CN115872870A - 一种小分子nqo2抑制剂及其制备方法与应用 - Google Patents
一种小分子nqo2抑制剂及其制备方法与应用 Download PDFInfo
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- CN115872870A CN115872870A CN202211462393.9A CN202211462393A CN115872870A CN 115872870 A CN115872870 A CN 115872870A CN 202211462393 A CN202211462393 A CN 202211462393A CN 115872870 A CN115872870 A CN 115872870A
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- 230000007774 longterm Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
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- 150000003252 quinoxalines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
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- 239000011550 stock solution Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明属于生物医药领域,涉及一种小分子NQO2抑制剂及其制备方法与应用。其为式(I)、(II)或(III)所示的化合物或其药学上可接受的盐,
Description
技术领域
本发明属于生物医药领域,涉及一种小分子NQO2抑制剂及其制备方法与应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
据发明人研究了解,白藜芦醇(反式3,4’,5-三羟基二苯乙烯)具有良好的化学预防作用,其直接作用靶点是NQO2,但其存在缺点:其一,白藜芦醇对靶点的选择性相对较弱,除NQO2外还能够作用于人体中其他受体和靶点,如芳香化酶、环氧化酶、NF-κB和鸟氨酸脱羧酶等,长期使用易导致毒副作用的产生;其二,白藜芦醇的生物学活性较弱,对NQO2的半抑制浓度在微摩尔级别,距离成药仍有较大差距,若提高剂量达到治疗效果,同样易导致毒副作用的发生;其三,白藜芦醇的生物利用度有限,在进入体内后其酚羟基会被迅速代谢为硫酸盐和葡萄糖醛酸等形式,这导致其在体内活性较体外明显减弱。上述三条原因很大程度上限制了白藜芦醇作为肿瘤疾病的化学预防药物进行开发和研制的潜力。
发明内容
为了解决现有技术的不足,本发明的目的是提供一种小分子NQO2抑制剂及其制备方法与应用,本发明提供的小分子NQO2抑制剂具有靶点明确、结构新颖、活性效果突出和制备成本低廉等优势,可以作为针对肿瘤疾病的很有前景的化学预防剂。
为了实现上述目的,本发明的技术方案为:
一方面,一种小分子NQO2抑制剂,其为式(I)所示的化合物或其药学上可接受的盐,
R1为氢原子、甲氧基或羟基;
R2为C1-C2烷氧基或羟基;
R3为氢原子或甲氧基
R4为氢原子、氰基、C1-C2烷氧基、氨甲基、氨基甲酰基或(Z)-N、-羟基脒基;
R5为硝基、氢原子、C1-C2烷氧基或氨基;
或者,其为式(II)所示的化合物或其药学上可接受的盐,
R6为溴原子、氢原子、甲氧基或氨基;
R7为氢原子、甲氧基、羟基或氨基;
R8为氢原子或甲氧基;
R9为硝基、氟原子、甲氧基、氨基或羟基;
X为碳原子或氮原子;
或者,其为式(III)所示的化合物或其药学上可接受的盐,
Y为硫原子或氧原子。
本发明所述的药学上可接受的盐为与无机酸或有机酸形成的盐,所述无机酸例如盐酸、硫酸、硝酸或氢溴酸等;所述有机酸例如甲磺酸、甲苯磺酸或三氟乙酸等。
进一步地,包括如下化合物:
另一方面,一种上述小分子NQO2抑制剂的制备方法,包括按照如下路线使式(G-1)的化合物与式(G-2)所示的化合物反应得到式(G-3)所示的化合物,进而通过还原、氧化和脱甲基等反应得到式(I)所示的化合物的过程;
或者,包括按照如下路线使式(G-4)所示的化合物和式(G-5)所示的化合物通过偶联反应得到式(II)所示的化合物的过程;
或者,包括按照如下路线使式(G-6)所示的化合物通过脱甲基和还原反应得到式(II)所示的化合物的过程;
或者,包括按照如下路线使(G-7)所示的化合物和式(G-8)所示的化合物通过偶联反应得到式(III)所示的化合物的过程;
进一步地,式(G-1)所示的化合物的制备方法为:以式(G-9)所示的化合物为起始原料发生还原方法得式(G-10)所示的化合物,进而通过与三苯基膦氢溴酸盐制得式(G-1)所示的化合物;
进一步地,式(G-6)所示的化合物的制备方法为:式(G-11)的化合物与式(G-12)所示的化合物反应得到式(G-6)所示的化合物;
或者,式(G-13)所示的化合物为起始原料发生氧化反应得式(G-14)所示的化合物,将式(G-14)所示的化合物与式(G-15)所示的化合物发生环化反应得到式(G-6)所示的化合物;
或者,式(G-16)的化合物与式(G-17)所示的化合物反应得到式(G-6)所示的化合物;
第三方面,一种药物组合物,包括上述小分子NQO2抑制剂和一种或多种药学上可接受的辅料。
所用的辅料可为固态或液态。固体辅料可以是碳酸镁、硬脂酸镁、滑石粉、糖或者乳糖。
固态形式的制剂包括粉剂、片剂、分散颗粒、胶囊、药丸及栓剂。粉剂及片剂可包含约5%至约95%的活性成分。液态形式的制剂包括溶液、悬浮液及乳液,其实施例为非经肠注射用水溶液或水-丙二醇溶液,或添加甜味剂及造影剂的口服溶液。此外,还可制成注射用小水针、注射用冻干粉针、大输液或小输液。
进一步地,其剂型为固体口服制剂、液体口服制剂或注射剂。
更进一步地,所述剂型为片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小水针、注射用冻干粉针、大输液或小输液。
第四方面,一种上述小分子NQO2抑制剂或药物组合物在制备预防肿瘤疾病的药物中的应用。
进一步地,所述肿瘤疾病包括肺癌、乳腺癌、胃癌、食管癌、肝癌、结直肠癌、甲状腺癌、前列腺癌、宫颈癌、卵巢癌及白血病等。
本发明的有益效果为:
本发明研究表明,本发明提供的化合物具有靶点明确、结构新颖,活性效果突出,通过体外NQO2抑制活性表明,本发明提供的部分化合物(例如合物I-10、I-38、I-45和I-46)中具有显著的体外NQO2抑制活性。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。
实施例1:化合物I-1~I-9的制备
步骤1:化合物3a、3b和3c的制备
实验方法a:将多取代苯甲醛(1a~1c,25.48mmol)溶于无水乙醇(,冰水浴搅拌,加入硼氢化钠(63.71mmol),继续搅拌15分钟后,室温反应1小时。向体系中加入蒸馏水猝灭反应,二氯甲烷萃取,合并有机相,无水硫酸钠干燥,抽滤,蒸除溶剂得到白色至黄色油状液体,粗品经柱层析纯化得到多取代苯甲醇(2a~2c,无色透明液体)。
实验方法b:将多取代苯甲醇(2a~2c,25.48mmol)溶于无水乙腈中,室温下加入三苯基膦氢溴酸盐(31.85mmol)。回流反应2-4小时,反应结束,蒸除溶剂,粗品经柱层析法分离纯化得到目标化合物3a~3c(白色至微黄色固体粉末)。
(2)步骤2:化合物I-1~I-9的制备
将化合物3a~3c(1.34mmol)溶于无水DCM中,加入多取代苯甲醛(4a~4c,1.22mmol)和碳酸钾(2.44mmol),最后加入痕量18-冠-6-醚,回流12-18小时。抽滤,滤液旋干顺反异构体,经柱层析纯化得到反式二苯乙烯衍生物中间体(黄色至橙色固体粉末I-1~I-3,白色固体粉末I-4~I-9,产率37%-49%)。
I-1:MS(ESI):316.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.22(d,J=8.8Hz,2H),7.63(d,J=8.7Hz,2H),7.20(d,J=16.2Hz,1H),7.05(d,J=16.3Hz,1H),6.78(s,2H),3.93(s,5H),3.89(s,3H).
I-2:MS(ESI):300.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.21(d,J=8.8Hz,2H),7.61(d,J=8.6Hz,2H),7.22(d,J=16.3Hz,1H),7.09(d,J=6.9Hz,2H),7.00(d,J=16.2Hz,1H),6.89(d,J=8.7Hz,1H),4.15(q,,J=7.0Hz,2H),3.95(s,3H),1.50(t,J=7.0Hz,3H).
I-3:MS(ESI):270.3[M+H]+.1H NMR(400 MHz,CDCl3)δ8.20(d,J=8.8Hz,2H),7.59(d,J=8.8 Hz,2H),7.49(d,J=8.7 Hz,2H),7.22(d,J=16.2 Hz,1H),7.00(d,J=16.3Hz,1H),6.92(d,2H),4.07(q,J=7.0 Hz,2H),1.44(t,J=7.0 Hz,3H).
I-4:MS(ESI):296.3[M+H]+.1H NMR(400 MHz,CDCl3)δ7.78(s,1H),7.71(d,J=7.8Hz,1H),7.53(d,J=7.7 Hz,1H),7.46(t,J=7.7 Hz,1H),7.09(d,J=16.2 Hz,1H),6.97(d,J=16.2 Hz,1H),6.75(s,2H),3.93(s,6H),3.88(s,3H).
I-5:MS(ESI):280.3[M+H]+.1H NMR(400 MHz,CDCl3)δ7.76(s,1H),7.69(d,J=7.8Hz,1H),7.50(d,J=7.7 Hz,1H),7.44(t,J=7.7 Hz,1H),7.10(d,J=16.3 Hz,1H),7.05(d,J=8.5 Hz,2H),6.94(s,1H),6.88(t,J=7.9 Hz 2H),4.14(q,J=7.0 Hz,2H),3.94(s,3H),1.49(t,J=7.0 Hz,3H).
I-6:MS(ESI):250.3[M+H]+.1H NMR(400 MHz,CDCl3)δ7.75(s,1H),7.68(d,J=7.87 Hz,1H),7.52–7.41(m,4H),7.10(d,J=16.3 Hz,1H),6.92(t,J=7.69 Hz,3H),4.07(q,J=7.0 Hz,2H),1.44(t,J=7.0 Hz,3H).
I-7:MS(ESI):345.4[M+H]+.1H NMR(400 MHz,CDCl3)δ7.07(d,J=2.0Hz,1H),7.04(d,J=8.2 Hz,1H),6.94–6.84(m,3H),6.72(s,2H),4.17(q,J=7.0Hz,2H),3.92(s,6H),3.90(s,3H),3.87(s,3H),1.50(t,J=7.1 Hz,3H).
I-8:MS(ESI):345.4[M+H]+.1H NMR(400 MHz,CDCl3)δ7.09(s,1H),7.05(d,J=8.2Hz,1H),6.95(d,J=10.5 Hz,2H),6.89(d,J=8.5 Hz,1H),6.75(s,2H),4.15(q,J=7.0Hz,2H),3.97(s,3H),3.94(s,6H),3.89(s,3H),1.51(t,J=7.0 Hz,3H).
I-9:MS(ESI):315.4[M+H]+.1H NMR(400 MHz,CDCl3)δ7.43(d,J=8.7Hz,2H),6.95(s,1H),6.91(s,1H),6.90(s,1H),6.88(s,1H),6.71(s,2H),4.06(q,J=6.9Hz,2H),3.92(s,6H),3.86(s,3H),1.43(t,J=7.0Hz,3H).
实施例2:化合物I-10、I-11和I-12的制备
将二苯乙烯中间体(I-1、I-3和I-3,0.3mmol)溶于95%的乙醇中,加入SnCl2(1.83mmol)和盐酸(1.65mmol),搅拌至完全溶解,回流反应4-7小时。滴加1N的NaOH水溶液调节体系pH=9,抽滤并蒸除滤液。乙酸乙酯萃取,无水硫酸钠干燥,抽滤并除去溶剂,粗品经柱层析纯化得到目标产物I-10、I-11和I-12(黄色固体粉末,产率60%左右)。
I-10:MS(ESI):286.3[M+H]+.1H NMR(400MHz,DMSO)δ7.26(d,J=8.2Hz,2H),7.02(d,J=16.3Hz,1H),6.83(d,J=14.0Hz,3H),6.56(d,J=8.2Hz,2H),5.28(s,2H),3.81(s,6H),3.65(s,3H).
I-11:MS(ESI):270.3[M+H]+.1H NMR(400MHz,DMSO)δ7.24(d,J=8.2Hz,2H),7.13(s,1H),6.95(d,J=2.0Hz,1H),6.92–6.86(m,2H),6.81(d,J=16.3Hz,1H),6.55(d,J=8.2Hz,2H),5.28(s,2H),3.99(q,J=6.9Hz,2H),3.80(s,3H),1.32(t,J=6.9Hz,3H).
I-12:MS(ESI):240.3[M+H]+.1H NMR(400MHz,DMSO)δ7.41(d,J=8.6Hz,2H),7.24(d,J=8.3Hz,2H),6.87(dd,J=9.8,5.8Hz,4H),6.56(d,J=8.2Hz,2H),5.44(s,2H),4.01(q,J=6.9Hz,2H),1.32(t,J=6.9Hz,3H).
实施例3:化合物I-13、I-14和I-15的制备
氮气保护的冰水浴条件下,向四氢铝锂(1.2mmol)的无水四氢呋喃悬浮液中缓慢滴加二苯乙烯中间体(I-4、I-5和I-6,0.2mmol)的无水四氢呋喃溶液,锡箔纸避光反应18-25小时。少量水和氢氧化钠水溶液,再加入水后室温搅拌1小时,抽滤并滤液。加入大量乙酸乙酯,分别使用水和饱和食盐水洗三次,无水硫酸钠干燥,抽滤并蒸除溶剂得到微黄色油状液体,粗品经柱层析纯化后得到目标产物I-13、I-14和I-15(白色至微黄色固体粉末,,产率55%左右)。
I-13:MS(ESI):300.4[M+H]+.1H NMR(400MHz,DMSO)δ7.58(s,1H),7.40(d,J=7.6Hz,1H),7.30(t,J=7.5Hz,1H),7.20–7.18(m,3H),6.93(s,2H),3.83(s,6H),3.75(s,2H),3.67(s,3H).
I-14:MS(ESI):284.4[M+H]+.1H NMR(400MHz,DMSO)δ7.26–7.18(m,3H),7.12–7.08(m,1H),6.84–6.75(m,3H),6.51(s,2H),3.97(q,J=7.0Hz,2H),3.66(s,2H),1.30(t,J=6.9Hz,3H).
I-15:MS(ESI):254.3[M+H]+.1H NMR(400MHz,DMSO)δ7.52(d,J=8.5Hz,2H),7.38(d,J=7.7Hz,1H),7.28(t,J=7.6Hz,1H),7.22–7.15(m,2H),7.07(d,J=16.5Hz,1H),6.93(d,J=8.4Hz,2H),4.04(q,J=7.0Hz,2H),3.73(s,2H),1.33(t,J=6.9Hz,3H).
实施例4:化合物I-16、I-17和I-18的制备
将二苯乙烯中间体(I-4、I-5和I-6,0.2mmol)溶于无水乙醇中,加入30%过氧化氢水溶液(0.6mmol)和0.5M的氢氧化钠水溶液(0..046mmol),50℃反应6-10小时。滴加HCl水溶液调节pH<7,加入适量硫代硫酸钠至溶解后使用水和乙酸乙酯体系对反应进行萃取,收集有机相,使用水和饱和食盐水各洗三次,无水硫酸钠干燥,减压抽滤并蒸除溶剂,粗品经柱层析纯化后得到目标产物I-16、I-17和I-18(白色固体粉末,产率75%左右)。
I-16:MS(ESI):314.4[M+H]+.1H NMR(400MHz,DMSO)δ8.13(d,J=1.7Hz,1H),8.02(s,1H),7.77–7.74(m,1H),7.70(d,J=7.8Hz,1H),7.48–7.39(m,2H),7.29(s,2H),6.96(s,2H),3.84(s,6H),3.68(s,3H).
I-17:MS(ESI):298.4[M+H]+.1H NMR(400MHz,DMSO)δ8.10(s,1H),8.01(s,1H),7.73(d,J=7.7Hz,1H),7.69(d,J=7.7Hz,1H),7.45(d,J=7.7Hz,1H),7.41(d,J=6.8Hz,1H),7.27(dd,J=9.1,7.2Hz,2H),7.19(d,J=16.4Hz,1H),7.10(d,J=8.2,1H),6.95(d,J=8.2Hz,1H),4.03(q,J=6.9Hz,2H),3.83(s,3H),1.34(t,J=6.9Hz,3H).
I-18:MS(ESI):268.3[M+H]+.1H NMR(400MHz,DMSO)δ8.11–8.00(m,2H),7.73(d,J=7.7Hz,1H),7.68(d,J=7.7Hz,1H),7.54(d,J=8.5Hz,2H),7.46–7.38(m,2H),7.28(d,J=16.5Hz,1H),7.13(d,J=16.6Hz,1H),6.94(d,J=8.5Hz,2H),4.04(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H).
实施例5:化合物I-19、I-20和I-21的制备
将二苯乙烯中间体(I-4、I-5和I-6,0.2mmol)溶于无水乙醇中,加入盐酸羟胺(0.3mmol)和三乙胺(0.3mmol),反应12-18小时。蒸发浓缩体系,再加入饱和食盐水和乙酸乙酯萃取,水相用乙酸乙酯萃三次,有机相汇总,无水硫酸钠干燥,抽滤并收集滤液,旋蒸除去溶剂。粗品经柱层析纯化后得到目标产物I-19、I-20和I-21(白色固体粉末,产率80%左右)。
I-19:MS(ESI):329.4[M+H]+.1H NMR(400MHz,DMSO)δ9.64(s,1H),7.92(d,J=1.7Hz,1H),7.58(dd,J=7.8,1.7Hz,2H),7.38(t,J=7.7Hz,1H),7.25(d,J=2.7Hz,2H),6.95(s,2H),5.86(s,2H),3.84(s,6H),3.68(s,3H).
I-20:MS(ESI):313.4[M+H]+.1H NMR(400MHz,DMSO)δ9.63(s,1H),7.89(s,1H),7.58–7.51(m,2H),7.36(t,J=7.7Hz,1H),7.25(t,J=2.7Hz,1H),7.19(d,J=12.3Hz,2H),7.09(dd,J=8.3,1.9Hz,1H),6.94(d,J=8.3Hz,1H),5.86(s,2H),4.02(q,J=6.9Hz,2H),3.83(s,3H),1.33(t,J=6.9Hz,3H).
I-21:MS(ESI):283.3[M+H]+.1H NMR(400MHz,DMSO)δ9.65(s,1H),7.88(d,J=1.8Hz,1H),7.58–7.52(m,4H),7.35(t,J=7.7Hz,1H),7.23(d,J=16.5Hz,1H),7.10(d,J=16.4Hz,1H),6.96–6.92(m,2H),5.87(s,2H),4.05(q,J=6.9Hz,2H),1.33(t,J=6.9Hz,3H).
实施例6:化合物I-22的制备
(1)化合物5的制备
将二苯乙烯中间体(I-9,0.5mmol)溶于乙酸乙酯中,加入10%的钯碳粉末(0.05mmol),氢气氛围搅拌12小时,抽滤除并收集浓缩滤液。粗品经柱层析纯化后得到中间化合物5(白色固体粉末,产率98%)。
5:MS(ESI):317.4[M+H]+.1H NMR(400MHz,CDCl3)δ7.08(d,J=8.51Hz,2H),6.82(d,J=8.51Hz,2H),6.36(s,2H),4.01(q,J=7.0Hz,2H),3.83(s,4H),3.82(s,6H),2.84(s,3H),1.41(t,J=7.0Hz,3H).
(2)化合物I-22的制备
将化合物5(0.145mmol)溶于无水二氯甲烷中,-78℃下向体系中加三溴化硼的无水二氯甲烷溶液(0.363mmol),反应30分钟,后于室温条件下反应8-12小时。加入饱和碳酸氢钠水溶液搅拌1小时,加水进行萃取,有机相用水洗三次,无水硫酸钠干燥后减压抽滤并浓缩收集滤液,柱层析法分离纯化得到目标产物I-22(白色固体粉末,产率48%)。
I-22:MS(ESI):289.3[M+H]+.1H NMR(400MHz,CDCl3)δ7.07(d,J=8.3Hz,2H),6.81(d,J=8.6Hz,2H),6.45(s,1H),6.24(s,1H),5.27(dd,J=10.9,3.7Hz,2H),4.01(q,J=7.0Hz,2H),3.82(s,3H),2.86–2.73(m,4H),1.40(t,J=6.9Hz,3H)。
实施例7:化合物I-23~I-30的制备
将对位取代的2-溴-4’-硝基苯乙酮(6a、6b和6c,0.2mmol)溶于无水四氢呋喃,室温搅拌加入取代邻苯二胺(5a、5b和5c,0.24mmol)及DABCO(0.04mmol)并于室温反应4-5小时。反应结束后加乙酸乙酯进行萃取,水相用乙酸乙酯萃取三次,有机相汇总后使用无水硫酸钠干燥,抽滤收集滤液并蒸除溶剂,使用柱层析法分离纯化得到苯并吡嗪类衍生物中间体(I-23~I-30)。
I-23:MS(ESI):331.1[M+H]+.1H NMR(400MHz,CDCl3)δ9.39(s,1H),8.44(d,J=9.0Hz,2H),8.42–8.38(m,3H),8.03(d,J=8.9Hz,1H),7.90(dd,J=8.9,2.2Hz,1H).
I-24:MS(ESI):282.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.40(q,J=9.0Hz,4H),8.04(d,J=9.0Hz,1H),7.47(d,J=8.4Hz,2H),4.30(t,J=6.7Hz,1H),4.02(s,3H).
I-25:MS(ESI):312.3[M+H]+.1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.38(d,J=8.6Hz,2H),8.33(d,J=8.5Hz,2H),7.40(d,J=10.5Hz,2H),4.09(d,J=2.2Hz,6H).
I-26:MS(ESI):304.1[M+H]+.1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.34(d,J=2.1Hz,1H),8.24–8.19(m,2H),8.01(d,J=8.9Hz,1H),7.83(dd,J=8.8,2.1Hz,1H),7.27(t,J=8.5Hz,2H).
I-27:MS(ESI):255.3[M+H]+.1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.18(dd,J=8.6,5.3Hz,2H),8.00(d,J=9.1Hz,1H),7.42(t,J=7.9Hz,2H),7.25(t,J=8.3Hz,2H),4.00(s,3H).
I-28:MS(ESI):316.2[M+H]+.1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.32(d,J=2.1Hz,1H),8.18(d,J=8.9Hz,2H),7.96(d,J=8.9Hz,1H),7.78(dd,J=8.8,2.1Hz,1H),7.09(d,J=8.9Hz,2H),3.91(s,3H).
I-29:MS(ESI):267.3[M+H]+.1H NMR(400MHz,CDCl3)δ9.14(s,1H),8.17(d,J=8.8Hz,2H),7.99(d,J=9.2Hz,1H),7.49(s,1H),7.37(dd,J=9.1,2.7Hz,1H),7.08(d,J=8.8Hz,2H),4.00(s,3H),3.91(s,3H).
I-30:MS(ESI):297.3[M+H]+.1H NMR(400MHz,CDCl3)δ9.08(s,1H),8.10(d,J=8.2Hz,2H),7.37(d,J=14.7Hz,2H),7.06(d,J=8.2Hz,2H),4.07(d,J=3.9Hz,6H),3.89(s,3H).
实施例8:化合物I-31、I-32和I-33的制备
化合物I-31、I-32和I-33的合成:将苯并吡嗪类衍生物中间体(I-23、I-24和I-25,0.3mmol)溶于95%的乙醇中,加入SnCl2(1.83mmol)和HCl(1.65mmol),回流反应4-7小时。加1N的NaOH水溶液调节体系pH=9,抽滤除蒸溶剂。乙酸乙酯进行萃取,无水硫酸钠干燥,抽滤并蒸除溶剂,粗品经柱层析纯化得到目标产物I-31、I-32和I-33(黄棕色固体粉末,产率55%~65%)。
I-31:MS(ESI):301.2[M+H]+.1H NMR(400MHz,DMSO)δ9.44(s,1H),8.18(s,1H),8.08(d,J=8.2Hz,2H),7.94(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),6.72(d,J=8.3Hz,2H),5.84(s,2H).
I-32:MS(ESI):252.3[M+H]+.1H NMR(400MHz,DMSO)δ9.24(s,1H),8.06(d,J=8.4Hz,2H),7.89(d,J=8.9Hz,1H),7.34(d,J=15.3Hz,2H),6.72(d,J=8.4Hz,2H),5.72(s,2H),3.95(s,3H).
I-33:MS(ESI):282.3[M+H]+.1H NMR(400MHz,DMSO)δ9.17(d,J=1.4Hz,1H),8.03–7.94(m,2H),7.38–7.29(m,2H),6.72–6.64(m,2H),5.62(s,2H),3.96(dd,J=7.1,1.4Hz,6H).
实施例9:化合物I-34、I-35和I-36的制备
化合物I-34、I-35和I-36的合成:将化合物I-28、I-29和I-30(0.145mmol)溶于无水二氯甲烷,-78℃下向体系中加三溴化硼的无水二氯甲烷溶液(14.5mmol),反应30分钟,后于室温条件下反应8-12小时。加饱和碳酸氢钠水溶液搅拌1小时,加水进行萃取,有机相用水洗三次,无水硫酸钠干燥后减压抽滤并浓缩收集滤液,柱层析法分离纯化得到目标产物I-34、I-35和I-36(白色固体粉末,产率30%~40%)。
I-34:MS(ESI):302.1[M+H]+.1H NMR(400MHz,DMSO)δ10.13(s,1H),9.52(s,1H),8.26(s,1H),8.21(d,J=8.4Hz,2H),7.99(d,J=8.8Hz,1H),7.89(d,J=8.8Hz,1H),6.97(d,J=8.3Hz,2H).
I-35:MS(ESI):253.3[M+H]+.1H NMR(400MHz,DMSO)δ10.03(s,1H),9.32(s,1H),8.19(d,J=8.3Hz,2H),7.95(d,J=8.7Hz,1H),7.41(d,J=9.2Hz,2H),6.95(d,J=8.1Hz,2H),3.96(s,3H).
I-36:MS(ESI):283.3[M+H]+.1H NMR(400MHz,DMSO)δ9.92(s,1H),9.24(s,1H),8.13(d,J=8.1Hz,2H),7.39(s,2H),6.94(d,J=8.1Hz,2H),3.98(d,J=5.7Hz,9H).
实施例10:化合物I-37的制备
I-37的合成:冰水浴搅拌条件下,原料I-27(30mg,0.118mmol)加入到AlCl3(37.76mg,0.283mmol)的甲苯溶液中,于80℃反应20-24小时。冰水浴搅拌,并加入适量冰水,再加入乙酸乙酯萃取。水相用乙酸乙酯萃取三次后将有机相汇总,无水硫酸钠干燥,抽滤并浓缩滤液,后采用柱层析法分离纯化得到目标产物I-37(白色固体粉末,产率42%)。
I-37:241.2[M+H]+.1H NMR(400MHz,CD3OD)δ9.13(s,1H),8.25(dd,J=8.3,5.4Hz,2H),7.92(d,J=9.0Hz,1H),7.40–7.26(m,4H).
实施例11:化合物I-38~I-41的制备
化合物I-38~I-41的合成:
将3,4,5-三甲氧基苯硼酸(0.35mmol)溶于DME/H2O(3:1,4ml)中,加入化合物9a~9d(0.22mmol)、无水碳酸钾(0.70mmol)和四(三苯基膦)钯(0.04mmol),100℃反应4-7小时。向体系中加入乙酸乙酯并水洗两次,收集有机相并加无水硫酸钠干燥,减压抽滤并蒸除滤液,粗品经柱层析纯化后得到目标产物I-38~I-41(白色固体粉末,产率75%左右)。
I-38:310.3[M+H]+.1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.72(d,J=8.5Hz,1H),7.65(d,J=8.4Hz,1H),7.60(d,J=8.5Hz,1H),7.00(s,1H),6.98(d,J=8.0Hz,1H),6.88(s,2H),3.96(s,6H),3.91(s,3H)
I-39:311.3[M+H]+.1H NMR(600MHz,CDCl3)δ8.98(d,J=2.1Hz,1H),8.10(d,J=1.9Hz,1H),7.68(d,J=8.7Hz,1H),7.25(d,J=2.4Hz,1H),7.02(dd,J=8.6,2.2Hz,1H),6.83(s,2H),3.95(s,6H),3.91(s,3H);
I-40:312.3[M+H]+.1H NMR(600MHz,CD3OD)δ8.93(d,J=2.6Hz,1H),8.29(d,J=2.6Hz,1H),8.02(d,J=8.8Hz,1H),6.97(s,2H),6.91(d,J=8.8Hz,1H),3.93(s,6H),3.81(s,3H).
I-41:312.3[M+H]+.1H NMR(600MHz,CD3OD)δ9.13(s,1H),8.03(dd,J=8.7,2.2Hz,1H),8.01(d,J=1.8Hz,1H),7.55(d,J=8.7Hz,1H),6.94(s,2H),3.92(s,6H),3.80(s,3H).
实施例12:化合物I-42和I-43的制备
化合物I-42和I-43的合成:
将3,4,5-三甲氧基苯硼酸(0.35mmol)溶于DME/H2O(3:1,4ml)中,加入化合物10a和10b(0.22mmol)、无水碳酸钾(0.70mmol)和四(三苯基膦)钯(0.04mmol),100℃反应4小时。加入乙酸乙酯并水洗两次,收集有机相并加无水硫酸钠干燥,减压抽滤并蒸除滤液,粗品经柱层析纯化后得到目标产物I-42和I-43(白色固体粉末,产率50%左右)。
I-42:301.3[M+H]+.1H NMR(600MHz,DMSO)δ7.47(d,J=1.7Hz,1H),7.43(s,2H),7.34(d,J=8.2Hz,1H),7.23(dd,J=8.2,1.8Hz,1H),6.85(s,2H),3.84(s,6H),3.66(s,3H).
I-43:317.3[M+H]+.1H NMR(400MHz,CDCl3):δ7.77(d,J=1.6Hz,1H),7.60(d,J=8.4Hz,1H),7.51(dd,J=8.4,1.7Hz,1H),6.78(s,2H),3.94(s,6H),3.90(s,3H).
实施例13:化合物I-44和I-45的制备
化合物12的合成:
将二氧化硒(1.50mmol)置于1,4-二氧六环中,加入化合物3',4',5'-三甲氧基苯乙酮(3.00mmol),105℃反应6-8小时。减压抽滤并蒸除滤液,粗品经柱层析纯化后得到目标产物12(白色固体粉末)。
化合物I-44和I-45的合成:
将化合物12(1.78mmol)和4-硝基邻苯二胺(1.96mmol)溶于水,105℃反应2-5h。减压抽滤并收集滤饼得黄色粗品。将黄色粗品溶于乙酸乙酯,加入钯碳(20%),室温反应30分钟。减压抽滤并蒸除滤液,粗品经柱层析纯化后得到目标产物I-44和I-45(黄色固体粉末,产率52%和19%)。
I-44:312.3[M+H]+.1H NMR(600MHz,DMSO)δ9.29(s,1H),7.78(d,J=8.0Hz,1H),7.49(s,2H),7.24(dd,J=8.0,1.8Hz,1H),6.95(d,J=2.1Hz,1H),6.07(s,2H),3.91(s,6H),3.74(s,3H);
I-45:312.3[M+H]+.1H NMR(600MHz,CD3OD)δ9.12(s,1H),7.83(d,J=9.0Hz,1H),7.44(s,2H),7.31(dd,J=9.1,2.5Hz,1H),7.05(d,,J=2.4Hz,1H),3.97(s,6H),3.84(s,3H)
实施例14:化合物I-46的制备
化合物16的合成:
将化合物14(0.60mmol)、化合物15(0.90mmol)和4-羟基-2,2,6,6-四甲基哌啶氧(9.03mmol)溶于邻二甲苯,160℃反应26h。减压蒸除溶剂,粗品经柱层析纯化后得到目标产物16(黄色固体粉末,产率70%)。
化合物I-46的合成:
将化合物16(0.21mmol)溶于乙酸乙酯,加入钯碳(20%),室温反应1.5小时。减压抽滤并蒸除滤液,粗品经柱层析纯化后得到目标产物I-46(黄色固体粉末,产率95%)。
I-46:312.1[M+H]+.1H NMR(600MHz,CDCl3)δ9.21(s,1H),7.93(d,J=8.8Hz,1H),7.86(s,2H),7.34(dd,J=9.0,2.5Hz,1H),6.98(d,J=2.5Hz,1H),4.03(s,6H),3.93(s,3H).
实施例15:化合物的生物活性(体外NQO2抑制活性)测定
1.溶液的配制
1.1酶溶液:实验中使用的重组人源NQO2(1mg)中包含5μM的FAD和200mM的蔗糖,最后使用pH=7.4浓度为50mM的磷酸盐缓冲溶液稀释至最终浓度为5mg/mL并于-80℃保存。
1.2EPR溶液:将NQO2的酶辅因子EPR使用pH=7.4浓度为50mM的磷酸盐缓冲溶液溶解并配置为10mM溶液,最终以200μM的浓度使用。
1.3DCPIP溶液:将反应底物DCPIP在蒸馏水中溶解并配置成2mM溶液,最终以40μM的浓度使用。在每个独立实验中,所使用的NQO2(5×10-3mg/mL)、EPR(10.0mM)和DCPIP(2.0mM)溶液均现配现用。
1.4抑制剂溶液:将所合成的系列衍生物使用100%二甲基亚砜溶解并稀释至10mM的储备浓度,于-20℃保存,使用时将每个待测化合物储备溶液连续稀释成10倍关系的5个梯度溶液(0.01μM~100μM)。
2.体外NQO2抑制活性测定
每个待测样品均配置为1mL混合液,包含940μL磷酸缓冲溶液、10μL重组人源NQO2溶液、20μL EPR溶液、20μL DCPIP溶液和10μL的抑制剂溶液,空白对照组使用100%的二甲基亚砜代替抑制剂溶液。混合均匀后加于96孔板中,使用预热至37℃的Model 680型酶标仪(美国Bio-Rad)测定待测样品于600nm的吸光度,实验所得数据使用GraphPad Prism 7.0软件进行相关分析。每个化合物平行测定三组,并且重复三次。
3.体外NQO2抑制活性结果
活性筛选结果表明:较阳性对照化合物白藜芦醇,化合物I-10、I-38、I-45和I-46具有显著的体外NQO2抑制活性,其中以I-45和I-46活性最佳,二者针对NQO2抑制活性的IC50值分别为36和1.6nM。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种小分子NQO2抑制剂,其特征是,其为式(I)所示的化合物或其药学上可接受的盐,
R1为氢原子、甲氧基或羟基;
R2为C1-C2烷氧基或羟基;
R3为氢原子或甲氧基
R4为氢原子、氰基、C1-C2烷氧基、氨甲基、氨基甲酰基或(Z)-N、-羟基脒基;
R5为硝基、氢原子、C1-C2烷氧基或氨基;
或者,其为式(II)所示的化合物或其药学上可接受的盐,
R6为溴原子、氢原子、甲氧基或氨基;
R7为氢原子、甲氧基、羟基或氨基;
R8为氢原子或甲氧基;
R9为硝基、氟原子、甲氧基、氨基或羟基;
X为碳原子或氮原子;
或者,其为式(III)所示的化合物或其药学上可接受的盐,
Y为硫原子或氧原子。
6.一种药物组合物,其特征是,包括权利要求1或2所述的小分子NQO2抑制剂和一种或多种药学上可接受的辅料。
7.如权利要求6所述的药物组合物,其特征是,其剂型为固体口服制剂、液体口服制剂或注射剂。
8.如权利要求7所述的药物组合物,其特征是,所述剂型为片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小水针、注射用冻干粉针、大输液或小输液。
9.一种权利要求1或2所述的小分子NQO2抑制剂或权利要求6~8任一所述的药物组合物在制备预防肿瘤疾病的药物中的应用。
10.如权利要求9所述的应用,其特征是,所述肿瘤疾病为肺癌、乳腺癌、胃癌、食管癌、肝癌、结直肠癌、甲状腺癌、前列腺癌、宫颈癌、卵巢癌或白血病。
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