CN117069793A - 双功能接头化合物、抗体药物偶联物及其制备方法和应用 - Google Patents
双功能接头化合物、抗体药物偶联物及其制备方法和应用 Download PDFInfo
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Abstract
本申请涉及双功能接头化合物、抗体药物偶联物及其制备方法和应用,所述双功能接头化合物为式(I)所示的化合物或其药学上可接受的盐、立体异构体或前药,式中各基团定义详见说明书,本申请化合物不仅能够制备具有改善的同质性的抗体药物缀合物还可以提升抗体结构稳定性。M‑L‑D(I)。
Description
技术领域
本发明涉及抗体偶联药物领域。具体地说,本发明提供一系列药物-双功能接头化合物、药物-抗体偶联物及其制备方法和应用。
背景技术
抗体偶联药物(Antibody drug conjugate or ADC)是一种新型、有效的靶向药物,由抗体,连接子和毒素三部分组成。其中,毒素(payload)是发挥药效的关键成分,抗体起着靶向作用的关键部分,而连接子不仅仅将两者连接在一起,也是影响ADC的稳定性,药物的释放机制,和抗体的偶联方式等。
传统的ADC产品采用两种偶联方式:抗体上的赖氨酸(Lys)和毒素-连接子(payload-linker)的一个羧酸基团形成酰胺键或马来酰亚胺接头和还原型的抗体中的4对二硫键的8个半胱氨酸进行迈克尔加成。因此,至今上市的大部分药物-抗体比例(DAR)为~4的ADC是随机偶联得到的平均DAR值的混合物,不是均一性的偶联物。
发明内容
本发明人通过大量研究,惊奇地发现一系列双功能接头化合物,这些双功能接头化合物可以将还原型抗体中的邻近半胱氨酸的巯基交联,形成均一的抗体偶联药物。这些双功能接头和抗体偶联形成的ADC药物不仅提高稳定性,也提高药效,对肿瘤的治疗具有重要的应用价值。
双功能连接头可以同时连接两个化学官能团,如同时连接一对二硫键被还原形成的两个半胱氨酸的巯基。因此,四对二硫键被还原形成的8个半胱氨酸的巯基可以被4个双功能接头进行饱和连接,形成定点、定量的抗体偶联药物。
本发明一方面涉及式(I)化合物或其药学上可接受的盐、立体异构体或前药。
本发明的另一方面提供药物-抗体偶联物或其药学上可接受的盐。
本发明的另一方面提供药物-抗体偶联物或其药学上可接受的盐的制备方法。
本发明的另一方面提供一种双功能接头化合物。
本发明的另一方面提供药物组合物。
本发明的另一方面提供上述药物-抗体偶联物或其药学上可接受的盐在制备治疗癌症的药物中应用。
本发明不仅能够制备具有改善的同质性的抗体药物缀合物还可以提升抗体结构稳定性。
附图说明
图1为示出了效果实施例2中药物-抗体偶联物抑制肿瘤(胰腺癌)的效果的图表。
图2为示出了药物-抗体偶联物在CFPAC-1模型中抑制肿瘤的效果的照片。
图3为示出了效果实施例2中药物-抗体偶联物抑制肿瘤(乳腺癌)的效果的图表。
图4为示出了药物-抗体偶联物在MCF-7模型中抑制肿瘤的效果的照片。
具体实施方式
I.定义
本申请使用的术语“抗体”以最广泛的意义使用并且具体地涵盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如双特异性抗体)和抗体片段,只要它们展现出所需生物活性。抗体可以是鼠的、人的、人源化的、嵌合的或衍生自其他物种。抗体是由免疫***生成的能够识别并结合特异性抗原的蛋白质。靶抗原通常具有多个结合位点,也称作表位,其由多种抗体上的CDR(互补决定区)识别。特异性结合不同表位的每一抗体具有不同结构。因此,一种抗原可具有多于一种的对应抗体。抗体包括全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分,即包含免疫特异性地结合目标靶标抗原或其部分的抗原结合位点的分子,这些靶标包括但不限于癌细胞或产生与自体免疫疾病相关的自身免疫抗体的细胞。
本申请使用的术语“抗体片段”包括全长抗体的一部分,通常是其抗原结合区或可变区。抗体片段的实例包括Fab、Fab’、F(ab’)2和Fv片段;双抗体;线性抗体;微型抗体,由Fab表达文库产生的片段,抗独特型(抗Id)抗体,CDR(互补决定区)和免疫特异性结合癌细胞抗原、病毒抗原或微生物抗原的本文所述的任何抗体的表位结合片段,单链抗体分子;和由抗体片段形成的多特异性抗体。
本申请使用的术语“单克隆抗体”是指自大致上均质抗体的群体获得的抗体,即除可以少量存在的可能天然存在的突变之外,构成所述群体的个别抗体是相同的。单克隆抗体是高度特异性的,从而针对单一抗原位点。此外,与包括针对不同决定子(表位)的不同抗体的多克隆抗体制剂不同,各单克隆抗体针对抗原上的单一决定子。除特异性外,单克隆抗体的优势还在于,其合成不会受到其他抗体的污染。修饰语“单克隆”指示抗体是从大致上均质的抗体群体获得的特性且不应解释为需要通过任何特定方法来产生所述抗体。例如,根据本发明使用的单克隆抗体可以通过首先由杂交瘤方法来制备,或者可以通过重组DNA方法制备。单克隆抗体也可以从噬菌体抗体文库中分离。
本说明书中的单克隆抗体尤其包括“嵌合”抗体,其中重链和/或轻链的一部分与来自特定物种或属于特定抗体种类或子类的抗体中的相应序列相同或同源,而链的其余部分与来自另一个物种或属于另一个抗体种类或子类的抗体中的相应序列相同或同源以及这类抗体的片段,只要其展现所需生物活性。本文中的目标嵌合抗体包括包含源于非人灵长类动物(例如旧世界猴、猿等)的可变结构域抗原结合序列和人恒定区序列的“灵长类化”抗体。
本申请使用的术语“嵌合”抗体是指这样的抗体,其中重链和/或轻链的一部分来自特定的来源或物种,而重链和/或轻链的其余部分来自不同的来源或物种。本申请使用的术语“完整抗体”是包含VL结构域和VH结构域以及轻链恒定结构域(CL)和重链恒定结构域、CH1、CH2及CH3的抗体。恒定结构域可为天然序列恒定结构域(例如人天然序列恒定结构域)或其氨基酸序列变体。完整抗体可具有一种或多种“效应子功能”,其指可归因于抗体Fc恒定区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物活性。抗体效应子功能的实例包括C1q结合;补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;以及细胞表面受体(诸如B细胞受体和BCR)的下调。
本申请使用的术语“抗体药物偶联物(antibody-drug conjugate,ADC)”是通过一个化学链接将具有生物活性的小分子药物连接到单抗上,单抗作为载体将小分子药物靶向运输到目标细胞中。
本申请使用的术语“双功能接头”是指可以同时连接两个化学官能团(具体而言,为抗体和细胞毒性药物部分)的结构。该结构中具有与抗体连接的基团和与细胞毒性药物部分连接的基团,其具体结构如下文记载的M所示。
本申请使用的术语“间隔单元E”又被称为***(selfimmolatIIIe)结构,是位于L和D之间的连接基团,间隔单元(E)选自对氨基苄基碳酸酯酰胺(PAB carbamate)、对氨基苄基碳酸二酯(PAB carbonate)、半缩醛胺(hemiaminal)和亚甲基二胺(methylenediamine)中的一种。
本申请使用的术语“间隔单元F”是指位于所述M和所述L之间的连接基团,所述间隔单元F为-NH-(CH2CH2-O)q-CH2CH2-C(=O)-或单键,其中,q表示1~6的整数。
本申请使用的术语“细胞毒性药物部分”也称为“小分子药物”,其是指对肿瘤细胞具有杀伤作用的化合物。作为细胞毒性药物部分可举出抗微管蛋白剂,DNA嵌入剂,DNA拓扑异构酶抑制剂、DNA合成抑制剂、RNA聚合酶抑制剂、splicesome抑制剂、蛋白水解-靶标嵌合体(proteolysis-targeting chimera,PROTAC)、和免疫调节物质(immunomodulators)中的至少一种。
免疫调节物质(immunomodulators)包括但不限于免疫抑制剂和激动剂,靶点包括PD-1/PD-L1、PD-L2、CTLA-4、LAG-3、IDO、TIM3、TIGIT、CD47、SIRPα、4-1BB、CSF-1/CSF1R、GITR、OX40、CD40、CD27、CD28、B7H4、B7H3、TGFβ、BTLA、VISTA、ICOS、CD39、CD73、A2AR、KIR和NKG2A等;以及与免疫治疗相关的细胞疗法。
本申请中使用的小分子药物可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。所述的立体异构体包括几何异构(如顺式、反式结构)和光学异构(如对映异构体),以单体、消旋体、外消旋混合物及其药学上可接受的盐组成的治疗物。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。外消旋体、非对映异构体、对映异构体都包括在本申请的范围之内。
本申请中使用的小分子药物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本申请使用的术语“前体”是指化合物以适当的给药方式进入人体后,前体化合物在病人体内进行代谢或简单的化学变化而转变成本发明通式1中所包含的化合物以及相应的盐的形式。化合物的前体包括但不限于各种羧酸酯、碳酸酯、磷酸酯、硫酸酯、磺酸酯、氨基酸酯、葡萄糖酸酯以及各种酰胺、缩醛、半缩醛、碳酸酰胺酯等形式。
本文中的数字范围,是指给定范围中的各个整数。例如,“C1-C6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子;“C3-C6”是指该基团可具有3个碳原子、4个碳原子、5个碳原子或6个碳原子。
当任何变量(例如Rn)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被1-5个R所取代,则所述基团可以任选地至多被5个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本申请使用的术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至8个碳原子的烷基,更优选1至6个碳原子的烷基,最优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2_二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、2,2-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基,本申请优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
本申请使用的术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物,由一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中,杂原子选自B、O、N和S,其中氮和硫原子任选地被氧化,氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置,包括该烃基附着于分子其余部分的位置,实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3。但术语“烷氧基”、“烷氨基”和“烷硫基”属于惯用表达,是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团,“烷氧基”指的是-O-烷基,“烷氨基”指的是-NH-烷基,“烷硫基”指的是-S-烷基,其中,烷基定义如上所定义。
本申请使用的术语“烯基”为不饱和直链或支链烃基,尤其是具有2至10个碳原子、双键位于任何所需位置的链烯基,例如C2-C6链烯基,如乙烯基、1-丙烯基、2-丙烯基、1-甲基-乙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-甲基-1-丙烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、2-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、1-甲基-2-丁烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、1-甲基-3-丁烯基、2-甲基-3-丁烯基、3-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1,2-二甲基-1-丙烯基、1,2-二甲基-2-丙烯基、1-乙基-1-丙烯基、1-乙基-2-丙烯基、1-己烯基、2-己烯基、3-乙烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、4-甲基-1-戊烯基、1-甲基-2-戊烯基、2-甲基-2-戊烯基、3-甲基-2-戊烯基、4-甲基-2-戊烯基、1-甲基-3-戊烯基、2-甲基-3-戊烯基、3-甲基-3-戊烯基、4-甲基-3-戊烯基、1-甲基-4-戊烯基、2-甲基-4-戊烯基、3-甲基-4-戊烯基、4-甲基-4-戊烯基、1,1-二甲基-2-丁烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-1-丁烯基、1,2-二甲基-2-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-1-丁烯基、1,3-二甲基-2-丁烯基、1,3-二甲基-3-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-1-丁烯基,2,3-二甲基-2-丁烯基、2,3-二甲基-3-丁烯基、3,3-二甲基-1-丁烯基、3,3-二甲基-2-丁烯基、1-乙基-1-丁烯基、1-乙基-2-丁烯基、1-乙基-3-丁烯基、2-乙基-1-丁烯基、2-乙基-2-丁烯基、2-乙基-3-丁烯基、1,1,2-三甲基-2-丙烯基、1-乙基-1-甲基-2-丙烯基、1-乙基-2-甲基-1-丙烯基和1-乙基-2-甲基-2-丙烯基;
本申请使用的术语“杂环基”或“杂环烷环”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1-4个是杂原子;更优选包含3至8个环原子;最优选包含3至8个环原子;进一步优选包含1-3氮原子的3-8元杂环基,任选地,被1-2个氧原子、硫原子、氧代基取代,包括含氮单环杂环基、含氮螺杂环基或含氮稠杂环基。
本申请使用的术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至12元,例如苯基和萘基。
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自(卤代)烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、琉基、氢基,硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
本申请使用的术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、氢基、硝基、氯基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
本申请使用的术语“杂芳基”在本申请中可互换使用且是指具有3至约20个环原子的饱和或部分不饱和(即在环中具有一个或多个双键和/或叁键)的碳环基团,其中至少一个环原子为选自氮、氧、磷和硫的杂原子,其余环原子为C,其中一个或多个环原子任选独立取代有一个或多个下述取代基。杂环可为具有3-7个环成员(2-6个碳原子和1-4个选自N、O、P和S的杂原子)的单环或具有7-10个环成员(4-9个碳原子和1-6个选自N、O、P和S的杂原子)的二环例如二环[4,5]、[5,5]、[5,6]或[6,6]***。“杂环基”还包括以下基团,其中杂环基团与饱和环、部分不饱和环或芳族碳环或杂环稠合。杂环的实例包括但不局限于吗啉-4-基、哌啶-1-基、哌嗪基、哌嗪-4-基-2-酮、哌嗪-4-基-3-酮、吡咯烷-1-基、硫吗啉-4-基、S,S-二氧代硫吗啉-4-基、氮杂环辛烷-1-基、氮杂环丁烷-1-基、八氢吡啶并[1,2-a]吡嗪-2-基、[1,4]二氮杂环庚烷-1-基、吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶子基、吗啉代、硫吗啉代、硫杂氧杂环己基、哌嗪基、高哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧杂氮杂基、二氮杂基、硫杂氮杂基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、2H-吡喃基、4H-吡喃基、二氧杂环己烷基、1,3-二氧杂环戊烷基、吡唑啉基、二硫杂环己烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂二环[3.1.0]己基、3-氮杂二环[4.1.0]庚基、氮杂二环[2.2.2]己基、3H-吲哚基、喹嗪基和N-吡啶基脲。螺环部分也包括在该定义的范围内。其中2个环原子取代有氧代(=O)部分的杂环基团的实例为嘧啶酮基和1,1-二氧代-硫吗啉基。杂环在本申请中任选独立取代有一个或多个本申请所描述的取代基
本申请使用的术语“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本申请使用的术语“药学上可接受的盐”是指相应的胺类化合物和无机酸或有机酸形成的盐,或相应的羧酸类化合物和碱金属或碱土金属形成的盐或和有机胺形成的盐。其中,无机酸包括但不限于盐酸,氢溴酸,氢碘酸,硫酸,磷酸等;有机酸包括但不限于乙酸,丙酸,丁酸,苯甲酸,甲磺酸,苯磺酸,对甲苯磺酸,草酸,丁二酸,乳酸,柠檬酸,琥珀酸,葡萄糖酸,马来酸,延胡索酸,酒石酸等;碱金属或碱土金属盐包括但不限于钠、钾、钙、镁盐等;有机胺盐包括但不限于氨、甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、三甲胺、三乙胺、叔丁胺、乙二胺、乙醇胺、二乙醇胺、三乙醇胺、吗啉、哌啶、哌嗪、氨基酸等组成的盐。
本申请的药物或药物组合物可以经口地、局部地、肠胃外地或粘膜地(例如,含服地、通过吸入或直肠地)以包含常规的非-毒性药学可接受的载体的剂量单位配制剂施用。通常希望使用口服途径。所述活性试剂可以经口地以胶囊、片剂等形式(参见Remington:The Science and Practice of Pharmacy,20th Edition)施用。
对于以片剂或胶囊形式的口服给药,活性药物组分可以与非-毒性的、药学可接受的辅料如粘结剂(例如,预胶化的玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填料(例如,乳糖、蔗糖、葡萄糖、甘露糖醇、山梨糖醇和其它还原性和非-还原性糖类、微晶纤维素、硫酸钙或磷酸氢钙);润滑剂(例如,硬脂酸镁、滑石粉或硅土、硬脂酸、硬脂基富马酸酯钠、甘油二十二烷酸酯、硬脂酸钙等);崩解剂(例如,马铃薯淀粉或羟乙酸淀粉钠);或润湿剂(例如,月桂基硫酸钠)、着色剂和调味剂、明胶、甜味剂、天然和合成的胶(如***胶、黄蓍胶或藻朊酸盐)、缓冲盐、羧甲纤维素、聚乙二醇、蜡、等。对于以液体形式的口服给药,所述药物组分可以与非-毒性、药学可接受的惰性载体(例如,乙醇、甘油、水)、防沉降剂(例如,山梨糖醇糖浆、纤维素衍生物或氢化的可食用脂肪)、乳化剂(例如,卵磷脂或***胶)、非-水性载体(例如,扁桃油、油酯类、乙醇或经分馏的植物油)、保藏剂(例如,p-羟基苯甲酸甲酯或p-羟基苯甲酸丙酯或山梨酸)等组合。还可以加入稳定剂如抗氧化剂(BHA、BHT、桔酸丙酯、抗坏血酸钠、柠檬酸)以稳定所述剂型。
包含作为活性化合物的片剂可以通过本领域熟知的方法包衣。包含作为活性化合物的式I化合物的本申请的所述组合物还可以引入小珠、微球或微胶囊,例如由聚乙醇酸/乳酸(PGLA)构建的。用于口服给药的液体的制剂可以采取例如溶液,糖浆剂,乳液或混悬液的形式或者它们可以呈现为在使用前用水或其它适宜的辅料重构的干产品。用于口服给药的制剂可以适宜地配制以使活性化合物受控或延迟地释放。
本申请使用的术语“治疗”包括抑制、缓解、预防或消除与所治疗的疾病、病症或失调相关的一种或多种症状或副作用。
本申请使用的术语“抑制”的使用是相对于对照的。本领域技术人员将容易地确定用于每个实验的适当对照。例如,将用化合物处理的受试者或细胞中的降低了的反应与未用化合物处理的受试者或细胞中的反应进行比较。
本申请使用的术语“药物组合物”意指包含本申请所述化合物或其药学上可接受的盐,以及依施用方式和剂型的性质而定的至少一种选自以下药学上可接受的成分的组合物,包括但不限于:载体、稀释剂、佐剂、赋形剂、防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂、香味剂、抗菌剂、抗真菌剂、润滑剂、分散剂、温敏材料、温度调节剂、黏附剂、稳定剂、助悬剂等。
本申请使用的术语“肿瘤”或“癌症”指的是一种以细胞或组织的病理性增生为特征的疾病,及其随后的迁移或侵袭其他组织或器官。肿瘤生长通常是不受控制的和进行性的,不诱导或抑制正常细胞增殖。肿瘤可影响多种细胞、组织或器官,包括但不限于选自膀胱、骨、脑、乳腺、软骨、神经胶质细胞、食管、输卵管、胆囊、心脏、肠、肾、肝、肺、***、神经组织、卵巢、胰腺、***、骨骼肌、皮肤、脊髓、脾、胃、睾丸、胸腺、甲状腺、气管、尿道、输尿管、尿道、子宫、***器官,或组织或相应的细胞。肿瘤包括癌症,如肉瘤,癌,或浆细胞瘤(浆细胞的恶性肿瘤)。本发明所述的肿瘤,可包括,但不限于白血病(如急性白血病、急性淋巴细胞白血病、急性髓细胞性白血病,急性粒细胞白血病,急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、慢性白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、真性红细胞增多症),淋巴瘤(霍奇金病、非霍奇金病)、原发性巨球蛋白血症,重链病,实体瘤如肉瘤和癌症(如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、***肉瘤、血管肉瘤、***内皮肉瘤,间皮瘤,尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、直肠癌、胰腺癌、乳腺癌、卵巢癌、***癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、***状癌、***状腺癌、支气管癌、髓样癌、肾细胞癌、肝癌,尼罗河管癌,绒癌、***瘤、胚胎癌、肾母细胞瘤、***、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤,颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤,听神经瘤,少突胶质瘤、神经鞘瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤)、食管癌、胆囊癌、肾癌、多发性骨髓瘤。较佳地,所述的“肿瘤”包括但不限于:胰腺癌、肝癌、肺癌、胃癌、食管癌、头颈部鳞状细胞癌、***癌、结肠癌、直肠癌、乳腺癌、淋巴瘤、胆囊癌、肾癌、白血病、多发性骨髓瘤、卵巢癌、***和胶质瘤。
II实施方式
第一方面,本申请提供一种式(I)所示的药物-双功能接头化合物或其药学上可接受的盐、立体异构体或前药:
M-L-D (I)
其中,
M是与抗体或其抗原结合片段连接的双功能接头;
L是双功能接头M和D之间的连接子;
D是细胞毒性药物部分;
所述M表示以下式(II)所示的结构:
式(II)中的A选自烯基、单环基团或稠环基团,所述单环基团为芳基、杂芳基,所述稠环基团为杂芳基与选自芳基、杂芳基中的一种稠合而成,R1表示单键、O、N、S或亚烷基;
所述A任选地被一个或多个选自X的取代基取代,X选自卤素、卤素取代或未取代的烷基、-NH-S(O)2-烯基或-C1-C6杂烷基-杂环烷基;所述杂环烷基任选地被一个或多个卤素取代的烷基或-C(O)-卤素取代的烷基取代;其中所述一个或多个X可以相应或不同;
式(II)中,m1、m2各自独立地选自0至10的整数,例如可以为0、1、2、3、4、5或6。
优选地,所述A任选地被1、2或3个选自X的取代基取代。
优选地,m1为0或1,m2为0或1。
在一个实施方式中,A选自C2-C6烯基、单环基团或稠环基团,所述单环基团为6至12元芳基或5至12元杂芳基,所述5至12元杂芳基含有1-3个氮原子;所述稠环基团为5至12元杂芳基与选自6至12元芳基、5至12元杂芳基中的一种稠合而成的环,所述5至12元杂芳基含有1-3个氮原子作为环原子;
优选地,A选自单环基团或稠环基团,所述单环基团为6元芳香环、5元杂芳环或6元杂芳环,所述稠环基团为6元杂芳基与6元芳基稠合而成,所述5元杂芳基或6元杂芳基含有1-3个氮原子;
优选地,A选自乙烯基、
优选地,A选自乙烯基、
在一个实施方式中,X表示卤素、卤素取代的C1-C6烷基、-NH-S(O)2-C2-C6烯基或-C1-C6杂烷基-3至8元杂环烷基;所述3至8元杂环烷基任选地被一个或多个卤素取代的C1-C6烷基或-C(O)-卤素取代的C1-C6烷基取代。
在一个实施方式中,M选自:
在一个实施方式中,L选自由以下一个或多个组成的二价结构:Val-Cit、Val-Ala、Val-Lys、Val-Lys(Ac)、Phe-Lys、Phe-Lys(Ac)、Gly-Lys、Gly-Phe、Gly-Leu、Gly-Gly-Lys、Gly-Val-Ala、Gly-Val-Cit、Gly-Phe-Gly、Val-Ala-Gly、D-Val-Leu-Lys、Gly-Gly-Arg、Ala-Ala-Asn、Ala-Ala-Ala、Val-Lys-Ala、Gly-Gly-Gly、Gly-Leu-Gly、Gly-Gly-Phe-Gly、Gly-Gly-Leu-Gly、Gly-Val-Ala-Gly、Gly-Val-Cit-Gly、Gly-Gly-Gly-Gly-Gly;
优选地,L选自Val-Cit、Val-Ala、Gly-Gly-Lys、Gly-Phe-Gly、Gly-Lys、Gly-Phe、Gly-Leu、Val-Ala-Gly、Gly-Gly-Phe-Gly、Gly-Val-Ala-Gly、Ala-Ala-Asn、Gly-Leu-Gly;
优选地,L选自Gly-Lys、Gly-Val-Ala。
在一个实施方式中,D为选自抗微管蛋白剂、DNA嵌入剂、DNA拓扑异构酶抑制剂、DNA合成抑制剂、RNA聚合酶抑制剂、splicesome抑制剂中的至少一种。
优选地,所述微管蛋白抑制剂为奥瑞他汀类化合物或美登素类化合物;奥瑞他汀干扰微管动力学、GTP水解以及核和细胞***并具有抗癌和抗真菌活性。例如,奥瑞他汀E可以与对乙酰基苯甲酸或苯甲酰基戊酸反应,分别产生AEB和AEVB。其他典型的奥瑞他汀衍生物包括AFP、MMAF(单甲基奥瑞他汀F)和MMAE(单甲基奥瑞他汀E)。
优选地,所述DNA嵌入剂为吡咯并苯二氮卓(PBD)。
优选地,所述DNA拓扑异构酶抑制剂非限制性实例包括拓扑异构酶I抑制剂或拓扑异构酶II抑制剂;优选地,所述拓扑异构酶I抑制剂非限制性实例包括喜树碱、羟基喜树碱、9-氨基喜树碱、10,11-亚甲基二氧喜树碱、SN-38、伊立替康、拓扑替康、贝洛替康、依喜替康或卢比替康、Genz-644282;优选地,拓扑异构酶II抑制剂非限制性实例包括非限制性实例包括阿霉素、多柔比星、PNU-159682、多卡米星、柔红霉素、米托蒽醌、鬼臼毒素、或依托泊苷;优选地,所述DNA合成抑制剂非限制性实例包括吉西他滨以及其他嘧啶核苷酸类似物;优选地,所述RNA聚合酶抑制剂非限制性实例包括α-鹅膏草碱(α-amanitin);优选地,所述splicesome抑制剂非限制性实例包括thailanstatin系列毒素及其药学上可接受的盐、酯和类似物。
在一个实施方式中,所述L直接和D连接,或者,在所述L和所述D之间连接有间隔单元E,所述间隔单元E选自对氨基苄基碳酸酯酰胺,对氨基苄基碳酸二酯,半缩醛胺(例如,氨甲基醚(也叫烷基氧胺))和亚甲基二胺中的一种。
在一个实施方式中,所述M直接和L连接,或者,在所述M和所述L之间连接有间隔单元F,所述间隔单元F为-NH-(CH2CH2-O)q-CH2CH2-C(=O)-或单键,其中,q表示1~6的整数,例如可以为0、1、2、3、4、5或6。
在一个实施方式中,所述化合物选自下组:
其中,L、D定义同前;
RX1、RX2各自独立地选自卤素或C2-C6烯基;
优选地,RX1选自溴或氯,RX2为乙烯基。
在一个实施方式中,所述化合物选自下组:
/>
第二方面,本申请提供一种式(III)所示的药物-抗体偶联物或其药学上可接受的盐:
Ab-M-L-D (III)
其中,M、L、D各自定义同式(I)化合物;Ab为抗体或其抗原结合片段;
在一实施方式中,所述药物-抗体偶联物上还连接有其它具有细胞毒性的药物;
优选地,所述药物-抗体偶联物具有式(IV)所示结构:
D’-L’-Ab-M-L-D (IV)
其中,所述L’是抗体和D’之间的连接子,其与L相同或不同;
D’是细胞毒性药物部分,其与D相同或不同。
优选地,所述D’为依喜替康或单甲基奥瑞他汀E。优选地,所述抗体为单克隆抗体;优选地,所述单克隆抗体为人抗体或人源化抗体;优选地,所述单克隆抗体为IgG;优选地,所述单克隆抗体为IgG1、IgG2、IgG3、或IgG4;优选地,所述单克隆抗体为IgG1或IgG4单克隆抗体;优选地,所述IgG1单克隆抗体为赫赛汀(曲妥珠单抗(美国专利第5821337号))。
在一个实施方式中,Ab为肿瘤相关抗原抗体;
优选地,Ab选自抗Her2抗体、抗Trop2抗体、抗B7H3抗体、抗5T4、抗Nectin-4抗体、抗CD20抗体和抗ROR1抗体。
优选地,Ab为帕妥珠单抗HS627。
在一个实施方式中,D或D’选自:
在一个实施方式中,本申请提供以下药物-抗体偶联物,
/>
其中,L、D的定义同式(I)化合物;Ab为抗体或其抗原结合片段。
n为选自1至12中的整数,优选为选自2至4的整数;优选地,所述抗体为单克隆抗体或多克隆抗体。
第三方面,本发明提供以下化合物双功能接头化合物:
RX1、RX2各自独立地选自卤素或C2-C6烯基;
优选地,RX1选自溴或氯,RX2为乙烯基。
本申请提供一种权利要求11或12所述的式(III)所示的药物-抗体偶联物或其药学上可接受的盐的制备方法,其包括以下步骤:
将式(I)所示的化合物或其药学上可接受的盐、立体异构体或前药连接至所述抗体或其抗原结合片段。
本申请提供一种药物组合物,其包括上述化合物或其药学上可接受的盐、立体异构体或前药或上述的抗体药物偶联物和药学上可接受的辅料。
本申请提供上述化合物或其药学上可接受的盐、立体异构体或前药,上述抗体药物偶联物、上述的药物组合物在制备治疗癌症的药物中应用,
实施例
缩写:
Fmoc:9-芴甲氧羰基;Val:缬氨酸,其结构式为Ala:丙氨酸,其结构式为Cit:瓜氨酸,其结构式为/>Lys:赖氨酸,其结构式为Gly:甘氨酸,其结构式为/>Phe:苯丙氨酸,其结构式为PAB:/>m:/>MC:6-马来酰亚胺己酰基;VC:Val-Cit缬氨酸-瓜氨酸;HATU:4-甲基吗啉;DIPEA:乙基二异丙胺;DMA:N,N-二甲基乙酰胺;mCPBA:间氯过氧苯甲酸;DIC:N,N-二异丙基碳二亚胺;
本实施例中制备ADC使用但不限于帕妥珠单抗,帕妥珠单抗(HS627,PERTUZUMAB,购自博瑞生物,批号为0362721003。
实施例1:4-((1,2-二溴乙酰吡唑啉-4-)氧)苯乙酸(CL-01)的合成
在冰浴冷却下,将氯甲基环氧乙烷(12g,129.70mmol,10.14mL)慢慢滴加到装有85%水合肼N2H4.H2O(8.12g,162.12mmol,7.90mL)的水(10mL)溶液中,加完后撤去冰浴,继续搅拌2小时,加入丙酮(30mL),继续搅拌2小时,乙酸乙酯萃取(3×50mL)非极性物,分出水相,在冰浴冷却下,向水相加入碳酸钾(22.41g,162.12mmol),THF(30mL)和Boc2O酸酐(35.38g,162.12mmol,37.21mL),继续搅拌2小时,乙酸乙酯(100mL)萃取,有机相分别用1NHCl(50mL),饱和NaHCO3水溶液(100mL),饱和食盐水洗涤,无水硫酸钠干燥,过滤、浓缩后得到双Boc取代的中间体CL-01-2(30g,产率83%)。向反应瓶中加入CL-01-2(6g,13.82mmol),THF(40mL),4-羟基苯甲酸叔丁酯(.02g,13.76mmol)和三苯基膦(1.69g,24,87mmol),在0℃搅拌下,向反应瓶中滴加DIAD(5.04g,24.87mmol,4.89mL),加完后室温下搅拌过夜。加入水(50mL),乙酸乙酯萃取,无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/EA=4:1)得到中间体CL-01-3(8g,产率81.93%,HPLC 99%);1H NMR(500MHz,CDCl3)δ7.88–7.84(m,2H),6.76-6.72(m,2H),5.01(t,J=4.7Hz,1H),4.23(d,J=12.9Hz,1H),4.03-3.98(m,1H),3.51(d,J=12.4Hz,1H),3.22(d,J=12.4Hz,1H),1.50(s,9H),1.42(s,9H),1.38(s,9H);13CNMR(126MHz,CDCl3)δ165.32,159.82,131.54,125.45,114.73,81.74,81.43,80.76,77.32,77.06,76.81,28.25,28.22,28.05;LCMS:m/z 487.30[M+H]+(理论值465.56)。
将CL-01-3(8g,17.22mmol),DCM(50mL)和TFA(15mL)加入到反应瓶中,室温下搅拌反应5小时,浓缩,加入甲基叔丁基醚搅拌,析出白色固体产物CL-01-4(3g,产率83%,HPLC99%);1H NMR(500MHz,DMSO-d6)δ7.93-7.91(d,J=10Hz,2H),7.07-7.05(d,J=10Hz,2H),5.36(q,J=3.5,1.9Hz,1H),3.52(d,J=5.2Hz,1H),3.49(d,J=5.1Hz,1H),3.37(d,J=1.6Hz,1H),3.36-3.33(d,J=1.6Hz,1H);13C NMR(126MHz,DMSO-d6)δ167.32,160.45,131.92,124.31,115.66,77.38,68.73,52.6;LCMS:m/z 209.61[M+H]+(理论值209.22)。
将CL-01-4(1.5g,7.2mmol)加入到反应瓶中,加入THF(50mL)和固体碳酸钾(2.99g,21.61mmol),在0℃搅拌下滴加溴乙酰溴(3.64g,18.01mmol,1.56mL)的THF(10mL)溶液,室温下搅拌反应2小时,搅拌下倒入到冰水中,用盐酸调节pH至酸性,过滤析出白色固体产物CL-01(2g,产率61%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.89(s,1H),7.02(s,2H),5.46-5.38(m,1H),4.52-4.45(m,2H),4.17-4.14(m,1H),3.51-3.44(m,1H);LCMS:m/z 451.08[M+H]+(理论值451.08)。
实施例2:2-((4,6-二氯-1,3,5-三嗪-2-)氧)乙酸(CL-02)的合成
在0℃下,向反应瓶中加入DIPEA(3.07g,23.73mmol,4.13mL),2-羟基乙酸叔丁酯(2.87g,21.58mmol),DCM(50mL)和2,4,6-三氯-1,3,5-三嗪(4g,21.57mmol)的DCM(150mL)溶液,反应液在0℃下继续搅拌1h,倒入到冰水中,分出有机相,饱和氯化钠溶液洗涤,浓缩溶剂,硅胶柱层析纯化(EA/PE=2-8%EA)获得粘稠状产物2-((4,6-二氯-1,3,5-三嗪-2-)氧)乙酸叔丁酯(4.9g,17.43mmol,产率80.80%,HPLC 99.9%),放置后变成固体;1H NMR(600MHz,CDCl3)δ4.81(s,2H),1.41(s,9H);13C NMR(151MHz,CDCl3)δ172.59,170.98,165.26,83.55,77.25,77.04,76.82,65.40,27.98。
取2-((4,6-二氯-1,3,5-三嗪-2-)氧)乙酸叔丁酯(6.5g,23.12mmol)溶解于4NHCl的乙酸乙酯溶液,室温搅拌过夜,浓缩溶剂,接入甲基叔丁基醚,过滤析出固体,干燥,得到产物2-((4,6-二氯-1,3,5-三嗪-2-)氧)乙酸CL-02(3.5g,15.24mmol,产率65.93%,HPLC98%);LC/MS m/z 223.38[M+H]+(理论值222.96)。
实施例3:4-(2-氯甲基环氧乙烷-2-甲氧基)苯甲酸(CL-03)的合成
在反应瓶中加入4-羟基苯甲酸叔丁酯(0.78g,4.00mmol),3-氯-2-氯甲基1-丙烯(998.77mg,7.93mmol),K2CO3(1.66g,12mmol)和乙腈(10mL),反应液搅拌下加热至70℃反应5h,过滤,滤液浓缩干,硅胶柱层析纯化(EA/PE=3-10%EA)得到4-((2-氯甲基)烯丙基氧)苯甲酸叔丁酯,CL-03-1(0.6g,2.09mmol,产率52.39%,HPLC 99%);1H NMR(600MHz,CDCl3)δ7.90-7.83(m,1H),6.90-6.81(m,1H),5.33(s,1H),5.29(s,1H),4.60(s,1H),4.11(s,1H),1.50(s,5);13C NMR(151MHz,CDCl3)δ165.50,161.73,140.30,131.42,124.99,117.81,114.17,80.61,77.27,77.06,76.85,67.95,44.97,34.94,31.52,30.15,29.71,28.26。
向反应瓶中加入mCPBA(1.09g,6.31mmol),CL-03-1(0.6g,2.11mmol)和DCM(10mL),室温下搅拌反应36h,加入饱和亚硫酸钠水溶液(10mL),分出有机相,硅胶柱层析纯化(EA/PE=5-12% EA)获得白色固体产物4-((2-氯甲基)环氧乙烷-2-甲氧基)苯甲酸叔丁酯,CL-03-2(0.42g,1.40mmol,产率66.00%,HPLC99.6%);1HNMR(600MHz,CDCl3)δ8.01-7.76(m,2H),6.96-6.72(m,2H),4.22(dd,J=10.7,1.1Hz,1H),4.11(d,J=10.5Hz,1H),3.79(dt,J=11.8,1.1Hz,1H),3.58(d,J=11.7Hz,1H),2.93(dd,J=4.4,1.0Hz,1H),2.87(dd,J=4.3,1.2Hz,1H),1.52(d,J=13.1Hz,8H);13C NMR(151MHz,CDCl3)δ165.41,161.55,131.46,125.35,114.06,80.69,77.28,77.07,76.85,67.47,57.46,51.28,44.81,29.70,28.24LCMS:m/z 298.86[M+H]+(理论298.10)。
反应瓶中加入TFA(1.5mL),CL-03-2(0.2g,667.18μmol)和DCM(6mL),室温下搅拌2h,减压下除去溶剂,得到,4-((2-氯甲基)环氧乙烷-2-甲氧基)苯甲酸,CL-03(0.16g,430.64μmol,产率64.55%,HPLC 96%);1HNMR(600MHz,DMSO-d6)δ7.86-7.79(m,2H),6.99(d,J=8.6Hz,2H),4.23(d,J=11.0Hz,1H),4.17(d,J=11.0Hz,1H),3.87-3.79(m,2H),2.96(d,J=4.9Hz,1H),2.92(d,J=4.9Hz,1H);13C NMR(151MHz,DMSO)δ167.47,162.07,131.84,124.08,114.85,67.34,57.53,50.50,45.76.LCMS:m/z[M+H]+243.45(理论值242.03)。
实施例4:2-(4,5-二氯甲基-1-H-1,2,3-三氮唑-1-)乙酸(CL-04)的合成
将溴乙酸叔丁酯(2g,10.20mmol,1.50mL)滴加到装有NaN3(663.06mg,10.20mmol)和DMF(10mL)的反应瓶中,加热至70℃下搅拌反应过夜,冷却,加入水(25mL),乙酸乙酯萃取,无水硫酸钠干燥,过滤浓缩后得到淡黄色油状物叠氮乙酸叔丁酯(1.2g,产率75%)。将叠氮乙酸叔丁酯CL-04-1(500mg,3.16mmol),甲苯(10mL)和1,4-二氯-2-丁炔(777.48mg,6.27mmol)加入到反应瓶中,加热搅拌过夜,减压浓缩溶剂,加入甲基叔丁基醚,搅拌析出灰白色固体产物2-(4,5-二氯甲基-1-H-1,2,3-三氮唑-1-)乙酸叔丁酯CL-04-2(500mg,产率56%);1H NMR(600MHz,CDCl3)δ5.16(s,2H),4.75(s,2H),4.73(s,2H),1.50(s,9H);LCMS:m/z 280.41[M+H]+(理论值280.15)。将2-(4,5-二氯甲基-1-H-1,2,3-三氮唑-1-)乙酸叔丁酯(200mg,0.7mmol),4.0M乙酸乙酯溶液HCl(25.94mg,0.7mmol,4mL)和乙酸乙酯(5mL)加入到反应瓶中,室温下搅拌反应6小时,减压浓缩溶剂,加入甲基叔丁基醚,搅拌,过滤析出灰色固体产物2-(4,5-二氯甲基-1-H-1,2,3-三氮唑-1-)乙酸CL-04(120mg,产率75%,HPLC98%);1H NMR(600MHz,DMSO-d6)δ5.34(s,2H),5.06(s,2H),4.94(s,2H);LCMS:m/z 224.45[M+H]+(理论值224.04)。
实施例5:2-(4,5-二溴甲基-1-H-1,2,3-三氮唑-1-)乙酸(CL-05)的合成
2-(4,5-二溴甲基-1-H-1,2,3-三氮唑-1-)乙酸可按照合成2-(4,5-二氯甲基-1-H-1,2,3-三氮唑-1-)乙酸(CL-04)的方法进行,获得灰色固体产物2-(4,5-二溴甲基-1-H-1,2,3-三氮唑-1-)乙酸叔丁酯(16g,产率58%,HPLC 98%);1H NMR(600MHz,CDCl3)δ5.14(s,2H),4.60(s,2H),4.53(s,2H),1.50(s,9H);LCMS:m/z 370.19[M+H]+(理论值370.06);接着用三氟乙酸处理,获得白色固体产物2-(4,5-二溴甲基-1-H-1,2,3-三氮唑-1-)乙酸,CL-05(10g,产率72%,HPLC 98%);1H NMR(600MHz,DMSO-d6)δ5.34(s,2H),5.06(s,2H),4.94(s,2H);LCMS:m/z 314.22[M+H]+(理论值313.95)。
实施例6:2-((2,6-二溴甲基)吡啶-4-氧)乙酸(CL-06)的合成
将4-羟基吡啶-2,6-二羧酸(5g,27.16mmol)溶解于甲醇(50mL),加入浓硫酸(0.6mL,27.16mmol),反应物搅拌下加热回流4h,冷却至室温,倒入冰水中,调节pH至5,过滤析出固体产物,乙酸乙酯/石油醚重结晶得到4-羟基吡啶-2,6-二羧酸甲酯(5.76g,产率70%);1H NMR(600MHz,DMSO-d6)δ11.60(s,1H),7.59(s,2H),3.90(s,6H);LCMS:m/z 212.5[M+H]+(理论值211.05)。
将4-羟基吡啶-2,6-二羧酸甲酯(1g,4.71mmol)溶解于THF(8mL),在冰浴冷却下慢慢滴加LAH(447.19mg,11.78mmol)的THF(15mL)溶液,加完后将反应液在50℃下搅拌反应18h,冷却至室温,加入饱和硫酸钠水溶液淬灭反应,过滤除去固体物,减压浓缩滤液,得到固体产物,CL-06-1(0.45g,产率72%);1H NMR(600MHz,DMSO-d6)δ6.16(s,2H),4.24(s,4H);LCMS:m/z 156.65[M+H]+(理论值155.06)。
反应瓶中加入2-溴乙酸叔丁酯(2.62g,13.38mmol,1.97mL),CL-06-1(2.1g,13.45mmol),K2CO3(2.7g,20mmol)和乙腈(25mL),反应液加热、搅拌回流2h,浓缩,DCM萃取,硅胶柱层析纯化(MeOH/DCM(3-10%MeOH)得到白色固体产物,CL-06-2(1g,产率24%);1HNMR(500MHz,DMSO-d6)δ6.81(s,2H),5.36(t,J=5.8Hz,2H),4.74(s,2H),4.46(d,J=5.7Hz,4H),1.43(s,9H);LCMS:m/z 270.86[M+H]+(理论值269.13)。
在反应瓶中加入三苯基膦(2.18g,8.32mmol),四溴化碳(2.76g,8.32mmol),CL-06-2(0.9g,3.33mmol)和DCM(30mL),室温下搅拌10h,减压浓缩,硅胶柱层析纯化(EtOAc/PE=0-30%EA)得到白色固体产物CL-06-3(1.06g,产率76%);1H NMR(500MHz,CDCl3)δ6.88(s,2H),4.59(s,2H),4.47(s,4H),1.50(s,9H);LCMS:m/z 394.23[M+H]+(理论值392.96)。
反应瓶中加入TFA(2mL),CL-06-3(1g,2.52mmol)和DCM(8mL),反应液在室温下搅拌15h,减压浓缩,加入甲基叔丁基醚,得到固体产物2-((2,6-二溴甲基)吡啶-4-氧)乙酸,CL-06(620mg,产率53%);LCMS:m/z338.27[M+H]+(理论值336.89)。
实施例7:3,4-二(乙烯磺酰胺基)苯甲酸(CL-07)的合成
向反应瓶中加入3,4-二氨基苯甲酸(2g,13.14mmol)和甲醇(80mL),在冰浴冷却下搅拌,滴加SOCl2(3.13g,26.29mmol,1.92mL),加完后室温搅拌反应5h,减压浓缩得到3,4-二氨基苯甲酸甲酯,CL-07-1(2g,12.04mmol,产率91.56%)直接用于下一步反应。
在反应瓶中加入CL-07-1(300mg,1.81mmol)和DCM(8mL),冰浴下搅拌,加入TEA(913.39mg,9.03mmol,1.26mL),然后慢慢滴加2-氯乙基磺酰氯(2-chloroethanesulfonylchloride)(588.61mg,3.61mmol),加完后在室温下继续搅拌2h,减压除去溶剂,加入THF和水(3mL,1:1),加入LiOH.H2O(16.96mg,404.18μmol),室温下搅拌1h,用2N HCl调节至pH<3,过滤析出白色固体产物CL-07(22mg,62.89μmol,产率31.12%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ13.04(s,1H),9.41(d,J=42.7Hz,2H),7.88(d,J=2.0Hz,1H),7.75(dd,J=8.5,2.0Hz,1H),7.47(d,J=8.5Hz,1H),6.92-6.89(m,1H),6.88-6.86(m,1H),6.21-6.11(m,2H),6.10-6.00(m,2H);13CNMR(126MHz,DMSO)δ166.75,136.30,135.45,129.41,128.90,128.12,128.07,127.52,126.76,121.67。
实施例8:3,5-二(乙烯磺酰胺基)苯甲酸(CL-08)的合成
按照上述制备CL-07的方法顺利的获得了CL-08(20mg,三步总产率26.80%,HPLC97%);1H NMR(600MHz,DMSO-d6)δ13.10(s,1H),10.32(d,J=6.7Hz,2H),7.42(d,J=6.1Hz,2H),7.28(d,J=6.2Hz,1H),6.77(dt,J=16.9,8.4Hz,2H),6.15(dd,J=16.5,7.2Hz,2H),6.09(t,J=8.4Hz,2H);13C NMR(151MHz,DMSO)δ166.88,139.38,136.26,132.96,128.93,115.36,113.73。
实施例9:4-氯-3-(氯甲基)丁-2-烯酸(CL-09)的合成
在反应瓶中加入1,3-二氯丙酮(678.14mg,5.30mmol)和三苯基磷乙酸叔丁酯(2g,5.30mmol)和DCM(20mL),反应液在室温下搅拌12h,减压除去溶剂,硅胶柱层析纯化(PE/EA=100:1)获得4-氯-3-(氯甲基)-2-丁烯酸叔丁酯(1g,4.29mmol,产率80.96%,HPLC97%);1H NMR(500MHz,CDCl3)δ5.92(s,1H),4.70(s,2H),4.17(s,2H),1.43(s,9H);13C NMR(126MHz,CDCl3)δ164.04,147.61,124.21,81.76,45.69,38.02,28.08。
反应瓶中加入4-氯-3-(氯甲基)-2-丁烯酸叔丁酯(400mg,1.77mmol),TFA(2mL)和DCM(3mL),室温下搅拌2h,减压除去溶剂,过滤析出白色固体产物4-氯-3-(氯甲基)-2-丁烯酸,CL-09(250mg,1.41mmol,产率79.80%,HPLC 96%);1H NMR(600MHz,CDCl3)δ11.55(s,1H),6.06(s,1H),4.72(s,2H),4.23(s,2H);13CNMR(151MHz,CDCl3)δ170.23,152.23,121.10,45.37,37.86。
实施例10:4-溴-3-(溴甲基)丁-2-烯酸(CL-10)的合成
按照类似于上述合成4-氯-3-(氯甲基)-2-丁烯酸叔丁酯的方法获得了4-溴-3-(溴甲基)-2-丁烯酸叔丁酯(1.5g,4.67mmol,产率88.06%,HPLC 98%);1H NMR(500MHz,CDCl3)δ5.89(s,1H),4.63(s,2H),4.08(s,2H),1.43(s,9H);13C NMR(126MHz,CDCl3)δ164.06,148.37,123.87,81.77,34.02,28.09,25.72。
用三氟乙酸处理上述产品得到4-溴-3-(溴甲基)-2-丁烯酸,CL-10(1.0g,3.79mmol,产率79.49%,HPLC 98%);1H NMR(500MHz,CDCl3)δ11.32(s,1H),6.00(s,1H),4.65(s,2H),4.12(s,2H);13C NMR(126MHz,CDCl3)δ170.09,153.05,120.73,33.41,25.20。
实施例11:4,5-二溴甲基三氮唑-1-乙酰胺乙氧基乙氧基丙酰-Gly-Lys-PAB-MMAE(C1)的合成
(1)Fmoc-GK(Trt)-PAB-PNP的合成
Fmoc-Lys(Trt)(8.01g,12.33mmol)与(4-aminophenyl)methanol(2.00g,12.33mmol)溶解于DCM(50mL)与MeOH(50ml)的混合溶剂中,搅拌下降温至0℃,加入EEDQ(3.05g,12.33mmol),0℃下搅拌反应6h。反应液中加入DBU(0.94g,6.16mmol),常温搅拌3h,反应液直接常温浓缩,然后用DCM(50ml)溶解后,滴加至MTBE(500ml)中,过滤析出白色固体,得到Lys(Trt)-PAB(5.2g,产率80%,HPLC 95%);LCMS:[M+2]+495.13(计算值:493.27)。
向反应瓶中加入Lys(Trt)-PAB(5.2g,10mmol),Fmoc-Gly(3.42g,10.2mmol)和DCM(50mL),搅拌至全部溶解,冷却至0℃,加入EDC hydrochloride(2.87g,15mmol),保持0℃反应3h,反应液萃取过柱(PE:EA=1:4)得到白色固体产物Fmoc-GK(Trt)-PAB(6.5g,产率84%,HPLC 94%);1H NMR(600MHz,DMSO-d6)δ10.00(s,1H),8.12(d,J=7.5Hz,1H),7.95-7.86(m,2H),7.74(d,J=7.4Hz,2H),7.68-7.57(m,3H),7.53-7.14(m,20H),5.16(t,J=5.3Hz,1H),4.47(dd,J=16.1,5.9Hz,3H),4.28(dd,J=24.2,6.7Hz,3H),3.72(s,2H),2.52(d,J=7.4Hz,1H),1.97(s,2H),1.52(ddd,J=109.0,87.5,50.6Hz,6H);LCMS:[M+1]+773.89(计算值:772.36)。
将Fmoc-GK(Trt)-PAB(5.4g,6.65mmol)溶解于DCM(50mL)中,加入TEA(2.02g,19.95mmol,2.78mL)和bis(4-nitrophenyl)carbonate(6.07g,19.95mmol),搅拌2hr,反应液直接加入硅胶拌样,过柱(DCM:EA=5:1),得到白色固体产物Fmoc-GK(Trt)-PAB-PNP(5.5g,产率85%,HPLC 97%);1H NMR(600MHz,DMSO-d6)δ10.12(s,1H),8.36-8.25(m,2H),8.12(t,J=8.3Hz,1H),7.88(d,J=7.5Hz,2H),7.72-7.52(m,6H),7.43-6.87(m,21H),4.48-4.37(m,1H),4.29-4.17(m,3H),3.68(d,J=2.6Hz,2H),3.35-3.16(m,1H),2.48(t,J=7.9Hz,1H),1.93(d,J=6.9Hz,2H),1.71-1.25(m,6H);LCMS:[M+1]+937.96(计算值:937.37)。
(2)Fmoc-GK(Trt)-PAB-MMAE的合成
在室温下,向100mL的反应瓶中依次加入Fmoc-GK(Trt)-PAB-PNP(1.58g,1.68mmol),MMAE(1.15g,1.60mmol),HOBT(244.88mg,1.60mmol),DIPEA(310.01mg,2.40mmol,417.80μL)和N-甲基吡咯烷酮(10mL),室温下继续搅拌反应3hr,在反应液中加入5g硅胶粉制砂,使用PE和EA进行柱层析纯化得到淡棕色固体Fmoc-GK(Trt)-PAB-MMAE(2.2g,1.20mmol,产率75.3%,HPLC 93%);LCMS:[M+1]+1517.58(计算值:1516.93)。
(3)GK(Trt)-PAB-MMAE的合成
在室温下,向反应瓶中加入Fmoc-GK(Trt)-PAB-MMAE(3.00g,1.98mmol),DBU(301.43mg,1.98mmol,296.10μL)和DMF(9mL),室温搅拌反应1h,加入5g硅胶粉制砂,使用DCM和MeOH进行柱层析纯化得到类白色固体GK(Trt)-PAB-MMAE(1.8g,1.25mmol,63.2%,HPLC 94%);LCMS:[M+1]+1295.35(计算值:1294.69)。
(4)Fmoc-PEG2-GK(Trt)-PAB-MMAE的合成
在室温下,向反应瓶中依次加入GK(Trt)-PAB-MMAE(1.8g,1.39mmol),Fmoc-PEG2-COOH(555.35mg,1.39mmol),HATU(528.52mg,1.39mmol),DIPEA(179.65mg,1.39mmol,242.11μL),在室温搅拌反应1hr,加入DCM(200mL)萃取,饱和氯化钠洗涤(100ml*3),无水硫酸镁干燥,过滤,在DCM滤液中加入5g硅胶粉制砂,使用石油醚和乙酸乙酯进行柱层析纯化得到淡黄色固体Fmoc-PEG2-GK(Trt)-PAB-MMAE(2g,1.15mmol,产率82.41%,HPLC 96%);LCMS:[M+1]+1677.48(计算值:1676.62)。
(5)PEG2-GK(Trt)-PAB-MMAE的合成
在室温下,向反应瓶中依次加入Fmoc-PEG2-GK(Trt)-PAB-MMAE(2g,1.19mmol),DBU(181.66mg,1.19mmol,178.45μL)和DMF(6mL),室温搅拌反应1hr,将反应液进行反向制备,使用C18 Spherical 20-35um 100A120g反相柱层析进行纯化,流动相使用乙腈(HPLC级别)和0.05%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214n波长监测):将6ml的样品DMF溶液注射入反相柱中,使用5min(流动相比例A2:B2=95:5)冲掉DMF溶剂,然后使用80min使乙腈比例提高到40%(流动相比例从A2:B2=95:5到A2:B2=60:40),然后乙腈比例保持在40%继续冲柱60min冲出产品,收集产品,使用HPLC(220nm)和LCMS检测产品纯度,冻干拿到白色固体粉末PEG2-GK(Trt)-PAB-MMAE(1.3g,867.36μmol,产率72.69%,HPLC 97%);1H NMR(500MHz,DMSO-d6)δ9.99(d,J=7.8Hz,1H),8.13(t,J=5.7Hz,1H),8.08(d,J=7.7Hz,1H),7.88(d,J=7.6Hz,1H),7.71-7.56(m,2H),7.52(ddd,J=8.5,4.4,2.2Hz,0H),7.45(s,1H),7.35(dtd,J=34.2,19.1,17.0,9.3Hz,10H),7.23-7.14(m,1H),5.76(s,0H),5.06(ddd,J=32.9,23.4,13.9Hz,1H),4.47(dt,J=29.1,5.9Hz,1H),4.38(p,J=7.7Hz,1H),4.31-4.17(m,2H),4.03(q,J=7.1Hz,1H),4.00(s,1H),3.74(d,J=5.6Hz,1H),3.59(t,J=6.5Hz,2H),3.47(s,2H),3.39(s,11H),3.22(dd,J=22.4,11.5Hz,4H),3.16-3.09(m,2H),2.98(s,1H),2.91-2.81(m,2H),2.54(s,1H),2.45-2.34(m,2H),2.27(dd,J=16.0,9.3Hz,1H),2.17-2.08(m,1H),1.99(s,1H),1.81(s,1H),1.57(s,3H),1.55-1.46(m,2H),1.32(s,2H),1.29-1.22(m,1H),1.18(t,J=7.1Hz,1H),1.08-0.96(m,3H),0.91-0.72(m,7H),0.80(s,3H);LCMS:[M+1]+1454.72(计算值:1453.88)。
(6)C1-01的合成
在室温下,向反应瓶中依次加入CL-07,2-[4,5-双(溴甲基)***-1-基]乙酸(86.10mg,275.13μmol),DCM(5mL),DIC(17.36mg,137.57μmol,21.30μL),室温搅拌反应5min,加入PEG2-GK(Trt)-PAB-MMAE(200mg,137.57μmol),室温下继续反应2hr,加入5g硅胶粉制砂,使用DCM和MeOH进行柱层析纯化得到淡黄色固体C1-01(190mg,产率72.66%,HPLC92%);LCMS:[M+1]+1749.64(计算值:1748.81)。
(7)C1的合成
室温下,向反应瓶中依次加入C1-01(190mg,108.65μmol),DCM(5mL),TFA(745.00mg,6.53mmol,500μL),室温搅拌反应1hr,浓缩,用3mL DMF溶解溶清,用C18反相柱层析纯化,流动相使用乙腈(HPLC级别)和0.1%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214n波长监测),冻干后得到白色固体粉末C1(110mg,产率65.86%,HPLC98%);1H NMR(600MHz,DMSO-d6)δ10.00(d,J=10.7Hz,1H),8.54(h,J=6.5Hz,1H),8.17(dd,J=17.1,7.0Hz,2H),8.07(d,J=8.3Hz,1H),7.89(d,J=8.6Hz,1H),7.61(dd,J=17.9,10.3Hz,5H),7.37-7.27(m,4H),7.26(td,J=7.6,2.7Hz,2H),7.17(q,J=6.0,4.9Hz,1H),5.14(s,1H),5.16-5.09(m,1H),5.04(d,J=13.7Hz,1H),4.94-4.80(m,3H),4.49(p,J=6.4,5.8Hz,1H),4.45-4.37(m,2H),4.26(dd,J=19.0,10.8Hz,1H),4.01(dd,J=15.0,7.2Hz,1H),4.00-3.91(m,1H),3.82-3.70(m,2H),3.62(t,J=6.4Hz,2H),3.57(s,5H),3.57(dd,J=12.1,5.1Hz,1H),3.48(s,6H),3.44(q,J=6.8,6.3Hz,2H),3.33-3.25(m,1H),3.24(t,J=9.0Hz,4H),3.19(d,J=16.0Hz,3H),3.12(s,2H),2.97(s,1H),2.86(dd,J=22.4,13.2Hz,3H),2.77(h,J=6.7Hz,2H),2.41(t,J=6.6Hz,3H),2.26(dd,J=15.4,9.2Hz,1H),2.16-2.03(m,2H),1.61(dd,J=9.3,4.8Hz,1H),1.55(qd,J=13.9,12.9,7.1Hz,3H),1.48(s,1H),1.36(td,J=16.2,13.4,7.1Hz,1H),1.33-1.26(m,2H),1.25-1.14(m,1H),1.01(ddd,J=18.8,17.1,6.7Hz,6H),0.93(s,2H),0.86(ddd,J=15.7,13.5,6.6Hz,6H),0.79(s,9H),0.76(dt,J=11.6,7.4Hz,4H);LCMS:[M+1]+1507.31(计算值:1506.49)。
实施例12:4,5-二溴甲基三氮唑-1-乙酰胺乙氧基乙氧基丙酰-Gly-Lys-PAB-(10,11-亚甲基二氧喜树碱-7-乙基)-(N-(S)-四氢呋喃-3-)胺(C2)的合成
(1)2505的合成
在反应瓶中分别加入(S)-3-氨基四氢呋喃(64.31mg,0.738mmol),浓盐酸(0.05mL,0.6mmol),DMSO(1.5mL)和7-甲基-10,11-亚甲基二氧喜树碱(50mg,0.12mmol),搅拌加热至120-130℃反应1h,冷却至室温,加入甲基叔丁基醚,过滤析出固体,硅胶柱层析纯化得到产物7-(2-(N-(S)-四氢呋喃-3-氨))乙基-10,11-亚甲基二氧喜树碱(18mg,产率33%,HPLC 95.9%);1H NMR(500MHz,DMSO-d6)δ7.61(d,J=3.4Hz,1H),7.47(d,J=3.9Hz,1H),7.22(d,J=4.2Hz,1H),6.50(s,1H),6.29(d,J=4.0Hz,2H),5.42(d,J=4.0Hz,2H),5.21(d,J=3.2Hz,2H),3.87-3.58(m,4H),3.21(s,2H),2.85(td,J=11.2,10.7,5.8Hz,2H),1.90(ddt,J=29.9,10.7,6.2Hz,3H),1.68-1.60(m,1H),1.08-0.76(m,3H);13C NMR(126MHz,DMSO)δ173.0,157.3,151.3,150.6,149.7,149.4,147.6,146.9,141.2,128.6,124.9,118.5,105.9,103.1,100.0,96.4,72.9,72.7,66.9,65.7,58.4,50.4,47.6,32.6,30.7,30.6,8.2;LC-MS:[M+H]+506.31(理论值505.18)。
(2)GK(Trt)-PAB-2505的合成
将2505(4g,7.57mmol)和Fmoc-GK(Trt)-PAB-PNP(7.27g,7.57mmol)溶于40ml NMP中,加入HOBT(1.74g,11.35mmol)和DIPEA(1.47g,11.35mmol,1.98mL),室温搅拌反应4h,HPLC检测反应产物Fmoc-GK(Trt)-PAB-2505(LCMS:[M+2]+1303.66;理论值1303.53),向反应液直接加入piperidine(3.45g,40.49mmol,4mL),室温搅拌0.5h,加入300ml甲基叔丁基醚,过滤析出;滤饼用80mlDCM复溶,加入500ml甲基叔丁基醚有固体析出,过滤;滤饼干燥得到GK(Trt)-PAB-2505(6.5g,2.96mmol,产率39.12%,HPLC 93%);LCMS:[M+1]+1081.86(理论值1081.46)。
(3)Fmoc-PEG2-GK(Trt)-PAB-2505的合成
将Fmoc-PEG2(2.48g,5.88mmol)溶于DCM(100mL)中,加入GK(Trt)-PAB-2505(6.5g,5.88mmol),HATU(3.35g,8.82mmol)和DIPEA(1.14g,8.82mmol,1.54mL),室温搅拌2h,加入20g硅胶,柱层析纯化得到Fmoc-PEG2-GK(Trt)-PAB-2505(5g,2.97mmol,产率50.53%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.13(s,1H),8.07(d,J=7.8Hz,1H),7.86(d,J=7.5Hz,2H),7.65(dd,J=18.6,7.9Hz,4H),7.53-7.47(m,2H),7.43-7.23(m,22H),6.49(s,1H),6.27(s,2H),5.76(s,1H),5.43(s,2H),5.25(s,2H),5.14(s,2H),4.58(s,1H),4.36(s,1H),4.27(d,J=6.9Hz,2H),4.18(s,1H),4.10(s,1H),3.90(s,1H),3.76-3.67(m,3H),3.65-3.54(m,5H),3.46(s,5H),3.38(d,J=5.7Hz,4H),3.17(s,3H),3.14-3.09(m,2H),2.69(s,1H),2.37(t,J=6.4Hz,2H),2.18-2.08(m,1H),1.85(dq,J=14.0,7.3Hz,3H),1.66(s,1H),1.53(d,J=9.2Hz,2H),1.36-1.21(m,2H),0.88(t,J=7.3Hz,3H);LCMS:[M+1]+1462.88(理论值1462.62)。
(4)PEG2-GK(Trt)-PAB-2505的合成
将Fmoc-PEG2-GK(Trt)-PAB-2505(5.0g,3.36mmol)溶于DCM(30mL)中加入DBU(512.02mg,3.36mmol,502.97μL),室温搅拌1h,将反应液加入到300ml的甲基叔丁基醚中有固体析出,过滤得到固体产物用DCM 50ml复溶,再加入到500ml甲基叔丁基醚中有固体析出,过滤,干燥得到PEG2-GK(Trt)-PAB-2505(4.5g,2.54mmol,产率75.45%,HPLC 93%);LCMS:[M+1]+1240.90(理论值1240.55)。
(5)C2的合成
将PEG2-GK-PAB-2505(100mg,80.56μmol)溶于DCM(2mL)中,加入2-[4,5-双(溴甲基)***-1-基]乙酸(25.21mg,80.56μmol)和DIC(12.20mg,96.67μmol,14.97μL),室温搅拌1h,检测反应完毕(LCMS:[M+2]+1535.82;理论值1533.43),加入TFA(447.00mg,3.92mmol,0.3mL),室温搅拌2h,浓缩,用2mL DMF溶解溶清,用C18 Spherical 20-35um 100A 40g反相柱层析进行纯化,流动相使用乙腈(HPLC级别)和0.1%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214n波长监测),冻干后得到黄色固体粉末产物C2(58mg,产率51.7%,HPLC 93%);1H NMR(600MHz,DMSO-d6)δ10.07(s,1H),8.20(d,J=7.6Hz,2H),7.85-7.61(m,9H),7.51(s,1H),7.24(s,1H),6.29(s,2H),5.43(s,2H),5.27(dd,J=12.2,7.8Hz,3H),5.14(s,3H),4.94(s,1H),4.84(s,1H),4.61(s,1H),4.60-4.56(m,2H),3.77(d,J=5.1Hz,2H),3.57(ddd,J=31.8,23.9,8.3Hz,12H),2.99-2.92(m,2H),2.81-2.73(m,2H),2.41(s,2H),1.86(dq,J=13.6,7.2Hz,3H),1.54(d,J=7.8Hz,2H),0.88(t,J=7.2Hz,3H);LCMS:[M+2]+1293.61(理论值1291.32)。
实施例13:4,5-二溴甲基三氮唑-1-乙酰胺乙氧基乙氧基丙酰-Gly-Val-Ala-ha-氨(甲基)氧乙酰依喜替康(C3)的合成
(1)C3-1的合成
将依喜替康甲磺酸盐(0.26g,0.5mmol),加入2mL DMF,HATU(0.19g,0.5mmol),DIPEA(0.129g.1mmol)和邻苯二甲酰-Ala-ha-胺(N-甲基)氧乙酸(200mg,0.59mmol),室温反应15h,加入200mL DCM稀释,饱和氯化钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化得黄色固体C3-1(0.3mg,产率81%,HPLC纯度92%);LCMS:[M+1]+753.12(计算值:752.26)。
(2)C3-2的合成
将C3-1(0.1g,0.13mmol)溶解在5ml MeOH中,加入水合肼(39.9mg,0.79mmol),封管、升温至60℃反应2h,降温,反应液倒入100ml饱和食盐水中,用200ml乙酸乙酯萃取,浓缩拿到产品粗品C3-2(0.07g,产率77%,HPLC纯度86%);LCMS:[M+1]+623.15(计算值:622.26)。
(3)C3-3的合成
将C3-2(70mg,0.112mmol)溶于2ml DMF中,加入DIPEA(29mg,0.224mmol)搅拌溶清,依次加入Fmoc-PEG2-Gly-Val(62.16mg,0.112mmol),HATU(42.56mg,0.112mmol),室温搅拌反应1h,反应液直接浓缩并加入硅胶,过硅胶柱层析纯化得到化合物C3-3(81mg,产率62%,HPLC纯度93%);LCMS:[M+1]+1160.24(计算值:1159.50)。
(4)C3-4的合成
在10ml的单口瓶中,加入C3-3(81mg,0.069mmol),用1ml的DMF溶解,然后加入100ul的哌啶,室温下反应1h反应完,将反应液滴加入20ml甲基叔丁基醚中,离心,去除上清液,干燥后得到C3-4(32mg,产率49%,HPLC纯度95%);LCMS:[M+1]+938.02(计算值:937.43)。
(5)C3的合成
将2-(4,5-二溴甲基-1-H-1,2,3-三氮唑-1-基)乙酸(129.7mg,0.416mmol)和DIC(52.4mg,0.416mmol)加入反应瓶中,用DCM(2.5mL)溶解,室温下搅拌5min后将混合液加入至溶有C3-4(300mg,0.320mmol)的DCM/DMF(2.5mL/1.0mL)的混合溶液中,室温25℃反应1小时,将反应液滴加至50mL叔丁基甲基醚中,析出白色固体,将固体用DMF(2mL)溶解,然后通过中压反相C18色谱法(梯度:乙腈/0.1%TFA水溶液,0%至55%,时间100min)洗脱,冻干,得到黄色固体C3(151.0mg,产率38.3%,HPLC 97%);1H NMR(500MHz,DMSO-d6)δ8.60-8.47(m,1H),8.47-8.35(m,11H),8.33-8.20(m,1H),8.17-8.05(m,1H),8.05-7.92(m,1H),7.85-7.70(m,2H),7.30(s,1H),5.65-5.55(m,1H),5.42(s,2H),5.05-5.32(m,4H),4.62-4.42(m,6H),4.33-4.24(m,1H),4.24-4.01(m,5H),3.80-3.65(m,2H),3.64-3.54(m,2H),3.54-3.38(m,6H),3.32-3.04(m,4H),2.47(s,2H),2.42-2.30(m,5H),2.24-2.10(m,2H),1.92-1.76(m,3H),1.28-1.18(m,1H),1.17-1.08(m,2H),0.92-0.76(m,5H),0.76-0.62(m,4H);LC-MS:[M+H]+1232.54(理论值1232.31)。
实施例14:2,3-二溴甲基喹喔啉-6-甲酰胺乙氧基乙氧基丙酰-Gly-Lys-PAB-MMAE(C4)的合成
(1)C4-01的合成
在室温下,向反应瓶中依次加入2,3-双(溴甲基)喹喔啉-6-羧酸(148.57mg,412.70μmol),DCC(42.58mg,206.35μmol),DCM(5mL),室温继续搅拌反应1hr,过滤,转移到100ml的反应瓶中,依次加入PEG-GK(Trt)-PAB-MMAE(300mg,206.35μmol),DMF(3mL)和DIPEA(26.67mg,206.35μmol,35.94μL),室温下搅拌反应1hr,加入5g硅胶粉制砂,使用DCM和MeOH进行柱层析纯化得到淡黄色固体C4-01(177mg,产率38.21%,HPLC 94%);LCMS:[M+1]+1796.52(计算值:1795.87)。
(2)C4的合成
室温下,向反应瓶中依次加入C4-1(177mg,98.56μmol),DCM(5mL),TFA(745.00mg,6.53mmol,500μL),室温搅拌反应1hr,浓缩,用3mL DMF溶解溶清,用C18反相柱层析纯化,流动相使用乙腈(HPLC级别)和0.1%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214n波长监测),冻干后得到白色固体粉末C4(29mg,17.92μmol,产率18.18%,HPLC96%);1H NMR(600MHz,DMSO-d6)δ9.99(s,1H),8.95(q,J=9.5,7.5Hz,1H),8.64-8.56(m,1H),8.29(dt,J=10.1,7.3Hz,1H),8.19-8.15(m,1H),8.13(d,J=8.1Hz,1H),8.07(d,J=7.8Hz,1H),7.89(d,J=8.7Hz,0H),7.61(qd,J=9.2,6.3,4.9Hz,5H),7.35-7.23(m,4H),7.16(s,1H),5.95(dd,J=14.0,5.1Hz,1H),5.41(s,0H),5.05(dd,J=13.3,3.6Hz,3H),4.73(s,0H),4.48(d,J=5.8Hz,1H),4.41(d,J=11.3Hz,2H),4.26(dd,J=19.2,10.8Hz,1H),3.99(s,1H),3.80-3.69(m,2H),3.64-3.53(m,5H),3.53-3.45(m,4H),3.26-3.19(m,5H),3.17(s,1H),3.11(s,2H),3.07-3.02(m,0H),2.97(s,1H),2.90-2.80(m,3H),2.77(q,J=6.8Hz,2H),2.44-2.36(m,2H),2.26(dd,J=16.0,9.5Hz,1H),2.11(s,1H),1.99(dq,J=21.7,8.3,7.8Hz,1H),1.81(s,1H),1.74(s,3H),1.53(q,J=8.4,8.0Hz,2H),1.49(s,3H),1.36(d,J=8.5Hz,1H),1.30(s,3H),1.24(s,1H),1.06-0.96(m,5H),0.85(tt,J=12.9,6.3Hz,5H),0.79(s,11H),0.76(dt,J=11.7,7.3Hz,3H);LCMS:[M+1]+1554.32(计算值:1553.54)。
实施例15:2,3-二溴甲基喹喔啉-6-甲酰胺乙氧基乙氧基丙酰-Gly-Lys-PAB-(10,11-亚甲基二氧喜树碱-7-乙基)-(N-(S)-四氢呋喃-3-)胺(C5)的合成
室温25℃条件下,取25ml单口瓶,依次加入DCM(2mL)、2,3-双(溴甲基)喹喔啉-6-羧酸(1.12g,3.10mmol),DCC(320mg,1.55mmol),室温搅拌反应6h,过滤,旋干,得到2,3-双(溴甲基)喹喔啉-6-羧酸酐直接用于下一步反应。
称取PEG2-GK(Trt)-PAB-2505(260mg,209.44μmol)溶于DCM(5mL)中,加入2,3-双(溴甲基)喹喔啉-6-羧酸酐(147.03mg,209.44μmol),室温搅拌1h(LCMS:[M+2]+1582.26(理论值1580.43),加入TFA(745.00mg,6.53mmol,0.5mL),室温搅拌2h,将反应液浓缩,用2mLDMF溶解溶清,使用C18 Spherical 20-35um 100A80g反相柱层析进行纯化,流动相使用乙腈(HPLC级别)和0.1%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214n波长监测),冻干,得到黄色固体粉末产物C5(38mg,26.88μmol,产率12.83%,HPLC 94%);1HNMR(500MHz,DMSO-d6)δ8.14(dd,J=23.0,15.1Hz,3H),7.64(d,J=8.1Hz,6H),7.41(s,2H),5.95(d,J=13.0Hz,1H),5.43(s,2H),5.27(s,2H),5.13(s,2H),4.41(s,1H),3.82(d,J=71.8Hz,7H),3.61-3.23(m,21H),2.77(d,J=6.0Hz,2H),2.39(s,2H),2.14(d,J=8.0Hz,1H),1.92-1.69(m,4H),1.68-1.47(m,4H),0.87(t,J=7.3Hz,3H);LCMS:[M+2]+1340.51(理论值1338.32)。
实施例16:2,3-二溴甲基喹喔啉-6-甲酰胺乙氧基乙氧基丙酰-Gly-Val-Ala-ha-氨(甲基)氧乙酰依喜替康(C6)的合成
在室温下,向反应瓶中依次加入DMF(5mL),C6-1(0.94g,1mmol)和2,3-双(溴甲基)喹喔啉-6-羧酸酐(0.7g,1mmol),室温搅拌反应0.5h,反应液进行反向制备,用C18Spherical 20-35um 100A 80g反相柱层析进行纯化,流动相使用乙腈(HPLC级别)和0.05%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214nm波长监测),冻干,得到黄固体粉末C6(456mg,0.36mmol,产率35%,HPLC 97%);1H NMR(500MHz,DMSO-d6)δ8.95(dt,J=10.0,5.4Hz,1H),8.71-8.49(m,2H),8.38-8.21(m,1H),8.25(s,1H),8.12(dt,J=8.3,4.5Hz,1H),7.98(d,J=7.2Hz,1H),7.72(dd,J=9.7,6.7Hz,2H),7.29(d,J=3.8Hz,1H),5.59(p,J=7.6,6.0Hz,1H),5.41(s,2H),5.30-5.20(m,1H),5.15-5.06(m,1H),4.80(s,8H),4.28(dd,J=13.2,6.6Hz,1H),4.24-4.11(m,2H),4.10(s,3H),4.08-3.94(m,1H),3.77-3.66(m,2H),3.69-3.59(m,1H),3.59(s,1H),3.59-3.51(m,6H),3.48(dt,J=11.5,5.3Hz,4H),3.11(d,J=17.2Hz,1H),2.92(d,J=8.3Hz,1H),2.47(s,3H),2.36(s,4H),2.34(d,J=6.3Hz,1H),2.18(p,J=6.6,5.6Hz,2H),2.07(s,1H),1.98(s,1H),1.93-1.76(m,4H),1.25-1.11(m,4H),0.91-0.78(m,4H),0.70(dd,J=12.8,6.8Hz,5H);LCMS:[M+2]+1280.01(理论值:1277.32)。
实施例17:2,6-二溴甲基吡啶-4-氧乙酰胺乙氧基乙氧基丙酰-Gly-Lys-PAB-MMAE(C7)的合成
(1)C7-1的合成
室温25℃下,取100ml单口瓶,依次加入PEG-GK(Trt)-PAB-MMAE(150mg,103.17μmol),CL-06(69.95mg,206.35μmol),DIC(13.02mg,103.17μmol,15.98μL),室温下继续搅拌反应1h,加入10g硅胶粉制砂,用DCM和MeOH进行柱层析纯化,得到棕色固体产品C7-1(130mg,产率70.99%);LCMS:[M+1]+1775.69(计算值:1774.84)。
(2)C7的合成
室温25℃下,取100ml单口瓶,依次加入C7-1(130mg,73.25μmol),DCM(5mL),TFA(83.52mg,732.47μmol,56.05μL),室温下搅拌反应1hr,用C18 Spherical 20-35um 100A120g反向柱进行纯化,流动相使用乙腈和0.1%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214n波长监测),收集产品,冻干得到白色固体产品C7(54mg,产率46.66%,HPLC 97%);1H NMR(600MHz,DMSO-d6)δ10.02-9.97(m,1H),8.25-8.12(m,3H),8.10-8.04(m,1H),7.61(dd,J=18.2,10.4Hz,7H),7.37-7.23(m,7H),7.17(td,J=11.7,10.4,4.2Hz,1H),7.08(s,1H),5.35(s,1H),5.04(d,J=13.3Hz,2H),4.61(d,J=10.3Hz,5H),4.49(d,J=6.2Hz,1H),4.41(dt,J=8.6,4.5Hz,2H),4.26(dd,J=18.8,10.7Hz,1H),4.03-3.93(m,2H),3.81-3.70(m,3H),3.61(t,J=6.5Hz,3H),3.48(s,5H),3.43(t,J=5.9Hz,2H),3.30-3.16(m,9H),3.12(s,2H),2.97(s,2H),2.86(dd,J=22.4,13.4Hz,3H),2.77(h,J=6.5Hz,3H),2.40(q,J=8.4,6.4Hz,4H),2.26(t,J=13.0Hz,1H),2.12(d,J=6.8Hz,2H),1.78-1.75(m,3H),1.75-1.70(m,2H),1.54(p,J=7.2Hz,4H),1.36(d,J=7.0Hz,1H),1.33-1.29(m,3H),1.06-0.96(m,7H),0.95-0.72(m,14H);LCMS:[M+1]+1533.38(计算值:1532.52)。
实施例18:2,6-二溴甲基吡啶-4-氧乙酰胺乙氧基乙氧基丙酰-Gly-Val-Ala-ha-氨(甲基)氧乙酰依喜替康(C8)的合成
在25℃下,在10ml单口茄型瓶中依次加入C6-1(100mg,106.61μmol),DCM(2mL),CL-06(36.14mg,106.61μmol),室温下搅拌反应1h,浓缩反应液,用3mL DMF溶解溶清,进行反向制备,用C18 Spherical 20-35um 100A40g反向柱进行纯化,流动相使用乙腈(HPLC级别)和0.1%TFA水溶液分别作为B2和A2流动相,HPLC制备方法(254nm和214n波长监测),收集产品,使用HPLC(220nm)和LCMS检测产品纯度,冻干得到黄色固体粉末C8(31mg,23.64μmol,产率22.17%,HPLC 96%);1H NMR(600MHz,DMSO-d6)δ8.51(d,J=8.9Hz,1H),8.23(dt,J=11.3,6.0Hz,2H),8.11(t,J=5.7Hz,1H),7.99(d,J=7.1Hz,1H),7.81-7.73(m,2H),7.31(s,1H),7.09(s,1H),5.61(dt,J=8.9,6.0Hz,1H),5.42(s,2H),5.32-5.08(m,2H),4.61(d,J=11.3Hz,5H),4.29(dd,J=13.2,6.7Hz,1H),4.22-4.11(m,3H),4.07(dd,J=11.6,5.3Hz,2H),3.72(td,J=16.2,5.6Hz,2H),3.58(t,J=6.5Hz,2H),3.48(qd,J=5.0,2.5Hz,4H),3.43(t,J=6.0Hz,2H),3.27(q,J=5.9Hz,2H),3.23-2.98(m,1H),2.47(s,3H),2.41-2.33(m,5H),2.19(q,J=6.4Hz,2H),1.93-1.79(m,3H),1.16-1.09(m,3H),0.87(t,J=7.3Hz,3H),0.71(dd,J=15.6,6.7Hz,5H).LCMS:[M+1]+1260.30(计算值:1258.99)。
实施例19:C1和HS627抗体的偶联及其双药ADC的制备
(1)HS627-(C1)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl(三(2-羧乙基)膦盐酸盐)溶液(2.86mg/ml,0.133ml)在0℃反应3h,向上述溶液体系加入溶解在DMA(N,N-二甲基乙酰胺)的C1化合物(10mg/ml,0.2ml),混匀,25℃反应4h。反应完毕,加入NAC(N-乙酰-L-半胱氨酸)溶液(10mg/ml,0.11ml)淬灭,通过超滤膜包去除小分子,得到HS627-(C1)n抗体偶联物。
UV-HPLC计算DAR值:n=2.1
(2)HS627-(C1)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的化合物C1(10mg/ml,0.3ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C1)n偶联物。
UV-HPLC计算DAR值:n=3.9
(3)(C6)4-HS627-(C1)2双药偶联物的制备
(3.1)C6的制备
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在10ml的单口瓶中,依次加入DCM(3mL),C3-4(32mg,0.034mmol),溴乙酸(9.5mg,0.068mmol)和DIC(8.6mg,0.068mmol),室温搅拌反应90min,浓缩,过硅胶柱(DCM:MeOH=95:5),得到淡黄色固体产物C6化合物(22mg,收率61%,HPLC 96%);1H NMR(500MHz,DMSO-d6)δ8.49(d,J=8.9Hz,1H),8.33(t,J=5.7Hz,1H),8.24(t,J=6.2Hz,1H),8.11(t,J=5.8Hz,1H),7.98(d,J=7.1Hz,1H),7.75(d,J=8.5Hz,1H),7.70(d,J=10.8Hz,1H),7.28(s,1H),5.64-5.54(m,1H),5.40(s,2H),5.23(d,J=18.9Hz,1H),5.04(d,J=18.9Hz,1H),4.33-3.97(m,6H),3.85(s,2H),3.70(qd,J=16.5,5.7Hz,3H),3.57(t,J=6.5Hz,4H),3.52-3.37(m,4H),3.26-3.17(m,4H),3.14-3.06(m,1H),2.47(s,3H),2.41-2.28(m,5H),2.24-2.11(m,J=6.9,6.0Hz,2H),1.84(dh,J=20.8,7.0Hz,3H),1.14(d,J=7.1Hz,3H),0.85(t,J=7.3Hz,3H),0.70(dd,J=11.4,6.8Hz,6H);LCMS:[M+1]+1058.24(计算值:1057.36)。
(3.2)(C6)4-HS627-(C1)2双药偶联物的制备
取上述HS627-(C1)2抗体偶联物(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,加入溶解在DMA的C6化合物(10mg/ml,0.15ml),混匀,25℃反应12h,加入NAC溶液(10mg/ml,0.08ml)淬灭,通过超滤膜包去除小分子,得到(C6)m-HS627-(C1)n偶联物。
UV-HPLC计算DAR值:m+n=5.9
实施例20:C2和HS627抗体的偶联及其双药ADC的制备
(1)HS627-(C2)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.133ml)在0℃反应3h,加入溶解在DMA的C2(10mg/ml,0.17ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C2)n偶联物。
UV-HPLC计算DAR值:n=1.9
(2)HS627-(C2)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C2(10mg/ml,0.26ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C2)n偶联物。
UV-HPLC计算DAR值:n=3.8
(3)(C0)4-HS627-(C2)2双药偶联物的制备
取上述HS627-(C2)2(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C0(mc-VC-PABC-MMAE)化合物(10mg/ml,0.18ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.08ml)淬灭,超滤膜包去除小分子,得到(C0)m-HS627-(C2)n偶联物。
其中,mc-VC-PABC-MMAE为单甲基奥瑞他汀E,其结构式如下:
UV-HPLC计算DAR值:m+n=5.7
实施例21:C3和HS627的抗体偶联及其双药ADC的制备
(1)HS627-(C3)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.133ml)在0℃反应3h,向上述溶液体系加入溶解在DMA的C3(10mg/ml,0.16ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C3)n偶联物。
UV-HPLC计算DAR值:n=2.1
(2)HS627-(C3)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C3(10mg/ml,0.25ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C3)n偶联物。
UV-HPLC计算DAR值:n=3.8
(3)(C0)4-HS627-(C3)2双药偶联物的制备
取上述HS627-(C3)2偶联物(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C0化合物(10mg/ml,0.18ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.08ml)淬灭,超滤膜包去除小分子,得到(C0)m-HS627-(C3)n偶联物产品。
UV-HPLC计算DAR值:m+n=5.8
实施例22:C4和HS627的抗体偶联及其双药ADC的制备
(1)HS627-(C4)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.133ml)在0℃反应3h,向上述溶液体系加入溶解在DMA的C4化合物(10mg/ml,0.2ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C4)n产品。
UV-HPLC计算DAR值:n=1.9
(2)HS627-(C4)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C4(10mg/ml,0.32ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C4)n偶联物。
UV-HPLC计算DAR值:n=3.7
(3)(C6)4-HS627-(C4)2双药偶联物的制备
取上述HS627-(C4)2(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,加入溶解在DMA的C6化合物(10mg/ml,0.15ml),混匀,25℃反应12h,加入NAC溶液(10mg/ml,0.08ml)淬灭,超滤膜包去除小分子,得到(C6)m-HS627-(C4)n偶联物。
UV-HPLC计算DAR值:m+n=5.7
实施例23:C5和HS627抗体的偶联及其双药ADC的制备
(1)HS627-(C5)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.133ml)在0℃反应3h,向上述溶液体系加入溶解在DMA的C5(10mg/ml,0.17ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C5)n偶联物。
UV-HPLC计算DAR值:n=2.0
(3)HS627-(C5)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA)的C5(10mg/ml,0.28ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C5)n偶联物。
UV-HPLC计算ADR值:n=3.9
(4)(C0)4-HS627-(C5)2双药偶联物的制备
取上述HS627-(C5)2(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,加入溶解在DMA的C0化合物(10mg/ml,0.18ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.08ml)淬灭,超滤膜包去除小分子,得到(C0)m-HS627-(C5)n偶联物。
UV-HPLC计算DAR值:m+n=5.8
实施例24:C6和HS627抗体的偶联及其双药ADC的制备
(1)HS627-(C6)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.133ml)在0℃反应3h,向上述溶液体系加入溶解在DMA的C6(10mg/ml,0.16ml),混匀,25℃反应4h,加入NAC水溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,终得到HS627-(C6)n偶联物。
UV-HPLC计算DAR值:n=1.9
(2)HS627-(C6)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C6(10mg/ml,0.27ml),混匀,25℃反应4h,加入NAC水溶液(10mg/ml,0.11ml)淬灭,超滤膜包去除小分子,得到HS627-(C6)n偶联物。
UV-HPLC计算DAR值:n=3.8
(3)(C0)4-HS627-(C6)2双药偶联物的制备
取以上HS627-(C6)2(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C0化合物(10mg/ml,0.18ml),混匀,25℃反应4h,加入NAC溶液(10mg/ml,0.08ml)淬灭,超滤膜包去除小分子,得到(C0)m-HS627-(C6)n偶联物。
UV-HPLC计算DAR值:m+n=5.9
实施例25:C7和HS627的抗体偶联及其双药ADC的制备
(1)HS627-(C7)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.133ml)在10℃反应3h,向上述溶液体系加入溶解在DMA的C7(10mg/ml,0.20ml),混匀,25℃反应4h。反应完毕,加入NAC溶液(10mg/ml,0.11ml)淬灭,再通过超滤膜包去除小分子,最到HS627-(C7)n偶联物:
UV-HPLC计算平均DAR值:n=2.0。
(2)HS627-(C7)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C7化合物(10mg/ml,0.33ml),混匀,25℃反应4h。反应完毕,加入NAC溶液(10mg/ml,0.11ml)淬灭,再通过超滤膜包去除小分子,最终得到HS627-(C7)n偶联物产品:
UV-HPLC计算平均DAR值:n=4.1
(3)(C6)4-HS627-(C7)2偶联药物的制备
取上述HS627-(C7)2抗体偶联物(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,加入溶解在DMA的C6化合物(10mg/ml,0.15ml),混匀,25℃反应12h,加入NAC溶液(10mg/ml,0.08ml)淬灭,通过超滤膜包去除小分子,得到DAR(2+4)产品(C6)m-HS627-(C7)n偶联物:
UV-HPLC计算平均DAR值:m+n=5.9
实施例26:C8和HS627的抗体偶联及其双药ADC的制备
(1)HS627-(C8)2偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.133ml)在10℃反应3h,向上述溶液体系加入溶解在DMA的C8(10mg/ml,0.16ml),混匀,25℃反应4h。反应完毕,加入NAC溶液(10mg/ml,0.11ml)淬灭,再通过超滤膜包去除小分子,最终得到HS627-(C8)n的抗体偶联物产品:
UV-HPLC计算平均DAR值:n=1.9
(2)HS627-(C8)4偶联药物的制备
取HS627抗体(10mg/ml,5ml),加入TCEP.HCl溶液(2.86mg/ml,0.2ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C8(10mg/ml,0.27ml),混匀,25℃反应4h。反应完毕,加入NAC溶液(10mg/ml,0.11ml)淬灭,再通过超滤膜包去除小分子,最终得到HS627-(C8)n的抗体偶联药物:
UV-HPLC计算平均DAR值:n=4.1
(3)(C0)4-HS627-(C8)2偶联药物的制备
取以上偶联的HS627-(C8)2(10mg/ml,2ml),加入TCEP.HCl溶液(2.86mg/ml,0.08ml)在25℃反应4h,向上述溶液体系加入溶解在DMA的C0(MC-VC-PAB-MMAE)化合物(10mg/ml,0.18ml),混匀,25℃反应4h。反应完毕,加入NAC溶液(10mg/ml,0.08ml)淬灭,再通过超滤膜包去除小分子,最终得到(C0)m-HS627-(C8)n抗体偶联药物:
UV-HPLC计算平均DAR值:m+n=6.1
效果实施例1:ADC的DAR值
实施例制备得到的ADC测定得到的DAR值见下表1。
表1本发明实施例涉及的ADC化合物DAR测定结果
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效果实施例2:ADC体内抑制肿瘤生长活性
ADC体外抑制活性测试方法:
人胰腺癌Her2低表达CFPAC-1细胞和乳腺癌MCE-7细胞于体外单层培养,细胞饱和度为80%-90%时,用胰酶-EDTA消化,离心弃上清,PBS重悬细胞,将细胞悬液调整至合适浓度,将细胞(2-10×106cells/0.1ml)皮下接种BALB/c裸小鼠,定期观察动物及移植瘤生长情况,待瘤体积长到100-200mm3左右,根据瘤体积和体重进行随机分组,即溶媒对照组(或Vehicle组,注射生理盐水)和ADC给药组(溶于生理盐水),每组6只动物。静脉注射给药,给药频率为Q7D,共给药2次(第一次给药的时间记为Day 1,Day 7第二次给药,给药量2mg/kg或5mg/kg),每周2次用游标卡尺测量肿瘤长径a(mm)、短径b(mm)和小鼠体重,根据以下公式计算肿瘤体积(tumor volume,V):V=1/2×a×b2(mm3),其中a和b分别表示肿瘤长和宽,并绘制生长曲线,最后剥取肿瘤并称重。统计分析基于试验结束时肿瘤体积和荷瘤鼠体重的数据运用GraphPad Prism软件进行分析得到抑瘤结果(图1、2、3、4),以HS627-Dxd为对照,其结构式如下:
n=8;主要评价指标:
肿瘤生长抑制率(tumor growth inhibition,TGI):
TGI(%)=[1-(avTi-0/avCi-0)]×100%;其中avTi-0是给药组在特定天的平均肿瘤体积,减去该给药组在开始给药当天的平均肿瘤体积;其中avCi-0是溶媒对照组在特定天的平均肿瘤体积,减去溶媒对照组在开始给药当天的平均肿瘤体积。
表1分组及给药设置
肿瘤抑制率:CFPAC-1模型基于day42的肿瘤体积进行计算;MCF-7基于day35的肿瘤体积进行计算。
从结果可见,本发明示例性ADC化合物Entry2(DAR2)、Entry5(DAR4)、Entry8(DAR4)、Entry17(DAR4)、Entry18(DAR2+4)、Entry24(DAR2+4)在胰腺癌和乳腺癌肿瘤模型中均显示出较佳的肿瘤抑制效果。
Claims (10)
1.式(I)所示的化合物或其药学上可接受的盐、立体异构体或前药:
M-L-D (I)
其中,
M是与抗体或其抗原结合片段连接的双功能接头;
L是双功能接头M和D之间的连接子;
D是细胞毒性药物部分;
所述M表示以下式(II)所示的结构:
式(II)中的A选自烯基、单环基团或稠环基团,所述单环基团为芳基、杂芳基,所述稠环基团为杂芳基与选自芳基、杂芳基中的一种稠合而成,R1表示单键、O、N、S或亚烷基;
所述A任选地被一个或多个选自X的取代基取代,X选自卤素、卤素取代或未取代的烷基、-NH-S(O)2-烯基或-C1-C6杂烷基-杂环烷基;所述杂环烷基任选地被一个或多个卤素取代的烷基或-C(O)-卤素取代的烷基取代;
式(II)中,m1、m2各自独立地选自0至10的整数;
优选地,A选自C2-C6烯基、单环基团或稠环基团,所述单环基团为6至12元芳基或5至12元杂芳基,所述5至12元杂芳基含有1-3个氮原子;所述稠环基团为5至12元杂芳基与选自6至12元芳基、5至12元杂芳基中的一种稠合而成的环,所述5至12元杂芳基含有1-3个氮原子作为环原子;
优选地,A选自单环基团或稠环基团,所述单环基团为6元芳香环、5元杂芳环或6元杂芳环,所述稠环基团为6元杂芳基与6元芳基稠合而成,所述5元杂芳基或6元杂芳基含有1-3个氮原子;
优选地,A选自乙烯基、
优选地,X表示卤素、卤素取代的C1-C6烷基、-NH-S(O)2-C2-C6烯基或-C1-C6杂烷基-3至8元杂环烷基;所述3至8元杂环烷基任选地被一个或多个卤素取代的C1-C6烷基或-C(O)-卤素取代的C1-C6烷基取代;
优选地,M选自
优选地,L选自由以下一个或多个组成的二价结构:Val-Cit、Val-Ala、Val-Lys、Val-Lys(Ac)、Phe-Lys、Phe-Lys(Ac)、Gly-Lys、Gly-Phe、Gly-Leu、Gly-Gly-Lys、Gly-Val-Ala、Gly-Val-Cit、Gly-Phe-Gly、Val-Ala-Gly、D-Val-Leu-Lys、Gly-Gly-Arg、Ala-Ala-Asn、Ala-Ala-Ala、Val-Lys-Ala、Gly-Gly-Gly、Gly-Leu-Gly、Gly-Gly-Phe-Gly、Gly-Gly-Leu-Gly、Gly-Val-Ala-Gly、Gly-Val-Cit-Gly、Gly-Gly-Gly-Gly-Gly;
优选地,L选自Val-Cit、Val-Ala、Gly-Gly-Lys、Gly-Phe-Gly、Gly-Lys、Gly-Phe、Gly-Leu、Val-Ala-Gly、Gly-Gly-Phe-Gly、Gly-Val-Ala-Gly、Ala-Ala-Asn、Gly-Leu-Gly;
优选地,L选自Gly-Lys、Gly-Val-Ala。
2.根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体或前药,其中,D为选自抗微管蛋白剂、DNA嵌入剂、DNA拓扑异构酶抑制剂、DNA合成抑制剂、RNA聚合酶抑制剂、Splicesome抑制剂中的至少一种,优选地为喜树碱或喜树碱衍生物、吡咯并苯并二氮杂卓(PBD)二聚体、甲基奥瑞他汀E、甲基奥瑞他汀F。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体或前药,其中,所述L直接和D连接,或者,
在所述L和所述D之间连接有间隔单元E,所述间隔单元E选自对氨基苄基碳酸酯酰胺、对氨基苄基碳酸二酯、氨甲基醚和亚甲基二胺。
4.根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐、立体异构体或前药,其中,所述M直接和L连接,或者,
在所述M和所述L之间连接有间隔单元F,所述间隔单元F选自-NH-(CH2CH2-O)q-CH2CH2-C(=O)-,其中,q表示1~6的整数。
5.根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐、立体异构体或前药,其中,所述化合物选自下组:
其中,L、D定义同前;
RX1、RX2各自独立地选自卤素或C2-C6烯基;
优选地,RX1选自溴或氯,RX2为乙烯基;
优选地,所述化合物选自下组:
6.式(III)所示的药物-抗体偶联物或其药学上可接受的盐:
Ab-M-L-D (III)
其中,M、L、D各自定义同式(I)化合物;Ab为抗体或其抗原结合片段;
优选地,Ab抗体为肿瘤相关抗原抗体;
优选地,Ab为抗Her2抗体;
优选地,Ab为帕妥珠单抗;
优选地,所述药物-抗体偶联化合物上还连接有其它具有细胞毒性的药物;
优选地,所述药物-抗体偶联化合物具有式(IV)所示结构:
D’-L’-Ab-M-L-D (IV)
其中,所述L’是抗体和D’之间的连接子,其与L相同或不同;
D’是细胞毒性药物部分,其与D相同或不同;
优选地,式(III)所示的药物-抗体偶联物或其药学上可接受的盐为以下药物-抗体偶联化合物,
其中,L、D定义同式(I)化合物;Ab为抗体或其抗原结合片段;
n为选自1至12中的整数,优选为选自2至4的整数;优选地,所述抗体为单克隆抗体或多克隆抗体。
7.以下双功能接头化合物:
其中,RX1、RX2各自独立地选自卤素或C2-C6烯基;
优选地,RX1选自溴或氯,RX2为乙烯基。
8.一种权利要求6所述的式(III)所示的药物-抗体偶联化合物或其药学上可接受的盐的制备方法,其包括以下步骤:
将式(I)所示的化合物或其药学上可接受的盐、立体异构体或前药连接至所述抗体或其抗原结合片段。
9.药物组合物,其特征在于,包括权利要求1-6中任一项所述的化合物或其药学上可接受的盐、立体异构体或前药或权利要求6所述的抗体药物偶联物和药学上可接受的辅料。
10.权利要求1-5中任一项所述的化合物或其药学上可接受的盐、立体异构体或前药、权利要求6所述的抗体药物偶联物、权利要求7所述的双功能接头化合物、权利要求9所述的药物组合物在制备治疗癌症的药物中应用,
优选地,所述癌症包括胃癌、食管癌、贲门癌、乳腺癌、卵巢癌、结肠癌、直肠癌、原发性肝癌、胰腺癌、急性和慢性粒细胞性白血病、绒毛膜上皮癌、肺癌、膀胱癌、肠癌或小细胞肺癌;更优选地,所述癌症为食管癌、胰腺癌或胃癌,进一步优选地,所述癌症为胰腺癌。
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