CN116478175A - 喜树碱-7-乙基胺衍生物及其制备方法和应用 - Google Patents
喜树碱-7-乙基胺衍生物及其制备方法和应用 Download PDFInfo
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- CN116478175A CN116478175A CN202310441877.3A CN202310441877A CN116478175A CN 116478175 A CN116478175 A CN 116478175A CN 202310441877 A CN202310441877 A CN 202310441877A CN 116478175 A CN116478175 A CN 116478175A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
- A61K47/68—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 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
本发明提供了喜树碱‑7‑乙基胺衍生物或其药学上可接受的盐、立体异构体或前药,及其制备方法和应用,所述喜树碱‑7‑乙基胺衍生物具有式(I)所示结构。
Description
技术领域
本发明涉及医药领域。具体地说,本发明提供一系列喜树碱-7-乙基胺衍生物的制备及其应用于肿瘤的治疗。
背景技术
喜树碱是从中国植物喜树中提取得到的天然产物,对拓扑异构酶Top1具有抑制活性,尤其对Top1-DNA形成的复合物具有很强的抑制活性。喜树碱对胃癌、食管癌、肺癌、膀胱癌等都具有显著的疗效,是一种广谱的抗肿瘤活性药物。其中Irinotecan和Topotecan已经在很多国家获批用于各种癌症的治疗。而另一个喜树碱衍生物Belotecan已经在韩国批准用于SCLC和卵巢癌的治疗。喜树碱类抗肿瘤药物的主要缺陷是其毒性,难溶性和肿瘤细胞对其产生耐药性。
本发明提供一系列喜树碱-7-乙基胺衍生物,其特征在于具有改进溶解度和提高抗肿瘤活性,对肿瘤的治疗具有潜在的应用价值。
发明内容
本发明提供了一系喜树碱-7-乙基胺衍生物或其药学上可接受的盐、立体异构体或前药,及其制备方法和在抗肿瘤领域的应用。
本发明的一方面,提供式1表示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和R2各自独立地表示卤素、羟基、烷基、烷氧基、或R1和R2共同组成亚甲基二氧桥或乙基二氧桥;
R3和R4各自独立地表示氢、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、酰基、磺酰基,或R3、R4和与之连接的氮原子共同形成杂环烷基或杂芳基,所述烷基、烷氧基、环烷基、烷基酰基、磺酰基、杂环烷基、芳基、或杂芳基任选地被R取代,
R选自卤素、羟基、烷基、烷氧基、环烷基、叠氮或5至7元杂芳基。
在一实施方案中,R1和R2各自独立地表示卤素、羟基、C1-C6烷基、C1-C6烷氧基,或R1和R2共同组成亚甲基二氧桥或乙基二氧桥。
在一实施方案中,R1和R2各自独立地表示卤素、甲基。
在一实施方案中,R1和R2各自独立地表示甲基、F、Cl、Br、I。
在一实施方案中,R1和R2各自独立地表示甲基、F。
在一实施方案中,R1和R2共同组成亚甲基二氧桥或乙基二氧桥。
在一实施方案中,R3和R4各自独立地表示氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4至8元杂环烷基、5至12元芳基、5至12元杂芳基、C1-C6烷基-酰基、C1-C6烷基-磺酰基、C3-C6环烷基-磺酰基,或者R3、R4和与之连接的氮原子共同形成4至8元杂环烷基,所述C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4至8元杂环烷基、5至12元芳基、5至12元杂芳基、C1-C6烷基-酰基、C1-C6烷基-磺酰基、C3-C6环烷基-磺酰基任选地被R取代。
在一实施方案中,R3和R4各自独立地表示C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基,或者R3、R4和与之连接的氮原子共同形成5至6元杂环烷基,所述C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基任选地被R取代。
在一实施方案中,R3和R4各自独立地表示C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基,或者R3、R4和与之连接的氮原子共同形成5至6元杂环烷基,所述C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基任选地被R取代,或者R3、R4和与之连接的氮原子共同形成5至6元杂环烷基,所述杂环烷基、杂芳基含有1-3个独立地选自N、O的杂原子。
在一实施方案中,R选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基或叠氮。
在一实施方案中,R选自F、Cl、Br、I、羟基、甲基、甲氧基、环丙基或叠氮。
在一实施方案中,R选自F、羟基、甲基、甲氧基、环丙基或叠氮。
在一实施方案中,R3和R4各自独立地选自以下基团:
在一实施方案中,R3、R4和与之连接的氮原子共同形成吡咯烷、哌啶、哌嗪。
在一实施方案中,R3、R4和与之连接的氮原子共同形成
在一实施方案中,R1、R2各自独立地或共同为以下结构:
在一实施方案中,所述-NR3R4各自独立地或共同为以下结构:
本发明提供以下化合物或其药学上可接受的盐、立体异构体或前药:
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,所述制备方法包含选自以下任意一种合称路线的步骤:
合成路线1,其中,包括以下工序:
(1)将3,4-取代的苯胺和卤代丙腈反应,得到3’,4’-二取代-3-卤代-6’-氨基苯丙酮;
(2)使3’,4’-二取代-3-卤代-6’-氨基苯丙酮和胺进行取代,得到3’,4’-二取代-3-烷氨基-6’-氨基苯丙酮;
(3)使3’,4’-二取代-3-烷氨基-6’-氨基苯丙酮和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮缩合,得到喜树碱-7-乙基胺衍生物。
合成路线2,其中,包括以下工序:
(1)使3’,4’-二取代-3-卤代苯丙酮和硝酸反应,得到6’-硝基-3’,4’-二取代-3-卤代苯丙酮;
(2)将6’-硝基-3’,4’-二取代-3-卤代苯丙酮和胺进行取代反应得到6’-硝基-3’,4’-二取代-3-烷氨基-苯丙酮;
(3)将6’-硝基-3’,4’-二取代-3-烷氨基-苯丙酮进行还原得到6’-氨基-3’,4’-二取代-3-烷氨基-苯丙酮:
(4)使3’,4’-二取代-3-烷氨基-6’-氨基苯丙酮和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮缩合,得到喜树碱-7-乙基胺衍生物。
合成路线3,其中,包括以下工序:
(1)将3’,4’-二取代的苯乙酮进行硝化反应,得到6’-硝基-3’,4’-二取代苯乙酮;
(2)将6’-硝基-3’,4’-二取代苯乙酮和甲醛缩合、酸化,得到6’-硝基-3’,4’-二取代苯丙烯酮;
(3)使6’-硝基-3’,4’-二取代苯丙烯酮和胺进行Michael加成反应,得到6’-硝基-3’,4’-二取代苯丙酮-3-胺;
(4)将6’-硝基-3’,4’-二取代苯丙酮-3-胺进行还原,得到6’-氨基-3’,4’-二取代苯丙酮-3-胺;
(5)使6’-氨基-3’,4’-二取代苯丙酮-3-胺和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮进行缩合反应,得到喜树碱-7-乙基胺衍生物。
合成路线4,其中,包括以下工序:
(1)使取代的2-乙酰基苯胺和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮缩合,得到7-甲基喜树碱;
(2)使7-甲基喜树碱和胺在DMSO中进行Mannich反应,得到喜树碱-7-乙基胺衍生物。
优选地,本发明的合成路线如下:
合成路线1.以3,4-二取代的苯胺为原料,进行付克酰化,硝化,胺取代,还原硝基,关环获得目标产物。
合成路线2.以3,4-二取代的3‘-氯苯丙酮为原料,进行胺取代,硝化,还原,关环获得目标产物。
合成路线3.以3,4-二取代的苯丙烯酮为原料,进行胺的Micheal加成,硝化,还原,关环获得目标产物
合成路线4.以7甲基喜树碱(中间体5)为底物和胺、DMSO进行Mannich反应得到7-胺乙基取代的喜树碱产物。
在一实施方案中,本发明的制备方法包括合成路线1至合成路线4。包括:1)将3,4-取代的苯胺和相应的卤代丙腈反应,得到中间体3‘,4‘-二取代-3-氯-6‘-氨基苯丙酮(中间体1);2)将中间体1和相应的胺进行取代,得到3‘,4‘-二取代-3-烷氨基-6’-氨基苯丙酮(中间体2);3)将中间体2和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮(以下简称“三环酮“)缩合,得到相应的产物;4)将3‘,4‘-二取代-3-氯苯丙酮和各种胺、取代的胺、保护的胺,保护的氨基羟基,甲氧基羟胺等反应得中间体3;5)中间体3经硝化、还原得到中间体4;6)中间体4和三环酮缩合得到相应的产物;7)将6’-硝基-3’,4’-二取代苯丙烯酮和胺进行Michael加成反应,得到6’-硝基-3’,4’-二取代苯丙酮-3-胺(中间体3);8)将6’-硝基-3’,4’-二取代苯丙酮-3-胺进行还原,得到6’-氨基-3’,4’-二取代苯丙酮-3-胺(中间体4);9)将6’-氨基-3’,4’-二取代苯丙酮-3-胺和”三环酮”进行缩合反应,得到相应的喜树碱-7-乙基胺衍生物;10)将取代的2-乙酰基苯胺和“三环酮”缩合得到7-甲基喜树碱;11)将7-甲基喜树碱和相应的胺在DMSO中进行Mannich反应得到相应的产物。
在一实施方案中,合成路线1步骤(1)中使用的卤代丙腈为氯丙腈或者溴丙腈,用量为1-2摩尔当量,优选为1.0~1.5摩尔当量,更优选为1.1~1.2摩尔当量。
在一实施方案中,合成路线1步骤(1)中使用AlCl3或BCl3进行催化,用量为1-3摩尔当量,优选为1.0~1.5摩尔当量。
在一实施方案中,合成路线1步骤(2)中使用PPTS进行催化,用量为1-2摩尔当量,优选为1.0-1.2当量。
在一实施方案中,合成路线1步骤(3)中胺的用量为1-20摩尔当量,优选为3-10摩尔当量。
在一实施方案中,合成路线2步骤(2)使用硝酸/醋酐进行硝化,反应温度为-10-10℃,优选温度为-5-0℃。
在一实施方案中,合成路线4步骤(2)胺的用量为1-20摩尔当量,优选为3-6摩尔当量。
在一实施方案中,合成方法3步骤(2)使用甲醛水溶液或多聚甲醛,用量为5-100摩尔当量,优选为30~40摩尔当量。
在一实施方案中,合成方法3步骤(3)的Michael加成反应在0-100℃下进行,优选为50-70℃。
在一实施方案中,合成方法4步骤(2)的Mannich反应中使用伯胺或仲胺的盐酸盐在DMSO加热至80-160℃下进行,优选温度为100-145℃,更优选为110-140℃。
本发明的另一方面,提供抗体药物偶联物,其以上述化合物或其药学上可接受的盐、立体异构体或前药为小分子药物。
本发明的另一方面,提供药物组合物,其包括上述化合物或其药学上可接受的盐、立体异构体或前药或抗体药物偶联物和药学上可接受的辅料。
本发明的另一方面,提供上述化合物或其药学上可接受的盐、立体异构体或前药、抗体药物偶联物、药物组合物在制备治疗肿瘤疾病的药物中的应用。
本发明的另一方面,提供一种治疗肿瘤疾病的方法,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、立体异构体或前药、抗体药物偶联物、药物组合物的施用量为治疗有效量。
在一实施方案中,所述肿瘤疾病包括胃癌、食管癌、贲门癌、乳腺癌、卵巢癌、结肠癌、直肠癌、原发性肝癌、急性和慢性粒细胞性白血病、绒毛膜上皮癌、肺癌、膀胱癌、肠癌和小细胞肺癌;更优选地,所述肿瘤疾病为食管癌、乳腺癌和胃癌。
具体实施方式
I.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。
II.具体实施例
本发明的筛选方法包括:化合物针对肿瘤细胞OE33细胞(人食管腺癌细胞),SKBR3细胞(人乳腺腺癌细胞)等的生长抑制活性。
实施例1:7-(2-乙酰氨)乙基-10-甲基-11-氟喜树碱(1)
向盛有160mL无水1,2二氯乙烷的单口烧瓶中,加入1M BCl3的二氯甲烷溶液(32mL,0.032mol),降温至0℃,加入3-氟-4-甲基苯胺(5.0g,0.04mmol),在0℃下反应10min.加入乙腈(16.40g,0.4mol)和三氯化铝(7g,0.05mol),缓慢升至室温搅拌10min,然后升温至80℃,搅拌12h,冷却后将反应液倒入冰水中,加入1M HCl溶液调节pH=2,二氯甲烷萃取,Na2SO4干燥,硅胶柱层析纯化得到中间体6-氨基-4-氟-3-甲基苯乙酮(2.5g,产率37.4%,HPLC 94%);LC-MS(M+H)+168.02(理论值167.07)。
取6-氨基-4-氟-3-甲基苯乙酮(1.5g,9.0mmol)溶于无水甲苯中,加入”三环酮“(2.36g,9.0mmol)和PPTS(0.6g,2.4mmol).反应加热到115℃搅拌12h,减压浓缩溶剂,加入10mL甲醇,过滤,滤饼干燥,得到7,10-二甲基-11-氟喜树碱(3.2g,产率90.4%,HPLC96%);LC-MS(M+H)+395.26(理论值394.13)。
将127.1mg胺盐酸盐和148μl盐酸加入1.5ml DMSO中,在油浴锅中反应升温至110℃,加入7,10-二甲基-11-氟喜树碱(100mg,0.25mmol),升温至130-140℃反应50分钟,冷却至室温,加甲醇,过滤,硅胶柱层析纯化得到脱甲氧基产物7-(2-氨基)乙基-10-甲基-11-氟喜树碱(41mg,产率38.7%,HPLC 94%);1H NMR(500MHz,DMSO-d6)δ8.02-7.92(m,3H),7.35(d,J=2.6Hz,1H),6.61-6.53(m,1H),5.43(d,J=33.0Hz,4H),3.59-3.47(m,2H),3.22(s,2H),1.89(dt,J=14.5,6.9Hz,2H),0.89(q,J=5.3Hz,3H);LC-MS(M+H)+424.02(理论值423.16)。
将7-(2-氨基)乙基-10-甲基-11-氟喜树(10mg,0.023mmol)加入到25mL单口瓶中,加入DMF(5mL),加入乙酸(2.8mg,0.046mmol),然后加入HATU(18mg,0.046mmol),DIPEA(6mg,0.046mmol),常温反应1小时。滴加0.5ml水淬灭反应,反应液用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-乙酰氨)乙基-10-甲基-11-氟喜树碱(4.78mg,产率45.5%,HPLC 97.5%):1H NMR(500MHz,DMSO-d6)δ8.32(d,J=8.0Hz,1H),7.90(d,J=10.5Hz,1H),7.30(s,1H),5.44(s,3H),5.41(s,2H),5.31(s,2H),2.47(s,2H),2.30(s,2H),1.90(d,J=7.1Hz,3H),1.85(dt,J=14.1,7.5Hz,2H),0.89(d,J=7.1Hz,3H);LC/MS(M+H)+
466.41(理论值465.17)。
实施例2:7-(2-二氟乙酰氨)乙基-10-甲基-11-氟喜树碱(2)
将7-(2-氨基)乙基-10-甲基-11-氟喜树(15mg,0.035mmol)加入到反应瓶中,加入DMF(5mL),加入二氟乙酸(8.8mg,0.092mmol),然后加入HATU(18mg,0.046mmol),DIPEA(6mg,0.046mmol),常温反应1小时。滴加0.5ml水淬灭反应,反应液用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-二氟乙酰氨)乙基-10-甲基-11-氟喜树碱(7.29mg,产率41.1%,HPLC 96%);1H NMR(500MHz,DMSO-d6)δ8.34(d,J=8.1Hz,1H),7.93(d,J=10.6Hz,1H),7.31(s,1H),6.53(d,J=4.9Hz,1H),5.44(s,3H),5.42(s,2H),5.34(s,2H),2.53(s,2H),2.30(s,1H),1.88(s,2H),0.89(d,J=7.3Hz,3H);LC/MS(M+H)+502.28(理论值501.46)。
实施例3:7-(2-甲磺酰氨)乙基-10-甲基-11-氟喜树碱(3)
将7-(2-氨基)乙基-10-甲基-11-氟喜树(10mg,0.023mmol,实施例1)加入到反应瓶中,加入DMF(5mL),加入甲磺酰氯(4mg,0.035mmol),DIPEA(6mg,0.046mmol),常温反应1小时。滴加0.5ml水淬灭反应,反应液用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-甲磺酰氨)乙基-10-甲基-11-氟喜树碱(6.22mg,产率54%,HPLC 97%):LC/MS(M+H)+502.23(理论值501.53)。
实施例4:7-(2-(四氢吡喃-4-基)氨)乙基-10-甲基-11-氟喜树碱(4)
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向反应瓶中分别加入4-氨基四氢吡喃(154mg,1.52mmol),7,10-二甲基-11-氟喜树碱(100mg,0.25mmol),盐酸(0.138mL,1.65mmol)和DMSO(1mL),加班下升温至120-130℃反应40分钟,冷却,加入异丙醇,过滤,硅胶柱层析纯化得到化合物7-(2-(四氢吡喃-4-基)氨)乙基-10-甲基-11-氟喜树碱(49.3mg,产率39%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ8.01(d,J=8.6Hz,1H),7.83(s,1H),7.35(s,1H),6.61(s,1H),5.77(s,3H),5.45(d,J=22.3Hz,4H),3.98-3.89(m,2H),3.57-3.52(m,2H),3.34-3.27(m,5H),1.96(d,J=10.6Hz,2H),1.88(dd,J=12.1,7.3Hz,2H),1.56(d,J=9.7Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+508.33(理论值507.22)。
实施例5:7-(2-(哌嗪-4-基))乙基-10-甲基-11-氟喜树碱(5)
向反应瓶中加入哌嗪(86.14mg,1mmol),盐酸(0.085mL,1.02mmol)和DMSO(1mL),搅拌下升温至110℃,加入7,10-二甲基-11-氟喜树碱(100mg,0.25mmol),继续搅拌在120-135C反应1h,冷却,加入异丙醇,过滤,硅胶柱层析纯化得到化合物7-(2-(哌嗪-4-基))乙基-10-甲基-11-氟喜树碱(43.75mg,产率35.5%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ8.21(d,J=8.1Hz,1H),7.89(d,J=10.7Hz,1H),7.31(s,1H),6.55(s,1H),5.44(s,2H),5.36(s,2H),3.62(s,6H),3.44(s,3H),3.24(s,4H),2.52(s,2H),1.87(dp,J=21.6,7.1Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+493.15(理论值492.22)。
实施例6:7-(2-(4-羟基环己基)氨)乙基-10-甲基-11-氟喜树碱(6)
将(反式)-4-氨基环己醇(175.22mg,1.52mmol),盐酸(0.138mL,1.65mmol)和DMSO(1mL)加入到反应瓶中,搅拌下升温至110℃,加入7,10-二甲基-11-氟喜树碱(100mg,0.25mmol),升温至120-130℃继续搅拌反应45分钟,冷却至室温,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-(4-羟基环己基)氨)乙基-10-甲基-11-氟喜树碱(54.8mg,产率42.0%,HPLC 97%);1H NMR(500MHz,DMSO-d6)δ8.85(d,J=63.5Hz,2H),8.15(dd,J=117.3,8.3Hz,1H),7.98-7.79(m,1H),7.38(d,J=6.1Hz,1H),6.62(s,1H),5.51(d,J=3.9Hz,2H),5.41(d,J=8.8Hz,2H),3.64-3.41(m,7H),3.26-3.09(m,1H),2.54-2.51(m,1H),2.10(d,J=10.0Hz,1H),2.00-1.87(m,3H),1.85-1.73(m,2H),1.47(dq,J=24.7,12.9Hz,2H),1.25(td,J=13.2,12.8,6.9Hz,1H),1.01-0.87(m,3H);LC-MS(M+H)+522.15(理论值521.23)。
实施例7:7-(2-(4-甲氧基环己基)氨)乙基-10-甲基-11-氟喜树碱(7)
向反应瓶中分别加入(反式)-4-甲氧环己胺(196.56mg,1.52mmol),盐酸(0.138mL,1.65mmol),7,10-二甲基-11-氟喜树碱(100mg,0.25mmol)和DMSO(1mL),搅拌下升温至120-130℃反应45分钟,冷却,加入异丙醇,过滤,硅胶柱层析纯化得到化合物7-(2-(4-甲氧基环己基)氨)乙基-10-甲基-11-氟喜树碱(49.6mg,产率37.0%,HPLC 97%);1HNMR(500MHz,DMSO-d6)δ8.71(s,2H),8.23-8.14(m,1H),8.00(d,J=8.6Hz,1H),7.82(s,1H),7.35(s,1H),5.46(s,2H),5.41(s,2H),3.81-3.73(m,1H),3.24(s,3H),3.12(q,J=10.4Hz,3H),2.63(s,2H),2.28(s,2H),1.95-1.81(m,4H),1.37(d,J=11.0Hz,4H),0.88(t,J=7.4Hz,3H);LC-MS(M+H)+536.41(理论值535.25)。
实施例8:7-(2-(2-叠氮乙基)氨)乙基-10-甲基-11-氟喜树碱(8)
向反应瓶中加入2-叠氮乙胺盐酸盐(218.30mg,2.54mmol),7,10-二甲基-11-氟喜树碱(500mg,1.27mmol)和DMSO(10mL),搅拌下升温至120-135℃反应50分钟,冷却至室温,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-(2-叠氮乙基)氨)乙基-10-甲基-11-氟喜树碱(294mg,产率47%,HPLC 95%);1H NMR(600MHz,DMSO-d6)δ8.33(d,J=8.1Hz,1H),8.24(s,2H),7.90(d,J=10.6Hz,1H),7.30(s,1H),6.55(s,1H),5.41(s,2H),5.31(s,2H),3.66(dd,J=12.9,4.7Hz,2H),3.54(dd,J=12.9,6.6Hz,2H),2.47(d,J=2.2Hz,2H),2.30(s,2H),1.90-1.86(m,2H),1.20(d,J=6.7Hz,3H),0.88(s,3H);LC-MS(M+H)+493.21(492.19)。
实施例9:7-(2-((S)-4-羟基丁-2-基)氨)乙基-10-甲基-11-氟喜树碱(9)
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向反应瓶中加入(R)-3-氨基丁醇(135.60mg,1.52mmol),盐酸(0.138mL,1.65mmol)和DMSO(1mL),搅拌下升温至110℃,加入7,10-二甲基-11-氟喜树碱(100mg,0.25mmol),升温至130-140℃继续搅拌反应50分钟,冷却,加入异丙醇,过滤,硅胶柱层析纯化得到化合物7-(2-((S)-4-羟基丁-2-)氨)乙基-10-甲基-11-氟喜树碱(53.4mg,产率43.1%,HPLC 99%);1H NMR(500MHz,DMSO-d6)δ8.77(d,J=68.4Hz,1H),8.25(d,J=8.0Hz,1H),7.91(d,J=10.7Hz,1H),7.32(s,1H),6.55(s,1H),5.40(d,J=51.6Hz,4H),3.84-3.70(m,2H),3.54-3.50(m,2H),3.27(s,2H),3.14-3.07(m,2H),2.53(s,3H),1.87(dq,J=21.6,7.2Hz,2H),1.64(dt,J=13.6,6.7Hz,1H),1.26(d,J=6.4Hz,3H),0.88(t,J=7.2Hz,3H);LC-MS(M+H)+496.36(理论值495.22)。
实施例10:7-(2-羟乙基氨)乙基-10,11-二氟喜树碱(10)
向装有无水1,2二氯乙烷(80mL)的单口烧瓶中,加入1M BCl3的二氯甲烷溶液(16mL,0.016mol),将反应瓶降温至0℃,加入3,4-二氟苯胺(2.5g,0.019mol),在0℃下反应10min.加入乙腈(8.2g,0.2mol)和三氯化铝(3.5g,0.025mol),缓慢升至室温搅拌10min,然后升温至80°,搅拌12h,将反应液倒入冰水中,加入1MHCl溶液调节pH=2,用二氯甲烷萃取,Na2SO4干燥,加入硅胶粉,柱层析(PE:EA=100%-80%)纯化得到6-氨基-3,4-二氟苯乙酮(1.0g,产率30.2%,HPLC 94%);LC-MS(M+H)+172.21(理论值171.05)。
取6-氨基-3,4-二氟苯乙酮(0.50g,2.9mmol)溶于无水甲苯(5mL)中,加入”三环酮”(769.07mg,2.9mmol)和PPTS(73mg,0.29mmol),反应加热到115°搅拌12h,冷却,减压出去溶剂,加入5mL甲醇,过滤,干燥,得到7-甲基-10,11-二氟喜树碱(0.82g,产率70.69%,HPLC 96%);LC-MS(M+H)+399.23(理论值398.11)。
向反应瓶中加入乙醇胺(46mg,0.75mmol),盐酸(0.07mL,0.8mmol)和DMSO(1mL),搅拌下升温至120℃,加入7-甲基-10,11-二氟喜树碱(50mg,0.125mmol),在120-140°下反应30分钟,冷却至室温,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到产物7-(2-羟乙基氨)乙基-10,11-二氟喜树碱(31mg,产率52.5%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ8.64(s,2H),8.39(dd,J=11.9,8.6Hz,1H),8.29(dd,J=11.3,8.1Hz,1H),7.35(s,1H),6.58(s,1H),5.46(s,2H),5.41(s,3H),3.69(s,2H),3.58-3.49(m,2H),3.30(d,J=5.4Hz,2H),3.10(s,2H),1.88(dt,J=18.5,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+472.09(理论值471.16)。
实施例11:7-(2-((S)-2-甲氧基异丙基)氨)乙基-10,11-二氟喜树碱(11)
向反应瓶中加入(S)-1-甲氧基2-丙胺(100mg,1.02mmol),盐酸(0.09mL,1.08mmol)和DMSO(1.5
mL),搅拌下升温至120℃,加入7-甲基-10,11-二氟喜树碱(50mg,0.125mmol),在120-140℃下反应35
分钟,冷却至室温,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-((S)-2-甲氧基异丙基)氨
)乙基-10,11-二氟喜树碱(42mg,产率67%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.37
(dd,J=11.9,8.6Hz,1H),8.30(dd,J=11.3,8.1Hz,1H),7.36(s,1H),6.58(s,1H),5.46(s,2H),5.41(d,J=4.5Hz,2H),
3.84-3.44(m,6H),3.32-3.25(m,4H),1.88(dd,J=11.6,7.3Hz,2H),1.24(d,J=6.4Hz,3H),0.88(t,J=7.2Hz,3H);LC-
MS(M+H)+500.39(理论值499.19)。
实施例12.:7-(2-(4-羟基环己基)氨)乙基-10,11-二氟喜树碱(12)
将4-氨基环己醇(87mg,0.75mmol)和盐酸(0.07mL,0.84mmol)加入到含有DMSO(1mL)的反应瓶中,搅拌下升温至110℃,加入7-甲基-10,11-二氟喜树碱(50mg,0.125mmol),在120-140℃下反应40分钟,冷却至室温,加入异丙醇,硅胶柱层析纯化得到化合物7-(2-(4-羟基环己基)氨)乙基-10,11-二氟喜树碱(33mg,产率50%,HPLC 97%);1HNMR(500MHz,DMSO-d6)δ8.71(s,1H),8.63(s,1H),8.34(dd,J=11.6,8.9Hz,1H),8.27(dd,J=11.2,8.1Hz,1H),7.34(s,1H),6.57(s,1H),5.46(s,2H),5.40(s,2H),3.81(s,1H),3.52-3.48(m,2H),3.29(d,J=4.4Hz,2H),3.19-3.09(m,1H),1.89(ddq,J=21.4,14.1,7.1Hz,2H),1.73(dd,J=18.8,9.0Hz,4H),1.45(t,J=14.5Hz,2H),1.37(d,J=12.3Hz,1H),1.21(dd,J=18.7,8.4Hz,1H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+526.15(理论值525.21)。
实施例13:7-(2-(四氢吡喃-4-基)氨基)乙基-10,11-二氟喜树碱(13)
向反应瓶中加入4-氨基四氢吡喃(88mg,0.86mmol),盐酸(0.072mL,0.86mmol),7-甲基-10,11-二氟喜树碱(50mg,0.125mmol)和DMSO(1.5mL),搅拌下加热至135-145℃ 30分钟,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-(四氢吡喃-4-基)氨基)乙基-10,11-二氟喜树碱(43mg,产率67%,HPLC 95%)
;1H NMR(500MHz,DMSO-d6)δ8.68(s,2H),8.32(ddd,J=19.2,11.4,8.4Hz,2H),7.35(s,1H),6.57(s,1H),5.44(d,
J=18.6Hz,4H),3.93(dd,J=11.2,3.5Hz,2H),3.50 3.47(m,3H),3.31(t,J=11.6Hz,4H),1.94(d,J=11.7Hz,2H),1.87(dd,J=15.5,7.5Hz,2H),1.56(d,J=12.0Hz,2H),0.87(t,J=7.3Hz,3H);LC-MS(M+H)+512.09(理论值511.19)。
实施例14:7-(2-(4-甲氧基环己基)氨)乙基-10,11-二氟喜树碱(14)
向反应瓶中加入4-甲氧基环己胺(0.12g,0.9mmol),盐酸(0.075mL,0.9mmol)和DMSO(1mL),搅拌下加热至120°,加入7-甲基-10,11-二氟喜树碱(50mg,0.125mmol),升温至130°后反应30分钟,冷却至室温,加甲醇,抽滤,硅胶柱层析纯化得到化合物7-(2-(4-甲氧基环己基)氨)乙基-10,11-二氟喜树碱(35.2mg,产率55.8%,HPLC 99%);1H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.32(ddd,J=21.8,11.6,8.3Hz,1H),7.36(s,1H),6.58(s,1H),5.44(d,J=19.1Hz,4H),3.48(s,2H),3.28(d,J=4.7Hz,2H),3.24(s,3H),3.14-3.05(m,2H),2.07(d,J=10.5Hz,4H),1.88(dt,J=18.8,7.0Hz,2H),1.37(dd,J=23.3,11.8Hz,2H),1.16(dd,J=23.0,10.6Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+540.30(理论值539.22)。
实施例15:7-(2-(2-叠氮乙基)氨)乙基-10,11-二氟喜树碱(15)
向反应瓶中加入2-叠氮乙胺盐酸盐(80mg,0.93mmol),7-甲基-10,11-二氟喜树碱(50mg,0.125mmol)和DMSO(1mL),搅拌升温至120-140℃反应30分钟,冷却至室温,加入异丙醇,过滤,硅胶柱层析纯化得到产物7-(2-(2-叠氮乙基)氨)乙基-10,11-二氟喜树碱(39mg,产率63%,HPLC 94%);1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.37(dd,J=11.9,8.6Hz,1H),8.30(dd,J=11.4,8.1Hz,1H),7.36(s,1H),6.58(s,1H),5.46(s,2H),5.41(s,2H),3.97-3.71(m,2H),3.53(d,J=4.2Hz,2H),3.37-3.26(m,2H),3.21(s,2H),1.88(dt,J=18.5,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+497.13(理论值496.17)。
实施例16:7-(2-(2-叠氮乙基)氨)乙基-10,11-亚甲基二氧喜树碱(16)
将3,4-亚甲基二氧-6-氨基苯乙酮(5g,0.028mol)溶于无水甲苯(10mL)中,加入”三环酮“(7.35g,0.028mol)和PPTS(0.7g,0.0028mol),反应加热到115°搅拌12h,冷却,减压浓缩溶剂,加入20mL甲醇,过滤,干燥,得到7-甲基-10,11-亚甲基二氧喜树碱(11.0g,产率97%);LC-MS(M+H)+407.15(理论值406.12)。
将2-叠氮乙胺盐酸盐(63.56mg,0.74mmol),DMSO(1mL)和7-甲基-10,11-亚甲基二氧喜树碱(50mg,0.12mmol),搅拌下反应液升温至110-130℃反应1h,加入异丙醇,过滤固体,硅胶柱层析纯化得到产物7-(2-(2-叠氮乙基)氨)乙基-10,11-亚甲基二氧喜树碱(29mg,产率47.9%,HPLC 99%);1H NMR(500MHz,DMSO-d6)δ8.91(s,2H),7.61(s,1H),7.48(s,1H),7.20(s,1H),6.26(d,J=2.4Hz,1H),5.39(s,1H),5.22(s,1H),3.75-3.69(m,2H),3.18(d,J=26.4Hz,4H),2.47-2.44(m,2H),1.83(dt,J=14.3,6.9Hz,2H),0.83(t,J=7.3Hz,3H);13C NMR(126MHz,DMSO)δ163.00,147.31,141.50,140.63,140.00,137.65,136.58,127.48,118.93,118.93,108.67,96.12,93.28,89.64,86.54,62.88,55.70,40.28,37.46,36.36,36.36,30.86,20.71,16.74;LC-MS(M+H)+505.17(理论值504.18)。
实施例17:7-(2-(2-甲氧基乙基)氨)乙基-10,11-亚甲基二氧喜树碱(17)
将2-甲氧基乙胺(2.5g,0.03mol)和盐酸(4mL,0.05mol)溶解于DMSO中(10mL),搅拌下加热至110℃,加入7-甲基-10,11-亚甲基二氧喜树碱(1.8g,4.4mmol),继续升温至120-130℃反应1h,冷却至室温,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-(2-甲氧基乙基)氨)乙基-10,11-亚甲基二氧喜树碱(739mg,产率34%,HPLC 97%);1HNMR(500MHz,DMSO-d6)δ7.55(s,1H),7.44(s,1H),7.20(s,1H),6.51(s,1H),6.27(d,J=3.6Hz,2H),5.41(d,J=4.6Hz,2H),5.13(q,J=18.6Hz,2H),3.31-3.18(m,7H),2.94(t,J=7.5Hz,2H),2.85(d,J=4.9Hz,2H),1.86(dt,J=19.4,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+494.12(理论值493.18)。
实施例18:7-(2-((S)-4-羟基丁基-2-)氨)乙基-10,11-亚甲基二氧喜树碱(18)
将(S)-3-氨基丁醇(146.7mg,1.65mmol),浓盐酸(0.14mL,1.68mmol),DMSO(5mL)和7-甲基-10,11-亚甲基二氧喜树碱(100mg,0.24mmol),反应液搅拌加入至110-125℃反应50分钟,冷却至室温,加入甲基叔丁基醚,过滤析出固体,硅胶柱层析得到化合物7-(2-((S)-4-羟基丁基-2-)氨)乙基-10,11-亚甲基二氧喜树碱(62mg,产率51%,HPLC 93%);1HNMR(500MHz,DMSO-d6)δ11.53(s,1H),8.45(d,J=7.7Hz,1H),7.57(s,1H),7.46(s,1H),7.31(d,J=7.7Hz,2H),6.93(s,2H),6.28(s,2H),5.31(s,2H),4.03(s,2H),3.56-3.48(m,3H),3.43(d,J=4.5Hz,3H),1.87-1.71(m,2H),1.66(dd,J=13.4,6.7Hz,1H),1.52(dd,J=13.4,6.4Hz,1H),1.10(d,J=6.5Hz,3H),0.84(t,J=7.3Hz,3H);LC-MS(M+H)+508.33(理论值507.20)。
实施例19:7-(2-((S)-2-甲氧基异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(19)
向反应瓶中加入(S)-1-甲氧基2-丙胺(100mg,1.12mmol),盐酸(0.7mL,0.8mmol),DMSO(3mL)和7-甲基-10,11-亚甲基二氧喜树碱(50mg,0.12mmol),搅拌下升温至120°反应50分钟,冷却至室温,加入甲基叔丁基醚,过滤析出固体,用硅胶柱层析纯化得到产物7-(2-((S)-2-甲氧基异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(36mg,产率61%,HPLC 99%);1H NMR(500MHz,DMSO-d6)δ8.64(s,2H),7.69(s,1H),7.57(s,1H),7.27(s,1H),6.53(s,1H),6.33(s,2H),5.44(s,1H),5.33(d,J=4.7Hz,2H),3.71-3.54(m,2H),3.47(dd,J=10.1,5.8Hz,6H),3.25(d,J=13.6Hz,2H),1.88(dt,J=14.2,9.2Hz,2H),1.24(d,J=6.4Hz,3H),0.88(dd,J=9.4,5.3Hz,3H);LC-MS(M+H)+508.37(理论值507.20)。
实施例20:7-(2-(3-氧杂环丁基)氨)乙基-10,11-亚甲基二氧喜树碱(20)
将3-氧杂环丁胺(84mg,1.14mmol)和盐酸(0.1ml,1.2mmol)溶解于DMSO(2mL)中,搅拌加热至120℃,加入7-甲基-10,11-亚甲基二氧喜树碱(100mg,0.24mmol),升温至130℃反应50分钟,冷却后加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-(3-氧杂环丁基)氨)乙基-10,11-亚甲基二氧喜树碱(49mg,产率41.5%,HPLC 94%);1H NMR(500MHz,DMSO-d6)δ7.72(s,1H),7.51(s,1H),7.24(s,1H),6.48(s,1H),6.30(s,2H),5.42(s,2H),5.27(d,J=3.4Hz,2H),4.28(d,J=8.4Hz,1H),4.13-4.00(m,1H),3.93(s,1H),3.61(d,J=11.7Hz,1H),3.55 3.40(m,5H),1.87(td,J=14.2,6.8Hz,2H),0.88(t,J=7.2Hz,3H);LC-MS(M+H)+492.01(理论值491.17)。
实施例21:7-(2-(1,3-二甲氧基异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(21)
在反应瓶中加入2-氨基-1,3-二甲氧基丙烷(100mg,0.84mmol),盐酸(0.072mL,0.86mmol),7-甲基-10,11-亚甲基二氧喜树碱(50mg,0.12mmol)和DMSO(1.5mL),搅拌加热至120℃反应1h,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-(1,3-二甲氧基异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(35mg,产率54.3%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ8.88(s,2H),7.64(s,1H),7.54(s,1H),7.24(s,1H),6.50(s,1H),6.30(s,2H),5.41(s,2H),5.27(s,2H),3.60(dt,J=10.7,6.7Hz,5H),3.41(s,2H),3.32(s,5H),3.28 3.21(m,3H),1.85(dt,J=14.3,6.9Hz,2H),0.85(t,J=7.3Hz,3H);LC-MS(M+H)+538.18(理论值537.21)。
实施例22:7-(2-(2-羟乙基)氨)乙基-10,11-亚甲基二氧喜树碱(22)
在反应瓶中加入乙醇胺(0.5mL,8.2mmol),浓盐酸(0.7mL,8.4mmol),DMSO(10mL)和7-甲基-10,11-亚甲基二氧喜树碱(0.5g,1.2mmol),快速升温至110-120℃搅拌反应0.5小时,冷却至室温,加入甲基叔丁基醚,过滤固体,用硅胶柱层析纯化得到7-(2-(2-羟乙基)氨)乙基-10,11-亚甲基二氧喜树碱(0.38g,产率66%,HPLC 97%);1H NMR(500MHz,DMSO-d6)δ8.70(s,2H),7.66(s,1H),7.53(s,1H),7.23(s,1H),6.50(s,1H),6.30(d,J=1.6Hz,2H),5.42(s,2H),5.27(s,2H),3.82-3.56(m,2H),3.39(s,2H),3.23(d,J=4.9Hz,2H),3.08(s,2H),1.86(dt,J=14.3,6.9Hz,2H),0.86(t,J=7.3Hz,3H);LC-MC(M+H)+480.05(理论值479.17)。
实施例23:7-(2-(2-三氟乙基)氨)乙基-10,11-亚甲基二氧喜树碱(23)
将三氟乙胺盐酸盐(100mg,0.74mmol)和7-甲基-10,11-亚甲基二氧喜树碱(100mg,0.25mmol)溶于DMSO(3mL)中,搅拌加热至120℃反应1h,冷却后加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到产物7-(2-(2-三氟乙基)氨)乙基-10,11-亚甲基二氧喜树碱(49mg,产率38%,HPLC 99%);1H NMR(500MHz,DMSO-d6)δ7.71(s,1H),7.54(s,1H),7.29(s,1H),6.55(s,1H),6.34(d,J=2.0Hz,2H),5.48(d,J=3.0Hz,2H),5.30(s,2H),3.42(s,2H),3.42(s,2H),3.29(s,2H),1.92(dd,J=14.4,7.3Hz,2H),0.94(t,J=7.3Hz,4H);LC-MS(M+H)+518.34(理论值517.15)。
实施例24:7-(2-(2-二氟乙基)氨)乙基-10,11-亚甲基二氧喜树碱(24)
向反应瓶中加入二氟乙胺(1.0g,12mmol),盐酸(1.4mL,16mmol)和7-甲基-10,11-亚甲基二氧喜树碱(1.0g,2.46mmol)和DMSO(5mL),搅拌加热至120℃反应1h,冷却,加异丙醇,抽滤,硅胶柱层析纯化得到产物7-(2-(2-二氟乙基)氨)乙基-10,11-亚甲基二氧喜树碱(393mg,产率32%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ7.68(s,1H),7.52(s,1H),7.28(s,1H),6.58(s,1H),6.33(s,2H),6.02(t,J=56.6Hz,1H),5.47(s,2H),5.26(s,2H),3.26(s,3H),2.94(s,4H),1.92(s,2H),0.93(s,3H);13C NMR(126MHz,DMSO)δ173.06,157.32,151.28,150.60,149.74,149.35,147.57,146.86,141.32,128.53,124.98,119.15,118.45,117.25,115.35,105.91,105.81,103.06,100.05,96.39,72.88,65.73,49.25,44.94,30.79;LC-MS(M+H)+500.13(理论值499.16)。
实施例25:7-(2-(四氢吡喃-4-基)氨)乙基-10,11-亚甲基二氧喜树碱(25)
将4-氨基四氢吡喃(0.75g,7.4mmol),浓盐酸(0.7mL,7.5mmol),DMSO(15mL),在油浴锅中反应升温至120℃,加入7-甲基-10,11-亚甲基二氧喜树碱(0.5g,1.2mmol),升温至130-140°后反应1h,加甲醇,抽滤,取滤液浓缩后用硅胶柱层析纯化,得到灰色固体7-(2-(四氢吡喃-4-基)氨)乙基-10,11-亚甲基二氧喜树碱(0.41g,产率63%,HPLC 96%);1HNMR(500MHz,DMSO-d6)δ7.59(s,1H),7.47-7.41(m,1H),7.25-7.14(m,1H),6.54(s,1H),6.27(t,J=9.9Hz,2H),5.77(s,1H),5.44(d,J=16.5Hz,2H),5.23-5.11(m,2H),3.83(d,J=9.5Hz,2H),3.23(t,J=24.9Hz,4H),2.93(d,J=32.7Hz,3H),1.99-1.72(m,4H),1.33(s,2H),0.96-0.81(m,3H);13C NMR(126MHz,DMSO)δ173.04,157.26,151.30,150.58,149.68,149.42,147.49,146.73,146.68,128.52,124.79,118.49,105.90,103.14,99.83,96.39,72.82,66.05,65.69,55.41,53.65,50.31,30.66,8.27;LC-MS(M+H)+520.11(理论值519.20)。
实施例26:7-(2-(4-羟基环己基)氨)乙基-10,11-亚甲基二氧喜树碱(26)
在反应瓶中加入4-氨基环己醇(107.05mg,0.93mmol),浓盐酸(0.1mL,1.2mmol),DMSO(4mL)中,在油浴锅中反应升温至100℃,加入7-甲基-10,11-亚甲基二氧喜树碱(100mg,0.25mmol),升温至140°后反应0.5h,倒入水中,过滤固体,硅胶柱层析纯化得到产物7-(2-(4-羟基环己基)氨)乙基-10,11-亚甲基二氧喜树碱(33mg,产率28%,HPLC 91%);1H NMR(500MHz,DMSO-d6)δ8.47(s,1H),7.67(s,1H),7.57(s,1H),7.27(s,1H),6.33(s,2H),5.44(s,2H),5.35(s,2H),3.81(s,2H),3.25(s,2H),3.13(d,J=4.6Hz,2H),1.87(ddd,J=21.5,12.6,5.8Hz,2H),1.72(d,J=20.0Hz,6H),1.46(d,J=10.8Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+534.08(理论值533.22)。
实施例27:7-(2-(4-甲氧基环己基)氨)乙基-10,11-亚甲基二氧喜树碱(27)
将4-甲氧基环己胺(117.7mg,0.91mmol),盐酸(0.08mL,0.96mmol),DMSO(2mL)和7-甲基-10,11-亚甲基二氧喜树碱(50mg,0.12mmol),搅拌下加热至115-125℃,反应1h,冷却,加入甲基叔丁基醚,过滤固体,硅胶柱层析纯化得到化合物7-(2-(4-甲氧基环己基)氨)乙基-10,11-亚甲基二氧喜树碱(37mg,产率56%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ8.76(s,1H),7.64(s,1H),7.53(s,1H),7.24(s,1H),6.31(d,J=3.2Hz,2H),5.43(s,2H),5.29(s,2H),3.44 3.36(m,2H),3.22(dd,J=11.4,4.0Hz,5H),3.12(d,J=3.9Hz,2H),1.93-1.80(m,2H),1.39(d,J=11.4Hz,4H),1.15(d,J=13.0Hz,4H),0.88(t,J=7.2Hz,3H);LC-MS(M+H)+548.35(理论值547.23)。
实施例28:7-(2-((S)-羟基异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(28)
在反应瓶中分别加入(S)-2-氨基1-丙醇(110.89mg,1.48mmol),浓盐酸(0.14ml,1.68mmol),DMSO(3mL)和7-甲基-10,11-亚甲基二氧喜树碱(100mg,0.25mmol),搅拌加热至120-130℃反应1h,冷却至室温,加入甲基叔丁基醚,过滤析出固体,硅胶柱层析纯化得到产物7-(2-((S)-羟基异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(84.94mg,产率69%,HPLC99%);1H NMR(500MHz,DMSO-d6)δ8.57(s,2H),7.70(s,IH),7.57(s,1H),7.27(s,1H),6.53(s,1H),6.33(d,J=2.0Hz,2H),5.50(s,1H),5.44(s,2H),5.34(d,J=4.6Hz,2H),3.70(d,J=8.5Hz,1H),3.57-3.45(m,4H),3.23(d,J=6.5Hz,2H),1.96-177(m,2H),1.21(d,J=6.6Hz,3H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+494.08(理论值493.18)。
实施例29:7-(2-((S)-叠氮异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(29)
在100ml三口瓶中和Ar2保护下,加入化合物(S)-2-N-Boc氨基丙醇(1g,0.57mmol),加入10ml干燥的DCM,搅拌溶解后,反应液冷却至0℃,加入TEA(0.87g,0.86mmol),然后滴加MsCl(0.78g,0.68mmol),保持在0℃下搅拌2小时,反应液加入水(10ml),DCM萃取,干燥,浓缩有机相得到化合物(S)-2-N-Boc氨基丙醇甲磺酸酯(1.4g,产率97.2%),不经进一步纯化直接用于下一步。
将(S)-2-N-Boc氨基丙醇甲磺酸酯(1.4g,0.55mmol)溶解于DMF(10ml)中,加入NaN3(0.36g,0.55mmol),40℃下搅拌反应过夜,反应液加入水(20ml),EA萃取三次后,合并有机相,用水洗3次,然后浓缩有机相,硅胶柱层析纯化,得到1-叠氮-2-(S)-N-Boc丙胺(0.8g,产率72%)。
将1-叠氮-2-(S)-N-Boc丙胺(0.8g,4mmol),溶于乙酸乙酯(2ml)中,滴加4N氯化氢的乙酸乙酯溶液(5ml 20mmol),搅拌2小时,浓缩得到1-叠氮-2-(S)-异丙胺(0.5g,产率92%);1H NMR(500MHz,CDCl3)δ4.72(s,1H),3.85(s,1H),3.39(s,1H),3.32(dd,J=12.0,4.6Hz,1H),1.45(s,9H),1.27-1.04(m,3H)。
将上述制备的1-叠氮-2-(S)-异丙胺盐酸盐(147.8mg,1.08mmol),7-甲基-10,11-亚甲基二氧喜树碱(100mg,0.25mmol)溶解于DMSO(1.5mL)中,搅拌下加热至115-125℃反应1h,加异丙醇,过滤,硅胶柱层析纯化,得到产物7-(2-((S)-叠氮异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(57mg,产率44%,HPLC 93%);1H NMR(600MHz,DMSO-d6)δ7.68(s,1H),7.55(m,1H),7.26(s,1H),6.52(s,1H),6.46(s,2H),5.45(d,J=16.7Hz,2H),5.36-5.25(m,2H),4.80-4.60(m,1H),3.85-3.8(m,z,2H)3.52-3.38(m,4H),1.86(m,J=28.9,14.5,7.3Hz,2H),1.57-1.46(m,3H),0.87(t,J=7.3Hz,3H);LC-MS(M+H)+519.02(理论值518.19)。
实施例30:7-(2-(N-羟基乙酰基((S)-甲氧基异丙基))氨)乙基-10,11-亚甲基二氧喜树碱(30)
将乙醇酸(7mg,0.09mmol)加入DMF(1mL)中,冰浴条件下依次加入HATU(25mg,0.065mmol)和DIPEA(7.0μL),冰浴条件下搅拌30min后,加入7-(2-((S)-2-甲氧基异丙基)氨)乙基-10,11-亚甲基二氧喜树碱(10mg,0.02mmol,实施例19),缓慢升至室温后搅拌18h,用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-(N-羟基乙酰基((S)-甲氧基异丙基))氨)乙基-10,11-亚甲基二氧喜树碱(6mg,产率54%,HPLC 95%);LC-MS(M+H)+566.58(理论值565.21)。
实施例31:7-(2-(N-羟基乙酰基(2-叠氮乙基))氨)乙基-10,11-亚甲基二氧喜树碱(31)
将乙醇酸(7mg,0.09mmol)加入DMF(1mL)中,冰浴条件下依次加入HATU(25mg,0.065mmol)和DIPEA(7.0μL),冰浴条件下搅拌30min后,加入7-(2-(2-叠氮乙基)氨)乙基-10,11-亚甲基二氧喜树碱(10mg,0.02mmol,实施例16),缓慢升至室温后搅拌18h,用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-(N-羟基乙酰基(2-叠氮乙基))氨)乙基-10,11-亚甲基二氧喜树碱(6mg,产率58%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ7.67(s,1H),7.55(s,1H),7.25(s,1H),6.51(s,1H),6.32(s,2H),5.43(s,2H),5.30(s,2H),3.91(s,2H),3.79 3.68(m,2H),3.26(s,2H),3.20(s,2H),2.62(d,J=4.6Hz,1H),2.54(d,J=7.6Hz,1H),1.86(ddd,J=21.5,14.2,7.0Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+563.54(理论值562.18)。
实施例32:7-(2-(N-羟基乙酰基(2-甲氧基乙基))氨)乙基-10,11-亚甲基二氧喜树碱(32)
将乙醇酸(7mg,0.09mmol)加入DMF(1mL)中,冰浴条件下依次加入HATU(25mg,0.065mmol)和DIPEA(7.0μL),冰浴条件下搅拌30min后,加入7-(2-(2-甲氧基乙基)氨)乙基-10,11-亚甲基二氧喜树碱(10mg,0.02mmol,实施例17),缓慢升至室温后搅拌18h,用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-(N-羟基乙酰基(2-甲氧基乙基))氨)乙基-10,11-亚甲基二氧喜树碱(6mg,产率60%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.48(s,1H),7.22-7.16(m,1H),6.29(d,J=2.8Hz,2H),5.42(s,2H),5.24(s,3H),3.56-3.45(m,8H),3.37-3.21(m,5H),1.99-1.77(m,2H),0.88(t,J=7.2Hz,3H);LC-MS(M+H)+552.55(理论值551.19)。
实施例33:7-(2-(N-羟基乙酰基(2-二氟乙基))氨)乙基-10,11-亚甲基二氧喜树碱(33)
将乙醇酸(7mg,0.09mmol)加入DMF(1mL)中,冰浴条件下依次加入HATU(23mg,0.06mmol)和DIPEA(7.0μL),冰浴条件下搅拌30min后,加入7-(2-(2-二氟乙基)氨)乙基-10,11-亚甲基二氧喜树碱(10mg,0.019mmol,实施例24),缓慢升至室温后搅拌18h,用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到化合物7-(2-(N-羟基乙酰基(2-二氟乙基))氨)乙基-10,11-亚甲基二氧喜树碱(6mg,产率54%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.51(d,J=5.2Hz,1H),7.24(d,J=3.2Hz,1H),6.30(s,2H),5.42(s,2H),5.30(d,J=6.1Hz,2H),4.16(d,J=31.8Hz,2H),3.92(t,J=12.6Hz,2H),3.66-3.54(m,2H),3.44(s,1H),3.38-3.24(m,2H),1.87(dt,J=14.2,6.9Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+
557.55(理论值557.16)。
实施例34:7-(2-(N-(R)-四氢呋喃-3-氨))乙基-10,11-亚甲基二氧喜树碱(34)
在反应瓶中分别加入(R)-3-氨基四氢呋喃(64.31mg,0.738mmol),浓盐酸(0.05mL,0.6mmol),DMSO(1.5mL)和7-甲基-10,11-亚甲基二氧喜树碱(50mg,0.12mmol),搅拌加热至120-130℃反应1h,冷却至室温,加入甲基叔丁基醚,过滤析出固体,硅胶柱层析纯化得到产物7-(2-(N-(R)-四氢呋喃-3-氨))乙基-10,11-亚甲基二氧喜树碱(16.2mg,产率32.3%,HPLC 96.2%);1H NMR(500MHz,DMSO-d6)δ7.61(s,1H),7.47(s,1H),7.22(s,1H),6.50(s,1H),6.28(s,2H),5.42(s,2H),5.21(s,2H),4.21-3.53(m,4H),3.21(t,J=7.6Hz,2H),2.84(q,J=8.7,8.1Hz,2H),1.90(ddt,J=31.9,16.2,7.1Hz,3H),1.63(dd,J=12.3,6.1Hz,1H),0.88(t,J=7.3Hz,3H);13C NMR(126MHz,DMSO)δ173.0,157.3,151.3,150.6,149.7,149.4,147.5,146.8,141.2,128.6,124.9,118.4,105.9,103.1,99.9,96.4,72.9,66.9,65.7,58.4,55.4,50.4,47.6,32.6,30.7,30.6,8.3;LC-MS(M+H)+506.34(理论值505.18)。
实施例35:7-(2-(N-(S)-四氢呋喃-3-氨))乙基-10,11-亚甲基二氧喜树碱(35)
在反应瓶中分别加入(S)-3-氨基四氢呋喃(64.31mg,0.738mmol),浓盐酸(0.05mL,0.6mmol),DMSO(1.5mL)和7-甲基-10,11-亚甲基二氧喜树碱(50mg,0.12mmol),搅拌加热至120-130℃反应1h,冷却至室温,加入甲基叔丁基醚,过滤析出固体,硅胶柱层析纯化得到产物7-(2-(N-(R)-四氢呋喃-3-氨))乙基-10,11-亚甲基二氧喜树碱(18mg,产率33%,HPLC 95.9%);1H NMR(500MHz,DMSO-d6)δ7.61(d,J=3.4Hz,1H),7.47(d,J=3.9Hz,1H),7.22(d,J=4.2Hz,1H),6.50(s,1H),6.29(d,J=4.0Hz,2H),5.42(d,J=4.0Hz,2H),5.21(d,J=3.2Hz,2H),3.87-3.58(m,4H),3.21(s,2H),2.85(td,J=11.2,10.7,5.8Hz,2H),1.90(ddt,J=29.9,10.7,6.2Hz,3H),1.68-1.60(m,1H),1.08-0.76(m,3H);13C NMR(126MHz,DMSO)δ173.0,157.3,151.3,150.6,149.7,149.4,147.6,146.9,141.2,128.6,124.9,118.5,105.9,103.1,100.0,96.4,72.9,72.7,66.9,65.7,58.4,50.4,47.6,32.6,30.7,30.6,8.2;LC-MS(M+H)+506.31(理论值505.18)。
实施例36:7-(2-二氟乙酰氨)乙基-10,11-亚甲基二氧喜树碱(36)
将160mg氯化铵和6滴盐酸加入DMSO(9mL)中,在油浴锅中反应升温至120℃,加入7-甲基-10,11-亚甲基二氧喜树碱(200mg,0.49mmol),升温至130℃反应1h,冷却至室温,加甲醇打浆,抽滤,浓缩掉部分DMSO,用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-氨乙基-10,11-亚甲基二氧喜树碱(99mg,产率46%,HPLC 96%);1H NMR(500MHz,DMSO-d6)δ7.99(s,2H),7.70(s,1H),7.59(s,1H),7.30(s,1H),6.37(s,2H),5.49(s,2H),5.32(s,2H),3.67-3.49(m,2H),3.18(s,2H),1.93(dd,J=10.5,7.3Hz,2H),0.94(t,J=7.3Hz,3H);13C NMR(126MHz,DMSO)δ173.01,157.29,151.46,150.63,150.01,149.76,147.65,146.66,137.76,129.10,124.77,118.63,106.14,103.25,99.61,96.48,72.88,65.69,50.31,38.50,30.70,27.97,8.23;LC-MS(M+H)+436.41(理论值435.14)。
将7-氨乙基-10,11-亚甲基二氧喜树碱(20mg,0.046mmol)加入到反应瓶中,加入DMF(5mL),加入二氟乙酸(8.8mg,0.092mmol),然后加入HATU(35mg,0.092mmol),DIPEA(12mg,0.092mmol),常温反应一小时,滴加0.5ml水淬灭反应,反应液用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到目标产物7-(2-二氟乙酰氨)乙基-10,11-亚甲基二氧喜树碱(14.6mg,产率62%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ9.00(s,1H),7.67(s,1H),7.51(s,1H),7.24(s,1H),6.30(s,2H),5.43(s,2H),5.24(s,2H),3.51(dd,J=13.6,6.8Hz,2H),3.31-3.23(m,2H),2.07-1.75(m,2H),0.90-0.80(m,3H);13C NMR(126MHz,DMSO)δ173.02,157.30,151.39,150.61,149.83,149.55,147.63,146.77,139.56,128.71,125.06,118.54,109.02,106.04,103.14,99.81,96.42,72.88,65.71,53.93,50.23,42.21,38.28,30.67,13.04;LC-MS(M+H)+514.25(理论值513.13)。
实施例37:7-(2-叠氮乙酰氨)乙基-10,11-亚甲基二氧喜树碱(37)
将7-氨乙基-10,11-亚甲基二氧喜树碱(15mg,0.035mmol)加入到反应瓶中,加入DMF(5mL),加入叠氮乙酸(7.2mg,0.071mmol),然后加入HATU(35mg,0.092mmol),DIPEA(12mg,0.092mmol),常温反应一小时,滴加0.5ml水淬灭反应,反应液用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到目标产物7-(2-叠氮乙酰氨)乙基-10,11-亚甲基二氧喜树碱(13.1mg,产率71%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ8.33(s,1H),7.69(s,1H),7.51(s,1H),7.23(s,1H),6.49(s,1H),6.30(s,2H),5.42(s,2H),5.24(s,2H),3.80(s,2H),3.46(d,J=6.3Hz,2H),3.25(s,2H),1.86(dt,J=18.9,6.9Hz,2H),0.87(d,J=7.3Hz,3H);LC-MS(M+H)+519.29(理论值518.15)。
实施例38:7-(2-甲磺酰氨)乙基-10,11-亚甲基二氧喜树碱(38)
将7-氨乙基-10,11-亚甲基二氧喜树碱(15mg,0.034mmol)加入到反应瓶中,加入DMF(5mL),加入甲磺酰氯(5mg,0.043mmol),然后加入DIPEA(47.5mg,0.368mmol),常温反应一小时,滴加0.5ml水淬灭反应,反应液用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-甲磺酰氨)乙基-10,11-亚甲基二氧喜树碱(14.2mg,产率80%,HPLC 96%);1H NMR(500MHz,DMSO-d6)δ7.56(s,1H),7.48(s,1H),7.21(d,J=8.4Hz,2H),6.28(d,J=2.1Hz,3H),5.42(d,J=3.1Hz,2H),5.19(s,2H),3.27(s,4H),2.84(s,3H),1.87(dt,J=14.5,7.0Hz,2H),0.89(t,J=7.3Hz,3H);LC-MS(M+H)+514.25(理论值513.12)。
实施例39:7-(2-环丙基磺酰氨)乙基-10,11-亚甲基二氧喜树碱(39)
将7-氨乙基-10,11-亚甲基二氧喜树碱(20mg,0.046mmol)加入到反应瓶中,加入DMF(5mL),加入环丙基磺酰氯(12.9mg,0.092mmol),然后加入DIPEA(47.5mg,0.368mmol),常温反应一小时,滴加0.5ml水淬灭反应,反应液用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到产物7-(2-环丙基磺酰氨)乙基-10,11-亚甲基二氧喜树碱(19.4mg,产率78%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ
7.60(s,IH),7.50(s,IH),7.28(s,IH),7.23(s,IH),6.49(s,IH),6.29(s,2H),5.42(s,2H),5.25(s,2H),3.35(s,2H),3.29-3.20(m,2H),1.87(td,J=I4.2,7.0Hz,2H),1.24(ddd,J=20.4,13.3,6.6Hz,2H),0.94-0.79(m,6H);LC-MS(M+H)+540.26(理论值539.14)。
实施例40:7-(2-(吡唑-5-氨))乙基-10,11-亚甲基二氧喜树碱(40)
将1H-3-吡唑甲胺(71.69mg,0.74mmol)和盐酸(72μL)加入DMSO(1.5mL)中,在油浴锅中反应升温至110℃,加入7-甲基-10,11-乙二氧喜树碱(50mg,0.12mmol),升温至135℃继续反应1h,冷却后加甲醇打浆,抽滤,用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到目标产物7-(2-(吡唑-5-氨))乙基-10,11-亚甲基二氧喜树碱(20.8mg,产率33.6%,HPLC 98%);LC-MS(M+H)+516.35(理论值515.18)。
实施例41:7-(2-(1,2,4-三氮唑-5-氨))乙基-10,11-亚甲基二氧喜树碱(41)
将1H-1,2,4-三唑-3-胺(62.07mg,0.74mmol)和盐酸(72μL)加入到DMSO(1.5mL)中,搅拌升温至120℃,加入7-甲基-10,11-乙二氧喜树碱(50mg,0.12mmol),升温至140℃继续反应1h,冷却至室温,加甲醇,抽滤,浓缩,用0.1%TFA(A)与乙腈(B)制备,0-4min:A:90%-75%,B:10%-25%;4-25min:A:75%-60%,B:25%-40%;25-35min:A:60%-50%,B-40%-50%;35-60min:A:50%-10%,B:50%-90%,得到目标产物7-(2-(1,2,4-三氮唑-5-氨))乙基-10,11-亚甲基二氧喜树碱(31.4mg,产率52%,HPLC 96%);LC-MS(M+H)+503.30(理论值502.16)。
实施例42:7-(2-(2-甲氧基乙基)氨)乙基-10,11-乙基二氧喜树碱(42)
向装有无水1,2二氯乙烷(160mL)的单口烧瓶中,加入1M BCl3的二氯甲烷溶液(32mL,32mmol溶在二氯甲烷中).将反应瓶降温至0℃.加入3.4-乙基二氧苯胺(5g,33.08mmol),0℃下反应10min.加入乙腈(16.40g,409.54mmol)和三氯化铝(7g,52.5mmol),缓慢升至室温搅拌10min,然后升温至80℃,搅拌12h,将反应液倒入冰水中,加入1MHCl溶液调节pH=2.用二氯甲烷萃取,Na2SO4干燥,硅胶柱层析纯化得到6-氨基-3,4-乙基二氧苯乙酮(2g,产率31.3%,HPLC 95%);LC-MS(M+H)+194.17(理论值193.07)。.
取6-氨基-3,4-乙基二氧苯乙酮(0.5g,0.26mmol)溶于无水甲苯(30mL)中,搅拌下加入”三环酮“(0.68g,0.26mmol)和PPTS(0.065g,0.026mmol),反应液加热到115℃搅拌12h.冷却,减压浓缩溶剂,加入5mL甲醇,过滤,滤饼干燥,得到7-甲基-10,11-乙基二氧喜树碱(1.0g,产率91%,HPLC 95%);1H NMR(500MHz,DMSO-d6)δ7.55(d,J=19.7Hz,2H),7.25(s,1H),6.48(s,1H),5.42(s,2H),5.19(s,2H),4.44(s,4H),2.66(s,3H),1.86(s,2H),0.88(s,3H);LC-MS(M+H)+421.15(理论值420.13)。
将2-甲氧基乙胺(33mg,0.44mmol),盐酸(0.035mL,0.42mmol),DMSO(1mL)和7-甲基-10,11-乙二氧喜树碱(25mg,0.06mmol),搅拌下升温至120-130℃,反应30分钟,冷却至室温,加入异丙醇,过滤,硅胶柱层析纯化得到产物7-(2-(2-甲氧基乙基)氨)乙基-10,11-乙基二氧喜树碱(17mg,产率55.7%,HPLC 97%);1H NMR(500MHz,DMSO-d6)δ8.68(s,2H),7.73(s,1H),7.60(s,1H),7.26(s,1H),6.52(s,1H),5.44(s,2H),5.31(s,2H),4.46(s,4H),3.67-3.55(m,2H),3.43(s,3H),3.27-3.15(m,5H),1.97-1.77(m,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+508.18(理论值507.20)。
实施例43:7-(2-(四氢吡喃-4-基)氨)乙基-10,11-乙基二氧喜树碱(43)
将4-氨基四氢吡喃(72mg,0.71mmol)和盐酸(0.06mL,0.72mmol)加入到DMSO(1.5.mL)中,搅拌下升温至120℃,加入7-甲基-10,11-乙二氧喜树碱(50mg,0.12mmol),升温至130℃继续反应30分钟,冷却至室温,加入甲基叔丁基醚,过滤,硅胶柱层析纯化得到化合物7-(2-(四氢吡喃-4-基)氨)乙基-10,11-乙基二氧喜树碱(37mg,产率57.8%,HPLC95%);LC-MS(M+H)+534.19(理论值533.22)。
实施例44:7-(2-(4-甲氧基环己基)氨)乙基-10,11-乙基二氧喜树碱(44)
向反应瓶中加入4-甲氧基环己胺(52mg,0.45mmol),盐酸(0.035mL,0.42mmol),DMSO(1.5mL)和7-甲基-10,11-乙二氧喜树碱(50mg,0.12mmol),搅拌下升温至120-130℃反应45分钟,加入异丙醇,过滤,硅胶柱层析纯化得到化合物7-(2-(4-甲氧基环己基)氨)乙基-10,11-乙基二氧喜树碱(34mg,产率50.5%,HPLC 97%);1H NMR(500MHz,DMSO-d6)δ8.56(s,2H),7.69(s,1H),7.60(s,1H),7.28(s,1H),5.44(s,2H),5.32(s,2H),4.46(s,4H),3.31(s,2H),3.24(s,5H),3.12(d,J=10.1Hz,2H),2.06(d,J=10.3Hz,4H),1.96-1.81(m,2H),1.37(dd,J=23.1,11.7Hz,2H),1.16(dd,J=22.9,10.6Hz,2H),0.88(t,J=7.3Hz,3H);LC-MS(M+H)+562.24(理论值561.25)。
实施例45:7-(2-((S)-甲氧异丙基)氨)乙基-10,11-乙基二氧喜树碱(45)
将(S)-1-甲氧基2-丙胺(47.5mg,0.53mmol)和盐酸(0.04mL,0.48mmol)加入到含有DMSO(1mL)的反应瓶中,搅拌下升温至110℃,加入7-甲基-10,11-乙二氧喜树碱(50mg,0.12mmol),升温至130℃下反应30分钟,冷却至室温,加入异丙醇,过滤,硅胶柱层析纯化得到产物7-(2-((S)-甲氧异丙基)氨)乙基-10,11-乙基二氧喜树碱(34.6mg,产率55.3%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ8.64(s,1H),7.70(s,1H),7.58(s,1H),7.25(s,1H),5.41(s,1H),5.29(d,J=4.7Hz,1H),4.44(s,4H),3.59-3.54(m,2H),3.44(dd,J=10.3,5.7Hz,4H),3.23(d,J=19.3Hz,4H),1.92-1.79(m,2H),1.21(d,J=6.5Hz,3H),0.85(t,J=7.3Hz,3H);LC-MS(M+H)+522.16(理论值521.22)。
实施例46:抑制肿瘤细胞生长活性
将人食管癌细胞OE33(人乳腺腺癌细胞SK-BR-3,或人胃癌细胞NCI-N87)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2)。
表2.化合物抑制肿瘤细胞生长的IC50(nM)值
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注:“-”表示未测试。
以上所述,仅为本发明的实施例而已,并非用于限定本发明的保护范围,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.式1表示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和R2各自独立地表示卤素、羟基、烷基、烷氧基、或R1和R2共同组成亚甲基二氧桥或乙基二氧桥;
R3和R4各自独立地表示氢、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、酰基、磺酰基,或R3、R4和与之连接的氮原子共同形成杂环烷基或杂芳基,所述烷基、烷氧基、环烷基、烷基酰基、磺酰基、杂环烷基、芳基、或杂芳基任选地被R取代,
R选自卤素、羟基、烷基、烷氧基、环烷基、叠氮或5至7元杂芳基。
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,其中,R1和R2各自独立地表示卤素、羟基、C1-C6烷基、C1-C6烷氧基,或R1和R2共同组成亚甲基二氧桥或乙基二氧桥;
优选地,R1和R2各自独立地表示卤素、甲基,或R1和R2共同组成亚甲基二氧桥或乙基二氧桥,
优选地,R1和R2各自独立地表示甲基、F、Cl、Br、I,或R1和R2共同组成亚甲基二氧桥或乙基二氧桥;
优选地,R1和R2各自独立地表示甲基、F,或R1和R2共同组成亚甲基二氧桥或乙基二氧桥。
3.根据权利要求1或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,R3和R4各自独立地表示氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4至8元杂环烷基、5至12元芳基、5至12元杂芳基、C1-C6烷基-酰基、C1-C6烷基-磺酰基、C3-C6环烷基-磺酰基,或者R3、R4和与之连接的氮原子共同形成4至8元杂环烷基,所述C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4至8元杂环烷基、5至12元芳基、5至12元杂芳基、C1-C6烷基-酰基、C1-C6烷基-磺酰基、C3-C6环烷基-磺酰基任选地被R取代;
优选地,R3和R4各自独立地表示C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基,或者R3、R4和与之连接的氮原子共同形成5至6元杂环烷基,所述C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基任选地被R取代;
优选地,R3和R4各自独立地表示C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基,或者R3、R4和与之连接的氮原子共同形成5至6元杂环烷基,所述C1-C6烷基、C3-C6环烷基、5至6元杂环烷基、5至6元杂芳基、C1-C3烷基-酰基、C1-C3烷基-磺酰基、C3-C6环烷基-磺酰基任选地被R取代,或者R3、R4和与之连接的氮原子共同形成5至6元杂环烷基,所述杂环烷基、杂芳基含有1-3个独立地选自N、O的杂原子;
优选地,R3和R4各自独立地选自以下基团:
或者R3、R4和与之连接的氮原子共同形成吡咯烷、哌啶、哌嗪,
优选地,所述-NR3R4各自独立地或共同为以下结构:
更优选地,R3、R4和与之连接的氮原子共同形成
4.根据权利要求1-3中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,其中,R选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基或叠氮;
优选地,R选自F、Cl、Br、I、羟基、甲基、甲氧基、环丙基或叠氮;
优选地,R选自F、羟基、甲基、甲氧基、环丙基或叠氮。
5.根据权利要求1-4中任一项所述的喜树碱-7-乙基胺衍生物或其药学上可接受的盐、立体异构体或前药,其中,所述R1、R2各自独立地或共同为以下结构:
6.根据权利要求1-5中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,其中,所述化合物选自:
7.一种权利要求1-6中任一项所述的化合物的制备方法,其特征在于,所述制备方法包含选自以下任意一种合称路线的步骤:
合成路线1,其中,包括以下工序:
(1)将3,4-取代的苯胺和卤代丙腈反应,得到3’,4’-二取代-3-卤代-6’-氨基苯丙酮;
(2)使3’,4’-二取代-3-卤代-6’-氨基苯丙酮和胺进行取代,得到3’,4’-二取代-3-烷氨基-6’-氨基苯丙酮;
(3)使3’,4’-二取代-3-烷氨基-6’-氨基苯丙酮和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮缩合,得到喜树碱-7-乙基胺衍生物;或,
合成路线2,其中,包括以下工序:
(1)使3’,4’-二取代-3-卤代苯丙酮和硝酸反应,得到6’-硝基-3’,4’-二取代-3-卤代苯丙酮;
(2)将6’-硝基-3’,4’-二取代-3-卤代苯丙酮和胺进行取代反应得到6’-硝基-3’,4’-二取代-3-烷氨基-苯丙酮;
(3)将6’-硝基-3’,4’-二取代-3-烷氨基-苯丙酮进行还原得到6’-氨基-3’,4’-二取代-3-烷氨基-苯丙酮:
(4)使3’,4’-二取代-3-烷氨基-6’-氨基苯丙酮和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮缩合,得到喜树碱-7-乙基胺衍生物;或,
合成路线3,其中,包括以下工序:
(1)将3’,4’-二取代的苯乙酮进行硝化反应,得到6’-硝基-3’,4’-二取代苯乙酮;
(2)将6’-硝基-3’,4’-二取代苯乙酮和甲醛缩合、酸化,得到6’-硝基-3’,4’-二取代苯丙烯酮;
(3)使6’-硝基-3’,4’-二取代苯丙烯酮和胺进行Michael加成反应,得到6’-硝基-3’,4’-二取代苯丙酮-3-胺;
(4)将6’-硝基-3’,4’-二取代苯丙酮-3-胺进行还原,得到6’-氨基-3’,4’-二取代苯丙酮-3-胺;
(5)使6’-氨基-3’,4’-二取代苯丙酮-3-胺和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮进行缩合反应,得到喜树碱-7-乙基胺衍生物;或,
合成路线4,其中,包括以下工序:
(1)使取代的2-乙酰基苯胺和(S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃酮-[3,4-f]吲哚嗪-3,6,10(4H)-三酮缩合,得到7-甲基喜树碱;
(2)使7-甲基喜树碱和胺在DMSO中进行Mannich反应,得到喜树碱-7-乙基胺衍生物。
8.抗体药物偶联物,其特征在于,以权利要求1-6中任一项所述的化合物或其药学上可接受的盐、立体异构体或前药为小分子药物。
9.药物组合物,其特征在于,包括权利要求1-6中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1-6中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,权利要求8的抗体药物偶联物、权利要求9的药物组合物在制备治疗肿瘤疾病的药物中的应用,
优选地,所述肿瘤疾病包括胃癌、食管癌、贲门癌、乳腺癌、卵巢癌、结肠癌、直肠癌、原发性肝癌、急性和慢性粒细胞性白血病、绒毛膜上皮癌、肺癌、膀胱癌、肠癌和小细胞肺癌;更优选地,所述肿瘤疾病为食管癌、乳腺癌和胃癌。
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CN116478175A (zh) * | 2022-09-09 | 2023-07-25 | 杭州爱科瑞思生物医药有限公司 | 喜树碱-7-乙基胺衍生物及其制备方法和应用 |
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CN116712561A (zh) * | 2022-12-29 | 2023-09-08 | 杭州爱科瑞思生物医药有限公司 | 含n-亚甲基酰胺连接子的抗体-药物偶联物 |
CN116726192A (zh) * | 2022-12-29 | 2023-09-12 | 杭州爱科瑞思生物医药有限公司 | N-烷氧烷基取代的喜树碱衍生物的抗体偶联药物 |
CN116712563A (zh) * | 2022-12-29 | 2023-09-08 | 杭州爱科瑞思生物医药有限公司 | N-卤代烷基取代的喜树碱衍生物的抗体偶联药物 |
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