CN107469089A - 一种peg连接子及配基药物偶联物 - Google Patents
一种peg连接子及配基药物偶联物 Download PDFInfo
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Abstract
本发明提供一种PEG连接子,具有如下式(I)所示的通式,其中,PEG连接子具有1~49个连接位点。本发明还提供一种配基药物偶联物,通过PEG连接子提高配基药物偶联物的药物载量和药物种类,使配基药物偶联物连接低毒性药物分子成为可能,从而扩展治疗窗口;此外,本发明PEG连接子中各连接位点分布均匀,避免药物局部密集分布造成疏水性间聚集从而造成药效降低的问题。Y1‑PEG1‑{R1‑PEG2‑{Y4}n}m(Ⅰ)。
Description
技术领域
本发明涉及配基药物偶联物(Ligand Drug Conjugates,LDC)领域,特别涉及一种具有PEG连接子的配基药物偶联物及包括该配基药物偶联物的药物组合物及其制备方法和应用。
背景技术
抗体偶联药物(Antibody-Drug Conjugates,ADC)的问世对癌症的治疗产生了革命性的影响。ADC通过一个连接子将具有生物学活性的小分子药物连接到单克隆抗体(Monoclonal Antibody,MAb)上,MAb作为载体将小分子药物靶向运输到目标细胞中,这不仅提高了单抗的抗癌效果,还能够减少小分子药物的毒性。目前,两个商品化的ADC和在治疗霍奇金淋巴瘤和乳腺癌方面取得了很好的效果,其中,利用抗体半胱氨酸的巯基与马来酰亚胺连接子偶联,利用抗体赖氨酸的氨基与连接子生成酰胺键。
目前的研究中,存在一种假设,药物载量越高,疗效越好,而实际的体内药效结果与此假设有悖,Hamblett等发现偶联有4个或者8个药物的奥瑞他汀在小鼠动物模型中发挥相似的活性(Hamblett等,Clinical Cancer Res.10:7063-70,2004)。Hamblett等进一步报导越高载量的ADC在动物体内越容易被清除,与低载量偶联药物相比,这种快速清除性状在高载量偶联药物中呈现PK依赖性。Hamblett等还发现高载量偶联药物在小鼠模型中表现出更低的药物耐受剂量(MTD),进而导致更窄的治疗窗。有研究报道表面,具有2个药物载量的ADC与携带4个药物的ADC比较,前者具有更好的PK特征和治疗窗(Junutula等,ClinicalCancer Res.16:4769,2010)。
连接子对于确定ADC的治疗潜能具有根本性的作用,就有效输送疏水性细胞毒性药物来说,若连接子本身都是疏水性的,这会增加偶联物聚集或降低抗体的亲和力,尤其在高药物负载时。同时,耐药肿瘤细胞可能会限制ADC的活性,大多数时候是由药物转运蛋白表达或活性增加、加快疏水性化合物外排造成的。因此,ADC的设计和开发所面临的一个挑战是生成适用于抗体和药物偶联的亲水性连接子。通过使用此种亲水性连接子,可达到更高的药物负载,并可将较高浓度的毒素传递至靶细胞。
本发明通过在配基药物偶联物中使用PEG连接子,能够达到掩盖药物或偶联物的疏水性,从而使得偶联物可以携带更多的药物,并保持与低药物载量偶联物一致的药代动力学等其它特征。此外,配基药物偶联物被进一步设计,保证在高药物载量的前提下,药物分子可选择低毒性分析,有效避免了因药物释放对个体损伤。此外,本发明PEG连接子中各连接位点分布均匀,避免药物(多为疏水性)局部密集分布造成疏水性间聚集从而造成药效降低的问题。
发明内容
本发明的一个目的是提供一种高载量、高纯度的PEG连接子。
本发明的另一个目的是提供一种高载量、低毒性的配基药物偶联物及其药学上可接受的盐和药物组合物。
本发明的还一个目的是提供一种高载量、低毒性配基药物偶联物的制备方法和应用。
为实现上述目的,本发明一方面提供了一种PEG连接子,具有通式(Ⅰ)所示的结构:
Y1-PEG1-{R1-PEG2-{Y4}n}m
(Ⅰ)
其中,
PEG1和PEG2为相同或不同的聚乙二醇残基;
m为1~7的整数,优选的,m为2~7的整数;
n为1~7的整数,优选的,n为2~7的整数;
R1为连接PEG1和PEG2的连接单元;
Y1具有Z1-X1-的结构,Y4具有-X4-Z4的结构;
其中,X1和X4独立的选自以下基团组成的组:-(CH2)i-、-(CH2)iNH-、-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCONH-、-(CH2)iNHCO-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-,i为从0-10的整数;优选的,i为0,1或2;
Z1选自以下基团组成的组:琥珀酰亚胺、巯基、羧基、丙酸基、醛基、丙烯酸基、戊二酸基、马来酰亚胺基、N-羟基-琥珀酰亚胺基、N-羟基-戊二酰亚胺基、琥珀酰亚胺碳酸酯基、琥珀酰亚胺乙酸酯基、琥珀酰亚胺丙酸酯基、琥珀酰亚胺琥珀酸酯基、亚胺酸酯基、对硝基苯碳酸酯基、三聚氰酰氯基、邻二硫吡啶基、巯酯基、酰肼基、异氰酸基、异硫氰酸基、乙烯砜;
Z4为羧酸、羟基或羰基。
在本发明实施方式中,所述PEG连接子具有1~49个连接位点,可与1~49个药物分子偶联。例如,当m为1,n为1时,偶联1个药物分子;当m为1,n为2时,偶联2个药物分子;当m为2,n为2时,偶联4个药物分子;当m为2,n为3时,偶联6个药物分子;当m为3,n为3时,偶联9个药物分子;当m为3,n为7时,偶联21个药物分子;当m为7,n为7时,偶联49个药物分子。
在本发明一具体实施方式中,优选的,m为2~7的整数(即2,3,4,5,6,7),n为2~7的整数(即2,3,4,5,6,7),所述配基药物偶联物能够偶联2-49个药物分子,更优选的,偶联4~49、6~42、9~36、12~30、15~25、21~24个药物分子。
在本发明实施方式中,通式(Ⅰ)所示PEG连接子中,其中所述连接PEG1和PEG2的连接单元R1的一种形式是硫醇反应性的,且活性端基独立的选自:巯基、巯基反应性基团,所述巯基反应性基团能够与巯基反应生成硫醚键或二硫键,包括但不限于:马来酰亚胺基、戊二酸基、乙烯砜基、卤代乙酰胺基、二硫化吡啶基、硫代磺酸酯基、乙烯亚胺、氮丙啶基、氨基磺酰基;所述巯基反应性基团优选自:巯基、马来酰亚胺基、乙烯砜基、卤代乙酰氨基。
在本发明另一具体实施方式中,其中所述连接PEG1和PEG2的连接单元R1的另一种形式是通过点击反应完成,且活性端基独立的选自叠氮基和炔基。
本发明所述PEG连接子可用于配基药物偶联物的制备。
本发明另一方面提供了一种配基药物偶联物,所述配基药物偶联物具有通式(Ⅱ)所示的结构:
TM-{R2-PEG1-{R1-PEG2-{R3-A’-药物}n}m}l
(Ⅱ)
其中,
TM:配基单元;
PEG1和PEG2为相同或不同的聚乙二醇残基;
l为1~10的整数(即1,2,3,4,5,6,7,8,9,10);
m为1~7的整数(即1,2,3,4,5,6,7);
n为1~7的整数(即1,2,3,4,5,6,7);
A’为视情况存在的间隔物;
R1为连接PEG1和PEG2的连接单元;
R2为连接配基单元与PEG1的偶联单元;
R3为连接PEG2和间隔物A’或药物的连接单元。
在本发明实施方式中,所述配基单元具备1~10个连接位点,可任选的,PEG连接子与任意一个或多个配基单元的连接位点相连。例如,当l为1时,配基单元的任意一个连接位点与一个PEG连接子相连;当l为2时,配基单元的任意两个连接位点分别与两个PEG连接子相连。
在本发明一个具体实施方式中,优选的,l为1~8的整数,更优选的,l为1~4的整数,最优选的,l为1,2或3。
在本发明实施方式中,当存在一个PEG连接子时,所述配基药物偶联物能够偶联1~49个药物分子。例如,当m为1,n为1时,偶联1个药物分子;当m为1,n为2时,偶联2个药物分子;当m为2,n为2时,偶联4个药物分子;当m为2,n为3时,偶联6个药物分子;当m为3,n为3时,偶联9个药物分子;当m为3,n为7时,偶联21个药物分子;当m为7,n为7时,偶联49个药物分子。当存在2个PEG连接子时,所述配基药物偶联物能够偶联2~98个药物分子。当存在3个PEG连接子时,所述配基药物偶联物能够偶联3~147个药物分子。
在本发明一具体实施方式中,优选的,n为1~3(即1,2,3)的整数,m为2~7的整数(即2,3,4,5,6,7),n为2~7的整数(即2,3,4,5,6,7),所述配基药物偶联物能够偶联2-147个药物分子,更优选的,偶联3~147、6~126、9~108、15~75、21~63个药物分子。
在本发明实施方式中,通式(Ⅱ)所示的配基药物偶联物中,优选的,所述TM配基单元为疾病靶向单元,所述疾病靶向部分可为抗体、蛋白质、多肽或寡核苷酸,其中所述抗体包括单克隆抗体、多克隆抗体,优选为单克隆抗体,更优选为内化单克隆抗体。本发明中,抗体其形式可例如为:嵌合抗体、人源化抗体、人抗体、可与抗原结合的抗体片段(Fab、Fab’、F(ab)2、F(ab’)2)、亚片段(单链构建体)或者抗体Fc融合蛋白等。
本发明一具体实施方式中,优选的,所述单克隆抗体对癌症、恶性细胞、感染性生物或自身免疫性疾病相关的抗原或其表位是反应性的。
本发明一具体实施方式中,优选的,所述单克隆抗体选自:抗HER2抗体、抗EGFR抗体、抗PMSA抗体、抗VEGFR抗体、抗CD30抗体、抗CD22抗体、抗CD56抗体、抗CD29抗体、抗GPNMB抗体、抗CD138抗体、抗CD74抗体、抗ENPP3抗体、抗Nectin-4抗体、抗EGFR Ⅷ抗体、抗SLC44A4抗体、抗mesothelin抗体(抗间皮素抗体)、抗ET8R抗体、抗CD37抗体、抗CEACAM5抗体、抗CD70抗体、抗MUC16抗体、抗CD79b抗体、抗MUC16抗体、抗Muc1抗体。
本发明一具体实施方式中,优选的,所述抗原选自:HER-2/neu、碳酸酐酶Ⅸ、B7、CCCL19、CCCL21、CSAp、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM-6、甲胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1、EGP-2、EGF受体(ErbB1)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga733、GROB、HMGB-1、缺氧诱导因子(HIF)、HM1.24、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节糖苷、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞移动抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5、胎盘生长因子(PIGF)、PSA、PSMA、PSMA二聚物、PAM4抗原、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、RANTES、T101、癌干细胞抗原、补体因子C3、C3a、C3b、C5a、C5和致癌基因产物等。
在本发明实施方式中,通式(Ⅱ)所示的配基药物偶联物中,所述A’间隔物选自化学不稳定连接子(如腙和二硫化物连接子);酶催化连接子(如肽连接子、β-葡糖甘酸连接子、酯酶不稳定的碳酸盐连接子);不可裂解连接子(丁二酰亚胺-硫醚键);一个或多个相同或不同的氨基酸残基或其衍生物;所述氨基酸选自:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸;优选的,所述氨基酸选自:天冬氨酸、谷氨酸、甘氨酸、异亮氨酸、亮氨酸、苯丙氨酸和缬氨酸。
在本发明一具体实施方式中,优选的,所述A’间隔物为碳酸酯残基、β-葡糖甘酸残基或一个或多个相同或不同的氨基酸残基或其衍生物。
在本发明一具体实施方式中,优选的,所述氨基酸选自:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸等。更优选的,所述氨基酸选自:天冬氨酸、谷氨酸、甘氨酸、异亮氨酸、亮氨酸、苯丙氨酸和缬氨酸。
在本发明一具体实施方式中,优选的,所述A’为碳酸酯残基、β-葡糖甘酸残基、缬氨酸残基、天冬氨酸-缬氨酸残基、谷氨酸-缬氨酸残基。
在本发明一具体实施方式中,通式(Ⅱ)所示的配基药物偶联物中,其中所述连接PEG1和PEG2的连接单元R1的一种形式是硫醇反应性的,且活性端基独立的选自:巯基、巯基反应性基团,所述巯基反应性基团能够与巯基反应生成硫醚键或二硫键,包括但不限于:马来酰亚胺基、戊二酸基、乙烯砜基、卤代乙酰胺基、二硫化吡啶基、硫代磺酸酯基、乙烯亚胺、氮丙啶基、氨基磺酰基;所述巯基反应性基团优选自:巯基、马来酰亚胺基、乙烯砜基、卤代乙酰氨基。
在本发明另一具体实施方式中,通式(Ⅱ)所示的配基药物偶联物中其中所述连接PEG1和PEG2的连接单元R1的另一种形式是通过点击反应完成,且活性端基独立的选自叠氮基和炔基。
在本发明实施方式中,通式(Ⅱ)所示的配基药物偶联物中,其中所述连接配基单元与PEG1的偶联单元R2具有-B-A-结构,其中:
A选自:-(CH2)i-、-(CH2)iNH-、-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCONH-、-(CH2)iNHCO-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-,i为从0-10的整数;优选的,i为0,1或2;
B选自:马来酰亚胺基、羧基、巯基、琥珀酰亚胺碳酸酯基、琥珀酰亚胺乙酸酯基、琥珀酰亚胺丙酸酯基、琥珀酰亚胺琥珀酸酯基、N-羟基-琥珀酰亚胺基、N-羟基-戊二酰亚胺基、亚胺酸酯基、对硝基苯碳酸酯基、三聚氰酰氯基、邻二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、戊二酸基、酰肼基、异氰酸基、异硫氰酸基、乙烯砜基。
在本发明一具体实施方式中,通式(Ⅱ)所示的配基药物偶联物中,所述连接配基单元与PEG1的偶联单元R2是通过配基单元的氨基与PEG1的活性端基相结合生成酰胺键,并选自以下组:琥珀酰亚胺琥珀酸酯(succinimidyl succinate,SS),琥珀酰亚胺碳酸酯(succinimidyl carbonate,SC),mPEG-亚氨酸酯(mPEG-imidate),对硝基苯碳酸酯(para-nitrophenylcarbonate,NPC),琥珀酰亚胺丙酸酯(succinimidyl propionate,SPA)以及三聚氰酰氯(cyanuric chloride)。
本领域技术人员知晓,配基单元上可与PEG1反应的常见基团还包括:-NH-、OH-、SH-、COOH-,此外还包括精氨酸的胍基、组氨酸的咪唑基、糖蛋白的糖基(含醛基、羟基、伯氨基、羧基、磷酸基等)。
在本发明实施方式中,通式(Ⅱ)所示的配基药物偶联物中,其中所述连接PEG2和间隔物A’或药物的连接单元R3选自-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCONH-、-(CH2)iNHCO-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-,i为从0-10的整数;优选的,i为0,1或2。
在本发明实施方式中,通式(Ⅱ)所示的配基药物偶联物中,其中所述药物选自:伊立替康、拓扑替康、贝洛替康、依沙替康、卢托替康、二氟替康、吉尼替康、卡尼替康、阿霉素(DOX)、表柔比星、吗啉代阿霉素、氰基吗啉代-阿霉素、2-吡咯啉基阿霉素、喜树碱(CPT)、10-羟基喜树碱、SN-38、9-氨基喜树碱、9-硝基喜树碱、紫杉烷、格尔德霉素、袢霉素和埃坡霉素。
在本发明一具体实施方式中,优选的,通式(Ⅱ)所示的配基药物偶联物中,其中所述药物选自:伊立替康、拓扑替康、贝洛替康、依沙替康、卢托替康、二氟替康、吉尼替康、卡尼替康、喜树碱(CPT)、10-羟基喜树碱、SN-38、9-氨基喜树碱和9-硝基喜树碱。更优选的,所述药物是伊立替康。
在本发明一具体实施方式中,优选的,通式(Ⅱ)所示的配基药物偶联物中,所述药物为低毒性药物。具体的,当药物为低毒性药物时,配基药物偶联物包含更多的药物分子。
在本发明一具体实施方式中,所述配基药物偶联物选自:APEGA-2(TM-NHS-4ARMPEG1-(MAL)3-(SH)-PEG2-伊立替康)、APEGA-4(TM-NHS-4ARMPEG1-(MAL)3-(SH)-4ARMPEG2-(伊立替康)3)、APEGA-5(TM-NHS-4ARMPEG1-(MAL)3-(SH)-8ARMPEG2-(伊立替康n)7)、APEGA-6(TM-NHS-8ARMPEG1-(MAL)7-(SH)-4ARMPEG2-(伊立替康)3),其结构如下所示:
其中,上述结构中TM为配基单元,优选的,TM为单克隆抗体;Val为缬氨酸;Iri为伊立替康;n可相同或不同,分别独立的选自1-240的整数,优选的,为1-120的整数,更优选的,为1-60的整数。
在本发明实施方式中,通式(Ⅰ)所示的PEG连接子或通式(Ⅱ)所示的配基药物偶联物中,其中所述PEG1为具有1-240个单体单元的确定的聚乙二醇残基,优选为具有1-120个单体单元的确定的聚乙二醇残基。
在本发明实施方式中,通式(Ⅰ)所示的PEG连接子或通式(Ⅱ)所示的配基药物偶联物中,所述PEG1为直链、Y型、多分支的聚乙二醇残基,例如包括直链双端PEG、Y型PEG、4臂支链PEG、6臂支链PEG或8臂支链PEG等,优选为Y型、多分支聚乙二醇残基。PEG的分子量为1~100KDa之间,例如1~20KDa(具体可为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20KDa),20~50KDa(具体可为20,25,30,35,40,45,50KDa),50~100KDa(具体可为50,55,60,65,70,75,80,85,90,95,100KDa)等;优选的,PEG的分子量为1~20KDa,更优选为1~10KDa,例如1~5KDa,5~10KDa。
在本发明一具体实施方式中,所述PEG1为直链聚乙二醇残基,具有如下所示的结构:
其中,p是1~240的整数,优选为1-120的整数。
在本发明一具体实施方式中,所述PEG1为Y型聚乙二醇残基,具有通式(Ⅲ)的结构:
其中,i是1~120的整数,优选为1-60的整数。
在本发明一具体实施方式中,所述PEG1为多分支聚乙二醇残基,具有通式(Ⅳ)的结构:
其中:k是1~80的整数,优选为1-40的整数;
J是3~8的整数;
R是多分支聚乙二醇的核心分子,R选自季戊四醇、寡聚季戊四醇、甲基葡萄糖苷、蔗糖、二甘醇、丙二醇、甘油和聚甘油的残基,优选的,R选自季戊四醇、二聚季戊四醇和三聚季戊四醇。
在本发明实施方式中,通式(Ⅰ)所示的PEG连接子或通式(Ⅱ)所示的配基药物偶联物中,其中所述PEG2为具有1-240个单体单元的确定的聚乙二醇残基,优选为具有1-120个单体单元的确定的聚乙二醇残基。
在本发明实施方式中,通式(Ⅰ)所示的PEG连接子或通式(Ⅱ)所示的配基药物偶联物中,所述PEG2为直链、Y型、多分支的聚乙二醇残基,例如包括直链双端PEG、Y型PEG、4臂支链PEG、6臂支链PEG或8臂支链PEG等,优选为Y型、多分支聚乙二醇残基。PEG的分子量为1~100KDa之间,例如1~20KDa(具体可为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20KDa),20~50KDa(具体可为20,25,30,35,40,45,50KDa),50~100KDa(具体可为50,55,60,65,70,75,80,85,90,95,100KDa)等;优选的,PEG的分子量为1~20KDa,更优选为1~10KDa,例如1~5KDa或5~10KDa。
在本发明一具体实施方式中,所述PEG2为直链聚乙二醇残基,具有通式(Ⅱ)的结构:
其中,p是1~240的整数,优选为1-120的整数。
在本发明一具体实施方式中,所述PEG2为Y型聚乙二醇残基,具有通式(Ⅲ)的结构:
其中,i是1~120的整数,优选为1-60的整数。
在本发明一具体实施方式中,所述PEG2为多分支聚乙二醇残基,具有通式(Ⅳ)的结构:
其中:k是1~80的整数,优选为1-40的整数;
J是3~8的整数;
R是多分支聚乙二醇的核心分子,R选自季戊四醇、寡聚季戊四醇、甲基葡萄糖苷、蔗糖、二甘醇、丙二醇、甘油和聚甘油的残基,优选的,R选自季戊四醇、二聚季戊四醇和三聚季戊四醇。
本发明还提供本发明配基药物偶联物药学上可接受的盐,所述药学上可接受的盐包括有机盐或无机盐,包括但不限于:钠盐、钾盐、铯盐、钙盐、镁盐、三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己基胺盐、N,N-二苄基乙二胺盐、盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、泛酸盐、琥珀酸盐、枸橼酸盐、酒石酸盐、富马酸盐、马来酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、苯甲酸盐、乳酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、精氨酸盐、天冬氨酸盐、谷氨酸盐、泛酸盐、抗坏血酸盐,及上述盐的组合。
本发明还提供包含本发明的配基药物偶联物以及其与药学上可接受的载体或赋形剂的药物组合物。
在本发明实施方式中,根据所需给药方式,药学上可接受的组合物将包含约1至约99重量%的本发明结合物、以及99至1重量%的适宜的载体或药用赋形剂。优选组合物包含约5至75重量%的本发明结合物,其余为适宜的载体或药用赋形剂。更优选组合物包含约10至50重量%的本发明结合物,其余为适宜的载体或药用赋形剂。
在本发明实施方式中,本发明的药物组合物还可包含少量的辅助物质,如润湿剂或乳化剂、pH缓冲剂、抗氧化剂等,例如:柠檬酸、脱水山梨醇单月桂酸酯、三乙醇胺油酸酯、丁基化羟基甲苯等。
在本发明实施方案中,所述的药物组合物为片剂、胶囊剂、丸剂、颗粒剂、散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、洗剂、滴剂、擦剂、喷雾剂等剂型。
在本发明实施方式中,本发明的结合物可以纯化合物形式或适宜的药物组合物形式进行给药,可采用任何可接受的给药方式或用于类似的用途的试剂进行。因此,采用的给药方式可选择通过口、鼻内、非肠道、局部、透皮或直肠方式,其形式为固体、半固体或液体药剂形式给药,例如,片剂、栓剂、丸剂、软和硬明胶胶囊剂、散剂、溶液剂、混悬剂和注射剂等,优选采用适用于精确剂量的简单给药的单元剂量形式。
可采用液体形式给药的药物组合物例如可通过溶解、分散等手段将本发明的结合物(约0.5至约20%)和选择性存在的药用辅剂溶解、分散于载体中,载体的实例为水、盐水、含水葡萄糖、甘油、乙醇等,从而形成溶液剂或混悬剂。
本发明另一方面提供了一种本发明配基药物偶联物或其盐以及药物组合物在疾病预防和/或治疗药物中的应用。
本发明实施方式中,所述疾病为癌症、病原性生物感染或自身免疫性疾病。
其中,所述癌症是造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤。
其中,所述病原性生物选自由以下组成的组:人免疫缺陷病毒(HIV)、结核分枝杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病柰瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、西尼罗病毒、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病毒、流感病毒、巨细胞病毒、Ⅰ型单纯疱疹病毒、Ⅱ型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼长孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫。
其中,所述自身免疫性疾病选自由以下组成的组:免疫介导的血小板减少症、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈症、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、类风湿性关节炎、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强制性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、原发性胆汁性感应变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急性肾小球肾炎、纤维化肺泡炎和青少年糖尿病。
本发明还提供一种疾病治疗的方法,所述方法包括向受治疗者施用本发明所述配基药物偶联物或其药学上可接受的盐或药物组合物。
在本发明一具体实施方式中,所述配基药物偶联物或其药学上可接受的盐或药物组合物与选自以下一种或多种治疗方法联合施用:未共轭抗体、放射性标记抗体、药物-共轭抗体、毒素-共轭抗体、基因疗法、化疗、治疗肽、寡核苷酸、局部放疗、手术和干扰RNA疗法。
在本发明实施方式中,所述疾病是癌症、病原性生物感染或自身免疫性疾病。
其中,所述癌症是造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤。
其中,所述病原性生物选自由以下组成的组:人免疫缺陷病毒(HIV)、结核分枝杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病柰瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、西尼罗病毒、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病毒、流感病毒、巨细胞病毒、Ⅰ型单纯疱疹病毒、Ⅱ型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼长孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫。
其中,所述自身免疫性疾病选自由以下组成的组:免疫介导的血小板减少症、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈症、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、类风湿性关节炎、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强制性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、原发性胆汁性感应变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急性肾小球肾炎、纤维化肺泡炎和青少年糖尿病。
本发明还一方面提供了一种配基药物偶联物的制备方法,所述制备方法的合成路线示意如下:
(1)PEG1+修饰基团=[PEG-1],
(2)[PEG-1]+配基单元=配基单元-[PEG-1](化合物A),
(3)PEG2+修饰基团=[PEG-2],
(4)药物+[PEG-2]=[PEG-2]-药物(化合物B),
(5)化合物A+化合物B=配基药物偶联物;
或者,
(1)PEG1+修饰基团=[PEG-1],
(2)PEG2+修饰基团=[PEG-2],
(3)药物+[PEG-2]=[PEG-2]-药物(化合物B),
(4)[PEG-1]+化合物B=[PEG-1]-[PEG-2]-药物(化合物C),
(5)配基单元+化合物C=配基药物偶联物;
或者,
(1)PEG1+修饰基团=[PEG-1],
(2)PEG2+修饰基团=[PEG-2],
(3)[PEG-1]+[PEG-2]=[PEG-1]-[PEG-2](化合物D),
(4)化合物D+药物=[PEG-1]-[PEG-2]-药物(化合物C),
(5)配基单元+化合物C=配基药物偶联物。
在本发明实施方式中,所述[PEG-1]为双端或多端修饰的聚乙二醇残基,至少一端包含与配基单元连接的活性端基Z1,至少一端包含与PEG2连接的活性端基Z2;
所述活性端基Z1选自琥珀酰亚胺、巯基、羧基、丙酸基、醛基、丙烯酸基、戊二酸基、马来酰亚胺基、N-羟基-琥珀酰亚胺基、N-羟基-戊二酰亚胺基、琥珀酰亚胺碳酸酯基、琥珀酰亚胺乙酸酯基、琥珀酰亚胺丙酸酯基、琥珀酰亚胺琥珀酸酯基、亚胺酸酯基、对硝基苯碳酸酯基、三聚氰酰氯基、邻二硫吡啶基、巯酯基、酰肼基、异氰酸基、异硫氰酸基、乙烯砜;
所述活性端基Z2选自:乙炔基、叠氮基、巯基、巯基反应性基团,所述巯基反应性基团能够巯基反应生成硫醚键或二硫键,包括但不限于:马来酰亚胺基、戊二酸基、乙烯砜基、卤代乙酰胺基、二硫化吡啶基、硫代磺酸酯基、乙烯亚胺、氮丙啶基、氨基磺酰基;
所述[PGE-2]为双端或多端修饰的聚乙二醇残基,至少一端包含与所述活性端基Z2反应的活性端基Z3,至少一端包含有活性端基Z4;
所述活性端基Z3选自:乙炔基、叠氮基、巯基、巯基反应性基团,所述巯基反应性基团能够巯基反应生成硫醚键或二硫键,包括但不限于:马来酰亚胺基、戊二酸基、乙烯砜基、卤代乙酰胺基、二硫化吡啶基、硫代磺酸酯基、乙烯亚胺、氮丙啶基、氨基磺酰基;
所述活性端基Z4为羧酸、羟基或羰基。
在本发明实施方式中,所述活性端基Z1和Z2、Z3、Z4与聚乙二醇残基之间根据实际需求,还可包括连接基团,所述连接基团包括但不限于:-(CH2)i-、-(CH2)iNH-、-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCONH-、-(CH2)iNHCO-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-,i为从0-10的整数;优选的,i为0,1或2。
与现有技术相比,本发明具有如下有益效果:
本发明配基药物偶联物采用PEG连接子用于偶联药物和配基单元,其中,在本发明优选的方式中,通过分支或多臂PEG连接多个药物分子,提高药物载量;同时由于PEG亲水性的特点,在保证高药物载量的同时,还保证其药代动力学特征与低载量抗体偶联药物接近。
本发明配基药物偶联物具备高载量、高药效、低毒、低风险特征,在优选的方式中,尤其可用于连接低毒性药物分子,从而扩展治疗窗口。
进一步的,本发明提供的PEG连接子,将两个或多个PEG采用分步连接的方式获得,纯度高,制备简单,克服了传统多臂PEG(尤其是8臂以上PEG)纯度较低,难以应用的瓶颈。此外,本发明PEG连接子中各连接位点分布均匀,使药物的分散分布更均匀,避免药物(多为疏水性)局部密集分布造成疏水性间聚集从而造成药效降低的问题。
附图说明
图1为大鼠药代动力学图谱(总抗体浓度,μg/mL Vs时间,天),Ab:裸抗;APEGA-2:抗体药物偶联物(四臂+单臂);APEGA-4:抗体药物偶联物(四臂+四臂);APEGA-5:抗体药物偶联物(四臂+八臂);APEGA-6:抗体药物偶联物(八臂+四臂)
图2为胃癌模型(NCI-N87)中平均肿瘤体积对应肿瘤移植后天数图谱,注射剂量30mg/kg。Ab:裸抗;APEGA-2:抗体药物偶联物(四臂+单臂);APEGA-4:抗体药物偶联物(四臂+四臂);APEGA-5:抗体药物偶联物(四臂+八臂);APEGA-6:抗体药物偶联物(八臂+四臂)
图3为卵巢癌模型(SKOV-3)平均肿瘤体积对应肿瘤移植后天数图谱,注射剂量30mg/kg。Ab:裸抗;APEGA-2:抗体药物偶联物(四臂+单臂);APEGA-4:抗体药物偶联物(四臂+四臂);APEGA-5:抗体药物偶联物(四臂+八臂);APEGA-6:抗体药物偶联物(八臂+四臂)
具体实施方式
除另有说明,本文中出现的如下术语具有以下含义。
本文的术语“抗体”以其最广泛的含义使用并且特别覆盖单克隆抗体、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,只要它们表现出所需的生物活性(Miller等(2003)Jour.of Immunology,170:4854-4861)。抗体可以为鼠、人、人源化、嵌合抗体或来源于其它物种。抗体为由能够识别和结合特异性抗原的免疫系统产生的蛋白质(Janeway,C.等(2001)ImmunoBiology,5th Ed.,Garland Publishing,NewYork)。靶抗原一般具有由多种抗体的CDRsa识别的大量结合位点,也称作表位。特异性结合不同表位的各抗体具有不同的结构。因此,一种抗原可以具有一种以上相应的抗体。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,即含有特异性结合所关注靶标的抗原或其部分的分子,这类靶标包括,但不限于癌细胞或产生与自身免疫性疾病相关的自身免疫抗体的细胞。特别的,本发明抗体对癌细胞、恶性细胞、感染性生物或自身免疫性疾病相关的抗原或其表位是反应性的。本文披露的免疫球蛋白可以具有免疫球蛋白分子的任意类型(例如IgG、IgE、IgM、IgD和IgA)、类别(例如IgG1、IgG2、IgG3、IgG4、IgA、IgA2)或亚类。免疫球蛋白可以来源于任意的物种。然而,在一个方面中,免疫球蛋白来源于人、鼠或兔。
本文的术语“抗体片段”包含全长抗体的一部分,一般为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;微抗体(minibody)(Olafsen等(2004)Protein Eng.Design&Sel.17(4):315-323);Fab表达文库制备的片段;抗-独特型(抗-Id)抗体;CDR(互补决定区);和以免疫特异性方式结合癌细胞抗原、病毒抗原或微生物抗原的上述任意的表位-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。
本文的术语“单克隆抗体”指从基本上同质的抗体群中获得的抗体,即除可能少量存在的天然发生的可能突变之外,包含在该群体中的各抗体是相同的。单克隆抗体是高度特异的靶向单个抗原位点的抗体。而且,与典型地包括靶向不同决定簇(表位)的不同抗体的多克隆抗体制品相反,每种单克隆隆抗体只靶向抗原上的单一决定簇。除其特异性外,单克隆抗体上的优点还在于他们可以以不被其它抗体污染的方式合成。修饰语“单克隆”表示获自基本上同质的抗体群的抗体特性,并非解释为需要由任何特定方法生产抗体。例如,可以通过首先由Kohler等(1975)Nature256:495描述的杂交瘤方法制备用于本发明的单克隆抗体或可以通过重组DNA方法制备(例如:US4816567;US5807715)。例如,还可以使用Clackson等(1991)Nature,352:626-628;Marks等(1991)J.Mol.Biol.,222:581-597所述的技术从噬菌体抗体文库分离单克隆抗体。
本文的“单克隆抗体”特别包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类型或亚型的抗体中的相应序列相同或同源,而所述链的剩余部分与来源于另一物种或属于另一抗体类型或亚型的抗体中的相应序列相同或同源,本文还包括嵌合抗体的片段,只要它们展示期望的生物学活性(US4816567;和Morrison等(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。本文关注的嵌合抗体包括“灵长化(primatized)”抗体,其包含来源于非人的灵长类的可变区抗原-结合序列和人恒定区序列。
本文的术语“完整抗体”包含VL和VH结构域以及轻链恒定域(CL)和重链恒定域CH1、CH2和CH3的抗体。恒定域可以为天然序列恒定域(例如人天然序列恒定域)或其氨基酸序列变体。完整抗体可以具有一种或多种“效应子功能”,意旨归因于抗体的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Clq结合;补体依赖的细胞毒性;Fc受体结合;抗体-依赖性细胞介导的细胞毒作用(ADCC);胞吞作用;和细胞表面受体,诸如B细胞受体和BCR的减量调节。
根据其重链恒定域的氨基酸序列的不同,可以将完整抗体指定为不同“类别”存在5种主要类别的完整免疫球蛋白抗体:IgA、IgD、IgE、IgG和IgM,且可以将其中的几种进一步分成“亚类”(亚型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同抗体类别的重链恒定域分别称作α、δ、ε、γ和μ。不同类别免疫球蛋白的亚单位结构和三维构型为众所周知的。Ig型包括铰链-修饰型或无铰链型(Roux等(1998)J.Immunol.161:4083-4090;Lund等(2000)Eur.J.Biochem.267:7246-7256;US2005/0048572;US2004/0229310)。
本文的术语“亲本抗体”为所含氨基酸序列中的一个或多个氨基酸残基将用一个或多个半胱氨酸残基替代的抗体。亲本抗体可以包括天然或野生型序列。亲本抗体可以包含天然或野生型序列。亲本抗体可以具有相对于其它天然、野生型或修饰形式的抗体而言预先存在的氨基酸序列修饰(诸如添加、缺失和/或替代)。亲本抗体可以针对所关注的靶抗原,例如生物学上重要的多肽。还关注针对非多肽抗原(诸如肿瘤相关糖脂抗原;参见US5,091,178)的抗体。例示性亲本抗体包括对细胞表面和跨膜受体和肿瘤相关抗原(TAA)具有亲和力的选择性抗体。
本文的术语“与抗体接合的抗原”包括但不限于HER-2/neu、碳酸酐酶Ⅸ、B7、CCCL19、CCCL21、CSAp、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM-6、甲胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1、EGP-2、EGF受体(ErbB1)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GROB、HMGB-1、缺氧诱导因子(HIF)、HM1.24、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节糖苷、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞移动抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5、胎盘生长因子(PIGF)、PSA、PSMA、PSMA二聚物、PAM4抗原、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、RANTES、T101、癌干细胞抗原、补体因子C3、C3a、C3b、C5a、C5和致癌基因产物等。
实施例
本发明的多个实施方案通过以下实施例来进行说明,但不用来限制本发明。
实施例中所用的伊立替康从上海龙翔生物医药开发有限公司购得,4-二甲基氨基吡啶(DMAP)及1-羟基苯并三氮唑(HOBT)从上海共价化学科技有限公司购得,其他试剂从国药集团购得,聚乙二醇衍生物由北京键凯科技有限公司提供。
[PEG-1]合成实施例
实施例1:合成四臂聚乙二醇羟基-单乙酸(III-1)
步骤:
三口圆底烧瓶中,通氮气,加入100g四臂聚乙二醇(4ARM-PEG-5K)和800mL四氢呋喃(THF),加热溶解,蒸出约20%溶剂,降温,加入4.48g叔丁醇钾,室温下反应2小时,滴加5.17mL溴乙酸叔丁酯,室温下过夜反应,次日过滤,反应液浓缩至粘稠,加入500mL碱解液(500mL水中加入8.16g氢氧化钠和77.52g磷酸钠),80℃碱解2小时,用2N盐酸溶液调节溶液PH为2-3,向溶液中加入15%氯化钠,用二氯甲烷萃取三次,合并有机相,用无水硫酸钠干燥,过滤,50℃浓缩至粘稠,加入乙醚沉淀,真空干燥。22g粗品配成电导率为100μs/cm的水溶液,DEAE阴离子柱分离,收集电导率为50μs/cm的氯化钠水溶液洗脱液,水相用2N盐酸调PH为2-3,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,浓缩,用乙醚沉淀,得到四臂聚乙二醇羟基-单乙酸(III-1)。
NMR(DMSO)δ:
四臂聚乙二醇羟基-单乙酸(III-1):4.01(s,2H,CH2COOH),4.54(t,3H,CH2OH)。
实施例2:四臂聚乙二醇羟基-单乙酸甲酯(IVA-1)
步骤:
单口圆底烧瓶中,加入3.2g四臂聚乙二醇羟基-单乙酸(III-1),用16mL无水甲醇溶解,冰水浴,滴加0.64mL浓硫酸,室温下反应3小时,用8%碳酸氢钠水溶液调节体系PH为7.0,用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸镁干燥,过滤,40℃浓缩至粘稠,用乙醚沉淀,真空干燥,得四臂聚乙二醇羟基-单乙酸甲酯(IVA-1)。
NMR(DMSO)δ:3.32(s,3H,CH2COOCH3),4.13(s,2H,CH2COOCH3),4.57(t,3H,CH2OH)。
实施例3:四臂聚乙二醇磺酸酯-单乙酸甲酯(IVB-1)
步骤:
三口圆底烧瓶中,通氮气,加入四臂聚乙二醇羟基-单乙酸甲酯3.0g,用50mL甲苯溶解,加热蒸出38mL甲苯至流馏出液清亮,降至室温,加入5mL二氯甲烷,搅拌10分钟,加入188μL三乙胺,搅拌5分钟,滴加入94μL甲基磺酰氯,密闭反应过夜,次日,加入720μL无水乙醇,搅拌15分钟,过滤,60℃浓缩至粘稠,用60mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂聚乙二醇磺酸酯-单乙酸甲酯(IVB-1)。
NMR(DMSO)δ:3.17(s,9H,CH2OSO2CH3),4.13(s,2H,CH2COOCH3),4.30(t,6H,CH2OSO2CH3)。
实施例4:四臂聚乙二醇叠氮-单乙酸甲酯(IVB-2)
步骤:
三口原地烧瓶中,通氮气,加入四臂聚乙二醇磺酸酯-单乙酸甲酯5.0g,叠氮化钠0.351g,用25mLDMF溶解,加热至90℃,反应3小时,降至室温,加入25mL水和15%氯化钠,用二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,浓缩,加入100mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂聚乙二醇叠氮-单乙酸甲酯(IVB-2)。
NMR(DMSO)δ:4.13(s,2H,CH2COOCH3)。
实施例5:四臂聚乙二醇叠氮-单乙酸(IVB-3)
步骤:
100mL烧杯中,加入四臂聚乙二醇叠氮-单乙酸甲酯4.5g,加入脱气水,用0.2N的氢氧化钠调节体系PH为12,室温搅拌反应3小时,用1N盐酸调节体系PH=2-3,加入15%氯化钠,用二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,浓缩,加入90mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂聚乙二醇叠氮-单乙酸(IVB-3)。
NMR(DMSO)δ:4.01(s,2H,CH2COOH)。
实施例6:四臂聚乙二醇叠氮-单乙酸琥珀酰亚胺酯(IVB-4)
步骤:
100mL烧杯中,加入四臂聚乙二醇叠氮-单乙酸2.0g,N,N-羟基琥珀酰亚胺(NHS)56mg,用20mL二氯甲烷溶解,加入165mg二环己基碳二亚胺(DCC),室温下搅拌反应2小时,过滤,浓缩,加入40mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂聚乙二醇叠氮-单乙酸琥珀酰亚胺酯(IVB-4)。
NMR(DMSO)δ:2.83(s,4H,),4.60(s,2H,CH2COO)。
实施例7:合成四臂聚乙二醇胺基-单乙酸(V-1)
步骤:
三口圆底烧瓶中,氮气保护,加入5g四臂聚乙二醇磺酸酯-单乙酸甲酯溶解在7.8mL脱气水中,用2N氢氧化钠水溶液调节溶液PH为12.0,室温下反应2-2.5小时,将26mL溶解有1.3g氯化铵的氨水溶液加入体系,室温下搅拌反应72小时,反应完毕后,加入7g氯化钠,溶解后,用二氯甲烷萃取反应液三次,合并有机相,40℃浓缩至干,加入30mL脱气水搅拌溶解至清亮,用2N盐酸调节溶液PH为2-3,加入5g氯化钠,再次用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸钠干燥至澄清,过滤,40℃浓缩至粘稠,用50mL乙醚沉淀,过滤,真空干燥,得四臂聚乙二醇胺基-单乙酸(V-1)。
NNMR(DMSO)δ:2.96(t,6H,CH2CH2NH2),4.00(s,2H,CH2COOH)。
实施例8:合成四臂聚乙二醇马来亚酰胺基-单乙酸(V-2)
步骤:
单口圆底烧瓶中,加入2.6g四臂聚乙二醇氨基-单乙酸,用二氯甲烷溶解,冰水浴,加入TEA 500μL,加入MAL-NHS 1.06g,室温下搅拌反应12小时以上,40℃浓缩至干,加入30mL脱气水搅拌,用20mL乙酸乙酯洗涤,水相用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸钠干燥至澄清,过滤,40℃浓缩至粘稠,用50mL异丙醇冰水浴沉淀,过滤,真空干燥,得四臂聚乙二醇马来西安亚胺基-单乙酸(V-2)。
NMR(DMSO)δ:2.32(t,6H,),3.13(q,6H,CH2CH2NH),4.00(s,2H,CH2COOH),6.99(s,6H,)。
实施例9:四臂聚乙二醇马来亚酰胺-单乙酸琥珀酰亚胺酯(V-3)
步骤:
100mL烧杯中,加入四臂聚乙二醇马来亚酰胺-单乙酸2.0g,NHS 53mg,用20mL二氯甲烷溶解,加入120mg DCC,室温下搅拌反应2小时,过滤,浓缩,加入40mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂聚乙二醇叠氮-单乙酸琥珀酰亚胺酯(V-3)。
NMR(DMSO)δ:2.32(t,6H,),2.82(s,4H,),3.15(q,6H,CH2CH2NH),4.60(s,2H,CH2COO),6.99(s,6H,)。
实施例10:合成八臂聚乙二醇羟基-单乙酸(III-2)
步骤:
三口圆底烧瓶中,通氮气,加入100g 8ARM-PEG-5000和800mlTHF,加热溶解,蒸出约20%溶剂,降温,加入17.92g叔丁醇钾,室温下反应2小时,滴加20.68ml溴乙酸叔丁酯,室温下过夜反应,次日过滤,反应液浓缩至粘稠,加入1000ml碱解液(1000ml水中加入16.32g氢氧化钠和155.04g磷酸钠),80℃碱解2小时,用2N盐酸溶液调节溶液PH为2-3,在溶液中加入15%氯化钠,用二氯甲烷萃取三次,合并有机相,用无水硫酸钠干燥,过滤,50℃浓缩至粘稠,加入乙醚沉淀,真空干燥。40g粗品配成电导率为100μs/cm的水溶液,DEAE阴离子柱分离,收集电导率为100μs/cm的氯化钠水溶液洗脱液,水相用2N盐酸调PH为2-3,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,浓缩至干,分别得到八臂聚乙二醇羟基-单乙酸(III-2)。
八臂聚乙二醇羟基-单乙酸(III-2):4.01(s,2H,CH2COOH),4.54(t,7H,CH2OH)。
实施例11:八臂聚乙二醇羟基-单乙酸甲酯(IIIB-2)
步骤:
单口圆底烧瓶中,加入4.0g八臂聚乙二醇羟基-单乙酸(III-2),用20ml无水甲醇溶解,冰水浴,滴加0.8ml浓硫酸,室温下反应3小时,用8%碳酸氢钠水溶液调节体系PH为7.0,用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸镁干燥,过滤,40℃浓缩至粘稠至干,得八臂聚乙二醇羟基-单乙酸甲酯(IIIB-2)。
NMR(DMSO)δ:3.32(s,3H,CH2COOCH3),4.13(s,2H,CH2COOCH3),4.57(t,7H,CH2OH)。
实施例12:八臂聚乙二醇磺酸酯-单乙酸甲酯(IIIC-2)
步骤:
三口圆底烧瓶中,通氮气,加入八臂聚乙二醇羟基-单乙酸甲酯3.0g,用50ml甲苯溶解,加热蒸出38ml甲苯至流馏出液清亮,降至室温,加入5ml二氯甲烷,搅拌10分钟,加入878μl三乙胺,搅拌5分钟,滴加入440μl甲基磺酰氯,密闭反应过夜,次日,加入3ml无水乙醇,搅拌15分钟,过滤,60℃浓缩至干,得八臂聚乙二醇磺酸酯-单乙酸甲酯(IIIC-2)。
NMR(DMSO)δ:3.17(s,21H,CH2OSO2CH3),4.13(s,2H,CH2COOCH3),4.30(t,14H,CH2OSO2CH3)。
实施例13:合成八臂聚乙二醇胺基-单乙酸(V-2)
步骤:
单口圆底烧瓶中,加入2.6g八臂聚乙二醇磺酸酯-单乙酸甲酯溶解在7.8ml脱气水中,用2N氢氧化钠水溶液调节溶液PH为12.0,室温下反应2-2.5小时,将26ml溶解有1.3g氯化铵的氨水溶液加入体系,室温下搅拌反应72小时,反应完毕后,加入7g氯化钠,溶解后,用二氯甲烷萃取反应液三次,合并有机相,40℃浓缩至干,加入30ml脱气水搅拌溶解至清亮,用2N盐酸调节溶液PH为2-3,加入5g氯化钠,再次用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸钠干燥至澄清,过滤,40℃浓缩至干得八臂聚乙二醇胺基-单乙酸(V-2)。
NMR(DMSO)δ:2.96(t,14H,CH2CH2NH2),4.00(s,2H,CH2COOH)。
实施例14:合成八臂聚乙二醇马来酰亚胺-单乙酸(VI-2)
步骤:
三口圆底烧瓶中,通氮气,称取2.0g八臂聚乙二醇羟基-单乙酸(III-2)和0.0005gBHT,用20ml二氯甲烷溶解,加入876μl三乙胺,搅拌5-10分钟,加入1.98g MAL-NHS,充氮气,避光,体系密闭搅拌反应过夜,次日,40℃浓缩至粘稠,加入40ml脱气水溶解至清亮,静置30分钟,加入15%氯化钠,用稀盐酸调节体系PH=2-3,用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸钠干燥至澄清,过滤,滤液40℃浓缩至干,得八臂聚乙二醇马来酰亚胺-单乙酸(VI-2)。
NMR(DMSO)δ:2.32(t,14H,),4.00(s,2H,CH2COOH),7.00(s,14H,)。
实施例15:合成八臂聚乙二醇马来酰亚胺-NHS酯(VII-2)
步骤:
三口圆底烧瓶中,通氮气,避光,称取2g八臂聚乙二醇马来酰亚胺-单乙酸(VI-2)和0.12g NHS,用40ml二氯甲烷溶解,固体全部溶解后,加入0.2312g DCC,体系避光密闭搅拌反应过夜,次日,过滤,滤液40℃浓缩至干,得八臂聚乙二醇马来酰亚胺-单NHS酯(VII-2)。
NMR(DMSO)δ:2.32(t,14H,),2.83(s,4H,),4.50(s,2H,),7.00(s,14H,)。
实施例16:合成八臂聚乙二醇叠氮-单乙酸(VI-3)
步骤:
三口圆底烧瓶中,通氮气,称取2.0g八臂聚乙二醇磺酸酯-单乙酸甲酯(IIIC-2)和0.0005g BHT,加入叠氮化钠0.32g,用40mlDMF溶解,加热至90℃,反应3小时,降至室温,加入40ml水和15%氯化钠,用二氯甲烷萃取,有机相用无水硫酸钠干燥至澄清,过滤,滤液40℃浓缩至干,得八臂聚乙二醇叠氮-单乙酸(VI-3)。
NMR(DMSO)δ:4.00(s,2H,CH2COOH)。
实施例17:合成八臂聚乙二醇叠氮-NHS酯(VI-4)
步骤:
三口圆底烧瓶中,通氮气,避光,称取2g八臂聚乙二醇叠氮-单乙酸(VI-3)和0.120g NHS,用40ml二氯甲烷溶解,固体全部溶解后,加入0.2312g DCC,体系避光密闭搅拌反应过夜,次日,过滤,滤液40℃浓缩至干,得八臂聚乙二醇叠氮-单NHS酯(VI-4)。
NMR(DMSO)δ:2.83(s,4H,),4.50(s,2H,(s,2H,)。
实施例18:合成四臂十二甘醇羟基-单乙酸
步骤:
三口圆底烧瓶中,通氮气,加入100g四臂十二甘醇(4ARM-PEG12-OH)和500mL四氢呋喃(THF),加热溶解,蒸出约20%溶剂,降温,加入2.99g叔丁醇钾,室温下反应2小时,滴加4.34g溴乙酸叔丁酯,室温下过夜反应,次日过滤,反应液浓缩至粘稠,加入500mL碱解液(500mL水中加入4.08g氢氧化钠和38.32g磷酸钠),80℃碱解2小时,用2N盐酸溶液调节溶液PH为2-3,向溶液中加入15%氯化钠,用二氯甲烷萃取三次,合并有机相,用无水硫酸钠干燥,过滤,50℃浓缩至粘稠,加入乙醚沉淀,真空干燥。20g粗品配成电导率为100μs/cm的水溶液,DEAE阴离子柱分离,收集电导率为50μs/cm的氯化钠水溶液洗脱液,水相用2N盐酸调PH为2-3,用二氯甲烷萃取,合并有机相,用无水硫酸钠干燥,过滤,浓缩,用乙醚沉淀,得到四臂十二甘醇羟基-单乙酸。
NMR(DMSO)δ:
四臂十二甘醇羟基-单乙酸(III-1):4.01(s,2H,CH2COOH),4.54(t,3H,CH2OH)。
实施例19:四臂十二甘醇羟基-单乙酸甲酯
步骤:
单口圆底烧瓶中,加入5g四臂十二甘醇羟基-单乙酸,用20mL无水甲醇溶解,冰水浴,滴加0.84mL浓硫酸,室温下反应3小时,用8%碳酸氢钠水溶液调节体系PH为7.0,用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸镁干燥,过滤,40℃浓缩至粘稠,用乙醚沉淀,真空干燥,得四臂十二甘醇羟基-单乙酸甲酯。
NMR(DMSO)δ:3.32(s,3H,CH2COOCH3),4.03(s,2H,CH2COOCH3),4.53(t,3H,CH2OH)。
实施例20:四臂十二甘醇磺酸酯-单乙酸甲酯
步骤:
三口圆底烧瓶中,通氮气,加入四臂十二甘醇羟基-单乙酸甲酯5.0g,用50mL甲苯溶解,加热蒸出38mL甲苯至流馏出液清亮,降至室温,加入13mL二氯甲烷,搅拌10分钟,加入278μL三乙胺,搅拌5分钟,滴加入150μL甲基磺酰氯,密闭反应过夜,次日,加入900μL无水乙醇,搅拌15分钟,过滤,60℃浓缩至粘稠,用60mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂十二甘醇磺酸酯-单乙酸甲酯。
NMR(DMSO)δ:3.13(s,9H,CH2OSO2CH3),4.19(s,2H,CH2COOCH3),4.31(t,6H,CH2OSO2CH3)。
实施例21:四臂十二甘醇叠氮-单乙酸甲酯
步骤:
三口原地烧瓶中,通氮气,加入四臂十二甘醇磺酸酯-单乙酸甲酯5.0g,叠氮化钠0.7g,用25mLDMF溶解,加热至90℃,反应3小时,降至室温,加入25mL水和15%氯化钠,用二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,浓缩,加入100mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂十二甘醇叠氮-单乙酸甲酯。
NMR(DMSO)δ:4.13(s,2H,CH2COOCH3)。
实施例22:四臂十二甘醇叠氮-单乙酸
步骤:
100mL烧杯中,加入四臂十二甘醇叠氮-单乙酸甲酯5.0g,加入脱气水,用0.2N的氢氧化钠调节体系PH为12,室温搅拌反应3小时,用1N盐酸调节体系PH=2-3,加入15%氯化钠,用二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,浓缩,加入90mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂十二甘醇叠氮-单乙酸。
NMR(DMSO)δ:4.01(s,2H,CH2COOH)。
实施例23:四臂十二甘醇叠氮-单乙酸琥珀酰亚胺酯
步骤:
100mL烧杯中,加入四臂十二甘醇叠氮-单乙酸2.0g,N,N-羟基琥珀酰亚胺(NHS)50mg,用20mL二氯甲烷溶解,加入135mg二环己基碳二亚胺(DCC),室温下搅拌反应2小时,过滤,浓缩,加入40mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂十二甘醇叠氮-单乙酸琥珀酰亚胺酯。
NMR(DMSO)δ:2.81(s,4H,),4.62(s,2H,CH2COO)。
实施例24:合成四臂十二甘醇胺基-单乙酸
步骤:
三口圆底烧瓶中,氮气保护,加入5g四臂十二甘醇磺酸酯-单乙酸甲酯溶解在7.8mL脱气水中,用2N氢氧化钠水溶液调节溶液PH为12.0,室温下反应2-2.5小时,将26mL溶解有1.3g氯化铵的氨水溶液加入体系,室温下搅拌反应72小时,反应完毕后,加入7g氯化钠,溶解后,用二氯甲烷萃取反应液三次,合并有机相,40℃浓缩至干,加入30mL脱气水搅拌溶解至清亮,用2N盐酸调节溶液PH为2-3,加入5g氯化钠,再次用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸钠干燥至澄清,过滤,40℃浓缩至粘稠,用50mL乙醚沉淀,过滤,真空干燥,得四臂十二甘醇胺基-单乙酸。
NMR(DMSO)δ:2.96(t,6H,CH2CH2NH2),4.03(s,2H,CH2COOH)。
实施例25:合成四臂十二甘醇马来亚酰胺基-单乙酸
步骤:
单口圆底烧瓶中,加入3.2g四臂十二甘醇氨基-单乙酸,用二氯甲烷溶解,冰水浴,加入TEA 500μL,加入MAL-NHS 1.06g,室温下搅拌反应12小时以上,40℃浓缩至干,加入30mL脱气水搅拌,用20mL乙酸乙酯洗涤,水相用二氯甲烷萃取三次,合并有机相,有机相用无水硫酸钠干燥至澄清,过滤,40℃浓缩至粘稠,用50mL异丙醇冰水浴沉淀,过滤,真空干燥,得四臂十二甘醇马来酰亚胺基-单乙酸。
NMR(DMSO)δ:2.32(t,6H,),3.13(q,6H,CH2CH2NH),4.00(s,2H,CH2COOH),6.99(s,6H,)。
实施例26:四臂十二甘醇马来亚酰胺-单乙酸琥珀酰亚胺酯
步骤:
100mL烧杯中,加入四臂十二甘醇马来亚酰胺-单乙酸3.2g,NHS75mg,用20mL二氯甲烷溶解,加入150mg DCC,室温下搅拌反应2小时,过滤,浓缩,加入40mL异丙醇热溶解后冰水浴沉淀,过滤,滤饼用异丙醇洗涤一次,真空干燥,得四臂十二甘醇叠氮-单乙酸琥珀酰亚胺酯。
NMR(DMSO)δ:2.32(t,6H,),2.82(s,4H,),3.15(q,6H,CH2CH2NH),
4.60(s,2H,CH2COO),6.99(s,6H,)。
[PEG-2]合成实施例
实施例27至35中反应如方案1所示。
实施例27:四臂聚乙二醇羧酸甲酯-单羟基(5K)(T1-1)的制备
将50克单羟基三羧基四臂聚乙二醇(5K)溶于甲醇中,滴入氯化亚砜,滴完后继续在室温下搅拌反应3h。反应液浓缩,残分用异丙醇加热溶清,冷却后洗出固体,过滤后真空干燥过夜,得白色固体产品。1H NMR(300MHz,DMSO-d6)δ:3.31(s,9H,CH2COOCH3),4.12(s,6H,CH2COOCH3),4.55(t,1H,CH2OH)。
实施例28:四臂聚乙二醇羧酸甲酯-单羟基甲磺酸酯(5K)(T1-2)的制备
将四臂聚乙二醇羧酸甲酯-单羟基(5K)45克溶于二氯甲烷中,加入三乙胺,搅拌均匀,再滴入甲磺酰氯,滴完后继续在室温下搅拌反应过夜。反应液浓缩,残分用异丙醇加热溶清,冷却后洗出固体,过滤后真空干燥过夜,得白色固体产品。1H NMR(300MHz,DMSO-d6)δ:3.13(s,3H,CH2OSO2CH3),4.17(s,6H,CH2COOCH3),4.30(t,2H,CH2OSO2CH3)。
实施例29:四臂聚乙二醇羧酸-单羟基甲磺酸酯(5K)(T1-3)的制备
将四臂聚乙二醇羧酸甲酯-单羟基甲磺酸酯42克溶于甲醇中,加入1N氢氧化钠溶液,体系加热,回流3h,冷却后用稀盐酸酸化,反应液减压浓缩,残分中加入水,用二氯甲烷萃取,提取液用饱和盐水洗涤,干燥,过滤后浓缩,残分用异丙醇加热溶清,冷却后洗出固体,过滤后真空干燥过夜,得白色固体产品。1H NMR(300MHz,DMSO-d6)δ:3.13(s,3H,CH2OSO2CH3),4.01(s,6H,CH2COOH),4.30(t,2H,CH2OSO2CH3)。
实施例30:N-叔丁氧羰基缬氨酸伊立替康酯(D1-1)的制备
将伊立替康碱(13.0g,22.2mmol)溶于二氯甲烷(500mL)中,加入N-叔丁氧羰基缬氨酸(9.63g,44.4mmol),DMAP(5.42g,44.4mmol)。在氮气保护下滴加EDC(12.80g,66.7mmol)的二氯甲烷(280mL)溶液,滴完后体系在室温下反应过夜。TLC监测反应完全,反应液用蒸馏水(500mL)洗涤,饱和氯化钠溶液(500mL)洗涤,无水硫酸钠干燥。浓缩至干,残留物经硅胶柱纯化,异丙醚沉淀,常温真空干燥得淡黄色固12.63g,收率72.4%。1H NMR(300MHz,DMSO-d6)δ:8.07(d,1H),7.92(d,1H),7.66(dd,1H),7.43(m,1H),7.15(s,1H),5.47(s,2H),5.12(s,2H),4.36(m,1H),3.86-3.61(m,4H),2.92-2.74(m,3H),2.49(m,4H),2.29(d,1H),2.16-2.10(m,2H),1.83-1.52(m,10H),1.47(s,9H),1.31(s,3H),0.93(m,9H)。
实施例31:缬氨酸伊立替康酯(D1-2)的制备
将N-叔丁氧羰基缬氨酸伊立替康酯(12.0g,16.1mmol)溶于二氯甲烷(240mL)中,加入三氟乙酸(120mL),室温搅拌反应3h。TLC监测反应完全,减压蒸除溶剂后,加二氯甲烷(500mL)溶解,再浓缩至干,反复数次,直至除去绝大部分三氟乙酸,加入异丙醚(500mL)沉淀,过滤,滤饼用异丙醚(200mL)洗涤,常温真空干燥得淡黄色固体13.4g,收率95.3%。1HNMR(300MHz,DMSO-d6)δ:7.93(d,1H),7.65(dd,1H),7.42(m,1H),7.11(s,1H),5.35(s,2H),5.07(s,2H),4.28(m,1H),3.81-3.59(m,4H),2.87-2.66(m,3H),2.33(m,4H),2.21(d,1H),2.06-1.97(m,2H),1.75-1.51(m,10H),1.32(s,3H),0.92(m,9H)。
实施例32:四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单羟基甲磺酰酯(5K)(T1-4)的制备
将四臂聚乙二醇羧酸-单羟基甲磺酸酯(5K)溶于二氯甲烷(500mL)中,加入缬氨酸伊立替康酯和DMAP。氮气保护下冷却,再滴加EDC(12.80g,66.6mmol)的二氯甲烷(280mL)溶液,滴完后撤去冰浴,体系自然升到室温反应过夜。HPLC监测表明大分子原料反应完全后处理,反应液浓缩,残分用异丙醇加热溶清,冷却后析晶,过滤后真空干燥过夜。得产品。1HNMR(300MHz,DMSO-d6)δ:8.09(d,3H),7.92(d,3H),7.67(dd,3H),7.43(m,3H),7.12(s,3H),5.37(s,6H),5.03(s,6H),4.35-4.22(m,9H),4.07(s,18H),3.81-3.49(m,450H),3.13(s,9H),2.86-2.67(m,9H),2.35(m,12H),2.28(d,3H),2.09-1.98(m,6H),1.76-1.53(m,30H),1.31(s,9H),0.91(m,27H)。
实施例33:四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单叠氮(5K)(T1-5)的制备
将四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单羟基甲磺酰酯(5K)溶于DMF中,加入叠氮化钠,体系升温到90℃反应3h,冷却后用异丙醇重结晶得产物。1H NMR(300MHz,DMSO-d6)δ:8.07(d,3H),7.93(d,3H),7.65(dd,3H),7.44(m,3H),7.15(s,3H),5.38(s,6H),5.04(s,6H),4.36-4.24(m,12H),4.05(s,18H),3.82-3.48(m,450H),2.88-2.69(m,9H),2.33(m,12H),2.25(d,3H),2.11-1.96(m,6H),1.77-1.54(m,30H),1.32(s,9H),0.92(m,27H)。
实施例34:四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单氨(5K)(T1-6)的制备
将四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单叠氮(5K)溶于二氯甲烷中,加入三苯基磷,室温下反应过夜。反应液浓缩,残分用异丙醇重结晶得产物。1H NMR(300MHz,DMSO-d6)δ:8.06(d,3H),7.91(d,3H),7.66(dd,3H),7.45(m,3H),7.17(s,3H),5.35(s,6H),5.02(s,6H),4.36-4.24(m,12H),4.07(s,18H),3.82-3.48(m,450H),2.88-2.69(m,9H),2.35(m,12H),2.26(d,3H),2.11-1.96(m,6H),1.77-1.54(m,30H),1.31(s,9H),0.91(m,27H)。
实施例35:四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单氨基丙炔酰胺(5K)(T1-7)的制备
将炔丙酸溶于二氯甲烷(500mL)中,加入四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单氨(5K)和DMAP。氮气保护下冷却,再滴加EDC(12.80g,66.6mmol)的二氯甲烷(280mL)溶液,滴完后撤去冰浴,体系自然升到室温反应过夜。HPLC检测表明大分子原料反应完全后处理,反应液浓缩,残分用异丙醇加热溶清,冷却后析晶,过滤后真空干燥过夜。得产品。1H NMR(300MHz,DMSO-d6)δ:8.09(s,1H),8.06(d,3H),7.91(d,3H),7.66(dd,3H),7.45(m,3H),7.17(s,3H),5.35(s,6H),5.02(s,6H),4.36-4.24(m,9H),4.07(s,18H),3.82-3.48(m,450H),2.88-2.69(m,12H),2.35(m,12H),2.26(d,3H),2.11-1.96(m,6H),1.77-1.54(m,30H),1.31(s,9H),0.92(m,27H)。
实施例36至39中反应如方案2所示。
实施例36:巯基聚乙二醇三羧酸(5K)(T2-1)的制备
HS-PEG-(COOH)3
T2-1
将聚乙二醇三羧酸甲酯-单羟基甲磺酸酯(5K)3.0克(0.6mmol)和硫脲274mg(3.6mmol)加到反应瓶中,加入无水乙醇30mL回流过夜,反应液浓缩,加入30mL水,转到三口瓶中,通氮气保护,加入DTT278mg(1.8mmol)和氢氧化钠溶液,室温下搅拌4h,反应液酸化,用乙酸乙酯洗涤,水层用二氯甲烷提取三次,合并有机相,用饱和盐水洗涤,干燥。过滤后浓缩,残分用异丙醇结晶,过滤,干燥得白色固体1.8克。1H NMR(300MHz,DMSO-d6)δ:4.19(s,6H)。
实施例37:巯基聚乙二醇七羧酸(5K)(T2-2)的保护
Py-S-S-PEG-(COOH)3
T2-2
将HS-PEG-(COOH)32.0g(0.4mmol)和Py-S-S-Py440.3mg(2mmol)加到反应瓶中,用甲醇溶解,室温搅拌反应过夜,反应液浓缩至干,残分用异丙醇结晶,过滤,干燥得白色固体1.6克。1H NMR(300MHz,DMSO-d6)δ:8.57(s,1H),7.66(s,1H),7.29(s,1H),7.24(s,1H),4.19(s,6H)。
实施例38:Py-S-S-PEG-(CONHI)3(5K)(T2-3)的制备
Py-S-S-PEG-(CONHI)3
T2-3
将Py-S-S-PEG-(COOH)32.5g(0.5mmol),缬氨酸伊立替康酯三氟乙酸盐4.3g(5.25mmol),HOBt932mg(7mmol)加到反应瓶中,用二氯甲烷溶解,再加入二异丙基乙基胺1.8mL(10.5mmol),搅拌均匀,加入EDCI1.34g(7mmol),加完后室温搅拌过夜,反应液浓缩至干,残分用异丙醇结晶,过滤,干燥得白色固体2.2克。1H NMR(300MHz,DMSO-d6)δ:8.57(s,1H),8.09(d,3H),7.92(d,3H),7.67(m,8H),7.43(m,3H),7.29(s,1H),7.24(s,1H),7.12(s,3H),5.37(s,2H),5.03(s,2H),4.35-4.22(m,9H),4.19(s,6H),4.07(s,6H),3.13(s,3H),2.86-2.67(m,9H),2.35(m,8H),2.28(d,3H),2.09-1.98(m,6H),1.76-1.53(m,30H),1.31(s,9H),0.91(m,9H).
实施例39:SH-PEG-(CONHI)3(5K)(T2-4)的制备
HS-PEG-(CONHI)3
T2-4
SH-4ARMPEG5K-(CONHI)3
取原料Py-S-S-PEG-(CONHI)31.5g(0.3mmol),用二氯甲烷溶解,加入DTT和三乙胺,室温搅拌过夜,反应液浓缩至干,残分用异丙醇结晶,过滤,抽干。得白色固体1.2克。1HNMR(300MHz,DMSO-d6)δ:8.09(d,3H),7.92(d,3H),7.67(m,3H),7.43(m,3H),7.12(s,3H),5.37(s,6H),5.03(s,6H),4.35-4.22(m,9H),4.19(s,6H),4.07(s,6H),3.13(s,9H),2.86-2.67(m,9H),2.35(m,4H),2.28(d,3H),2.09-1.98(m,6H),1.76-1.53(m,30H),1.31(s,9H),0.91(m,9H).
实施例40-41中反应如方案3所示。
实施例40:四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单溴(5K)(T3-1)的制备
将四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单羟基甲磺酰酯(5K)10克溶于二氯甲烷中,加入四丁基溴化铵,室温反应过夜后处理,反应液浓缩,残分用异丙醇加热溶清,冷却后析晶,过滤后干燥得产品。1H NMR(300MHz,DMSO-d6)δ:8.06(d,3H),7.91(d,3H),7.66(dd,3H),7.45(m,3H),7.17(s,3H),5.35(s,6H),5.02(s,6H),4.36-4.24(m,9H),4.07(s,18H),3.82-3.48(m,450H),2.88-2.69(m,9H),2.35(m,12H),2.26(d,3H),2.11-1.96(m,6H),1.77-1.54(m,30H),1.31(s,9H),0.92(m,27H)。
实施例41:四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单羟基(丙炔酸)酯(5K)(T3-2)的制备
将炔丙酸溶于二氯甲烷(500mL)中,加入四臂聚乙二醇三羧基(缬氨酸伊立替康酯基)酯-单溴(5K)和DMAP。氮气保护下冷却,再滴加EDC(12.80g,66.6mmol)的二氯甲烷(280mL)溶液,滴完后撤去冰浴,体系自然升到室温反应过夜。HPLC检测表明大分子原料反应完全后处理,反应液浓缩,残分用异丙醇加热溶清,冷却后析晶,过滤后真空干燥过夜。得产品。1H NMR(300MHz,DMSO-d6)δ:8.06(d,3H),7.91(d,3H),7.66(dd,3H),7.45(m,3H),7.17(s,3H),5.35(s,6H),5.02(s,6H),4.36-4.24(m,9H),4.07(s,18H),3.82-3.48(m,450H),2.88-2.69(m,12H),2.35(m,12H),2.26(d,3H),2.11-1.96(m,6H),1.77-1.54(m,30H),1.31(s,9H),0.91(m,27H)。
实施例42至45的反应如方案4所示。
实施例42:四臂聚乙二醇羟基-单乙酸甲酯(5K)(T4-1)的制备
将50克四臂聚乙二醇羟基-单乙酸(5K)溶于甲醇中,滴入氯化亚砜,滴完后继续在室温下搅拌反应3h。反应液浓缩,残分用异丙醇加热溶清,冷却后洗出固体,过滤后真空干燥过夜,得白色固体产品。1H NMR(DMSO-d6)δ:3.32(s,3H,CH2COOCH3),4.13(s,2H,CH2COOCH3),4.57(t,3H,CH2OH)。
实施例43:四臂聚乙二醇单乙酸甲酯三(伊立替康基)碳酸酯(5K)(T4-2)的制备
将5.9克伊立替康溶于二氯甲烷中,加入4,4-二甲基氨基吡啶3.7克,氮气保护下冷却,再滴加三光气3克溶于二氯甲烷的溶液,滴完后自然升到室温,反应30分钟后再加入四臂聚乙二醇羟基-单乙酸甲酯(5K),加完后室温反应过夜。反应液浓缩,残分用异丙醇加热溶清,冷却后析出固体,过滤后真空干燥过夜,得淡黄色固体产品。1H NMR(300MHz,DMSO-d6)δ:7.93(d,3H),7.65(dd,3H),7.44(m,3H),7.15(s,3H),5.38(s,6H),5.04(s,6H),4.36-4.24(m,9H),4.05(s,18H),3.82-3.48(m,450H),3.12(s,9H),2.88-2.69(m,9H),2.33(m,12H),2.25(d,3H),2.11-1.96(m,2H),1.77-1.54(m,10H),1.32(s,3H),0.95(m,3H)。
实施例44:四臂聚乙二醇单乙酸三(伊立替康基)碳酸酯(5K)(T4-3)的制备
将四臂聚乙二醇单乙酸甲酯三(伊立替康基)碳酸酯(5K)10克溶于甲醇中,加入1N氢氧化钠溶液,加热回流,反应完全后冷却,反应液用稀盐酸酸化,再浓缩。残分用异丙醇加热溶清,冷却后洗出固体,过滤后真空干燥过夜,得产品。1H NMR(300MHz,DMSO-d6)δ:7.93(d,3H),7.65(dd,3H),7.44(m,3H),7.15(s,3H),5.38(s,6H),5.04(s,6H),4.36-4.24(m,9H),4.05(s,18H),3.82-3.48(m,450H),2.88-2.69(m,9H),2.33(m,12H),2.25(d,3H),2.11-1.96(m,6H),1.77-1.54(m,30H),1.32(s,9H),0.95(m,9H)。
实施例45:四臂聚乙二醇单乙酸(N-炔丙基)酰胺三(伊立替康基)碳酸酯(5K)(T4-4)的制备
将四臂聚乙二醇单乙酸三(伊立替康基)碳酸酯(5K)5克溶于二氯甲烷中,加入炔丙胺和DMAP。氮气保护下冷却,再滴加EDC的二氯甲烷溶液,滴完后撤去冰浴,体系自然升到室温反应过夜。HPLC检测表明大分子原料反应完全后处理,反应液浓缩,残分用异丙醇加热溶清,冷却后析晶,过滤后真空干燥过夜。得产品。1H NMR(300MHz,DMSO-d6)δ:7.93(d,3H),7.65(dd,3H),7.44(m,3H),7.15(s,3H),5.38(s,6H),5.04(s,6H),4.36-4.24(m,9H),4.05(s,18H),3.82-3.48(m,450H),2.88-2.69(m,12H),2.33(m,12H),2.25(d,3H),2.11-1.96(m,6H),1.77-1.54(m,30H),1.32(s,9H),0.94(m,3H)。
实施例46至51的反应如方案5所示。
SH-PEG-CONHI的制备
实施例46:羟基聚乙二醇羧酸甲酯(3.5K)(T5-1)的制备
HO-PEG-COOMe
T5-1
将50克单羟基聚乙二醇羧酸(3.5K)溶于甲醇中,滴入氯化亚砜,滴完后继续在室温下搅拌反应3h。反应液浓缩,残分用异丙醇加热溶清,冷却后洗出固体,过滤后真空干燥过夜,得白色固体产品。1H NMR(300MHz,DMSO-d6)δ:4.55(t,1H),4.12(s,2H),3.31(s,3H)。
实施例47:聚乙二醇羧酸甲酯-单羟基甲磺酸酯(3.5K)(T5-2)的制备
MsO-PEG-COOMe
T5-2
将聚乙二醇羧酸甲酯-单羟基(5K)45克溶于二氯甲烷中,加入三乙胺,搅拌均匀,再滴入甲磺酰氯,滴完后继续在室温下搅拌反应过夜。反应液浓缩,残分用异丙醇加热溶清,冷却后洗出固体,过滤后真空干燥过夜,得白色固体产品。1H NMR(300MHz,DMSO-d6)δ:4.30(t,2H),4.17(s,2H),3.13(s,3H)。
实施例48:巯基聚乙二醇羧酸(3.5K)(T5-3)的制备
HS-PEG-COOH
T5-3
将聚乙二醇羧酸甲酯-单羟基甲磺酸酯(3.5K)2.1克(0.6mmol)和硫脲274mg(3.6mmol)加到反应瓶中,加入无水乙醇30mL回流过夜,反应液浓缩,加入30mL水,转到三口瓶中,通氮气保护,加入DTT278mg(1.8mmol)和氢氧化钠溶液,室温下搅拌4h,反应液酸化,用乙酸乙酯洗涤,水层用二氯甲烷提取三次,合并有机相,用饱和盐水洗涤,干燥。过滤后浓缩,残分用异丙醇结晶,过滤,干燥得白色固体1.8克。1H NMR(300MHz,DMSO-d6)δ:4.19(s,2H)。
实施例49:巯基聚乙二醇羧酸(3.5K)(T5-4)的保护
Py-S-S-PEG-COOH
T5-4
将HS-PEG-COOH 1.4g(0.4mmol)和Py-S-S-Py440.3mg(2mmol)加到反应瓶中,用甲醇溶解,室温搅拌反应过夜,反应液浓缩至干,残分用异丙醇结晶,过滤,干燥得白色固体1.2克。1H NMR(300MHz,DMSO-d6)δ:8.57(s,1H),7.66(s,1H),7.29(s,1H),7.24(s,1H),4.19(s,2H)。
实施例50:Py-S-S-PEG-CONHI(3.5K)(T5-5)的制备
Py-S-S-PEG-CONHI
T5-5
将Py-S-S-PEG-COOH 1.7g(0.486mmol),缬氨酸伊立替康酯三氟乙酸盐1.19g(1.457mmol),HOBt131mg(0.971mmol)加到反应瓶中,用二氯甲烷溶解,再加入二异丙基乙基胺760μL(4.371mmol),搅拌均匀,加入EDCI 186.1mg(0.971mmol),加完后室温搅拌过夜,反应液浓缩至干,残分用异丙醇结晶,过滤,干燥得白色固体1.5克。1H NMR(300MHz,DMSO-d6)δ:8.57(s,1H),8.09(d,1H),7.92(d,1H),7.67(m,2H),7.43(m,1H),7.29(s,1H),7.24(s,1H),7.12(s,1H),5.37(s,2H),5.03(s,2H),4.35-4.22(m,3H),4.19(s,2H),4.07(s,6H),3.81-3.49(m,150H),3.13(s,3H),2.86-2.67(m,3H),2.35(m,4H),2.28(d,1H),2.09-1.98(m,2H),1.76-1.53(m,10H),1.31(s,9H),0.91(m,9H).
实施例51:SH-PEG-CONHI(3.5K)(T5-6)的制备
HS-PEG-CONHI
T5-6
SH-PEG3.5K-CONHI
取原料Py-S-S-PEG-CONHI 1.5g(0.428mmol),用二氯甲烷溶解,加入DTT和三乙胺,室温搅拌过夜,反应液浓缩至干,残分用异丙醇结晶,过滤,抽干。得白色固体1.1克。1HNMR(300MHz,DMSO-d6)δ:8.09(d,1H),7.92(d,1H),7.67(m,1H),7.43(m,1H),7.12(s,1H),5.37(s,2H),5.03(s,2H),4.35-4.22(m,3H),4.19(s,2H),4.07(s,6H),3.81-3.49(m,150H),3.13(s,3H),2.86-2.67(m,3H),2.35(m,4H),2.28(d,1H),2.09-1.98(m,2H),1.76-1.53(m,10H),1.31(s,9H),0.91(m,9H).
实施例52:SH-PEG6-CONHI的制备
原料SH-PEG6-COOH购买自博美生物,其余合成过程参照实施例49-51。
实施例53至58的反应如方案6所示。
SH-PEG-(CONHI)7的制备
实施例53:羟基聚乙二醇七羧酸甲酯(5K)(T6-1)的制备
HO-PEG-(COOMe)7
T6-1
将50克单羟基聚乙二醇七羧酸(5K)溶于甲醇中,滴入氯化亚砜,滴完后继续在室温下搅拌反应3h。反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:4.55(t,1H),4.12(s,14H),3.31(s,21H)。
实施例54:聚乙二醇七羧酸甲酯-单羟基甲磺酸酯(5K)(T6-2)的制备
MsO-PEG-(COOMe)7
T6-2
将聚乙二醇七羧酸甲酯-单羟基(5K)45克溶于二氯甲烷中,加入三乙胺,搅拌均匀,再滴入甲磺酰氯,滴完后继续在室温下搅拌反应过夜。反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:4.30(t,2H),4.17(s,14H),3.31(s,21H),3.13(s,3H)。
实施例55:巯基聚乙二醇七羧酸(5K)(T6-3)的制备
HS-PEG-(COOH)7
T6-3
将聚乙二醇七羧酸甲酯-单羟基甲磺酸酯(5K)3.0克(0.6mmol)和硫脲274mg(3.6mmol)加到反应瓶中,加入无水乙醇30mL回流过夜,反应液浓缩,加入30mL水,转到三口瓶中,通氮气保护,加入DTT278mg(1.8mmol)和氢氧化钠溶液,室温下搅拌4h,反应液酸化,用乙酸乙酯洗涤,水层用二氯甲烷提取三次,合并有机相,用饱和盐水洗涤,干燥。过滤后浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:4.19(s,14H)。
实施例56:巯基聚乙二醇七羧酸(5K)(T6-4)的保护
Py-S-S-PEG-(COOH)7
T6-4
将HS-PEG-(COOH)7 2.0g(0.4mmol)和Py-S-S-Py440.3mg(2mmol)加到反应瓶中,用甲醇溶解,室温搅拌反应过夜,反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:8.57(s,1H),7.66(s,1H),7.29(s,1H),7.24(s,1H),4.19(s,14H)。
实施例57:Py-S-S-PEG-(CONHI)7(5K)(T6-5)的制备
Py-S-S-PEG-(CONHI)7
T6-5
将Py-S-S-PEG-(COOH)7 2.5g(0.5mmol),缬氨酸伊立替康酯三氟乙酸盐4.3g(5.25mmol),HOBt932mg(7mmol)加到反应瓶中,用二氯甲烷溶解,再加入二异丙基乙基胺1.8mL(10.5mmol),搅拌均匀,加入EDCI1.34g(7mmol),加完后室温搅拌过夜,反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:8.57(s,1H),8.09(d,7H),7.92(d,7H),7.67(m,8H),7.43(m,7H),7.29(s,1H),7.24(s,1H),7.12(s,7H),5.37(s,14H),5.03(s,14H),4.35-4.22(m,21H),4.19(s,14H),4.07(s,14H),3.13(s,3H),2.86-2.67(m,21H),2.35(m,8H),2.28(d,7H),2.09-1.98(m,14H),1.76-1.53(m,70H),1.31(s,21H),0.91(m,21H).
实施例58:SH-PEG-(CONHI)7(5K)(T6-6)的制备
HS-PEG-(CONHI)7
T6-6
SH-8ARMPEG5K-(CONHI)7
取原料Py-S-S-PEG-(CONHI)7 1.5g(0.3mmol),用二氯甲烷溶解,加入DTT和三乙胺,室温搅拌过夜,反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:8.09(d,7H),7.92(d,7H),7.67(m,7H),7.43(m,7H),7.12(s,7H),5.37(s,14H),5.03(s,14H),4.35-4.22(m,21H),4.19(s,14H),4.07(s,14H),3.13(s,21H),2.86-2.67(m,21H),2.35(m,4H),2.28(d,7H),2.09-1.98(m,14H),1.76-1.53(m,70H),1.31(s,21H),0.91(m,21H).
实施例59至65的反应如方案7所示。
炔基-PEG-(CONHI)7的制备
实施例59:羟基聚乙二醇羧酸甲酯(5K)的制备
制备同实施例54。
实施例60:聚乙二醇七羧酸甲酯-单羟基甲磺酸酯(5K)的制备
制备同实施例55。
实施例61:MsO-PEG-(COOH)7(5K)(T7-1)的制备
MsO-PEG-(COOH)7
T7-1
将聚乙二醇七羧酸甲酯-单羟基甲磺酸酯(5K)3.0克(0.6mmol)溶于甲醇中,加入1N氢氧化钠溶液,体系加热,回流3h,冷却后用稀盐酸酸化,反应液减压浓缩,残分中加入水,用二氯甲烷萃取,提取液用饱和盐水洗涤,干燥,过滤后浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:3.13(s,3H,CH2OSO2CH3),4.01(s,14H)。
实施例62:MsO-PEG-(CONHI)7(5K)(T7-2)的制备
MsO-PEG-(CONHI)7
T7-2
将MsO-PEG-(COOH)7 2.5g(0.5mmol),缬氨酸伊立替康酯三氟乙酸盐4.3g(5.25mmol),HOBt 932mg(7mmol)加到反应瓶中,用二氯甲烷溶解,再加入二异丙基乙基胺1.8mL(10.5mmol),搅拌均匀,加入EDCI1.34g(7mmol),加完后室温搅拌过夜,反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:8.09(d,7H),7.92(d,7H),7.67(m,7H),7.43(m,7H),7.12(s,7H),5.37(s,14H),5.03(s,14H),4.35-4.22(m,21H),4.19(s,14H),4.07(s,14H),3.13(s,3H),2.86-2.67(m,21H),2.35(m,8H),2.28(d,7H),2.09-1.98(m,14H),1.76-1.53(m,70H),1.31(s,21H),0.91(m,42H).
实施例63:N3-PEG-(CONHI)7(5K)(T7-3)的制备
N3-PEG-(CONHI)7
T7-3
将MsO-PEG-(CONHI)7(5K)溶于DMF中,加入叠氮化钠,体系升温到90℃反应3h,冷却后用异丙醇重结晶得产物。1H NMR(300MHz,DMSO-d6)δ:8.07(d,7H),7.93(d,21H),7.65(dd,21H),7.44(m,21H),7.15(s,21H),5.38(s,14H),5.04(s,14H),4.36-4.24(m,28H),4.05(s,42H),2.88-2.69(m,21H),2.33(m,28H),2.25(d,7H),2.11-1.96(m,14H),1.77-1.54(m,70H),1.32(s,21H),0.92(m,42H)。
实施例64:NH2-PEG-(CONHI)7(5K)(T7-4)的制备
NH2-PEG-(CONHI)7
T7-4
将NH2-PEG-(CONHI)7(5K)溶于二氯甲烷中,加入三苯基磷,室温下反应过夜。反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:8.07(d,7H),7.93(d,21H),7.65(dd,21H),7.44(m,21H),7.15(s,21H),5.38(s,14H),5.04(s,14H),4.36-4.24(m,28H),4.05(s,42H),2.88-2.69(m,21H),2.33(m,28H),2.25(d,7H),2.11-1.96(m,14H),1.77-1.54(m,70H),1.32(s,21H),0.92(m,42H)。
实施例65:HC≡CCONH-PEG-(CONHI)7(5K)(T7-5)的制备
HC≡CCONH-PEG-(CONHI)7
T7-5
将炔丙酸溶于二氯甲烷(500mL)中,加入NH2-PEG-(CONHI)7(5K)和DMAP。氮气保护下冷却,再滴加EDC(12.80g,66.6mmol)的二氯甲烷(280mL)溶液,滴完后撤去冰浴,体系自然升到室温反应过夜。HPLC检测表明大分子原料反应完全后处理,反应液浓缩至干得产品。1H NMR(300MHz,DMSO-d6)δ:8.33(s,1H),8.07(d,7H),7.93(d,21H),7.65(dd,21H),7.44(m,21H),7.15(s,21H),5.38(s,14H),5.04(s,14H),4.36-4.24(m,28H),4.05(s,42H),2.88-2.69(m,22H),2.33(m,28H),2.25(d,7H),2.11-1.96(m,14H),1.77-1.54(m,70H),1.32(s,21H),0.92(m,42H)。
实施例66至67的反应如方案8所示。
本发明中甘氨酸雷帕霉素酯参照文献(CN201410715522.X)制备。
实施例66:Py-S-S-PEG-CONHR(5K)(T8-1)的制备
Py-S-S-PEG-CONHR
T8-1
将Py-S-S-PEG-COOH 1.75g(0.5mmoL),甘氨酸雷帕霉素酯(970mg,1mmoL),1-羟基苯并三氮唑(HOBt,68mg,0.5mmoL)和DMAP(122mg,1mmoL)加到反应瓶中,用二氯甲烷溶解,冰浴冷却,再滴入DCC(155mg,0.75mmoL)溶于二氯甲烷的溶液,滴完后自然升到室温,反应过夜,次日将反应液浓缩,残分用异丙醇结晶得白色固体1.4克。1H-NMR(300MHz,CDCl3):0.90(Me,3H,43),0.92(Me,3H,49),0.94(Me,3H,46),0.96(Me,3H,48),0.97(Me,3H,45),1.10(CH2,2H,24),1.11(CH2,2H,36),1.20(CH2,2H,42),1.33(CH2,2H,41),1.37(CH,1H,37),1.45(CH2,2H,5),1.47(CH2,2H,4),1.60(CH2,2H,13),1.61(CH2,2H,12),1.65(CH2,2H,15),1.65(CH2,2H,44),1.74(Me,3H,47),1.75(CH,1H,35),2.07(CH,4H,3,11,23,25),2.08(CH2,2H,33),3.14(Me,3H,50),3.33(CH,1H,31),3.36(Me,3H,51),3.37(CH2,2H,6),3.42(CH,1H,40),3.44(Me,3H,52),3.56(CH,1H,39),3.64(CH2,1800H,PEG),3.71(CH,1H,16),3.72(CH,1H,27),3.86(CH,1H,14),4.17(CH2,2H,54),4.19(CH,1H,28),5.16(CH,1H,2),5.17(CH,1H,34),5.29(=CH,1H,30),5.39(=CH,1H,22),5.95(=CH,1H,18),6.13(=CH,1H,21),6.31(=CH,1H,20),6.38(=CH,1H,19),7.23(-Py,1H),7.29(-Py,1H),7.67(-Py,1H),8.34(CH,1H,55),8.62(-Py,1H).
实施例67:SH-PEG-CONHR(T8-2)(5K)(T8-2)的制备
HS-PEG-CONHR
T8-2
取原料Py-S-S-PEG-CONHR 1.4g(0.4mmol),用二氯甲烷溶解,加入DTT和三乙胺,室温搅拌过夜,反应液浓缩至干,残分用异丙醇结晶,过滤,抽干。得白色固体。1H-NMR(300MHz,CDCl3):0.90(Me,3H,43),0.92(Me,3H,49),0.94(Me,3H,46),0.96(Me,3H,48),0.97(Me,3H,45),1.10(CH2,2H,24),1.11(CH2,2H,36),1.20(CH2,2H,42),1.33(CH2,2H,41),1.37(CH,1H,37),1.45(CH2,2H,5),1.47(CH2,2H,4),1.60(CH2,2H,13),1.61(CH2,2H,12),1.65(CH2,2H,15),1.65(CH2,2H,44),1.74(Me,3H,47),1.75(CH,1H,35),2.07(CH,4H,3,11,23,25),2.08(CH2,2H,33),3.14(Me,3H,50),3.33(CH,1H,31),3.36(Me,3H,51),3.37(CH2,2H,6),3.42(CH,1H,40),3.44(Me,3H,52),3.56(CH,1H,39),3.64(CH2,1800H,PEG),3.71(CH,1H,16),3.72(CH,1H,27),3.86(CH,1H,14),4.17(CH2,2H,54),4.19(CH,1H,28),5.16(CH,1H,2),5.17(CH,1H,34),5.29(=CH,1H,30),5.39(=CH,1H,22),5.95(=CH,1H,18),6.13(=CH,1H,21),6.31(=CH,1H,20),6.38(=CH,1H,19),8.34(CH,1H,55).
偶联-实施例
实施例68:式(Ⅱ)配基药物偶联物(APEGA-2)的制备
(TM-[PEG-1A]-[PEG-2A]-Drug),A体系为马来酰亚胺、巯基体系,PEG1为(MAL)3-4ARMPEG5K-NHS(实施例9),PEG2为SH-PEG3.5K-CONHI(实施例51),TM为重组抗HER2人源化单克隆抗体,I为伊立替康。
步骤1,式(Ⅱ)配基药物偶联物的合成-第一步偶联
按照抗体:[PEG-1]摩尔比1:60比例投料。采用1mM HCl配制100mg/mL的PEG1溶液,取40μL,200μg,迅速加入到含1.0mg的抗体偶联缓冲体系(50mM磷酸钠pH6.0,50mM氯化钠,1mM EDTA)中(42μL 24.5mg/mL抗体加入118μL偶联缓冲液),室温温和振荡,反应2小时;-20℃保存以终止反应。
步骤2,纯化及偶联,去除裸抗分子
一次偶联纯化:对偶联反应组4倍稀释后进行阳离子交换层析法纯化,收集穿透峰以及洗脱峰(裸抗以及低偶联度的PEG-抗体偶联物)。穿透峰冷冻保存;洗脱峰4倍稀释浓缩后冷藏过夜,用于二次偶联,制备方法参照步骤1。
二次偶联纯化:对偶联反应组进行阳离子交换层析法纯化,收集穿透峰以及洗脱峰(裸抗以及低偶联度的PEG-抗体偶联物)。穿透峰冷冻保存;洗脱峰4倍稀释浓缩后,冷藏过夜用于三次偶联,制备方法参照步骤1。
三次偶联纯化:对三次偶联反应组进行阳离子交换层析法纯化,收集穿透峰,与一次、二次偶联中收集的穿透峰合并。
穿透峰处理:对合并后穿透峰进行浓缩,至抗体浓度5.0mg/ml,用于第二步偶联。
步骤3,第二步偶联:[PEG-2]偶联反应
按照[PEG-1]:[PEG-2]摩尔比1:1比例投料。采用1mM HCl分别配制42mg/mL的PEG2溶液,取40μL迅速加入到PEG1-抗体偶联反应物溶液(1:60)偶联物溶液中(80μL),室温温和振荡,反应2小时;-20℃保存以终止反应。采用超滤法去除游离的PEG2分子并替换溶液至50mM PB,pH6.0,97mMNacl溶液中。进一步过滤除菌得偶联物。
实施例69:式(Ⅱ)抗体药物偶联物(APEGA-4)的制备(TM-[PEG-1A]-[PEG-2A]-Drug),A体系为马来酰亚胺、巯基体系,PEG1为(MAL)3-4ARMPEG5K-NHS(实施例9),PEG2为SH-4ARMPEG5K-(CONHI)3(实施例39),TM为重组抗HER2人源化单克隆抗体,I为伊立替康。其制备方法参照实施例68。
实施例70:式(Ⅱ)抗体药物偶联物(APEGA-5)的制备(TM-[PEG-1A]-[PEG-2A]-Drug),A体系为马来酰亚胺、巯基体系,PEG1为(MAL)3-4ARMPEG5K-NHS(实施例9),PEG2为SH-8ARMPEG5K-(CONHI)7(实施例58),TM为重组抗HER2人源化单克隆抗体,I为伊立替康。其制备方法参照实施例68。
实施例71:式(Ⅱ)抗体药物偶联物(APEGA-6)的制备(TM-[PEG-1A]-[PEG-2A]-Drug),A体系为马来酰亚胺、巯基体系,PEG1为(MAL)7-8ARMPEG5K-NHS(实施例15),PEG2为SH-4ARMPEG5K-(CONHI)3(实施例39),TM为重组抗HER2人源化单克隆抗体,I为伊立替康。其制备方法主要参照实施例68,不同之处在于偶联缓冲液体系为,50mM磷酸钠pH7.2,50mM氯化钠,1mMEDTA。
实施例72:实施例68、69、70、71中抗体药物偶联物抗体含量测定
方法:UV/Vis法
式(1)中,药物和抗体在280nm处的吸光度之和构成总吸光度(A280):
式中,是药物在280nm处的消光系数;Cdrug是药物浓度(mg/ml);是抗体在280nm处的消光系数;CmAb是抗体的浓度。
式(2)是药物在最大吸收λ(D)处的总吸光度的平行方程式:
式中,是药物在λ(D)nm处的消光系数;Cdrug是药物浓度;是抗体在λ(D)nm处的消光系数;CmAb是抗体的浓度(mg/ml)。
通过上面的两个方程式可以分别抗体和药物的浓度。
用除以计算得到平均药物抗体偶联比率(DAR),表示为药物摩尔数除以抗体摩尔数:
结果参见表1:
表1:二步偶联产物UV-Vis定量汇总
实施例73:式(Ⅱ)抗体药物偶联物的制备(TM-[PEG-1A]-[PEG-2A]-Drug),A体系为马来酰亚胺、巯基体系,PEG1为(MAL)3-4ARMPEG5K-NHS(实施例9),PEG2为SH-PEG3.5K-CONHR(实施例51),TM为重组抗CD3人源化单克隆抗体(器官移植排斥和自身免疫性疾病相关抗体),R为雷帕霉素(用于预防和治疗肾移植排斥)。其制备方法参照实施例68。
实施例74:实施例73中抗体药物偶联物抗体含量测定
抗体含量的测定方法同实施例72,检测结果参见表2。
表2:二步偶联产物UV-Vis定量汇总
实施例75:式(Ⅱ)抗体药物偶联物的制备(TM-[PEG-1A]-[PEG-2A]-Drug),A体系为马来酰亚胺、巯基体系,PEG1为(MAL)3-PEG12-NHS(实施例26),PEG2为SH-PEG6-CONHI(实施例52),TM为重组抗HER2人源化单克隆抗体,I为伊立替康。其制备方法参照实施例68。
实施例76:实施例75中抗体药物偶联物抗体含量测定
抗体含量的测定方法同实施例72,检测结果参见表3。
表3:二步偶联产物UV-Vis定量汇总
药代、药效
实施例77:实施例68、69、70、71中抗体药物偶联物大鼠药代动力学试验
实验方法:SD大鼠经腹腔注射40mg/kg的1%戊巴比妥钠麻醉后,颈后、颈前部备皮,碘伏消毒。于颈部正中偏右剪开皮肤,暴露颈静脉。将静脉导管插入血管后,结扎,并缝合开口处皮肤。手术结束后,在导管内注射肝素钠溶液约0.2ml,封闭液0.1ml,此后每天进行更换,持续一周。一周后大鼠手术伤口全部愈合,导管固定确切,反复取血通畅,可用于本项目的药代动力学研究。分别经尾静脉给予重组抗HER2人源化单克隆抗体及APEGA2,4,5,6,并于给药后既定时间点对动物进行取血、分析。
将100μl/孔0.05μg/ml人HER2蛋白用0.05M碳酸盐缓冲液包被于微孔中,4℃培养过夜。400μL PBST洗板,加入封闭液300μL,37℃封闭1h,400μLPBST洗板。加标准品和待检样品100μl/孔于上述已包被之反应孔中,置37℃孵育1小时。然后洗涤。加酶标抗体:于各反应孔中,加入羊抗人IgG酶标抗体100μl/孔。37℃孵育1小时,洗涤。加底物液显色:于各反应孔中加入临时配制的TMB底物溶液50μl/孔,37℃15-30分钟。终止反应:于各反应孔中加入2M硫酸50μl/孔。在ELISA检测仪上,于450nm检测吸光度。以标准品吸光值对应吸光度值(扣除空白)做线性回归,得回归方程;将待检品吸光度值(扣除空白)代入标准曲线方程,得待检品中抗体浓度。
实验结果:结果参见附图1,本实验证实,在连接药物后,各样品的消除速度较重组抗HER2人源化单克隆抗体都出现一定程度的增加,但下降趋势并不十分显著。
实施例78:实施例68、69、70、71中抗体药物偶联物药效试验
方法:样品药效的评价选用HER2高表达的N87胃癌模型及SKOV-3卵巢癌模型。取对数生长期细胞株接种免疫缺陷小鼠右侧背部皮下,细胞接种量为5×106细胞/只,形成移植瘤后再在小鼠体内传2代后使用。取生长旺盛期的瘤组织剪切成直径为2mm左右的瘤块,在无菌条件下,接种于裸鼠或NOD/SCID小鼠右侧躯干皮下。形成的肿瘤组织用游标卡尺测量直径,长短径分别以a和b表示,肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2。待肿瘤生长至100-150mm3后将动物随机分组。两个模型都分为溶媒组、阳性对照组(重组抗HER2人源化单克隆抗体,30mg/kg)及受试品组(分别给予APEGA2,4,5,6,剂量以重组抗HER2人源化单克隆抗体计,都为30mg/kg)。受试品及对照药都是一周尾静脉给药一次,共给药四次。整个实验过程中,每周2次测量移植瘤直径,同时称量小鼠体重。给药结束后,继续观察两周后处死动物。
实验结果:试验结果如附图2、表4和附图3、表5所示。
表4:胃癌模型(NCI-N87)中不同受试品给药第五周抑瘤率比较
受试品 | 抑瘤率(%) |
Ab 30mg/kg QW×4 | 62.1 |
APEGA-2 30mg/kg QW×4 | 41.3 |
APEGA-4 30mg/kg QW×4 | 56.0 |
APEGA-5 30mg/kg QW×4 | 90.4 |
APEGA-6 30mg/kg QW×4 | 80.0 |
表5:卵巢癌模(SKOV-3)中受试品给药第五周抑瘤率比较
受试品 | 抑瘤率(%) |
Ab 30mg/kg QW×4 | 57.2 |
APEGA-2 30mg/kg QW×4 | 37.9 |
APEGA-4 30mg/kg QW×4 | 65.4 |
APEGA-5 30mg/kg QW×4 | 86.4 |
APEGA-6 30mg/kg QW×4 | 77.1 |
结果表明,受试品APEGA5和APEGA6在两个肿瘤模型都表现出明显的抗肿瘤活性,药效明显好于相同剂量及给药方案的重组抗HER2人源化单克隆抗体。其中APEGA5的抗癌活性更强,在两个模型中均好于APEGA6。另外两个受试品APEGA2和APEGA4相对药效稍弱,APEGA2在两个模型中药效均较重组抗HER2人源化单克隆抗体弱,APEGA4则与重组抗HER2人源化单克隆抗体作用相近。在整个实验过程中,未观察到动物明显的异常反应,对药物的耐受都较好。
Claims (18)
1.一种PEG连接子,具有通式(Ⅰ)所示的结构:
Y1-PEG1-{R1-PEG2-{Y4}n}m
(Ⅰ)
其中,
PEG1和PEG2为相同或不同的聚乙二醇残基;
m为1~7的整数,优选的,m为2~7的整数;
n为1~7的整数,优选的,n为2~7的整数;
R1为连接PEG1和PEG2的连接单元;
Y1具有Z1-X1-的结构,Y4具有-X4-Z4的结构;
其中,X1和X4独立的选自以下基团组成的组:-(CH2)i-、-(CH2)iNH-、-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCONH-、-(CH2)iNHCO-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-,i为从0-10的整数;优选的,i为0,1或2;
Z1选自以下基团组成的组:琥珀酰亚胺、巯基、羧基、丙酸基、醛基、丙烯酸基、戊二酸基、马来酰亚胺基、N-羟基-琥珀酰亚胺基、N-羟基-戊二酰亚胺基、琥珀酰亚胺碳酸酯基、琥珀酰亚胺乙酸酯基、琥珀酰亚胺丙酸酯基、琥珀酰亚胺琥珀酸酯基、亚胺酸酯基、对硝基苯碳酸酯基、三聚氰酰氯基、邻二硫吡啶基、巯酯基、酰肼基、异氰酸基、异硫氰酸基、乙烯砜;
Z4为羧酸、羟基或羰基。
2.如权利要求1所述的PEG连接子,其特征在于:所述R1为硫醇反应性的,且活性端基独立的选自:巯基、巯基反应性基团,所述巯基反应性基团能够与巯基反应生成硫醚键或二硫键,选自:马来酰亚胺基、戊二酸基、乙烯砜基、卤代乙酰胺基、二硫化吡啶基、硫代磺酸酯基、乙烯亚胺、氮丙啶基、氨基磺酰基;优选的,所述巯基反应性基团选自:巯基、马来酰亚胺基、乙烯砜基、卤代乙酰氨基;或者,
所述连接PEG1和PEG2的连接单元R1通过点击反应获得,且活性端基独立的为叠氮基或炔基。
3.如权利要求1所述的PEG连接子,其特征在于:所述m为3,4,5,6或7,所述n为3,4,5,6或7。
4.一种配基药物偶联物或其药学上可接受的盐,所述配基药物偶联物具有通式(Ⅱ)所示的结构:
TM-{R2-PEG1-{R1-PEG2-{R3-A’-药物}n}m}l
(Ⅱ)
其中,
TM为配基单元;
PEG1和PEG2为相同或不同的聚乙二醇残基;
l为1~10的整数,优选的,l为1~8的整数;
m为1~7的整数,优选的,m为2~7的整数;
n为1~7的整数,优选的,n为2~7的整数;
A’为视情况存在的间隔物;
R1为连接PEG1和PEG2的连接单元;
R2为连接配基单元与PEG1的偶联单元;
R3为连接PEG2和间隔物A’或药物的连接单元。
5.如权利要求4所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述TM配基单元选自单克隆抗体、多克隆抗体、蛋白质、多肽和寡核苷酸;优选的,所述TM配基单元为单克隆抗体;更优选的,所述单克隆抗体对癌症、恶性细胞、感染性生物或自身免疫性疾病相关的抗原或其表位是反应性的;最优选的,所述单克隆抗体选自:抗HER2抗体、抗EGFR抗体、抗PMSA抗体、抗VEGFR抗体、抗CD30抗体、抗CD22抗体、抗CD56抗体、抗CD29抗体、抗GPNMB抗体、抗CD138抗体、抗CD74抗体、抗ENPP3抗体、抗Nectin-4抗体、抗EGFRⅧ抗体、抗SLC44A4抗体、抗间皮素抗体、抗ET8R抗体、抗CD37抗体、抗CEACAM5抗体、抗CD70抗体、抗MUC16抗体、抗CD79b抗体、抗MUC16抗体、抗Muc1抗体。
6.如权利要求4所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述A’选自碳酸酯残基、β-葡糖甘酸残基、一个或多个相同或不同的氨基酸残基及其衍生物;所述氨基酸选自:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸;优选的,所述氨基酸选自:天冬氨酸、谷氨酸、甘氨酸、异亮氨酸、亮氨酸、苯丙氨酸和缬氨酸。
7.如权利要求1所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述R1为硫醇反应性的,且活性端基独立的选自:巯基、巯基反应性基团;所述巯基反应性基团能够与巯基反应生成硫醚键或二硫键,选自:马来酰亚胺基、戊二酸基、乙烯砜基、卤代乙酰胺基、二硫化吡啶基、硫代磺酸酯基、乙烯亚胺、氮丙啶基、氨基磺酰基;优选的,所述巯基反应性基团选自:巯基、马来酰亚胺基、乙烯砜基、卤代乙酰氨基;或者,
所述连接PEG1和PEG2的连接单元R1通过点击反应获得,且活性端基独立的为叠氮基或炔基。
8.如权利要求4所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述R2具有-B-A-结构,其中:
A选自:-(CH2)i-、-(CH2)iNH-、-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCONH-、-(CH2)iNHCO-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-,i为从0-10的整数;优选的,i为0,1或2;
B选自:马来酰亚胺基、氨基、羧基、巯基、琥珀酰亚胺碳酸酯基、琥珀酰亚胺乙酸酯基、琥珀酰亚胺丙酸酯基、琥珀酰亚胺琥珀酸酯基、N-羟基-琥珀酰亚胺基、N-羟基-戊二酰亚胺基、亚胺酸酯基、对硝基苯碳酸酯基、三聚氰酰氯基、邻二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、戊二酸基、酰肼基、异氰酸基、异硫氰酸基、乙烯砜基。
9.如权利要求4所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述R3选自:-(CH2)iOCOO-、-(CH2)iOCONH-、-(CH2)iNHCONH-、-(CH2)iNHCO-、-OC(CH2)iCOO-、-(CH2)iCOO-、-(CH2)iCONH-,i为从0-10的整数;优选的,i为0,1或2。
10.如权利要求4-9任一项所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述PEG1和PEG2独立的选自具有1-240个单体单元的确定的聚乙二醇残基,优选自具有1-120个单体单元的确定的聚乙二醇残基。
11.如权利要求10所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述PEG1和PEG2独立的选自直链、Y型、多分支的聚乙二醇残基。
12.如权利要求11所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述PEG1和/或PEG2为Y型聚乙二醇残基,具有通式(Ⅲ)的结构:
其中,i是1~120的整数,优选为1-60的整数;
或者,
所述PEG1和/或PEG2为多分支聚乙二醇残基,具有通式(Ⅳ)的结构:
其中:k是1~80的整数,优选为1-40的整数;
J是3~8的整数;
R是多分支聚乙二醇的核心分子,R选自季戊四醇、甲基葡萄糖苷、蔗糖、二甘醇、丙二醇、甘油和聚甘油的残基。
13.如权利要求4所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述药物选自:伊立替康、拓扑替康、贝洛替康、依沙替康、卢托替康、二氟替康、吉尼替康、卡尼替康、阿霉素、表柔比星、吗啉代阿霉素、氰基吗啉代-阿霉素、2-吡咯啉基阿霉素、喜树碱、10-羟基喜树碱、SN-38、9-氨基喜树碱、9-硝基喜树碱、紫杉烷、格尔德霉素、袢霉素和埃坡霉素;优选的,所述药物选自:伊立替康、拓扑替康、贝洛替康、依沙替康、卢托替康、二氟替康、吉尼替康、卡尼替康、喜树碱、10-羟基喜树碱、SN-38、9-氨基喜树碱和9-硝基喜树碱;更优选的,所述药物为伊立替康。
14.如权利要求4所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述配基药物偶联物选自APEGA-2、APEGA-4、APEGA-5和APEGA-6,分别具有如下所示的结构式:
其中,TM为配基单元,Val为缬氨酸,Iri为伊立替康,n可相同或不同,分别独立的选自1-240的整数,优选的,选自1-120的整数,更优选的,为1-60的整数。
15.如权利要求4所述的配基药物偶联物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐包括钠盐、钾盐、铯盐、钙盐、镁盐、三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己基胺盐、N,N-二苄基乙二胺盐、盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、泛酸盐、琥珀酸盐、枸橼酸盐、酒石酸盐、富马酸盐、马来酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、苯甲酸盐、乳酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、精氨酸盐、天冬氨酸盐、谷氨酸盐、泛酸盐、抗坏血酸盐,及上述盐的组合。
16.包含如权利要求4-15任一项所述的配基药物偶联物或其药学上可接受的盐与药学上可接受的载体或赋形剂的药物组合物。
17.如权利要求4-15任一项所述的配基药物偶联物或其药学上可接受的盐或如权利要求16所述的药物组合物在疾病预防和/或治疗药物中的应用。
18.如权利要求17所述的应用,其特征在于:所述疾病为癌症、病原性生物感染或自身免疫性疾病。
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CN107469089B (zh) | 2022-01-07 |
US11759528B2 (en) | 2023-09-19 |
US20190117790A1 (en) | 2019-04-25 |
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