Use of a naphthalene nitrile derivative in the preparation of an antitumor pharmaceutical composition

Abstract

The application discloses application of a naphthalene nitrile derivative in preparation of an antitumor pharmaceutical composition, in particular, application of a 2-(imino)-naphthalene nitrile derivative in preparation of an antitumor pharmaceutical composition. The 2-(imino)-naphthalene nitrile 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, exhibits 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] This invention relates to the field of antitumor drug technology, and specifically to the application of a naphthonitrile derivative in the preparation of an antitumor drug composition, particularly the application of a 2-(imino)-naphthonitrile derivative in the preparation of an antitumor drug composition. [Background Technology]

[0002] Cancer is a malignant tumor originating from epithelial tissue, characterized by rapid cell proliferation and metastasis, and has the leading cause of death among all diseases. Currently, there are four main clinical treatments for cancer: surgery, radiation therapy, chemotherapy, and immunotherapy. Compared to the other three methods, chemotherapy is generally painless and its ability to kill cancer cells is unparalleled by other treatments. However, most chemotherapy drugs are not specific; while killing cancer cells, they damage the normal tissue cells surrounding the tumor, which usually only repair themselves after chemotherapy. Therefore, developing new anti-tumor drugs to save more patients suffering from cancer is a highly competitive health priority for many countries.

[0003] Currently, numerous studies have been conducted on antitumor drugs. For example, Chinese patent application CN202010276756.4 discloses a novel class of dihydronaphthoisoxazole derivatives, as well as pharmaceutically acceptable salts, hydrates, solvates, or prodrugs of the compounds, and provides methods for preparing the derivatives and their uses. MTT results show that these compounds have significant inhibitory effects on various tumor cells. Another example is Chinese patent application CN201210447111.8, which discloses the application of a benzonitrile compound in the preparation of antitumor drugs. The compound exhibits excellent antitumor activity, particularly against human lung cancer A549 and human leukemia HL60. Yet another example is Chinese patent application CN201611090776.2, which provides an aromatic nitrile derivative and its preparation method. Compared with existing technologies, this invention provides a novel method for preparing multi-substituted aromatic nitrile derivatives, generating a series of new aromatic nitrile derivatives and their derivatives. Compared to other aromatic nitrile derivatives, the aromatic nitrile derivatives prepared in this invention have more rings and more complex and diverse structures, and have very important applications in the fields of natural product synthesis, new drug development, organic pesticide and dye synthesis.

[0004] There are currently no research reports on the antitumor bioactivity or clinical application of 2-(imino)-naphthol derivatives. [Summary of the Invention]

[0005] The present invention provides the application of naphthonitrile derivatives in the preparation of antitumor drug compositions.

[0006] The chemical structural formula of the 2-(imino)-naphthol derivatives described in this invention is shown below:

[0007]

[0008] Wherein, R1 is one of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, naphth-2-yl, 4-trifluoromethylphenyl, thiophene-2-yl, and anthracene-9-yl; R2 is one of methyl and neopentyl; the tumors mentioned include, but are not limited to, colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma, and breast cancer.

[0009] To further clarify, R1 is a phenyl group. 2-Chlorophenyl 3-Chlorophenyl 4-Chlorophenyl 4-Fluorophenyl 4-Bromophenyl 4-Methoxyphenyl 4-Methylphenyl 4-tert-butylphenyl Naphthyl-2-yl 4-Trifluoromethylphenyl Thiophene-2-yl Anthracene-9-yl One of them; R2 is methyl (CH3) or neopentyl. One of them.

[0010] The above-mentioned 2-(imino)-naphthol nitrile derivatives were obtained through the following synthetic route, with the specific steps as follows:

[0011]

[0012] Take a 25 mL reaction tube and add o-alkenylphenylacetonitrile 1 (0.2 mmol), isocyanate 2 (0.4 mmol), Pd(TFA) 2 (5 mol%), K3PO4 (3 equiv), and toluene (1 mL) sequentially. Stir the mixture at 100 °C for 8 hours. After the reaction is complete, quench the reaction with 10 mL of water and extract three times with ethyl acetate (3 × 10 mL). Recover the organic layer and concentrate it using a rotary evaporator. Separate the crude product by column chromatography to obtain the target product 3. The developing solvent used was petroleum ether / ethyl acetate (40 / 1). The product was then characterized by NMR and high-resolution mass spectrometry for structural confirmation.

[0013] The application of the above-mentioned 2-(imino)-naphthol derivatives in the preparation of antitumor drug compositions.

[0014] The application of the 2-(imino)-naphthonitrile derivatives in the preparation of antitumor drug compositions involves using 2-(imino)-naphthonitrile derivatives as candidate drugs or lead compounds for the treatment of tumors. The 2-(imino)-naphthonitrile derivatives exhibit inhibitory activity against a variety of tumor cells, laying the foundation for the development of new antitumor drugs.

[0015] The application of the 2-(imino)-naphthol derivative in the preparation of antitumor drug compositions, wherein the drug compositions are used to treat mammals or humans.

[0016] Furthermore, the application of the 2-(imino)-naphthonitrile derivative in the preparation of antitumor drug compositions, wherein the drug composition is prepared into a clinically acceptable drug formulation by using the 2-(imino)-naphthonitrile derivative as the main component, plus pharmaceutically acceptable excipients or auxiliary components, and the content of the 2-(imino)-naphthonitrile derivative in the drug composition is generally 0.1-95.0% (w / w).

[0017] Furthermore, the 2-(imino)-naphthol derivatives are 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 2-(imino)-naphthol 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 2-(imino)-naphthonitrile derivatives of the present invention in the preparation of antitumor drug compositions has good antitumor effects. The inhibitory effect of the 2-(imino)-naphthonitrile derivatives on tumor cells is better than that of the positive control drug 5-fluorouracil.

[0029] 2. The application of the 2-(imino)-naphthonitrile derivatives of the present invention in the preparation of antitumor drug compositions has a broad antitumor range. The 2-(imino)-naphthonitrile derivatives show good inhibitory activity against liver cancer, lung cancer, cervical cancer, breast cancer, gastric cancer, and breast cancer.

[0030] 3. The application of the 2-(imino)-naphthonitrile derivatives described in this invention in the preparation of antitumor drug compositions has significant cost advantages. The 2-(imino)-naphthonitrile derivatives are synthesized by catalysis of o-alkenyl phenylacetonitrile and isocyanate via Pd(TFA)2 (5 mol%). The chemical catalytic synthesis is mild, inexpensive, and can reduce the economic burden on patients. [Attached Image Description]

[0031] Figure 1 This is a diagram of the chemical structural formula of the 2-(imino)-naphthonitrile derivatives described in this invention.

Detailed Implementation Methods

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

[0033] Example 1:

[0034] 2-(imino)-naphthyl nitrile derivatives were obtained through the following synthetic route, with the specific steps outlined in the following reaction:

[0035]

[0036] Take a 25 mL reaction tube and add o-alkenylphenylacetonitrile 1 (0.2 mmol), isocyanate 2 (0.4 mmol), Pd(TFA) 2 (5 mol%), K3PO4 (3 equiv), and toluene (1 mL) sequentially. Stir the mixture at 100 °C for 8 hours. After the reaction is complete, quench the reaction with 10 mL of water and extract three times with ethyl acetate (3 × 10 mL). Recover the organic layer and concentrate it using a rotary evaporator. Separate the crude product by column chromatography to obtain the target product 3. The developing solvent used was petroleum ether / ethyl acetate (40 / 1). The product was then characterized by NMR and high-resolution mass spectrometry for structural confirmation.

[0037] Example 2:

[0038] Compound 1 (2-tert-butylamino-3-phenyl-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-styrylphenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain compound 1 (its structural formula is shown below), with a yield of 89%.

[0039] The technical route for compound 1 is as follows:

[0040]

[0041] The characterization data of compound 1 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.15 (d, J = 8.4Hz, 1H), 7.82-7.76 (m, 2H), 7.62 (t, J = 7.7Hz, 1H), 7.50-7.43 (m, 6H), 1.14 (s, 9H). 13 C NMR (101MHz, CDCl3, δppm) δ149.1,139.2,137.1,134.1,133.4,129.6,128.8,128.7 ,128.5,128.1,128.0,125.5,124.4,119.3,100.7,56.9,30.8.HRMS(ESI)m / z:calcd for C 21 H 20 N₂Na[M+Na] + 323.1524; found 323.1523.

[0042] Example 3:

[0043] Compound 2 (2-tert-butylamino-3-(4-chlorophenyl)-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-chlorostyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain compound 2 (its structural formula is shown below), with a yield of 61%.

[0044] The technical route for compound 2 is as follows:

[0045]

[0046] The characterization data of compound 2 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.14(d,J=8.4Hz,1H),7.79(d,J=9.6Hz,2H),7.64(t, J=7.7Hz,1H),7.50-7.46(m,4H),7.44(d,J=2.1Hz,1H),3.36(s,1H),1.11(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ148.7,138.1,136.2,134.4,134.0,133.2,131.0,129.0 ,128.9,128.7,128.2,125.8,124.4,118.8,102.4,57.3,30.8.HRMS(ESI)m / z:calcd for C 21 H 19 ClN2Na[M+Na] + 357.1134; found 357.1132.

[0047] Example 4:

[0048] Compound 3 (2-tert-butylamino-3-(2-chlorophenyl)-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(2-chlorostyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain compound 3 (its structural formula is shown below), with a yield of 56%.

[0049] The technical route for compound 3 is as follows:

[0050]

[0051] The characterization data for compound 3 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.18 (d, J = 8.4Hz, 1H), 7.77 (d, J = 7.0Hz, 2H), 7.66-7. 62(m,1H),7.57-7.53(m,1H),7.47-7.43(m,1H),7.42-7.36(m,3H),1.22(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ149.0,137.1,134.5,134.0,133.9,133.8,132.3,130.1,130.0 ,128.8,128.2,128.1,127.2,125.2,124.4,119.6,99.0,56.2,30.8.HRMS(ESI)m / z:calcd for C 21 H 20 ClN2[M+H] + 335.1315; found 335.1318.

[0052] Example 5:

[0053] Compound 4 (2-tert-butylamino-3-(4-fluorophenyl)-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-fluorostyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 4 (its structural formula is shown below), with a yield of 59%.

[0054] The technical route for compound 4 is as follows:

[0055]

[0056] The characterization data for compound 4 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.14 (d, J = 8.4Hz, 1H), 7.80-7.76 (m, 2H), 7.65-7.61 (m, 1H), 7.50-7.45 (m, 3H), 7.19-7.15 (m, 2H), 1.12 (s, 9H). 13 CNMR(101MHz, CDCl3, δppm) δ162.5(d,J=248.8Hz),149.0,136.3,135.5(d,J=3.5Hz),134.4,133.2,131.4(d,J= 8.0Hz),128.9,128.6,128.1,125.7,124.4,119.0,115.7(d,J=21.5Hz),101.7,57.0,30.8.HRMS(ESI)m / z:calcd for C 21 H 19 FN2Na[M+Na] + 341.1430; found 341.1431.

[0057] Example 6:

[0058] Compound 5 (2-tert-butylamino-3-(3-chlorophenyl)-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(3-chlorostyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain compound 5 (its structural formula is shown below), with a yield of 63%.

[0059] The technical route for compound 5 is as follows:

[0060]

[0061] The characterization data of compound 5 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.14 (d, J = 8.4Hz, 1H), 7.82-7.78 (m, 2H), 7.66-7.62 ( m,1H),7.56(d,J=1.1Hz,1H),7.50-7.46(m,1H),7.42-7.39(m,3H),1.12(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ148.7,141.4,135.9,134.5,134.4,133.3,129.9,129.8,129.0 ,128.8,128.2,128.0,127.8,125.8,124.4,118.8,102.3,57.2,30.8.HRMS(ESI)m / z:calcd for C 21 H 19 ClN2Na[M+Na] + 357.1134; found 357.1137.

[0062] Example 7:

[0063] Compound 6 (3-(4-bromophenyl)-2-tert-butylamino-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-bromostyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 6 (its structural formula is shown below), with a yield of 46%.

[0064] The technical route for compound 6 is as follows:

[0065]

[0066] The characterization data for compound 6 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.15-8.12(m,1H),7.79(t,J=4.5Hz,2H),7.66-7.59(m,3H),7.49-7.46(m,1H),7.43-7.40(m,2H),1.11(s,9H). 13 CNMR (101MHz, CDCl3, δppm) δ148.7,138.7,136.2,134.4,133.2,131.9,131.3,129.1 ,128.8,128.2,125.8,124.5,122.1,118.8,102.5,57.3,30.7.HRMS(ESI)m / z:calcd forC 21 H 19 BrN2Na[M+Na] + 401.0629; found 401.0631.

[0067] Example 8:

[0068] Compound 7 (2-tert-butylamino-3-(4-methoxyphenyl)-1-naphthonitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-methoxystyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 7 (its structural formula is shown below), with a yield of 59%.

[0069] The technical route for compound 7 is as follows:

[0070]

[0071] The characterization data for compound 7 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.14 (d, J = 8.4Hz, 1H), 7.78-7.74 (m, 2H), 7.63-7.58 (m, 1H ),7.46-7.42(m,1H),7.40-7.37(m,2H),7.02-6.99(m,2H),3.88(s,3H),1.16(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ159.4,149.3,136.7,134.1,133.3,131.4,130.8,128.8,12 8.3,128.0,125.4,124.3,119.4,114.2,100.2,56.8,55.3,30.9.HRMS(ESI)m / z:calcd for C 22 H 23 N₂O[M+H] + 331.1810; found 331.1808.

[0072] Example 9:

[0073] Compound 8 (3-(4-chlorophenyl)-2-(2,4,4-trimethylpentan-2-yl)amino)-1-naphthonitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-chlorostyryl)phenyl)acetonitrile (0.2 mmol), 1,1,3,3-tetramethylbutylisocyanurate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 8 (its structural formula is shown below), with a yield of 67%.

[0074] The technical route for compound 8 is as follows:

[0075]

[0076] The characterization data for compound 8 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.14 (d, J = 8.4Hz, 1H), 7.76 (t, J = 3.9Hz, 2H), 7.65-7. 60(m,1H),7.48-7.42(m,5H),4.09(s,1H),1.58(s,2H),1.12(s,6H),0.98(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ148.7,138.2,136.1,134.3,134.0,133.4,131.1,129.0,128.7,1 28.6,128.1,125.5,124.4,119.3,101.0,61.1,56.0,31.7,31.6,30.2.HRMS(ESI)m / z:calcd for C 25 H 27 ClN2Na[M+Na] + 413.1760; found 413.1765.

[0077] Example 10:

[0078] Compound 9 (3-(4-fluorophenyl)-2-(2,4,4-trimethylpentan-2-yl)amino)-1-naphthonitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-fluorostyryl)phenyl)acetonitrile (0.2 mmol), 1,1,3,3-tetramethylbutylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 9 (its structural formula is shown below), with a yield of 73%.

[0079] The technical route for compound 9 is as follows:

[0080]

[0081] The characterization data for compound 9 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.14(d,J=8.4Hz,1H),7.75(d,J=6.2Hz,2H),7.64-7.60(m,1H) ,7.47-7.43(m,3H),7.21-7.16(m,2H),4.13(s,1H),1.60(s,2H),1.14(s,6H),0.97(s,9H). 13 C NMR(101MHz, CDCl3, δppm) δ162.5(d,J=248.9Hz),148.9,136.1,135.5(d,J=3.4Hz),134.3,133.5,131.5(d,J=8.1Hz),1 28.6,128.5,128.1,125.4,124.3,119.5,115.8(d,J=21.5Hz),100.2,60.9,56.0,31.7,31.6,30.2.HRMS(ESI)m / z:calcd for C 25 H 27 FN2Na[M+Na] + 397.2056; found 397.2061.

[0082] Example 11:

[0083] Compound 10 (3-(4-methoxyphenyl)-2-(2,4,4-trimethylpentan-2-yl)amino)-1-naphthonitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-methoxystyryl)phenyl)acetonitrile (0.2 mmol), 1,1,3,3-tetramethylbutylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 10 (its structural formula is shown below), with a yield of 74%.

[0084] The technical route for compound 10 is as follows:

[0085]

[0086] The characterization data of compound 10 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.14(d,J=8.3Hz,1H),7.73(d,J=7.2Hz,2H),7.62-7.57(m,1H),7.44-7. 39(m,1H),7.37-7.34(m,2H),7.04-7.01(m,2H),3.88(s,3H),1.65(s,2H),1.19(s,6H),0.97(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ159.5,149.2,136.5,133.9,133.5,131.3,130.9,128.3,128.2,128 .0,125.0,124.2,119.9,114.3,98.3,60.6,55.7,55.4,31.7,31.6,30.4.HRMS(ESI)m / z:calcd for C 26 H 31 N₂O[M+H] + 387.2436; found 387.2435.

[0087] Example 12:

[0088] Compound 11 (2-tert-butylamino-3-(4-methylphenyl)-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-methylstyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 11 (its structural formula is shown below), with a yield of 50%.

[0089] The technical route for compound 11 is as follows:

[0090]

[0091] The characterization data of compound 11 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.15 (d, J=8.3Hz, 1H), 7.78-7.74 (m, 2H), 7.63-7.59 (m, 1H) ,7.47-7.42(m,1H),7.36-7.33(m,2H),7.29(d,J=8.0Hz,2H),2.43(s,3H),1.16(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ149.2,137.9,137.1,136.1,134.0,133.3,129.5,129.4,12 8.7,128.4,128.1,125.3,124.3,119.5,100.1,56.8,30.9,21.3.HRMS(ESI)m / z:calcd for C 22 H 22 N₂Na[M+Na] + 337.1681; found 337.1683.

[0092] Example 13:

[0093] Compound 12 (2-tert-butylamino-3-(4-tert-butylphenyl)-1-naphthonitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-tert-butylstyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 12 (its structural formula is shown below), with a yield of 41%.

[0094] The technical route for compound 12 is as follows:

[0095]

[0096] The characterization data of compound 12 are as follows: 1 H NMR (400MHz, CDCl3, δppm) δ8.15(d,J=8.4Hz,1H),7.80(s,1H),7.76(d,J=8.1Hz,1H),7.61(t,J=7. 7Hz,1H),7.50(d,J=8.1Hz,2H),7.46-7.42(m,1H),7.38(d,J=8.2Hz,2H),1.38(s,9H),1.16(s,9H). 13 C NMR (101MHz, CDCl3, δppm) δ151.3,149.1,137.0,136.0,134.0,133.3,129.2,128.7,128. 4,128.1,125.7,125.4,124.4,119.5,100.1,56.9,34.7,31.3,30.8.HRMS(ESI)m / z:calcd for C 25 H 28 N₂Na[M+Na] + 379.2150; found 379.2156.

[0097] Example 14:

[0098] Compound 13 (3-tert-butylamino-[2,2'-dinaphthyl]-4-carboxynitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(2-(naphth-2-yl)vinyl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 13 (its structural formula is shown below), with a yield of 55%.

[0099] The technical route for compound 13 is as follows:

[0100]

[0101] The characterization data of compound 13 are as follows: 1 H NMR (600MHz, CDCl3, δppm) δ8.23(d,J=8.5Hz,1H),7.98-7.94(m,2H),7.85(s,1H),7.75(d,J=8.0Hz,1H),7.67-7.6 5(m,1H),7.61-7.58(m,1H),7.54(t,J=7.4Hz,1H),7.51-7.47(m,2H),7.47-7.44(m,2H),3.90(s,1H),1.08(s,9H). 13 C NMR (151MHz, CDCl3, δppm) δ149.8,135.4,134.7,134.2,134.1,133.7,131.9,129.1,128.7,128.5,128.3 ,128.1,127.9,126.9,126.5,125.6,125.4,125.0,124.3,120.1,96.7,55.8,30.8.HRMS(ESI)m / z:calcd for C 25 H 22 N₂Na[M+Na] + 373.1681; found 373.1678.

[0102] Example 15:

[0103] Compound 14 (2-tert-butylamino-3-(4-trifluoromethylphenyl)-1-naphthyl nitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(4-trifluoromethylstyryl)phenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 14 (its structural formula is shown below), with a yield of 64%.

[0104] The technical route for compound 14 is as follows:

[0105]

[0106] The characterization data of compound 14 are as follows: 1 H NMR (600MHz, CDCl3, δppm) δ8.15(d,J=8.4Hz,1H),7.84(s,1H),7.81(d,J=8.1Hz,1H),7.73(d,J=8.2H z,2H),7.69(d,J=8.2Hz,2H),7.66(t,J=7.6Hz,1H),7.50(t,J=7.5Hz,1H),3.91(s,1H),1.07(s,9H). 13 C NMR (151MHz, CDCl3, δppm) δ148.6, 143.6, 136.2, 134.8, 133.2, 130.1, 130.0 (q, J = 32.6Hz) 129.2, 129.0, 128 .3,126.0,125.5(q,J=3.9Hz),124.1(q,J=272.4Hz),124.5,118.5,103.4,57.4,30.7.HRMS(ESI)m / z:calcd for C 22 H 19 F3N2Na[M+Na] + 391.1398; found 391.1394.

[0107] Example 16:

[0108] Compound 15 (3-thiophene-2-yl-2-(2,4,4-trimethyl-2-ylpentanamino)-1-naphthonitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(2-(thiophene-2-yl)vinyl)phenyl)acetonitrile (0.2 mmol), 1,1,3,3-tetramethylbutylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound 15 (its structural formula is shown below), with a yield of 69%.

[0109] The technical route for compound 15 is as follows:

[0110]

[0111] The characterization data of compound 15 are as follows: 1 H NMR (600MHz, CDCl3, δppm) δ8.13(d,J=8.4Hz,1H),7.91(s,1H),7.74(d,J=8.0Hz,1H),7.63-7.60(m,1H),7. 45-7.42(m,2H),7.23-7.22(m,1H),7.16-7.14(m,1H),4.51(s,1H),1.74(s,2H),1.24(s,6H),1.02(s,9H). 13 C NMR (151MHz, CDCl3, δppm) δ148.9,140.1,135.0,133.7,129.6,128.9,128.1,128.0,127.7, 127.4,126.8,125.3,124.3,119.6,99.1,60.9,55.6,31.7,31.6,30.0.HRMS(ESI)m / z:calcd for C 23 H 26 N₂SNa[M+Na] + 385.1714; found 385.1720.

[0112] Example 17:

[0113] Compound 16 (3-(anthracene-9-yl)-2-(2,4,4-trimethyl-2-ylpentanamino)-1-naphthonitrile) was synthesized via the following route, with the specific steps as follows: A 25 mL reaction tube was filled sequentially with (E)-2-(2-(2-(anthracene-9-yl)vinyl)phenyl)acetonitrile (0.2 mmol), 1,1,3,3-tetramethylbutylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 8 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic layer was recovered and concentrated using a rotary evaporator. The crude product was separated by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain compound 16 (its structural formula is shown below), with a yield of 58%.

[0114] The technical route for compound 16 is as follows:

[0115]

[0116] The characterization data of compound 16 are as follows: 1 H NMR (600MHz, CDCl3, δppm) δ8.62(s,1H),8.30(d,J=8.5Hz,1H),8.10(d,J=8.5Hz,2H),7.84(s,1H),7.72(d,J=7.9Hz,1H),7.69(t ,J=7.7Hz,1H),7.58(d,J=8.8Hz,2H),7.53-7.50(m,2H),7.44-7.40(m,3H),3.93(s,1H),1.28(s,2H),1.09(s,6H),0.50(s,9H). 13 C NMR (151MHz, CDCl3, δppm) δ150.1,135.6,134.8,131.4,131.3,130.8,130.7,128.8,128.7,128.2,128.1, 127.4,126.6,125.7,125.6,124.5,124.2,120.9,93.5,59.1,55.2,31.2,31.1,29.9.HRMS(ESI)m / z:calcd for C 33 H 32 N₂Na[M+Na] + 479.2463; found 479.2470.

[0117] 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.

[0118] In vitro antitumor cell activity assay of 2-(imino)-naphthyl nitrile derivatives:

[0119] 1. Cells and drugs:

[0120] 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.

[0121] Positive reagent: 5-fluorouracil (5-Fu), purchased from Sigma Aldrich Company (St. Louis, MO, USA), purity >99.5% (HPLC).

[0122] 2. Experimental Methods

[0123] 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.

[0124] 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.

[0125] 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;

[0126] 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.

[0127] 3. Experimental Results

[0128] As shown in Table 1, the experimental results indicate that 2-(imino)-naphthyl nitrile derivatives have significant inhibitory effects 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 glial cancer cells U87, and human malignant breast cancer cells 4T1. Their IC50 inhibitory activity against these tumor cells is also significant. 50 The values ​​ranged from 0.83 to 71.26 μmol / L.

[0129] Table 12. IC50 of (imino)-naphthyl nitrile derivatives on various tumor cells. 50 value

[0130]

[0131]

[0132] In summary, the 2-(imino)-naphthyl nitrile 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 prospects for development and application in the research and development of antitumor drugs.

[0133] 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 a 2-(imino)-naphthyl nitrile derivative in the preparation of an antitumor drug composition, characterized in that: in, The structural formula of the 2-(imino)-naphthyl nitrile derivative is: ； The tumors are selected from colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma, and breast cancer; the pharmaceutical composition is prepared into a clinically acceptable pharmaceutical formulation with 2-(imino)-naphthonitrile derivatives as the main component, plus pharmaceutically acceptable excipients or auxiliary components, and the content of the 2-(imino)-naphthonitrile derivatives in the pharmaceutical composition is 0.1-95.0% w / w.

2. The application according to claim 1, characterized in that: The 2-(imino)-naphthol derivatives are synthesized via the following catalytic steps: Take a 25 mL reaction tube and add (E)-2-(2-styrylphenyl)acetonitrile (0.2 mmol), tert-butylisocyanate (0.4 mmol), Pd(TFA)₂ (5 mol%), K₃PO₄ (3 equiv), and toluene (1 mL) sequentially. Stir the mixture at 100 °C for 8 hours. After the reaction is complete, quench the reaction with 10 mL of water and extract three times with ethyl acetate (3 × 10 mL). Recover the organic layer, concentrate it using a rotary evaporator, and separate the crude product by column chromatography using petroleum ether / ethyl acetate (40 / 1) as the eluent to obtain the target compound.

3. The application according to claim 1, characterized in that: The 2-(imino)-naphthol derivatives are used as candidate drugs or lead compounds for the treatment of tumors.

4. The application according to claim 1, characterized in that: The therapeutic target of the pharmaceutical composition is a mammal or a human.

5. The application according to claim 1, characterized in that: The pharmaceutical preparations include two dosage forms: oral preparations and injectable preparations.

6. The application according to claim 5, characterized in that: The oral preparation is an oral capsule, and the injectable preparation is an intravenous injection solution.

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