CN110655505A - 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -ones - Google Patents
6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -ones Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
The invention discloses a 6- (2-amino-1H-benzo [ d ]]Imidazole-6-yl) quinazoline-4 (3H) -ketone compounds, a preparation method and application thereof, and the structural general formula (I) is as follows, wherein: r1Is hydrogen atom, morpholine methyl, piperazine methyl or substituted piperazine methyl; r2Is hydrogen atom, butyl, morpholine substituted alkyl, benzyl, substituted benzyl, tryptamine, substituted tryptamine or N, N-dimethylamino; r3is-C (O) R4or-SO2R5Wherein R is4、R5Is alkyl (alkyl with 3-6 carbon atoms), cycloalkyl (3-6 membered ring), alkoxy or alkyl substituted amino; n is 1, 2, 3 or 4. The invention has the functions of inhibiting the activity of breast cancer, prostate cancer and human neuroblastoma.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a 6- (2-amino-1H-benzo [ d ] imidazole aromatic group substituted quinazoline-4 (3H) -ketone compound, a preparation method of the 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compound, and application of the 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compound in preparation of antitumor drugs.
Background
The aurora kinase family is an important class of serine/threonine kinases in the cell mitotic regulatory network, and includes three family members of aurora kinase A, B, C. In cell mitosis, aurora kinase participates in the processes of centrosome maturation separation, chromosome contraction, spindle assembly and maintenance, chromosome separation, cytokinesis and the like, and aurora kinase A and B are abnormally expressed and activated in a plurality of tumor tissues such as breast cancer, colorectal cancer, prostate cancer, lung cancer, glioma, leukemia and the like. Aurora kinase A is considered to participate in the generation and development of tumors through various molecular mechanisms, and the expression level of aurora kinase A in tumors is closely related to the drug resistance and poor prognosis of tumor patients. Secondly, aurora kinase B induces tumor metastasis by expression, and compared with aurora kinase a inhibitors, aurora kinase B inhibitors have more obvious bone marrow inhibition side effects, so that most of the current researches are carried out on aurora kinase a inhibitors, and the search for high-efficiency and low-toxicity aurora kinase a inhibitors becomes a hotspot of antitumor drug researches.
Quinazolinones are very important nitrogen-containing heterocyclic compounds, and various derivatives thereof have wide biological activity, especially remarkable antitumor activity, so that the quinazolinones are hot spots for developing new antitumor drugs in recent years. Quinazolinone rings can be modified at multiple sites, exhibiting different biological activities, especially substitution at their 6-position, which is the most widely studied; the benzimidazole structure is a dominant framework in drug research and development, and compounds containing the framework have wide biological activity and are common in research of antitumor drugs. At present, no research and report related to the synthesis and drug-forming properties of the 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazoline-4 (3H) -ketone compounds exist.
Disclosure of Invention
The invention aims to provide a 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compound with the activity of inhibiting breast cancer, prostate cancer and human neuroblastoma.
The invention also aims to provide a preparation method of the 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compound.
The invention also aims to provide the application of the 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compound in the preparation of antitumor drugs.
The 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compound has the following structural general formula (I):
wherein:
R1is hydrogen atom, morpholine methyl, piperazine methyl or substituted piperazine methyl;
R2is hydrogen atom, butyl, morpholine substituted alkyl, benzyl, substituted benzyl, tryptamine, substituted tryptamine or N, N-dimethylamino;
R3is-C (O) R4or-SO2R5Wherein R is4、R5Is alkyl (alkyl with 3-6 carbon atoms), cycloalkyl (3-6 membered ring), alkoxy or alkyl substituted amino;
n is 1, 2, 3 or 4.
The above-mentioned 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -one compound is preferably a specific compound:
(a) n- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(b)1, 1-diethyl-3- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) urea;
(c) n- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) cyclopropylcarboxamide;
(d) n- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) pentanamide;
(e) n- (6- (3- (3-morpholinopropyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(f) n- (6- (3-methyl-2- (morpholinomethyl) -4-oxo-3, 4 dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(g) n- (6- (4-oxo-3- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(h) n- (6- (3- (2- (1H-indol-2-yl) ethyl) -4-oxo-3, 4-dihydro-quinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(i) n- (6- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(j) n- (6- (3- (2- (dimethylamino) ethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propanamide.
The preparation method of the 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compound comprises the following steps:
(1) using 2-amino-5-bromobenzoic acid as a starting material, different substituted 6-bromoquinazolin-4 (3H) -ones were prepared by one of two general methods:
(2) preparing 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline by taking 4-bromo-2-nitroaniline and pinacol diboron as raw materials, dioxane as a solvent and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst:
(3) preparing 6- (4-amino-3-nitrophenyl) -3-quinazolin-4 (3H) -one from 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline and various substituted 6-bromoquinazolin-4 (3H) -ones as raw materials and dioxane/deionized water (v: v ═ 4:1) as a solvent:
(4) nitro reduction, hydrazine monohydrate as a reducing agent, palladium/carbon as a catalyst, and methanol as a solvent to prepare the corresponding o-phenylenediamine:
(5) preparing 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -one using 6- (3, 4-diaminophenyl) quinazolin- (3H) -one and nitrile bromide as raw materials and tetrahydrofuran/deionized water (v: v ═ 1:1) as solvent:
(6) preparing the 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone derivative by using 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone and different acyl chloride as raw materials, triethylamine as an acid-binding agent and tetrahydrofuran as a solvent:
the invention relates to application of 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compounds in preparing antitumor drugs.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can show that: the invention combines two active chemical entities of benzimidazole and quinazolinone, and carries out structure optimization on the compounds to screen out anti-tumor effect targets, thus obtaining a series of novel aurora kinase A inhibitors with anti-tumor activity. The invention has the characteristics of high efficiency and high yield.
Drawings
FIG. 1 Compounds a, i and j induced G2/M phase cycle arrest in breast cancer MDA-MB-231 cells.
FIG. 2 Compounds a, i and j induce apoptosis in breast cancer MDA-MB-231 cells.
Detailed description of the preferred embodiments
Example 1
Synthesis of N- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide (compound No. a) comprising the steps of:
(1) synthesis of 6-bromo-3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
2-amino-4-bromobenzoic acid (10.8g,50mmol) was dissolved in 150mL of anhydrous ethanol, triethyl orthoformate (11.1g,75mmol) was added, N- (2-aminoethyl) morpholine (9.75g,75mmol) and iodine (0.127g,0.5mmol) were added, and the mixture was heated to reflux under argon atmosphere and protected from light for 5 hours. After the reaction was cooled to room temperature, after removing ethanol by concentration under reduced pressure, 200mL of ethyl acetate was added, and after dissolution, the reaction mixture was washed once with 1N sodium hydroxide solution, the aqueous layer was extracted three times with ethyl acetate, the organic layers were combined, washed three times with 1N sodium hydroxide solution and saturated brine, respectively, the organic layer was collected, and dried over anhydrous sodium sulfate overnight. Sodium sulfate was removed by filtration and ethyl acetate was removed by concentration to give 6-bromo-3- (2-morpholinoethyl) quinazolin-4 (3H) -one (yellow solid), 14.21g, 84.1% yield.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
4-bromo-2-nitroaniline (10.85g, 50mmol) was dissolved in 150mL of 1, 4-dioxane, and after pinacol ester of boronic acid (25.4g,100mmol) and potassium acetate (14.7g,150mmol) were added and the reaction was warmed to 100 ℃ under an argon atmosphere, palladium [1,1' -bis (diphenylphosphino) ferrocene ] dichloride (1.83g,2.5mmol) was added and the reaction was continued for 2 hours. After cooling to room temperature and subsequent removal of the solvent by rotary evaporation under reduced pressure, purification by flash column chromatography (dichloromethane as eluent) gave a yellow solid, 12.13g, 91.9% yield.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
dissolving the compound 6-bromo-3- (2-morpholinoethyl) quinazoline-4 (3H) -ketone (5.28g,15mmol) prepared in the step (1) in a mixed solution of 1, 4-dioxane (40mL) and water (10mL), adding 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaoxopentaborane-2-yl) aniline (3.96g,15mmol) and potassium carbonate (6.21g,45mmol), fully stirring, heating to 100 ℃ under an argon atmosphere, adding a catalyst [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.548g,0.75mmol), reacting for 4 hours, and cooling to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and methylene chloride (50mL) and methanol (50mL) were added to the mixture, followed by filtration to obtain a filtrate. Purification by column chromatography [ V (dichloromethane): v (methanol) ═ 25:1], gave a yellow solid, 4.87g, 82.2% yield.
(4) Synthesis of 6- (3, 4-diaminophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
dissolving 6- (4-amino-3-nitrophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one (4.09g,10mmol) prepared in step (3) in 50ml of methanol, adding 10% palladium/carbon (1.08 g), fully stirring at room temperature, adding hydrazine monohydrate (5g,100mmol), and reacting at the temperature of 80 ℃ under an argon atmosphere for 2 hours. The hot residue was filtered and the solvent and hydrazine hydrate removed by rotary evaporation under reduced pressure to give a pale yellow solid, 3.75 g.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
dissolving 6- ((3, 4-diaminophenyl) -3- (2-morpholino-2-oxoethyl) quinazolin-4 (3H) -one (3.79,10mmol) prepared in step (4) in a mixed solution of methanol (25mL) and water (25mL), stirring at room temperature, dissolving cyanogen bromide (3.18g,30mmol) in 25mL of anhydrous acetonitrile, dropwise adding into the reaction solution at room temperature, after completion of dropwise adding, heating to 60 ℃, reacting for 2 hours, cooling to room temperature, removing methanol and acetonitrile by rotary evaporation under reduced pressure, adding 2N sodium hydroxide solution to the remaining residue, stirring for 30 minutes, adding N-butanol, extracting (50 mL. times.3) after combining the organic layers, washing 3 times with 1N sodium hydroxide solution and saturated saline water respectively, drying by adding anhydrous sodium sulfate, filtering, removing the solvent under reduced pressure, and separating and purifying by chromatography column chromatography [ V (dichloromethane): V (methanol): 10:1 Obtained was a white solid, 2.29g, 58.6% yield.
(6) Synthesis of N- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide:
the 6- (2-amino-1H-benzo [ d) prepared in the step (5)]Imidazol-6-yl) -3- (2-morpholino-2-oxoethyl) quinazolin-4 (3H) -one (2.02g,5mmol) was dissolved in 40mL dry tetrahydrofuran, triethylamine (1.52g,15mmol) was added, and the mixture was stirred under argon in an ice-water bath for 30 minutes. Propionyl chloride (0.56g,6mmol) was dissolved in 10mL of dry tetrahydrofuran and slowly added dropwise to the reaction solution under ice-water bath conditions. After the completion of the dropwise addition, the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the reaction solvent was removed, 50mL of saturated sodium carbonate solution was added and washed, n-butanol was added and extracted (50 mL. times.3), and the organic layers were combined and washed three times with saturated brine. The n-butanol layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. Separating and purifying by chromatography column chromatography (V (dichloromethane): V (methanol): 25: 1)]) To obtain a white solid, 1.06g, yield 47.6%, melting point 237-]+447.2132；[M+Na]+469.1948。
Example 2
Synthesis of 1, 1-diethyl-3- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) urea (compound No. b) comprising the following steps:
(1) synthesis of 6-bromo-3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in step (1) of example 1.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in a yield of 4.81g and 81.1%.
(4) Synthesis of 6- (3, 4-diaminophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.37g and 92.3%.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in 2.25g, yield 57.6%.
(6) Synthesis of 1, 1-diethyl-3- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) urea:
as in the step (6) in example 1, a white solid was obtained in 1.01g, yield 41.3%, melting point 130-]+490.2553；[M+Na]+512.2372。
Example 3
Synthesis of N- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) cyclopropylcarboxamide (compound No. c) comprising the following steps:
(1) synthesis of 6-bromo-3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in step (1) of example 1.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in a yield of 4.81g and 81.1%.
(4) Synthesis of 6- (3, 4-diaminophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.37g and 92.3%.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in 2.25g, yield 57.6%.
(6) Synthesis of N- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) cyclopropylcarboxamide:
as in the step (6) in example 1, a white solid was obtained in 0.89g, a yield of 38.7%, a melting point of 239-]+459.2132；[M+Na]+481.1950。
Example 4
Synthesis of N- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) pentanamide (compound No. d) comprising the following steps:
(1) synthesis of 6-bromo-3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in step (1) of example 1.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in a yield of 4.81g and 81.1%.
(4) Synthesis of 6- (3, 4-diaminophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.37g and 92.3%.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in 2.25g, yield 57.6%.
(6) Synthesis of N- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) pentanamide:
as in the step (6) in example 1, a white solid was obtained in 1.11g, a yield of 46.8%, a melting point of 238-]+475.2448；[M+Na]+497.2260。
Example 5
Synthesis of N- (6- (3- (3-morpholinopropyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide (compound No. e) comprising the following steps:
(1) synthesis of 6-bromo-3- (2-morpholinopropyl) quinazolin-4 (3H) -one:
as in the step (1) in example 1, a pale yellow solid was obtained in 14.71g, yield 83.6%.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3- (2-morpholinopropyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in a yield of 4.94g and 80.4%.
(4) Synthesis of 6- (3, 4-diaminophenyl) -3- (2-morpholinoethyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.54g and 93.3%.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) -3- (2-morpholinopropyl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in 2.01g, yield 49.8%.
(6) Synthesis of N- (6- (3- (2-morpholinopropyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazole-2-propionamide:
white solid was obtained in 0.93g, yield 40.4%, melting point 243-; HRMS (ESI) [ M + H ]]+461.2289；[M+Na]+483.2104。
Example 6
Synthesis of N- (6- (3-methyl-2- (morpholinomethyl) -4-oxo-3, 4 dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide (compound No. f) comprising the following steps:
(1) synthesis of 6-bromo-2-chloromethylquinazolin-4 (3H) -one:
a sodium block (0.23g,10mmol) was weighed out, placed in a three-necked flask, 50mL of anhydrous methanol was added thereto, and after stirring sufficiently, chloroacetonitrile (11.4g,150mmol) was slowly added dropwise to the reaction flask under an argon atmosphere at room temperature. 4-bromo-2-aminobenzoic acid (10.8g,50mmol) was dissolved in 150mL of anhydrous methanol and slowly added dropwise to the reaction flask. The reaction was continued at room temperature for 3 hours. A white precipitate was precipitated and filtered to give a pure white floc, 11.09g, 81.1% yield.
(2) Synthesis of 6-bromo-2- (morpholinomethyl) quinazolin-4 (3H) -one:
the 6-bromo-2-chloromethylquinazolin-4 (3H) -one (5.46g,20mmol) obtained in step (1) was put into a three-necked flask, and after adding 100mL of anhydrous ethanol, it was stirred well. Morpholine (2.09g,24mmol) was added dropwise at room temperature under an argon atmosphere. After the addition, potassium carbonate (5.52g,40mmol) was added to the reaction solution in portions at room temperature, and the reaction was continued for 8 hours while heating to 80 ℃ under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature, then ethanol was removed by rotary evaporation under reduced pressure, 100mL of saturated brine was added, extraction was performed with dichloromethane (100mL × 3), the organic layers were combined, washed with saturated brine (100mL × 3), dried over anhydrous sodium sulfate, and then filtered. The solvent was removed, and the mixture was separated and purified by silica gel column chromatography [ V (dichloromethane): v (methanol) ═ 50:1], yielding a white solid, 6.69g, yield 79.1%.
(3) Synthesis of 6-bromo-3-methyl-2- (morpholinomethyl) quinazolin-4 (3H) -one:
dissolving the synthesis (3.38g and 10mmol) of 6-bromo-2- (morpholinomethyl) quinazolin-4 (3H) -one prepared in the step (2) in 30mL of N, N-dimethylformamide, adding sodium hydride (0.24g and 10mmol), fully stirring at room temperature under an argon atmosphere, dissolving iodomethane (2.84g and 20mmol) in 20mL of N, N-dimethylformamide, and slowly dropwise adding into a reaction bottle. After the completion of the dropwise addition, the reaction was continued at room temperature for 10 hours, and then stopped. 150mL of saturated brine was added, extraction was performed with dichloromethane (100 mL. times.3), the organic layers were combined, washed with saturated brine (200 mL. times.3), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give 2.93g of a yellow solid with a yield of 86.6%.
(4) Synthesis of 6- (4-amino-3-nitrophenyl) -3-methyl-2- (morpholinomethyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in 4.94g, yield 83.4%.
(5) Synthesis of 6- (3, 4-diaminophenyl) -3-methyl-2- (morpholinomethyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.42g and 93.7%.
(6) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) -3-methyl-2- (morpholinomethyl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in a yield of 1.89g, 48.5%.
(7) Synthesis of N- (6- (3-methyl-2- (morpholinomethyl) -4-oxo-3, 4 dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide:
as in the step (6) in example 1, a white solid was obtained in 1.02g, a yield of 45.6%, a melting point of 219- & gt, 221 ℃ and HRMS (ESI) & gt [ M + H-]+447.2133；[M+Na]+469.1949。
Example 7
Synthesis of N- (6- (4-oxo-3- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide (compound No. g) comprising the following steps:
(1) synthesis of 6-bromo-3- (2- (piperidin-1-yl) ethyl) quinazolin-4 (3H) -one:
as in the step (1) in example 1, a pale yellow solid was obtained in 14.21g, yield 84.6%.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3- (2- (piperidin-1-yl) ethyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in 4.92g, yield 83.4%.
(4) Synthesis of 6- (3, 4-diaminophenyl) -3- (2- (piperidin-1-yl) ethyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.39g and 93.3%.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) - (2- (piperidin-1-yl) ethyl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in 2.02g, yield 52.1%.
(6) Synthesis of N- (6- (4-oxo-3- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide:
as in the step (6) in example 1, a white solid was obtained in 1.03g, a yield of 46.3%, a melting point of 245-]+445.2341。
Example 8
Synthesis of N- (6- (3- (2- (1H-indol-2-yl) ethyl) -4-oxo-3, 4-dihydro-quinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide (compound number H) comprising the following steps:
(1) synthesis of (3- (2- (1H-indol-2-yl) ethyl) -6-bromoquinazolin-4 (3H) -one:
as in the step (1) in example 1, a pale yellow solid was obtained in 14.63g, yield 79.5%.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 3- (2- (1H-indol-2-yl) ethyl) -6- (4-amino-3-nitrophenyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in a yield of 5.03g and 78.9%.
(4) Synthesis of 3- (2- (1H-indol-2-yl) ethyl) -6- (3, 4-diaminophenyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.60g and 91.1%.
(5) Synthesis of 3- (2- (1H-indol-2-yl) ethyl) -6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in a yield of 1.96g, 46.6%.
(6) Synthesis of N- (6- (3- (2- (1H-indol-2-yl) ethyl) -4-oxo-3, 4-dihydro-quinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide:
as in step (6) of example 1, a white solid was obtained in a yield of 1.01g and 42.5%Melting point 292-]+477.2024。
Example 9
Synthesis of N- (6- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide (compound number i) comprising the following steps:
(1) synthesis of 3-benzyl-6-bromoquinazolin-4 (3H) -one:
as in the step (1) in example 1, a pale yellow solid was obtained in 13.40g, yield 85.1%.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3-benzylquinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in a yield of 4.51g and 80.9%.
(4) Synthesis of 3-benzyl-6- (3, 4-diaminophenyl) -quinazolin-4 (3H) -one
As in the step (4) in example 1, a yellow solid was obtained in a yield of 3.15g and 92.2%.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) -3-benzylquinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in a yield of 1.53g and 41.7%.
(6) Synthesis of N- (6- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide:
as in the step (6) in example 1, a white solid was obtained in 0.91g, yield 43.1%, melting point 214-]+423.1726。
Example 10
Synthesis of N- (6- (3- (2- (dimethylamino) ethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide (compound No. j), comprising the steps of:
(1) synthesis of 6-bromo-3- (2- (dimethylamino) ethyl) quinazolin-4 (3H) -one:
as in the step (1) in example 1, a pale yellow solid was obtained in a yield of 12.82g and 86.6%.
(2) Synthesis of 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline:
as in step (2) of example 1.
(3) Synthesis of 6- (4-amino-3-nitrophenyl) -3- (2- (dimethylamino) ethyl) quinazolin-4 (3H) -one:
as in the step (3) in example 1, a yellow solid was obtained in a yield of 4.35g and 82.1%.
(4) Synthesis of 6- (3, 4-diaminophenyl) -3- (2- (dimethylamino) ethyl) quinazolin-4 (3H) -one:
as in the step (4) in example 1, a yellow solid was obtained in a yield of 3.03g and 93.7%.
(5) Synthesis of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl)) -3- (2- (dimethylamino) ethyl) quinazolin-4 (3H) -one:
as in the step (5) in example 1, a pale yellow solid was obtained in a yield of 1.69g, 48.6%.
(6) Synthesis of N- (6- (3- (2- (dimethylamino) ethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide:
as in the step (6) in example 1, a white solid was obtained in 1.00g, a yield of 49.7%, a melting point of 217 ℃ and 219 ℃. HRMS (ESI) [ M + H ]]+404.2026。
TABLE 1 preparation of the title Compounds from examples 1-101H NMR data
TABLE 2 carbon spectra data of the target compounds obtained in examples 1-10
Test example 1: the compounds prepared in examples 1 to 10 (Nos. a to j) were tested for their proliferation inhibitory activities against breast cancer, prostate cancer, non-small cell lung cancer and neuroblastoma.
(a) The test uses MTT method to detect the tumor proliferation inhibition activity of the compound of the invention, and the specific method is as follows: taking cell lines of five cancers such as breast cancer, prostate cancer, non-small cell lung cancer, neuroblastoma and the like in a logarithmic growth phase, counting and adjusting the cells to proper concentration, inoculating 100 mu L of the cells to a 96-well plate to enable the final cell density, adding 100 mu L of a drug with a corresponding concentration after culturing for 12h or adding 20 mu L of MTT to enable the final concentration to be 0.5mg/mL after DMSO treatment for 72 h. Co-incubation was carried out at 37 ℃ for 4 h. The supernatant was carefully aspirated, 200. mu.L of DMSO solution was added to each well, and OD was measured at 490nM or 570nM using a microplate reader after shaking for dissolution.
The inhibition rate is 100-cell survival rate%.
(b) The compounds prepared in examples 1-10 induced G2/M arrest in breast cancer cells.
MDA-MB-231 cells were seeded in 60mm dishes and incubated for 12h, then treated with different concentrations of active compounds a, i and j for 24 h. Cells were harvested and fixed overnight with pre-chilled 70% ethanol. The cells were centrifuged (2500rpm,5min,4 ℃), and then washed twice with 1 × PBS. After staining with propidium iodide staining solution at 37 ℃ for 30min, cell cycle detection was performed.
(c) The compounds prepared in examples 1-10 induced apoptosis of breast cancer cells.
The breast cancer cells in the logarithmic growth phase are taken and inoculated into a culture dish with the thickness of 100mm, and after 12 hours of culture, the cells are added with the compound with the corresponding concentration for treating for 48 hours. The cells were collected, resuspended in 500. mu.L Binding Buffer, Annexin V-FITC 5. mu.L and PI 5. mu.L were added and mixed gently, stained in the dark at room temperature for about 15min, and the samples were analyzed by flow cytometry.
(d) Inhibitory Activity of the Compounds prepared in examples 1 to 10 on aurora A
The aurora kinase inhibitory activity kit used in this test: (HTRF) KinEASE STK S2 kit (cat. 62T2PEB, Cisbio, France)) aurora kinase A kinase Activity assay was performed according to the kit instructions.
(e) Test results
TABLE 3 inhibitory Activity of the Compounds obtained in examples 1 to 10 on tumor cell proliferation
Analysis according to table 3 test results: (1) when the 2-position morpholine ethyl side chain of the quinazolinone ring is replaced by a dimethylamino ethyl side chain with strong electron donating effect (compound j), the anti-tumor activity is greatly improved; (2) when the hydrophilic side chain at position 2 of the quinazolinone ring is substituted with a hydrophobic aromatic ring (compound i), the water solubility is greatly reduced, and good antitumor activity can be exhibited only at a low concentration, resulting in a reduction in the pharmaceutical efficacy. Thus, this position may incorporate an aromatic ring with hydrophilic side chains in order to improve its anti-tumor activity while retaining its water solubility. From the results of the above table, it can be seen that R1The anti-tumor activity of the compound can be reduced by group substitution; r3When the amide side chain is used for prolonging the alkyl side chain or replacing the alkyl with a substituent group with larger steric hindrance, or when the amide side chain with weak electron supply function is replaced with sulfamide with medium electron-withdrawing function, the antitumor activity of the compound is greatly reduced. Hydrophilic and strongly charged R2The introduction of the group is beneficial to the improvement of the antitumor activity of the compound.
TABLE 4 aurora kinase inhibitory Activity of the Compounds prepared in examples 1-10
As shown in table 4, the active compounds a, i and j preferred in the present invention are capable of inhibiting the kinase activity of aurora kinase well. Wherein i has the best kinase inhibitory activity, and j has the best tumor cell proliferation inhibitory activity, but the kinase inhibitory activity is relatively weaker and weakest.
The results of the cycle block of the breast cancer cell by the representative active compounds a, i and j in the invention are shown in figure 1, and the compounds a, i and j can induce the breast cancer cell MDA-MB-231 to generate obvious G2/M phase block after acting on the breast cancer cell MDA-MB-231 for 24 hours. As shown in FIG. 2, representative active compounds a, i and j of the present invention all induced apoptosis of the breast cancer cell MDA-MB-231 after 48 hours.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.
Claims (4)
1. A6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -one compound has the following structural formula (I):
wherein:
R1is hydrogen atom, morpholine methyl, piperazine methyl or substituted piperazine methyl;
R2is hydrogen atom, butyl, morpholine substituted alkyl, benzyl, substituted benzyl, tryptamine, substituted tryptamine or N, N-dimethylamino;
R3is-C (O) R4or-SO2R5Wherein R is4、R5Is alkyl (alkyl with 3-6 carbon atoms), cycloalkyl (3-6 membered ring), alkoxy or alkyl substituted amino;
n is 1, 2, 3 or 4.
2. The 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -one compound according to claim 1, the specific compound is:
(a) n- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(b)1, 1-diethyl-3- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) urea;
(c) n- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) cyclopropylcarboxamide;
(d) n- (6- (3- (2-morpholinoethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) pentanamide;
(e) n- (6- (3- (3-morpholinopropyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(f) n- (6- (3-methyl-2- (morpholinomethyl) -4-oxo-3, 4 dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(g) n- (6- (4-oxo-3- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(h) n- (6- (3- (2- (1H-indol-2-yl) ethyl) -4-oxo-3, 4-dihydro-quinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(i) n- (6- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propionamide;
(j) n- (6- (3- (2- (dimethylamino) ethyl) -4-oxo-3, 4-dihydroquinazolin-6-yl) -1H-benzo [ d ] imidazol-2-yl) propanamide.
3. A process for the preparation of 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -one compounds according to claim 1, comprising the steps of:
(1) using 2-amino-5-bromobenzoic acid as a starting material, different substituted 6-bromoquinazolin-4 (3H) -ones were prepared by one of two general methods:
method 1
Method two
(2) Preparing 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline by taking 4-bromo-2-nitroaniline and pinacol diboron as raw materials, dioxane as a solvent and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst:
(3) preparing 6- (4-amino-3-nitrophenyl) -3-quinazolin-4 (3H) -one from 2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline and various substituted 6-bromoquinazolin-4 (3H) -ones as raw materials and dioxane/deionized water (v: v ═ 4:1) as a solvent:
(4) nitro reduction, hydrazine monohydrate as a reducing agent, palladium/carbon as a catalyst, and methanol as a solvent to prepare the corresponding o-phenylenediamine:
(5) preparing 6- (2-amino-1H-benzo [ d ] imidazol-6-yl) quinazolin-4 (3H) -one using 6- (3, 4-diaminophenyl) quinazolin- (3H) -one and nitrile bromide as raw materials and tetrahydrofuran/deionized water (v: v ═ 1:1) as solvent:
(6) preparing the 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone derivative by using 6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone and different acyl chloride as raw materials, triethylamine as an acid-binding agent and tetrahydrofuran as a solvent:
4.6- (2-amino-1H-benzo [ d ] imidazole-6-yl) quinazoline-4 (3H) -ketone compounds in the preparation of antitumor drugs.
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| CN116253686A (en) * | 2022-12-09 | 2023-06-13 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Aminobenzimidazole benzamide derivative and application thereof |
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| CN116253686A (en) * | 2022-12-09 | 2023-06-13 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Aminobenzimidazole benzamide derivative and application thereof |
| CN116253686B (en) * | 2022-12-09 | 2023-11-17 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Aminobenzimidazole benzamide derivative and application thereof |
| CN116239594A (en) * | 2023-03-05 | 2023-06-09 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof |
| CN116239594B (en) * | 2023-03-05 | 2023-09-22 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 6- (imidazo [1,2-a ] pyridin-6-yl) quinazoline derivatives and uses thereof |
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