CN108947912B - 一种靶向Neddylation通路的抗肿瘤化合物 - Google Patents

一种靶向Neddylation通路的抗肿瘤化合物 Download PDF

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CN108947912B
CN108947912B CN201810856670.1A CN201810856670A CN108947912B CN 108947912 B CN108947912 B CN 108947912B CN 201810856670 A CN201810856670 A CN 201810856670A CN 108947912 B CN108947912 B CN 108947912B
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张明华
范皎
陈香岭
刘庆艳
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Abstract

本发明公开了一种靶向Neddylation通路的抗肿瘤化合物。该化合物可由通式I，通式II，通式III，通式IV，通式V，通式VI或通式VII所述的结构式表示。本发明的化合物具有良好的抗肿瘤活性，多个化合物接近阳性对照药MLN4924，可作为良好的抗肿瘤化合物。本发明的化合物和组合物可与其他药物一起使用以提供组合治疗，其他的药物可形成相同组合物的一部分，或者在同时或不同时候作为单独的组分给药。

Description

一种靶向Neddylation通路的抗肿瘤化合物
技术领域
本发明属于医药技术领域，具体涉及一种靶向Neddylation通路的抗肿瘤化合物。
背景技术
Neddylation通路负责将类泛素分子NEDD8共价结合到蛋白分子上，调控该蛋白的活性。该通路可以广泛调控细胞内多种重要蛋白的降解和功能，对于负责信号转导的蛋白非常重要。Neddylation通路由一系列酶催化进行：首先，NEDD8由激活酶E1进行活化，后转移至结合酶E2，并由E2联合连接酶E3将NEDD8分子共价结合到底物蛋白，调节其功能。Cullin类分子就是NEDD8修饰的底物之一。Cullin类分子是CRLs(cullin-RING ubiquitinligases)类泛素连接酶的支架分子。NEDD8修饰到Cullin类分子上，是CRLs类泛素连接酶具有活性的前提。CRLs类泛素连接酶可降解多种底物，包括P21、P27等多种重要分子，可调控细胞的周期、凋亡、衰老等重要过程，与神经退行性疾病和肿瘤存在密切关系。Neddylation通路在很多肿瘤中异常高表达和过度活跃，通过抑制该通路的功能，可以达到治疗多发性骨髓瘤等多种肿瘤的目的。
近年来，靶向Neddylation通路的关键分子筛选抑制剂，成为发现新型抗肿瘤药物的一个重要领域。目前，国外研究机构和制药公司靶向Neddylation通路关键分子(如UBA3等)筛选获得多种具有抗肿瘤活性的化合物，部分高活性化合物已经进入I期临床阶段。
发明内容
本发明的目的在于提供一种靶向Neddylation通路的抗肿瘤化合物。
一种靶向Neddylation通路的抗肿瘤化合物，包括如下结构通式的化合物：
Figure BDA0001748701660000021
式中，R1、R5选自氢、卤素、羟基、低级烷基；R2、R3、R4选自氢、卤素、硝基、羟基、低级烷基、低级烷氧基、低级卤代烷基、苄氧基、任选取代的胺基；R6选自氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基；X选自甲基、乙基、丙烯基、酰胺基、甲氧基、氧代乙基；Y选自硫原子、氨基、肼基、环氧烷基、杂环基；
Figure BDA0001748701660000022
式中，R7、R11选自氢、卤素、羟基、低级烷基；R8、R9、R10选自氢、卤素、硝基、羟基、低级烷基、低级烷氧基、低级卤代烷基、苄氧基、任选取代的胺基；R12选自氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基、-CH(CH2OH)R13、-CH2CH(OH)R13、-C(R13)2CH2OH；
Figure BDA0001748701660000031
式中，R14、R18选自氢、卤素、羟基、低级烷基；R15、R16、R17选自氢、卤素、硝基、羟基、低级烷基、低级烷氧基、低级卤代烷基、苄氧基、任选取代的胺基；R19选自氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基；
Figure BDA0001748701660000032
式中，R20、R24选自氢、卤素、羟基、低级烷基；R21、R22、R23选自氢、卤素、硝基、羟基、低级烷基、低级烷氧基、低级卤代烷基、苄氧基、任选取代的胺基；R25选自氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环基、酰胺基、羟基、低级烷基、-CH(CH2OH)R26、-CH2CH(OH)R26、-C(R26)2CH2OH；X1选自甲基、乙基、-CH2NH-、丙烯基、酰胺基、甲氧基、氧代乙基；Y1选自氨基、甲基、乙基、丙基、异丙基、-CH2CH2NH-、硫原子、肼基、环氧烷基、杂环基；
Figure BDA0001748701660000041
式中，R27、R31选自氢、卤素、羟基、低级烷基；R28、R29、R30选自氢、卤素、硝基、羟基、低级烷基、低级烷氧基、低级卤代烷基、苄氧基、任选取代的胺基；R32选自氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基、-CH(CH2OH)R33、-CH2CH(OH)R33、-C(R33)2CH2OH；X2选自甲基、乙基、酰胺基、-CH2NH-、丙烯基、甲氧基、氧代乙基；Y2选自氨基、甲基、乙基、丙基、异丙基、-CH2CH2NH-、硫原子、肼基、环氧烷基、杂环基；
Figure BDA0001748701660000042
式中，R34、R38选自氢、卤素、羟基、低级烷基；R35、R36、R37选自氢、卤素、硝基、羟基、低级烷基、低级烷氧基、低级卤代烷基、苄氧基、任选取代的胺基；R39选自氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基、任意取代的杂环基、-CH(CH2OH)R40、-CH2CH(OH)R40；X3选自甲基、乙基、丙基、异丙基、氨基、-CH2CH2NH-、硫原子、肼基、环氧烷基、杂环基；
Figure BDA0001748701660000051
式中，R41、R44选自氢、卤素、羟基、低级烷基；R42、R43选自氢、卤素、硝基、羟基、低级烷基、低级烷氧基、低级卤代烷基、苄氧基、任选取代的胺基；R45选自氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基、-CH(CH2OH)R46、-CH2CH(OH)R46；X4选自甲基、乙基、酰胺基、-CH2NH-、丙烯基、甲氧基、氧代乙基；Y4选自氨基、甲基、乙基、丙基、异丙基、-CH2CH2NH-、硫原子、肼基、环氧烷基、杂环基。
所述R13为低级烷基。
所述R26为低级烷基。
所述R33为低级烷基。
所述R40为低级烷基。
所述R46为低级烷基。
所述的化合物的药用盐，所述化合物与无机酸或有机酸反应制成相应的药用盐；所述无机酸是指盐酸、硫酸、磷酸、二磷酸、氢溴酸或硝酸；有机酸是指乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、对甲苯磺酸、水杨酸或草酸。
所述的化合物及所述药用盐在制备抗肿瘤药物或抗炎药物中的应用，其中的肿瘤是指食道、胃、肠、口腔、咽、喉、肺、乳腺、子宫、卵巢、前列腺、睾丸、膀胱、肾、肝、胰腺、骨、结缔组织、皮肤、眼、脑、和中枢神经系统部位发生的癌症，或甲状腺癌、白血病、霍金氏病、淋巴瘤、骨髓瘤。
本发明的化合物，还包括其外消旋体、非对映体、光学异构体、顺反异构及任意组合或其药用盐。
本发明的有益效果：本发明的化合物具有良好的抗肿瘤活性，多个化合物接近阳性对照药MLN4924，可作为良好的抗肿瘤化合物。本发明的化合物和组合物可与其他药物一起使用以提供组合治疗，其他的药物可形成相同组合物的一部分，或者在同时或不同时候作为单独的组分给药。
具体实施方式
下面结合具体实施例对本发明做进一步说明。
实施例1化合物31的合成
2-(2-氨乙基)-6-(4-甲氧基苯基)哒嗪-3(2H)-酮；Chemdiv ID 8018-1746，化学结构式如下：
Figure BDA0001748701660000061
制备方法：
Figure BDA0001748701660000071
6-(4-甲氧基苯基)-4,5-二氢-2H-哒嗪-3-酮购自Apichemical(Shanghai)Product List。
6-(4-甲氧基苯基)-4,5-二氢-2H-哒嗪-3-酮(2.02g，0.01mol)氯乙腈(1.56g，0.02mol)K2CO3(2.76g，0.02mol)溶于40mL丙酮，70℃回流反应过夜。反应结束后冷却至室温，过滤除去K2CO3，旋转蒸发除去丙酮，得化合物1。将化合物1(1.21g，1mmol)，雷尼镍(0.1g)，正丙醇钠(0.92g，11mmol)溶于50mL 1,2-二甲氧基乙烷，60℃反应10h，冷却至室温，过滤收集有机相，旋转蒸发除去1,2-二甲氧基乙烷，用乙腈/二氯甲烷(体积比5:1)过色谱柱纯化的化合物31.
1H-NMRδ(300MHz,DMSO-d6):3.05(t,2H),3.70(t,2H),3.80(s,3H),6.50(d,1H),6.70(d,1H),7.05(d,2H),7.80(d,2H),8.30(s,3H).
实施例2化合物32的合成
(1S,2S)-2-甲基-1-(5-((4-甲基苄基)硫基)-1,3,4-恶二唑-2-基)丁烷-1-胺，Chemdiv ID 8388-0801，化学结构式如下：
Figure BDA0001748701660000072
制备方法：
Figure BDA0001748701660000081
BOC-L-异亮氨酸乙酯购自Arch Bioscience Product List。
BOC-L-异亮氨酸乙酯(0.778g，3mmol)，水合肼(0.192g，6mmol)溶于10mL乙醇，60℃反应1h，除去溶剂，将产物在乙醚中沉淀的化合物1(0.632g，产率86％)；将化合物1(0.735g，3mmol)，二硫化碳(397μL,6.60mmol)和三乙胺(469μL,3.30mmol)溶于5mL乙醇，80℃回流反应过夜，反应液中加入适量乙酸乙酯，先后用0.1mol/L的HCl和饱和食盐水萃洗，收集有机相，用无水Na2SO4干燥，旋转蒸发除去乙酸乙酯，所得固体在环己烷/乙酸乙酯混合液中重结晶，得化合物2(0.68g，79％)；将化合物2(0.574g，2mmol)，1mol/L NaOH(2mL,2mmol)，4-甲基苄溴(0.555g，3mmol)溶于20mLDMF，室温下反应5h，反应结束后过滤，将固体用适量DMF洗涤一次，在用乙醇洗涤3次，真空干燥得化合物3(0.72g，64％)；最后将化合物3(0.375g，1mmol)溶于二氯甲烷(2mL)，再加入三氟乙酸(1mL)，室温下反应3h。反应结束后加入饱和Na2CO3溶液调节溶液pH至9.0，用二氯甲烷萃取2次(每次30mL)，收集的有机相用无水MgSO4干燥，过滤，旋转蒸发除去二氯甲烷得产物32(0.262g，90％)。
1H-NMRδ(300MHz,DMSO-d6):0.77-0.93(m,6H),1.15(brs,1H),1.46(brs,1H),2.09(brs,1H),2.27(s,3H),4.43-4.55(m,2H),7.13(d,2H),7.34(d,2H),9.12(brs,3H).
实施例3化合物36的合成
4-(2,5-二甲苯基)哌嗪-1-甲脒，Chemdiv ID C607-1019，化学结构式如下：
Figure BDA0001748701660000091
制备方法：
Figure BDA0001748701660000092
将双-(2-氯乙基)胺盐酸盐(氮芥)(21.42g，0.12mol))，2,5-二甲基苯胺(14.5g，0.12mol))溶于正丁醇(40ml)，回流反应24h，再加入无水K2CO3(8.28g，0.06mol)，继续回流48h，将反应液抽滤，滤液浓缩至一半体积，加入无水乙醇10ml，静至析晶，得产物1；将产物1(0.665g，3.5mmol)，S-甲基异硫脲硫酸盐(1.96g，10.4mmol)和2mol/L的NaOH(52mL)溶于20mL水中，80℃反应3h，过滤的固体产物，水洗3次后溶于pH6.0的稀盐酸，将溶液浓缩后结晶，将结晶后的产物溶于20mL水，加入适量的Na2CO3调节溶液pH至8.0，用乙酸乙酯萃取3次(每次30mL)，收集有机相用无水硫酸镁干燥后，旋转蒸发除去乙酸乙酯得到产物36。
1H-NMRδ(300MHz,DMSO-d6):2.25(d,6H),2.85(m,2H),3.35(s,2H),3.55(s,4H),6.70-6.90(t,2H),7.04(d,1H),7.10-7.70(s,4H).
实施例4化合物43的合成
(R)-2-(((5-(2,4-二氯苯基)呋喃-2-基)甲基)氨基)正丁醇；Chemdiv ID D665-0507，化学结构式如下：
Figure BDA0001748701660000101
制备方法：
Figure BDA0001748701660000102
将1mol化合物1和1.1mol化合物2溶于20mL乙醇，80℃回流反应8h，旋转蒸发除去乙醇，用乙腈/二氯甲烷(体积比3:1)过色谱柱纯化的化合物3；将0.5mol化合物1溶于20mL四氢呋喃，通氢气，用Pb/C还原10h，过滤除去四氢呋喃，用石油醚/乙酸乙酯(体积比3:1)过色谱柱纯化的化合物43。
1H-NMRδ(400MHz,CDCl3):0.95(d,3H),1.55-1.90(m,2H),2.5(d,2H),2.85-3.35(d,2H),3.55-3.90(dd,2H),4.35(s,2H),5.20-5.50(brs,1H)，6.85(s,1H),7.15(s,1H),7.60(d,1H),7.70(s,1H),8.05(d,1H),9.30-9.65(brs,2H).
实施例5化合物44的合成
N-((5-(2-氟苯基)呋喃-2-基)甲基)-3-(1H-咪唑-1-基)-1-氨基丙烷，ChemdivID D665-1438，化学结构式如下：
Figure BDA0001748701660000111
制备方法：
Figure BDA0001748701660000112
化合物1购自American Custom Chemicals Corporation。
化合物2购自百灵威科技有限公司。
化合物1(0.191g，1mmol)和化合物2(0.189g，1mmol)溶于10ml乙腈，70℃反应过夜，冷却至室温，过滤，旋转蒸发除去乙腈，所得固体粗产物用凝胶色谱法(乙酸乙酯：二氯甲烷＝1：5为流动相)纯化，得产物44。
1H-NMRδ(400MHz,DMSO-d6):2.35(t,2H),2.5(d,2H),2.85-3.72(m,4H),4.26(s,2H),4.35-4.55(t,2H),6.80(s,2H),7.15-7.45(m,3H),7.60(s,1H)，7.75-8.05(m,2H),9.35(s,1H),9.83-10.65(brs,1H).
实施例6化合物47的合成
(S)-1-((2-(((5-(4-溴苯肼)呋喃-2-基)甲基)氨基)乙基)氨基)异丙醇，ChemdivID F019-4338，化学结构式如下：
Figure BDA0001748701660000121
制备方法：
Figure BDA0001748701660000122
将化合物1(10mmol)，雷尼镍(1g)，正丙醇钠(110mmol)溶于50mL 1,2-二甲氧基乙烷，60℃反应12h，冷却至室温，过滤收集有机相，旋转蒸发除去1,2-二甲氧基乙烷，用乙腈/二氯甲烷(体积比5:1)过色谱柱纯化的化合物2；
将化合物2(5mmol)和化合物3(5mmol)溶液10mL乙腈，加入K2CO3(4mol)，60℃反应24h，过滤收集滤液，旋转蒸发除去乙腈，用乙腈/二氯甲烷(体积比1:6)过色谱柱纯化的化合物47。
1H-NMRδ(400MHz,DMSO-d6):1.05(d,3H),2.50(s,3H),2.70-3.05(m,2H),3.05(m,16H),4.00(m,1H),4.30(s,2H),6.70-7.10(d,2H),7.50-7.80(d,4H),8.95-10.35(m,3H).
实施例7化合物46的合成
(S)-N-(2-(二甲氨基)乙基)-5-((邻甲基亚磺酰基)甲基)呋喃-2-甲酰胺，Chemdiv ID E535-1569，化学结构式如下：
Figure BDA0001748701660000131
制备方法：
Figure BDA0001748701660000132
将0.5mol化合物1和0.5mol化合物2溶于20mL乙腈，加入0.2mol K2CO3，80℃反应24h，反应液冷却至室温，过滤，旋转蒸发除去乙腈，通过凝胶色谱纯化(流动相石油醚/乙酸乙酯＝4:1)，的化合物3；将0.3mol化合物3溶于10mL四氢呋喃，加入5mL双氧水，室温下反应24h，用乙酸乙酯萃取，干燥、旋蒸除去乙酸乙酯的化合物4；将化合物0.2mol化合物4、0.2mol N,N-二甲基乙二胺和0.3molEDC·HCl溶于20mL乙酸乙酯，60℃24h，用水萃洗三次，收集有机相，旋转蒸发浓缩后，用乙腈/二氯甲烷(体积比3:1)过色谱柱纯化的化合物46。
1H-NMRδ(300MHz,DMSO-d6):2.25(s,3H),2.85(s,6H),3.40(t,2H),3.50(t,2H),3.90(s,2H),6.31(d,1H),7.20(m,2H),7.35-7.50(m,4H),7.78(s,1H).
实施例8化合物62的合成
4-(二甲胺基)-N-((2,6-二甲基咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲基)苯甲酰胺，Chemdiv ID P169-0071，化学结构式如下：
Figure BDA0001748701660000141
制备方法：
Figure BDA0001748701660000142
将10mmol化合物1、10mmol化合物2和1mmol K2CO3和10mLPEG400加入反应瓶中，80℃反应24h，反应液冷却至室温，在乙醚中沉淀，过滤收集滤液，通过凝胶色谱纯化(流动相石油醚/乙酸乙酯＝5:1)，的化合物3；将化合物3(1mmol)，雷尼镍(0.1g)，正丙醇钠(0.92g，11mmol)溶于50mL1,2-二甲氧基乙烷，60℃反应10h，冷却至室温，过滤收集有机相，旋转蒸发除去1,2-二甲氧基乙烷，用乙腈/二氯甲烷(体积比5:1)过色谱柱纯化的化合物62。
1H-NMRδ(300MHz,DMSO-d6):2.64(s,3H),2.91(s,3H),3.02(s,6H),4.14(s,2H),7.00(d,2H),7.51(d,2H),8.77(s,1H),11.12(s,1H).
实施例9化合物67的合成
(S)-1-((6-丙氧基吡啶-3-基)甲基)吡咯-3-胺，Chemdiv ID S056-0710，化学结构式如下：
Figure BDA0001748701660000151
制备方法：
Figure BDA0001748701660000152
将0.3mol化合物1和0.4mol化合物2溶于10mL乙腈，再加入0.4mol K2CO3 60℃反应12小时，过滤将滤液蒸干后，通过柱层析纯化(石油醚/乙酸乙酯＝6:1)，得化合物3；将0.2mol化合物3溶液10mL四氢呋喃，加入适量Pb/C，通H2，室温下反应24h，过滤，旋转蒸发除去四氢呋喃，通过柱层析纯化(石油醚/乙酸乙酯＝1:3)，得产物67。
1H-NMRδ(300MHz,DMSO-d6):0.98(t,3H),1.10-1.40(m,2H),1.75(m,2H),1.80-2.20(m,4H),2.30-2.70(m,3H),3.30(s,1H),3.60(m,2H),4.15(t,2H),6.65(d,1H),7.55(d,1H),7.95(s,1H).
试验例：肿瘤细胞增殖抑制实验
对本发明的部分化合物进行肿瘤细胞增殖抑制实验，方法采用CCK8法(日本同仁化学)。
细胞株采用人结直肠癌细胞株HCT116+/+、人大细胞肺癌细胞株H460、人肺腺癌H1299细胞、人乳腺癌细胞MCF7。培养液为DMEM(Hyclone)+10％FBS(Hyclone)+双抗。
样品配制：用DMSO(sigma)溶解为10mM溶液，用前使用细胞培养基稀释至所需浓度。将化合物MLN4924以同样条件配制成阳性对照溶液。
CCK8检测方法：96孔板每孔加入浓度为5-6×104个/ml的细胞悬液100ul，于细胞培养箱(37℃，5％二氧化碳)培养。24小时后，弃去培养基，加入含有化合物样品的培养基300ul，设双复孔，37℃，5％二氧化碳继续培养48小时。弃去培养基溶液，加入含有10％的CCK8溶液的无血清DMEM(Hyclone)培养基，继续培养2小时后，使用Tecan F50酶标仪检测450nm OD值。计算细胞半数抑制浓度IC50。结果见表1和表2。
表1
Figure BDA0001748701660000171
表2
Figure BDA0001748701660000172
以上实验结果表明，本发明的大多数化合物具有良好的抗肿瘤活性，多个化合物接近阳性对照药MLN4924，可作为良好的抗肿瘤化合物。
以上描述和显示了本发明的基本原理、主要特征。本领域的专业人员应该了解，本发明不受上述实施例的限制，上述实施例和描述只是说明本发明的基本原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附属的权利要求及其等同物界定。

Claims (1)

1.一种化合物在制备抗肿瘤细胞的药物中的应用，其特征在于，所述的肿瘤细胞为肿瘤细胞株HCT116、H1299、H460或MCF7；
所述化合物为如下结构式的化合物：
Figure FDA0003198079790000011
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