CN114555607B - 一类靶向蛋白质水解通路的功能分子及其制备和应用 - Google Patents
一类靶向蛋白质水解通路的功能分子及其制备和应用 Download PDFInfo
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- CN114555607B CN114555607B CN202080070688.4A CN202080070688A CN114555607B CN 114555607 B CN114555607 B CN 114555607B CN 202080070688 A CN202080070688 A CN 202080070688A CN 114555607 B CN114555607 B CN 114555607B
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Classifications
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- C07K—PEPTIDES
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
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Abstract
本发明属于医药技术领域,涉及一类靶向蛋白质水解通路的功能小分子及其制备和应用。具体涉及如式(M)所示的功能小分子及其药学上可接受的盐,以及这些化合物和其药用组合物在制备治疗肿瘤药物中的应用。本发明将含有过氧桥键的化合物和E3泛素连接酶复合体的底物连接获得功能化小分子。本发明涉及的功能分子能够混杂靶向结合包括蛋白质水解通路中功能蛋白的多种蛋白质,具有抗肿瘤生物活性。
Description
技术领域
本发明属于医药技术领域,涉及一类靶向蛋白质水解通路的功能分子及其制备和应用,以及其药学上可接受的盐和其药学组合物在治疗肿瘤中的应用。本发明通过使用连接臂将含有过氧桥键的化合物和E3泛素连接酶复合体中的小分子配体连接获得功能化小分子,属于医药技术领域。
背景技术
泛素蛋白酶体途径(ubiquitin proteasome pathway,UPP)是细胞内蛋白质降解的主要途径。泛素蛋白酶体途径由泛素、泛素活化酶E1、泛素结合酶E2、泛素连接酶E3、蛋白酶体及其底物(蛋白质)构成。泛素蛋白酶体途径特异性降解蛋白质时,首先发生酶催化的蛋白底物泛素化。随后,被泛素化的蛋白分子能够被蛋白酶体识别,并进入蛋白酶体体降解成短链的多肽分子,发生蛋白底物降解。这个蛋白降解系统能够清除老化或者受损蛋白,对维持正常的细胞动态平衡和生理功能发挥重要的作用。
发明内容
本发明解决的棘手问题在于提供一种混杂靶向包括蛋白降解系统的多种蛋白的化合物及其应用,具体为一系列小分子化合物及其制备方法,以及该类化合物在制备治疗肿瘤药物中的应用。
为了实现上述技术问题,本发明提供了如下技术方案:
本发明技术方案的第一方面是提供了一类如式(M)所示化合物或其药学上可接受的盐:
其中:
R”选自如下结构:
L选自C1-C8亚烷基,含氧亚烷基,
所述的含氧亚烷基,其氧原子的个数选自1、2、3、4或5,并且每个氧原子用亚乙烷基连接;当R”为R3时,n独立选自0、1、2、3、4或5;X选自氧或-CH2-。
优选的,本发明所述的化合物或其药学上可接受的盐如式(I)和(II)所示:
其中:
R选自如下结构:
n独立选自0、1、2、3、4、5
X选自氧,-CH2-
L选自C1-C8亚烷基,含氧亚烷基,或
所述的含氧亚烷基,其氧原子的个数选自1、2、3、4或5,并且每个氧原子用亚乙烷基连接。
优选的L选自C1-C6亚烷基,更优选的L选自C1-C4亚烷基;
式(I)优选的化合物为式(I-1)所示:
其中:
n独立选自0、1、2、3、4或5;
X选自氧或-CH2-;
L选自C1-C8亚烷基,含氧亚烷基,
所述的含氧亚烷基,其氧原子的个数选自1、2、3、4或5,并且每个氧原子用亚乙烷基连接。
L最优选的结构如下:
本发明更优选的化合物选自:
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本发明最优选的化合物选自:
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本发明技术方案的第二方面提供了一组药物组合物,包含本发明第一方面所述的化合物或其药学上可接受的盐或药学上可接受的载体,赋形剂,稀释剂,辅剂,媒介物或它们的组合。上述化合物或其药学上可接受的盐或所述组合物在制备预防和/或治疗癌症疾病药物中的应用。根据本发明,药学上可接受的盐包括与下列酸形成的加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、苯二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等以及类似的已知可以接受的酸成盐。
本发明可以含有第一方面所述的双功能小分子及其药学上可接受的盐作为活性成份,与药学上可接受的赋形剂混合制备成组合物,并制备成临床上可接受的剂型,上述赋形剂是指可用于药学领域的稀释剂、辅助剂或载体。上述剂型是指临床上常用的注射剂、片剂、胶囊剂等。
本发明技术方案的第三方面是提供了本发明第一方面涉及的化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用,其可以单独使用或者可以与现已上市的抗肿瘤药物联合使用,用于治疗预防肿瘤。优选的,所述的肿瘤包括白血病、淋巴瘤。
本发明技术方案的第四方面是提供了本发明第一方面涉及化合物或其药学上可接受的盐的制备方法。
通式I的化合物的制备方法,方法如下:
步骤a:化合物I-a与对硝基苯氧酰氯反应得到化合物I-b;
步骤b:化合物I-c与I-d反应得到化合物I-e;
步骤c:化合物I-e与三氟乙酸反应脱Boc后与N Boc L叔亮氨酸反应得到化合物I-f;
步骤d:化合物I-f与三氟乙酸反应脱Boc后与含L的酸缩合得到化合物I-g;
步骤e:化合物I-g与三氟乙酸反应脱Boc后与I-b或I-i反应得到通式为I的化合物。
通式II的化合物制备方法,方法如下:
步骤:化合物I-g与三氟乙酸反应脱Boc后与V-a或V-b反应得到通式为II的化合物。
有益技术效果:
本发明的化合物可以混杂共价性结合包括蛋白降解系统中的关键蛋白,为癌症的防治提供具有独特作用机制的方法。
附图说明
图1人白血病细胞占小鼠外周血的比例。QHS:青蒿琥酯;QV:实施例CL8。
图2人白血病细胞占骨髓的比例。QHS:青蒿琥酯;QV:实施例CL8。
图3人白血病细胞占脾脏的比例。QHS:青蒿琥酯;QV:实施例CL8。
图4小鼠的脾脏重量。QHS:青蒿琥酯;QV:实施例CL8;cm:厘米。
图5关键中间体1的核磁共振氢谱。
图6关键中间体1的质谱图。ES-API Positive:ES-API正离子信号。
图7关键中间体2的核磁共振氢谱。
图8关键中间体2的质谱图。ES-API Positive:ES-API正离子信号。
图9关键中间体3的核磁共振氢谱。
图10关键中间体3的核磁共振氢谱局部放大图。
图11关键中间体3的质谱图。
具体实施方式
不需进一步详细说明,认为本领域熟练技术人员借助前面的描述,可以最大程度的利用本发明。因此,下面提供的实施例仅仅是进一步阐明本发明而已,并不意味着以任何方式限制本发明范围。
原料可以从商业途径获得,或者通过本领域已知的方法制备,或根据本文所述方法制备。
化合物的结构通过高分辨质谱(HRMS)来确定。HRMS的测定用Thermo ExactivePlus(USA)型质谱仪。柱层析采用200-300目硅胶(烟台银龙化工厂生产)。
实施例合成所需的关键中间体1-3(其结构式如下)通过商业途径获得,即委托北京保诺科技有限公司按照经典的青蒿素衍生化方法(Org.Lett.2005,7,1561-1564;Org.Lett.2010,12,1420-1423;Bioorg.Med.Chem.2009,17,1325-1338;J.Med.Chem.2002,45,1052-1063)合成,均经核磁共振和质谱鉴定(附图5-10)。
实施例合成所需的两个氨基被保护的非天然氨基酸(其结构式如下)从商业途径获得。
实施例1:化合物CL-1的制备,其结构式如下:
步骤1)I-b-3的制备
将化合物I-a-3(化合物I-a中n=3,即中间体1)(240mg,0.74mmol,1eq.)用10mL二氯甲烷溶解,置于冰水浴中,再加入4-硝基苯基氯甲酸酯(180mg,0.90mmol,1.2eq.)和吡啶(183μL,2.28mmol,3eq.)。然后撤去冰水浴,将反应液置于室温下搅拌。搅拌9小时后,反应液中加入10mL水淬灭反应,用50mL饱和氯化铵水溶液萃取两次,50mL饱和食盐水萃取一次。收集有机相,用无水硫酸钠干燥,过滤后,减压浓缩。粗产物用硅胶柱层析纯化,流动相为石油醚∶乙酸乙酯=30/1至5/1,得I-b-3,无色油状物(300mg,82.5%)。
步骤2)I-e的制备
将(4-(4-甲基噻唑-5-基)苯基)甲胺(I-c,3g,14.58mmol,1eq.)用二氯甲烷溶解,然后加入1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸3.39g,14.58mmol,1eq.)和HATU(4.96g,16.08mmol,1.1eq.)。最后,加入N,N-二异丙基乙胺(1.70ml,9.72mmol,4eq.)。反应液在常温下搅拌4个小时。然后反应液依次用饱和氯化铵水溶液和饱和氯化钠水溶液萃取。合并有机相用无水硫酸钠干燥,真空除去溶剂后,残留物用硅胶柱层析分离纯化,流动相为纯二氯甲烷至含5%甲醇的二氯甲烷溶液,得I-e,黄色固体,3.97g,产率65.24%。
步骤3)I-f的制备
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将I-e(3.97g,9.51mmol,1eq.)溶于含20%三氟乙酸的二氯甲烷溶液搅拌2小时,脱去Boc保护基,真空除去溶剂与三氟乙酸。将其用200mL二氯甲烷溶解,加入2-((叔丁氧基羰基)氨基)-3,3-二甲基丁酸2.64g,11.41mmol,1.2eq.)。然后加入HATU(5.43g,14.27mmol,1.5eq.),加入N,N-二异丙基乙胺(6.29mL,38.04mmol,4eq.)调节pH,使反应液pH大于9。将反应液置于常温下搅拌2个小时。反应完成后,反应液依次用饱和氯化铵水溶液(200mL×2)萃取和饱和氯化钠水溶液(200mL)萃取,合并有机相,用无水硫酸钠干燥,过滤后滤液真空除去溶剂,残留物硅胶柱层析纯化,流动相梯度为纯二氯甲烷至含2.5%甲醇的二氯甲烷溶液,得I-f,淡黄色产物3.45g,产率为68.32%。
步骤4)I-g-L1的制备
将I-f(190mg,0.36mmol,1eq.)溶于含20%三氟乙酸的二氯甲烷溶液搅拌2小时,脱去Boc保护基,真空除去溶剂与三氟乙酸。将其用5mL二氯甲烷溶解,加入3-(2-((叔丁氧基羰基)氨基)乙氧基)丙酸83.5mg,0.38mmol,1.2eq.)。然后加入HATU(163.3mg,0.43mmol,1.2eq.),加入N,N-二异丙基乙胺调节pH,使反应液pH大于9。将反应液置于常温下搅拌2个小时。反应完成后,反应液依次用饱和氯化铵水溶液(20mL×2)萃取和饱和氯化钠水溶液(20mL)萃取,合并有机相,用无水硫酸钠干燥,过滤后滤液真空除去溶剂,残留物硅胶柱层析纯化,流动相梯度为纯二氯甲烷至含5%甲醇的二氯甲烷溶液。得I-g-L1,淡黄色固体166mg,产率为71.9%。
步骤5)CL-1的制备
将I-g-L1(30mg,0.046mmol,1eq.)溶于含20%三氟乙酸的二氯甲烷溶液搅拌2小时,脱去Boc保护基,真空除去溶剂与三氟乙酸。将其用5mL二氯甲烷溶解,加入I-b-3(23mg,0.046mmol,1eq.)。然后加入HATU(21mg,0.055mmol,1.2eq.),加入N,N-二异丙基乙胺调节pH,使反应液pH大于9。将反应液置于常温下搅拌2个小时。反应完成后,反应液依次用饱和氯化铵水溶液(20mL×2)萃取和饱和氯化钠水溶液(20mL)萃取,合并有机相,用无水硫酸钠干燥,过滤后滤液真空除去溶剂,残留物高效制备液相纯化。最后得CL-1(白色固体,32mg),产率为81.6%。HRMS(ESI)测得分子离子峰m/z898.4650[M+H]+,理论计算值898.4631。
实施例2:化合物CL-2的制备,其结构式如下:
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用I-g-L2(I-g中的L部分为L2)代替I-g-L1,参考实施例CL-1的操作过程,得到CL-2。HRMS(ESI)测得分子离子峰m/z 942.4867[M+H]+,理论计算值942.4893。
实施例3:化合物CL-3的制备,其结构式如下:
用I-g-L3(I-g中的L部分为L3)代替I-g-L1,参考实施例CL-1的操作过程,得到CL-3。HRMS测得分子离子峰m/z 986.5146[M+H]+,理论计算值986.5155。
实施例4:化合物CL-4的制备,其机构式如下:
用I-g-L4(I-g中的L部分为L4)代替I-g-L1,参考实施例CL-1的操作过程,得到CL-4。HRMS测得分子离子峰m/z 840.4188[M+H]+,理论计算值840.4212。
实施例5:
化合物CL-5的制备,其结构式如下:
用I-g-L6(I-g中的L部分为L6)代替I-g-L1,参考实施例CL-1的操作过程,得到CL-5。HRMS测得分子离子峰m/z 868.4507[M+H]+,理论计算值868.4525。
实施例6:
化合物CL-6的制备,其结构式如下:
用I-g-L7(I-g中的L部分为L7)代替I-g-L1,参考实施例CL-1的操作过程,得到CL-6。HRMS测得分子离子峰m/z 882.4680[M+H]+,理论计算值882.4687。
实施例7:
化合物CL-7的制备,其结构式如下:
用I-g-L8(I-g中的L部分为L8)代替I-g-L1,参考实施例CL-1的操作过程,得到CL-7。HRMS测得分子离子峰m/z 930.4639[M+H]+,理论计算值930.4681。
实施例8:
化合物CL-8的制备,其结构式如下:
用I-g-L5(I-g中的L部分为L5)代替I-g-L1,参考实施例CL-1的操作过程,得到CL-8。HRMS测得分子离子峰m/z 854.4366[M+H]+,理论计算值854.4368。
实施例9:
化合物CL-9的制备,其结构式如下:
CL-9的合成路线如下:
将I-g-L1(48mg,0.0743mmol)加到30%的三氟乙酸的二氯甲烷溶液3ml中,室温搅拌30min后,旋蒸除去二氯甲烷及大部分三氟乙酸,而后加入适量DMSO溶解,加入适量DIEA使溶液PH值在中性或弱碱性,备用。另取单口瓶,加入青蒿素酸(I-i-1)(24.3mg,0.0743mmol),加入EDCI(28.5mg,0.1486mmol),加入适量DMSO溶解,然后加入上述备用的溶液,加入DMAP(18mg,0.1486mmol),加入适量DIEA使溶液PH值大于9。室温搅拌过夜后,加入饱和的氯化铵水溶液,用二氯甲烷萃取,并用饱和食盐水洗,收集有机层,无水硫酸钠干燥,减压蒸去有机溶剂,残留物通过HPLC纯化,得CL9,无色固体,重7.98mg,收率12.58%。HRMS测得分子离子峰m/z 854.4340[M+H]+,理论计算值854.4368。
实施例10:
化合物CL-10的制备,其结构式如下:
用I-g-L2(I-g中的L部分为L2)代替I-g-L1,参考实施例CL-9的操作过程,得到CL-10。HRMS测得分子离子峰m/z 898.4656[M+H]+,理论计算值898.4631。
实施例11:
化合物CL-11的制备,其结构式如下:
用I-g-L3(I-g中的L部分为L3)代替I-g-L1,参考实施例CL-9的操作过程,得到CL-11。HRMS测得分子离子峰m/z 942.4852[M+H]+,942.4893。
实施例12:
化合物CL-12的制备,其结构式如下:
用I-g-L4(I-g中的L部分为L4)代替I-g-L1,参考实施例CL-9的操作过程,得到CL-12。HRMS测得分子离子峰m/z 796.3928[M+H]+,理论计算值796.3950。
实施例13:
化合物CL-13的制备,其结构式如下:
用I-g-L6(I-g中的L部分为L6)代替I-g-L1,参考实施例CL-9的操作过程,得到CL-13。HRMS测得分子离子峰m/z 824.4242[M+H]+,理论计算值824.4263。
实施例14:
化合物CL-14的制备,其结构式如下:
用I-g-L7(I-g中的L部分为L7)代替I-g-L1,参考实施例CL-9的操作过程,得到CL-14。HRMS测得分子离子峰m/z 838.4400[M+H]+,理论计算值838.4419。
实施例15:
化合物CL-15的制备,其结构式如下:
用I-g-L8(I-g中的L部分为L8)代替I-g-L1,参考实施例CL-9的操作过程,得到CL-15。HRMS测得分子离子峰m/z 886.4406[M+H]+,理论计算值886.4419。
实施例16:
化合物CL-16的制备,其结构式如下:
用I-g-L5(I-g中的L部分为L5)代替I-g-L1,参考实施例CL-9的操作过程,得到CL-16。HRMS测得分子离子峰m/z 810.4080[M+H]+,理论计算值810.4106。
实施例17:
化合物CL-17的制备,其结构式如下:
用I-a-2(I-a中的n为2)代替I-a-3,参考实施例CL-1的操作过程,得到CL-17。1HNMR(400MHz,DMSO-d6)δ8.99(s.1H),8.57(t,J=6.0Hz,1H),7.94(d,J=9.2Hz,1H),7.37-7.43(m,4H),7.02(t,J=5.6Hz,1H),5.32(s,1H),4.56(d,J=9.6Hz,1H),4.40-4.46(m,2H),4.34(m,1H),4.18-4.23(dd,J1=5.6Hz,J2=16Hz,1H),4.02-4.08(m,2H),3.89-3.96(m,1H),3.54-3.69(m,4H),3.33-3.39(m,2H),3.12(q,J=6.0Hz,2H),2.44(s,3H),2.31-2.38(m,2H),2.09-2.16(m,1H),1.79-2.13(m,6H),1.46-1.69(m,4H),1.23-1.41(m,6H),1.11-1.16(m,1H),0.93(s,9H),0.89(d,J=6.4Hz,3H),0.79(d,J=7.6Hz,3H);HRMS测得分子离子峰m/z 884.4458[M+H]+,理论计算值884.4474。
实施例18:
化合物CL-18的制备,其结构式如下:
用I-g-L2(I-g中的L部分为L2)代替I-g-L1,参考实施例CL-17的操作过程,得到CL-18。1H NMR(400MHz,DMSO-d6)δ8.99(s.1H),8.57(t,J=6.0Hz,1H),7.93(d,J=9.2Hz,1H),7.37-7.43(m,4H),7.07(t,J=5.6Hz,1H),5.32(s,1H),4.56(m,1H),4.40-4.44(m,2H),4.34(m,1H),4.19-4.23(m,2H),4.05(m,2H),3.90-3.96(m,1H),3.55-3.69(m,7H,混杂水峰),3.44-3.47(m,4H),3.36-3.39(t,J=6.0Hz,2H),3.11(m,2H),2.66-2.67(m,1H),2.44(s,3H),2.31-2.38(m,2H),1.79-2.17(m,8H),1.47-1.70(m,5H),1.25-1.39(m,7H),1.09-1.16(m,2H),0.93(s,9H),0.89(d,J=6.4Hz,3H),0.79(d,J=7.6Hz,3H);HRMS测得分子离子峰m/z 928.4713[M+H]+,理论计算值928.4736。
实施例19:
化合物CL-19的制备,其结构式如下:
用I-g-L3(I-g中的L部分为L3)代替I-g-L1,参考实施例CL-17的操作过程,得到CL-19。HRMS测得分子离子峰m/z 972.4986[M+H]+,理论计算值972.4998。
实施例20:
化合物CL-20的制备,其结构式如下:
用I-g-L4(I-g中的L部分为L4)代替I-g-L1,参考实施例CL-17的操作过程,得到CL-20。1H NMR(400MHz,DMSO-d6)δ8.98(s.1H),8.59(t,J=6.0Hz,1H),7.75(d,J=9.6Hz,1H),7.37-7.43(m,4H),7.30(t,J=5.6Hz,1H),5.33(s,1H),4.54(m,1H),4.39-4.45(m,2H),4.34(m,1H),4.19-4.24(dd,J1=5.2Hz,J2=16Hz,1H),4.07(m,2H),3.59-3.96(m,38H,混杂水峰),2.44(s,3H),1.78-2.17(m,7H),1.45-1.69(m,5H),1.25-1.36(m,6H),1.09-1.16(m,2H),0.92(s,9H),0.89(d,J=6.0Hz,3H),0.79(d,J=7.6Hz,3H);HRMS测得分子离子峰m/z 826.4021[M+H]+,理论计算值826.4055。
实施例21:
化合物CL-21的制备,其结构式如下:
用I-g-L6(I-g中的L部分为L6)代替I-g-L1,参考实施例CL-17的操作过程,得到CL-21。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.57(t,J=6.0Hz,1H),7.90(d,J=9.2Hz,1H),7.37-7.43(m,4H),7.30(t,J=6.0Hz,1H),5.33(s,1H),4.54(m,1H),4.40-4.46(m,2H),4.34(m,1H),4.01-4.09(m,1H),3.95(m,1H),3.61-3.69(m,2H),2.90-2.98(m,3H),2.67(m,1H),2.44(s,3H),2.33(m,1H),2.21-2.28(m,1H),1.79-2.17(m,8H),1.47-1.70(m,7H),1.25-1.39(m,6H),1.09-1.16(m,2H),0.93(s,9H),0.89(d,J=6.4Hz,3H),0.79(d,J=7.2Hz,3H);HRMS测得分子离子峰m/z 854.4340[M+H]+,理论计算值854.4368。
实施例22:
化合物CL-22的制备,其结构式如下:
用I-g-L7(I-g中的L部分为L7)代替I-g-L1,参考实施例CL-17的操作过程,得到CL-22。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.57(t,J=6.0Hz,1H),7.85(d,J=9.2Hz,1H),7.37-7.43(m,4H),7.06(t,J=6.0Hz,1H),5.32(s,1H),4.54(m,1H),4.40-4.47(m,2H),4.36(m,1H),4.18-4.23(m,1H),4.01-4.09(m,2H),3.89-3.96(m,1H),3.61-3.68(m,2H),2.95(m,2H),2.44(s,3H),2.33(m,1H),2.24(m,1H),1.79-2.17(m,9H),1.25-1.70(m,16H),1.09-1.16(m,2H),0.93(s,9H),0.89(d,J=6.0Hz,3H),0.79(d,J=7.6Hz,3H);HRMS测得分子离子峰m/z 868.4482[M+H]+,理论计算值868.4525。
实施例23:
化合物CL-23的制备,其结构式如下:
用I-g-L8(I-g中的L部分为L8)代替I-g-L1,参考实施例CL-17的操作过程,得到CL-23。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.59(t,J=6.0Hz,1H),8.10(d,J=9.2Hz,1H),7.61(t,J=6.0Hz,1H),7.37-7.43(m,4H),7.21(d,J=8.0Hz,2H),7.15(d,J=8.0Hz,2H),5.33(s,1H),4.52(m,1H),4.40-4.46(m,2H),4.34(m,1H),4.19-4.24(dd,J1=5.2Hz,J2=8.0Hz,1H),4.05-4.13(m,2H),3.60-3.67(m,2H),3.42(d,J=13.6Hz,1H),2.44(s,3H),2.10-2.17(m,1H),1.95-2.05(m,2H),1.79-1.92(m,3H),1.47-1.69(m,4H),1.25-1.39(m,6H),1.09-1.17(m,1H),0.91(s,9H),0.89(d,J=6.8Hz,3H),0.79(d,J=7.2Hz,3H);HRMS测得分子离子峰m/z 916.4500[M+H]+,理论计算值916.4525。
实施例24:
化合物CL-24的制备,其结构式如下:
用I-g-L5(I-g中的L部分为L5)代替I-g-L1,参考实施例CL-17的操作过程,得到CL-24。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.96(d,J=9.2Hz,1H),7.37-7.44(m,4H),6.98(t,J=5.6Hz,1H),4.54(m,1H),4.40-4.45(m,2H),4.34(m,1H),4.22(m,1H),4.05(m,2H),3.96(m,1H),3.61-3.69(m,2H),3.17(m,2H),2.44(s,3H),2.30-2.34(m,1H),2.09-2.16(m,1H),1.79-2.07(m,5H),1.46-1.70(m,4H),1.23-1.39(m,6H),1.09-1.16(m,2H),0.93(s,9H),0.89(d,J=6.4Hz,3H),0.79(d,J=7.6Hz,3H);HRMS测得分子离子峰m/z 840.4193[M+H]+,理论计算值840.4212。
实施例25:
化合物CL-25的制备,其结构式如下:
CL-25的合成路线如下:
将I-g-L1(32mg,0.049mmol,1eq.)溶于含20%三氟乙酸的二氯甲烷溶液搅拌2小时,脱去Boc保护基,真空除去溶剂与三氟乙酸。将其用5mL二氯甲烷溶解,加入N,N-二异丙基乙胺调节pH至中性,加入V-a(15mg,0.049mmol,1eq.)。然后加入EDCI(14mg,0.073mmol,1.5eq.),DMAP(9mg,0.073mmol,1.5eq.)。将反应液置于常温下搅拌4个小时。反应完成后,反应液依次用饱和氯化铵水溶液(20mL×2)萃取和饱和氯化钠水溶液(20mL)萃取,合并有机相,用无水硫酸钠干燥,过滤后滤液真空除去溶剂,残留物高效制备液相纯化,得CL-25,白色产物29mg,产率为70.0%。HRMS测得分子离子峰m/z 836.4239[M+H]+,理论计算值836.4263。
实施例26:
化合物CL-26的制备,其结构式如下:
用I-g-L2(I-g中的L部分为L2)代替I-g-L1,参考实施例CL-25的操作过程,得到CL-26。HRMS测得分子离子峰m/z 880.4515[M+H]+,理论计算值880.4525。
实施例27:
化合物CL-27的制备,其结构式如下:
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用I-g-L3(I-g中的L部分为L3)代替I-g-L1,参考实施例CL-25的操作过程,得到CL-27。HRMS测得分子离子峰m/z 924.4787[M+H]+,理论计算值924.4777。
实施例28:
化合物CL-28的制备,其结构式如下:
用I-g-L4(I-g中的L部分为L4)代替I-g-L1,参考实施例CL-25的操作过程,得到CL-28。HRMS测得分子离子峰m/z 778.3817[M+H]+,理论计算值778.3844。
实施例29:
化合物CL-29的制备,其结构式如下:
用I-g-L6(I-g中的L部分为L6)代替I-g-L1,参考实施例CL-25的操作过程,得到CL-29。HRMS测得分子离子峰m/z 806.4160[M+H]+,806.4163。
实施例30:
化合物CL-30的制备,其结构式如下:
用I-g-L7(I-g中的L部分为L7)代替I-g-L1,参考实施例CL-25的操作过程,得到CL-30。HRMS测得分子离子峰m/z820.4295[M+H]+,理论计算值820.4314。
实施例31:
化合物CL-31的制备,其结构式如下:
用I-g-L8(I-g中的L部分为L8)代替I-g-L1,参考实施例CL-25的操作过程,得到CL-31。HRMS测得分子离子峰m/z 868.4293[M+H]+,理论计算值868.4314。
实施例32:
化合物CL-32的制备,其结构式如下:
用I-g-L5(I-g中的L部分为L5)代替I-g-L1,参考实施例CL-25的操作过程,得到CL-32。HRMS测得分子离子峰m/z 792.3968[M+H]+,理论计算值792.4001。
实施例33:
化合物CL-40的制备,其结构式如下:
CL-40的合成路线如下:
用I-g-L5(I-g中的L部分为L5)代替I-g-L1,用V-b代替V-a,参考实施例CL-25的操作过程,得到CL-40。HRMS测得分子离子峰m/z 880.4284[M+H]+,理论计算值880.4278。
实验例1体外活性评价
MTT测试方法:
用DMSO将合成的实施例化合物配成20mM,10mM,5mM,2.5mM,1.25mM,0.625mM,0.3125mM,0.15625mM,0.078mM,0mM的不同浓度的溶液。然后用完全培养基将上述浓度的溶液分别稀释1000倍(即1μL药液加入999μL完全培养基)。将药液分别加入96孔板中,每个浓度3个复孔,每孔50μL。MV4-11细胞计数后,将细胞悬液稀释到100000个/mL,在含有化合物的孔中每孔加入50μL稀释的细胞悬液。96孔板外圈每孔加入200μL PBS溶液。培养48h。每孔加入100μL CellTiter-Glo Luminescent检测试剂,培养箱孵育10min,酶标仪检测。计算得出细胞存活率和化合物对肿瘤细胞的生长的半数抑制浓度(IC50)。具体试验结果见表1。
表1部分实施例化合物的MTT测试结果
实验例2体内活性评价
试验方法:
通过尾静脉注射将100μL重悬的2×106个U937白血病细胞移植到NSG小鼠中。移植后每3天从眼底静脉丛取外周血50-100μL,置于含肝素钠EP管中,即刻加入500μL的红细胞裂解液破坏红细胞,通过流式细胞术检测human-CD45阳性细胞比例。当平均植入率为0.4%时,即认为模型成功,将小鼠随机分组。每周连续给药5天(灌胃,溶媒为玉米油),每天给药1次,休息2天。共持续2周。给药2周后,即第15天取材,分离小鼠外周血、脾脏、骨髓,并完成检测。
试验结果:
化合物CL8对小鼠体内的U937白血病细胞具有很强的抑制作用。试验结果见表2、图1、图2、图3和图4。
表2化合物CL-8的在动物体内抗白血病作用
尽管已经通过特定实施方案描述了本发明,但修改和等价变化对于精通此领域的技术人员而言是显见的,且它们都包含在本发明范围之内。
Claims (8)
1.式(M)所示化合物或其药学上可接受的盐:
其中:
R”为如下结构:
L选自C1-C8亚烷基,含氧亚烷基,所述的含氧亚烷基选自如下结构:
2.根据权利要求1所述的化合物或其药学上可接受的盐:
L选自如下结构:
3.化合物或其药学上可接受的盐,其特征在于,化合物选自如下:
4.化合物或其药学上可接受的盐,所述的化合物为式(I-1)所示:
其中:
n独立选自0、1、2、3、4或5;
X选自氧或-CH2-;
L选自C1-C8亚烷基,含氧亚烷基,
所述的含氧亚烷基选自如下结构:
5.根据权利要求4所述的化合物或其药学上可接受的盐:
L选自如下结构:
6.化合物或其药学上可接受的盐,其特征在于,化合物选自如下:
7.一种药物组合物,包含权利要求1-6任一项所述的化合物或其药学上可接受的盐,以及
药学上可接受的赋形剂。
8.权利要求1-6任一项所述的化合物或其药学上可接受的盐或权利要求7所述的药物组合物在制备预防和/或治疗肿瘤疾病药物中的应用,其特征在于,所述的肿瘤包括白血病、淋巴瘤。
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