CN117964682A - Dolastatin衍生物及其制备方法和应用 - Google Patents
Dolastatin衍生物及其制备方法和应用 Download PDFInfo
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- CN117964682A CN117964682A CN202410052116.3A CN202410052116A CN117964682A CN 117964682 A CN117964682 A CN 117964682A CN 202410052116 A CN202410052116 A CN 202410052116A CN 117964682 A CN117964682 A CN 117964682A
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- alkyl
- antibody
- hydrogen
- pharmaceutically acceptable
- compound
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- 238000002360 preparation method Methods 0.000 title abstract description 15
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical class CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 49
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- 210000004027 cell Anatomy 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
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- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 239000000427 antigen Substances 0.000 claims description 14
- 102000036639 antigens Human genes 0.000 claims description 14
- 108091007433 antigens Proteins 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
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- 101710043865 Nectin-4 Proteins 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 9
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- 238000000034 method Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
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- 125000006413 ring segment Chemical group 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
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- 238000004458 analytical method Methods 0.000 description 5
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 5
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Abstract
本说明书提供一种Dolastatin衍生物、或其药学上可接受的盐、立体异构体或前药,其制备方法和在制备抗肿瘤药物中的应用,所述Dolastatin衍生物如下式(I)所示,式中各基团定义详见说明书。所述Dolastatin衍生物具备较佳的抗肿瘤活性。
Description
技术领域
本发明涉及生物医药领域,具体涉及Dolastatin衍生物及其制备方法和应用。
背景技术
Dolastatin-10(多拉司他汀)是从海洋动物海兔分离出来的天然产物,由4个氨基酸组成的线性缩肽类天然细胞毒性蛋白,对细胞微管蛋白聚集具有极强的抑制活性,从而抑制细胞扩增和肿瘤的生长。
由于其天然来源非常有限,多种合成的dolastatin-10衍生物(又称为auristatins)已被广泛研究。其中微管蛋白相关抑制剂MMAE(monomethyl auristatin E)和MMAF(monomethyl auristatin F)合成的dolastatin-10衍生物被广泛用作ADC的payload,用于多种抗体偶联药物的研究与开发。
发明内容
本发明的目的在于提供一系列Dolastatin衍生物及其制备方法,以及在制备抗肿瘤药物(ADC)和抗体偶联药物中的应用。
具体而言,本发明对dolastatin结构的N-端或C-端进行优化,包括将dolastatin的N-端的N-甲基Valine进行二甲基化,替换,环化等修饰,或将dolastatin的C-端的苯乙基骨架进行修饰。这些化合物的特点是具有良好的抑制细胞微管蛋白聚集的活性,导致肿瘤细胞凋亡,因而可以用于抗体偶联药物的开发以及肿瘤的治疗。
研究表明dolastatin-10的N-端的N,N-二甲基缬氨酸可以被修饰或替换而不显著影响其活性。另外,C-端的苯乙基基团也可以进行修饰也不显著影响其生物活性。
本发明的一方面,提供式(I)化合物或其药学上可接受的盐、立体异构体或前药:
式中,M选自中的任意一种;
R1、R2各自独立地选自C1-C6烷基、卤素取代的C1-C6烷基或C3-C6环烷基中的任意一种;
R3选自氢、C1-C6烷基或C3-C6环烷基中的任意一种;
R4选自氢、C1-C6烷基、C3-C6环烷基、-C1-C6烷基-NR6-O-C1-C6烷基或-C1-C6烷基-O-NR6-C1-C6烷基中的任意一种:
R5选自氢、羟基、C3-C6环烷基或-O-NR6-C1-C6烷基中的任意一种;
R6选自氢或C1-C6烷基;
X选自卤素:
m1、m2各自独立地选自0、1或2。
在一实施方案中,R1、R2各自独立地选自氢、卤素取代或未取代的甲基、乙基、丙基、异丙基、丁基或异丁基;
在一实施方案中,R1、R2各自独立地选自氢、甲基、三氟甲基或三氟乙基。
在一实施方案中,R3选自氢、甲基、乙基、丙基、异丙基、丁基或异丁基。
在一实施方案中,选自/>
在一实施方案中,所述卤素选自-F、-Cl、-Br或-I。
在一实施方案中,m1、m2各自独立地选自1或2。
在一实施方案中,选自/>
在一实施方案中,R4选自C1-C6烷基、-C1-C6烷基-NH-O-C1-C6烷基或-C1-C6烷基-O-NH-C1-C6烷基。
在一实施方案中,R4选自甲基、-CH2-NH-O-CH3或-CH2-O-NH-CH3。
在一实施方案中,R5选自氢、羟基或-O-NH-C1-C6烷基。
在一实施方案中,R5选自氢、羟基或-O-NH-CH3。
本发明提供以下化合物或其药学上可接受的盐、立体异构体或前药:
本发明提供前述化合物的抗体偶联药物。
在一实施方案中,所述抗体偶联药物具有以下式(II)所示结构:
(D-L)n-Ab (II)
其中,D为前述化合物;
Ab为肿瘤相关抗原抗体;
L为用于连接D和Ab的连接子:
n=3-8;例如3.2、3.9、4.3或7.9。
在一实施方案中,所述连接子为亲水性连接子。
在一实施方案中,所述连接子选自以下结构:
其中,所示位置表示与抗体相连,/>所示位置表示与D相连;
在一实施方案中,所述抗体偶联物由以下化合物与抗体偶联得到:
本发明提供以下抗体偶联药物:
其中,n=3-8;例如3.2、3.9、4.3或7.9。
在一实施方案中,Ab为肿瘤相关抗原抗体或其抗原结合片段。
在一实施方案中,Ab为Nectin-4抗体或其抗原结合片段。
在一实施方案中,所述Nectin-4抗体包含如SEQ ID NO:1或其任何变体所示的抗体重链氨基酸序列,和如SEQ ID NO:2或其任何变体所示的抗体轻链氨基酸序列。
本发明提供一种药物组合物,其包括前述的化合物或其药学上可接受的盐、立体异构体或前药或前述抗体偶联药物和药学上可接受的辅料。
本发明提供前述化合物或其药学上可接受的盐、立体异构体或前药或前述抗体偶联药物或前述药物组合物在制备用于抑制肿瘤细胞生长药物中的应用。
在一实施方案中,所述肿瘤细胞包括食管癌细胞、乳腺癌细胞、胃癌细胞、肺癌细胞中的任意一种。
本发明的另一方面,提供一种治疗癌症的方法,其包括向有需要的患者施用治疗有效量的前述化合物或其药学上可接受的盐、立体异构体或前药或前述抗体偶联药物或前述药物组合物的步骤。
在一实施方案中,所述癌症为实体瘤。
在一实施方案中,所述癌症包括食管癌、乳腺癌、胃癌、肺癌中的任意一种。
附图说明
图1为抗体偶联药物ADC2的LCMS谱图;其中A和B为HPLC结果,C和D为MS结果。
图2为抗体偶联药物ADC4的LCMS谱图;其中A和B为HPLC结果,C和D为MS结果。
图3为抗体偶联药物ADC5的LCMS谱图;其中A和B为HPLC结果,C为MS结果。
图4为抗体偶联药物ADC6的LCMS谱图;其中A和B为HPLC结果,C为MS结果。
图5为测试例2中体内抑制NCI-H292模型肿瘤生长曲线图(3mg/kg)。
图6为测试例2中体内抑制NCI-H292模型肿瘤生长曲线图(10mg/kg)。
具体实施方式
I.定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文使用的和除非另作说明,术语“包含”,“包括”,“具有”,“含有”,包括其语法上的等同形式,通常应当理解为开放式且非限制性的,例如,不排除其他未列举的要素或步骤。
本发明化合物可以是不对称的,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。本发明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发明的范围之内。
本发明化合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。
如本文所用,“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。
如本文所用,“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。
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。
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,本发明优选甲基、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。
术语“杂环基”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。
本发明所述的氢原子均可被其同位素氘所取代。
“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。
是指化学键连接处。
药物或药物组合物
本发明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(如阿拉伯胶、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,卵磷脂或阿拉伯胶)、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化合物的本发明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。
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。
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。
术语“药物组合物”意指包含本发明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。
术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中,在根据本发明对患者进行治疗时,给定药物的量取决于诸多因素,如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重),但是,根据特定的周围情况,包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主,施用剂量可由本领域已知的方法常规决定。通常,就成人治疗使用的剂量而言,施用剂量典型地在0.02-5000mg/天,例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量,例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是,尽管给出了上述剂量范围,但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
术语“抗体药物偶联物(antibody-drug conjugate,ADC)”抗体药物偶联物是通过一个化学链接将具有生物活性的小分子药物(毒素)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“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。抗体是由免疫系统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。术语“抗体”是能够与特异性抗原结合的免疫球蛋白分子。包括两条分子量较轻的轻链和两条分子量较重的重链,重链(H链)和轻链(L链)由二硫键连接形成一个四肽链分子。
本申请使用的术语“毒素”也称为“细胞毒性药物部分”或“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。
如本文所用,术语“减少”、“抑制”、“减轻”或“减小”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。
术语“MMAE(monomethyl auristatin E)”指的是
术语“MMAF(monomethyl auristatin F)”指的是
术语“Dolastatin-10”指的是
II.具体实施例
为了使本发明的目的、技术方案和优点更加清楚,下面将对本发明作进一步地详细描述,所描述的实施例不应视为对本发明的限制,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
对本发明实施例进行进一步详细说明之前,对本发明实施例中涉及的名词和术语进行说明,本发明实施例中涉及的名词和术语适用于如下的解释。
本公开具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
DAR值测试与计算:基于RP-HPLC-MS测试结果,使用Waters Acquity UPLC I-Class/Xevo G2-XS QTOF仪器分析ADC的DAR值。
RP-HPLC参数设置:色谱柱PLRP-S1000A5UM,柱温为70℃。流动相A为0.1%甲酸水溶液,流动相B为0.1%甲酸乙腈溶液,流速为0.2ml/min。流动相梯度为20-50%B,18分钟;50-95%B,5分钟;95-20%B,0.1分钟;20-20%B,6.9分钟。
MS参数参设设置:毛细管电压2.50kV,锥孔电压100V,质量分析范围m/z 200至4000,MSE碰撞能量20至45eV,离子源温度120℃,雾化温度500℃,雾化流速1000L/Hr,内标为亮氨酸脑啡肽。供试品用样品缓冲液稀释到1mg/ml,加入终浓度为50mmol/L的TCEP,37℃孵育20min,进样5ul。识别轻链峰并计算峰面积百分比,峰面积总和为100。同样识别重链峰并计算峰面积百分比,峰面积总和为100。通过峰面积百分比与相应的药物负荷相乘分别计算重链和轻链的加权峰面积。DAR值计算公式为:DAR=2*(∑轻链加权峰面积+∑重链加权峰面积)/100。
本实施例中制备ADC使用但不限于Nectin-4抗体。
Nectin-4抗体重链重链氨基酸序列如下(SEQ ID NO:1):
Nectin-4抗体轻链氨基酸序列如下(SEQ ID NO:2):
实施例1:三氟乙基dolastatin衍生物(D1)
中间体D1-1的合成
在室温下,向1000mL单口瓶中依次加入tert-butyl(3R,4S)-3-methoxy-5-methyl-4-(methylamino)heptanoate(8.0g,30.84mmol),DCM(200mL),Fmoc-Val-OH(20.93g,61.68mmol),HATU(23.45g,61.68mmol),DIPEA(15.94g,123.37mmol,21.49mL),室温下搅拌反应2h,加入50g硅胶粉制砂,硅胶柱层析纯化,得到类白色固体D1-1(17.78g,产率94.30%,HPLC 95%);LCMS:[M+1]+ 581.23(计算值:580.77)。
D1-2的合成
室在温下,向1000ml单口茄型瓶中依次加入D1-1(17.78g,30.62mmol),DCM(200mL),TFA(174.54g,1.53mol,117.14mL),反应液在室温搅拌反应1h,浓缩,加入DCM(200mL),用水洗(100ml*6)洗去三氟乙酸,无水硫酸镁干燥,过滤,浓缩得到类白色固体D1-2(15.5g,产率92.64%,HPLC96%);LCMS:[M+1]+525.53(计算值:524.66)。
D1-4的合成
室温下,向1000mL反应瓶中依次加入D1-2(10g,19.06mmol),DCM(93.36mL),(2R,3R)-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-y1]propenamide(D1-3,Dap-NE)(6.11g,19.06mmol),HATU(10.87g,28.59mmol),DIPEA(7.39g,57.18mmol,9.96mL),反应混合液在室温搅拌反应1h,取加入50g硅胶粉制砂,使用DCM和MeOH进行柱层析,得到类白色固体D1-4(14.1g,产率85.87%,HPLC96%);LCMS:[M+1]+ 828.01(计算值:827.08)。
D1-5的合成
室温下,向100mL单口茄型瓶中依次加入D1-4(2.84g,3.43mmol),ACN(30mL),DBU(522.75mg,3.43mmol,513.50μL),混合物在室温搅拌反应2h,加入N-cbz-N-2,2,2-三氟乙基甘氨酸(1g,3.43mmol)和HATU(1.96g,5.15mmol)继续反应1.5h,浓缩,DCM萃取,饱和食盐水洗涤,无水硫酸镁干燥,过滤、浓缩,硅胶柱层析纯化,得到类白色固体D1-5(2.98g,产率94.89%,HPLC 96%);LCMS:[M+1]+879.03(计算值:878.04)。
D1的合成
室温下,向1000mL单口茄型瓶中依次加入D1-5(2.98g,3.39mmol),甲醇(30mL),Pd/C(10%on Carbon,wetted with ca.55%Water)(1.08g,10.18mmol),氢气置换三次,氢气氛围下室温搅拌反应1h,过滤,浓缩,得到类白色固体D1(2.42g,产率91.06%,HPLC95%);1H NMR(500MHz,DMSO-d6)δ7.98(dd,J=8.8,3.6Hz,1H),7.89(d,J=8.7Hz,1H),7.63(d,J=8.6Hz,0H),7.34-7.22(m,4H),7.22-7.15(m,1H),5.42(d,J=4.5Hz,1H),5.35(d,J=4.6Hz,0H),4.74(s,0H),4.67(dd,J=9.0,7.4Hz,1H),4.49(s,0H),4.43(s,0H),4.01(s,2H),3.60(s,0H),3.57(s,0H),3.46(s,1H),3.29-3.15(m,11H),3.12-3.01(m,2H),2.96(s,1H),2.95(dp,J=20.5,6.8Hz,1H),2.70(s,1H),2.41(d,J=15.9Hz,1H),2.28(dt,J=15.8,10.2Hz,1H),2.12(td,J=10.1,9.6,6.4Hz,1H),1.86-1.68(m,1H),1.57(dd,J=13.3,7.2Hz,1H),1.50(s,1H),1.30(s,1H),1.08-0.94(m,6H),0.96-0.73(m,12H);LCMS:[M+1]+744.25(计算值:743.91)。
实施例2:二氟脯氨酸dolastatin衍生物(D2)
D2-1的合成
向反应瓶中依次加入D1-4(3.29g,3.98mmol),ACN(30mL),DBU(605.97mg,3.98mmol,595.26μL),在室温搅拌反应0.5h,然后向反应瓶中加入(2S)-1-tert.butoxycarbonyl-4,4-difluoro-pyrrolidine-2-carboxylic acid(1g,3.98mmol)和HATU(1.51g,3.98mmol),继续反应1.5h,浓缩反应液,加入DCM(100mL),水洗(100ml*6),硅胶柱层析纯化,旋蒸浓缩后得到类白色固体D2-1(3.33g,产率94.84%,HPLC 95%);LCMS:[M+1]+839.04(计算值:838.05)。
D2的合成
向反应瓶中依次加入D2-1(3.33g,3.97mmol),DCM(15.10mL),TFA(22.65g,198.68mmol,15.20mL),在室温搅拌反应1h,将反应液浓缩,加入DCM(200mL),水洗(100ml*6),无水硫酸镁干燥,过滤,浓缩后得到类白色固体D2(2.35g,产率76.94%,HPLC 96%);1HNMR(500MHz,DMSO-d6)δ7.98(d,J=8.9Hz,1H),7.70(d,J=8.5Hz,1H),7.32-7.28(m,4H),7.19(d,J=3.1Hz,1H),3.26-3.16(m,15H),3.09(s,2H),2.96(d,J=7.1Hz,3H),2.69(s,3H),2.28(dtt,J=18.6,12.9,7.5Hz,3H),2.17-1.98(m,3H),1.61-1.45(m,2H),1.34-1.18(m,4H),1.05(dd,J=6.9,2.2Hz,4H),0.94-0.88(m,13H),0.79(d,J=7.5Hz,3H);LCMS:[M+1]+738.86(计算值:737.93)。
实施例3:N-三氟乙基溴瑞他汀E(D3)
向反应瓶中加入D1-4(600mg,0.726mmol),乙腈(10mL)和DBU(111.1mg,0.726mmol),室温下搅拌4小时,监测反应完全(LCMS/ESI(m/z):[M+H]+605.80(理论值604.83)。向反应液中依次加入HOBT(98.16mg,0.726mmol),ATU(276.05mg,0.726mmol),Fmoc-L-缬氨酸(246.47mg,0.726mmol),DIEA(112.82mg,0.871mmol)和DMF 5(mL),混合物在室温下搅拌4小时,加入硅胶拌样使用正相柱层析法纯化,用PE/EA=8/92洗脱,得到白色片状固体产物D3-1(150mg,两步合并产率22.3%);LCMS/ESI(m/z):[M+H]+927.40(理论值926.21)。
向反应瓶中加入D3-1(150mg,0.162mmol),乙腈(5mL),DBU(24.87mg,0.162mmol),在室温下搅拌4小时,LCMS监测反应完全(LCMS/ESI(m/z):[M+H]+705.40(理论值703.97)。向反应液中加入DMF(5mL),减压除去乙腈,加入2,2,2-三氟乙基三氟甲磺酸酯(150mg,0.648mmol),DIEA(105mg,0.81mmol),在室温下搅拌1小时,反应液直接由反相色谱纯化在ACN%=45-60%间得到固体产物D3,N-三氟乙基澳瑞他汀E(50mg,两步产率39.27%);LCMS/ESI(m/z):[M+H]+786.80(理论值785.99);1H NMR(500MHz,DMSO-d6)δ8.26(d,J=8.8Hz,1H),8.23(d,J=8.6Hz,1H),7.89(d,J=8.7Hz,1H),7.62(d,J=8.5Hz,1H),7.32-7.30(m,2H),7.28-7.25(m,2H),7.17(td,J=4.0,1.6Hz,1H),4.79-4.71(m,1H),4.61(t,J=8.8Hz,1H),4.54(t,J=8.8Hz,1H),4.49(d,J=5.9Hz,1H),4.44(d,J=6.6Hz,1H),4.02(ddd,J=13.3,7.6,4.1Hz,2H),3.78(dd,J=9.4,2.4Hz,1H),3.61-3.46(m,2H),3.26-3.18(m,9H),3.12(s,1H),2.98(s,1H),2.44-2.39(m,1H),2.30-2.25(m,1H),2.15-2.10(m,1H),2.05-1.99(m,1H),1.06-0.97(m,9H),0.87(ddd,J=13.9,6.8,2.6Hz,19H),0.76(dt,J=9.2,7.4Hz,5H).
实施例4:N-甲氧基胺dolastatin衍生物(D4)
D4-1的合成
将MMAF(3.0g,4.09mmol)溶解在DMF(2mL)中,依次加入甲醛(533.48mg,17.19mmol),醋酸(4.92g,81.86mmol)和NaBH3CN(514.15mg,8.19mmol),室温下搅拌2h,硅胶柱层析纯化,得到淡白色粉末状固体甲基MMAF D4-1(2.65g,产率86.6%);1H NMR(600MHz,DMSO-d6)δ9.64(s,1H),9.01(dd,J=8.5,4.1Hz,1H),8.57(d,J=8.7Hz,1H),7.27-7.15(m,5H),4.74(dd,J=11.0,4.6Hz,1H),4.65(t,J=8.5Hz,1H),4.58(t,J=8.5Hz,1H),4.33-4.24(m,1H),4.18(q,J=7.9Hz,1H),4.00(d,J=12.2Hz,2H),3.55(ddd,J=11.6,7.9,5.4Hz,3H),3.46(d,J=8.3Hz,5H),3.28-3.15(m,7H),3.10(s,2H),3.00(s,2H),2.87-2.73(m,7H),2.47(s,3H),2.34-2.21(m,2H),2.16-1.98(m,2H),1.90-1.65(m,3H),1.60-1.41(m,2H),1.36-1.26(m,2H),1.06(dd,J=17.8,6.7Hz,3H),1.01-0.83(m,16H),0.77(t,J=8.7Hz,3H);LCMS:[M+1]+745.85(计算值:745.50)。
D4-2的合成
在25mL的单口瓶中加入D4-1(600mg,803.22μmol))和N-methoxy-N-methanamine(86.18mg,883.54μmol)溶解在DMF(3mL)中,依次加入HATU(305.41mg,803.22μmol)和DIEA(103.81mg,803.22μmol,139.91μL),室温下搅拌2h,加水淬灭,分别加入二氯甲烷和饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩得到淡白色固体D4-2(432mg,产率68.08%);LCMS:[M+1]+ 791.37(计算值:788.54)。
D4-3的合成
在-78℃条件下,向25mL的单口瓶中加入D4-2(200mg,253.14μmol)溶解在THF(3mL)中,再加入DIBAL-H(1.0M in THF)(278μL,278.46μmol),在-78℃下搅拌2h,加入酒石酸钠钾淬灭,分别加入二氯甲烷和饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩得到淡黄色固体D4-3(150mg,产率72.14%,HPLC 95%);MS:[M+1]+730.42(计算值:729.50)。
D4的合成
在25mL的单口瓶中加入D4-3(168.54mg,205.20μmol)溶解在EtOH(5mL)中,再依次加入O-methylhydroxylamine(17.14mg,205.20μmol)和NaOAc(16.83mg,205.20μmol),在室温下搅拌2h,再加入乙酰氯(51.38mg,654.59μmol,39.71μL)和EtOH(2mL)的混合溶液,最后加入NaBH3CN(25.79mg,410.40μmol),在室温继续搅拌1h,加入饱和碳酸氢钠溶液,再加入二氯甲烷洗涤三次,无水硫酸钠干燥,浓缩得到淡黄色固体D4(35mg,产率18.61%,HPLC97%);1H NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.92(dd,J=8.5,4.1Hz,1H),7.87(d,J=8.7Hz,1H),7.30-7.08(m,5H),4.74(dd,J=11.0,4.6Hz,1H),4.65(t,J=8.5Hz,1H),4.58(t,J=8.5Hz,1H),4.33-4.24(m,1H),4.18(q,J=7.9Hz,1H),4.00(d,J=12.2Hz,2H),3.55(ddd,J=11.6,7.9,5.4Hz,3H),3.46(d,J=8.3Hz,5H),3.28-3.15(m,7H),3.10(s,2H),3.00(s,2H),2.87-2.73(m,7H),2.34-2.21(m,2H),2.16-1.98(m,2H),1.90-1.65(m,3H),1.60-1.41(m,2H),1.36-1.26(m,2H),1.06(dd,J=17.8,6.7Hz,3H),1.01-0.83(m,16H),0.77(t,J=8.7Hz,3H);MS:(M+1)+761.46(计算值:760.55)。
实施例5:N-2’,2’,2’-三氟乙基胺dolastatin衍生物(D5)
在50ml单口瓶中,加入tert-butyl(2S)-2-[(1R,2R)-3-[(2,5-dioxopyrrolidin-1-yl)oxy]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidine-1-carboxylate,D5-1(0.1g,2.60mmol),DCM(10mL),(2S)-2-amino-3-phenylpropan-1-ol,D5-2(0.39g,2.6mmol)和二异丙基乙胺(0.50g,3.90mmol),反应在室温下搅拌2h,加入5g硅胶粉,蒸干溶剂,硅胶柱层析纯化,得到tert-butyl(2S)-2-[(1R,2R)-2-{[(2S)-1-hydroxy-3-phenylpropan-2-yl]carbamoyl}-1-methoxy-2-methylethyl]pyrrolidine-1-carboxylate,D5-3(1.1g,严率96.53%);LCMS[M+1]+421.54(理论值420.55);1H NMR(500MHz,DMSO-d6)δ7.62(d,J=8.3Hz,1H),7.20(q,J=5.4,4.2Hz,4H),7.15-7.06(m,1H),4.78(s,1H),3.97(d,J=4.4Hz,1H),3.39(dt,J=10.1,4.9Hz,1H),3.35-3.25(m,3H),3.12(s,1H),2.98(s,1H),2.90(d,J=10.7Hz,1H),2.58(d,J=9.7Hz,1H),2.11(dq,J=9.5,6.7Hz,1H),1.75-1.59(m,2H),1.45(dt,J=15.0,7.5Hz,2H),1.36(s,9H),1.02(d,J=6.1Hz,3H).
在50ml单口瓶中,将D5-3(600mg,1.43mmol)溶于DCM(10mL)中,加入Dess-Martinperiodinane(1.21g,2.86mmol),反应液在室温下搅拌4h,加入10ml饱和碳酸氢钠水溶液,萃取分液,有机相加入10ml饱和食盐水,萃取分液,有机相加入5g无水硫酸镁,干燥,过滤,蒸干溶剂得到tert-butyl(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[(2S)-1-oxo-3-phenylpropan-2-yl]carbamoyl}ethyl]pyrrolidine-1-carboxylate,D5-4(800mg,产率80.38%);LCMS[M+1]+419.47(理论值418.53)。
在50ml单口瓶中,将D5-4(0.8g,1.15mmol)溶于methanol(8mL)中,加入2,2,2-trifluoroethan-1-amine(0.34g,3.45mmol)和sodium acetate(0.28g,3.45mmol),反应在室温下搅拌4h,加入Sodiumcyanoborohydride(0.22g,3.45mmpl)和acetic acid(0.35g,5.75mmol),反应液在室温下搅拌2h,反应液蒸干溶剂,加入10ml饱和碳酸氢钠水溶液和20ml乙酸乙酯,萃取分液,有机相加入10ml饱和食盐水,萃取分液,加入5g无水硫酸镁,过滤、蒸干溶剂得到tert-butyl(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[(2S)-1-phenyl-3-[(2,2,2-trifluoroethyl)amino]propan-2-y1]carbamoyl}ethyl]pyrrolidine-1-carboxylate,D5-5(0.55g,产率47.81%,);LCMS[M+1]+ 502.39(理论值501.59)。
在50ml单口瓶中,将D5-5(0.5g,1.0mmol)溶于DCM(5mL)中,加入trifluoroaceticacid(0.23g,2mmol),反应在室温下搅拌1h,蒸干溶剂,粗品中加入10ml蒸馏水,20ml乙酸乙酯,萃取分液,干燥得到粗品D5-6直接用于下一步反应,LCMS[M+1]+402.50(理论值401.47)。
在50ml单口瓶中,将D5-6(0.4g,1.0mmol)的水溶液,加入sodiumhydrogencarbonate(0.42g,5mmol),然后将2,5-dioxopyrrolidin-1-yl(3R,4R,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate,D5-7(0.4g,1.0mmol)的1,4-dioxane(5mL)缓慢滴加到反应液中,反应在室温下搅拌2h,加入20ml乙酸乙酯,萃取分液,有机相用无水硫酸镁干燥,过滤,硅胶柱层析纯化得到(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanamido]-N-[(3R,5S)-3-methoxy-1-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-2-{[(2S)-1-phenyl-3-[(2,2,2-trifluoroethyl)amino]propan-2-yl]carbamoyl}ethyl]pyrrθlidin-1-y1]-5-methyl-1-oxoheptan-4-yl]-N,3-dimethylbutanamide,D5(0.11g,产率12.36%);LCMS[M+1]+813.33(理论值812.54);1H NMR(500MHz,DMSO-d6)δ8.02(d,J=8.3Hz,1H),7.25-7.16(m,4H),7.15-7.07(m,1H),4.78-4.62(m,1H),4.61-4.48(m,1H),4.21-4.02(m,1H),3.98(s,1H),3.61(s,1H),3.32(s,3H),3.30-3.13(m,9H),3.10(s,1H),3.00(d,J=10.6Hz,2H),2.69-2.60(m,3H),2.44(d,J=15.3Hz,1H),2.36-2.25(m,1H),2.20(d,J=8.2Hz,6H),2.14-2.04(m,1H),1.92(dt,J=13.9,7.9Hz,2H),1.80-1.65(m,2H),1.57-1.47(m,1H),1.35-1.18(m,4H),1.05(dd,J=15.4,6.8Hz,3H),0.96-0.80(m,14H),0.79-0.60(m,7H).
实施例6:BrAc-PEG2-GVA-ha-D1的制备(A1)
A1-1的合成
在100ml单口烧瓶中,将D1(1.2g,1.56mmol)和(2R)-N-(chloromethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide(Int101)(497.07mg,1.72mmol)溶于DCM(15mL)中,加入DIPEA(201.62mg,1.56mmol,271.72μL),在室温下搅拌2h,在反应液中加入5g硅胶粉,蒸干溶剂,硅胶柱层析分离得到A1-1(1.3g,产率83.58%);1H NMR(500MHz,CDCl3)δ7.81(td,J=8.0,6.7,3.1Hz,2H),7.73-7.65(m,2H),7.40-7.30(m,4H),7.26(q,J=6.9Hz,2H),4.98-4.81(m,2H),4.74-4.58(m,2H),4.38-4.17(m,2H),4.15-3.98(m,2H),3.89-3.78(m,1H),3.65-3.15(m,15H),3.01(d,J=50.1Hz,2H),2.63(s,1H),2.51-2.33(m,2H),2.16-2.01(m,2H),1.90-1.77(m,3H),1.75-1.62(m,4H),1.35(d,J=18.9Hz,1H),1.25(dd,J=10.9,4.8Hz,4H),1.12-1.05(m,1H),0.98(td,J=20.4,19.2,6.8Hz,7H),0.86(dt,J=23.3,8.9Hz,6H),0.70(d,J=6.5Hz,2H);LCMS:[M+1]+974.62(计算值973.51)。
A1-2的合成
在100ml单口瓶中,将A1-1(0.8g,802.32μmol)溶于ACN(10mL),加入80%的hydrazine;hydrate(602.47mg,9.63mmol),在室温下搅拌12h,向反应液中加入20ml水,DCM萃取三次,饱和NaCl水溶液洗涤,无水硫酸镁干燥,过滤,浓缩得到A1-2(750mg,产率99.68%yield,HPLC 93%);LCMS:[M+1]+844.21(计算值843.51)。
A1-3的合成
在100ml单口瓶中,加入A1-2(750mg,778.54μmol,)溶于DCM(10mL),加入FmocPEG2-GV-OSu(526.05mg,778.54μmol),在室温下搅拌2h,加入5g硅胶粉蒸干溶剂,硅胶柱层析分离得到A1-3(1g,产率91.45%);1H NMR(500MHz,CDCl3)δ7.76(d,J=7.2Hz,2H),7.60(d,J=7.2Hz,3H),7.47-7.36(m,4H),7.33(dd,J=13.2,5.7Hz,5H),4.95(s,3H),4.39(s,3H),4.31-3.98(m,7H),3.85(d,J=8.1Hz,4H),3.66-3.20(m,24H),2.58-2.26(m,4H),1.86(s,13H),1.35(dd,J=21.0,7.0Hz,4H),1.25(d,J=6.8Hz,4H),1.09(d,J=6.5Hz,2H),0.96(ddd,J=32.7,17.0,7.4Hz,17H),0.83(t,J=7.3Hz,3H);LCMS:[M+1]+1381.72(计算值1380.76)。
A1的合成
在25ml单口瓶中,将A1-3(300mg,213.58μmol)溶于DCM(3mL)中,加入DBU(32.52mg,213.58μmol,31.94μL),在25℃条件下搅拌0.5h,得到A1-4(LCMS:[M+1]+1159.39;计算值:1158.69),不经处理,直接加入DIC(32.34mg,256.30μmol,39.69μL)和2-bromoacetic acid(32.64mg,234.94μmol),在25℃条件下搅拌1h,中加入3g硅胶粉蒸干溶剂,硅胶柱层析分离得到A1(150mg,两步产率53.89%);1H NMR(500MHz,DMSO-d6)δ8.17-8.10(m,1H),7.82(dt,J=16.6,7.7Hz,1H),7.29(dt,J=14.8,7.6Hz,3H),7.22-7.13(m,1H),4.78-4.54(m,2H),4.46(dd,J=31.9,6.4Hz,1H),4.28-4.11(m,3H),4.08-3.93(m,3H),3.86(s,1H),3.80-3.73(m,3H),3.71-3.56(m,10H),3.45-3.30(m,15H),3.24(dt,J=11.7,7.0Hz,8H),3.18(d,J=4.7Hz,1H),3.07(d,J=19.2Hz,2H),2.95(s,1H),2.38(t,J=6.4Hz,2H),2.29(d,J=8.5Hz,1H),2.16-1.89(m,3H),1.87-1.45(m,5H),1.39-1.19(m,6H),1.07-0.97(m,5H),0.96-0.69(m,16H);LCMS:[M+1]+ 1281.75(计算值1280.33)。
实施例7:BrAc-PEG2-GVA-ha-D2的制备(A2)
A2-1的合成
室温下向10ml反应瓶中依次加入D2(1.85g,2.51mmol),DMF(10mL),(2R)-N-(chloromethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide(668.58mg,2.51mm01),DIPEA(324.02mg,2.51mmol,436.68μL),室温搅拌反应0.5h,向在反应液中加入5g硅胶粉制砂,进行柱层析,得到A2-1(2.11g,产率83.46%,HPLC 96%);LCMS:[M+1]+968.07(计算值:967.52)。
A2-2的合成
在室温下,向反应瓶中依次加入A2-1(1g,1.03mmol),甲醇(10mL),hydrazinehydrate(620.50mg,12.39mmol),反应物在室温搅拌反应5h,加入DCM(100mL)萃取,水洗涤,无水硫酸镁干燥,过滤,浓缩,得到淡黄色固体A2-2(740mg,产率76.94%,HPLC 94%);1HNMR(500MHz,DMSO-d6)δ8.42(s,1H),8.07(dd,J=9.1,3.1Hz,1H),7.88(d,J=8.7Hz,1H),7.63(d,J=8.5Hz,0H),7.34-7.26(m,4H),7.28-7.20(m,0H),7.19(td,J=6.9,2.2Hz,1H),5.42(d,J=5.0Hz,1H),5.35(d,J=5.0Hz,0H),4.74(s,0H),4.68(dd,J=9.1,6.9Hz,0H),4.62-4.55(m,0H),4.50(t,J=5.4Hz,0H),4.43(t,J=5.8Hz,1H),4.14(td,J=16.1,15.2,4.5Hz,1H),4.08-4.01(m,1H),4.02(s,1H),4.00(s,1H),3.95(dd,J=14.4,7.1Hz,0H),3.84-3.74(m,0H),3.70-3.55(m,2H),3.25(s,3H),3.23(d,J=10.0Hz,3H),3.19(s,1H),3.10(s,2H),3.04(dt,J=11.6,9.2Hz,0H),2.96(s,1H),2.90(s,0H),2.56(dd,J=15.5,9.7Hz,1H),2.42(dd,J=15.8,8.5Hz,1H),2.30(t,J=10.2Hz,1H),2.26(s,1H),2.18-2.05(m,2H),2.00(dt,J=13.0,6.7Hz,1H),1.83(d,J=8.3Hz,1H),1.81-1.67(m,1H),1.55(s,1H),1.49(q,J=8.2Hz,1H),1.30(s,2H),1.25(d,J=2.7Hz,1H),1.20-1.09(m,4H),1.04(dd,J=11.9,5.9Hz,4H),1.01(s,1H),0.99(d,J=6.6Hz,2H),0.97-0.72(m,12H).LCMS:[M+1]+839.05(计算值:837.52)。
A2-3的合成
室温下向反应瓶中依次加入A2-2(740mg,883.02μmol),DMF(5mL),Fmoc-PEG2-GV-OSu(576.34mg,883.02μmol),室温搅拌反应0.5h,加入5g硅胶粉制砂,硅胶柱层析纯化得到淡黄色固体A2-3(814mg,产率62%,产率92%);LCMS:[M+1]+ 1376.32(计算值:1375.66)。
A2-4的合成
室温下,在10ml单口瓶中依次加入A2-3(400mg,290.77μmol),DMF(1.2mL),DBU(44.27mg,290.77μmol,43.48μL),室温搅拌反应1h,加入10ml甲基叔丁基醚,离心(10000r/min)5min得到淡黄色固体A2-4(300mg,产率83.19%,HPLC 93%);LCMS:[M+1]+1154.26(计算值:1153.42)。
A2的合成
室温下,在10ml单口瓶中依次加入A2-4(300mg,260.10μmol),DMF(3mL),(2-bromoacetyl)2-bromoacetate(67.60mg,260.10μmol),室温搅拌反应1h,在反应液中加入5g硅胶粉制砂,硅胶柱层析纯化得到类白色固体A2(250mg,产率72.41%,HPLC 96%);1HNMR(500MHz,DMS0-d6)δ8.41(dt,J=11.1,6.2Hz,1H),8.14(dq,J=15.6,6.0,4.7Hz,2H),7.98(dd,J=8.3,4.0Hz,1H),7.81(t,J=8.3Hz,1H),7.34-7.24(m,4H),7.22-7.15(m,1H),4.65-4.54(m,1H),4.49(d,J=6.3Hz,1H),4.18(dtt,J=26.7,13.1,5.9Hz,3H),4.08-4.00(m,1H),4.00(s,2H),3.98-3.90(m,1H),3.87(s,1H),3.81-3.73(m,3H),3.64-3.55(m,3H),3.50(s,4H),3.27-3.20(m,8H),3.19(s,1H),3.09(s,2H),2.95(s,1H),2.71-2.58(m,3H),2.39(t,J=6.6Hz,3H),2.31-2.23(m,2H),2.12(dq,J=11.9,6.5Hz,1H),2.05-1.88(m,3H),1.83(s,1H),1.74-1.64(m,1H),1.63(dq,J=9.1,4.9,4.5Hz,1H),1.55(d,J=7.0Hz,1H),1.48(s,1H),1.36(p,J=10.4,9.6Hz,1H),1.32-1.22(m,10H),1.25-1.19(m,1H),1.07-0.95(m,6H),0.93(s,1H),0.97-0.86(m,4H),0.84(dt,J=20.6,6.3Hz,12H),0.81-0.73(m,2H);LCMS:[M+1]+1275.22(计算值:1274.35)。
实施例8:mc-PEG2-GVA-ha-D4的制备(A4)
A4-1的合成
室温下将D4(200mg,257.72μmol)溶解在DCM(2.89mL)中,依次加入TEA(78.24mg,773.16μmol,107.76μL)和中间体Int1(68.99mg,257.72μmol),在室温搅拌2h,旋干,反相柱层析纯化得到淡黄色固体A4-1(259.33mg,产率95%);1H NMR(500MHz,DMSO-d6)δ8.62(dt,J=22.0,6.1Hz,1H),8.05(dd,J=13.2,8.6Hz,1H),7.90(p,J=5.9,5.3Hz,5H),7.31-7.12(m,6H),4.79(pd,J=9.0,8.1,4.3Hz,2H),4.64(t,J=8.8Hz,1H),4.56(t,J=8.8Hz,1H),4.41-4.26(m,2H),4.14(ddd,J=29.2,13.3,5.8Hz,2H),4.02(dd,J=9.3,5.1Hz,1H),3.84(dd,J=9.3,2.4Hz,1H),3.68(t,J=6.7Hz,1H),3.60(ddd,J=12.5,7.9,5.4Hz,1H),3.52(s,3H),3.46(s,2H),2.65(dh,J=20.2,4.3Hz,5H),2.23(s,8H),2.15(d,J=3.1Hz,1H),1.62(d,J=7.3Hz,3H),1.42-1.15(m,9H),1.15-1.01(m,7H),1.00-0.85(m,16H),0.78(tt,J=13.7,6.6Hz,9H);MS:[M+1]+ 991.24(计算值:990.62)。
A4-2的合成
室温下将A4-1(177.50mg,178.88μmol)溶解在DCM(8mL)中,加入水合肼(35.82mg,715.53μmol),在30℃下搅拌26h,旋干,反相柱层析纯化得到淡黄色固体A4-2(119.5mg,产率72.83%);1H NMR(500MHz,DMSO-d6)δ8.30(dt,J=24.8,6.4Hz,1H),8.08(t,J=7.6Hz,1H),7.91(d,J=8.9Hz,0H),7.31-7.20(m,4H),7.22-7.15(m,1H),4.79(dd,J=11.0,4.9Hz,1H),4.67(q,J=9.2Hz,1H),4.58(t,J=8.8Hz,0H),4.34(tt,J=16.8,7.0Hz,1H),4.22(ddd,J=26.3,13.2,6.0Hz,1H),4.04(dd,J=9.4,5.1Hz,1H),3.62(ddd,J=12.4,7.8,5.2Hz,1H),3.55(s,2H),3.49(d,J=9.2Hz,1H),3.43(s,0H),3.30(d,J=9.0Hz,3H),3.24(d,J=11.8Hz,3H),3.18(s,1H),3.10(dt,J=11.7,7.1Hz,0H),3.05(s,1H),3.05-2.98(m,1H),2.95(s,1H),2.79(s,1H),2.71(q,J=9.1Hz,1H),2.67(s,0H),2.63(d,J=8.2Hz,2H),2.48(t,J=15.9Hz,1H),2.37-2.31(m,1H),2.26(d,J=8.1Hz,6H),2.21-2.15(m,1H),2.18-2.10(m,1H),2.07-1.96(m,1H),1.98-1.91(m,0H),1.88(d,J=7.8Hz,1H),1.86(s,2H),1.79(ddt,J=22.4,10.9,5.5Hz,1H),1.59(dq,J=12.4,7.3Hz,1H),1.53(s,1H),1.46-1.30(m,3H),1.29(s,1H),1.18(d,J=6.9Hz,3H),1.10(dd,J=16.3,6.7Hz,3H),1.04-0.86(m,13H),0.80(dt,J=10.0,5.6Hz,5H),0.76(s,1H);MS:[M+1]+862.24(计算值:861.18)。
A4-3的合成
室温下,将Fmoc-PEG2-GV-OSu(148.99mg,227.92μmol)加入DCM(2mL)中,加入A4-2(200mg,228.27μmol)的DCM(6mL)溶液,在室温搅拌1h,旋干,反相柱层析纯化,得到淡黄色固体A4-3(185mg,产率57.90%);1H NMR(500MHz,DMSO-d6)δ8.29(dt,J=27.4,6.1Hz,1H),8.11(td,J=7.6,4.7Hz,2H),8.03(s,1H),7.89(d,J=7.6Hz,2H),7.84-7.73(m,2H),7.69(d,J=7.5Hz,2H),7.42(t,J=7.4Hz,2H),7.33(t,J=7.2Hz,3H),7.25-7.09(m,6H),4.32(s,3H),4.36-4.27(m,3H),4.25-4.09(m,3H),3.78-3.72(m,2H),3.59(q,J=9.5,8.0Hz,3H),3.49(d,J=6.0Hz,6H),3.41(d,J=15.0Hz,2H),3.28-3.19(m,6H),3.16(d,J=19.4Hz,3H),3.13(s,3H),2.69-2.52(m,7H),2.47-2.35(m,4H),2.21(d,J=6.2Hz,7H),2.03-1.90(m,2H),1.31(s,3H),1.28-1.17(m,4H),1.05(dd,J=16.3,6.6Hz,3H),0.91(t,J=7.2Hz,6H),0.91-0.84(m,14H),0.84-0.80(m,3H),0.83-0.72(m,6H),0.72(d,J=9.5Hz,2H);MS:[M+1]+ 1399.00(计算值:1397.86)。
A4-4的合成
室温下,将A4-3(185mg,133.50μmol)加入DCM(6mL)中,再加入DBU(10.16mg,66.75μmol,9.98μL),在室温搅拌1h,旋干,反向柱层析纯化,得到淡黄色固体A4-4(145mg,产率88.68%);1HNMR(500MHz,DMSO-d6)δ9.74(s,1H),8.93(t,J=6.8Hz,1H),8.28(q,J=6.8Hz,1H),8.22-8.09(m,2H),7.88-7.82(m,2H),7.81(dd,J=8.9,3.0Hz,1H),7.29(dd,J=17.2,7.5Hz,1H),7.16(ddt,J=32.2,14.8,7.5Hz,5H),4.65(q,J=7.2,5.9Hz,1H),4.31(td,J=7.2,2.9Hz,2H),4.16(ddt,J=37.0,13.6,7.4Hz,3H),4.08-3.97(m,1H),3.75(t,J=9.3Hz,3H),3.65-3.58(m,4H),3.55(dd,J=15.1,10.2Hz,7H),3.43(s,3H),3.33(dd,J=19.1,10.6Hz,3H),3.27-3.19(m,5H),3.14(d,J=29.6Hz,3H),3.08-2.90(m,5H),2.78(d,J=8.0Hz,6H),2.58(ddq,J=18.3,11.8,7.5,6.4Hz,4H),2.49-2.36(m,3H),2.29(tq,J=14.9,6.8Hz,2H),2.03(dddt,J=53.0,18.9,12.8,6.5Hz,4H),1.85(d,J=8.4Hz,1H),1.77(p,J=6.3Hz,1H),1.73-1.66(m,1H),1.53(dd,J=13.2,6.7Hz,1H),1.32(dq,J=17.9,9.7,8.0Hz,2H),1.26-1.18(m,3H),1.05(dd,J=17.3,6.7Hz,3H),1.00-0.74(m,26H);MS:[M+1]+ 1177.48(计算值:1176.55)。
A4的合成
室温下,将(2,5-dioxopyrrolidin-1-y1)6-(2,5-dioxopyrrol-1-y1)hexanoateor mc-Osu(31.80mg,102.80μmol)溶于DCM(20mL),再加入A4-4(118.56mg,103.14μmol),继续再室温下搅拌0.5h,直接旋干,反相层析柱纯化得到淡黄色固体A4(106mg,产率72.77%);1H NMR(500MHz,DMSO-d6)δ8.33(t,J=5.6Hz,2H),8.28(t,J=6.3Hz,2H),8.13-8.05(m,4H),7.65(d,J=8.8Hz,2H),7.52(s,4H),7.25(s,2H),6.30(s,4H),5.43(d,J=2.3Hz,4H),5.28(s,4H),4.24(dt,J=33.4,13.1,6.2Hz,7H),4.13(dd,J=8.9,6.7Hz,2H),3.86(s,4H),3.74(d,J=6.3Hz,4H),3.60(t,J=6.4Hz,5H),3.56(s,7H),3.49(s,12H),3.31(t,J=8.0Hz,5H),2.89(dq,J=22.7,8.2,7.3Hz,4H),2.38(t,J=6.4Hz,5H),1.86(dh,J=21.4,7.2Hz,5H),1.76(h,J=6.8Hz,3H),1.17(d,J=7.1Hz,6H),0.88(t,j=7.3Hz,7H),0.67(d,J=6.7Hz,11H);MS:[M+1]+1370.47(计算值:1369.76)。
实施例9:dBPA-PEG2-GVA-ha-D4的制备(A5)
室温下向反应烧瓶中加入2,6-二溴甲基吡啶4-氧基乙酸2-[[2,6-bis(bromomethyl)-4-pyridyl]oxy]acetic acid(27.82mg,81.82μmol)溶于DCM(3mL),加入DIC(8.60mg,68.18μmol,10.56μL),搅拌5分钟,再加入A4-4(78.38mg,68.18μmol)的DCM(3mL)溶液,室温下搅拌反应0.5小时,将反应液浓缩,反相柱层析纯化得到淡黄色固体A5(35.4mg,产率33.54%);1H NMR(500MHz,DMSO-d6)δ9.57(s,1H),8.15(dt,J=22.9,6.0Hz,1H),7.88-7.74(m,1H),7.38-7.26(m,2H),7.26-7.19(m,2H),7.19-7.11(m,2H),4.92(s,1H),4.76(s,3H),4.35-4.25(m,2H),4.17(dt,J=23.5,15.5,7.4Hz,3H),3.76(t,J=6.3Hz,6H),3.64(s,14H),3.63-3.58(m,17H),3.49-3.41(m,5H),3.40-3.10(m,12H),3.01(d,J=3.8Hz,1H),2.79(q,J=11.5,8.2Hz,5H),2.58(dd,J=18.6,9.5Hz,2H),2.39(dq,J=6.4,4.0,2.7Hz,2H),2.30(dq,J=15.8,8.4,7.8Hz,2H),1.98(tt,J=16.9,6.8Hz,2H),1.49(dt,J=21.9,6.8Hz,1H),1.30(t,J=13.0Hz,2H),1.26-1.17(m,4H),1.11-1.01(m,2H),0.87(ddd,J=48.9,28.3,15.6,7.5Hz,19H);MS:[M+1]+ 1496.72(计算值:1497.52)。
实施例10:Nectin-4-Ac-PEG2-GVA-ha-D2(DAR4)的制备(ADC2)
取Nectin-4抗体(10.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl(三(2-羧乙基)膦盐酸盐)溶液(10mM,0.02ml),10℃反应3h。
将化合物A2(0.58mg,0.45mmol)溶于0.1ml的DMA中,加入到上述溶液体系中,混匀,10℃反应4h,反应完毕后用NAP-5凝胶柱(Cytiva)去除小分子并将缓冲液置换为20mM组氨酸-盐酸组氨酸溶液,pH=6.2,得到抗体偶联药物ADC2(3.0mg/ml,2ml)。
RP-MS分析方法:RP-HPLC-MS分析ADC的DAR值使用仪器为Waters Acquity UPLCI-Class/XevoG2-XS QTOF。RP-HPLC参数设置:色谱柱PLRP-S1000A5UM,柱温为70℃。流动相A为0.1%甲酸水溶液,流动相B为0.1%甲酸乙腈溶液,流速为0.2ml/min。流动相梯度为20-50%B,18分钟;50-95%B,5分钟;95-20%B,0.1分钟;20-20%B,6.9分钟。MS参数参设设置:毛细管电压2.50kV,锥孔电压100V,质量分析范围m/z 200至4000,MSE碰撞能量20至45eV,离子源温度120℃,雾化温度500℃,雾化流速1000L/Hr,内标为亮氨酸脑啡肽。供试品用样品缓冲液稀释到1mg/ml,加入终浓度为50mmol/L的TCEP,37℃孵育20min,进样5ul。识别轻链峰并计算峰面积百分比,峰面积总和为100。同样识别重链峰并计算峰面积百分比,峰面积总和为100。通过峰面积百分比与相应的药物负荷相乘分别计算重链和轻链的加权峰面积。DAR值计算公式为:DAR=2*(∑轻链加权峰面积+∑重链加权峰面积)/100。
RP-MS计算平均值:n=3.2;MS结果显示轻链重链(HL)连接了一个与两个linker-payload(图1)。
实施例11:Nectin-4-mc-PEG2-GVA-ha-D4(DAR8)的制备(ADC4)
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取Nectin-4抗体(10.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25uL),加入配置好的TCEP·HCl溶液(10mM,0.04ml),室温25℃旋转转盘反应4h。
将化合物A4(1.27mg,0.93mmol)溶于0.1ml的DMA中,加入到上述溶液体系中,混匀,室温旋转转盘反应16h,反应完毕后用NAP-5凝胶柱(Cytiva)去除小分子并将缓冲液置换为20mM组氨酸-盐酸组氨酸溶液,pH=6.2,得到抗体偶联药物ADC4(3.0mg/ml,2ml)。
RP-MS计算平均值:n=7.9;MS结果显示轻链(L)连接了一个linker-payload,重链(H)连接了3个linker-payload(图2)。
实施例12:Nectin-4-mc-PEG2-GVA-ha-D4(DAR4)的制备(ADC5)
取Nectin-4抗体(10.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl溶液(10mM,0.02ml),10℃反应3h。
将化合物A4(0.63mg,0.45mmol)溶于0.1ml的DMA中,加入到上述溶液体系中,混匀,10℃反应4h,反应完毕后用NAP-5凝胶柱(Cytiva)去除小分子并将缓冲液置换为20mM组氨酸-盐酸组氨酸溶液,pH=6.2,得到抗体偶联药物ADC5(3.0mg/ml,2ml)。
RP-MS计算平均值:n=3.9;MS结果显示轻链重链(HL)连接了两个linker-payload(图3)。
实施例13:Nectin-4-PA-PEG2-GVA-ha-D4(DAR4)的制备(ADC6)
取Nectin-4抗体(10.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl溶液(10mM,0.04ml),室温25℃旋转转盘反应4h。
将化合物A5(1.11mg,0.74mmol)溶于0.1ml的DMA中,加入到上述溶液体系中,混匀,室温旋转转盘反应16h,反应完毕后用NAP-5凝胶柱(Cytiva)去除小分子并将缓冲液置换为20mM组氨酸-盐酸组氨酸溶液,pH=6.2,得到抗体偶联药物ACN100546-CL60-D4(3.0mg/ml,2ml)。
RP-MS计算平均值:n=4.3;MS结果显示轻重链(HL)连接了两个linker-payload(图4)。
测试例1:抑制肿瘤细胞生长活性
将人食管癌细胞OE33,人乳腺癌细胞SK-BR-3,人乳腺癌细胞MDA-MB-231,人胃癌细胞NCI-N87,人肺癌细胞NCI-H1975,人食道癌细胞TE12等在含有10%胎牛血清(Cellmax)的RPMI1640(Cellmax)中培养。将处于指数增长期的肿瘤细胞用培养基稀释至1×105cells/mL,以每孔100μL加入到96孔细胞培养板中,放回37℃,5%CO2的培养箱中过夜培养。第二天,使用培养基将化合物稀释至10000nM、2000nM、400nM、80nM、16nM、3.2nM、0.64nM、0.13nM,并以每孔2μL将稀释后的化合物加入到96孔细胞培养板中,每个浓度设置3个复孔,未添加化合物的阴性对照和空白对照组每孔加入2μL的稀释液。加样完成后,放回37℃,5%CO2的培养箱中继续孵育72h。孵育完成后,取出细胞培养板,用移液器将培养板中的培养基吸弃,每孔加入100μL含有10%CCK-8的培养基,37℃孵育3h。孵育完成后,取出培养板,避光,置于酶标板中,选择630nm为参比波长,450nm为测定波长测定吸光度。根据吸光值,使用GraphPad中四参数回归计算IC50值(表1)。
对于IC50值,其中“++++”表示10nM>IC50;“+++”表示100nM>IC50≥10nM;“++”表示500nM>IC50≥100nM;“+”表示1000nM>IC50≥500μM。
表1化合物抑制肿瘤细胞生长的IC50(nM)值
注:“-”表示未测试。
本发明提供的实施例化合物均对肿瘤细胞例的生长均具有较好的抑制作用,其活性抑制IC50值均低于500nM,甚至低于0.5nM,具有显著的抗癌活性。
测试例2:ADC体内抑制肿瘤生长活性
ADC体外抑制活性测试方法:NCI-H292肺癌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NCI-H292细胞(2-10×106cells/0.1ml)皮下接种于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,每组6只动物。定期静脉注射给药一次,给药后监测至第22天,其实验分组见下表2。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(tumorvolume,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GraphPadPrism软件进行分析得到抑瘤结果(图5、图6)。
表2给药方案
其中,DXd-Nectin-4为与本申请实施例所述Nectin-4抗体偶联得到。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式,并且很显然,根据上述教导,可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用,从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。
Claims (10)
1.式(I)化合物或其药学上可接受的盐、立体异构体或前药:
式中,M选自中的任意一种;
R1、R2各自独立地选自C1-C6烷基、卤素取代的C1-C6烷基或C3-C6环烷基中的任意一种;
R3选自氢、C1-C6烷基或C3-C6环烷基中的任意一种;
R4选自氢、C1-C6烷基、C3-C6环烷基、-C1-C6烷基-NR6-O-C1-C6烷基或-C1-C6烷基-O-NR6-C1-C6烷基中的任意一种;
R5选自氢、羟基、C3-C6环烷基或-O-NR6-C1-C6烷基中的任意一种;
R6选自氢或C1-C6烷基;
X选自卤素;
m1、m2各自独立地选自0、1或2。
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,R1、R2各自独立地选自氢、卤素取代或未取代的甲基、乙基、丙基、异丙基、丁基或异丁基;
优选地,R1、R2各自独立地选自氢、甲基、三氟甲基或三氟乙基;
优选地,R3选自氢、甲基、乙基、丙基、异丙基、丁基或异丁基。
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,选自/>
4.根据权利要求1-3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,所述卤素选自-F、-Cl、-Br或-I;
优选地,m1、m2各自独立地选自1或2;
优选的,选自/>
5.根据权利要求1-4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,R4选自C1-C6烷基、-C1-C6烷基-NH-O-C1-C6烷基或-C1-C6烷基-O-NH-C1-C6烷基;
优选地,R4选自甲基、-CH2-NH-O-CH3或-CH2-O-NH-CH3;
优选地,R5选自氢、羟基或-O-NH-C1-C6烷基;
优选地,R5选自氢、羟基或-O-NH-CH3。
6.根据权利要求1-5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,所述式(I)化合物包括以下化合物:
7.包含权利要求1-6任一项所述的化合物的抗体偶联药物;
优选地,所述抗体偶联药物具有以下式(II)所示结构:
(D-L)n-Ab(II)
其中,D为权利要求1-6任一项所述的化合物;
Ab为肿瘤相关抗原抗体;
L为用于连接D和Ab的连接子;
n=3-8;
优选地,所述连接子为亲水性连接子;
优选地,所述连接子选自以下结构:
其中,所示位置表示与抗体相连,/>所示位置表示与D相连;
优选地,所述抗体偶联物由以下化合物与抗体偶联得到:
8.以下抗体偶联药物:
其中,n=3-8;
优选地,Ab为肿瘤相关抗原抗体或其抗原结合片段;优选为Nectin-4抗体或其抗原结合片段;
优选地,所述Nectin-4抗体包含如SEQ ID NO:1或其任何变体所示的抗体重链氨基酸序列,和如SEQ ID NO:2或其任何变体所示的抗体轻链氨基酸序列。
9.一种药物组合物,包括权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体或前药或权利要求7或8所述的抗体偶联药物和药学上可接受的辅料。
10.一种权利要求1-6任一项所述的化合物或其药学上可接受的盐、立体异构体或前药或权利要求7或8所述的抗体偶联药物或权利要求9所述的药物组合物在制备用于抑制肿瘤细胞生长药物中的应用;
优选地,所述肿瘤细胞包括食管癌细胞、乳腺癌细胞、胃癌细胞、肺癌细胞中的任意一种。
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