Application of indoloquinazolinone derivative in preparation of antitumor drug composition

Abstract

The invention belongs to the technical field of antitumor drugs. In particular discloses application of indoloquinazolinone derivatives in preparation of anti-tumor pharmaceutical compositions, the derivatives have remarkable inhibition effects on colon cancer, liver cancer, lung cancer, prostatic cancer, cervical cancer, glial cancer and breast cancer, show excellent anti-tumor characteristics, can be used as anti-tumor lead pharmaceutical molecules, and have broad application prospects. Good development and application prospects are realized in the aspect of developing anti-tumor drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of antitumor drugs, and relates to application of an indoloquinazolinone derivative in preparation of an antitumor drug composition, in particular to application of a 12-aminoisoindoloquinazolinone derivative in preparation of an antitumor drug composition. BACKGROUND

[0002] Cancer, also known as malignant tumor, has long been a serious threat to human health due to its high incidence, high mortality, high recurrence rate and great difficulty in treatment. In the 21st century, it still remains a second health killer after cardiovascular disease, and continues to pose a great challenge to global public health. Therefore, it is particularly urgent to seek more effective cancer treatment strategies. At present, the main weapons against tumors include surgical resection, radiotherapy and drug therapy. Among them, drug therapy has become an indispensable core means in clinical tumor treatment due to its systemic effect and non-invasive characteristics. Although decades of development have resulted in dozens of chemotherapeutic drugs and adjuvant therapy drugs being applied in clinical practice, and significant effects or even cure possibilities have been achieved in some tumor types, the limitations of existing drugs are still prominent. Most drugs can only temporarily inhibit tumor growth and relieve clinical symptoms when fighting advanced or invasive tumors, and it is difficult to achieve a cure, often accompanied by significant toxic side effects and drug resistance problems. Therefore, in the face of this complex and stubborn disease, continuous research and development of new and efficient antitumor drugs is still the core direction and relentless pursuit of current and future antitumor drug research. SUMMARY

[0003] The present application provides a new compound and its application in antitumor, in particular, application of an indoloquinazolinone derivative in preparation of an antitumor drug composition.

[0004] The present application provides an indoloquinazolinone derivative, in particular, a 12-aminoisoindoloquinazolinone derivative, whose chemical structural formula is shown in the following:

[0005]

[0006] wherein, R1 is one of -H, -Cl and -CH3; R2 is one of -H, -Cl, -F and -CH3; and R3 is one of isobutyl and 1,1,3,3-tetramethylbutyl.

[0007] Further, the 12-aminoisoindoloquinazolinone derivative is selected from any one of the compounds shown in the following structural formula:

[0008]

[0009] The 12-aminoisoindoloquinazolinone derivative is synthesized by the following synthetic route, and the specific steps are as follows:

[0010]

[0011] A 25ml reaction tube is taken, and first, the reaction tube is sequentially added with o-aminobenzamide derivative 1 (0.1mmol), o-bromobenzaldehyde derivative 2 (0.1mmol) and 1,4-dioxane (1mL), and then the reaction is continuously carried out at 100℃ for 8 hours, and then the reaction solution is cooled to room temperature. Subsequently, bis-cyanobenzene dichloropalladium (10mol%), triphenylphosphine (20.0mol%), sodium acetate (3.0equiv) and isonitrile derivative 3 (0.15mmol) are sequentially added, and the reaction is continuously carried out at 100℃ for 8 hours. After the reaction is completed, 10mL of water is added to quench the reaction, and the reaction is extracted with ethyl acetate for three times (3x10mL), and then the organic layer is recovered and concentrated by a rotary evaporator. The crude product is separated by column chromatography to obtain the target product 4, and the product is subjected to structure confirmation by nuclear magnetic resonance and high-resolution mass spectrometry testing methods.

[0012] The present application also provides the use of the 12-aminoisoindoloquinazolinone derivative in the preparation of an antitumor pharmaceutical composition.

[0013] Further, the use of the 12-aminoisoindoloquinazolinone derivative in the preparation of an antitumor pharmaceutical composition is to use the 12-aminoisoindoloquinazolinone derivative as a candidate drug or a lead compound for treating tumors, and to lay a foundation for the development of new antitumor drugs by virtue of the inhibitory activity of the 12-aminoisoindoloquinazolinone derivative on various tumor cells.

[0014] Further, the use of the 12-aminoisoindoloquinazolinone derivative in the preparation of an antitumor pharmaceutical composition is to use the 12-aminoisoindoloquinazolinone derivative as a candidate drug or a lead compound for treating tumors, and to lay a foundation for the development of new antitumor drugs by virtue of the inhibitory activity of the 12-aminoisoindoloquinazolinone derivative on various tumor cells.

[0015] Further, the use of the 12-aminoisoindoloquinazolinone derivative in the preparation of an antitumor pharmaceutical composition is to use the 12-aminoisoindoloquinazolinone derivative as a candidate drug or a lead compound for treating tumors, and to lay a foundation for the development of new antitumor drugs by virtue of the inhibitory activity of the 12-aminoisoindoloquinazolinone derivative on various tumor cells.

[0016] Further, the use of the 12-aminoisoindoloquinazolinone derivative in the preparation of an antitumor pharmaceutical composition is to use the 12-aminoisoindoloquinazolinone derivative as a candidate drug or a lead compound for treating tumors, and to lay a foundation for the development of new antitumor drugs by virtue of the inhibitory activity of the 12-aminoisoindoloquinazolinone derivative on various tumor cells. Further, the use of the 12-aminoisoindoloquinazolinone derivative in the preparation of an antitumor pharmaceutical composition is to use the 12-aminoisoindoloquinazolinone derivative as a candidate drug or a lead compound for treating tumors, and to lay a foundation for the development of new antitumor drugs by virtue of the inhibitory activity of the 12-aminoisoindoloquinazolinone derivative on various tumor cells.

[0017] Furthermore, the 12-aminoisoindolylquinazolinone derivative is used in the preparation of antitumor drug compositions, wherein the drug formulation includes both oral and injectable dosage forms.

[0018] Furthermore, in the application of the 12-aminoisoindolylquinazolinone derivative in the preparation of antitumor drug compositions, the oral formulation is an oral capsule, and the injectable formulation is an intravenous injection solution.

[0019] Typically, pharmaceuticals are clinically used only after being formulated into a pharmaceutical composition. The pharmaceutical compositions described in this invention can be prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use by combining the pharmaceutical compositions of this invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0020] The pharmaceutical composition of the present invention, or a pharmaceutical composition containing it, can be administered in unit dose form, and the route of administration can be enteric or non-enteric, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0021] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0022] The pharmaceutical compositions of the present invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various particulate delivery systems. To formulate the pharmaceutical compositions of the present invention into tablets, a wide range of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0023] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0024] To formulate the drug delivery unit into capsules, the active ingredient, the pharmaceutical composition of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the pharmaceutical composition of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the pharmaceutical composition of the present invention can also be used to prepare capsules of the pharmaceutical composition of the present invention.

[0025] To prepare the pharmaceutical composition of the present invention into an injection, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure regulators can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing a lyophilized powder injection, mannitol, glucose, etc., can also be added as a support agent.

[0026] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] 1. The application of the 12-aminoisoindolequinazolinone derivatives of the present invention in the preparation of antitumor drug compositions has good antitumor effects. The inhibitory effect of the 12-aminoisoindolequinazolinone derivatives on tumor cells is close to that of the positive control drug 5-fluorouracil.

[0029] 2. The 12-aminoisoindolequinazolinone derivatives of the present invention have a broad range of antitumor effects in the preparation of antitumor drug compositions. The 12-aminoisoindolequinazolinone derivatives show good inhibitory activity against colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma and breast cancer.

[0030] 3. The application of the 12-aminoisoindolequinazolinone derivatives described in this invention in the preparation of antitumor drug compositions has significant cost advantages. The 12-aminoisoindolequinazolinone derivatives are synthesized by chemical catalysis, with mild catalytic conditions and low price, which can reduce the economic burden on patients. Attached Figure Description

[0031] Figure 1 This is a diagram of the chemical structural formula of the 12-aminoisoindolylquinazolinone derivatives described in this invention. Detailed Implementation

[0032] The specific embodiments of the present invention will be further described below with reference to examples.

[0033] The 12-aminoisoindoloquinazolinone derivatives were obtained through the following synthetic route, with the specific steps as follows:

[0034]

[0035] Take a 25 mL reaction tube and add o-aminobenzamide derivative 1 (0.1 mmol), o-bromobenzaldehyde derivative 2 (0.1 mmol), and 1,4-dioxane (1 mL) sequentially. React at 100 °C for 8 hours, then cool the reaction solution to room temperature. Next, add dicyandiphenylpalladium dichloride (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and isonitrile derivative 3 (0.15 mmol) sequentially, and react at 100 °C for 8 hours. After the reaction is complete, quench the reaction with 10 mL of water, extract three times with ethyl acetate (3 × 10 mL), recover the organic layer, and concentrate using a rotary evaporator. Separate the crude product by column chromatography to obtain target product 4. The product's structure was then confirmed by NMR and high-resolution mass spectrometry.

[0036] Example 1:

[0037] Preparation of Compound 1: A 25 mL reaction tube was used. First, o-aminobenzamide 1 (0.1 mmol), o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dichloride dicyanophthalate (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (Compound 1, whose structural formula is shown in the table below), with a yield of 81%.

[0038] The technical route for preparing compound 1 is as follows:

[0039]

[0040] The NMR and high-resolution data for compound 1 are as follows: 1 H NMR(400MHz, CDCl3)δ8.33(d,J=7.9Hz,1H),8.16–8.01(m,1H),7.79-7.73(m,3H) ),7.62-7.52(m,2H),7.48-7.44(m,1H),6.48(s,1H),2.93(s,1H),0.84(s,9H). 13 C NMR (101MHz, CDCl3) δ161.8,153.5,149.5,142.6,134.2,132.0,131.6,129.8,1 27.4,126.4,126.4,125.5,123.1,121.7,75.3,52.5,31.3.HRMS(ESI)m / z:calcd for C 19 H 20 N3O[M+H] + 306.1606; found 306.1609.

[0041] Example 2:

[0042] Preparation of Compound 2: A 25 mL reaction tube was used. First, o-aminobenzamide 1 (0.1 mmol), o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dicyanophthalic acid (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and 1,1,3,3-tetramethylbutylisocyanate 3 (0.15 mmol) were added sequentially. The reaction was continued at 100 °C for 8 hours to obtain the target compound (Compound 2, whose structural formula is shown in the table below), with a yield of 35%.

[0043] The technical route for preparing compound 2 is as follows:

[0044]

[0045] The NMR and high-resolution data for compound 2 are as follows: 1 H NMR(400MHz, CDCl3)δ8.35(d,J=7.8Hz,1H),8.12(d,J=7.2Hz,1H),7.88–7.71(m,3H),7.66–7.54(m,2H) ,7.49-7.46(m,1H),6.53(s,1H),2.96(s,1H),1.36–1.24(m,3H),0.98(s,9H),0.91(s,3H),0.76(s,2H). 13 C NMR (101MHz, CDCl3) δ161.9,153.6,149.5,134.2,132.0,131.6,129.9,129.7,127.4,126 .5,126.4,125.5,123.1,121.8,75.2,58.0,57.0,31.9,29.5,31.1.HRMS(ESI)m / z:calcd forC 23 H 28 N3O[M+H] + 362.2232; found 362.2233.

[0046] Example 3:

[0047] Preparation of compound 3: A 25 mL reaction tube was used. First, 4-chloro-o-aminobenzamide 1 (0.1 mmol), o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the reaction tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dicyanophthalic acid (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (compound 3, the structural formula of which is shown in the table below), with a yield of 85%.

[0048] The technical route for preparing compound 3 is as follows:

[0049]

[0050] The NMR and high-resolution data for compound 3 are as follows: 1 H NMR(400MHz, CDCl3)δ8.25(d,J=8.5Hz,1H),8.10(d,J=7.1Hz,1H),7.78-7.75(m, 2H),7.64-7.58(m,2H),7.42-7.40(m,1H),6.48(s,1H),3.00(s,1H),0.86(s,9H). 13 C NMR (101MHz, CDCl3) δ161.2,154.6,150.6,142.7,140.4,132.4,131.4,129.9,1 27.8,127.0,126.9,125.6,123.3,120.2,75.5,52.6,31.3.HRMS(ESI)m / z:calcd for C 23 H 28 N3O[M+H] + 340.1217; found 340.1220.

[0051] Example 4:

[0052] Preparation of compound 4: A 25 mL reaction tube was used. First, o-aminobenzamide 1 (0.1 mmol), 4-chloro-o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dichloride dicyanophthalate (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (compound 4, the structural formula of which is shown in the table below), with a yield of 56%.

[0053] The technical route for preparing compound 4 is as follows:

[0054] The NMR and high-resolution data for compound 4 are as follows: 1 HNMR (400MHz, CDCl3) δ8.29(d,J=7.5Hz,1H),7.99(d,J=8.0Hz,1H),7.71(d,J=21.5Hz,3H),7.51-7.45(m,2H),6.41(s,1H),2.76(s,1H),0.86(s,9H). 13 C NMR (101MHz, CDCl3) δ161.6,152.5,149.3,144.5,138.4,134.3,130.4,130.0,1 27.3,126.6,126.4,125.7,124.2,121.6,74.8,52.5,31.3.HRMS(ESI)m / z:calcd for C 19 H 19 N3OCl[M+H] + 340.1217; found 340.1220.

[0055] Example 5:

[0056] Preparation of Compound 5: A 25 mL reaction tube was used. First, 4-methyl-o-aminobenzamide 1 (0.1 mmol), 4-chloro-o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dicyanophenyl dichloride (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (compound 5, the structural formula of which is shown in the table below), with a yield of 49%.

[0057] The technical route for preparing compound 5 is as follows:

[0058] The NMR and high-resolution data for compound 5 are as follows: 1 HNMR(400MHz, CDCl3)δ8.21(d,J=8.1Hz,1H),8.03(d,J=8.2Hz,1H),7.73(s,1H),7.59–7.53 (m,2H),7.31(d,J=8.1Hz,1H),6.44(s,1H),2.52(s,3H),1.25(d,J=2.2Hz,1H),0.86(s,9H). 13 C NMR (101MHz, CDCl3) δ161.7,152.7,149.5,145.4,144.5,138.4,130.4,130.2,128.2, 127.2,126.3,125.8,124.2,119.2,76.7,74.8,52.7,31.3,21.9.HRMS(ESI)m / z:calcd for C 20 H 21 N3OCl[M+H] + 354.1373; found 354.1375.

[0059] Example 6:

[0060] Preparation of Compound 6: A 25 mL reaction tube was used. First, 4-methyl-o-aminobenzamide 1 (0.1 mmol), 5-chloro-o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dicyanophthalic acid (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (Compound 6, whose structural formula is shown in the table below), with a yield of 56%.

[0061] The technical route for preparing compound 6 is as follows:

[0062] The NMR and high-resolution data for compound 6 are as follows: 1H NMR (400MHz, CDCl3) δ8.21(d,J=8.1Hz,1H),8.09(d,J=1.6Hz,1H),7.68(d,J=8.2Hz,1H),7. 59–7.54(m,2H),7.31(d,J=8.1Hz,1H),6.44(s,1H),2.52(s,3H),1.24(s,1H),0.84(s,9H). 13 C NMR (101MHz, CDCl3) δ161.7,152.3,149.4,145.4,140.9,136.0,133.4,132.1,128 .4,127.4,126.7126.3,123.1,119.4,75.0,52.5,31.4,21.9.HRMS(ESI)m / z:calcd for C 20 H 21 N3OCl[M+H] + 354.1373; found 354.1375.

[0063] Example 7:

[0064] Preparation of Compound 7: A 25 mL reaction tube was used. First, o-aminobenzamide 1 (0.1 mmol), 5-chloro-o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dichloride dicyanophthalate (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (Compound 7, whose structural formula is shown in the table below), with a yield of 76%.

[0065] The technical route for preparing compound 7 is as follows:

[0066] The NMR and high-resolution data for compound 7 are as follows: 1 H NMR (400MHz, CDCl3) δ8.34(d,J=7.7Hz,1H),8.11(s,1H),7.79(s,2H),7.69(d,J=8.0Hz ,1H),7.57(d,J=7.9Hz,1H),7.51-7.48(m,1H),6.47(s,1H),1.25(s,1H),0.86(s,9H). 13C NMR (101MHz, CDCl3) δ161.8,152.3,149.3,140.9,136.1,134.4,133.4,132.2,1 27.6,126.8,126.8,126.5,123.2,121.8,75.2,52.6,31.4.HRMS(ESI)m / z:calcd for C 19 H 19 N3OCl[M+H] + 340.1217; found 340.1221.

[0067] Example 8:

[0068] Preparation of Compound 8: A 25 mL reaction tube was used. First, o-aminobenzamide 1 (0.1 mmol), 5-fluoro-o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dichloride dicyanophthalate (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (Compound 8, whose structural formula is shown in the table below), with a yield of 71%.

[0069] The technical route for preparing compound 8 is as follows:

[0070] The NMR and high-resolution data for compound 8 are as follows: 1 H NMR(400MHz, CDCl3)δ8.33(d,J=7.8Hz,1H),7.80–7.75(m,3H),7.71(dd,J=8.4,4.6Hz,1H ),7.51–7.46(m,1H),7.30(td,J=8.6,2.3Hz,1H),6.45(s,1H),2.54(s,1H),0.84(s,9H). 13C NMR (101MHz, CDCl3) δ165.0, 162.6, 161.7, 152.5 (d, J = 4.0Hz), 149.3, 138.2 (d, J = 2.6Hz), 134.3, 133.7 (d, J = 9.6Hz), 127.5, 12 7.2(d,J=8.7Hz),126.6(d,J=29.3Hz),121.74(s),119.7(d,J=24.2),109.8(d,J=25.3),75.1,52.1,31.3.HRMS(ESI)m / z:calcd for C 19 H 19 N3OF[M+H] + 324.1512; found 324.1510.

[0071] Example 9:

[0072] Preparation of Compound 9: A 25 mL reaction tube was used. First, o-aminobenzamide 1 (0.1 mmol), 4-fluoro-o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dichloride dicyanophthalate (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (Compound 9, its structural formula is shown in the table below), with a yield of 56%.

[0073] The technical route for preparing compound 9 is as follows:

[0074] The NMR and high-resolution data for compound 9 are as follows: 1 H NMR (400MHz, CDCl3) δ8.33 (d, J = 7.8Hz, 1H), 8.12-8.09 (m, 1H), 7.78-7.65 (m, 2H ),7.51–7.43(m,2H),7.31–7.27(m,1H),6.45(s,1H),2.52(s,1H),0.88(s,9H). 13C NMR(101MHz, CDCl3)δ166.61(s),164.09(s),161.74(s),152.58(s),149.42 (s),145.51(d,J=9.5Hz),134.33(s),127.60(d,J=2.3Hz),127.31(s),126.4 8(d,J=5.2Hz),125.11(d,J=9.6Hz),121.39(s),117.8(d,J=24.2),112.8(d ,J=24.2),74.82(d,J=2.9Hz),52.57(s),31.30(s).HRMS(ESI)m / z:calcdfor C 19 H 19 N3OF[M+H] + 324.1512; found 324.1516.

[0075] Example 10:

[0076] Preparation of Compound 10: A 25 mL reaction tube was used. First, o-aminobenzamide 1 (0.1 mmol), 5-methyl-o-bromobenzaldehyde 2 (0.1 mmol), and 1,4-dioxane (1 mL) were added sequentially to the tube. The reaction was continued at 100 °C for 8 hours, and then the reaction solution was cooled to room temperature. Subsequently, palladium dicyanophthalic acid (10 mol%), triphenylphosphine (20.0 mol%), sodium acetate (3.0 equiv), and tert-butylisocyanate 3 (0.15 mmol) were added sequentially, and the reaction was continued at 100 °C for 8 hours to obtain the target compound (Compound 10, whose structural formula is shown in the table below), with a yield of 48%.

[0077] The technical route for preparing compound 10 is as follows:

[0078] The NMR and high-resolution data for compound 10 are as follows: 1 H NMR(400MHz, CDCl3)δ8.33(d,J=7.8Hz,1H),7.94(s,1H),7.82–7.75(m,2H),7.62(d, J=7.8Hz,1H),7.49–7.40(m,2H),6.45(s,1H),2.49(s,3H),1.24(s,1H),0.85(s,9H). 13C NMR (101MHz, CDCl3) δ161.9,153.7,149.6,140.1,139.8,134.2,133.2,131.7,127 .3,126.4,126.3125.3,123.3,121.7,75.3,52.4,31.3,21.4.HRMS(ESI)m / z:calcd for C 20 H 22 N3OF[M+H] + 320.1763; found 320.1767.

[0079] The beneficial effects of the drug described in this invention will be further illustrated below through pharmacodynamic and comparative experiments. The tumor cell lines used in the experiments of this invention are those used to prepare tumors formed from 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 glial cancer cells U87, and human malignant breast cancer cells 4T1.

[0080] In vitro antitumor cell activity assay of 12-aminoisoindolequinazolinone derivatives:

[0081] 1. Cells and drugs:

[0082] 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 glial cancer cells U87, and human malignant breast cancer cells 4T1 were all purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.

[0083] Positive reagent: 5-fluorouracil (5-Fu), purchased from Sigma Aldrich Company (St. Louis, MO, USA), purity >99.5% (HPLC).

[0084] 2. Experimental Methods

[0085] 5.0 × 10⁵ tumor cells in the logarithmic growth phase were collected. 4 200 μL of cells / mL was seeded into each well of a 96-well plate and incubated at 37°C and 5% CO2 for 24 h.

[0086] The test sample was 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. The solution was added to a 96-well plate and incubated at 37°C and 5% CO2 for 24 h.

[0087] Remove the culture medium, add 100 μL of 0.5 mg / mL MTT to each well, and incubate at 37 °C and 5% CO2 for 3-4 h; carefully remove the culture medium, add 100 μL of DMSO, and shake thoroughly to dissolve the crystals;

[0088] The microplate reader uses 570nm as the experimental wavelength and 630nm as the reference wavelength to detect absorbance. IC50 50 The value was calculated using the LOGIT method.

[0089] 3. Experimental Results

[0090] As shown in Table 1, the experimental results indicate that 12-aminoisoindolinone derivatives significantly inhibited the activity of 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 glial cancer cells U87, and human malignant breast cancer cells 4T1. Their IC50 inhibitory activity against these tumor cells was also significantly reduced. 50 The values ​​ranged from 16.33 to 88.18 μmol / L.

[0091] Table 112-Aminoisoindolequinazolinone derivatives' IC50 efficacy against various tumor cells 50 value

[0092]

[0093]

[0094] In summary, the 12-aminoisoindolanoquinazolinone derivatives involved in this invention have significant inhibitory effects on colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma, and breast cancer, exhibiting excellent antitumor properties. They can serve as lead drug molecules for antitumor treatment and have promising development and application prospects in the research and development of antitumor drugs.

[0095] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. The use of an indolequinazolinone derivative in the preparation of an antitumor drug composition, characterized in that: Specifically, the application of 12-aminoisoindolequinazolinone derivatives in the preparation of antitumor drug compositions; The chemical structural formula of the 12-aminoisoindolanoquinazolinone derivative is shown below: R1 is one of hydrogen, chlorine, and methyl; R2 is one of hydrogen, chlorine, fluorine, and methyl; and R3 is one of isobutyl and 1,1,3,3-tetramethylbutyl.

2. The application of an indole-quinazolinone derivative according to claim 1 in the preparation of an antitumor drug composition, characterized in that: The 12-aminoisoindoloquinazolinone derivatives are selected from any one of the compounds shown in the following structural formulas:

3. The application of an indole-quinazolinone derivative according to claim 1 in the preparation of an antitumor drug composition, characterized in that: The goal is to use 12-aminoisoindolylquinazolinone derivatives as candidate drugs or lead compounds for the treatment of tumors.

4. The use of an indolequinazolinone derivative according to claim 1 in the preparation of an antitumor drug composition, characterized in that: The therapeutic target of the pharmaceutical composition is mammals.

5. The use of an indole-quinazolinone derivative according to claim 1 in the preparation of an antitumor drug composition, characterized in that: The tumors mentioned include colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma, and / or breast cancer.

6. The use of an indolequinazolinone derivative according to claim 1 in the preparation of an antitumor drug composition, characterized in that: The pharmaceutical composition is prepared into a clinically acceptable pharmaceutical formulation by using 12-aminoisoindolinoquinazolinone derivatives as the main component, plus pharmaceutically acceptable excipients or auxiliary components. The content of the 12-aminoisoindolinoquinazolinone derivatives in the pharmaceutical composition is usually 0.1-95.0% w / w.

7. The use of an indolequinazolinone derivative according to claim 6 in the preparation of an antitumor drug composition, characterized in that: The pharmaceutical preparations include two dosage forms: oral preparations and injectable preparations.

8. The use of an indolequinazolinone derivative according to claim 7 in the preparation of an antitumor drug composition, characterized in that: The oral preparation is an oral capsule, and the injectable preparation is an intravenous injection solution.

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