4-aryloxyphenyl-1, 4-dihydroquinoline-3-formamide compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of preparation of compounds, and provides a 4-aryloxyphenyl-1, 4-dihydroquinoline-3-formamide compound as well as a preparation method and application of the 4-aryloxyphenyl-1, 4-dihydroquinoline-3-formamide compound. The method comprises the following steps: reacting a compound 1, potassium carbonate and a phenol compound, and mixing a compound 2, methanol, water and lithium hydroxide to obtain a compound 3; performing acylation reaction on the compound 3, thionyl chloride and sodium bromide, and then reacting with tin chloride dehydrate and ethanol to obtain a compound 4; reacting the compound 5 with DMF-DMA, reacting the compound 6, substituted aniline and cesium carbonate, and hydrolyzing to obtain a compound 8; the compound 4, the compound 8, HATU and DIPEA are subjected to a reaction. The compound provided by the invention is used for preparing anti-inflammatory drugs, and inflammation and inflammation-related diseases are treated by inhibiting macrophages from releasing inflammatory factors (TNF-alpha and / or IL-6).

Description

Technical Field

[0001] The present invention relates to the technical field of compound preparation, and in particular to a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound and a preparation method and application thereof. Background Art

[0002] Inflammation is a defensive response of the body to injury or infection, usually manifested 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, clear pathogens and promote tissue repair. However, excessive inflammatory response may lead to tissue damage and disease.

[0003] Acute lung injury (ALI) is a serious 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 gas exchange disorders. Inflammatory mediators play a key role in the pathogenesis of ALI. They increase vascular permeability, causing fluid to infiltrate the alveolar cavity, further triggering respiratory failure. The treatment of ALI mainly includes 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 the main treatment approach at present. There is no specific drug yet.

[0004] Therefore, it is of great significance to develop 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds and their drugs for inflammatory diseases such as ALI. Summary of the invention

[0005] The purpose of the present invention is to provide a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound and a preparation method and application thereof in order to overcome the deficiencies of the prior art.

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

[0007] The present invention provides a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, and the structural formula of the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound is:

[0008]

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

[0010]

[0011] Wherein, R1 is H or F, R2 is R3 is F or Br;

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

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

[0014] 2) Compound 2, methanol, water and lithium hydroxide are mixed for reaction, and then the pH value of the reaction system is adjusted to obtain Compound 3;

[0015] 3) Acylation reaction is performed on compound 3, thionyl chloride and sodium bromide to obtain an acylated product; the acylated product, dichloromethane, triethylamine and an amine compound are mixed to obtain an intermediate; the intermediate, tin chloride dihydrate and ethanol are reacted to obtain compound 4;

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

[0017] 4) reacting compound 5 with N,N-dimethylformamide dimethyl acetal to obtain compound 6;

[0018] 5) reacting compound 6, substituted aniline and cesium carbonate in chlorobenzene to obtain compound 7; hydrolyzing compound 7 to obtain compound 8;

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

[0020] Preferably, the mixing reaction time in step 2) is 1.5 to 2.5 hours, and the methanol is removed by rotary evaporation to stop the reaction; the pH value of the reaction system is adjusted to 2 to 3, and the reagent for adjusting the pH value 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 use of the 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 an auxiliary material; the active ingredient is the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound or a pharmaceutically acceptable salt thereof.

[0026] Preferably, the preparation form of the anti-inflammatory drug comprises injection, tablet, capsule, aerosol, suppository, film, pellet, ointment, controlled release agent, sustained release agent or nano preparation.

[0027] Preferably, inflammation includes inflammatory diseases and related diseases, inflammation includes sepsis, acute lung injury, arthritis, colorectalitis, hepatitis, fatty liver, 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 to prevent and / or treat inflammatory diseases and diseases related to inflammation (such as sepsis, acute lung injury, arthritis, colorectal inflammation, hepatitis, fatty liver, diabetic nephropathy, diabetic cardiomyopathy, atherosclerosis, obesity complications, and hypertension complications); the anti-inflammatory drugs treat inflammatory diseases and diseases related to inflammation by inhibiting the release of inflammatory factors (TNF-α and / or IL-6) by macrophages. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The graph is a dose-effect relationship of the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds of Examples 1 and 2 in inhibiting the release of IL-6 from J774A.1 cells stimulated by LPS, wherein A is Example 1 and B is Example 2;

[0031] Figure 2This is a diagram showing physiological changes in rats with acute lung injury alleviated by 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds of Example 1, wherein A is the lung wet weight / dry weight ratio, B is the total cell count in the alveolar lavage fluid, C is the total protein content in the alveolar lavage fluid, D is the inhibitory effect on IL-6 transcription in lung tissue, E is the concentration of proinflammatory cytokine IL-6 in the alveolar lavage fluid, F is the concentration of TNF-α in the alveolar 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 diagram shows the pathological changes of lung tissue in the relief of acute lung injury by 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds of Example 1, wherein 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 DESCRIPTION

[0033] The present invention provides a 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, and the structural formula of the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound is:

[0034]

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

[0036]

[0037] Wherein, R1 is H or F, R2 is R3 is F or Br;

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

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

[0040] 2) Compound 2, methanol, water and lithium hydroxide are mixed for reaction, and then the pH value of the reaction system is adjusted to obtain Compound 3;

[0041] 3) Acylation reaction is performed on compound 3, thionyl chloride and sodium bromide to obtain an acylated product; the acylated product, dichloromethane, triethylamine and an amine compound are mixed to obtain an intermediate; the intermediate, tin chloride dihydrate and ethanol are reacted to obtain compound 4;

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

[0043] 4) reacting compound 5 with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to obtain compound 6;

[0044] 5) reacting compound 6, substituted aniline and cesium carbonate in chlorobenzene to obtain compound 7; hydrolyzing compound 7 to obtain compound 8;

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

[0046] In the present invention, the temperature of the reaction in step 1) is preferably 75-85°C, more preferably 80°C, the reaction time is preferably 5.5-6.5h, more preferably 6h, the molar ratio of compound 1, potassium carbonate and phenol compound is 1:1.5-2.5:1.5-2.5, and the molar mass ratio of compound 1 and isopropanol is preferably 1mmol:9-11g, more preferably 1mmol:10g; the reaction product obtained by the reaction 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 reagents for column chromatography are petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate is preferably 2-4:1, more preferably 3:1; and purification is performed by column chromatography.

[0047] In the present invention, the time of the mixed reaction in step 2) is preferably 1.5 to 2.5 hours, more preferably 2 hours, and the methanol is removed by rotary evaporation to stop the reaction; 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 the present invention, the mass ratio of compound 2, methanol, water and lithium hydroxide is preferably 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, a solid precipitates and is filtered to obtain compound 3.

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

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

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

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

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

[0054] In the present 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 the present invention, the molar ratio of compound 6, substituted aniline and cesium carbonate in step 5) is 1:1-2:1-3, more preferably 1:1.5:2, the molar mass ratio of compound 6 and chlorobenzene is 1mmol:8-12g, more preferably 1mmol:10g; the substituted aniline is p-fluoroaniline or p-bromoaniline; after the reaction is completed, the filtrate is filtered and collected, the filtrate is vacuum concentrated to obtain a crude product, the crude product is subjected to column chromatography to obtain compound 7; the reagents for column chromatography are preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate is preferably 2-4:1, more preferably 3:1.

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

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

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

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

[0060] In the present invention, the anti-inflammatory drug comprises an active ingredient and an auxiliary material; the active ingredient is the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound or a pharmaceutically acceptable salt thereof.

[0061] In the present invention, 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds or pharmaceutically acceptable salts thereof are the only active ingredients; and conventional pharmaceutical excipients in the art may be used as excipients.

[0062] In the present invention, the preparation forms of the anti-inflammatory drug include injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release agents, sustained-release agents or nano-preparations.

[0063] In the present invention, inflammation includes inflammatory diseases and related diseases. Inflammation includes sepsis, acute lung injury, arthritis, colorectalitis, 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 are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0065] In the embodiment, the synthesis route of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds is:

[0066]

[0067] Example 1

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

[0069]

[0070] Preparation method of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds: Compound 1, potassium carbonate, and p-nitrophenol are added to 15 mL of isopropanol in sequence, the molar ratio of compound 1, potassium carbonate, and phenol compound is 1:2:2, and the molar mass ratio of compound 1 to isopropanol is 1mmol:10g, and the reaction is refluxed at 80°C for 6 hours. After the reaction is completed, isopropanol is removed by vacuum concentration, and then the crude product is extracted with a mixed solution of dichloromethane and saturated sodium bicarbonate (the volume ratio of dichloromethane and saturated sodium bicarbonate is 2:1). The crude product is purified by column chromatography (the volume ratio of petroleum ether and ethyl acetate is 3:1) to obtain compound 2. Lithium hydroxide is added to a mixed solution of methanol and water of compound 2 (the mass ratio of compound 2, methanol, water and lithium hydroxide is 1:5:15:2), the reaction solution is stirred at room temperature for 2 hours, and methanol is removed by rotary evaporation to stop the reaction. Concentrated hydrochloric acid with a mass concentration of 37% was added to adjust the pH value of the reaction system to 2, and the solid was precipitated and filtered to obtain compound 3. Thionyl chloride, an acylating agent, was added to compound 3, and then sodium bromide (the mass ratio of compound 3, thionyl chloride and sodium bromide was 1:15:0.2), and the acylation reaction was carried out at 80°C for 1 hour. After the reaction, the solvent thionyl chloride was evaporated, and the acylated product was added to a system containing dichloromethane, triethylamine and 3-morpholine propylamine (the molar ratio of the acylated product, triethylamine and 3-morpholine propylamine was 1:3:2, and the molar mass ratio of the acylated product and dichloromethane was 1mmol:10g), stirred at room temperature for 0.5h, and then concentrated in vacuo to obtain an intermediate. The intermediate and SnCl2·2H2O (the mass ratio of the intermediate, SnCl2·2H2O and anhydrous ethanol is 1:5:10) were added to 15 mL of anhydrous ethanol, and 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 aqueous sodium hydroxide solution (the mass ratio of ethyl acetate and aqueous sodium hydroxide solution was 2:1), and purified by column chromatography (the volume ratio of dichloromethane and methanol was 80:1) to obtain compound 4.

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

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

[0073] The 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound of 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 example is 54.6% and the purity is 97%.

[0076] Example 2

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

[0078]

[0079] Preparation method of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds: Compound 1, potassium carbonate, and 2-fluoro-4-nitrophenol are added to 15 mL of isopropanol in sequence, the molar ratio of compound 1, potassium carbonate, and phenol compound is 1:2:2, and the molar mass ratio of compound 1 to isopropanol is 1mmol:10g, and the reaction is refluxed at 80°C for 6 hours. After the reaction is completed, isopropanol is removed by vacuum concentration, and then the crude product is extracted with a mixed solution of dichloromethane and saturated sodium bicarbonate (the volume ratio of dichloromethane and saturated sodium bicarbonate is 2:1). The crude product is purified by column chromatography (the volume ratio of petroleum ether and ethyl acetate is 3:1) to obtain compound 2. Lithium hydroxide is added to a mixed solution of methanol and water of compound 2 (the mass ratio of compound 2, methanol, water and lithium hydroxide is 1:5:15:2), the reaction solution is stirred at room temperature for 2 hours, and methanol is removed by rotary evaporation to stop the reaction. Concentrated hydrochloric acid with a mass concentration of 37% was added to adjust the pH value of the reaction system to 3, and the solid was precipitated and filtered to obtain compound 3. Thionyl chloride, an acylating agent, was added to compound 3, and then sodium bromide (the mass ratio of compound 3, thionyl chloride and sodium bromide was 1:15:0.2), and the acylation reaction was carried out at 80°C for 1 hour. After the reaction, the solvent thionyl chloride was evaporated, and the acylated product was added to a system containing dichloromethane, triethylamine and 2-thiopheneethylamine (the molar ratio of the acylated product, triethylamine and 2-thiopheneethylamine was 1:3:2, and the molar mass ratio of the acylated product and dichloromethane was 1mmol:10g), stirred at room temperature for 0.5h, and then concentrated in vacuo to obtain an intermediate. The intermediate and SnCl2·2H2O (the mass ratio of the intermediate, SnCl2·2H2O and anhydrous ethanol is 1:5:10) were added to 15 mL of anhydrous ethanol, and 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 aqueous sodium hydroxide solution (the mass ratio of ethyl acetate and aqueous sodium hydroxide solution was 2:1), and purified by column chromatography (the volume ratio of dichloromethane and methanol was 80:1) to obtain compound 4.

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

[0081] The 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound of 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 example is 52.1% and the purity is 96%.

[0084] Application Example 1 Dose-effect relationship of the compounds of Example 1 and Example 2 in inhibiting the release of IL-6 by LPS-stimulated macrophage J774A.1

[0085] The dose-effect relationship of the compounds in Examples 1 and 2 in inhibiting the release of the proinflammatory cytokine IL-6 by J774A.1 cells stimulated by LPS was tested. The specific method is as follows: J774A.1 cells were cultured in DMEM medium (containing 10% mass concentration of fetal bovine serum) at 37°C, and the same medium was updated after 24 hours, and the compounds in Example 1 or Example 2 (the concentrations of the compounds were 10 μM, 5 μM, 2.5 μM, and 1.25 μM, respectively) were added for 1 hour, and then stimulated with 0.5 μg / mL of lipopolysaccharide (LPS) for 23 hours, and the culture medium was absorbed for detection. The detection steps were carried out according to the instructions of the ELISA kit. The content of IL-6 was recorded and calculated. In the cell experiment, the protein in the above culture medium was lysed with a lysate, and its total protein content was detected. The ELISA data was standardized according to the test results.

[0086] The dose-effect relationship of the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds of Example 1 and Example 2 in inhibiting the release of IL-6 from J774A.1 cells stimulated by LPS is as follows: Figure 1 As shown, wherein A is embodiment 1, B is embodiment 2, and IC of embodiments 1 and 2 50 They are 3.00μM and 6.16μM respectively.

[0087] Application Example 2 The compound of Example 1 alleviates the physiological changes of rats with acute lung injury and the pathological changes of lung tissue in acute lung injury

[0088] C57BL / 6 mice were divided into 4 groups, 8 mice in each group, and were named control (CON) group, LPS group, LPS+Example 1 compound group and LPS+curcumin (Cur) group. 30 minutes before modeling, mice were gavaged with Example 1 compound and curcumin at a dose of 20 mg / kg, and then LPS was injected through the trachea at a dose of 5 mg / kg for 6 hours. Finally, mice were killed according to ethical requirements, and lung tissue, serum and bronchoalveolar lavage fluid (BALF) were collected according to experimental requirements.

[0089] The 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds of Example 1 alleviate the physiological changes of rats with acute lung injury. Figure 2 As shown in the figure, A is the lung wet weight / dry weight ratio, B is the total cell count in the alveolar lavage fluid, C is the total protein content in the alveolar lavage fluid, D is the inhibitory effect on IL-6 transcription in lung tissue, E is the proinflammatory cytokine IL-6 concentration in the alveolar lavage fluid, F is the TNF-α concentration in the alveolar lavage fluid, G is the IL-6 concentration in serum, and H is the TNF-α concentration in serum.

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

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

[0092] 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 principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound, characterized in that: The structural formula of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds is:

2. The method for preparing the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound according to claim 1, characterized in that: The synthetic route of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds is: Wherein, R1 is H or F, R2 is R3 is F or Br; The preparation method of 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds comprises the following steps: 1) reacting compound 1, potassium carbonate and a phenol compound in isopropanol to obtain compound 2; the phenol compound is p-nitrophenol or 2-fluoro-4-nitrophenol; 2) Compound 2, methanol, water and lithium hydroxide are mixed for reaction, and then the pH value of the reaction system is adjusted to obtain Compound 3; 3) Acylation reaction is performed on compound 3, thionyl chloride and sodium bromide to obtain an acylated product; the acylated product, dichloromethane, triethylamine and an amine compound are mixed to obtain an intermediate; the intermediate, tin chloride dihydrate and ethanol are reacted to obtain compound 4; The amine compound is 3-morpholinepropylamine or 2-thiopheneethylamine; 4) reacting compound 5 with N,N-dimethylformamide dimethyl acetal to obtain compound 6; 5) reacting compound 6, substituted aniline and cesium carbonate in chlorobenzene to obtain compound 7; hydrolyzing compound 7 to obtain compound 8; 6) Compound 4, compound 8, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine are reacted in N,N-dimethylformamide to obtain 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds.

3. The preparation method according to claim 2, characterized in that: Step 2) The mixing reaction time is 1.5 to 2.5 hours, and the methanol is removed by rotary evaporation to stop the reaction; the pH value of the reaction system is adjusted to 2 to 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°C 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°C 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° C. and the reaction time is 3.5-4.5 h.

7. Use of the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compounds according to claim 1 in the preparation of anti-inflammatory drugs.

8. The use according to claim 7, characterized in that: The anti-inflammatory drug comprises an active ingredient and an auxiliary material; the active ingredient is the 4-aryloxyphenyl-1,4-dihydroquinoline-3-carboxamide compound or a pharmaceutically acceptable salt thereof as described in claim 1.

9. The use according to claim 7 or 8, characterized in that: The preparation forms of the anti-inflammatory drug include injection, tablet, capsule, aerosol, suppository, film, pellet, ointment, controlled release, sustained release or nano preparation.

10. The use according to claim 9, characterized in that: Inflammation includes inflammatory diseases and their related diseases. Inflammation includes sepsis, acute lung injury, arthritis, colorectalitis, hepatitis, fatty liver, and chronic inflammatory diseases; chronic inflammatory diseases include diabetic nephropathy, diabetic cardiomyopathy, atherosclerosis, obesity complications, and hypertension complications.

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