CN108727295A - 一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途 - Google Patents

一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途 Download PDF

Info

Publication number
CN108727295A
CN108727295A CN201810643763.6A CN201810643763A CN108727295A CN 108727295 A CN108727295 A CN 108727295A CN 201810643763 A CN201810643763 A CN 201810643763A CN 108727295 A CN108727295 A CN 108727295A
Authority
CN
China
Prior art keywords
bromomethyl
compound
formula
aminophenyls
benzene
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.)
Granted
Application number
CN201810643763.6A
Other languages
English (en)
Other versions
CN108727295B (zh
Inventor
张华�
江成世
朱孔凯
成志强
宋佳丽
陶洪瑞
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.)
University of Jinan
Original Assignee
University of Jinan
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 University of Jinan filed Critical University of Jinan
Priority to CN201810643763.6A priority Critical patent/CN108727295B/zh
Publication of CN108727295A publication Critical patent/CN108727295A/zh
Application granted granted Critical
Publication of CN108727295B publication Critical patent/CN108727295B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及药物化学领域，具体涉及一种具有抗肿瘤活性的2‑(3‑氨基苯基)‑苯并噻唑衍生物(通式I)。初步活性测试证明，本发明化合物对多种恶性肿瘤细胞，如A549、Hela、HepG2、MCF7、DB和MV4‑11的增值具有显著抑制活性。本发明涉及的化合物制备简单，为新型抗肿瘤药物的研发提供了指导。

Description

一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途
技术领域
本发明涉及一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和在制备预防和/或治疗肿瘤药物中的用途。
背景技术
癌症(恶性肿瘤)是一种以不受控制的细胞生长为特征的疾病，它是世界上最主要的死亡原因之一。据统计，2015年全球患癌人数为九千万，且每年新增患病人数约为一千四百万。目前，化疗是主要的治疗方式，然而，大多数抗肿瘤药物副作用高，如毒性、易产生耐药性和其他副作用等。因此，开发新的、更加安全的抗肿瘤药物是目前一项十分紧迫的任务。
众所周知，杂环化合物在发现新的抗肿瘤药物中起着极其重要的作用。苯并噻唑作为一种典型的杂环化合物，在药物设计中占有重要地位。苯并噻唑衍生物已被证明具有多种生物药理活性，如神经保护、抗菌、抗结核和抗肿瘤等。
本发明公开了一种2-(3-氨基苯基)-苯并噻唑衍生物，可用于制备抗肿瘤药物。
发明内容
本发明涉及了一类结构相对简单、对多种恶性肿瘤细胞具有抑制活性的通式I所示的新化合物，及其合成与其可能具有预防和/或治疗肿瘤的作用，从而在制药领域具有潜在的用途。迄今为止，未见关于式I所示化合物的结构、制备方法及用途的报道。
本发明采用以下技术方案：
一种2-(3-氨基苯基)-苯并噻唑衍生物，它具有如下通式I所示的结构：
其中，R为含有取代基的苯基、萘基、吡啶、喹啉、吲哚；X为氢或氧。
上述的2-(3-氨基苯基)-苯并噻唑衍生物的制备方法，它包括以下步骤：
(1)将3-硝基苯甲酸(式1)与2-氨基苯硫酚(式2)反应，得到式3化合物；
(2)将式3化合物经催化还原反应，得到式4化合物；
(3)将式4化合物与卤代物或羧酸衍生物在碱参与下反应，得到通式I化合物。
所述步骤(1)中反应溶剂为二甲亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃、二氯甲烷、1,4-二氧六环及甲苯中至少一种；该反应温度为0℃～150℃，反应时间为1～36小时。
所述步骤(2)中反应所用催化剂为钯、铁、锌、镍；所用溶剂为乙醇、甲醇、正丁醇、二甲基亚砜、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、四氢呋喃、1,4-二氧六环或水，该反应温度为0℃～120℃，反应时间为1～24小时。
所述步骤(3)中所述卤代物为1-溴-4-(溴甲基)苯、溴甲基苯、1-(溴甲基)-4-溴苯、1-(溴甲基)-4-氟苯、2-溴-4-(溴甲基)-1-氟苯、2-溴-1-(溴甲基)-4-氟苯、4-(溴甲基)-1,2-二氟苯、1-(溴甲基)-4-氟-2-甲苯、4-(溴甲基)-1-氟-2-硝基苯、1-(溴甲基)-4-(三氟甲氧基)苯、1-(溴甲基)-4-(三氟甲基)苯、4-(溴甲基)苯甲氰、1-(溴甲基)-4-(甲磺酰基)苯、2-(溴甲基)萘、1-(溴甲基)萘、4-(溴甲基)苯硼酸酯；所述羧酸衍生物为2-吡啶甲酸、3-吡啶甲酸、4-吡啶甲酸、喹啉-2-甲酸、吲哚-3-乙酸、6-三氟甲基烟酸、6-氯烟酸、6-溴烟酸、6-甲基烟酸；所述碱为三乙胺、N,N-二异丙基乙胺、哌啶、哌嗪、吡啶、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或1-4个碳的醇钾及醇钠；所用溶剂为甲醇、乙醇、丙醇、异丙醇、乙腈、1,4-二氧六环、二氯乙烷、N,N-二甲基甲酰胺、N,N-二异丙基乙胺和水中的一种或一种以上；反应温度为0℃～100℃；反应时间为6～36小时。
本发明还提供了上述的2-(3-氨基苯基)-苯并噻唑衍生物的用途，其可用于制备抗肿瘤药物。
本发明还提供了一种用于预防和/或治疗肿瘤的药物，它是以上述通式I所示的衍生物为活性成分或主要活性成分，辅以药学上可接受的辅料制成。
本发明的有益效果是：本发明的化合物为首次合成的一类2-(3-氨基苯基)-苯并噻唑衍生物，在对合成化合物抗肿瘤活性测试实验中，首次发现部分类化合物对多种恶性肿瘤细胞具有较强的抑制活性。因而，它们在制备预防和/或治疗肿瘤的药物中具有潜在的应用前景。
具体实施方式
下面结合具体实施例对本发明做进一步的详细说明。这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1：式3化合物的制备
将3.02g式1化合物和2.50g式2化合物溶于10mL二甲亚砜中，140℃加热搅拌12小时。之后将反应液倒入二氯甲烷中，水洗。有机层用无水硫酸镁干燥，过滤，减压浓缩后，残余物经柱层析纯化后得到2.87g白色固体化合物式2，产率56％。ESI-MS m/z 257.0[M+H]+.
实施例2：式4化合物的制备
将2.82g式3化合物溶于20mL甲醇中，加入1.54g铁粉和6.60g乙酸，反应液75℃加热搅拌12小时。反应液过滤出去不溶物，滤液减压浓缩后得到4.14g的黄色油体式3化合物，产率77.4％。1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.53(dd,J＝7.9,7.1Hz,1H),7.44(dd,J＝8.1,7.1Hz,1H),7.35(brs,1H),7.24–7.16(m,2H),6.78–6.71(m,1H),5.46(s,2H,NH).13C NMR(150MHz,DMSO-d6)δ168.2,153.6,149.4,134.3,133.4,129.8,126.5,125.3,122.7,122.3,116.8,114.6,111.8.ESI-MS m/z 227.0[M+H]+.
实施例3：通式I化合物的制备
50mg(1当量)式4化合物溶于3mL N,N-二甲基甲酰胺中，加入相应的溴代物(1当量)和碳酸钠(3当量)或加入相应的羧酸(1当量)，O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1当量)，室温搅拌过夜。反应液浓缩，残余物经柱层析纯化后得到目标通式I化合物。化合物编号、具体结构式以及原料如下表1所示。
表1化合物编号、具体结构式、所用原料以及活性结果
化合物I-1,白色固体，产率57％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝8.1Hz,1H),8.02(d,J＝8.1Hz,1H),7.53(d,J＝8.1Hz,2H),7.52(dd,J＝8.1,7.2Hz,1H),7.44(dd,J＝8.1,7.2Hz,1H),7.35(d,J＝8.1Hz,2H),7.32(brs,1H,NH),7.25–7.21(m,2H),6.77–6.68(m,2H),4.34(d,J＝6.1Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.1,153.5,149.0,139.4,134.3,133.5,131.2,129.9,129.4,126.5,125.4,122.7,122.3,122.3,119.7,115.0,110.6,45.6.ESI-MS m/z394.9[M+H]+.
化合物I-2,白色固体，产率58％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.52(dd,J＝7.9,7.2Hz,1H),7.44(dd,J＝8.1,7.2Hz,1H),7.40(d,J＝7.4Hz,2H),7.36–7.32(m,3H),7.25–7.20(m,3H),6.78–6.74(m,1H),6.68(t,J＝6.0Hz,1H,NH),4.36(d,J＝6.0Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.2,153.5,149.3,139.8,134.3,133.4,129.9,128.4,128.4,127.2,127.2,126.8,126.5,125.3,122.7,122.3,115.1,114.8,110.5,46.3.ESI-MS m/z 317.6[M+H]+.
化合物I-3,白色固体，产率37％.1H NMR(600MHz,CD3OD)δ7.96(d,J＝8.1Hz,1H),7.94(d,J＝7.9Hz,1H),7.49(dd,J＝8.1,7.1Hz,1H),7.39(dd,J＝7.9,7.1Hz,1H),7.32(dd,J＝2.0,1.8Hz,1H),7.30–7.25(m,3H),7.20(dd,J＝7.9,7.8Hz,1H),7.12(d,J＝7.9Hz,2H),6.77(dd,J＝7.9,2.0Hz,1H),4.33(s,2H),2.29(s,3H).13C NMR(150MHz,CD3OD)δ171.2,154.9,150.8,137.9,137.6,135.9,135.0,130.8,130.1,128.4,127.5,126.4,123.5,122.9,117.0,116.8,112.1,48.2,21.1.ESI-MS m/z 331.0[M+H]+.
化合物I-4,黄色固体，产率43％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.52(dd,J＝7.9,7.1Hz,1H),7.46–7.41(m,3H),7.33(brs,1H),7.25–7.21(m,2H),7.17(dd,J＝8.9,8.8Hz,2H),6.77–6.74(m,1H),6.68(t,J＝6.0Hz,1H,NH),4.35(d,J＝6.0Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.1,161.2(d,J＝241.6Hz),153.5,149.1,135.9(d,J＝3.2Hz),134.3,133.4,129.9,129.1(d,J＝8.24Hz),126.5,125.3,122.7,122.3,115.2,115.0(d,J＝15.3Hz),115.0,110.6,45.6.ESI-MS m/z 335.1[M+H]+.
化合物I-5,白色固体，产率41％.1H NMR(600MHz,DMSO-d6)δ8.12(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.67(dd,J＝7.9,7.2Hz,1H),7.53(dd,J＝8.0,7.2Hz,1H),7.44(dd,J＝7.8,7.2Hz,1H),7.38(dd,J＝7.8,1.3Hz,1H),7.33(brs,1H),7.27–7.19(m,3H),6.78–6.72(m,2H),4.38(d,J＝6.1Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.0,158.2(d,J＝244.3Hz),153.5,148.8,143.0(d,J＝6.5Hz),134.3,133.5,133.4,130.0,126.5,125.4,124.7(d,J＝3.12Hz),122.7,122.3,115.3(d,J＝11.1Hz),115.2(d,J＝10.4Hz),115.0,110.7,105.6(d,J＝20.8Hz),45.3.ESI-MS m/z 413.0[M+H]+.
化合物I-6,白色固体，产率41％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.62(dd,J＝8.5,2.5Hz,1H),7.52(dd,J＝7.9,7.1Hz,1H),7.48–7.45(m,1H),7.44(dd,J＝8.1,7.1Hz,1H),7.32(brs,1H),7.30–7.22(m,3H),6.74(t,J＝5.9Hz,1H,NH),6.72–6.69(m,1H),4.36(d,J＝5.9Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.0,160.8(d,J＝246.9Hz),153.5,148.8,134.4(d,J＝3.5Hz),134.3,133.6,130.2(d,J＝8.1Hz),130.1,126.5,125.4,122.8(d,J＝10.1Hz),122.7,122.3,119.7(d,J＝24.0Hz),115.3,114.9(d,J＝8.35Hz),114.8,110.4,46.1.ESI-MS m/z 413.0[M+H]+.
化合物I-7,黄色固体，产率43％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.52(dd,J＝7.9,7.3Hz,1H),7.46–7.41(m,2H),7.39(dd,J＝8.1,7.3Hz,1H),7.33(brs,1H),7.27–7.22(m,3H),6.77–6.73(m,1H),6.71(t,J＝6.0Hz,1H,NH),4.36(d,J＝6.0Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.1,153.6,148.9,137.9,137.9,134.3,133.5,130.0,126.6,125.4,123.8(d,J＝3.2Hz),123.8(d,J＝3.6Hz),122.8,122.3,117.5(d,J＝16.5Hz),116.1(d,J＝16.8Hz),115.2,115.1,110.7,45.3.ESI-MS m/z 353.0[M+H]+.
化合物I-8,黄色油体，产率46％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.52(dd,J＝7.9,7.2Hz,1H),7.44(dd,J＝8.1,7.2Hz,1H),7.36(brs,1H),7.32(dd,J＝8.4,6.3Hz,1H),7.27–7.22(m,2H),7.07(dd,J＝10.0,2.6Hz,1H),6.97(ddd,J＝8.7,8.4,2.6Hz,1H),6.80–6.73(m,1H),6.49(t,J＝5.6Hz,1H),4.28(d,J＝5.6Hz,2H),2.37(s,3H).13C NMR(150MHz,DMSO-d6)δ168.2,161.1(d,J＝242.5Hz),153.6,149.3,138.8(d,J＝8.7Hz),134.3,133.5,133.3(d,J＝2.6Hz),129.9,129.2(d,J＝7.2Hz),126.5,125.3,122.7,122.3,116.6(d,J＝19.6Hz),114.9,114.9,112.1(d,J＝20.0Hz),110.3,44.0,18.64.ESI-MS m/z 349.1[M+H]+.
化合物I-9,黄色油体，产率73％.1H NMR(600MHz,DMSO-d6)δ8.18(dd,J＝7.2,2.0Hz,1H),8.11(d,J＝8.0Hz,1H),8.02(d,J＝8.1Hz,1H),7.84(ddd,J＝8.4,4.1,2.0Hz,1H),7.58(dd,J＝11.3,8.6Hz,1H),7.53(dd,J＝8.0,7.1Hz,1H),7.44(dd,J＝8.1,7.1Hz,1H),7.37–7.34(m,1H),7.28–7.22(m,2H),6.82(t,J＝6.2Hz,1H,NH),6.78–6.75(m,1H),4.47(d,J＝6.2Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.0,154.4,153.1(d,J＝127.8Hz),148.7,137.8(d,J＝3.7Hz),136.7(d,J＝7.6Hz),135.0(d,J＝8.8Hz),134.3,133.5,130.1,126.6,125.4,124.4,122.8,122.3,118.5(d,J＝20.82Hz),115.4,115.0,110.8,44.9.ESI-MS m/z 380.0[M+H]+.
化合物I-10,白色固体，产率55％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝8.0Hz,1H),8.02(d,J＝8.0Hz,1H),7.54–7.50(m,3H),7.44(dd,J＝8.0,7.1Hz,1H),7.37–7.32(m,3H),7.26–7.22(m,2H),6.78–6.75(m,1H),6.73(t,J＝6.0Hz,1H,NH),4.40(d,J＝6.0Hz,2H).13CNMR(150MHz,DMSO-d6)δ168.1,153.5,149.1,147.2,139.4,134.3,133.5,129.9,129.9,129.0,126.5,125.3,122.7,122.3,121.0,115.1,115.0,110.6,45.5.ESI-MS m/z401.0[M+H]+.
化合物I-11,白色固体，产率35％.1H NMR(600MHz,DMSO-d6)δ8.11(d,J＝7.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.71(d,J＝8.1Hz,2H),7.61(d,J＝8.1Hz,2H),7.52(dd,J＝7.9,7.2Hz,1H),7.44(dd,J＝8.1,7.2Hz,1H),7.35(brs,1H),7.26–7.21(m,2H),6.81(t,J＝6.1Hz,1H,NH),6.74–6.71(m,1H),4.48(d,J＝6.1Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.1,153.5,149.0,145.1,134.3,133.5,130.0,127.8,126.6,125.3(q,J＝308.1Hz),125.3,125.3,125.3,122.8,122.3,115.2,114.9,110.6,45.8.ESI-MS m/z 385.0[M+H]+.
化合物I-12,黄色固体，产率82.6％.1H NMR(600MHz,CDCl3)δ8.05(d,J＝8.0Hz,1H),7.89(d,J＝8.0Hz,1H),7.62(d,J＝8.3Hz,2H),7.50–7.46(m,3H),7.42–7.39(m,2H),7.38(dd,J＝8.0,7.0Hz,1H),7.28–7.25(m,1H),6.69–6.65(m,1H),4.50(d,J＝5.6Hz,2H),4.42(t,J＝5.6Hz,1H,NH).13C NMR(150MHz,CDCl3)δ168.5,154.1,148.0,144.9,135.1,134.7,132.6,130.2,127.9,126.4,125.3,123.3,121.7,118.9,117.8,115.4,111.5,111.2,47.8.ESI-MS m/z 342.6[M+H]+.
化合物I-13,白色固体，产率55％.1H NMR(600MHz,CDCl3)δ8.05(d,J＝8.1Hz,1H),7.92(d,J＝8.3Hz,2H),7.89(d,J＝8.0Hz,1H),7.59(d,J＝8.3Hz,2H),7.48(dd,J＝8.1,7.2Hz,1H),7.38(dd,J＝8.0,7.2Hz,1H),7.43–7.39(m,1H),7.27(dd,J＝7.8,7.2Hz,1H),6.68(dd,J＝7.9,1.8Hz,1H),4.55(brs,2H),4.45(brs,1H,NH),3.05(s,3H).13C NMR(150MHz,CDCl3)δ168.5,154.1,148.0,146.0,139.6,135.1,134.7,130.2,128.1,128.0,126.4,125.3,123.3,121.7,117.8,115.4,111.5,47.7,44.7.ESI-MS m/z 395.0[M+H]+.
化合物I-14,黄色油体，产率56％.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝7.6Hz,1H),8.01(d,J＝7.9Hz,1H),7.93–7.85(m,4H),7.57(dd,J＝8.5,1.5Hz,1H),7.52(dd,J＝7.6,7.0Hz,1H),7.50–7.45(m,2H),7.43(dd,J＝7.9,7.0Hz,1H),7.41(brs,1H),7.25–7.20(m,2H),6.83–6.78(m,2H),4.54(d,J＝6.0Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.2,153.5,149.3,137.5,134.3,133.4,133.0,132.2,129.9,128.0,127.6,127.5,126.5,126.2,125.9,125.6,125.3,125.3,122.7,122.3,115.1,114.9,110.6,46.6.ESI-MS m/z367.0[M+H]+.
化合物I-15,白色固体，产率50％.1H NMR(600MHz,DMSO-d6)δ8.19(d,J＝8.3Hz,1H),8.10(d,J＝7.7Hz,1H),8.01(d,J＝8.0Hz,1H),7.97(d,J＝7.3Hz,1H),7.85(d,J＝8.1Hz,1H),7.60(dd,J＝8.0,7.8Hz,1H),7.58–7.55(m,2H),7.51(dd,J＝8.1,7.8Hz,1H),7.48(dd,J＝8.3,7.2Hz,1H),7.43(dd,J＝7.9,7.3Hz,1H),7.42(brs,1H),7.27–7.23(m,2H),6.86–6.81(m,1H),6.69(t,J＝5.6Hz,1H,NH),4.81(d,J＝5.6Hz,2H).13C NMR(150MHz,DMSO-d6)δ168.2,153.5,149.5,134.6,134.3,133.5,133.4,131.1,129.9,128.5,127.5,126.5,126.2,125.8,125.5,125.3,125.1,123.7,122.7,122.3,115.0,114.9,110.2,44.5.ESI-MS m/z 367.0[M+H]+.
化合物I-16,白色固体，产率69％.1H NMR(600MHz,CDCl3)δ10.23(brs,1H,NH),8.65(d,J＝4.3Hz,1H),8.45(dd,J＝1.7,1.8Hz,1H),8.33(d,J＝7.6Hz,1H),8.11(dd,J＝8.1,1.8Hz,1H),8.09(d,J＝8.1Hz,1H),7.96–7.91(m,2H),7.86(d,J＝7.7Hz,1H),7.55–7.49(m,3H),7.40(dd,J＝7.7,7.1Hz,1H).13C NMR(150MHz,CDCl3)δ167.8,162.4,154.2,149.7,148.2,138.7,137.9,135.3,134.5,130.1,126.8,126.5,125.4,123.5,123.4,122.6,122.1,121.8,118.4.ESI-MS m/z 332.1[M+H]+.
化合物I-17,白色固体，产率51％.1H NMR(600MHz,DMSO-d6)δ10.76(brs,1H,NH),8.84–8.81(m,2H),8.66(dd,J＝1.8,1.7Hz,1H),8.17(d,J＝7.6Hz,1H),8.09(d,J＝8.0Hz,1H),8.02(dd,J＝8.1,1.2Hz,1H),7.94–7.92(m,2H),7.88–7.84(m,1H),7.59(dd,J＝8.0,7.9Hz,1H),7.57(dd,J＝7.6,7.1Hz,1H),7.49(dd,J＝8.0,7.1Hz,1H).13C NMR(150MHz,DMSO-d6)δ167.1,164.3,153.5,150.3,141.6,139.6,134.5,133.3,129.9,126.8,125.7,123.0,122.9,122.5,121.6,118.6.ESI-MS m/z 332.0[M+H]+.
化合物I-18,白色固体，产率62％.1H NMR(600MHz,DMSO-d6)δ10.71(brs,1H,NH),9.17(d,J＝1.7Hz,1H),8.79(dd,J＝4.8,1.7Hz,1H),8.66(brs,1H),8.38–8.34(m,1H),8.17(d,J＝7.9Hz,1H),8.09(d,J＝8.0Hz,1H),8.02(d,J＝8.1Hz,1H),7.85(d,J＝7.9Hz,1H),7.62–7.55(m,3H),7.48(dd,J＝8.0,7.1Hz,1H).13C NMR(150MHz,DMSO-d6)δ167.1,164.4,153.5,152.3,148.8,139.8,135.5,134.5,133.3,130.3,129.9,126.7,125.6,123.5,122.9,122.9,122.7,122.5,118.5.ESI-MS m/z 332.1[M+H]+.
化合物I-19,白色固体，产率82％.1H NMR(600MHz,CDCl3)δ10.44(brs,1H,NH),8.48(brs,1H),8.42(d,J＝8.8Hz,1H),8.39(d,J＝8.4Hz,1H),8.27–8.21(m,2H),8.11(d,J＝8.0Hz,1H),7.96–7.90(m,2H),7.88–7.81(m,2H),7.67(dd,J＝8.4,7.8Hz,1H),7.56(dd,J＝8.8,7.8Hz,1H),7.52(dd,J＝7.6,7.4Hz,1H),7.41(dd,J＝7.4,7.4Hz,1H).13C NMR(150MHz,CDCl3)δ167.8,162.6,154.2,149.5,146.5,138.8,138.1,135.3,134.5,130.6,130.1,129.9,129.7,128.4,128.0,126.6,125.5,123.6,123.4,122.2,121.8,118.8,118.3.ESI-MS m/z 382.1[M+H]+.
化合物I-20,白色固体，产率63％.1H NMR(600MHz,DMSO-d6)δ10.95(brs,1H,NH),10.40(brs,1H,NH),8.51(dd,J＝1.8,1.7Hz,1H),8.14(d,J＝7.9Hz,1H),8.06(d,J＝8.1Hz,1H),7.79(d,J＝8.1Hz,1H),7.74(d,J＝7.7Hz,1H),7.64(d,J＝8.0Hz,1H),7.55(dd,J＝7.9,7.0Hz,1H),7.49(dd,J＝8.4,8.0Hz,1H),7.47(dd,J＝8.1,7.0Hz,1H),7.37(d,J＝8.4Hz,1H),7.30(d,J＝2.4Hz,1H),7.08(dd,J＝7.7,7.0Hz,1H),7.00(dd,J＝8.1,7.0Hz,1H),3.79(s,2H).13C NMR(150MHz,DMSO-d6)δ170.2,167.2,153.5,140.3,136.1,134.4,133.3,129.9,127.2,126.7,125.6,124.0,122.9,122.4,121.9,121.7,121.0,118.7,118.5,117.2,111.4,108.3,33.9.ESI-MS m/z 384.1[M+H]+.
化合物I-21,黄色固体，产率63％.1H NMR(600MHz,DMSO-d6)δ8.10(d,J＝7.9Hz,1H),8.02(d,J＝7.9Hz,1H),7.65(d,J＝8.0Hz,2H),7.52(dd,J＝7.9,7.0Hz,1H),7.43(dd,J＝7.9,7.0Hz,1H),7.41(d,J＝8.1Hz,2H),7.33(brs,1H),7.23–7.19(m,2H),6.74(brs,1H,NH),6.74–6.71(m,1H),4.39(d,J＝4.8Hz,2H),1.27(s,12H).13C NMR(150MHz,DMSO-d6)δ168.1,153.5,149.2,143.5,134.6,134.3,133.4,129.9,126.6,126.5,126.1,125.3,122.7,122.3,115.0,114.9,110.5,83.5,46.3,24.7.ESI-MS m/z 443.2[M+H]+.
化合物I-22,白色固体，产率45％.1H NMR(600MHz,DMSO-d6)δ10.90(s,1H,NH),9.31(d,J＝1.7Hz,1H),8.65(dd,J＝1.7,1.6Hz,1H),8.63(dd,J＝8.3,1.7Hz,1H),8.17(d,J＝8.5Hz,1H),8.14(d,J＝8.3Hz,1H),8.09(d,J＝7.7Hz,1H),8.01(dd,J＝7.9,1.7Hz,1H),7.87(dd,J＝7.9,1.6Hz,1H),7.60(dd,J＝7.9,7.9Hz,1H),7.57(dd,J＝8.5,7.3Hz,1H),7.49(dd,J＝7.7,7.3Hz,1H).13C NMR(150MHz,DMSO-d6)δ167.0,163.2,153.5,149.4,139.5,138.0,134.5,133.5,133.4,130.0,126.8,125.7,123.0,122.9,122.9,122.5,121.6(q,J＝272.0Hz),120.7,120.7,118.6.ESI-MS m/z 400.0[M+H]+.
化合物I-23,黄色油体，产率13％.1H NMR(600MHz,DMSO-d6)δ10.90(s,1H,NH),9.01(d,J＝2.0Hz,1H),8.63(brs,1H),8.41(dd,J＝8.3,2.0Hz,1H),8.17(d,J＝8.0Hz,1H),8.08(d,J＝7.9Hz,1H),8.00(d,J＝7.6Hz,1H),7.85(d,J＝7.7Hz,1H),7.74(d,J＝8.3Hz,1H),7.61–7.54(m,2H),7.48(dd,J＝7.9,7.4Hz,1H).13C NMR(150MHz,DMSO-d6)δ167.1,163.2,153.5,153.0,149.4,139.6,139.1,134.4,133.3,129.9,129.7,126.7,125.7,124.2,122.9,122.9,122.9,122.4,118.5.ESI-MS m/z 388.0[M+Na]+.
化合物I-24,白色固体，产率52％.1H NMR(600MHz,DMSO-d6)δ10.75(s,1H,NH),9.12(brs,1H),8.93(brs,1H),8.68–8.56(m,2H),8.17(d,J＝7.6Hz,1H),8.08(d,J＝7.6Hz,1H),8.01(d,J＝7.3Hz,1H),7.85(d,J＝7.6Hz,1H),7.64–7.54(m,2H),7.48(dd,J＝7.6,6.8Hz,1H).13C NMR(150MHz,DMSO-d6)δ167.0,162.8,153.5,152.9,147.5,139.6,137.8,134.5,133.3,131.8,129.9,126.7,125.7,122.9,122.9,122.8,122.4,120.0,118.5.ESI-MS m/z 410.0,411.9[M+H]+.
化合物I-25,黄色固体，产率39％.1H NMR(600MHz,DMSO-d6)δ10.61(s,1H,NH),9.06(d,J＝2.2Hz,1H),8.65(dd,J＝1.8,1.3Hz,1H),8.26(dd,J＝8.2,2.2Hz,1H),8.17(d,J＝7.8Hz,1H),8.08(d,J＝7.9Hz,1H),8.02(dd,J＝8.2,1.3Hz,1H),7.83(d,J＝7.9Hz,1H),7.59–7.55(m,2H),7.48(ddd,J＝7.9,7.8,1.0Hz,1H),7.44(d,J＝8.2Hz,1H),2.57(s,3H).13C NMR(150MHz,DMSO-d6)δ167.2,164.3,161.4,153.5,148.3,139.9,135.8,134.4,133.3,129.8,127.5,125.7,125.5,122.9,122.9,122.7,122.5,122.4,118.5,24.15.ESI-MS m/z 346.1[M+H]+.
实施例5：化合物对恶性肿瘤细胞A549、Hela、HepG2、MCF7、DB和MV4-11的抑制作用测定
MTT比色法：根据细胞生长速率，将处于对数生长期的肿瘤细胞以100μL/孔接种于96孔板中，贴壁生长24小时再加浓度梯度药物，设6个梯度(0,1.563,3.125,6.25,12.5,25,50,100μM/孔)，每个浓度设三个复孔。在37℃、5％CO2条件下培养48h，然后弃去培养液，每孔加入100μL含10％MTT的培养液，继续培养4h后吸去培养液。最后每孔加入100μL的二甲基亚砜，在全自动多功能酶标仪检测OD值为490nm波长下测定，计算细胞的存活率。
通过Graph Pad Prism 5软件计算存活率达50％时的药物浓度即IC50值。结果如表1所示。
表1.化合物对人肺癌细胞A549的抑制活性结果(单位：μM)
表1说明：各测试化合物对不同肿瘤细胞具有不同程度的抑制作用。其中，化合物I-17对所有测试细胞均具有抑制活性。结果表明，这些化合物对肿瘤细胞具有明显的抑制作用，为新型抗癌药物的研发提供了新的分子模板。
因而，本发明所制备的具有抗肿瘤活性的2-(3-氨基苯基)-苯并噻唑衍生物可以用于制备抗肿瘤的药物，以其为活性成分或主要活性成分，辅以药学上可接受的辅料制成可用于预防和/或治疗肿瘤的药物，在制药领域具有广泛的潜在应用前景。

Claims (7)

1.一种2-(3-氨基苯基)-苯并噻唑衍生物，其特征在于，它具有如下通式I所示的结构：
其中，R为含有取代基的苯基、萘基、吡啶、喹啉、吲哚；X为氢或氧。
2.一种权利要求1所述的2-(3-氨基苯基)-苯并噻唑衍生物的制备方法，其特征在于，它包括以下步骤：
(1)将3-硝基苯甲酸与2-氨基苯硫酚反应，得到式3化合物；所述式3化合物结构式如下：
(2)将式3化合物经催化还原反应，得到式4化合物；所述式4化合物结构式如下：
(3)将式4化合物与卤代物或羧酸衍生物在碱参与下反应，得到通式I化合物。
3.根据权利要求2所述的2-(3-氨基苯基)-苯并噻唑衍生物的制备方法，其特征在于，所述步骤(1)中反应溶剂为二甲亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃、二氯甲烷、1,4-二氧六环及甲苯中至少一种；该反应温度为0℃～150℃，反应时间为1～36小时。
4.根据权利要求2所述的2-(3-氨基苯基)-苯并噻唑衍生物的制备方法，其特征在于，所述步骤(2)中反应所用催化剂为钯、铁、锌、镍；所用溶剂为乙醇、甲醇、正丁醇、二甲基亚砜、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、四氢呋喃、1,4-二氧六环或水，该反应温度为0℃～120℃，反应时间为1～24小时。
5.根据权利要求2所述的2-(3-氨基苯基)-苯并噻唑衍生物的制备方法，其特征在于，所述步骤(3)中所述卤代物为1-溴-4-(溴甲基)苯、溴甲基苯、1-(溴甲基)-4-溴苯、1-(溴甲基)-4-氟苯、2-溴-4-(溴甲基)-1-氟苯、2-溴-1-(溴甲基)-4-氟苯、4-(溴甲基)-1,2-二氟苯、1-(溴甲基)-4-氟-2-甲苯、4-(溴甲基)-1-氟-2-硝基苯、1-(溴甲基)-4-(三氟甲氧基)苯、1-(溴甲基)-4-(三氟甲基)苯、4-(溴甲基)苯甲氰、1-(溴甲基)-4-(甲磺酰基)苯、2-(溴甲基)萘、1-(溴甲基)萘、4-(溴甲基)苯硼酸酯；所述羧酸衍生物为2-吡啶甲酸、3-吡啶甲酸、4-吡啶甲酸、喹啉-2-甲酸、吲哚-3-乙酸、6-三氟甲基烟酸、6-氯烟酸、6-溴烟酸、6-甲基烟酸；所述碱为三乙胺、N,N-二异丙基乙胺、哌啶、哌嗪、吡啶、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或1-4个碳的醇钾及醇钠；所用溶剂为甲醇、乙醇、丙醇、异丙醇、乙腈、1,4-二氧六环、二氯乙烷、N,N-二甲基甲酰胺、N,N-二异丙基乙胺和水中的一种或一种以上；反应温度为0℃～100℃；反应时间为6～36小时。
6.一种权利要求1所述的2-(3-氨基苯基)-苯并噻唑衍生物的用途，其特征在于，用于制备抗肿瘤药物。
7.一种用于预防和/或治疗肿瘤的药物，其特征在于，它是以权利要求1中所述的2-(3-氨基苯基)-苯并噻唑衍生物为活性成分或主要活性成分，辅以药学上可接受的辅料制成。
CN201810643763.6A 2018-06-21 2018-06-21 一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途 Active CN108727295B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810643763.6A CN108727295B (zh) 2018-06-21 2018-06-21 一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810643763.6A CN108727295B (zh) 2018-06-21 2018-06-21 一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途

Publications (2)

Publication Number Publication Date
CN108727295A true CN108727295A (zh) 2018-11-02
CN108727295B CN108727295B (zh) 2022-04-01

Family

ID=63930243

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810643763.6A Active CN108727295B (zh) 2018-06-21 2018-06-21 一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途

Country Status (1)

Country Link
CN (1) CN108727295B (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110885318A (zh) * 2019-11-28 2020-03-17 苏州大学 苯并恶唑衍生物及其制备方法和应用
CN111825619A (zh) * 2020-07-15 2020-10-27 济南大学 一种苯并咪唑类衍生物及其用途
US11084825B2 (en) 2018-12-31 2021-08-10 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11174263B2 (en) 2018-12-31 2021-11-16 Biomea Fusion, Inc. Inhibitors of menin-MLL interaction
US12018032B2 (en) 2021-08-20 2024-06-25 Biomea Fusion, Inc. Crystalline forms of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(r)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide as an irreversible inhibitor of menin-MLL interaction

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101007802A (zh) * 2001-07-27 2007-08-01 柯里斯公司 Hedgehog信号转导途径介质、其相关组合物以及应用
AU2008290864A1 (en) * 2007-08-23 2009-02-26 Sanofi-Aventis Azoloraine derivatives, method for the production thereof, pharmaceuticals containing these compounds, and the use thereof
CN102391207A (zh) * 2011-07-26 2012-03-28 贵州大学 N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-苯甲酰胺及其制备方法和用途
CN107074839A (zh) * 2013-08-29 2017-08-18 贝勒医学院 用于治疗代谢和体重相关的病症的组合物和方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101007802A (zh) * 2001-07-27 2007-08-01 柯里斯公司 Hedgehog信号转导途径介质、其相关组合物以及应用
AU2008290864A1 (en) * 2007-08-23 2009-02-26 Sanofi-Aventis Azoloraine derivatives, method for the production thereof, pharmaceuticals containing these compounds, and the use thereof
CN102391207A (zh) * 2011-07-26 2012-03-28 贵州大学 N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-苯甲酰胺及其制备方法和用途
CN107074839A (zh) * 2013-08-29 2017-08-18 贝勒医学院 用于治疗代谢和体重相关的病症的组合物和方法

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ACS: "STN检索报告", 《STN REGISTRY 数据库》 *
ANITA BUTTNER等: "Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
JONG YEON HWANG等: "Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
MEENAKSHI SINGH等: "Benzothiazole derivatives bearing amide moiety: potential cytotoxic and apoptosis-inducing agents against cervical cancer", 《ANTI-CANCER DRUGS》 *
SAMIA A. ELSEGINY等: "Computer-aided identification of novel anticancer compounds with a possible dual HER1/HER2 inhibition mechanism", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
花尔并等: "苯并噻唑类化合物对高脂模型小鼠抗氧化能力的影响", 《天津科技大学学报》 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11084825B2 (en) 2018-12-31 2021-08-10 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11174263B2 (en) 2018-12-31 2021-11-16 Biomea Fusion, Inc. Inhibitors of menin-MLL interaction
US11702421B2 (en) 2018-12-31 2023-07-18 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11845753B2 (en) 2018-12-31 2023-12-19 Biomea Fusion, Inc. Inhibitors of menin-mll interaction
CN110885318A (zh) * 2019-11-28 2020-03-17 苏州大学 苯并恶唑衍生物及其制备方法和应用
CN110885318B (zh) * 2019-11-28 2022-12-23 苏州大学 苯并恶唑衍生物及其制备方法和应用
CN111825619A (zh) * 2020-07-15 2020-10-27 济南大学 一种苯并咪唑类衍生物及其用途
US12018032B2 (en) 2021-08-20 2024-06-25 Biomea Fusion, Inc. Crystalline forms of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(r)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide as an irreversible inhibitor of menin-MLL interaction

Also Published As

Publication number Publication date
CN108727295B (zh) 2022-04-01

Similar Documents

Publication Publication Date Title
CN108727295A (zh) 一种2-(3-氨基苯基)-苯并噻唑衍生物及其制备方法和用途
EP3733659B1 (en) Aromatic vinyl or aromatic ethyl derivative, preparation method therefor, intermediate, pharmaceutical composition, and application
JP6621486B2 (ja) ピリド−アザヘテロサイクリック化合物及びその製造方法と用途
CN102869256B (zh) 儿茶酚o-甲基转移酶抑制剂及其在治疗精神障碍中的用途
EP2978759B1 (en) Benzimidazolone derivatives as bromodomain inhibitors
EP2598481B1 (en) Sulfonamide compounds useful as cyp17 inhibitors
KR20160132470A (ko) 피페리딘-다이온 유도체
JP2005521698A (ja) 新規な三環式化合物
CN103003262A (zh) 含氮芳香族杂环衍生物
CN107474011A (zh) 一类2‑苯基‑4‑苯乙烯基吡啶类lsd1抑制剂、其制备方法及应用
CN108530310A (zh) 2-(取代苯杂基)芳香甲酸类fto抑制剂，其制备方法及其应用
KR102441864B1 (ko) 괴사의 억제제로서 헤테로아릴 화합물, 이의 조성물 및 이의 용도
CN107501169A (zh) 一类反式二芳基乙烯类lsd1抑制剂、其制备方法及应用
AU2004276268B2 (en) Isoquinoline potassium channel inhibitors
WO2014029726A1 (en) Novel phenyl-pyridine/pyrazine amides for the treatment of cancer
ES2927529T3 (es) Compuesto heterocíclico condensado
EP2340249B1 (en) Poly-heteroaryl derivatives for the treatment of cancer
EP3760633B1 (en) Oxazino-quinazoline and oxazino-quinazoline type compound, preparation method therefor, and uses thereof
CN108689982A (zh) 一种具有α,β-不饱和酮结构片段的香豆素衍生物及其制备方法和用途
CN106117182B (zh) 喹唑啉-n-苯乙基四氢异喹啉类化合物及其制备方法和应用
WO2017161555A1 (zh) 用于合成被芳基或杂芳基取代的5-羟基-1,7-萘啶化合物的中间体及其制备方法
WO2018130227A1 (zh) 一种含芳环化合物、其制备方法、药物组合物及应用
WO2021098716A1 (zh) 一种稠环化合物的晶型、其组合物、制备方法及其应用
CN106565599A (zh) 2‑氨甲基吡啶基烟酰胺类化合物及其制备方法和应用
JP2009073743A (ja) 新規な縮合環式ピリミジン化合物又はその塩、及びその医薬組成物

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
GR01 Patent grant
GR01 Patent grant