Benzonaphthyridine-5-ketone derivative as well as preparation method and application thereof

Abstract

The invention provides a benzonaphthyridine-5-ketone derivative as well as a preparation method and application thereof, and relates to biological medicines. The benzonaphthyridine-5-ketone derivative provided by the invention is a compound with a unique structure, has ROCK kinase inhibition activity, and can play a remarkable anti-tumor effect by inhibiting proliferation, migration and invasion of tumor cells and improving the tumor microenvironment. The benzonaphthyridine-5-ketone derivative provided by the invention shows important application potential in the fields of drug development, new material design, organic electronic devices and the like. Especially in pharmaceutical chemistry, the compound is expected to become a core skeleton of novel anticancer, antibacterial, antiviral and anti-inflammatory drugs. Benzonaphthyridine-5-ketone derivatives are complex in structure, so that efficient synthesis of the derivatives is always challenged. The preparation method of the benzonaphthyridine-5-ketone derivative provided by the invention is simple in process, high in synthesis efficiency, low in production cost and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a benzonaphthyl-5-one derivative, its preparation method, and its application. Background Technology

[0002] Benzonaphthidine-5-one derivatives are a class of compounds with polycyclic aromatic structures, the core of which includes a benzene ring and a nitrogen-containing naphthidine one structure. They possess unique physicochemical properties and a wide range of biological activities, showing significant potential application value in anticancer, antitumor, anti-inflammatory, antibacterial, antiviral, and neuroprotective applications. For example, the compounds shown in Formulas 1 and 2 all exhibit ROCK kinase inhibitory activity, with the compound shown in Formula 2 being a small-molecule amyloid protein regulator that can increase the levels of synaptophysin and synaptic proteins. By inhibiting tumor cell proliferation, migration, and invasion, it improves the tumor microenvironment and exerts a significant antitumor effect. However, the number of existing compounds with ROCK kinase inhibitory activity is relatively small, limiting their application.

[0003] Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a benzonaphthidine-5-one derivative, its preparation method, and its application. The benzonaphthidine-5-one derivative provided by the present invention has ROCK kinase inhibitory activity.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a benzonaphthyl-5-one derivative, characterized in that it has the structure shown in Formula I:

[0007]

[0008] Among them, R 1 including hydrogen, methyl, methoxy or chlorine; R 2 including benzyl, methyl or ethyl; R 3 Including hydrogen, methyl, methoxy, or chlorine, with R on a single benzene ring. 3 The number is 1 to 2.

[0009] Preferably, the benzonaphthidine-5-one derivative has the structure shown in formula 3aa, 3ba, 3ca, 3da, 3ea, 3ab, 3ac, 3ad or 3ae:

[0010]

[0011] This invention provides a method for preparing the benzonaphthyl-5-one derivative described in the above technical solution, comprising the following steps:

[0012] Compound 1 and compound 2 were subjected to a ring-expansion reaction in the presence of an organometallic catalyst to obtain the benzonaphthidine-5-one derivative.

[0013]

[0014] Preferably, the organometallic catalyst comprises one or more of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, dichloro(pentamethylcyclopentadienyl)ruthenium(III) polymer, and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate).

[0015] Preferably, the molar ratio of compound 1 to the organometallic catalyst is 1:0.01 to 0.05.

[0016] Preferably, the ring expansion reaction is carried out in the presence of an additive, which includes cuprous salt and / or cuprous oxide.

[0017] Preferably, the molar ratio of compound 1 to the additive is 1:0.5 to 2.5.

[0018] Preferably, the molar ratio of compound 1 to compound 2 is 1:1.25 to 5.

[0019] Preferably, the ring expansion reaction is carried out at a temperature of 80–150°C for a time of 10–20 h.

[0020] The organic solvents used in the ring expansion reaction include chlorinated alkanes and / or ester solvents;

[0021] The ring expansion reaction was carried out under a protective atmosphere.

[0022] The present invention also provides the application of the benzonaphthyl-5-one derivative described in the above technical solution in the preparation of antitumor drugs, anti-inflammatory drugs, antibacterial drugs, antiviral drugs, neuroprotective drugs, drugs for reducing amyloid load, drugs for treating cardiovascular diseases, or organic electronic devices.

[0023] The benzonaphthyl-5-one derivatives provided by this invention are compounds with a unique structure and ROCK kinase inhibitory activity. They exert significant anti-tumor effects by inhibiting tumor cell proliferation, migration, and invasion, thereby improving the tumor microenvironment. These benzonaphthyl-5-one derivatives show significant application potential in drug development, new material design, and organic electronic devices. Especially in medicinal chemistry, they are expected to become the core framework for novel anticancer, antibacterial, antiviral, and anti-inflammatory drugs.

[0024] Due to the complex structure of benzonaphthyridine-5-one derivatives, their efficient synthesis has always been a challenge. The preparation method of benzonaphthyridine-5-one derivatives provided by the present invention has a simple process, simple operation, high synthesis efficiency, cheap and readily available raw materials, low production cost, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the hydrogen spectrum of compound 3aa;

[0026] Figure 2 is the carbon spectrum of compound 3aa;

[0027] Figure 3 is the hydrogen spectrum of compound 3ba;

[0028] Figure 4 is the carbon spectrum of compound 3ba;

[0029] Figure 5 is the hydrogen spectrum of compound 3ca;

[0030] Figure 6 is the carbon spectrum of compound 3ca;

[0031] Figure 7 is the hydrogen spectrum of compound 3da;

[0032] Figure 8 is the carbon spectrum of compound 3da;

[0033] Figure 9 is the hydrogen spectrum of compound 3ea;

[0034] Figure 10 is the carbon spectrum of compound 3ea;

[0035] Figure 11 is the hydrogen spectrum of compound 3ab;

[0036] Figure 12 is the carbon spectrum of compound 3ab;

[0037] Figure 13 is the hydrogen spectrum of compound 3ac;

[0038] Figure 14 is the carbon spectrum of compound 3ac;

[0039] Figure 15 is the hydrogen spectrum of compound 3ad;

[0040] Figure 16 is the carbon spectrum of compound 3ad;

[0041] Figure 17 is the hydrogen spectrum of compound 3ae;

[0042] Figure 18 This is the carbon spectrum of compound 3ae. DETAILED DESCRIPTION

[0043] This invention provides a benzonaphthyl-5-one derivative, characterized in that it has the structure shown in Formula I:

[0044]

[0045] Among them, R 1 including hydrogen, methyl, methoxy or chlorine; R 2 including benzyl, methyl or ethyl; R 3 Including hydrogen, methyl, methoxy, or chlorine, with R on a single benzene ring. 3 The preferred number is 1 to 2.

[0046] In this invention, the benzonaphthidine-5-one derivative preferably has the structure shown in formula 3aa, 3ba, 3ca, 3da, 3ea, 3ab, 3ac, 3ad or 3ae:

[0047]

[0048] The present invention also provides a method for preparing the benzonaphthyl-5-one derivative described in the above technical solution, comprising the following steps:

[0049] Compound 1 and compound 2 were subjected to a ring-expansion reaction in the presence of an organometallic catalyst to obtain the benzonaphthidine-5-one derivative.

[0050]

[0051] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.

[0052] In this invention, the molar ratio of compound 1 to compound 2 is preferably 1:1.25 to 5, and in specific embodiments it can be 1:1.25, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.

[0053] In this invention, the organometallic catalyst preferably comprises one or more of the following: dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, dichloro(pentamethylcyclopentadienyl)ruthenium(III) polymer, and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate). When the organometallic catalyst is a mixture of two or more, this invention does not have a particular limitation on the mass ratio of different organometallic catalysts, and any ratio is acceptable. In this invention, the molar ratio of compound 1 to the organometallic catalyst is preferably 1:0.01 to 0.05, and in specific embodiments it can be 1:0.01, 1:0.02, 1:0.03, 1:0.04, or 1:0.05.

[0054] In this invention, the ring expansion reaction is preferably carried out in the presence of an additive, which preferably includes a cuprous salt and / or cuprous oxide; the cuprous salt preferably includes cuprous halide, more preferably cuprous chloride and / or cuprous bromide. In this invention, the molar ratio of compound 1 to the additive is preferably 1:0.5 to 2.5, and in specific experiments it can be 1:0.5, 1:1, 1:1.5, 1:2 or 1:2.5. In this invention, the use of the additive can improve the product yield.

[0055] In this invention, the organic solvent used in the ring expansion reaction preferably includes chloroalkanes and / or ester solvents, more preferably a mixture of chloroalkanes and ester solvents; the chloroalkanes preferably include dichloromethane and / or dichloroethane; the ester solvents preferably include ethyl acetate and / or butyl acetate. In this invention, the volume ratio of chloroalkanes to ester solvents in the mixed solvent is preferably 0.5 to 2:1, and in specific embodiments it can be 0.5:1, 1:1, 1.5:1 or 2:1; when a mixture of chloroalkanes and ester solvents is used in this invention, the yield of the target product is higher. In this invention, the preferred ratio of the amount of compound 1 to the volume of the organic solvent is 1 mol: 5 to 15 L. In specific embodiments, it can be 1 mol: 5 L, 1 mol: 6 L, 1 mol: 7 L, 1 mol: 8 L, 1 mol: 9 L, 1 mol: 10 L, 1 mol: 11 L, 1 mol: 12 L, 1 mol: 13 L, 1 mol: 14 L, or 1 mol: 15 L.

[0056] In the present invention, the temperature of the ring expansion reaction is preferably 80 to 150°C, and in specific embodiments, it can be 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C or 150°C; the time of the ring expansion reaction is preferably 10 to 20 hours, and in specific embodiments, it can be 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours or 20 hours. In the present invention, the ring expansion reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon or helium. In the present invention, taking the organic solvents of dichloromethane and ethyl acetate as an example, the reaction formula of the ring expansion reaction is as follows:

[0057]

[0058] After completing the ring-expansion reaction, the present invention preferably further comprises: extracting the resulting ring-expansion reaction liquid with ethyl acetate and saturated brine, drying with anhydrous sodium sulfate, filtering to remove the sodium sulfate, distilling off the solvent under reduced pressure, and performing silica gel column chromatography to separate and purify the benzonaphthyridin-5-one derivative. In the present invention, the eluent used for the silica gel column chromatography separation and purification preferably comprises a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate in the mixed solvent is preferably 1 to 4:1, and in specific embodiments can be 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, or 4:1.

[0059] The present invention also provides the use of the benzonaphthyridine-5-one derivatives described in the above technical solution in the preparation of anti-tumor drugs, anti-inflammatory drugs, antibacterial drugs, antiviral drugs, neuroprotective drugs, drugs for reducing amyloid protein load, drugs for treating cardiovascular diseases, or organic electronic devices. In the present invention, the tumor preferably includes lung cancer.

[0060] To further illustrate the present invention, a benzonaphthyridin-5-one derivative provided by the present invention, its preparation method and application, and pharmaceutical composition are described in detail below in conjunction with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0061] Example 1

[0062]

[0063] Compound 1a (0.2 mmol), compound 2a (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3aa in 80% yield.

[0064] Figure 1 This is the proton NMR spectrum of compound 3aa. Figure 2 This is the carbon spectrum of compound 3aa. 1 H NMR (400MHz, CDCl3, ppm): δ8.49 (s, 1H), 8.44 (d, J = 8.4Hz, 1H), 8.24-8.22 (m, 2H), 7.6 9-7.66(m,1H),7.61-7.59(m,2H),7.55-7.45(m,6H),7.43-7.37(m,2H),3.69(s,3H); 13 C NMR (100MHz, CDCl3, ppm): δ 163.4, 160.3, 157.2, 143.1, 142.7, 139.9, 138.5, 131.9, 129.8, 128.9, 128.6, 127.9, 127.6, 124.2, 122.5, 117.6, 116.9, 115.2, 110.3, 30.0. Therefore, the target compound was successfully prepared in this invention.

[0065] Example 2

[0066]

[0067] Compound 1b (0.2 mmol), compound 2a (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3ba in 62% yield.

[0068] Figure 3 This is the proton NMR spectrum of compound 3ba. Figure 4 This is the carbon spectrum of compound 3ba.1 HNMR (400MHz, CDCl3, ppm): δ9.54 (s, 1H), 8.22 (d, J = 6.8Hz, 2H), 7.64-7.62 (m, 2H), 7.54-7.44 (m, 8H), 7.37-7.35 (m, 1H), 3.66 (s, 3H); 13 C10 NMR (100MHz, CDCl3, ppm): δ 162.9, 159.8, 156.6, 143.2, 141.8, 141.7, 138.5, 133.3, 130.7, 129.9, 128.9, 128.9, 128.2, 127.6, 127.7, 126.5, 117.7, 116.1, 115.1, 114.0, 31.1. Therefore, the target compound was successfully prepared in this invention.

[0069] Example 3

[0070]

[0071] Compound 1c (0.2 mmol), compound 2a (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3ca in 70% yield.

[0072] Figure 5 This is the proton NMR spectrum of compound 3ca. Figure 6 This is the carbon spectrum of compound 3ca. 1 H NMR (400MHz, CDCl3, ppm): δ8.42(s,1H),8.23-8.20(m,2H),8.15(s,1H),7.60 -7.58(m,2H),7.52-7.41(m,7H),7.26-7.24(m,1H),3.62(s,3H),2.50(s,3H); 13C10 NMR (100MHz, CDCl3, ppm): δ 163.3, 160.1, 156.9, 143.2, 142.6, 138.6, 137.8, 132.9, 132.0, 129.8, 128.8, 128.7, 127.9, 127.6, 127.6, 124.2, 117.4, 117.1, 115.1, 110.2, 30.0, 20.9. Therefore, the target compound was successfully prepared in this invention.

[0073] Example 4

[0074]

[0075] Compound 1d (0.2 mmol), compound 2a (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3da in 70% yield.

[0076] Figure 7 This is the proton NMR spectrum of compound 3da. Figure 8 This is the carbon spectrum of compound 3da. 1 HNMR (400MHz, CDCl3, ppm): δ8.54(s,1H),8.47(d,J=8.0Hz,1H),8.28(d,J=7.2Hz ,2H),7.68-7.67(m,2H),7.59-7.46(m,7H),7.37-7.22(m,7H),5.59-5.58(m,2H); 13 CNMR (100MHz, CDCl3, ppm): δ 163.5, 160.5, 157.4, 143.1, 142.8, 139.2, 138.5, 136.4, 131.8, 129.9, 128.9, 128.9, 128.8, 128.1, 127.6, 127.2, 126.5, 124.2, 122.6, 117.9, 116.8, 116.2, 110.2, 46.2. Therefore, the target compound was successfully prepared in this invention.

[0077] Example 5

[0078]

[0079] Compound 1e (0.2 mmol), compound 2a (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3ea in 70% yield.

[0080] Figure 9 The image shows the proton NMR spectrum of compound 3ea. Figure 10 This is the carbon spectrum of compound 3ea. 1 H NMR (400MHz, CDCl3, ppm): δ8.46 (d, J = 6.8Hz, 2H), 8.25-8.22 (m, 2H), 7.68-7.62 (m ,3H),7.55-7.43(m,7H),7.38-7.34(m,1H),4.38-4.33(m,2H),1.36-1.33(m,3H); 13 CNMR (100MHz, CDCl3, ppm): δ 163.2, 159.8, 157.1, 143.1, 142.7, 138.8, 138.6, 131.9, 129.8, 128.9, 128.8, 128.0, 127.6, 124.5, 122.3, 117.9, 117.0, 115.1, 110.1, 37.7, 12.6. Therefore, the target compound was successfully prepared in this invention.

[0081] Example 6

[0082]

[0083] Compound 1a (0.2 mmol), compound 2b (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3ab in 76% yield.

[0084] Figure 11 The hydrogen spectrum of compound 3ab is shown. Figure 12 This is the carbon spectrum of compound 3ab.1 H NMR (400MHz, CDCl3, ppm): δ8.40-8.35(m,2H),8.20(d,J=8.8Hz,2H),7.66-7.57( m,3H),7.40-7.33(m,2H),7.03-7.01(m,4H),3.88(d,J=4.0Hz,6H),3.69(s,3H); 13 C NMR (100MHz, CDCl3, ppm): δ 162.7, 161.2, 160.5, 159.6, 156.6, 142.7, 139.9, 135.5, 131.6, 131.1, 130.4, 129.1, 124.1, 122.4, 117.8, 116.1, 116.1, 114.2, 113.0, 108.7, 55.4, 55.3, 30.0. It can be seen that the target compound was successfully prepared in this invention.

[0085] Example 7

[0086]

[0087] Compound 1a (0.2 mmol), compound 2c (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3ac in 64% yield.

[0088] Figure 13 This is the proton NMR spectrum of compound 3ac. Figure 14 This is the carbon spectrum of compound 3ac. 1 HNMR (400MHz, CDCl3, ppm): δ8.51 (s, 1H), 8.38 (s, 1H), 8.23 ​​(d, J = 7.6Hz, 2H ),7.73(d,J=8.8Hz,1H),7.59-7.47(m,8H),7.29-7.26(m,1H),3.66(s,3H); 13C NMR (100MHz, CDCl3, ppm): δ 163.5, 159.9, 157.6, 142.8, 141.5, 138.9, 138.2, 134.5, 130.0, 128.9, 128.6, 128.1, 127.6, 127.6, 126.9, 119.4, 116.9, 116.9, 115.6, 110.1, 77.4, 77.0, 76.7, 30.1. Therefore, the target compound was successfully prepared in this invention.

[0089] Example 8

[0090]

[0091] Compound 1a (0.2 mmol), compound 2d (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), and solvents dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially, and the reaction was stirred at 120° C. under a nitrogen atmosphere for 10 h. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, and the sodium sulfate was removed by filtration. The solvent was evaporated under reduced pressure, and the mixture was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate, volume ratio = 2:1) to give compound 3ad in a yield of 77%.

[0092] Figure 15 The hydrogen spectrum of compound 3ad is shown. Figure 16 This is the carbon spectrum of compound 3ad. 1 H NMR (400MHz, CDCl3, ppm): δ8.29-8.26 (m, 2H), 8.01 (d, J = 6.4Hz, 2H), 7.53-7.49 ( m,1H),7.41-7.39(m,2H),7.27-7.14(m,6H),3.56(s,3H),3.33(d,J=14.4Hz,6H); 13 C NMR (100MHz, CDCl3, ppm): δ 163.2, 160.3, 157.04, 142.6, 140.3, 140.1, 140.0, 137.6, 135.7, 131.7, 129.547, 128.7, 128.4, 127.5, 124.2, 122.4, 117.8, 116.7, 115.1, 109.5, 30.0, 21.6, 21.4. Therefore, the target compound was successfully prepared in this invention.

[0093] Example 9

[0094]

[0095] Compound 1a (0.2 mmol), compound 2e (0.5 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.004 mmol), cuprous chloride (0.4 mmol), dichloroethane and ethyl acetate (volume ratio = 2:1, 2 mL) were added sequentially. The mixture was reacted for 10 h under nitrogen atmosphere, 120 °C and stirring. The mixture was extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 2:1) to give compound 3ae in 66% yield.

[0096] Figure 17 The image shows the proton NMR spectrum of compound 3ae. Figure 18 This is the carbon spectrum of compound 3ae. 1 HNMR (400MHz, CDCl3, ppm): δ8.35-8.33(m,2H),7.93-7.85(m,2H),7.58-7.54( m,1H),7.32-7.26(m,3H),7.21-7.14(m,3H),3.60(s,3H),2.28-2.25(m,12H); 13 C NMR (100MHz, CDCl3, ppm): δ 163.4, 160.4, 157.3, 142.5, 141.0, 140.0, 138.6, 137.1, 136.3, 136.2, 135.8, 131.7, 130.1, 129.6, 128.9, 128.7, 126.2, 125.1, 124.2, 122.4, 117.8, 116.7, 115.1, 109.6, 77.4, 77.1, 76.7, 30.0, 20.1, 20.0, 19.9, 19.8. It can be seen that the target compound was successfully prepared in this invention.

[0097] Test Example 1

[0098] Human non-small cell lung cancer cell line (A549) was selected as the research object. The CCK-8 assay was used to evaluate the preliminary antitumor activity of the synthesized benzonaphthyl-5-one derivative. A549 was purchased from Shanghai Huzhen Industrial Co., Ltd. The experimental steps are as follows:

[0099] 1. Cell thawing: Open the clean bench and sterilize with ultraviolet light for 30 minutes. Open the liquid nitrogen tank, locate the A549 cell cryovials, add 37°C room temperature water to a beaker, and gently shake the cryovials in the beaker to thaw them quickly. Wipe the surface dry and transfer to a centrifuge. Centrifuge at 1000 rpm for 4 minutes. Remove and transfer to the clean bench. First, sterilize the outer surface of the cryovials with medical alcohol. Open the tube, discard the supernatant, add 1 mL of culture medium, and gently and slowly disperse the cells using a pipette. Transfer to a 25 cm³ container. 2 Add another 4 mL of culture medium to the culture flask. Observe under an inverted microscope; the cells appear normal. Transfer to a 5% CO2, 37°C incubator. After 24 hours, observe the cells, remove the culture medium, and replace with fresh medium. During this step, the mouth and cap of the culture flask must be sterilized by passing them through the outer flame of an alcohol lamp before opening and closing.

[0100] 2. Cell passage: Microscopic observation revealed that the cells had largely covered the bottom of the culture flask, indicating they were ready for passage. Before the procedure, the workbench and all experimental supplies were sterilized by UV irradiation for 30 minutes. The culture flask was opened, and the culture medium was removed using a pipette. 3 mL of buffer was used to wash the bottom cells twice, and the solution was removed. 1 mL of 0.25% trypsin was added, and the flask was gently shaken horizontally. The cells were observed again, showing a tendency for cytoplasmic retraction; digestion was immediately stopped. 2 mL of RPMI 1640 medium was added, and adherent cells were slowly dislodged. The cell culture was transferred to a centrifuge and centrifuged at 1000 rpm for 4 minutes. The supernatant was removed, and another 1.5 mL of medium was added. The cells were gently dispersed, and the cell culture was aliquoted into three culture flasks. 5 mL of medium was added to each flask. The cells were observed under a microscope; no abnormalities were found. The outer surface of the flasks was disinfected with medical alcohol, and the flasks were transferred to a 5% CO2, 37°C incubator.

[0101] 3. Cell cryopreservation: Under a microscope, select cells in the logarithmic growth phase, aspirate the supernatant, add 1 mL of 0.25% trypsin, and observe the cells showing a tendency for cytoplasmic retraction before stopping digestion. Add 1.5 mL of culture medium, gently pipette off the adherent cells, transfer to a centrifuge, centrifuge at 1000 rpm for 3 min, aspirate the culture medium, add an appropriate amount of cryopreservation solution, and aliquot into sterile cryovials, approximately 1.5 mL per vial. Temporarily store the prepared cryovials at 4°C for 40 min, then transfer to -20°C for 2.5 h, then to -80°C for 12 h, and finally transfer to a liquid nitrogen tank.

[0102] 4. Cell viability assay: Under a microscope, human lung cancer cells (A549) covered more than 80% of the bottom of the culture flask and were in good condition. The culture medium was aspirated, the cells were washed twice with PBS buffer, digested with trypsin for 1 minute, and then diluted with an appropriate amount of culture medium. Cell counting was performed to achieve a cell density of approximately 4 × 10⁻⁶ cells / mL.3 Cells / mL. Add 100 μL of buffer to the outer edge of a 96-well plate, then add 100 μL of cell suspension to each of the remaining wells and transfer to an incubator for culture. The control group was added 100 μL of culture medium, while the experimental groups were added 100 μL of culture medium containing different concentrations of benzonaphthyl-5-one derivatives (0.2 μmol / L, 0.4 μmol / L, 0.6 μmol / L, 0.8 μmol / L, 1 μmol / L, 2 μmol / L, 3 μmol / L, and 4 μmol / L). Three replicates were used, and the cells were cultured for 48 h. 10 μL of CCK-8 indicator was added to each well, and the cells were cultured for another 4 h before being transferred to a microplate reader for detection at a wavelength of 450 nm. Data were processed based on the measured absorbance (OD) values. The corresponding half-maximal inhibitory concentration (IC50) was calculated by applying different concentration gradients to each compound. 50 The value was used to assess its inhibitory effect on tumor cell proliferation.

[0103] 5. Experimental results: Graphpadprism software was used to process the compound experimental data, and a line graph showing the dependence of experimental concentration and inhibition rate was fitted to obtain the IC value of each monomer compound. 50 The values ​​are shown in Table 1.

[0104] Table 1 IC50 of benzonaphthyl-5-one derivatives 50 value

[0105] Compound <![CDATA[A549IC 50 (μM)]]> Compound <![CDATA[A549IC 50 (μM)]]> 3aa 83.25±7.04 3ab 49.84±4.73 3ca 122.16±8.41 3ad 93.25±5.14 3da 108.19±5.66 3ae 87.25±6.23 3ea 103.25±6.03

[0106] As shown in Table 1, among the benzonaphthidine-5-one derivatives provided by this invention, compound 3ab (methoxy-substituted benzonaphthidine-5-one derivative) exhibits the most significant inhibitory effect, IC50. 50 The lowest IC50 value indicates strong antitumor potential; the IC50 values ​​of the other compounds are... 50 The values ​​were relatively low, indicating a certain inhibitory effect, suggesting that these compounds have moderate levels of cytotoxicity.

[0107] The preliminary results indicate that benzonaphthyl-5-one derivatives possess potential pharmacological activity in inhibiting the proliferation of non-small cell lung cancer cells in vitro, especially the activity of compound 3ab, which warrants further investigation. This provides important evidence for subsequent chemical structure optimization and the development of more potent antitumor candidate compounds, and also lays the foundation for clarifying the mechanisms of action of these compounds and their potential clinical applications.

[0108] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A benzonaphthyridin-5-one derivative, characterized in that: It has the structure shown in Formula I: Among them, R 1 includes hydrogen, methyl, methoxy or chlorine; R 2 including benzyl, methyl or ethyl; R 3 Including hydrogen, methyl, methoxy or chlorine, R 3 The number is 1 to 2.

2. The benzonaphthyridin-5-one derivative according to claim 1, characterized in that The benzonaphthyridine-5-one derivative has a structure shown in Formula 3aa, Formula 3ba, Formula 3ca, Formula 3da, Formula 3ea, Formula 3ab, Formula 3ac, Formula 3ad or Formula 3ae:

3. The method for preparing the benzonaphthyridin-5-one derivative according to claim 1 or 2, comprising the following steps: Compound 1 and compound 2 are subjected to a ring-expansion reaction in the presence of an organic metal catalyst to obtain the benzonaphthyridine-5-one derivative; 4. The preparation method according to claim 3, characterized in that: The organic metal catalyst comprises one or more of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, dichloro(pentamethylcyclopentadienyl)ruthenium(III) polymer and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt.

5. The preparation method according to claim 3, characterized in that: The molar ratio of the compound 1 to the organic metal catalyst is 1:0.01-0.

05.

6. The preparation method according to claim 4, characterized in that: The ring expansion reaction is carried out in the presence of an additive, which includes cuprous salt and / or cuprous oxide.

7. The preparation method according to claim 3, characterized in that: The molar ratio of the compound 1 to the additive is 1:0.5-2.

5.

8. The preparation method according to claim 4, characterized in that: The molar ratio of the compound 1 to the compound 2 is 1:1.25-5.

9. The preparation method according to any one of claims 3 to 8, characterized in that: The ring expansion reaction is carried out at a temperature of 80 to 150° C. and for a time of 10 to 20 hours; The organic solvent used in the ring expansion reaction includes chloroalkane and / or ester solvent; The ring expansion reaction is carried out under a protective atmosphere.

10. Use of the benzonaphthyridine-5-one derivative according to any one of claims 1 to 2 in the preparation of anti-tumor drugs, anti-inflammatory drugs, antibacterial drugs, antiviral drugs, neuroprotective drugs, drugs for reducing amyloid protein load, drugs for treating cardiovascular diseases or organic electronic devices.

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