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CN117964685A - 抗体药物偶联物及其中间体、制备方法、应用 - Google Patents

抗体药物偶联物及其中间体、制备方法、应用 Download PDF

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CN117964685A
CN117964685A CN202211299160.1A CN202211299160A CN117964685A CN 117964685 A CN117964685 A CN 117964685A CN 202211299160 A CN202211299160 A CN 202211299160A CN 117964685 A CN117964685 A CN 117964685A
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drug conjugate
antibody drug
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宋云松
顾家宁
宁元标
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Borui Pharmaceutical Suzhou Co ltd
Brightgene Bio Medical Technology Co Ltd
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Borui Pharmaceutical Suzhou Co ltd
Brightgene Bio Medical Technology Co Ltd
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Abstract

本发明涉及生物医药技术领域，具体的涉及结构如式I、Ⅱ、Ⅲ所示抗体药物偶联物中间体及其制备方法、应用。本发明提供一种抗体药物偶联物中间体的制备方法及其在制备抗肿瘤药物中的应用。所用制备方法反应条件温和，步骤简单，后处理方便，成本低，适合工业化生产。

Description

抗体药物偶联物及其中间体、制备方法、应用
技术领域
本发明涉及生物医药领域，具体的涉及一种抗体药物偶联物及其中间体、制备方法、应用。
背景技术
抗体药物偶联物(Antibody drug conjugate,ADC)利用抗体作为载体，通过共价连接的方式将细胞毒性分子携带进入肿瘤细胞，然后利用偶联物在肿瘤特殊环境中解离出的小分子杀伤肿瘤细胞，与传统的细胞毒药物相比，ADC具有靶向性强、毒副作用小等优势，在临床上展现较好的治疗潜力，是目前癌症治疗的一种策略。
喜树碱(Camptothecin，CPT)类似物及衍生物是具有细胞毒性的小分子，其通过抑制拓扑异构酶I(Topoisomerase,Topo I)而具有抗肿瘤作用，对很多肿瘤类型都表现出了显著的活性。伊沙替康(Exatecan)为一种水溶性的CPT衍生物，对Topo I有强抑制活性，在体外针对多种肿瘤细胞表现出优异的抗肿瘤效果。
连接子设计在调节ADC在体循环中的稳定性和肿瘤中的有效载荷释放效率方面起着关键作用，目前已经至少从两个方面清楚地证明了连接子是整个ADC设计的关键元素：第一，连接子可以进行架构修饰以优化治疗指数(Therapeutic index,TI)；第二，连接子必须确保将正确数量的细胞毒素递送到正确的细胞。连接子的不同结构元素，包括连接位点、释放部分、增溶部分的存在，以及这些不同单元的适当设计，可以影响ADC的药代动力学、疗效和毒性特征，理想的连接子应在循环系统中保持稳定，并在肿瘤中释放细胞毒性有效载荷。
因此，开发新的细胞毒性小分子及连接子在ADC药物开发中显得尤为重要。
发明内容
本发明的目的在于提供一种抗体药物偶联物中间体；
本发明的第二个目的在于提供抗体药物偶联物中间体的制备方法；
本发明的第三个目的在于提供一种连接子化合物；
本发明的第四个目的在于提供所述抗体药物偶联物中间体、连接子化合物在制备抗肿瘤药物中的应用。
为实现上述目的，本发明的技术方案是：
一种抗体药物偶联物中间体，结构如式I、Ⅱ、式Ⅲ所示：
本发明的式Ⅱ化合物作为ADC药物中的linker，其羧酸端连接毒素药物分子，比如在式Ⅱ化合物羧酸的一端连接伊沙替康得到本发明式Ⅲ化合物。当然，式Ⅱ化合物的羧酸端也可以连接其它的毒素分子。
本发明的式Ⅱ化合物作为ADC药物中的linker，其马来亚酰胺端可以连接抗体，比如Herceptin。
化合物I的制备方法，反应路线如下：
作为本发明所述抗体药物偶联物中间体化合物I的制备方法的具体技术方案：将伊沙替康、3-羟基丙酸、有机溶剂混合后降温至10℃以下，加入DEPC、DIEA，升至室温反应1～3h，得化合物I。其中，所述的伊沙替康和3-羟基丙酸的摩尔比为1:1～1:5；DEPC与伊沙替康的摩尔比为1.5:1，DIEA与伊沙替康的摩尔比为3:1。
式Ⅱ化合物采用一种固相合成方法得到，反应路线如下：
其中甘氨酸类似物为Fmoc-Gly-OH或Fmoc-Gly-Gly-OH，Fmoc为芴甲氧羰基。
采用Fmoc固相合成法，偶联试剂采用碳二亚胺型缩合剂、磷正离子型缩合剂、脲正离子型缩合剂及其它类型的缩合剂。所述缩合剂为HOBt、HOAt、HOOBt、HOPyU、TBTU、HBPyU、HBPipU、HBMDU、HATU、HAPyU、HAMDU、TAPipU、HDTU、HPyOPfp、HPySPfp、HAPyTU、TOTU、HAPipU、BOP-Cl、FDP、FDPP、DEPBT、EEDQ、EDC.HCl、DCC、DIC中的任意一种或几种。
所用化合物5的制备方法，反应路线如下：
化合物Ⅲ的制备方法，反应路线如下:
作为本发明所述抗体药物偶联物中间体化合物Ⅲ的制备方法的具体技术方案：将式Ⅱ化合物、伊沙替康、有机溶剂混合后降温至10℃以下，然后加入TBTU、DIEA，升至室温反应0.5～3h，得化合物Ⅲ。
本发明所提供的抗体偶联物中间体Ⅲ所用连接子是一种可切割的亲水多肽连接子，在进入肿瘤细胞后，就可以被溶酶体蛋白酶所裂解，在保证系统循环稳定性的同时，可以限制系统毒性。
本发明固相合成式Ⅱ化合物的方法，先将化合物5的羟基端偶联至固相树脂上，再依次拼接Fmoc-Phe-OH、甘氨酸类似物、6-马来酰亚胺己酸或其琥珀酰亚胺酯，使用固相合成方法快速、高效的合成linker片段，固相合成不需要每步纯化，每步缩合完毕后只需要将剩余的试剂/原料洗涤即可，最后将linker从树枝上切割下来，即可得到纯度较高的linker，步骤简单，成本低，适合工业化生产。
本发明提供抗体偶联中间体的制备方法，先采用固相肽合成制备linker，再采用TBTU、DIEA缩合剂将linker与伊沙替康缩合拼接，室温反应1～3h即可得到化合物Ⅲ，既降低了生产成本，又提高了生产效率。
本发明的抗体药物偶联物，具有靶向作用，当到达肿瘤部位时，linker断裂有效释放出毒素分子即化合物Ⅰ，杀死肿瘤细胞。
附图说明
图1为化合物I质谱图；
图2为化合物I核磁图；
图3为化合物II质谱图；
图4为化合物II核磁图；
图5为化合物II的制备流程图；
图6为化合物Ⅲ质谱图；
图7为化合物Ⅲ核磁图。
具体实施方案
除非另有说明，本文中所用的术语具有如下含义：
DCM：二氯甲烷
DMF：N,N-二甲基甲酰胺
DEPC：氰基磷酸二乙酯
DIEA：N,N-二异丙基乙胺
DIC：N,N'-二异丙基碳二亚胺
TFA：三氟乙酸
TLC：薄层色谱
TBTU：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐硼酸酯
MeOH：甲醇
实施例1、式I化合物的合成
向5mL反应瓶中加入3-羟基丙酸(38mg,1.2eq)，伊沙替康(200mg,1eq)，以2mLDMF作溶剂，降温至10℃以下，加入DEPC(80μL,1.5eq)，DIEA(175μL,3eq)，升至室温反应1h，TLC监控反应完毕后，浓缩至干得粗品，粗品经反相高效液相纯化后得类白色固体化合物150mg，收率83.9％。LC/MS(m/z):calcd for C27H26FN3O6,507.18；found 508.20[M+H]+，506.20[M-H]-，化合物I的质谱图、核磁图如附图1、2所示。
实施例2、化合物5的合成
化合物4的合成
向250mL三口瓶中加入化合物2(10.00g,1.0eq)，化合物3(14.70g,3.0eq)，200mL四氢呋喃，叔丁醇钾(9.15g,2.0eq)，室温搅拌0.5h后向反应液中加入水、DCM，萃取分液，收集有机相，有机相浓缩后加入100mL水、用碳酸氢钠调节pH值至7-8,，加入Fmoc-OSU(7.30g,0.8eq)溶于100mL乙二醇二甲醚的溶液，再加入50mL四氢呋喃，室温搅拌，TLC监控反应完毕后，浓缩后加入乙酸乙酯萃取，稀盐酸洗涤，碳酸氢钠洗涤后浓缩，柱层析得类白色固体化合物4,3.90g，收率29.5％。LC/MS(m/z):calcd for C28H28N2O6,488.19；found 511.10[M+Na]+.
化合物5的合成
在250mL氢化釜中加入化合物4(3.90g,1.0eq)，50mL MeOH，0.4g钯碳，氮气置换后通入氢气，保持4个大气压，室温反应2h，TLC监控反应完毕后，过滤，浓缩得类白色固体化合物5，1.50g，收率47.2％。LC/MS(m/z):calcd for C21H22N2O6,398.15；found 421.15[M+Na]+.
实施例3式II化合物的合成
称取代度为0.75mmol/g的2-CTC Resin(4.76g,1.9eq)于200mL固相反应柱中，加入50mL DCM，化合物5(0.75g,1eq)，DIEA(1.21g,5eq)，氮气鼓泡反应2h；再加入5mL MeOH反应1h。DMF洗涤树脂三次，用20％哌啶/DMF脱除Fmoc保护基团20min，用DMF洗涤5次。称取Fmoc-Phe-OH(1.46g,2eq)，HOBt(0.63g,2.2eq)，DIC(0.52g,2.2eq)，用DMF溶解，加入反应柱，反应2h后，DMF洗涤树脂3次，用20％哌啶/DMF脱除Fmoc保护基团20min，用DMF洗涤6次，DCM洗涤3次。重复上述偶联操作，按照肽序依次偶联Fmoc-Gly-OH、Fmoc-Gly-OH、6-马来酰亚胺己酸。反应结束后，用甲醇收缩树脂，真空干燥后得到肽树脂。将得到肽树脂加入到预先配置1％TFA的DCM溶液70mL中，室温反应2.0h，滤掉树脂，加入吡啶中和TFA，浓缩除去溶剂，加入100mL甲基叔丁基醚打浆，过滤，收集滤饼真空干燥得到白色的式II化合物，0.83g收率70.0％。LC/MS(m/z):calcd for C29H38N6O10,630.26；found 653.25[M+Na]+，629.20[M-H]-。式II化合物的质谱图、核磁图如附图3、4所示，式II化合物的制备流程图如图5所示。
实施例4化合物Ⅲ的合成
向25mL三口瓶中加入式II化合物(0.80g,1.2eq)，化合物7(0.60g,1.00eq)，8mLDMF，降温至10℃以下，加入TBTU(0.41g,1.2eq)，DIEA(0.53mL,3.0eq)，升至室温反应1h，TLC监控反应完毕后，将反应液倒入水中，DCM/MeOH混合溶剂萃取2次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗品，粗品经柱层析(DCM:MeOH＝200:1～10:1)后得淡黄色固体化合物Ⅲ0.79g，收率71.4％。LC/MS(m/z):calcd for C53H58FN9O13,1047.41；found 1048.35[M+H]+，1046.30.25[M-H]-，化合物Ⅲ的质谱图、核磁图如附图6、7所示。
对本领域的技术人员来说，可根据以上描述的技术方案以及构思，做出其它各种相应的改变以及形变，而所有的这些改变以及形变都应该属于本发明权利要求的保护范围之内。

Claims (10)

1.抗体药物偶联物中间体，其特征在于，结构如式I、式Ⅱ或式Ⅲ所示的化合物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式及药学上可接受的盐：
2.如权利要求1所述的抗体药物偶联物中间体的制备方法，其特征在于，式I所示的化合物合成路线为：
3.如权利要求2所述的抗体药物偶联物中间体的制备方法，其特征在于：将伊沙替康、3-羟基丙酸、有机溶剂混合后降温至10℃以下，加入DEPC、DIEA，升至室温反应1～3h，得
式I所示的化合物。
4.如权利要求1所述的抗体药物偶联物中间体的制备方法，其特征在于，式Ⅱ所示的化合物采用固相合成方法得到，反应路线如下：
其中甘氨酸类似物为Fmoc-Gly-OH或Fmoc-Gly-Gly-OH，Fmoc为芴甲氧羰基。
5.根据权利要求4所述的抗体药物偶联物中间体的制备方法，其特征在于，采用Fmoc固相合成法，将化合物5、Fmoc-Phe-OH、甘氨酸类似物、6-马来酰亚胺己酸或其琥珀酰亚胺酯依次偶联到固相树脂上，然后洗涤干燥，加入裂解试剂裂解反应，得式II所示化合物。
6.如权利要求4所述的抗体药物偶联物中间体的制备方法，其特征在于，化合物5的合成路线如下：
7.如权利要求1所述的抗体药物偶联物中间体的制备方法，其特征在于，式Ⅲ所示化合物的制备方法包括：将式Ⅱ所示化合物、伊沙替康、有机溶剂混合后降温至10℃以下，然后加入TBTU、DIEA，升至室温反应0.5～3 h，得式Ⅲ所示化合物。
8.一种抗体药物偶联物，其特征在于，具有如下结构：
Ab为抗体。
9.如权利要求1所述的抗体药物偶联物中间体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式及药学上可接受的盐或者权利要求8所述的抗体药物偶联物在制备预防和/治疗肿瘤药物中的用途。
10.如权利要求9所述的用途，其特征在于，所述肿瘤包括胃癌、胰腺癌、乳腺癌、结肠癌。
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