHCH 3 ),2.29(s,2H,Ar- 3 CH),1.34(t,J＝7.2Hz,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.58,147.27,143.59,142.92,138.66,134.93,131.67,130.61,129.95,129.54,127.81,127.08,126.45,123.62,123.47,123.01,119.95,109.40,53.77,38.17,20.82,15.52.
HRMS(ESL):caICd.for C 24 H 23 N 5 O 397.19766,found:[M+H] + 398.19775.
Compound 15
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methoxybenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 40%, and the melting point is 225-227 ℃.
The molecular formula: c (C) 24 H 23 N 5 O 2
1 H NMR(400MHz,DMSO)δ(ppm):8.56(s,1H,trLzol-H),7.80(s,1H,Ar-CH＝),7.77–7.71(m,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.71–7.65(m,2H,ArH),7.42(d,J＝16.0Hz,1H,ArH),7.34(s,1H,＝CH-CO),7.31(d,J＝4.0Hz,2H,ArH),7.30–7.25(m,1H,＝CH-CO),6.97(s,1H,ArH),6.95(s,1H,ArH),5.60(s,2H,Ar- 2 CH-trLzol),4.53(q,J＝7.0Hz,2H,- 2 CHCH 3 ),3.75(s,3H,O 3 CH),1.34(t,J＝7.1Hz,3H,-CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.58,147.27,143.56,142.94,134.94,131.67,129.93,129.38,127.07,126.47,125.57,123.61,123.35,123.01,119.96,114.21,109.40,103.48,54.98,53.52,38.17,15.52.
HRMS(ESL):caICd.for C 24 H 23 N 5 O 2 413.19218,found:[M+H] + 414.19237.
Compound 16
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-fluorobenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid with the yield of 45 percent and the melting point of 230-232 ℃.
The molecular formula: c (C) 23 H 20 FN 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.60(s,1H,trLzol-H),7.81(s,1H,LmLdazol-CH＝),7.76(d,J＝8.2Hz,1H,trLzol-CH＝),7.70(d,J＝7.9Hz,1H,ArH),7.67(s,1H,ArH),7.48–7.39(m,3H,ArH),7.34(d,J＝6.8Hz,1H,ArH),7.30(d,J＝3.4Hz,1H,ArH),7.27(d,J＝4.2Hz,1H,ArH),7.24(d,J＝8.9Hz,2H,＝CH-CO),5.68(d,J＝10.2Hz,2H,Ar- 2 CH-trLzol),4.53(q,J＝7.0Hz,2H,- 2 CHCH 3 ),1.34(t,J＝7.1Hz,3H,O 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.52,147.23,143.73,142.94,134.94,131.40,129.83,129.67,129.62,127.29,126.54,123.63,123.42,123.02,122.83,119.95,115.99,115.85,109.40,108.89,53.18,38.16,15.52.
HRMS(ESL):caICd.for C 23 H 20 FN 5 O 401.17319,found:[M+H] + 402.17339.
Compound 17
1- (1-ethyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-chlorobenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 60 percent, and the melting point is 241-243 ℃.
The molecular formula: c (C) 23 H 20 ClN 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.62(s,1H,trLzol-H),7.82(t,J＝14.5Hz,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.77–7.69(m,2H,ArH),7.68(d,J＝8.0Hz,1H,ArH),7.48(d,J＝8.3Hz,2H,ArH),7.44(d,J＝16.2Hz,1H,ArH),7.38(d,J＝8.2Hz,2H,ArH),7.35–7.31(m,1H,＝CH-CO),7.31–7.25(m,1H,＝CH-CO),5.70(d,J＝9.8Hz,2H,Ar- 2 CH-trLzol),4.53(q,J＝6.8Hz,2H,- 2 CHCH 3 ),1.34(t,J＝7.1Hz,3H,O 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.57,147.21,143.78,142.86,134.92,134.72,132.17,131.38,129.88,129.09,129.05,127.36,126.53,123.67,123.52,123.06,119.91,109.43,53.19,38.18,15.52.
HRMS(ESL):caICd.for C 23 H 20 ClN 5 O 417.14254,found:[M+H] + 418.14259.
Compound 18
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-benzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid with a yield of 50% and a melting point of 233-235 ℃.
The molecular formula: c (C) 25 H 25 N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.61(s,1H,trLzol-H),7.81(t,J＝14.8Hz,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.76–7.69(m,2H,ArH),7.67(d,J＝8.1Hz,1H,ArH),7.47–7.42(m,1H,ArH),7.41(d,J＝5.7Hz,1H,ArH),7.39(d,J＝5.1Hz,1H,ArH),7.37(d,J＝5.3Hz,2H,ArH),7.34(s,1H,ArH),7.32(d,J＝8.5Hz,1H,＝CH-CO),7.30–7.25(m,1H,＝CH-CO),5.68(d,J＝10.5Hz,2H,Ar- 2 CH-trLzol),4.53(t,J＝6.5Hz,2H,-CH 2 CH 2 CH 2 CH 3 ),1.79–1.70(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.91(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.60,147.64,143.66,135.38,133.65,131.58,129.81,128.90,128.80,128.67,127.75,127.27,126.65,123.57,123.00,119.87,109.64,53.96,43.22,32.31,19.79,13.32.
HRMS(ESL):caICd.for C 25 H 25 N 5 O 411.21301,found:[M+H] + 412.21310.
Compound 19
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methylbenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 48%, and the melting point is 241-243 ℃.
The molecular formula:C 26 H 27 N 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.57(s,1H,trLzol-H),7.80(t,J＝16.4Hz,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.73(d,J＝13.2Hz,1H,ArH),7.71–7.65(m,2H,ArH),7.42(d,J＝16.0Hz,1H,ArH),7.35–7.30(m,1H,ArH),7.29(d,J＝7.6Hz,1H,ArH),7.25(d,J＝8.0Hz,2H,ArH),7.21(d,J＝7.9Hz,2H,＝CH-CO),5.68–5.59(m,2H,Ar- 2 CH-trLzol),4.53(t,J＝6.5Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),2.29(s,2H,Ar- 3 CH),1.79–1.71(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.0Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.90(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.61,147.64,143.59,142.76,138.67,135.37,131.67,130.59,129.84,129.55,127.82,127.18,126.61,123.58,123.47,122.99,119.86,109.63,53.78,43.22,32.30,20.82,19.79,13.32.
HRMS(ESL):caICd.for C 26 H 27 N 5 O 425.22906,found:[M+H] + 426.22900.
compound 20
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-methoxybenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The obtained pure product is yellow solid, the yield is 50%, and the melting point is 228-230 ℃.
The molecular formula: c (C) 26 H 27 N 5 O 2
1 H NMR(400MHz,DMSO)δ(ppm):8.56(s,1H,trLzol-H),7.80(s,1H,Ar-CH＝),7.77–7.71(m,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.71–7.65(m,2H,ArH),7.42(d,J＝16.0Hz,1H,ArH),7.34(s,1H,＝CH-CO),7.31(d,J＝4.0Hz,2H,ArH),7.30–7.25(m,1H,＝CH-CO),6.97(s,1H,ArH),6.95(s,1H,ArH),5.60(s,2H,Ar- 2 CH-trLzol),4.53(t,J＝6.5Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),3.75(s,3H,O 3 CH),1.79–1.70(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.91(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.57,159.68,147.65,143.56,142.80,135.39,131.66,129.80,129.38,127.15,126.63,125.58,123.56,123.34,122.97,119.89,114.20,109.63,54.97,53.51,43.21,32.30,19.79,13.32.
HRMS(ESL):caICd.for C 26 H 27 N 5 O 2 441.22380,found:[M+H] + 442.22370.
Compound 21
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-fluorobenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The pure product obtained is yellow solid, the yield is 53%, and the melting point is 235-237 ℃.
The molecular formula: c (C) 25 H 24 FN 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.60(s,1H,trLzol-H),7.81(s,1H,LmLdazol-CH＝),7.76(d,J＝8.2Hz,1H,trLzol-CH＝),7.70(d,J＝7.9Hz,1H,ArH),7.67(s,1H,ArH),7.48–7.39(m,3H,ArH),7.34(d,J＝6.8Hz,1H,ArH),7.30(d,J＝3.4Hz,1H,ArH),7.27(d,J＝4.2Hz,1H,ArH),7.24(d,J＝8.9Hz,2H,＝CH-CO),5.68(d,J＝10.2Hz,2H,Ar- 2 CH-trLzol),4.53(t,J＝6.5Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),1.79–1.70(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.91(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.54,147.63,143.76,142.80,135.40,131.40,129.72,129.68,129.63,128.86,127.40,126.72,123.59,123.40,123.00,119.89,116.00,115.86,109.64,103.48,53.19,43.22,32.31,19.79,13.32.
HRMS(ESL):caICd.for C 25 H 24 FN 5 O 429.20449,found:[M+H] + 430.20404.
Compound 22
1- (1-butyl-1H-benzo [ d ] imidazol-2-yl) -5- (1-p-chlorobenzyl-1H-1, 2, 3-triazol-4-yl) -1-, 4-pentadien-3-one
The obtained pure product is yellow solid, the yield is 42 percent, and the melting point is 250-252 ℃.
The molecular formula: c (C) 25 H 24 ClN 5 O
1 H NMR(400MHz,DMSO)δ(ppm):8.62(s,1H,trLzol-H),7.82(t,J＝14.5Hz,2H,1H,LmLdazol-CH＝；1H,trLzol-CH＝),7.77–7.69(m,2H,ArH),7.68(d,J＝8.0Hz,1H,ArH),7.48(d,J＝8.3Hz,2H,ArH),7.44(d,J＝16.2Hz,1H,ArH),7.38(d,J＝8.2Hz,2H,ArH),7.35–7.31(m,1H,＝CH-CO),7.31–7.25(m,1H,＝CH-CO),5.70(d,J＝9.8Hz,2H,Ar- 2 CH-trLzol),4.53(t,J＝6.5Hz,2H,- 2 CHCH 2 CH 2 CH 3 ),1.79–1.70(m,2H,-CH 2 2 CHCH 2 CH 3 ),1.30(dd,J＝14.2,6.6Hz,2H,-CH 2 CH 2 2 CHCH 3 ),0.91(t,J＝7.2Hz,3H,-CH 2 CH 2 CH 2 3 CH).
13 C NMR(151MHz,CDCl 3 )δ(ppm):187.61,147.64,143.55,142.65,138.67,135.37,131.67,130.59,129.84,129.55,127.82,127.18,126.61,123.58,123.47,122.99,119.86,109.63,53.78,43.22,32.30,19.79,13.32.
HRMS(ESL):caICd.for C 25 H 24 ClN 5 O 445.17384,found:[M+H] + 446.17393.
Example 2 test of antitumor Activity
Test target: human large cell lung cancer cell H460, human osteosarcoma cancer cell MG63, human basal cavity cancer cell KB and human lung cancer cell PC9.
The test method comprises the following steps: MTT in vitro cytotoxicity test method
Taking human cancer cells in logarithmic growth phase, and making into 2×10 4 Each cell/mL of the cell suspension was seeded at 0.19 mL/well in 96-well plates at 37℃and 5% CO 2 After 24 hours of incubation, 0.01 mL/well of sample solution was added, a physiological saline control well was additionally provided, 4 parallel wells were provided for each concentration, incubation was further performed for 72 hours after dosing, 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyltetrazolium bromide (MTT) was added at a concentration of 10mg/mL per well for 3 hours before the end of incubation, the culture broth was aspirated at the end of incubation, 0.1mL of dimethyl sulfoxide (DMSO) was added per well, and OD was measured at a reference wavelength of 655nm at a measurement wavelength of 540 nm. Cell growth inhibition (LR) was calculated as follows, and half Inhibition Concentration (IC) was calculated in a simplified probability unit method 50 ). LR% = (1-average OD value Dosing group Average OD value Control group ) X 100%. The measurement results are shown in Table 1. In the table, 5-fluorouracil (5-Fu) was used as a positive control. In the table, H460 represents a human large cell lung cancer cell, MG63 represents an osteosarcoma cancer cell, KB represents a human oral basal cancer cell, and PC9 represents a human lung cancer cell.
TABLE 1 anti-tumor Activity data for Compounds of formula L (IC 50 Value of
From the data in table 1, it can be seen that: for cancer cell H460, 12 Compound ICs 50 A value below 5. Mu.M, wherein Compound 15 exhibits optimal inhibitory activity against H460, IC 50 The value is 2.18 mu M, and the activity is slightly lower than that of the control medicament 5-fluoroUracil (IC) 50 =0.81 μm). For cancer cell MG63, 21 compounds have activity superior to that of control 5-fluorouracil, wherein Compound 4 exhibits optimal MG63 inhibition activity, IC 50 The value was 1.02. Mu.M, and the inhibitory activity against MG63 was 5-fluorouracil (IC) 50 =6.15). For cancer cell KB, the inhibition activity of the synthesized target compound on KB is superior to that of a control medicament 5-fluorouracil, wherein the compound 20 shows the optimal KB inhibition activity, and IC thereof 50 The value is 0.51 mu M, and the activity on KB is 18 times that of the control drug 5-fluorouracil. In contrast, for cancer cell PC9, 14 compounds showed better activity on PC9 than the control 5-fluorouracil, wherein compound 17 showed the best PC9 inhibitory activity, IC 50 The value was 0.57. Mu.M, and the inhibition activity against PC9 was 4 times that of the control drug 5-fluorouracil.
EXAMPLE 3 antifungal Activity assay
Test target: the fungi are apple ring rot, wheat sheath blight, tomato early blight, wheat gibberella, rice blast, phytophthora capsici, rape sclerotium and rice sheath blight germ.
The test method comprises the following steps: ex vivo plating.
PDA culture medium is prepared: peeling and cleaning potato, weighing 800g, slicing, boiling in a pot with 4L distilled water, thoroughly boiling until the potato is soft, filtering with gauze to obtain clear liquid, adding 400mL into conical bottles containing 8g glucose and 6g agar, shaking, sealing, and sterilizing under high pressure.
Dispensing and pouring: an amount of the target compound was weighed by an analytical balance and prepared as a 50mg/mL DMSO solution. 400. Mu.L of the target compound solution was added to PDA medium heated to a liquid state by a microwave oven using a pipette to give a compound concentration of 50. Mu.g/mL. The medium was shaken well and poured into a petri dish, approximately 20 mL/dish. After cooling and solidification, the compound number is written.
Inoculating and culturing: the activated fungi are beaten into fungus blocks at the edge of hypha by a puncher with the diameter of 5mm, the fungus blocks are inoculated to the center of a culture medium by an inoculating knife, a sealing film is used for sealing, and then the culture medium is placed in a constant temperature incubator for culture. 3 replicates were run for each compound. The results were then observed according to the hyphal growth of the control group.
Measuring and calculating: before hyphae of the control group grew to the edge of the dish (about 60-80 mm), the dish was removed, the diameter thereof was measured by the crisscross method, and data were recorded, and an average value was taken at the time of calculation. Inhibition rate formula:
colony growth inhibition ratio = (control diameter-experimental diameter) ×100%/(control diameter-5 mm). The measurement results are shown in tables 2 to 6.
TABLE 2 data on the antifungal Activity of some of the compounds of formula L (50 ppm in vitro inhibition,%)
TABLE 3 data on the antifungal Activity of some of the compounds of formula L (50 ppm in vitro inhibition,%)
| Compounds of formula (I) | Tomato early blight |
| 13 | 60.0 |
| 14 | 53.3 |
| 15 | 53.3 |
TABLE 4 data on the antifungal Activity of some of the compounds of formula L (50 ppm in vitro inhibition,%)
| Compounds of formula (I) | Gibberella wheat | Rice blast | Phytophthora capsici |
| 3 | 69.2 | 60.0 | 48.3 |
| 13 | 57.7 | 40.0 | 65.5 |
| 15 | 57.7 | 53.3 | 65.5 |
| 17 | 38.5 | 40.0 | 55.2 |
| 21 | 38.5 | 53.3 | 44.8 |
TABLE 5 data on the antifungal Activity of some of the compounds of formula L (50 ppm in vitro inhibition,%)
| Compounds of formula (I) | Sclerotium of rape |
| 11 | 61.9 |
| 15 | 61.9 |
TABLE 6 data on the antifungal Activity of some of the compounds of formula L (50 ppm in vitro inhibition,%)
| Compounds of formula (I) | Rice sheath blight |
| 10 | 50.0 |
| 13 | 61.1 |
| 22 | 50.0 |
As can be seen from the data in tables 2 to 6: in general, the tested compounds showed good in vitro inhibitory activity against Rhizoctonia cerealis and Rhizoctonia cerealis at a concentration of 50 ppm. Wherein, the compound 19 shows optimal inhibition activity to the apple ring rot fungi, and the inhibition rate is 86.7%; the compounds 8, 10, 20 and 21 show optimal inhibition activity on the Rhizoctonia cerealis, and the inhibition rate is more than 60% at the concentration of 50 ppm; some of the compounds tested showed higher inhibitory activity against tomato early blight, wheat gibberella, rice blast, phytophthora capsici, sclerotium of colza and sheath blight of rice. The inhibition rate of the compound 13 to the tomato early blight bacteria reaches 60% at the concentration of 50ppm, the inhibition rates of the compound 3 to the wheat gibberella and rice blast bacteria reach 69% and 60% respectively at the concentration of 50ppm, the inhibition rates of the compounds 13 and 15 to the phytophthora capsici bacteria reach 65% at the concentration of 50ppm, and the inhibition rates of the compounds 11 and 15 to the sclerotium bacteria exceed 60% at the concentration of 50 ppm; the inhibition rate of the compound 13 to the sheath blight of rice at the concentration of 50ppm exceeds 60 percent.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (7)
1. A benzimidazole compound, characterized in that the compound is a compound represented by the formula L or a pharmaceutically acceptable salt of the compound represented by the formula L,
wherein R is 1 Is H, halogen, methyl or methoxy; r is R 2 Ethyl or n-butyl; n is 0 or 1.
2. A compound according to claim 1, wherein R 1 The halogen is F, cl or Br.
3. The compound of claim 1 or 2, wherein the compound is the following compound or a pharmaceutically acceptable salt of the following compound:
。
4. a method for producing the benzimidazole compound according to any one of claims 1 to 3, comprising the steps of:
(1) Contacting a compound represented by formula a with propynyl alcohol to obtain a compound represented by formula B;
(2) Contacting a compound represented by formula B with manganese dioxide to obtain a compound represented by formula C;
(3) Contacting a compound represented by formula D with glycolic acid to obtain a compound represented by formula E;
(4) Contacting a compound represented by formula E with a bromoalkane to obtain a compound represented by formula F;
(5) Contacting a compound represented by formula F with manganese dioxide to obtain a compound represented by formula G;
(6) Contacting a compound represented by formula G with a compound represented by formula H to obtain a compound represented by formula I;
(7) Contacting a compound represented by formula C with a compound represented by formula I to obtain a compound represented by formula L;
wherein R is 1 、R 2 The same definition as in any one of claims 1 to 3.
5. A pharmaceutical composition comprising the benzimidazole compound according to any one of claims 1 to 4.
6. The use of the benzimidazole compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating cancer, wherein the cancer cells are human large cell lung cancer cells H460, human osteosarcoma cancer cells MG63, human cavity bottom cancer cells KB and human lung cancer cells PC9.
7. Use of the compounds 2-6, 8, 10-13, 15-22 according to claim 3 for controlling alternaria alternata;
use of the compounds 3, 5, 6, 8, 10, 15-22 according to claim 3 for controlling rhizoctonia cerealis;
the use of the compounds 13-15 according to claim 3 for controlling phytophthora infestans;
the use of the compounds 3, 13, 15, 17 and 21 according to claim 3 for controlling gibberella wheat, rice blast and phytophthora capsici;
the use of the compounds 11 and 15 according to claim 3 for combating sclerotinia sclerotiorum;
use of the compounds 10, 13 and 22 according to claim 3 for controlling sheath blight of rice.
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| CN105481781A (en) * | 2014-09-17 | 2016-04-13 | 华中师范大学 | Compound, preparation method therefor and application of compound |
| AU2015208269A1 (en) * | 2014-01-23 | 2016-09-01 | Galapagos Nv | Benzimidazole derivatives and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
| CN107311933A (en) * | 2017-06-28 | 2017-11-03 | 中国人民解放军军事医学科学院毒物药物研究所 | One class benzimidizole derivatives, and its production and use |
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| CN105439966A (en) * | 2014-09-17 | 2016-03-30 | 华中师范大学 | Compounds, and preparation method and application thereof |
| CN105481781A (en) * | 2014-09-17 | 2016-04-13 | 华中师范大学 | Compound, preparation method therefor and application of compound |
| CN107311933A (en) * | 2017-06-28 | 2017-11-03 | 中国人民解放军军事医学科学院毒物药物研究所 | One class benzimidizole derivatives, and its production and use |
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