CN118598856A - 一种靶向降解xpo1蛋白的化合物及其应用 - Google Patents
一种靶向降解xpo1蛋白的化合物及其应用 Download PDFInfo
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Abstract
本发明涉及药物化学领域，具体涉及一种可靶向泛素化降解XPO1蛋白的化合物，及其药学上可接受的盐、水合物，和以该化合物为活性成分的药物组合，以及在制备XPO1蛋白降解剂及其用于治疗和/或预防癌症中的用途。本发明所述的化合物、及其药学上可接受的盐，水合物结构如下：其变量如权利要求和说明书所述。
Description
技术领域
本发明涉及医药技术领域，特别是涉及一种可靶向降解XPO1蛋白的化合物，及其药学上可接受的盐，水合物和以该化合物为活性成分的药物组合，以及在制备XPO1蛋白抑制和降解剂及其用于治疗和/或预防肿瘤中的应用。
背景技术
核输出蛋白1(exportin 1，XPO1)是一种转运受体蛋白，能转运富含亮氨酸的蛋白质从细胞核通过核孔复合体进入细胞质。在恶性肿瘤中，XPO1过度表达而导致细胞生长凋亡调节异常或细胞周期异常。因此，XPO1抑制或敲除可阻碍过度表达的XPO1转运作用，从而达到治疗恶性肿瘤的作用。
PROTAC是一种通过双功能小分子将目标蛋白和细胞内的E3拉近，从而导致靶向蛋白泛素化降解的技术。相对于传统靶向药物具有可突破不可成药靶点和抗耐药等优点。本发明设计合成一种新型PROTAC化合物，选用沙利度胺类似物作为PROTAC中与E3连接酶进行结合的部位，选用不同长度和不同类型连接链将其与具有XPO1蛋白抑制活性的结构相连接构建PROTAC。体外抗肿瘤活性测试及体外XPO1蛋白和p53蛋白表达实验表明，系列化合物可将XPO1蛋白降解并激活p53蛋白，协同发挥抗癌作用，具有良好的抗肿瘤活性。
发明内容
本发明目的在于提供一种具有泛素化降解XPO1蛋白的化合物及其制备方法，以及该类化合物作为XPO1蛋白降解剂在预防和/或治疗肿瘤中的应用。
本发明设及通式Ⅰ所示的化合物、及其药学上可接受的盐或水合物：
其中连接链l i nker各自独立的选自烷基链n为1-20；
PEG链n为1、2、3、4、5或6。
此外，本发明包括药物组合物，该组合物含有通式Ⅰ化合物和药物上可接受的赋形剂。所述药物上可接受的赋形剂是指任何可用于药物领域的稀释剂、辅助剂和/或载体。本发明的化合物可以与其他活性成分组合使用，只要它们不产生其它不利作用，例如过敏反应。
本发明的药物组合可配置成若干剂型，其中含有药物领域中常用的一些赋形剂，例如，口服制剂(如片剂，胶囊剂，溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬剂，或者是可注射的干燥粉末，在注射前加入注射用水可立即使用)；局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等；可注射制剂用的防腐剂、加溶剂、稳定剂等；局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下是不稳定的，可将其配制成肠衣片剂。通过体外试验筛选，我们发现本化合物具有降解XPO1蛋白活力。因此，本发明化合物可用于与XPO1蛋白异常表达相关的疾病中的应用，如各种癌症。
通过体外活性筛选，我们发现本发明化合物具有抗肿瘤活性，因此本发明化合物可以用于制备治疗和/或预防各种癌症的药物，如人神经胶质瘤细胞，乳腺癌，结肠癌，前列腺癌，胰腺癌，非小细胞肺癌，甲状腺乳头状癌，卵巢癌、黑色素瘤、或各种白血病。
本发明化合物可作为唯一的抗癌药物使用，或者与一种或多种其它抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时，顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本化合物及其制备方法。应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的通式I化合物的制备，所有的原料都是通过这些路线中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些路线中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的通式I化合物，合成路线中各取代基如发明内容部分所定义。
本发明制备方法操作简单，条件温和，所得化合物均具有XPO1蛋白降解活性，抗肿瘤作用显著。
中间体2的制备
2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮(0.1g,0.36mmol)、单Boc二氨基衍生物(0.36mmol)和DIPEA 0.1mL加入DMF 5mL,100℃反应10h,加水50mL,乙酸乙酯萃取三次，有机相无水硫酸钠干燥，减压蒸干硅胶柱层析(甲醇：二氯甲烷＝1：20)，得化合物2。
1H NMR(CDCl3,400MHz):δ7.98(brs,1H),7.50(t,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.99(d,J＝8.0Hz,1H),6.39(brs,1H),4.94-4.90(m,1H),4.81(brs,1H),3.45(q,J＝8.0Hz,2H),3.37(q,J＝8.0Hz,2H),2.92-2.69(m,3H),2.16-2.11(m,1H),1.45(s,9H).
1H NMR(CDCl3,400MHz):δ8.01(brs,1H),7.49(t,J＝8.0Hz,1H),7.10(d,J＝4.0Hz,1H),6.89(d,J＝8.0Hz,1H),6.24(brs,1H),4.93-4.89(m,1H),4.56(brs,1H),3.30(q,J＝8.0Hz,2H),3.18(q,J＝8.0Hz,2H),2.92-2.69(m,3H),2.16-2.11(m,1H),1.72-1.66(m,2H),1.64-1.59(m,2H),1.44(s,9H).
1H NMR(CDCl3,400MHz):δ8.57(brs,1H),7.48(t,J＝8.0Hz,1H),7.07(d,J＝4.0Hz,1H),6.87(d,J＝8.0Hz,1H),6.23(t,J＝4.0Hz,1H),4.95-4.90(m,1H),4.61(brs,1H),3.28-3.23(m,2H),3.14-3.09(m,2H),2.89-2.70(m,3H),2.14-2.09(m,1H),1.70-1.62(m,2H),1.53-1.34(m,15H)。
1H NMR(CDCl3,400MHz):δ8.30(brs,1H),7.49(t,J＝8.0Hz,1H),7.08(d,J＝4.0Hz,1H),6.88(d,J＝8.0Hz,1H),6.23(t,J＝4.0Hz,1H),4.94-4.90(m,1H),4.55(brs,1H),3.25(q,J＝8.0Hz,2H),3.13-3.06(m,2H),2.90-2.69(m,3H),2.15-2.10(m,1H),1.69-1.62(m,2H),1.48-1.25(m,19H)。
1H NMR(CDCl3,400MHz):δ8.57(brs,1H),7.47(t,J＝8.0Hz,1H),7.07(d,J＝4.0Hz,1H),6.90(d,J＝8.0Hz,1H),6.49(t,J＝4.0Hz,1H),5.03(t,J＝4.0Hz,1H),4.94-4.89(m,1H),3.67(t,J＝4.0Hz,2H),3.54(t,J＝4.0Hz,2H),3.44(q,J＝4.0Hz,2H),3.30(q,J＝4.0Hz,2H),2.88-2.68(m,3H),2.11-2.07(m,1H),1.41(s,9H)。
1H NMR(400 MHz，DMSO):δ11.1(s,1H),7.58(t,J＝8.0 Hz,1H),7.13(d,J＝8.0Hz,1H),7.03(d,J＝4.0 H,1H),6.71(t,J＝4.0 Hz,1H),6.60(t,J＝4.0 Hz,1H),5.08-5.03(m,1H),3.63-3.44(m,8H),3.38(t,J＝4.0 Hz,2H),3.08-3.04(m,2H),2.93-2.84(m,1H),2.62-2.52(m,2H),2.06-2.00(m,1H),1.36(s,9H).
1H NMR(CDCl3,400MHz):δ8.32(brs,1H),7.49(t,J＝8.0Hz,1H),7.09(d,J＝4.0Hz,1H),6.92(d,J＝8.0Hz,1H),6.49(t,J＝4.0Hz,1H),5.04(brs,1H),4.94-4.90(m,1H),3.73(t,J＝4.0Hz,2H),3.68(s,4H),3.66-3.60(m,4H),3.53(t,J＝4.0Hz,2H),3.47(q,J＝4.0Hz,2H),2.90-2.69(m,3H),2.14-2.10(m,1H),1.44(s,9H).
1H NMR(CDCl3,400MHz):δ8.19(brs,1H),7.56(t,J＝8.0Hz,1H),7.36(d,J＝4.0Hz,1H),7.17(d,J＝8.0Hz,1H),4.99-4.93(m,1H),4.69(brs,1H),3.78-3.72(m,2H),3.10(t,J＝4.0Hz,2H),2.93-2.67(m,5H),2.13-2.08(m,1H),1.86-1.82(m,2H),1.72-1.68(m,1H),1.55-1.45(m,11H).
中间体3的制备
化合物2(0.1g)、三氟乙酸2mL加入二氯甲烷4mL中，室温搅拌过夜。减压蒸干得化合物3粗品，直接用于下步反应。
中间体5的制备
化合物4(1.0g，4.65mmol)加入乙醇5mL,滴加水合肼(0.9g，85％，24mmol)。将反应混合物在室温下搅拌4小时，减压蒸干，加水10mL,乙酸乙酯萃取。有机相无水硫酸钠干燥。硅胶柱层析(石油醚：乙酸乙酯＝5：1)得化合物50.5g(产率：51％)。
1H NMR(DMSO-d6,400MHz):δ8.71(brs,1H),7.79(d,J＝8.0Hz,1H),6.76(brs,1H),4.49(brs,2H).
中间体6的制备
化合物5(1.0g，5.43mmol)和3-(4-甲基-2,5-二氧代-2,5-二氢呋喃-3-基)丙酸(1.15g，5.43mmol)溶解于20mL氯仿，回流反应48h冷却到室温，过滤得化合物6(1.4g，68.2％)。
1H NMR(DMSO-d6,400MHz):δ12.30(brs,1H),10.03(brs,1H),8.00(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),2.67(t,J＝8.0Hz,1H),2.52(t,J＝8.0Hz,1H),2.02(s,2H)。
中间体7的制备
化合物6(100mg，0.26mmol)、化合物3(0.26mmol)、HATU(152mg,0.40mmol)和DIPEA0.1mL加入到THF 10mL中，室温搅拌过夜，减压蒸干，加水10mL，乙酸乙酯萃取，有机相无水硫酸钠干燥，减压蒸干，硅胶柱层析(甲醇:二氯甲烷＝1：20)得化合物7。
具体实施方式
实施例1：3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基(7a)
1H NMR(400MHz,CD3OD):δ7.83(d,J＝12.0Hz,1H),7.49(t,J＝8.0Hz,1H),7.05-7.00(m,2H),6.73(d,J＝8.0Hz,1H),5.05-5.01(m,1H),3.42(s,4H),2.88-2.63(m,5H),2.50(t,J＝8.0Hz,2H),2.11-2.07(m,1H),2.02(s,3H).LC-MS[M+H]+＝676.2.
实施例2：3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基(7b)
1H NMR(400MHz,CD3OD):δ7.85(d,J＝8.0Hz,1H),7.49(t,J＝8.0Hz,1H),7.01-6.97(m,2H),6.73(d,J＝8.0Hz,1H),5.06-5.01(m,1H),3.31-3.28(m,2H),3.21(t,,J＝4.0Hz,2H),2.88-2.65(m,5H),2.49(t,J＝8.0Hz,2H),2.11-2.08(m,1H),2.04(s,3H),1.67-1.57(m,4H).LC-MS[M+H]+＝704.2.
实施例3:3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基(7c)
1H NMR(400MHz,CD3OD):δ7.86(d,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.01-6.98(m,2H),6.72(d,J＝8.0Hz,1H),5.06-5.02(m,1H),3.32-3.26(m,2H),3.15(t,J＝4.0Hz,2H),2.88-2.66(m,5H),2.48(t,J＝8.0Hz,2H),2.13-2.06(m,1H),2.05(s,3H),1.67-1.60(m,2H),1.53-1.46(m,2H),1.44-1.32(m,4H).LC-MS[M+H]+＝732.2
实施例4:3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基(7d)
1H NMR(400MHz,CD3OD):δ7.87(d,J＝8.0Hz,1H),7.52(t,J＝8.0Hz,1H),7.02-7.00(m,2H),6.73(d,J＝8.0Hz,1H),5.07-5.02(m,1H),3.31-3.27(m,2H),3.14(t,J＝4.0Hz,2H),2.90-2.67(m,5H),2.48(t,J＝8.0Hz,2H),2.13-2.07(m,1H),2.05(s,3H),1.68-1.60(m,2H),1.49-1.29(m,8H).LC-MS[M+H]+＝760.2.
实施例5:3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基(7e)
1H NMR(400MHz,CD3OD):δ7.85(d,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.03-7.01(m,2H),6.73(d,J＝8.0Hz,1H),5.07-5.02(m,1H),3.67(t,J＝8.0Hz,2H),3.55(t,J＝8.0Hz,2H),3.44(t,J＝8.0Hz,2H),3.39-3.34(m,2H),2.89-2.63(m,5H),2.52(t,J＝8.0Hz,2H),2.13-2.03(m,4H).LC-MS[M+H]+＝720.2.
实施例6:3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基(7f)
1H NMR(400MHz,CD3OD):δ7.87(d,J＝8.0Hz,1H),7.53(t,J＝8.0Hz,1H),7.08-7.03(m,2H),6.73(d,J＝8.0Hz,1H),5.07-5.02(m,1H),3.72(t,J＝4.0Hz,2H),3.66-3.60(m,4H),3.55-3.48(m,4H),3.33(t,J＝4.0Hz,2H),2.90-2.64(m,5H),2.48(t,J＝8.0Hz,2H),2.13-2.08(m,1H),2.04(s,3H).LC-MS[M+H]+＝764.2.
实施例7:3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基(7g)
1H NMR(400MHz,CD3OD):δ7.86(d,J＝8.0Hz,1H),7.53(t,J＝8.0Hz,1H),7.08-7.03(m,2H),6.73(d,J＝8.0Hz,1H),5.07-5.03(m,1H),3.71(t,J＝4.0Hz,2H),3.66-3.61(m,6H),3.58-3.55(m,2H),3.51-3.47(m,4H),3.33-3.31(m,2H),2.90-2.65(m,5H),2.49(t,J＝8.0Hz,2H),2.11-2.07(m,1H),2.04(s,3H).LC-MS[M+H]+＝808.2.
实施例8:3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌啶-4-基)甲基)丙酰胺(7h)
1H NMR(400MHz,CD3OD):δ7.87(d,J＝8.0Hz,1H),7.59(t,J＝8.0Hz,1H),7.31-7.24(m,2H),6.74(d,J＝8.0Hz,1H),5.10-5.06(m,1H),3.71(d,J＝12.0Hz,2H),3.13-3.12(m,2H),2.87-2.69(m,7H),2.53(t,J＝8.0Hz,2H),2.13-2.08(m,1H),2.07(s,3H),1.79-1.76(d,J＝12.0Hz,2H),1.69-1.62(m,1H),1.50-1.40(m,2H).LC-MS[M+H]+＝730.2
实施例9：MTT法测定肿瘤细胞增殖抑制活性
将处于细胞对数生长期的要进行实验的肿瘤细胞(MM1S细胞或U251MG细胞)按一定的细胞量接种于培养板内，培育24h，加入不同浓度抑制剂，细胞在37℃、5％CO2条件下继续培养72h，每孔加入20μL MTT溶液继续培养4h，用DMSO溶解结晶，用酶联免疫检测仪在570nm波长处测定其OD值计算IC50。
| 化合物编号 | MM1SIC50(nM) | U251MGIC50(nM) |
| 7a | 926 | >1000 |
| 7b | 738 | 849 |
| 7c | 546 | 646 |
| 7d | 329 | 543 |
| 7e | 357 | 420 |
| 7f | 106 | 124 |
| 7g | 156 | 289 |
| 7h | 89 | 112 |
实施例10：Western-b lot测定XPO1和p53蛋白表达
将药物0.5μM干预12h的MM 1S细胞收集，用预冷的PBS洗涤2次，PMSF与RIPA裂解液以1：100的比例混合，冰上裂解细胞20min，4℃，12000r/min×20min离心，取上清，即细胞总蛋白，用BCA法定量检测蛋白量，用5×蛋白上样缓冲液稀释蛋白后100℃变性5min。蛋白在SDS-PAGE电泳分离，转膜，封闭2h，一抗4℃孵育过夜。TBST洗膜，二抗1:1000孵育2h，化学发光后X胶片显影，用Image J软件分析每个条带的灰度值，以0nM给药浓度下细胞蛋白表达作为100％，计算CK1α和p53蛋白表达量。实验结果表明化合物可降解XPO1蛋白，并激活p53蛋白表达。
| 化合物 | CK1α蛋白降解率(％) | P53蛋白增长率(％) |
| 7a | 89 | 112 |
| 7b | 76 | 154 |
| 7c | 70 | 146 |
| 7d | 65 | 187 |
| 7e | 54 | 128 |
| 7f | 90 | 386 |
| 7g | 89 | 285 |
| 7h | 92 | 425 |
Claims (6)
1.如通式Ⅰ所示的化合物、及其药学上可接受的盐或水合物：
其中连接链linker各自独立的选自烷基链n为1-20；
PEG链n为1、2、3、4、5或6。
2.根据权利要求1所述的化合物、及其药学上可接受的盐或水合物：选自，
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基；
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基；
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基；
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基；
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基；
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基；
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基；
3-(1-((6-氯-5-(三氟甲基)吡啶-2-基)氨基)-4-甲基-2,5-二氧代-2,5-双氢-1H-吡咯-3-基)-N-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌啶-4-基)甲基)丙酰胺。
3.一种药物组合，其特征在于：包含权利要求1，2中任意一项的化合物、及其药学上可接受的盐或水合物以及药学上可接受的赋形剂。
4.权利要求1，2中任意一项的化合物、及其药学上可接受的盐或水合物和权利要求3所述药物组合在制备与XPO1蛋白活性异常表达相关的疾病药物中的应用。
5.权利要求1，2中任意一项的化合物、及其药学上可接受的盐或水合物和权利要求3所述药物组合在制备抗肿瘤药物中的应用。
6.权利要求1，2中任意一项的化合物、及其药学上可接受的盐或水合物和权利要求3所述药物组合在制备治疗和/或预防人神经胶质瘤细胞，乳腺癌，结肠癌，前列腺癌，胰腺癌，非小细胞肺癌，甲状腺乳头状癌，卵巢癌、黑色素瘤、或各种白血病中的应用。
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