CN111892516A - 抗肿瘤化合物 - Google Patents

抗肿瘤化合物 Download PDF

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CN111892516A
CN111892516A CN202010771763.1A CN202010771763A CN111892516A CN 111892516 A CN111892516 A CN 111892516A CN 202010771763 A CN202010771763 A CN 202010771763A CN 111892516 A CN111892516 A CN 111892516A
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hydrogen
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张明华
范皎
陈香岭
刘庆艳
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Chinese PLA General Hospital
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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V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

抗肿瘤化合物
原案申请号：2018108980519
原案申请日：20180808
原案申请人：中国人民解放军总医院
原案申请名称：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 BDA0002616899760000021
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、取代胺基；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 BDA0002616899760000022
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、羟基、氨基、甲脒、硫脲基、任选取代的胺基、氮杂环、酰胺基、低级烷基；
Figure BDA0002616899760000031
式中，R13、R16选自氢、卤素、羟基、低级烷基；R14、R15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；R17选自氢、氨基、甲脒、硫脲基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基；X1选自甲基、乙基、丙烯基、酰胺基、甲氧基、氧代乙基；Y1选自硫原子、氨基、肼基、环氧烷基、杂环基；
Figure BDA0002616899760000032
式中，R18、R22选自氢、卤素、羟基、低级烷基；R19、R20、R21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；R23选自羧基、羟基、氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、低级烷基；
Figure BDA0002616899760000041
式中，R24、R27选自氢、卤素、羟基、低级烷基；R25、R26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；R28选自氢、氨基、甲脒、硫脲基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基；X2选自甲基、乙基、丙烯基、酰胺基、甲氧基、氧代乙基；Y2选自硫原子、氨基、肼基、环氧烷基、杂环基；
Figure BDA0002616899760000042
式中，R29、R33选自氢、卤素、羟基、低级烷基；R30、R31、R32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；R34选自羟基、氢、甲脒、硫脲基、氨基、任选取代的胺基、氮杂环、酰胺基、低级烷基、-C(R35)2CH2OH、-CH(CH2OH)R35、-CH2CH(OH)R35；；X3选自甲基、乙基、乙胺基、丙烯基、酰胺基、甲氧基、氧代乙基；Y3选自硫原子、氨基、肼基、异丁烷基、环氧烷基、杂环基。
所述R35为低级烷基。
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。
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。
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、***、睾丸、膀胱、肾、肝、胰腺、骨、***、皮肤、眼、脑、和中枢神经***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2的合成
(E)-2-((E)-3-(3-硝基苯基)亚2-丙烯基)肼基-1-甲脒，Chemdiv ID 0589-0011，化学结构式如下：
Figure BDA0002616899760000061
制备方法
Figure BDA0002616899760000062
3-(3-硝基)-1-丙醇(54.36mg，0.3mmol)，DMSO 0.6mL，乙腈0.9mL，二碘甲酸(210mg，0.75mmol)，催化剂(0.12mg，0.06mmol)，室温下反应8h，旋转蒸发除去挥发性溶剂，得粗产品，以环己烷/乙酸乙酯(70:1)为流动相，过硅胶柱分离，得化合物1(42.3mg，产率80％)。
化合物1(177.16mg，1mmol)，氨基胍盐酸盐(110mg，1mmol)无水乙醇(6mL)和浓盐酸(0.2mL)，回流反应24h，旋转蒸发除去溶剂，粗产物用水洗3次，再用无水乙醇洗3次，最后以丙酮/无水乙醇/甲醇的混合液为流动相，用柱层析法纯化的化合物2(157.21mg，产率64.5％)。
1H-NMRδ(300MHz DMSO):5.24(s,1H),6.81(s,2H),7.10(d,1H),7.33(d,1H),7.69(t,1H),8.00(m,2H),8.14(d,1H),8.31(s,1H),9.36(s,2H).
实施例2化合物12的合成
4-甲氧基-3-溴苄基异硫脲，Chemdiv ID 4298-0374，化学结构式如下：
Figure BDA0002616899760000071
制备方法：
Figure BDA0002616899760000072
3-(3-硝基)-1-丙醇(54.36mg，0.3mmol)，DMSO 0.6mL，乙腈0.9mL，二碘甲酸(210mg，0.75mmol)，催化剂(0.12mg，0.06mmol)，室温下反应8h，旋转蒸发除去挥发性溶剂，得粗产品，以环己烷/乙酸乙酯(70:1)为流动相，过硅胶柱分离，得化合物1(42.3mg，产率80％)。
化合物1(177.16mg，1mmol)，氨基胍盐酸盐(110mg，1mmol)无水乙醇(6mL)和浓盐酸(0.2mL)，回流反应24h，旋转蒸发除去溶剂，粗产物用水洗3次，再用无水乙醇洗3次，最后以丙酮/无水乙醇/甲醇的混合液为流动相，用柱层析法纯化的化合物2(157.21mg，产率64.5％)。
1H-NMRδ(400MHz,DMSO+CCl4):3.85(s,3H),4.93(s,2H),6.97(d,1H),7.42(d,1H),7.60(s,1H).
实施例3化合物90的合成
(R)-4-(4-氟苄基)-1-氧杂-9-氮杂螺[5.5]十一烷，Chemdiv ID T500-0182，化学结构式如下：
Figure BDA0002616899760000081
制备方法
Figure BDA0002616899760000082
0.5mol化合物1溶于10mL乙酸乙酯，加入适量沙瑞特试剂，室温下反应8h，过滤收集滤液，旋转蒸发除去乙酸乙酯，所得固体通过柱层析纯化(石油醚/乙酸乙酯＝20:1)，得化合物2。将0.5mol化合物3溶于10mL乙腈后加入三苯基膦，室温下反应10h，加入0.6mol化合物2和等摩尔的C4H9Li，零下20℃反应14h，浓缩后过柱层析纯化(石油醚/乙酸乙酯＝10:1)纯化的化合物5。将0.2mol化合物5溶于5mL乙腈加入等摩尔的AlCl3 50℃反应8h，再加入Pb/C还原，浓缩后过柱层析纯化(石油醚/乙酸乙酯＝8:1)纯化，经手性拆分后的化合物90。
1H-NMRδ(400MHz,DMSO):1.05(m,2H),1.50(dd,4H),1.75(m,1H),1.85(brs,1H),2.30(t,1H),2.50(m,5H),2.80(m,1H),3.00(s,3H),3.3(m,4H),3.6(d,1H),7.15(dq,4H),8.85(brs,2H).
实施例4化合物10的合成
6-羟基-2-((2-(4-甲氧基苯基)-2-氧代乙基)硫基)嘧啶-4(3H)-酮，ChemdivID4112-3276，化学结构式如下：
Figure BDA0002616899760000091
制备方法：
Figure BDA0002616899760000092
化合物1购自3B Scientific(Wuhan)Product List，China。
化合物2购自AbovChem Product List，United States。
将NaOH(80mg，2mmol)溶于6ml H2O，再加入化合物2(144mg，1mmol)，搅拌下将2mL含有化合物1(228mg，1mmol)的乙醇滴加到上述体系中，室温下反应2h，用0.1mol/L的盐酸调节反应后的溶液的pH至7.0，产物析出后过滤，用去离子水洗涤后真空干燥，得白色化合物10(142mg，产率49％)。
1H-NMRδ(300MHz,DMSO):3.81(s,3H),4.84(s,2H),7.08(d,2H),7.48(s,1H),7.96(d,2H),12.02(s,1H).
实施例5化合物13的合成
2-(5-(苄氧基)-1H-吲哚-3-基)乙基-1-胺，Chemdiv ID 4513-1373，化学结构式如下：
Figure BDA0002616899760000101
将5-苄氧基吲哚-3-甲醛(251.3mg，1mmol)和醋酸铵(231mg，3mmol)溶于5mL硝基甲烷，回流反应2h，减压蒸馏除去硝基甲烷，产物用水洗后过滤，真空干燥得到产物1，不用纯化，将产物1(294mg，1mmol)溶于10mL四氢呋喃后滴加至10mL含有LiAlH4(228mg，6mmol)的四氢呋喃中，0℃开始反应，逐渐升温至25℃，继续反应36h，向反应体系中滴加水，至无气泡产生为止。向反应体系中再加入适量的罗谢尔盐饱和溶液和适量的***，室温下搅拌24h后，分液收集***层，用1mol/L的盐酸溶液将***层萃洗3次，收集水相，用3mol/L的氢氧化钾溶液中和，最后用***萃取，无水硫酸钠干燥后旋转蒸发的到化合物13。
1H-NMRδ(400MHz,DMSO):2.50(d,4H),2.95(dd,1H),3.30(s,1H),5.10(s,1H),6.80(d,1H),7.35(m,8H),7.95(s,3H),10.85(s,1H).
实施例6化合物16的合成
2-(5-甲氧基-1H-吲哚-3-基)乙基异硫脲，Chemdiv ID 5911-0003，化学结构式如下：
Figure BDA0002616899760000111
制备方法
Figure BDA0002616899760000112
3-(2-溴-乙基)-5-甲氧基-1H-吲哚购买自Apichemical(Shanghai)ProductList。
将硫脲(150m g，1.97mmol)和3-(2-溴-乙基)-5-甲氧基-1H-吲哚(581.66mg，2.29m mol)溶于20mL无水乙醇，60℃反应3h。反应结束后旋转蒸发除去乙醇，得到的油状产物转入500mL的烧杯中静置结晶，过滤后真空干燥得到产物16。
1H-NMRδ(400MHz,DMSO):3.05(m,2H),3.40(m,2H),3.75(s,3H),6.65(d,1H),6.93(s,1H),7.15(m,2H),9.60(brs,2H),10.65(s,1H).
实施例7化合物17的合成
(R)-2-(2,3-二氢苯并[b][1,4]二噁英-2-基)甲基异硫脲，Chemdiv ID 5914-0610，化学结构式如下：
Figure BDA0002616899760000121
制备方法
Figure BDA0002616899760000122
2-溴甲基-1,4-苯并二恶烷购买自梯希爱(上海)化成工业发展有限公司。
将硫脲(150g，1.97mmol)和2-溴甲基-1,4-苯并二恶烷(524.41g，2.29mol)溶于200mL无水乙醇，60℃反应3h。反应结束后旋转蒸发除去乙醇，得到的油状产物转入500mL的烧杯中静置结晶，过滤后真空干燥得到产物17。
1H-NMRδ(400MHz,DMSO-d6+CCl4):3.50(dd,1H),3.75(d,1H),4.05(dd,1H),4.40(d,2H),6.80(m,4H),9.20(d,4H).
实施例8化合物20的合成
2-((3-(4-氯苄氧基)苄基)氨基)-2-甲基-1丙醇，Chemdiv ID 6408-0439，化学结构式如下：
Figure BDA0002616899760000123
制备方法
Figure BDA0002616899760000131
3-(4-氯苄基)氧基苯甲醛和2-氨基-2-甲基-1-丙醇购自百灵威科技。
2-氨基-2-甲基-1-丙醇(0.97g,10.89mmol)and 3-(4-氯苄基)氧基苯甲醛(2.819g,11.44mmol)溶于25mL甲苯，回流反应4h后冷却至室温，旋转蒸发除去甲苯，加入25mL乙醇后冷却至0℃并加入NaBH4(1.03g,27.2mmol)，滴加4.0mol/L的盐酸和二氧六环的混合液调节溶液的pH至2.0，室温下将上述混合液搅拌过夜。将搅拌后的混合液浓缩后加入等体积的1.0mol/L的盐酸和二氯甲烷(20mL)，分层后，分别收集水相，将水相用适量的二氯甲烷萃取3次，有机相弃掉后，再将水相用10mol/L的NaOH调节至8.0，并用二氯甲烷萃取有机相3次，收集有机相并用无水MgSO4干燥，过滤，旋转蒸发除去二氯甲烷得产物20。
1H-NMRδ(300MHz,DMSO-d6):1.30(s,6H),4.00(s,2H),4.15(s,2H),4.26(s,1H),5.15(s,2H),6.85(d,3H),7.25(m,5H),7.40(d,2H).
实施例9化合物25的合成
(2R,4S)-2-(2,3-二羟基苯基)噻唑烷-4-甲酸，Chemdiv ID 8010-6264，化学结构式如下：
Figure BDA0002616899760000141
制备方法：
Figure BDA0002616899760000142
将L-半胱氨酸(0.175g，1.1mmol)、NaHCO3(0.084g，1mmol)和2,3-二羟基苯甲醛(0.124g，0.9mmol)溶于10mL10％的DMSO水溶液，室温下反应，TLC检测反应结束后，将反应液在冰水浴中沉淀，得白色固体，干燥后通过液相手性分离法得产物20。
1H-NMRδ(300MHz,DMSO-d6):2.85(dq,2H),3.76(t,1H),6.35(s,1H),6.70(m,2H),6.85(d,1H),7.90(s,1H),9.48(s,1H),9.58(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 BDA0002616899760000151
表2
Figure BDA0002616899760000161
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 (3)

1.一种靶向Neddylation通路的抗肿瘤化合物，其特征在于，包括如下结构通式的化合物：
Figure FDA0002616899750000011
式中，R24、R27选自氢、卤素、羟基、低级烷基；R25、R26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；R28选自氢、氨基、甲脒、硫脲基、任选取代的胺基、氮杂环、酰胺基、羟基、低级烷基；X2选自甲基、乙基、丙烯基、酰胺基、甲氧基、氧代乙基；Y2选自硫原子、氨基、肼基、环氧烷基、杂环基。
2.权利要求1所述的化合物的药用盐，其特征在于，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。
3.权利要求1所述的化合物及权利要求2所述药用盐在制备抗肿瘤药物或抗炎药物中的应用，其特征在于，其中的肿瘤是指食道、胃、肠、口腔、咽、喉、肺、乳腺、子宫、卵巢、***、睾丸、膀胱、肾、肝、胰腺、骨、***、皮肤、眼、脑、和中枢神经***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。
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