CN108358841A - 一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 - Google Patents
一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 Download PDFInfo
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- CN108358841A CN108358841A CN201810253238.3A CN201810253238A CN108358841A CN 108358841 A CN108358841 A CN 108358841A CN 201810253238 A CN201810253238 A CN 201810253238A CN 108358841 A CN108358841 A CN 108358841A
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- 229940111121 antirheumatic drug quinolines Drugs 0.000 title claims abstract description 47
- 150000003248 quinolines Chemical class 0.000 title claims abstract description 47
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical class NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 31
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- 101100405118 Mus musculus Nr4a1 gene Proteins 0.000 claims abstract description 23
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
一类4‑((2‑取代喹啉‑4‑基)氨基)苯甲酰肼类衍生物及其制备方法与应用,涉及N'‑取代亚甲基‑4‑((2‑取代喹啉‑4‑基)氨基)苯甲酰肼类衍生物。所述一类N'‑取代亚甲基‑4‑((2‑取代喹啉‑4‑基)氨基)苯甲酰肼类衍生物可在制备抗肿瘤药物中应用。提供一类新颖的激动Nur77信号通路的衍生物,它们可以通过激动Nur77相关信号通路活性,阻断肿瘤细胞增殖,诱导细胞凋亡,从而可以用于人和动物的多种疾病如恶性肿瘤、炎症等的治疗和预防。所述激动Nur77信号通路的衍生物可在制备用于人和动物的多种疾病药物中应用,所述疾病包括恶性肿瘤、炎症等。
Description
技术领域
本发明涉及N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物,尤其是涉及一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用。
背景技术
恶性肿瘤依旧是严重影响人类生命安全的主要疾病之一,现有的治疗恶性肿瘤的小分子药物虽然具有一定的疗效,但依然存在着较为严重的毒副作用。因此,越来越多的研究者将目标从传统的的细胞毒性药物转移到具有靶向性的新型抗肿瘤药物方向。
核受体(Nuclear Receptors,NRs)超家族是真核细胞生物体内广泛分布一大类功能蛋白,其对机体生长发育、新陈代谢、细胞分化及各种病理生理过程均有重要的调节作用,被视为潜在的治疗恶性肿瘤的重要靶点之一。Nur77(又名TR3,NGFI-B和NAK1)是由立早基因NR4A1编码的孤儿受体,属于核受体超家族的一员。近年来的研究表明,Nur77在细胞凋亡过程中具有重要作用([1]Gronemeyer H,Gustafsson J,Laudet V.Principles formodulation of the nuclear receptor superfamily.Nature Reviews Drug Discovery,2004,3(11):950-64)。其出核与细胞凋亡之间的相互关系已在肺癌、卵巢癌、肠癌、前列腺癌、胃癌、胸腺癌等多种肿瘤细胞中被证实。因此,Nur77被视为一个很有前景的新型治疗恶性肿瘤的潜在靶点([2]Hazel T G,Nathans D,Lau L F.Hazel TG,Nathans D,Lau LF.Agene inducible by serum growth factors encodes a member of the steroid andthyroid hormone receptor superfamily.Proc Natl AcadSci USA 85:8444-8448[J].Proceedings of the NationalAcademy of Sciences of the United States ofAmerica,1988,85(22):8444-8。同时,近年来研究证明,Nur77和炎症相关,所以,Nur77可视为一个潜在的抗炎靶点([3]Hu M,Luo Q,Alitongbieke G,et al.Celastrol-InducedNur77Interaction with TRAF2 Alleviates Inflammation by PromotingMitochondrial Ubiquitination and Autophagy.Molecular Cell,2017,66(1):141)。
发明内容
本发明的第一目的在于提供一类具有新颖结构的N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法。
本发明的第二目的在于提供一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物在制备抗肿瘤药物的应用。
本发明的第三目的在于提供一类新颖的激动Nur77信号通路的衍生物。它们可以通过激动Nur77相关信号通路活性,阻断肿瘤细胞增殖,诱导细胞凋亡,从而可以用于人和动物的多种疾病如恶性肿瘤、炎症等的治疗和预防。
所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的结构式为:
其中,R1代表H或甲基;R2代表取代或未取代的芳香基团,优选为2-萘基、1-萘基、2,3,4-三甲氧基苯基、4-羟基-3-甲氧基苯基、1-氢吡咯-2-基、3-苯氧基苯基、4-羟基-3-乙氧基苯基、4-甲氧基苯基、吡啶-3-基、吡啶-4-基、2-甲基-5-甲氧基吲哚-3-基等中的一种。
所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法包括以下步骤:
1)以苯胺(1)和取代乙酰乙酸乙酯为原料,多聚磷酸为溶剂,加热反应,得白色固体2-取代喹啉-4-醇(2);
2)2-取代喹啉-4-醇(2)在三氯氧磷溶剂中反应,得白色中间体4-氯-2-取代喹啉(3);
3)4-氯-2-取代喹啉(3)与对氨基苯甲酸乙酯反应得4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4),再将(4)与水合肼反应得4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5),最后(5)与不同的醛或酮缩合得目标化合物N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼。
在步骤1)中,所述搅拌的温度可为110℃;所述苯胺(1)的结构式为:
其中,R1代表H或CH3。
所述2-取代喹啉-4-醇(2)的结构式为:
其中,R1代表H或CH3。
在步骤2)中,所述反应的温度可为130℃;所述4-氯-2-取代喹啉(3)的结构式为:
其中,R1代表H或CH3。
在步骤3)中,所述4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4)的结构式为:
其中,R1代表H或CH3;
所述4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5)的结构式为:
其中,R1代表H或CH3。
所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的反应路线为:
其中,R1代表H或CH3;R2代表取代或未取代的芳香基团,优选为2-萘基、1-萘基、2,3,4-三甲氧基苯基、4-羟基-3-甲氧基苯基、1-氢吡咯-2-基、3-苯氧基苯基、4-羟基-3-乙氧基苯基、4-甲氧基苯基、吡啶-3-基、吡啶-4-基、2-甲基-5-甲氧基吲哚-3-基。
所述一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物可在制备抗肿瘤药物中应用。
本发明提供一类新颖的激动Nur77信号通路的衍生物,它们可以通过激动Nur77相关信号通路活性,阻断肿瘤细胞增殖,诱导细胞凋亡,从而可以用于人和动物的多种疾病如恶性肿瘤、炎症等的治疗和预防。
所述激动Nur77信号通路的衍生物可在制备用于人和动物的多种疾病药物中应用,所述疾病包括恶性肿瘤、炎症等。
本发明涉及了一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物,该类衍生物在结构上具有创造性。
本发明涉及了一类具有新结构的N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备,其反应条件温和,产率高,成本低廉,反应过程简单易控制,适用于工业化生产。本发明涉及的N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物具有抗肿瘤活性,可用于制备抗肿瘤药物。对上述衍生物进行了激动Nur77信号通路的相关活性测试,发现其抗肿瘤活性与其激动Nur77信号通路的活性呈正相关,上述的衍生物可用于预防和治疗Nur77信号通路受扰有关的疾病,如恶性肿瘤和炎症等。
附图说明
图1为HepG2、QGY-7703细胞经不同浓度的F21(1.5μM,2.0μM,3.0μM,4.0μM,4.5μM,6.0μM)处理24h后,PARP、Bcl-2、Nur77的免疫印迹分析结果。
具体实施方式
为了便于理解本发明,现结合具体实施方式对本发明作进一步说明,以进一步诠释本发明,但不构成对本发明的任何方式的限制。
以下给出本发明化合物的体外抗肿瘤增殖活性及其代表化合物对Nur77相关信号通路活性激动的研究。
体外抗肿瘤增殖活性测试实验:利用MTT法测定合成化合物对HepG2、QGY-7703、SMMC-7721等人癌细胞系和人正常细胞系Lo2生长抑制活性。表1列举了本发明部分化合物对各测试细胞系的IC50值,由此说明该系列化合物具有明显的抗肿瘤活性,但对正常细胞Lo2也具有较强的毒性。
表1本发明部分化合物对体外细胞的生长抑制活性
本发明代表化合物F21对Nur77相关信号通路活性激动的研究:图1显示了HepG2、QGY-7703细胞经不同浓度的F21(1.5μM,2.0μM,3.0μM,4.0μM,4.5μM,6.0μM)处理24h后,PARP、Bcl-2、Nur77的免疫印迹分析结果。结果显示,F21能上调Nur77、下调促生存蛋白Bcl-2的表达,这表明F21可以通过促进Nur77-Bcl-2的相关信号通路,抑制肿瘤细胞增殖,促进肿瘤细胞凋亡。因此,本发明所述化合物可用于Nur77-Bcl-2信号通路相关疾病的预防和治疗,如用于人和动物的恶性肿瘤治疗和预防。
以下给出具体实施例。
实施例1:N'-((萘-2-基)亚甲基)-4-((喹啉-4-基)氨基)苯肼酰肼的制备:
4-((喹啉-4-基)氨基)苯甲酸乙酯的制备:
在干燥密封的100mL反应瓶中加入4-羟基喹啉(2.90g,0.020mol),三氯氧磷(30mL),搅拌反应,密封加热至120℃继续反应3h后,TLC检测反应已完全,停止反应。反应液冷却至室温,减压浓缩除去溶剂,加入50mL冰水,活性炭脱色,抽滤,收集滤液,冰浴下用10%NaOH调pH为8~9,蒸馏,得到无色液体4-氯喹啉2.80g,收率87%。
在干燥的100mL圆底烧瓶中依次加入4-氯喹啉(1.60g,0.010mol),对氨基苯甲酸乙酯(1.70g,0.010mol),正丁醇(35mL),2滴浓盐酸,回流反应15h。TLC检测反应已完全。反应液充分冷却,有固体析出,抽滤,收集滤饼,烘干得白色固体4-((喹啉-4-基)氨基)苯甲酸乙酯2.36g,收率81%。
N'-((萘-2-基)亚甲基)-4-((喹啉-4-基)氨基)苯肼酰肼的制备:
在干燥的50mL圆底烧瓶中依次加入4-((喹啉-4-基)氨基)苯甲酸乙酯(2.90g,0.010mol),乙醇(5mL),水合肼(20mL),回流反应24h。TLC检测反应已完全。反应液充分冷却,抽滤,收集滤饼,烘干得白色固体4-((喹啉-4-基)氨基)苯甲酰肼2.20g,收率78%。
在干燥的10mL圆底烧瓶中依次加入4-((喹啉-4-基)氨基)苯甲酰肼(27.8mg,0.10mmol),2-萘甲醛(17.1mg,0.11mmol),乙醇(5mL),1滴三氟乙酸,回流反应12h,TLC反应已完全。加压浓缩除去溶剂,得粗产物,硅胶柱层析分离(洗脱剂为二氯甲烷︰甲醇=10︰1v/v),得到固体20.0mg,收率50%,其中所述的4-((喹啉-4-基)氨基)苯甲酰肼,2-萘甲醛的摩尔配比为1︰1.1。波谱数据:1H NMR(600MHz,DMSO-d6):12.13(s,1H),10.96(br.s.,1H),8.74(d,J=8.4Hz,1H),8.63~8.69(m,2H),8.15~8.20(m,3H),7.95~8.13(m,6H),7.86(ddd,J=2.8,5.6,8.4Hz,1H),7.69(d,J=8.4Hz,2H),7.56~7.64(m,2H),7.05(d,J=7.0Hz,1H);13C NMR(151MHz,DMSO-d6):162.8,158.8,158.6,154.8,148.4,144.0,141.0,139.1,134.5,134.2,133.3,132.5,132.1,131.5,129.9,129.3,129.0,128.8,128.3,127.8,127.7,127.3,123.9,123.1,121.2,118.0,101.0;ESI-MS(+):[M+H]+,405.5。
实施例2:4-((喹啉-4-基)氨基)-N'-((2,3,4-三甲氧基苯基)亚甲基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成2,3,4-三甲氧基苯甲醛(21.6mg,0.11mmol),最后分离得到淡黄色固体状产物24.6mg,收率54%。波谱数据:1H NMR(600MHz,DMSO-d6):11.96(s,1H),10.96(br.s.,1H),8.73(d,J=8.4Hz,1H),8.68(s,1H),8.64(d,J=6.8Hz,1H),8.13(d,J=8.6Hz,2H),8.04~8.07(m,2H),7.85(ddd,J=2.3,6.0,8.4Hz,1H),7.61~7.69(m,3H),7.04(d,J=7.0Hz,1H),6.96(d,J=9.0Hz,1H),3.87(d,J=3.95Hz,6H),3.79(s,3H);13C NMR(151MHz,DMSO-d6):162.4,159.1,158.8,158.6,155.7,154.8,153.1,144.0,143.9,142.0,140.9,139.0,134.5,132.2,129.8,127.8,125.0,123.9,121.1,121.0,120.8,118.0,116.7,109.2,101.0,62.3,61.0,56.5;ESI-MS(+):[M+H]+,457.5。
实施例3:N'-((4-羟基-3-甲氧基苯基)亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成4-羟基-3甲氧基苯甲醛(16.7mg,0.11mmol),最后分离得到黄白色固体状产物23.0mg,收率56%。波谱数据:1H NMR(600MHz,DMSO-d6):11.88(s,1H),10.99(br.s.,1H),9.70(br.s.,1H),8.74(d,J=8.4Hz,1H),8.64(d,J=7.0Hz,1H),8.39(s,1H),8.13(d,J=8.4Hz,2H),8.05~8.08(m,2H),7.86(ddd,J=2.3,5.9,8.3Hz,1H),7.67(d,J=8.4Hz,2H),7.36(d,J=1.5Hz,1H),7.11(dd,J=1.7,8.1Hz,1H),7.04(d,J=7.0Hz,1H),6.9(d,J=8.07Hz,1H),3.85(s,3H);ESI-MS(+):[M+H]+,413.4。
实施例4:N'-((萘-1-基)亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成1-萘甲醛(17.1mg,0.11mmol),最后分离得到白色固体状产物21.2mg,收率51%。波谱数据:1H NMR(600MHz,DMSO-d6):12.14(s,1H),10.98(br.s.,1H),9.18(s,1H),8.91(d,J=8.6Hz,1H),8.75(d,J=8.4Hz,1H),8.65(d,J=6.8Hz,1H),8.20(d,J=8.4Hz,2H),8.02~8.09(m,4H),7.97(d,J=7.0Hz,1H),7.82~7.91(m,1H),7.67~7.76(m,3H),7.60~7.67(m,2H),7.07(d,J=6.8Hz,1H);13C NMR(151MHz,DMSO-d6:162.7,158.9,158.7,154.8,148.4,144.0,141.1,139.1,134.5,134.0,132.0,131.1,130.7,130.0,129.9,129.3,128.3,127.8,127.8,126.8,126.1,125.1,124.7,123.9,121.1,118.0,101.0;ESI-MS(+):[M+H]+,417.5。
实施例5:N'-(3-苯氧基亚苄基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成3-苯氧基苯甲醛(21.8mg,0.11mmol),最后分离得到淡黄色固体状产物24.3mg,收率53%。波谱数据:1H NMR(600MHz,DMSO-d6):11.96(br.s.,1H),8.61(d,J=5.87Hz,1H),8.57(d,J=8.25Hz,1H),8.48(s,1H),8.05(d,J=7.89Hz,2H),8.00(d,J=8.44Hz,1H),7.91(t,J=7.52Hz,1H),7.69~7.78(m,1H),7.58(d,J=7.89Hz,2H),7.47~7.53(m,2H),7.41~7.47(m,3H),7.35~7.40(m,1H),7.16~7.24(m,1H),7.07~7.14(m,4H);ESI-MS(+):[M+H]+,459.5。
实施例6:N’-((1-氢-吡咯-2-基)亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成2-吡咯甲醛(10.5mg,0.11mmol),最后分离得到白色固体状产物19.9mg,收率56%。波谱数据:1H NMR(600MHz,DMSO-d6):11.66(s,1H),11.57(br.s.,1H),10.92(br.s.,1H),8.73(d,J=8.4Hz,1H),8.63(d,J=7.0Hz,1H),8.33(s,1H),8.11(d,J=8.4Hz,2H),8.03~8.07(m,2H),7.85(ddd,J=1.9,6.4,8.3Hz,1H),7.65(d,J=8.4Hz,2H),7.01(d,J=7.0Hz,1H),6.89~6.96(m,1H),6.52(br.s.,1H),6.11~6.19(m,1H);13C NMR(151MHz,DMSO-d6):162.2,158.7,158.5,154.8,144.0,141.6,140.7,139.1,134.5,132.5,129.8,127.7,127.5,125.0,123.9,123.1,121.2,118.0,113.9,109.8,101.0;ESI-MS(+):[M+H]+,356.4。
实施例7:N’-(4-甲氧基苯亚苄基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成4-甲氧基苯甲醛(15.0mg,0.11mmol),最后分离得到白色固体状产物20.2mg,收率51%。波谱数据:1H NMR(600MHz,DMSO-d6):11.90(s,1H),8.74(d,J=8.44Hz,1H),8.64(d,J=6.97Hz,1H),8.45(s,1H),8.13(d,J=8.44Hz,2H),8.06~8.08(m,2H),7.85(ddd,J=3.39,4.86,8.44Hz,1H),7.70(d,J=8.62Hz,2H),7.67(d,J=8.44Hz,2H),7.01~7.08(m,3H),3.83(s,3H);13C NMR(151MHz,DMSO-d6):162.5,161.4,158.9,158.7,154.8,148.4,143.9,140.9,139.0,134.5,132.2,129.8,129.2,127.7,127.3,125.0,123.9,121.1,118.0,114.8,101.0,55.8;ESI-MS(+):[M+H]+,397.4。
实施例8:N'-((3-乙氧基-4-羟基苯)亚苄基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成3-乙氧基-4-羟基苯甲醛(18.3mg,0.11mmol),最后分离得到白色固体状产物22.2mg,收率52%。波谱数据:1H NMR(600MHz,DMSO-d6):11.84(s,1H),10.96(br.s.,1H),9.57(br.s.,1H),8.74(d,J=8.4Hz,1H),8.64(d,J=7.0Hz,1H),8.38(s,1H),8.12(d,J=8.4Hz,2H),8.05~8.08(m,2H),7.85(ddd,J=3.0,5.2,8.5Hz,1H),7.66(d,J=8.4Hz,2H),7.29~7.35(m,1H),7.08~7.13(m,1H),7.03(d,J=6.8Hz,1H),6.88(d,J=8.1Hz,1H),4.08(q,J=7.0Hz,2H),1.38(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6):162.5,158.9,158.7,154.8,149.8,149.1,147.7,143.9,140.8,139.0,134.5,132.3,129.8,127.7,126.1,125.0,123.9,122.6,121.1,118.0,116.0,110.8,101.0,64.3,15.2;ESI-MS(+):[M+H]+,427.5。
实施例9:N’-(吡啶-4-基亚甲基)-4-(喹啉-4-基氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成吡啶-4-甲醛(11.8mg,0.11mol),最后分离得到白色固体状产物20.1mg,收率55%。波谱数据:1H NMR(600MHz,DMSO-d6):12.23(br.s.,1H),8.68(br.s.,2H),8.63(d,J=6.2Hz,1H),8.61(d,J=8.4Hz,1H),8.50(br.s.,1H),8.06~8.12(m,2H),7.99~8.04(m,1H),7.92~7.98(m,1H),7.76(t,J=7.6Hz,1H),7.69(br.s.,2H),7.62(d,J=8.6Hz,2H),7.13(d,J=6.2Hz,1H);13C NMR(151MHz,DMSO-d6):163.1,158.8,158.6,151.6,150.8,146.7,145.7,142.9,142.0,132.8,129.9,129.8,126.9,124.4,123.5,123.0,121.5,119.2,116.8,102.4;ESI-MS(+):[M+H]+,368.4。
实施例10:N’-(吡啶-3-基亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,收2-萘甲醛换成吡啶-3-甲醛(11.8mg,0.11mmol),最后分离得到白色固体状产物20.1mg,收率55%。波谱数据:1H NMR(600MHZ,SMSO-d6):12.17(s,1H),8.89(br.s.,1H),8.71(d,J=8.4Hz,1H),8.64(d,J=6.60Hz,2H),8.56(s,1H),8.18(d,J=7.5Hz,1H),8.11~8.15(m,2H),8.02~8.07(m,2H),7.84(ddd,J=3.0,5.3,8.4Hz,1H),7.63~7.70(m,2H),7.49~7.55(m,1H),7.07(d,J=6.6Hz,1H);13C NMR(151MHz,DMSO-d6):166.7,162.9,153.8,151.2,150.7,149.2,145.7,144.6,141.5,137.4,134.1,134.0,130.7,129.9,127.6,124.6,124.5,123.8,121.9,118.3,101.4;ESI-MS(+):[M+H]+,368.4。
实施例11:N’-((5-甲氧基-2-甲基-1-氢吲哚-3-基)亚甲基)-4-((2-甲基喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将4-(喹啉-4-基氨基)苯甲酰肼换成4-((2-甲基喹啉-4-基氨基)氨基)苯甲酰肼(29.2mg,0.10mmol),将2-萘甲醛换成2-甲基-5-甲氧基-1-氢吲哚-3-甲醛(20.8mg,0.11mmol),最后分离得到淡黄色固体状产物23.6mg,收率51%。波谱数据:1H NMR(600MHz,DMSO-d6):11.64(s,1H),11.43(s,1H),10.85(br.s.,1H),8.75~8.82(m,2H),8.15(d,J=8.4Hz,2H),8.09(d,J=8.3Hz,1H),8.00(t,J=7.7Hz,1H),7.82(d,J=2.6Hz,1H),7.77(t,J=7.7Hz,1H),7.65(d,J=8.3Hz,2H),7.24(d,J=8.6Hz,1H),6.93(s,1H),6.78(dd,J=2.6,8.8Hz,1H),3.80(s,3H),3.39(br.s.,3H),2.62~2.68(m,3H);13CNMR(151MHz,DMSO-d6):161.7,155.6,154.8,153.9,145.2,141.0,140.8,139.4,134.0,132.4,131.2,129.5,127.0,126.5,124.8,124.0,117.1,111.8,111.1,107.9,104.7,101.3,55.8,20.6,12.0;ESI-MS(+):[M+H]+,464.5。
实施例12:N'-((5-甲氧基-2-甲基-1-氢吲哚-3-基)亚甲基)-4-((2-甲基喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将4-(喹啉-4-基氨基)苯甲酰肼换成4-(2-甲基喹啉-4-基氨基)苯甲酰肼(29.2mg,0.10mmol),将2-萘甲醛换成2,3,4-三甲氧基苯甲醛(21.6mg,0.11mmol),最后分离得到白色固体状产物22.5mg,收率49%。波谱数据:1H NMR(600MHz,DMSO-d6):11.96(s,1H),10.79(br.s.,1H),8.66~8.70(m,2H),8.13(d,J=8.4Hz,2H),8.00~8.05(m,1H),7.96~8.00(m,1H),7.78~7.83(m,1H),7.65(d,J=8.6Hz,3H),6.94~6.98(m,2H),3.87(s,3H),3.87(s,3H),3.79(s,3H),2.66(s,3H);13C NMR(151MHz,DMSO-d6):162.5,155.7,155.6,154.2,153.1,144.0,142.0,141.0,139.0,134.3,131.9,129.8,127.3,124.9,123.7,121.0,120.8,120.4,116.9,109.2,101.3,62.3,61.0,56.4,20.5;ESI-MS(+):[M+H]+,471.5。
Claims (10)
1.N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物,其特征在于其结构式为:
其中,R1代表H或甲基;R2代表取代或未取代的芳香基团。
2.如权利要求1所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物,其特征在于所述R2为2-萘基、1-萘基、2,3,4-三甲氧基苯基、4-羟基-3-甲氧基苯基、1-氢吡咯-2-基、3-苯氧基苯基、4-羟基-3-乙氧基苯基、4-甲氧基苯基、吡啶-3-基、吡啶-4-基、2-甲基-5-甲氧基吲哚-3-基中的一种。
3.如权利要求1所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于包括以下步骤:
1)以苯胺(1)和取代乙酰乙酸乙酯为原料,多聚磷酸为溶剂,加热反应,得白色固体2-取代喹啉-4-醇(2);
2)2-取代喹啉-4-醇(2)在三氯氧磷溶剂中反应,得白色中间体4-氯-2-取代喹啉(3);
3)4-氯-2-取代喹啉(3)与对氨基苯甲酸乙酯反应得4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4),再将(4)与水合肼反应得4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5),最后(5)与不同的醛或酮缩合,得目标化合物N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼。
4.如权利要求3所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于在步骤1)中,所述搅拌的温度为110℃。
5.如权利要求3所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于在步骤1)中,所述苯胺(1)的结构式为:
其中,R1代表H或CH3;
所述2-取代喹啉-4-醇(2)的结构式为:
其中,R1代表H或CH3。
6.如权利要求3所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于在步骤2)中,所述反应的温度为130℃。
7.如权利要求3所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于在步骤2)中,所述4-氯-2-取代喹啉(3)的结构式为:
其中,R1代表H或CH3;
所述4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4)的结构式为:
其中,R1代表H或CH3;
所述4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5)的结构式为:
其中,R1代表H或CH3。
8.如权利要求1所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物,其特征在于其反应路线为:
其中,R1代表H或CH3;R2代表取代或未取代的芳香基团,优选为2-萘基、1-萘基、2,3,4-三甲氧基苯基、4-羟基-3-甲氧基苯基、1-氢吡咯-2-基、3-苯氧基苯基、4-羟基-3-乙氧基苯基、4-甲氧基苯基、吡啶-3-基、吡啶-4-基、2-甲基-5-甲氧基吲哚-3-基。
9.一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物在制备抗肿瘤药物中应用。
10.激动Nur77信号通路的衍生物,所述激动Nur77信号通路的衍生物可在制备用于人和动物的多种疾病药物中应用,所述疾病包括恶性肿瘤、炎症。
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