技术领域Technical field
本发明涉及药物有机物技术领域，尤其涉及一种N-取代苯基-哒嗪酮-3-甲酰胺类化合物及其制备方法和应用及一种药物组合物。The present invention relates to the technical field of pharmaceutical organic matter, and in particular to an N-substituted phenyl-pyridazinone-3-carboxamide compound, its preparation method and application and a pharmaceutical composition.
背景技术Background technique
炎症(inflammation)是机体对于刺激的一种防御反应，通常情况下，炎症是有益的，是人体自动的防御反应，但炎症反应失调导致过度炎症时，机体会产生大量的炎性细胞因子而造成组织或细胞的破坏，严重影响人类生命健康。Inflammation is a defensive response of the body to stimulation. Normally, inflammation is beneficial and is the body's automatic defense response. However, when an imbalance in the inflammatory response leads to excessive inflammation, the body will produce a large amount of inflammatory cytokines and cause The destruction of tissues or cells seriously affects human life and health.
脓毒症(sepsis)是由细菌等病原微生物侵入机体引起的全身炎症反应综合征。除全身炎症反应综合征和原发感染病灶的表现外，重症患者还常有器官灌注不足的表现。脓毒症的病死率高达30～70％。近年来，尽管抗感染治疗和器官功能支持技术取得了长足的进步，但目前临床上仍缺少有效的治疗脓毒症的药物。Sepsis is a systemic inflammatory response syndrome caused by bacteria and other pathogenic microorganisms invading the body. In addition to manifestations of systemic inflammatory response syndrome and primary infection lesions, critically ill patients often also have symptoms of organ hypoperfusion. The mortality rate of sepsis is as high as 30 to 70%. Although anti-infective treatment and organ function support technologies have made great progress in recent years, there is still a lack of effective drugs to treat sepsis in the clinic.
临床和动物实验证实，脂多糖(LPS)可以激活多种下游促炎信号通路，并触发炎症因子的过度生成，如肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)，进而导致脓毒症。目前，糖皮质激素等多种药物对炎症风暴的阻断已被广泛探索，作为一种潜在的有希望的预防和治疗脓毒症的方法。然而，鉴于临床使用的药物因其低效和不良反应而对脓毒症患者没有显示出明显的治疗效果，仍然需要开发更有效和更安全的新型抗炎药来治疗脓毒症。因此抑制TNF-α和IL-6等炎症因子的释放成为了治疗脓毒症的重要手段。Clinical and animal experiments have confirmed that lipopolysaccharide (LPS) can activate a variety of downstream pro-inflammatory signaling pathways and trigger the overproduction of inflammatory factors, such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). This leads to sepsis. Currently, the blocking of inflammatory storm by various drugs such as glucocorticoids has been widely explored as a potentially promising approach to prevent and treat sepsis. However, given that clinically used drugs have not shown significant therapeutic effects on sepsis patients due to their low efficacy and adverse effects, there is still a need to develop more effective and safer new anti-inflammatory drugs to treat sepsis. Therefore, inhibiting the release of inflammatory factors such as TNF-α and IL-6 has become an important means to treat sepsis.
发明内容Contents of the invention
本发明的目的在于提供一种N-取代苯基-哒嗪酮-3-甲酰胺类化合物及其制备方法和应用及一种药物组合物，以弥补现有技术的不足。The object of the present invention is to provide an N-substituted phenyl-pyridazinone-3-carboxamide compound, its preparation method and application and a pharmaceutical composition to make up for the shortcomings of the existing technology.
为了实现上述发明目的，本发明提供以下技术方案：In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:
本发明提供了一种N-(4-(6,7-二甲氧基喹啉-4-基)氧基)苯基)-6-氧代-1,6-二氢哒嗪-3-甲酰胺类化合物，包含如下结构式中的一种：The invention provides a kind of N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridazine-3- Formamide compounds include one of the following structural formulas:
本发明还提供了所述N-(4-(6,7-二甲氧基喹啉-4-基)氧基)苯基)-6-氧代-1,6-二氢哒嗪-3-甲酰胺类化合物的制备方法，包含如下步骤：The invention also provides the N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridazine-3 -The preparation method of formamide compounds includes the following steps:
(1)将水、乙醇、乙酰乙酸乙酯和醋酸钠混合后降温，得到体系1；(1) Mix water, ethanol, ethyl acetoacetate and sodium acetate and then cool down to obtain system 1;
调节苯胺类化合物水溶液的pH值至1～2后降温，然后与亚硝酸钠溶液混合，得到体系2；Adjust the pH value of the aniline compound aqueous solution to 1 to 2, then lower the temperature, and then mix it with the sodium nitrite solution to obtain system 2;
将体系2和体系1混合后进行反应，生成化合物2；System 2 and system 1 are mixed and reacted to generate compound 2;
所述苯胺类化合物包含苯胺、对氟苯胺、对甲基苯胺、对甲氧基苯胺、对乙基苯胺或2-乙基苯胺；The aniline compound includes aniline, p-fluoroaniline, p-methylaniline, p-methoxyaniline, p-ethylaniline or 2-ethylaniline;
(2)将所得化合物2、溶剂、乙氧羰基亚甲基三苯基膦和二乙胺混合后反应，生成化合物3；(2) Mix the obtained compound 2, solvent, ethoxycarbonylmethylenetriphenylphosphine and diethylamine and react to generate compound 3;
(3)将所得化合物3、乙醇、1,4-二氧六环和碱液混合后反应，得到反应液；(3) The obtained compound 3, ethanol, 1,4-dioxane and alkali are mixed and reacted to obtain a reaction liquid;
调节所述反应液的pH值至2～3，生成化合物4；Adjust the pH value of the reaction solution to 2-3 to generate compound 4;
(4)将4-氯6,7-二甲氧基喹啉、4-硝基苯酚、碘化钾、碳酸铯和溶剂混合后进行反应，生成化合物7；(4) 4-chloro6,7-dimethoxyquinoline, 4-nitrophenol, potassium iodide, cesium carbonate and a solvent are mixed and reacted to generate compound 7;
(5)将化合物7、水、乙醇、还原性铁粉和氯化铵混合以后进行反应，生成4-[(6,7-二甲氧基喹啉-4-基)氧基]苯胺，记为化合物8；(5) Mix compound 7, water, ethanol, reducing iron powder and ammonium chloride and then react to generate 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline, recorded For compound 8;
(6)将化合物8、化合物4、溶剂、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑和三乙胺混合后进行酸胺缩合反应，生成N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-4-氧代-1-苯基-1,4-二氢喹啉-3-甲酰胺类化合物；(6) Mix compound 8, compound 4, solvent, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine. Acid-amine condensation reaction produces N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-di Hydroquinoline-3-carboxamide compounds;
步骤(1)～(3)制备化合物4和步骤(4)～(5)制备化合物8没有先后顺序的限定。The order of steps (1) to (3) to prepare compound 4 and steps (4) to (5) to prepare compound 8 is not limited.
优选的，步骤(1)中水、乙醇、乙酰乙酸乙酯和醋酸钠的用量比为1mL：2～6mL：2～3mL：1～2g；Preferably, the usage ratio of water, ethanol, ethyl acetoacetate and sodium acetate in step (1) is 1 mL: 2-6 mL: 2-3 mL: 1-2 g;
所述降温独立的为降至-2～-6℃；The independent cooling is to -2~-6°C;
使用浓盐酸调节pH值；Use concentrated hydrochloric acid to adjust pH;
苯胺类化合物与亚硝酸钠溶液的用量比为1.5～2g：15～25mL，亚硝酸钠溶液的质量浓度为45～55％；The dosage ratio of aniline compounds and sodium nitrite solution is 1.5~2g:15~25mL, and the mass concentration of sodium nitrite solution is 45~55%;
苯胺类化合物与乙酰乙酸乙酯的用量比为1.5～2g：2～3mL；The dosage ratio of aniline compounds and ethyl acetoacetate is 1.5~2g:2~3mL;
苯胺类化合物水溶液中苯胺类化合物和水的体积比为1.5～2.5:1；The volume ratio of aniline compounds and water in the aqueous solution of aniline compounds is 1.5 to 2.5:1;
反应的温度为-5～5℃，时间为1～5h。The reaction temperature is -5~5℃, and the reaction time is 1~5h.
优选的，步骤(2)中溶剂包含二甲基亚砜；Preferably, the solvent in step (2) contains dimethyl sulfoxide;
苯胺类化合物、溶剂、乙氧羰基亚甲基三苯基膦和二乙胺的用量比为1.5～2g：3～5mL：2～3g：0.05～0.1mL；The dosage ratio of aniline compounds, solvents, ethoxycarbonylmethylene triphenylphosphine and diethylamine is 1.5~2g: 3~5mL: 2~3g: 0.05~0.1mL;
反应的温度为80～90℃，时间为2～8h；The reaction temperature is 80~90℃, and the reaction time is 2~8h;
步骤(3)中碱液的质量浓度为5～15％；The mass concentration of the alkali solution in step (3) is 5 to 15%;
碱液包含氢氧化钠溶液或氢氧化钾溶液；Lye contains sodium hydroxide solution or potassium hydroxide solution;
苯胺类化合物、乙醇、1,4-二氧六环和碱液的用量比为1.5～2g：15～25mL：15～25mL：4～5mL；The dosage ratio of aniline compounds, ethanol, 1,4-dioxane and alkali solution is 1.5~2g: 15~25mL: 15~25mL: 4~5mL;
反应的时间为0.5～2h；The reaction time is 0.5~2h;
使用浓盐酸调节pH值。Use concentrated hydrochloric acid to adjust pH.
优选的，所述步骤(4)中4-氯6,7-二甲氧基喹啉、4-硝基苯酚、碘化钾、碳酸铯和溶剂的用量比为0.2～0.8mmol:0.2～0.8mmol:0.02～0.08mmol:1～3mmol:3～8mL；Preferably, the usage ratio of 4-chloro6,7-dimethoxyquinoline, 4-nitrophenol, potassium iodide, cesium carbonate and solvent in step (4) is 0.2~0.8mmol:0.2~0.8mmol: 0.02～0.08mmol:1～3mmol:3～8mL;
所述溶剂为甲苯；The solvent is toluene;
所述反应的温度为120～160℃，时间为10～15h；The temperature of the reaction is 120~160°C, and the time is 10~15h;
所述步骤(5)中化合物7、水、乙醇、还原性铁粉和氯化铵的用量比为0.5～1.5mmol:3～7mL:8～12mL:8～13mmol:1～3mmol；In the step (5), the dosage ratio of compound 7, water, ethanol, reducing iron powder and ammonium chloride is 0.5~1.5mmol:3~7mL:8~12mL:8~13mmol:1~3mmol;
所述反应的温度为40～80℃，时间为2～8h。The temperature of the reaction is 40-80°C, and the reaction time is 2-8 hours.
优选的，所述步骤(6)中化合物8、化合物4、溶剂、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑和三乙胺的用量比为0.05～0.2mmol:0.1～0.3mmol:4～8mL:0.1～0.3mmol:0.1～0.3mmol:0.2～0.4mmol；Preferably, in the step (6), compound 8, compound 4, solvent, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole and The dosage ratio of triethylamine is 0.05~0.2mmol:0.1~0.3mmol:4~8mL:0.1~0.3mmol:0.1~0.3mmol:0.2~0.4mmol;
所述溶剂为二氯甲烷；The solvent is methylene chloride;
反应时间为10～20h。The reaction time is 10~20h.
本发明还提供了所述N-(4-(6,7-二甲氧基喹啉-4-基)氧基)苯基)-6-氧代-1,6-二氢哒嗪-3-甲酰胺类化合物在制备抗炎药物中的应用，所述抗炎药物通过抑制巨噬细胞释放炎症因子的释放而治疗炎症，所述抗炎药物用于预防或者治疗炎症以及与炎症相关的疾病。The invention also provides the N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridazine-3 - The use of carboxamide compounds in the preparation of anti-inflammatory drugs, which treat inflammation by inhibiting the release of inflammatory factors from macrophages, and the anti-inflammatory drugs are used to prevent or treat inflammation and inflammation-related diseases .
优选的，所述炎症或与炎症相关疾病包括但不限于脓毒症、急性肺损伤、关节炎、结直肠炎、肝炎、脂肪肝或慢性炎症性疾病。Preferably, the inflammation or inflammation-related diseases include but are not limited to sepsis, acute lung injury, arthritis, colorectitis, hepatitis, fatty liver or chronic inflammatory diseases.
本发明还提供了一种用于预防或治疗炎症以及与炎症相关疾病的药物组合物，包含所述N-(4-(6,7-二甲氧基喹啉-4-基)氧基)苯基)-6-氧代-1,6-二氢哒嗪-3-甲酰胺类化合物或其可药用盐，还包含药用辅料。The present invention also provides a pharmaceutical composition for preventing or treating inflammation and inflammation-related diseases, comprising the N-(4-(6,7-dimethoxyquinolin-4-yl)oxy) Phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide compounds or pharmaceutically acceptable salts thereof, and also include pharmaceutical excipients.
优选的，所述药物组合物的制剂形式包含注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂和纳米制剂。Preferably, the preparation form of the pharmaceutical composition includes injections, tablets, capsules, aerosols, suppositories, films, pills, ointments, controlled-release or sustained-release agents and nano-preparations.
本发明提供的N-(4-(6,7-二甲氧基喹啉-4-基)氧基)苯基)-6-氧代-1,6-二氢哒嗪-3-甲酰胺类化合物用于治疗脓毒症、急性肺损伤，可制备的制剂形式包含注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂和纳米制剂。N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide provided by the invention Compounds are used to treat sepsis and acute lung injury. The preparation forms that can be prepared include injections, tablets, capsules, aerosols, suppositories, films, pills, ointments, controlled-release or sustained-release formulations and nanoparticles. preparation.
附图说明Description of the drawings
图1为化合物抑制LPS刺激巨噬细胞释放IL-6和TNF-α的量效关系；Figure 1 shows the dose-effect relationship of compounds inhibiting the release of IL-6 and TNF-α from macrophages stimulated by LPS;
图2为优选化合物(J27)提高脓毒血症小鼠生存率和缓解小鼠体重下降速率图。Figure 2 is a graph showing that the preferred compound (J27) improves the survival rate of septic mice and alleviates the weight loss rate of mice.
具体实施方式Detailed ways
本发明提供了所述N-(4-(6,7-二甲氧基喹啉-4-基)氧基)苯基)-6-氧代-1,6-二氢哒嗪-3-甲酰胺类化合物的制备方法，包含如下步骤：The invention provides the N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-6-oxo-1,6-dihydropyridazine-3- The preparation method of formamide compounds includes the following steps:
(1)将水、乙醇、乙酰乙酸乙酯和醋酸钠混合后降温，得到体系1；(1) Mix water, ethanol, ethyl acetoacetate and sodium acetate and then cool down to obtain system 1;
调节苯胺类化合物水溶液的pH值至1～2后降温，然后与亚硝酸钠溶液混合，得到体系2；Adjust the pH value of the aniline compound aqueous solution to 1 to 2, then lower the temperature, and then mix it with the sodium nitrite solution to obtain system 2;
将体系2和体系1混合后进行反应，生成化合物2；System 2 and system 1 are mixed and reacted to generate compound 2;
所述苯胺类化合物包含苯胺、对氟苯胺、对甲基苯胺、对甲氧基苯胺、对乙基苯胺或2-乙基苯胺；The aniline compound includes aniline, p-fluoroaniline, p-methylaniline, p-methoxyaniline, p-ethylaniline or 2-ethylaniline;
(2)将所得化合物2、溶剂、乙氧羰基亚甲基三苯基膦和二乙胺混合后反应，生成化合物3；(2) Mix the obtained compound 2, solvent, ethoxycarbonylmethylenetriphenylphosphine and diethylamine and react to generate compound 3;
(3)将所得化合物3、乙醇、1,4-二氧六环和碱液混合后反应，得到反应液；(3) The obtained compound 3, ethanol, 1,4-dioxane and alkali are mixed and reacted to obtain a reaction liquid;
调节所述反应液的pH值至2～3，生成化合物4；Adjust the pH value of the reaction solution to 2-3 to generate compound 4;
(4)将4-氯6,7-二甲氧基喹啉、4-硝基苯酚、碘化钾、碳酸铯和溶剂混合后进行反应，生成化合物7；(4) 4-chloro6,7-dimethoxyquinoline, 4-nitrophenol, potassium iodide, cesium carbonate and a solvent are mixed and reacted to generate compound 7;
(5)将化合物7、水、乙醇、还原性铁粉和氯化铵混合以后进行反应，生成4-[(6,7-二甲氧基喹啉-4-基)氧基]苯胺，记为化合物8；(5) Mix compound 7, water, ethanol, reducing iron powder and ammonium chloride and then react to generate 4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline, recorded For compound 8;
(6)将化合物8、化合物4、溶剂、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑和三乙胺混合后进行酸胺缩合反应，生成N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-4-氧代-1-苯基-1,4-二氢喹啉-3-甲酰胺类化合物；(6) Mix compound 8, compound 4, solvent, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine. Acid-amine condensation reaction produces N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-oxo-1-phenyl-1,4-di Hydroquinoline-3-carboxamide compounds;
步骤(1)～(3)制备化合物4和步骤(4)～(5)制备化合物8没有先后顺序的限定。The order of steps (1) to (3) to prepare compound 4 and steps (4) to (5) to prepare compound 8 is not limited.
在本发明中，步骤(1)中水、乙醇、乙酰乙酸乙酯和醋酸钠的用量比为1mL：2～6mL：2～3mL：1～2g，优选为1mL：4～5mL：2.5～2.8mL：1.5～1.8g；In the present invention, the usage ratio of water, ethanol, ethyl acetoacetate and sodium acetate in step (1) is 1mL: 2-6mL: 2-3mL: 1-2g, preferably 1mL: 4-5mL: 2.5-2.8 mL: 1.5～1.8g;
所述降温独立的为降至-2～-6℃，优选为-4～-5℃；The temperature reduction is independently -2 to -6°C, preferably -4 to -5°C;
使用浓盐酸调节pH值；Use concentrated hydrochloric acid to adjust pH;
苯胺类化合物与亚硝酸钠溶液的用量比为1.5～2g：15～25mL，优选为1.6～1.8g：18～20mL；亚硝酸钠溶液的质量浓度为45～55％，优选为48～50％；The dosage ratio of aniline compounds and sodium nitrite solution is 1.5~2g:15~25mL, preferably 1.6~1.8g:18~20mL; the mass concentration of sodium nitrite solution is 45~55%, preferably 48~50% ;
苯胺类化合物与乙酰乙酸乙酯的用量比为1.5～2g：2～3mL，优选为1.8～1.9g：2.3～2.5mL；The dosage ratio of aniline compounds and ethyl acetoacetate is 1.5-2g:2-3mL, preferably 1.8-1.9g:2.3-2.5mL;
苯胺类化合物水溶液中苯胺类化合物和水的体积比为1.5～2.5:1，优选为2:1；The volume ratio of the aniline compound and water in the aqueous solution of the aniline compound is 1.5 to 2.5:1, preferably 2:1;
反应的温度为-5～5℃，优选为-4～4℃，进一步优选为-3～2℃，更进一步优选为-1～0℃；时间为1～5h，优选为2～3h。The temperature of the reaction is -5~5°C, preferably -4~4°C, more preferably -3~2°C, even more preferably -1~0°C; the time is 1~5h, preferably 2~3h.
在本发明中，步骤(2)中溶剂包含二甲基亚砜；In the present invention, the solvent in step (2) includes dimethyl sulfoxide;
苯胺类化合物、溶剂、乙氧羰基亚甲基三苯基膦和二乙胺的用量比为1.5～2g：3～5mL：2～3g：0.05～0.1mL，优选为1.6～1.8g：4mL：2.3～2.6g：0.06～0.08mL；The usage ratio of aniline compounds, solvents, ethoxycarbonylmethylene triphenylphosphine and diethylamine is 1.5-2g: 3-5mL: 2-3g: 0.05-0.1mL, preferably 1.6-1.8g: 4mL: 2.3～2.6g: 0.06～0.08mL;
反应的温度为80～90℃，优选为82～88℃，进一步优选为85～86℃；时间为2～8h，优选为4～6h；The temperature of the reaction is 80-90°C, preferably 82-88°C, and more preferably 85-86°C; the time is 2-8h, preferably 4-6h;
步骤(3)中碱液的质量浓度为5～15％，优选为8～12％，进一步优选为9～10％；碱液包含氢氧化钠溶液或氢氧化钾溶液；The mass concentration of the alkali solution in step (3) is 5 to 15%, preferably 8 to 12%, and more preferably 9 to 10%; the alkali solution contains sodium hydroxide solution or potassium hydroxide solution;
苯胺类化合物、乙醇、1,4-二氧六环和碱液的用量比为1.5～2g：15～25mL：15～25mL：4～5mL，优选为1.6～1.8g：18～20mL：18～20mL：4.5mL；The dosage ratio of aniline compounds, ethanol, 1,4-dioxane and alkali is 1.5~2g: 15~25mL: 15~25mL: 4~5mL, preferably 1.6~1.8g: 18~20mL: 18~ 20mL: 4.5mL;
反应的时间为0.5～2h，优选为1～1.5h；The reaction time is 0.5 to 2h, preferably 1 to 1.5h;
使用浓盐酸调节pH值。Use concentrated hydrochloric acid to adjust pH.
在本发明中，所述步骤(4)中4-氯6,7-二甲氧基喹啉、4-硝基苯酚、碘化钾、碳酸铯和溶剂的用量比为0.2～0.8mmol:0.2～0.8mmol:0.02～0.08mmol:1～3mmol:3～8mL，优选为0.4～0.6mmol:0.4～0.6mmol:0.04～0.05mmol:1.5～2mmol:5～6mL；In the present invention, the usage ratio of 4-chloro6,7-dimethoxyquinoline, 4-nitrophenol, potassium iodide, cesium carbonate and solvent in step (4) is 0.2~0.8mmol:0.2~0.8 mmol: 0.02～0.08mmol: 1～3mmol: 3～8mL, preferably 0.4～0.6mmol: 0.4～0.6mmol: 0.04～0.05mmol: 1.5～2mmol: 5～6mL;
所述溶剂为甲苯；The solvent is toluene;
所述反应的温度为120～160℃，优选为130～150℃，进一步优选为140～145℃；时间为10～15h，优选为12～13h；The temperature of the reaction is 120-160°C, preferably 130-150°C, and further preferably 140-145°C; the time is 10-15h, preferably 12-13h;
所述步骤(5)中化合物7、水、乙醇、还原性铁粉和氯化铵的用量比为0.5～1.5mmol:3～7mL:8～12mL:8～13mmol:1～3mmol，优选为0.8～1.2mmol:4～6mL:9～10mL:10～11mmol:2～2.3mmol；In the step (5), the usage ratio of compound 7, water, ethanol, reducing iron powder and ammonium chloride is 0.5~1.5mmol:3~7mL:8~12mL:8~13mmol:1~3mmol, preferably 0.8 ～1.2mmol: 4～6mL: 9～10mL: 10～11mmol: 2～2.3mmol;
所述反应的温度为40～80℃，优选为50～70℃，进一步优选为55～60℃；时间为2～8h，优选为4～6h。The temperature of the reaction is 40-80°C, preferably 50-70°C, more preferably 55-60°C; the time is 2-8h, preferably 4-6h.
在本发明中，所述步骤(6)中化合物8、化合物4、溶剂、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、1-羟基苯并三唑和三乙胺的用量比为0.05～0.2mmol:0.1～0.3mmol:4～8mL:0.1～0.3mmol:0.1～0.3mmol:0.2～0.4mmol，优选为0.1～0.1.5mmol:0.18～0.23mmol:6～7mL:0.15～0.2mmol:0.2～0.23mmol:0.3～0.34mmol；In the present invention, in step (6), compound 8, compound 4, solvent, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotris The usage ratio of azole and triethylamine is 0.05~0.2mmol:0.1~0.3mmol:4~8mL:0.1~0.3mmol:0.1~0.3mmol:0.2~0.4mmol, preferably 0.1~0.1.5mmol:0.18~0.23mmol :6～7mL:0.15～0.2mmol:0.2～0.23mmol:0.3～0.34mmol;
所述溶剂为二氯甲烷；The solvent is methylene chloride;
反应时间为10～20h，优选为14～17h。The reaction time is 10 to 20 hours, preferably 14 to 17 hours.
下面结合实施例对本发明提供的技术方案进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。The technical solutions provided by the present invention will be described in detail below with reference to the examples, but they should not be understood as limiting the protection scope of the present invention.
本发明各实施例的制备路线如下所示：The preparation routes of each embodiment of the present invention are as follows:
实施例1Example 1
4-甲基-6-氧代-1-苯基-1,6-二氢哒嗪-3-羧酸(4a)4-Methyl-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid (4a)
步骤一：在50mL圆底烧瓶中依次加入水(1mL)、乙醇(4mL)、乙酰乙酸乙酯(2.31mL，0.0177mol)和无水醋酸钠(1.59g，0.0194mol)，混合均匀后在室温下搅拌1h，然后通过盐冰浴将体系温度降至-4℃，备用。然后将苯胺1a(1.79g，0.019mol)充分溶解在去离子水中(苯胺和水的体积比为2:1)，随后加入浓盐酸将体系PH值调至1-2，后转至盐冰浴将温度降至-4℃以下，随后缓慢滴加50％亚硝酸钠溶液(20mL)，在低温条件下搅拌30min，形成体系2。30min后，将体系2加入体系1中，此过程会有大量黄色固体析出，维持0℃反应2h，随后抽滤、洗涤，烘干后得到2a。将制备得到的2a在250mL圆底烧瓶中加入4mLDMSO充分溶解，随后加入乙氧羰基亚甲基三苯基膦(CBMTPP)(2.23g，0.0064mol)和二乙胺(Et2NH)(0.0669mL，0.0006mol)，在85℃下反应4h。反应完成后将反应物冷却至室温倒入冰水中，用二氯甲烷萃取，饱和食盐水洗涤，最后通过柱层析分离得到3a。最后将得到的3a与乙醇(20mL)和1,4-二氧六环(20mL)在100mL圆底烧瓶中搅匀，随后向混合液中加入10％NaOH溶液5mL，室温搅拌1h，反应完毕后，往体系中加入浓盐酸将PH值调至2-3，此过程会有淡黄色固体析出，抽滤、洗涤及烘干后得到4-甲基-6-氧代-1-苯基-1,6-二氢哒嗪-3-羧酸4a。Step 1: Add water (1 mL), ethanol (4 mL), ethyl acetoacetate (2.31 mL, 0.0177 mol) and anhydrous sodium acetate (1.59 g, 0.0194 mol) into a 50 mL round-bottomed flask in sequence, mix evenly and place at room temperature. Stir for 1 hour, then lower the system temperature to -4°C in a salt ice bath and set aside. Then fully dissolve aniline 1a (1.79g, 0.019mol) in deionized water (the volume ratio of aniline and water is 2:1), then add concentrated hydrochloric acid to adjust the pH value of the system to 1-2, and then transfer to a salt ice bath Lower the temperature to below -4°C, then slowly add 50% sodium nitrite solution (20 mL) dropwise, and stir at low temperature for 30 minutes to form system 2. After 30 minutes, add system 2 to system 1. This process will produce a large amount of A yellow solid precipitated, and the reaction was maintained at 0°C for 2 hours, followed by suction filtration, washing, and drying to obtain 2a. Add 4 mL of DMSO to the prepared 2a in a 250 mL round-bottomed flask to fully dissolve it, and then add carbonyl ethoxymethylene triphenylphosphine (CBMTPP) (2.23 g, 0.0064 mol) and diethylamine (Et2 NH) (0.0669 mL) , 0.0006mol), reacted at 85°C for 4h. After the reaction is completed, the reactant is cooled to room temperature and poured into ice water, extracted with dichloromethane, washed with saturated brine, and finally separated by column chromatography to obtain 3a. Finally, mix the obtained 3a with ethanol (20 mL) and 1,4-dioxane (20 mL) in a 100 mL round-bottom flask, then add 5 mL of 10% NaOH solution to the mixture, and stir at room temperature for 1 h. After the reaction is completed , add concentrated hydrochloric acid to the system to adjust the pH value to 2-3. During this process, a light yellow solid will precipitate. After filtration, washing and drying, 4-methyl-6-oxo-1-phenyl-1 is obtained. ,6-dihydropyridazine-3-carboxylic acid 4a.
White power；yield:50.1％.1H NMR(400MHz,CDCl3)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).White power; yield: 50.1%.1 H NMR (400MHz, CDCl3 ) 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).
按照步骤一的方法，以对氟苯胺为原料，制得1-(4-氟苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸4b。According to the method of step 1, using p-fluoroaniline as raw material, 1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid 4b was prepared.
Yellowpower；yield:56.5％.1H NMR(400MHz,CDCl3)δ7.53(dd,J＝8.0,Yellowpower; yield: 56.5%.1 H NMR (400MHz, CDCl3 ) δ7.53 (dd, J=8.0,
4.9Hz,2H),7.11(t,J＝8.2Hz,2H),6.81(s,1H),2.46(s,3H).4.9Hz,2H),7.11(t,J＝8.2Hz,2H),6.81(s,1H),2.46(s,3H).
按照步骤一的方法，以对甲基苯胺为原料，制得4-甲基-6-氧代-1-(对甲苯)-1,6-二氢哒嗪-3-羧酸4c。According to the method of step 1, using p-methylaniline as raw material, 4-methyl-6-oxo-1-(p-toluene)-1,6-dihydropyridazine-3-carboxylic acid 4c was prepared.
Yellow power；yield:52.3％.1H 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).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).
按照步骤一的方法，以对甲氧基为原料，制得1-(4-甲氧基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸4d。According to the method of step 1, use p-methoxy as raw material to prepare 1-(4-methoxyphenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid Acid 4d.
Yellow power；yield:59.8％.1H NMR(400MHz,CDCl3)δ7.01(d,J＝9.0Yellow power; yield: 59.8%.1 H NMR (400MHz, CDCl3 ) 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).Hz, 2H), 6.49 (d, J = 9.0Hz, 2H), 6.37 (s, 1H), 3.35 (s, 3H), 2.03 (s, 3H).
按照步骤一的方法，以对乙基苯胺为原料，制得1-(4-乙基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸4e。According to the method of step 1, use p-ethylaniline as raw material to prepare 1-(4-ethylphenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid 4e.
Yellow power；yield:55.3％.1H NMR(400MHz,CDCl3)δ7.42(d,J＝8.3Yellow power; yield: 55.3%.1 H NMR (400MHz, CDCl3 ) 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).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).
按照步骤一的方法，以2-乙基苯胺为原料，制得1-(2-基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸4f。According to the method of step 1, use 2-ethylaniline as raw material to prepare 1-(2-ylphenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid 4f.
Yellow power；yield:58.1％.1H NMR(400MHz,CDCl3)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).Yellow power; yield: 58.1%.1 H NMR (400MHz, CDCl3 ) 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).
步骤二：在50mL的圆底烧瓶中将4-氯-6,7-二甲氧基喹啉5(100mg，0.448mmol)，4-硝基苯酚6(62.33mg，0.5mmol)，碘化钾(7.44mg,0.045mmol)和碳酸铯(292.21mg，2mmol)在5mL的甲苯溶液中溶解,在140℃下反应12h。通过TLC监测反应完成时，通过用石油醚搅拌冲洗得到淡黄色固体7，将7(110mg,1mmol)溶于水(5mL)和乙醇(10mL)的混合溶液中，然后将还原性铁粉(560mg,10mmol)和氯化铵(130mg,2mmol)加入溶液中，在65℃下反应4h。用TLC监测反应完成后，通过过滤去除无机残留物，滤液真空干燥得到粗产物。最后用柱层析法分离(DCM:CH3OH＝30:1)得到8。即为目标化合物4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺。Step 2: In a 50 mL round bottom flask, combine 4-chloro-6,7-dimethoxyquinoline 5 (100 mg, 0.448 mmol), 4-nitrophenol 6 (62.33 mg, 0.5 mmol), potassium iodide (7.44 mg, 0.045mmol) and cesium carbonate (292.21mg, 2mmol) were dissolved in 5mL of toluene solution and reacted at 140°C for 12h. When the reaction was completed by monitoring TLC, light yellow solid 7 was obtained by stirring and washing with petroleum ether. Dissolve 7 (110 mg, 1 mmol) in a mixed solution of water (5 mL) and ethanol (10 mL), and then add reducing iron powder (560 mg ,10mmol) and ammonium chloride (130mg, 2mmol) were added to the solution and reacted at 65°C for 4h. After the completion of the reaction was monitored by TLC, the inorganic residue was removed by filtration, and the filtrate was dried under vacuum to obtain the crude product. Finally, column chromatography was used to separate (DCM:CH3 OH = 30:1) to obtain 8. That is, the target compound 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline.
White power；yield:64.7％.1H 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).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).
步骤三：将4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺(50mg,0.169mmol)和4-甲基-6-氧代-1-苯基-1,6-二氢哒嗪-3-羧酸(46.63mg,0.2mmol)溶于超干二氯甲烷中(6mL)，加入EDCI(38.84mg,0.2mmol)、HOBT(27.4mg,0.21mmol)和TEA(36.81mL，0.3mmol)，在室温下进行酸胺缩合反应13h。用TLC监测反应完成后，蒸干二氯甲烷后用DCM:MeOH(60：1)混合溶剂萃取，萃取完后用无水硫酸镁干燥，过滤后蒸干，再采用柱层析分离(DCM:MeOH＝10：1)得到J25，即N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-4-甲基-6-氧代-1-苯基-1,6-二氢哒嗪-3-甲酰胺。Step 3: Combine 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (50mg, 0.169mmol) and 4-methyl-6-oxo-1-phenyl-1 , 6-dihydropyridazine-3-carboxylic acid (46.63mg, 0.2mmol) was dissolved in ultra-dry dichloromethane (6mL), and EDCI (38.84mg, 0.2mmol), HOBT (27.4mg, 0.21mmol) and TEA (36.81 mL, 0.3 mmol) was used for acid amine condensation reaction at room temperature for 13 h. After monitoring the reaction with TLC, the methylene chloride was evaporated to dryness and extracted with a mixed solvent of DCM:MeOH (60:1). After extraction, it was dried with anhydrous magnesium sulfate, filtered and evaporated to dryness, and then separated by column chromatography (DCM: MeOH=10:1) gives J25, which is N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-methyl-6-oxo-1 -Phenyl-1,6-dihydropyridazine-3-carboxamide.
N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-4-甲基-6-氧代-1-苯基-1,6-二氢哒嗪-3-甲酰胺(J25)N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-methyl-6-oxo-1-phenyl-1,6-dihydro Pyridazine-3-carboxamide (J25)
White solid；yiled:69.3％；m.p.:124.7–126.7℃.1H NMR(400MHz,CDCl3)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).13CNMR(100MHz,CDCl3)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]+.White solid; yield: 69.3%; mp: 124.7–126.7℃.1 H NMR (400MHz, CDCl3 ) δ9.02 (s, 1H), 8.46 (d, J = 5.0 Hz, 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 CNMR(100MHz,CDCl3 )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]+.
按照步骤三的方法，以4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺和1-(4-氟苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸为原料，制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-1-(4-氟苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-甲酰胺(J26)。According to the method of step three, use 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline and 1-(4-fluorophenyl)-4-methyl-6-oxo -1,6-dihydropyridazine-3-carboxylic acid is used as raw material to prepare N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-1- (4-Fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (J26).
White solid；yield 87.5％；m.p.:126.7-128.0℃；1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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]+.White solid; yield 87.5%; mp: 126.7-128.0℃;1 H NMR (400MHz, CDCl3 ) 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, CDCl3 )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]+ .
按照步骤三的方法，以4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺和4-甲基-6-氧代-1-(对甲苯)-1,6-二氢哒嗪-3-羧酸为原料，制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-4-甲基-6-氧代-1-(对甲苯基)-1,6-二氢哒嗪-3-甲酰胺(J27)。According to the method of step three, use 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline and 4-methyl-6-oxo-1-(p-toluene)-1, Using 6-dihydropyridazine-3-carboxylic acid as raw material, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-4-methyl- 6-Oxo-1-(p-tolyl)-1,6-dihydropyridazine-3-carboxamide (J27).
White solid；yield 85.2％；m.p.:150.9-151.3℃；1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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]+.White solid; yield 85.2%; mp: 150.9-151.3℃;1 H NMR (400MHz, CDCl3 ) 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, CDCl3 ) δ160.70,160.63,159.55,152.90,150.93,149.58,148.80,146.87,144.47,139.17,138.24,137.99,134.65,130.83,1 29.70(×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]+ .
按照步骤三的方法，以4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺和1-(4-甲氧基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸为原料，制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-1-(4-甲氧基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-甲酰胺(J28)。According to the method of step three, use 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline and 1-(4-methoxyphenyl)-4-methyl-6- Using oxo-1,6-dihydropyridazine-3-carboxylic acid as raw material, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)- 1-(4-methoxyphenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (J28).
White solid；yield 88.6％；m.p.:199.1-200.6℃；1H NMR(400MHz,CDCl3)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).13CNMR(100MHz,CDCl3)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]+.White solid; yield 88.6%; mp: 199.1-200.6℃;1 H NMR (400MHz, CDCl3 ) 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, CDCl3 )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]+ .
按照步骤三的方法，以4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺和1-(4-乙基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸为原料，制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-1-(4-乙基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-甲酰胺(J29)。According to the method of step three, use 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline and 1-(4-ethylphenyl)-4-methyl-6-oxo Using 1,6-dihydropyridazine-3-carboxylic acid as raw material, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-1 -(4-ethylphenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (J29).
White solid；yield 70.9％；m.p.:145.0-146.1℃；1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,CDCl3)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]+.White solid; yield 70.9%; mp: 145.0-146.1℃;1 H NMR (400MHz, CDCl3 ) 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, CDCl3 ) δ 160.75, 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]+ .
按照步骤三的方法，以4-((6,7-二甲氧基喹啉-4-基)氧基)苯胺和1-(2-基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-羧酸为原料，制得N-(4-((6,7-二甲氧基喹啉-4-基)氧基)苯基)-1-(2-乙基苯基)-4-甲基-6-氧代-1,6-二氢哒嗪-3-甲酰胺(J30)。According to the method of step three, use 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline and 1-(2-ylphenyl)-4-methyl-6-oxo -1,6-dihydropyridazine-3-carboxylic acid is used as raw material to prepare N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-1- (2-ethylphenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (J30).
White solid；yield 81.3％；m.p.:248.9-250.7℃；1H NMR(400MHz,CDCl3)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).13C NMR(100MHz,DMSO-d6)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]+.White solid; yield 81.3%; mp: 248.9-250.7℃;1 H NMR (400MHz, CDCl3 ) 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-d6 ) 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]+ .
本发明产物的药理研究Pharmacological research on the product of the present invention
实施例化合物抑制LPS刺激巨噬细胞(J774A.1)释放IL-6和TNF-α的量效关系Dose-effect relationship of compounds in Examples inhibiting the release of IL-6 and TNF-α from macrophages (J774A.1) stimulated by LPS
当用LPS刺激时，J774A.1会分泌过多的促炎细胞因子(如IL-6和TNF-α)。本发明建立了酶联免疫吸附试验(ELISA)，以测试化合物在LPS刺激的J774A.1中对IL-6和TNF-α释放的抗炎活性。二甲基亚砜(DMSO)作为溶媒对照，用10μΜ化合物处理J774A.1巨噬细胞0.5小时后，用LPS(0.5μg/mL)刺激细胞并培养24小时。然后，用ELISA试剂盒测定的IL-6和TNF-α数量。化合物的细胞因子抑制活性如图1所示，结果表明，6种化合物可明显抑制LPS刺激巨噬细胞释放的IL-6和TNF-α，表现出明显的抗炎作用。When stimulated with LPS, J774A.1 secretes excessive amounts of pro-inflammatory cytokines (such as IL-6 and TNF-α). The present invention established an enzyme-linked immunosorbent assay (ELISA) to test the anti-inflammatory activity of compounds on IL-6 and TNF-α release in LPS-stimulated J774A.1. Dimethyl sulfoxide (DMSO) was used as a vehicle control. After treating J774A.1 macrophages with 10 μM compound for 0.5 hours, the cells were stimulated with LPS (0.5 μg/mL) and cultured for 24 hours. Then, use an ELISA kit to determine the amount of IL-6 and TNF-α. The cytokine inhibitory activities of the compounds are shown in Figure 1. The results show that the six compounds can significantly inhibit the release of IL-6 and TNF-α from macrophages stimulated by LPS, showing obvious anti-inflammatory effects.
实施优选化合物J27缓解脓毒症小鼠的生理学和病理学变化Implementation of preferred compound J27 to alleviate physiological and pathological changes in septic mice
本发明进一步探索了优选化合物J27对腹腔注射LPS诱导的C57/BL6小鼠脓毒症模型的保护作用。二甲基亚砜作为溶媒对照，小鼠给与优选化合物J27(20mg/kg，腹腔注射)或溶媒的预处理，然后以15mg/kg的LPS刺激。如图2所示，优选化合物J27可增加脓毒症小鼠的生存率并且可以减轻小鼠体重减轻的症状，如图所示，注射高剂量的LPS引发脓毒血症后，小鼠在36小时内全部死亡，而给予J27治疗的小鼠，有一半的小鼠存活，并且接受治疗的小鼠在48小时后体重逐渐恢复增长。此外，在实验过程中发现，48小时后，药物治疗小组的小鼠的生命活动与阴性对照组无明显异。说明该化合物可有效缓解脓毒症小鼠的生理学变化。The present invention further explores the protective effect of the preferred compound J27 on the C57/BL6 mouse sepsis model induced by intraperitoneal injection of LPS. Dimethyl sulfoxide was used as vehicle control, and mice were pretreated with the preferred compound J27 (20 mg/kg, intraperitoneal injection) or vehicle, and then stimulated with 15 mg/kg LPS. As shown in Figure 2, the preferred compound J27 can increase the survival rate of septic mice and reduce the symptoms of weight loss in mice. As shown in the figure, after injection of high doses of LPS to induce sepsis, the mice died at 36 All died within hours, while half of the mice treated with J27 survived, and the treated mice gradually resumed weight gain after 48 hours. In addition, during the experiment, it was found that after 48 hours, the life activities of the mice in the drug treatment group were not significantly different from those in the negative control group. This shows that this compound can effectively alleviate the physiological changes in septic mice.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above are only preferred embodiments of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can also be made. should be regarded as the protection scope of the present invention.
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