CN115611867B - (1,1,1-三氯-2)氨基甲酸酯类衍生物及其制备方法和应用 - Google Patents
(1,1,1-三氯-2)氨基甲酸酯类衍生物及其制备方法和应用 Download PDFInfo
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- CN115611867B CN115611867B CN202211387962.8A CN202211387962A CN115611867B CN 115611867 B CN115611867 B CN 115611867B CN 202211387962 A CN202211387962 A CN 202211387962A CN 115611867 B CN115611867 B CN 115611867B
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明涉及(1,1,1‑三氯‑2)氨基甲酸酯类衍生物,本发明还涉及它们的制备方法以及相关的医药用途。为实现上述目的,本发明提出一种(1,1,1‑三氯‑2)氨基甲酸酯类衍生物,结构通式如式(I)所示:
Description
技术领域
本发明涉及(1,1,1-三氯-2)氨基甲酸酯类衍生物,本发明还涉及它们的制备方法以及相关的医药用途。
背景技术
恶性肿瘤是当今世界大多数国家人口主要死因之一,严重威胁着人类健康。调查表明,恶性肿瘤的发病率呈逐年上升的趋势。随着分子生物学的快速发展,科学家们对恶性肿瘤发生、发展的相关信号通路和靶点有了更为深入、全面的认识,并且基于这些信号通路和靶点来设计抗肿瘤药物已经取得了重要成果。随着“恶性肿瘤是一类细胞周期性疾病”的观点得到广泛认同,针对细胞周期调控的抗肿瘤药物研究成为热点。
细胞周期失调是人类癌症的共同特征,肿瘤细胞积累的突变会导致增殖异常,基因组不稳定和染色体不稳定。基于这种现象,已经开发出许多药物来抑制不同的细胞周期阶段用于癌症治疗。抑制细胞周期的初始阶段可能会产生活的静止细胞,而靶向有丝***则有几种杀死癌细胞的可能性。靶向有丝***是一种经过长期验证的方法,目前广泛研究的是靶向有丝***的纺锤体微管元件以及靶向有丝***的非微管效应物的新型药物,其中影响有丝***纺锤体的药物是诸多癌症治疗方案中公认的成分。
通常,细胞有丝***过程受到复杂而精细的调控,并最终将复制的基因组分成两个相同的子细胞。有丝***分为五个不同的阶段:前期,前中期,中期,后期和末期。前期从G2过渡到有丝***,伴随染色体浓缩和核被膜的分解开始。在前中期,染色体着丝点通过搜索和捕获机制附着在纺锤体微管上。在中期,染色体在赤道板上汇聚,与中心体等距。着丝粒微管在后期变短,分离姐妹染色单体并将其移向相反的两极,这称为分离。最后,细胞在末期和胞质***过程中被一分为二,形成两个子细胞(图1)。针对有丝***期相关蛋白已设计研究出了大量的小分子化合物。
抗微管药物是靶向有丝***的第一种治疗方法,微管在维持细胞形态、细胞***、信号转导以及物质输送等过程中起着重要作用。微管在有丝***前期聚合成为纺锤体,而纺锤体在有丝***中牵引染色体向两极移动进入两个自细胞中,完成细胞增殖。由于微管在细胞***中发挥极其重要的作用,现已成为抗癌药物的重要靶点之一,并且微管抑制剂在临床上被证明对多种恶性肿瘤具有显著疗效。微管聚合剂(包括紫杉醇和多西紫杉醇)和微管解聚剂(包括长春瑞滨)靶向初级微管蛋白,破坏微管聚合-解聚的动力学稳定性,从而阻断有丝***期的细胞周期并诱导肿瘤的细胞凋亡。但是,这些药物不仅作用于增殖的肿瘤细胞,而且还对非异常增殖的正常细胞表现出明显的副作用。此外,多药耐药性(MDR)蛋白和微管蛋白同种型(例如微管蛋白的突变)的表达也与微管抑制类药物有关。
因此,除微管蛋白以外的新型有丝***药物靶标的鉴定近来引起了广泛关注。近年来,已经探索了几种有丝***靶标,包括靶向微管,激酶,运动蛋白和多蛋白复合物的药物。其中泛素-蛋白酶体(UPS)途径介导的底物泛素化及其随后的有序降解过程贯穿于整个细胞的质膜***,是细胞在整个细胞周期中进行有丝***所必需的,并且,其在治疗由泛素***紊乱而引起的各种疾病,尤其是恶性肿瘤中具有重要意义。一般情况下,泛素化过程需要泛素激活酶(ubiquitin-activatingenzyme,E1)、泛素结合酶(ubiquitin-conjugatingenzyme,E2)和泛素连接酶(ubiquitinligase,E3)的共同参与。在此过程中,泛素(一种高度保守的76个残基蛋白)首先在ATP供能的反应中与泛素激活酶(E1)连接。然后活化的泛素被转移到小的泛素结合酶(E2)上,形成硫酯键连接的E2-泛素中间体(E2~Ub)。E2单独或与E3泛素连接酶一起作用,将泛素缀合到底物蛋白中赖氨酸残基的ε-氨基上,形成异肽键。严格控制E1-E2-E3的这些看似简单的顺序作用可以实现准确且适当的定时泛素化/蛋白水解。
而泛素化***降解蛋白的特异性由泛素连接酶E3决定。其中,细胞***后期促进复合物(Anaphase Promoting Complex,APC)是最大的E3泛素连接酶,由至少14个亚基和一个共活化因子组成,经细胞***周期蛋白20(Cdc20)或Cdc20同系物1(Cdh1)活化后形成两种不同的E3泛素连接酶复合物APCCdc20或APCCdh1(图2),APCCdc20在有丝***中期进入后期的过渡阶段破坏细胞生长周期中的关键调控子,调节细胞周期进程,而APCCdh1在主要在G1期发挥重要作用。
越来越多的研究表明,Cdc20促进肿瘤的发生发展,在很多肿瘤中都发现了Cdc20高表达的现象,且其表达程度与肿瘤患者的病理程度、预后关系密切,Cdc20表达水平越高,风险越大。总而言之,Cdc20的表达水平是一个有效的肿瘤患者预后指标,为Cdc20作为一个新型抗肿瘤药物研发靶点提供了依据。相反的,APC/C的另一个共激活因子,Cdh1,则被认为是一个抑癌因子。
目前,随着针对Cdc20的研究不断深入,越来越多的APCCdc20底物被发现(表1),有些底物直接或间接参与细胞***过程,Cdc20能调节这些底物的泛素化或降解过程,从而调节细胞周期进程,因此,发现更多的APCCdc20底物有助于了解Cdc20在调节细胞周期进展的分子机制。
表1APCCdc20下游底物及其功能
使用化合物抑制Cdc20通路是***的新思路。Cdc20靶向抑制剂能直接作用于Cdc20,抑制APCCdc20复合物的活性。Apcin是目前唯一报道的Cdc20特异性抑制剂,它作用于Cdc20 N末端的WD40区域,阻断Cdc20与下游底物结合,抑制下游底物的泛素化及降解过程(图3)。另外,很多化合物被报道可以间接影响Cdc20通路,发挥抗肿瘤作用。此外,某些天然产物中活性成分也有调节Cdc20通路的作用(表2)
表2部分Cdc20抑制剂的结构及功能
过早通过有丝***滑脱而退出细胞有丝***被认为是细胞对抗有丝***药物产生抗药性的主要机制之一。微管抑制剂的两种作用机制均通过药物结合长春花,紫杉烷或秋水仙碱位点,产生未连接的着丝粒从而激活SAC,因此,观察到有丝***细胞死亡或有丝***滑移。
而在正常细胞周期中,有丝***退出是由APC/C–Cdc20依赖性细胞周期蛋白B1降解驱动的。抑制有丝***进程可触发SAC,并抑制APC/C–Cdc20。但是,这种抑制作用是短暂而缓慢的,尽管有丝***检查点未通过,但细胞周期蛋白B1可能会逐渐降解。逃脱有丝***细胞死亡的细胞可以在随后的细胞周期阶段死亡,停在四倍体状态或经历几轮***。因此,可以预见,完全阻断有丝***退出可能是诱导有丝***细胞死亡的有效策略。经证明,通过基因消除Cdc20来体内抑制细胞周期蛋白B1降解在杀死肿瘤细胞方面比用传统靶向纺锤体组装的化合物更为有效。另一方面,经典的微管抑制类抗有丝***药物(长春新碱或紫杉醇)仅在侵袭性肿瘤中诱导部分反应,Cdc20切除则可导致完全的***期停滞,导致大量凋亡细胞死亡并在体内完全消除肿瘤。同时,研究表明在体外,无Cdc20的肿瘤细胞无法在6-30小时内摆脱中期停滞并死于有丝***细胞死亡。重要的是,有丝***退出抑制也影响pRb-null,p53-null或SAC缺陷细胞,表明其用途广泛,弥补了微管抑制剂对SAC失活的细胞疗效差的不足。总体而言,这些结果表明靶向Cdc20抑制Cyclin B1降解可能非常有效地杀死肿瘤细胞。
因此,设计同时靶向抑制有丝***退出的Cdc20与激活SAC的微管蛋白的小分子抑制剂是触发有丝***细胞死亡的有效方法。有丝***退出抑制剂的目的是防止细胞周期蛋白B的消耗,从而导致细胞在有丝***中被阻滞并死亡。一项临床前研究证实,与紫杉醇治疗相比,敲除Cdc20在杀死具有抗性的细胞方面更为有效。另一项研究将APC抑制剂proTAME与紫杉醇或MLN-8054两种抗有丝***药物联合使用,导致癌细胞凋亡激活。通过回顾抗有丝***剂的临床试验,很明显,当采用设计双靶抑制剂时,可获得更好的癌症治疗效果。
目前的抗有丝***策略专注于SAC激活,主要癌症治疗方法是使用微管药物激活SAC并诱导细胞凋亡,但由于残留的APC/C-Cdc20活性,导致其有效性受到背景Cyclin B1降解和有丝***滑移的限制。特别是癌细胞,由于破坏SAC的突变而显示出高的有丝***滑移率,使得治疗失败。因此,针对检查点下游的因子如Cdc20的化合物,与其他有丝***抑制剂(包括MIA和驱动蛋白抑制剂)相比,在杀死细胞方面,特别是在易滑移和抗凋亡的细胞中更有效。
Apcin作为目前唯一报导的CDC20特异性抑制剂,其抗肿瘤活性较弱,没有办法应用与临床,可能与CDC20与底物较广泛的蛋白-蛋白相互作用有关。
目前没有针对CDC20和微管网络双功能的抗肿瘤化合物报导,这种“双功能策略”可以减少核内复制,阻止背景Cyclin B1的蛋白水解,从而增强有丝***的阻滞作用,同时有效地防止有丝***滑移的发生,可以提高癌细胞对药物的敏感度,为基于微管抑制剂的癌症治疗方法的开发开辟了新的途径。
发明内容
本发明目的在于提供了一种新的(1,1,1-三氯-2)氨基甲酸酯类衍生物,并提供了所述化合物的制备方法以及它们作为可能的抗肝癌药物的应用。
为实现上述目的,本发明的技术方案是:
一种(1,1,1-三氯-2)氨基甲酸酯类衍生物,结构通式如式(I-III)所示:
n为0-1;
X为O;
其中,R1选自氢、芳环、取代芳环、芳杂环、取代芳杂环、脂肪杂环、取代脂肪杂环、C1-C4开链胺基、C1-C6直链或支链烷氧基、C1-C6直链或支链烷烃、C3-C6脂肪环和取代C3-C6脂肪环、脂肪来那度胺取代的C1-C8直链或支链烷基、来那度胺取代的C1-C8直链或支链烷氧基烷基其中一种。
结构式I中,R2,R3,R4独立选自氢、氨基、羟基、卤素、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基,C1-C3烷胺基,喹啉环的苯基部分;Y选自N,CH;Y为N时,R2,R3,R4不同时为氢;
结构式II-III中,Y选自N,CH;R5以及R6独立选自氨基、H、卤素、C1-C8烷基、C1-C8烷氧基、C1-C8卤代烷基,C1-C8烷胺基、
优选方案,所述芳环选自苯、萘和蒽;所述芳杂环选自吡咯、呋喃、噻吩、咪唑、噻唑、噁唑、吡唑、异噁唑、噻二唑、噁二唑、三氮唑、四氮唑、吡啶、嘧啶、吡嗪、哒嗪、嘌呤、喹啉、异喹啉、吲哚、吖啶和咔唑;所述脂肪杂环选自吡咯烷、哌嗪、哌啶、吗啉和四氢呋喃;所述取代芳环、取代芳杂环、取代脂肪杂环中的取代基选自C1-C6直链或支链烷氧基、C1-C6直链或支链烷基、C1-C6羟烷基、羟基、氨基、硝基、卤代烷基和卤素。
优选方案,所述取代芳环、取代芳杂环、取代脂肪杂环中的取代基选自甲基、乙基、丙基、异丙基、甲氧基、羟乙基、羟基、氨基、硝基、三氟甲基和卤素。
优选方案,所述(1,1,1-三氯-2)氨基甲酸酯类衍生物,结构通式如式I所示:
其中,n为1;
X为O;
R1选自氢、C1-C4直链或支链烷氧基、C1-C4直链或支链烷烃、C3-C6脂肪环和取代C3-C6脂肪环、苯环、取代苯环、芳杂环、取代芳杂环、脂肪杂环、取代脂肪杂环其中一种;
所述芳杂环选自吡咯、咪唑、噻唑、噁唑、吡唑、吡啶、嘧啶、吲哚;
所述脂肪杂环选自吡咯烷、哌嗪、哌啶、吗啉;
所述取代芳环、取代芳杂环、取代脂肪杂环中的取代基选自甲基、乙基、甲氧基、羟乙基、氨基、硝基、三氟甲基和卤素;
R2,R3,R4选自氨基、H、=O、卤素、C1-C3烷基、C1-C3烷氧基,喹啉环的苯基部分;Y选自N,CH;R2,R3,R4不同时为氢。
优选方案,所述(1,1,1-三氯-2)氨基甲酸酯类衍生物,结构通式如式II所示:
其中,n为0-1;
X为O;
R1选自C1-C4直链或支链烷氧基、C1-C4直链或支链烷烃、C3-C6脂肪环和取代C3-C6脂肪环苯环、取代苯环、芳杂环、取代芳杂环、脂肪杂环、取代脂肪杂环其中一种。
所述芳杂环选自吡咯、咪唑、噻唑、噁唑、吡唑、吡啶、嘧啶、吲哚;
所述脂肪杂环选自吡咯烷、哌嗪、哌啶、吗啉;
所述取代芳环、取代芳杂环、取代脂肪杂环中的取代基选自甲基、乙基、甲氧基、羟乙基、氨基、硝基、三氟甲基和卤素;
R5以及R6选自氨基、H、卤素、C1-C7烷基、C1-C7烷氧基、C1-C7卤代烷基,C1-C7烷胺基、
Y为N,CH。
优选方案,所述(1,1,1-三氯-2)氨基甲酸酯类衍生物,结构通式如式III所示:
其中,n为1;
X为O;
R1选自C1-C4直链或支链烷氧基、C1-C4直链或支链烷烃、C3-C6脂肪环和取代C3-C6脂肪环苯环、取代苯环、芳杂环、取代芳杂环、脂肪杂环、取代脂肪杂环其中一种。
所述芳杂环选自吡咯、咪唑、噻唑、噁唑、吡唑、吡啶、嘧啶、吲哚;
所述脂肪杂环选自吡咯烷、哌嗪、哌啶、吗啉;
所述取代芳环、取代芳杂环、取代脂肪杂环中的取代基选自甲基、乙基、甲氧基、羟乙基、氨基、硝基、三氟甲基和卤素;
R5以及R6选自氨基、H、卤素、Y为N,CH。
优选方案,所述(1,1,1-三氯-2)氨基甲酸酯类衍生物,其结构式如下:
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本发明还提供式(I)、式(II)和式(III)化合物的合成方法,合成路线如下:
所述(1,1,1-三氯-2)氨基甲酸酯类衍生物的合成步骤包括:
1、将羟基取代化合物在无水非质子性溶剂中,与氯甲酸对硝基苯基酯反应得到中间体;
2、中间体在卤代烷烃和甲醇的混合溶剂中与氨水反应得到氨基甲酸酯产物;
3、氨基甲酸酯产物与水合氯醛在80-100℃条件下回流得到(1,1,1-三氯-2)氨基甲酸酯部分;
4、(1,1,1-三氯-2)氨基甲酸酯部分先由氯化亚砜氯化后,在与胺反应得到目标化合物。
优选的,步骤1反应摩尔投料比为羟基取代化合物:氯甲酸对硝基苯基酯:水合氯醛=1:(1.2-1.5):(8-12)。
优选的,步骤1反应4-12h得到中间体。
优选的,步骤1反应可加弱碱催化加快反应进程。
优选的,所述弱碱为三乙胺、二异丙基乙胺任意一种或者其组合,摩尔投料比:羟基取代化合物:碱=1:1.2-1:1.5。
优选的,所述无水非质子性溶剂为二氯甲烷。
优选的,步骤2卤代烷烃和甲醇混合溶剂中卤代烷烃:甲醇质量为1:1-5:1。
优选的,步骤2中氨水浓度为10-35%。
优选的,步骤3反应摩尔投料比:氨基甲酸酯:水合氯醛=1:8–1:12
优选的,步骤3回流时间为6-48h。
优选的,步骤3反应温度为100℃。
优选的,步骤4在温度rt-50℃的条件下反应。
优选的,步骤4中(1,1,1-三氯-2)氨基甲酸酯部分(1倍当量)先经无水非质子性溶剂溶解,由氯化亚砜氯化后(5倍当量),再通过无水二氯甲烷:无水乙腈(1:1)做混合溶剂与原料胺(1.2倍当量)发生取代反应生成相应的目标化合物。
本发明还提供了上述的(1,1,1-三氯-2)氨基甲酸酯类衍生物在制备治疗乳腺癌、黑色素瘤、肺腺癌、肝细胞癌、***以及卵巢癌药物中的应用。
下面对本发明做进一步的解释:
本发明基于cdc20特异性抑制剂apcin的结构,在其嘧啶环上引入不同的取代基团得到多种衍生物(结构母核I),发现引入氯原子后,化合物与cdc20具有更多相互作用位点,亲和力增强,使得其对肿瘤细胞的抑制作用大大增强。
而将apcin结构中嘧啶替换为嘌呤(结构母核II)或者苯并吡唑(结构母核III)后,对肿瘤细胞的抑制作用进一步增强。化合物在保持了一定的cdc20的抑制作用基础上,由于嘌呤或苯并吡唑的引入,使得其与微管蛋白二聚体之间的相互作用增强,产生微管聚集抑制作用。化合物从而具有双功能抗肿瘤作用,有望成为新型的抗肿瘤先导化合物。
与现有技术相比,本发明的有益效果如下:
1、本发明在apcin的基础上丰富了cdc20抑制剂的结构,获得了三种结构母核;
2、本发明的目标化合物的肿瘤抑制活性较apcin大为增强,在多个肿瘤细胞株中均显示出良好抑制作用;
3、本发明通过对化合物的抗肿瘤活性机制研究发现,新化合物除了具有apcin原有的cdc20抑制活性以外,还有较好的微管聚集抑制作用,为寻找针对APC通路和微管抑制双功能癌症治疗方法开辟了新的途径。
附图说明
图1是有丝***进程简图以及相关靶标蛋白和复合物;
图2是APC/C RING E3泛素连接酶与其共激活剂Cdc20/Cdh1结合促进底物泛素化;
图3是小分子化合物Apcin结合WD40区域侧边的D-box结合口袋(左)以及小分子化合物TAME通过模拟Cdc20和Cdh1的isoleucine-arginine(IR)尾部与APC3结合,干扰IR尾部结合位点;
图4是药物处理HepG2细胞株的免疫荧光实验结果;
图5是为药物处理HepG2细胞株的凋亡实验结果(化合物促细胞凋亡荧光图)。
具体实施方式
以下将结合实施例来详细说明本发明。需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
实施例1
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((4-甲基嘧啶-2-)氨基)-乙基)-氨基甲酸酯(5b)
步骤1
2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基氨基甲酸酯的合成
称取30.0g甲硝唑(0.175mol)放入500mL茄型瓶中,然后依次加入300mL无水二氯甲烷溶解、30mL无水三乙胺(0.210mol),搅拌均匀后于冰浴条件下加入42.5g氯甲酸对硝基苯基酯(0.210mol),最后再补加30mL无水二氯甲烷润洗瓶口。移至室温搅拌反应过夜,TLC监测甲硝唑反应基本完成,停止反应。在10℃条件下将62mL氨水(28%)用恒压滴液漏斗缓慢加入反应液中,反应3h,反应完全。将反应液抽虑得到固体58.3g,所得固体用200mL氢氧化钠溶液(1mol/L)溶解后,用200mL二氯甲烷萃取3次,合并有机层,减压浓缩,干燥得到18.6g黄色色晶体化合物2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基氨基甲酸酯。两步收率:50%,熔点:151.5~153.1℃。
步骤2
2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯的合成
称取77.0g水合氯醛(0.467mol)放入100mL茄型瓶中,置于油浴锅上加热,待水合氯醛熔融后,缓慢加入10.0g化合物2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基氨基甲酸酯(0.047mol),100℃下搅拌反应,反应48h后,停止反应。将反应溶液冷却至室温,加入50mL乙酸乙酯,超声成混浊液后抽滤,得到11.6g白色化合物。收率:68%,熔点:168.7~169.7℃。
步骤3
以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-甲基-2-氨基嘧啶为原料,得到化合物5b。
具体操作是:称取0.50g中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯(1.38mmol)放入50mL茄型瓶中,然后量取30mL无水二氯甲烷加入反应瓶中,滴加1滴三乙胺,搅拌均匀后于冰浴下用恒压滴液漏斗缓慢滴加0.50mL氯化亚砜(6.91mmol),滴加完毕后,转移至油浴锅中,氮气保护下40℃下回流反应过夜,停止反应。待反应液冷却至室温后,减压浓缩,加入20mL无水二氯甲烷充分溶解,减压浓缩,重复3次,以除去残留的氯化亚砜,得到黄色固体。将所得黄色固体用15mL无水二氯甲烷和15mL无水乙腈溶解,加入另一原料胺(1.66mmol)至反应液,24h后加入10mL甲醇搅拌30min淬灭反应。将反应液减压浓缩后用50mL二氯甲烷溶解,50mL饱和食盐水洗涤3次,减压浓缩得到粗品。将粗品用20mL甲醇溶解后,用80~100目硅胶拌样,200~300目硅胶装柱,柱层析纯化,洗脱体系用二氯甲烷和甲醇溶液,分离纯化后得到目标化合物。
目标化合物为白色固体,收率:21.42%,熔点:209.0~209.9℃,HPLC:97.19%。1HNMR(500MHz,DMSO-d6):δ8.27(d,J=5.0Hz,1H),8.00(s,1H),7.97(d,J=8.8Hz,1H),6.97(d,J=9.5Hz,1H),6.73(d,J=5.0Hz,1H),6.60(t,J=9.2Hz,1H),4.56–4.46(m,3H),4.35(dd,J=10.7,5.7Hz,1H),2.39(s,3H),2.31(s,3H).13C NMR(500MHz,DMSO-d6):δ160.69,155.24,152.06,138.88,133.53,112.85,102.88,70.12,63.46,45.90,24.10,14.37.HRMS(ESI)m/z calcd for[C14H16Cl3N7O4+H]+:452.0329,found:452.0401.
实施例2
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((4-甲氧基嘧啶-2-)氨基)-乙基)-氨基甲酸酯(5c)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-甲氧基-2-氨基嘧啶为原料,得到化合物5c。淡黄色固体,收率:32.66%,熔点:81.6~83.3℃,HPLC:98.63%。1H NMR(500MHz,DMSO-d6):δ8.14(d,J=5.7Hz,1H),8.01(d,J=16.7Hz,2H),7.05(s,1H),6.57(d,J=13.3Hz,1H),6.28(d,J=5.7Hz,1H),4.51(dd,J=17.4,4.3Hz,3H),4.38–4.33(m,1H),3.85(s,3H),2.39(s,3H).13C NMR(500MHz,DMSO-d6):δ170.22,160.87,158.59,155.27,152.06,138.88,133.51,102.59,99.44,70.35,63.48,53.74,45.89,14.36.HRMS(ESI)m/z calcd for[C14H16Cl3N7O5+H]+:468.0278,found:468.0370.
实施例3
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((6-氧代-1,6-二氢嘧啶-2-)氨基)乙基)氨基甲酸(5d)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和异胞嘧啶为原料,得到化合物5d。淡黄色固体,收率:16.24%,熔点:192.3~193.2℃,HPLC:98.39%。1H NMR(500MHz,DMSO-d6):δ11.14(s,1H),8.71(d,J=8.4Hz,1H),8.01(s,1H),7.64(d,J=6.1Hz,1H),7.11(d,J=9.3Hz,1H),6.49(t,J=9.1Hz,1H),5.72(d,J=6.1Hz,1H),4.55–4.48(m,3H),4.37(dd,J=7.5,5.0Hz,1H),2.41(s,3H).13C NMR(500MHz,DMSO-d6):δ162.08,155.74,155.43,153.95,152.10,138.89,133.56,105.94,101.66,69.29,63.28,46.00,14.41.HRMS(ESI)m/z calcd for[C13H14Cl3N7O5+H]+:454.0122,found:454.0200.
实施例4
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((4-氨基嘧啶-2-)氨基)-乙基)-氨基甲酸酯(5e)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2,4-二氨基嘧啶为原料,得到化合物5e。淡黄色固体,收率:28.69%,熔点:104.2~105.0℃,HPLC:98.55%。1H NMR(500MHz,DMSO-d6):δ8.02(s,1H),7.95(d,J=8.5Hz,1H),7.74(d,J=5.3Hz,1H),6.64(s,2H),6.53(t,J=9.0Hz,1H),6.15(s,1H),5.87(d,J=5.1Hz,1H),4.56-4.46(m,3H),4.32(d,J=11.4Hz,1H),2.40(s,3H).13C NMR(500MHz,DMSO-d6):δ164.54,160.64,156.04,155.13,152.07,138.88,133.52,103.38,97.97,69.98,63.36,45.92,14.37.HRMS(ESI)m/z calcd for[C13H15Cl3N8O4+H]+:453.0282,found:453.0360.
实施例5
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((4-氯嘧啶-2-)氨基)-乙基)-氨基甲酸酯(5f)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-氯-2-氨基嘧啶为原料,得到化合物5f。白色固体,收率:20.18%,熔点:182.3~183.4℃,HPLC:98.75%。1H NMR(500MHz,DMSO-d6):δ8.40(d,J=4.8Hz,1H),8.06(d,J=8.4Hz,1H),7.99(s,1H),7.87(s,1H),6.98(d,J=5.0Hz,1H),6.55(s,1H),4.56–4.47(m,3H),4.40–4.35(m,1H),2.41(s,3H).13C NMR(500MHz,DMSO-d6):δ161.18,155.35,152.08,138.90,133.51,112.61,102.13,70.30,63.51,45.88,14.41.HRMS(ESI)m/z calcd for[C13H13Cl4N7O4+H]+:471.9783,found:471.9864.
实施例6
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((4-三氟甲基嘧啶-2-)氨基)-乙基)-氨基甲酸酯(5g)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-三氟甲基-2-氨基嘧啶为原料,得到化合物5g。黄色油状,收率:5.26%,HPLC:97.81%。1H NMR(500MHz,DMSO-d6):δ8.79(d,J=4.4Hz,1H),8.12(s,1H),8.03(d,J=8.6Hz,1H),7.98(s,1H),7.28(d,J=4.9Hz,1H),6.61(s,1H),4.57–4.46(m,3H),4.40–4.34(m,1H),2.40(s,3H).HRMS(ESI)m/z calcd for[C14H13Cl3F3N7O4+H]+:506.0047,found:506.0140.
实施例7
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((嘧啶-4-)氨基)-乙基)-氨基甲酸酯(6a)
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步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-氨基嘧啶为原料,得到化合物6a。黄色固体,收率:32.24%,熔点:179.4~180.2℃,HPLC:99.79%。1H NMR(500MHz,DMSO-d6):δ8.59–8.48(m,2H),8.21(d,J=5.9Hz,1H),8.04–7.94(m,2H),6.88(d,J=5.9Hz,1H),6.77(t,J=8.6Hz,1H),4.50(d,J=11.0Hz,3H),4.35(dd,J=10.7,4.5Hz,1H),2.39(s,3H).13C NMR(500MHz,DMSO-d6):δ161.10,158.30,155.81,155.59,152.14,138.87,133.56,107.09,101.98,68.80,63.24,46.04,14.41.HRMS(ESI)m/z calcd for[C13H14Cl3N7O4+H]+:438.0173,found:438.0264.
实施例8
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((喹啉-2-)氨基)-乙基)-氨基甲酸酯(6b)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氨基喹啉为原料,得到化合物6b。深黄色固体,收率:25.62%,熔点:119.9~121.0℃,HPLC:99.75%。1H NMR(500MHz,DMSO-d6):δ8.35(d,J=8.8Hz,1H),8.03–7.98(m,2H),7.71(d,J=7.9Hz,1H),7.59–7.54(m,2H),7.49(d,J=9.2Hz,1H),7.27(t,J=7.2Hz,1H),7.13(d,J=8.9Hz,1H),6.94(t,J=9.0Hz,1H),4.51(dd,J=11.7,4.8Hz,3H),4.35–4.30(m,1H),2.34(s,3H).13C NMR(500MHz,DMSO-d6):δ155.57,155.16,152.16,147.19,138.82,137.80,133.55,129.84,127.96,126.72,124.23,123.01,113.30,102.69,69.54,63.17,46.07,14.38.HRMS(ESI)m/z calcd for[C18H17Cl3N6O4+H]+:487.0377,found:487.0463.
实施例9
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((异喹啉-3-)氨基-)乙基)-氨基甲酸酯(6c)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和3-氨基异喹啉为原料,得到化合物6c。黄色固体,收率:28.32%,熔点:122.6~124.2℃,HPLC:99.50%。1H NMR(500MHz,DMSO-d6):δ8.96(s,1H),8.27(d,J=8.7Hz,1H),7.99(s,1H),7.90(d,J=8.2Hz,1H),7.64(d,J=8.3Hz,1H),7.58–7.54(m,1H),7.32–7.28(m,1H),7.05(s,1H),6.81–6.72(m,2H),4.49(d,J=11.5Hz,3H),4.33(d,J=5.3Hz,1H),2.34(s,3H).13C NMR(500MHz,DMSO-d6):δ155.57,152.99,152.12,151.48,138.86,138.56,133.53,131.03,128.23,125.27,124.18,123.73,103.23,100.17,70.84,63.23,46.02,14.36.HRMS(ESI)m/z calcd for[C18H17Cl3N6O4+H]+:487.0377,found:487.0469.
实施例10
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((异喹啉-1-)氨基)-乙基)-氨基甲酸酯(6d)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和1-氨基异喹啉为原料,得到化合物6d。白色固体,收率:27.43%,熔点:113.5~114.8℃,HPLC:97.92%。1H NMR(500MHz,DMSO-d6):δ8.06(d,J=8.4Hz,1H),8.02–7.94(m,2H),7.84(d,J=8.0Hz,1H),7.78(d,J=8.7Hz,1H),7.73(t,J=7.5Hz,1H),7.64(t,J=7.6Hz,1H),7.35(d,J=8.8Hz,1H),7.18(d,J=5.7Hz,1H),7.07(t,J=8.7Hz,1H),4.49(dd,J=21.6,11.7Hz,3H),4.37–4.31(m,1H),2.36(s,3H).13C NMR(500MHz,DMSO-d6):δ155.11,152.99,151.98,140.88,138.89,137.32,133.50,130.92,127.44,127.06,122.66,117.67,113.11,103.34,69.26,63.53,45.81,14.34.HRMS(ESI)m/z calcd for[C18H17Cl3N6O4+H]+:487.0377,found:487.0463.
实施例11
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(1H-苯并[d]咪唑-1-基)-2,2,2-三氯乙基)-氨基甲酸酯(6e)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和苯并咪唑为原料,得到化合物6e。白色固体,收率:22.13%,熔点:123.6~124.9℃,HPLC:97.97%。1H NMR(500MHz,DMSO-d6):δ9.68(d,J=9.8Hz,1H),8.63(s,1H),8.00(d,J=6.1Hz,1H),7.96(t,J=11.1Hz,1H),7.71(t,J=7.8Hz,1H),7.33(t,J=7.4Hz,1H),7.27(t,J=7.4Hz,1H),6.88(t,J=14.6Hz,1H),4.60–4.51(m,3H),4.40(dt,J=8.5,3.8Hz,1H),2.38(s,3H).13C NMR(500MHz,DMSO-d6):δ155.67,152.01,142.82,142.73,138.91,134.14,133.57,123.96,123.03,120.18,112.05,99.86,73.06,63.74,45.86,14.34.HRMS(ESI)m/z calcd for[C16H15Cl3N6O4+H]+:461.0220,found:461.0127.
实施例12
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-(6-(2,2,2-三氯-1-((2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙氧羰氨基-)-乙基)-氨基)-9H-嘌呤-9-基-乙基)-氨基甲酸酯(6f)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和腺嘌呤为原料,得到化合物6f。深黄色固体,收率:10.56%,熔点:173.8~175.3℃,HPLC:97.12%。1H NMR(500MHz,DMSO-d6):δ9.63(d,J=9.3Hz,1H),8.62(s,1H),8.48(s,1H),7.97(s,2H),7.87(d,J=21.2Hz,2H),6.95(d,J=10.0Hz,1H),6.90(s,1H),4.58–4.34(m,8H),2.39(s,3H),2.37(s,3H).HRMS(ESI)m/zcalcd for[C23H23Cl6N13O8+H]+:819.9924,found:820.0001.
实施例13
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((4,6-二氯嘧啶-2-)氨基)-乙基)-氨基甲酸酯(7a)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氨基-4,6二氯嘧啶为原料,得到化合物7a。淡黄色固体,收率:46.23%,熔点:2175.5~176.3℃,HPLC:99.73%。1H NMR(500MHz,DMSO-d6):δ8.56(d,J=9.2Hz,1H),8.17(d,J=9.0Hz,1H),7.98(s,1H),7.21(s,1H),6.45(t,J=9.1Hz,1H),4.55–4.48(m,3H),4.38(dt,J=9.5,4.4Hz,1H),2.42(s,3H).13C NMR(500MHz,DMSO-d6):δ160.73,155.42,152.12,138.90,133.50,111.40,101.52,70.47,63.53,45.90,14.45.HRMS(ESI)m/z calcd for[C13H12Cl5N7O4+H]+:505.9393,found:505.9472.
实施例14
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((4,6-二氯-5-甲基嘧啶-2-)氨基)-乙基)-氨基甲酸酯(7b)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氨基-4,6二氯-5-甲基嘧啶为原料,得到化合物7b。白色固体,收率:46.66%,熔点:140.3~142.1℃,HPLC:99.82%。1H NMR(400MHz,DMSO-d6):δ8.24(d,J=9.3Hz,1H),8.15(d,J=9.0Hz,1H),7.99(s,1H),6.40(t,J=9.1Hz,1H),4.56–4.46(m,3H),4.37(dt,J=9.3,3.9Hz,1H),2.42(s,3H),2.26(s,3H).13C NMR(400MHz,DMSO-d6):δ158.23,155.43,152.15,138.90,133.55,117.65,101.74,70.55,63.51,45.92,15.41,14.47.HRMS(ESI)m/z calcd for[C14H14Cl5N7O4+H]+:519.9550,found:519.9629.
实施例15
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((5-氨基-4,6-二氯嘧啶-2-)氨基)-乙基)-氨基甲酸酯(7c)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2,5-二氨基-4,6二氯嘧啶为原料,得到化合物7c。黄褐色固体,收率:27.68%,熔点:92.9~93.7℃,HPLC:99.73%。1H NMR(500MHz,DMSO-d6):δ8.00(d,J=8.9Hz,1H),7.98(s,1H),7.21(d,J=9.5Hz,1H),6.26(t,J=9.2Hz,1H),5.16(s,2H),4.56–4.45(m,3H),4.37(dt,J=9.6,4.6Hz,1H),2.40(s,3H).13C NMR(500MHz,DMSO-d6):δ155.34,152.07,151.11,145.55,138.88,133.49,129.80,102.40,71.00,63.41,45.92,14.40.HRMS(ESI)m/z calcd for[C13H13Cl5N8O4+H]+:520.9502,found:520.9581.
实施例16
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-((2-氨基-4,6-二氯嘧啶-5-)氨基)-2,2,2-三氯乙基)-氨基甲酸酯(7d)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2,5-二氨基-4,6二氯嘧啶为原料,得到化合物7d。白色固体,收率:20.18%,熔点:125.1~125.7℃,HPLC:99.14%。1H NMR(500MHz,DMSO-d6):δ8.35(s,1H),8.34(d,J=9.5Hz,1H),8.01(s,1H),7.76–7.74(m,1H),7.26(s,2H),5.58(t,J=10.0Hz,1H),4.61(d,J=10.6Hz,1H),4.47(d,J=11.9Hz,3H),4.42–4.35(m,1H),2.40(s,3H).13C NMR(500MHz,DMSO-d6):δ158.85,156.40,155.83,152.17,138.83,133.53,121.90,102.23,75.27,63.21,46.09,14.45.HRMS(ESI)m/z calcd for[C13H13Cl5N8O4+H]+:520.9502,found:520.9574.
实施例17
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((6-氯-9H-嘌呤-9-基)-乙基)-氨基甲酸酯(8a)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和6-氯嘌呤为原料,得到化合物8a。淡黄色固体,收率:21.32%,熔点:101.4~101.8℃,HPLC:96.82%。1H NMR(500MHz,DMSO-d6):δ9.76(d,J=10.0Hz,1H),8.98(s,1H),8.93(s,1H),7.91(s,1H),7.00(d,J=10.0Hz,1H),4.57–4.45(m,4H),2.37(s,3H).13C NMR(500MHz,DMSO-d6):δ155.56,153.11,152.38,151.86,150.38,144.65,138.98,133.45,130.31,98.77,71.56,63.87,45.75,14.35.HRMS(ESI)m/zcalcd for[C14H12Cl4N8O4+H]+:496.9736,found:496.9782.
实施例18
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((6-(N,N-二甲基氨基)-9H-嘌呤-9-基)-乙基)-氨基甲酸酯(8b)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和6-二甲基氨基嘌呤为原料,得到化合物8b。白色固体,收率:20.23%,熔点:113.6~115.2℃,HPLC:98.22%。1H NMR(500MHz,CDCl3):δ8.51(s,1H),8.31(s,1H),7.96(s,1H),7.94(s,1H),6.65(d,J=9.7Hz,1H),4.64–4.58(m,3H),4.54–4.49(m,1H),3.58(s,6H),2.47(s,3H).13C NMR(500MHz,DMSO-d6):δ155.52,154.74,153.01,151.93,151.01,138.94,137.06,133.50,118.26,99.65,70.73,63.80,45.81,14.32.HRMS(ESI)m/z calcd for[C16H18Cl3N9O4+H]+:506.0547,found:506.0638.
实施例19
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(6-苯甲酰胺基-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8c)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和N6-苯甲酰基腺嘌呤为原料,得到化合物8c。白色固体,收率:22.65%,熔点:183.7~184.9℃,HPLC:97.27%。1H NMR(500MHz,DMSO-d6):δ11.35(s,1H),9.71(d,J=9.9Hz,1H),8.85(s,1H),8.78(s,1H),8.06(d,J=7.4Hz,2H),7.97(s,1H),7.66(t,J=7.2Hz,1H),7.57(t,J=7.3Hz,2H),7.05(d,J=9.9Hz,1H),4.58(d,J=11.0Hz,3H),4.45(s,1H),2.38(s,3H).13C NMR(500MHz,DMSO-d6):δ166.08,155.59,152.94,152.91,151.92,151.30,141.70,138.97,133.61,133.49,133.05,129.01,128.97,124.43,99.26,71.09,63.89,45.78,14.33.HRMS(ESI)m/z calcd for[C21H18Cl3N9O5+H]+:582.0496,found:582.0577.
实施例20
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(6-苄胺基-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8d)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和6-苄氨基嘌呤为原料,得到化合物8d。白色固体,收率:23.21%,熔点:121.0~121.8℃,HPLC:98.42%。1H NMR(500MHz,DMSO-d6):δ9.60(d,J=10.1Hz,1H),8.60(s,1H),8.48(s,1H),8.29(s,1H),7.98(s,1H),7.35(d,J=7.4Hz,2H),7.29(t,J=7.5Hz,2H),7.21(t,J=7.2Hz,1H),6.92(d,J=10.1Hz,1H),4.72(s,2H),4.56(t,J=9.3Hz,3H),4.42(dd,J=8.8,5.6Hz,1H),2.38(s,3H).13C NMR(500MHz,DMSO-d6):δ155.52,154.90,153.76,151.93,149.63,140.31,138.94,138.30,133.50,128.68,127.68,127.13,118.14,99.55,70.82,63.81,45.80,43.45,14.33.HRMS(ESI)m/z calcdfor[C21H20Cl3N9O4+H]+:568.0704,found:568.0795.
实施例21
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(6-氨基-2-氯-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8e)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氯腺嘌呤为原料,得到化合物8e。白色固体,收率:20.18%,熔点:196.5~197.6℃,HPLC:98.62%。1H NMR(500MHz,DMSO-d6):δ9.61(d,J=10.0Hz,1H),8.45(s,1H),7.99(d,J=20.3Hz,3H),6.73(d,J=9.8Hz,1H),4.57(d,J=9.3Hz,3H),4.44(d,J=8.1Hz,1H),2.38(s,3H).13C NMR(500MHz,DMSO-d6):δ157.40,155.54,154.23,151.91,151.23,138.96,138.72,133.47,116.94,99.23,70.90,63.85,45.79,14.32.HRMS(ESI)m/z calcd for[C14H13Cl4N9O4+H]+:511.9845,found:511.9915.
实施例22
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-((2,6-二氨基)-9H-嘌呤-9-基)-乙基)-氨基甲酸酯(8f)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2,6-二氨基嘌呤为原料,得到化合物8f。淡黄色固体,收率:25.36%,熔点:165.8~166.6℃,HPLC:98.68%。1H NMR(400MHz,DMSO):δ9.47(d,J=10.2Hz,1H),8.03(d,J=7.8Hz,2H),6.85(s,2H),6.73(d,J=10.1Hz,1H),6.07(s,2H),4.58(ddd,J=16.2,9.9,5.1Hz,3H),4.39(dd,J=7.6,4.6Hz,1H),2.40(s,3H).13C NMR(400MHz,DMSO):δ161.21,156.74,155.56,152.60,152.00,138.97,134.48,133.53,111.95,100.10,70.22,63.64,45.88,14.35.HRMS(ESI)m/z calcd for[C14H15Cl3N10O4+H]+:493.0343,found:493.0416.
实施例23
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(6-氨基-2-氟-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8g)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氟腺嘌呤为原料,得到化合物8g。白色固体,收率:19.26%,熔点:168.1~169.6℃,HPLC:96.92%。1H NMR(500MHz,DMSO-d6):δ9.60(d,J=10.0Hz,1H),8.42(s,1H),8.00(d,J=31.1Hz,3H),6.70(d,J=10.0Hz,1H),4.57(d,J=10.1Hz,3H),4.44(d,J=7.5Hz,1H),2.38(s,3H).13C NMR(500MHz,DMSO-d6)δ160.25,158.62,158.40,158.23,155.54,151.91,151.71,151.55,138.96,138.61,133.46,116.28,99.26,71.02,63.85,45.79,14.30.HRMS(ESI)m/z calcd for[C14H13Cl3FN9O4+H]+:496.0140,found:496.0222.
实施例24
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(2-氨基-6-氯-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8h)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氨基-6-氯嘌呤为原料,得到化合物8h。白色固体,收率:22.16%,熔点:140.4~140.9℃,HPLC:97.69%。1H NMR(500MHz,DMSO-d6):δ9.61(d,J=9.9Hz,1H),8.40(s,1H),7.96(s,1H),7.26(s,2H),6.78(d,J=10.0Hz,1H),4.53(t,J=35.8Hz,4H),2.38(s,3H).13C NMR(500MHz,DMSO-d6):δ160.75,155.58,154.62,151.90,150.53,139.79,139.01,133.45,122.32,99.33,70.70,63.74,45.83,14.33.HRMS(ESI)m/z calcd for[C14H13Cl4N9O4+H]+:511.9845,found:511.9923.
实施例25
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-(6-氯-2-氟-9H-嘌呤-9-基)-乙基)-氨基甲酸酯(8i)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氟-6-氯嘌呤为原料,得到化合物8i。白色固体,收率:23.16%,熔点:171.3~172.9℃,HPLC:98.85%。1H NMR(500MHz,DMSO-d6):δ9.80(d,J=9.7Hz,1H),8.97(s,1H),7.92(s,1H),6.82(d,J=10.0Hz,1H),4.60–4.47(m,4H),2.38(s,3H).13C NMR(500MHz,DMSO-d6):δ157.93,156.21,155.56,154.42,154.28,152.12,151.98,151.87,145.47,138.99,133.39,129.60,98.42,71.92,63.92,45.76,14.36.HRMS(ESI)m/z calcd for[C14H11Cl4N8O4+H]+:514.9641,found:514.9718.
实施例26
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(2-氨基-6-苄氧基-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8j)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和O-6-苄基鸟嘌呤为原料,得到化合物8j。白色固体,收率:24.53%,熔点:171.6~172.8℃,HPLC:96.77%。1H NMR(500MHz,DMSO-d6):δ9.54(d,J=10.1Hz,1H),8.17(s,1H),8.00(s,1H),7.52(d,J=7.3Hz,2H),7.40(t,J=7.3Hz,2H),7.38–7.34(m,1H),6.79(d,J=7.3Hz,3H),5.50(s,2H),4.56(t,J=10.3Hz,3H),4.41(d,J=10.3Hz,1H),2.39(s,3H).13C NMR(500MHz,DMSO-d6):δ160.69,155.57,155.03,151.95,138.98,136.91,136.74,133.50,129.04,128.89,128.59,112.66,99.77,70.47,67.61,63.68,45.86,14.33.HRMS(ESI)m/z calcd for[C21H20Cl3N9O5+H]+:584.0653,found:584.0735.
实施例27
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-(2,6-二氯-9H-嘌呤-9-基)-乙基)-氨基甲酸酯(8k)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2,6-二氯嘌呤为原料,得到化合物8k。白色固体,收率:19.33%,熔点:129.9~131.7℃,HPLC:99.76%。1H NMR(500MHz,DMSO-d6):δ9.77(d,J=9.8Hz,1H),9.01(d,J=21.3Hz,1H),7.91(s,1H),6.86(d,J=9.8Hz,1H),4.59–4.46(m,4H),2.37(s,3H).13C NMR(500MHz,DMSO-d6):δ155.56,153.83,152.55,151.87,151.22,145.42,139.01,133.38,130.10,98.46,71.80,63.92,45.76,14.37.HRMS(ESI)m/z calcdfor[C14H11Cl5N8O4+H]+:530.9346,found:530.9421.
实施例28
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(2乙酰-氨基-6-氧代-3,6-二氢-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8l)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和N-2-乙酰鸟嘌呤为原料,得到化合物8l。淡黄色固体,收率:22.16%,熔点:197.5~198.3℃,HPLC:99.67%。1H NMR(400MHz,DMSO-d6):δ12.13(s,1H),11.90(s,1H),9.67(d,J=9.1Hz,1H),8.29(s,1H),7.99(s,1H),6.76(d,J=9.8Hz,1H),4.50(d,J=54.2Hz,4H),2.38(s,3H),2.19(s,3H).13C NMR(500MHz,DMSO-d6):δ174.19,155.64,155.20,151.91,149.53,149.04,139.04,136.98,133.50,119.25,99.23,70.80,63.69,45.89,24.24,14.32.HRMS(ESI)m/z calcd for[C16H16Cl3N9O6+H]+:536.0289,found:536.0362.
实施例29
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(6-氨基-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(8m)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和腺嘌呤为原料,得到化合物8m。白色固体,收率:12.36%,熔点:187.1~187.9℃,HPLC:98.68%。1H NMR(400MHz,DMSO-d6):δ9.59(d,J=10.1Hz,1H),8.46(s,1H),8.21(s,1H),7.98(s,1H),7.48(s,2H),6.89(d,J=10.1Hz,1H),4.61-4.52(m,3H),4.47-4.39(m,1H),2.38(s,3H).13C NMR(101MHz,DMSO-d6):δ156.60,155.57,153.74,151.98,150.22,138.96,138.31,133.47,117.59,99.66,70.90,63.84,45.90,14.51.HRMS(ESI)m/z calcd for[C14H14Cl3N9O4+H]+:478.0234,found:478.0313.
实施例30
苄基-(1-(6-氨基-2-氯-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9a)
以氨基甲酸苄酯为起始原料,制备方法同实施例1步骤2。得到中间体(2,2,2-三氯-1-羟乙基)氨基甲酸苄酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体(2,2,2-三氯-1-羟乙基)氨基甲酸苄酯和2-氯腺嘌呤为原料,得到化合物9a。白色固体,收率:21.32%,熔点:198.6~199.9℃,HPLC:98.49%。1H NMR(400MHz,DMSO-d6):δ9.69(d,J=10.1Hz,1H),8.49(s,1H),8.05(s,2H),7.37(dd,J=15.1,7.4Hz,5H),6.87(d,J=10.2Hz,1H),5.21–5.12(m,2H).13C NMR(400MHz,DMSO-d6):δ157.42,155.85,154.31,151.25,138.78,136.18,128.95,128.86,128.80,116.92,99.48,70.91,67.70.HRMS(ESI)m/z calcd for[C15H12Cl4N6O2+H]+:448.9776,found:448.9853.
实施例31
(1-甲基-5-硝基-1H-咪唑-2-基)-甲基-(1-(6-氨基-2-氯-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9b)
以洛硝哒唑为起始原料,制备方法同实施例1步骤2。得到中间体(1-甲基-5-硝基-1H-咪唑啉-2-基)甲基(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体(1-甲基-5-硝基-1H-咪唑啉-2-基)甲基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氯腺嘌呤为原料,得到化合物9b。白色固体,收率:23.16%,熔点:185.8~186.3℃,HPLC:98.24%。1H NMR(500MHz,DMSO-d6):δ9.87(d,J=10.0Hz,1H),8.48(s,1H),8.06(d,J=12.8Hz,3H),6.83(d,J=10.0Hz,1H),5.32(q,J=13.6Hz,2H),3.91(s,3H).13C NMR(500MHz,DMSO-d6):δ157.42,155.27,154.30,151.26,147.57,139.93,138.75,132.24,116.90,99.37,70.93,59.34,33.98.HRMS(ESI)m/z calcdfor[C13H11Cl4N9O4+H]+:497.9688,found:497.9766.
实施例32
乙基-(1-(6-氨基-2-氯-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9c)
以氨基甲酸乙酯为起始原料,制备方法同实施例1步骤2。得到中间体(2,2,2-三氯-1-羟乙基)氨基甲酸乙酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体(2,2,2-三氯-1-羟乙基)氨基甲酸乙酯和2-氯腺嘌呤为原料,得到化合物9c。白色固体,收率:19.89%,熔点:219.5~220.4℃,HPLC:98.67%。1H NMR(400MHz,DMSO-d6):δ9.53(d,J=10.2Hz,1H),8.51(s,1H),8.04(s,2H),6.83(d,J=10.2Hz,1H),4.14(ddd,J=10.7,7.0,3.7Hz,2H),1.22(t,J=7.1Hz,3H).13C NMR(400MHz,DMSO-d6):δ157.42,155.92,154.28,151.25,138.86,116.91,99.57,70.85,62.25,14.77.HRMS(ESI)m/z calcd for[C10H10Cl4N6O2+H]+:386.9616,found:386.96970.
实施例33
(1-甲基-5-硝基-1H-咪唑-2-基)-甲基-(1-(6-氨基-2-氟-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9d)
以洛硝哒唑为起始原料,制备方法同实施例1步骤2。得到中间体(1-甲基-5-硝基-1H-咪唑啉-2-基)甲基(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体(1-甲基-5-硝基-1H-咪唑啉-2-基)甲基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氟腺嘌呤为原料,得到化合物9d。白色固体,收率:21.63%,熔点:205.8~206.9℃,HPLC:99.00%。1H NMR(500MHz,DMSO-d6):δ9.85(d,J=9.9Hz,1H),8.45(s,1H),8.04(d,J=24.3Hz,3H),6.80(d,J=9.9Hz,1H),5.33(q,J=13.6Hz,2H),3.92(s,3H).13C NMR(500MHz,DMSO-d6):δ160.29,158.66,158.41,158.24,155.26,151.73,151.57,147.58,139.91,138.62,132.22,116.24,102.69,99.37,84.10,71.03,59.33,33.96.HRMS(ESI)m/z calcd for[C13H11Cl4N9O4+H]+:481.9984,found:482.0055.
实施例34
乙基-(1-(6-氨基-2-氟-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9e)
以氨基甲酸乙酯为起始原料,制备方法同实施例1步骤2。得到中间体(2,2,2-三氯-1-羟乙基)氨基甲酸乙酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体(2,2,2-三氯-1-羟乙基)氨基甲酸乙酯和2-氟腺嘌呤为原料,得到化合物9e。白色固体,收率:18.21%,熔点:208.3~209.8℃,HPLC:99.12%。1H NMR(400MHz,DMSO-d6):δ9.50(d,J=10.1Hz,1H),8.48(s,1H),8.05(d,J=45.7Hz,2H),6.80(d,J=10.2Hz,1H),4.14(dd,J=13.3,6.4Hz,2H),1.21(t,J=7.0Hz,3H).13C NMR(400MHz,DMSO-d6):δ160.29,158.65,158.41,158.24,155.91,151.73,151.57,138.73,116.29,116.26,99.60,70.96,62.21,14.75.HRMS(ESI)m/z calcd for[C10H10Cl4N6O2+H]+:370.9915,found:370.9988.
实施例35
2-N-吗啉乙基-(1-(6-氨基-2-氟-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9f)
以羟乙基吗啉为起始原料,制备方法同实施例1步骤2。得到中间体2-吗啉乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-N-吗啉乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氟腺嘌呤为原料,得到化合物9f。淡黄色固体,收率:10.42%,HPLC:96.96%。1H NMR(500MHz,DMSO-d6):δ9.68(d,J=9.1Hz,1H),8.55(s,1H),8.03(d,J=38.0Hz,2H),6.79(d,J=10.0Hz,1H),4.21(s,2H),3.03(d,J=7.3Hz,4H),2.60(s,2H),2.46(s,4H).13C NMR(126MHz,DMSO-d6):δ158.32(d,J=5.9Hz),155.78(s),138.96(s),130.10(s),102.96(s),99.51(s),83.94(s),71.03(s),70.20(s),65.83(s),65.54(s),56.68(d,J=5.6Hz),53.32(s).HRMS(ESI)m/z calcd for[C14H18Cl3FN7O3+H]+:456.0515,found:456.0517.
实施例36
2-N-吗啉乙基-(2,2,2-三氯-1-(2,6-二氨基-9H-嘌呤-9-基)-乙基)-氨基甲酸酯(9g)
以羟乙基吗啉为起始原料,制备方法同实施例1步骤2。得到中间体2-吗啉乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-吗啉代乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氨基腺嘌呤为原料,得到化合物9g。白色固体,收率:10.07%,HPLC:97.8%。1H NMR(500MHz,DMSO-d6):δ9.44(d,J=10.1Hz,1H),8.11(s,1H),6.90-6.80(m,3H),6.08(s,2H),4.18(s,2H),3.51(s,4H),2.51(s,2H),2.38(s,4H).NMR HRMS(ESI)m/zcalcd for[C14H19Cl3N8O3+H]+:453.0718,found:453.0724.
实施例37
2-(吡啶-2-基)-乙基-(1-(6-氨基-2-氟-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9h)
以2-羟乙基吡啶为起始原料,制备方法同实施例步骤2。得到中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氟腺嘌呤为原料,得到化合物9h。白色固体,收率:26.58%,HPLC:97.28%。1H NMR(500MHz,DMSO-d6)δ9.78(d,J=9.7Hz,1H),8.75(s,1H),8.55(s,1H),8.37(s,1H),8.07–7.92(m,3H),7.81(s,1H),6.70(d,J=9.9Hz,1H),4.51(d,J=6.9Hz,2H),3.39(s,2H).13C NMR(126MHz,DMSO-d6)δ160.22(s),158.58(s),158.33(s),155.69(s),154.21(s),142.99(s),139.02(d,J=3.0Hz),127.59(s),125.26(s),116.20(s),99.37(s),70.98(s),64.02(s),33.43(s).HRMS(ESI)m/z calcd for[C15H13Cl3FN7O2+H]+:448.0253,found:448.0257.
实施例38
2-(吡啶-2-基)-乙基-(2,2,2-三氯-1-(2,6-二氨基-9H-嘌呤-9-基)-乙基)-氨基甲酸酯(9i)
以2-羟乙基吡啶为起始原料,制备方法同实施例步骤2。得到中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和2-氨基腺嘌呤为原料,得到化合物9i。白色固体,收率:27.38%,HPLC:95.32%。1H NMR(500MHz,DMSO)δ9.34(d,J=10.1Hz,1H),8.48(d,J=3.9Hz,1H),8.07(s,1H),7.69(t,J=7.1Hz,1H),7.29(d,J=7.6Hz,1H),7.24–7.19(m,1H),6.91–6.77(m,3H),6.08(s,2H),4.52–4.43(m,2H),3.08(t,J=6.5Hz,2H).13C NMR(101MHz,DMSO)δ161.23(s),158.02(s),156.75(s),152.59(s),149.56(s),137.00(s),134.68(s),123.90(s),122.23(s),111.95(s),100.45(s),70.19(s),64.90(s),60.23(s),37.14(s).HRMS(ESI)m/z calcd for[C15H15Cl3N8O2+H]+:445.0456,found:445.0460.
实施例39
苄基-(1-(6-氨基-2-氟-9H-嘌呤-9-基)-2,2,2-三氯乙基)-氨基甲酸酯(9j)
以氨基甲酸苄酯为起始原料,制备方法同实施例1步骤2。得到中间体(2,2,2-三氯-1-羟乙基)氨基甲酸苄酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体(2,2,2-三氯-1-羟乙基)氨基甲酸苄酯和2-氟腺嘌呤为原料,得到化合物9j。白色固体,收率:19.82%,熔点:234.8~235.7℃,HPLC:96.24%。1H NMR(500MHz,DMSO-d6):δ9.67(d,J=10.1Hz,1H),8.46(s,1H),8.06(d,J=47.0Hz,2H),7.46-7.31(m,5H),6.82(d,J=10.2Hz,1H),5.16(q,J=12.2Hz,2H).13CNMR(126MHz,DMSO-d6):δ160.30,158.67,158.42,158.25,155.85,151.72,151.56,138.65,136.20,128.94,128.82,116.29,99.53,71.01,67.68.HRMS(ESI)m/z calcd for[C15H12Cl4N6O2+H]+:433.0071,found:433.0146.
实施例40
2-N-吗啉乙基-(1-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)-2,2,2-三氯乙基)-氨基甲酸酯(10a)
以羟乙基吗啉为起始原料,制备方法同实施例步骤2。得到中间体2-吗啉代乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-吗啉代乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-氨基吡唑并[3,4-d]嘧啶为原料,得到化合物10a。白色固体,收率:19.56%,HPLC:95.17%。1H NMR(500MHz,DMSO)δ9.27(d,J=7.9Hz,1H),8.38(s,1H),8.22(d,J=23.0Hz,2H),7.79(s,1H),7.15(d,J=9.7Hz,1H),4.14(s,2H),3.48(s,4H),2.51(s,2H),2.37(s,4H).13C NMR(126MHz,DMSO)δ158.49(s),157.03(s),155.34(s),135.09(s),99.91(s),99.65(s),71.72(s),66.48(s),62.90(s),57.14(s),53.79(s).HRMS(ESI)m/zcalcd for[C14H18Cl3N7O3+H]+:438.0604,found:438.0610.
实施例41
2-(吡啶-1-基)-乙基-(2,2,2-三氯-1-(4-(2,2,2-三氯-1-((2-(2-吡啶-2-基)-乙氧羰氨基-)-乙基)-氨基)-1H-吡唑并[3,4-d]嘧啶-1-基-乙基)-氨基甲酸酯(10b)
以2-羟乙基吡啶为起始原料,制备方法同实施例步骤2。得到中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-氨基吡唑并[3,4-d]嘧啶为原料,得到化合物10b。白色固体,收率:9.84%,HPLC:97.73%。1H NMR(500MHz,DMSO)δ9.34(d,J=9.2Hz,1H),9.06(d,J=7.8Hz,1H),8.61(s,1H),8.51(s,1H),8.48–8.43(m,2H),8.39–8.31(m,1H),7.66(s,2H),7.29(d,J=7.3Hz,2H),7.19(d,J=4.4Hz,4H),4.42(dd,J=8.0,5.7Hz,4H),3.04(d,J=7.7Hz,4H).13C NMR(126MHz,DMSO)δ158.09(d,J=12.8Hz),156.30(s),155.89(s),155.31(s),149.51(d,J=5.0Hz),136.89(s),134.91(s),123.91(d,J=6.1Hz),122.14(s),101.65(s),100.39(s),99.39(s),71.92(s),68.88(s),64.88(s),64.50(s),37.27(d,J=11.4Hz).HRMS(ESI)m/z calcd for[C25H23Cl6N9O4+H]+:724.0077,found:724.0083.
实施例42
2-(吡啶-2-基)-乙基-(2,2,2-三氯-1-(4-羟基-1H-吡唑并[3,4-d]嘧啶-1-基)-乙基)-氨基甲酸酯(10c)
以2-羟乙基吡啶为起始原料,制备方法同实施例步骤2。得到中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-羟基吡唑并[3,4-d]嘧啶为原料,得到化合物10c。淡黄色色固体,收率:7.22%,HPLC:95.06%。1H NMR(500MHz,DMSO)δ12.49(s,1H),9.41(d,J=9.6Hz,1H),8.46(s,1H),8.28(s,1H),8.22(s,1H),7.68(t,J=6.7Hz,1H),7.31(d,J=7.0Hz,1H),7.25–7.19(m,1H),7.12(d,J=9.8Hz,1H),4.42(dd,J=13.4,6.5Hz,2H),3.05(t,J=6.3Hz,2H).13C NMR(101MHz,DMSO)δ157.99(s),157.44(s),154.15(s),149.73(s),149.45(s),137.04(s),136.81(s),124.05(s),122.17(s),116.17(s),106.07(s),99.15(s),72.11(s),64.92(s),37.14(s)HRMS(ESI)m/z calculated for[C15H13Cl3N6O3+H]+:431.0187,found:431.0193
实施例43
2-(吡啶-1-基)-乙基-(2,2,2-三氯-1-(4-(2,2,2-三氯-1-(2-(2-吡啶-2-基)-乙氧羰氨基-)-乙氧基)-1H-吡唑并[3,4-d]嘧啶-1-基-乙基)-氨基甲酸酯(10d)
以2-羟乙基吡啶为起始原料,制备方法同实施例步骤2。得到中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯粗品后直接投入下一步反应。
按照实施例1步骤3的合成方法,以中间体2-(吡啶-2-基)乙基-(2,2,2-三氯-1-羟乙基)氨基甲酸酯和4-羟基吡唑并[3,4-d]嘧啶为原料,得到化合物10d。淡黄色色固体,收率:7.22%,HPLC:96.23%。1H NMR(500MHz,DMSO)δ9.48(s,1H),9.36(d,J=9.4Hz,1H),9.14(s,1H),8.65(s,1H),8.46(s,2H),7.68(s,2H),7.39(d,J=10.0Hz,1H),7.30(d,J=6.7Hz,2H),7.20(s,2H),6.91(d,J=14.1Hz,1H),4.48(dd,J=15.2,7.7Hz,4H),3.15–3.01(m,4H).
实施例44
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(1-(6-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)-2,2,2-三氯乙基)-氨基甲酸酯(10e)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和6-氨基吡唑并[3,4-d]嘧啶为原料,得到化合物10e。淡黄色固体,收率:14.65%,HPLC:98.62%。1H NMR(500MHz,DMSO)δ9.63(d,J=10.9Hz,1H),8.53(s,1H),8.05(d,J=47.0Hz,3H),7.73(s,1H),6.81(d,J=9.8Hz,1H),4.19(d,J=5.7Hz,4H),2.37(s,3H).HRMS(ESI)m/z calcd for[C14H14Cl3N9O4+H]+:478.0302,found:478.0309.
实施例45
2-(2-甲基-5-硝基-1H-咪唑-1-基)-乙基-(2,2,2-三氯-1-(6-氯-1H-吡唑并[3,4-d]嘧啶-1-基)-乙基)-氨基甲酸酯(10f)
步骤1和2与实施例1相同。
按照实施例1步骤3的合成方法,以中间体2-(2-甲基-5-硝基-1H-咪唑啉-1-基)乙基(2,2,2-三氯-1-羟乙基)氨基甲酸酯和6-氯吡唑并[3,4-d]嘧啶为原料,得到化合物10f的盐酸盐。淡黄色固体,收率:9.08%,HPLC:95.06%。1H NMR(500MHz,DMSO)δ11.89(d,J=3.4Hz,1H),9.64(d,J=9.5Hz,1H),8.98(s,1H),8.01(d,J=3.7Hz,1H),7.99(s,1H),6.89(d,J=10.0Hz,1H),4.54(s,4H),2.40(s,3H).HRMS(ESI)m/z calcd for[C14H12Cl4N8O4+H]+:496.9803,found:497.0073.
实施例46
癌细胞增殖抑制实验
为了验证所设计合成化合物的抗癌活性,本课题设计了两大部分的活性测试。首先使用MTT法对所有化合物进行乳腺癌MCF-7、黑色素瘤A375、肺腺癌A549、肝细胞癌HepG2、***Hela以及卵巢癌Carvo-3,6种细胞系的增殖抑制活性筛选,选用的阳性对照药为Cdc20的特异性抑制剂Apcin。
MTT法的原理是活细胞线粒体中的琥珀酸脱氢酶能使外源性的溴化四氮唑蓝(MTT)还原为难溶性的蓝紫色结晶物并沉积在细胞中,而死细胞无此功能。DMSO能溶解细胞中的紫色结晶物,用酶联免疫检测仪在490nm波长下检测吸光值,可反映活细胞数量。
通过上述的MTT法,三次平行实验得到最终的IC50值。
(1)实验材料
a.细胞株:MCF-7、A375、A549、HepG2、Hela、Carvo-3细胞系
b.试剂与仪器:四甲基偶氮唑盐(MTT)和二甲基亚砜(DMSO)购于Sigma-Aldrich公司;新生牛血清、胎牛血清、胰酶、RPMI-1640、DMEM和青霉素-链霉素购于Gibco公司;其它试剂未经特殊说明均购于Sigma-Aldrich公司;CO2培养箱(Thermo)、酶标仪(Thermo)和荧光倒置显微镜(Olympus)。
(2)实验内容
a.取活细胞比例达90%以上的细胞进行实验(MTT法)。收集对数期细胞,调整细胞悬液浓度4-5×104个/mL,每孔加入100μL,铺板使待测细胞调密度4000-5000/孔。
b.5%CO2,37℃孵育,至细胞单层铺满孔底(96孔平底板),加入不同浓度梯度的药物,使孔中化合物终浓度为300、100、30、10、3、1、0.3、0.1、0.03、0μM/mL,每孔100μL,同时做3个复孔,用于对比组间差异。
c.放入5%CO2,37℃恒温培养箱孵育48h,放在倒置显微镜下观察。
d.每孔加入10μL MTT溶液(5mg/mL,即0.5%MTT),继续培养4h。
e.4h后终止培养,小心吸去孔内培养液。
f.每孔加入150μL DMSO,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪检测波长490nm处测量各孔的吸光值,并计算抑制率。
g.同时设置调零孔(培养基、MTT、DMSO),对照孔(细胞、相同浓度的药物溶解介质、培养液、MTT、DMSO)。
(3)数据处理
每个浓度梯度重复三个复孔,采用SPSS13.0软件,以浓度为横坐标,抑制率为纵坐标拟合曲线,计算化合物的抑制率(IC50值)。酶标仪上于检测波长490nm处测定每孔的吸光度OD值,细胞生长抑制率按下式计算:
表1:被测化合物对癌细胞株的抑制数据
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结果显示:
与特异性Cdc20抑制剂Apcin相比,所得到的大部分目标化合物的抗癌活性都有所提高。含有二氯取代嘧啶的化合物(7a-7d)和2-氟腺嘌呤侧链的化合物(8g、9d、9e、9f、9h)表现出最有效的抗增殖活性。为了进一步确证化合物的靶向性,在其中选择活性最好的7d和9f继续进行本发明设计的细胞周期和细胞凋亡研究。
实施例47
人肝癌细胞(Hep-G2)周期实验
(1)实验材料
a.细胞株:人肝癌细胞HepG2
b.试剂和仪器:多功能成像***购于Biotek公司;磷酸化组蛋白H3抗体购于CST;PBS、胰酶消化液、DMSO、胎牛血清、DMEM、96孔细胞培养板、T25细胞培养瓶、CO2细胞培养箱、低速离心机、细胞计数器、生物洁净工作台的厂家与癌细胞增殖抑制实验中的相同。
(2)实验内容
a.取对数期生长的HepG2细胞,用1×PBS洗3次,每次2min;向培养瓶/培养皿中加入胰酶消化,CO2培养箱中消化2min。培养瓶/培养皿中加入培基(DMEM)终止消化,用灭菌吸管吹打细胞至细胞呈单个悬浮状态;
b.用细胞计数板计数,铺板。
c.上药,恒温箱孵育2d。
d.吸出每孔的培基,向每孔中加入100μl的4%多聚甲醛,室温孵育15min。
e.吸出并用PBS冲洗三次。
f.每孔中加入0.1ml的渗透液室温孵育15min。
g.吸出渗透液并用PBS冲洗三次。
h.每孔加入100μl的封闭缓冲液,室温孵育15min。
i.吸出封闭缓冲液,每孔加入50μl的一抗溶液,4℃孵育过夜。
j.吸出一抗溶液并用PBS冲洗三次,每孔加入50μl的二抗溶液在室温孵育60min(避光)。
k.吸出二抗溶液并用PBS冲洗三次,每孔加入100μlPBS,进行成像。
如图4所示为药物处理HepG2细胞株的免疫荧光实验结果。药物组:化合物Apcin(100μM),7d(30μM),9f(0.3μM)。药物处理时间:48h。
与HepG2细胞中的溶剂对照组相比,30μM的化合物7d和0.3μM的化合物9f分别诱导了磷酸组蛋白H3阳性细胞的增加,即分别由3.8%增长至6.9%和10.0%。而与DMSO对照相比,100μM的阳性化合物Apcin则导致PHH3阳性细胞数增加了约2.2倍。与阳性对照药Apcin相比,化合物7d和9f在阻滞细胞有丝***退出方面显示出了更强的效力,而化合物9f是最有效的有丝***阻滞剂,其在0.3μM时即显示出强烈的M期阻滞作用。
实施例48
人肝癌细胞(Hep-G2)凋亡实验
(1)实验材料
a.细胞株:人肝癌细胞HepG2
b.试剂和仪器:多功能成像***购于Biotek公司;Annexin-FITC/PI凋亡试剂盒购于索莱宝公司;PBS、胰酶消化液、DMSO、胎牛血清、RPMI 1640、24孔细胞培养板、T25细胞培养瓶、CO2细胞培养箱、低速离心机、细胞计数器、生物洁净工作台的厂家与癌细胞增殖抑制实验中的相同。
(2)实验步骤
a.取对数期生长的HepG2细胞,用1×PBS洗3次,每次2min,向培养瓶/培养皿中加入胰酶消化,CO2培养箱中消化2min。向培养瓶/培养皿中加入培基(DMEM)终止消化,用灭菌吸管吹打细胞至细胞呈单个悬浮状态。用细胞计数板进行计数,铺板。
b.加药,37℃孵育过夜。
c.用27ml的去离子水稀释3ml Binding Buffer(10×)至30ml,每次用3ml。
d.加入2μl ANNEXIN V-FITC染色10分钟,室温,避光,也宜用摇床,或手动晃动数次。
e.加入5μl PI,室温,避光,孵育5min。
f.吸出染色液,加入PBS润洗,用于成像。
如图5所示为药物处理HepG2细胞株的凋亡实验结果。药物组:化合物Apcin(100μM),9f(0.3μM);药物处理时间:24h。当药物处理24h时,高浓度的Apcin具有显著的促细胞凋亡作用,多数细胞处于早凋阶段,但也存在晚凋细胞。而高浓度的9f具有显著的促细胞凋亡作用,且大多数细胞处于早凋阶段。化合物7d(30μM)也具有促细胞凋亡作用。
上述机制研究初步表明,化合物9f以及7d可以显著抑制癌细胞增殖,同时,研究表明,本课题所设计的化合物是通过阻滞细胞周期和促进细胞凋亡而发挥抑制癌细胞增殖作用。
上述实施例阐明的内容应当理解为这些实施例仅用于更清楚地说明本发明,而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本发明的各种等价形式的修改均落入本申请所附权利要求所限定的范围。
Claims (2)
1.一种(1,1,1-三氯-2)氨基甲酸酯类衍生物,其特征在于,结构式如下:
2.权利要求1所述的(1,1,1-三氯-2)氨基甲酸酯类衍生物在制备治疗肺腺癌A549、肝细胞癌HepG2以及卵巢癌Carvo-3药物中的应用。
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