CN110167599B - 包含引入β-半乳糖苷的自我牺牲型连接基团的化合物 - Google Patents
包含引入β-半乳糖苷的自我牺牲型连接基团的化合物 Download PDFInfo
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Abstract
本发明涉及含有引入β‑半乳糖苷(β‑galactoside)的自我牺牲型连接基团(self‑immolative linker)的化合物,更详细而言,本发明的引入有β‑半乳糖苷的自我牺牲型连接基团的化合物包含:对目标靶具有结合特异性蛋白质(例:寡肽、多肽、抗体等)或配体,具有特定功能或活性的活性剂(例:药物、毒素、配体、检测探针等),能够在靶细胞内选择性地释放活性剂而形成糖苷键(glycosidic bond)的自我牺牲型连接基团。
Description
技术领域
本发明涉及含有引入β-半乳糖苷(β-galactoside)的自我牺牲型连接基团(self-immolative linker)的化合物,更详细而言,本发明的引入有β-半乳糖苷的自我牺牲型连接基团的化合物包含:对目标靶具有结合特异性蛋白质(例:寡肽、多肽、抗体等)或配体,具有特定功能或活性的活性剂(例:药物、毒素、配体、检测探针等),能够在靶细胞内选择性地释放活性剂而形成糖苷键(glycosidic bond)的自我牺牲型连接基团。
背景技术
许多用作化学治疗剂的低分子药物除癌组织外还作用于正常细胞及组织,并引起各种副作用。为了解决这种非选择性问题,积极开展抗体-药物、肽类-药物、低分子配体-药物等靶向偶联物的开发研究(Recent Patents onAnti-Cancer Drug Discovery 2014,9,35-65;Bioorganic&Medicinal Chemistry 2015,23,2187-2194;Nature Reviews DrugDiscovery 2015,14,203-219)。
抗体-药物偶联物(antibody-drug conjugate,ADC)属于靶向抗癌剂中最具代表性的治疗物质范畴,旨在通过抗原和抗体之间的选择性结合力使结合在抗体的药物在靶向癌细胞内有效释放。本妥昔单抗(Brentuximab vedotin,商品名Adcetris)是一种霍奇金淋巴瘤治疗剂,ado曲妥珠单抗(ado-trastuzumab emtansine,商品名Kadcyla)是一种HER2阳性乳腺癌治疗剂,分别于2011年和2013年得到了FDA认证。这些物质以将药物连接到半胱氨酸的硫醇及赖氨酸的氨基的形式的混合物状态存在。2016年到目前,有15种以上的ADC正处于临床实验阶段。
最近的研究结果表明,对于ADC而言,经给药ADC进入癌组织的小于1%。这暗示药物也可能作用于正常细胞(例:肝脏或内皮组织),导致副作用(Cancer Immunol Res 2013,134-143;World ADC Summit,October 27-28,2010,ImmunoGen)。此外,据报道,在经过依靠抗原-抗体偶联物的内化(internalization)过程并向细胞内递送药物的过程中,具有高分子量的抗体(~150kDa)不能渗透到癌组织内部(J.Med.Chem.2015,58,8751-8761)。用于ADC的抗体在其自身的研究和开发中需要大量的成本和努力。为找出克服这些问题的新的治疗策略,已尝试使用小分子配体-药物偶联物(small molecule drug conjugates,SMDC)(J.Med.Chem.2015,58,8751-8761;Journal of Pharmaceutical and biomedicalanalysis 2016,122,148-156)。
与具有大分子量的抗体相比,小分子配体-药物偶联物的优点在于其易于制造并具有高的癌组织渗透性。正在进行对叶酸(folic acid;Acc.Chem.Res.2008,41,120-129)及前列腺特异性膜抗原(Prostate-specific membrane antigen,PSMA,J.Nucl.Med.2014,55,1791-1798)、生长抑素类似物(somatostatin analogues,Proc.Natl.Acad.Sci.U.S.A.2006,103,16436-16441)、碳酸酐酶9(Carbonic anhydraseIX,CAIX,Nat.Chem.2015,7,241-249;Chem.Sci.2014,5,3640-3644)、整合素靶向肽(Integrin targeted peptide,Bioorg.Med.Chem.2016,24,294-303;Current Topics inMedicinal Chemistry,2016,16,314-329)的研究,其中,对利用叶酸及PSMA的研究是最活跃的(Nat.Rev.Drug Discovery 2015,14,203-219)。
靶向抗癌剂由可以选择性地结合在癌细胞的靶向基团(targeting group)和药物及将靶向基团(targeting group)与药物连接的连接子(linker)组成。靶向基团(targeting group)包括抗体(antibody)、蛋白质(protein)和配体(ligand)等,特异性结合于癌细胞中过量表达的抗原或受体,从而起到有效地将药物传递到癌细胞的作用。因此,与现有抗癌剂相比,靶向抗癌剂可以显着降低副作用的危险性。然而,实际上,癌细胞表面上表达的抗原或受体的数量很少的情况(约1×105个受体/细胞(receptors/cell))较多,有必要连接细胞毒性比一般抗癌剂高100-1000倍以上的药物,才有足够的癌细胞死亡效果。
就偶联物研究中使用的强毒性药物(例:吡咯并苯并二氮杂衍生物:pyrrolobenzodiazepine derivatives,美登素:maytansinoids,auristatinoid(s)等)而言,设计成在体内血液循环期间不会分离而传递到癌细胞中是至关重要的。大部分的偶联物结合为将半胱氨酸与马来酰亚胺(maleimide)连接在一起的硫醇-马来酰亚胺(thiol-maleimide)连接子形式。然而,硫醇-马来酰亚胺结构由于在体内容易发生逆反应(逆迈克尔加成:retro-Michael addition),显现出还原为硫醇与马来酰亚胺的不稳定性质,因而毒性问题越来越引起关注(Bioconjugate Chemistry 2008,19,759-765;BioconjugateChemistry 2010,21,5-13)。即,在制备偶联物时使用不稳定的连接子会影响到药效及毒性、PK等,开发稳定的连接子是制备偶联物的核心技术。
到目前为止,主要用于偶联物研究的连接子可分为不可裂解连接子(non-cleavable linker)与可裂解连接子(Cleavable linker)。
不可裂解连接子主要由硫醚(thioether)键组成,通过硫醇(thiol)基团与马来酰亚胺(maleimide)或卤代乙酰胺(haloacetamide)基团反应形成。T-DM1(Cancer Res 2008,68,9280-9290)与anti-CD70-mc-MMAF(SGN-75,Clin Cancer Res 2008,14,6171-6180)的偶联物属于该情况。然而,将药物直接与抗体或配体等偶联制备时,由于药物(Cytotoxicdrug)表现出非活性化(inactive)或活性比药物本身的功效显著降低的倾向,因此开发偶联物伴随有诸多困难。因此,适当引入可裂解的连接子(Cleavable linker)以使药物可在靶细胞内裂解/水解是非常重要的。
可裂解连接子(Cleavable linker)可分为化学不稳定连接子(Chemicallylabilelinker)和酶可裂解连接子(enzyme cleavable linker)(Bioconjugate Chem.2010,21,5-13)。
化学不稳定连接子主要利用通过二硫键(disulfide bond)、腙(hydrazone)或肟(oxime)键等水解(hydrolysis)或二硫化物交换(disulfide exchange)反应释放药物的机制。形成二硫键的连接子利用细胞内谷胱甘肽(glutathione)浓度高于细胞外部的这一点以在细胞内释放药物的原理,但是在体循环(systemic circulation)期间,虽然比细胞内低,但不能避免药物因血液中的谷胱甘肽(glutathione)、半胱氨酸(Cysteine)等的游离硫醇(free thiol)而分离的缺点(Bioconjugate Chemistry 2008(19)759-765)。腙或肟连接子在血液中相对稳定,但在高酸性环境下不稳定并且快速水解,不仅作用于靶癌细胞而且作用于正常细胞,从而会产生诱发毒性的副作用(Bioconjugate Chemistry 2010,21,5-13)。
酶可裂解连接子主要使用设计成通过在癌细胞内过量表达的组织蛋白酶B(Cathepsin B)或β-葡糖苷酸酶(β-glucuronidase)等的溶酶体水解酶的作用对药物进行特异性分离的结构。
已知,主要用作肽类连接子的Val-Cit(valine-citrulline)和Phe-Lys(phenylalanine-lysine)被组织蛋白酶B选择性水解。已知,虽然稳定性优于化学不稳定连接子,但在水中的溶解性差而存在产生聚合体(aggregation)的问题(US8,568,728/US7,091,186)。因此,对设计为能够通过比肽类连接子亲水性大且在溶酶体中过表达并在正常人血液中几乎不表达而尤其在癌细胞的溶酶体中高度表达的酶(例,β-葡糖苷酸酶(β-glucuronidase)、β-半乳糖苷酶(β-galactosidase)来分离药物的β-葡糖苷酸(β-glucuronide)及β-半乳糖苷(β-galatoside)的研究正在进行(Chem.Rev.2015,115,3388-3432;European Journal of Med.Chem.,2014,74,302-313;Chem Commun.,2015,51,15792-15795)。
人β-葡糖苷酸酶(β-glucuronidase,EC 3.2.1.31)对β-构型(β-configuration)葡糖苷酸(glucuronide)的糖苷键(glycosidic bond)水解,虽然在血液中几乎不存在,但在癌细胞和其周围组织中高度表达。就含有被该酶水解的β-葡糖苷酸的偶联物-药物而言,该药物几乎不在血液中释放,但是会在靶癌细胞中选择性释放。尤其,β-葡糖苷酸连接子比肽类连接子更亲水,因此具有改善偶联物物理性质的效果大的优点,被广泛用于抗体-药物偶联物的制备(J.Med.Chem.1999,42,3623-3628)。
人β-半乳糖苷酶(β-galactosidase,EC 3.2.1.23,β-Gal)作为细胞内溶酶体中存在的蛋白质,是一种水解β-半乳糖苷键(β-galactosidic bond)的酶。由于这种酶仅在低pH下形成有活性的二聚体(dimer),并且在7.4的生理pH下以非活性形式的单体(monomer)存在,因此引入新的β-半乳糖苷连接子,可以显着降低在体内循环过程中药物释放的风险(JBiol Chem 2012,287,1801-1812,J Biol Chem 1974,249,7969-7976)。
另外,据报道,在癌症患者血液中β-葡糖苷酸酶和β-半乳糖苷酶活性增加,β-葡糖苷酸酶在乳腺癌症患者血清中显现比正常人高两倍的活性,但β-半乳糖苷酶在浸润性结大肠癌症患者的血清中活性仅增加了24%(Journ al of Chinese Clinical Medicine,2010.Vol 5,480-482;Postepy Hig MedDosw(online),2013;67:896-900)。这些结果表明,预计在癌症患者血液中引入活性较弱的酶底物β-半乳糖苷的连接子比引入β-葡糖苷酸的连接子在癌症患者血液中的稳定性及安全性方面更有优势。
Jeffrey(Bioconjugate Chem.2009,20,1242-1250;ACS Med.Chem.Lett.2010,1,277-280)等报告了将β-葡糖苷酸与多种药物(例,多柔比星:doxorubicin,喜树碱类似物:Camptothecin analog,CBI,奥瑞他汀:Auris tatins)结合来制备偶联物的例子。据此,由β-葡糖苷酸制成的抗体-药物偶联物在大鼠血浆中非常稳定,但没有报告小鼠血浆中的稳定性。
KR10-2015-0137015开发了一种与Jeffrey等人开发的利用β-葡糖苷酸制备的偶联物相比,在小鼠血浆中稍微更稳定的与β-葡糖苷酸偶联的自我牺牲型连接基团。然而,利用β-葡糖苷酸的偶联物的研究开发存在药物结构复杂、难以偶联根据条件处理困难的如美登素(maytansinods)、隐藻素(Cryptophycin)等药物的缺点。
通过将多柔比星(doxorubicin)与β-半乳糖苷连接而制备的前药(prodrug)与直接对药物进行给药的情况相比,表现出1000倍以上的安全性(Arch Pharm Res,2007,30,723-732)。向小鼠给药这些前药(prodrug)时,表现出比给药药物本身时更高的最大耐受剂量(MTD)(Drug Development and Industrial Pharmacy 2008,34,789-795)。就如上所述的Papot等的β-葡糖苷酸和甲基奥瑞他汀(monomethylauristatin E,MMAE)偶联物而言,与活性比给药药物本身低100倍的情况相比,在安全性方面,判断β-半乳糖苷比β-葡糖苷酸更优秀。
另外,Papot(Angew.Chem.Int.Ed.2012,51,11606-11610;US 9,000,135)等开发了一种与低分子物质(例,诸如叶酸的配体)偶联的半乳糖苷前药(galactoside prodrug),来代替由于分子量大而难以渗透癌细胞的抗体。然而,根据该报道,存在的缺点在于,当为利用β-半乳糖苷的偶联物时,制备成异构体的混合物而不是单一物质。
因此,本发明提供一种弥补迄今为止描述的现有β-葡糖苷酸和β-半乳糖苷的缺点,在血液中非常稳定并且仅在靶向癌细胞中释放药物且有利于改善偶联物的物理性质及制备工艺的偶联有β-半乳糖苷的自我牺牲型连接基团,进一步提供一种对曾经难以应用于β-葡糖苷酸的药物也能够适用的具有优秀的通用性的含有自我牺牲型连接基团的化合物。
发明内容
发明要解决的问题
本发明的目的在于提供一种偶联有β-半乳糖苷的自我牺牲型连接基团的化合物,其被设计成具有高亲水力并且能够被癌细胞中过表达的β-半乳糖苷选择性地裂解,从而显示出活性剂的功效。
用于解决问题的方案
本发明提供有以下化学式1表示的含有引入β-半乳糖苷的自我牺牲型连接基团(self-immolative linker)的化合物,
化学式1
在上述化学式1中,
R是氢或羟基保护基;
X是-C(=O)-、-NH-、-O-或-S-;
T是活性剂;
n是0或1的整数;
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
z是1至3的整数,z是2以上的整数时,各Y可以彼此相同或不同;
z1是0或1的整数;
Wa1及Wa2各自独立为-NH-、-C(=O)-或-CH2-;
Wa3及Wa4各自独立为-NH-、-C(=O)-、-CH2-、-C(=O)NH-、-NHC(=O)-或亚三唑基;
Wb1是酰胺键或亚三唑基;
L是连接Wa2和Z的连接子,是氨基酸、肽或酰胺键;
Z是单键、-Wa5-(CH2)a2-Wb2-(CH2)a3-Wa6-或–Wa7-(CH2)a4-CR’R”-X”-;
R’是C1-C8烷基或B-Wa8-Q3-Wc1-(CH2)a5-;
R”是B-Wa8-Q3-Wc1-(CH2)a5-;
Q1及Q3各自独立为–(CH2)a6-(X1CH2CH2)b1-(CH2)a7-;
X1及X3各自独立为-O-、-S-、-NH-或-CH2-;
X”是–NHC(=O)-(CH2)a8-Wa9-或–C(=O)NH-(CH2)a8-Wa9-;
Wa5、Wa6、Wa7、Wa8及Wa9各自独立为-NH-、-C(=O)-或-CH2-;
Wb2是酰胺键或亚三唑基;
Wc1是–NHC(=O)-或–C(=O)NH-;
Q2是具有碳原子为1-50的直链或支链的饱和或不饱和的亚烷基,满足下述(i)至(iii)中的至少一个;
(i)所述亚烷基中的至少一个-CH2-被选自-NH-、-C(=O)、-O-及-S-的一个以上的杂原子取代,
(ii)在所述亚烷基中至少包括一个亚芳基或亚杂芳基,
(iii)所述亚烷基进一步被选自由C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5构成的组中选择的一个以上取代;
所述(ii)的亚芳基或亚杂芳基可进一步被硝基取代;
R3、R4及R5各自独立为氢或C1-C15烷基;
X2是-O-、-S-、-NH-或-CH2-;
U1是选自下述结构的连接基团,B’键合到星号“*”位置;
R是C1-C10烷基,C6-20芳基或C2-C20杂芳基;
B及B’各自独立为具有选择性靶向结合到特定器官、组织或细胞,即具有与受体结合的药物特性的配体或蛋白质;
a1、a2、a3、a4、a5、a6、a8、b1、p1、p2、p3及p4各自独立为1至10的整数;
a7、y、s1、s2及s4各自独立为0至10的整数;
R1及R2各自独立为氢、C1-C8烷基或C3-C8环烷基。
另外,本发明还提供由下化学式2表示的化合物作为制备式1的中间体。
化学式2
在上述化学式2中,
R是氢或羟基保护基;
X是-C(=O)-、-NH-、-O-、-CH2-或-S-;
Wa1是-NH-、-CH2-或-C(=O)-;
T是活性剂;
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
U是单键或
Wa2是-NH-、-C(=O)-或-CH2-;
Wa3及Wa4各自独立为-NH-、-C(=O)-、-CH2-、-C(=O)NH-、-NHC(=O)-或亚三唑基;
R21是C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
s1及s2各自独立为0至10的整数;
a1各自独立为1至10的整数;
s4是0至10的整数;
p3及p4各自独立为1至10的整数;
FG是-NH2、-C≡CH、C4-C10环炔、–N3、-COOH、-SO3H、-OH、-NHOH、-NHNH2、-SH、卤代乙酰胺(-NHC(O)CH2-hal,hal是卤素)、马来酰亚胺卤素、甲苯磺酸酯(TsO-)、醛(-COH)、酮(-COR,R是C1-C10烷基、C6-C20芳基、C2-C20杂芳基)、二烯、或-OP(=O)(OH)2;
X1及X3各自独立为-O-、-S-、-NH-或–CH2-;
a6及b1各自独立为1至10的整数;
a7是0至10的整数;
z是1至3的整数,z是2以上的整数时,各Y可以彼此相同或不同;
z1是0或1的整数;
R1及R2各自独立为氢、C1-C8烷基或C3-C8环烷基。
发明效果
本发明的引入β-半乳糖苷的自我牺牲型连接基团与现有的连接子的制备方法简单且没有副反应,因此易于分离纯化。另外,还具有良好的亲水性,并改善了使用它制备的偶联物的物理性能。
另外,引入有本发明的β-半乳糖苷的自我牺牲型连接基团的化合物包含:对目标靶具有结合特异性蛋白质(例:寡肽、多肽、抗体等)或配体,具有特定功能或活性的活性剂(例:药物、毒素、配体、检测探针等),能够在靶细胞内选择性地释放活性剂而形成糖苷键(glycosidic bond)的自我牺牲型连接基团,具有设计成使用在靶细胞中过表达的酶β-半乳糖苷选择性地释放活性剂。尤其,可适用于难以应用于β-葡糖苷酸的药物,因此广泛用于靶向治疗性抗癌药物的开发。
附图说明
图1是实施例1的半乳糖基溴(Galactosyl bromide)与韩国公开专利第10-2015-0137015号的实施例1的葡糖醛酸溴(glucuronyl bromide)的制备工艺步骤及收率的比较。
图2是β-葡糖苷酸(BG;上)及β-半乳糖苷(BGal;下)的脱保护步骤的比较。
图3是实验例1的酶切分析(Enzymatic cleavage assay)结果。
图4是实验例2的人血浆内稳定性评价结果。
图5是实验例2的小鼠血浆内稳定性评价结果。
图6是实验例3的配体-药物偶联物的受体键合力(binding affinity)结果。
图7是实验例4的配体-药物偶联物的体外细胞毒性(in vitro cytotoxicity)评价。
图8是实验例7的配体-药物偶联物的酶切分析(Enzymatic cleavage assay)评价。
图9是实验例5中制备的thiomab药物偶联物(thiomab drug conjugate,TDC)Ab-17及Ab-18的结构。
具体实施方式
本发明涉及含有引入β-半乳糖苷(β-galactoside)的自我牺牲型连接基团(self-immolative linker)的化合物,自我牺牲型连接基团将被取代的苯甲酸衍生物作为基本骨架,且在邻位(ortho-position)上偶联有通过酶促反应水解的β-半乳糖苷,在苯甲酸的间位偶联有具有特异性功能或活性的活性剂(例:药物、毒素、配体、检测探针等),苯甲酸的羧基包含引入有连接子的酰胺键,该连接子可偶联对目标靶具有结合特异性的蛋白质(例:寡肽、多肽、抗体等)或配体等。
更具体而言,本发明的含有引入β-半乳糖苷的自我牺牲型连接基团的化合物由下述化学式1表示。
[化学式1]
在上述化学式1中,
R是氢或羟基保护基;
X是-C(=O)-、-NH-、-O-或-S-;
T是活性剂;
n是0或1的整数;
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
z是1至3的整数,当z是2以上的整数时,各Y可以彼此相同或不同;
z1是0或1的整数;
Wa1及Wa2各自独立为-NH-、-C(=O)-或-CH2-;
Wa3及Wa4各自独立为-NH-、-C(=O)-、-CH2-、-C(=O)NH-、-NHC(=O)-或亚三唑基;
Wb1是酰胺键或亚三唑基;
L是连接Wa2和Z的连接子,是氨基酸、肽或酰胺键;
Z是单键、-Wa5-(CH2)a2-Wb2-(CH2)a3-Wa6-或–Wa7-(CH2)a4-CR’R”-X”-;
R'是C1-C8烷基或B-Wa8-Q3-Wc1-(CH2)a5-;
R"是B-Wa8-Q3-Wc1-(CH2)a5-;
Q1及Q3各自独立为–(CH2)a6-(X1CH2CH2)b1-(CH2)a7-;
X1及X3各自独立为-O-、-S-、-NH-或-CH2-;
X"是–NHC(=O)-(CH2)a8-Wa9-或–C(=O)NH-(CH2)a8-Wa9-;
Wa5、Wa6、Wa7、Wa8及Wa9各自独立为-NH-、-C(=O)-或-CH2-;
Wb2是酰胺键或亚三唑基;
Wc1是–NHC(=O)-或–C(=O)NH-;
Q2是具有碳原子为1-50的直链或支链的饱和或不饱和的亚烷基,满足下述(i)至(iii)中的至少一个;
(i)所述亚烷基中的至少一个-CH2-被选自-NH-、-C(=O)、-O-及-S-的一个以上的杂原子取代,
(ii)所述亚烷基中至少包括一个亚芳基或亚杂芳基,
(iii)所述亚烷基进一步被选自由C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5构成的组中的一个以上取代;
所述(ii)的亚芳基或亚杂芳基可进一步被硝基取代;
R3、R4及R5各自独立为氢或C1-C15烷基;
X2是-O-、-S-、-NH-或-CH2-;
U1是选自下述结构的连接基团,B’耦合到星号(*)位置;
R是C1-C10烷基,C6-20芳基或C2-C20杂芳基;
B及B’各自独立为具有选择性靶向结合到特定器官、组织或细胞,即与受体结合的药物特性的配体或蛋白质;
a1、a2、a3、a4、a5、a6、a8、b1、p1、p2、p3及p4各自独立为1至10的整数;
a7、y、s1、s2及s4各自独立为0至10的整数;
R1及R2各自独立为氢、C1-C8烷基或C3-C8环烷基。
在本发明的含有自我牺牲型连接基团的化合物中,所述羟基保护基不限于可用于有机合成的常规保护基,更优选为甲醚(methyl ether)、甲氧基甲基醚(methoxymethylether、MOM)、甲硫基甲基醚(methylthiomethyl ether、MTM)、2-甲氧基乙氧基甲基醚(2-methoxyethoxymethyl ether、MEM)、双(2-氯乙氧基)甲基醚(bis(2-chloroethyoxy)methyl ether)、四氢吡喃醚(tetrahydropyranyl ether、THP)、四氢噻喃基醚(tetrahydrothiopyranyl ether)、4-甲氧基四氢吡喃醚(4-methyoxytetrahydropyranylether)、4-甲氧基四氢噻喃基醚(4-methoxytetrahydrothiopyranyl ether)、四氢呋喃醚(tetrahydrofuranyl ether)、1-乙氧基乙基醚(1-ethoxyethyl ether)、1-甲基-1-甲氧基乙基醚(1-methyl-1-methoxyethyl ether)、2-(苯基硒基)乙基醚(2-(phenylselenyl)ethyl ether)、叔丁基醚(t-butyl ether)、烯丙基醚(allyl ether)、苄基醚(benzylether)、邻硝基苄基醚(o-nitrobenzyl ether)、三苯甲醚(triphenylmethyl ether)、α-萘基二苯基甲基醚(α-naphtyldiphenylmethyl ether)、对甲氧基苯基二苯基甲基醚(p-methoxyphenyldiphenylmethyl ether)、9-(9-苯基-10-氧代)蒽基醚(9-(9-phenyl-10-oxo)anthryl ether)、三甲基甲硅烷基醚(trimethylsilyl ether,TMS)、异丙基二甲基甲硅烷基醚(isopropyldimethylsilyl ether)、叔丁基二甲基甲硅烷基醚(t-butyldimethylsilyl ether,TBDMS)、叔丁基二苯基甲硅烷基醚(t-butyldiphenylsilylether)、三苄基甲硅烷基醚(tribenzylsilyl ether)、三异丙基甲硅烷基醚(triisopropylsilyl ether)、甲酸酯(formate ester)、乙酸酯(acetate)、酯(ester)、三氯乙酸酯(trichloroacetate ester)、苯氧乙酸酯(phenoxyacetateester)、异丁酸酯(isobutyrate ester)、新戊酸酯(pivaloate ester)、金刚烷酸酯(adamantate ester)、苯甲酸酯(benzoate ester)、2,4,6-三甲基苯甲酸酯(Mesitoate)酯(2,4,6-trimethylbenzoate(Mesitoate)ester)、碳酸甲酯(methyl carbonate)、2,2,2-三氯乙基碳酸酯(2,2,2-tricloroethyl carbonate)、烯丙基碳酸酯(allyl carbonate)、对硝基苯基碳酸酯(p-nitrophenyl carbonate)、碳酸苄酯(benzyl carbonate)、对硝基苄基碳酸酯(p-nitrobenzyl carbonate)、S-苄基硫代碳酸酯(S-benzyl thiocarbonate)、N-苯氨基甲酸酯(N-phenylcarbamate)、硝酸酯(nitrate ester)、2,4-二硝基苯基亚磺酸酯(2,4-dinitrophenylsulfenate ester)等,但不限于此。
在本发明的含有自我牺牲型连接基团的化合物中,所述L是连接Wa2和Z的连接子,可以是氨基酸、肽单元或酰胺键,所述氨基酸或肽单元可以重复一次以上,可在作为氨基酸残基的胺基、羧酸基、硫醇基等包含一个或两个以上的官能团。
点击化学反应在温和的条件下进行,使得能够容易地处理蛋白质。点击化学反应显示出极高的反应特异性。因此,即使当蛋白质具有不同的官能团时(例:在侧链残基或C-末端或N-末端),该官能团也不受点击化学反应的影响。例如,蛋白质的叠氮基团和乙炔基团之间的点击化学反应可在蛋白质的其他官能团不受点击化学反应的影响期间发生。另外,点击化学反应不受伴随的配体种类的影响而特异性地发生。在部分情况下,可以选择配体以提高整体反应效率。例如,叠氮化物-乙炔点击化学可以以高收率生成三唑。
叠氮化物和乙炔基团是天然蛋白质的氨基酸序列中不存在的官能团。当使用该官能团发生键合反应时,侧链残基中的任意一个以及N-末端或C-末端官能团中的任意一个都不受点击化学反应的影响。
在本发明的含有自我牺牲型连接基团的化合物中,所述L可包含以下述化学式A或化学式B表示的一个以上单元。
[化学式A]
[化学式B]
在所述化学式A及B中,
R11是氢、C1-C8烷基、-(CH2)s3COOR13、-(CH2)s3COR13、–(CH2)s3CONR14R15或–(CH2)s4NR14R15;
R13、R14及R15各自独立为氢或C1-C15烷基;
s3及s4各自独立为0至10的整数;
X3是-O-、-S-、-NH-或-CH2-;
p3及p4各自独立为1至10的整数。
在本发明的含有自我牺牲型连接基团的化合物中,所述R11可以是-(CH2)s3COOH或–(CH2)s4NH2,s3及s4可以各自独立为0至10的整数。
在本发明的含有自我牺牲型连接基团的化合物中,所述X优选为-C(=O)-,Wa1优选为-NH-。
在本发明的含有自我牺牲型连接基团的化合物中,所述Z是单键或在下述结构中选择。
在上述结构中,
R'是C1-C8烷基或B-NH-(CH2)a6-(X1CH2CH2)b1-NH-C(=O)-(CH2)a5-;
R"B-NH-(CH2)a6-(X1CH2CH2)b1-NH-C(=O)-(CH2)a5-;
X"是–NHC(=O)-(CH2)a8-NH-或–C(=O)NH-(CH2)a8-NH-;
a2、a3、a4、a5、a6、a8及b1各自独立为1至10的整数;
X1是-O-、-S-、-NH-或-CH2-;
B与上述化学式1中的定义相同。
在本发明的含有自我牺牲型连接基团的化合物中,所述Z可以是单键或在下述结构中选择。
R'是C1-C8烷基或B-NH-(CH2)a6-(X1CH2CH2)b1-NH-C(=O)-(CH2)a5-;
R"是B-NH-(CH2)a6-(X1CH2CH2)b1-NH-C(=O)-(CH2)a5-;
a4、a5、a6、a8及b1各自独立为1至10的整数;
X1是-O-、-S-、-NH-或-CH2-;
B与上述化学式1中的定义相同。
在本发明的含有自我牺牲型连接基团的化合物中,所述Q2优选选自下述化学式C至化学式I。
[化学式C]
[化学式D]
[化学式E]
[化学式F]
[化学式G]
[化学式H]
[化学式I]
在上述化学式C至I中,
X11及X12各自独立为-O-、-S-、-NH-或-CH2-;
R12至R14各自独立为氢、C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5或–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
X2是-O-、-S-、-NH-或-CH2-;
Ra是氢或硝基;
c1、c2、c3、c4及d1各自独立为1至10的整数;
q1及q2各自独立为0至5的整数;
s1及s2各自独立为0至5的整数;
p1及p2各自独立为1至10的整数。
在本发明的含有自我牺牲型连接基团的化合物中,与自我牺牲型连接基团偶联的β-半乳糖苷具有被β-半乳糖苷酶一次水解后通过1,6-消除反应释放活性剂的机制(反应式1)。
[反应式1]
结果可确认,本发明的含有与β-半乳糖苷偶联的自我牺牲型连接基团的化合物比现有的已知类似形式的自我牺牲型连接基团衍生物更容易合成,细胞穿透性(Cell-penetration)和血浆内稳定性及对癌细胞的体外(in vitro)效果优异。
US8,568,728和KR10-2015-037015说明了引入含有β-葡糖苷酸的自我牺牲型连接基团的抗体-药物偶联物的制备例。KR10-2015-037015中描述的含有β-葡糖苷酸的自我牺牲型连接基团与US8,568,728中记载的类似结构的自我牺牲型衍生物相比,改善了血浆内的稳定性,但在制备上存在多种问题。
如图1所示,β-葡糖苷酸比本发明要开发的含有β-半乳糖苷的自我牺牲型衍生物的制备工艺长,且用作中间体的葡糖醛酸溴化物(glucuronyl bromide;methyl 2,3,4-tri-O-acetyl-alpha-D-glucopyranosyluronate bromide:2,3,4-三-O-乙酰基-α-D-溴代葡萄糖醛酸甲酯,目录编号(Catalog number)A8292,334,000元/1g,www.sigmaaldrich.com)的收率低(50%)(Carbohydrate Research 2000,328,445-448中描述的内容中以更低的38%的收率制备)。
在制备工艺中,就β-葡糖苷酸而言,反应在碱性条件下进行,以除去用于保护醇基和羧酸基的乙酰基和甲基。然而,在这些条件下,两种不同保护基团之间的反应速率存在差异,会导致消除反应,此时,在分离和纯化过程中不易除去已产生的副产物,因此具有导致最终产物的收率和纯度下降的缺点。
Papot团队发表了能够被β-半乳糖苷酶水解的β-半乳糖苷衍生物的研究结果。自我牺牲型连接基团的结构具有引入苄醇基团结构特征,使得药物可以通过1,6-消除反应(1,6-elimination)得到释放(US 9,000,135;Arch Pharm Res Vol 30,No 6,723-732,2007;Journal of Medicinal Chemistry,2009,52,537-543;Drug Development andIndustrial Pharmacy,34:789-795,2008)。然而,就该物质而言,在将药物与仲醇结合的过程中,由于反应速率慢于伯醇的反应速率,有收率低的缺点,仲醇基团合成为具有手性碳的立体异构体(stereoisomer),存在难以用单一物质制备偶联物的问题。另外,由于制备过程中的NO2基团在还原反应的条件下不稳定,因此,在物质制备过程中受到诸多限制,并且当在体内代谢为胺时,药物分解的可能性增加,有可能引发毒性。
本发明要开发的含有β-半乳糖苷的自我牺牲型连接基团通过定量执行半乳糖基溴衍生物(2,3,4,6-四-O-乙酰基-alpha-D-吡喃葡萄糖溴化物(2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide)目录编号(catalog number)A1750,872,000元/100g,www.sigmaaldrich.com)的合成,由于在β-半乳糖苷的四个醇基团中使用相同的保护基团(例,乙酰基),不会产生使用不同保护基团的β-葡糖苷酸衍生物的制备时产生的副反应,因此具有收率高的优点。尤其,使用单一保护基团,还可用于难以引入β-葡糖苷酸的药物(美登素(maytansinoids)、隐藻素(Cryptophycin)系列等),从而可以开发为在通用性方面优于β-葡糖苷酸的连接子。
在本发明的含有自我牺牲型连接基团的化合物中,所述活性剂可以是药物、毒素、亲和配体、检测探针或其组合。
所述药物可在由厄洛替尼(erlotinib,TARCEVA;Genentech/OSI Pharm.)、硼替佐米(bortezomib,VELCADE;MilleniumPharm.)、氟维司群(fulvestrant,FASLODEX;AstraZeneca)、索坦(sutent,SU11248;Pfizer)、来曲唑(letrozole,FEMARA;Novartis)、甲磺酸伊马替尼(imatinib mesylate,GLEEVEC,Novartis)、PTK787/ZK222584(Novartis)、奥沙利铂(oxaliplatin,Eloxatin;Sanofi)、5-氟尿嘧啶(5-fluorouracil,5-FU)、甲酰四氢叶酸(leucovorin)、雷帕霉素(rapamycin,Sirolimus(西罗莫司),RAPAMUNE;Wyeth)、拉帕替尼(lapatinib,TYKERB,GSK572016;GlaxoSmithKline)、洛那法尼(lonafarnib,SCH66336)、索拉非尼(sorafenib,BAY43-9006,Bayer Labs.)、吉非替尼(gefitinib,IRESSA;Astrazeneca)、AG1478,AG1571(SU 5271;Sugen)、烷化剂(alkylatingagent)(例:噻替哌(thiotepa)或环磷酰胺(Cyclophosphamide))、烷基磺酸盐(alkylsulfonate)(例:白消安(busulfan)、英丙舒凡(improsulfan)或哌泊舒凡(piposulfan))、氮丙啶(aziridine)(例:苯佐替哌(benzodopa)、卡波醌(Carboquone)、美妥替哌(meturedopa)或乌瑞替哌(uredopa))、乙烯亚胺(ethylenimine)、甲基三聚氰胺(methylmelamine)、六甲蜜胺(altretamine)、曲他胺(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphoramide)、三羟甲基三聚氰胺(trimethylolmelamine)、番荔素(acetogenins)(例:布拉它辛(bullatacin)或布拉它辛酮(bullatacinone))、包含合成类似物拓扑替康(synthetic analogue topotecan)的喜树碱(Camptothecin)、苔藓虫素(bryostatin)、卡莉他汀(Callystatin)、CC-1065(包含其阿多来新(adozelesin)、卡折来新(Carzelesin)或比折来新(bizelesin)合成类似物(synthetic analogues))、隐藻素(Cryptophycins)(例:隐藻素1(Cryptophycins1)或隐藻素8(Cryptophycins8))、多拉斯他丁(dolastatin)、倍癌霉素(duocarmycin)(包含合成类似物、KW-2189及CB1-TM1)、艾榴素(eleutherobin)、水鬼蕉碱(pancratistatin)、匍枝珊瑚醇(sarcodictyin)、海绵抑制素(spongistatin)、氮芥子气(nitrogen mustard)(例:苯丁酸氮芥(Chlorambucil)、萘氮芥(Chlornaphazine)、环磷酰胺(Cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、氮芥(mechlorethamine)、盐酸氮芥(mechlorethamineoxidehydrochloride)、美法仑(melphalan)、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)或尿嘧啶氮芥(uracil mustard))、亚硝酸盐尿素(nitrousurea)(例:卡莫司汀(Carmustine)、氯脲霉素(Chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)或雷莫司汀(ranimnustine))、抗生素(antibiotics)(例:作为烯二炔抗生素(enediyneantibiotics),包含选自刺孢霉素γ1I(Calicheamycin gamma1I)及刺孢霉素ΩI1(Calicheamycin omegaI1)的刺孢霉素(Calicheamycin)或包含达内霉素A(dynemicin A)的达内霉素(dynemicin))、双磷酸盐(bisphosphonate)(例:氯膦酸盐(Clodronate))、埃斯培拉霉素(esperamicin)、新制癌菌素发色团(neocarzinostatin chromophore)或相关的色素蛋白烯二炔抗生素发色团(related chromoprotein enediyne antibioticchromophores)、阿克拉霉素(aclacinomycins)、放线菌素(actinomycin)、氨茴霉素(anthramycin)、重氮丝氨酸(azaserine)、博来霉素(bleomycins)、放线菌素C(cactinomycin)、卡柔比星(Carabicin)、洋红霉素(Caminomycin)、嗜癌素(Carzinophilin)、色霉素(Chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、多柔比星( doxorubicin)(例:吗啉代多柔比星(morpholino-doxorubicin)、氰基吗啉代多柔比星(Cyanomorpholino-doxorubicin)、2-吡咯啉多柔比星(2-pyrrolino-doxorubucin)、脂质体多柔比星(liposomal doxorubicin)或脱氧多柔比星(deoxydoxorubicin))、表柔比星(epirubicin)、依索比星(esorubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycins)(例:丝裂霉素C(mitomycins C)、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌罗霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)或佐柔比星(zorubicin))、抗代谢产物(anti-metabolites)(例:5-氟尿嘧啶(5-fluorouracil,5-FU));叶酸类似物(folic acid analogues)(例:迪诺特宁(denopterin)、氨甲蝶呤(methotrexate)、蝶罗呤(pteropterin)或曲美沙特(trimetrexate));嘌呤类似物(purine analogs)(例:氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硝咪硫鸟嘌呤(thiamiprine)、硫鸟嘌呤(thiguanine));嘧啶类似物(pyrimidine analogs),(例:环胞苷(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(Carmofur)、阿糖胞苷(Cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)或氟尿苷(floxuridine));雄激素(androgens)(例:卡芦睾酮(Calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)或睾内酯(testolactone));抗肾上腺药(anti-adrenals)(例:氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane));叶酸补充剂(folic acid replenisher),(例:亚叶酸(folinicacid));醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);贝斯布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依洛尼塞(elfomithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);乙环氧啶(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);蘑菇多糖(lentinan);氯尼达明(lonidainine);类美登素(maytansinoid)(例:美登素(maytansine)或安丝菌素(ansamitocin);毒素是T-2毒素(T-2toxin)、粘液霉素A(verracurin A)、杆孢菌素A(roridin A)或蛇形菌素(anguidine));米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙酰肼(2-ethylhydrazide);丙卡巴肼(procarbazine);多糖类(polysaccharide);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofuran);锗螺胺(spirogermanium);替奴佐酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2"-三氯三乙胺(2,2',2"-trichlorotriethylamine);单端孢霉烯(trichothecene)(尤其T-2毒素、粘液霉素A、杆孢菌素A和蛇形菌素);聚氨酯(urethane);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿糖胞苷(arabinoside,“Ara-C”);环磷酰胺(Cyclophosphamide);噻替派(thiotepa);紫杉醇(taxoids)(例:紫杉醇(paclitaxel)(Bristol-Myers SquibbOncology,Princeton,N.J)、ABRAXANETM不含聚氧乙烯化蓖麻油(ABRAXANETM cremophor-free)、紫杉醇的经白蛋白工艺改造纳米粒子制剂(albumin-engineered nanoparticle formulation ofpaclitaxel,American Pharmaceutical Partners,Schaumber,I11.)或多西他赛( doxetaxel)(Rhone-Poulenc Rorer,Antony,France));苯丁酸氮芥(Chloranbucil);吉西他滨(gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);铂类似物(platinum analog)(例:顺铂(Cisplatin)或卡铂(Carboplatin));长春碱(vinblastine);铂(platinum);依托泊苷(etoposide);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);诺消灵(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);柔红霉素(daunomycin);氨基喋呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂(topoisomerase inhibitor)RFS 2000;二氟甲基鸟氨酸(difluoromethylornithine,DMFO);类视黄素(retinoid)(例:视黄酸(retinoic acid));卡培他滨(Capecitabine);及药学可接受的盐、溶剂化物、酸或其衍生物构成的组中选择,但并非必须限定于此。
其他药物包括但不限于,(i)用于调节或抑制激素对肿瘤的作用的抗激素剂,比如抗雌激素药和选择性雌激素受体调节剂(SERM),例如,他莫昔芬(包括他莫昔芬)、雷洛昔芬、屈洛昔芬、4-羟基三苯氧胺、曲沃昔芬、那洛昔芬、LYl17018、奥那司酮和托瑞米芬等;(ii)抑制在肾上腺中调节雌激素产生的芳香酶的芳香酶抑制剂,例如,4(5)-咪唑、氨鲁米特、醋酸甲地孕酮、依西美坦、来曲唑及阿那曲唑;(iii)抗雄性激素药,例如,氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林及戈舍瑞林,还有曲沙他滨(1,3-二氧戍环核苷胞嘧啶类似物);(iv)芳香酶抑制剂;(v)蛋白激酶抑制剂;(vi)脂质激酶抑制剂;(vii)反义寡核苷酸,尤其是抑制在涉及粘附细胞的信号通路中的基因表达,例如,PKC-a、Raf和H-Ras;(viii)核酶,例如,VEGF抑制剂,如ANGIOZΥΜΕ核酶及HER2表达抑制剂;(ix)疫苗,例如,基因疗法疫苗、疫苗、LEUVECTIN疫苗及VAXID疫苗,rIL-2,LURTOTECAN拓扑异构酶I抑制剂, rmRH;(x)抗血管生成剂,例如贝伐单抗(AVASTIN,Genentech)及(xi)药学上可接受的盐、溶剂化物、酸或衍生物。
另外,所述药物可以是细胞因子(Cytokine)、免疫调节化合物、抗癌剂、抗病毒剂、抗菌剂、抗真菌剂、驱虫剂或其组合。
所述细胞因子(Cytokine)是由许多细胞分泌的小细胞-信号蛋白分子,属于广泛用于细胞内信息交换的信号分子的范畴。其包括单核因子(monokine)、淋巴因子(lymphokine)、传统多肽激素(traditional polypeptidehormone)等。细胞因子的例不限于这些,还包括生长激素(growth hormone)(例:人生长激素(human growth hormone)、N-甲硫氨酰人生长激素(N-methionyl humangrowth hormone)或牛生长激素(bovinegrowthhormone));甲状旁腺激素(parathyroid hormone);甲状腺素(thyroxine);胰岛素(insulin);胰岛素原(proinsulin);松弛素(relaxin);松弛素原(prorelaxin);糖蛋白激素(glycoprotein hormone)(例:卵泡刺激激素(follicle stimulating hormone,FSH)、促甲状腺激素(thyroid stimulatinghormone,TSH)或黄体生成素(luteinizinghormone,LH));肝细胞生长因子(hepatic growthfactor);成纤维细胞生长因子(fibroblastgrowth factor);催乳素(prolactin);胎盘催乳素(placental lactogen);肿瘤坏死因子-α(tumornecrosis factor-α)和肿瘤坏死因子-β(tumornecrosis factor-β);米勒氏抑制物质(mullerian-inhibitingsubstance);小鼠促性腺激素相关肽(mousegonadotropin-associated peptide);抑制素(inhibin);活化素(activin);血管内皮生长因子(vascularendothelialgrowth factor);整联蛋白(integrin);血小板生成素(thrombopoietin,TPO);神经生长因子(nervegrowth factor)(例:NGF-α);血小板生长因子(platelet-growth factor);转化生长因子(transforming growth factor,TGF)(例:TGF-α或TGF-β);胰岛素样生长因子I(insulin-likegrowth factor-I)和胰岛素样生长因子II(insulin-likegrowth factor-II);促红细胞生成素(erythropoietin,EPO);骨诱导因子(osteoinductive factor);干扰素(interferon)(例:干扰素-α(interferon-α)、干扰素-β(interferon-β)或干扰素-γ(interferon-γ));集落刺激因子(Colony stimulatingfactor,CSF)(例:巨噬细胞-CSF(macrophage-CSF,M-CSF)、粒细胞-巨噬细胞-CSF(granulocyte-macrophage-CSF,GM-CSF)或粒细胞CSF(granulocyte-CSF,G-CSF));白介素(interleukin,IL)(例:IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11或IL-12);肿瘤坏死因子(tumor necrosis factor)(例:TNF-a或TNF-β);及多肽因子(polypeptide factor)(例:LIF和kit配体(kit ligand,KL))。另外,术语细胞因子包括来自天然来源或来自天然序列细胞因子的重组细胞培养物和生物活性等价物(biologicallyactive equivalents of a cytokine)。
所述免疫调节化合物可选自由氨基己酸(aminocaproic acid)、硫唑嘌呤(azathioprine)、溴隐亭(bromocriptine)、氯喹(Chloroquine)、苯丁酸氮芥(Chlorambucil)、环孢素(Cyclosporine)、环孢菌素A(Cyclosporine A)、达那唑(danazol)、脱氢表雄酮(dehydroepiandrosterone DHEA)、地塞米松(dexamethasone)、依那西普(etanercept)、羟基氯喹(hydroxychloroquine)、氢化可的松(hydrocortisone)、英夫利昔单抗(infliximab)、美洛昔康(meloxicam)、甲氨蝶呤(methotrexate)、环磷酰胺(Cyclophosphamide)、霉酚酸酯(mycophenolate mofetil)、泼尼松(prednisone)、西罗莫司(sirolimus)及他克莫司(tacrolimus)构成的组。所述抗癌剂可选自由甲氨蝶呤(methotrexate)、紫杉醇(taxol),L-天冬酰胺酶(L-asparaginase)、巯基嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、羟基脲(hydroxyurea)、阿糖胞苷(Cytarabine)、环磷酰胺(Cyclophosphamide)、异环磷酰胺(ifosfamide)、亚硝脲(nitrosourea)、顺铂(Cisplatin)、卡铂(Carboplatin)、丝裂霉素(mitomycin)、达卡巴嗪(dacarbazine)、丙卡巴肼(procarbazine)、托泊替康(topotecan)、氮芥(nitrogenmustard)、癌得星(Cytoxan)、依托泊苷(etoposide)、5-氟尿嘧啶(5-fluorouracil)、二氯乙基亚硝基脲(bis-chloroethylnitrosourea,BCNU)、伊立替康(irinotecan)、喜树碱(Camptothecin),博来霉素(bleomycin)、多柔比星(doxorubicin)、伊达比星(idarubicin)、柔红霉素(daunorubicin)、达克霉素(dactinomycin)、普卡霉素(plicamycin)、米托蒽醌(mitoxantrone)、门冬酰胺酶(asparaginase)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、紫杉醇(paclitaxel)、多西他赛(docetaxel)、苯丁酸氮芥(Chlorambucil)、马法兰(melphalan)、卡莫司汀(Carmustine)、洛莫司汀(lomustine)、白消安(busulfan)、苏消安(treosulfan)、达卡巴嗪(decarbazine)、依托泊苷(etoposide)、替尼泊苷(teniposide)、拓扑替康(topotecan)、9-氨基喜树碱(9-aminocamptothecin)、克立那托(Crisnatol)、丝裂霉素C(mitomycin C)、曲美沙特(trimetrexate)、酶酚酸(mycophenolic acid)、噻唑呋林(tiazofurin),利巴韦林(ribavirin)、5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺(5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide,EICAR)、羟基脲(hydroxyurea)、去铁胺(deferoxamine)、氟尿苷(floxuridine)、去氧氟尿苷(doxifluridine)、雷替曲塞(raltitrexed)、阿糖胞苷(Cytarabine(ara C))、胞嘧啶阿拉伯糖苷(Cytosinearabinoside)、氟达拉滨(fludarabine)、他莫昔芬(tamoxifen)、雷诺昔芬(raloxifene)、甲地孕酮(megestrol)、戈舍瑞林(goserelin)、醋酸亮丙瑞林(leuprolide acetate)、氟他胺(flutamide)、比卡鲁胺(bicalutamide)、EB1089、CB1093、KH1060、维替泊芬(verteporfin)、酞菁(phthalocyanine)、光敏剂Pe4(photosensitizer Pe4)、去甲氧基-竹红菌素A(demethoxy-hypocrellin A)、干扰素-α(Interferon-α)、干扰素-γ(Interferon-γ)、肿瘤坏死因子(tumor necrosis factor)、吉西他滨(Gemcitabine)、万柯(velcade)、瑞复美(revalmid)、沙利度胺(thaladomid)、洛伐他汀(lovastatin)、1-甲基-4-苯基吡啶离子(1-methyl-4-phenylpyridinium ion)、星孢菌素(staurosporine)、放线菌素D(actinomycin D)、放线菌素(dactinomycin)、博来霉素A2(bleomycin A2)、博来霉素B2(bleomycin B2)、培洛霉素(peplomycin)、表柔比星(epirubicin)、吡柔比星(pirarubicin)、佐柔比星(zorubicin)、米托蒽醌(mitoxantrone)、维拉帕米(verapamil)及毒胡萝卜素(thapsigargin)构成的组。所述抗病毒剂选自喷昔洛韦(penciclovir)、伐昔洛韦(valacyclovir)、更昔洛韦(ganciclovir)、膦甲酸(foscarnet)、利巴韦林(rivavirin)、疱疹净(idoxuridine)、阿糖腺苷(vidarabine)、三氟胸苷(trifluridine)、阿昔洛韦(acyclovir)、泛昔洛韦(famcicyclovir)、金刚烷胺(amantadine)、金刚乙胺(rimantadine)、西多福韦(Cidofovir)、反义寡核苷酸(antisense oligonucleotide)、免疫球蛋白(immunoglobulin)及干扰素(interferon)构成的组。所述抗菌剂选自氯霉素(Chloramphenicol)、万古霉素(vancomycin)、甲硝唑(metronidazole)、甲氧苄啶(trimethoprin)、磺胺甲恶唑(sulfamethazole)、奎奴普汀(quinupristin)、达福普汀(dalfopristin)、利福平(rifampin)、大观霉素(spectinomycin)及呋喃妥因(nitrofurantoin)构成的组。所述抗真菌剂选自两性霉素B(amphotericin B)、杀念菌素(Candicidin)、非律平(filipin)、哈霉素(hamycin)、纳他霉素(natamycin)、制霉菌素(nystatin)、龟裂杀菌素(rimocidin)、联苯苄唑(Bifonazole)、布康唑(Butoconazole)、克霉唑(Clotrimazole)、益康唑(Econazole)、芬替康唑(Fenticonazole)、异康唑(Isoconazole)、酮康唑(Ketoconazole)、鲁利康唑(Luliconazole)、咪康唑(Miconazole)、奥莫康唑(Omoconazole)、奥昔康唑(Oxiconazole)、舍他康唑(Sertaconazole)、硫康唑(Sulconazole)、噻康唑(Tioconazole)、阿巴康唑(Albaconazole)、氟康唑(Fluconazole)、艾沙康唑(Isavuconazole)、伊曲康唑(Itraconazole)、泊沙康唑(Posaconazole)、雷夫康唑(Ravuconazole)、特康唑(Terconazole)、伏立康唑(Voriconazole)、阿巴芬净(Abafungin)、阿莫罗芬(Amorolfin)、布替萘芬(Butenafine)、萘替芬(Naftifine)、特比萘芬(Terbinafine)、阿尼芬净(Anidulafungin)、卡泊芬净(Caspofungin)、米卡芬净(Micafungin)、苯甲酸(benzoic acid)、环吡酮(Ciclopirox)、氟胞嘧啶(flucytosine)、灰黄霉素(griseofulvin)、卤普罗(haloprogin)、托萘酯(tolnaftate)、十一烯酸(undecylenic acid)、结晶紫(Crystal violet)、秘鲁香脂(balsam of peru)、环己吡酮乙醇胺(Ciclopirox olamine)、吡罗克酮乙醇胺(Piroctone olamine)、吡啶硫酮锌(Zincpyrithione)及硫化硒(Selenium sulfide)构成的组。所述驱虫剂选自甲苯咪唑(mebendazole)、双羟萘酸噻嘧啶(pyrantel pamoate)、噻苯咪唑(thiabendazole)、乙胺嗪(diethylcarbamazine)、依维菌素(ivermectin)、氯硝柳胺(niclosamide)、吡喹酮(praziquantel)、阿苯达唑(albendazole)、利福平(rifampin)、两性霉素B(amphotericinB)、美拉胂醇(melarsoprol)、依氟鸟氨酸(eflornithine)、灭滴灵(metronidazole)、替硝唑(tinidazole)及米替福新(miltefosine)构成的组。
所述毒素是在活细胞或生物体中产生的有毒物质,是一种小分子、肽或蛋白质,其能够在与生物大分子,例如,与酶或细胞受体相互作用的身体组织接触或吸收时引起疾病。另外,毒素包括植物毒素及动物毒素。动物毒素的例包括但不限于白喉毒素(diphtheriatoxin)、肉毒杆菌毒素(botulinum toxin)、破伤风毒素(tetanus toxin)、痢疾毒素(dysentery toxin)、霍乱毒素(Cholera toxin)、河豚毒素(tetrodotoxin)、短裸甲藻毒素(brevetoxin)、雪卡毒素(Ciguatoxin)。植物毒素的例包括但不限于蓖麻毒素(ricin)及AM-毒素(AM-toxin)。
小分子毒素的例包括但不限于奥瑞斯他汀(auristatin)、微管溶素(tubulysin)、格尔德霉素(geldanamycin)(Kerr等,1997,Bioconjugate Chem.8(6):781-784)、美登素(maytansinoid)(EP 1391213,ACR 2008,41,98-107)、刺孢霉素(Calicheamycin)(US2009105461,Cancer Res.1993,53,3336-3342)、柔红霉素(daunomycin)、多柔比星(doxorubicin)、甲氨蝶呤(methotrexate)、长春地辛(vindesine)、SG2285(CancerRes.2010,70(17),6849-6858)、多拉司他汀(dolastatin)、多拉司他丁类似物的奥瑞斯他汀(dolastatin analog's auristatin)(US563548603)、隐藻素(Cryptophycin)、喜树碱(Camptothecin)、根霉素衍生物(rhizoxin derivative)、CC-1065类似物或衍生物(CC-1065analogue or derivative)、多卡米新(duocarmycin)、烯二炔抗生素(enediyneantibiotic)、埃斯培拉霉素(esperamicin)、埃博霉素(epothilone)、PBD(pyrrolobenzodiazepine:吡咯开苯并吖庚三烯)衍生物、α-鹅膏蕈碱(α-amanitin)及类毒素(toxoid)。毒素可通过微管蛋白结合、DNA结合和拓扑异构酶抑制等,表现出细胞毒性和细胞生长抑制活性。
所述亲和配体是能够与靶生物分子形成络合物的分子,并且是结合在靶蛋白的规定位置并传递信号的分子。其可以是基质、抑制剂、兴奋剂、神经递质或放射性同位素。
“可检测部分残基(detection moiety)”或“标记”是指可通过分光、光化学、生化学、免疫化学、放射性或化学方法检测的组合物。例如,有用的标记包括32P、35S、荧光染料(fluorescent dyes)、电子致密试剂(electron-dense reagents)、酶(enzymes)(例:通常用于ELISA的)、生物素链霉亲和素(biotin-streptavidin)、地高辛(digoxigenin)、半抗原(haptens)、及可获得抗血清或单克隆抗体的蛋白质(proteins for which antisera ormonoclonal antibodies are available)或者具有与靶标互补的序列的核酸分子(nucleic acid molecules with a sequence complementary to a target)。可检测部分残基往往产生可测量的信号,例如放射性、显色性或荧光信号,这些信号可用于定量样品中结合的可检测部件残基的量。信号的定量通过例如闪烁计数、密度计、流动细胞分析、ELISA或通过完整或随后消化的肽的质谱法直接分析(可以测定一种以上的肽)。本领域技术人员熟悉所感兴趣的标记化合物的技术和检测手段。这些技术和方法是常规的并且是本领域公知的。
所述检测探针是指如下所述的物质:(i)可提供可检测信号的物质;(ii)使第一探针或第二探针相互作用以产生如荧光共振能量转移(FRET)这种可改变由第一或第二探针提供的可检测信号的物质;(iii)可稳定与抗原或配体的相互作用或增加结合亲和力的物质;(iv)通过物理参数如电荷、疏水性等改变电泳率或细胞介导的响应的物质;(V)能够调节配体亲和力、抗原-抗体结合或离子络合物形成的物质。
在本发明的含有自我牺牲型连接基团的化合物中,所述B的配体是指结合于受体的抗体、激素、药剂等分子。配体是将药物选择性靶向特定器官(organ)、组织(tissue)或细胞内的物质。与正常细胞相比,配体特异性结合于癌细胞中过表达的受体,并且可分为单克隆抗体(monoclonal antibodies,mAbs)或抗体片段(antibody fragment)和低分子非抗体(non-antibody)配体。优选选自在筛选库(library screen)中确认的肽、肿瘤细胞特异性肽(tumor cell-specific peptides)、肿瘤细胞特异性适体(tumor cell-specificaptamers)、肿瘤细胞特异性碳水化合物(tumor cell-specific carbohydrates)、肿瘤细胞特异性单克隆或多克隆抗体(tumor cell-specific monoclonal or polyclonalantibodies)、抗体片段构成的组。
配体的例包括但不限于肉毒碱(Carnitine)、肌醇(inositol)、硫辛酸(lipoicacid)、吡哆醛(pyridoxal)、抗坏血酸(ascorbic acid)、烟酸(niacin)、泛酸(pantothenicacid)、叶酸(folic acid)、核黄素(riboflavin)、硫胺素(thiamine)、生物素(biotin)、维生素B12(vitamin B12)、其他水溶性维生素如维生素B、脂溶性维生素类(维生素A、D、E、K)、RGD(Arg-Gly-Asp)、NGR(Asn-Gly-Arg)、转铁蛋白(transferrin)、VIP(vasoactiveintestinal peptide:血管活性肠肽)受体(receptor)、APRPG(Ala-Pro-Arg-Pro-Gly)肽(peptide)、TRX-20(thioredoxin-20:硫氧还蛋白-20)、整联蛋白(integrin)、核仁素(nucleolin)、氨肽酶N(Aminopeptidase N,CD13)、内皮糖蛋白(endoglin)、血管上皮生长因子受体(vascular epithelial growth factor receptor)、低密度脂蛋白受体(lowdensity lipoproteinreceptor)、转铁蛋白受体(transferrin receptor)、生长抑素受体(somatostatin receptor)、蛙皮素(bombesin)、神经肽(Neuropeptide Y)、促黄体激素释放激素受体(lutenizing hormone releasing hormone receptor)、叶酸受体(folic acidreceptor)、表皮生长因子受体(epidermal growth factor receptor)、转化生长因子受体(transforming growth factor receptor)、成纤维细胞生长因子受体(fibroblastgrowth factor receptor)、去唾液酸糖蛋白受体(asialoglycoprotein receptor)、半乳糖凝集素-3受体(galectin-3 receptor)、E-选择素受体(E-selectin receptor)、透明质酸受体(hyaluronic acid receptor)、前列腺特异性膜抗原(Prostate-specificmembrane antigen,PSMA)、胆囊收缩素A受体(Cholecystokinin A receptor)、胆囊收缩素B受体(Cholecystokinin B receptor)、盘状结构域受体(Discoidin domain receptor)、粘蛋白受体(mucin receptor)、阿片受体(Opioid receptor)、纤溶酶原受体(Plasminogenreceptor)、缓激肽受体(Bradykinin receptor)、胰岛素受体(insulin receptor)、胰岛素样生长因子受体(insulin-like growth factor receptor)、血管紧张素AT1受体(angiotensin AT1 receptor)、血管紧张素AT2受体(angiotensin AT2 receptor)、粒细胞巨噬细胞集落刺激因子受体(GM-CSF receptor)、半乳糖胺受体(Galactosaminereceptor)、Sigma-2受体(Sigma-2 receptor)、Delta-样3(DLL-3)、氨肽酶P(Aminopeptidase P)、黑素转铁蛋白(melanotransferrin)、瘦素(leptin)、破伤风毒素Tet1(tetanus toxin Tet1)、破伤风毒素G23(tetanus toxin G23)、RVG(Rabies VirusGlycoprotein:狂犬病毒糖蛋白)肽(peptide)、HER2(human epidermal growth factorreceptor 2:人表皮生长因子受体2)、GPNMB(glycoprotein non-metastatic b:非转移性黑色素瘤糖蛋白b)、Ley、CA6、CanAng、SLC44A4(Solute carrier family 44member 4:溶质载体家庭44成员4)、CEACAM5(Carcinoembryonic antigen-related cell adhesionmolecule 5:癌胚抗原相关细胞粘附分子5)、结合素-4(Nectin-4)、碳酸酐酶9(CarbonicAnhydrase 9)、TNNB2、5T4、CD30、CD37、CD74、CD70、PMEL17、EphA2(EphrinA2 receptor:肝配蛋白A2受体)、Trop-2、SC-16、组织因子(Tissue factor)、ENPP-3(AGS-16)、SLITRK6(SLIT and NTRK like family member 6:SLIT和NTRK样家族成员6)、CD27、Lewis Y抗原(Lewis Y antigen)、LIV1、GPR161(G Protein-Coupled Receptor 161:G蛋白偶联受体161)、PBR(peripheral-type benzodiazeoine receptor:外周型苯二氮卓受体)、MERTK(Mer receptor tyrosine kinase:Mer受体酪氨酸激酶)受体(receptor)、CD71、LLT1(Lectin-like transcript 1(凝集素样转录物1)or CLED2D)、白介素-22受体(interleukin-22 receptor)、σ1受体(sigma 1 receptor)、过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor)、DLL3、C4.4a、cKIT、肝配蛋白A(EphrinA)、CTLA4(Cytotoxic T-Lymphocyte Associated Protein 4:细胞毒性T淋巴细胞相关蛋白4)、FGFR2b(fibroblast growth factor receptor 2b:成纤维细胞生长因子受体2b)、N-乙酰胆碱受体(N-acetylcholine receptor)、促性腺激素释放激素受体(gonadotropin releasing hormone receptor)、胃泌素释放肽受体(gastrin-releasingpeptide receptor)、骨形态发生蛋白受体1B型(Bone morphogeneticprotein receptor-type 1B,BMPR1B)、E16(LAT1,SLC7A5)、STEAP1(six transmembrane epithelial antigenof prostate:前列腺六跨膜表皮抗原)、0772P(CA125,MUC16)、MPF(MSLN,mesothelin:间皮素)、Napi3b(SLC34A2)、Sema5b(semaphorin 5b)、ETBR(Endothelin type B receptor:内皮素B型受体)、MSG783(RNF124)、STEAP2(six transmembrane epithelial antigen ofprostate 2:前列腺六跨膜表皮抗原2)、TrpM4(transient receptor potential cation 5channel,subfamily M,member 4:瞬时受体电位阳离子5通道,亚家族M,成员4)、CRIPTO(teratocarcinoma-derived growth factor:畸胎瘤衍化生长因子)、CD21、CD79b、FcRH2(IFGP4)、HER2(ErbB2)、NCA(CEACM6)、MDP(DPEP1)、IL20R-alpha(IN20Ra),短蛋白聚糖(Brevican)(BCAN)、EphB2R、ASLG659(B7h)、PSCA(prostate stem cell antigenprecursor:前列腺干细胞抗原前体)、GEDA、BAFF-R(BR3)、CD22(BL-CAM)、CD79a、CXCR5、HLA-DOB、P2X5、CD72、LY64、FcRH1、IRTA2、TENB2、SSTR2、SSTR5、SSTR1、SSTR3、SSTR4、ITGAV(Integrin:整联蛋白,alpha 5)、ITGB6(Integrin:整联蛋白,beta 6)、MET、MUC1、EGFRvIII、CD33、CD19、IL2RA(interleukin 2 receptor:白介素2受体,alpha)、AXL、BCMA、CTA(Cancer testis antigens:睾丸癌)、CD174、CLEC14A、GPR78、CD25、CD32、LGR5(GPR49)、CD133(Prominin:凸素)、ASG5、ENPP3((Ectonucleotide Pyrophosphatase/Phosphodiesterase 3:外核苷酸焦磷酸酶/磷酸二酯酶3)、PRR4(Proline-rich protein4:富含脯氨酸蛋白质4)、GCC(guanylate cyclase 2C:鸟苷酸环化酶2C)、Liv-1(SLC39A6)、CD56、CanAg、TIM-1、RG-1、B7-H4、PTK7、CD138、蜜蛋白(Claudins)、Her3(ErbB3)、RON(MST1R)、CD20、TNC(Tenascin C:腱生蛋白C)、FAP、DKK-1、CD52、CS1(SLAMF7)、膜联蛋白(Annexin A1)、V-CAM、gp100、MART-1、MAGE-1(Melanoma antigen-encoding gene-1:黑素瘤抗原编码基因-1)、MAGE-3(Melanoma-associated antigen 3:黑素瘤相关抗原3)、BAGE、GAGE-1、MUM-1(multiple myeloma oncogene 1:多发性骨髓瘤癌基因1)、CDK4、TRP-1(gp75)、TAG-72(Tumor-Associated Glycoprotein-72:肿瘤相关糖蛋白-72)、神经节苷脂(ganglioside)GD2、GD3、GM2、GM3、VEP8、VEP9、My1、VIM-D5、D156-22、OX40、RNAK、PD-L1、TNFR1、TNFR2等。
在本发明的含有自我牺牲型连接基团的化合物中,所述B的蛋白质包括寡肽、多肽、抗体、抗原多肽片段及人工抗体(Repebody)。
所述蛋白质是两个以上的独立选择的通过共价键(例如,肽键)接合的天然或非天然氨基酸,其中肽可以包含通过肽键接合的2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或以上的天然或非天然氨基酸。多肽不仅包括全长蛋白质(例:预加工的蛋白质),还包括较短的氨基酸序列(例:天然蛋白质片段或合成多肽片段)。
所述抗体指一种免疫球蛋白分子,其可以通过免疫球蛋白分子的可变区内的一个以上的抗原识别位点来识别并特异性结合于靶,例如蛋白质、多肽、肽、碳水化合物、多核苷酸、脂质或其组合。只要显示出抗体所需的生物活性,所述抗体即包括完整多克隆抗体(intact polyclonal antibody)、完整单克隆抗体(intact monoclonal antibody)、抗体片段(antibody fragment)(例:Fab、Fab'、F(ab')2、Fd及Fv片段)、单链Fv(scFv)突变体(single chain Fv(scFv)mutant)、多特异性抗体(multispecific antibody)、例如来自两种或多种完整抗体的双特异性抗体(bispecific antibody)、嵌合抗体(Chimericantibody)、人源化抗体(humanized antibody)、人抗体(human antibody)、包含抗体的抗原决定簇部分的融合蛋白(fusion protein comprising an antigenic determinantportion of an antibody)及包含抗原识别位点的其他修饰的免疫球蛋白分子(modifiedimmunoglobulin molecule comprising an antigen recognition site)。抗体可以具有免疫球蛋白的任何五种主要类别:基于分别以α、δ、ε、γ、μ表示的其重链恒定结构域的同一性的IgA、IgD、IgE、IgG及IgM或其下位分类(同源型)(例:IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)。不同类别的免疫球蛋白具有不同的众所周知的亚单位(subunit)结构和三维形态。
术语“抗体片段”是指完整抗体的一部分,并且表示完整抗体的抗原决定簇可变区。抗体片段的例包括但不限于由Fab、Fab'、F(ab’)2、Fd及Fv片段和线性抗体、单链抗体和抗体片段形成的多特异性抗体。
“单克隆抗体”是指参与高度特异性识别和结合的单一抗原决定簇或表位的同源抗体群。这与通常含有针对不同抗原决定簇的不同抗体的多克隆抗体形成对比。术语“单克隆抗体”不仅包括完整及全长单克隆抗体,还包括抗体片段(例:Fab、Fab'、F(ab’)2、Fd、Fv)、单链(scFv)突变体、包含抗体部分融合蛋白及包含抗原识别位点的任意其他免疫球蛋白分子。并且,“单克隆抗体”是指以多种方式制备的抗体,包括但不限于杂交瘤、噬菌体选择、重组表达及转基因动物。
术语“人源化抗体”是指非人(例如,μ类)抗体的形式,其包含特异性免疫球蛋白链、嵌合免疫球蛋白或至少含有非人(例如,μ类)序列的片段。通常,人源化抗体是人免疫球蛋白,其来自互补决定区(CDR)的残基已经被具有所需的特异性、亲和力和潜力的来自非人物种(例:小鼠、大鼠、兔子、仓鼠)的CDR的残基替换(参照:Jones等,1986,Nature,321:522-525;Riechmann等,1988,Nature,332:323-327;Verhoeyen等,1988,Science,239:1534-1536)。在部分例中,人免疫球蛋白的Fv框架区(FR)残基被具有所需的特异性、亲和力和潜力的来自非人物种的抗体中的相应残基替换。通过替换Fv框架区内的其他残基及/或替换的非人残基,可以进一步修饰人源化抗体,以改善和优化抗体特异性、亲和力和/或潜力。通常,人源化抗体包含一个以上,通常两个或三个可变结构域,该可变结构域包含与非人免疫球蛋白对应的完全或基本上所有CDR区域,而整个FR区域或基本上全部都具有人免疫球蛋白匹配序列。人源化抗体可包含免疫球蛋白恒定区或结构域(Fc),通常可包含人免疫球蛋白的至少一部分。用于产生人源化抗体的方法的例记载于美国专利No.5225539中。
术语“人抗体”是指由人产生的抗体或人使用本领域公知的任何技术产生的具有对应于人产生的抗体的氨基酸序列的抗体。人抗体的这种定义包含含有一种或多种人重链及/或轻链多肽的抗体,例如完整或全长抗体,其片段及/或包含例如μ类轻链和人重链多肽的抗体。
术语“嵌合抗体”是指免疫球蛋白分子的氨基酸序列衍生自两个以上物种的抗体。通常,轻链和重链的可变部分对应于衍生自具有所需特异性、亲和力和潜力的一种哺乳动物(例:小鼠、大鼠、兔等)的抗体的可变部分,这些位点与来自彼此(通常是人)的体内序列同源,从而避免诱导所述物种的免疫反应。
本文中术语“表位”或“抗原决定簇”可相互换着使用都表示可以被特定抗体识别并特异性结合的抗原的一部分。当抗原是多肽时,通过蛋白质的三级折叠,可以从平行的非相邻氨基酸和相邻氨基酸形成表位。由相邻氨基酸形成的表位通常在蛋白质变性时保留,而通过三级折叠形成的表位通常在蛋白质变性时丢失。表位通常以独特的空间形式包含三个以上、五个以上、或八至十个以上的氨基酸。
抗体与表位或抗原分子进行“特异性结合”是指,抗体比含有不相关蛋白质的代替物质以更频繁、更快速、更长时间、以更大的亲和力或以上述部分组合结合表位或抗原分子。在特定实施方式中,“特异性结合”是指抗体结合于例如KD约在1.0mM以下的蛋白质,更通常KD大致小于1μM的蛋白质。在特定实施方式中,“特异性结合”是指抗体有时结合于KD至少大致在0.1μM以下的蛋白质,在其他情况下结合于KD至少在0.01μM以下的蛋白质。由于不同化学物种的同源蛋白质之间的序列同一性,特异性结合可包括识别超过一种特定蛋白质的抗体。应理解,特异性结合于第一靶标的抗体或结合残基可以特异性结合或不结合于第二靶标。因此,“特异性结合”不一定需要专有结合,即不一定需要结合单个靶标(尽管可能包括)。通常,尽管不是必须的,但是对结合的说明指特异性结合。
可以使用本领域已知的方法获得包含其片段/衍生物和单克隆抗体的抗体。(参照:McCafferty等,Nature 348:552-554(1990);Clackson等,Nature 352:624-628;Marks等,J.Mol.Biol.222:581-597(1991);Marks等,Bio/Technology 10:779-783(1992);Waterhouse等,Nucleic.Acids Res.21:2265-2266(1993);Morimoto等,Journal ofBiochemical and Biophysical Methods 24:107-117(1992);Brennan等,Science 229:81(1985);Carter等,Bio/Technology 10:163-167(1992);Kohler等,Nature 256:495(1975);U.S.Pat.No.4,816,567);Kilpatrick等,Hybridoma 16(4):381-389(1997);Wring等,J.Pharm.Biomed.Anal.19(5):695-707(1999);Bynum等,Hybridoma 18(5):407-411(1999);Jakobovits等,Proc.Natl.Acad.Sci.USA,90:2551(1993);Jakobovits等,Nature,362:255-258(1993);Bruggemann等,Year in Immuno.7:33(1993);Barbas等,Proc.Nat.Acad.Sci.USA 91:3809-3813(1994);Schier等,Gene 169:147-155(1995);Yelton等,J.Immunol.155:1994-2004(1995);Jackson et.al.,J.Immunol.154(7):3310-9(1995);Hawkins等,J.Mol.Biol.226:889-896(1992),U.S.Pat.Nos.5514548,5545806,5569825,5591669,5545807;WO 97/17852均通过引用整体并入本文。)
所述抗体不受限制,但优选于由莫罗莫那-CD3-阿昔单抗(Muromonab-CD3Abciximab)、利妥昔单抗(Rituximab)、达克珠单抗(Daclizumab)、帕利珠单抗(Palivizumab)、英夫利昔单抗(Infliximab)、曲妥珠单抗(Trastuzumab、还称为“赫赛汀”)、依那西普(Etanercept)、巴利昔单抗(Basiliximab)、吉妥单抗(Gemtuzumabozogamicin)、阿仑单抗(Alemtuzumab)、替伊莫单抗(Ibritumomab tiuxetan)、阿达木单抗(Adalimumab)、阿法赛特(Alefacept)、奥马珠单抗(Omalizumab)、依法珠单抗(Efalizumab)、托西莫单抗-I131(Tositumomab-I131)、西妥昔单抗(Cetuximab)、贝伐单抗(Bevacizumab)、那他珠单抗(Natalizumab)、雷珠单抗(Ranibizumab)、帕尼单抗(Panitumumab)、依库珠单抗(Eculizumab)、利洛纳塞(Rilonacept)、赛妥珠单抗(Certolizumab pegol)、罗米司亭(Romiplostim)、AMG-531、CNTO-148、CNTO-1275、ABT-874、LEA-29Y、贝利木单抗(Belimumab)、TACI-Ig、第二代抗CD20(Second generationanti-CD20)、ACZ-885、托珠单抗(Tocilizumab)、阿特利珠单抗(Atlizumab)、美泊利单抗(Mepolizumab)、帕妥珠单抗(Pertuzumab)、Humax CD20、曲美替尼(Tremelimumab,CP-675206)、CTLA-4单抗(Ticilimumab:替西木单抗)、MDX-010、IDEC-114、伊曲木单抗奥佐米星(Inotuzumab ozogamycin)、HuMax EGFR、阿帕西普(Aflibercept)、VEGFTrap-Eye、HuMax-CD4、Ala-Ala、ChAglyCD3、TRX4、卡妥索单抗(Catumaxomab)、IGN101、MT-201、奥戈伏单抗(Oregovomab)、CH-14.18、WX-G250、AMG-162、AAB-001、莫维珠单抗(Motavizumab)、MEDI-524、依福谷单抗(efumgumab)、瑞西巴库(Raxibacumab)、第三代抗-CD20(Thirdgeneration anti-CD20)、LY2469298及维妥珠单抗(Veltuzumab)构成的组。
所述人工抗体(Repebody)是基于具有LRR蛋白结构的内含肽的N-末端与VLR结构的相似性融合并通过共识设计优化的多肽,可以包括对具有重复单元的所有属于LRR家族的所有蛋白质以所述方式改善蛋白质的水溶性表达和生物学特性的所有融合LRR家族蛋白质。
当所述蛋白质是单克隆抗体时,单克隆抗体的一条以上的轻链,单克隆抗体的一条以上的重链或两者可包含具有可被类异戊二烯转移酶识别的氨基酸基序的氨基酸部分。
本领域技术人员可以即刻对选择性结合于靶标的蛋白质(例:受试者的靶细胞)进行选择。不限于所述示例性蛋白质,但包括特异性结合所关注的靶标的抗体或抗原片段。
在本发明的含有自我牺牲型连接基团的化合物中,所述蛋白质更优选为抗体或人工抗体(Repebody)。
在本发明的含有自我牺牲型连接基团的化合物更优选地选自以下结构。
在所述结构中,
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
z是1至3的整数,z是2以上的整数时,各Y可以彼此相同或不同;
z1是0或1的整数;
W1在下述结构中选择;
W2在下述结构中选择;
X1、X11及X12各自独立为-O-、-S-、-NH-或-CH2-;
R11是氢、C1-C8烷基、-(CH2)s3COOR13、-(CH2)s3COR13、–(CH2)s3CONR14R15或–(CH2)s4NR14R15;
R13、R14及R15各自独立为氢或C1-C15烷基;
X3是-O-、-S-、-NH-或-CH2-;
R12至R14各自独立为氢、C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5或–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
X2是-O-、-S-、-NH-或-CH2-;
Ra是氢或硝基;
R’是C1-C8烷基或B-NH-(CH2)a6-(X1CH2CH2)b1-NH-C(=O)-(CH2)a5-;
X”是–NHC(=O)-(CH2)a8-NH-或–C(=O)NH-(CH2)a8-NH-;
a1、a2、a3、a4、a5、a6、a8、b1、c1、c2、c3、c4、d1、p1、p2、p3及p4各自独立为1至10的整数;
q1及q2各自独立为0至5的整数;
s1、s2、s3及s4各自独立为0至5的整数;
B’是抗体;
B是从下述结构中选择的配体;
T是从下述结构中选择的药物;
w是1至10的整数。
本发明的含有自我牺牲型连接基团的化合物中,所述W1可在下述结构中选择。
在上述结构中,X1是-O-、-S-、-NH-或-CH2-,更优选为-O-,a1、a6及b1各自独立为1至10的整数。
本发明的含有自我牺牲型连接基团的化合物中,所述W2可在下述结构中选择。
在上述结构中,R12至R14各自独立为C6-C20芳基C1-C8烷基、-(CH2)s1COOH、–(CH2)s2NH2或-(CH2)s1COR3;R3是C1-C8烷氧基;Ra是氢或硝基;c1、c2、c3、c4及d1各自独立为1至10的整数;s1及s2各自独立为0至5的整数;q1及q2各自独立为1至5的整数。
本发明的化学式1的含有自我牺牲型连接基团的化合物中,当B为蛋白质且T为活性剂时,可以使用本领域技术人员已知的组合物的制备法将活性剂传递至受试者(例:需要活性剂的受试者)的靶细胞来治疗受试者。
组合物以可注射的形式制备成液体溶液或悬浮液。适于注射的固体形式可以是乳剂,或制备成包封在脂质体中的多肽。所述含有自我牺牲型连接基团的化合物可以与药学上可接受的载体组合,所述载体包括不诱导载体受试者生成有害抗体的任何载体。合适的载体通常包括缓慢代谢的大分子,例如蛋白质、多糖、聚乳酸、聚乙醇酸、聚合氨基酸、氨基酸共聚物、脂质聚集体等。这些载体是本领域技术人员所公知的。
所述组合物还可含有例如水、盐水、甘油、乙醇等稀释剂,。还可以存在例如润湿剂或乳化剂、pH缓冲物质等辅助剂。蛋白质可以配制成中性或盐形式的疫苗。组合物可以通过注射肠外给药,可以在皮下或肌肉内注射。其他制剂适用于其他给药方式,例如通过栓剂或口服给药。口服组合物可以以溶液、悬浮剂、片剂、丸剂、胶囊或缓释制剂形式给药。
所述组合物以与剂量剂型相配合的方式给药。组合物包含含有治疗剂量的自我牺牲型连接基团的化合物。治疗剂量是指,以对治疗或预防疾病或病症有效的单剂量或多剂量方案给药的组合物。给药剂量根据所治疗的受试者、受试者的健康及身体状况、所要达到的保护程度和其他相关因素而变化。活性成分的确切所需量取决于医生的判断。
例如,包含治疗剂量的自我牺牲型连接基团的化合物或包含其的组合物可以给药给深受癌症或肿瘤痛苦的患者以治疗癌症或肿瘤。
包含治疗剂量的自我牺牲型连接基团的化合物或包含其的组合物可以给药给患者以治疗或预防病原体(例:病毒、细菌、真菌、寄生虫等)的感染。这种方法包括如下所述的步骤:在预防或治疗疾病或病症的条件下给哺乳动物给药包含足以治疗疾病或病症或其症状的治疗或预防剂量的自我牺牲型连接基团的化合物。
本发明的含有自我牺牲型连接基团的化合物或包含其的组合物,可以以其药学上可接受的盐或溶剂化物的形式给药。在一些实施方式中,其可以与药学上可接受的载体、药学上可接受的赋形剂及/或药学上可接受的添加剂一起给药。药学剂量和药学上可接受的盐或溶剂化物、赋形剂和添加剂的类型可采用标准方法(参照:Remington'sPharmaceutical Sciences,Mack Publishing Co.,Easton,PA,18th edition,1990)进行测定。
与癌症或肿瘤有关的术语“治疗剂量”指能够减少癌细胞数量、能够减少癌细胞大小、能够抑制癌细胞入侵周围系统或减少入侵、能够抑制癌细胞向其他系统扩散或减少扩散;能够抑制癌细胞生长、能够改善与癌症相关的一种或多种症状的量。在癌症的治疗中,可以通过肿瘤-肿瘤进展(TTP)和/或响应(反应)速率(RR)来验证药物的有效性。
与病原体感染有关的术语“治疗剂量”指可预防、治疗或减轻与感染相关的症状的量。
本文所使用的术语“药学上可接受的盐”包括有机盐和无机盐。其例包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐及双羟萘酸(即,1,1'-亚甲基双-(2-羟基-3-萘甲酸))。药学上可接受的盐可包括其他分子(例:醋酸根离子、琥珀酸离子及其他抗衡离子)。还可包含一个或多个带电原子。还可以包括一种或多种抗衡离子(Counter ion)。
可用于本发明的含有自我牺牲型连接基团的化合物的药学上可接受的溶剂化物中的示例性溶剂化物包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸及乙醇胺。
另外,本发明提供一种由下述化学式2表示的化合物,其用于制备上述化学式1化合物的中间体:
[化学式2]
在所述化学式2中,
R是氢或羟基保护基团;
X是-C(=O)-、-NH-、-O-、-CH2-或-S-;
Wa1是-NH-、-CH2-或-C(=O)-;
T是活性剂;
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
U是单键或
Wa2是-NH-、-C(=O)-或-CH2-;
Wa3及Wa4各自独立为-NH-、-C(=O)-、-CH2-、-C(=O)NH-、-NHC(=O)-或亚三唑基;
R21是C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
s1及s2各自独立为0至10的整数;
a1各自独立为1至10的整数;
s4是0至10的整数;
p3及p4各自独立为1至10的整数;
FG是-NH2、-C≡CH、C4-C10环炔、–N3、-COOH、-SO3H、-OH、-NHOH、-NHNH2、-SH、卤代乙酰胺(-NHC(O)CH2-hal,hal是卤素)、马来酰亚胺卤素、甲苯磺酸酯(TsO-)、醛(-COH)、酮(-COR,R是C1-C10烷基、C6-C20芳基、C2-C20杂芳基)、二烯、或-OP(=O)(OH)2;
X1及X3各自独立为-O-、-S-、-NH-或–CH2-;
a6及b1各自独立为1至10的整数;
a7是0至10的整数;
z是1至3的整数,z是2以上的整数时,各Y可以彼此相同或不同;
z1是0或1的整数;
R1及R2各自独立为氢、C1-C8烷基或C3-C8环烷基。
在本发明的一实施例中,所述化学式2的化合物可由下述化学式3表示。
[化学式3]
在所述化学式3中,
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
z是1至3的整数,z是2以上的整数时,各Y可以彼此相同或不同;
z1是0或1的整数;
R21是C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
s1及s2各自独立为0至10的整数;
a1各自独立为1至10的整数;
s4是0至10的整数;
p3及p4各自独立为1至10的整数;
FG是-NH2、-C≡CH、C4-C10环炔、–N3、-COOH、-SO3H、-OH、-NHOH、-NHNH2、-SH、卤代乙酰胺(-NHC(O)CH2-hal,hal是卤素)、马来酰亚胺卤素、甲苯磺酸酯(TsO-)、醛(-COH)、酮(-COR,R是C1-C10烷基、C6-C20芳基、C2-C20杂芳基)、二烯、或-OP(=O)(OH)2;
X1及X3各自独立为-O-、-S-、-NH-或–CH2-;
a6及b1各自独立为1至10的整数;
T是在下述结构中选择的药物;
w是1至10的整数。
在本发明的含有自我牺牲型连接基团的混合物中,所述FG进一步包括可执行异(hetero)第尔斯反应、亲核取代反应、1,3-双极环加成反应、非醛醇型羰基反应、碳-碳多键加成反应、氧化反应或点击反应的官能团。另外,所述化学式2的FG可包含可与B直接连接的官能团(硫醇(thiol)、卤代乙酰胺(haloacetamide)、马来酰亚胺(maleimide)、卤化物(halide)、甲苯磺酸酯(tosylate)、醛(aldehyde)、磺酸酯(sulfonate)、膦酸(phsphonicacid)、酮(ketone)、羧酸、乙炔、叠氮化物、胺、羟基、羟胺、肼等)。
在根据本发明一实施例的化学式3的化合物中,所述FG更优选为-C≡CH或–N3。
可通过末端具有可与所述化学式2的FG进行点击反应的官能团的配体或蛋白质与所述化学式2的化合物进行点击反应来制备所述化学式1的化合物。
以下,将通过实施例更加具体地说明本发明的结构,但是下面的实施例有助于理解本发明,本发明的范围不限于此。
【制备例1】连接子L-1的制备
化合物L-1a的制备
在氮气气氛常温下,将2-氯乙氧基-2-乙氧基二乙醇(2-(2-(2-chloroethoxy)ethoxy)ethanol)(5g,29.65mmol)溶于N,N-二甲基甲酰胺(N,N-Dimethylformamide,DMF)(10mL)后,添加NaN3(2.89g,44.47mmol),在100℃搅拌16个小时。反应完成后,添加二氯甲烷(Dichloromethane,DCM)(25mL×3)和盐水(brine)(25mL)并萃取,用无水Na2SO4干燥有机层、过滤后减压浓缩,获得化合物L-1a(4.96g,95.5%)。
1H NMR(400MHz,CDCl3)δ3.75-3.73(m,2H),3.70-3.67(m,6H),3.63-3.61(t,J=4.8Hz,2H),3.41-3.39(t,J=4.8Hz,2H)。
化合物L-1b的制备
在氮气气氛常温下,将化合物L-1a(3g,17.12mmol)溶于DMF(28mL)后,冷却至0℃并添加60%NaH(822mg,20.55mmol)。在所述混合物中滴加20分钟炔丙基溴(2.6mL,34.25mmol)后,将温度升至常温,并将混合物搅拌2小时。反应完成后,冷却至0℃并用蒸馏水淬灭(quenching)。添加蒸馏水(20mL)和乙酸乙酯(Ethyl acetate,EA)(30mL×3)萃取后,收集有机层并用盐水(brine)(20mL)洗涤三次,并将汇聚在一起的有机层用无水Na2SO4干燥,过滤并减压浓缩。将残余物进行柱层析,获得化合物L-1b(3.41g,93%)。
1H NMR(400MHz,CDCl3)δ4.21(d,J=2.4Hz,2H),3.72-3.67(m,10H),3.41-3.38(t,J=5.2Hz,2H),2.44-2.43(t,J=2.4Hz,1H)。
化合物L-1的制备
在氮气气氛常温下,将化合物L-1b(3.41g,15.99mmol)溶于四氢呋喃(Terahydrofuran,THF)(30mL)蒸馏水(3mL)后,添加三苯基膦(4.40g,16.79mmol)并将所述混合物在常温搅拌了16小时。反应完成后,减压浓缩除去所述混合物中的溶剂,添加蒸馏水(30mL)和EA(30mL),搅拌,用1N HCl溶液调节至pH2,进行萃取。用EA(30mL)将水层再洗涤两次,用2N NaOH溶液调节至pH10并用DCM(30mL)萃取10次。收集有机层并用无水Na2SO4干燥,过滤并减压浓缩。将残余物进行柱层析,获得目标化合物L-1(2.75g,92%)。
1H NMR(400MHz,CDCl3)δ4.21(d,J=2.4Hz,2H),3.72-3.53(m,8H),3.53-3.51(t,J=4.8Hz,2H),2.88-2.86(t,J=5.2Hz,2H),2.44-2.43(t,J=2.4Hz,1H);EI-MS m/z:188(M+)。
【制备例2】连接子L-2的合成
在氮气气氛常温下,将化合物L-2a(50g,337.4mmol)溶于DCM(300mL)后,向其中滴加溶于DCM(200mL)的(Boc)2O(14.7g,67.47mmol)并在常温搅拌13小时。反应完成后,添加蒸馏水(500mL)萃取后,收集有机层并用盐水(brine)(150mL)洗涤三次。将有机层用无水硫酸钠干燥,过滤,减压浓缩,获得化合物L-2(14.4g,86%)。
1H NMR(400MHz,CDCl3)δ5.14(s,1H),3.64-3.50(m,8H),3.35-3.31(m,2H),2.89-2.87(t,J=5.6Hz,2H),1.44(s,9H);EI-MS m/z:249(M+)。
【制备例3】连接子L-3的合成
化合物L-3a的制备
在氮气气氛常温下,将(5-氯-1-戊炔基)三甲基硅烷((5-chloro-1-pentynyl)trimethylsilane)(5.0g,28.61mmol)溶于DMF(30mL)后,添加NaN3(2.05g,31.47mmol)。将所述混合物在50℃下搅拌5小时后,添加EA(500mL)和蒸馏水(200mL)萃取,获得的有机层用无水Na2SO4干燥。过滤后减压浓缩,获得化合物L-3a(5.18g,99%)。
1H NMR(400MHz,CDCl3)δ3.41(t,J=6.4Hz,2H),2.35(t,J=6.4Hz,2H),1.82-1.74(m,2H)1.15(s,9H)。
化合物L-3的制备
在氮气气氛常温下,将化合物L-3a(5.18g,28.61mmol)溶于THF(200mL)和蒸馏水(200mL)后,添加三苯基膦(9.38g,35.77mmol),在50℃下搅拌了13小时。反应完成后,添加二乙醚(500mL)和蒸馏水(10mL)。所获得的有机层用无水Na2SO4干燥,过滤后减压浓缩,获得化合物L-3(3.12g,71%)。
1H NMR(400MHz,CDCl3)δ2.80(t,J=6.8Hz,2H),2.30(t,J=6.8Hz,2H),1.69-1.61(m,2H)1.35(br,2H),1.15(s,9H)。
【制备例4】连接子L-4的合成
化合物L-4a的制备
在氮气气氛0℃下,将三乙二醇(15.14g,100.87mmol)溶于THF(500mL)后,添加NaH(60%wt,672mg,16.81mmol)后搅拌5分钟。在所述混合物添加炔丙基溴(80%w/w溶于甲苯中(in toluene),2.5g,16.81mmol)后,在常温搅拌了5小时。反应完成后,添加EA(150mL)、蒸馏水(300mL)、以及盐水(brine)(100mL)萃取后,对有机层用无水Na2SO4干燥,过滤后减压浓缩。将残余物进行柱层析,获得化合物L-4a(1.63g,52%)。
1H NMR(400MHz,CDCl3)δ4.2-4.20(m,2H),3.77-3.65(m,10H),3.62(t,J=4.8Hz,2H),2.50(s,1H),2.44(s,1H)。
化合物L-4的制备
在氮气气氛0℃下,将化合物L-4a(1.0g,5.31mmol)溶于丙酮(20mL)后,添加琼斯试剂(Jones reagent)(8mL)并搅拌了3小时。反应完成后,添加EA(150mL)、蒸馏水(50mL)萃取后,用无水Na2SO4干燥有机层,过滤后减压浓缩,获得化合物L-4(903mg,84%)。
1H NMR(400MHz,CDCl3)δ4.25-4.17(m,4H),3.82-3.68(m,8H),2.45(s,1H).
【制备例5】连接子L-5的合成
化合物L-5a的制备
在氮气气氛常温下,将Z-L-谷氨酸5-叔丁酯(Z-L-glutamic acid 5-tert-butylester,z-Glu(OtBu)-OH)(5g,14.82mmol)和4-二甲氨基吡啶(362mg,,1.48mmol)溶于DCM(50mL),添加甲醇(2mL,44.13mmol)在常温搅拌了30分钟。在0℃下,在所述混合物中添加N,N'-二环己基碳二亚胺(N,N’-dicyclohexylcarbodiimide,DCC)(3.05g,14.82mmol)后,在常温搅拌了15小时。反应完成后,使用氟镁石过滤器除去生成的固体化合物,减压浓缩滤液后,将残余物进行柱层析,获得化合物L-5a(4.66g,90%)。
1H NMR(400MHz,CDCl3)δ7.40-7.28(m,5H),5.46-5.36(d,J=7.2Hz 2H),5.10(s,2H),4.40(q,J=8.0,5.2Hz,1H),3.75(s,3H),2.42-2.24(m,2H),2.20-2.08(m,1H),2.02-1.88(m,1H);EI-MS m/z:352(M+)。
化合物L-5b的制备
在氮气气氛0℃下,将化合物L-5a(4.6g,13.10mmol)溶于DCM(50mL)后,添加三氟醋酸(Trifluoroacetic acid,TFA)(5mL)后,在常温搅拌了2小时30分钟。反应完成后,减压浓缩反应物,加入甲苯(20mL)再次减压浓缩。进行该减压浓缩步骤四次以除去过量的TFA,获得化合物L-5b(4.0g,99%)。
1H NMR(400MHz,CDCl3)δ7.40-7.30(m,5H),5.47(d,J=7.2Hz,2H),5.10(s,2H),4.42(q,J=7.6Hz,J=5.6Hz,1H),3.76(s,3H),2.54-2.38(m,2H),2.30-2.14(m,1H),2.04-1.92(m,1H);EI-MS m/z:296(M+)。
化合物L-5c的制备
在氮气气氛常温下,将化合物L-5b(3.87g,13.1mmol)溶于THF(40mL)后,添加化合物L-2(3.6g,14.41mmol)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluron ium hexafluorophosphate,HBTU)(6g,15.72mmol)、N,N-二异丙基乙胺(N,N-Diisopropylethylamine,DIPEA)(3.4mL,19.65mmol)后,在常温搅拌了一整晚。反应完成后,减压浓缩除去THF,加入EA(100mL)和蒸馏水(100mL)萃取,对有机层用无水Na2SO4干燥,过滤,减压浓缩。残余物进行柱层析,获得化合物L-5c(3.8g,56%)。
1H NMR(400MHz,CDCl3)δ7.40-7.30(m,5H),6.30(br,1H),5.85(br,1H),5.10(s,2H),4.38(q,J=8.0,3.2Hz,1H),3.74(s,3H),3.55(s,3H),3.54(t,J=8.0Hz,4H),3.58-3.36(m,2H),3.34-3.22(m,2H),3.0(br,1H),2.36-2.26(m,2H),2.26-2.16(m,1H),2.06-1.96(m,1H);EI-MS m/z:526(M+)。
化合物L-5的制备
将化合物L-5c(3.8g,7.23mmol)溶于甲醇(20mL)后,添加5%Pd/C(2.3g,1.09mmol)并注入氢气,在常温搅拌3个小时。反应完成后,使用氟镁石过滤器除去Pd/C,减压浓缩滤液后,获得化合物L-5(2.8g,quant.)。EI-MS m/z:392(M+)
【制备例6】连接子L-6及连接子L-7的合成
化合物L-6a的制备
在氮气气氛常温下,将9-芴基甲氧基羰基(Fmoc-Lys(Boc)-OH:Fmoc=9-Fluorenylmethoxycarbonyl,4g,8.54mmol)溶于DCM(40mL)后,在0℃下,添加1-羟基苯并三唑(1-Hydroxybenzotriazole,HOBT)(1.27g,9.39mmol)、N,N'-二异丙基碳二亚胺(N,N'-diisopropylcarbodiimide,DIC)(1.45mL,9.39mmol)后,搅拌了30分钟。在所述混合物添加甲醇(0.35mL,8.54mmol)并在常温下搅拌了15小时。反应完成后,添加DCM与蒸馏水萃取后,对有机层用无水Na2SO4干燥,过滤,减压浓缩。残余物进行柱层析,获得化合物L-6a(3.55g,86%)。
1H NMR(400MHz,CDCl3)δ7.88-7.64(m,4H),7.42-7.26(m,4H),6.80-6.76(m,1H),4.30-4.15(m,3H),4.00-3.84(m,1H),3.58(s,3H),2.95-2.82(m,2H),1.67-1.47(m,2H),1.38-1.15(m,13H);EI-MS m/z:483(M+)。
化合物L-6b的制备
在氮气气氛常温下,将化合物L-6a(3.45g,7.15mmol)溶于DCM(25mL)后,添加二乙胺(diethylamine)(20mL)并在常温搅拌后减压浓缩。在0℃下,在所述反应溶液添加4M氯化氢的二恶烷(HCl in Dioxane)(17.8mL)后,利用EA固化,获得混合物L-6b(2g,95%)。
1H NMR(400MHz,DMSO-d6)δ8.49(br,3H),6.80-6.76(m,1H),3.95(t,J=6.4Hz,1H),3.71(s,3H),2.88-2.83(m,2H),1.77-1.71(m,2H),1.40-1.19(m,13H);EI-MS m/z:261(M+)。
化合物L-6c的制备
在氮气气氛常温下,将3-溴丙酸(3-bromopropionic acid)(10g,65.37mmol)溶于乙腈(100mL)后,添加NaN3(4.7g,71.91mmol)并在50℃搅拌了12小时。反应完成后,在所述混合物添加乙酸乙酯(500mL)、蒸馏水(300mL)及2N HCl水溶液(50mL)并萃取。对有机层用无水Na2SO4干燥,过滤,减压浓缩,获得化合物L-6c(5.1g,68%)。
1H NMR(400MHz,CDCl3)δ3.60(t,J=6.4Hz,2H),2.65(t,J=6.4Hz,2H).
化合物L-6d的制备
在氮气气氛常温下,将化合物L-6b(1.8g,6.13mmol)和化合物L-6c(1.06g,9.19mmol)溶于DMF(10mL)。在0℃下,在所述混合物中添加六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate,PyBOP)(4.78g,9.19mmol)、DIPEA(1.6mL,9.19mmol)并在常温搅拌3小时。反应完成后,在混合物添加EA和蒸馏水进行萃取。对有机层用无水Na2SO4干燥,过滤,减压浓缩。对残余物进行柱层析,获得化合物L-6d(1.57g,72%)。
1H NMR(400MHz,CDCl3)δ6.36-6.33(m,1H),4.68-4.56(m,2H),3.76(s,3H),3.70-3.56(m,2H),3.14-3.04(m,2H),2.45(t,J=6.4Hz,2H),1.92-1.82(m,1H),1.76-1.66(m,1H),1.58-1.26(m,13H);EI-MS m/z:358(M+)。
化合物L-6e的制备
在氮气气氛常温下,将化合物L-6d(2.9g,8.11mmol)溶于1,4-二恶烷(30mL)、蒸馏水(30mL)后,在0℃下,添加LiOH(340.5mg,8.11mmol)并在常温搅拌90分钟。反应完成后,在所述混合物添加2N HCl水溶液以将pH调节至2~3后,用DCM和蒸馏水萃取。用无水Na2SO4干燥有机层,过滤,减压浓缩,获得化合物L-6e(2.7g,99%)。
1H NMR(400MHz,CDCl3)δ6.82-6.78(m,1H),4.78-4.58(m,2H),3.71-3.56(m,2H),3.14-3.08(m,2H),2.58-2.44(m,2H),1.96-1.74(m,2H),1.58-1.36(m,13H);EI-MS m/z:344(M+)。
化合物L-6的制备
在氮气气氛常温下,将化合物L-6e(56mg,0.16mmol)溶于DMF(2mL)后,添加1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide,EDCI)(37.5mg,0.20mmol)、N-羟基琥珀酰亚胺(N-hydroxysuccinimide,NHS)(22.5mg,0.20mmol)后,在常温搅拌了2小时30分钟。反应完成后,化合物L-6没进行纯化直接用于下一步反应。EI-MS m/z:441(M+)。
化合物L-7的制备
在氮气气氛0℃下,将化合物L-6e(1.44g,4.20mmol)与制备例3中制备的L-3(782mg,5.04mmol)溶于DMF(20mL)后,添加了DIPEA(1.10mL,6.29mmol)和PyBOP(3.27g,6.29mmol)。将所述混合物在常温搅拌了3小时。反应完成后,添加EA(200mL)和蒸馏水(100mL)萃取,过滤,获得的有机层用无水Na2SO4干燥后减压浓缩。残余物进行柱层析,获得化合物L-7(1.60g,80%)。EI-MS m/z:481(M+)
【制备例7】MMAF的合成
MMAF以与US61/483,698,ChemPharmBull,1995.43(10).1706-1718、US7423116、US7498298、及WO2002/088172中描述的类似的方式进行制备。
【制备例8】配体-连接子L-8及L-9的制备
化合物L-8a的制备
以类似于US20070276018中记载的类似的方法获得了化合物L-8a(7.1g,88%)。EI-MS m/z:505(M+).
化合物L-8b的制备
在氮气气氛常温下,将化合物L-8a(3.6g,7.1mmol)、制备例5中制备的L-5(2.8g,7.15mmol)溶于DMF(10mL)后,添加HBTU(3.3g,8.58mmol)、DIPEA(1.87mL,10.73mmol)后,在常温搅拌了15个小时。反应完成后,添加EA和水进行萃取,对有机层用无水Na2SO4干燥后减压浓缩。残余物进行柱层析,获得化合物L-8b(4.7g,75%)。EI-MS m/z:878(M+).
化合物L-8c的制备
在氮气气氛0℃下,将化合物L-8b(1.76g,1.94mmol)溶于DCM(50mL)后,滴加TFA(5mL)。将所述混合物在常温搅拌30分钟。反应完成后,加入甲苯(20mL),并减压浓缩以除去TFA。加入少量甲醇和过量的二乙醚进行重结晶,对所得到的固体化合物进行过滤,用二乙醚洗涤固体化合物,获得化合物L-8c(1.5g,85%)。EI-MS m/z:682(M+).
化合物L-8d的制备
在氮气气氛常温下,在制备例6中获得的L-6(71.8mg,0.16mmol)中添加TEA(22μL,0.16mmol)和化合物L-8c(92.6mg,0.14mmol)并搅拌2.5小时。反应完成后,将所述混合物进行减压浓缩,添加EA和水进行萃取,对有机层用无水Na2SO4干燥后减压浓缩。残余物进行柱层析,获得化合物L-8d(44.8mg,33%)。EI-MS m/z:1008(M+).
化合物L-8e的制备
在0℃下,将化合物L-8d(200mg,0.20mmol)溶于1,4-二恶烷(4mL)、蒸馏水(4mL)并添加LiOH(21mg,0.50mmol)后,在常温搅拌2.5小时。反应完成后,将反应溶液降至0℃,使用2N盐酸水溶液将pH调节至2~3。对所述混合液进行减压浓缩,尽可能地除去水,然后进行下一步反应。EI-MS m/z:897(M+).
化合物L-8的制备
在0℃下,在L-8e中添加DCM(5mL)并滴加TFA(1mL)后,在常温搅拌了2小时。反应完成后,对反应溶液进行减压浓缩,通过prep-HPLC分离纯化,获得化合物L-8(155.9mg,两步69%/L-8e to L-8)。EI-MS m/z:797(M+).
化合物L-9b的制备
以类似于制备例8的化合物L-8b的制备方法来制备化合物L-9b(收率62.4%)。EI-MS m/z:1010(M+).
化合物L-9c的制备
以类似于制备例8的化合物L-8c的制备方法来制备化合物L-9c(定量收率)。EI-MSm/z:814(M+).
化合物L-9d的制备
以类似于制备例8的化合物L-8d的制备方法来制备化合物L-9d(收率33%)。EI-MSm/z:1130(M+).
化合物L-9e的制备
以类似于制备例8的化合物L-8e的制备方法来制备化合物L-9e。EI-MS m/z:1030(M+).
化合物L-9的制备
以类似于制备例8的化合物L-8的制备方法来制备化合物L-9(收率40%)。EI-MSm/z:930(M+).
【制备例9】配体-连接子(L-10)的制备
化合物L-10a的制备
在氮气气氛常温下,在制备例8中制备的化合物L-8b(260mg,0.29mmol)中添加6N盐酸(7mL)后,以50℃加热30分钟。减压浓缩后,用6N NaOH调节至pH10并搅拌20分钟。反应完成后,减压浓缩并用prep HPLC分离纯化,获得化合物L-10a(84mg,50%)。EI-MS m/z:572(M+).
化合物L-10b的制备
在氮气气氛常温下,将4-戊炔酸(4-pentynoic acid)(0.5g,5.09mmol)溶于THF(10mL)后,添加N-羟基丁二酰亚胺(N-hydroxysuccimide)(0.59g,5.09mmol)。将所述混合物冷却至0℃后,添加DCC(1.26g,6.11mmol)后在常温搅拌一小时。反应完成后,过滤沉淀物后减压浓缩滤液,将获得的物质(57mg,0.29mmol)与化合物L-10a(84mg,0.15mmol)溶于DMSO(3mL)后,添加TEA(62μL,0.44mmol),在常温搅拌了2小时。反应完成后,用prep HPLC分离纯化,获得化合物L-10b(25mg,26%)。EI-MS m/z:652(M+).
化合物L-10c的制备
在氮气气氛常温下,将L-10b(25mg,0.03mmol)和制备例6中制备的L-7(17.2mg,0.04mmol)溶于EtOH(3mL)、蒸馏水(0.5mL)后,在常温放入1M抗坏血酸钠(Sodiumascorbate)(64μL,0.06mmol)、0.1M CuSO4(128μL,0.01mmol)后,搅拌17小时。反应完成后,在氮气气氛0℃下,在反应混合物中添加四丁基氟化铵(1M溶于THF(in THF))(60μL,0.06mmol)并搅拌30分钟。反应完成后,用prep HPLC分离纯化,获得化合物L-10c(8.0mg)。EI-MS m/z:1061(M+).
化合物L-10的制备
在氮气气氛0℃下,将化合物L-10c(8mg)溶于DCM(1.0mL)后,添加TFA(0.2mL)后,在常温搅拌1.5小时。反应完成后,减压浓缩,获得化合物L-10(12mg)。EI-MS m/z:961(M+).
【制备例11】连接子L-11-1及L-11-2的制备
化合物L-11a的制备
在氮气气氛常温下,将六乙二醇(Hexaethylene glycol)(5.0g,17.71mmol)溶于无水二氯甲烷(dichloromethane,DCM)(178mL)后,滴加KI(249mg,1.17mmol)、Ag2O(4.92g,21.25mmol)、对甲苯磺酰氯(p-Toluenesulfonyl chloride,p-TsCl)(3.71g,19.48mmol)后,在常温搅拌一整晚。反应完成后,用氟镁石过滤器去除Ag2O后,将经过滤的滤液减压浓缩后,残余物进行柱层析,获得化合物L-11a(5.98g,73%)。
1H NMR(400MHz,CDCl3)δ7.80(d,J=8.4Hz,2H),7.35(d,J=8.0Hz,2H),4.16(t,J=4.8Hz,2H),3.71-3.58(m,22H),2.88(brs,1H),2.45(s,3H)。
化合物L-11-1的制备
在氮气气氛常温下,将化合物L-11a(5.98g,13.70mmol)溶于DMF(30mL)后,滴加NaN3(1.34g,20.55mmol)并在110℃下搅拌1小时。反应完成后,过滤固体化合物,减压浓缩经过滤的滤液后,残余物进行柱层析,获得化合物L-11-1(4.1g,91%)。
1H NMR(400MHz,CDCl3)δ3.72-3.60(m,22H),3.39(t,J=4.8Hz,2H)2.78(brs,1H)。
化合物L-11b的制备
在氮气气氛0℃下,将六乙二醇(15.0g,77.23mmol)溶于DCM(400mL)后,添加KOH(35.0g,617.8mmol)和p-TsCl(29.5g,154.5mmol)后,在常温搅拌一整晚。反应完成后,添加DCM(500mL)、蒸馏水(200mL)、及盐水(brine)(100mL)并萃取后,有机层用无水Na2SO4干燥后过滤并减压浓缩,不经过纯化而直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ7.30(d,J=8.1Hz,4H),7.30(d,J=8.1Hz,4H),4.18(t,J=4.8Hz,4H)3.70(t,J=4.8Hz,4H),3.64(s,8H),3.55(s,8H),2.42(s,6H)。
化合物L-11c的制备
在氮气气氛常温下,将混合的化合物L-11b(1.4g)溶于DMF(10mL)后,添加NaN3(0.2g)并在100℃搅拌15小时。反应完成后,减压浓缩反应溶液。残余物进行柱层析,获得化合物L-11c(510mg)。
1H NMR(400MHz,CDCl3)δ3.69-3.67(m,20H),3.39(t,J=5.2Hz,2H)。
化合物L-11d的制备
在氮气气氛常温下,将化合物L-11c(510mg,1.53mmol)溶于THF(4mL)、蒸馏水(2mL)和二乙醚(2mL)后,添加三苯基膦(423mg,1.61mmol)并搅拌14小时。反应完成后,滴加溶于1,4-二恶烷(2mL)和蒸馏水(3mL)的(Boc)2O(670mg,3.07mmol)并添加NaHCO3(387mg,4.60mmol)后,在常温搅拌3小时后,对反应溶液减压浓缩。对残余物进行柱层析,获得化合物L-11d(360mg,58%)。
1H NMR(400MHz,CDCl3)δ5.11(brs,1H),3.69-3.63(m,18H),3.54(t,J=4.8Hz,2H),3.39(t,J=4.8Hz,2H),3.32-3.31(m,2H),1.45(s,9H)。
化合物L-11-2的制备
在氢气气氛常温下,将化合物L-11d(360mg,0.89mmol)溶于乙醇(10mL)后,添加10%Pd/C(94mg,0.89mmol)并搅拌5小时。反应完成后,氟镁石过滤后,减压浓缩经过滤的滤液,获得化合物L-11-2(315mg,94%)。
1H NMR(400MHz,CDCl3)δ5.19(brs,1H),3.67-3.50(m,20H),3.32-3.31(m,2H),2.88-2.79(m,2H),1.45(s,9H).
【制备例12】连接子L-12的制备
化合物L-12a的制备
以类似于制备例11的化合物L-11a的制备方法来制备化合物L-12a。
1H NMR(400MHz,CDCl3)δ7.79(d,J=8.8Hz,2H),7.34(d,J=8.0Hz,2H),4.16(t,J=4.8Hz,2H),3.70(t,J=4.8Hz,4H),3.58(s,4H),3.56(t,J=5.0Hz,2H),2.44(s,3H),2.32(brs,1H)。
化合物L-12b的制备
以类似于制备例11的化合物L-11-1的制备方法来制备化合物L-12b。
1H NMR(400MHz,CDCl3)δ3.75–3.69(m,8H),3.62(t,J=4.8Hz,2H),3.41(t,J=4.8Hz,2H),2.41(brs,1H).
化合物L-12c的制备
以类似于制备例11的化合物L-11a的制备方法来制备化合物L-12c。
1H NMR(400MHz,CDCl3)δ7.80(d,J=8.8Hz,2H),7.35(d,J=8.0Hz,2H),4.17(t,J=4.8Hz,2H),3.70(t,J=4.8Hz,2H),3.64(t,J=4.8Hz,2H),3.34(t,J=4.8Hz,2H),2.45(s,3H)。
化合物L-12d的制备
以类似于制备例11的化合物L-11-1的制备方法来制备化合物L-12d。
1H NMR(400MHz,CDCl3)δ3.68-3.64(m,32H),3.38(t,J=4.8Hz,4H).EI-MS m/z:487(M+Na).
化合物L-12e的制备
在氮气气氛常温下,将化合物溶于L-12d(1.22g,2.63mmol)溶于乙醚(Ether)(5mL)、THF(10mL)、蒸馏水(5mL)后,添加三苯基膦(758mg,2.89mmol)并将所述混合物在常温搅拌一整晚。反应完成后,对所述化合物的溶剂进行减压浓缩,去除THF和乙醚(Ether),溶于1,4-二恶烷(1,4-dioxane)(6mL)后,滴加NaHCO3(441.2mg,5.25mmol)、Boc2O(678mg,3.15mmol)后,在常温搅拌6小时。反应完成后,添加EA(50mL)、蒸馏水(20mL)进行萃取后,收集有机层并用无水Na2SO4干燥,过滤后,进行减压浓缩。对残余物进行柱层析,获得化合物L-12e(1.0g,79%)。EI-MS m/z:538(M+).
化合物L-12的制备
将化合物L-12e(1.0g,1.86mmol)溶于乙醇(5mL)后,添加5%Pd/C(435mg,0.204mmol)并注入氢气,在常温搅拌1小时。反应完成后,用氟镁石过滤器以去除Pd/C,对滤液进行减压浓缩,获得化合物L-12(909.3mg,96%)。
【制备例13】连接子L-13-1及L-13-2的制备
化合物L-13a的制备
以类似于制备例5的化合物L-5c的制备方法来制备化合物L-13a(收率80%)。EI-MS m/z:790(M+).
化合物L-13-1的制备
以类似于制备例5的化合物L-5的制备方法来制备化合物L-13-1(收率98%)。EI-MS m/z:656(M+).
化合物L-13b的制备
以类似于制备例5的化合物L-5c的制备方法来制备化合物L-13b(收率98%)。EI-MS m/z:658(M+).
化合物L-13-2的制备
以类似于制备例5的化合物L-5的制备方法来制备化合物L-13-2(收率99%)。EI-MS m/z:524(M+).
【制备例14】配体-连接子L-14的制备
化合物L-14a的制备
以类似于制备例8的化合物L-8b的制备方法来制备化合物L-14a(收率53%)。EI-MS m/z:1046(M+).
化合物L-14的制备
以类似于制备例8的化合物L-8c的制备方法来制备化合物L-14(收率99%)。EI-MSm/z:946(M+).
【制备例15】连接子L-16的制备
化合物L-16a的制备
将硝基乙烷(Nitroethane)(7.5g,100mmol)溶于1,2-二甲氧基乙烷(1,2-dimethoxyethane,DME)(20mL)后,添加四甲基氢氧化铵五水合物(tetramethylammoniumhydroxide pentahydrate)(540mg)并在75℃下搅拌10分钟后,滴加(dropwise)丙烯酸叔丁酯(t-butyl acrylate)(30.7mL,210mmol)后,添加四甲基氢氧化铵五水合物(tetramethylammonium hydroxide pentahydrate)(540mg)后,搅拌30分钟。在室温下,添加四甲基氢氧化铵五水合物(tetramethylammonium hydroxide pentahydrate)(540mg)后,减压浓缩反应溶液,利用EA(200mL)和0.1N HCl溶液(solution)(50mL)萃取后,用无水Na2SO4干燥有机层,过滤后减压浓缩,获得化合物L-16a(30.9g,93.3%)。
化合物L-16b的制备
将化合物L-16a(3.0g,9.05mmol)溶于乙醇(20mL)后,添加雷尼镍(Raney Ni)并注入氢气,在常温搅拌3小时。反应完成后,利用氟镁石过滤器以去除雷尼镍(Raney Ni),减压浓缩过滤液,获得化合物L-16b(2.72g,quant.)。EI-MS m/z:302(M+).
化合物L-16c的制备
在氮气气氛常温下,将化合物L-16b(1.5g,4.98mmol)溶于DMF(10mL)后,添加N-芴甲氧羰基-6-氨基已酸(6-(Fmoc-amino)hexanoic acid)(1.76g,4.98mmol,CAS No.88574-06-5)、PyBOP(3.11g,5.97mmol)、DIPEA(1.3mL,7.46mmol)后,在常温搅拌5小时。反应完成后,添加EA(20mL)和蒸馏水(20mL)进行萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物L-16c(2.66g,84%)。
1H NMR(400MHz,CDCl3)δ7.76(d,J=8.0Hz,2H),7.60(d,J=7.2Hz,2H),7.40(t,J=7.6Hz,2H),7.31(t,J=7.6Hz,2H),5.79(s,1H),5.30(s.1H),4.39(d,J=7.2Hz,2H),4.21(t,J=7.2Hz,1H),3.20(q,J=6.0,5.2Hz,1H),5.10(s,2H),4.38(q,J=8.0,3.2Hz,1H),2.24(t,J=7.6Hz,4H),2.12–2.04(m,4H),1.92–1.85(m,2H),1.66–1.59(m,2H),1.55-1.51(m,2H),1.43(s,18H),1.36–1.32(m,2H),1.29(s,3H);EI-MS m/z:637(M+)。
化合物L-16d的制备
在氮气气氛0℃下,将化合物L-16c(2.66g,4.18mmol)溶于DCM(20mL)后,添加TFA(5mL)后,在常温搅拌4小时30分钟。反应完成后,对反应物进行减压浓缩,放入甲苯(20mL)再次进行减压浓缩。进行4次这种减压浓缩过程,以去除过量的TFA,获得化合物L-16d(1.77g,81%)。
1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),7.89(d,J=8.0Hz,2H),7.53(d,J=7.6Hz,2H),7.41(t,J=7.2Hz,2H),7.33(t,J=7.2Hz,2H),7.26(t,J=7.6Hz,1H)7.20(s,1H),4.28(d,J=6.8Hz,2H),4.20(t,J=7.2Hz,1H),2.95(q,J=8.0,6.4Hz,2H),2.16-2.10(m,4H),2.04–2.01(m,4H),1.73–1.66(m,2H),1.46-1.37(m,4H),1.26-1.16(m,2H),1.08(s,3H);EI-MS m/z:525(M+)。
化合物L-16的制备
在氮气气氛常温下,将化合物L-16d(500mg,0.95mmol)溶于THF(5mL)后,添加DCC(432.6mg,2.10mmol)、N-羟基琥珀酰亚胺(N-hydroxysuccinimide,NHS)(241.3mg,2.10mmol)后,在常温搅拌一整晚。反应完成后,在化合物中放入EA(1mL)、乙醚(Ether)(10mL),利用氟镁石过滤器过滤后,减压浓缩滤液,获得L-16(526mg,77%)。EI-MS m/z:719(M+).
【制备例16】配体-连接子L-18及L-19的制备
化合物L-18a的制备
利用化合物L-16及化合物L-14,以类似于所述制备例8的化合物L-8d的制备方法来制备化合物L-18a(收率52%)。EI-MS m/z:2381(M+).
化合物L-18b的制备
在氮气气氛下,将化合物L-18a(261.3mg,0.1mmol)溶于DMF(4mL)后,滴加哌啶(Piperidine)(0.06mL,0.6mmol)。将所述混合物在常温搅拌4小时。反应完成后,添加甲醇(5mL)和EA(15mL),析出褐色固体化合物并过滤。利用EA和乙醚(Ether)洗涤过滤后的褐色固体化合物,获得化合物L-18b(172.5mg,80%)。EI-MS m/z:2484(M+).
化合物L-18c的制备
利用化合物L-18b及化合物L-6,以类似于所述制备例8的化合物L-8d的制备方法来制备化合物L-18c。EI-MS m/z:2484(M+).
化合物L-18的制备
利用化合物L-18c,以类似于所述制备例8的化合物L-8的制备方法来制备化合物L-18(30%)。EI-MS m/z:2164(M+).
化合物L-19a的制备
利用化合物L-16及化合物L-9c,以类似于所述化合物L-18a的制备方法来制备化合物L-19a(40%)。EI-MS m/z:2117(M+).
化合物L-19b的制备
利用化合物L-19a,以类似于所述化合物L-18b的制备方法来制备化合物L-19b(57%;EI-MS m/z:1894(M+)。
化合物L-19c的制备
利用化合物L-19c及化合物L-6,以类似于所述化合物L-18c的制备方法来制备化合物L-19c(63%)。EI-MS m/z:2219(M+).
化合物L-19的制备
利用化合物L-19c,以类似于所述化合物L-18d的制备方法来制备化合物L-19(20%)。EI-MS m/z:1899(M+).
【制备例17】连接子L-20的制备
化合物L-20a的制备
在氮气气氛0℃下,将4-氟-3-硝基苯甲酸(4-fluoro-3-nitrobenzoic acid)(500mg,2.70mM)和N-叔丁氧羰基乙二胺(N-Boc-ethylenediamine)(433mg,2.70mM)溶于DCM(10mL)后,添加1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,EDC·HCl)(621mg,3.24mM)并在同样的温度搅拌2小时。反应完成后,利用DCM(100mL)、蒸馏水(100mL)及盐水(brine)(100mL)进行萃取,用无水Na2SO4过滤有机层后减压浓缩。对残余物进行柱层析纯化,获得化合物L-20a(814g,97%)。
1H NMR(400MHz,CD3OD)δ8.58(m,1H),8.20(m,1H),7.53(m,1H),3.45(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,2H),1.41(s,9H)。
化合物L-20b的制备
将溶于ACN(6mL)的化合物L-20a(375mg,1.14mM)溶液冷却至0℃,滴加4M盐酸/二恶烷(HCl/dioxane)(2mL)并搅拌1小时。反应完成后,减压浓缩并干燥,获得化合物L-20b(302mg,99%)。
1H NMR(400MHz,CD3OD)δ8.64(dd,J=6.8,2.0Hz,1H),8.24(m,1H),7.56(dd,J=10.8,8.8Hz,1H),3.68(t,J=6.0Hz,2H),3.18(t,J=6.0Hz,2H)。
化合物L-20的制备
在氮气气氛0℃下,将化合物L-20b(302mg,1.14mM)和L-6e(377mg,1.14mM)溶于DMF(6mL)后,依次添加三乙胺(Triethylamine,TEA)(320μl,2.29mM)、EDC·HCl(220mg,1.37mM)并在相同的温度下搅拌2小时。反应完成后,利用EA(100mL)、蒸馏水(100mL)及盐水(brine)(100mL)进行萃取,用无水Na2SO4对有机层进行干燥后过滤、在进行减压浓缩。残余物进行柱层析纯化,获得化合物L-20(417mg,69%)。EI-MS m/z:553(M+).
【制备例18】配体-连接子L-21的制备
化合物L-21b的制备
在氮气气氛0℃下,以与“J.AM.CHEM.SOC.2010,132,12711–12716”中记载的类似的方法合成的化合物L-21a(166mg,0.172mM)和化合物L-20(57mg,0.103mM)溶于DCM(2mL)后,添加二异丙基胺(Diisopropylamine,DIPEA)(60μL,0.34mM)并在常温搅拌3小时。反应完成后,利用EA(100mL)、蒸馏水(100mL)及盐水(brine)(100mL)进行萃取,用无水Na2SO4干燥有机层后减压浓缩。残余物进行柱层析纯化,获得化合物L-21b(87mg,56%)。EI-MS m/z:1498(M+).
化合物L-21的制备
将溶于DCM(1.5mL)的化合物L-21b(32mg,0.021mM)冷却至0℃后,慢慢滴加TFA(0.5mL)并在常温搅拌3小时。反应完成后,减压浓缩并干燥,获得化合物L-21(26.2mg,99%)。EI-MS m/z:1498(M+),615(M+/2).
【制备例19】连接子L-22的制备
化合物L-22a的制备
在氮气气氛常温下,将2,4-二甲基-1-硝基苯(2,4-dimethyl-1-nitrobenzene)(4.0g,26.46mmol)溶于蒸馏水(100mL)后,添加KMnO4(21g,132.30mmol)并在110℃搅拌28小时。反应完成后,过滤,在过滤的溶液中添加2N HCl水溶液(300mL)萃取,用无水Na2SO4干燥有机层后减压浓缩。残余物进行柱层析,获得化合物L-22a(4.42g,81%)。
1H NMR(400MHz,DMDO-d6)δ8.32(s,1H),8.25(d,J=8.4Hz,1H),8.07(d J=8.4Hz,1H)。
化合物L-22b的制备
在氮气气氛常温下,将化合物L-22a(4.4g,20.84mmol)溶于甲醇(50mL)后,添加H2SO4(2mL)并在75℃下搅拌3小时。反应完成后,减压浓缩溶液后,添加EA(500mL)和NaHCO3水溶液(300mL)进行萃取,用无水Na2SO4过滤有机层后减压浓缩。对残余物进行柱层析,获得化合物L-22b(2.0g,40%)。
1H NMR(400MHz,CDCl3)δ8.45(s,1H),8.29(d,J=7.2Hz,1H),7.93(d,J=8.0Hz,1H),3.99(s,3H),3.96(s,3H).
化合物L-22c的制备
在氮气气氛常温下,将化合物L-22b(2.0g,8.36mmol)溶于THF(50mL)后,添加溶于THF的LiBH4(17mL,33.45mmol)并搅拌24小时。反应完成后,添加甲醇(0.5mL)并添加EA(500mL)和2N HCl水溶液(200mL)进行萃取,用无水Na2SO4干燥有机层后过滤并减压浓缩。残余物进行柱层析,获得化合物L-22c(751mg,51%)。
1H NMR(400MHz,CDCl3)δ8.13(d,J=8.4Hz,1H),7.74(s,1H),7.48(d,J=8.4Hz,1H),5.00(d,J=6.0Hz,2H),4.84(d,J=4.8Hz,2H),2.53(t,J=6.4Hz,1H),1.91(t,J=5.6Hz,1H)。
化合物L-22d的制备
在氮气气氛0℃下,将化合物L-22c(750mg,4.09mmol)溶于THF(20mL)后,添加叔丁基二甲基氯硅烷(tert-butyldimethylsilyl chloride,TBDMS-Cl)(1.54g,10.24mmol)和咪唑(imidazole)(697mg,10.24mmol)并在常温搅拌3小时。反应完成后,添加EA(500mL)和蒸馏水(200mL)萃取,用无水Na2SO4干燥有机层后过滤并减压浓缩。对残余物进行柱层析,获得化合物L-22d(1.2g,75%)。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.4Hz,1H),7.88(s,1H),7.36(d,J=8.4Hz,1H),5.11(s,2H),4.82(s,2H),0.97(s,9H),0.95(s,9H),0.15(s,6H),0.13(s,6H)。
化合物L-22的制备
在氢气气氛常温下,将化合物L-22d(1g,2.43mmol)溶于甲醇(25mL)后,添加10%Pd/C(78mg,0.73mmol)并搅拌1小时。反应完成后,减压浓缩氟镁石过滤后的溶液,获得化合物L-22(578mg,62%)。
1H NMR(400MHz,CDCl3)δ7.05(d,J=7.6Hz,1H),6.99(s,1H),6.63(d,J=8.0Hz,1H),4.67(s,2H),4.61(s,2H),4.15(br,2S),0.92(s,9H),0.89(s,9H),0.07(s,12H)。
【制备例20】配体-连接子L-23的制备
化合物L-23a的制备
以类似于WO2009/026177和J.Med.Chem.2015,58,30943103中记载的方法来获得化合物L-23a。
化合物L-23b的制备
在氮气气氛0℃下,将化合物L-23a(90mg,0.097mM)和N-苄基乙二胺(N-Benzylethylenediamine)(17.5mg,0.116mM)溶于DMF(3mL)后,依次添加HBTU(48mg,0.126mM)、DIPEA(52μl,0.29mM),并在常温搅拌2小时。反应完成后,利用Prep-HPLC分离纯化后,冻结干燥,获得化合物L-23b(35mg,30%)。EI-MS m/z:1079(M+Na),1057(M+),529(M+/2)。
化合物L-23c的制备
将化合物L-23b(30mg,0.028mM)溶于乙醇(Ethanol)(10mL)后,添加10%Pd/C(20mg)并在氢气气氛下搅拌3小时。反应完成后,利用硅藻土(Celite)过滤反应溶液并减压浓缩,获得化合物L-23c(27mg,99%)。EI-MS m/z:989(M+Na)+,967(M+),484(M+/2).
化合物L-23d的制备
在氮气气氛0℃下,将化合物L-23c(25mg,0.025mM)和化合物L-6e(17.7mg,0.050mM)溶于DMF(2mL)后,依次添加HBTU(14.7mg,0.037mM)、DIPEA(13.8μl,0.075mM),并在常温搅拌3小时。反应完成后,利用Prep-HPLC分离纯化及冻结干燥,获得化合物L-23d(18mg,54%)。EI-MS m/z:1292(M+),646(M+/2)。
化合物L-23的制备
将溶于DCM(2mL)的化合物L-23d(8mg,0.006mM)溶液冷却至0℃后,慢慢滴加TFA(1mL)并在常温搅拌2小时。反应完成后,减压浓缩并干燥,获得化合物L-23(7mg,99%)。EI-MS m/z:1024(M+).
【制备例21】连接子L-24的制备
化合物L-24a的制备
在氮气气氛0℃下,将8-溴辛酸(8-bromooctonoic acid)(1g,4.48mM)溶于无水甲醇(Methanol)(20mL)后,慢慢滴加氯化亚砜(thionyl chloride)(3mL)并在常温搅拌12小时。反应完成后,减压浓缩并干燥,获得化合物L-24a(1.06g,99%)。
1H NMR(400MHz,CDCl3)δ3.66(s,3H),3.40(t,J=7.2Hz,2H),2.30(t,J=7.2Hz,2H),1.84(q,J=7.2Hz,2H),1.61(m,2H),1.43(m,2H),1.36-1.31(m,4H)。
化合物L-24c的制备
在氮气气氛0℃下,在已添加有DMF(5mL)的NaH(60%分散在矿物油中(dispersionin mineral oil),70mg)悬浮液中添加丙炔醇(Propargyl alcohol)(147mg,2.52mM)并搅拌10分钟后,慢慢滴加溶于DMF(1mL)的化合物L-24a(300mg,1.26mM),将反应溶液在50℃搅拌2小时。冷却反应溶液后,利用EA(50mL)和2M-HCl水溶液(50mL)萃取有机层,用无水MgSO4干燥并减压浓缩。将获得的化合物L-24b溶于甲醇(Methanol)(5mL)并添加6N NaOH水溶液(2mL)后,在常温搅拌4小时。反应完成后,利用EA(100mL)、2M-HCl水溶液(100mL)进行萃取,用用无水Na2SO4干燥有几层后过滤并减压浓缩。残余物进行柱层析纯化,获得化合物L-24c(150mg,60%)。
1H NMR(400MHz,CDCl3)δ4.13(s,2H),3.50(t,J=6.4Hz,2H),2.41(s,1H),2.35(t,J=7.2Hz,2H),1.65-1.56(m,4H),1.40-1.30(m,6H)。
化合物L-24d的制备
L-苯丙氨酸(L-phenylalanine)(3g,18.16mM)溶于H2O(15mL)、1,4-二恶烷(1,4-dioxane)(15mL)后,在0℃下,慢慢滴加NaHCO3(2.28g,27.24mM)和BOC酐(anhydride)(4.75g,21.79mmol)并在常温搅拌16小时。反应完成后,浓缩使反应溶液的体积减为一半,利用二乙醚(diethylether)(200mL)和H2O(100mL)萃取并去除有机层,将分离的水层用2MHCl水溶液(200mL)酸化,加入EA(200mL),用无水Na2SO4干燥、过滤及减压浓缩,获得BOC-L-苯丙氨酸(phenylalanine)(4g,83%)。将在此获得的BOC-L-Phe-OH(460mg,1.73mM)和H-Phe-OMe.HCl(411mg,1.90mM)溶于DMF(5mL),依次添加HBTU(790mg,2.07mM)、DIPEA(617μL,3.46mM)并在常温搅拌3小时。反应完成后,利用EA(100mL)、蒸馏水(100mL)及盐水(brine)(100mL)萃取,以无水Na2SO4干燥有机层,过滤后减压浓缩。残余物进行柱层析纯化,获得化合物BOC-L-Phe-Phe-OMe(680mg,92%)。将BOC-L-Phe-Phe-OMe(300mg,0.70mM)溶于DCM(8mL)后,在0℃下慢慢滴加4M-溶于二恶烷的HCl(HClin Dioxane)(1.5mL),并在常温搅拌2小时。反应完成后,减压浓缩并用n-己烷(n-Hexane)(100mL)洗涤干燥,获得化合物L-24d(255mg,99%)。
1H NMR(400MHz,CD3OD)δ7.37-7.27(m,7H),7.23-7.21(m,3H),4.92(m,1H),4.72(m,1H),4.04(m,1H),3.65(s,3H),3.34-3.17(m,2H),3.04-2.94(m,2H);EI-MS m/z:327(M+),654(2M+)。
化合物L-24的制备
在氮气气氛0℃下,将化合物L-24d(140mg,0.385mM)和L-24c(70mg,0.35mM)溶于DMF(3mL)后,依次添加HBTU(160mg,0.42mM)、DIPEA(188μL,1.05mM)并在常温搅拌1小时。反应完成后,利用EA(100mL)、盐水(brine)(100mL)萃取,以无水Na2SO4干燥有机层,过滤及减压浓缩。对残余物进行柱层析纯化,获得化合物L-24(156mg,87%)。
1H NMR(400MHz,CDCl3)δ7.30-7.18(m,8H),7.00-6.97(m,2H),6.17(d,J=7.6Hz,1H),5.93(d,J=8.0Hz,1H),4.73(m,1H),4.61(m,1H),4.15-4.09(m,2H),3.68(s,3H),3.49(t,J=6.8Hz,2H),3.10-2.94(m,4H),2.41(t,J=2.4Hz,1H),2.11(m,2H),1.59-1.49(m,4H),1.36-1.23(m,6H);EI-MS m/z:507(M+)。
【制备例22】配体-连接子L-25的制备
化合物L-25a的制备
将化合物L-24(150mg,0.23mM)和化合物L-21a’(152mg,0.23mM)溶于乙醇(Ethanol)(5mL)、DMSO(1mL)后,依次添加1M-抗坏血酸钠(1M-sodium ascorbate)(50μL)、0.1M-CuSO4(500μL)后,在常温搅拌1小时。反应完成后,利用EA(100mL)、盐水(brine)(100mL)萃取,以无水MgSO4干燥有机层,过滤及减压浓缩。对残余物进行柱层析纯化,获得化合物L-25a(227mg,75%)。
1H NMR(400MHz,CDCl3)δ7.54(s,1H),7.29-7.16(m,8H),7.03-6.99(m,2H),6.44(d,J=7.6Hz,1H),6.23(d,J=7.6Hz,1H),5.47(d,J=8.2Hz,1H),5.38(d,J=8.0Hz,1H),4.79(m,1H),4.67(m,1H),4.61(s,2H),4.37-4.22(m,4H),3.67(s,3H),3.49(t,J=6.8Hz,2H),3.10-2.96(m,4H),2.37-2.26(m,2H),2.13-2.04(m,3H),1.92-1.72(m,3H),1.65-1.48(m,6H),1.45(s,9H),1.42(s,18H),1.31-1.22(m,6H);EI-MS m/z:1021(M+)。
化合物L-25b的制备
通过将化合物L-25a(50mg,0.049mM)溶解在甲醇(Methanol)(3mL)中获得反应溶液,在0℃下慢慢滴加将NaOH(20mg)溶解在H2O(1mL)中而得的水溶液,在常温搅拌1小时。反应完成后,利用EA(50mL)、2M-HCl水溶液(50mL)萃取,用无水MgSO4干燥有机层,过滤及减压浓缩获得化合物L-25b(49mg,99%)。EI-MS m/z:1007(M+).
化合物L-25c的制备
利用所述化合物L-25b,以类似于化合物L-8a、L-8b及L-8c及化合物L-18a及L-18b的制备方法的方法来制备L-25c(19%)。EI-MS m/z:1270(M+/2).
化合物L-25的制备
利用所述化合物L-25c,以类似于化合物L-18c及L-18的制备方法的方法来制备L-25。EI-MS m/z:1215.3(M+/2).
【制备例23】配体-连接子L-26的制备
化合物L-26a-1的制备
将N-Boc-Dap-OH(1g,4.89mM)溶于1,4-二恶烷(1,4-dioxane)(15mL)后,在0℃下,依次添加溶于H2O(10mL)的Na2CO3(1.14g,10.76mM)水溶液、氯甲酸苄酯(Benzylchloroformate)(770mg,5.38mM)并在常温搅拌2小时,反应完成后,利用EA(100mL)、2M-HCl(100mL)萃取,用无水MgSO4干燥有机层,过滤及减压浓缩。残余物进行柱层析纯化,获得化合物L-26a(1.25g,75%)。
1H NMR(400MHz,CDCl3)δ7.34(m,5H),5.79(brs,1H),5.41(brs,1H),5.10(m,2H),4.31(m,1H),3.70-3.57(m,2H),1.44(s,9H)。
化合物L-26a-2的制备
在氮气气氛0℃下,将化合物L-26a(1.1g,3.25mM)溶于DMF(15mL)后,添加K2CO3(494mg,3.57mM)并搅拌15分钟。添加碘甲烷(Iodomethane)(810μL,13.0mM)并大约搅拌2小时。反应完成后,通过慢慢滴加2M-HCl水溶液(300mL)中和反应溶液的pH,利用EA(300mL)萃取,以无水MgSO4干燥有机层,过滤及减压浓缩。残余物进行柱层析纯化,获得化合物L-26a-2(1.04g,91%)。
1H NMR(400MHz,CDCl3)δ7.36-7.28(m,5H),5.38(m,1H),5.16-5.04(m,3H),4.35(m,1H),3.73(s,3H),3.58(m,2H),1.42(s,9H)。
化合物L-26a-3的制备
以类似于化合物L-6b的制备方法的方法获得化合物L-26a-3(86%)。EI-MS m/z:253(M+)。
化合物L-26a-4的制备
利用Fmoc-Asp(OtBu)-OH(705mg,1.705mM)和化合物L-26a-3(450mg,1.55mM),以类似于化合物L-8b的制备方法的方法来获得化合物L-26a-4(99%)。
1H NMR(400MHz,CDCl3)δ7.76(m,2H),7.59(m,2H),7.40(m,2H),7.36-7.26(m,7H),5.86(d,J=7.6Hz,1H),5.38(m,1H),5.06(m,2H),4.60-4.53(m,2H),4.50-4.38(m,2H),4.28(m,1H),3.75(s,3H),3.68(m,2H),3.01(m,1H),2.64(m,1H),1.42(s,9H);EI-MS m/z:646(M+)。
化合物L-26a-5的制备
将化合物L-26a-4(1g,1.54mM)溶于THF(25mL)后,在0℃下,慢慢滴加哌啶(piperidine)(3mL)并搅拌30分钟。反应完成后,减压浓缩,利用正己烷(n-Hexane)(100mL)洗涤三次,干燥后获得化合物L-26a-5(510mg,78%)。
化合物L-26a-6的制备
以类似于化合物L-26a-4的制备方法的方法来获得化合物L-26a-6(40%)。
化合物L-26a的制备
以类似于化合物L-26a-5的制备方法的方法来获得化合物L-26a(99%)。
化合物L-26c的制备
将以类似于化合物L-26a和(45mg,0.074mM)和WO2014078484的方法制备的化合物L-26b(30mg,0.044mM)溶于DMF(3mL)后,在氮气气氛0℃下,添加HBTU(18.4mg,0.048mM)、DIPEA(23.6μL,0.132mM)后,在常温搅拌1小时。反应完成后,利用EA(50mL)、盐水(brine)萃取,以无水MgSO4干燥有机层,过滤及减压浓缩。残余物进行柱层析纯化,获得化合物L-26c(50mg,90%)。EI-MS m/z:1256(M+)。
化合物L-26d的制备
以类似于化合物L-5的制备方法的方法来获得化合物L-26d(90%)。EI-MS m/z:1122(M+)。
化合物L-26e的制备
以类似于化合物L-8d的制备方法的方法来获得化合物L-26e(21%)。EI-MS m/z:1447(M+),724(M+/2)。
化合物L-26的制备
将化合物L-26e(11mg,0.0076mM)溶于甲醇(Methanol)(1mL)后,在0℃下添加NaOH水溶液(20mg溶于1mL水中(in 1mL H2O),0.2mL)并搅拌1小时。反应完成后,慢慢滴加2M-HCl水溶液(50mL)酸化反应溶液的pH后,利用EA(50mL),以无水MgSO4干燥有机层,将其过滤及减压浓缩。将残余物溶于DCM(2mL)并添加TFA(1mL)后,在常温搅拌1小时。减压浓缩反应溶液,获得化合物L-26(8mg,99%)。EI-MS m/z:1052(M+)。
【制备例24】连接子L-27的制备
化合物L-27a的制备
以类似于化合物L-16c的制备方法的方法来获得化合物L-27a(50%)。
1H NMR(400MHz,CDCl3)δ6.06(brs,1H),3.58(t,J=6.4Hz,2H),2.33(t,J=6.4Hz,2H),2.27(t,J=7.6Hz,4H),2.05(m,2H),1.89(m,2H),1.44(s,18H),1.31(s,3H)。
化合物L-27b的制备
以类似于化合物L-16d的制备方法的方法来获得化合物L-27b(99%)。
1H NMR(400MHz,CD3OD)δ3.58(t,J=6.4Hz,2H),2.41(m,2H),2.35-2.21(m,6H),1.85(m,2H),1.21(s,3H)。
化合物L-27的制备
以类似于化合物L-16的制备方法的方法来获得化合物L-27(99%)。
1H NMR(400MHz,CDCl3)δ5.67(s,1H),3.57(t,J=6.4Hz,2H),2.90-2.81(m,8H),2.68-2.55(m,4H),2.33(t,J=6.4Hz,2H),1.99-1.88(m,4H),1.30(s,1H)。
【制备例25】配体-连接子L-28的制备
利用化合物L-28a及化合物L-27,以类似于制备例16的方法来获得L-28(80%)。EI-MS m/z:1586(M+)。
1H NMR(400MHz,CD3OD)δ8.83(s,2H),7.95(d,J=8.0Hz,2H),7.68(d,J=8.0Hz,2H),5.23(s,4H),4.57(m,2H),3.58-3.46(m,20H),3.43-3.33(m,4H),2.44~2.26(m,9H),2.23-2.07(m,3H),1.84(m,2H)。
【制备例26】连接子L-29的制备
化合物L-29a的制备
在氮气气氛常温下,将化合物L-6e(98mg,0.29mmol)溶于DMF(2mL)后,添加甲胺(Methylamine)(171μL,0.34mmol,CAS No.74-89-5)、PyBOP(215.1mg,0.43mmol)、DIPEA(147.1μL,0.86mmol)后,在常温搅拌5小时。反应完成后,添加EA(20mL)和蒸馏水(20mL)萃取,以无水Na2SO4干燥有机层,过滤及减压浓缩。残余物进行柱层析,获得化合物L-29a(101.7mg,99%)。
1H NMR(400MHz,CDCl3)δ6.45(brs,1H),6.23(brs,1H),4.64(brs,1H),4.38(q,J=7.6,5.6Hz,1H),3.63(t,J=6.4Hz,2H),3.16-3.04(m,2H),2.82(d,J=4.8Hz,3H),2.47(t,J=6.4Hz,2H),1.92–1.80(m,1H),1.56–1.46(m,2H),1.44(s,9H),1.40–1.32(m,2H);EI-MSm/z:357(M+)。
化合物L-29的制备
在氮气气氛0℃下,将化合物L-29a(101.7mg,0.29mmol)溶于DCM(50mL)后,添加TFA(1mL)后,在常温搅拌2小时。反应完成后,对反应物进行减压浓缩,添加甲苯(20mL)并再次进行减压浓缩。进行四次这种减压浓缩过程以除去过量的TFA,获得化合物L-29(68.3mg,64%)。EI-MS m/z:257(M+).
【制备例27】连接子L-30的制备
化合物MPS-D1a的制备
在氮气气氛常温下,将4-乙酰基苯甲酸(9g,54.82mmol)溶于EtOH(50mL)。添加哌啶盐酸盐(6.66g,54.82mmol)和多聚甲醛(4.95g,164.5mmol)后,添加浓盐酸(0.6mL)后,在100℃下搅拌16小时。反应完成后,冷却至常温,滴加丙酮(90mL)后,在0℃下搅拌一小时,过滤固体,用乙醚(30mLx2)洗涤,获得化合物MPS-D1a(6.11g,38%)。
1H NMR(400MHz,DMSO-d6)δ8.08(s,4H),5.73(s,1H),3.65(t,J=7.2Hz,2H),3.35(t,J=7.2Hz,2H),3.31(m,6H),1.74(s,4H)。
化合物MPS-D1b的制备
在氮气气氛常温下,将MPS-D1a(6.11g,20.52mmol)溶于EtOH(40mL)、MeOH(26mL)后,添加4-甲氧基苯硫酚(4-Methoxybenzenethiol)(2.55g,20.52mmol)和哌啶(piperidine)(0.3mL,3.08mmol)后,在100℃下搅拌16小时。反应完成后,冷却至0℃后搅拌1小时,过滤固体,用乙醚(30mLx2)洗涤,获得化合物MPS-D1b(5.56g,90%)。
1H NMR(400MHz,CDCl3)δ8.04-7.99(m,4H),7.27(d,J=8.4Hz,2H),7.15(d,J=7.6Hz,2H),3.39-3.36(m,2H),3.25-3.21(m,2H),2.27(s,3H)。
化合物MPS-D1的制备
在氮气气氛常温下,将MPS-D1b(5.56g,18.51mmol)溶于MeOH(90mL)、蒸馏水(90mL)后,冷却至0℃并添加过氧单磺酸钾(Oxone)(25.03g,40.72mmol)后,在常温搅拌14小时。反应完结后,添加蒸馏水(100mL)溶解后,萃取三氯甲烷(150mLx3),用盐水(200mL)洗涤。将获取的有机层用无水Na2SO4干燥,过滤后减压浓缩,获得化合物MPS-D1(5.29g,86%)。
1H NMR(400MHz,CDCl3)δ8.04-7.99(m,4H),7.81(d,J=8.4Hz,2H),7.46(d,J=8.4Hz,2H),3.63(t,J=7.2Hz,2H),3.41(t,J=7.2Hz,2H),2.44(s,3H).EI-MS m/z:333(M+)。
化合物L-30a的制备
在氮气气氛下,将化合物L-11-1(2g,6.51mmol)溶解到丙酮(Acetone)(56mL)后,在-5℃下慢慢滴加(drop wise)Jone试剂溶液(Jone reagent solution)(5mL),添加完成后,在常温搅拌2小时。反应完成后,利用硅藻土过滤器(Celite filter)去除盐(salt),并将滤液减压浓缩以去除溶剂。之后,利用DCM(20mLx2)、水(5mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。残余物进行柱层析,获得化合物L-30a(1.85g,89%)。
1H NMR(400MHz,CDCl3)δ4.15(s,2H),3.76-3.67(m,18H),3.40(t,J=4.8Hz,2H)。
化合物L-30b的制备
在氮气气氛下,将化合物L-30a(500mg,1.56mmol)溶于DCM(10mL)后,添加t-BuOH(305μL,3.11mmol)、DIC(292.5μL,1.87mmol)、DMPA(19mg,0.16mmol)后,在常温搅拌4小时。反应完成后,利用DCM(30mLx2)、水(5mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。残余物进行柱层析,获得化合物L-30b(278.5mg,47%)。
1H NMR(400MHz,CDCl3)δ4.01(s,2H),3.70-3.66(m,18H),3.38(t,J=4.8Hz,2H),1.47(s,9H)。
化合物L-30c的制备
将化合物L-30b(278mg,0.74mmol)溶于EtOH(5mL)后,添加Pd/C(236mg,0.11mmol)、4M-HCl(溶于1,4二恶烷(in1,4-Dioxane))溶液(solution)(2滴),注入氢气并在常温搅拌1小时。反应完成后,利用硅藻土过滤器(Celite filter)去除Pd/C后,浓缩滤液,获得化合物L-30c(255.3mg,89.2%)。
1H NMR(400MHz,DMSO)δ8.32(s,1H),3.98(s,2H),3.55-3.40(m,18H),3.86(t,J=5.6Hz,2H),2.70-2.64(m,2H),1.42(s,9H)。
化合物L-30d的制备
以类似于化合物L-8b的制备方法的方法来获得化合物L-30d(71%)。
1H NMR(400MHz,CDCl3)δ7.95(s,4H),7.82(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.33-7.30(m,1H),3.98(s,2H),3.68-3.63(m,18H),3.55-3.53(m,2H),3.49-3.47(m,2H),2.95(s,1H),2.88(s,1H),2.46(s,3H)1.46(s,9H).EI-MSm/z:666(M+)。
化合物L-30的制备
在氮气气氛下,将化合物L-30d(120mg,0.18mmol)溶于DCM(8mL)后,冷却至0℃。在0℃下,添加TFA(4mL)且在相同温度下逐渐升温至常温,并搅拌2小时。反应完成后,为去除TFA将甲苯(Toluene)作为助溶剂(Co-solven)减压浓缩三次后,再次溶于DMF后,添加NSH(31mg,0.27mmol)和EDCI(52mg,0.27mmol)并在常温搅拌一整晚。完成后,化合物L-30没有进行纯化,直接进行下一步反应(127mg,crude)。EI-MS m/z:707(M+)。
【制备例28】连接子L-31的制备
化合物L-31a的制备
将硝基乙烷(Nitroethane)(6.1g,100mmol)溶于1,2-二甲氧基乙烷(1,2-Dimethoxyethane,DME)(20mL)后,添加四甲基氢氧化铵五水合物(tetramethylammoniumhydroxide pentahydrate)(540mg)并在70℃下搅拌10分钟后,滴加(dropwise)丙烯酸叔丁酯(t-butyl acrylate)(45.4mL,310mmol)。在这里,追加添加四甲基氢氧化铵五水合物(tetramethylammonium hydroxide pentahydrate)(540mg)并搅拌30分钟后,将温度降至常温,再次添加四甲基氢氧化铵五水合物(tetramethylammonium hydroxidepentahydrate)(540mg)。反应完成后,减压浓缩溶剂之后,利用EA(200mL)和0.1N HCl溶液(solution)(50mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩,利用EtOH再结晶残余物,并获得化合物L-31a(30.3g,68%)。
化合物L-31b的制备
将化合物L-31a(1.5g,3.37mmol)溶于乙醇(20mL)后,添加雷尼镍(Raney Ni)并注入氢气,在常温搅拌5小时。反应完成后,利用氟镁石过滤器以去除雷尼镍(Raney Ni),对过滤液进行减压浓缩,获得化合物L-31b(1.3g,93%)。
1H NMR(400MHz,CDCl3)δ2.25(t,J=8.0Hz,5H),2.24-2.18(m,1H),1.61(t,J=9.2Hz,5H),1.45(s,27H).
化合物L-31c的制备
在氮气气氛常温下,将化合物L-31b(988mg,2.38mmol)溶于DMF(10mL)后,添加N-芴甲氧羰基-6-氨基已酸(6-(Fmoc-amino)hexanoicacid)(840mg,2.38mmol)、PyBop(1.48g,2.85mmol)、DIPEA(0.6mL,3.57mmol)后,在常温搅拌一整晚。反应完成后,添加EA(20mL)和蒸馏水(20mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。残余物进行柱层析,获得化合物L-31-c(951.9g,54%)。
1H NMR(400MHz,CDCl3)δ7.76(d,J=8.0Hz,2H),7.60(d,J=7.6Hz,2H),7.40(t,J=7.2Hz,2H),7.31(t,J=7.6Hz,2H),5.90(s,1H),5.02-4.92(m,1H),4.39(d,J=6.4Hz,2H),4.22(t,J=6.8Hz,1H),3.20(q,J=7.2,6.8,1H),2.22(t,J=7.6Hz,6H),2.12(t,J=7.6Hz,2H),1.97(t,J=8.0Hz,6H),1.64–1.59(m,2H),1.55–1.48(m,2H),1.43(s,27H),1.38–1.32(m,2H);EI-MS m/z:751(M+)。
化合物L-31的制备
在氮气气氛0℃下,将化合物L-31c(951.9mg,1.27mmol)溶于DCM(10mL)后,添加TFA(4mL)后,在常温搅拌6小时。反应完成后,减压浓缩反应物,添加甲苯(20mL)再次减压浓缩。进行四次这种减压浓缩过程以去除过量的TFA,获得化合物L-31(720mg,crude.quant)。
1H NMR(400MHz,DMSO-d6)δ7.88(d,J=7.6Hz,2H),7.68(d,J=7.6Hz,2H),7.41(t,J=7.2Hz,2H),7.33(t,J=7.2Hz,2H),7.25(t,J=5.2Hz,1H),7.13(s,1H),4.28(d,J=6.8Hz,2H),4.20(t,J=6.4Hz,1H),2.95(q,J=8.8 6.8,1H),2.11(t,J=6.8Hz,6H),2.04(t,J=7.2Hz,2H),1.87-1.77(m,6H),1.50–1.42(m,2H),1.42–1.34(m,2H),1.26–1.15(m,2H);EI-MS m/z:583(M+)。
【制备例29】配体-连接子L-32的制备
化合物L-32a的制备
在氮气气氛常温下,将化合物L-31(300mg,0.52mmol)溶于DMF(5mL)后,添加EDCI(345.5mg,1.80mmol)、N-羟基琥珀酰亚胺(n-hydroxysuccinimide)(207.4mg,1.802mmol)搅拌一整晚。之后,添加化合物L-8c(1.41g,1.55mmol)、DIPEA(879μL,5.15mmol)后,在常温搅拌6小时。反应完成后,添加MeOH析出,对析出的固体化合物进行过滤,利用MeOH和乙醚(Ether),获得化合物L-32a(1.3g,crude.)。EI-MS m/z::1288(M+/2).
化合物L-32b的制备
在氮气下,将化合物L-32a(500mg,0.19mmol)溶于DMF(2mL)后,滴加哌啶(Piperidine)(29μL,0.29mmol)后,在常温搅拌两小时。反应完成后,添加甲醇(5mL)和EA(15ml)析出褐色固体化合物并过滤。将过滤的褐色固体化合物利用EA和乙醚(Ether)获得化合物L-32b(337mg,74%)。EI-MS m/z::1176(M+/2).
化合物L-32c的制备
在氮气气氛常温下,将化合物L-32b(150mg,0.064mmol)溶于DMF(2mL)后,添加化合物L-6(31mg,0.07mmol)、DIPEA(17μL、0.096mmol)后,在常温搅拌3小时。反应完成后,添加EA(10mL)析出褐色固体化合物过滤后,将褐色固体化合物利用EA和乙醚(Ether)获得化合物L-32c(220.6mg,crude).EI-MS m/z:1339(M+/2)。
化合物L-32的制备
在氮气气氛常温下,将化合物L-32c(70mg,0.0.23mmol)溶于DCM(2mL)后,添加TFA(0.2mL)并在常温搅拌2小时。反应完成后,减压浓缩后,利用prepHPLC纯化残余物,获得化合物L-32(17.8mg,23%)。EI-MS m/z:1289(M+/2).
【制备例30】连接子L-33的制备
化合物L-33a的制备
在氮气气氛常温下,将均苯三酸(trimesic acid)(5.0g,23.73mmol)溶于甲醇(200mL)后,添加H2SO4(1.5mL)并在60℃下搅拌19小时。反应完成后,减压浓缩溶液,添加EA(500mL)和NaHCO3水溶液(300mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。残余物进行柱层析,获得化合物L-33a(5.88g,98%)。
1H NMR(400MHz,CDCl3)δ8.80(s,3H),3.96(s,9H)。
化合物L-33b的制备
氮气气氛0℃下,将化合物L-33a(2.0g,,7.93mmol)溶于THF(40mL)后,添加LAH(1.2g,31.72mmol)并在60℃搅拌5小时。反应完成后,添加水(1.6mL)、15%NaOH水溶液(0.8mL),添加EA(500mL)后,用硅藻土(Celite)过滤,减压浓缩过滤液。对残余物进行柱层析,获得化合物L-33b(1.1g,83%)。
1H NMR(400MHz,CD3OD)δ7.26(s,3H),4.61(s,6H)。
化合物L-33c的制备
在氮气气氛0℃下,将化合物L-33b(1.1g,6.54mmol)溶于DMF(25mL)后,添加TBDMS-Cl(4.9g,32.7mmol)和咪唑(imidazole)(2.2g,32.7mmol)并在常温搅拌3小时。反应完成后,添加EA(500mL)和蒸馏水(200mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物L-33c(3.02g,90%)。
1H NMR(400MHz,CDCl3)δ7.16(s,3H),4.73(s,6H),0.94(s,27H),0.10(s,18H).
化合物L-33d的制备
在氮气气氛0℃下,将化合物L-33c(0.5g,0.98mmol)溶于Ac2O(4mL)后,添加61%硝酸(Nitric acid)(0.2mL)并搅拌1小时。反应完成后,添加EA(500mL)和NaHCO3水溶液(300mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物L-33d(370mg,68%)。
1H NMR(400MHz,CDCl3)δ7.51(s,2H),4.77(s,6H),0.94(s,27H),0.94(s,18H)。
化合物L-33e的制备
在氢气气氛常温下,将化合物L-33d(370mg,0.67mmol)溶于甲醇(5mL)后,添加5%Pd/C(43mg,0.02mmol)并搅拌30分钟。反应完成后,氟镁石过滤后,减压浓缩经过滤的溶液,获得化合物L-33e(283mg,81%)。
1H NMR(400MHz,CDCl3)δ6.94(s,2),4.73(s,6H),0.89(s,27H),0.05(s,18H)。
化合物L-33的制备
在氮气气氛常温下,将化合物L-33e(0.6g,1.14mmol)溶于DCM(20mL)后,添加三光气(Triphosgene)(406mg,1.37mmol)、TEA(0.8mL,5.47mmol)并搅拌1小时后,添加实施例1中获得的化合物S-6(759mg,1.14mmol)和TEA(0.24mL,1.17mmol)并搅拌15小时。反应完成后,添加DCM(100mL)和水(100mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。残余物进行柱层析,获得化合物L-33(914mg,66%)。
1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.52-7.46(m,2H),7.38-7.32(m,1H),7.29(s,2H),7.08-7.02(m,1H),5.56-5.46(m,2H),5.22-5.08(m,4H),4.71-4.62(m,6H),4.26-4.08(m,5H),3.82-3.74(m,1H),3.72-3.62(m,10H),3.58-3.48(m,1H),2.44-2.40(m,1H),2.23(s,3H),2.06(s,6H),2.03(s,3H),0.93-0.90(m,27H),0.09-0.06(s,18H);EI-MS m/z:1242(M++Na)。
【制备例31】连接子L-34的制备
利用化合物L-25b,以类似于化合物L-8b的方法获得化合物L-34(27%)。EI-MS m/z:1193(M+).
【制备例32】配体-连接子L-35的制备
化合物L-35a的制备
在氮气气氛0℃下,将Fmoc-Asp-(OtBu)(1g,2.43mM)溶于MeOH(2mL)和DCM(10mL)后,依次添加DIC(490μL,3.16mM)、DMAP(59mg,0.48mM)并在常温搅拌12小时。反应完成后,减压浓缩,残余物进行柱层析纯化,获得化合物L-35a(1.0g,97%)。
1H NMR(400MHz,CDCl3)δ7.75(d,J=8.0Hz,2H),7.61(d,J=7.2Hz,2H),7.42(t,J=7.6Hz,2H),7.33(t,J=7.2Hz,2H),5.76(d,J=8.4Hz,1H),4.54(m,1H),4.40(m,2H),4.25(m,1H),3.71(s,3H),2.97,(m,2H),1.45(s,9H)。
化合物L-35b的制备
在氮气气氛0℃下,将化合物L-35a(590mg,1.38mM)溶于DCM(6mL)后,添加TFA(3mL)并在常温搅拌4.5小时。反应完成后,减压浓缩,获得化合物L-35b(510mg,99%)。
1H NMR(400MHz,CDCl3)δ7.78(d,J=8.0Hz,2H),7.61(d,J=7.2Hz,2H),7.43(t,J=7.6Hz,2H),7.32(t,J=7.2Hz,2H),5.86(d,J=8.4Hz,1H),4.69(m,1H),4.43(m,2H),4.25(m,1H),3.74(s,3H),3.07,(m,2H)。
化合物L-35c的制备
在氮气气氛0℃下,将化合物L-35b(510mg,1.38mM)和N-Boc-乙二胺(N-Boc-ethylenediamine)(265mg,1.66mM)溶于DMF(10mL)后,依次添加HBTU(789mg,2.08mM)和DIPEA(483μL,2.77mM)并在常温搅拌4小时。反应完成后,利用EA(50mL)、盐水(brine)(50mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析纯化,获得化合物L-35c(430mg,61%)。
1H NMR(400MHz,CDCl3)δ7.78(d,J=8.0Hz,2H),7.61(d,J=7.2Hz,2H),7.43(t,J=7.6Hz,2H),7.33(t,J=7.2Hz,2H),6.87(m,1H),5.87(d,J=6.0Hz,1H),4.89(m,1H),4.53(m,3H),4.24(m,1H),3.71(s,3H),3.38-3.25(m,4H),3.07(m,1H),2.70(m,1H),1.42(2,9H);EI-MS m/z:512(M+).
化合物L-35d的制备
在氮气气氛0℃下,将化合物L-35c(280mg,0.54mM)溶于CH2Cl2(10mL)后,添加4NHCl的1,4-二恶烷(2.3mL),在常温搅拌3小时。反应完成后,减压浓缩,获得化合物L-35d(245mg,99%)。EI-MS m/z:448(M+).
化合物L-35e的制备
在氮气气氛0℃下,将化合物L-35d(245mg,0.54mM)和化合物L-6e(225mg,0.65mM)溶于DMF(5mL)后,依次添加HBTU(250mg,0.65mM)和DIPEA(293μL,1.62mM),并在常温搅拌30分钟。反应完成后,利用EA(20mL)、盐水(brine)(20mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析纯化,获得化合物L-35e(270mg,67%)。
1H NMR(400MHz,CDCl3)δ7.78(d,J=7.2Hz,2H),7.61(m,2H),7.43(t,J=7.2Hz,2H),7.34(t,J=7.2Hz,2H),6.92(m,1H),6.85(m,1H),6.50(m,1H),6.15(m,1H),4.74(m,1H),4.53(m,3H),4.32(m,1H),4.24(m,1H),3.72(s,3H),3.54-3.40(m,5H),3.25(m,1H),3.09(m,3H),2.78(m,1H),2.40(m,2H),1.42(2,9H);EI-MS m/z:737(M+)。
化合物L-35f的制备
在氮气气氛常温下,将化合物L-35e(50mg,0.067mM)溶于THF(4mL)后,添加哌啶(Piperidine)(0.2mL)并在常温搅拌30分钟。反应完成后,用EA(20mL)稀释后减压浓缩。浓缩物利用己烷(Hexane)(20mL)洗涤两次,减压干燥后利用prep-HPLC分离纯化后,冻结干燥,获得化合物L-35f。产量(Yield)18mg,53%;EI-MS m/z:515(M+)。
化合物L-35的制备
在氮气气氛0℃下,将化合物L-35f(6mg,0.005mM)和化合物L-34(3.9mg,0.0075mM)溶于DMF(1mL)后,依次添加HBTU(2.5mg,0.0065mM)和DIPEA(2.7μL,0.015mM),并在常温搅拌1小时。反应完成后,利用EA(20mL)、盐水(brine)(10mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩后,在0℃下,将残余物溶于THF(1mL)和蒸馏水(0.3mL)后,添加2NNaOH水溶液(1mL),在0℃下搅拌20分钟。利用EA(10mL)、2N HCl水溶液(5mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩并直接溶于DCM(3mL)后,添加TFA(1mL)并在0℃下搅拌30分钟。反应完成后,对化合物进行减压浓缩,将残余物利用prep-HPLC分离纯化后,冻结干燥,获得化合物L-35(5mg,75%)。EI-MS m/z:1307(M+)。
【制备例33】配体-连接子L-36的制备
化合物L-36a的制备
利用化合物L-25(制备例22),以类似于制备例20的化合物L-23b的制备方法的方法来获得化合物L-36a(70%)。EI-MS m/z:1139(M+)。
化合物L-36b的制备
利用化合物L-36a,以类似于制备例20的化合物L-23c的制备方法的方法来获得化合物L-36b(75%)。EI-MS m/z:1049(M+)。
化合物L-36c的制备
利用化合物L-36b,以类似于制备例20的化合物L-23d的制备方法的方法来获得化合物L-36c(49%)。EI-MS m/z:688(M+/2)。
化合物L-36的制备
利用化合物L-36c,以类似于制备例20的化合物L-23的制备方法的方法来获得化合物L-36(99%)。EI-MS m/z:1106(M+)。
【实施例1】BGal-SIG-Toxin(S-9)的合成
化合物S-1的制备
在氮气气氛0℃下,在β-D-半乳糖五乙酸酯(β-D-galactose pentaacetate)(Alfa,CAS 4163-60-4,5.0g,12.81mmol)添加33%溶于AcOH中的HBr(HBr in AcOH)(20mL)后,在常温搅拌4小时。反应完成后,减压蒸馏以去除反应溶剂后,添加EA(1000mL)和碳酸氢钠水溶液(1000mL)。用无水Na2SO4对获得的有机层进行干燥,过滤后减压浓缩。残余物进行柱层析,获得化合物S-1(5.2g,99%)。
1H NMR(400MHz,CDCl3)δ6.70(d,J=4.0Hz,1H),5.52(d,J=2.4Hz,1H),5.41(dd,J=7.6,2.8Hz,1H),5.05(dd,J=6.4,4.0Hz,1H),4.49(t,J=6.4Hz,1H),4.22-4.09(m,2H),2.16-2.01(m,12H)。
化合物S-2的制备
在氮气气氛常温下,将5-甲酰水杨酸(5-formylsalicylic acid)(8.3g,49.96mmol)溶于THF(100mL)后,依次添加DIPA(17.4mL,99.92mmol)、烯丙基溴(21.62mL,249.8mmol)并升温,回流搅拌14小时。反应完成后,添加蒸馏水(100mL)和EA(100mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。残余物进行柱层析,获得化合物S-2(9.4g,91.2%)。
1H NMR(400MHz,CDCl3)δ11.37(s,1H),9.90(s,1H),8.42(d,J=1.2Hz,1H),8.02(dd,J=8.4,1.2Hz,1H),7.12(d,J=8.4Hz,1H),6.11-6.01(m,1H),5.49-5.36(m,2H),4.90(d,J=6.0Hz,2H)。
化合物S-3的制备
在圆底烧瓶中放入分子筛(molecular sieve)(5.0g)并减压加热干燥。在氮气气氛下,将化合物S-1(5.0g,12.12mmol)和化合物S-2(2.5g,12.12mmol)溶于乙腈(100mL)。在所述混合物中添加Ag2O(8.43g,36.37mmol)后,在常温搅拌1小时30分钟。反应完成后,添加蒸馏水(100mL)和EA(100mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物S-3(3.77g,58%)。
1H NMR(400MHz,CDCl3)δ10.02(s,1H),8.28(d,J=1.6Hz,1H),8.00(dd,J=6.8,1.6Hz,1H),7.29(d,J=8.8Hz,1H),6.09-5.98(m,1H),5.62-5.57(m,1H),5.49(d,J=3.2Hz,1H),5.40(d,J=17.2Hz,1H),5.32-5.28(m,1H),5.18(d,J=8.0Hz,1H),5.12(dd,J=7.2,3.2Hz,1H),4.82(d,J=6.0Hz,2H),4.28-4.10(m,4H),2.20(s,3H),2.08(s,6H),2.02(s,3H)。
化合物S-4的制备
在氮气气氛常温下,将化合物S-3(3.70g,6.90mmol)溶于异丙醇(20mL)和氯仿(100mL)后,添加硅胶(29g)。将所述混合物在0℃下,添加NaBH4(653mg,17.24mmol)后,搅拌1小时30分钟。反应完成后,添加蒸馏水(200mL)和DCM(200mL)萃取,用无水硫酸钠干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物S-4(3.51g,95%)。
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.46(d,J=8.0Hz,1H),7.18(d,J=8.8Hz,1H),6.08-5.97(m,1H),5.58-5.52(m,1H),5.46(d,J=3.2Hz,1H),5.39(d,J=17.2Hz,1H),5.28(d,J=10.4Hz,1H),5.10(dd,J=6.8,3.6Hz,1H),5.06(d,J=8.0Hz,1H),4.78(d,J=5.2Hz,1H),4.68(d,J=6.0Hz,2H),4.27-4.04(m,3H),2.19(S,3H),2.08(S,3H),2.07(S,3H),2.02(S,3H),1.72(t,J=6.0Hz,1H)。
化合物S-5的制备
在氮气气氛下,将化合物S-4(3.5g,6.50mmol)溶于DCM(70mL)后,添加Pd(PPh3)4(376mg,0.33mmol)、三苯基膦(426mg,1.62mmol)、吡咯烷(555mg,7.80mmol)并在常温搅拌30分钟。反应完成后,在所述混合物中添加蒸馏水(100mL),滴加2N盐酸水溶液调节为pH3后,添加DCM(100mL)萃取。收集有机层并用无水Na2SO4干燥,过滤后减压浓缩,获得化合物S-5(3.2g,crude)。
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.60(d,J=7.6Hz,1H),7.18(d,J=8.4Hz,1H)5.61-5.55(m,1H),5.49(s,1H),5.24(d,J=7.6Hz,1H),5.16(d,J=10.4Hz,1H),4.72(s,2H),4.26-4.10(m,3H),2.21(s,3H),2.11(s,3H),2.07(s,3H),2.03(s,3H)。
化合物S-6的制备
在氮气气氛常温下,将化合物S-5(1.1g,2.21mmol)和化合物L-1(455mg,2.43mmol)溶于DMF(15mL)后,添加PyBOP(1.5g,2.87mmol)和DIPEA(0.57mL,3.31mmol)并在常温搅拌2小时。反应完成后,添加蒸馏水(20mL)和EA(20mL)萃取,收集有机层用无水Na2SO4干燥,过滤后减压浓缩。残余物进行柱层析,获得化合物S-6(1.24g,84%)。
1H NMR(400MHz,CDCl3)δ8.03(d,J=1.6HZ,1H),7.46(d,J=8.4Hz,1H),7.35(t,J=4.8Hz,1H),7.06(d,J=8.4Hz,1H),5.56-5.48(m,2H),5.17-5.12(m,2H),4.69(s,2H),4.27-4.10(m,5H),3.82-3.48(m,12H),2.42(s,1H),2.23(s,3H),2.07(s,3H),2.06(s,3H),2.03(s,3H);EI-MS m/z:668(M+)。
BGal-SIG连接子化合物S-7的制备
在氮气气氛下,将化合物S-6(2.36g,3.61mmol)溶于DMF(30mL)后,依次添加双(4-硝基苯基)碳酸酯(Bis(4-nitrophenyl)carbonate)(1.21g,3.97mmol)和DIPEA(943μL,5.42mmol)并在常温搅拌3小时。反应完成后,添加盐水(brine)(30mL)和EA(30mL)萃取,收集有机层用无水Na2SO4干燥,过滤后减压浓缩。对残余物进行柱层析,获得BGal-SIG连接子化合物S-7(2.57g,87%)。
1H NMR(400MHz,CDCl3)δ8.29-8.26(d,J=8.8Hz,2H),8.15(s,1H),7.53-7.51(dd,J=8.8Hz,1H),7.39-7.37(d,J=8.8Hz,2H),7.08-7.06(d,J=8.8Hz,1H)5.41-5.27(m,6H),4.23-4.19(m,3H),4.21-4.18(m,3H),3.77-3.52(m,15H),2.43(s,1H),2.06(s,9H);EI-MS m/z:833(M+)。
化合物S-8的制备
在氮气气氛常温下,将化合物S-7(200mg,0.24mmol)溶于DMF(3mL)后,依次添加MMAF-OMe(制备例7,179mg,0.24mmol)、HOBT(7.4mg,0.05mmol)、吡啶(1.0mL)及二异丙基乙胺(42μL,0.24mmol)。将所述混合物在常温搅拌19小时。反应完成后,添加EA(100mL)、蒸馏水(300mL)、盐水(brine)(100mL)及1N盐酸水溶液(20mL)萃取。用无水Na2SO4干燥有机层,减压浓缩。对残余物进行柱层析,获得化合物S-8(247mg,72%)。
EI-MS m/z:1440(M+)
BGal-SIG-Toxin化合物S-9的制备
在氮气气氛-20℃下,将化合物S-8(100mg,0.07mmol)溶于甲醇(1.8mL)后,逐渐滴加溶于水(1.8mL)的LiOH(22mg,0.52mmol)后在-5℃下搅拌4小时。反应完成后,添加2N盐酸水溶液(3mL),利用prep-HPLC分离纯化,获得BGal-SIG-Toxin化合物S-9(78mg,89%)。EI-MS m/z:1258(M+).
【实施例2】配体-药物偶联物(1)和(2)的制备
配体-药物偶联物(1)的制备
在氮气常温下,将制备例8中制备的化合物L-8(20mg,0.02mmol)和实施例1中制备的化合物S-9(22.08mg,0.02mmol)溶于乙醇(2mL)、蒸馏水(0.5mL),在反应溶液中添加1M抗坏血酸钠(35μL,0.04mmol)和0.1M CuSO4(70μL,0.01mmol)后,搅拌2.5小时。反应完成后,利用prep-HPLC分离纯化所述混合溶液,获得配体-药物偶联物(1)(32.2mg,77%)。EI-MSm/z:2055(M+)。
配体-药物偶联物(2)的制备
利用化合物L-9(制备例8)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(2)。EI-MS m/z:2187(M+)。
【实施例3】配体-药物偶联物(3)的制备
利用化合物L-23(制备例20)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(3)(29.7%)。EI-MS m/z:1141(M+/2).
【实施例4】配体-药物偶联物(4)的制备
利用化合物L-21(制备例18)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(4)。EI-MS m/z:2487(M+),1244(M+/2),830(M+/3).
【实施例5】配体-药物偶联物(5)的制备
化合物5-1的制备
在氮气气氛常温下,将化合物S-7(260mg,0.31mmol)和化合物L-22(122mg,0.32mmol)溶于DMF(2mL)后,添加HOBt(24mg,0.16mmol)、哌啶(Pyridine)(2mL)和DIPEA(108μL,0.62mmol)并在40℃下搅拌28小时。反应完成后,添加EA(250mL)、蒸馏水(50mL)和2NHCl水溶液(50mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物5-1(208mg,62%)。
1H NMR(400MHz,CDCl3)δ8.35(s,1H),8.10(s,1H),7.95(s,1H),7.52-7.46(m,1H),7.38-7.18(m,3H),7.08-7.02(m,1H),5.58-5.48(m,2H),5.20-5.11(m,4H),4.71(s,2H),4.66(S,2H),4.24-4.08(m,5H),3.82-3.74(m,1H),3.72-3.62(m,10H),3.58-3.48(m,1H),2.44-2.40(m,1H),2.23(s,3H),2.06(s,6H),2.03(s,3H),0.92(s,9H),0.88(s,9H),0.08(s,6H),0.07(s,6H);EI-MS m/z:1076(M+)。
化合物5-2的制备
在氮气气氛常温下,将化合物5-1(205mg,0.19mmol)溶于DCM(3mL)后,在0℃下添加TFA(0.8mL)并搅拌1.5小时。反应完成后,添加DCM(50mL)和NaHCO3水溶液(150mL)萃取,在有机层添加TEA(20mL)并搅拌30分钟。在反应溶液中添加蒸馏水(100mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩,对残余物进行柱层析,获得化合物5-2(122mg,75%)。
1H NMR(400MHz,CDCl3)δ8.11(s,1H),8.01(s,1H),7.90(s,1H),7.48(d,J=8.8Hz,1H),7.38-7.33(m,1H),7.31(d,J=8.4Hz,1H),7.20(s,1H),7.06(d,J=8.4Hz,1H),5.55-5.49(m,2H),5.20-5.12(m,4H),4.71(d,J=4.8Hz,2H),4.64(d,J=8.8Hz,2H),4.26-4.10(m,5H),3.81-3.74(m,1H),3.72-3.62(m,10H),3.58-3.48(m,1H),2.42-2.41(m,1H),2.33(s,1H),2.22(s,3H),2.07(s,3H),2.06(s,3H),2.03(s,3H),1.74(s,1H);EI-MS m/z:847(M+)。
化合物5-3的制备
在氮气气氛常温下,将化合物5-2(70mg,0.08mmol)溶于DMF(1mL)后,添加Bis(PNP)(63mg,0.21mmol)和DIPEA(36μL,0.21mmol)并在常温搅拌2小时。反应完成后,添加EA(100mL)和蒸馏水(100mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物5-3(72mg,74%)。
1H NMR(400MHz,CDCl3)δ8.29-8.25(m,4H),8.17(s,1H),7.96-7.91(m,1H),7.52-7.48(m,4H),7.47-7.35(m,5H),7.06(d,J=8.0Hz,1H),5.54-5.49(m,2H),5.31(s,2H),5.27(s,2H),5.20-5.16(m,4H),4.28-4.10(m,5H),3.81-3.74(m,1H),3.72-3.62(m,10H),3.58-3.48(m,1H),2.43-2.41(m,1H),2.23(s,3H),2.06(s,6H),2.03(s,3H);EI-MS m/z:1178(M+)。
化合物5-4的制备
在氮气气氛常温下,将化合物5-3(60mg,0.05mmol)和MMAF(76mg,0.10mmol)溶于DMF(1.5mL)后,添加HOBt·H2O(8mg,0.05mmol)、哌啶(Pyridine)(0.5mL)和DIPEA(35μL,0.20mmol)并搅拌14小时。反应完成后,添加EA(250mL)、蒸馏水(50mL)和2N HCL水溶液(50mL)萃取,用无水Na2SO4干燥有机层,过滤后减压浓缩。对残余物进行柱层析,获得化合物5-4(68.7mg,56%)。EI-MS m/z:2391(M+)。
化合物5-5的制备
在-5℃下,将化合物5-4(50mg,0.02mmol)溶于甲醇(2mL)、蒸馏水(1mL)并添加LiOH·H2O(18mg,0.42mmol)后,在0℃下搅拌5小时。反应完成后,利用2N盐酸水溶液将反应溶液的pH调节至2~3后,利用Per-HPLC分离纯化,获得化合物5-5(32mg,70%)。EI-MS m/z:2195(M+)。
配体-药物偶联物(5)的制备
利用化合物L-8(制备例8)及化合物5-5,以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(5)。EI-MS m/z:2992(M+)。
【实施例6】配体-药物偶联物(6)的制备
利用化合物L-33e(制备例30),以类似于配体-药物偶联物(5)的制备方法的方法来制备配体-药物偶联物(6)。
【实施例7】配体-药物偶联物(7)、(8)、(9)的制备
配体-药物偶联物(7)的制备
利用化合物7-1及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(7)(14%)。EI-MS m/z:1446(M+/2)。
配体-药物偶联物(8)的制备
利用化合物L-19(制备例16)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(8)(17.4%)。EI-MS m/z:1578(M+)。
配体-药物偶联物(9)的制备
利用化合物L-18(制备例16)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(9)(24%)。EI-MS m/z:1710(M+)。
【实施例8】配体-药物偶联物(10)及(11)的制备
配体-药物偶联物(10)的制备
利用化合物7-1,以类似于配体-药物偶联物(5)的制备方法的方法来制备配体-药物偶联物(10)(26%)。EI-MS m/z:1277(M+/3)。
配体-药物偶联物(11)的制备
利用化合物7-1,以类似于配体-药物偶联物(6)的制备方法的方法来制备配体-药物偶联物(11)(52%)。EI-MS m/z:1540(M+/3)。
【实施例9】配体-药物偶联物(12)的制备
化合物12-1的制备
利用化合物L-33(制备例30),以类似于实施例5的化合物5-2的制备方法的方法来制备化合物12-1(82%)。
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.69(s,1H),7.52-7.46(m,1H),7.44-7.36(m,1H),7.31(s,2H),7.06-7.02(m,1H),5.56-5.46(m,2H),5.26-5.10(m,4H),4.67-4.48(m,6H),4.26-4.08(m,5H),3.84-3.50(m,12H),2.48-2.44(m,1H),2.22(s,3H),2.07(s,3H),2.06(s,3H),2.03(s,3H);EI-MS m/z:877(M+)。
化合物12-2的制备
利用化合物12-1,以类似于实施例5的化合物5-3的制备方法的方法来制备化合物12-2(81%)。
1H NMR(400MHz,CDCl3)δ8.29-8.24(m,6H),8.17(s,1H),7.66(s,2H),7.48-7.32(m,9H),7.06-7.02(m,1H),5.56-5.46(m,2H),5.36-5.34(m,6H),5.20-5.10(m,4H),4.26-4.08(m,5H),3.82-3.50(m,12H),2.46-2.40(m,1H),2.23(s,3H),2.06(s,6H),2.03(s,3H);EI-MS m/z:1373(M+)。
化合物12-3的制备
利用化合物12-2,以类似于实施例5的化合物5-4的制备方法的方法来制备化合物12-3(56%)。EI-MS m/z:1065(M+/3)。
化合物12-4的制备
利用化合物12-3,以类似于实施例5的化合物5-5的制备方法的方法来制备化合物12-4(61%)。EI-MS m/z:995(M+/3)。
化合物12-5的制备
在氮气气氛常温下,将化合物L-32(制备例29)(7.0mg,0.0023mmol)和化合物12-4(6.9,0.0023mmol)溶于乙醇(2.0mL)、蒸馏水(0.5mL)。在所述混合物中添加1M抗坏血酸钠(23μL,0.023mmol)、0.1M CuSO4(46μL,0.0046mmol)并在室温搅拌6小时。反应完成后,利用prep-HPLC分离纯化,获得偶联物12-5(5.6mg,40%)。EI-MS m/z:1854(M+/3)。
配体-药物偶联物(12)的制备
在氮气气氛0℃下,将化合物12-5(5.6mg,0.0009mmol)溶于MeOH(1.5mL)、蒸馏水(0.5mL)后,添加LiOH(2.8mg,0.065mmol)后,在0℃下搅拌15小时。反应完成后,利用2N盐酸水溶液调节pH至2~3。之后。然后利用prepHPLC纯化反应物,获得配体-药物偶联物(12)(2.0mg,41%)。EI-MS m/z::1744(M/3+1)。
【实施例10】配体-荧光物质(FA-Cy5)制备
FA-Cy5以类似于Anal.Biochem.2013,432,59-62中所述的方法来制备,Cy5 NHSester购买自(株)LapService Korea。
【实施例11】配体-药物偶联物(13)的制备
利用化合物L-25(制备例22)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(13)(23%)。EI-MS m/z:922(M+/3),1229(M+/2)。
【实施例12】配体-药物偶联物(14)的制备
利用化合物L-36(制备例33)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(14)(23%)。EI-MS m/z:788(M+/3),1182(M+/2)。
【实施例13】配体-药物偶联物(15)的制备
利用化合物L-35(制备例32)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(15)(23%)。EI-MS m/z:855(M+/3),1282(M+/2)。
【实施例14】配体-药物偶联物(16)的制备
利用化合物L-35(制备例32)及化合物S-9(实施例1),以类似于配体-药物偶联物(1)的制备方法的方法来制备配体-药物偶联物(16)(23%)。EI-MS m/z:855(M+/3),1282(M+/2)。
【实施例15】配体-药物偶联物(17)的制备
化合物17-a的制备
在氮气气氛常温下,将化合物L-29(制备例26)(9.0mg,0.024mmol)和化合物S-9(实施例1)(20mg,0.016mmol)溶于乙醇(2mL)、蒸馏水(0.5mL),在反应溶液中添加1M抗坏血酸钠(32μL,0.032mmol)和0.1M CuSO4(64μL,0.0064mmol)后,搅拌1小时。反应完成后,利用prep-HPLC分离纯化所述混合溶液,获得化合物17-a(14.3mg,55%)。EI-MS m/z:1514(M+).
化合物17的制备
在氮气气氛下,将化合物17-a(13.4mg,0.008mmol)和化合物L-30(制备例27)(5.8mg,0.008mmol)溶于DMF(1mL)后,添加DIPEA(4.3μL,0.02mmol),并在常温搅拌1小时。反应完成后,通过prep-HPLC获得化合物(17)(7.2mg,42%)EI-MS m/z:2106(M+)。
【实施例16】偶联物制备用化合物(18)的制备
化合物18-a的制备
利用化合物L-29(制备例26)及化合物(12-4)(实施例9),以类似于化合物17-a的制备方法的方法来获得化合物18-a(71%)。EI-MS m/z:1080(M+/3)。
化合物18的制备
利用化合物18-a以及化合物L-30(制备例27),以类似于化合物(17)的制备方法的方法来获得化合物(18)(33%)。EI-MS m/z:1277(M+/3)。
【比较例1】BG-MMAF(A-6,A-7)的制备
化合物A-1、A-2、A-3制备
以类似于韩国公开专利第10-2015-0137015号实施例2至3中所述的方法来制备并获得各物质。
化合物A-4制备
在氮气气氛0℃下,将化合物A-3(360mg,0.29mmol)和制备例1中制备的L-1(64mg,0.34mmol)溶于DMF(5mL)后,添加DIPEA(75μL,0.43mmol)及PyBOP(224mg,0.43mmol)。将所述混合物在常温搅拌2小时。反应完成后,添加EA(100mL)、蒸馏水(50mL)及盐水(brine)(50mL)萃取,用无水Na2SO4对获得的有机层进行干燥,减压浓缩后获得化合物A-4(410mg,crude)。EI-MS m/z:1426(M+).
化合物A-5制备
以类似于化合物A-4的制备方法,利用化合物A-3(100mg,0.08mmol)和2-[2-(2-叠氮乙氧基)乙氧基]乙胺(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethanamine)(64mg,0.34mmol)获得化合物A-5(86mg,75%)。EI-MS m/z:1457(M+).
化合物A-6制备
在氮气气氛-20℃下,将化合物A-4(410mg,0.29mmol)溶于甲醇(7mL)后,逐渐滴加溶于水(7mL)的LiOH(91mg,2.16mmol),在-5℃搅拌4小时。反应完成后,添加2N盐酸水溶液(7mL),利用prep-HPLC分离纯化,获得化合物A-6(230mg,63%,两步)。EI-MS m/z:1272(M+)。
化合物A-7制备
以类似于化合物A-6的制备方法,在化合物A-5(1.0g,0.69mmol)中获得化合物A-7(801mg,89%)。EI-MS m/z:1303(M+)。
【比较例2】配体-药物偶联物(β-葡糖苷酸连接子)(B)的制备
在氮气气氛常温下,将化合物L-10(制备例9)(12mg)和化合物A-7(比较例1)(11mg,0.01mmol)溶于乙醇(2mL)、蒸馏水(0.5mL)。在所述混合物中添加1M抗坏血酸钠(64μL,0.06mmol)、0.1M CuSO4(128μL,0.01mmol)后,在室温搅拌17小时。反应完成后,利用Prep-HPLC分离纯化,获得配体-药物偶联物B(10mg,三步42%)。EI-MS m/z:2263(M+)。
【比较例3】配体-药物偶联物(β-葡糖苷酸连接子)C的制备
化合物C-1的制备
利用化合物L-8(制备例8)和化合物A-6(比较例1),以类似于比较例2的方法来获得化合物C。EI-MS m/z:2069(M+)。
化合物C的制备
在氮气气氛常温下,将化合物L-4(制备例4)(0.78mg,0.004mmol)溶于DMF(1mL)后,添加N-羟基丁二酰亚胺(N-hydroxy-succinimide)(0.53mg,0.005mmol)和EDCI·HCl(0.88mg,0.005mmol)后搅拌4小时。反应完成后,利用LC/MS确认化合物C-2的生成,在反应溶液中添加化合物C-1(8.4mg,0.003mmol)和三乙胺(5μL,0.04mmol)并搅拌3小时。利用Prep-HPLC分离纯化所述混合溶液,获得配体-药物偶联物C(6.6mg)EI-MS m/z:2253(M+)。
【比较例4】配体-药物偶联物(β-葡糖苷酸连接子)D的制备
利用化合物L-10a(制备例9)、化合物L-27(制备例24)、化合物L-7(制备例6)和化合物S-1(实施例1),以类似于实施例7的方法获得配体-药物偶联物D。EI-MS m/z:1487(M+/2),991(M+/3)。
【实验例1】连接子-药物(化合物S-9和A-6)的酶切分析(enzymatic cleavageassay)评价
为确认实施例1的化合物S-9的对于β-半乳糖苷酶(β-galactosidase)的反应性,与比较例1的化合物A-6的对于β-葡糖苷酸酶(β-glucuronidase)反应性差异进行了比较。
将实施例1的化合物S-9及比较例1的化合物A-6分别以10mM的浓度溶于DMSO后,与PBS(phosphate buffered saline:磷酸盐缓冲溶液)缓冲溶液混合,分别制备了500mM溶液。
在包含2640μL的PBS缓冲溶液和300μL的500μM化合物S-9溶液的混合液中添加60μL的1mg/mL的酶溶液,制备对于实施例1的化合物S-9的酶反应溶液后,在37℃恒温培养基开始反应。
在包含2640μL的PBS缓冲溶液和300μL的500μM化合物A-6溶液的混合液中添加60μL的1mg/mL的酶溶液,制备对于比较例1的化合物A-6的酶反应溶液后,在37℃恒温培养基开始反应。
在包含化合物S-9的反应混合物中使用了大肠菌β-半乳糖苷酶(Sigma G4155),包含用于比较试验的化合物A-6的反应混合物中使用了大肠菌β-葡糖苷酸酶酶(SigmaG7396)。
所述酶反应也在反应前0分钟、反应后15分钟、30分钟、45分钟、90分钟各收取500μL,以HPLC方法定量分析与剩余的化合物S-9及化合物A-6酶反应而释放的MMAF。所述实验结果示出在图3中,确认到化合物S-9和化合物A-6的通过酶的水解半衰期分别为10.7分钟(化合物S-9)、26.0分钟(化合物A-6)。
另外,可以确认,两种化合物均通过β-半乳糖苷酶或β-葡糖苷酸酶的酶作用迅速通过1,6-消除反应释放MMAF。
尤其,确认了,就对酶反应的反应性而言,使用β-半乳糖苷酶的实验结果比β-葡糖苷酸酶的反应性快两倍以上。
由此可知,本发明的包含与β-半乳糖苷(β-galactoside)结合的自我牺牲型连接基团的化合物与现有的与葡糖苷酸(glucuronide)结合的化合物相比,药物释放效果优秀。
【实验例2】连接子-药物(化合物S-9和A-6)的人及小鼠血浆内稳定性评价
为了解实施例1的化合物S-9和比较例1的化合物A-6的人及小鼠血浆内的稳定性,进行了如下实验。
将化合物S-9(实施例1)及化合物A-6(比较例1)以10mM浓度溶于DMSO后,混合到小鼠血浆(Innovative research,产品编号IGMS-N)和人血浆(Innovative research,产品编号IPLA-N)中,使得各自最终浓度达到100μM(最终1%DMSO)。将各化合物S-9(实施例1)和化合物A-6(比较例1)的血浆混合液在37℃下搅拌(shaking)使其反应。反应前及反应后第1、2、5、7、9天时,分别收取所述样品50μL,为反应终止血浆蛋白沉淀,添加200μL的内部包含标准物质(5ng/mL disopyramide:丙吡胺)的乙腈,混合后离心分离(4℃,20分钟,4000rpm)。收集离心分离后获得的各上清液并以LC-MS/MS分析。
在图4及图5中示出利用LC-MS/MS测量样品中残留的化合物S-9和化合物A-6和释放的药物MMAF的量的结果。由此可知,直到第9天,本发明的引入半乳糖苷连接子的化合物S-9在小鼠和人血浆中保持85%以上,与对比化合物A-6一样极其稳定。
【实验例3】配体-药物的受体键合力(binding affinity)
为测定具有β-半乳糖苷连接子的配体-药物偶联物1(实施例2)及具有β-葡糖苷酸连接子的配体-药物偶联物B(比较例2)的对于叶酸受体(folate receptor)的结合亲和力,以类似于[Analytical Biochemistry(2013),432,59–62]中记载的方法进行实验。
在KB人癌细胞系培养液中,使用Abcam公司的质膜蛋白提取试剂盒(plasmamembrane protein extraction kit)(ab65400)来分离可溶性质膜(soluble plasmamembrane)。在96孔板(96-well plate)的每孔(well)添加0.5μg的质膜蛋白(plasmamembrane protein),以0.0305–2000nM(4倍连续稀释)浓度处理用于比较(Competition)的叶酸(folic acid)和在所述比较例2中制备的配体-药物偶联物(B)和在所述实施例2中制备的配体-药物偶联物(1)。预培养(preincubation)15分钟后,以1nM浓度处理在所述制备例10中制备的FA-Cy5示踪物,在37℃反应2小时后,利用BioTek公司的synergy2微型读板器(microplate reader)(ex/em=635/688nm)测定偏光。在图6及表1中示出所述实验结果,导入键合力(binding affinity)(IC50)概念进行比较的配体-药物偶联物(1)比配体-药物偶联物(B)体现出优异2.5倍的亲和力。因此可以确认,引入半乳糖苷连接子的化合物(1)比引入葡糖苷酸连接子的化合物(B),对于叶酸受体的键合力更优异。
【表一】配体-药物偶联物对于叶酸受体的亲和力
【实验例4】配体-药物偶联物的体外细胞毒性(in vitro cytotoxicity)评价
将KB癌细胞系以每孔30000个接种(seeding)于96孔板中并培养24小时后,以0.0097~10nM(4倍连续稀释)浓度处理药物MMAF-OMe、并以0.0244–100nM(4倍连续稀释)浓度处理在所述比较例2中制备的配体-药物偶联物(B)和在实施例2制备的配体-药物偶联物(1)。72小时后,使用显色试剂3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT)染料后,将在活细胞中被氧化还原酶(oxidoreductase)还原的甲臜(formazan)溶解在DMSO中并定量。在图7和表2中示出所述实验结果,配体-药物偶联物(1)比(B)表现出优异约2倍的细胞毒性活性。可确认,引入半乳糖苷连接子的化合物(1)比引入葡糖苷酸连接子的化合物(B)功效更优异。
【表二】配体-药物偶联物的细胞毒性(Cell cytotoxicity)
【实验例5】蛋白质-药物偶联物(antibody-drug conjugates)的制备
将实施例15中获得的化合物17和实施例16中获得的化合物18,参照NatureBiotechnology,2008,26,925-932,Bioconjugate Chem.,2013,24,1256-1263,Bioconjugate Chem.,2016,27,1324-1331,Bioconjugate Chem.2014,25,460-469中公开的方法等,对在特定位置(例,抗体的重链heavy chain)121)被巯基置换的曲妥珠单抗(Herceptin)进行特异结合反应,分别制备thiomab药物偶联物(thiomab drug conjugate,TDC)Ab-17和Ab-18,并在图9中示出其结果。
本实验中使用的曲妥珠单抗(https://www.drugbank.ca/drugs/DB00072,购买处:(株)YBIOLOGICS)通过基因重组,将存在于抗体重链(heavy chain)的第121个的丙氨酸(Alanine)置换为半胱氨酸(Cysteine),以瞬时转染(transient transfection)在HEK293细胞中注入DNA,并纯化在培养液分泌的抗体而制得。
为了制备Ab-17和Ab-18,每1当量引入半胱氨酸并纯化的抗体中加入10至50当量的作为还原剂的三(2-羧乙基)膦(Tris(2-Carboxyethyl)Phosphine,TCEP),在37℃反应1小时,使引入的半胱氨酸的巯基还原后,使用PD-10脱盐柱(desailting column)(GEhealthcare,17-0851-01)除去剩余的TCEP,并在4℃下缓慢进行氧化反应3天,并将因TCEP处理而被部分还原的抗体中的二硫键恢复到原始状态。以2~10当量的量加入在实施例15中得到的化合物17和在实施例16中得到的化合物18,在常温下反应3小时后,再加入该化合物的100当量的NaBH4,在常温下反应1小时,还原化合物内的酮基,从而改善药物稳定性。反应后,使用PD-10除去剩余的化合物17、化合物18或NaBH4等,制备抗体药物复合物。此时,通过HPLC色谱分析法(HPLC chromatography)测量药物-抗体比(DAR:drug-antibodyratio)。
【实验例6】抗体-药物偶联物的体外细胞毒性(in vitro cytotoxicity)评价
将SKBR-3癌细胞系以每孔2000个~8000个细胞接种(seeding)于96孔板中并培养24小时。对在实验例6中获得的Ab-17和Ab-18进行50nM至0.0008nM的1/4连续稀释处理,并且对对照药物T-DM1(Roche CASNo.1018448-65-1)进行50nM至0.0008nM的1/4连续稀释处理。为了定量96小时后的活细胞,将MTT染料溶解在PBS缓冲液中,使得浓度达到5mg/mL,并以1/10添加到板的每个孔中。通过细胞中线粒体氧化还原酶(oxidoreductase)还原MTT染料形成的甲臜(formazan)溶于DMSO中,在550nm处测量吸光度后定量,结果如下表3所示。
【表三】抗体-药物杂合体的细胞毒性(Cell cytotoxicity)
抗体-药物杂合体 | DAR | <![CDATA[SKBR-3IC<sub>50</sub>(nM)]]> |
Ab-17 | 3.5 | 0.005 |
Ab-18 | 1.41 | 0.009 |
TDM-1 | 4.18 | 0.021 |
【实验例7】配体-药物偶联物(1)和(B)的酶切分析(enzymatic cleavage assay)评价
为确认实施例2的配体-药物偶联物(1)对于β-半乳糖苷酶(β-galactosidase)的反应性,与作为比较物质的比较例2的配体-药物偶联物(B)的对于β-葡糖苷酸酶的反应性的差异进行比较。
将实施例2的配体-药物偶联物(1)和比较例2的配体-药物偶联物(B)分别以9mM的浓度溶解在DMSO中并与PBS缓冲溶液混合,从而分别制备成500μM溶液。
将10μL的1mg/mL酶溶液加入到含有440μL PBS缓冲液和500μM实施例2的配体-药物偶联物(1)溶液的混合溶液中,制备实施例2的配体-药物偶联物(1)的酶反应溶液后,在37℃的恒温培养箱中开始反应。
将10μL的1mg/mL酶溶液加入到含有440μL PBS缓冲液和500μM比较例2的配体-药物偶联物(B)溶液的混合溶液中,制备比较例2的配体-药物偶联物(B)的酶反应溶液后,在37℃的恒温培养箱中开始反应。
包含实施例2的配体-药物偶联物(1)的反应混合物使用了大肠菌β-半乳糖苷酶(Sigma G4155),用于比较试验的包含比较例2的配体-药物偶联物(B)的反应混合物使用了大肠菌β-葡糖苷酸酶(Sigma G7396)。
在反应前0分钟,反应后30分钟、90分钟和270分钟分别取500μL酶反应溶液,通过HPLC定量分析剩余的配体-药物偶联物(1)或配体-药物偶联物(B)及以通过酶反应释放的MMAF。所述实验结果在图8中示出,测定出配体-药物偶联物(1)和比较化合物(B)的通过酶的水解半衰期分别为34.68分钟(配体-药物偶联物(1))、270分钟以上(配体-药物偶联物(B))。即,可以确认,引入半乳糖苷连接子的化合物(1)的水解速率比引入葡糖苷酸酶连接子的化合物(B)快6倍以上。
另外,就配体-药物偶联物(1)而言,可确认,通过β-半乳糖苷的酶作用,MMAF通过1,6-消除反应快速释放。
由此可知,本发明的与β-半乳糖苷(β-galactoside)结合的自我牺牲型连接基团的化合物比现有的结合有葡糖苷酸(glucuronide)的化合物,药物释放效果更优秀。
产业上的利用可能性
本发明的引入β-半乳糖苷的自我牺牲型连接基团与现有已知的连接子相比,制备方法简单,不会产生副反应,容易分离纯化。另外,对于水的亲水性良好,从而改善利用这一点制备的偶联物的物性。
另外,本发明的包含引入β-半乳糖苷的自我牺牲型连接基团的化合物的优点在于,通过包含对目标靶具有结合特异性的蛋白质(例:寡肽、多肽、抗体等)或配体、具有特异性功能或活性的活性剂(例:药物、毒素、配体、检测探针等)以及为了能够在靶细胞内选择性地释放活性剂而形成糖苷键(glycosidic bond)的自我牺牲型连接基团,利用在靶细胞过量表达的酶、β-半乳糖苷酶,能够选择性地释放活性剂。尤其,可以用于难以适用β-葡糖苷酸酶的药物等,因此能够广泛用于靶向治疗抗癌剂的开发。
Claims (11)
1.一种以下述化学式1表示的含有引入β-半乳糖苷的自我牺牲型连接基团(self-immolative linker)的化合物,
化学式1
在上述化学式1中,
R是氢或羟基保护基;
X是-C(=O)-;
Wa1是-NH-;
T是药物、毒素、亲和配体、检测探针或其组合;
n是0或1的整数;
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
z是1至3的整数,z是2以上的整数时,各Y彼此相同或不同;
z1是0或1的整数;
Wa2是-NH-、-C(=O)-或-CH2-;
Wa3及Wa4各自独立为-NH-、-C(=O)-、-CH2-、-C(=O)NH-、-NHC(=O)-或亚三唑基;
Wb1是酰胺键或亚三唑基;
L是如以下化学式A或化学式B表示的单元;
化学式A
化学式B
在所述化学式A及B中,
R11是氢、C1-C8烷基、-(CH2)s3COOR13、-(CH2)s3COR13、–(CH2)s3CON R14R15或–(CH2)s4NR14R15;
R13、R14及R15各自独立为氢或C1-C15烷基;
Z是单键、-Wa5-(CH2)a2-Wb2-(CH2)a3-Wa6-或–Wa7-(CH2)a4-CR’R”-X”-;
R’是C1-C8烷基或B-Wa8-Q3-Wc1-(CH2)a5-;
R”是B-Wa8-Q3-Wc1-(CH2)a5-;
Q1及Q3各自独立为–(CH2)a6-(X1CH2CH2)b1-(CH2)a7-;
X1及X3各自独立为-O-、-S-、-NH-或-CH2-;
X”是–NHC(=O)-(CH2)a8-Wa9-或–C(=O)NH-(CH2)a8-Wa9-;
Wa5、Wa6、Wa7、Wa8及Wa9各自独立为-NH-、-C(=O)-或-CH2-;
Wb2是酰胺键或亚三唑基;
Wc1是–NHC(=O)-或–C(=O)NH-;
Q2是具有碳原子为1-50的直链或支链的饱和或不饱和的亚烷基,满足下述(i)至(iii)中的至少一个;
(i)所述亚烷基中的至少一个-CH2-被选自-NH-、-C(=O)、-O-及-S-的一个以上的杂原子取代,
(ii)在所述亚烷基中至少包括一个亚芳基或亚杂芳基,
(iii)所述亚烷基进一步被选自由C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5构成的组中选择的一个以上取代;
所述(ii)的亚芳基或亚杂芳基任选地被硝基取代;
R3、R4及R5各自独立为氢或C1-C15烷基;
U1是选自下述结构的连接基团,B’键合到星号“*”位置,
在所述结构中,R是C1-C10烷基,C6-20芳基或C2-C20杂芳基;
B及B’各自独立为具有选择性靶向结合到特定器官、组织或细胞,即具有与受体结合的药物特性的配体或蛋白质;
a1、a2、a3、a4、a5、a6、a8、b1、p3及p4各自独立为1至10的整数;
a7、y、s1、s2、s3及s4各自独立为0至10的整数;
R1及R2各自独立为氢、C1-C8烷基或C3-C8环烷基。
3.根据权利要求1所述的化合物,其中,所述Q2选自下述化学式C至化学式I,
化学式C
化学式D
化学式E
化学式F
化学式G
化学式H
化学式I
在上述化学式C至化学式I中,
X11及X12各自独立为-O-、-S-、-NH-或-CH2-;
R12至R14各自独立为氢、C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5或–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
Ra是氢或硝基;
c1、c2、c3、c4及d1各自独立为1至10的整数;
q1及q2各自独立为0至5的整数;
s1及s2各自独立为0至5的整数。
4.根据权利要求1所述的化合物,其中,所述药物是细胞因子、免疫调节化合物、抗癌剂、抗病毒剂、抗菌剂、抗真菌剂、驱虫剂或其组合。
5.根据权利要求1所述的化合物,其中,所述配体选自肽、肿瘤细胞特异性适体、肿瘤细胞特异性碳水化合物、肿瘤细胞特异性单克隆或多克隆抗体、抗体片段构成的组。
6.根据权利要求1所述的化合物,其中,所述蛋白质是寡肽、多肽、抗体、抗原多肽片段或人工抗体。
7.根据权利要求6所述的化合物,其中,所述抗体选自由包括完整多克隆抗体、完整单克隆抗体、抗体片段、单链Fv(scFv)突变体、多特异性抗体、双抗体、嵌合抗体、人源化抗体、人抗体、包含抗体的抗原决定簇部分融合蛋白及包含抗原识别位点的修饰的免疫球蛋白分子构成的组。
8.根据权利要求7所述的化合物,其中,所述抗体选自由由莫罗莫那-CD3-阿昔单抗、利妥昔单抗、达克珠单抗、帕利珠单抗、英夫利昔单抗、曲妥珠单抗、依那西普、巴利昔单抗、吉妥单抗、阿仑单抗、替伊莫单抗、阿达木单抗、阿法赛特、奥马珠单抗、依法珠单抗、托西莫单抗-I131、西妥昔单抗、贝伐单抗、那他珠单抗、雷珠单抗、帕尼单抗、依库珠单抗、利洛纳塞、赛妥珠单抗、罗米司亭、罗米司亭AMG-531、戈利木单抗CNTO-148、优特克单抗CNTO-1275、布雷奴单抗ABT-874、贝拉西普LEA-29Y、贝利木单抗、跨膜激活剂及钙调亲环素配体相互作用因子-免疫球蛋白TAC I-Ig、第二代抗CD20、卡那奴单抗ACZ-885、托珠单抗、阿特利单抗、美泊利单抗、帕妥珠单抗、Humax CD20、曲美替尼、CTLA-4单抗、伊匹单抗MDX-010、加利昔单抗IDEC-114、伊曲木单抗奥佐米星、HuMax EGF R、阿帕西普、HuMax-CD4、Ala-Ala、奥昔组单抗ChAglyCD3、卡妥索单抗、阿德木单抗MT-201、奥戈伏单抗、地努妥昔单抗CH-14.18、吉利妥昔单抗WX-G250、地诺单抗AMG-162、巴匹组单抗AAB-001、莫维珠单抗、依福谷单抗、瑞西巴库、第三代抗-CD20、奥卡妥珠单抗LY2469298及维妥珠单抗构成的组。
9.根据权利要求1所述的化合物,其中,所述化合物选自下述结构,
在上述结构中,
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;z是1至3的整数,z是2以上的整数时,各Y彼此相同或不同;z1是0或1的整数;
W1选自下述结构:
W2选自下述结构:
X1、X11及X12各自独立为-O-、-S-、-NH-或-CH2-;
R11是氢、C1-C8烷基、-(CH2)s3COOR13、-(CH2)s3COR13、–(CH2)s3CON R14R15或–(CH2)s4NR14R15;
R13、R14及R15各自独立为氢或C1-C15烷基;
X3是-O-、-S-、-NH-或-CH2-;
R12至R14各自独立为氢、C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1COR3、–(CH2)s2CONR4R5或–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
Ra是氢或硝基;
R’是C1-C8烷基或B-NH-(CH2)a6-(X1CH2CH2)b1-NH-C(=O)-(CH2)a5-;
X”是–NHC(=O)-(CH2)a8-NH-或–C(=O)NH-(CH2)a8-NH-;
a1、a2、a3、a4、a5、a6、a8、b1、c1、c2、c3、c4、d1、p3及p4各自独立为1至10的整数;
q1及q2各自独立为0至5的整数;
s1、s2、s3及s4各自独立为0至5的整数;
B’是抗体;
B是从下述结构中选择的配体:
T是从下述结构中选择的药物:
w是1至10的整数。
10.一种以下述化学式2表示的化合物,
化学式2
在所述化学式2中,
R是氢或羟基保护基团;
X是-C(=O)-;
Wa1是-NH-;
T是药物、毒素、亲和配体、检测探针或其组合;
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
Wa2是-NH-、-C(=O)-或-CH2-;
Wa3及Wa4各自独立为-NH-、-C(=O)-、-CH2-、-C(=O)NH-、-NHC(=O)-或亚三唑基;
R21是C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1C OR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
s1及s2各自独立为0至10的整数;
a1各自独立为1至10的整数;
s4是0至10的整数;
p3及p4各自独立为1至10的整数;
FG是-NH2、-C≡CH、C4-C10环炔、–N3、-COOH、-SO3H、-OH、-NH OH、-NHNH2、-SH、卤代乙酰胺、马来酰亚胺、卤素、甲苯磺酸酯、醛、-C(=O)Rc、二烯、或-O P(=O)(OH)2,其中,所述Rc是C1-C10烷基、C6-C20芳基、C2-C20杂芳基;
X1及X3各自独立为-O-、-S-、-NH-或–CH2-;
a6及b1各自独立为1至10的整数;
a7是0至10的整数;
z是1至3的整数,z是2以上的整数时,各Y彼此相同或不同;
z1是0或1的整数;
z1是0或1的整数;
R1及R2各自独立为氢、C1-C8烷基或C3-C8环烷基。
11.根据权利要求10所述的化合物,其中,所述化合物由下述化学式3表示,
化学式3
在所述化学式3中,
Y是氢、卤代C1-C8烷基、卤素、氰基或硝基;
z是1至3的整数,z是2以上的整数时,各Y彼此相同或不同;
z1是0或1的整数;
R21是C1-C20烷基、C6-C20芳基C1-C8烷基、-(CH2)s1COOR3、-(CH2)s1C OR3、–(CH2)s2CONR4R5及–(CH2)s2NR4R5;
R3、R4及R5各自独立为氢或C1-C15烷基;
s1及s2各自独立为0至10的整数;
a1各自独立为1至10的整数;
s4是0至10的整数;
p3及p4各自独立为1至10的整数;
FG是-NH2、-C≡CH、C4-C10环炔、–N3、-COOH、-SO3H、-OH、-NH OH、-NHNH2、-SH、卤代乙酰胺、马来酰亚胺、卤素、甲苯磺酸酯、醛、-C(=O)Rc、二烯、或-O P(=O)(OH)2,其中,所述Rc是C1-C10烷基、C6-C20芳基、C2-C20杂芳基;
X1及X3各自独立为-O-、-S-、-NH-或–CH2-;
a6及b1各自独立为1至10的整数;
T是在下述结构中选择的药物:
w是1至10的整数。
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