A 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, its preparation method and application

Abstract

This invention belongs to the field of compound preparation technology, and provides a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, its preparation method, and its application. The method of this invention includes the following steps: reacting compound 1, potassium carbonate, and a phenol compound; mixing compound 2, methanol, water, and lithium hydroxide to obtain compound 3; acylating compound 3, thionyl chloride, and sodium bromide, followed by reaction with tin chloride dihydrate and ethanol to obtain compound 4; reacting compound 5 with DMF-DMA; reacting compound 6, substituted aniline, and cesium carbonate followed by hydrolysis to obtain compound 8; and reacting compound 4, compound 8, HATU, and DIPEA. The compounds of this invention are used to prepare anti-inflammatory drugs, treating inflammation and inflammation-related diseases by inhibiting the release of inflammatory factors (TNF-α and / or IL-6) from macrophages.

Description

Technical Field

[0001] This invention relates to the field of compound preparation technology, and in particular to a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, its preparation method, and its application. Background Technology

[0002] Inflammation is a defensive response of the body to injury or infection, typically manifesting as redness, swelling, heat, pain, and dysfunction. The core of the inflammatory response is the activation of immune cells and the release of inflammatory mediators, such as cytokines (TNF-α, IL-1β, IL-6) and chemokines. These inflammatory mediators recruit more immune cells to the site of injury, clearing pathogens and promoting tissue repair. However, excessive inflammatory responses can lead to tissue damage and disease.

[0003] Acute lung injury (ALI) is a severe respiratory disease, usually caused by infection, trauma, or inhalation of harmful substances. It is characterized by damage to alveolar epithelial cells and vascular endothelial cells, leading to pulmonary edema, inflammatory cell infiltration, and impaired gas exchange. Inflammatory mediators play a crucial role in the pathogenesis of ALI; they increase vascular permeability, causing fluid to leak into the alveolar spaces, further leading to respiratory failure. Treatment for ALI primarily involves controlling the inflammatory response, improving oxygenation, and protecting lung tissue. Anti-inflammatory drugs (such as glucocorticoids) can inhibit the release of excessive inflammatory mediators and reduce lung damage. Mechanical ventilation provides respiratory support and is currently the main treatment approach; there is no specific cure.

[0004] Therefore, the development of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds and drugs targeting inflammatory diseases such as ALI is of great significance. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art by providing a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, its preparation method, and its application.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, the structural formula of which is as follows:

[0008]

[0009] This invention also provides a method for preparing the aforementioned 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds. The synthetic route for the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds is as follows:

[0010]

[0011] Where R1 is H or F, and R2 is R3 is either F or Br;

[0012] The preparation method of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds includes the following steps:

[0013] 1) Compound 1, potassium carbonate, and phenol compound are reacted in isopropanol to obtain compound 2; the phenol compound is p-nitrophenol or 2-fluoro-4-nitrophenol;

[0014] 2) After mixing compound 2, methanol, water and lithium hydroxide and reacting, the pH value of the reaction system was adjusted to obtain compound 3;

[0015] 3) Compound 3, thionyl chloride, and sodium bromide were subjected to an acylation reaction to obtain an acylated product; the acylated product, dichloromethane, triethylamine, and an amine compound were mixed to obtain an intermediate; the intermediate, tin chloride dihydrate, and ethanol were reacted to obtain compound 4;

[0016] The amine compound is 3-morpholinopropylamine or 2-thiopheneethylamine;

[0017] 4) Compound 5 was reacted with N,N-dimethylformamide dimethyl acetal to give compound 6;

[0018] 5) Compound 6, substituted aniline, and cesium carbonate were reacted in chlorobenzene to give compound 7; compound 7 was then hydrolyzed to give compound 8.

[0019] 6) Compound 4, compound 8, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine were reacted in N,N-dimethylformamide to obtain 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds.

[0020] Preferably, the mixing reaction in step 2) takes 1.5 to 2.5 hours, and the reaction is stopped by rotary evaporation to remove methanol; the pH of the reaction system is adjusted to 2 to 3, and the reagent for adjusting the pH of the reaction system is concentrated hydrochloric acid.

[0021] Preferably, the reaction temperature in step 3) is 70–80°C and the reaction time is 5–6 h.

[0022] Preferably, the reaction temperature in step 4) is 105–115°C, and the reaction time is 2–3 h.

[0023] Preferably, the reaction temperature in step 5) is 115–125°C, and the reaction time is 3.5–4.5 h.

[0024] The present invention also provides the application of the aforementioned 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds in the preparation of anti-inflammatory drugs.

[0025] Preferably, the anti-inflammatory drug comprises an active ingredient and excipients; the active ingredient is the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound or a pharmaceutically acceptable salt thereof.

[0026] Preferably, the formulations of anti-inflammatory drugs include injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release formulations, sustained-release formulations, or nanoformulations.

[0027] Preferably, inflammation includes inflammatory diseases and related diseases, including sepsis, acute lung injury, arthritis, colitis, hepatitis, fatty liver, and chronic inflammatory diseases; chronic inflammatory diseases include diabetic nephropathy, diabetic cardiomyopathy, atherosclerosis, obesity complications, and hypertension complications.

[0028] The beneficial effects of the present invention include:

[0029] The 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds of the present invention are used to prepare anti-inflammatory drugs for the prevention and / or treatment of inflammatory diseases and inflammation-related diseases (such as sepsis, acute lung injury, arthritis, colitis, hepatitis, fatty liver, diabetic nephropathy, diabetic cardiomyopathy, atherosclerosis, obesity complications, and hypertension complications). The anti-inflammatory drugs treat inflammatory diseases and inflammation-related diseases by inhibiting the release of inflammatory factors (TNF-α and / or IL-6) from macrophages. Attached Figure Description

[0030] Figure 1 The diagram shows the dose-response relationship between the inhibition of LPS-stimulated IL-6 release from J774A.1 cells by 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds in Examples 1 and 2, where A represents Example 1 and B represents Example 2.

[0031] Figure 2The figure shows the physiological changes in rats with acute lung injury alleviated by 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds in Example 1. In the figure, A is the wet weight / dry weight ratio of the lungs, B is the total cell count in the bronchoalveolar lavage fluid, C is the total protein content in the bronchoalveolar lavage fluid, D is the inhibitory effect on IL-6 transcription in lung tissue, E is the concentration of the pro-inflammatory cytokine IL-6 in the bronchoalveolar lavage fluid, F is the concentration of TNF-α in the bronchoalveolar lavage fluid, G is the concentration of IL-6 in serum, and H is the concentration of TNF-α in serum.

[0032] Figure 3 The image shows the pathological changes in lung tissue during the relief of acute lung injury by the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound in Example 1. In the image, A is a pathological image of mouse lung tissue, and B and C are immunohistochemical staining of macrophage markers F4 / 80 and MPO in LPS-induced mouse lung tissue, respectively. Detailed Implementation

[0033] This invention provides a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, the structural formula of which is as follows:

[0034]

[0035] This invention also provides a method for preparing the aforementioned 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds. The synthetic route for the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds is as follows:

[0036]

[0037] Where R1 is H or F, and R2 is R3 is either F or Br;

[0038] The preparation method of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds includes the following steps:

[0039] 1) Compound 1, potassium carbonate, and phenol compound are reacted in isopropanol to obtain compound 2; the phenol compound is p-nitrophenol or 2-fluoro-4-nitrophenol;

[0040] 2) After mixing compound 2, methanol, water and lithium hydroxide and reacting, the pH value of the reaction system was adjusted to obtain compound 3;

[0041] 3) Compound 3, thionyl chloride, and sodium bromide were subjected to an acylation reaction to obtain an acylated product; the acylated product, dichloromethane, triethylamine, and an amine compound were mixed to obtain an intermediate; the intermediate, tin chloride dihydrate, and ethanol were reacted to obtain compound 4;

[0042] The amine compound is 3-morpholinopropylamine or 2-thiopheneethylamine;

[0043] 4) Compound 5 was reacted with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to give compound 6;

[0044] 5) Compound 6, substituted aniline, and cesium carbonate were reacted in chlorobenzene to give compound 7; compound 7 was then hydrolyzed to give compound 8.

[0045] 6) Compound 4, compound 8, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) were reacted in N,N-dimethylformamide (DMF) to give 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds.

[0046] In this invention, the reaction temperature in step 1) is preferably 75–85°C, more preferably 80°C, the reaction time is preferably 5.5–6.5 h, more preferably 6 h, the molar ratio of compound 1, potassium carbonate, and phenol is 1:1.5–2.5:1.5–2.5, and the molar mass ratio of compound 1 to isopropanol is preferably 1 mmol:9–11 g, more preferably 1 mmol:10 g. The reaction product obtained in step 1) is sequentially subjected to vacuum concentration, extraction, and column chromatography to obtain compound 2. The extraction reagents are dichloromethane and saturated sodium bicarbonate, and the crude product is obtained by extraction. The column chromatography reagents are petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 2–4:1, more preferably 3:1. The product is purified by column chromatography.

[0047] In this invention, the mixing reaction time in step 2) is preferably 1.5 to 2.5 hours, more preferably 2 hours, and the reaction is stopped by rotary evaporation to remove methanol; the pH value of the reaction system is preferably adjusted to 2 to 3, and the reagent for adjusting the pH value of the reaction system is preferably concentrated hydrochloric acid.

[0048] In step 2) of this invention, the preferred mass ratio of compound 2, methanol, water and lithium hydroxide is 1:4-6:13-17:1.5-2.5, and more preferably 1:5:15:2; after adjusting the pH value of the reaction system, the solid precipitates out and is filtered to obtain compound 3.

[0049] In this invention, the reaction temperature in step 3) is preferably 70-80°C, more preferably 75°C, and the reaction time is preferably 5-6 hours, more preferably 5.5 hours.

[0050] In this invention, the preferred mass ratio of compound 3, thionyl chloride, and sodium bromide in step 3) is 1:10-20:0.1-0.3, more preferably 1:15:0.2; thionyl chloride serves as both the acylation reagent and solvent; the preferred molar ratio of the acylation product, triethylamine, and amine compound is 1:2.5-3.5:1.5-2.5, more preferably 1:3:2; the preferred molar mass ratio of the acylation product and dichloromethane is 1 mmol:9-11 g, more preferably 1 mmol:10 g; the preferred mass ratio of the intermediate, tin chloride dihydrate, and ethanol is 1:4-6:8-12, more preferably 1:5:10; the preferred temperature for the acylation reaction is 75-85°C, more preferably 80°C; the preferred reaction time is 0.5-1.5 h, more preferably 1 h; the preferred mixing time is 0.3-0.8 h, more preferably 0.5 h.

[0051] In this invention, the reaction solution after the reaction in step 3) is completed is sequentially extracted and subjected to column chromatography to obtain compound 4; the extraction reagent preferably includes ethyl acetate and sodium hydroxide aqueous solution; the column chromatography reagent is preferably dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 75-85:1, more preferably 78-82:1, and more preferably 80:1; the column chromatography is used for purification.

[0052] In this invention, the reaction temperature in step 4) is preferably 105-115°C, more preferably 110°C, and the reaction time is preferably 2-3 hours, more preferably 2.5 hours.

[0053] In this invention, the molar ratio of compound 5 and N,N-dimethylformamide dimethyl acetal in step 4) is preferably 1:1.5-2.5, more preferably 1:2; compound 5 and N,N-dimethylformamide dimethyl acetal are reacted in chlorobenzene; the molar mass ratio of compound 5 to chlorobenzene is 1 mmol:9-11 g, more preferably 1 mmol:10 g; the reaction product obtained from the reaction is sequentially extracted, dried, and concentrated to obtain compound 6; the extraction reagent is preferably dichloromethane and a saturated salt solution; N,N-dimethylformamide dimethyl acetal is removed by extraction.

[0054] In this invention, the reaction temperature in step 5) is preferably 115-125°C, more preferably 120°C, and the reaction time is preferably 3.5-4.5 h, more preferably 4 h.

[0055] In this invention, the molar ratio of compound 6, substituted aniline, and cesium carbonate in step 5) is 1:1 to 2:1 to 3, more preferably 1:1.5:2; the molar mass ratio of compound 6 to chlorobenzene is 1 mmol: 8 to 12 g, more preferably 1 mmol: 10 g; the substituted aniline is p-fluoroaniline or p-bromoaniline; after the reaction is completed, the mixture is filtered and the filtrate is collected, the filtrate is concentrated under vacuum to obtain a crude product, and the crude product is subjected to column chromatography to obtain compound 7; the preferred reagents for column chromatography are petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 2 to 4:1, more preferably 3:1.

[0056] In this invention, the molar ratio of compound 4, compound 8, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine in step 6) is preferably 1:0.8-1.2:2-4:2-4, more preferably 1:1:3:3; the molar mass ratio of compound 4 to N,N-dimethylformamide is preferably 1 mmol:8-12 g, more preferably 1 mmol:10 g; the reaction time is preferably 5-7 h, more preferably 6 h; the reaction is carried out at room temperature.

[0057] In this invention, the reaction solution obtained in step 6) is poured into ice water to precipitate a solid. The solid is subjected to column chromatography to obtain 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds. The preferred reagents for column chromatography are dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 9 to 11:1, more preferably 10:1.

[0058] The present invention also provides the application of the aforementioned 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds in the preparation of anti-inflammatory drugs.

[0059] In this invention, anti-inflammatory drugs are used to prevent and / or treat inflammatory diseases and inflammation-related diseases; the anti-inflammatory drugs treat inflammatory diseases and inflammation-related diseases by inhibiting the release of inflammatory factors from macrophages; the inflammatory factors released by macrophages are TNF-α and / or IL-6.

[0060] In this invention, the anti-inflammatory drug comprises an active ingredient and excipients; the active ingredient is the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound or its pharmaceutically acceptable salt.

[0061] In this invention, 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds or their pharmaceutically acceptable salts are the sole active ingredients; excipients can be conventional pharmaceutical excipients in the art.

[0062] In this invention, the formulation of anti-inflammatory drugs includes injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release agents, sustained-release agents, or nano-formulations.

[0063] In this invention, inflammation includes inflammatory diseases and related diseases. Inflammation includes sepsis, acute lung injury, arthritis, colitis, hepatitis, fatty liver, and chronic inflammatory diseases; chronic inflammatory diseases include diabetic nephropathy, diabetic cardiomyopathy, atherosclerosis, obesity complications, and hypertension complications.

[0064] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0065] In the examples, the synthetic route for 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds is as follows:

[0066]

[0067] Example 1

[0068] In this embodiment, R1 in compounds 2-4 is H, and R2 in compound 4 is H. In compounds 7 and 8, R3 is F, and the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds are...

[0069]

[0070] Preparation of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds: Compound 1, potassium carbonate, and p-nitrophenol were added sequentially to 15 mL of isopropanol. The molar ratio of Compound 1, potassium carbonate, and phenol was 1:2:2, and the molar mass ratio of Compound 1 to isopropanol was 1 mmol:10 g. The mixture was refluxed at 80 °C for 6 h. After the reaction, isopropanol was removed by vacuum concentration, and the crude product was obtained by extraction with a mixture of dichloromethane and saturated sodium bicarbonate (volume ratio of dichloromethane to saturated sodium bicarbonate was 2:1). The crude product was purified by column chromatography (volume ratio of petroleum ether to ethyl acetate was 3:1) to obtain Compound 2. Lithium hydroxide (mass ratio of Compound 2, methanol, water, and lithium hydroxide was 1:5:15:2) was added to a mixed solution of methanol and water of Compound 2. The reaction mixture was stirred at room temperature for 2 h, and the reaction was stopped by rotary evaporation to remove methanol. The pH of the reaction system was adjusted to 2 by adding 37% hydrochloric acid. After the solid precipitated, it was filtered to obtain compound 3. The acylation reagent thionyl chloride was added to compound 3, followed by sodium bromide (the mass ratio of compound 3, thionyl chloride, and sodium bromide was 1:15:0.2). The acylation reaction was carried out at 80°C for 1 h. After the reaction was completed, the solvent thionyl chloride was evaporated. The acylation product was added to a system containing dichloromethane, triethylamine, and 3-morpholinopropylamine (the molar ratio of acylation product, triethylamine, and 3-morpholinopropylamine was 1:3:2, and the molar mass ratio of acylation product to dichloromethane was 1 mmol:10 g). The mixture was stirred at room temperature for 0.5 h, and then concentrated under vacuum to obtain the intermediate. The intermediate and SnCl2·2H2O (mass ratio of intermediate, SnCl2·2H2O and anhydrous ethanol 1:5:10) were added to 15 mL of anhydrous ethanol. The reaction solution was reduced at 75 °C for 5.5 h. The reaction product was extracted with a mixture of ethyl acetate and 1 mol / L sodium hydroxide aqueous solution (mass ratio of ethyl acetate to sodium hydroxide aqueous solution 2:1) and purified by column chromatography (volume ratio of dichloromethane to methanol 80:1) to obtain compound 4.

[0071] DMF-DMA (molar ratio of compound 5 to DMF-DMA 1:2, molar mass ratio of compound 5 to chlorobenzene 1 mmol: 10 g) was added to a chlorobenzene solution of compound 5, and the mixture was heated in an oil bath at 110 °C for 2.5 h. DMF-DMA was removed by extraction with a mixture of dichloromethane and saturated sodium chloride solution (volume ratio of dichloromethane to saturated sodium chloride solution 1:1), followed by drying and concentration to obtain compound 6. Chlorobenzene solvent, p-fluoroaniline, and Cs₂CO₃ catalyst were added to compound 6 (molar ratio of compound 6, p-fluoroaniline, and Cs₂CO₃ 1:1.5:2, molar mass ratio of compound 6 to chlorobenzene 1 mmol: 10 g). The reaction system was heated in an oil bath at 120 °C for 4 h. The filtrate was filtered and collected, and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (volume ratio of petroleum ether to ethyl acetate 3:1) to obtain compound 7. Compound 7 was treated with 37% hydrochloric acid to adjust the pH of the reaction system to 2. After the solid precipitated, it was filtered to obtain compound 8.

[0072] Solvents DMF, compound 4, compound 8, HATU, and DIPEA were added to a reaction flask in a molar ratio of 1:1:3:3, and the molar mass ratio of compound 4 to DMF was 1 mmol:10 g. The mixture was stirred at room temperature for 6 h. The reaction solution was poured into 7 mL of ice water, and a solid precipitated. The solid was purified by column chromatography (dichloromethane to methanol in a volume ratio of 10:1) to give the final product, a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound.

[0073] The 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound in this embodiment is (4-fluorophenyl)-4-oxo-N-(4-((2-((2-(thiophen-2-yl)ethyl)carbamoyl)pyridin-4-yl)oxy)phenyl)-1,4-dihydroquinoline-3-carboxamide (D9).

[0074] 1H NMR (400MHz, CDCl3) δ12.33(s,1H),8.87(s,1H),8.58(d,J=8.0Hz,1H),8.34(d,J=5.6Hz,1H),8 .24(t,J=6.4Hz,1H),7.84(d,J=8.4Hz,2H),7.74(s,1H),7.62(t,J=7.8Hz,1H),7.52(t,J=7.8H z,1H),7.46(dd,J=8.5,4.5Hz,2H),7.33(t,J=8.2Hz,2H),7.14(d,J=5.1Hz,1H),7.08(d,J=8.4 Hz,3H),6.94(d,J=5.0Hz,2H),6.89–6.84(m,1H),3.72(q,J=6.8Hz,2H),3.14(t,J=6.8Hz,2H). 13 C NMR (100MHz, CDCl3) δ177.01,166.58,164.02,162.76,161.91,152.14,149.76, 149.51,147.95,141.34,140.85,136.55,136.50,133.12,129.43,129.35,127. 14,127.08(2C),125.83,125.38,123.92,122.14(2C),121.43(2C),117.90,117 .77,117.54,113.98,112.19,110.52,40.98,30.10.HRMS(ESI):605.1636[M+H] + .

[0075] The yield of D9 in this embodiment was 54.6%, and the purity was 97%.

[0076] Example 2

[0077] In this embodiment, R1 in compounds 2-4 is F, and R2 in compound 4 is F. In compounds 7 and 8, R3 is Br, and the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds are...

[0078]

[0079] Preparation of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds: Compound 1, potassium carbonate, and 2-fluoro-4-nitrophenol were added sequentially to 15 mL of isopropanol. The molar ratio of Compound 1, potassium carbonate, and phenol was 1:2:2, and the molar mass ratio of Compound 1 to isopropanol was 1 mmol:10 g. The mixture was refluxed at 80 °C for 6 h. After the reaction, isopropanol was removed by vacuum concentration, and the crude product was obtained by extraction with a mixture of dichloromethane and saturated sodium bicarbonate (volume ratio of dichloromethane to saturated sodium bicarbonate was 2:1). The crude product was purified by column chromatography (volume ratio of petroleum ether to ethyl acetate was 3:1) to obtain Compound 2. Lithium hydroxide (mass ratio of Compound 2, methanol, water, and lithium hydroxide was 1:5:15:2) was added to a mixed solution of methanol and water of Compound 2. The reaction mixture was stirred at room temperature for 2 h, and the reaction was stopped by rotary evaporation to remove methanol. The pH of the reaction system was adjusted to 3 by adding 37% hydrochloric acid. After the solid precipitated, it was filtered to obtain compound 3. The acylation reagent thionyl chloride was added to compound 3, followed by sodium bromide (the mass ratio of compound 3, thionyl chloride, and sodium bromide was 1:15:0.2). The acylation reaction was carried out at 80°C for 1 h. After the reaction was completed, the solvent thionyl chloride was evaporated. The acylation product was added to a system containing dichloromethane, triethylamine, and 2-thiopheneethylamine (the molar ratio of acylation product, triethylamine, and 2-thiopheneethylamine was 1:3:2, and the molar mass ratio of acylation product to dichloromethane was 1 mmol:10 g). The mixture was stirred at room temperature for 0.5 h, and then concentrated under vacuum to obtain the intermediate. The intermediate and SnCl2·2H2O (mass ratio of intermediate, SnCl2·2H2O and anhydrous ethanol 1:5:10) were added to 15 mL of anhydrous ethanol. The reaction solution was reduced at 75 °C for 5.5 h. The reaction product was extracted with a mixture of ethyl acetate and 1 mol / L sodium hydroxide aqueous solution (mass ratio of ethyl acetate to sodium hydroxide aqueous solution 2:1) and purified by column chromatography (volume ratio of dichloromethane to methanol 80:1) to obtain compound 4.

[0080] In Example 1, p-fluoroaniline was replaced with p-bromoaniline in the process of preparing compound 7 from compound 6, while the other reaction steps and parameters were the same as in Example 1.

[0081] The 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound in this embodiment is 1-(4-bromophenyl)-N-(3-fluoro-4-((2-((3-morpholinopropyl)carbamoyl)pyridin-4-yl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (D17).

[0082] 1H NMR (400MHz, DMSO-d6) δ12.58(s,1H),9.13(t,J=5.6Hz,1H),,8.77(s,1H),8.57(d,J=5.6Hz,1H),8.49 (d,J=7.9Hz,1H),8.10(d,J=12.8Hz,1H),7.94(d,J=8.6Hz,2H),7.80(t,J=7.8Hz,1H),7.73(d,J=8.6H z,2H),7.65(t,J=7.5Hz,1H),7.61(d,J=9.0Hz,1H),7.48(d,J=8.9Hz,1H),7.45–7.43(m,1H),7.25(dd ,J=5.6,2.6Hz,1H),7.17(d,J=8.6Hz,1H),3.61(m,4H),3.33(s,2H),2.37(br,6H),1.73–1.66(m,2H). 13 C NMR (100MHz, CDCl3) δ176.13,165.21,162.93,162.51,152.63,150.47,148.12, 140.40,139.51,137.64,135.19,133.56,133.31(2C),129.76(2C),126.27,126 .02,125.83,124.04,123.39,118.39,116.62,113.40,110.57,108.75,108.52, 108.11,65.99(2C),56.51,53.25(2C),38.04,25.29.HRMS(ESI):700.1570[M+H] + .

[0083] The yield of D17 in this embodiment was 52.1%, and the purity was 96%.

[0084] Application Example 1: Dose-response relationship of compounds from Examples 1 and 2 in inhibiting LPS-stimulated release of IL-6 from macrophages J774A.1

[0085] The dose-response relationship of the compounds from Examples 1 and 2 in inhibiting the release of the pro-inflammatory cytokine IL-6 from J774A.1 cells stimulated by LPS was tested. Specifically, J774A.1 cells were cultured in DMEM medium (containing 10% fetal bovine serum) at 37°C for 24 hours. The medium was then replaced with the same medium, and the compounds from Examples 1 or 2 (concentrations of 10 μM, 5 μM, 2.5 μM, and 1.25 μM, respectively) were added for 1 hour. Cells were then stimulated with 0.5 μg / mL lipopolysaccharide (LPS) for 23 hours. The cells were then reabsorbed for detection, following the instructions of the ELISA kit. The IL-6 levels were recorded and calculated. In the cell experiments, proteins in the above-mentioned medium were lysed with lysis buffer, and the total protein content was measured. ELISA data were standardized based on the detection results.

[0086] The dose-response relationship of the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds in Examples 1 and 2 in inhibiting IL-6 release from LPS-stimulated J774A.1 cells is as follows: Figure 1 As shown, A represents Example 1, B represents Example 2, and the ICs of Examples 1 and 2 are shown. 50 The values ​​are 3.00 μM and 6.16 μM, respectively.

[0087] Application Example 2: The compound from Example 1 alleviated physiological changes and pathological changes in lung tissue of rats with acute lung injury.

[0088] C57BL / 6 mice were divided into four groups of eight each, named the control (CON) group, LPS group, LPS + compound from Example 1 group, and LPS + curcumin group (Cur). Thirty minutes before modeling, mice were administered compound from Example 1 and curcumin at a dose of 20 mg / kg via gavage, respectively. Then, LPS was injected intratracheally at a dose of 5 mg / kg over 6 hours. Finally, the mice were sacrificed according to ethical requirements, and lung tissue, serum, and bronchoalveolar lavage fluid (BALF) were collected according to experimental requirements.

[0089] Physiological changes in rats with acute lung injury alleviated by 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds in Example 1 are as follows: Figure 2 As shown, A represents the lung wet weight / dry weight ratio, B represents the total cell count in the bronchoalveolar lavage fluid, C represents the total protein content in the bronchoalveolar lavage fluid, D represents the inhibitory effect on IL-6 transcription in lung tissue, E represents the concentration of the pro-inflammatory cytokine IL-6 in the bronchoalveolar lavage fluid, F represents the concentration of TNF-α in the bronchoalveolar lavage fluid, G represents the serum IL-6 concentration, and H represents the serum TNF-α concentration.

[0090] The 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound in Example 1 alleviated the pathological changes in lung tissue during acute lung injury, as shown in the following example. Figure 3 As shown, A is a pathological image of mouse lung tissue, and B and C are immunohistochemical staining of macrophage markers F4 / 80 (B) and MPO (C) in LPS-induced mouse lung tissue, respectively. Immunoreactivity is shown in brown.

[0091] Pathological examination of the left lung lesions in mice showed that, compared with the control group (CON), LPS-induced lung tissue damage and alveolar septal thickening were more pronounced. The lung condition of mice treated with the compound of Example 1 improved; immunohistochemical staining using macrophage-specific F4 / 80 antibodies and MPO antibodies showed a significant increase in macrophage infiltration in the model group, while fibrosis thinning and cell infiltration were restored in the compound of Example 1 group and the curcumin (LPS+Cur) group.

[0092] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, characterized in that, The structural formulas of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds are as follows: or .

2. The method for preparing the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound according to claim 1, characterized in that, The synthetic route for 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds is as follows: Where R1 is H, R2 is R3 is F; or R1 is F, R2 is R3 is Br; The preparation method of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds includes the following steps: 1) Compound 1, potassium carbonate, and phenol were reacted in isopropanol to obtain compound 2; 2) Compound 2, methanol, water, and lithium hydroxide were mixed and reacted, and the pH of the reaction system was adjusted to obtain compound 3. 3) Compound 3, thionyl chloride, and sodium bromide were subjected to an acylation reaction to obtain an acylated product; the acylated product, dichloromethane, triethylamine, and an amine compound were mixed to obtain an intermediate; the intermediate, tin chloride dihydrate, and ethanol were reacted to obtain compound 4; 4) Compound 5 was reacted with N,N-dimethylformamide dimethyl acetal to give compound 6; 5) Compound 6, substituted aniline, and cesium carbonate were reacted in chlorobenzene to give compound 7; compound 7 was then hydrolyzed to give compound 8. 6) Compound 4, compound 8, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine were reacted in N,N-dimethylformamide to give 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds; Step 1) The phenol compound is p-nitrophenol, Step 3) The amine compound is 2-thiopheneethylamine, and Step 5) The substituted aniline is p-fluoroaniline; or Step 1) The phenol compound is 2-fluoro-4-nitrophenol, Step 3) The amine compound is 3-morpholinopropylamine, and Step 5) The substituted aniline is p-bromoaniline.

3. The preparation method according to claim 2, characterized in that, Step 2) The mixing reaction time is 1.5~2.5h, and the reaction is stopped by rotary evaporation to remove methanol; the pH value of the reaction system is adjusted to 2~3, and the reagent for adjusting the pH value of the reaction system is concentrated hydrochloric acid.

4. The preparation method according to claim 2 or 3, characterized in that, Step 3) The reaction temperature is 70~80℃ and the reaction time is 5~6h.

5. The preparation method according to claim 4, characterized in that, Step 4) The reaction temperature is 105~115℃ and the reaction time is 2~3h.

6. The preparation method according to claim 5, characterized in that, Step 5) The reaction temperature is 115~125℃ and the reaction time is 3.5~4.5h.

7. The use of the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound according to claim 1 in the preparation of anti-inflammatory drugs, characterized in that, The active ingredient in the anti-inflammatory drug is the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound or its pharmaceutically acceptable salt as described in claim 1.

8. The application according to claim 7, characterized in that, Anti-inflammatory drugs contain active ingredients and excipients.

9. The application according to claim 7 or 8, characterized in that, The formulation of anti-inflammatory drugs can be selected from injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release agents, sustained-release agents, or nano-formulations.

10. The application according to claim 9, characterized in that, Inflammation is selected from sepsis and acute lung injury.

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