A compound related to pneumonia, its preparation method and application, and a pharmaceutical composition

Abstract

The present invention provides a pneumonia-related compound, a preparation method and application thereof, and a pharmaceutical composition, belonging to the technical field of pharmaceutical organic compounds. The pneumonia-related compound is an N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound, which is used for treating sepsis and acute lung injury, and the preparation forms that can be prepared include injections, tablets, capsules, aerosols, suppositories, membranes, dripping pills, ointments, controlled-release or sustained-release agents, and nano-formulations.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical organic compounds, and particularly relates to a compound related to pneumonia, a preparation method and application thereof, and a pharmaceutical composition. Background Art

[0002] Inflammation is a defensive response of the body to stimuli. Usually, inflammation is beneficial and is an automatic defensive response of the human body. However, when the inflammatory response is dysregulated and leads to excessive inflammation, the body will produce a large number of inflammatory cytokines, causing damage to tissues or cells, seriously affecting human life and health.

[0003] Acute Lung Injury (ALI) is an acute and persistent pulmonary inflammatory response syndrome. This inflammatory response causes damage to the alveolar capillary endothelium and leads to an increase in capillary permeability, resulting in diffuse interstitial and alveolar edema, and acute hypoxic respiratory insufficiency, with high morbidity and mortality. Sepsis is a systemic inflammatory response syndrome caused by the invasion of pathogenic microorganisms such as bacteria into the body. In addition to the manifestations of systemic inflammatory response syndrome and the primary infection focus, critically ill patients often also have manifestations of insufficient organ perfusion. The fatality rate of sepsis is as high as 30-70%. In recent years, although great progress has been made in anti-infection treatment and organ function support technologies, there are still a lack of effective drugs for the treatment of acute lung injury and sepsis in clinical practice.

[0004] Clinical and animal experiments have confirmed that lipopolysaccharide (LPS) can activate a variety of downstream pro-inflammatory signaling pathways and trigger the excessive production of inflammatory factors such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), thereby leading to acute lung injury and sepsis. At present, the blockade of the cytokine storm by various drugs such as glucocorticoids has been widely explored as a potentially promising method for the prevention and treatment of acute lung injury and sepsis. However, considering that the drugs used clinically do not show obvious therapeutic effects on patients with acute lung injury and sepsis due to their low efficiency and adverse reactions, there is still a need to develop more effective and safer new anti-inflammatory drugs for the treatment of acute lung injury and sepsis. Therefore, inhibiting the release of inflammatory factors such as TNF-α and IL-6 has become an important means for the treatment of acute lung injury and sepsis. Summary of the Invention

[0005] The purpose of the present invention is to provide a new compound related to pneumonia, a preparation method and application thereof, and a pharmaceutical composition to make up for the deficiencies of the prior art.

[0006] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0007] The present invention provides an N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound, which includes one of the following structural formulas:

[0008]

[0009] The present invention also provides a preparation method of the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound, which includes the following steps:

[0010] (1) 3-Acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and a solvent are mixed and then subjected to a low-temperature reaction and a heating reaction in sequence to generate methyl 3-(2-chlorophenyl)-3-oxopropionate, denoted as compound 2;

[0011] (2) Methyl 3-(2-chlorophenyl)-3-oxopropionate, N,N-dimethylformamide dimethyl acetal and a solvent are mixed and then reacted to generate compound 3;

[0012] (3) Compound 3, an aniline raw material and a solvent are mixed and then reacted to obtain a compound 4 product system;

[0013] The aniline raw material includes aniline, p-fluoroaniline, p-chloroaniline, p-bromoaniline, 3-chloro-4-fluoroaniline or 4-(trifluoromethoxy)aniline;

[0014] (4) Cesium carbonate is added to the compound 4 product system and reacted to generate compound 5;

[0015] (5) Compound 5, 1,4-dioxane, sodium hydroxide and water are mixed and then reacted to generate compound 6;

[0016] Compound 6 includes N-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-fluorophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-chlorophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-bromophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-(3-chloro-4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or 4-oxo-1-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxylic acid;

[0017] (6) 4-Chloro-6,7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and a solvent are mixed and then reacted to generate compound 9;

[0018] (7) Mix compound 9, water, ethanol, reduced iron powder and ammonium chloride and then carry out a reaction to generate 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline, denoted as compound 10;

[0019] (8) Mix compound 10, compound 6, a solvent, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine and then carry out an acid amide condensation reaction to generate N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compounds;

[0020] There is no limitation on the order of steps (1)-(5) for preparing compound 6 and steps (6)-(7) for preparing compound 10.

[0021] Preferably, in step (1), the dosage ratio of 3-acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and the solvent is 2-4 mmol: 8-12 mmol: 18-22 mmol: 8-12 mL;

[0022] The solvent is anhydrous tetrahydrofuran;

[0023] The temperature of the low-temperature reaction is -5 to 5 °C and the time is 25 to 35 min;

[0024] The temperature of the heating reaction is 80 to 90 °C and the time is 1 to 3 h;

[0025] Preferably, in step (2), the dosage ratio of methyl 3-(2-chlorophenyl)-3-oxopropionate, N,N-dimethylformamide dimethyl acetal and the solvent is 2-3 mmol: 8-9 mmol: 8-12 mL;

[0026] The solvent is toluene;

[0027] The temperature of the reaction is 110 to 130 °C and the time is 1 to 3 h;

[0028] Preferably, in step (3), the dosage ratio of compound 3, aniline raw material and the solvent is 2-4 mmol: 2-4 mmol: 8-12 mL;

[0029] The solvent is toluene;

[0030] The temperature of the reaction is 100 to 120 °C and the time is 2 to 4 h;

[0031] Preferably, in step (4), the dosage ratio of cesium carbonate and compound 3 is 2-4 mmol: 2-4 mmol;

[0032] The temperature of the reaction is 140 to 160 °C and the time is 2 to 4 h;

[0033] In step (5), the dosage ratio of compound 5, 1,4-dioxane, sodium hydroxide and water is 2-3 mmol: 8-12 mL: 1-3 mmol: 1-3 mL.

[0034] Preferably, in step (6), the dosage ratio of 4-chloro-6,7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and the solvent is 0.2-0.8 mmol: 0.2-0.8 mmol: 0.05-0.2 mmol: 15-25 mmol: 10-20 mL;

[0035] The solvent is toluene;

[0036] The temperature of the reaction is 120-140 °C and the time is 10-15 h;

[0037] In step (7), the dosage ratio of compound 9, water, ethanol, reducing iron powder and ammonium chloride is 0.5-1.5 mmol: 3-7 mL: 8-12 mL: 1-3 mmol: 1-3 mmol;

[0038] The temperature of the reaction is 40-60 °C and the time is 4-8 h.

[0039] Preferably, in step (8), the dosage ratio of compound 10, compound 6, the solvent, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine is 0.05-0.15 mmol: 0.05-0.15 mmol: 4-8 mL: 0.05-0.15 mmol: 0.1-0.15 mmol;

[0040] The solvent is N,N-dimethylformamide;

[0041] The temperature of the acid amide condensation reaction is room temperature and the time is 12-20 h.

[0042] The present invention also provides the use of the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compounds in the preparation of anti-inflammatory drugs, and the anti-inflammatory drugs treat inflammation by inhibiting the release of inflammatory factors by macrophages.

[0043] Preferably, the anti-inflammatory drugs are used for preventing or treating inflammation and diseases related to inflammation.

[0044] Preferably, the inflammation or diseases related to inflammation include but are not limited to sepsis, acute lung injury.

[0045] The present invention also provides a pharmaceutical composition for preventing or treating inflammation and inflammation-related diseases, which comprises the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound or a pharmaceutically acceptable salt thereof, and also comprises pharmaceutical excipients.

[0046] Preferably, the preparation form of the pharmaceutical composition includes injection, tablet, capsule, aerosol, suppository, film, dripping pill, ointment, controlled release or sustained release agent, and nano preparation.

[0047] The N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound provided by the present invention is used for treating sepsis and acute lung injury, and the preparation forms that can be prepared include injection, tablet, capsule, aerosol, suppository, film, dripping pill, ointment, controlled release or sustained release agent, and nano preparation. Description of the Drawings

[0048] Figure 1 It is the dose-effect relationship of the compound inhibiting the release of IL-6 and TNF-α from LPS-stimulated macrophages;

[0049] Figure 2 It is the toxicity test of the compound on macrophages;

[0050] Figure 3 It is the effect of compound 11a on alleviating the physiological changes of acute lung injury mice;

[0051] Figure 4 It is the pathological changes of the lung tissue of acute lung injury mice alleviated by compound 11a;

[0052] Figure 5 It is the physiological and pathological changes of sepsis mice alleviated by compound 11a. Detailed Embodiments

[0053] The present invention provides an N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound, which comprises one of the following structural formulas:

[0054]

[0055] The present invention also provides a preparation method of the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound, which comprises the following steps:

[0056] (1) 3-Acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and a solvent are mixed and then subjected to a low-temperature reaction and a heating reaction in sequence to form methyl 3-(2-chlorophenyl)-3-oxopropionate, denoted as Compound 2;

[0057] (2) Methyl 3-(2-chlorophenyl)-3-oxopropionate, N,N-dimethylformamide dimethyl acetal and a solvent are mixed and reacted to form Compound 3;

[0058] (3) Compound 3, an aniline raw material and a solvent are mixed and reacted to obtain a Compound 4 product system;

[0059] The aniline raw material includes aniline, p-fluoroaniline, p-chloroaniline, p-bromoaniline, 3-chloro-4-fluoroaniline or 4-(trifluoromethoxy)aniline;

[0060] (4) Cesium carbonate is added to the Compound 4 product system for reaction to form Compound 5;

[0061] (5) Compound 5, 1,4-dioxane, sodium hydroxide and water are mixed and reacted to form Compound 6;

[0062] Compound 6 includes N-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-fluorophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-chlorophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-bromophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-(3-chloro-4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or 4-oxo-1-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxylic acid;

[0063] (6) 4-Chloro-6,7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and a solvent are mixed and reacted to form Compound 9;

[0064] (7) Compound 9, water, ethanol, reducing iron powder and ammonium chloride are mixed and reacted to form 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline, denoted as Compound 10;

[0065] (8) Compound 10, Compound 6, a solvent, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine are mixed and subjected to an acid amide condensation reaction to form N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compounds;

[0066] There is no limitation on the sequence of steps (1)-(5) for preparing compound 6 and steps (6)-(7) for preparing compound 10.

[0067] In the present invention, the synthetic route of the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compounds is as follows:

[0068]

[0069] In the present invention, the dosage ratio of 3-acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and the solvent in step (1) is 2-4 mmol: 8-12 mmol: 18-22 mmol: 8-12 mL, preferably 3 mmol: 9-11 mmol: 19-21 mmol: 9-11 mL, and more preferably 3 mmol: 10 mmol: 20 mmol: 10 mL;

[0070] The solvent is anhydrous tetrahydrofuran;

[0071] The temperature of the low-temperature reaction is -5 to 5 °C, preferably -2 to 2 °C, and more preferably 0 °C; the time is 25 to 35 min, preferably 28 to 32 min, and more preferably 30 to 31 min;

[0072] The temperature of the heating reaction is 80 to 90 °C, preferably 83 to 87 °C, and more preferably 84 to 86 °C; the time is 1 to 3 h, preferably 2 h;

[0073] In step (2), the dosage ratio of methyl 3-(2-chlorophenyl)-3-oxopropionate, N,N-dimethylformamide dimethyl acetal and the solvent is 2-3 mmol: 8-9 mmol: 8-12 mL, preferably 2-3 mmol: 8-9 mmol: 9-11 mL, and more preferably 2.5 mmol: 8.5 mmol: 10 mL;

[0074] The solvent is toluene;

[0075] The temperature of the reaction is 110 to 130 °C, preferably 115 to 125 °C, and more preferably 120 to 122 °C; the time is 1 to 3 h, preferably 2 h;

[0076] In step (3), the dosage ratio of compound 3, aniline raw material and the solvent is 2-4 mmol: 2-4 mmol: 8-12 mL, preferably 2-3 mmol: 2-3.5 mmol: 9-11 mL, and more preferably 2.5-3 mmol: 2.5-3 mmol: 10 mL;

[0077] The solvent is toluene;

[0078] The temperature of the reaction is 100 - 120 °C, preferably 105 - 115 °C, more preferably 110 - 112 °C; the time is 2 - 4 h, preferably 3 h;

[0079] In the step (4), the dosage ratio of cesium carbonate to compound 3 is 2 - 4 mmol:2 - 4 mmol, preferably 2.5 - 3.5 mmol:2.5 - 3.5 mmol, more preferably 3 mmol:3 - 3.5 mmol;

[0080] The temperature of the reaction is 140 - 160 °C, preferably 145 - 155 °C, more preferably 150 - 152 °C; the time is 2 - 4 h, preferably 3 h;

[0081] In the step (5), the dosage ratio of compound 5, 1,4 - dioxane, sodium hydroxide and water is 2 - 3 mmol:8 - 12 mL:1 - 3 mmol:1 - 3 mL, preferably 2 - 3 mmol:9 - 11 mL:2 - 3 mmol:2 - 3 mL, more preferably 2.5 mmol:10 mL:2.5 - 3 mmol:2 - 2.5 mL.

[0082] In the present invention, in the step (6), the dosage ratio of 4 - chloro - 6,7 - dimethoxyquinoline, 4 - nitrophenol, sodium iodide, sodium carbonate and the solvent is 0.2 - 0.8 mmol:0.2 - 0.8 mmol:0.05 - 0.2 mmol:15 - 25 mmol:10 - 20 mL, preferably 0.4 - 0.6 mmol:0.4 - 0.6 mmol:0.1 - 0.15 mmol:17 - 23 mmol:13 - 18 mL, more preferably 0.5 mmol:0.5 mmol:0.12 - 0.13 mmol:20 - 21 mmol:15 - 16 mL;

[0083] The solvent is toluene;

[0084] The temperature of the reaction is 120 - 140 °C, preferably 125 - 135 °C, more preferably 130 - 132 °C; the time is 10 - 15 h, preferably 11 - 14 h, more preferably 12 - 13 h;

[0085] In the step (7), the dosage ratio of compound 9, water, ethanol, reducing iron powder and ammonium chloride is 0.5 - 1.5 mmol:3 - 7 mL:8 - 12 mL:1 - 3 mmol:1 - 3 mmol, preferably 0.8 - 1.3 mmol:4 - 6 mL:9 - 11 mL:2 mmol:2 mmol, more preferably 1 - 1.1 mmol:5 mL:10 mL:2 mmol:2 mmol;

[0086] The temperature of the reaction is 40 to 60 °C, preferably 45 to 55 °C, and more preferably 50 to 52 °C; the time is 4 to 8 h, preferably 5 to 7 h, and more preferably 6 h.

[0087] In the present invention, the dosage ratio of compound 10, compound 6, solvent, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and N,N-diisopropylethylamine in step (8) is 0.05 to 0.15 mmol: 0.05 to 0.15 mmol: 4 to 8 mL: 0.05 to 0.15 mmol: 0.1 to 0.15 mmol, preferably 0.08 to 0.13 mmol: 0.07 to 0.12 mmol: 5 to 7 mL: 0.08 to 0.12 mmol: 0.11 to 0.14 mmol, and more preferably 0.1 to 0.11 mmol: 0.08 to 0.10 mmol: 6 mL: 0.09 to 0.10 mmol: 0.12 to 0.13 mmol;

[0088] The solvent is N,N-dimethylformamide;

[0089] The temperature of the acid amide condensation reaction is room temperature, and the time is 12 to 20 h, preferably 14 to 18 h, and more preferably 15 to 16 h.

[0090] The present invention also provides the use of the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compounds in the preparation of anti-inflammatory drugs, and the anti-inflammatory drugs treat inflammation by inhibiting the release of inflammatory factors from macrophages.

[0091] In the present invention, the anti-inflammatory drugs are used for preventing or treating inflammation and diseases related to inflammation.

[0092] In the present invention, the inflammation or diseases related to inflammation include but are not limited to sepsis, acute lung injury.

[0093] The present invention also provides a pharmaceutical composition for preventing or treating inflammation and diseases related to inflammation, which contains the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compounds or their pharmaceutically acceptable salts, and also contains pharmaceutical excipients.

[0094] In the present invention, the dosage forms of the pharmaceutical composition include injections, tablets, capsules, aerosols, suppositories, membranes, dripping pills, ointments, controlled release or sustained release agents, and nano-formulations.

[0095] The technical solutions provided by the present invention will be described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0096] Example 1

[0097] N-Phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6a)

[0098] Step 1: Add 3-acetyl-2-chlorobenzene 1 (465 mg, 3 mmol), dimethyl carbonate (900 mg, 10 mmol) and sodium hydride (480 mg, 20 mmol) to 10 mL of anhydrous tetrahydrofuran solvent in a 50 mL round-bottom flask, stir the reaction at 0 °C for 30 minutes, and then heat it to 85 °C for 2 hours. When the reaction is completed monitored by TLC, slowly add concentrated hydrochloric acid to the mixture to remove the excess sodium hydride. When the pH is about 2-3, extract with dichloromethane (CH 2 CL 2 ). Wash the organic layer with water three times and dry it over anhydrous magnesium sulfate. Evaporate CH 2 CL 2 under reduced pressure to obtain the yellow oily liquid methyl 3-(2-chlorophenyl)-3-oxopropionate 2. React 2 (610 mg, 2.64 mmol) with N,N-dimethylformamide dimethyl acetal (DMF-DMA) (1.022 g, 8.5 mmol) in toluene (10 mL) at 120 °C for 2 hours. When the reaction is completed monitored by TLC, extract with CH 2 CL 2 . Wash the organic layer with water three times and dry it over anhydrous magnesium sulfate. Evaporate CH 2 CL 2 under reduced pressure to obtain the orange-yellow liquid 3. Dissolve 3 (0.64 mg, 3 mmol) and aniline (0.333 mg, 3 mmol) in toluene (10 mL) and pour them into a 50 mL round-bottom flask, react at 110 °C for 3 hours. When the reaction is completed monitored by TLC, obtain the product 4a. Then continue to add cesium carbonate (790 mg, 3 mmol) to the 50 mL round-bottom flask and react at 150 °C for 3 hours. When the reaction is completed monitored by TLC, extract with CH 2 CL 2 . Wash the organic layer with water three times and dry it over anhydrous magnesium sulfate. Evaporate CH 2 CL 2The orange-yellow solid methyl N-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylate 5a was obtained. 5a (660 mg, 2.5 mmol) was dissolved in 1,4-dioxane (10 mL), and sodium hydroxide (80 mg, 2 mmol) dissolved in water (2 mL) were added together to a 50 mL round-bottom flask. The reaction was carried out at 110 °C for 1 hour. When the reaction was completed monitored by TLC, 1,4-dioxane was evaporated under reduced pressure. Saturated brine was added to dissolve, and the pH was adjusted to 3 - 4 with dilute hydrochloric acid. Then 2 CL 2 was used for extraction. The organic layer was washed three times with water, dried over anhydrous magnesium sulfate, and CH 2 CL 2 was evaporated under reduced pressure. Column chromatography separation (DCM:CH 3 OH = 10:1) gave the orange-yellow solid N-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6a.

[0099] 6a; Yield: 63.1%. 1 HNMR (400 MHz, CDCl 3 ) δ 14.91 (s, 1H), 8.84 (s, 1H), 8.60 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.69 (d, J = 3.2 Hz,, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H).

[0100] According to the method of step one, using p-fluoroaniline as the raw material, N-(p-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6b was prepared.

[0101] 6b; Yield: 66.5%. 1 HNMR (400 MHz, CDCl 3 ) δ 14.82 (s, 1H), 8.82 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.47 (d, J = 4.3 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H).

[0102] According to the method of step one, using p-chloroaniline as the raw material, N-(p-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6c was prepared.

[0103] 6c; Yield: 70.3%. 1 HNMR(400MHz, CDCl 3 ) δ 14.79 (s, 1H), 8.80 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H).

[0104] According to the method of Step 1, using 4-bromoaniline as the raw material, N-(4-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6d was prepared.

[0105] 6d; Yield: 60.9%. 1 HNMR(400MHz, CDCl 3 ) δ 14.78 (s, 1H), 8.79 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H).

[0106] According to the method of Step 1, using 3-chloro-4-fluoroaniline as the raw material, 1-(3-chloro-4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 6e was prepared.

[0107] 6e; Yield: 55.1%. 1 HNMR(400MHz, CDCl 3 ) δ 14.71 (s, 1H), 8.76 (s, 1H), 8.56 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H).

[0108] According to the method of Step 1, using 4-(trifluoromethoxy)aniline as the raw material, 4-oxo-1-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxylic acid 6f was prepared.

[0109] 6f; Yield 68.1%. 1 HNMR(400MHz, CDCl 3)δ14.71(s,1H),8.76(s,1H),8.56(d,J=8.1Hz,1H),7.71(t,J=7.8Hz,1H),7.59(t,J=7.6Hz,1H),7.53(s,1H),7.51(s,1H),7.51(s,1H),7.49(s,1H),7.12(d,J=8.6Hz,1H).

[0110] Step 2: Dissolve 4-chloro-6,7-dimethoxyquinoline 7 (84.60 mg, 0.5 mmol), 4-nitrophenol 8 (103.05 mg, 0.5 mmol), sodium iodide (24.44 mg, 0.1 mmol) and sodium carbonate (20 mmol) in 15 mL of toluene solution in a 50 mL round-bottom flask, and react at 130 °C for 12 h. When the reaction is completed monitored by TLC, evaporate toluene under reduced pressure to obtain a white solid 9. Dissolve 9 (110 mg, 1 mmol) in a mixed solution of water (5 ml) and ethanol (10 ml), then add reduced iron powder (112 mg, 2 mmol) and ammonium chloride (130 mg, 2 mmol) to the solution, and react at 50 °C for 6 h. After monitoring the completion of the reaction by TLC, remove the inorganic residue by filtration, and dry the filtrate under vacuum to obtain the crude product. Finally, separate by column chromatography (DCM:CH 3 OH = 10:1) to obtain 10. That is the target compound 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline.

[0111] 10; Yield: 59.7%. 1 HNMR(400MHz,CDCl 3 )δ8.53(d,J=5.3Hz,1H),7.57(s,1H),7.45(s,1H),7.25(t,J=8.0Hz,1H),6.62(d,J=8.0Hz,1H),6.60(s,1H),6.58(s,1H),6.53(d,J=2.1Hz,1H),5.22(s,2H),4.08(d,J=4.3Hz,6H).

[0112] Step 3: Dissolve 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (34.3 mg, 0.1 mmol) and N-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (30 mg, 0.1 mmol) in N,N-dimethylformamide (6 mL), add HATU (2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (25.8 mg, 0.1 mmol) and DIPEA (N,N-diisopropylethylamine) (45.6 mg, 0.12 mmol), and carry out the acid-amine condensation reaction at room temperature for 16 h. After monitoring the completion of the reaction by TLC, extract with ethyl acetate. Wash the organic layer three times with water and dry over anhydrous magnesium sulfate. Evaporate the ethyl acetate under reduced pressure and separate by column chromatography (DCM:CH 3 OH = 15:1) to obtain N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide.

[0113] N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide (11a); Yield: 55.7%; m.p.: 225.1–226.6 °C. 1 HNMR (400 MHz, CDCl 3 ) δ 12.47 (s, 1H), 8.97 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.54 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.68 (s, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 5.0 Hz, 1H), 4.10 (s, 6H). 13CNMR (101 MHz, CDCl 3) δ 177.03, 163.47, 163.08, 154.72, 150.59, 149.06, 147.95, 144.86, 140.77, 142.46, 140.46, 137.18, 133.06, 130.55(2C), 130.36, 127.26(2C), 127.09, 126.89, 125.80, 122.30(2C), 121.57(2C), 118.19, 116.08, 111.84, 104.31, 102.91, 99.76, 56.74, 56.42. ESI-MS: m / z 544.2 [M+H] + 。

[0114] According to the method of Step 3, using 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline and N-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as raw materials, N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (11b) was prepared.

[0115] 11b; Yield: 59.3%; m.p.: 256.9–258.8 °C. 1 1H NMR (400 MHz, CDCl 3 ) δ 12.40 (s, 1H), 8.93 (d, J = 3.1 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.91 (d, J = 2.9 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 3.0 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.53–7.45 (m, 3H), 7.38 (t, J = 9.7 Hz, 2H), 7.24 (d, J = 3.0 Hz, 1H), 7.22 (d, J = 3.0 Hz, 1H), 7.12 (d, J = 10.4 Hz, 1H), 6.55 (s, 1H), 4.09 (s, 6H). 13C NMR (101 MHz, CDCl 3) δ 176.98, 162.79, 161.47, 153.22, 149.96, 149.71, 148.00, 147.90, 145.84, 140.81, 136.49, 136.46, 133.12, 130.94, 129.38, 129.29, 128.85, 127.08, 127.01, 125.82, 122.13(2C), 121.61(2C), 117.88, 117.76, 117.53, 112.10, 107.02, 103.26, 99.61, 56.26(2C). ESI-MS: m / z 562.2 [M + H] + .

[0116] According to the method of Step 3, using 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline and N-(4-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as raw materials, 1-(4-chlorophenyl)-N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (11c) was prepared.

[0117] 11c; Yield: 55.2%; m.p.: 249.1–250.2 °C. 1 HNMR (400 MHz, CDCl 3 ) δ 12.41 (s, 1H), 8.93 (s, 1H), 8.64 (dd, J = 8.1, 1.4 Hz, 1H), 8.53 (d, J = 5.4 Hz, 1H), 7.96–7.94 (m, 1H), 7.93–7.91 (m, 1H), 7.71–7.69 (m, 1H), 7.68 (s, 1H), 7.66 (d, J = 2.8 Hz, 1H), 7.63 (s, 1H), 7.62–7.56 (m, 1H), 7.54 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.46–7.44 (m, 1H), 7.26–7.24 (m, 1H), 7.23 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 5.4 Hz, 1H), 4.10 (s, 6H). 13CNMR (101 MHz, CDCl 3)δ177.01,162.73,160.91,152.81,150.25,149.48,148.94,147.68,146.84,140.60,138.94,136.51,136.21,133.15,130.82(2C),128.72(2C),127.09,125.88,122.12(2C),121.64(2C),117.82(2C),116.12,112.28,107.83,103.38,99.59,56.21,56.16.ESI-MS:m / z578.2[M+H] + .

[0118] According to the method of Step 3, using 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline and N-(4-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as raw materials, 1-(4-bromophenyl)-N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (11d) was prepared.

[0119] 11d; Yield: 58.8%; m.p.: 257.1–259.0 °C. 1 HNMR(400MHz,CDCl 3 )δ12.38(s,1H),8.92(s,1H),8.64(d,J = 8.0Hz,1H),8.53(d,J = 5.2Hz,1H),7.93(s,1H),7.91(s,1H),7.84(s,1H),7.82(s,1H),7.68(t,J = 7.8Hz,1H),7.62(s,1H),7.58(d,J = 7.2Hz,1H),7.47(s,1H),7.40(s,1H),7.38(s,1H),7.24(s,1H),7.22(s,1H),7.15(d,J = 8.5Hz,1H),6.55(d,J = 5.3Hz,1H),4.09(d,J = 1.8Hz,6H).ESI-MS:m / z622.1[M+H] + .

[0120] According to the method of Step 3, using 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline and 1-(3-chloro-4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as raw materials, compound 11e was prepared.

[0121] 11e; Yield: 54.5%; m.p.: 210.1–211.2 °C. 1 HNMR(400MHz,CDCl3 ) δ 12.33 (s, 1H), 8.90 (s, 1H), 8.63 (d, J = 7.4 Hz, 1H), 8.52 (d, J = 5.3 Hz, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.63 (d, J = 6.3 Hz, 1H), 7.61 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.24 (s, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 5.3 Hz, 1H), 4.09 (d, J = 2.1 Hz, 6H). ESI-MS: m / z 596.2 [M+H] + .

[0122] According to the method of Step 3, using 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline and 4-oxo-1-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxylic acid as raw materials, N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxamide (11f) was prepared.

[0123] 11f; Yield: 60.3%; m.p.: 248.5–250.1 °C. 1 1H NMR (400 MHz, CDCl 3 ) δ 12.44 (s, 1H), 8.94 (s, 1H), 8.64 (dd, J = 8.1, 1.3 Hz, 1H), 8.53 (d, J = 5.5 Hz, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.69 (dd, J = 8.6, 1.5 Hz, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.57–7.51 (m, 1H), 7.49 (d, J = 4.6 Hz, 1H), 7.43–7.33 (m, 2H), 7.25 (s, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 5.5 Hz, 1H), 4.11 (d, J = 2.0 Hz, 6H). ESI-MS: m / z 628.2 [M+H] + 。

[0124] Pharmacological research on the product of the present invention

[0125] (1) Dose - effect relationship of the example compounds in inhibiting the release of IL - 6 and TNF - α from LPS - stimulated macrophages (J774A.1)

[0126] When stimulated with LPS, J774A.1 secretes excessive pro - inflammatory cytokines (such as IL - 6 and TNF - α). An enzyme - linked immunosorbent assay (ELISA) was established to test the anti - inflammatory activity of the compounds on the release of IL - 6 and TNF - α in LPS - stimulated J774A.1. Dimethyl sulfoxide (DMSO) was used as a vehicle control. After treating J774A.1 macrophages with 10 μM compound for 0.5 h, the cells were stimulated with LPS (0.5 μg / mL) and cultured for 24 h. Then, the amounts of IL - 6 and TNF - α were measured using an ELISA kit. The cytokine inhibitory activity of the compounds is as Figure 1 shown. The results showed that 6 compounds could significantly inhibit the release of IL - 6( Figure 1 A) and TNF - α( Figure 1 B) from LPS - stimulated macrophages, showing significant anti - inflammatory effects.

[0127] (2) Toxicity test of the example compounds on macrophages

[0128] To evaluate the safety of the compounds, the cytotoxicity of the compounds was tested in J774A.1. Briefly, J774A.1 was placed in a 96 - well plate containing DMEM medium, with 2.0×104 cells per well, supplemented with 10% FBS, 100 U / mL penicillin, and 100 mg / mL streptomycin. Next, the cells were cultured with the compound at a concentration of 10 μM for 24 h, and a fresh solution of MTT (5 mg / mL) dissolved in NaCl solution (0.9%) was added to each well. Then, the culture dish was incubated in 5% CO 2 at 37 °C for 4 h. The absorbance was measured at 490 nm using a microplate reader. The test results are as Figure 2 shown. At a concentration of 10 μM, there was no significant toxicity to cell proliferation activity, indicating that the compounds are non - toxic.

[0129] (3) Effect of compound 11a in alleviating physiological changes in mice with acute lung injury

[0130] The protective effect of compound 11a on an acute lung injury model in C57 / BL6 mice induced by intratracheal instillation of LPS was studied. Dimethyl sulfoxide was used as a vehicle control. Mice were pretreated with compound 11a (20 mg / kg, intraperitoneal injection) or vehicle, and then stimulated with 5 mg / kg LPS. The lung wet / dry ratio was used to quantify the degree of pulmonary edema. LPS could increase the degree of pulmonary edema, and after using compound 11a, the degree of pulmonary edema could be effectively reduced, as Figure 3 shown in A. In addition, Figure 3The results in B showed that compound 11a could inhibit the increase in the total cell number of bronchoalveolar lavage fluid (BALF) induced by LPS. As Figure 3 shown in C, 3D, 3E and 3F, the release of IL-6 and TNF-α in the bronchoalveolar lavage fluid (BALF) and serum of mice in the acute lung injury model was significantly increased, while compound 11a significantly reversed this change. The above experimental results indicated that compound 11a had excellent in vivo anti-inflammatory effects on mice in the acute lung injury model.

[0131] (4) Compound 11a alleviated the pathological changes in the lung tissue of mice with acute lung injury

[0132] To evaluate the histological changes in the lungs of mice with acute lung injury, hematoxylin-eosin (H&E) staining was performed on lung tissues. Mice stimulated with LPS showed typical pathological changes of acute lung injury, such as obvious pulmonary edema, increased alveolar wall thickness, pulmonary congestion, inflammatory cell infiltration and lung tissue destruction, while mice pretreated with compound 11a significantly reduced these pathological changes and even significantly restored the normal physiological state, as Figure 4 shown, indicating that the compound could effectively alleviate lung tissue injury in mice with acute lung injury.

[0133] (5) Compound 11a alleviated the physiological and pathological changes in septic mice

[0134] The protective effect of compound 11a on a sepsis model of C57 / BL6 mice induced by intraperitoneal injection of LPS was studied. Dimethyl sulfoxide was used as a vehicle control, and mice were pretreated with compound 11a (20 mg / kg, intraperitoneal injection) or vehicle, and then stimulated with 20 mg / kg of LPS. As Figure 5 shown in A and 5B, compound 11a could increase the survival rate of septic mice and alleviate the symptom of weight loss in mice. The spleen tissue was weighed and stained with H&E. Mice stimulated with LPS showed typical splenic tissue edema, and the pathological changes in the splenic tissue were manifested as obvious hyperplasia of white pulp and lymph nodes, as Figure 5 shown in C and 5D. Mice pretreated with compound 11a significantly alleviated the edema and pathological changes, indicating that the compound could effectively alleviate the physiological and pathological changes in septic mice.

[0135] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A compound of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide, characterized in that, it contains one of the following structural formulas:

2. A preparation method of the compound of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide according to claim 1, characterized in that, it comprises the following steps: (1) 3-Acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and a solvent are mixed and successively subjected to a low-temperature reaction and a heating reaction to generate methyl 3-(2-chlorophenyl)-3-oxopropionate, denoted as compound 2; (2) Methyl 3-(2-chlorophenyl)-3-oxopropionate, N,N-dimethylformamide dimethyl acetal and a solvent are mixed and reacted to generate compound 3; (3) Compound 3, an aniline raw material and a solvent are mixed and reacted to obtain a compound 4 product system; The aniline raw material is selected from aniline, p-fluoroaniline, p-chloroaniline, p-bromoaniline, 3-chloro-4-fluoroaniline or 4-(trifluoromethoxy)aniline; (4) Cesium carbonate is added to the compound 4 product system for reaction to generate compound 5; (5) Compound 5, 1,4-dioxane, sodium hydroxide and water are mixed and reacted to generate compound 6; The compound 6 is selected from N-phenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-fluorophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-chlorophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, N-p-bromophenyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1-(3-chloro-4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or 4-oxo-1-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxylic acid; (6) 4-Chloro-6,7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and a solvent are mixed and reacted to generate compound 9; (7) Compound 9, water, ethanol, reducing iron powder and ammonium chloride are mixed and reacted to generate 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline, denoted as compound 10; (8) Compound 10, compound 6, a solvent, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine are mixed and subjected to an acid amide condensation reaction to generate a compound of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide; There is no limitation on the order of preparing compound 6 in steps (1) to (5) and preparing compound 10 in steps (6) to (7).

3. According to the preparation method described in claim 2, characterized in that, In the step (1), the dosage ratio of 3-acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and the solvent is 2-4 mmol: 8-12 mmol: 18-22 mmol: 8-12 mL; The solvent is anhydrous tetrahydrofuran; The temperature of the low-temperature reaction is -5 to 5 °C, and the time is 25 to 35 min; The temperature of the heating reaction is 80 to 90 °C, and the time is 1 to 3 h; In the step (2), the dosage ratio of methyl 3-(2-chlorophenyl)-3-oxopropionate, N,N-dimethylformamide dimethyl acetal and the solvent is 2-3 mmol: 8-9 mmol: 8-12 mL; The solvent is toluene; The temperature of the reaction is 110 to 130 °C, and the time is 1 to 3 h; In the step (3), the dosage ratio of compound 3, aniline raw material and the solvent is 2-4 mmol: 2-4 mmol: 8-12 mL; The solvent is toluene; The temperature of the reaction is 100 to 120 °C, and the time is 2 to 4 h; In the step (4), the dosage ratio of cesium carbonate and compound 3 is 2-4 mmol: 2-4 mmol; The temperature of the reaction is 140 to 160 °C, and the time is 2 to 4 h; In the step (5), the dosage ratio of compound 5, 1,4-dioxane, sodium hydroxide and water is 2-3 mmol: 8-12 mL: 1-3 mmol: 1-3 mL.

4. The preparation method according to claim 2 or 3, wherein, In the step (6), the dosage ratio of 4-chloro-6,7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and the solvent is 0.2-0.8 mmol: 0.2-0.8 mmol: 0.05-0.2 mmol: 15-25 mmol: 10-20 mL; The solvent is toluene; The temperature of the reaction is 120 to 140 °C, and the time is 10 to 15 h; In the step (7), the dosage ratio of compound 9, water, ethanol, reducing iron powder and ammonium chloride is 0.5-1.5 mmol: 3-7 mL: 8-12 mL: 1-3 mmol: 1-3 mmol; The temperature of the reaction is 40 to 60 °C, and the time is 4 to 8 h.

5. The preparation method according to claim 4, wherein, In the step (8), the dosage ratio of compound 10, compound 6, the solvent, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine is 0.05-0.15 mmol: 0.05-0.15 mmol: 4-8 mL: 0.05-0.15 mmol: 0.1-0.15 mmol; The solvent is N,N-dimethylformamide; The temperature of the acid amide condensation reaction is room temperature, and the time is 12 to 20 h.

6. Use of the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound according to claim 1 in the preparation of an anti-inflammatory drug, wherein the anti-inflammatory drug treats inflammation by inhibiting the release of inflammatory factors from macrophages; The anti-inflammatory drug is used for preventing or treating inflammation and diseases related to inflammation; The inflammation is the inflammation caused by the release of inflammatory factors from macrophages; The diseases related to inflammation are sepsis and acute lung injury.

7. A pharmaceutical composition for preventing or treating inflammation and diseases related to inflammation, characterized in that, it contains the N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide compound according to claim 1 or a pharmaceutically acceptable salt thereof, and also contains pharmaceutical excipients.

8. According to the pharmaceutical composition of claim 7, characterized in that, the preparation form of the pharmaceutical composition includes injection, tablet, capsule, aerosol, suppository, film, dropping pill, ointment, controlled release or sustained release agent, and nano preparation.

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