CN115974847A - 3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物及其制法和应用 - Google Patents
3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物及其制法和应用 Download PDFInfo
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- CN115974847A CN115974847A CN202211621863.1A CN202211621863A CN115974847A CN 115974847 A CN115974847 A CN 115974847A CN 202211621863 A CN202211621863 A CN 202211621863A CN 115974847 A CN115974847 A CN 115974847A
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- acid
- tetrahydroquinazoline
- methyl
- dione
- compound
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- -1 1,2,3-triazole-4-yl Chemical group 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 239000003814 drug Substances 0.000 claims abstract description 22
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 claims abstract description 21
- 101000973778 Homo sapiens NAD(P)H dehydrogenase [quinone] 1 Proteins 0.000 claims abstract description 20
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 9
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 9
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
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- 229940125532 enzyme inhibitor Drugs 0.000 claims abstract description 6
- 239000002532 enzyme inhibitor Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
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- 125000003118 aryl group Chemical group 0.000 claims description 6
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 2
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- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
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Abstract
本发明公开了3‑(1,2,3‑三氮唑‑4‑基)四氢喹唑啉‑2,4‑二酮类衍生物及其制备方法和应用,所述3‑(1,2,3‑三氮唑‑4‑基)四氢喹唑啉‑2,4‑二酮类衍生物具有式(I)结构的化合物或其药学上可接受的盐。该类化合物为NQO1酶的抑制剂,其可与多种临床抗肿瘤药物联合用药治疗胰腺癌、非小细胞肺癌,从而降低抗肿瘤药物用药剂量,提高用药安全性。
Description
技术领域
本发明涉及一类化合物及其制法和应用,具体涉及3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物及其制法和应用。
背景技术
NQO1酶又称为D-硫辛酰胺脱氢酶,它以黄素腺嘌呤二核苷酸(FAD)为辅基,以还原型烟酰胺腺嘌呤二核苷酸NAD(P)H为辅酶,可以通过双电子还原过程将醌类化合物还原得到氢醌类化合物。NQO1酶的双电子还原过程可以有效避免体内醌类化合物经单电子还原过程生成有毒的活性氧(ROS)及其他自由基,从而起到保护细胞的作用。
NQO1酶在正常组织中的表达较低,但受肿瘤细胞中更高的氧化应激水平影响,NQO1酶会在核转录因子NRF2的调控下大量转录表达。研究表明,NQO1蛋白与肿瘤的发生、发展存在较多联系,因此被认为是一种有效的肿瘤标志物,也被开发成为治疗多种肿瘤的药物作用靶点。NQO1蛋白尤其是在肺癌、胰腺癌等许多实体肿瘤中高表达,且高表达NQO1的患者预后显著更差;也有研究报道表明NQO1蛋白活性的增加可能与肿瘤细胞对抗肿瘤药物的耐药性增加有相关联系。
当前治疗晚期胰腺癌、非小细胞肺癌的方法是使用吉西他滨、顺铂和5-氟尿嘧啶等药物进行化疗,应用此类抗肿瘤药物时患者常会出现骨髓抑制、器官损伤等不良反应。
发明目的
发明目的:本发明的目的在于提供了3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物,该化合物可以作为NQO1酶的抑制剂,可与抗肿瘤药物联合用药,治疗胰腺癌、非小细胞肺癌,同时减少抗肿瘤药物用药剂量,减小副作用,保证用药安全性。本发明的另一个目的是提供所述3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物的制备方法和在制备与抗肿瘤药物联合使用治疗胰腺癌、非小细胞肺癌药物中的应用。
技术方案:本发明所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物,具有式(I)结构的化合物或其药学上可接受的盐:
其中,Ar1代表含有碳原子和氮原子的5~6元的芳环;
Ar2代表含有5~6个原子的芳基,或8~10元的双环芳基或杂芳基,其中杂芳基是指环成员中含有1~2个选自氮、氧的相同或不同杂原子的芳基;
R1代表位于Ar1环上任意位置一个或多个取代基,取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、酰基、羟基;
R2代表位于Ar上任意位置一个或多个取代基,取代基选自氢、C1-C4烷基、C1-C4烷氧基、C1-C4烷氨基、C1-C4卤代烷基、卤素、苯基、三氟甲氧基、氰基、羟基、氨基、羧基、氨磺酰基、C1-C4烷磺酰基、C1-C4酰氨基、C1-C4烷氨酰基;
X可代表亚氨基、氧原子或化学键;m为1或2;n为0或1。
所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物,所述结构中:
m为1,n为1。
所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物,所述化合物选自以下化合物:
所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物,所述药学上可接受的盐为所述化合物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸;所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱,胆碱、二乙醇胺或吗啉。
所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物的制备方法,包括以下步骤:
化合物(II)经铜催化叠氮与端炔1,3-偶极环加成反应得到化合物(I);
药物组合物,所述药物组合物包含所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物以及药学上可接受的载体;上述3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物可以添加药学上可接受的载体制成药用制剂。
所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物在制备NQO1酶抑制剂药物中的应用。
所述的药物组合物在制备NQO1酶抑制剂药物中的应用。
所述的应用,所述药物用于与抗肿瘤药物联合用药治疗肿瘤疾病。
所述的应用,所述肿瘤疾病选自胰腺癌、非小细胞肺癌。
有益效果:本发明与现有技术相比,具有如下优点:本发明的化合物或其可药用的盐可与多种临床抗肿瘤药物联合用药治疗胰腺癌、非小细胞肺癌等癌症,从而降低抗肿瘤药物用药剂量。本发明的化合物为NQO1抑制剂与抗肿瘤药物联合用药可以起到促进肿瘤细胞凋亡的协同作用,在提高药效同时可以有效降低抗肿瘤药物用药剂量,减小副作用,保证用药安全性,具有良好的应用前景。
附图说明
图1为代表性化合物与吉西他滨联用时增强其杀伤癌细胞的图;
图2为代表性化合物与顺铂联用时增强其杀伤癌细胞的图。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好的阐述本发明,并不是用来限制本发明的范围。
实施例1 3-({1-[(4-氟苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-8-羟基-1,2,3,4-四氢喹唑啉-2,4-二酮
8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮(40mg,0.19mmol),1-叠氮甲基-4-氟苯(0.25mmol,43μL),五水合硫酸铜(5%equiv,2.4mg),抗坏血酸钠(5%equiv,1.9mg)溶于1mL无水N,N-二甲基甲酰胺中,将反应液在80℃下反应8小时,反应结束后向反应液中加入过量水,抽滤收集固体,得到的滤渣以石油醚:乙酸乙酯=1:1为展开剂经硅胶柱层析分离得到目标物3-({1-[(4-氟苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-8-羟基-1,2,3,4-四氢喹唑啉-2,4-二酮48mg,产率68.4%,白色固体。mp>300℃,该化合物的1H-NMR(400MHz,DMSO-d6)δ10.57(s,2H),8.04(s,1H),7.44–7.34(m,3H),7.19(t,J=8.7Hz,2H),7.10(d,J=7.7Hz,1H),7.03(t,J=7.8Hz,1H),5.52(s,2H),5.13(s,2H).HRMS(ESI):calcd.For C18H14FN5O3[M+H]+368.1153,found 368.1150.
实施例2 3-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-8-羟基-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用1-叠氮甲基-4-氯苯替代1-叠氮甲基-4-氟苯(0.25mmol,44μL),得目标物3-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-8-羟基-1,2,3,4-四氢喹唑啉-2,4-二酮52mg,产率71.2%,为白色固体。mp>300℃,该化合物的1H-NMR(400MHz,DMSO-d6)δ10.60(s,2H),8.06(s,1H),7.46–7.38(m,3H),7.36–7.28(m,2H),7.11(dd,J=7.9,1.4Hz,1H),7.03(t,J=7.8Hz,1H),5.54(s,2H),5.14(s,2H).HRMS(ESI):calcd.For C18H14ClN5O3[M+H]+384.0858,found 384.0862.
实施例3 3-({1-[(4-溴苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-8-羟基-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用1-叠氮甲基-4-溴苯(48μL,0.25mmol)替代1-叠氮甲基-4-氟苯,得目标物3-({1-[(4-溴苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-8-羟基-1,2,3,4-四氢喹唑啉-2,4-二酮57mg,为白色固体,产率69.8%。mp>300℃,该化合物的1H-NMR(400MHz,DMSO-d6)δ10.66(s,1H),10.47(s,1H),8.05(s,1H),7.56(d,J=8.0Hz,2H),7.40(d,J=7.8Hz,1H),7.25(d,J=8.0Hz,2H),7.11(d,J=7.8Hz,1H),7.04(t,J=7.9Hz,1H),5.52(s,2H),5.14(s,2H).HRMS(ESI):calcd.For C18H14BrN5O3[M+H]+428.0353,found 428.0355.
实施例4 8-羟基-3-[(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用1-(叠氮甲基)-4-(三氟甲基)苯(43μL,0.25mmol)替代1-叠氮甲基-4-氟苯,得目标物8-羟基-3-[(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢喹唑啉-2,4-二酮52mg,产率65.1%,为白色固体。mp>300℃,该化合物的1H-NMR(400MHz,DMSO-d6)δ10.70(s,1H),10.47(s,1H),8.11(s,1H),7.74(d,J=7.8Hz,2H),7.48(d,J=7.9Hz,2H),7.40(d,J=7.8Hz,1H),7.08(dd,J=24.6,7.8Hz,2H),5.66(s,2H),5.15(s,2H).HRMS(ESI):calcd.For C19H14F3N5O3[M+H]+418.1122,found 418.1127.
实施例5 8-羟基-3-[(1-{[4-(甲基二氧亚基-λ6-硫基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用[4-(叠氮甲基)苯基](甲基)二氧亚基-λ6-硫烷(53mg,0.25mmol)替代1-叠氮甲基-4-氟苯,得目标物8-羟基-3-[(1-{[4-(甲基二氧亚基-λ6-硫基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢喹唑啉-2,4-二酮50mg,产率61.0%,为白色固体。mp>300℃,该化合物的1H-NMR(400MHz,DMSO-d6)δ10.62(s,2H),8.12(s,1H),7.92(d,J=7.9Hz,2H),7.53(d,J=7.9Hz,2H),7.40(d,J=7.9Hz,1H),7.11(d,J=7.8Hz,1H),7.04(t,J=7.8Hz,1H),5.68(s,2H),5.15(s,2H),3.19(s,3H).HRMS(ESI):calcd.For C19H17N5O5S[M+H]+428.1023,found428.1018.
实施例6 4-({4-[(8-羟基-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯-1-磺酰胺
制备方法同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用4-(叠氮甲基)苯-1-磺酰胺(53mg,0.25mmol)替代1-叠氮甲基-4-氟苯,得目标物4-({4-[(8-羟基-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯-1-磺酰胺44mg,产率54.6%,为白色固体。mp>300℃,该化合物的1H NMR(300MHz,DMSO-d6)δ10.95(s,1H),8.09(s,1H),7.80(d,J=7.9Hz,2H),7.48(dd,J=17.6,8.0Hz,3H),7.35(s,1H),7.17(t,J=8.1Hz,1H),5.63(s,2H),5.14(s,2H),3.89(s,3H)..HRMS(ESI):calcd.For C18H16N6O5S[M+H]+429.0976,found 429.0974.
实施例7 8-羟基-3-{[1-({4-[(三氟甲基)氧基]苯基}甲基)-1,2,3-三氮杂环戊熳-4-基]甲基}-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用1-(叠氮甲基)-4-[(三氟甲基)氧基]苯(50μL,0.25mmol)替代1-叠氮甲基-4-氟苯,得目标物8-羟基-3-{[1-({4-[(三氟甲基)氧基]苯基}甲基)-1,2,3-三氮杂环戊熳-4-基]甲基}-1,2,3,4-四氢喹唑啉-2,4-二酮51mg,产率61.7%,为白色固体。mp>300℃,该化合物的1H-NMR(300MHz,DMSO-d6)δ8.11(s,1H),7.42(q,J=8.9Hz,5H),7.10(dd,J=17.3,7.7Hz,2H),5.60(s,2H),5.16(s,2H).HRMS(ESI):calcd.For C19H14F3N5O4[M+H]+434.1071,found 434.1066.
实施例8 4-({4-[(8-羟基-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯-1-甲腈
制备方法同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用4-(叠氮甲基)苯-1-甲腈(0.25mmol,39.5mg)替代1-叠氮甲基-4-氟苯,得目标物4-({4-[(8-羟基-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯-1-甲腈47mg,产率66.2%,为白色固体。mp>300℃,该化合物的1H-NMR(400MHz,DMSO-d6)δ10.62(s,2H),8.11(s,1H),7.84(d,J=8.0Hz,2H),7.42(dd,J=14.4,7.9Hz,3H),7.11(d,J=7.6Hz,1H),7.03(t,J=7.9Hz,1H),5.66(s,2H),5.15(s,2H).HRMS(ESI):calcd.ForC19H14N6O3[M+H]+375.1200,found 375.1194.
实施例9 8-羟基-3-({1-[(4-甲基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用4-(叠氮甲基)-1-甲基苯(0.25mmol,48μL)替代1-叠氮甲基-4-氟苯,得目标物3-({1-[(4-甲基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮43mg,产率62.3%,为白色固体。mp>300℃。该化合物的1HNMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.46(t,J=7.5Hz,1H),7.15(dt,J=7.8,1.0Hz,2H),7.12–7.08(m,2H),6.90(dd,J=7.5,2.0Hz,1H),5.29(t,J=1.0Hz,2H),5.01(s,2H),2.34(d,J=1.9Hz,3H).HRMS(ESI):calcd.For C19H17N5O3[M+H]+364.1404,found364.1407.
实施例10 4-({4-[(8-羟基-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯甲酸
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用4-(叠氮甲基)苯甲酸(0.25mmol,44.3mg)替代1-叠氮甲基-4-氟苯,得目标物4-({4-[(2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯甲酸38mg,产率50.9%,为白色固体。mp>300℃。该化合物的1H NMR(500MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.94–7.88(m,3H),7.80(s,1H),7.50–7.39(m,2H),7.34(ddt,J=7.3,2.4,1.2Hz,2H),6.90(dd,J=7.5,2.0Hz,1H),5.30(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C19H15N5O5[M+H]-392.1000,found 392.0993.
实施例11 8-羟基-3-({1-[(4-硝基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用4-(叠氮甲基)-1-硝基苯(0.25mmol,44.54mg)替代1-叠氮甲基-4-氟苯,得目标物8-羟基-3-({1-[(4-硝基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮40mg,产率53.4%,为白色固体。mp>300℃。该化合物的1H NMR 400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),8.22–8.12(m,2H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.64–7.56(m,2H),7.46(t,J=7.5Hz,1H),6.90(dd,J=7.5,2.0Hz,1H),5.32(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C18H14N6O5[M+H]+395.1098,found395.1101.
实施例12 8-羟基-3-({1-[(4-羟基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用4-(叠氮甲基)苯酚(0.25mmol,37.29mg)替代1-叠氮甲基-4-氟苯,得目标物8-羟基-3-({1-[(4-羟基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮36mg,产率51.9%,为白色固体。mp>300℃。该化合物的1H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.46(t,J=7.5Hz,1H),7.22(s,1H),7.11–7.04(m,2H),6.90(dd,J=7.5,2.0Hz,1H),6.80–6.74(m,2H),5.30(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C18H15N5O4[M+H]+366.1197,found 366.1203.
实施例13 8-羟基-3-{[1-(吡啶-2-基甲基)-1,2,3-三氮杂环戊熳-4-基]甲基}-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用2-(叠氮甲基)吡啶(0.25mmol,54μL)替代1-叠氮甲基-4-氟苯。得目标物8-羟基-3-{[1-(吡啶-2-基甲基)-1,2,3-三氮杂环戊熳-4-基]甲基}-1,2,3,4-四氢喹唑啉-2,4-二酮44mg,产率66.1%,为白色固体。mp>300℃。该化合物的1HNMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),8.51(dd,J=5.0,1.2Hz,1H),7.97(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.73(td,J=8.0,1.2Hz,1H),7.46(t,J=7.5Hz,1H),7.32(dd,J=8.0,1.0Hz,1H),7.26(ddd,J=8.0,5.1,1.1Hz,1H),6.90(dd,J=7.5,2.0Hz,1H),5.61(s,2H),5.01(s,2H).HRMS(ESI):calcd.For C17H14N6O3[M+H]+351.1200,found 351.1201.
实施例14 8-羟基-3-({1-[(4-苯基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用1-(叠氮甲基)-4-苯基苯(0.25mmol,53μL)替代1-叠氮甲基-4-氟苯。得目标物8-羟基-3-({1-[(4-苯基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮42mg,产率52.0%。该化合物的1H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.62–7.58(m,2H),7.57–7.53(m,2H),7.48–7.35(m,4H),7.24–7.20(m,2H),6.90(dd,J=7.5,2.0Hz,1H),5.30(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C24H19N5O3[M+H]+426.1591,found426.1596
实施例15 8-羟基-3-({1-[(3-甲氧基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用1-(叠氮甲基)-3-甲氧基苯(0.25mmol,41μL)替代1-叠氮甲基-4-氟苯。得目标物8-羟基-3-({1-[(3-甲氧基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮47mg,产率65.2%。该化合物的1H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.46(t,J=7.5Hz,1H),7.19(t,J=7.5Hz,1H),7.07(dtt,J=7.5,2.0,1.0Hz,1H),6.90(dd,J=7.5,2.0Hz,1H),6.84(dq,J=5.1,2.0Hz,2H),5.34(t,J=1.0Hz,2H),5.01(s,2H),3.82(s,3H).HRMS(ESI):calcd.For C19H17N5O4[M+H]+380.1353,found 380.1355.
实施例16 8-羟基-3-[(1-{[3-(甲基氨基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同同实施例1,8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮原料不变,用[2-(叠氮甲基)苯基](甲基)胺(0.25mmol,48μL)替代1-叠氮甲基-4-氟苯。得目标物8-羟基-3-({1-[(3-甲氧基苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-1,2,3,4-四氢喹唑啉-2,4-二酮43mg,产率59.7%,为白色固体。该化合物的1H-NMR(400MHz,Chloroform-d)δ7.94(dd,J=7.5,2.0Hz,1H),7.79(s,1H),7.44(td,J=7.5,2.0Hz,1H),7.29(dd,J=7.5,2.0Hz,1H),7.21–7.14(m,2H),7.13–7.07(m,2H),6.94(dd,J=7.4,1.8Hz,1H),6.64(s,1H),5.37(d,J=0.9Hz,2H),5.01(s,2H),3.13(s,3H).HRMS(ESI):calcd.For C19H18N6O3[M+H]+379.1513,found 379.1510.
实施例17 2-{[1-(4-氯苯基)-1,2,3-三氮杂环戊熳-4-基]甲基}异吲哚-1,3-二酮
制备方法同实施例1,用2-(丙-2-炔基)异吲哚-1,3-二酮(0.19mmol,35.2mg)替代8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用4-叠氮-1-氯苯(0.25mmol,46μL)替代1-叠氮甲基-4-氟苯,得目标物2-{[1-(4-氯苯基)-1,2,3-三氮杂环戊熳-4-基]甲基}异吲哚-1,3-二酮51mg,产率78.9%,该化合物为白色固体。1H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.89(dd,J=5.4,3.0Hz,2H),7.75(dd,J=5.5,3.0Hz,2H),7.70–7.65(m,2H),7.52–7.47(m,2H),5.10(s,2H).HRMS(ESI):calcd.For C17H11ClN4O2[M+H]+339.0643,found 339.0645.
实施例18 2-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)异吲哚-1,3-二酮
制备方法同实施例1。用2-(丙-2-炔基)异吲哚-1,3-二酮(0.19mmol,35.2mg)替代8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用4-(叠氮甲基)-1-氯苯(0.25mmol,44μL)替换1-叠氮甲基-4-氟苯。得到目标物2-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)异吲哚-1,3-二酮49.4mg,产率74.1%。该化合物为白色固体。1HNMR(400MHz,Chloroform-d)δ7.87(dd,J=5.5,3.0Hz,2H),7.74(dd,J=5.5,3.0Hz,2H),7.53(s,1H),7.38–7.33(m,2H),7.24–7.18(m,2H),5.47(s,2H),4.99(s,2H).HRMS(ESI):calcd.For C18H13ClN4O2[M+H]+353.0800,found 353.0809.
实施例19 2-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)异吲哚-1,3-二酮
制备方法同实施例1,用3-(丙-2-炔基)-3,4-二氢-2H-苯并[2,1-e][1,3]氧杂氮杂环己熳-2,4-二酮(0.19mmol,38.2mg)替代8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用4-叠氮-1-氯苯(0.25mmol,46μL)替换1-叠氮甲基-4-氟苯,得到目标物2-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)异吲哚-1,3-二酮48.6mg,产率72.1%。该化合物为白色固体,1H NMR(400MHz,Chloroform-d)δ8.14(dd,J=7.9,1.6Hz,1H),8.12(s,1H),7.78–7.71(m,1H),7.71–7.67(m,2H),7.53–7.48(m,2H),7.41(ddd,J=8.2,7.4,1.0Hz,1H),7.31(dd,J=8.3,1.0Hz,1H).HRMS(ESI):calcd.For C18H13ClN4O3[M+H]+355.0592,found 369.0751.
实施例20 3-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-3,4-二氢-2H-苯并[2,1-e][1,3]氧杂氮杂环己熳-2,4-二酮
制备方法同实施例1。用3-(丙-2-炔基)-3,4-二氢-2H-苯并[2,1-e][1,3]氧杂氮杂环己熳-2,4-二酮(0.19mmol,38.2mg)替代8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用4-(叠氮甲基)-1-氯苯(0.25mmol,44μL)替换1-叠氮甲基-4-氟苯。得到目标物3-({1-[(4-氯苯基)甲基]-1,2,3-三氮杂环戊熳-4-基}甲基)-3,4-二氢-2H-苯并[2,1-e][1,3]氧杂氮杂环己熳-2,4-二酮49.5mg,产率70.1%。该化合物为白色固体。1H-NMR(400MHz,Chloroform-d)δ8.00(dd,J=7.5,2.0Hz,1H),7.78(s,1H),7.46(td,J=7.5,2.0Hz,1H),7.36–7.23(m,6H),5.31(d,J=1.1Hz,2H),5.09(s,2H).HRMS(ESI):calcd.ForC18H13ClN4O3[M+H]+369.0749,found369.0744.
实施例21 3-[2-(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)乙基]-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1,用3-(丁-3-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮(40mg,0.19mmol)替代8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用1-(叠氮甲基)-4-(三氟甲基)苯(0.25mmol,44μL)替代1-叠氮甲基-4-氟苯,得目标物3-[2-(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)乙基]-1,2,3,4-四氢喹唑啉-2,4-二酮44mg,产率56.7%。该化合物的HRMS(ESI):calcd.For C20H16F3N5O2[M+H]+416.1329,found416.1325.
实施例22 3-[2-(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)乙基]-3,4-二氢-2H-苯并[2,1-e][1,3]氧杂氮杂环己熳-2,4-二酮
制备方法同实施例1,用3-(丁-3-炔基)-3,4-二氢-2H-苯并[2,1-e][1,3]氧杂氮杂环己熳-2,4-二酮(41mg,0.19mmol)替代8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用1-(叠氮甲基)-4-(三氟甲基)苯(0.25mmol,44μL)替代1-叠氮甲基-4-氟苯,得白色固体3-[2-(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)乙基]-3,4-二氢-2H-苯并[2,1-e][1,3]氧杂氮杂环己熳-2,4-二酮57mg,产率72.1%,为白色固体。该化合物的HRMS(ESI):calcd.For C20H15F3N4O3[M+H]+417.1169,found 417.1171.
实施例23 2-[2-(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)乙基]异吲哚-1,3-二酮
制备方法同实施例1,用2-(丁-3-炔基)异吲哚-1,3-二酮(38mg,0.19mmol)替代8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用1-(叠氮甲基)-4-(三氟甲基)苯(0.25mmol,44μL)替代1-叠氮甲基-4-氟苯,得目标物2-[2-(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)乙基]异吲哚-1,3-二酮52mg,产率68.4%,为白色固体。该化合物的HRMS(ESI):calcd.For C20H15F3N4O2[M+H]+401.1220,found 401.1228.
实施例24 3-[(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-2,4-二酮
制备方法同实施例1,用3-(丙-2-炔基)-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-2,4-二酮(38mg,0.19mmol)替代8-甲氧基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用1-(叠氮甲基)-4-(三氟甲基)苯(0.25mmol,44μL)替代1-叠氮甲基-4-氟苯,得目标物3-[(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢吡啶并[3,2-d]嘧啶-2,4-二酮48mg,产率62.4%。该化合物的HRMS(ESI):calcd.For C18H13F3N6O2[M+H]+403.1125,found 403.1127.
实施例25 3-{[1-(1H-吲哚-3-基甲基)-1,2,3-三氮杂环戊熳-4-基]甲基}-7-甲氧基-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1,用7-甲氧基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮(44mg,0.19mmol)替换8-羟基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用3-(叠氮甲基)-1H-吲哚(0.25mmol,44μL)替代1-叠氮甲基-4-氟苯,得目标物3-{[1-(1H-吲哚-3-基甲基)-1,2,3-三氮杂环戊熳-4-基]甲基}-7-甲氧基-1,2,3,4-四氢喹唑啉-2,4-二酮44mg,产率54.1%,为白色固体。该化合物的HRMS(ESI):calcd.For C21H18N6O3[M+H]+403.1513,found 403.1508.
实施例26 4-({4-[(5-氯-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯-1-甲酰胺
制备方法同实施例1,用5-氯-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮替代8-甲氧基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用4-(叠氮甲基)苯-1-甲酰胺(0.25mmol,44mg)替代1-叠氮甲基-4-氟苯,得到目标物4-({4-[(5-氯-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯-1-甲酰胺,为白色固体。该化合物的HRMS(ESI):calcd.For C21H16F3N5O3[M+H]+444.1278,found 444.1274.
实施例27N-[4-({4-[(6-甲基-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯基]乙酰胺
制备方法同实施例1,用6-甲基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮(41mg,0.19mmol)替代8-甲氧基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用N-[4-(叠氮甲基)苯基]乙酰胺(0.25mmol,44μL)替代1-叠氮甲基-4-氟苯,得到目标物N-[4-({4-[(6-甲基-2,4-二氧亚基-1H-喹唑啉-3-基)甲基]-1,2,3-三氮杂环戊熳-1-基}甲基)苯基]乙酰胺50mg,产率63.3%,为白色固体。该化合物的HRMS(ESI):calcd.For C21H20N6O3[M+H]+405.1670,found 405.1677.
实施例28 6-乙酰基-3-[(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢喹唑啉-2,4-二酮
制备方法同实施例1.用6-乙酰基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮(46mg,0.19mmol)替换8-甲氧基-3-(丙-2-炔基)-1,2,3,4-四氢喹唑啉-2,4-二酮,用1-(叠氮甲基)-4-(三氟甲基)苯(0.25mmol,44μL)替代1-叠氮甲基-4-氟苯,得到目标物6-乙酰基-3-[(1-{[4-(三氟甲基)苯基]甲基}-1,2,3-三氮杂环戊熳-4-基)甲基]-1,2,3,4-四氢喹唑啉-2,4-二酮51mg,产率61.1%,为白色固体。该化合物的HRMS(ESI):calcd.ForC18H14ClN5O3[M+H]+384.0858,found 384.0862.
实施例29
本发明部分化合物的药理学实验及结果:
1.分光光度法测试本发明化合物对NQO1蛋白的抑制作用。
为评价本系列发明化合物对NQO1蛋白的抑制作用,本发明使用分光光度法(Spectrophotometry)测试系列化合物对NQO1蛋白与其底物β-拉帕醌结合的抑制作用。测试方法如下:测试选用器材为96孔白板,测试体积为200μL,所测试的系列化合物母液经缓冲溶液稀释后,得到三个不同浓度后,每孔加入2μL化合物、2μLNQO1蛋白、2μLβ-拉帕醌、190μL缓冲溶液。37℃下孵育5min后,每孔加入4μLNADPH,随后立即使用Spectra Max i3x多功能酶标仪检测340nm吸光度。测试结果使用Graphpad Prism 8进行分析。测试中使用的空白对照为192μL缓冲溶液、2μLNQO1蛋白、2μLβ-拉帕醌、4μLNADPH,,阳性对照为等浓度的天然NQO1抑制剂双香豆素。缓冲溶液配置方法为:0.2M Na2HPO4,0.2M NaH2PO4,0.9% NaCl。
表1实施例化合物的NAD(P)H:醌氧化还原酶1的抑制活性
由表1可知,本发明的3-烷基取代1,2,3-三氮唑-2,4-喹唑啉二酮类化合物具有较强的NAD(P)H:醌氧化还原酶1抑制活性。大部分实施例化合物的活性优于天然NAD(P)H:醌氧化还原酶1抑制剂双香豆素。实施例化合物中,实施例-4化合物的NQO1蛋白抑制活性最优。
2.MTT比色法(MTT assay)测试本发明中部分化合物与吉西他滨联合用药对人体胰腺癌细胞株MIAPaCa-2的细胞毒性及与顺铂或5-氟尿嘧啶联合用药对人体肺癌细胞株A549的细胞毒性
实验方法如下:将不同肿瘤细胞接种在96孔板中,随后放置入孵箱等待至细胞贴壁。将所有化合物配置成100mM的母液,并将化合物用缓冲溶液稀释至200μM后,再进行三倍稀释连续得到六个浓度。取100μL化合物溶液与100μL缓冲溶液添加至96孔板的每个孔中。在37℃条件下将96孔板孵育72小时,随后向每个空中加入20μL 5mg/ml的MTT溶液,在孵箱中孵育4小时。待孵育结束,吸取并除去每个孔中的溶液,向每个孔中加入150μL的DMSO溶液,在摇床上震摇10分钟,检测570nm处吸光度,测试结果使用Graphpad Prism 8进行分析。
表2部分实施例化合物与吉西他滨联用细胞毒性
表3部分实施例化合物与顺铂联用细胞毒性
表4实施例化合物与抗肿瘤药物作用情况
由表2、3可见,本发明的代表性化合物的联合用药实验结果显示代表性化合物与吉西他滨、顺铂或5-氟尿嘧啶联用时能够增强其杀伤癌细胞的药效。进一步的,本发明实施例中最优的化合物4在较高浓度下与吉西他滨或顺铂联用时表现出较好的细胞毒性(图1、2)。
Claims (10)
1.一种3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物,其特征在于,具有式(I)结构的化合物或其药学上可接受的盐:
其中,Ar1代表含有碳原子和氮原子的5~6元的芳环;
Ar2代表含有5~6个原子的芳基,或8~10元的双环芳基或杂芳基,其中杂芳基是指环成员中含有1~2个选自氮、氧的相同或不同杂原子的芳基;
R1代表位于Ar1环上任意位置一个或多个取代基,取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4卤代烷基、卤素、酰基、羟基;
R2代表位于Ar上任意位置一个或多个取代基,取代基选自氢、C1-C4烷基、C1-C4烷氧基、C1-C4烷氨基、C1-C4卤代烷基、卤素、苯基、三氟甲氧基、氰基、羟基、氨基、羧基、氨磺酰基、C1-C4烷磺酰基、C1-C4酰氨基、C1-C4烷氨酰基;
X可代表亚氨基、氧原子或化学键;m为1或2;n为0或1。
4.根据权利要求1或2所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物,其特征在于,所述药学上可接受的盐为所述化合物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸;所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱,胆碱、二乙醇胺或吗啉。
6.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~4任一所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物以及药学上可接受的载体;上述3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物可以添加药学上可接受的载体制成药用制剂。
7.权利要求1~4任一所述的3-(1,2,3-三氮唑-4-基)四氢喹唑啉-2,4-二酮类衍生物在制备NQO1酶抑制剂药物中的应用。
8.权利要求6所述的药物组合物在制备NQO1酶抑制剂药物中的应用。
9.根据权利要求7或8所述的应用,其特征在于,所述药物用于与抗肿瘤药物联合用药治疗肿瘤疾病。
10.根据权利要求9所述的应用,其特征在于,所述肿瘤疾病选自胰腺癌、非小细胞肺癌。
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