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CN114874214A - 可偶联巯基的双功能大环螯合剂衍生物及其制备方法 - Google Patents

可偶联巯基的双功能大环螯合剂衍生物及其制备方法 Download PDF

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CN114874214A
CN114874214A CN202210607227.7A CN202210607227A CN114874214A CN 114874214 A CN114874214 A CN 114874214A CN 202210607227 A CN202210607227 A CN 202210607227A CN 114874214 A CN114874214 A CN 114874214A
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bifunctional
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macrocyclic chelator
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CN114874214B (zh
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徐建锋
王正
汤晓斌
蔡飞
耿长冉
罗志刚
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Nanjing Pet Tracer Co ltd
Nanjing University of Aeronautics and Astronautics
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract

本发明属于放射性药物制备领域，特别是涉及双功能大环螯合剂衍生物的制备领域，更为具体的说是涉及可偶联巯基的双功能大环螯合剂衍生物及其制备方法。本发明所获得的新的双功能大环螯合剂为巯基偶联提供了基础，从而不仅可以偶联带有巯基的小分子或大分子药物，譬如多肽、抗体，同时还能够实现定点偶联的目的。另外需要说明的是，本发明公开的式I化合物偶联条件温和，适合于抗体等敏感分子的偶联，同时具有更高的偶联效率。

Description

可偶联巯基的双功能大环螯合剂衍生物及其制备方法
技术领域
本发明属于放射性药物制备领域，特别是涉及双功能大环螯合剂衍生物的制备领域，更为具体的说是涉及可偶联巯基的双功能大环螯合剂衍生物及其制备方法。
背景技术
双功能螯合剂是放射性核素与靶向载体连接必不可少的桥梁，在分子影像学研究中起着至关重要的作用。所谓双功能螯合剂就是同时含有两个反应基团的一类螯合剂。
双功能螯合剂可分为大环配体类螯合剂、多氨基多羧基类螯合剂、β-二酮体类螯合剂、杂环芳基为骨架的螯合剂。
化合物A是一类新的双功能大环螯合剂，其化学结构式如下：
Figure BDA0003671826750000011
上述螯合剂仅能螯合含有氨基的靶分子，对于不带有氨基的靶分子来说，无法与此种双功能大环螯合剂螯合，这极大限制了螯合剂的应用。
发明内容
本发明所要解决的技术问题是对化合物A进行修饰，从而扩大其螯合应用范围，提高螯合能力。
为了解决这一技术问题，本发明公开了可偶联巯基的双功能大环螯合剂衍生物化合物，具有式(I)所示结构：
Figure BDA0003671826750000021
其中：n为1～10的整数。
优选n为2，可偶联巯基的双功能大环螯合剂衍生物结构如下：
Figure BDA0003671826750000022
进一步地，本发明还公开了式(I)化合物的合成路线如下：
Figure BDA0003671826750000023
化合物A在缩合剂作用下与化合物X反应制得式(I)化合物。
优选地，所述缩合剂选自DIEA、EDCI、HOAt、HBTU、HOBT、TBTU、DCC中任意一种或两种及以上组合物。
进一步优选地，缩合剂为DIEA、EDCI和HOAt三者的组合物。
进一步，所述反应溶剂选自DCM、DMF、THF、DMSO、乙腈中的任意一种。
优选地，所述反应溶剂为DMSO。
进一步地，所述反应温度0～50℃；优选温度为20℃。
本发明所获得的新的双功能大环螯合剂为巯基偶联提供了基础，从而不仅可以偶联带有巯基的小分子或大分子药物，譬如多肽、抗体，同时还能够实现定点偶联的目的。另外需要说明的是，本发明公开的式(I)化合物偶联条件温和，适合于抗体等敏感分子的偶联，同时具有更高的偶联效率。
附图说明
图1为化合物B的1HNMR谱图。
具体实施方式
为了更好的理解本发明，下面我们结合具体的实施例对本发明进行进一步的阐述。
实施例1化合物B的制备
Figure BDA0003671826750000031
向化合物A(500mg,648μmol,1.00eq)和1H-吡咯-2,5-二酮-1-(2-氨基乙基)盐酸盐(139mg,778μmol,1.2eq)的DMSO(15.0mL)溶液中添加DIEA(251mg,1.95mmol,338μL,3.00eq)、EDCI(124mg,648μmol,1.00eq)和HOAt(88.2mg,648μmol,90.7uL,1.00eq)。将混合物在20℃搅拌1小时。反应混合物直接通过制备型HPLC(TFA)纯化，得到化合物B(126mg，141μmol，纯度96.3％)为棕色固体。LCMS：[M+H]+＝893.8
化合物B的氢核磁共振谱图见图1，1H NMR(DMSO-d6,400MHz):δ8.34(t,J＝6.0Hz,1H),7.82(q,J＝7.6Hz,2H),7.48-7.36(m,4H),7.03-6.94(m,6H),4.20-4.11(m,8H),4.10-4.02(m,8H),3.64(br s,2H),3.52(br d,J＝10.0Hz,4H),3.48-3.39(m,4H),3.17(q,J＝5.2Hz,2H),2.14(s,6H)。
实施例2抗体偶联实验
2.1化合物A与抗体偶联
Figure BDA0003671826750000041
步骤：
取50mg化合物A置于西林瓶，加入2mlTris缓冲液(pH 5，0.2M)，再加入10mg EDC与10mg NHS，室温反应1h。向西林瓶内加入20mg曲妥珠单抗，使用1M碳酸钠溶液将反应液pH调至7.5，室温反应2h。使用PD-10柱对上述液体进行纯化。得化合物A与曲妥珠单抗的偶联物C。
通过LC-MS测定偶联物A-曲妥珠单抗的螯合剂-抗体比值(DAR值)为1.56。
2.2化合物B与抗体偶联
Figure BDA0003671826750000042
步骤：
取0.5mg化合物B置于西林瓶中，加入2ml的醋酸缓冲溶液(pH 6，0.2M),向西林瓶内加入20mg曲妥珠单抗，37℃反应1h；再使用PD-10柱对上述液体进行纯化，得化合物B与曲妥珠单抗的偶联物D。
通过LC-MS测定偶联物B-曲妥珠单抗的DAR值为2.01。
以上所述是本发明的具体实施方式。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明的保护范围。

Claims (9)

1.可偶联巯基的双功能大环螯合剂衍生物化合物，具有式(I)所示结构：
Figure FDA0003671826740000011
其中：n为1～10的整数。
2.如权利要求1所述的可偶联巯基的双功能大环螯合剂衍生物化合物，其特征在于，所述n为2，其结构式如下：
Figure FDA0003671826740000012
3.权利要求1所述的可偶联巯基的双功能大环螯合剂衍生物化合物的制备方法，其特征在于，合成路线如下：
Figure FDA0003671826740000013
4.如权利要求3所述的可偶联巯基的双功能大环螯合剂衍生物化合物的制备方法，其特征在于，化合物A在缩合剂作用下与化合物X反应制得式(I)化合物；所述缩合剂选自DIEA、EDCI、HOAt、HBTU、HOBT、TBTU、DCC中任意一种或两种及以上组合物。
5.如权利要求4所述的可偶联巯基的双功能大环螯合剂衍生物化合物的制备方法，其特征在于，缩合剂为DIEA、EDCI和HOAt三者的组合物。
6.如权利要求3所述的可偶联巯基的双功能大环螯合剂衍生物化合物的制备方法，其特征在于，所述反应溶剂选自DCM、DMF、THF、DMSO、乙腈中的任意一种。
7.如权利要求6所述的可偶联巯基的双功能大环螯合剂衍生物化合物的制备方法，其特征在于，所述反应溶剂为DMSO。
8.如权利要求3所述的可偶联巯基的双功能大环螯合剂衍生物化合物的制备方法，其特征在于，所述反应温度0～50℃。
9.如权利要求8所述的可偶联巯基的双功能大环螯合剂衍生物化合物的制备方法，其特征在于，所述反应温度20℃。
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