CN111556870B - 用于合成接头-药物vc-seco-duba的改进方法 - Google Patents
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- CN111556870B CN111556870B CN201880075808.2A CN201880075808A CN111556870B CN 111556870 B CN111556870 B CN 111556870B CN 201880075808 A CN201880075808 A CN 201880075808A CN 111556870 B CN111556870 B CN 111556870B
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Abstract
本发明涉及用于合成接头‑药物vc‑seco‑DUBA及其中间体的改进方法,以及所述改进方法在制备包含所述vc‑seco‑DUBA接头‑药物的抗体‑药物缀合物的方法中的用途。
Description
技术领域
本发明涉及用于合成接头-药物vc-seco-DUBA及其中间体的改进方法,以及所述改进方法在制备包含所述vc-seco-DUBA接头-药物的抗体-药物缀合物的方法中的用途。
背景技术
倍癌霉素是抗肿瘤抗生素家族的成员,其包括倍癌霉素A、倍癌霉素SA和CC-1065。它们以其强大的抗肿瘤特性而为人所知,但由于其极高的毒性通常不单独使用。目前,倍癌霉素正在被探索为抗体-药物缀合物(antibody-drug conjugate,ADC)中的细胞毒性药物。
ADC通过将高效的细胞毒性药物特异性地指向癌细胞,从而有可能解决对癌症中有效新治疗的巨大未满足需求,从而提高效力,同时降低小分子药物的潜在系统毒性副作用。
ADC未来的商业成功的关键方面之一是合成细胞毒性药物和相应的接头-药物结构的方法,其中将接头部分连接至细胞毒性药物以促进与抗体的缀合,该方法适合工业规模上的生产。
式(I)的接头-药物vc-seco-DUBA
首先在WO2011/133039中作为化合物18b公开于p.210,11.21-27,其是高效的CC-1065类似物的一个实例。具有抗HER2抗体曲妥珠单抗的vc-seco-DUBA的ADC(即SYD985或(vic-)曲妥珠单抗duocarmazine)已成功用于多项临床前研究(M.M.C.van der Lee etal.,Molecular Cancer Therapeutics,2015,14(3),692-703;J.Black et al.,MolecularCancer Therapeutics,2016,15(8),1900-1909)和I期临床试验(ClinicalTrials.govNCT02277717)。目前,在患有HER2阳性的局部晚期或转移性乳腺癌患者的III期临床试验中,将SYD985治疗与医师选择的治疗直接进行比较(TULIP;ClinicalTrials.govNCT03262935)。
接头-药物vc-seco-DUBA的合成在WO2011/133039中描述为四步法。按照此方法在50至100mg实验室规模上制备vc-seco-DUBA为接头-药物提供了仅21%至25%的总产率。该过程的后两个步骤,即步骤3和4,对于来自整个过程的vc-seco-DUBA的总产率至关重要,示出了仅约50%的组合产率。在工业规模上,该四步法的产率将甚至更低。
因此,需要用于制备vc-seco-DUBA的改进方法。特别地,需要一种方法,该方法在产率和化学纯度方面是有效的,在试剂和反应条件方面是成本有效的,并且适合于工业规模上的生产。
发明内容
本发明涉及合成接头-药物vc-seco-DUBA及其中间体的改进方法,其具有适合于工业规模上的生产的工艺条件,并提供了改进产率的所需的vc-seco-DUBA产物。
在第一方面中,本发明涉及式(II)化合物
在第二方面中,本发明提供了包括使式(III)化合物与1,4-二氧六环中的氯化氢反应以形成式(II)化合物的方法
在第三方面中,本发明涉及式(II)化合物在用于制备式(I)的vc-seco-DUBA的方法中的用途
在第四方面中,本发明涉及制备vc-seco-DUBA的方法在制备包含vc-seco-DUBA的抗体-药物缀合物的方法中的用途。
具体实施方式
倍癌霉素是一类结构相关毒素,首先从链霉菌(Streptomyces)物种的培养液(culture broth)中分离出来。它们是包括倍癌霉素A、倍癌霉素SA和CC-1065在内的抗肿瘤抗生素家族的成员。倍癌霉素与DNA的小沟结合,随后引起DNA的不可逆烷基化。这破坏了核酸结构,最终导致肿瘤细胞死亡。
WO2011/133039特别公开了高效的包含CC-1065的倍癌霉素衍生物的式(I)接头-药物vc-seco-DUBA(p.210,11.21-27的化合物18b)
本发明涉及产生vc-seco-DUBA的改进方法,其具有出乎意料的高产率,并且可在工业规模上成功地应用。
将WO2011/133039的实施例10中的vc-seco-DUBA接头-药物的化学合成描述为四步法,其中PNP-Cl是4-硝基苯基氯甲酸酯,Et3N是三乙胺,Boc是叔丁氧羰基,TFA是三氟乙酸,CHCl3是氯仿,并且DMF是N,N-二甲基甲酰胺
在50至100mg的实验室规模上,该四步法显示总产率仅为21%至25%。在工业规模上,该产率将显著更低。
该四步法的低总产率在很大程度上可归因于后两步(即步骤3和4)的实验室规模上的低组合产率,仅为约50%。本发明人出乎意料地发现修改后的程序(包括在步骤3中更改酸试剂)产生了新的中间体,其可通过结晶进行分离。出乎意料的是,发现步骤3的这种修改的程序和新中间体的使用导致vc-seco-DUBA的产率大大提高。
通常,当需要提高产物的纯度时,将结晶步骤引入化学合成中。然而,由于母液中保留了相当数量的产物,因此引入该步骤通常会降低所述产物的产率。出乎意料地,本发明人发现在如上所述的vc-seco-DUBA的合成中引入结晶步骤,产生了式(II)的新中间体,其不仅引起纯度提高(从94%至96%提高至≥99.0%),而且还显示出vc-seco-DUBA的产率出乎意料地显著提高(从53%提高至~79%)
因此,在一个实施方案中,本发明涉及式(II)化合物。
在第二个实施方案中,本发明涉及用于制备式(II)化合物的方法,其包括使式(III)化合物与1,4-二氧六环中的氯化氢反应以形成式(II)化合物。通常,使式(III)化合物与1,4-二氧六环中的10质量%至20质量%的氯化氢反应。优选地,使式(III)化合物与1,4-二氧六环中的12%至18%的氯化氢反应,更优选与1,4-二氧六环中的15%的氯化氢反应。通常,式(III)化合物:1,4-二氧六环中的HCl的质量比为1∶0.5至1∶25。优选地,式(III)化合物:1,4-二氧六环中的HCl的质量比为1∶1至1∶10。更优选1∶5至1∶10
通常,氯化氢的量在摩尔上超过式(III)化合物的量。优选地,氯化氢的量为式(III)化合物的量的至少2摩尔当量,更优选地为2至50当量。
优选地,所述反应在清除剂例如三异丙基硅烷的存在下在水和/或甲醇中发生。所述水和/或甲醇可以小于总溶剂质量的25质量%,优选小于15%,更优选小于10%的量存在。
式(III)化合物可如例如R.C.Elgersma et al.,Molecular CancerTherapeutics,2015,12(6),1813-1835中所述通过以下来制备:使式(IV)化合物与4-硝基苯基氯甲酸酯反应来形成式(V)化合物,随后使式(V)化合物与式(VI)化合物在1-羟基苯并三唑水合物的存在下反应以形成式(III)化合物
通常,式(IV)化合物与4-硝基苯基氯甲酸酯的反应在0至20℃的温度下进行。优选地,温度为0至10℃,更优选为0至6℃,甚至更优选为2至6℃,最优选为3至5℃。
用于制备式(V)化合物的合适溶剂是但不限于有机溶剂,优选非质子溶剂,更优选极性非质子溶剂。优选的溶剂是醚溶剂、酰胺溶剂或其混合物。特别优选的溶剂是四氢呋喃(THF)、N,N-二甲基乙酰胺(DMA)或其混合物。最优选的是THF与DMA的混合物。
用于制备式(V)化合物的合适的碱是有机碱,例如叔胺。一种特别合适的碱是Et3N。
通常,式(V)化合物与式(VI)化合物的反应在0至20℃的温度下进行。优选地,温度为0至10℃,更优选地为4至10℃。
用于制备式(III)化合物的合适溶剂是但不限于有机溶剂,优选非质子溶剂、极性溶剂或其混合物。优选的溶剂是醚溶剂、酰胺溶剂或其混合物。特别优选的溶剂是THF、DMA或其混合物。最优选的是THF与DMA的混合物。
式(IV)化合物可通过现有技术中已知的任何合适的方法或与其类似的方法来产生,例如,在WO2015/185142的实施例6a中描述的方法。
在另一个实施方案中,本发明涉及式(II)化合物用于制备vc-seco-DUBA的用途。
在另一个实施方案中,本发明涉及用于制备vc-seco-DUBA的方法,其中式(II)化合物与式(VII)化合物反应
出乎意料的是,当式(II)化合物与式(VII)化合物在使用N,N-二异丙基胺(DIPEA)作为碱代替在WO2011/133039的实施例10中使用的三乙胺(Et3N)反应时,vc-seco-DUBA的产率甚至进一步提高。通常,式(II)化合物:DIPEA的摩尔比为1∶1至1∶15。优选地,该比为1∶1至1∶10,更优选地为1∶2至1∶7,甚至更优选地为1∶3至1∶5,最优选地该比为约1∶4。
通常,式(II)化合物与式(VII)化合物的反应在0至20℃的温度下进行。优选地,温度为0至10℃,更优选地为0至5℃。
用于式(II)与式(VII)化合物的反应以制备vc-seco-DUBA的合适溶剂是但不限于有机溶剂,优选非质子溶剂,更优选极性非质子溶剂。优选的溶剂是醚溶剂、酰胺溶剂或其混合物。特别优选的溶剂是THF、DMA、N,N-二甲基甲酰胺(DMF)或其混合物。最优选的是DMA。
在一个优选的实施方案中,该方法在1-羟基苯并三唑水合物的存在下进行。通常,式(II)化合物:1-羟基苯并三唑水合物的摩尔比为1∶1至1∶10。优选地,该比为1∶1至1∶7,更优选地为1∶2至1∶5,甚至更优选地为1∶2至1∶3,最优选地该比为约1∶2.5。
本发明另外涉及用于制备式(VIII)的vc-seco-DUBAADC的方法,其中vc-seco-DUBA接头-药物化合物是用如上所述的根据本发明的方法制备的
m表示1至8,优选1至6,更优选1至4的平均药物-抗体比(DAR)。
在本发明的上下文中,任何抗体(特别是已知具有治疗活性的任何抗体或ADC领域中已知的任何抗体)或其任何抗原结合片段,例如F(ab′)2或Fab′片段、单链(sc)抗体、scFv、单结构域(sd)抗体、双抗体或微型抗体(minibody),可用于vc-seco-DUBA的(野生型或位点特异性)缀合。抗体可以是任何同种型,例如IgG、IgA或IgM抗体。优选地,该抗体是IgG抗体,更优选地是IgG1或IgG2抗体。抗体可以是嵌合的、人源化的或人的。优选地,抗体是人源化的。甚至更优选地,抗体是人源化或人IgG抗体,最优选人源化或人IgG1单克隆抗体(mAb)。
优选地,所述抗体具有κ(kappa)轻链,即人源化或人IgG1-κ抗体。
在人源化抗体中,重链(heavy chain,HC)和轻链(light chain,LC)可变区中的抗原结合的互补决定区(complementarity determining region,CDR)来源于来自非人物种的抗体,通常是小鼠、大鼠或兔。可将这些非人CDR置于HC和LC可变区的人框架(框架区(framework region,FR)FR1、FR2、FR3和FR4)内。可将人FR中的选定氨基酸交换为相应的原始非人物种氨基酸,例如以提高结合亲和力同时保持低免疫原性。或者,保留非人框架,并且可将非人物种FR的选定氨基酸交换为其相应的人氨基酸以降低免疫原性,同时保留抗体的结合亲和力。由此人源化可变区与人恒定区组合在一起。
这些抗体可重组产生、合成产生或通过本领域已知的其他合适方法产生。
通常,抗体是单特异性抗体(即对一个抗原具有特异性;这样的抗原可以是物种之间共同的或在物种之间具有相似的氨基酸序列)或双特异性抗体(即对一种物种的两种不同的抗原具有特异性),其包含与选自以下的靶标结合的至少一个HC和LC可变区:膜联蛋白A1、B7H4、CA6、CA9、CA15-3、CA19-9、CA27-29、CA125、CA242(癌抗原242)、CCR2、CCR5、CD2、CDl9、CD20、CD22、CD30(肿瘤坏死因子8)、CD33、CD37、CD38(环状ADP核糖水解酶)、CD40、CD44、CD47(整联蛋白相关蛋白)、CD56(神经细胞黏附分子)、CD70、CD74、CD79、CD115(集落刺激因子1受体)、CD123(白介素3受体)、CD138(黏结蛋白聚糖1(Syndecan 1))、CD203c(ENPP3)、CD303、CD333、CEA、CEACAM、CLCA-1(C型凝集素样分子-1)、CLL-1、c-MET(肝细胞生长因子受体)、Cripto、DLL3、EGFL、EGFR、EPCAM、EPh(例如EphA2或EPhB3)、ETBR(内皮素B型受体)、FAP、FcRL5(Fc受体样蛋白5,CD307)、FGFR(例如FGFR3)、FOLRl(叶酸受体α)、GCC(鸟苷酰环化酶C)、GPNMB、HER2、HMW-MAA(高分子量黑素瘤相关抗原)、整联蛋白α(例如αvβ3和αvβ5)、IGFlR、TM4SFl(或L6抗原))、路易斯A类碳水化合物、路易斯X、路易斯Y(CDl74)、LIVl、间皮素(MSLN)、MN(CA9)、MUC1、MUC16、NaPi2b、连接蛋白-4、PD-1、PD-L1、PSMA、PTK7、SLC44A4、STEAP-1、5T4抗原(或TPBG,滋养层糖蛋白)、TF(组织因子,促凝血酶原激酶,CDl42)、TF-Ag、Tag72、TNFR、TROP2(肿瘤相关钙信号转导因子2)、VEGFR和VLA。
合适抗体的实例包括博纳吐单抗(blinatumomab)(CDl9)、依帕珠单抗(epratuzumab)(CD22)、伊妥木单抗(iratumumab)和布妥昔单抗(brentuximab)(CD30)、vadastuximab(CD33)、tetulumab(CD37)、isatuximab(CD38)、bivatuzumab(CD44)、lorvotuzumab(CD56)、vorsetuzumab(CD70)、milatuzumab(CD74)、polatuzumab(CD79)、rovalpituzumab(DLL3)、富妥昔单抗(futuximab)(EGFR)、oportuzumab(EPCAM)、farletuzumab(FOLR1)、glembatumumab(GPNMB)、曲妥珠单抗(trastuzumab)和帕妥珠单抗(pertuzumab)(HER2)、伊瑞西珠单抗(etaracizumab)(整联蛋白)、anetumab(间皮素)、pankomab(MUC1)、enfortumab(连接蛋白-4)和H8、A1和A3(5T4抗原)。
vc-seco-DUBA接头-药物与抗体的缀合可如例如在WO2011/133039、WO2015/177360和WO2017/137628中所述进行。
野生型ADC是通过接头-药物与抗体通过由还原链间二硫键而产生的半胱氨酸侧链的游离硫醇(thiol)进行缀合而产生的。制备包括对溶剂暴露的链间二硫化物进行部分还原,随后用含马来酰亚胺的接头-药物对所得的硫醇进行修饰。半胱氨酸连接策略每还原一个二硫化物最多可产生两个药物。大多数人IgG分子具有四个溶剂暴露的二硫键,因此每个抗体零至八个药物是可能的。每个抗体的确切药物数量取决于二硫键还原的程度以及随后发生的缀合反应中所用接头-药物的摩尔当量数。全部四个二硫键的完全还原得到每个抗体八个药物的均一构建体,而部分还原通常会导致每个抗体零、二、四、六或八个药物的异质混合物。
通过在突变的抗体的合适位置上经由工程化半胱氨酸残基的侧链将接头-药物与抗体缀合来产生位点特异性ADC。工程化半胱氨酸通常被其他硫醇(例如半胱氨酸或谷胱甘肽)封端(cap)以形成二硫键。这些经封端的残基需要先解封才能发生药物连接。通过以下步骤可实现药物与工程化残基的连接:对天然链间和突变二硫键二者进行还原,然后使用温和的氧化剂(例如CuSO4或脱氢抗坏血酸)对天然链间半胱氨酸进行再氧化,随后将未封端的工程化半胱氨酸与接头-药物进行标准缀合;或者通过使用温和的还原剂以比链间二硫键更高的速率还原突变二硫键,随后将未封端的工程化半胱氨酸与接头-药物进行标准缀合。在最佳条件下,每个抗体将连接两个药物(即药物-抗体比DAR为2)(如果将一个半胱氨酸工程化为mAb的重链或轻链的话)。
在一个优选的实施方案中,根据本发明使用的抗体是抗HER2抗体,甚至更优选抗HER2抗体曲妥珠单抗。
在一个特定的实施方案中,本发明涉及用于制备式(IX)的曲妥珠单抗vc-seco-DUBA ADC的方法,其中所述vc-seco-DUBA接头-药物化合物是用如上所述的根据本发明的方法制备的。2.6-2.9表示2.6至2.9的平均DAR
实施例
实施例1-甲基CBI-氮杂吲哚-苯甲酰胺-MOM-Boc-乙二胺-D(4)的制备
使甲基CBI-氮杂吲哚-苯甲酰胺-MOM(1)(1.0g,1.75mmol)与四氢呋喃(THF)(4.5g)和N,N-二甲基乙酰胺(DMA)(3.0g)的混合物中的4-硝基苯基氯甲酸酯(PNP-Cl)(0.43g,2.12mmol)在三乙胺(Et3N)(0.55g,4.94mmol)存在下,在0℃允许升温至6℃的温度下反应约1.5小时。获得包含甲基CBI-氮杂吲哚-苯甲酰胺-MOM-PNP(2)的浆状物。
在第二步中,将(2-((2-(2-羟基乙氧基)乙基)氨基)乙基)(甲基)-氨基甲酸叔丁酯(3)(0.58g,2.19mmol)溶于DMA(1.7g)中并添加1-羟基苯并三唑水合物(HOBt)(0.35g,2.28mmol)。将该获得的溶液在4℃允许升温至10℃的温度下与所述浆状物反应1.5小时。
反应完成后,将乙酸乙酯(EtOAc)(8.8g)添加到反应混合物,溶液用盐水(11.3g)、饱和碳酸氢钠溶液(3.8g)洗涤并再次用盐水(3.8g)洗涤。分离有机层,并通过碳过滤纯化。在旋转真空蒸发器上蒸发溶剂。将获得的甲基CBI-氮杂吲哚-苯甲酰胺-MOM-Boc-乙二胺-D(4)溶解在丙酮(20g)中,并最终通过碳过滤再次纯化。
粗制产物通过硅胶柱色谱法纯化,用流动相-DCM∶MeOH=97∶3至94∶6洗脱。将合并的产物级分浓缩并真空干燥,以得到甲基CBI-氮杂吲哚-苯甲酰胺-MOM-Boc-乙二胺-D(4)(1.27g,1.48mmol;84%产率,纯度93.82%)。
实施例2-制备vc-seco-DUBA
甲基CBI-氮杂吲哚-苯甲酰胺-乙二胺-D盐酸盐的制备(5)
在清除剂(三异丙基硅烷(0.63g)、水(0.4g)和甲醇(0.3g))的存在下通过1,4-二氧六环中的15%氯化氢(HCl)(7.5g)除去甲基CBI-氮杂吲哚-苯甲酰胺-MOM-Boc-乙二胺-D(4)(1.27g,1.48mmol)的甲氧基甲基(MOM)和叔丁氧基羰基(Boc)。从反应溶液中结晶作为黄色固体的甲基CBI-氮杂吲哚-苯甲酰胺-乙二胺-D盐酸盐(5)。
滤出所获得的黄色固体,用丙酮洗涤,并在氮气和真空下在滤器上干燥,从而得到纯产物(5)(1.0g,1.33mmol;90%产率,≥90%纯度)。
vc-seco-DUBA的制备
在N,N-二异丙基胺(DIPEA)(0.65g,5.10mmol)和HOBt(0.47g,3.16mmol)的存在下使甲基CBI-氮杂吲哚-苯甲酰胺-乙二胺-D盐酸盐(5)(1.0g,1.33mmol)与DMA(17.8g)中的马来酰亚胺-OEG2-val-cit-PABA-PNP(6)(0.98g,1.29mmol)在黑暗中在0℃允许升温至5℃的温度下反应1.5小时。将反应混合物在23至25℃的温度下滴加到水(201.1g)(50至60分钟),并获得vc-seco-DUBA粗制产物的沉淀。搅拌30分钟之后,将沉淀的粗制产物在压力滤器中过滤。用水彻底洗涤滤饼,并在真空和少量氮气流下在滤器中干燥。
首先将vc-seco-DUBA粗制产物进行低压快速色谱法(固定相-硅胶0.040至0.063mm;流动相-二氯甲烷∶甲醇=90∶10)。将符合要求的级分(其中vc-seco-DUBA的UPLC-IN纯度≥90%)收集在烧瓶中,将其过滤并蒸发。通过制备色谱法进行进一步纯化(固定相-硅胶0.015至0.040mm;流动相-二氯甲烷∶甲醇=90∶10至85∶15)。将符合要求的级分(其中vc-seco-DUBA的UPLC-IN纯度≥90%)收集在烧瓶中,并将溶剂转换为DMA。浓缩在最高温度25℃下进行。合并浓缩的溶液,将其通过0.2μm的滤器过滤,并添加至水以沉淀作为黄色细粉末的纯的vc-seco-DUBA(产率:35%至45%;纯度:≥99.0%)。
将产物过滤,用水洗涤,并在滤器中使用氮气和真空在最高25℃的温度下干燥。
比较例-vc-seco-DUBA的制备
vc-seco-DUBA的合成按照WO2011/133039的实施例10中所述的程序进行。
步骤1
将甲基CBI-氮杂吲哚-苯甲酰胺-MOM-Boc-乙二胺-D(4)(0.1mmol)混悬于氯仿(CHCl3)(6ml)中,并在冰中冷却。添加2ml酸(三氟乙酸(TFA)或1,4-二氧六环中的15%HCl(7.5g),并将混合物搅拌3小时。然后将混合物真空浓缩。
步骤2
将剩余物溶于N,N-二甲基甲酰胺(DMF)(4ml)中,将溶液在冰中冷却,并添加马来酰亚胺-OEG2-val-cit-PABA-PNP(6)(0.13mmol)和碱(1mmol,Et3N或DIPEA)。将混合物搅拌2小时,真空浓缩,并将剩余物通过柱色谱法(SiO2,二氯甲烷∶甲醇,1∶0至8∶2)纯化。
以上程序是如下进行的:在第一步中,使用1,4-二氧六环中的HCl或现有技术的酸TFA以除去甲基CBI-氮杂吲哚-苯甲酰胺-MOM-Boc-乙二胺-D(4)的MOM和Boc基团,并在第2步中使用DIPEA或现有技术的碱Et3N以促进甲基CBI-氮杂吲哚-苯甲酰胺-乙二胺-D盐酸盐(5)与马来酰亚胺-OEG2-val-cit-PABA-PNP(6)的偶联反应,以确定酸和碱的选择对制备vc-seco-DUBA的效率的影响。
下表示出了vc-seco-DUBA的产率。
步骤1中使用的酸 | 步骤2中使用的碱 | 分离中间体(5) | 产率(%) |
TFA* | Et3N* | 否 | 52.96 |
TFA | DIPEA | 否 | 29.32 |
1,4-二氧六环中的HCl | Et3N | 是 | 78.76 |
1,4-二氧六环中的HCl | DIPEA | 是 | 82.80 |
*现有技术方法(WO2011/133039)中使用的酸和试剂
如通过HPLC所测定的,在步骤1中使用1,4-二氧六环中的HCl代替TFA导致vc-seco-DUBA的总产率提高25.8%。如通过HPLC所测定的,在步骤2中使用DIPEA代替Et3N导致vc-seco-DUBA的总产率降低了23.6%。然而,如通过HPLC所测定的,在步骤1中使用1,4-二氧六环中的HCl并且在步骤2中使用DIPEA,导致vc-seco-DUBA的总产率提高了29.8%。
Claims (13)
1.式(II)化合物
2.包括使式(III)化合物与1,4-二氧六环中的氯化氢反应以形成根据权利要求1所述式(II)化合物的方法
3.根据权利要求1所述式(II)化合物用于制备式(I)的vc-seco-DUBA的用途
4.用于合成式(I)的vc-seco-DUBA的方法,其包括使根据权利要求1所述式(II)化合物与式(VII)化合物反应以形成式(I)化合物
5.根据权利要求4所述的方法,其中式(II)化合物与式(VII)化合物的反应在N,N-二异丙胺的存在下进行。
6.根据权利要求4所述的方法,其中式(II)化合物与式(VII)化合物的反应在N,N-二甲基乙酰胺中,在N,N-二异丙胺和1-羟基苯并三唑水合物的存在下进行。
7.根据权利要求4至6中任一项所述的方法,其中通过使式(III)化合物与1,4-二氧六环中的氯化氢反应以形成式(II)化合物来制备式(II)化合物
8.根据权利要求7所述的方法,其中通过使式(IV)化合物与4-硝基苯基氯甲酸酯反应来形成式(V)化合物,随后使式(V)化合物与式(VI)化合物在1-羟基苯并三唑水合物的存在下反应以形成式(III)化合物来制备式(III)化合物
9.用于合成式(VIII)的抗体-药物缀合物的方法,其包括根据权利要求4至8中任一项所述的方法以形成式(I)化合物,随后将式(I)化合物与抗体或其抗原结合片段缀合,
其中抗体是抗体或其抗原结合片段,并且m表示1至8的平均药物-抗体比
10.根据权利要求9所述的方法,其中m表示1至6的平均药物-抗体比。
11.根据权利要求9所述的方法,其中m表示1至4的平均药物-抗体比。
12.根据权利要求9至11中任一项所述的方法,其中式(I)化合物与抗HER2抗体曲妥珠单抗缀合。
13.用于合成式(IX)的抗体-药物缀合物的方法,其包括根据权利要求4至8中任一项所述的方法以形成式(I)化合物,随后将式(I)化合物与抗HER2抗体曲妥珠单抗缀合,其中2.6-2.9表示2.6至2.9的平均药物-抗体比
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2018
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- 2018-11-22 CN CN201880075808.2A patent/CN111556870B/zh active Active
- 2018-11-22 PL PL18811180T patent/PL3713939T3/pl unknown
- 2018-11-22 EP EP18811180.1A patent/EP3713939B1/en active Active
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WO2011133039A2 (en) * | 2010-04-21 | 2011-10-27 | Syntarga B.V. | Novel conjugates of cc-1065 analogs and bifunctional linkers |
CN106456794A (zh) * | 2014-05-22 | 2017-02-22 | 斯索恩生物制药有限公司 | 接头药物与抗体的位点特异性缀合以及所得adc |
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CA3083169A1 (en) | 2019-05-31 |
US20200368362A1 (en) | 2020-11-26 |
PT3713939T (pt) | 2021-09-16 |
AU2018371966A1 (en) | 2020-06-18 |
JP2021504351A (ja) | 2021-02-15 |
DK3713939T3 (da) | 2021-09-13 |
CY1124480T1 (el) | 2022-07-22 |
RU2020120838A (ru) | 2021-12-24 |
PL3713939T3 (pl) | 2021-12-13 |
KR20200091431A (ko) | 2020-07-30 |
LT3713939T (lt) | 2021-10-25 |
JP7279042B2 (ja) | 2023-05-22 |
RU2020120838A3 (zh) | 2022-03-03 |
HRP20211435T1 (hr) | 2022-01-07 |
EP3713939A1 (en) | 2020-09-30 |
HUE055305T2 (hu) | 2021-11-29 |
ES2889775T3 (es) | 2022-01-13 |
AU2018371966B2 (en) | 2021-02-25 |
WO2019101850A1 (en) | 2019-05-31 |
CN111556870A (zh) | 2020-08-18 |
EP3713939B1 (en) | 2021-07-21 |
US11633492B2 (en) | 2023-04-25 |
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