CN110343088B - 一种基于PARP抑制剂Niraparib的衍生物及其制备方法和应用 - Google Patents
一种基于PARP抑制剂Niraparib的衍生物及其制备方法和应用 Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
本发明公开了一种基于PARP抑制剂Niraparib的衍生物，结构如式I所示，其中，R1选自烷基、烷氧基、环烷基、芳基烷基、环烷基烷基、杂环基、杂芳环基、卤代烷氧基、卤代烷基或羟烷基。本发明还提供了该衍生物的制备方法及其制备抗肿瘤药物的应用，本发明的化合物是聚(ADP‑核糖)聚合酶的抑制剂，因此具有治疗乳腺癌、卵巢癌、前列腺癌及胰腺癌等肿瘤疾病，并可以作为癌症治疗的化学/辐射增敏剂。
Description
技术领域
本发明属于PARP抑制剂技术领域，具体涉及一种基于PARP抑制剂Niraparib的衍生物及其制备方法和应用。
背景技术
DNA损伤在细胞周期中时刻发生，除了紫外辐射，化学毒物等外界因素，细胞自身代谢产物刺激，及DNA复制产生错误等都会让基因组变的不稳定进而引起癌变。因此，细胞必须有多种DNA损伤发现和修复机制，使受损的DNA得到及时精确的修复来维持正常的生理功能。PARP是一种聚ADP核糖聚合酶，它能够识别DNA损伤，启动DNA修复。对于带有BRCA突变的癌细胞来说，抑制PARP活性使得癌细胞分裂产生大量DNA损伤，因不能正确修复导致细胞死亡。而正常细胞因为有BRCA存在，仍能修复DNA，使细胞存活，这是PARP抑制剂作为靶向药物，选择杀死BRCA突变细胞的原因。
目前已报到了多种结构的PARP小分子抑制剂，它们都可以特异性的靶向PARP结合口袋发挥抑制作用。Niraparib是一种口服的PARP-1/2抑制剂，2017年3月27日，FDA批准其用于复发性铂敏感上皮卵巢癌，输卵管癌或腹膜癌患者的维持治疗。Niraparib也是首个不论BRCA基因是否突变都有具有良好效果的PARP抑制剂。但是也存在耐药性差、抑制活性不高的问题。
发明内容
发明目的：为了解决上述技术问题，本发明提供一种基于PARP抑制剂Niraparib的衍生物及其制备方法和应用，该衍生物能够显著提高抑制PARP的活性。
技术方案：为了实现上述目的，本发明采用以下技术方案：
一种基于PARP抑制剂Niraparib的衍生物，结构如式I所示：
R1选自烷基、烷氧基、环烷基、芳基烷基、环烷基烷基、杂环、杂芳环、卤代烷氧基、卤代烷基或羟烷基。
优选，所述R1选自C1-C8烷基、3-6元环烷基或3-6元杂环基。
最优选的，所述R1选自C3-C5的直链烷基(3-5个碳原子的直链烷基)。
进一步优选，所述R1选自正丙基、异丙基、正丁基、异丁基、正戊基、正己基、环丙基、环戊基、环己基、四氢吡喃基、N-boc-哌啶基或N-boc-哌啶苄基。所述的基于PARP抑制剂Niraparib的衍生物，其结构式如式M1-2、M2-2、M3-2、M4-2、M5-2、M6-2、M7-2、M8-2、M9-2、M10-2、M11-2或M12-2所示：
所述的基于PARP抑制剂Niraparib的衍生物的制备方法，包括以下步骤：
(1)在碱性条件下，式6化合物水解得式7化合物；
(2)式7化合物与式8化合物在缩合剂的催化作用下，得式9化合物；
(3)式9化合物在酸性条件下脱Boc得式10化合物；
其中，R1同权利要求1所述。
作为优选：
步骤(1)中，反应在有机溶剂和水的混合溶液中进行，有机溶剂选自甲醇或乙醇，优选甲醇；有机溶剂与水的混合比例v/v为1:1～10，优选为1:10；反应温度为25～50℃，优选为35℃；反应时间为2～8h，优选4h。所用的碱为氢氧化钠、氢氧化锂或氢氧化钾，式6化合物与碱的摩尔比为1:1～10，优选为1:10。
步骤(2)中，式7化合物与式8化合物在有机溶剂中进行，有机溶剂选自：二氯甲烷、二氯乙烷、N，N-二甲基甲酰胺、二甲基亚砜中的一种或几种。所述缩合剂选自HBTU、HATU、HCTU、EDCI或HOBT，优选HBTU；反应在碱性条件下进行，反应在碱性条件下进行，需要的碱选自TEA或DIPEA，优选TEA；式7化合物与式8化合物的摩尔比1：1～1.5，优选1:1.2；反应温度为0～45℃；反应时间为4～12h，优选6h。
步骤(3)中，反应在有机溶剂中进行，有机溶剂选自：二氯甲烷、二氯乙烷、DMF或DMSO中的一种或几种，优选为二氯甲烷。反应所需要的酸选自盐酸或三氟乙酸，优选三氟乙酸；反应温度为25～30℃，优选为30℃；反应时间为1～3h，优选2h；式9化合物与酸的摩尔比为1：1～4，优选为1:3。
化合物6可以通过常规方法制备，例如通过以下方法制备：
(1)将化合物1分散于有机溶剂如四氯化碳溶液中，加入过氧化苯甲酰和NBS，在氮气保护下加热回流12～14h，得化合物2。
(2)将化合物2分散于乙腈中，氮气保护下，加入N-甲基吗啉-N-氧化物室温下反应2～12h后得化合物3。
(3)将化合物3和化合物4分散于有机溶剂如无水乙醇中，在0～80℃之间反应6～8h，得化合物5。
(4)将化合物5分散于有机溶剂如无水DMF中，加入NaN3，在氮气回流下反应过夜，得化合物6。
反应路线如下：
本发明进一步提供了所述基于PARP抑制剂Niraparib的衍生物在制备用于治疗肿瘤药物中的应用。所述肿瘤包括卵巢癌、乳腺癌、前列腺癌或胰腺癌等。并且该衍生物还可以作为癌症治疗的化学/辐射曾敏剂。
本发明的设计思想是：通过新基团的引入可以增加抑制剂分子的紧密性，使新化合物能够更稳定的占据PARP-1结合口袋，提高对蛋白的亲和力，进而达到提高抑制活性，延长药物作用时间和改善药物生物利用度的目的。
本发明的衍生物如M3-2、M5-2、M1-2抑制活性得到了提升，毒性更低，提升了用药安全性。
技术效果：相对于现有技术，本发明提供了一种新的PARP抑制剂，通过新基团的引入可以增加抑制剂分子的紧密性，使新化合物能够更稳定的占据PARP-1结合口袋，提高对蛋白的亲和力，进而达到提高抑制活性，延长药物作用时间和改善药物生物利用度的目的。
附图说明
图1为本发明化合物M3-2的氢谱。
图2为本发明化合物M3-2的质谱。
具体实施方式
下面结合具体实例，进一步阐明本发明。
实施例1：
(1)制备化合物2
称取化合物1(2.34g,12mmol)，用0.2M四氯化碳溶液将其溶解，加入过氧化苯甲酰(0.17g,0.72mmol)，NBS(2.18g,14.16mmol)，氮气保护下回流12小时。待混合物冷却至室温，滤液减压浓缩，加入30mL水，用EA萃取三次，有机相经卤水洗涤，无水硫酸钠干燥，过滤，减压蒸馏得到黄色混合物，经柱层析(洗脱剂为石油醚：乙酸乙酯＝90:1)，得到白色絮状固体化合物2(1.15g,35％)。
目标产物的数据如下：
1H NMR(300MHz,CDCl3)δ:7.96(dd,J＝7.8,1.4Hz,1H),7.75(dd,J＝7.9,1.5Hz,1H),7.59(t,J＝7.8Hz,1H),4.46(s,2H),3.91(s,3H).
MS:[M+H]+m/z calcd 273.9709for C9H8BrNO4,found 273.9709.
(2)制备化合物3
称取化合物2(2.74g,10mmol)于150mL单口烧瓶中，加入
分子筛在乙腈中的混合物(0.2M)将其溶解，在氮气保护下，加入N-甲基吗啉-N-氧化物(2.34g,20mmol)，室温下反应2小时，浓缩后倾入水中，用EA萃取三次，有机相用分别用1N HCl，卤水洗涤，干燥，过滤，浓缩，经柱层析(洗脱剂为石油醚：乙酸乙酯＝80:1)得淡黄色固体即化合物3(1.63g,78％)。
目标产物的数据如下：
1H NMR(300MHz,CDCl3)δ:9.87(s,1H),8.12(dd,J＝7.8,1.7Hz,1H),7.65(dd,J＝7.5,1.8Hz,1H),6.69(t,J＝7.7Hz,1H),3.89(s,3H).
MS:[M+H]+m/z calcd 210.0397for C9H7NO5,found 210.0397.
(3)制备化合物5
称取化合物3(2.13g,10.2mmol)于100mL茄型烧瓶内，加入0.2M无水乙醇溶解并加入化合物4(3S)-3-(4-氨基苯基)哌啶-1-甲酸叔丁酯(2.76g,10mmol)，80℃回流下搅拌4小时，直至TLC显示反应完全(石油醚：乙酸乙酯＝20:4)，待反应物冷却，结晶，过滤，所得滤饼用甲醇重结晶，过滤干燥，得到白色固体化合物5(3.03g,92％)可直接用于下一步。
目标产物的数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.55(s,1H),8.38(dd,J＝7.9,1.5Hz,1H),8.15(dd,J＝7.7,1.5Hz,1H),7.90(t,J＝7.8Hz,1H),7.35(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),3.97-3.95(m,2H),3.88(s,3H),2.79-2.64(m,3H),1.90-1.78(m,1H),1.68-1.53(m,2H),1.47(s,1H),1.41(s,9H).
MS:[M+Na]+m/z calcd 490.1948for C25H29N3O6,found 490.1988.
(4)制备化合物6
在100mL茄型烧瓶内加入化合物5(1.4g,2.99mmol)，加入0.2M无水DMF，加入叠氮化钠(0.2g,3.13mmol)，在氮气保护下，110℃回流反应过夜，点板确定反应终点。混合物加水稀释，用EA萃取三次，经卤水洗涤有机相，无水硫酸钠干燥，过滤，浓缩粗产物经柱层析分离纯化(洗脱剂为石油醚：乙酸乙酯＝10:1)，得褐色油状目标产物化合物6(0.88g,68％)。
目标化合物的数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.25(d,J＝1.5Hz,1H),8.13-7.98(m,4H),7.53(d,J＝8.4Hz,2H),7.27-7.19(m,1H),4.10-4.01(m,2H),3.97(s,3H),2.85-2.72(m,3H),1.98-1.90(m,1H),1.83-1.72(m,2H),1.55-1.50(m,1H),1.42(s,9H).
MS:[M+H]+m/z calcd 436.2285for C25H29N3O4,found 436.2285.
(5)制备化合物7
称取固体氢氧化钠(0.79g,19.7mmol)溶于25mL水中，将化合物6(0.86g,1.97mmol)溶于25mL甲醇溶液中，在混合液中加入已配制好的10％氢氧化钠溶液，在35℃下搅拌4小时，点板确定反应终点(展开剂为石油醚：乙酸乙酯＝5:1,一滴冰醋酸)，在混合溶液中滴加1M稀盐酸溶液，调至pH为3，过滤，用少量清水洗涤滤饼，然后将滤饼在45℃条件下烘干，得白色固体即化合物7(0.56g,68％)，无需进一步提纯，直接投入下一步。
目标化合物的数据如下：
MS:[M+Na]+m/z calcd 444.1893for C24H27N3O4,found 444.1893.
(6)制备化合物9-1
在100mL茄型烧瓶中，加入化合物7(1.05g,2.5mmol)溶于18mL无水DMF中，在0℃时，依次向反应瓶加入HBTU(1.87g,5mmol)，三乙胺(0.42mL,3mmol)，正丙胺(0.25mL,3mmol)，随后在45℃下反应6小时，待反应结束，将混合液倾入水中，用EA萃取三次，用卤水洗涤，Na2SO4干燥，过滤，减压浓缩得粗产品经柱层析分离(洗脱剂为石油醚：乙酸乙酯＝8:1)得黄色油状液体化合物9-1(0.87g,76％)。
目标化合物的数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.45(d,J＝1.3Hz,1H),8.35(t,J＝6.5Hz,1H),8.18(dd,J＝7.6,1.5Hz,1H),7.80(dd,J＝7.6,1.5Hz,1H),7.45(dd,J＝7.4,5.9Hz,3H),7.31(d,J＝7.5Hz,2H),3.69(d,J＝7.1Hz,2H),3.55(td,J＝6.9,2.8Hz,2H),3.25-3.12(m,1H),3.10-2.99(m,1H),2.91-2.80(m,1H),1.80-1.76(m,3H),1.74-1.62(m,1H),1.52-1.39(m,1H),1.43(s,9H),1.37-1.30(m,1H),0.81(t,J＝8.0Hz,3H).
MS:[M+Na]+m/z calcd 485.2523for C27H34N4O3,found 485.2523.
(7)制备化合物M1-2
称取化合物9-1(0.5g,1.08mmol)溶于8mL DCM，滴加0.4mL三氟乙酸溶液后，在30℃下搅拌2小时，待混合物冷却至室温，加入饱和Na2CO3水溶液调至pH为7，静置分离有机相，水相用DCM萃取三次，合并有机相经卤水洗涤后，干燥过夜，过滤，减压浓缩粗产品经柱层析纯化(洗脱剂为二氯甲烷：甲醇＝25:3)，得淡黄色固体即最终化合物M1-2(0.25g,64％)。
目标化合物的数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.32(d,J＝1.3Hz,1H),9.11(t,J＝5.3Hz,1H),8.36-7.89(m,4H),7.57(d,J＝8.5Hz,2H),7.34-7.22(m,1H),3.56(q,J＝7.2Hz,1H),3.45(dd,J＝12.7,6.7Hz,4H),1.99(d,J＝35.2Hz,2H),1.79(t,J＝8.9Hz,1H),1.72-1.60(m,2H),1.18(t,J＝7.3Hz,4H),1.02(t,J＝7.4Hz,3H).
13C NMR(75MHz,DMSO-d6)δ:168.67,150.68,146.94,143.06,134.18,133.33,129.84,128.32,128.14,126.82,126.21,125.59,62.67,52.51,50.48,47.77,45.56,34.10,27.24,16.21,13.32,12.33.
MS:[M+H]+m/z calcd 363.2179for C22H26N4O,found 363.2182.
实施例2
(1)制备化合物9-2
在100mL茄型烧瓶中，加入化合物7(1.05g,2.5mmol)溶于18mL无水DMF中，在冰水浴下，依次向反应瓶加入HBTU(1.87g,5mmol)，三乙胺(0.42mL,3mmol)，异丙胺(0.26mL,3mmol)，随后在45℃下反应6小时，待反应结束，将混合液倾入水中，用EA萃取三次，经卤水洗涤，干燥过夜，过滤，减压浓缩得粗产品经柱层析纯化(洗脱剂为石油醚：乙酸乙酯＝7:1)得褐色油状液体9-2(0.87g,76％)。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.45(d,J＝1.3Hz,1H),8.17(dd,J＝7.4,1.6Hz,1H),7.82(dd,J＝7.6,1.5Hz,1H),7.51(d,J＝7.9Hz,1H),7.48-7.40(m,3H),7.31(d,J＝7.4Hz,2H),4.00(d,J＝14.0,7.0Hz,1H),3.69(d,J＝7.1Hz,2H),3.55(td,J＝6.8,2.8Hz,2H),2.85(m,1H),1.88-1.72(m,3H),1.68-1.60(m,1H),1.43(s,9H),1.13(d,J＝6.7Hz,3H),1.08(d,J＝7.0Hz,3H).
MS:[M+H]+m/z calcd 485.2523for C27H34N4O3,found 485.2521.
(2)制备化合物M2-2
称取化合物9-2(0.5g,1.08mmol)溶于8mL DCM，滴加0.4mL三氟乙酸溶液后，在30℃下搅拌2小时，待混合物冷却至室温，加入饱和NaHCO3水溶液调至pH为7，静置分离有机相，水相用DCM萃取三次，合并有机相经卤水洗涤后，用无水硫酸镁干燥过夜，过滤，减压浓缩粗产品经柱层析纯化(洗脱剂为二氯甲烷：甲醇＝25:3)，得淡黄色固体即最终化合物M2-2(0.27g,70％)。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.31(d,J＝1.5Hz,1H),9.06(d,J＝7.2Hz,1H),8.05(dd,J＝8.6,2.6Hz,4H),7.58(dd,J＝7.6,1.5Hz,2H),7.28(t,J＝7.6Hz,1H),4.47(s,1H),4.19(dd,J＝7.6,1.5Hz,4H),2.05(s,1H),1.97(d,J＝8.6Hz,3H),1.79(s,2H),1.31(d,J＝6.4Hz,3H),1.23(t,J＝7.2Hz,3H).
13C NMR(75MHz,DMSO-d6)δ:168.56,150.61,147.32,144.44,133.04,131.23,126.10,125.83,125.00,123.50,122.32,120.98,119.96,119.12,52.46,46.83,44.80,43.69,31.46,26.14,22.92,21.80.
MS:[M+H]+m/z calcd 363.2179for C22H26N4O,found 363.2182.
实施例3
(1)制备化合物9-3
制备方法同实施例1，加入正丁胺，得黄色油状液体化合物9-3。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.45(d,J＝1.3Hz,1H),8.38(t,J＝7.0Hz,1H),8.17(d,J＝7.3Hz,1H),7.80(dd,J＝7.6,1.5Hz,1H),7.46(dd,J＝7.5,6.3Hz,3H),7.30(d,J＝7.3Hz,2H),3.69(d,J＝7.1Hz,2H),3.61-3.49(m,2H),3.29(m,2H),2.85(m,1H),1.87-1.78(m,1H),1.80-1.71(m,2H),1.74-1.62(m,1H),1.62-1.46(m,2H),1.41(s,9H),1.38(dd,J＝13.6,6.2Hz,1H),1.36-1.25(m,1H),0.91(t,J＝8.0Hz,3H).
MS:[M+Na]+m/z calcd 499.2679for C28H36N4O3,found 499.2677.
(2)制备化合物M3-2
制备方法同实施例1，得黄色固体化合物M3-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.48(d,J＝1.4Hz,1H),9.05(t,J＝7.0Hz,1H),8.03-7.95(m,5H),7.84-7.77(m,2H),7.53(t,J＝7.5Hz,1H),3.65(q,J＝6.9Hz,2H),3.47-3.42(m,4H),2.15-2.06(m,2H),2.11-2.03(m,2H),2.01-1.79(m,2H),1.20-1.14(m,4H),1.03(d,J＝7.2Hz,3H).
13C NMR(75MHz,DMSO-d6)δ:168.65,149.69,145.23,140.51,134.62,133.91,131.69,127.25,125.74,122.97,122.01,120.71,119.13,117.43,63.64,55.59,51.88,48.98,34.31,26.40,17.86,13.74,11.64.
MS:[M+H]+m/z calcd 377.2335for C23H28N4O,found 377.2340.
实施例4
(1)制备化合物9-4
制备方法同实施例1，加入异丁胺，得黄色油状液体化合物9-4。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.47-8.40(m,2H),8.17(d,J＝7.3Hz,1H),7.80(dd,J＝7.6,1.5Hz,1H),7.46(dd,J＝7.5,2.3Hz,3H),7.30(d,J＝7.3Hz,2H),3.69(d,J＝7.2Hz,2H),3.61-3.49(m,2H),3.28-3.14(m,2H),2.85(m,1H),1.97-1.90(m,1H),1.87-1.78(m,1H),1.80-1.71(m,2H),1.74-1.62(m,1H),1.41(s,9H),1.01(dd,J＝6.7,2.7Hz,6H).
MS:[M+H]+m/z calcd 499.2679for C28H36N4O3,found 499.2678.
(2)制备化合物M4-2
制备方法同实施例1，得黄色固体化合物M4-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.30(d,J＝1.3Hz,1H),9.05(d,J＝7.1Hz,1H),8.02-7.94(m,4H),7.76-7.65(m,2H),7.27(t,J＝7.5Hz,1H),4.47(t,J＝5.8Hz,1H),4.12(t,J＝7.0Hz,2H),3.10(dd,J＝7.0,2.7Hz,2H),2.85(d,J＝7.0Hz,2H),2.03(t,J＝7.0Hz,1H),1.89-1.81(m,1H),1.72-1.60(m,2H),1.50-1.45(m,2H),1.05(dd,J＝6.7,2.7Hz,6H).
13C NMR(75MHz,DMSO-d6)δ:168.65,150.40,146.25,145.66,145.62,134.89,134.16,128.83,128.77,128.33,127.61,126.54,125.23,125.09,65.84,53.70,50.79,48.56,33.60,28.26,26.40,20.12,20.06.
MS:[M+H]+m/z calcd 377.2335for C23H28N4O,found 377.2338.
实施例5
(1)制备化合物9-5
制备方法同实施例1，加入正戊胺，得化合物9-5。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.47-8.41(m,2H),8.16(d,J＝7.3Hz,1H),7.80(dd,J＝7.3,1.5Hz,1H),7.46(dd,J＝7.5,6.5Hz,3H),7.30(d,J＝7.4Hz,2H),3.69(d,J＝7.1Hz,2H),3.55(td,J＝6.8,3.4Hz,2H),3.42-3.93(m,1H),3.29-3.20(m,1H),2.85-2.76(m,1H),1.87-1.78(m,1H),1.80-1.72(m,2H),1.70-1.66(m,1H),1.65-1.49(m,2H),1.41(s,9H),1.40-1.31(m,2H),1.34-1.25(m,2H),0.94-0.84(m,3H).
MS:[M+H]+m/z calcd 513.2839for C29H38N4O3,found 513.2839.
(2)制备化合物M5-2
制备方法同实施例1，得黄色固体化合物M5-2
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.31(d,J＝1.4Hz,1H),9.01(t,J＝6.8Hz,1H),8.11-8.01(m,4H),7.76-7.65(m,2H),7.29(t,J＝7.6Hz,1H),3.88-3.68(m,2H),3.51(t,J＝6.5Hz,2H),2.20-2.16(m,3H),1.95-1.90(m,1H),1.76(q,J＝6.7Hz,2H),1.70-1.66(m,2H),1.63-1.58(m,2H),1.06-1.02(m,4H),0.88-0.84(m,4H).
13C NMR(75MHz,DMSO-d6)δ:168.65,148.98,146.37,141.93,133.51,131.38,131.36,129.72,127.86,127.04,126.69,126.09,125.24,125.22,63.63,53.69,51.17,49.35,35.43,30.26,26.50,18.93,16.35,14.03.
MS:[M+H]+m/z calcd 391.2492for C24H30N4O,found 391.2496.
实施例6
(1)制备化合物9-6
制备方法同实施例1，加入正己胺，得化合物9-6。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.48-8.41(m,2H),8.16(d,J＝7.6Hz,1H),7.81(dd,J＝7.6,1.5Hz,1H),7.52-7.43(m,3H),7.30(d,J＝7.5Hz,2H),3.69(d,J＝7.1Hz,2H),3.55-3.48(m,2H),3.42-3.32(m,1H),3.28(m,1H),2.85(m,1H),1.87-1.78(m,1H),1.80-1.71(m,2H),1.74-1.62(m,1H),1.56(m,2H),1.43(s,9H),1.34-1.26(m,6H),0.94-0.86(m,3H).
MS:[M+Na]+m/z calcd 527.2992for C30H40N4O3,found 527.2991.
(2)制备化合物M6-2
制备方法同实施例1，得黄色固体化合物M6-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.33(d,J＝1.5Hz,1H),9.22-9.13(m,2H),8.13-8.03(m,5H),7.57(t,J＝8.5Hz,2H),7.33(t,J＝7.7Hz,1H),3.54-3.48(m,3H),3.08-3.01(m,1H),2.80(d,J＝8.9Hz,1H),1.68(q,J＝7.8Hz,2H),1.60-1.46(m,5H),1.46-1.33(m,6H),0.93-0.89(m,3H).
13C NMR(75MHz,DMSO-d6)δ:165.33,143.61,142.41,139.21,132.51,130.53,130.51,128.55,127.44,126.34,125.18,123.21,122.41,122.39,52.35,50.06,47.56,46.67,34.00,30.48,28.91,26.71,18.57,14.28,12.34.
MS:[M+H]+m/z calcd 405.2648for C25H32N4O,found 405.2649.
实施例7
(1)制备化合物9-7
制备方法同实施例1，加入环丙胺，得化合物9-7。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.45(d,J＝1.3Hz,1H),8.31(d,J＝9.4Hz,1H),8.17(dd,J＝7.3,1.5Hz,1H),7.82(dd,J＝7.6,1.5Hz,1H),7.45(dd,J＝7.5,4.2Hz,3H),7.31(d,J＝7.4Hz,2H),3.69(d,J＝7.1Hz,2H),3.61-3.49(m,2H),2.86-2.67(m,2H),1.87-1.78(m,1H),1.80-1.72(m,2H),1.68-1.59(m,1H),1.43(s,9H),0.78-0.71(m,2H),0.52-0.46(m,2H).
MS:[M-H]-m/z calcd 459.2401for C27H32N4O3,found 459.2403.
(2)制备化合物M7-2
制备方法同实施例1，得黄色固体化合物M7-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.33(d,J＝1.5Hz,1H),9.10(t,J＝4.4Hz,1H),8.05(dd,J＝7.5,1.5Hz,4H),7.89(d,J＝4.3Hz,2H),7.26(d,J＝8.4Hz,1H),3.61-3.53(m,3H),3.16-3.09(m,1H),3.02-2.96(m,2H),1.97-1.85(m,2H),1.71-1.62(m,2H),0.98-0.86(m,4H).
13C NMR(75MHz,DMSO-d6)δ:168.64,147.45,145.21,140.54,130.64,129.63,129.61,128.92,128.07,126.36,125.24,123.69,123.67,122.61,52.38,50.45,46.60,30.26,26.43,23.56,12.73,12.71.
MS:[M+H]+m/z calcd 361.2022for C22H24N4O,found 361.2026.
实施例8
(1)制备化合物9-8
制备方法同实施例1，加入环戊胺，得化合物9-8。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.45(d,J＝1.3Hz,1H),8.21(d,J＝9.7Hz,1H),8.16(dd,J＝7.6,1.5Hz,1H),7.82(dd,J＝7.6,1.5Hz,1H),7.46(dd,J＝7.5,2.5Hz,3H),7.30(d,J＝7.3Hz,2H),4.16-4.09(m,1H),3.69(d,J＝7.1Hz,2H),3.61-3.49(m,2H),2.85-2.79(m,1H),1.87-1.62(m,8H),1.64-1.54(m,4H),1.41(s,9H).
MS:[M+H]+m/z calcd 489.2860for C29H36N4O3,found 489.2861.
(2)制备化合物M8-2
制备方法同实施例1，得黄色固体化合物M8-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.36(d,J＝1.6Hz,1H),9.30-9.20(m,1H),8.18-8.02(m,4H),7.57(dd,J＝7.5,1.5Hz,2H),7.38-7.22(m,1H),4.43-4.35(m,1H),4.02-3.96(m,1H),3.18(dd,J＝12.6,6.4Hz,2H),2.94-2.66(m,1H),2.11-1.96(m,2H),1.87-1.53(m,6H),1.29(d,J＝5.8Hz,2H).
13C NMR(75MHz,DMSO-d6)δ:166.39,147.57,140.87,134.02,132.32,131.58,130.01,128.15,126.57,125.80,125.08,124.22,123.85,123.50,54.92,54.27,53.96,47.81,44.46,35.97,33.99,32.05,27.92,26.32.
MS:[M+H]+m/z calcd 389.2335for C24H28N4O,found 389.2336.
实施例9
(1)制备化合物9-9
制备方法同实施例1，加入环己胺，得化合物9-9。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.46(d,J＝1.4Hz,1H),8.18-8.13(m,2H),7.84(dd,J＝7.3,1.5Hz,1H),7.51-7.43(m,3H),7.30(d,J＝7.5Hz,2H),3.82-3.74(m,1H),3.69(d,J＝7.1Hz,2H),3.55-3.46(m,2H),2.85-2.75(m,1H),1.87-1.78(m,1H),1.80-1.69(m,3H),1.72-1.64(m,2H),1.67-1.54(m,2H),1.54-1.33(m,6H),1.43(s,9H).
MS:[M+H]+m/z calcd 503.3016for C30H38N4O3,found 503.3017.
(2)制备化合物M9-2
制备方法同实施例1，得黄色固体化合物M9-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.31(d,J＝1.6Hz,1H),9.22(d,J＝7.8Hz,1H),8.16-7.97(m,4H),7.51(dd,J＝7.6,1.7Hz,2H),7.27(dd,J＝7.2,1.5Hz,1H),3.10-2.92(m,5H),2.75-2.69(m,1H),2.61(dd,J＝7.5,1.0Hz,1H),2.58-2.53(m,1H),2.52-2.43(m,1H),2.01-1.93(m,2H),1.87-1.66(m,3H),1.64-1.59(m,2H),1.56-1.38(m,4H),1.32-1.25(m,1H).
13C NMR(75MHz,DMSO-d6)δ:165.97,148.96,140.59,133.95,132.39,131.49,129.98,128.13,126.50,125.70,125.04,124.48,124.16,123.44,56.59,54.91,50.37,49.05,46.17,35.29,34.93,32.05,29.63,28.29,26.94.
MS:[M+Na]+m/z calcd 425.2311for C25H30N4O,found 425.2313.
实施例10
(1)制备化合物9-10
制备方法同实施例1，加入4-氨基四氢吡喃，得化合物9-10。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.46(d,J＝1.4Hz,1H),8.16(dd,J＝7.3,1.5Hz,1H),8.10(d,J＝10.0Hz,1H),7.84(dd,J＝7.3,1.5Hz,1H),7.47(dd,J＝6.8,1.5Hz,3H),7.30(d,J＝7.5Hz,2H),3.94-3.87(m,1H),3.74-3.62(m,4H),3.61(dd,J＝12.5,7.0Hz,2H),3.59-3.49(m,2H),2.85-2.76(m,1H),1.95-1.87(m,4H),1.86-1.78(m,1H),1.80-1.71(m,2H),1.74-1.62(m,1H),1.43(s,9H).
MS:[M+H]+m/z calcd 505.2809for C29H36N4O4,found 505.2817.
(2)制备化合物M10-2
制备方法同实施例1，得黄色固体化合物M10-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.26(d,J＝1.6Hz,1H),9.17(d,J＝7.3Hz,1H),8.05-7.93(m,4H),7.48(d,J＝8.4Hz,2H),7.28-7.20(m,1H),4.21-4.05(m,1H),3.95-3.87(m,2H),3.49-3.41(m,2H),2.95(dd,J＝7.0,3.2Hz,2H),2.73-2.66(m,1H),2.60-2.47(m,1H),1.93-1.87(m,4H),1.69-1.58(m,4H),1.54-1.42(m,1H),1.19(d,J＝3.2Hz,1H).
13C NMR(75MHz,DMSO-d6)δ:166.27,148.91,140.58,132.43,131.51,131.23,128.29,126.53,126.43,125.03,124.27,123.76,123.51,123.44,68.66,56.52,49.03,48.18,46.12,35.66,34.91,29.59,28.29,26.94.
MS:[M+H]+m/z calcd 405.2285for C24H28N4O2,found 405.2287.
实施例11
(1)制备化合物9-11
制备方法同实施例1，加入1-Boc-4-氨基哌啶，得化合物9-11。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.42(d,J＝1.7Hz,1H),8.20-8.15(m,1H),8.12(d,J＝10.0Hz,1H),7.81(dd,J＝7.3,1.5Hz,1H),7.47(dd,J＝7.6,1.5Hz,3H),7.30(d,J＝7.4Hz,2H),3.85-3.73(m 1H),3.69(d,J＝7.0Hz,2H),3.63(t,J＝7.1Hz,4H),3.54(t,J＝6.8Hz,2H),2.89-2.83(m,1H),1.97-1.88(m,2H),1.90-1.71(m,5H),1.74-1.63(m,1H),1.43(s,18H).
MS:[M+H]+m/z calcd 604.3493for C34H45N5O5,found 604.3492.
(2)制备化合物M11-2
制备方法同实施例1，得黄色固体化合物M11-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.36(d,J＝10.0Hz,1H),9.25(t,J＝7.6Hz,1H),8.14-8.05(m,4H),7.66-7.60(m,2H),7.31(dd,J＝7.6,1.5Hz,1H),4.18-4.12(m,3H),3.60(t,J＝7.1Hz,4H),3.04-2.97(m,2H),2.82-2.73(m,2H),1.97-1.86(m,4H),1.69-1.61(m,2H),1.58-1.51(m,2H),1.43(s,9H).
13C NMR(75MHz,DMSO-d6)δ:166.33,165.99,156.98,148.92,147.18,140.95,140.60,132.47,131.64,128.22,126.59,125.09,124.42,123.58,56.59,56.40,49.51,48.95,47.51,46.04,44.59,36.01,34.87,34.42,32.05,31.17,29.50,28.01,26.94.
MS:[M+H]+m/z calcd 504.2969for C29H37N5O3,found 405.2970.
实施例12
(1)制备化合物9-12
制备方法同实施例1，加入1-叔丁氧羰基-4-氨甲基哌啶，得化合物9-12。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:8.44(d,J＝1.4Hz,1H),8.33(t,J＝7.6Hz,1H),8.17(d,J＝7.3Hz,1H),7.81(dd,J＝7.3,1.5Hz,1H),7.45(dd,J＝7.7,2.8Hz,3H),7.30(d,J＝7.4Hz,2H),3.74-3.65(m,3H),3.63(d,J＝7.0Hz,1H),3.62-3.48(m,4H),3.50-3.44(m,1H),3.40(d,J＝7.3Hz,1H),2.86(m,1H),1.87-1.79(m,5H),1.82-1.71(m,3H),1.68-1.61(m,1H),1.43(s,18H).
MS:[M+Na]+m/z calcd 640.3469for C35H47N5O5,found 640.3470.
(2)制备化合物M12-2
制备方法同实施例1，得黄色固体化合物M12-2。
目标化合物数据如下：
1H NMR(300MHz,DMSO-d6)δ:9.24(d,J＝1.5Hz,1H),9.12(t,J＝7.6Hz,1H),8.04-7.96(m,4H),7.54(d,J＝7.5Hz,2H),7.27(t,J＝7.5Hz,1H),3.93(t,J＝7.1Hz,4H),3.41(t,J＝7.2Hz,2H),2.74-2.67(m,2H),1.98-1.92(m,1H),1.86-1.78(m,2H),1.78-1.70(m,4H),1.67-1.59(m,2H),1.55-1.47(m,4H),1.42(s,9H).
13C NMR(75MHz,DMSO-d6)δ:165.90,164.65,155.48,148.59,146.72,140.52,132.11,130.63,129.88,127.62,126.57,124.08,122.98,122.16,81.19,57.40,51.48,50.47,49.35,48.19,36.53,33.22,33.21,33.19,31.41,31.02,30.99,29.60,29.57,28.36.
MS:[M+H]+m/z calcd 518.3125for C30H39N5O3,found 518.3139.
实施例13PARP-1酶活性评价。
本发明所述基于PARP抑制剂Niraparib的衍生物包括M1-2、M2-2、M3-2、M4-2、M5-2、M6-2、M7-2、M8-2、M9-2、M10-2、M11-2、M12-2及阳性对照化合物Niraparib。
试剂盒：HT同源PAPR荧光法抑制分析试剂盒。
操作步骤：
1.将组蛋白包被的96-孔板在25℃下放置2h，用PBS缓冲液洗涤4次，加入Strep-diluent至孔板，设置空白、标准和待测样品孔。空白孔不加酶和样品，其余操作相同。
2.加入浓度为1μM的待测化合物(5％DMSO/H2O)，对照为Niraparib。每孔加入PARP-1酶和PARP混合物，在25℃下孵育60min。
3.用PBS缓冲液洗涤4次后加入Strep-HRP(稀释比例为1:1000)，在37℃下孵育60min。
4.每孔用PBS缓冲液洗涤4次后，加入TACS-Sapphire底物，在25℃下孵化15min。注意避免光照。
5.最后加入0.2N HCl终止反应，测定各孔在450nm下的吸光度。
所有数据为三次测量的平均值。用SigmaPlot 12.5进行数据处理，计算化合物的IC50值，实验结果如表Ⅰ所示。
表Ⅰ化合物抑制PARP-1酶活性数据(IC50nM)
结果分析：
通过上表数据可以看出，本发明提供的化合物均表现出一定的活性，说明在酰胺氮氢上引入基团对化合物活性有利。但是申请人意外的发现，化合物M1-2、M3-2和M5-2均表现出巨大的活性提升，即当引入的基团为3-5个碳原子的直链烷基链时，其活性具有巨大的提高，不仅仅是相对于其他类型的基团，与阳性对照Niraparib相比，也具有巨大的提升。这可能因为烷基链的引入使新化合物分子更加紧密、能够更稳定的占据结合口袋，与PARP蛋白的结合力增强，而直链烷基可以发生一定程度的弯曲，使得新化合物可以更紧密的与口袋结合。
实施例14细胞水平上的PARylation实验。
本发明所述基于PARP抑制剂Niraparib的衍生物包括M1-2、M2-2、M3-2、M4-2、M5-2、M6-2、M7-2、M8-2、M9-2、M10-2、M11-2、M12-2及阳性对照化合物Niraparib。
操作步骤：
1.将Hela细胞接种于96-孔板上，每孔10000个细胞，加入100μL包含10％FCS，0.1mg/mL的青-链霉素和2mM的L-谷氨酰胺的培养液，在37℃、5％CO2条件下培养4h。
2.将待测样品用5％DMSO/H2O稀释范围至0.3-100nM，每孔加入10μL。在37℃、5％CO2条件下孵育18h，之后加入5μL的H2O2水溶液，最终浓度达到200μM。将培养皿置于37℃下5min，然后用平板倒置法除去培养基，每孔加冰冷的甲醇100μL，在-20℃保持20min。
3.去除甲醇，用300μL PBS缓冲液洗涤10次，每孔加入100μL检测液(包含PBS缓冲液，1mg/mL的BSA和PAR mAb一级抗体(1:2000)，二级抗体Alexa Fluor 488(1:3000)，加入核染料Draq5 5μM(Alexis Bos 889001R200)，室温下避光孵育3h。
4.去除核染料溶液，用300μL PBS缓冲液洗涤10次。通过测量PARP阳性细胞核数目与Draq5标记细胞核总数的比值，计算出PARP阳性细胞的百分比，并计算出化合物的EC50值。化合物对PARP-1的抑制活性数据如表Ⅱ所示。
表Ⅱ化合物对Hela细胞PAR试验活性数据(EC50nM)
结果分析：由上表数据可以看出，本发明化合物在酰胺氮氢上引入基团，仍然具有一定的活性效果，而且与酶活性评价结果类似，在细胞水平上，化合物M1-2、M3-2和M5-2均表现出预料不到的活性提升。
Claims (7)
1.一种基于PARP抑制剂Niraparib的衍生物，其特征在于，所述衍生物的结构式如式M1-2、M3-2或M5-2所示：
2.权利要求1所述的基于PARP抑制剂Niraparib的衍生物的制备方法，其特征在于，包括以下步骤：
（1）在碱性条件下，式6化合物水解得式7化合物；
（2）式7化合物与式8化合物在缩合剂的催化作用下，得式9化合物；
（3）式9化合物在酸性条件下脱Boc得式10化合物；
其中，R1同权利要求1所述。
3.根据权利要求2所述的基于PARP抑制剂Niraparib的衍生物的制备方法，其特征在于，步骤（1）中：
反应在有机溶剂和水的混合溶液中进行，有机溶剂选自甲醇或乙醇；有机溶剂与水的混合比例v/v为1:1~10；反应温度为25~50°C，反应时间为2~8h；
所用的碱为氢氧化钠、氢氧化锂或氢氧化钾，碱与式6所示化合物的摩尔比为1:1~10。
4.根据权利要求2所述的基于PARP抑制剂Niraparib的衍生物的制备方法，其特征在于，步骤（2）中：
反应在有机溶剂中进行，有机溶剂选自：二氯甲烷、二氯乙烷、N，N-二甲基甲酰胺、二甲基亚砜中的一种或几种；式7化合物与式8化合物的摩尔比1：1~1.5；反应温度为0~45°C；反应时间为4~12h；
所述的缩合剂选自HBTU、HATU、HCTU、EDCI或HOBT；反应在碱性条件下进行，所用的碱选自TEA或DIPEA。
5.根据权利要求2所述的基于PARP抑制剂Niraparib的衍生物的制备方法，其特征在于，步骤（3）中：
反应在有机溶剂中进行，有机溶剂选自：二氯甲烷、二氯乙烷、DMF或DMSO中的一种或几种；所需要的酸选自盐酸或三氟乙酸；反应温度为25~30°C，反应时间为1~3h；式9化合物与酸的摩尔比为1：1~4。
6.权利要求1所述的基于PARP抑制剂Niraparib的衍生物在制备用于治疗肿瘤药物中的应用。
7.根据权利要求6所述的应用，其特征在于，所述肿瘤为卵巢癌、乳腺癌、前列腺癌或胰腺癌。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101415686A (zh) * | 2006-04-03 | 2009-04-22 | P.安杰莱蒂分子生物学研究所 | 作为聚(adp-核糖)聚合酶(parp)抑制剂的酰胺取代的吲唑和苯并三唑衍生物 |
| CN106496187A (zh) * | 2016-09-14 | 2017-03-15 | 陕西科技大学 | 一种制备PARP抑制剂Niraparib的合成方法 |
| CN106749181A (zh) * | 2016-12-21 | 2017-05-31 | 南京艾德凯腾生物医药有限责任公司 | 一种制备尼拉帕尼的方法 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101415686A (zh) * | 2006-04-03 | 2009-04-22 | P.安杰莱蒂分子生物学研究所 | 作为聚(adp-核糖)聚合酶(parp)抑制剂的酰胺取代的吲唑和苯并三唑衍生物 |
| CN106496187A (zh) * | 2016-09-14 | 2017-03-15 | 陕西科技大学 | 一种制备PARP抑制剂Niraparib的合成方法 |
| CN106749181A (zh) * | 2016-12-21 | 2017-05-31 | 南京艾德凯腾生物医药有限责任公司 | 一种制备尼拉帕尼的方法 |
Non-Patent Citations (2)
| Title |
|---|
| Process Development of C−N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib;Cheol K. Chung等;《Org. Process Res. Dev.》;20131025;第18卷;第215-227页 * |
| 新型PARP-1抑制剂的设计、合成以及抗肿瘤活性研究;李福卫;《南京中医药大学硕士学位论文》;20161231;第23页 * |
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