CN117024438A - 依沙替康衍生物及其应用 - Google Patents
依沙替康衍生物及其应用 Download PDFInfo
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- CN117024438A CN117024438A CN202310723322.8A CN202310723322A CN117024438A CN 117024438 A CN117024438 A CN 117024438A CN 202310723322 A CN202310723322 A CN 202310723322A CN 117024438 A CN117024438 A CN 117024438A
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- compound
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- alkyl
- irinotecan
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- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 135
- -1 hydroxy, amino Chemical group 0.000 claims description 111
- 229960004768 irinotecan Drugs 0.000 claims description 41
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 28
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 20
- 239000000611 antibody drug conjugate Substances 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
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- 239000001257 hydrogen Substances 0.000 claims description 16
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 10
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- HXUVTXPOZRFMOY-NSHDSACASA-N 2-[[(2s)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-phenylpropanoyl]amino]acetic acid Chemical group NCC(=O)NCC(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 HXUVTXPOZRFMOY-NSHDSACASA-N 0.000 claims description 5
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- IKAIKUBBJHFNBZ-LURJTMIESA-N Gly-Lys Chemical group NCCCC[C@@H](C(O)=O)NC(=O)CN IKAIKUBBJHFNBZ-LURJTMIESA-N 0.000 claims description 3
- HSRXSKHRSXRCFC-WDSKDSINSA-N Val-Ala Chemical group CC(C)[C@H](N)C(=O)N[C@@H](C)C(O)=O HSRXSKHRSXRCFC-WDSKDSINSA-N 0.000 claims description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 claims 1
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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- C07B2200/07—Optical isomers
Abstract
本发明提供了一系结构新颖的依沙替康衍生物、其药学上可接受的盐、立体异构体或前药,及其在抗肿瘤领域的应用,所述依沙替康衍生物具有式(I)所示结构。
Description
技术领域
本发明涉及生物医药领域,具体涉及依沙替康衍生物及其应用。
背景技术
依沙替康(Exatecan)是一种全合成的天然产物喜树碱的衍生物,对拓扑异构酶Top1具有极强的抑制活性,能促进肿瘤细胞凋亡,具有广谱的抗肿瘤活性。依沙替康由于其毒副作用大限制了其本身在抗肿瘤药物领域的应用,以其羟基乙酰胺衍生物(Dxd)为毒素和曲妥珠(trastuzumab,Herceptin)形成的抗体偶联药物DS-8201a(antibody-drugconjugate,ADC)对Her2表达的肿瘤具有非常好的治疗效果。DS-8201a是一款性能优良的ADC抗肿瘤药物。除Herceptin外,针对其它抗原如B7-H3、Trop2等的ADC药物也正在被广泛研究。
本发明在保持依沙替康的药效骨架的基础上对依沙替康进行羟胺和肼的衍生,形成一系列具有偶联位点的依沙替康衍生物,这些化合物兼备高抗肿瘤活性、低毒副作用、易溶于水的特点,作为抗肿瘤单药或抗体偶联药物具有潜在的应用价值。
发明内容
本发明提供了一系结构新颖的依沙替康衍生物、其药学上可接受的盐、立体异构体或前药,及其在抗肿瘤领域的应用。
本发明的一方面,提供式(I)化合物或其药学上可接受的盐、立体异构体或前药:
式中,
R选自-Z-R1,其中,Z为单键或C=O;
R1选自-(CH2)nNRaRb、-CH2ORa、-NORa、-(CH2)nONRaRb或-R3;n选自0、1、2或3;
Ra、Rb各自独立地选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基、氨基C1-C6烷基或C1-C6烷氧基;
R3选自3至6元环烷基或含N、O、或S杂原子的3至6元杂环烷基,R3任选地进一步地被Rc取代;
Rc选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基;
条件是,-Z-R1不为-NH2、-CH2OH、-CH2NH2或-CH2OCH2NH2。
在一实施方案中,R1不为-CH2ONH2或羟基氧杂环丁烷基。
在一实施方案中,R1选自-NRaRb、-CH2NRaRb、-CH2ORa、-NORa、-(CH2)nONRaRb或-R3。
优选地,R1选自-NRaRb、-C(O)NRaRb、-CH2NRaRb、-CH2ONRaRb或-R3。
在一实施方案中,Ra、Rb各自独立地选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基。
优选地,Ra、Rb各自独立地选自氢、羟基、氨基、甲基、甲氨基或甲氧基。
在一实施方案中,R3选自含N、O、或S杂原子的3至6元杂环烷基,R3任选地进一步地被Rc取代;所述Rc选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基。
在一实施方案中,R1选自-NHNH2、-N(CH3)NH2、-N(CH3)NHCH3、-C(O)NHNH2、-C(O)N(CH3)NH2、-CH2NHOH、-CH2NHOCH3、-CH2ONH2、-CH2ONHCH3、-CH2NCH3NH2、-CH2N(CH3)NHCH3、-CH2N(CH3)OH、-CH2NHOCH2CH3、羟基氧杂环丁烷基氨基氧杂环丁烷基/>
在一实施方案中,R1选自-NHNH2、-N(CH3)NH2、-N(CH3)NHCH3、-C(O)NHNH2、-C(O)N(CH3)NH2、-CH2NHOH、-CH2NHOCH3、-CH2ONHCH3、-CH2NCH3NH2、-CH2N(CH3)NHCH3、-CH2N(CH3)OH、-CH2NHOCH2CH3、氨基氧杂环丁烷基
在一实施方案中,所述式(I)化合物为式(Ia)化合物:
式中,R1定义同式(I)化合物。
优选地,R1为-NHNH2或-N(CH3)NH2。
在一实施方案中,所述式(I)化合物为式(Ib)化合物:
式中,R2选自-NHOH、-ONH2、-NHO(C1-C3烷基)、-ONH(C1-C3烷基)、-N(C1-C3烷氨基)、-N(C1-C3烷基)NH(C1-C3烷基)、-N(C1-C3烷基)OH或-NHO(C1-C3烷基)。
优选地,R2选自-NHOH、-NHOCH3、ONH2、-ONHCH3、-NCH3NH2、-N(CH3)NHCH3、-N(CH3)OH或-NHOCH2CH3。
在一实施方案中,R2选自-NHOH、-NHO(C1-C3烷基)、-ONH(C1-C3烷基)、-N(C1-C3烷氨基)、-N(C1-C3烷基)NH(C1-C3烷基)、-N(C1-C3烷基)OH或-NHO(C1-C3烷基)。
优选地,R2选自-NHOH、-NHOCH3、-ONHCH3、-NCH3NH2、-N(CH3)NHCH3、-N(CH3)OH或-NHOCH2CH3。
在一实施方案中,所述式(I)化合物为式(Ic)化合物:
式中,Ra、Rb定义同式(I)化合物;条件是,Ra、Rb不同时为H。
优选地,Ra、Rb各自独立地选自氢、氨基、C1-C3烷基、C1-C3烷氨基。
优选地,-NRaRb选自-NHNH2、-N(CH3)NH2或-N(CH3)NHCH3。
在一实施方案中,所述式(I)化合物为式(Id)化合物:
式中,X为CH2、NH、O或S。
优选地,X为CH2或O;更优选地,X为O。
在一实施方案中,Rc选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基。
优选地,Rc选自羟基或氨基,更优选为氨基。
在一实施方案中,所述式(I)化合物选自以下化合物:
值得注意的是,R1为-CH2ONH2时,其与化合物8(R1为-CH2ONHCH3)对OE33细胞生长抑制的IC50值虽然均低于10nM,但化合物8的IC50值仍显著低于R1为-CH2ONH2时得到的依沙替康衍生物化合物。
本发明的另一方面,提供上述任一项所述化合物的制备方法,其选自以下反应路线:
反应路线1:
将依沙替康和N,N'-羰基二咪唑反应,再和肼或取代的肼反应得到相应的N-氨基脲依沙替康衍生物。
例如,
反应路线2:
将取代的肼和草酰氯反应,再和依沙替康反应,得到相应的草酰胺肼依沙替康衍生物。
例如,
反应路线3:
依沙替康和溴乙酸反应得到溴乙酰基依沙替康,溴乙酰基依沙替康和胺类化合物进行缩合得到相应的酰胺依沙替康衍生物。
例如,
反应路线4:
依沙替康和羧酸类化合物直接反应得到相应的酰胺依沙替康衍生物。
例如,
式中,R、L定义同式(I)化合物。
本发明的再一方面,提供一种式(II)所示的药物-连接子化合物或其药学上可接受的盐、立体异构体或前药:
式中,R定义同式(I)化合物。
在一实施方案中,L为-L1-Q-L2;R与L1部分相连。
其中,L1选自其中,/>所示位置表示与R基团相连,/>所示位置表示与Q基团相连。
在一实施方案中,L2选自
在一实施方案中,Q选自Val-Cit、Val-Ala、Ala-Ala-Asn、Gly-Gly-Phe-Gly、Gly-Lys、Gly-Gly-lys、(CH2)m1O(CH2)m2、(CH2)m3,其中,m1和m2各自独立地选自1-4的整数。
优选地,m1为2。
优选地,m2为2。
优选地,m3为6。
在一实施方案中,Q选自Val-Cit、Gly-Gly-Phe-Gly、(CH2)2O(CH2)2、或(CH2)6;
优选地,L1为优选地,L2为/>本发明的再一方面,提供一种式(III)所示的药物-抗体偶联化合物或其药学上可接受的盐:
式中,R定义同式(I)或化合物,L定义同式(II)或化合物。
Ab为肿瘤相关抗原抗体,n选自1-8的整数。
优选地,所述肿瘤相关抗原选自Her2、Trop2、5T4、ROR1或B7-H3。
优选地,Ab为帕妥珠单抗(Pertuzumab)。
在一实施方案中,所述式(III)药物-抗体偶联化合物选自以下化合物:
优选地,所述式(II)药物-抗体偶联化合物选自以下化合物:
本发明的再一方面,提供一种药物组合物,其包括上述化合物、药物-连接子化合物或其药学上可接受的盐、立体异构体、前药或抗体药物偶联物。
所述药物组合物进一步还包括药学上可接受的辅料。
本发明的再一方面,提供一种上述化合物、药物-连接子化合物或其药学上可接受的盐、立体异构体、前药或抗体药物偶联物、药物组合物在制备用于治疗癌症的药物中的应用。
优选地,所述癌症包括胃癌、食管癌、乳腺癌和肺腺癌。
本发明的另一方面,提供一种治疗癌症的方法,其包括向有需要的患者施用上述化合物或其药学上可接受的盐、立体异构体、前药、抗体药物偶联物或药物组合物的步骤。
在一实施方案中,上述化合物或其药学上可接受的盐、立体异构体、前药、抗体药物偶联物或药物组合物的施用量为治疗有效量。
具体实施方式
1·定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文使用的和除非另作说明,术语“包含”,“包括”,“具有”,“含有”,包括其语法上的等同形式,通常应当理解为开放式且非限制性的,例如,不排除其他未列举的要素或步骤。
本公开化合物可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。所述的立体异构体包括几何异构(如顺式、反式结构)和光学异构(如对映异构体),以单体、消旋体、外消旋混合物及其药学上可接受的盐组成的治疗物。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。外消旋体、非对映异构体、对映异构体都包括在本公开的范围之内。
本公开化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
如本文所用,“药学上可接受的盐”是指相应的胺类化合物和无机酸或有机酸形成的盐,或相应的羧酸类化合物和碱金属或碱土金属形成的盐或和有机胺形成的盐。其中,无机酸包括但不限于盐酸,氢溴酸,氢碘酸,硫酸,磷酸等;有机酸包括但不限于乙酸,丙酸,丁酸,苯甲酸,甲磺酸,苯磺酸,对甲苯磺酸,草酸,丁二酸,乳酸,柠檬酸,琥珀酸,葡萄糖酸,马来酸,延胡索酸,酒石酸等;碱金属或碱土金属盐包括但不限于钠、钾、钙、镁盐等;有机胺盐包括但不限于氨、甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、三甲胺、三乙胺、叔丁胺、乙二胺、乙醇胺、二乙醇胺、三乙醇胺、吗啉、哌啶、哌嗪、氨基酸等组成的盐。
如本文所用,“前体”是指化合物以适当的给药方式进入人体后,前体化合物在病人体内进行代谢或简单的化学变化而转变成本发明通式1中所包含的化合物以及相应的盐的形式。化合物的前体包括但不限于各种羧酸酯、碳酸酯、磷酸酯、硫酸酯、磺酸酯、氨基酸酯、葡萄糖酸酯以及各种酰胺、缩醛、半缩醛、碳酸酰胺酯等形式。
本文中的数字范围,是指给定范围中的各个整数。例如,“C1-C6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子;“C3-C6”是指该基团可具有3个碳原子、4个碳原子、5个碳原子或6个碳原子。
当任何变量(例如Rn)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被1-5个R所取代,则所述基团可以任选地至多被5个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至8个碳原子的烷基,更优选1至6个碳原子的烷基,最优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2_二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、2,2-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基,本公开优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1-4个是杂原子;更优选包含3至8个环原子;最优选包含3至8个环原子;进一步优选包含1-3氮原子的3-8元杂环基,任选地,被1-2个氧原子、硫原子、氧代基取代,包括含氮单环杂环基、含氮螺杂环基或含氮稠杂环基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至12元,例如苯基和萘基。
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、琉基、氢基,硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、氢基、硝基、氯基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
本公开所述的氢原子均可被其同位素氘所取代。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
是指化学键连接处。
药物或药物组合物
如本文所用,“药学上可接受的盐”是指相应的胺类化合物和无机酸或有机酸形成的盐,或相应的羧酸类化合物和碱金属或碱土金属形成的盐或和有机胺形成的盐。其中,无机酸包括但不限于盐酸,氢溴酸,氢碘酸,硫酸,磷酸等;有机酸包括但不限于乙酸,丙酸,丁酸,苯甲酸,甲磺酸,苯磺酸,对甲苯磺酸,草酸,丁二酸,乳酸,柠檬酸,琥珀酸,葡萄糖酸,马来酸,延胡索酸,酒石酸等;碱金属或碱土金属盐包括但不限于钠、钾、钙、镁盐等;有机胺盐包括但不限于氨、甲胺、乙胺、丙胺、异丙胺、二甲胺、二乙胺、三甲胺、三乙胺、叔丁胺、乙二胺、乙醇胺、二乙醇胺、三乙醇胺、吗啉、哌啶、哌嗪、氨基酸等组成的盐。
如本文所用,“前体”是指化合物以适当的给药方式进入人体后,前体化合物在病人体内进行代谢或简单的化学变化而转变成本发明通式1中所包含的化合物以及相应的盐的形式。化合物的前体包括但不限于各种羧酸酯、碳酸酯、磷酸酯、硫酸酯、磺酸酯、氨基酸酯、葡萄糖酸酯以及各种酰胺、缩醛、半缩醛、碳酸酰胺酯等形式。
本公开的药物或药物组合物可以经口地、局部地、肠胃外地或粘膜地(例如,含服地、通过吸入或直肠地)以包含常规的非-毒性药学可接受的载体的剂量单位配制剂施用。通常希望使用口服途径。所述活性试剂可以经口地以胶囊、片剂等形式(参见Remington:The Science and Practice of Pharmacy,20th Edition)施用。
对于以片剂或胶囊形式的口服给药,活性药物组分可以与非-毒性的、药学可接受的辅料如粘结剂(例如,预胶化的玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填料(例如,乳糖、蔗糖、葡萄糖、甘露糖醇、山梨糖醇和其它还原性和非-还原性糖类、微晶纤维素、硫酸钙或磷酸氢钙);润滑剂(例如,硬脂酸镁、滑石粉或硅土、硬脂酸、硬脂基富马酸酯钠、甘油二十二烷酸酯、硬脂酸钙等);崩解剂(例如,马铃薯淀粉或羟乙酸淀粉钠);或润湿剂(例如,月桂基硫酸钠)、着色剂和调味剂、明胶、甜味剂、天然和合成的胶(如阿拉伯胶、黄蓍胶或藻朊酸盐)、缓冲盐、羧甲纤维素、聚乙二醇、蜡、等。对于以液体形式的口服给药,所述药物组分可以与非-毒性、药学可接受的惰性载体(例如,乙醇、甘油、水)、防沉降剂(例如,山梨糖醇糖浆、纤维素衍生物或氢化的可食用脂肪)、乳化剂(例如,卵磷脂或阿拉伯胶)、非-水性载体(例如,扁桃油、油酯类、乙醇或经分馏的植物油)、保藏剂(例如,p-羟基苯甲酸甲酯或p-羟基苯甲酸丙酯或山梨酸)等组合。还可以加入稳定剂如抗氧化剂(BHA、BHT、桔酸丙酯、抗坏血酸钠、柠檬酸)以稳定所述剂型。
包含作为活性化合物的片剂可以通过本领域熟知的方法包衣。包含作为活性化合物的式I化合物的本公开的所述组合物还可以引入小珠、微球或微胶囊,例如由聚乙醇酸/乳酸(PGLA)构建的。用于口服给药的液体的制剂可以采取例如溶液,糖浆剂,乳液或混悬液的形式或者它们可以呈现为在使用前用水或其它适宜的辅料重构的干产品。用于口服给药的制剂可以适宜地配制以使活性化合物受控或延迟地释放。
术语“治疗”包括抑制、缓解、预防或消除与所治疗的疾病、病症或失调相关的一种或多种症状或副作用。
术语“抑制”的使用是相对于对照的。本领域技术人员将容易地确定用于每个实验的适当对照。例如,将用化合物处理的受试者或细胞中的降低了的反应与未用化合物处理的受试者或细胞中的反应进行比较。
术语“药物组合物”意指包含本公开所述化合物或其药学上可接受的盐,以及依施用方式和剂型的性质而定的至少一种选自以下药学上可接受的成分的组合物,包括但不限于:载体、稀释剂、佐剂、赋形剂、防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂、香味剂、抗菌剂、抗真菌剂、润滑剂、分散剂、温敏材料、温度调节剂、黏附剂、稳定剂、助悬剂等。
术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中,在根据本发明对患者进行治疗时,给定药物的量取决于诸多因素,如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重),但是,根据特定的周围情况,包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主,施用剂量可由本领域已知的方法常规决定。通常,就成人治疗使用的剂量而言,施用剂量典型地在0.02-5000mg/天,例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量,例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是,尽管给出了上述剂量范围,但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
术语“抗体药物偶联物(antibody-drug conjugate,ADC)”抗体药物偶联物是通过一个化学链接将具有生物活性的小分子药物连接到单抗上,单抗作为载体将小分子药物靶向运输到目标细胞中。
如本文所用,术语“减少”、“抑制”、“减轻”或“减小”的使用是相对于对照的。本领域技术人员将容易地确定用于每个实验的适当对照。例如,将用化合物处理的受试者或细胞中的降低了的反应与未用化合物处理的受试者或细胞中的反应进行比较。
如无特别说明,本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
缩写
CDI:N,N′-羰基二咪唑;EA:乙酸乙酯;DCM:二氯甲烷;HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯;DIPEA:N,N-二异丙基乙胺;NMP:N-甲基吡咯烷酮;HOBt:1-羟基苯并三唑;
Val:缬氨酸,其结构式为Cit:瓜氨酸,其结构式为/>Gly:甘氨酸,其结构式为/>Phe:苯丙氨酸,其结构式为/>Fmoc:苏氨酸磷酸苄酯,其结构式为/>Val-Cit:/>Gly-Gly-Phe-Gly:
Val-Ala、Ala-Ala-Asn、Gly-Lys、Gly-Gly-lys等连接链的连接方式可采用本领公知的氨基酸缩合方法。
-Pab-:-ha-:/>mc-:/>ba-:/>bp-:
II.具体实施例
本实施例中制备ADC使用但不限于帕妥珠单抗(PERTUZUMAB),其重链氨基酸序列如下(SEQ ID NO:1):
轻链氨基酸序列如下(SEQ ID NO:2):
实施例1:依沙替康-N-氨基脲(1)
在1ml的DMF中,加入依沙替康甲磺酸盐(30mg,56.44μmol)和三乙胺(11.42mg,112.88μmol),搅拌均匀后,加入CDI(9.15mg,56.44μmol),在氩气保护下,室温反应1h,依次加入三乙胺(80mg)和盐酸肼(19.33mg,0.28mmol),室温搅拌反应10h,加入50ml的EA,饱和食盐水洗涤,萃取、分相,无水硫酸钠干燥,硅胶柱层析分离纯化,得到化合物1(25mg,产率90%);1H NMR(500MHz,DMSO-d6)δ7.77(d,J=10.9Hz,1H),7.54(s,1H),7.30(s,1H),6.52(m,1H),5.41(m,2H),5.39-5.33(m,1H),5.22(m,J=7.0Hz,2H),3.15(m,J=13.6,6.9Hz,2H),3.06(s,2H),2.38(s,3H),2.24-2.11(m,2H),1.86(m,J=21.4,7.0Hz,2H),0.87(t,J=7.3Hz,3H);LCMS:(M+1)+493.98(计算值:493.18)。
实施例2:依沙替康-N-甲基-N-氨基脲0
在1ml的DMF中,加入依沙替康甲磺酸盐(30mg,56.44μmol)和三乙胺(11.42mg,112.88μmol),搅拌均匀后,加入CDI(9.15mg,56.44μmol),在氩气保护下,室温反应1h,依次加入三乙胺(80mg)和1-Boc-2-甲基肼(45.05mg,0.3mmol),室温搅拌反应10h,加入50ml的EA,饱和食盐水洗涤,萃取、分相,无水硫酸钠干燥,硅胶柱层析分离纯化得到化合物Boc-产物,将Boc-产物溶于1ml DCM中,加入0.5ml 4M盐酸的乙酸乙酯溶液,室温搅拌反应30min,得到化合物2(22mg,产率80%);1H NMR(500MHz,DMSO-d6)δ7.81(d,J=10.9Hz,1H),7.32(s,1H),6.54(s,1H),5.43(m,J=18Hz,3H),5.29(d,J=4.1Hz,2H),3.29(s,3H)3.17(t,J=6.4Hz,2H),2.41(d,J=1.7Hz,3H),2.20(m,J=13.0,6.9Hz,2H),1.86(m,J=20.7,13.7,6.8Hz,2H),0.87(t,J=7.3Hz,3H);LCMS:(M+1)+508.02(计算值:507.19)。
实施例3:依沙替康-N',N-二甲氨基脲(3)
在1ml的DMF中,加入依沙替康甲磺酸盐(30mg,56.44μmol)和三乙胺(11.42mg,112.88μmol),搅拌均匀后,加入CDI(9.15mg,56.44μmol),在氩气保护下,室温反应1h,依次加入TEA(80mg)和N’N-二甲基肼盐酸盐(45.05mg,
0.33mmol),室温下搅拌反应10h,加入50ml的EA,饱和食盐水洗涤,分相,无水硫酸钠干燥,硅胶柱层析分离纯化,得到化合物3(18mg,产率62%;1H NMR(500MHz,DMSO-d6)δ7.76(d,J=10.9Hz,1H),7.48(d,J=9.2Hz,1H),7.30(s,1H),6.51(s,1H),5.41(s,2H),5.31(dd,J=17.0,8.5Hz,2H),5.16(s,1H),4.64(q,J=5.7Hz,2H),3.09(dt,J=16.8,7.8Hz,2H),3.01(s,3H),2.38(s,3H),2.18(t,J=7.2Hz,3H),1.86(dq,J=19.3,7.1Hz,2H),1.47(s,1H),0.86(d,J=8.2Hz,3H);LCMS:(M+1)+522.02(计算值:521.21)。
实施例4:依沙替康-N'-氨基草豌二胺(4)
在30ml的DCM中,加入Boc-肼(5.93g,44.90mmol),TEA(6.2g,61.21mmol),搅拌溶清后,0℃下滴加草酰氯甲酯(5g,40.81mmol)的DCM溶液(50ml),室温下搅拌反应1h,饱和食盐水洗涤(20ml*3),无水硫酸钠干燥,浓缩得到化合物4-a N’-Boc-N-草酰肼单甲酯(7.1g,产率79%);LCMS:(M+1)+219.01(计算值:218.21)。
将化合物4-a(7.1g,32.56mmol)溶于70ml的乙醇中,然后滴加1M的LiOH水溶液32.53ml,室温搅拌过夜,然后滴加0.5M HCl水溶液调节反应液pH至5,减压去除水分和乙醇,浓缩液中加入5ml的甲醇和15ml DCM,搅拌1h,过滤,滤液浓缩得到化合物4-b N’-Boc-N-草酰肼(6g,产率89%),LCMS:(M+1)+205.2(计算值:204.18)。
在2ml的DMF中,依次加入依沙替康甲磺酸盐(200mg,0.37mmol),二异丙基乙胺(6.15mg,0.047mmol),N’-Boc-N-草酰肼(164mg,0.8mmol),HATU(286mg,0.75mmol),室温搅拌反应4小时,减压除去DMF,浓缩液加入到20ml的DCM,硅胶柱层析纯化得到化合物4-c依沙替康-N’-Boc-氨基草酰二胺(180mg,产率77%),LCMS:(M+1)+622.1(计算值:621.22)。
将依沙替康-N’-Boc-氨基草酰二胺(180mg,0.29mmol)溶于2ml DCM中,加入1ml4M盐酸的乙酸乙酯溶液,室温搅拌反应30min,浓缩得到化合物4即依沙替康-N’-氨基草酰二胺(162mg,100%);1H NMR(500MHz,DMSO-d6)δ9.54(d,J=8.9Hz,1H),7.77(m,J=11.3,4.1Hz,1H),7.30(s,1H),6.52(s,1H),5.53(m,J=8.3,5.0Hz,1H),5.39(s,2H),5.12(d,J=4.0Hz,2H),3.23(s,1H),2.38(s,3H),2.28-2.15(m,2H),1.85(m,J=25.0,7.2Hz,2H),0.86(t,J=7.4Hz,3H);LCMS:(M+1)+522.00(计算值:521.17)。
实施例5:依沙替康N’-氨基-N-甲基草酰二胺(5)
在20ml的DCM中,加入1-甲基-2-Boc肼(2.4g,26mmol),TEA(1.65g,16.3mmol),搅拌溶清后,0℃下滴加草酰氯甲酯(2g,16.3mmol)的DCM溶液(20ml),室温下搅拌反应1h,萃取,饱和食盐水洗涤(10ml*3),无水硫酸钠干燥,浓缩后得到中间体化合物5-a1-甲基-2-Boc-草酰肼单甲酯(3.5g,产率92%),LCMS:(M+1)+233.10(计算值:232.24)。
将化合物5-a(3.5g,15mmol)溶于40ml的乙醇中,滴加1M的LiOH水溶液16.37ml,室温搅拌过夜,然后滴加0.5M HCl水溶液调节反应液pH至5,减压除水分和乙醇,浓缩液中加入2ml的甲醇和8ml DCM,搅拌1h,过滤,滤液浓缩得到中间体化合物5-b 1-甲基-2-Boc-草酰肼(3.21g,产率90%),LCMS:(M+1)+219.01(计算值:218.21)。
在2ml的DMF中,依次加入依沙替康甲磺酸盐(100mg,0.19mmol),DIPEA(48.58mg,0.37mmol),化合物5-b(82mg,0.37mol),HATU(118mg,0.32mmol),室温搅拌反应4小时,减压除去DMF,硅胶纸层析分离纯化得到中间体化合物5-c依沙替康N’-Boc氨基-N-甲基草酰二胺(91mg,收率75%),LCMS:(M+1)+636.14(计算值:635.65)。
将化合物5-c(91mg,0.14mmol)溶于2ml DCM中,加入1ml 4M盐酸的乙酸乙酯溶液,室温搅拌反应30min,浓缩得到化合物5即依沙替康N’-氨基-N-甲基草酰二胺(85mg,收率100%);1H NMR(500MHz,DMSO-d6)δ8.87(d,J=8.7Hz,1H),7.79(d,J=10.9Hz,1H),7.31(s,1H),5.59-5.62(m,J=18Hz,1H),5.46-5.32(m,J=84Hz,4H),3.16-3.10(m,2H),2.95(s,2H),2.40(s,3H),2.17(ddq,J=28.2,14.0,5.5,4.9Hz,2H),1.86(dp,J=20.9,7.0Hz,2H),0.86(t,J=7.4Hz,3H);LCMS:(M+1)+536.03(计算值:535.53)。
实施例6:2-羟氨基乙酰依沙替康(6)
在1ml的DMF中,加入依沙替康甲磺酸盐(100mg,0.19mmol),TEA(25mg,0.24mmol),搅拌溶清后加入溴乙酸(40mg,0.28mmol),HATU(85mg,0.22mmol),室温搅拌反应1h,减压去除DMF,硅胶柱层析分离纯化得到中间体6-a依沙替康-N-溴乙酰胺(90mg,产率86%),LCMS:(M+1)+557.1(计算值:556.39)。
在10ml的瓶子里,加入1ml的DMF,然后依次加入盐酸羟胺(113mg,1.63mmol),TEA(164mg,1.62mmol),化合物6-a(90mg,0.16mmol),室温搅拌反应1h,减压除去DMF,硅胶柱层析分离纯化得到化合物6即2-羟氨基乙酰依沙替康(90mg,产率86%);1H NMR(500MHz,DMSO-d6)δ10.86-10.38(m,1H),8.96(d,J=8.7Hz,1H),7.82(t,J=11.9Hz,1H),7.32(s,1H),6.55(s,1H),5.77-5.54(m,1H),5.41(d,J=10.6Hz,2H),5.37-5.16(m,2H),3.86(m,J=11.7,8.0Hz,2H),3.31-3.02(m,3H),2.40(d,J=14.0Hz,3H),2.29-2.07(m,2H),1.86(m,J=21.6,7.2Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+1)+509.3(计算值:508.18)。
实施例7:2-甲氧氨基乙酰依沙替康(7)
在10ml的瓶子里,加入1ml的DMF,然后依次加入盐酸甲氧基胺(126mg,1.5mmol),TEA(182mg,1.79mmol),化合物6-a(100mg,0.18mmol),室温搅拌反应1h,减压去除DMF,硅胶柱层析分离纯化得到化合物7即2-甲氧氨基乙酰依沙替康(80mg,产率86%);1H NMR(500MHz,DMSO-d6)δ8.50-8.46(m,1H),7.80(d,J=10.8Hz,1H),7.30(d,J=1.9Hz,1H),6.83(td,J=6.2,1.8Hz,1H),6.52(d,J=1.9Hz,1H),5.61-5.55(m,1H),5.42(s,2H),5.22(s,2H),4.01-3.87(m,1H),3.42(d,J=6.1Hz,3H),3.17(t,J=6.4Hz,2H),2.40(s,3H),2.22-2.11(m,2H),1.86(dp,J=21.1,7.1Hz,2H),0.90-0.83(m,3H);LCMS:(M+1)+523.20(计算值:522.19)。
实施例8:2-甲氨氧基乙酰依沙替康(8)
在40ml的水和40ml THF的混合液中,加入N-甲基羟胺盐酸盐(10g,119.7mmol),搅拌溶清,加入碳酸钾(8.27g,60mmol),缓慢滴加Boc酸酐(28.75g,131.7mmol)的50ml THF溶液,滴毕,室温搅拌过夜,减压去除THF,用DCM(100ml*3)萃取,无水硫酸钠干燥,浓缩得到化合物8-a N-Boc-N-甲基羟胺(15g,收率88%),LCMS:(M+1)+148.01(计算值:147.17)。
将化合物8-a(15g,101.9mmol)溶解在100ml异丙醇中,加入溴乙酸甲酯(18.58g,121.4mmol)和DIPEA(15.7g,121.7mmol)氩气保护下升温至85℃反应3h,浓缩反应液,100mlEA溶解,饱和食盐水洗涤(30ml*3),无水硫酸钠干燥,浓缩得到化合物8-b N-Boc-N-甲基胺氧基乙酸甲酯(18g,产率81.8%),LCMS:(M+1)+220.21(计算值:219.24)。
在180ml甲醇中溶解化合物8-b(18g,82mmol),加入82.2ml的1M氢氧化锂水溶液,室温搅拌反应,反应完,浓缩反应液,去除甲醇,加入0.5mmol/L的盐酸水溶液调节酸性至pH=3左右,EA萃取,分相,干燥,过滤,浓缩得到化合物8-c N-Boc-N-甲基胺氧基乙酸(13.1g,产率77.3%),LCMS:(M+1)+206.01(计算值:205.21)。
在2ml的DMF中,依次加入依沙替康甲磺酸盐(100mg,0.19mmol),DIPEA(48.58mg,0.37mmol)化合物8-c(77.3mg,0.37mmol),HATU(118mg,0.31mmol),室温搅拌反应6小时,减压除去DMF,硅胶柱层析分离纯化得到化合物8-d N-Boc-N-甲氨氧基乙酰依沙替康(68mg,产率75%),LCMS:(M+1)+623.30(计算值:622.65)。
将化合物8-d(68mg,0.109mmol)溶于2ml DCM中,加入1ml 4M盐酸的乙酸乙酯溶液,室温搅拌反应30min,浓缩得到化合物8即2-甲氨氧基乙酰依沙替康盐酸盐(61mg,产率100%);1H NMR(500MHz,DMSO-d6)δ8.93(d,J=8.5Hz,1H),7.79(d,J=10.5Hz,1H),7.30(s,1H),5.60(dt,J=8.3,4.1Hz,1H),5.42(s,2H),5.29(s,2H),4.73-4.64(m,2H),3.18(s,2H),2.85(s,3H),2.39(s,3H),2.25(dt,J=8.8,4.6Hz,1H),2.19-2.10(m,1H),1.85(dp,J=21.4,7.2Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+1)+523.10(计算值:522.19)。
实施例9:2-N-甲基-N-氨基乙豌依沙替康(9)
在10ml的瓶子里,加入1ml的DMF,然后依次加入1-甲基-2-Boc肼(36.41mg,0.25mmol)TEA(54.6mg,0.54mmol),6-a(100mg,0.18mmol),室温搅拌反应1h,减压去除DMF,硅胶柱层析分离纯化得到化合物9-a2-N-甲基-N-Boc氨基乙酰依沙替康(72mg,产率63%);LCMS:(M+1)+622.30(计算值:621.21)。
将化合物9-a(72mg,0.115mmol)溶于2ml DCM中,加入1ml 4M盐酸的乙酸乙酯溶液,室温搅拌反应30min,得到9即2-N-甲基-N-氨基乙酰依沙替康(64mg,产率100%);1HNMR(500MHz,DMSO-d6)δ8.53(d,J=8.9Hz,1H),8.33(s,1H),7.79(d,J=10.9Hz,1H),7.32-7.27(m,1H),6.53(d,J=1.6Hz,1H),5.60(dt,J=9.3,5.1Hz,1H),5.41(s,2H),5.29-5.15(m,2H),3.42-3.40(m,2H),3.38-3.37(m,2H),3.37(s,3H),3.19(d,J=5.6Hz,1H),2.39(s,3H),2.15(q,J=6.0Hz,2H),1.85(dp,J=21.7,7.0Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+H)+522.1(计算值:521.18)。
实施例10:2-N-甲基-N-甲氨基乙酰依沙替康(10)
在10ml的瓶子里,加入1ml的DMF,然后依次加入1,2-二甲基-二盐酸肼(71.72mg,0.54mmol),TEA(91mg,0.89mmol),6-a(100mg,0.18mmol),室温搅拌反应1h,反应完,减压去除DMF,硅胶柱层析分离纯化得到化合物10即2-N-甲基-N-甲氨基乙酰依沙替康(85mg,产率88%);1H NMR(500MHz,DMSO-d6)δ10.05(s,1H),8.85(d,J=9.1Hz,1H),7.81(m J=19.4,10.9Hz,1H),7.32(d,J=11.1Hz,1H),6.54(s,1H),5.66-5.51(m,1H),5.49-5.38(m,2H),5.35-5.17(m,2H),3.73-3.55(m,1H),3.19(m,J=19.8,15.3,9.5Hz,3H),2.73(s,3H),2.41(d,J=9.0Hz,3H),2.19(m,J=31.1,13.1,5.4Hz,2H),1.86(m,J=21.7,14.7,7.5Hz,2H),0.87(t,J=7.3Hz,3H);LCMS:(M+1)+536.20(计算值:535.22)。
实施例11:2-N-甲基羟氨基乙豌依沙替康(11)
在10ml的瓶子里,加入1ml的DMF,然后依次加入氮甲基羟胺盐酸盐(30mg,0.36mmol),TEA(58mg,0.57mmol),化合物6-a(100mg,0.18mmol),室温搅拌反应1h,减压去除DMF,硅胶柱层析分离纯化得到化合物11即2-N-甲基羟氨基乙酰依沙替康(70mg,产率75%);1H NMR(500MHz,DMSO-d6)δ8.44(d,J=12.4Hz,1H),7.79(t,J=10.7Hz,1H),7.30(d,J=4.9Hz,1H),6.63-6.41(m,1H),5.59(m,J=8.6,5.0Hz,1H),5.41(d,J=3.0Hz,2H),5.32-5.12(m,2H),3.17(m,J=5.3Hz,2H),2.73(d,J=6.7Hz,3H),2.39(d,J=6.0Hz,3H),2.24-2.08(m,2H),1.85(m,J=21.3,7.1Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+H)+523.20(计算值:522.19)。
实施例12:2-乙氧氨基乙酰依沙替康(12)
在10ml的瓶子里,加入1ml的DMF,然后依次加入乙氧基羟胺盐酸盐(126mg,1.29mmol),TEA(182mg,1.8mmol),化合物6-a(100mg,0.18mmol),室温搅拌反应1h,减压去除DMF,硅胶柱层析分离纯化得到化合物12即2-乙氧氨基乙酰依沙替康(81mg,产率83%);1H NMR(500MHz,DMSO-d6)δ7.79(m,J=11.0,5.7Hz,1H),7.31(s,1H),5.63(m,J=9.2,5.4Hz,1H),5.42(s,2H),5.31-5.16(m,2H),3.72-3.68(m,2H),3.45-3.42(m,2H),3.18(m,J=17.3,9.0Hz,2H),2.40(d,J=6.4Hz,3H),2.27-2.10(m,2H),1.86(m,J=21.7,14.6,7.3Hz,2H),1.24(m,J=7.1Hz,1H),1.00(m,J=6.9Hz,2H),0.87(m,J=6.8Hz,3H);LCMS:(M+1)+537.10(计算值:536.21)。
实施例13:3-氨基氧杂环丁烷-3-乙酰依沙替康(13)
在10ml的水和10ml EtOH的混合液中,加入3-氨基氧杂环丁烷-3-羧酸(0.5g,4.27mmol),搅拌溶清,加入碳酸氢钠(0.72g,8.54mmol),缓慢滴加Boc酸酐(0.98g,4.48mmol)的5ml EtOH溶液,滴毕,室温搅拌2h,减压去除乙醇,滴加盐酸,调节PH至4左右,用DCM(100ml*3)萃取产品,无水硫酸钠干燥,浓缩得到化合物15-a,N-Boc-3-氨基氧杂环丁烷-3-羧酸(0.8g,收率86%),LCMS:(M+1)+118.01(计算值:117.10)。
在1ml的DMF中,依次加入依沙替康甲磺酸盐(20mg,0.038mmol),DIPEA(9.7mg,0.074mmol)化合物13-a(16.5mg,0.075mmol),HATU(23.6mg,0.062mmol),室温搅拌反应6小时,减压除去DMF,硅胶柱层析分离纯化得到化合物15-b,N-Boc-3-氨基氧杂环丁烷-3-乙酰依沙替康(15mg,产率65%),LCMS:(M+1)+635.20(计算值:634.66)。
将化合物13-b(15mg,0.023mmol)溶于2ml DCM中,加入1ml 4M盐酸的乙酸乙酯溶液,室温搅拌反应30min,浓缩得到化合物13即3-氨基氧杂环丁烷-3-乙酰依沙替康(61mg,产率100%);1H NMR(500MHz,DMSO-d6)δ8.55(m,2H),8.10(d,J=8.8Hz,1H),7.76(m,1H),7.30(d,J=7.1Hz,1H),5.60-5.49(m,1H),5.42(m,2H),5.00-4.95(m,1H),4.88(d,J=6.2Hz,1H),4.57(d,J=6.3Hz,1H),4.51(d,J=6.2Hz,1H),3.62(m,1H),3.46(m,1H),3.23(m,1H),3.16-3.11(m,2H),2.38(m,3H),2.25-2.13(m,2H),1.92-1.78(m,2H),0.87(m,3H);LCMS:(M+1)+535.31(计算值:534.54)。
实施例14:mc-Val-Cit-pab-甲酰-2-N-甲基-N-氨基乙豌依沙替康(DC-l)
在0.3ml的NMP中,依次加入化合物9(14.14mg,0.027mmol),DIPEA(17.52mg,0.135mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(7.33mg,0.054mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:10%至55%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-1即mc-Val-Cit-pab-甲酰-2-N-甲基-N-氨基乙酰依沙替康(15.2mg,产率50%)黄色固体;LCMS:(M+1)+1121.09(计算值:1120.21)。
实施例15:mc-Val-Cit-pab-甲酰-2-N-甲基-N-甲氨基乙酰依沙替康(DC-2)
在0.3mL的NMP中,依次加入化合物10(14.52mg,0.027mmol),DIPEA(10.51mg,0.081mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(7.33mg,0.054mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:10%至55%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-2即mc-Val-Cit-pab-甲酰-2-N-甲基-N-甲氨基乙酰依沙替康(12.2mg,40%)黄色固体;LCMS:(M+1)+1135.02(计算值:1134.23)。
实施例16:mc-Val-Cit-pab-甲酰-依沙替康-N-氨基脲(DC-3)
在0.3ml的NMP中,依次加入化合物1(13.38mg,0.027mmol),DIPEA(10.51mg,0.081mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:10%至55%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-3即mc-Val-Cit-pab-甲酰-依沙替康-N-氨基脲(13mg,45%)黄色固体;LCMS:(M+1)+1093.03(计算值:1092.15)。
实施例17:mc-Val-Cit-pab-甲酰-依沙替康-N-甲基-N-氨基脲(DC-4)
在0.3ml的NMP中,依次加入化合物2(13.7mg,0.027mmol),DIPEA(10.51mg,0.081mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25gC18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:15%至60%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-4即mc-Val-Cit-pab-甲酰-依沙替康-N-甲基-N-氨基脲(9mg,30%)黄色固体;LCMS:(M+1)+1107.11(计算值:1106.18)。
实施例18:mc-Val-Cit-pab-甲酰-依沙替康-N,,N-二甲氨基脲(DC-5)
在0.3ml的NMP中,依次加入化合物3(14.11mg,0.027mmol),DIPEA(10.51mg,0.081mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:15%至60%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-5即mc-Val-Cit-pab-甲酰-依沙替康-N’,N-二甲氨基脲(12.1mg,40%)黄色固体;LCMS:(M+1)+1121.02(计算值:1120.21)。
实施例19:mc-Val-Cit-pab-甲酰-2-氨氧基乙豌依沙替康(DC-6)
在2ml的DMF中,依次加入依沙替康甲磺酸盐(100mg,0.19mmol),DIPEA(48.58mg,0.37mmol),叔丁氧羰酰氨氧基乙酸(45mg,0.23mmol),HATU(118mg,0.31mmol),室温搅拌反应4小时,减压除去DMF,硅胶柱层析纯化得到中间体化合物2-Boc-氨氧基乙酰依沙替康(95mg,产率83%);1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),8.73(d,J=8.6Hz,1H),7.75(d,J=10.8Hz,1H),7.28(d,J=2.1Hz,1H),6.52(d,J=1.5Hz,1H),5.62(dt,J=8.8,4.4Hz,1H),5.40(d,J=3.3Hz,2H),5.23(d,J=17.9Hz,1H),5.19-5.11(m,1H),4.32(d,J=15.8Hz,1H),4.23(d,J=15.9Hz,1H),3.23-3.15(m,2H),2.37(d,J=6.5Hz,3H),2.24(dq,J=14.1,4.9Hz,1H),2.17(tt,J=8.3,5.1Hz,1H),1.84(ddp,J=21.4,14.3,7.2Hz,2H),1.15(s,9H),0.85(t,J=7.2Hz,3H);LCMS:(M+1)+609.30(计算值:608.18)。
将化合物2-Boc-氨氧基乙酰依沙替康(95mg,0.16mmol)溶于1ml DCM中,加入1ml4M盐酸的乙酸乙酯溶液,室温搅拌反应30min,浓缩得到化合物14即2-氨氧基乙酰依沙替康(85mg,产率100%);1H NMR(500MHz,DMSO-d6)δ8.93(d,J=8.5Hz,1H),7.79(d,J=10.5Hz,1H),7.30(s,1H),5.60(dt,J=8.3,4.1Hz,1H),5.42(s,2H),5.29(s,2H),4.73-4.64(m,2H),3.18(s,2H),2.85(s,3H),2.39(s,3H),2.25(dt,J=8.8,4.6Hz,1H),2.19-2.10(m,1H),1.85(dp,J=21.4,7.2Hz,2H),0.86(t,J=7.3Hz,3H);LCMS:(M+1)+509.20(计算值:508.18)。
在0.7ml的NMP中,依次加入化合物14(32.17mg,0.063mmol),DIPEA(24.53mg,0.189mmol),mc-Val-Cit-pab-PNP(70mg,0.095mmol),HOBt(8.55mg,0.063mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:10%至55%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-6即mc-Val-Cit-pab-甲酰-2-氨氧基乙酰依沙替康(31.5mg,31%)黄色固体;LCMS:(M+1)+1108.10(计算值:1107.16)。
实施例20:mc-Val-Cit-pab-甲豌-N-甲基氨氧乙豌依沙替康(DC-7)
在0.7ml的NMP中,依次加入化合物8(33.05mg,0.063mmol),DIPEA(24.53mg,0.189mmol),mc-Val-Cit-pab-PNP(70mg,0.095mmol),HOBt(8.55mg,0.063mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:10%至55%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-7即mc-Val-Cit-pab-甲酰-2-甲氨氧基乙酰依沙替康(42mg,39%)黄色固体;LCMS:(M+1)+1122.05(计算值:1121.09)。
实施例21:mc-Val-Cit-pab-甲酰-依沙替康-N’-氨基草酰二胺(DC-8)
在0.3ml的NMP中,依次加入化合物4(14.14mg,0.027mmol),DIPEA(17.52mg,0.135mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:10%至55%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-8即mc-Val-Cit-pab-甲酰-依沙替康-N’-氨基草酰二胺(13mg,45%)黄色固体;LCMS:(M+1)+1121.02(计算值:1120.16)。
实施例22:mc-Val-Cit-pab-甲酰-依沙替康N’-氨基-N-甲基草酰二胺(DC-9)
在0.3ml的NMP中,依次加入化合物5(14.52mg,0,027mmol),DIPEA(17.52mg,0,135mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25gC18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:10%至55%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-9即mc-Val-Cit-pab-甲酰-依沙替康N’-氨基-N-甲基草酰二胺(13mg,45%)黄色固体;LCMS:(M+1)+1135.10(计算值:1134.19)。
实施例23:mc-Val-Cit-pab-甲酰-N-羟基氨乙酰依沙替康(DC-10)
在0.3ml的NMP中,依次加入化合物6(13.79mg,0.027mmol),DIPEA(10.51mg,0.081mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25gC18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:5%至50%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-10即mc-Val-Cit-pab-甲酰-N-羟基氨乙酰依沙替康(13mg,45%)黄色固体;LCMS:(M+1)+1108.03(计算值:1107.16)。
实施例24:mc-Val-Cit-pab-甲酰-N-甲氧氨乙酰依沙替康(DC-11)
在0.3ml的NMP中,依次加入化合物7(14.17mg,0.027mmol),DIPEA(10.51mg,0.081mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:15%至50%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-11即mc-Val-Cit-pab-甲酰-N-甲氧氨乙酰依沙替康(13mg,45%)黄色固体;LCMS:(M+1)+1122.06(计算值:1121.19)。
实施例25:mc-Val-Cit-pab-甲酰-N-乙氧基氨乙豌依沙替康(DC-l2)
在0.3ml的NMP中,依次加入化合物12(14.17mg,0.027mmol),DIPEA(10.51mg,0.081mmol),mc-Val-Cit-pab-PNP(20mg,0.027mmol),HOBt(3.66mg,0.027mmol),室温反应1h,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:15%至50%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-12即mc-Val-Cit-pab-甲酰-N-乙氧基氨乙酰依沙替康(13mg,45%)黄色固体;LCMS:(M+1)+1136.02(计算值:1135.20)。
实施例26:mc-Gly-Gly-Phe-Gly-甲氧-N-甲基氨乙酰依沙替康(DC-13)
取Fmoc-Gly-Gly-Phe-OH(10g,19.9mmol),加入200mL DCM,HATU(11.43g,29.85mmol),DIPEA(5.13g.39.8mmol)和Gly-Gly-OtBu(4.11g,21.89mmol),室温反应15h,加入200mL DCM稀释,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,硅胶柱层析纯化得白色固体DC-13-a,Fmoc-Gly-Gly-Phe-Gly-Gly-OtBu(10.7g,79%);LCMS:(M+1)+672.5(计算值:671.75)。
取DC-13-a(10.7g,15.9mmol),加入110mL DCM和50mL TFA,室温反应15h反浓缩应液,加入100mlEA,过滤,滤饼在40℃烘箱干燥,得类白色固体DC-13-b,Fmoc-Gly-Gly-Phe-Gly-Gly(8.8g,90%);LCMS:(M+1)+616.10(计算值:615.23)。
取DC-13-b(3g,4.8mmol)溶于30mL DMF中,搅拌溶解,依次加入醋酸铜(1.46mmol,0.26g),醋酸(9.7mmol,0.58g),四乙酸铅(5.3mmol,2.38g),升温至60℃,反应20min,将反应液倒进冰水中,加入乙酸乙酯萃取,无水硫酸钠干燥后,浓缩拿到类白色固体产品DC-13-c,Fmoc-Gly-Gly-Phe-Gly-N-羟甲基醋酸酯(1.81g,59%);LCMS:(M+1)+630.10(计算值:629.25)。
取DC-13-c(0.05g,0.076mmol),加入5mL THF,再加入化合物11(0.04g,0.076mmol)和PPTS(3.8mg,0.015mmol),氩气保护下,60℃回流反应16h,硅胶柱层析纯化得白色固体DC-13-d,Fmoc-Gly-Gly-Phe-Gly-甲氧-N-甲基氨乙酰依沙替康(43mg,50%);LCMS:(M+1)+1093.05(计算值:1092.15)。
将DC-13-d(43mg,0.039mmol)溶于0.5ml的DMF中,加入哌啶(33mg,0.39mmol),室温搅拌反应1h,浓缩反应液,得到黄棕色固体DC-13-e,Gly-Gly-Phe-Gly-甲氧-N-甲基氨乙酰依沙替康(34mg,100%);LCMS:(M+1)+871.02(计算值:869.91)。
将DC-13-e(34mg,0.039mmol)溶解于0.5ml无水DMF中,依次加入6-(马来酰亚胺基)己酸琥珀酰亚胺酯(12mg,0.039mmol),DIPEA(5mg,0.039mmol),室温反应30min,将反应液注射入25g C18预柱(先用乙腈平衡,然后用水平衡,水相含0.1%TFA),然后通过中压反相C18色谱法(梯度:15%至50%乙腈在水中,时间40min)洗脱,冻干,得到化合物DC-13即mc-Gly-Gly-Phe-Gly-甲氧-N-甲基氨乙酰依沙替康(12.4mg,30%)黄色固体;LCMS:(M+1)+1064.05(计算值:1063.11)。
实施例27:4-(马来酰亚胺己基氧)苯甲醛-氨氧乙酰依沙替康肟(DC-14)
在100ml单口瓶中,依次加入6-氨基-1-己醇(6.0g 51.20mmol),60ml 48%浓度HBr水溶液,90℃回流搅拌反应18h,在冰浴条件下使用碳酸氢钠固体将反应液pH调节至8-9之间,加入Boc酸酐(11.2g 51.20mmol),缓慢升至室温搅拌过夜,过滤反应液,滤液使用EtOAc萃取目标产物,有机相使用5%NaCl溶液洗涤三次后使用无水Na2SO4干燥,过滤干燥后的有机相,浓缩后得到类白色固体产品N-Boc-6-溴己胺(10.0g,产率71.4%);LCMS:
(M+1)+281.12(计算值:280.21)。
在100ml单口瓶中加入50ml的乙腈,依次加入N-Boc-6-溴己胺(5.0g 17.84mmol),对羟基苯甲醛(2.2g
17.84mmol),无水碳酸钾(6.2g 44.61mmol),60℃回流搅拌反应18h,过滤反应液,滤液中加入10.0g硅胶制砂,使用PE和EA进行柱层析,浓缩拿到类白色固体产品4-(N-Boc-己烷氧基)苯甲醛(5.0g,产率87.7%);LCMS:
(M+1)+322.14(计算值:321.42)。
在100ml单口瓶中加入3ml 1,4-二氧六环,依次加入4-(N-Boc-己烷氧基)苯甲醛(1.0g 4.52mmol),3ml 4mol/LHCl/1,4-二氧六环溶液,常温条件下搅拌反应3h,在冰浴条件下使用饱和碳酸氢钠溶液调节反应液的pH至9,加入N-甲氧基羰基顺丁烯二酰亚胺(700.90mg 4.52mmol),在冰浴条件下搅拌反应2h,过滤固体,滤饼使用10ml纯化水洗涤,滤饼在35度条件下烘干后拿到类白色固体产品L-20(1.0g,产率73.5%);LCMS:(M+1)+302.23(计算值:301.34)。
在3ml的甲醇中,加入L-20(24.59mg,0.081mmol),吡啶(14.2mg,0.179mmol),无水硫酸钠(23.18mg,0.163mmol),最后加入化合物14(83mg,0.163mmol),室温搅拌反应1h,反应完,加入1g硅胶柱层析拿到产品DC-14,4-(马来酰亚胺己基氧)苯甲醛-氨氧乙酰依沙替康肟(36mg,产率56%);LCMS:(M+1)+792.11(计算值:791.30)。
实施例28:4-(马来豌亚胺乙基氧乙氧基)苯甲醛-氨氧乙酰依沙替康肟(DC-15)
在100ml单口瓶中,依次加入二甘醇胺(6.0g 57.07mmol),60ml 48%浓度HBr水溶液,90℃回流搅拌反应18h,在冰浴条件下使用碳酸氢钠固体将反应液pH调节至8-9之间,加入Boc酸酐(12.46g 57.07mmol),缓慢升至室温搅拌过夜,过滤反应液,用EtOAc萃取目标产物,有机相使用5%NaCl溶液洗涤三次后使用无水Na2SO4干燥,过滤干燥后的有机相,浓缩后得到类白色固体产品N-Boc-溴乙氧基乙胺(10.8g,产率70.6%);LCMS:(M+1)+269.02(计算值:268.15)。
在100ml单口瓶中加入50ml的乙腈,依次加入N-Boc-溴乙氧基乙胺(5.0g18.65mmol),对羟基苯甲醛(2.28g18.65mmol),无水碳酸钾(6.44g 46.62mmol),60℃回流搅拌反应18h,过滤反应液,滤液中加入10.0g硅胶制砂,使用PE和EA进行柱层析,浓缩拿到类白色固体产品4-(N-Boc-氨乙氧基乙氧基)苯甲醛(5.3g,产率91.8%);LCMS:(M+1)+310.24(计算值:309.36)。
在100ml单口瓶中加入3ml 1,4-二氧六环,依次加入4-(N-Boc-氨乙氧基乙氧基)苯甲醛(0.6g 1.94mmol),3ml4mol/L HCl/1,4-二氧六环溶液,常温条件下搅拌反应3h,在冰浴条件下使用饱和碳酸氢钠溶液调节反应液的pH至9,加入N-甲氧基羰基顺丁烯二酰亚胺(300.83mg 1.94mmol),在冰浴条件下搅拌反应2h,过滤固体,滤饼使用10ml纯化水洗涤,滤饼在35度条件下烘干后拿到类白色固体产品L-021(500mg,产率89%);LCMS:(M+1)+
290.13(计算值:289.29)。
在3ml的甲醇中,加入L-021(23.61mg,0.082mmol),吡啶(14.2mg,0.179mmol),无水硫酸钠(23.18mg,0.163mmol),最后加入化合物14(83mg,0.163mmol),室温搅拌反应1h,反应完,加入1g硅胶柱层析拿到产品DC-15,4-(马来酰亚胺乙基氧乙氧基)苯甲醛-氨氧乙酰依沙替康肟(42mg,产率66%);LCMS:(M+1)+780.12(计算值:779.26)。
实施例29:HS627-丁二豌亚胺-N-己酰-Val-Cit-pab-甲酰-依沙替康-N-氨基脲(ADC-3a)
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取HS627抗体(20.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl(三(2-羧乙基)膦盐酸盐)溶液(10mM,0.04ml),室温25℃旋转转盘反应90min。
将DC-3(0.9mg,0.8mmol)溶于0.09ml的DMA中,加入到上述溶液体系中,混匀,室温旋转转盘反应2h,反应完毕后用NAP-5凝胶柱(Cytiva)将缓冲液置换为20mM L-组氨酸醋酸盐缓冲液,pH6.0,120mM蔗糖,0.2g/L聚山梨酯20,得到ADC-3a(1.8mg/ml,3ml)。
UV-HPLC计算平均值:n=7.40
实施例30:HS627-丁二酰亚胺-N-己酰-Val-Cit-pab-甲酰-2-氨氧基乙酰依沙替康(ADC-6a)
取HS627抗体(20.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl(三(2-羧乙基)膦盐酸盐)溶液(10mM,0.04ml),室温25℃旋转转盘反应90min。
将DC-6(0.9mg,0.8mmol)溶于0.09ml的DMA中,加入到上述溶液体系中,混匀,室温旋转转盘反应2h,反应完毕后用NAP-5凝胶柱(Cytiva)将缓冲液置换为20mML-组氨酸醋酸盐缓冲液,pH6.0,120mM蔗糖,0.2g/L聚山梨酯20,得到ADC-6a(3.2mg/ml,2ml)。
UV-HPLC计算平均值:n=7.70
实施例31:HS627-丁二酰亚胺-N-己酰-Val-Cit-pab-甲酰-N-甲基氨氧乙酰依沙替康(ADC-7a)
取HS627抗体(20.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl(三(2-羧乙基)膦盐酸盐)溶液(10mM,0.04ml),室温25℃旋转转盘反应90min。
将DC-7(0.9mg,0.8mmol)溶于0.09ml的DMA中,加入到上述溶液体系中,混匀,室温旋转转盘反应2h,反应完毕后用NAP-5凝胶柱(Cytiva)将缓冲液置换为20mML-组氨酸醋酸盐缓冲液,pH6.0,120mM蔗糖,0.2g/L聚山梨酯20,得到ADC-7a(3.1mg/ml,2ml)。
UV-HPLC计算平均值:n=7.30
实施例32:HS627-丁二酰亚胺-4-(N-己基氧)苯甲醛好氧乙酰依沙替康(ADC-14a)
取HS627抗体(20.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl(三(2-羧乙基)膦盐酸盐)溶液(10mM,0.04ml),室温25℃旋转转盘反应90min。
将DC-14(0.63mg,0.8mmol)溶于0.063ml的DMA中,加入到上述溶液体系中,混匀,室温旋转转盘反应2h,反应完毕后用NAP-5凝胶柱(Cytiva)将缓冲液置换为20mML-组氨酸醋酸盐缓冲液,pH6.0,120mM蔗糖,0.2g/L聚山梨酯20,得到ADC-14a(2.9mg/ml,2ml)。
UV-HPLC计算平均值:n=4.3。
实施例33:HS627-丁二酰亚胺-4-(N-乙氧基乙氧基)苯甲醛肟氧乙酰依沙替康(ADC-15a)
取HS627抗体(20.0mg/mL,10mg,0.066mmol),用1M Na2HPO4溶液调pH至7.2,然后再加入0.1M乙二胺四乙酸二钠的溶液(25μL),加入配置好的TCEP·HCl(三(2-羧乙基)膦盐酸盐)溶液(10mM,0.04ml),室温25℃旋转转盘反应90min。
将DC-15(0.62mg,0.8mmol)溶于0.062ml的DMA中,加入到上述溶液体系中,混匀,室温旋转转盘反应2h,反应完毕后用NAP-5凝胶柱(Cytiva)将缓冲液置换为20mM L-组氨酸醋酸盐缓冲液,pH6.0,120mM蔗糖,0.2g/L聚山梨酯20,得到ADC-15a(3.2mg/ml,2ml)。
UV-HPLC计算平均值:n=7.6。
效果例1:抑制肿瘤细胞生长活性
化合物(小分子毒素)体外抑制活性测试方法
将人食管癌细胞OE33、人乳腺腺癌细胞SK-BR-3分别在含有10%胎牛血清(Cellmax)的RPMI1640(Cellmax)中培养。将处于指数增长期的肿瘤细胞用培养基稀释至1×105cells/mL,以每孔100μL加入到96孔细胞培养板中,放回37℃,5%CO2的培养箱中过夜培养。第二天,使用培养基将小分子分别化合物稀释至10000nM、2000nM、400nM、80nM、16nM、3.2nM、0.64nM、0.13nM,并以每孔2μL将稀释后的化合物加入到96孔细胞培养板中,每个浓度设置3个复孔,未添加化合物的阴性对照和空白对照组每孔加入2μL的稀释液。加样完成后,放回37℃,5%CO2的培养箱中继续孵育72h。孵育完成后,取出细胞培养板,用移液器将培养板中的培养基吸弃,每孔加入100μL含有10%CCK-8的培养基,37℃孵育3h。孵育完成后,取出培养板,避光,置于酶标板中,选择630nm为参比波长,450nm为测定波长测定吸光度。根据吸光值,使用GraphPad中四参数回归计算IC50值(表1-3)。以DNA拓扑异构酶I抑制剂Dxd为阳性对照药物。对于IC50值,其中“++++”表示IC50<10nM;“+++”表示IC50介于10nM-100nM之间;“++”表示IC50介于100-500nM之间;“+”表示IC50>500μM。
ADC体外抑制活性测试方法
将作为活性检测的人食管癌细胞OE33、肺癌细胞NCI-H1975和乳腺癌细胞MDA-MB-231细胞分别在含有10%胎牛血清(Cellmax)的RPMI1640(Cellmax)、RPMI1640(Cellmax)和DMEM(Cellmax)培养基中培养至指数增长期,胰酶消化后,离心弃上清,用培养基稀释至分别稀释至3×104cells/mL、0.5×104cells/mL和1.5×104cells/mL,以每孔100μL加入到96孔细胞培养板中,放回37℃,5%CO2的培养箱中过夜培养。第二天,使用培养基将待测ADC稀释至2000nM、400nM、80nM、16nM、3.2nM、0.64nM、0.128nM、0.026nM,并以每孔100μL将稀释后的ADC加入到96孔细胞培养板中,每个浓度设置3个复孔,未添加ADC的阴性对照和空白对照组每孔加入100μL的培养基。加样完成后,放回37℃,5%CO2的培养箱中继续孵育6天。孵育完成后,取出细胞培养板,用移液器将培养板中的培养基吸弃,每孔加入100μL含有10%CCK-8的培养基,37℃孵育3h。孵育完成后,取出培养板,避光,置于酶标板中,选择630nm为参比波长,450nm为测定波长测定吸光度。根据吸光值,使用GraphPad中四参数回归计算IC50(表1、3)。以ADC药物DS-8201a为阳性对照药物。对于IC50值,其中“++++”表示IC50<10nM;“+++”表示IC50介于10nM-100nM之间;“++”表示IC50介于100-500nM之间;“+”表示IC50>500μM。
阳性对照化合物DXD结构式为:
表1对OE33的抑制活性
表2对SK-BR-3的抑制活性
化合物编号 | IC50/nM | 化合物编号 | IC50/nM | 化合物编号 | IC50/nM |
1 | +++ | 5 | ++++ | 13 | ++++ |
3 | ++++ | 8 | ++++ | Dxd | ++++ |
4 | +++ |
表3 ADC药物对NCI-H1975和MDA-MB-231的抑制活性
本发明提供的实施例化合物均对癌细胞例如食管癌细胞、乳腺腺癌细胞3的生长均具有较好的抑制作用,大部分化合物例如化合物2、3、7、8、9、13对食管癌细胞生长抑制的IC50值均低于10nM,具有显著的抗癌活性。
本发明实施例化合物用于构建抗体-药物偶联物,其得到的偶联物对食管癌细胞、肺癌细胞和乳腺癌细胞均具有显著的抑制活性,示例性偶联物ADC-3a、ADC-6a和ADC-7a对上述细胞均具有明显的抑制活性,ADC-7a的抑制活性甚至均低于10nM。
Claims (10)
1.式(I)化合物或其药学上可接受的盐、立体异构体或前药:
式中,
R选自-Z-R1,其中,Z为单键或C=O;
R1选自-(CH2)nNRaRb、-CH2ORa、-NORa、-(CH2)nONRaRb或-R3;n选自0、1、2或3;
Ra、Rb各自独立地选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基、氨基C1-C6烷基或C1-C6烷氧基;
R3选自3至6元环烷基或含N、O、或S杂原子的3至6元杂环烷基,R3任选地进一步地被Rc取代;
Rc选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基;
条件是,-Z-R1不为-NH2、-CH2OH、-CH2NH2或-CH2OCH2NH2。
2.根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体或前药,其特征在于,R1选自-NRaRb、-CH2NRaRb、-CH2ORa、-NORa、-(CH2)nONRaRb或-R3;
优选地,R1选自-NRaRb、-C(O)NRaRb、-CH2NRaRb或-CH2ONRaRb或-R3;
优选地,Ra、Rb各自独立地选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基;
优选地,Ra、Rb各自独立地选自氢、羟基、氨基、甲基、甲氨基或甲氧基;
R3选自含N、O、或S杂原子的3至6元杂环烷基,R3任选地进一步地被Rc取代;
Rc选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基。
3.根据权利要求2所述的化合物或其药学上可接受的盐、立体异构体或前药,其中,R1选自-NHNH2、-N(CH3)NH2、-N(CH3)NHCH3、-C(O)NHNH2、-C(O)N(CH3)NH2、-CH2NHOH、-CH2NHOCH3、-CH2ONH2、-CH2ONHCH3、-CH2NCH3NH2、-CH2N(CH3)NHCH3、-CH2N(CH3)OH、-CH2NHOCH2CH3、羟基氧杂环丁烷基、氨基氧杂环丁烷基。
4.根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、立体异构体或前药,所述式(I)化合物为式(Ia)、(Ib)、(Ic)或(Id)所示化合物:
式(Ia)中,R1定义同式(I)化合物;
优选地,R1为-NHNH2或-N(CH3)NH2;
式(Ib)中,R2选自-NHOH、-ONH2、-NHO(C1-C3烷基)、-ONH(C1-C3烷基)、-N(C1-C3烷氨基)、-N(C1-C3烷基)NH(C1-C3烷基)、-N(C1-C3烷基)OH或-NHO(C1-C3烷基);
优选地,R2选自-NHOH、-NHOCH3、-ONH2、-ONHCH3、-NCH3NH2、-N(CH3)NHCH3、-N(CH3)OH或-NHOCH2CH3;
式(Ic)中,Ra、Rb定义同式(I)化合物;条件是,Ra、Rb不同时为H;
优选地,Ra、Rb各自独立地选自氢、氨基、C1-C3烷基、C1-C3烷氨基;
优选地,-NRaRb选自-NHNH2、-N(CH3)NH2或-N(CH3)NHCH3;
式(Id)中,X为CH2、NH、O或S;优选地,X为CH2或O;更优选地,X为O;
Rc选自氢、羟基、氨基、C1-C6烷基、C1-C6烷氨基或C1-C6烷氧基;
优选地,Rc选自羟基或氨基。
5.以下化合物或其药学上可接受的盐、立体异构体或前药:
6.权利要求1-5任一项所述化合物的制备方法,其选自以下反应路线:
反应路线1:
将依沙替康和N,N'-羰基二咪唑反应,再和肼或取代的肼反应得到相应的N-氨基脲依沙替康衍生物;
反应路线2:
将取代的肼和草酰氯反应,再和依沙替康反应,得到相应的草酰胺肼依沙替康衍生物;
反应路线3:
依沙替康和溴乙酸反应得到溴乙酰基依沙替康,溴乙酰基依沙替康和胺类化合物进行缩合得到相应的酰胺依沙替康衍生物;
反应路线4:
依沙替康和羧酸类化合物直接反应得到相应的酰胺依沙替康衍生物。
7.式(II)所示的药物-连接子化合物或其药学上可接受的盐、立体异构体或前药:
式中,R定义同式(I)化合物;
L为-L1-Q-L2;R与L1部分相连;
其中,L1选自其中,/>所示位置表示与R基团相连,/>所示位置表示与Q基团相连;
L2选自
Q选自Val-Cit、Val-Ala、Ala-Ala-Asn、Gly-Gly-Phe-Gly、Gly-Lys、Gly-Gly-lys、(CH2)m1O(CH2)m2或(CH2)m3,其中,m1和m2各自独立地选自1-4的整数;m1优选为2;m2优选为2;m3优选为6;优选地,Q选自Val-Cit、Gly-Gly-Phe-Gly、(CH2)2O(CH2)2、或(CH2)6;
优选地,L1为
优选地,L2为
8.式(III)所示的药物-抗体偶联化合物或其药学上可接受的盐:
式中,R定义同式(I)或化合物,L定义同式(II)或化合物;
Ab为肿瘤相关抗原抗体,n选自1-8的整数;
优选地,所述肿瘤相关抗原选自Her2、Trop2、5T4、ROR1或B7-H3;
优选地,所述式(III)药物-抗体偶联化合物选自以下化合物:
优选地,所述式(III)药物-抗体偶联化合物选自以下化合物:
9.药物组合物,其特征在于,包括权利要求1-5任一项所述的化合物、权利要求7所述的药物-连接子化合物或其药学上可接受的盐、立体异构体、前药或权利要求8所述的抗体药物偶联物和药学上可接受的辅料。
10.权利要求1-5任一项所述的化合物、权利要求7所述的药物-连接子化合物或其药学上可接受的盐、立体异构体、前药或权利要求8所述的抗体药物偶联物或权利要求9所述的药物组合物在制备用于治疗癌症的药物中的应用;
优选地,所述癌症包括胃癌、食管癌、乳腺癌和肺腺癌。
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