CN115784987A - Compound related to pneumonia, preparation method and application thereof, and pharmaceutical composition - Google Patents
Compound related to pneumonia, preparation method and application thereof, and pharmaceutical composition Download PDFInfo
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Abstract
The invention provides a compound related to pneumonia, a preparation method and application thereof, and a pharmaceutical composition, and belongs to the technical field of pharmaceutical organics. The compound related to pneumonia is an N- (4- ((6, 7-dimethoxyquinoline-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound, is used for treating sepsis and acute lung injury, and can be prepared into preparations including injections, tablets, capsules, aerosols, suppositories, films, dropping pills, ointments, controlled-release or sustained-release agents and nano preparations.
Description
Technical Field
The invention relates to the technical field of medicinal organic matters, in particular to a compound related to pneumonia, a preparation method and application thereof and a medicinal composition.
Background
Inflammation (inflammation) is a defense response of an organism to stimulation, generally, inflammation is beneficial and is an automatic defense response of a human body, but when excessive inflammation is caused by disorder of an inflammatory response, the organism can generate a large amount of inflammatory cytokines to damage tissues or cells, and the life and health of human beings are seriously influenced.
Acute Lung Injury (ALI) is an acute and persistent inflammatory reaction syndrome of the lung that causes damage to the alveolar-capillary intima and leads to increased capillary permeability, diffuse interstitial pulmonary and alveolar edema, resulting in acute hypoxic respiratory insufficiency with high morbidity and mortality. Sepsis is a systemic inflammatory response syndrome caused by invasion of pathogenic microorganisms such as bacteria into the body. In addition to the manifestations of systemic inflammatory response syndrome and primary infection foci, severe patients often have manifestations of organ hypoperfusion. The mortality rate of sepsis is as high as 30-70%. In recent years, despite significant advances in anti-infective therapy and organ function support technologies, there is still a lack of clinically effective drugs for the treatment of acute lung injury and sepsis.
Clinical and animal experiments prove that Lipopolysaccharide (LPS) can activate various downstream proinflammatory signal pathways and trigger the overproduction of inflammatory factors, such as tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), so that acute lung injury and sepsis are caused. At present, the blockade of inflammatory storms by various drugs such as glucocorticoids is widely explored and serves as a potential promising method for preventing and treating acute lung injury and sepsis. However, in view of the fact that clinically used drugs do not show significant therapeutic effects on patients with acute lung injury and sepsis due to their low efficacy and adverse reactions, there is still a need to develop new anti-inflammatory agents for the treatment of acute lung injury and sepsis that are more effective and safer. Therefore, inhibition of the release of inflammatory factors such as TNF-alpha and IL-6 is an important means for treating acute lung injury and sepsis.
Disclosure of Invention
The invention aims to provide a novel compound related to pneumonia, a preparation method and application thereof and a pharmaceutical composition, so as to make up for the defects of the prior art.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound, which comprises one of the following structural formulas:
the 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-formamide compound, which comprises the following steps:
(1) Mixing 3-acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and a solvent, and then sequentially carrying out low-temperature reaction and heating reaction to generate 3- (2-chlorobenzene) -3-oxopropanoic acid methyl ester which is marked as a compound 2;
(2) Mixing 3- (2-chlorobenzene) -3-oxopropanoic acid methyl ester, N-dimethylformamide dimethyl acetal and a solvent, and reacting to generate a compound 3;
(3) Mixing the compound 3, aniline raw materials and a solvent, and then reacting to obtain a compound 4 product system;
the aniline raw material comprises aniline, para-fluoroaniline, para-chloroaniline, para-bromoaniline, 3-chloro-4-fluoroaniline or 4- (trifluoromethoxy) aniline;
(4) Adding cesium carbonate into a product system of the compound 4 to react to generate a compound 5;
(5) Mixing the compound 5, 1, 4-dioxane, sodium hydroxide and water, and reacting to generate a compound 6;
the compound 6 comprises 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) Mixing 4-chloro-6, 7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and a solvent, and reacting to generate a compound 9;
(7) Mixing the compound 9, water, ethanol, reducing iron powder and ammonium chloride, and reacting to generate 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] aniline which is marked as a compound 10;
(8) Mixing the compound 10, the compound 6, a solvent, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, and then carrying out acid-amine condensation reaction to generate an N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound;
there is no restriction on the order of the preparation of compound 6 in steps (1) to (5) and the preparation of compound 10 in steps (6) to (7).
Preferably, the dosage ratio of the 3-acetyl-2-chlorobenzene, the dimethyl carbonate, the sodium hydride and the solvent in the step (1) is 2-4mmol;
the solvent is anhydrous tetrahydrofuran;
the temperature of the low-temperature reaction is-5 to 5 ℃, and the time is 25 to 35min;
the temperature of the heating reaction is 80-90 ℃, and the time is 1-3 h;
the using amount ratio of the 3- (2-chlorobenzene) -3-oxopropionic acid methyl ester, the N, N-dimethylformamide dimethyl acetal and the solvent in the step (2) is 2-3mmol;
the solvent is toluene;
the reaction temperature is 110-130 ℃, and the reaction time is 1-3 h;
the dosage ratio of the compound 3, the aniline raw materials and the solvent in the step (3) is 2-4mmol;
the solvent is toluene;
the reaction temperature is 100-120 ℃, and the reaction time is 2-4 h;
the dosage ratio of the cesium carbonate to the compound 3 in the step (4) is 2-4 mmol;
the reaction temperature is 140-160 ℃, and the reaction time is 2-4 h;
the dosage ratio of the compound 5, 1, 4-dioxane, sodium hydroxide and water in the step (5) is 2-3mL.
Preferably, the dosage ratio of the 4-chloro-6, 7-dimethoxyquinoline, the 4-nitrophenol, the sodium iodide, the sodium carbonate and the solvent in the step (6) is 0.2-0.8 mmol;
the solvent is toluene;
the reaction temperature is 120-140 ℃ and the reaction time is 10-15 h;
the dosage ratio of the compound 9, water, ethanol, reducing iron powder and ammonium chloride in the step (7) is 0.5-1.5mmol;
the reaction temperature is 40-60 ℃ and the reaction time is 4-8 h.
Preferably, in the step (8), the use ratio of the compound 10, the compound 6, the solvent, the 2- (7-azabenzotriazole) -N, N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 0.05 to 0.15mmol;
the solvent is N, N-dimethylformamide;
the temperature of the acid amine condensation reaction is room temperature, and the time is 12-20 h.
The invention also provides application of the N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound in preparing an anti-inflammatory medicament, wherein the anti-inflammatory medicament treats inflammation by inhibiting the release of inflammatory factors released by macrophages.
Preferably, the anti-inflammatory agent is used for preventing or treating inflammation and inflammation-related diseases.
Preferably, the inflammation or inflammation-associated disorder includes, but is not limited to sepsis, acute lung injury.
The invention also provides a pharmaceutical composition for preventing or treating inflammation and diseases related to inflammation, which comprises the N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound or the pharmaceutically acceptable salt thereof and also comprises pharmaceutic adjuvant.
Preferably, the preparation form of the pharmaceutical composition comprises injection, tablets, capsules, aerosol, suppositories, membranes, dropping pills, ointments, controlled release or sustained release agents and nano preparations.
The N- (4- ((6, 7-dimethoxyquinoline-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound provided by the invention is used for treating sepsis and acute lung injury, and the prepared preparation forms comprise injections, tablets, capsules, aerosols, suppositories, films, dripping pills, ointments, controlled release or sustained release agents and nano preparations.
Drawings
FIG. 1 is a dose-effect relationship between compounds inhibiting LPS stimulating macrophages to release IL-6 and TNF-alpha;
FIG. 2 is a test of toxicity of compounds on macrophages;
FIG. 3 shows that Compound 11a relieves physiological changes in mice with acute lung injury;
FIG. 4 shows that Compound 11a ameliorates pathological changes in lung tissue in mice with acute lung injury;
figure 5 is a graph of compound 11a alleviating physiological and pathological changes in septic mice.
Detailed Description
The invention provides an N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound, which comprises one of the following structural formulas:
the 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-formamide compound, which comprises the following steps:
(1) Mixing 3-acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and a solvent, and then sequentially carrying out low-temperature reaction and heating reaction to generate 3- (2-chlorobenzene) -3-oxopropanoic acid methyl ester which is marked as a compound 2;
(2) Mixing 3- (2-chlorobenzene) -3-oxopropanoic acid methyl ester, N-dimethylformamide dimethyl acetal and a solvent, and reacting to generate a compound 3;
(3) Mixing the compound 3, aniline raw materials and a solvent, and then reacting to obtain a compound 4 product system;
the aniline raw material comprises aniline, para-fluoroaniline, para-chloroaniline, para-bromoaniline, 3-chloro-4-fluoroaniline or 4- (trifluoromethoxy) aniline;
(4) Adding cesium carbonate into a product system of the compound 4 to react to generate a compound 5;
(5) Mixing the compound 5, 1, 4-dioxane, sodium hydroxide and water, and reacting to generate a compound 6;
the compound 6 comprises 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) Mixing 4-chloro-6, 7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and a solvent, and reacting to generate a compound 9;
(7) Mixing the compound 9, water, ethanol, reducing iron powder and ammonium chloride, and reacting to generate 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] aniline which is marked as a compound 10;
(8) Mixing the compound 10, the compound 6, a solvent, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, and then carrying out acid-amine condensation reaction to generate an N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound;
there is no restriction on the order of the preparation of compound 6 in steps (1) to (5) and the preparation of compound 10 in steps (6) to (7).
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 compound is as follows:
in the invention, the usage ratio of the 3-acetyl-2-chlorobenzene, the dimethyl carbonate, the sodium hydride and the solvent in the step (1) is 2-4mmol, 18-222mmol, preferably 3mmol, 9-11mmol, and more preferably 3mmol;
the solvent is anhydrous tetrahydrofuran;
the temperature of the low-temperature reaction is-5 ℃, preferably-2 ℃, and further preferably 0 ℃; the time is 25 to 35min, preferably 28 to 32min, and more preferably 30 to 31min;
the temperature of the heating reaction is 80-90 ℃, preferably 83-87 ℃, and further preferably 84-86 ℃; the time is 1 to 3 hours, preferably 2 hours;
the use amount ratio of the methyl 3- (2-chlorobenzene) -3-oxopropionate, the N, N-dimethylformamide dimethyl acetal and the solvent in the step (2) is 2 to 3mmol, preferably 2 to 3mmol, 8 to 9mmol, 9 to 11mL, and more preferably 2.5mmol;
the solvent is toluene;
the reaction temperature is 110-130 ℃, preferably 115-125 ℃, and more preferably 120-122 ℃; the time is 1 to 3 hours, preferably 2 hours;
the dosage ratio of the compound 3, the aniline raw material and the solvent in the step (3) is 2-4mmol, preferably 2-3mmol, 2-3.5mmol, and more preferably 2.5-3mmol;
the solvent is toluene;
the reaction temperature is 100-120 ℃, preferably 105-115 ℃, and more preferably 110-112 ℃; the time is 2 to 4 hours, preferably 3 hours;
the dosage ratio of cesium carbonate to the compound 3 in the step (4) is 2 to 4mmol, preferably 2.5 to 3.5mmol, and more preferably 3 to 3.5mmol;
the reaction temperature is 140-160 ℃, preferably 145-155 ℃, and further preferably 150-152 ℃; the time is 2 to 4 hours, preferably 3 hours;
the use amount ratio of the compound 5, 1, 4-dioxane, sodium hydroxide and water in the step (5) is 2 to 3mmol.
In the present invention, in the step (6), the ratio of the amount of 4-chloro-6, 7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and solvent is 0.2 to 0.8 mmol;
the solvent is toluene;
the reaction temperature is 120-140 ℃, preferably 125-135 ℃, and further preferably 130-132 ℃; the time is 10 to 15 hours, preferably 11 to 14 hours, and more preferably 12 to 13 hours;
the use amount ratio of the compound 9, water, ethanol, reducing iron powder and ammonium chloride in the step (7) is 0.5 to 1.5mmol;
the reaction temperature is 40-60 ℃, preferably 45-55 ℃, and more preferably 50-52 ℃; the time is 4 to 8 hours, preferably 5 to 7 hours, and more preferably 6 hours.
In the present invention, the ratio of the amount of the compound 10, the compound 6, the solvent, 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate to N, N-diisopropylethylamine in the step (8) is 0.05 to 0.15mmol;
the solvent is N, N-dimethylformamide;
the temperature of the acid amine condensation reaction is room temperature, and the time is 12-20 h, preferably 14-18 h, and more preferably 15-16 h.
The invention also provides application of the N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound in preparing an anti-inflammatory medicament, wherein the anti-inflammatory medicament treats inflammation by inhibiting the release of inflammatory factors released by macrophages.
In the present invention, the anti-inflammatory agent is used for preventing or treating inflammation and inflammation-related diseases.
In the present invention, the inflammation or inflammation-related disease includes, but is not limited to sepsis, acute lung injury.
The 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 the pharmaceutically acceptable salt thereof and also comprises pharmaceutic adjuvant.
In the invention, the preparation form of the pharmaceutical composition comprises injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, ointment, controlled release or sustained release agent and nano preparation.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
N-phenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (6 a)
The method comprises the following steps: in a 50mL round-bottomed flask, 3-acetyl-2-chlorobenzene 1 (465mg, 3mmol), dimethyl carbonate (900mg, 10mmol) and sodium hydride (480mg, 20mmol) were added to 10mL of an anhydrous tetrahydrofuran solvent, and the reaction was stirred at 0 ℃ for 30 minutes, followed by heating to 85 ℃ for 2 hours. When the reaction was completed as monitored by TLC, concentrated hydrochloric acid was slowly added dropwise to the mixture to remove excess sodium hydride. When the pH is about 2-3, dichloromethane (CH) is used 2 CL 2 ) The organic layer was washed with water three times, and dried over anhydrous magnesium sulfate. Evaporation of CH under reduced pressure 2 CL 2 To obtain methyl 3- (2-chlorobenzene) -3-oxopropanoate 2 as a yellow oily liquid, 2 (610mg, 2.64mmol) was reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) (1.022g, 8.5 mmol) in toluene (10 mL) at 120 ℃ for 2 hours, and when completion of the reaction was monitored by TLC, CH was added 2 CL 2 Extracting, washing organic layer with water for three times, drying with anhydrous magnesium sulfate, and evaporating CH under reduced pressure 2 CL 2 An orange-yellow liquid 3 is obtained. 3 (0.64mg, 3mmol) and aniline (0.333mg, 3mmol) were dissolved in toluene (10 mL) and poured into a 50mL round bottom flask at 110 ℃ for 3 hours, to give product 4a when the reaction was complete as monitored by TLC, cesium carbonate (790mg, 3mmol) was added to the 50mL round bottom flask and the reaction was continued at 150 ℃ for 3 hours, when the reaction was complete as monitored by TLC, CH was used 2 CL 2 Extracting, washing organic layer with water for three times, drying with anhydrous magnesium sulfate, and evaporating CH under reduced pressure 2 CL 2 Obtaining orange yellow solid N-phenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid methyl ester 5a, dissolving 5a (660mg, 2.5mmol) by using 1, 4-dioxane (10 mL), adding sodium hydroxide (80mg, 2mmol) dissolved by water (2 mL) into a 50mL round-bottom flask, reacting for 1 hour at 110 ℃, when the reaction is monitored to be completed by TLC, evaporating 1, 4-dioxane under reduced pressure, adding saturated saline solution for dissolving, adjusting the pH to 3-4 by using dilute hydrochloric acid, and using CH 2 CL 2 Extracting, washing organic layer with water for three times, drying with anhydrous magnesium sulfate, and evaporating CH under reduced pressure 2 CL 2 And separating by column chromatography (DCM: CH) 3 OH = 10) to give N-phenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid 6a as an orange yellow solid.
6a; the yield was 63.1%. 1 HNMR(400MHz,CDCl 3 )δ14.91(s,1H),8.84(s,1H),8.60(d,J＝8.1Hz,1H),7.73(d,J＝8.4Hz,1H),7.70(s,1H),7.69(d,J＝3.2Hz,,2H),7.61(t,J＝7.6Hz,1H),7.48(d,J＝3.2Hz,1H),7.47(d,J＝2.5Hz,1H),7.19(d,J＝8.6Hz,1H).
According to the method of the first step, the N-p-fluorophenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid 6b is prepared by taking p-fluoroaniline as a raw material.
6b; the yield was 66.5%. 1 HNMR(400MHz,CDCl 3 )δ14.82(s,1H),8.82(s,1H),8.62(d,J＝7.9Hz,1H),7.73(t,J＝7.9Hz,1H),7.63(t,J＝7.3Hz,1H),7.49(d,J＝4.8Hz,1H),7.47(d,J＝4.3Hz,1H),7.41(s,1H),7.38(d,J＝8.4Hz,1H),7.15(d,J＝8.4Hz,1H).
According to the method of the step one, p-chloroaniline is used as a raw material to prepare the N-p-chlorophenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid 6c.
6c, and (c); the yield was 70.3%. 1 HNMR(400MHz,CDCl 3 )δ14.79(s,1H),8.80(s,1H),8.60(d,J＝8.0Hz,1H),7.74(t,J＝7.7Hz,1H),7.69(s,1H),7.67(s,1H),7.63(t,J＝7.6Hz,1H),7.45(s,1H),7.43(s,1H),7.17(d,J＝8.5Hz,1H).
According to the method of the step one, p-bromoaniline is used as a raw material to prepare N-p-bromophenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid 6d.
6d; the yield was 60.9%. 1 HNMR(400MHz,CDCl 3 )δ14.78(s,1H),8.79(s,1H),8.60(d,J＝8.0Hz,1H),7.85(s,1H),7.83(s,1H),7.74(t,J＝7.8Hz,1H),7.63(t,J＝7.6Hz,1H),7.38(s,1H),7.36(s,1H),7.17(d,J＝8.6Hz,1H).
According to the method of the first step, 3-chloro-4-fluoroaniline is used as a raw material to prepare 1- (3-chloro-4-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid 6e.
6e, performing a chemical reaction; the yield was 55.1%. 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).
According to the method of the step one, 4- (trifluoromethoxy) aniline is used as a raw material to prepare 4-oxo-1- (4- (trifluoromethoxy) phenyl) -1, 4-dihydroquinoline-3-carboxylic acid 6f.
6f; the yield was 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).
Step two: in a 50mL round-bottom flask, 4-chloro 6, 7-dimethoxyquinoline 7 (84.60mg, 0.5 mmol), 4-nitrophenol 8 (103.05mg, 0.5 mmol), sodium iodide (24.44mg, 0.1 mmol) and sodium carbonate (20 mmol) were dissolved in 15mL of a toluene solution and reacted at 130 ℃ for 12 hours. Upon completion of the reaction as monitored by TLC, toluene was evaporated under reduced pressure to give 9 as a white solid, and 9 (110mg, 1mmol) was dissolved in a mixed solution of water (5 ml) and ethanol (10 ml), and then reduced iron powder (112mg, 2mmol) and ammonium chloride (130mg, 2mmol) were added to the solution and reacted at 50 ℃ for 6 hours. After completion of the reaction monitored by TLC, the inorganic residue was removed by filtration and the filtrate was dried in vacuo to give the crude product. Finally, column chromatography is carried out (DCM: CH) 3 OH = 10) to yield 10. Namely the target compound 4- [ (6, 7-dimethoxy quinoline-4-yl) oxy]Aniline.
10; the yield was 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).
Step three: reacting 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy]Aniline (34.3mg, 0.1mmol) and N-phenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (30mg, 0.1mmol) were dissolved in N, N-dimethylformamide (6 mL), HATU (2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate) (25.8mg, 0.1mmol) and DIPEA (N, N-diisopropylethylamine) (45.6mg, 0.12mmol) were added, and acid-amine condensation reaction was carried out at room temperature for 16h. After completion of the reaction was monitored by TLC, extraction was performed with ethyl acetate, and the organic layer was washed three times with water and dried over anhydrous magnesium sulfate. Evaporating ethyl acetate under reduced pressure, and separating by column chromatography (DCM: CH) 3 OH = 15) from 1), i.e. N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide.
N- (4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroQuinoline-3-carboxamide (11 a); the yield is 55.7 percent; m.p. 225.1-226.6 ℃. 1 HNMR(400MHz,CDCl 3 )δ12.47(s,1H),8.97(s,1H),8.64(d,J＝7.8Hz,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＝7.8Hz,1H),7.60(s,1H),7.57(d,J＝7.5Hz,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＝8.5Hz,1H),6.57(d,J＝5.0Hz,1H),4.10(s,6H).13CNMR(101MHz,CDCl 3 )δ177.03,163.47,163.08,154.72,150.59,149.06,147.95,144.86,140.77,142.46,140.46,137.18,133.06,130.55(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/z544.2[M+H] + 。
Starting from 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] aniline and N-p-fluorophenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, N- (4- (6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide (11 b) is prepared according to the procedure in step three.
11b; the yield is 59.3%; 256.9-258.8 ℃ in m.p. 1 HNMR(400MHz,CDCl 3 )δ12.40(s,1H),8.93(d,J＝3.1Hz,1H),8.63(d,J＝8.0Hz,1H),8.52(d,J＝5.1Hz,1H),7.93(s,1H),7.91(d,J＝2.9Hz,1H),7.68(t,J＝7.7Hz,1H),7.61(d,J＝3.0Hz,1H),7.57(d,J＝8.1Hz,1H),7.53–7.45(m,3H),7.38(t,J＝9.7Hz,2H),7.24(d,J＝3.0Hz,1H),7.22(d,J＝3.0Hz,1H),7.12(d,J＝10.4Hz,1H),6.55(s,1H),4.09(s,6H).13CNMR(101MHz,CDCl 3 )δ176.98,162.79,161.47,153.22,149.96,149.71,148.00,147.90,145.84,140.81,136.49,136.46,133.12,130.94,129.38,129.29,128.85,127.08,127.01,125.82,122.13(2C),121.61(2C),117.88,117.76,117.53,112.10,107.02,103.26,99.61,56.26(2C).ESI-MS:m/z562.2[M+H] + .
Starting from 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] aniline and N-p-chlorophenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 1- (4-chlorophenyl) -N- (4- (6, 7-dimethoxyquinolin-4-oxy) phenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide (11 c) was prepared according to the procedure in step three.
11c, and; the yield is 55.2%; m.p. 249.1-250.2 deg.c. 1 HNMR(400MHz,CDCl 3 )δ12.41(s,1H),8.93(s,1H),8.64(dd,J＝8.1,1.4Hz,1H),8.53(d,J＝5.4Hz,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＝2.8Hz,1H),7.63(s,1H),7.62–7.56(m,1H),7.54(s,1H),7.47(d,J＝1.9Hz,1H),7.46–7.44(m,1H),7.26–7.24(m,1H),7.23(s,1H),7.15(d,J＝8.5Hz,1H),6.58(d,J＝5.4Hz,1H),4.10(s,6H).13CNMR(101MHz,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] + .
Starting from 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] aniline and N-p-bromophenyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 1- (4-bromophenyl) -N- (4- (6, 7-dimethoxyquinolin-4-oxy) phenyl) -4-oxo-1, 4-dihydroquinoline-3-carboxamide (11 d) was prepared according to the procedure in step three.
11d; the yield is 58.8 percent; m.p. 257.1-259.0 ℃. 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] + .
11e, and (e); the yield is 54.5 percent; m.p. 210.1-211.2 ℃. 1 HNMR(400MHz,CDCl 3 )δ12.33(s,1H),8.90(s,1H),8.63(d,J＝7.4Hz,1H),8.52(d,J＝5.3Hz,1H),7.93(s,1H),7.90(s,1H),7.70(t,J＝7.2Hz,1H),7.63(d,J＝6.3Hz,1H),7.61(s,1H),7.59(d,J＝7.5Hz,1H),7.49(d,J＝8.6Hz,1H),7.45(d,J＝7.6Hz,2H),7.24(s,1H),7.22(s,1H),7.13(d,J＝8.5Hz,1H),6.54(d,J＝5.3Hz,1H),4.09(d,J＝2.1Hz,6H).ESI-MS:m/z596.2[M+H] + .
Starting from 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] aniline and 4-oxo-1- (4- (trifluoromethoxy) phenyl) -1, 4-dihydroquinoline-3-carboxylic acid, N- (4- (6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1- (4- (trifluoromethoxy) phenyl) -1, 4-dihydroquinoline-3-carboxamide (11 f) was prepared according to the procedure of step three.
11f; the yield is 60.3%; m.p. 248.5-250.1 ℃. 1 HNMR(400MHz,CDCl 3 )δ12.44(s,1H),8.94(s,1H),8.64(dd,J＝8.1,1.3Hz,1H),8.53(d,J＝5.5Hz,1H),7.96(s,1H),7.94(s,1H),7.69(dd,J＝8.6,1.5Hz,1H),7.63(s,1H),7.61(s,1H),7.58(d,J＝8.0Hz,1H),7.57–7.51(m,1H),7.49(d,J＝4.6Hz,1H),7.43–7.33(m,2H),7.25(s,1H),7.23(s,1H),7.13(d,J＝8.4Hz,1H),6.60(d,J＝5.5Hz,1H),4.11(d,J＝2.0Hz,6H).ESI-MS:m/z628.2[M+H] + 。
Pharmacological study of the products of the invention
(1) EXAMPLE the dose-effect relationship between the inhibition of LPS-stimulated macrophage (J774A.1) release of IL-6 and TNF-alpha
J774A.1 secretes excessive proinflammatory cytokines (e.g., IL-6 and TNF-alpha) when stimulated with LPS. An enzyme-linked immunosorbent assay (ELISA) was established to test the anti-inflammatory activity of compounds on IL-6 and TNF- α release in LPS stimulated J774A.1. Dimethylsulfoxide (DMSO) was used as a vehicle control, and after treating J774A.1 macrophages with 10 μm of a compound for 0.5 hours, cells were stimulated with LPS (0.5 μ g/mL) and cultured for 24 hours. The amounts of IL-6 and TNF-. Alpha.were then determined using an ELISA kit. The cytokine inhibitory activity of the compounds is shown in figure 1, and the results show that 6 compounds can obviously inhibit IL-6 (figure 1A) and TNF-alpha (figure 1B) released by macrophages stimulated by LPS and show obvious anti-inflammatory effect.
(2) Toxicity testing of the Compounds of the examples on macrophages
To assess the safety of the compounds, the cytotoxicity of the compounds was tested in j774a.1. Briefly, J774A.1 was plated in 96-well plates containing DMEM medium, 2.0X 104 cells per well, supplemented with 10% FBS, 100U/mL penicillin and 100mg/mL streptomycin. Next, the cells were cultured with a compound having a concentration of 10 μm for 24 hours, and MTT (5 mg/mL) dissolved in NaCl solution (0.9%) was added to each wellFresh solution. Then, 5% CO at 37 ℃% 2 The dishes were incubated for 4 hours. The absorbance was measured at 490nm with a multiwell plate reader. The test results are shown in fig. 2, and no obvious toxicity is caused to the cell proliferation activity under the condition of 10 mu m concentration, which indicates that the compound is non-toxic.
(3) Effect of Compound 11a on alleviating physiological Change in mice with acute Lung injury
The protective effect of compound 11a on the acute lung injury model of C57/BL6 mice induced by intratracheal instillation of LPS was investigated. Dimethylsulfoxide as vehicle control, mice were pre-treated with Compound 11a (20 mg/kg i.p.) or vehicle and then stimulated with 5mg/kg LPS. The lung wet/dry ratio was used to quantify the degree of pulmonary edema, which was increased by LPS and effectively decreased by compound 11a, as shown in figure 3A. Furthermore, the results in fig. 3B show that compound 11a inhibits LPS-induced increase in total cell number of bronchoalveolar lavage fluid (BALF). As shown in FIGS. 3C,3D,3E and 3F, release of IL-6 and TNF- α was significantly increased in alveolar lavage fluid (BALF) and serum (sera) from mice in the acute lung injury model, while compound 11a significantly reversed this change. The experimental results show that the compound 11a has excellent in-vivo anti-inflammatory effect on acute lung injury model mice.
(4) Compound 11a alleviates pathological changes in lung tissues of mice with acute lung injury
To assess histological changes in the lungs of mice with acute lung injury, hematoxylin-eosin (H & E) staining was performed on lung tissue. Mice challenged with LPS showed typical acute lung injury histopathological changes such as marked 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 normal physiological status, as shown in fig. 4, indicating that the compound was effective in alleviating lung tissue injury in acute lung injury mice.
(5) Compound 11a ameliorates physiological and pathological changes in septic mice
The protective effect of compound 11a on LPS-induced C57/BL6 mouse sepsis model injected intraperitoneally was investigated. Dimethylsulfoxide as vehicle control, mice were pre-treated with Compound 11a (20 mg/kg i.p.) or vehicle and then stimulated with 20mg/kg LPS. As shown in fig. 5A and 5B, compound 11a can increase survival of septic mice and can reduce symptoms of weight loss in mice. Upon weighing and H & E staining of spleen tissue, LPS-stimulated mice exhibited typical spleen tissue edema and spleen histopathological changes were manifested as marked white marrow and lymph node hyperplasia, as shown in fig. 5C and 5D, compound 11 a-pretreated mice significantly reduced edema and histopathological changes, indicating that the compound was effective in alleviating physiological and pathological changes in septic mice.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. An N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide compound comprising one of the following structural formulae:
2. a process for the preparation 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) Mixing 3-acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and a solvent, and then sequentially carrying out low-temperature reaction and heating reaction to generate 3- (2-chlorobenzene) -3-oxopropanoic acid methyl ester which is marked as a compound 2;
(2) Mixing 3- (2-chlorobenzene) -3-oxopropanoic acid methyl ester, N-dimethylformamide dimethyl acetal and a solvent, and reacting to generate a compound 3;
(3) Mixing the compound 3, aniline raw materials and a solvent, and then reacting to obtain a compound 4 product system;
the aniline raw material comprises aniline, para-fluoroaniline, para-chloroaniline, para-bromoaniline, 3-chloro-4-fluoroaniline or 4- (trifluoromethoxy) aniline;
(4) Adding cesium carbonate into a product system of the compound 4 for reaction to generate a compound 5;
(5) Mixing the compound 5, 1, 4-dioxane, sodium hydroxide and water, and reacting to generate a compound 6;
the compound 6 comprises 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) Mixing 4-chloro-6, 7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and a solvent, and reacting to generate a compound 9;
(7) Mixing the compound 9, water, ethanol, reducing iron powder and ammonium chloride, and reacting to generate 4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] aniline which is marked as a compound 10;
(8) Mixing the compound 10, the compound 6, a solvent, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, and then carrying out acid-amine condensation reaction to generate an N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-formamide compound;
there is no restriction on the order of the preparation of compound 6 in steps (1) to (5) and the preparation of compound 10 in steps (6) to (7).
3. The preparation method according to claim 2, characterized in that the ratio of the amount of 3-acetyl-2-chlorobenzene, dimethyl carbonate, sodium hydride and solvent used in step (1) is 2-4 mmol;
the solvent is anhydrous tetrahydrofuran;
the temperature of the low-temperature reaction is-5 to 5 ℃, and the time is 25 to 35min;
the temperature of the heating reaction is 80-90 ℃, and the time is 1-3 h;
the using amount ratio of the 3- (2-chlorobenzene) -3-oxopropionic acid methyl ester, the N, N-dimethylformamide dimethyl acetal and the solvent in the step (2) is 2-3mmol;
the solvent is toluene;
the reaction temperature is 110-130 ℃, and the reaction time is 1-3 h;
the dosage ratio of the compound 3, the aniline raw materials and the solvent in the step (3) is 2-4mmol;
the solvent is toluene;
the reaction temperature is 100-120 ℃, and the reaction time is 2-4 h;
the dosage ratio of the cesium carbonate to the compound 3 in the step (4) is 2-4 mmol;
the reaction temperature is 140-160 ℃, and the reaction time is 2-4 h;
the dosage ratio of the compound 5, 1, 4-dioxane, sodium hydroxide and water in the step (5) is 2-3mL.
4. The production method according to claim 2 or 3, wherein the amount ratio of 4-chloro-6, 7-dimethoxyquinoline, 4-nitrophenol, sodium iodide, sodium carbonate and solvent in step (6) is 0.2 to 0.8 mmol;
the solvent is toluene;
the reaction temperature is 120-140 ℃ and the reaction time is 10-15 h;
the dosage ratio of the compound 9, water, ethanol, reducing iron powder and ammonium chloride in the step (7) is 0.5-1.5mmol;
the reaction temperature is 40-60 ℃ and the reaction time is 4-8 h.
5. The preparation method according to claim 4, wherein the ratio of the compound 10, the compound 6, the solvent, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine in the step (8) is 0.05 to 0.15mmol;
the solvent is N, N-dimethylformamide;
the temperature of the acid amine condensation reaction is room temperature, and the time is 12-20 h.
6. Use of a compound of the N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide according to claim 1 for the preparation of an anti-inflammatory medicament for the treatment of inflammation by inhibiting the release of inflammatory factors from macrophages.
7. The use according to claim 6, wherein the anti-inflammatory medicament is for the prevention or treatment of inflammation and inflammation-related diseases.
8. Use according to claim 7, wherein said inflammation or inflammation-related disorder includes, but is not limited to sepsis, acute lung injury.
9. A pharmaceutical composition for preventing or treating inflammation and inflammation-related diseases, comprising the N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydroquinoline-3-carboxamide compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is in the form of injection, tablet, capsule, aerosol, suppository, membrane, drop pill, ointment, controlled-release or sustained-release preparation, or nano-preparation.
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