CN116891455A - N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition - Google Patents

N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition Download PDF

Info

Publication number
CN116891455A
CN116891455A CN202310874392.3A CN202310874392A CN116891455A CN 116891455 A CN116891455 A CN 116891455A CN 202310874392 A CN202310874392 A CN 202310874392A CN 116891455 A CN116891455 A CN 116891455A
Authority
CN
China
Prior art keywords
compound
reaction
mmol
aniline
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310874392.3A
Other languages
Chinese (zh)
Inventor
梁广
唐启东
廖晶
伍文奇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wenzhou Research Institute Of Guoke Wenzhou Institute Of Biomaterials And Engineering
Original Assignee
Wenzhou Research Institute Of Guoke Wenzhou Institute Of Biomaterials And Engineering
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wenzhou Research Institute Of Guoke Wenzhou Institute Of Biomaterials And Engineering filed Critical Wenzhou Research Institute Of Guoke Wenzhou Institute Of Biomaterials And Engineering
Priority to CN202310874392.3A priority Critical patent/CN116891455A/en
Publication of CN116891455A publication Critical patent/CN116891455A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Abstract

The invention relates to the technical field of medicinal organic matters, in particular to an N-substituted phenyl-pyridazinone-3-carboxamide compound, a preparation method and application thereof and a medicinal composition. The compound related to pneumonia is an N- (4- (6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydro-pyridazine-3-carboxamide compound, which is used for treating sepsis and acute lung injury, and can be prepared into a preparation form comprising injection, tablet, capsule, aerosol, suppository, film, dripping pill, ointment, controlled release or sustained release preparation and nano preparation.

Description

N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition
Technical Field
The invention relates to the technical field of medicinal organic matters, in particular to an N-substituted phenyl-pyridazinone-3-carboxamide compound, a preparation method and application thereof and a medicinal composition.
Background
Inflammation (inflammation) is a defensive reaction of the body to stimulus, and is usually beneficial, and is an automatic defensive reaction of the human body, but when the inflammatory reaction is disregulated to cause excessive inflammation, the body can generate a large amount of inflammatory cytokines to damage tissues or cells, so that the life health of the human body is seriously influenced.
Sepsis (sepsis) is a systemic inflammatory response syndrome caused by invasion of pathogenic microorganisms such as bacteria into the body. In addition to manifestations of systemic inflammatory response syndrome and primary infection focus, critically ill patients often have manifestations of organ hypoperfusion. The death rate of sepsis is as high as 30-70%. In recent years, despite the long-felt advances in anti-infective therapy and organ function support techniques, there is currently a clinical lack of effective sepsis treatment drugs.
Clinical and animal experiments have shown that Lipopolysaccharide (LPS) activates a variety of downstream pro-inflammatory signaling pathways and triggers the overproduction of inflammatory factors such as tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), which in turn lead to sepsis. At present, the blocking of inflammatory storm by various medicines such as glucocorticoid and the like has been widely explored as a potential and promising method for preventing and treating sepsis. However, given that clinically used drugs do not show significant therapeutic effects on sepsis patients due to their inefficiency and adverse reactions, there is still a need to develop new anti-inflammatory drugs that are more effective and safer to treat sepsis. Therefore, inhibition of the release of inflammatory factors such as TNF- α and IL-6 is an important means for treating sepsis.
Disclosure of Invention
The invention aims to provide an N-substituted phenyl-pyridazinone-3-formamide compound, a preparation method and application thereof and a pharmaceutical composition, so as to make up 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-dimethoxy quinoline-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-formamide compound, which comprises one of the following structural formulas:
the invention also provides a preparation method of the N- (4- (6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-formamide compound, which comprises the following steps:
(1) Mixing water, ethanol, ethyl acetoacetate and sodium acetate, and cooling to obtain a system 1;
regulating the pH value of the aqueous solution of the aniline compound to 1-2, cooling, and then mixing with the sodium nitrite solution to obtain a system 2;
mixing the system 2 and the system 1, and then reacting to generate a compound 2;
the aniline compound comprises aniline, p-fluoroaniline, p-methylaniline, p-methoxyaniline, p-ethylaniline or 2-ethylaniline;
(2) Mixing the obtained compound 2, a solvent, ethoxycarbonylmethylene triphenylphosphine and diethylamine for reaction to generate a compound 3;
(3) Mixing the obtained compound 3, ethanol, 1, 4-dioxane and alkali liquor for reaction to obtain a reaction solution;
regulating the pH value of the reaction liquid to 2-3 to generate a compound 4;
(4) Mixing 4-chloro 6, 7-dimethoxy quinoline, 4-nitrophenol, potassium iodide, cesium carbonate and a solvent for reaction to generate a compound 7;
(5) Mixing the compound 7, water, ethanol, reduced iron powder and ammonium chloride, and reacting to obtain 4- [ (6, 7-dimethoxy quinolin-4-yl) oxy ] aniline, which is designated as a compound 8;
(6) Mixing a compound 8, a compound 4, a solvent, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine, and performing an acid amine condensation reaction to generate an N- (4- ((6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydro quinoline-3-carboxamide compound;
the preparation of compound 4 in steps (1) to (3) and the preparation of compound 8 in steps (4) to (5) are not limited in order.
Preferably, the water, ethanol, ethyl acetoacetate and sodium acetate in the dosage ratio of step (1) is 1mL: 2-6 mL: 2-3 mL: 1-2 g;
the temperature is independently reduced to-2 to-6 ℃;
adjusting the pH value by using concentrated hydrochloric acid;
the dosage ratio of the aniline compound to the sodium nitrite solution is 1.5-2 g: 15-25 mL, the mass concentration of the sodium nitrite solution is 45-55%;
the dosage ratio of the aniline compound to the acetoacetic ester is 1.5-2 g: 2-3 mL;
the volume ratio of the aniline compound to the water in the aniline compound aqueous solution is 1.5-2.5:1;
the reaction temperature is-5 ℃ and the reaction time is 1-5 h.
Preferably, the solvent in step (2) comprises dimethyl sulfoxide;
the dosage ratio of the aniline compound, the solvent, the ethoxycarbonyl methylene triphenylphosphine and the diethylamine is 1.5-2 g: 3-5 mL: 2-3 g: 0.05-0.1 mL;
the reaction temperature is 80-90 ℃ and the reaction time is 2-8 h;
the mass concentration of the alkali liquor in the step (3) is 5-15%;
the alkali liquor comprises sodium hydroxide solution or potassium hydroxide solution;
the dosage ratio of the aniline compound, the ethanol, the 1, 4-dioxane and the alkali liquor is 1.5-2 g: 15-25 mL: 15-25 mL: 4-5 mL;
the reaction time is 0.5-2 h;
the pH was adjusted using concentrated hydrochloric acid.
Preferably, the dosage ratio of the 4-chloro-6, 7-dimethoxy quinoline, the 4-nitrophenol, the potassium iodide, the cesium carbonate and the solvent in the step (4) is 0.2-0.8 mmol/0.02-0.08 mmol/1-3 mmol/3-8 mL;
the solvent is toluene;
the reaction temperature is 120-160 ℃ and the reaction time is 10-15 h;
the dosage ratio of the compound 7, the water, the ethanol, the reduced iron powder and the ammonium chloride in the step (5) is 0.5-1.5 mmol:3-7 mL:8-12 mL:8-13 mmol:1-3 mmol;
the reaction temperature is 40-80 ℃ and the reaction time is 2-8 h.
Preferably, the dosage ratio of the compound 8, the compound 4, the solvent, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, the 1-hydroxybenzotriazole and the triethylamine in the step (6) is 0.05-0.2 mmol, 0.1-0.3 mmol, 4-8 mL, 0.1-0.3 mmol and 0.2-0.4 mmol;
the solvent is dichloromethane;
the reaction time is 10-20 h.
The invention also provides application of the N- (4- (6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide compound in preparing anti-inflammatory drugs for treating inflammation by inhibiting release of inflammatory factors by macrophages, wherein the anti-inflammatory drugs are used for preventing or treating inflammation and diseases related to the inflammation.
Preferably, the inflammation or inflammation-related disorder includes, but is not limited to, sepsis, acute lung injury, arthritis, proctitis, hepatitis, fatty liver, or chronic inflammatory disease.
The invention also provides a pharmaceutical composition for preventing or treating inflammation and diseases related to inflammation, which comprises the N- (4- (6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide compound or pharmaceutically acceptable salts thereof and pharmaceutical excipients.
Preferably, the pharmaceutical composition is in the form of a preparation comprising an injection, a tablet, a capsule, an aerosol, a suppository, a film, a drop pill, an ointment, a controlled or sustained release agent and a nano-preparation.
The N- (4- (6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-formamide compound provided by the invention is used for treating sepsis and acute lung injury, and the preparation forms which can be prepared comprise injection, tablet, capsule, aerosol, suppository, film, dripping pill, ointment, controlled release or sustained release preparation and nano preparation.
Drawings
FIG. 1 is a graph showing the dose-response of compounds inhibiting LPS-stimulated macrophage release of IL-6 and TNF- α;
FIG. 2 is a graph of the rate of weight loss in mice with sepsis improvement and alleviation of mice with the preferred compound (J27).
Detailed Description
The invention provides a preparation method of the N- (4- (6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-formamide compound, which comprises the following steps:
(1) Mixing water, ethanol, ethyl acetoacetate and sodium acetate, and cooling to obtain a system 1;
regulating the pH value of the aqueous solution of the aniline compound to 1-2, cooling, and then mixing with the sodium nitrite solution to obtain a system 2;
mixing the system 2 and the system 1, and then reacting to generate a compound 2;
the aniline compound comprises aniline, p-fluoroaniline, p-methylaniline, p-methoxyaniline, p-ethylaniline or 2-ethylaniline;
(2) Mixing the obtained compound 2, a solvent, ethoxycarbonylmethylene triphenylphosphine and diethylamine for reaction to generate a compound 3;
(3) Mixing the obtained compound 3, ethanol, 1, 4-dioxane and alkali liquor for reaction to obtain a reaction solution;
regulating the pH value of the reaction liquid to 2-3 to generate a compound 4;
(4) Mixing 4-chloro 6, 7-dimethoxy quinoline, 4-nitrophenol, potassium iodide, cesium carbonate and a solvent for reaction to generate a compound 7;
(5) Mixing the compound 7, water, ethanol, reduced iron powder and ammonium chloride, and reacting to obtain 4- [ (6, 7-dimethoxy quinolin-4-yl) oxy ] aniline, which is designated as a compound 8;
(6) Mixing a compound 8, a compound 4, a solvent, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine, and performing an acid amine condensation reaction to generate an N- (4- ((6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydro quinoline-3-carboxamide compound;
the preparation of compound 4 in steps (1) to (3) and the preparation of compound 8 in steps (4) to (5) are not limited in order.
In the invention, the dosage ratio of water, ethanol, ethyl acetoacetate and sodium acetate in the step (1) is 1mL: 2-6 mL: 2-3 mL: 1-2 g, preferably 1mL: 4-5 mL: 2.5-2.8 mL:1.5 g to 1.8g;
the temperature is independently reduced to-2 to-6 ℃, preferably-4 to-5 ℃;
adjusting the pH value by using concentrated hydrochloric acid;
the dosage ratio of the aniline compound to the sodium nitrite solution is 1.5-2 g: 15-25 mL, preferably 1.6-1.8 g: 18-20 mL; the mass concentration of the sodium nitrite solution is 45-55%, preferably 48-50%;
the dosage ratio of the aniline compound to the acetoacetic ester is 1.5-2 g:2 to 3mL, preferably 1.8 to 1.9g: 2.3-2.5 mL;
the volume ratio of the aniline compound to the water in the aniline compound aqueous solution is 1.5-2.5:1, preferably 2:1;
the reaction temperature is-5 to 5 ℃, preferably-4 to 4 ℃, more preferably-3 to 2 ℃, still more preferably-1 to 0 ℃; the time is 1 to 5 hours, preferably 2 to 3 hours.
In the present invention, the solvent in step (2) comprises dimethyl sulfoxide;
the dosage ratio of the aniline compound, the solvent, the ethoxycarbonyl methylene triphenylphosphine and the diethylamine is 1.5-2 g: 3-5 mL: 2-3 g:0.05 to 0.1mL, preferably 1.6 to 1.8g:4mL:2.3 to 2.6g: 0.06-0.08 mL;
the reaction temperature is 80-90 ℃, preferably 82-88 ℃, and more preferably 85-86 ℃; the time is 2 to 8 hours, preferably 4 to 6 hours;
the mass concentration of the alkali liquor in the step (3) is 5-15%, preferably 8-12%, and more preferably 9-10%; the alkali liquor comprises sodium hydroxide solution or potassium hydroxide solution;
the dosage ratio of the aniline compound, the ethanol, the 1, 4-dioxane and the alkali liquor is 1.5-2 g: 15-25 mL: 15-25 mL:4 to 5mL, preferably 1.6 to 1.8g: 18-20 mL: 18-20 mL:4.5mL;
the reaction time is 0.5 to 2 hours, preferably 1 to 1.5 hours;
the pH was adjusted using concentrated hydrochloric acid.
In the invention, the dosage ratio of the 4-chloro 6, 7-dimethoxy quinoline, 4-nitrophenol, potassium iodide, cesium carbonate and the solvent in the step (4) is 0.2-0.8 mmol:0.2-0.8 mmol:0.02-0.08 mmol:1-3 mmol:3-8 mL, preferably 0.4-0.6 mmol:0.4-0.6 mmol:0.04-0.05 mmol:1.5-2 mmol:5-6 mL;
the solvent is toluene;
the temperature of the reaction is 120-160 ℃, preferably 130-150 ℃, and more preferably 140-145 ℃; the time is 10 to 15 hours, preferably 12 to 13 hours;
the dosage ratio of the compound 7, the water, the ethanol, the reduced iron powder and the ammonium chloride in the step (5) is 0.5-1.5 mmol:3-7 mL:8-12 mL:8-13 mmol:1-3 mmol, preferably 0.8-1.2 mmol:4-6 mL:9-10 mL:10-11 mmol:2-2.3 mmol;
the reaction temperature is 40-80 ℃, preferably 50-70 ℃, and more preferably 55-60 ℃; the time is 2 to 8 hours, preferably 4 to 6 hours.
In the invention, the dosage ratio of the compound 8, the compound 4, the solvent, the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, the 1-hydroxybenzotriazole and the triethylamine in the step (6) is 0.05-0.2 mmol:0.1-0.3 mmol:4-8 mL:0.1-0.3 mmol:0.1-0.3 mmol:0.2-0.4 mmol, preferably 0.1-0.1.5 mmol:0.18-0.23 mmol:6-7 mL:0.15-0.2 mmol:0.2-0.23 mmol:0.3-0.34 mmol;
the solvent is dichloromethane;
the reaction time is 10 to 20 hours, preferably 14 to 17 hours.
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.
The preparation routes of the examples of the invention are shown below:
example 1
4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxylic acid (4 a)
Step one: to a 50mL round bottom flask were added water (1 mL), ethanol (4 mL), ethyl acetoacetate (2.31 mL,0.0177 mol) and anhydrous sodium acetate (1.59 g,0.0194 mol) in this order, and after mixing well, stirring was performed at room temperature for 1h, and then the system temperature was lowered to-4℃by salt ice bath for use. Aniline 1a (1.79 g,0.019 mol) was then fully dissolved in deionized water (the volume ratio of aniline to water was 2:1), then concentrated hydrochloric acid was added to adjust the pH of the system to 1-2, then the system was transferred to a salt ice bath to reduce the temperature below-4 ℃, then 50% sodium nitrite solution (20 mL) was slowly added dropwise, and stirred at low temperature for 30min to form system 2. After 30min, system 2 was added to system 1, which had a large amount of yellow solids precipitated, and reacted at 0℃for 2h, followed by suction filtration, washing and drying to give 2a. The 2a thus obtained was sufficiently dissolved in a 250mL round bottom flask with 4mL of LDMSO followed by addition of ethoxycarbonylmethylene triphenylphosphine (CBMTPP) (2.23 g,0.0064 mol) and diethylamine (Et 2 NH) (0.0669 mL,0.0006 mol) was reacted at 85℃for 4h. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into ice water, extracted with methylene chloride, washed with saturated brine, and finally separated by column chromatography to obtain 3a. Finally, the obtained 3a, ethanol (20 mL) and 1, 4-dioxane (20 mL) are stirred uniformly in a 100mL round bottom flask, then 5mL of 10 percent NaOH solution is added into the mixed solution, the mixture is stirred for 1h at room temperature, after the reaction is finished, concentrated hydrochloric acid is added into the system to adjust the PH value to 2And (3) separating out a light yellow solid in the process, and carrying out suction filtration, washing and drying to obtain the 4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxylic acid 4a.
White power；yield:50.1％. 1 H NMR(400MHz,CDCl 3 )δ7.49(t,J＝7.5Hz,2H),7.41(dd,J＝15.4,7.6Hz,2H),7.37–7.28(m,1H),6.80(d,J＝6.8Hz,1H),2.44(d,J＝6.9Hz,3H).
According to the method of the first step, p-fluoroaniline is used as a raw material to prepare the 1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid 4b.
Yellowpower；yield:56.5％. 1 H NMR(400MHz,CDCl 3 )δ7.53(dd,J＝8.0,
4.9Hz,2H),7.11(t,J＝8.2Hz,2H),6.81(s,1H),2.46(s,3H).
According to the method of the first step, 4-methyl-6-oxo-1- (p-toluene) -1, 6-dihydropyridazine-3-carboxylic acid 4c is prepared by using p-methylaniline as a raw material.
Yellow power；yield:52.3％. 1 H NMR(400MHz,MeOD)δ7.40(d,J＝8.4Hz,2H),7.28(s,1H),7.26(s,1H),6.87(d,J＝1.1Hz,1H),2.44(d,J＝0.9Hz,3H),2.36(s,3H).
According to the method of the first step, 1- (4-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid 4d is prepared by using p-methoxy group as a raw material.
Yellow power；yield:59.8％. 1 H NMR(400MHz,CDCl 3 )δ7.01(d,J＝9.0
Hz,2H),6.49(d,J＝9.0Hz,2H),6.37(s,1H),3.35(s,3H),2.03(s,3H).
According to the method of the first step, 1- (4-ethylphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid 4e is prepared from p-ethylaniline.
Yellow power；yield:55.3％. 1 H NMR(400MHz,CDCl 3 )δ7.42(d,J＝8.3
Hz,2H),7.24(s,1H),6.82(s,1H),2.64(q,J＝7.6Hz,2H),2.46(s,3H),1.19(t,J＝7.6Hz,3H).
According to the method of the first step, 1- (2-methylphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid 4f is prepared from 2-ethylaniline.
Yellow power；yield:58.1％. 1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,2H),7.24(d,J＝7.0Hz,1H),7.16(d,J＝7.8Hz,1H),6.82(s,1H),2.47(s,3H),2.38(q,J＝7.5Hz,2H),1.07(t,J＝7.6Hz,3H).
Step two: 4-chloro-6, 7-dimethoxyquinoline 5 (100 mg, 0.447 mmol), 4-nitrophenol 6 (62.33 mg,0.5 mmol), potassium iodide (7.44 mg,0.045 mmol) and cesium carbonate (292.21 mg,2 mmol) were dissolved in 5mL of toluene solution in a 50mL round bottom flask and reacted at 140℃for 12h. Upon completion of the reaction monitored by TLC, 7 (110 mg,1 mmol) was dissolved in a mixed solution of water (5 mL) and ethanol (10 mL) to give a pale yellow solid 7 by washing with petroleum ether with stirring, and then reduced iron powder (560 mg,10 mmol) and ammonium chloride (130 mg,2 mmol) were added to the solution to react at 65℃for 4 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, the mixture was separated by column chromatography (DCM: CH) 3 Oh=30:1) to give 8. Namely the target compound 4- ((6, 7-dimethoxy quinoline-4-yl) oxy) aniline.
White power；yield:64.7％. 1 H NMR(400MHz,MeOD)δ8.65(s,2H),8.34(d,J＝8.3Hz,2H),8.05(dd,J＝8.2,7.4Hz,2H),7.83–7.73(m,4H),4.92(s,3H),4.92(s,3H).
Step three: 4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) aniline (50 mg,0.169 mmol) and 4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxylic acid (46.63 mg,0.2 mmol) were dissolved in ultra-dry dichloromethane (6 mL), EDCI (38.84 mg,0.2 mmol), HOBT (27.4 mg,0.21 mmol) and TEA (36.81 mL,0.3 mmol) were added and the acid amine condensation reaction was performed at room temperature for 13h. After completion of the reaction, the dichloromethane was evaporated to dryness, extracted with DCM to MeOH (60:1) mixed solvent, dried over anhydrous magnesium sulfate after extraction, filtered and evaporated to dryness, and then column chromatographed (DCM: meoh=10:1) to give J25, i.e. N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide.
N- (4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1-phenyl-1, 6-dihydropyridazine-3-carboxamide (J25)
White solid；yiled:69.3％；m.p.:124.7–126.7℃. 1 H NMR(400MHz,CDCl 3 )δ9.02(s,1H),8.46(d,J＝5.0Hz,1H),7.71(d,J＝8.9Hz,2H),7.60(d,J＝7.8Hz,2H),7.54(s,1H),7.51(d,J＝8.0Hz,1H),7.46(t,J＝7.3Hz,1H),7.41(s,1H),7.19(s,1H),7.17(s,1H),6.90(d,J＝0.9Hz,1H),6.44(d,J＝5.3Hz,1H),4.03(s,3H),3.98(s,3H),2.66(s,3H). 13 C NMR(100MHz,CDCl 3 )δ160.73,160.58,159.44,152.96,150.98,149.63,148.70,146.80,144.56,140.69,138.23,134.63,130.92,129.11(×2),128.94,125.45(×2),122.04(×2),121.76(×2),116.08,107.76,103.36,99.48,56.18(×2),20.48.ESI-MS:m/z 509.2[M+H]+.
N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide (J26) was prepared according to the method of step three starting from 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline and 1- (4-fluorophenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid.
White solid；yield 87.5％；m.p.:126.7-128.0℃； 1 H NMR(400MHz,CDCl 3 )δ9.04(s,1H),8.53(s,1H),7.78(s,2H),7.66(s,2H),7.60(s,1H),7.50(s,2H),7.28(s,1H),7.25–7.19(m,1H),6.97(s,1H),6.51(s,1H),4.11(s,3H),4.10(s,3H),2.73(s,3H). 13 C NMR(100MHz,CDCl 3 )δ163.59,160.78,160.46,159.38,152.99,150.97,149.63,148.58,146.66,144.72,138.43,136.59,134.58,130.90,128.85,127.42,127.34,122.05(×2),121.81(×2),116.17,115.94,107.60,103.30,99.44,56.19(×2),20.50.ESI-MS:m/z:527.2[M+H] + .
N- (4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) phenyl) -4-methyl-6-oxo-1- (p-tolyl) -1, 6-dihydropyridazine-3-carboxamide (J27) was prepared according to the procedure of step three starting from 4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) aniline and 4-methyl-6-oxo-1- (p-toluene) -1, 6-dihydropyridazine-3-carboxylic acid.
White solid；yield 85.2％；m.p.:150.9-151.3℃； 1 H NMR(400MHz,CDCl 3 )δ9.03(s,1H),8.46(d,J＝5.2Hz,1H),7.70(d,J＝8.7Hz,2H),7.54(s,1H),7.47(d,J＝8.0Hz,2H),7.40(s,1H),7.32(d,J＝7.9Hz,2H),7.18(d,J＝8.6Hz,2H),6.88(s,1H),6.44(d,J＝5.2Hz,1H),4.03(s,3H),3.97(s,3H),2.65(s,3H),2.42(s,3H). 13 C NMR(100MHz,CDCl 3 )δ160.70,160.63,159.55,152.90,150.93,149.58,148.80,146.87,144.47,139.17,138.24,137.99,134.65,130.83,129.70(×2),125.26(×2),122.00(×2),121.78(×2),116.06,107.82,103.34,99.45,56.20,56.18,21.29,20.53.ESI-MS:m/z:523.2[M+H] + .
N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -1- (4-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide (J28) was prepared according to the procedure of step three starting from 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline and 1- (4-methoxyphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid.
White solid；yield 88.6％；m.p.:199.1-200.6℃； 1 H NMR(400MHz,CDCl 3 )δ8.99(s,1H),8.47(d,J＝5.3Hz,1H),7.70(d,J＝8.8Hz,2H),7.57–7.49(m,3H),7.41(s,1H),7.19(d,J＝8.7Hz,2H),7.03(d,J＝8.9Hz,2H),6.90(s,1H),6.45(d,J＝5.2Hz,1H),4.04(s,3H),4.00(s,3H),3.87(s,3H),2.66(s,3H). 13 CNMR(100MHz,CDCl 3 )δ161.68,160.69,159.76,159.71,153.65,150.49,149.97,147.61,145.28,144.49,138.09,135.01,133.60,130.72,126.72(×2),122.09(×2),121.76(×2),116.05,114.24(×2),106.45,103.29,99.58,56.36,56.29,55.66,20.47.ESI-MS:m/z:539.2[M+H] + .
N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -1- (4-ethylphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide (J29) was prepared according to the procedure of step three starting from 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline and 1- (4-ethylphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid.
White solid；yield 70.9％；m.p.:145.0-146.1℃； 1 H NMR(400MHz,CDCl 3 )δ8.98(s,1H),8.47(d,J＝5.1Hz,1H),7.70(d,J＝8.6Hz,2H),7.57–7.48(m,3H),7.41(s,1H),7.36(d,J＝8.0Hz,2H),7.19(d,J＝8.6Hz,2H),6.91(s,1H),6.45(d,J＝5.1Hz,1H),4.09(s,3H),4.04(s,3H),2.74(q,J＝7.5Hz,2H),2.67(s,3H),1.29(t,J＝7.6Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ160.75,160.62,159.56,152.94,150.92,149.60,148.73,146.80,145.39,144.49,138.38,137.96,134.64,130.87,128.57(×2),125.32(×2),122.01(×2),121.79(×2),116.07,107.77,103.34,99.46,56.21(×2),28.64,20.55,15.51.ESI-MS:m/z:537.2[M+H] + .
N- (4- ((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -1- (2-ethylphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxamide (J30) was prepared according to the procedure of step three starting from 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) aniline and 1- (2-ylphenyl) -4-methyl-6-oxo-1, 6-dihydropyridazine-3-carboxylic acid.
White solid；yield 81.3％；m.p.:248.9-250.7℃； 1 H NMR(400MHz,CDCl 3 )δ8.87(d,J＝10.4Hz,1H),8.47(d,J＝4.2Hz,1H),7.68(d,J＝6.7Hz,2H),7.45(dd,J＝35.4,21.3Hz,5H),7.30(s,1H),7.17(d,J＝6.7Hz,2H),6.94(s,1H),6.45(s,1H),4.07(s,3H),4.04(s,3H),2.71(s,3H),2.52(d,J＝6.3Hz,2H),1.20(d,J＝2.1Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ162.80,162.18,160.31,159.46,153.06,150.52,149.84,149.29,146.95,143.47,142.15,140.67,140.13,136.11,129.86,129.37,128.26,127.14,122.56(×2),121.88(×2),115.70,108.32,103.69,99.57,36.25,31.24,23.90,18.80,14.39.ESI-MS:m/z:537.2[M+H] + .
Pharmacological investigation of the products of the invention
Example compounds inhibit the quantitative relationship of LPS-stimulated macrophage (J774A.1) release of IL-6 and TNF-alpha
When stimulated with LPS, J774A.1 secretes excessive amounts of pro-inflammatory cytokines (e.g., IL-6 and TNF- α). The present invention establishes an enzyme-linked immunosorbent assay (ELISA) to test compounds for anti-inflammatory activity against IL-6 and TNF-alpha release in LPS stimulated J774A.1. Dimethyl sulfoxide (DMSO) was used as a vehicle control, and after treatment of J774A.1 macrophages with 10. Mu.m compound for 0.5 hours, the cells were stimulated with LPS (0.5. Mu.g/mL) and cultured for 24 hours. IL-6 and TNF- α amounts were then determined using ELISA kits. The cytokine inhibitory activity of the compounds is shown in figure 1, and the results show that 6 compounds can obviously inhibit IL-6 and TNF-alpha released by macrophages stimulated by LPS, and have obvious anti-inflammatory effect.
Implementation of the preferred Compound J27 to alleviate physiological and pathological changes in sepsis mice
The invention further explores the protective effect of the preferred compound J27 on the sepsis model of C57/BL6 mice induced by intraperitoneal injection of LPS. Dimethyl sulfoxide was used as vehicle control, mice were pre-treated with the preferred compound J27 (20 mg/kg, intraperitoneal injection) or vehicle, and then stimulated with 15mg/kg LPS. As shown in FIG. 2, preferred compound J27 increased survival in sepsis mice and reduced weight loss in mice, as shown by total death within 36 hours after injection of high doses of LPS to elicit sepsis, while half of the mice given J27 survived and mice receiving treatment had a gradual recovery of weight gain after 48 hours. In addition, it was found during the course of the experiment that after 48 hours, the vital activity of mice in the drug-treated group was not significantly different from that in the negative control group. The compound is effective in alleviating physiological changes in sepsis mice.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. An N- (4- (6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide compound characterised by comprising one of the following structural formulae:
2. the process for producing N- (4- (6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide compound according to claim 1, comprising the steps of:
(1) Mixing water, ethanol, ethyl acetoacetate and sodium acetate, and cooling to obtain a system 1;
regulating the pH value of the aqueous solution of the aniline compound to 1-2, cooling, and then mixing with the sodium nitrite solution to obtain a system 2;
mixing the system 2 and the system 1, and then reacting to generate a compound 2;
the aniline compound comprises aniline, p-fluoroaniline, p-methylaniline, p-methoxyaniline, p-ethylaniline or 2-ethylaniline;
(2) Mixing the obtained compound 2, a solvent, ethoxycarbonylmethylene triphenylphosphine and diethylamine for reaction to generate a compound 3;
(3) Mixing the obtained compound 3, ethanol, 1, 4-dioxane and alkali liquor for reaction to obtain a reaction solution;
regulating the pH value of the reaction liquid to 2-3 to generate a compound 4;
(4) Mixing 4-chloro 6, 7-dimethoxy quinoline, 4-nitrophenol, potassium iodide, cesium carbonate and a solvent for reaction to generate a compound 7;
(5) Mixing the compound 7, water, ethanol, reduced iron powder and ammonium chloride, and reacting to obtain 4- [ (6, 7-dimethoxy quinolin-4-yl) oxy ] aniline, which is designated as a compound 8;
(6) Mixing a compound 8, a compound 4, a solvent, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine, and performing an acid amine condensation reaction to generate an N- (4- ((6, 7-dimethoxy quinoline-4-yl) oxy) phenyl) -4-oxo-1-phenyl-1, 4-dihydro quinoline-3-carboxamide compound;
the preparation of compound 4 in steps (1) to (3) and the preparation of compound 8 in steps (4) to (5) are not limited in order.
3. The method according to claim 2, wherein the water, ethanol, ethyl acetoacetate and sodium acetate are used in the amount ratio of 1mL in the step (1): 2-6 mL: 2-3 mL: 1-2 g;
the temperature is independently reduced to-2 to-6 ℃;
adjusting the pH value by using concentrated hydrochloric acid;
the dosage ratio of the aniline compound to the sodium nitrite solution is 1.5-2 g: 15-25 mL, the mass concentration of the sodium nitrite solution is 45-55%;
the dosage ratio of the aniline compound to the acetoacetic ester is 1.5-2 g: 2-3 mL;
the volume ratio of the aniline compound to the water in the aniline compound aqueous solution is 1.5-2.5:1;
the reaction temperature is-5 ℃ and the reaction time is 1-5 h.
4. A process according to claim 2 or 3, wherein the solvent in step (2) comprises dimethyl sulfoxide;
the dosage ratio of the aniline compound, the solvent, the ethoxycarbonyl methylene triphenylphosphine and the diethylamine is 1.5-2 g: 3-5 mL: 2-3 g: 0.05-0.1 mL;
the reaction temperature is 80-90 ℃ and the reaction time is 2-8 h;
the mass concentration of the alkali liquor in the step (3) is 5-15%;
the alkali liquor comprises sodium hydroxide solution or potassium hydroxide solution;
the dosage ratio of the aniline compound, the ethanol, the 1, 4-dioxane and the alkali liquor is 1.5-2 g: 15-25 mL: 15-25 mL: 4-5 mL;
the reaction time is 0.5-2 h;
the pH was adjusted using concentrated hydrochloric acid.
5. The method according to claim 4, wherein the ratio of the amounts of 4-chloro-6, 7-dimethoxyquinoline, 4-nitrophenol, potassium iodide, cesium carbonate and solvent in the step (4) is 0.2 to 0.8 mmol/0.02 to 0.08 mmol/1 to 3 mmol/3 to 8mL;
the solvent is toluene;
the reaction temperature is 120-160 ℃ and the reaction time is 10-15 h;
the dosage ratio of the compound 7, the water, the ethanol, the reduced iron powder and the ammonium chloride in the step (5) is 0.5-1.5 mmol:3-7 mL:8-12 mL:8-13 mmol:1-3 mmol;
the reaction temperature is 40-80 ℃ and the reaction time is 2-8 h.
6. The process according to claim 2, 3 or 5, wherein the amount ratio of compound 8, compound 4, solvent, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine in step (6) is 0.05 to 0.2mmol:0.1 to 0.3mmol:4 to 8mL:0.1 to 0.3mmol:0.1 to 0.3mmol:0.2 to 0.4mmol;
the solvent is dichloromethane;
the reaction time is 10-20 h.
7. Use of N- (4- (6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamides 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, for the prophylaxis or treatment of inflammation and diseases associated with inflammation.
8. The use according to claim 7, wherein the inflammation or inflammation-related disorder includes, but is not limited to, sepsis, acute lung injury, arthritis, proctitis, hepatitis, fatty liver, or chronic inflammatory disorder.
9. A pharmaceutical composition for preventing or treating inflammation and diseases associated with inflammation, which comprises the N- (4- (6, 7-dimethoxyquinolin-4-yl) oxy) phenyl) -6-oxo-1, 6-dihydropyridazine-3-carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 1, and further comprises a pharmaceutically acceptable adjuvant.
10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is in the form of a formulation comprising an injection, a tablet, a capsule, an aerosol, a suppository, a film, a drop pill, an ointment, a controlled or sustained release formulation and a nano-formulation.
CN202310874392.3A 2023-07-17 2023-07-17 N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition Pending CN116891455A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310874392.3A CN116891455A (en) 2023-07-17 2023-07-17 N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310874392.3A CN116891455A (en) 2023-07-17 2023-07-17 N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition

Publications (1)

Publication Number Publication Date
CN116891455A true CN116891455A (en) 2023-10-17

Family

ID=88313255

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310874392.3A Pending CN116891455A (en) 2023-07-17 2023-07-17 N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition

Country Status (1)

Country Link
CN (1) CN116891455A (en)

Similar Documents

Publication Publication Date Title
SU1248533A3 (en) Method of producing sulfamoyl-substituted derivatives of phenethylamine or hydrochloride thereof
CZ196A3 (en) Substituted benzamides, process of their preparation and pharmaceutical compositions containing thereof
JP5844354B2 (en) Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for the treatment of proliferative diseases
CN109467549B (en) Quinoline-substituted chalcone compound, preparation method and application thereof
WO2020177744A1 (en) Salicylic acid berberine-type alkaloid quaternary ammonium compound and use thereof for preparing medicines
CN111518031B (en) Hydroxamic acid-containing compound and preparation method and application thereof
CN114736214B (en) Sesquiterpene derivative, pharmaceutical composition thereof, and preparation method and application thereof
EP1330444B1 (en) Nitrogenous heterocyclic compounds and process for making them
US10617679B2 (en) Deuterated compounds and medical uses thereof
KR20170133493A (en) As the A2B antagonist, xanthine-substituted alkynyl carbamate / reverse carbamate
US4970301A (en) 2-(piperazinyl)-2-oxoethylene-substituted flavonoid compounds
EP3006432B1 (en) 2,3-butanediamide epoxide compound and preparation method and use thereof
CN111943906B (en) Amidine derivatives, preparation method, pharmaceutical composition and application thereof
CN116891455A (en) N-substituted phenyl-pyridazinone-3-formamide compound, preparation method and application thereof, and pharmaceutical composition
JPH0278675A (en) Benzofuranyl acetic acid derivative, its production, viscous liquid controller and antihistamines
EP3022177B1 (en) Indole-3-carbinol derivatives
EP3318257A1 (en) Drug for preventing or treating inflammatory bowel disease
CN113549046B (en) Bisbecklonin S derivative and preparation method and application thereof
CN116478050B (en) Chiral aryl propionic acid derivative, and pharmaceutical composition and application thereof
CN114940696B (en) Toosendanin derivative and application thereof in breast cancer treatment
CN112062732B (en) IDO inhibitor and composition, preparation method and application thereof
CN112480141A (en) Pyranocoumarin derivative and preparation method and application thereof
TW202411231A (en) Substituted purinone derivatives as ubiquitin-specific protease inhibitors
CA3169000A1 (en) Crystal of imidazopyridinone compound or salt thereof
CN114957260A (en) Baricitinib derivative and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination