CN113563346A - 吡咯[3,4-c]并吡唑二酰胺类衍生物及其在抗肿瘤药物中的应用 - Google Patents
吡咯[3,4-c]并吡唑二酰胺类衍生物及其在抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明属于药物化学技术领域，尤其涉及吡咯[3,4‑c]并吡唑二酰胺类衍生物及其作为USP7抑制剂在抗肿瘤药物中的应用。本发明所述USP7抑制剂可以提高药物的抗肿瘤活性，具有特异性和有效性，具有广阔的发展前景。
Description
技术领域
本发明属于药物化学技术领域，尤其涉及吡咯[3,4-c]并吡唑二酰胺类衍生物及其作为USP7抑制剂作为抗肿瘤药物中的应用。
背景技术
泛素特异性蛋白酶7(USP7)又叫做疱疹病毒相关的泛素特异性蛋白酶(HAUSP)。它属于去泛素化酶家族中的泛素特异性蛋白酶(USP)家族，USPs大约有50多种，是DUB中所占数目最多的家族。目前去泛素化酶可分为5个亚类：泛素特异性蛋白酶(USPs)、泛素C末端水解酶(UCH)、卵巢肿瘤蛋白酶(OTU)、Machado.Joseph病蛋白酶(fMJDs)和JABl/MPN/Mov34金属蛋白酶(JAMMs)。研究表明，P53是重要的肿瘤抑制因子，在超过50％的人类癌症中发现P53会发生突变。USP7在通过多种机制拮抗P53功能中起重要作用，其中MDM2是主要的E3泛素连接酶之一，也可作为USP7的底物，在正常细胞体内，MDM2的表达量较少，且可以通过泛素降解，当疾病发生时，体内的USP7会呈现过表达，因此会形成USP7－MDM2－P53信号通路，进而通过此信号途径下调P53。USP7是目前被研究比较深入的USPs之一，主要是由于USP7与p53蛋白以及MDM2蛋白有着密切的联系，并且有一半以上的癌症与p53的异常表达有关。除此之外，USP7与肿瘤相关蛋白以及免疫系统有着密切的联系，如PTEN、FOX04、NOTCHl、DNMTl等。目前许多疾病都与USP7的不正常表达有着密切的关系，如卵巢癌、慢性淋巴细胞白血病、骨髓瘤和乳腺癌等。
多项研究表明，USP7能作用于HDM2蛋白，进而影响细胞内p53的含量，参与调控细胞凋亡过程；除此之外，USP7还参与免疫等细胞活动。因为这些原因，USP7抑制剂被寄予很大的期望。自2005年以来，USP7抑制剂被广泛关注并研发，但由于没有明确活性小分子与USP7的作用模式，只能通过传统方法筛选出新的小分子或者在已有的基础上进行官能团的探究，USP7抑制剂的研发非常缓慢，2017年以后，借助计算机手段以及共晶结构，大量的USP7抑制剂被研发了出来。以往的小分子抑制剂由于选择性以及活性不高，一些以往生物实验的结论在现可能不完全适用，甚至有重复实验得出相反结论。
综上所述，研究新型的特异性更强的USP7抑制剂，对肿瘤药物患者的临床治疗至关重要。
发明内容
本发明针对现有技术的不足，提供一种吡咯[3,4-c]并吡唑二酰胺类衍生物；以及该衍生物的制备方法和其作为USP7抑制剂作为抗肿瘤药物中的应用。
为实现上述目的，本发明采取的技术方案是：本发明的提供一种通式(I)所示的吡咯[3,4-c]并吡唑二酰胺类衍生物，
所述n为1-3。
所述R1、R2选自氢、C1-C6烷基、烯烃基、炔烃基或芳香基；所述R3选自氢、卤素、C1-C6烷基、烯烃基、炔烃基或芳香基。
本发明通式(I)所示的4,5-二氢萘并异噁唑类衍生物，选自：
按照本发明的式I化合物，均可按照路线1的方法进行合成，以取代的3-氨基-5-叔丁氧羰基-吡咯并[3,4-C]吡唑为起始原料，首先与4-甲基-1-哌嗪基丙酸/4-甲基-1-哌嗪乙酸在缩合剂存在下发生缩合反应得到中间体2，再在盐酸乙酸乙酯条件下脱Boc得到中间体3，最后与取代3-苯基丙酸经缩合反应得到目标产物。
合成路线1试剂和条件：(a)HATU,DIEA,DMF,rt.；(b)HCl-EA,rt；(c)HATU,DIEA,DMF,rt.
本发明所述的吡咯[3,4-c]并吡唑二酰胺类衍生物可以作为USP7抑制剂在抗肿瘤药物中的应用。
本发明所述的肿瘤细胞可以为RS4；11或LNCaP细胞。
具体实施方式
下述实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定，质谱用Agilent 1100LC/MS测定；所用试剂均为分析纯或化学纯。
实施例1。
步骤1中间体2的合成
将4-甲基-1-哌嗪基丙酸(0.71g,4.46mmol)溶于DMF中，然后向溶液中依次加入HATU(2.03g,5.35mmol)、DIEA(1.15g,8.92mmol)和3-氨基-5-叔丁氧羰基-吡咯并[3,4-c]吡唑(1.00g,4.46mmol)，升温至70℃反应。8小时后TLC检测反应完成，将反应液倒入冰水中，析出固体，过滤得粗品，再经硅胶色谱柱纯化，得类白色粉末状固体1.06g,收率65.23％。
步骤2中间体3的合成
将中间体2(1.00g,2.74mmol)溶于乙酸乙酯(10mL)中，冰浴条件下加入饱和盐酸-乙酸乙酯溶液(10mL)，逐渐升温至室温反应1h，抽滤，乙酸乙酯(5mL×3)洗涤，干燥，得类白色固体0.74g，收率89.66％。
步骤3实施例1的合成
将3-苯基丙酸(0.25g,1.66mmol)溶于DMF中，然后向溶液中依次加入HATU(0.88g,2.33mmol)、DIEA(0.64g,4.99mmol)和中间体3(0.50g,1.66mmol)，升温至70℃反应。8小时后TLC检测反应完成，将反应液倒入水中，析出固体，过滤得粗品，再经硅胶色谱柱纯化，得类白色粉末状固体0.43g,收率65.24％。
1H-NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.68(s,1H),7.28–7.23(m,4H),7.19(dd,J＝8.4,2.2Hz,1H),5.12(s,2H),4.46(s,2H),3.11(s,2H),2.88(d,J＝7.0Hz,2H),2.55(d,J＝7.2Hz,2H),2.42(s,3H),2.24–2.12(m,4H).ESI-MS m/z:397.2[M+H]+.
实施例2。
1H-NMR(400MHz,DMSO-d6)δ12.01(s,1H),10.64(s,1H),7.27–7.21(m,4H),7.18(dd,J＝8.2,2.1Hz,1H),5.11(s,2H),4.45(s,2H),3.18–3.11(m,3H),2.58(dd,J＝14.1,9.9Hz,1H),2.42(s,3H),2.31–2.13(m,5H),1.24(d,J＝7.2Hz,3H).ESI-MS m/z:411.2[M+H]+.
实施例3。
1H-NMR(400MHz,DMSO-d6)δ12.03(s,1H),10.60(s,1H),7.26–7.20(m,4H),7.17(dd,J＝8.0,2.2Hz,1H),4.46(s,2H),3.20–3.13(m,3H),2.58(dd,J＝14.4,9.6Hz,1H),2.42(s,3H),2.33–2.23(m,5H),1.44(s,6H),1.24(d,J＝7.0Hz,3H).ESI-MS m/z:439.2[M+H]+.
实施例4。
1H-NMR(400MHz,DMSO-d6)δ12.02(s,1H),10.64(s,1H),7.10(d,J＝8.0Hz,2H),7.01(d,J＝8.4Hz,2H),5.10(s,2H),4.45(s,2H),3.65(t,J＝7.0Hz,2H),2.88(t,J＝7.0Hz,2H),2.56–2.50(m,4H),2.40(s,3H),2.24–2.14(m,4H),2.20(s,3H).ESI-MS m/z:425.2[M+H]+.
实施例5。
1H-NMR(400MHz,DMSO-d6)δ12.02(s,1H),10.64(s,1H),7.28(d,J＝8.4Hz,1H),7.11-7.02(m,3H),5.12(s,2H),4.46(s,2H),3.64(t,J＝7.2Hz,2H),2.87(t,J＝7.0Hz,2H),2.55–2.50(m,4H),2.41(s,3H),2.24–2.15(m,4H),2.24(s,3H).ESI-MS m/z:425.2[M+H]+.
实施例6。
1H-NMR(400MHz,DMSO-d6)δ11.96(s,1H),10.62(s,1H),7.18–7.14(m,4H),5.11(s,2H),4.44(s,2H),3.64(t,J＝7.4Hz,2H),2.86(t,J＝7.1Hz,2H),2.55–2.50(m,4H),2.41(s,3H),2.26–2.15(m,4H).ESI-MS m/z:429.2[M+H]+.
实施例7。
1H-NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.68(s,1H),7.29–7.23(m,4H),7.18(dd,J＝8.0,2.1Hz,1H),5.13(s,2H),4.46(s,2H),3.66(t,J＝7.2Hz,2H),3.18–3.14(m,1H),2.58(dd,J＝14.1,9.9Hz,1H),2.50(t,J＝7.4Hz,2H),2.42(s,3H),2.31–2.24(m,5H),1.24(d,J＝7.1Hz,3H).ESI-MS m/z:425.2[M+H]+.
实施例8。
1H-NMR(400MHz,DMSO-d6)δ12.02(s,1H),10.62(s,1H),7.29–7.24(m,4H),7.16(dd,J＝8.0,2.1Hz,1H),5.11(s,2H),4.47(s,2H),3.66(t,J＝7.4Hz,2H),3.18–3.14(m,1H),2.58(dd,J＝14.0,9.8Hz,1H),2.51(t,J＝7.4Hz,2H),2.42(s,3H),2.33–2.25(m,5H),1.25(d,J＝7.4Hz,3H).ESI-MS m/z:425.2[M+H]+.
实施例9。
1H-NMR(400MHz,DMSO-d6)δ12.01(s,1H),10.65(s,1H),7.27–7.22(m,4H),7.19(dd,J＝8.1,2.2Hz,1H),4.45(s,2H),3.64(t,J＝7.0Hz,2H),3.18–3.14(m,1H),2.56(dd,J＝14.2,9.9Hz,1H),2.50(t,J＝7.4Hz,2H),2.40(s,3H),2.32–2.24(m,5H),1.45(s,6H),1.24(d,J＝7.0Hz,3H).ESI-MS m/z:453.2[M+H]+.
一、药理研究
测试方法：利用Ub-AMC测试方法检测实施例化合物对USP7的抑制活性。试剂盒为：USP7 inhibitor screening assay kit试剂盒，将实验分为化合物组、空白组合对照组。缓冲液为50mM Tris-HCl(pH 7.6)、0.5mM EDTA、5mM DTT和0.05mg/mL BSA。在384孔板中，将10μLUSP7酶(100pM)和化合物在室温下孵化30分钟，然后加入10μLUb-AMC(300nM),然后继续在室温黑暗条件下孵化2小时后，用Enspire(PerkinElmer)多功能酶标仪检测荧光强度(excitation at 345nm，emission at 445nm)。
表1实施例化合物在对USP71抑制活性。
| 实施例 | IC<sub>50</sub>(μM) | 实施例 | IC<sub>50</sub>(μM) |
| 实施例1 | 14.51 | 实施例6 | 0.64 |
| 实施例2 | 20.33 | 实施例7 | 0.31 |
| 实施例3 | 10.17 | 实施例8 | 1.62 |
| 实施例4 | 0.97 | 实施例9 | 0.44 |
| 实施例5 | 4.56 |
细胞增殖抑制实验(MTT)：肿瘤细胞选择RS4；11和LNCaP细胞，培养上述细胞至对数生长期，使用胰蛋白酶消化处理贴壁细胞，收集细胞至含10％胎牛血清的DMEM培养基中。离心细胞悬液(1000×rpm)，将细胞稀释至2.5-5.0×103个/mL，每孔加入2.0-3.0×103个细胞，37℃培养24h。加入2μL不同浓度药物溶液，37℃培养，分别于不同的时间点加入10μLMTT[3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐]溶液。37℃温育4h，弃去培养基，每孔加入200μL DMSO，以溶解残留的甲臜结晶，15min后，在490nm处记录吸光值。
表1实施例1-9对肿瘤细胞的抑制活性。
Claims (4)
1.吡咯[3,4-c]并吡唑二酰胺类衍生物，其特征在于，所述的衍生物结构式如下：
其中，所述n为1-3；
所述R1、R2选自氢、C1-C6烷基、烯烃基、炔烃基或芳香基；所述R3选自氢、卤素、C1-C6烷基、烯烃基、炔烃基或芳香基。
2.如权利要求1所述的吡咯[3,4-c]并吡唑二酰胺类衍生物，选自：
3.如权利要求1-2任一所述的4,5-二氢萘并异噁唑类衍生物的制备方法，具体为：以取代的3-氨基-5-叔丁氧羰基-吡咯并[3,4-C]吡唑为起始原料，首先与4-甲基-1-哌嗪基丙酸/4-甲基-1-哌嗪乙酸在缩合剂存在下发生缩合反应得到中间体2，再在盐酸乙酸乙酯条件下脱Boc得到中间体3，最后与取代3-苯基丙酸经缩合反应得到目标产物。
4.如权利要求1-3任一所述的吡咯[3,4-c]并吡唑二酰胺类衍生物可以作为USP7抑制剂在抗肿瘤药物中的应用。
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| CN1447810A (zh) * | 2000-08-10 | 2003-10-08 | 法玛西雅意大利公司 | 具有激酶抑制剂活性的二环吡唑类、其制备方法和包含它们的药物组合物 |
| CN1820009A (zh) * | 2003-07-09 | 2006-08-16 | 法玛西雅意大利公司 | 作为激酶抑制剂的吡咯并[3,4－c]吡唑衍生物 |
| CN101646673A (zh) * | 2007-02-07 | 2010-02-10 | 辉瑞大药厂 | 作为pkc抑制剂的3-氨基-吡咯并[3,4-c]吡唑-5(1h,4h,6h)甲醛衍生物 |
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| CN1447810A (zh) * | 2000-08-10 | 2003-10-08 | 法玛西雅意大利公司 | 具有激酶抑制剂活性的二环吡唑类、其制备方法和包含它们的药物组合物 |
| CN1820009A (zh) * | 2003-07-09 | 2006-08-16 | 法玛西雅意大利公司 | 作为激酶抑制剂的吡咯并[3,4－c]吡唑衍生物 |
| CN101646673A (zh) * | 2007-02-07 | 2010-02-10 | 辉瑞大药厂 | 作为pkc抑制剂的3-氨基-吡咯并[3,4-c]吡唑-5(1h,4h,6h)甲醛衍生物 |
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