Use of a benzimidazole amine derivative in the preparation of an antitumor pharmaceutical composition

Abstract

The application discloses application of a benzimidazole amine derivative in preparation of an antitumor pharmaceutical composition, in particular, application of a benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative in preparation of an antitumor pharmaceutical composition. The benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative provided by the application has a significant inhibiting effect on colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, neuroglioma and breast cancer, shows excellent antitumor characteristics, can be used as a leading drug molecule for resisting tumors, and has a good development and application prospect in development of antitumor drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of antitumor drugs, and relates to application of a benzimidazole amine derivative in preparation of an antitumor drug composition, in particular to application of a benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative in preparation of an antitumor drug composition.

BACKGROUND TECHNIQUE

[0002] Cancer is a malignant tumor originating from epithelial tissue, a disease characterized by rapid cell proliferation and metastasis, and the mortality rate ranks first among all diseases. At present, there are mainly four ways to treat cancer in clinic: surgical treatment, radiotherapy, chemical drug treatment and immunotherapy. Compared with the other three methods, chemical drug treatment is generally painless, and the killing power of cancer cells is difficult to achieve by other means of treating cancer. However, most of the chemical drugs do not have specificity, and while killing cancer cells, they will cause damage to normal tissue cells around the tumor, and these tissues can only be self-repaired after chemotherapy. Therefore, the development of new antitumor drugs to save more patients suffering from cancer is a health high point that countries compete for.

[0003] At present, there have been a lot of research on anti-tumor drugs, for example, Chinese patent application No. CN201210008715.2 discloses a 6-phenyl imidazo [2, 1-b] thiazole-3-amide derivative and its preparation method and application. The structural formula of the compound is shown as formula I, R1 is H, or R1 is one or more of the following groups: fluorine, chlorine, bromine, methyl, methoxy, hydroxyl, nitro, amino, trifluoromethyl and cyano, which are single or multiple substituted on the benzene ring; R2 is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, hydroxyl, thiol, amino, methylamino, ethylamino, morpholine, piperazine, methylpiperazine, ethylpiperazine, benzylpiperazine, p-methoxybenzylpiperazine or p-chlorobenzylpiperazine; n is 0 or 1 or 2. The raw material for preparing the above derivative is easy to obtain, the reaction is simple, the synthesis process is simple and easy to operate. The compound has good anti-tumor activity, and has important practical value and application prospect in the field of anti-tumor drugs. CN201710692103.2 A preparation method of N-phenyl-3-benzylidene isoindole-1-ketone phosphine derivative, comprising the following steps: the substituted N-phenyl-3-benzylidene isoindole-1-ketone derivative of formula (1) and the diphenyl phosphine oxide of formula (2) are reacted under the catalysis of silver salt in an organic solvent containing nitrate at 0-35 DEG C to obtain the N-phenyl-3-benzylidene isoindole-1-ketone phosphine derivative of formula (3), and the reaction route is as follows: wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 are independently selected from hydrogen, alkyl, alkoxy, halogen or trifluoromethyl. The method of the present application can obtain a plurality of N-phenyl-3-benzylidene isoindole-1-ketone phosphine derivatives with high yield; the reaction condition is mild, the operation and post-treatment process are simple, and it is suitable for large-scale production.

[0004] At present, there is no related research report on the anti-tumor biological activity or clinical application of benz(4, 5) imidazo (2, 1-a) isoindole-2-methyl prop-2-amine derivative.

SUMMARY

[0005] The application provides a benzimidazole amine derivative in the preparation of an antitumor drug composition.

[0006] The application provides a benzimidazole amine derivative in the preparation of an antitumor drug composition.

[0007] The benzimidazole amine derivative is specifically a benz(4, 5) imidazo (2, 1-a) isoindole-2-methyl prop-2-amine derivative, and the chemical structural formula is as follows:

[0008]

[0009] wherein R1 is one of -H, -Cl, -CH3,

[0010] further, R1 is one of -H, -Cl, R2 is one of -H, -CH3,

[0011] The above-mentioned benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives are realized by the following synthetic route, the specific steps are as follows:

[0012]

[0013] Take a 25 mL reaction tube, add 2-(2-bromophenyl)-1H-benzo[d]imidazole 1 (0.2 mmol), isonitrile 2 (0.3 mmol), Pd(OAc)2 (10 mol%), PPh3 (10 mol%), toluene (1 mL) in turn, and stir at 100℃ for 8 hours. After the reaction is completed, quench the reaction by adding 10 mL of water, extract 3 times (3×10 mL) with ethyl acetate, recover the organic layer, and concentrate with a rotary evaporator. The crude product is separated by column chromatography to obtain the target product 3, and the developing agent used is n-hexane / ethyl acetate (5 / 1). The product is further subjected to structure confirmation by nuclear magnetic resonance and high-resolution mass spectrometry testing methods.

[0014] The above-mentioned benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives are used in the preparation of antitumor pharmaceutical compositions.

[0015] The application of the above-mentioned benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives in the preparation of antitumor pharmaceutical compositions is to use benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives as candidate drugs or lead compounds for treating tumors. Benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives have inhibitory activity on various tumor cells, which lays a foundation for the development of new antitumor drugs.

[0016] The application of the above-mentioned benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives in the preparation of antitumor pharmaceutical compositions is to use benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives as candidate drugs or lead compounds for treating tumors. Benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivatives have inhibitory activity on various tumor cells, which lays a foundation for the development of new antitumor drugs.​​

[0017] The use of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative in the preparation of an antitumor pharmaceutical composition, wherein the tumor includes, but is not limited to, colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma and breast cancer.

[0018] Further, the use of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative in the preparation of an antitumor pharmaceutical composition, wherein the pharmaceutical composition is prepared into a clinically acceptable pharmaceutical preparation with the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative as the main component, plus pharmaceutically acceptable excipients or auxiliary components, and the content of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative in the pharmaceutical composition is usually 0.1-95.0% (w / w).

[0019] Further, the use of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative in the preparation of an antitumor pharmaceutical composition, wherein the pharmaceutical preparation includes two dosage forms of oral preparation and injection preparation.

[0020] Further, the use of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative in the preparation of an antitumor pharmaceutical composition, wherein the oral preparation is an oral capsule, and the injection preparation is an intravenous injection.

[0021] Generally, as a drug, it is clinically used only after being prepared into a preparation. The pharmaceutical composition of the present application, as a pharmaceutical composition, can be prepared according to the methods known in the art. It can be prepared into any dosage form suitable for human or animal use by combining the pharmaceutical composition of the present application with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0022] The pharmaceutical composition of the present application or the pharmaceutical composition containing it can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0023] The administration form can be a liquid form, a solid form or a semi-solid form. The liquid form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), eye drops, nose drops, lotion and liniment, etc.; the solid form can be a tablet (including ordinary tablet, enteric-coated tablet, chewable tablet, dispersible tablet, effervescent tablet, oral disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric-coated capsule), a granule, a powder, a pellet, a drop, a suppository, a film, a patch, an aerosol (powder) spray, a spray, etc.; the semi-solid form can be an ointment, a gel, a paste, etc.

[0024] The pharmaceutical composition of the present application can be prepared into a common preparation, a sustained-release preparation, a controlled-release preparation, a targeted preparation and various micro-particle administration systems. In order to prepare the tablet of the pharmaceutical composition of the present application, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0025] The tablet can be further prepared into a coated tablet, such as a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, or a double-layer tablet and a multi-layer tablet.

[0026] In order to prepare the capsule of the administration unit, the effective component, i.e. the pharmaceutical composition of the present application, can be mixed with diluents and glidants, and the mixture can be directly placed in a hard capsule or a soft capsule. Alternatively, the effective component, i.e. the pharmaceutical composition of the present application, can be mixed with diluents, binders and disintegrants to prepare granules or pellets, and then the granules or pellets can be placed in a hard capsule or a soft capsule. The various diluents, binders, wetting agents, disintegrants and glidants used for preparing the tablet of the pharmaceutical composition of the present application can also be used for preparing the capsule of the pharmaceutical composition of the present application.

[0027] For preparing the injection of the pharmaceutical composition of the present application, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent and proper amount of solubilizer, co-solvent, pH regulator, osmotic pressure regulator commonly used in the art can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin and the like; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like. If lyophilized powder injection is prepared, mannitol, glucose and the like can also be added as supporting agent.

[0028] In addition, if necessary, coloring agent, preservative, flavoring agent, odorant or other additive can also be added to the pharmaceutical preparation.

[0029] Compared with the prior art, the present application has the following advantages:

[0030] 1. The application of the benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivative in the preparation of an antitumor pharmaceutical composition has good antitumor effect, and the benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivative has better inhibitory effect on tumor cells than the positive drug 5-fluorouracil.

[0031] 2. The application of the benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivative in the preparation of an antitumor pharmaceutical composition has wide antitumor range, and the benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivative shows good inhibitory activity on liver cancer, lung cancer, cervical cancer, breast cancer, gastric cancer and breast cancer.

[0032] 3. The application of the benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivative in the preparation of an antitumor pharmaceutical composition has obvious cost advantage, the benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivative is synthesized by chemical catalysis, the catalytic condition is mild, the price is low, and the economic burden of patients can be reduced. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 is the diagram of the chemical structural formula of the benzene (4, 5) imidazole (2, 1-a) isoindole-2-methyl prop-2-amine derivative of the present application. DETAILED DESCRIPTION

[0034] The specific embodiments of the present application are further illustrated below in conjunction with examples.

[0035] Benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives are achieved by the following synthetic route, the specific steps are as follows:

[0036]

[0037] Take a 25 mL reaction tube, add 2-(2-bromophenyl)-1H-benzo[d]imidazole 1 (0.2 mmol), isonitrile 2 (0.3 mmol), Pd(OAc)2(10 mol%), PPh3(10 mol%), toluene (1 mL) in turn, and stir the reaction at 100°C for 8 hours. After the reaction is completed, quench the reaction by adding 10 mL of water and extract 3 times with ethyl acetate (3 x 10 mL), recover the organic layer, and concentrate it with a rotary evaporator. The crude product is separated by column chromatography to obtain the target product 3, using n-hexane / ethyl acetate (5 / 1) as the developing agent. The product is further characterized by nuclear magnetic resonance and high-resolution mass spectrometry.

[0038] Example 1:

[0039] Preparation of compound 1: 2-(2-bromophenyl)-1H-benzo[d]imidazole is reacted with tert-butyl isonitrile in the presence of palladium acetate (10% mmol), triphenylphosphine (10% mmol), potassium phosphate (3 equiv) at 100°C for 8 hours to obtain the target compound (compound 1, whose structural formula is shown below), with a yield of 80%.

[0040] The technical route for preparing compound 1 is:

[0041]

[0042] The nuclear magnetic resonance data of compound 1 are as follows: 1 H NMR (600 MHz, CDCl 3, δ ppm) 7.95 (dd, J = 14.2, 7.8 Hz, 2H), 7.91 (d, J = 7.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.24 (dd, J = 11.2, 4.0 Hz, 1H), 7.21-7.18 (m, 1H), 1.59 (s, 9H). 13 C NMR (151 MHz, CDCl 3,δppm)154.5,148.2,142.6,132.5,131.6,131.3,130.4,129.5,128.5,124.2,1 23.0,121.7,119.9,112.5,76.8,76.5,76.3,53.9,30.1.HRMS(ESI)m / z:calcd for C 18 H 17 N3Na[M+Na] + 298.1320; found 298.1313.

[0043] Example 2:

[0044] Preparation of compound 2: 2-(6-bromobenzo[d][1,3]dihydroxy-5-yl)-1H-benzo[d]imidazolium was reacted with tert-butylisocyanate in palladium acetate (10% mmol), triphenylphosphine (10% mmol), and tripotassium phosphate (3 equiv) at 100 °C for 8 hours to obtain the target compound (compound 2, the structural formula of which is shown below), with a yield of 81.2%.

[0045] The technical route for preparing compound 2 is as follows:

[0046]

[0047] The NMR data for compound 2 are as follows: 1 H NMR (600MHz, CDCl) 3, δppm)7.84(d,J=7.8Hz,1H),7.60(d,J=7.9Hz,1H),7.38(s,1H),7.29(s, 1H),7.19(d,J=2.4Hz,1H),7.15-7.12(m,1H),6.06(s,2H),1.53(s,9H). 13 C NMR (151MHz, CDCl) 3, δppm)154.8,150.4,149.5,148.3,142.5,131.1,128.6,126.3,124.6,123.2,120.1,112.6,109.6,102.6,54.2,30.7.HRMS(ESI)m / z:calcd for C 19 H 17 N3O2Na[M+Na] + 342.1218; found 342.1213.

[0048] Example 3:

[0049] Preparation of compound 3: 2-(2-bromo-4-(trifluoromethyl)phenyl)-1H- benzo[d]imidazole was reacted with tert-butyl isocyanide in the presence of palladium acetate (10% mmol), triphenylphosphine (10% mmol), potassium phosphate tribasic (3 equiv) at 100 °C for 8 hours to give the target compound (compound 3, whose structural formula is shown in the figure below), with a yield of 68.8%.

[0050] The technical route for preparing compound 3 is as follows:

[0051]

[0052] The nuclear magnetic resonance data of compound 3 are as follows: 1 H NMR (600 MHz, CDC13) δ 8.22 (s, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.36-7.32 (m, 1H), 7.31-7.27 (m, 1H), 1.66 (s, 9H). 3, C NMR (151 MHz, CDC13) δ 153.1, 148.3, 141.3, 135.8, 132.1, 131.7 (q, J = 32.8 Hz), 131.6, 130.5, 128.9, 128.8, 128.7 (q, J = 2.1 Hz), 125.9, 125.3 (q, J = 3.7 Hz), 123.9, 122.3 (d, J = 19.7 Hz), 120.6, 113.1, 54.5, 30.6. 13 H 3, δ ppm) 153.1, 148.3, 141.3, 135.8, 132.1, 131.7 (q, J = 32.8 Hz), 131.6, 130.5, 128.9, 128.8, 128.7 (q, J = 2.1 Hz), 125.9, 125.3 (q, J = 3.7 Hz), 123.9, 122.3 (d, J = 19.7 Hz), 120.6, 113.1, 54.5, 30.6. HRMS (ESI) m / z: calcd for C 19 H 17 N3O2Na[M+Na] + 366.1194; found 366.1184.

[0053] Example 4:

[0054] Preparation of compound 4: 2-(2-bromo-4-chlorophenyl)-1H-benzo[d]imidazole was reacted with tert-butyl isocyanide in the presence of palladium acetate (10% mmol), triphenylphosphine (10% mmol), potassium phosphate tribasic (3 equiv) at 100 °C for 8 hours to give the target compound (compound 4, whose structural formula is shown in the figure below), with a yield of 77%.

[0055] The technical route for preparing compound 4 is as follows:

[0056]

[0057] The NMR data of compound 4 is as follows: 1 H NMR (400 MHz, CDCb 3, δ ppm) 7.95 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.68 - 7.53 (m, 2H), 7.51 - 7.42 (m, 2H), 6.97 - 6.86 (m, 1H), 1.57 (s, 9H). 13 C NMR (101 MHz, CDCb 3, δ ppm) 161.94 (s), 159.6, 145.2, 142.6, 131.9, 130.1, 129.0, 122.1, 120.9, 120.8, 111.5, 111.2, 100.3, 100.0, 54.5, 30.6. HRMS (ESI) m / z: calcd for C 18 H 16 CLN3Na [M + Na] + 332.0930; found 332.0940.

[0058] Example 5:

[0059] Preparation of compound 5: 2-(2-bromo-4-(trifluoromethyl)phenyl)-5-methoxy-1H- benzo[d]imidazole was reacted with tert-butyl isocyanide in the presence of palladium acetate (10% mmol), triphenylphosphine (10% mmol), potassium phosphate tribasic (3 equiv) at 100 °C for 8 hours to obtain the target compound (compound 5, whose structural formula is shown in the figure below), with a yield of 76%.

[0060] The technical route for preparing compound 5 is as follows:

[0061]

[0062] The NMR data of compound 5 is as follows: 1 H NMR (400 MHz, CDCb 3, δ ppm) 8.21 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.9, 2.6 Hz, 1H), 3.89 (s, 3H), 1.65 (s, 9H). 13 C NMR (101 MHz, CDCb 3,δ ppm) 167.3, 158.5, 152.4, 143.0, 141.6 (q, J = 5.4 Hz), 141.4, 132.1, 131.6, 131.5, 129.21, 128.96 (q, J = 3.7 Hz), 125.5 (q, J = 4.1 Hz), 125.4, 122.0, 121.3, 112.8, 97.1, 55.7, 54.6, 30.8. HRMS (ESI) m / z: calcd for C 20 H 18 F3N3ONa[M+Na] + 396.1300; found 396.1293.

[0063] Example 6:

[0064] Preparation of compound 6: 2-(2-bromo-5-methylphenyl)-lH-benzo[d]imidazole was reacted with tert-butyl isocyanide in the presence of palladium acetate (10% mmol), triphenylphosphine (10% mmol), potassium phosphate tribasic (3 equiv) at 100 °C for 8 h to give the target compound (compound 6, whose structural formula is shown in the figure below), with a yield of 75%.

[0065] The technical route for preparing compound 6 is:

[0066]

[0067] The nuclear magnetic resonance data of compound 6 are as follows: 1 H NMR (400 MHz, DMSO , δ ppm) 8.00 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 7.8, 0.9 Hz, 1H), 7.26-7.21 (m, 1H), 2.45 (s, 3H), 1.57 (s, 9H). 13 CNMR (101 MHz, DMSO , δ ppm) 155.0, 148.8, 143.6, 143.4, 132.6, 132.0, 130.8, 129.8, 129.1, 125.1, 123.9, 122.9, 120.8, 112.9, 54.4, 30.7, 21.5. HRMS (ESI) m / z: calcd for C 19 H 19 N3Na[M+Na] +312.1477; found 312.1476.

[0068] Example 7:

[0069] Preparation of compound 7: 2-(2-bromo-4-methoxyphenyl)-1H-benzo[d]imidazole was reacted with tert-butylisocyanate in palladium acetate (10% mmol), triphenylphosphine (10% mmol), and tripotassium phosphate (3 equiv) at 100 °C for 8 hours to obtain the target compound (compound 7, the structural formula of which is shown in the figure below), with a yield of 63%.

[0070] The technical route for preparing compound 7 is as follows:

[0071]

[0072] The NMR data for compound 7 are as follows: 1 H NMR (600MHz, CDCl) 3, δppm)7.99(d,J=7.8Hz,1H),7.90(d,J=8.7Hz,1H),7.72(d,J=8.0Hz,1H),7.47(d,J=2.5Hz,1H ),7.32-7.28(m,1H),7.27-7.23(m,1H),6.98(dd,J=8.7,2.5Hz,1H),3.93(s,3H),1.62(s,9H). 13 C NMR (151MHz, CDCl) 3, δppm)161.33,153.9,147.7,142.4,134.2,130.0,129.4,123.8,123.5,122.4,119.4,115.3,112.1,105.7,54.9,53.2,29.7.HRMS(ESI)m / z:calcdfor C 19 H 19 N3ONa[M+Na] + 328.1426; found 328.1428.

[0073] Example 8:

[0074] Preparation of compound 8: 2-(2-bromo-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole was reacted with 1,1,3,3-tetramethylbutylisocyanurate at 100 °C for 8 hours in palladium acetate (10% mmol), triphenylphosphine (10% mmol), and tripotassium phosphate (3 equiv) to obtain the target compound (compound 8, the structural formula of which is shown in the figure below), with a yield of 68.8%.

[0075] The technical route for preparing compound 8 is as follows:

[0076]

[0077] The NMR data for compound 8 are as follows: 1 H NMR (600MHz, CDCl) 3, δppm)8.29(s,1H),7.86(d,J=7.9Hz,1H),7.77(d,J=8.0Hz,1H),7.35(d,J=15.1Hz,1H),2.04(s,2H),1.70(s,6H),1.05(s,9H). 13 C NMR (151MHz, CDCl) 3, δppm)152.80(t,J=5.7Hz),140.0,132.1,128.51(q,J=3.2Hz),125.4,125.3,125.1(q,J=2.9Hz),125.0,124.9,124.1,124. 0(q,J=5.7Hz),128.9,123.8,123.7,122.3,122.2,122.0,120.3,112.8,58.6,54.8,31.7,31.5,30.6.HRMS(ESI)m / z:calcd for C 23 H 24 F3N3Na[M+Na] + 422.1820; found 422.1813.

[0078] Example 9:

[0079] Preparation of compound 9: 2-(2-bromophenyl)-1H-benzo[d]imidazole was reacted with 1,1,3,3-tetramethylbutylisocyanurate in palladium acetate (10% mmol), triphenylphosphine (10% mmol), and tripotassium phosphate (3 equiv) at 100 °C for 8 hours to obtain the target compound (compound 9, the structural formula of which is shown in the figure below), with a yield of 86%.

[0080] The technical route for preparing compound 9 is as follows:

[0081]

[0082] The NMR data for compound 9 are as follows: 1 H NMR (600MHz, DMSO) ,δ ppm) 8.18 (d, J = 7.4 Hz, 1H), 7.94 - 7.92 (m, 2H), 7.71 - 7.67 (m, 3H), 7.32 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 2.03 (s, 2H), 1.64 (s, 6H), 0.98 (s, 9H). 13 C NMR (151 MHz, DMSO , δ ppm) 154.9, 148.8, 142.4, 132.9, 132.5, 132.0, 131.6, 130.9, 129.8, 125.2, 124.0, 122.6, 120.8, 112.9, 58.7, 55.0, 39.5, 32.3, 31.2. HRMS (ESI) m / z: calcd for C 22 H 25 N3Na[M + Na] + 354.1946; found 354.1949.

[0083] Example 10:

[0084] Preparation of compound 10: 2-(2-bromophenyl)-1H-naphtho[2,3-d]imidazole was reacted with tert-butyl isocyanide in the presence of palladium acetate (10% mmol), triphenylphosphine (10% mmol), potassium phosphate tribasic (3 equiv) at 100 °C for 8 hours to give the target compound (compound 10, whose structural formula is shown below), with a yield of 76%.

[0085] The technical route for preparing compound 10 is:

[0086]

[0087] The nuclear magnetic resonance data of compound 10 are as follows: 1 H NMR (400 MHz, CDC13) 3, δ ppm) 8.29 (s, 1H), 8.08 (s, 1H), 7.98 (t, J = 8.3 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 12.1, 4.2 Hz, 2H), 7.34 (td, J = 7.2, 1.3 Hz, 2H), 1.61 (s, 9H). 13 C NMR (101 MHz, CDC13) 3,δ ppm) 157.8, 148.5, 142.7, 132.8, 132.2, 131.7, 131.4, 130.7, 130.6, 130.5, 130.3, 128.7, 128.4, 127.8, 124.8, 123.9, 122.7, 117.5, 109.2, 54.2, 30.6. HRMS (ESI) m / z: calcd for C 22 H 19 N3Na[M+Na] + 348.1477; found 348.1478.

[0088] The beneficial effects of the drugs of the present application are further illustrated by pharmacodynamic tests and comparative tests. The tumor cell lines used in the experiments of the present application are human colon cancer cell HCT116, human hepatoma cell HepG-2, human lung cancer cell A549, human prostate cancer cell PC3, human cervical cancer cell Hela, human glioma cancer cell U87, and human malignant breast cancer cell 4T1.

[0089] In vitro anti-tumor cell activity test of benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives:

[0090] 1. Cells and drugs:

[0091] Human colon cancer cell HCT116, human hepatoma cell HepG-2, human lung cancer cell A549, human prostate cancer cell PC3, human cervical cancer cell Hela, human glioma cancer cell U87, and human malignant breast cancer cell 4T1 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.

[0092] Positive drug: 5-fluorouracil (5-Fu), purchased from Sigma Aldrich Company (St. Louis, MO, USA), purity > 99.5% (HPLC).

[0093] 2. Experimental method

[0094] Logarithmic growth phase tumor cells 5.0 x 10 4 cells / mL were inoculated into 96-well plates, 200 μL per well, and cultured at 37°C and 5% CO2 for 24 h;

[0095] The test samples were dissolved in dimethyl sulfoxide (DMSO), and then a sample culture solution with a final concentration of 1.0-100 μM was prepared using fresh culture medium and added to the 96-well plates, which were then incubated at 37°C and 5% CO2 for 24 h;

[0096] Remove the culture medium, add 100 μL of MTT with a concentration of 0.5 mg / mL per well, and incubate at 37°C and 5% CO2 for 3-4 h; carefully remove the culture solution, add 100 μL of DMSO, and shake well to dissolve the crystals;

[0097] Determine the absorbance value by using an enzyme-labeled instrument at 570 nm as the experimental wavelength and 630 nm as the reference wavelength, and IC 50 The IC50 value is calculated by using the LOGIT method.

[0098] 3. Experimental results

[0099] As shown in Table 1, the experimental results show that the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative has obvious inhibitory effect on human colon cancer cells HCT116, human liver cancer cells HepG-2, human lung cancer cells A549, human prostate cancer cells PC3, human cervical cancer cells Hela, human glioma cancer cells U87, and human breast cancer cells 4T1, and the IC 50 value of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative on the above tumor cells is 53.33-94.58 μmol / L.

[0100] Table 1 IC50 value of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative on various tumor cells 50

[0101]

[0102] In summary, the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivative has obvious inhibitory effect on colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma cancer, and breast cancer, exhibits excellent anti-tumor properties, can be used as a lead drug molecule for anti-tumor, and has good development and application prospects in the development of anti-tumor drugs.

[0103] Although the present application has been described in detail in the foregoing description with general principles and specific embodiments, some modifications or improvements can be made on the basis of the present application, which is obvious to those skilled in the art. Therefore, these modifications or improvements made on the basis of not deviating from the spirit of the present application, all belong to the scope of protection claimed by the present application.​

Claims

1. The use of a benzimidazole amine derivative in the preparation of an antitumor drug composition, characterized in that: Specifically, the application of benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives in the preparation of antitumor pharmaceutical compositions; the tumors include colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma and breast cancer; The chemical structural formula of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives is as follows: ， R1 is hydrogen, chlorine or methoxy; R2 is hydrogen, methyl, methoxy or trifluoromethyl; and R3 is isobutyl. The benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives also include the following compounds: , , and / or .

2. The use of a benzimidazole amine derivative according to claim 1 in the preparation of an antitumor pharmaceutical composition, characterized in that: The benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives are used as candidate drugs for treating tumors.

3. The use of a benzimidazole amine derivative according to claim 1 in the preparation of an antitumor pharmaceutical composition, characterized in that: The therapeutic object of the pharmaceutical composition is a mammal.

4. The use of a benzimidazole amine derivative according to claim 1 in the preparation of an antitumor pharmaceutical composition, characterized in that: The pharmaceutical composition is prepared by using benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives as the main component, adding pharmaceutically acceptable adjuvants or auxiliary components, and then preparing clinically acceptable pharmaceutical preparations; the content of the benz(4,5)imidazo(2,1-a)isoindole-2-methylprop-2-amine derivatives in the pharmaceutical composition is 0.1-95.0% w / w.

5. Use of a benzimidazole amine derivative according to claim 4 for the preparation of antitumor pharmaceutical compositions, characterized in that: The pharmaceutical preparation includes two dosage forms of oral preparations and injection preparations.

6. The use of a benzimidazole amine derivative according to claim 5 for the preparation of an antitumor pharmaceutical composition, characterized in that: The oral preparation is an oral capsule, and the injection preparation is an intravenous injection solution.

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