CN108409608B - 芳香氮芥类组蛋白去乙酰化酶抑制剂及其制备方法和应用 - Google Patents
芳香氮芥类组蛋白去乙酰化酶抑制剂及其制备方法和应用 Download PDFInfo
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- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明公开了一类强效的组蛋白去乙酰化酶抑制剂，本发明涉及具有式I结构的化合物，还涉及其各种光学异构体，药学上可接受的盐和溶剂合物。本发明还涉及含有式I结构化合物的药物组合物及其制药用途。可有效治疗组蛋白去乙酰化酶活性异常表达的疾病，
Description
技术领域
本发明涉及药物化学技术领域，具体涉及一种芳香氮芥类组蛋白去乙酰化酶抑制剂及其制备方法和应用。
背景技术
组蛋白去乙酰化酶(HDACs)是一类功能复杂的水解酶。在细胞核中，由DNA链缠绕着的组蛋白八聚体构成的核小体是构成染色体的结构单元，组蛋白去乙酰化酶(HDACs)能将组蛋白中的赖氨酸残基末端氨基上的乙酰基水解掉(如反应式I)，从而导致组蛋白的正电荷密度增高，继而引起组蛋白与负电性的DNA的亲和力增强，基因转录被抑制，(参见Christian,A.H.,et al.Curr.Opin.Chem.Biol.,1997,1,300；Kouzarides,T.,Curr.Opin.Genet.Dev.,1999,9,40)；Wolffe,A.P.Sci.Washington,1996,272,371。此外，核小体组蛋白的去乙酰化还与染色质组装，DNA修复与重组密切相关，(参见Polo,S.E.,etal.Cancer Lett.,2005,220,1；Vidanes,G.M.,et al.Cell,2005,121,973)。近来，越来越多的非组蛋白被证实为HDACs的底物，如转录因子，细胞骨架蛋白，分子伴侣等，(参见Glozak,M.A.,et al.Gene,2005,363,15)。正是由于HDACs具有如此复杂的功能，它的表达和活性失调与许多疾病密切相关，包括：癌症，神经变性疾病，病毒感染，炎症，白血病，疟疾和糖尿病等，其中，癌症无疑是对人类生命健康威胁最为严重的疾病。研究表明，HDACs与肿瘤细胞发生发展密切相关，如：抑制肿瘤细胞分化和凋亡，促进肿瘤细胞增殖，迁移和血管生成，增强肿瘤细胞对化疗药物的抵抗力等，(参见Witt,O.,et al.Cancer Letter.,2009,277,8)。
目前在人体中发现了HDACs家族有18个成员，根据其结构，功能和分布的不同可分为四类。其中，I类(HDAC1，2，3和8)，II类(IIa：HDAC4，5，7和9；IIb：HDAC6，10)，IV类(HDAC11)属于锌离子依赖性水解酶，而III类HDACs(SIRT 1-7)是NAD+依赖性的。研究表明，与肿瘤密切相关的主要是锌离子依赖性HDACs，HDAC抑制剂(HDACs Inhibitors，HDACi)能有效抑制癌细胞增殖，促进细胞凋亡。而且，HDACi具有抗瘤谱广，毒副作用低的优点，它们对实体瘤，白血病，淋巴瘤都具有很好的抑制活性。因此，针对HDACs为靶点设计抑制剂已成为抗肿瘤药物研究的热点。
发明内容
针对上述现有技术的不足，本发明的目的是提供一种全新的组蛋白去乙酰化酶抑制剂及其制备方法和应用。本发明采用异羟肟酸和胺基苯基酰胺结构为锌离子螯合基团，创新性地在分子中引入具有显著抗肿瘤活性的氮芥结构来提高其抗肿瘤活性和选择性，以及改善其脂水分配系数，促进药物的吸收。
为实现上述目的，本发明采用如下技术方案：
本发明的第一方面，提供一种式I所示的化合物，或其光学异构体、非对映异构体、消旋体或三者的混合物，或其药学上可接受的盐；
其中，X是-NH-或-NHCH2-；
Y是-CO-或-CH＝CHCO-；
R是-OH或2-氨基苯基。
优选的，上述式I所示的化合物，是下述化合物之一：
4-(双(2-氯乙基)胺基)-N-(4-(羟基氨甲酰基)苯基)苯甲酰胺(D1)；
4-(双(2-氯乙基)胺基)-N-(4-(3-(羟基胺基)-3-羰基丙-1-烯-1-基)苯基)苯甲酰胺(D2)；
4-(双(2-氯乙基)胺基)-N-(4-(羟基氨甲酰基)苯甲基)苯甲酰胺(D3)；
N-(2-氨基苯基)-4-(4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酰胺(E1)；
N-(4-(3-((2-氨基苯基)胺基)-3-羰基丙-1-烯-1-基)苯基)-4-(双(2-氯乙基)胺基)苯甲酰胺(E2)；
N-(2-氨基苯基)-4-((4-(双(2-氯乙基)胺基)苯甲酰胺基)甲基)苯甲酰胺(E3)。
本发明的第二方面，提供上述式I所示化合物的制备方法，包括如下步骤：
以对氨基苯甲酸为原料，先进行羧基保护，再分别进行亲电取代和亲核反应，羧基脱保护，引入linker，再进行羧基脱保护，最后引入异羟肟酸或与邻苯二胺缩合，制得式I所示化合物。
其合成路线如下：
上述合成路线反应式中的试剂：(1)乙酰氯，甲醇；(2)环氧乙烷，水/冰醋酸；(3)三氯氧磷，甲苯；(4)6M盐酸；(5)TBTU，相应氨基酸甲酯，Et3N，DCM；(6)NHOK，CH3OH；(7)6M盐酸；(8)邻苯二胺，CDI，四氢呋喃。
本发明的第三方面，提供上述式I所示的化合物，或其光学异构体、非对映异构体、消旋体或三者的混合物，或其药学上可接受的盐在制备组蛋白去乙酰化酶抑制剂中的应用。
本发明的第四方面，提供上述式I所示的化合物，或其光学异构体、非对映异构体、消旋体或三者的混合物，或其药学上可接受的盐在制备预防或治疗与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病的药物中的应用。
优选的，所述与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病包括：癌症，神经变性疾病，病毒感染，炎症和糖尿病。
本发明的第五方面，提供一种药物组合物，所述药物组合物的活性成分为式I所示的化合物，或其光学异构体、非对映异构体、消旋体或三者的混合物，或其药学上可接受的盐。
进一步的，所述药物组合物中还包括一种或多种药学上可接受的载体或赋形剂。
优选的，所述药物组合物为口服制剂或注射制剂。
上述药物组合物在制备治疗肿瘤疾病的药物制剂中的应用也是本发明的保护范围。优选的，所述肿瘤疾病包括：淋巴癌、白血病和直肠癌。
本发明的第六方面，一种治疗与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病的方法，该方法包括给予面临与组蛋白去乙酰化酶活性异常表达相关的疾病风险或经诊断患有与组蛋白去乙酰化酶活性异常表达相关的疾病的受试者治疗有效量的式I所示的化合物或其其药学上可接受的盐。
本文使用的术语“治疗有效量”表示，治疗、改善靶向的疾病或病症或者表现出可检测的治疗效果所需的治疗剂的量。
本发明的化合物在相当宽的剂量范围内是有效的。实际服用本发明式I所示的化合物的剂量可由医生根据有关的情况来决定。这些情况包括：受试者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
在治疗过程中，上述式I化合物或其药学上可接受的盐可还以与至少一种其它药物合用。所涵盖的其它药物的原子组成或结构均异于式I的化合物。
本发明的有益效果：
本发明中的芳香氮芥类化合物对组蛋白去乙酰化酶的抑制活性优于阳性对照药，具有良好的开发前景，并可作为发现新型高效组蛋白去乙酰化酶抑制剂的先导化合物。此外，本发明的芳香氮芥类化合物在体外抗肿瘤细胞增殖的试验中显示出优于阳性对照Vorinostat(SAHA)的活性，具有良好的开发前景。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
本文中所用的术语和定义含义如下：
“药学上可接受的盐”是指化合物具有疗效且无毒的盐形式。其可由任一酸性基团(如羧基)形成阴离子盐，或由任一碱性基团(如氨基)形成阳离子盐。本领域已知许多这样的盐。在任何酸性基团(如羧基)上形成的阳离子盐，或是在任何碱性基团(如氨基)上形成的阴离子盐。这些盐有许多是本领域已知的，如阳离子盐包括碱金属(如钠和钾)和碱土金属(如镁和钙)的盐以及有机盐(如铵盐)。还可通过使用相应的酸处理碱性形式的(I)方便地获得阴离子盐，这样的酸包括无机酸如硫酸、硝酸、磷酸等；或有机酸如乙酸、丙酸、羟基乙酸、2-羟基丙酸、2-氧代丙酸、草酸、丙二酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、2-羟基-1,2,3-丙三酸、甲磺酸、乙磺酸、苯甲磺酸、4-甲基苯磺酸、环己基亚磺酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸等。这些盐是熟练技术人员熟知的，熟练的技术人员可制备本领域知识所提供的任何盐。此外，熟练技术人员可根据溶解度、稳定性、容易制剂等因素取某种盐而舍另一种盐。这些盐的测定和最优化在熟练技术人员的经验范围内。
“前药”是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。
正如背景技术部分所介绍的，现有的组蛋白去乙酰化酶抑制剂存在选择性差、半衰期短、难吸收和药物代谢动力学性质差等缺点。目前报道的HDACi药效团大都包括如下三个部分：锌离子螯合基团(ZBG)，疏水性的长链(Linker)和蛋白表面识别区(SurfaceRecognition Domain)。本申请发明人在前期研究中得到含有氮芥结构的N-(2-胺基苯基)-4-(双(2-氯乙基)胺基)苯甲酰胺作为新型HDACi先导化合物。然而，该化合物虽然具有较好的体外抑制HDACs和肿瘤细胞增殖的活性，但是在动物体内易代谢失活。为了改善其ADMET性质，本发明在N-(2-胺基苯基)-4-(双(2-氯乙基)胺基)苯甲酰胺结构基础上增加了一个芳香环(苯环)，通过引入空间位阻降低其代谢速率；并同时引入了螯合能力更强的异羟肟酸结构作为ZBG，来保持或增强其活性。为了考察不同结构linker对活性的影响，本发明在苯环之间的结合部位引入了柔性更强的linker，活性测试结果显示具有柔性linker(CONHCH2)的分子(D3)比刚性linker(CONH)的分子活性都好，说明柔性linker有助于目标化合物活性的提高。
本发明的组蛋白去乙酰化酶抑制剂具有如下结构：
其中，X是-NH-或-NHCH2-；Y是-CO-或-CH＝CHCO-；R是-OH或2-氨基苯基。
所述组蛋白去乙酰化酶抑制剂由如下方法制备而成：
合成路线：以对氨基苯甲酸为原料，先进行羧基保护，再分别进行亲电取代和亲核反应，羧基脱保护，引入linker，再进行羧基脱保护，最后引入异羟肟酸或与邻苯二胺缩合制得终产物。反应式如下：
上述合成路线反应式中的试剂：(1)乙酰氯，甲醇；(2)环氧乙烷，水/冰醋酸；(3)三氯氧磷，甲苯；(4)6M盐酸；(5)TBTU，相应氨基酸甲酯，Et3N，DCM；(6)NHOK，CH3OH；(7)6M盐酸；(8)邻苯二胺，CDI，四氢呋喃。
反应路线中制备所述组蛋白去乙酰化酶抑制剂中间体，该路线中的中间体包括：对氨基苯甲酸甲酯盐酸盐，甲基4-(双(2-羟基乙基)胺基)苯甲酸酯，甲基4-(双(2-氯乙基)胺基)苯甲酸酯，4-(双(2-氯乙基)胺基)苯甲酸，4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸，3-(4-(4-(双(2-氯乙基)胺基)苯甲酰胺基)苯基)丙烯酸，4-((4-(双(2-氯乙基)胺基)苯甲酰胺基)甲基)苯甲酸，4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸甲酯，3-(4-(4-(双(2-氯乙基)胺基)苯甲酰胺基)苯基)丙烯酸甲酯，4-((4-(双(2-氯乙基)胺基)苯甲酰胺基)甲基)苯甲酸甲酯。
由于锌离子依赖性组蛋白去乙酰化酶(HDACs)各亚型催化中心的高度同源性，我们选择含有组蛋白去乙酰化酶的Hela细胞提取物(包含HDAC1,HDAC2,HDAC3和HDAC8)来进行酶活性测试。HDACs活性荧光分析方法(两步法)，能快速、方便检测HDACs活性，操作简单，灵敏度高。第一步，含一个乙酰化侧链的赖氨酸HDACs荧光底物(Boc-Lys(acetyl)-AMC)，用含有组蛋白去乙酰化酶的Hela细胞提取物样本孵育，使底物脱去乙酰基，激活底物。第二步，用胰酶水解Boc-Lys-AMC，产生AMC这一荧光基团(即发色团)，在发射波长/激发波长(390nm/460nm)测定荧光强度，从而根据抑制剂组及对照组的荧光强度计算抑制率，并求算IC50值。酶活性测试原理见反应式II。
反应式II中Histone deacetylase为组蛋白去乙酰化酶，Trypsin为胰蛋白酶，4-amino-7-methylcoumarin为4-氨基-7-甲基香豆素。
化合物的细胞活性的测试使用噻唑兰检测方法(MTT法)，人组织细胞淋巴瘤细胞株(U937)，人红白血病细胞株(K562)，人急性白血病细胞株(HL60)和人直肠癌细胞株(HCT116)的细胞悬液分别接种于96孔板，每孔中加入含不同浓度化合物的培养基，经孵育后，用MTT染色，继续孵育后，于酶标仪上在570nm处测定每孔的吸光度(OD值)，计算出细胞生长抑制率，从而确定化合物的活性。
式I的化合物的体外抑酶试验证明该类化合物为有效的组蛋白去乙酰化酶抑制剂。
含有本发明化合物的药物组合物
本发明的部分衍生物可以游离形式或以盐形式存在。本领域技术人员已知许多化合物类型的药学上可接受的盐及其制备方法。药学上可接受的盐包括常规的无毒性的盐，包括这样的化合物碱与无机或有机酸形成的季铵盐。
本发明的化合物可形成水合物或溶剂合物。本领域熟练人员已知将化合物与水一起冻干时所形成的水合物或在溶液中与合适的有机溶剂浓缩时形成溶剂合物的方法。
本发明包含含有治疗量本发明化合物的药物，和一种或多种药学上可接受载体和/或赋形剂的药物组合物。载体包括如盐水，缓冲盐水，葡萄糖，水，甘油，乙醇和它们的结合物，下文更详细地论述。如果需要，该组合物还可以包含较小量的润湿剂或乳化剂，或pH缓冲剂。该组合物可以是液体，悬浮液，乳剂，片剂，丸剂，胶囊，持续释放制剂或粉末。该组合物可以用传统的黏合剂和载体如三酸甘油酯配制成栓剂。口服制剂可以包括标准载体如药物品级的甘露糖醇，乳糖，淀粉，硬脂酸镁，糖精钠，纤维素和碳酸镁等等。视需要制剂而定，配制可以设计混合，制粒和压缩或溶解成分。在另一个途径中，该组合物可以配制成纳米颗粒。
使用的药物载体可以为固体或者液体。
典型的固体载体包括乳糖，石膏粉，蔗糖，滑石，凝胶，琼脂，果胶，阿拉伯胶，硬脂酸镁，硬脂酸等等。固体载体可以包括一种或多种可能同时作为增香剂，润滑剂，增溶剂，悬浮剂，填料，助流剂，压缩助剂，粘合剂或片剂-崩解剂的物质；它还可以是包封材料。在粉末中，载体为精细粉碎的固体，它与精细粉碎的活性成分的混合。在片剂中活性成分与具有必要的压缩性质的载体以合适的比例混合，以需要的形状和大小压缩。粉末和片剂优选包含至多99％活性成分。合适的固体载体包括，例如，磷酸钙，硬脂酸镁，滑石，糖，乳糖，糊精，淀粉，凝胶，纤维素，甲基纤维素，羧甲基纤维素钠盐，聚乙烯吡咯烷酮烷酮，低熔点蜡和离子交换树脂。
典型的液体载体包括糖浆，花生油，橄榄油，水等等。液体载体用于制备溶液，悬浮液，乳剂，糖浆，酊剂和密封的组合物。活性成分可以溶解或悬浮于药学上可接受的液体载体如水，有机溶剂，二者的混合物或药学上可接受的油类或脂肪。液体载体可以包含其他合适的药物添加剂如增溶剂，乳化剂，缓冲剂，防腐剂，增甜剂，增香剂，悬浮剂，增稠剂，颜料，粘度调节剂，稳定形或渗透压-调节剂。用于口服和肠胃外给药的液体载体的合适的例子包括水(部分地包含如同上述的添加剂，例如纤维素衍生物，优选羧甲基纤维素钠盐溶液)，醇(包括一元醇和多元醇，例如乙二醇)和它们的衍生物，和油类(例如分馏椰子油和花生油)。用于肠胃外给药的载体还可以为油脂如油酸乙酯和异丙基肉豆蔻酸盐。无菌的液体载体用于肠胃外给药的无菌的液态组合物。用于加压组合物的液体载体可以为卤代烃或其他药学上可接受的推进剂。无菌溶液或悬浮溶液液体药物组合物可以用来，例如，静脉内，肌内，腹膜内或皮下注射。注射时可单次推入或逐渐注入，入30分钟的经脉内灌注。该化合物还可以以液体或者固体组合物的形式口服给药。
载体或赋形剂可以包括本领域已知的时间延迟材料，如单硬脂酸甘油酯或二硬脂酸甘油酯，还可包括蜡，乙基纤维素，羟丙基甲基纤维素，异丁烯酸甲酯等等。当制剂用于口服时，公认PHOSALPG-50(磷脂(phospholipid)与1,2-丙二醇浓缩，A.Nattermann&Cie.GmbH)中的0.01％吐温80用于其他化合物的可接受的口服制剂的配制，可以适应于本发明各种化合物的配制。
给予本发明化合物时可以使用各式各样的药物形式。如果使用固体载体，制剂可以为片剂，被放入硬胶囊中的粉末或小药丸形式或锭剂或糖锭形式。固体载体的量在很大程度上变化，但是优选从约25mg到约1.0g。如果使用液体载体，制剂可以为糖浆，乳剂，软胶囊，在安瓿或小瓶或非水的液体悬浮液中的无菌注射溶液或悬浮液。
为了获得稳定的水溶性的剂型，可以将化合物或其药学上可接受的盐溶于有机或无机酸的水溶液，0.3M琥珀酸或柠檬酸溶液。选择性地，酸性的衍生物可以溶于合适的碱性溶液。如果得不到可溶形式，可将化合物溶于合适的共溶剂或它们的结合。这样的合适的共溶剂的例子包括，但是不局限于，浓度范围从0-60％总体积的乙醇，丙二醇，聚乙二醇300，聚山梨酸酯80，甘油，聚氧乙烯脂肪酸酯，脂肪醇或甘油羟脂肪酸酯等等。
各种释放系统是已知的并且可以用于化合物或其他各种制剂的给药，这些制剂包括片剂，胶囊，可注射的溶液，脂质体中的胶囊，微粒，微胶囊，等等。引入的方法包括但是不局限于皮肤的，皮内，肌内，腹膜内的，静脉内的，皮下的，鼻腔内的，肺的，硬膜外的，眼睛的和(通常优选的)口服途径。化合物可以通过任何方便的或者其它适当的途径给药，例如通过注入或快速浓注，通过上皮的或粘膜线路(例如，口腔粘膜，直肠和肠粘膜，等等)吸收或通过负载药物的支架以及可以于其他生物活性剂一起给药。可以全身或局部给药。用于鼻，支气管或肺疾病的治疗或预防时，优选的给药途径为口服，鼻给药或支气管烟雾剂或喷雾器。
本发明中的芳香氮芥类化合物对组蛋白去乙酰化酶的抑制活性优于阳性对照药，具有良好的开发前景，并可作为发现新型高效组蛋白去乙酰化酶抑制剂的先导化合物。此外，化合物D3在体外抗肿瘤细胞增殖的试验中显示出优于阳性对照Vorinostat(SAHA)的活性，并明显优于(N-(2-胺基苯基)-4-(双(2-氯乙基)胺基)苯甲酰胺)，具有良好的开发前景。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案，以下将结合具体的实施例详细说明本申请的技术方案。
本发明实施例中所用的未进行具体说明试验材料均为本领域常规的试验材料，均可通过商业渠道购买得到。
实施例1：化合物D1的制备
(1)制备对氨基苯甲酸甲酯盐酸盐
将对氨基苯甲酸(13.7g,100mmol)溶于100mL甲醇中，冰浴条件下滴加23.6g乙酰氯。加毕，7540℃回流4小时后，蒸除甲醇和剩余的乙酰氯，用乙醚重结晶得白色结晶，即为对氨基苯甲酸甲酯盐酸盐。产率：86％，ESI-MS m/z：152.2[M+H+]。
(2)制备甲基4-(双(2-羟基乙基)胺基)苯甲酸酯
将对氨基苯甲酸甲酯盐酸盐(0.5g,2.67mmol)溶于20mL水/冰醋酸(1/1)中，加2mL环氧乙烷，室温反应18小时后，用1M NaOH调至中性，用乙酸乙酯萃取，重结晶，制得甲基4-(双(2-羟基乙基)胺基)苯甲酸酯。产率：74％，ESI-MS m/z：240.3[M+H+]。
(3)制备甲基4-(双(2-氯乙基)胺基)苯甲酸酯
将甲基4-(双(2-羟基乙基)胺基)苯甲酸酯(0.48g,2mmol)溶于20mL甲苯中，加2mL三氯氧磷，回流4小时后，蒸除溶剂，用乙酸乙酯/正己烷(1/3)重结晶，制得甲基4-(双(2-氯乙基)胺基)苯甲酸酯。产率：66％，ESI-MS m/z：277.2[M+H+]。
(4)制备4-(双(2-氯乙基)胺基)苯甲酸
将甲基4-(双(2-氯乙基)胺基)苯甲酸酯(0.56g,2mmol)溶于20mL盐酸(6M)中，回流2小时后，蒸除溶剂，用乙酸乙酯/正己烷(1/1)重结晶，制得甲基4-(双(2-氯乙基)胺基)苯甲酸。产率：89％，ESI-MS m/z：263.1[M+H+]。
(5)制备4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸甲酯
将4-(双(2-氯乙基)胺基)苯甲酸(1.3g,5mmol)溶于25mL四氢呋喃中，加入三乙胺(0.55g,5.5mmol)，加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)(1.8g,5.5mmol)。室温反应20分钟后，加入对氨基苯甲酸甲酯盐酸盐(0.94g,50mmol)，再加三乙胺(0.5g,5mmol)。室温反应6小时后，蒸除反应液中的四氢呋喃，用乙酸乙酯溶解产物，分别用1mol/L的柠檬酸溶液，饱和碳酸氢钠溶液，饱和食盐水各洗涤3遍，无水硫酸镁干燥，蒸干溶剂得粗品，粗品经乙酸乙酯重结晶得1.2g浅白色固体。产率：29％，ESI-MS m/z：396.3[M+H+]。
(6)制备4-(双(2-氯乙基)胺基)-N-(4-(羟基氨甲酰基)苯基)苯甲酰胺(D1)
将4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸甲酯(1.0g,2.5mmol)溶于10mL无水甲醇后，向其中加入3.5mL上述羟胺钾(NH2OK)溶液。0.5小时后，蒸除甲醇，2mol/L的盐酸溶液酸化至pH3-4，然后用乙酸乙酯萃取，合并乙酸乙酯层后用饱和食盐水洗涤，经无水硫酸镁干燥，蒸干溶剂得粗品，粗品经乙酸乙酯重结晶得0.52g白色粉末，即为化合物D1。产率：52％，1H NMR(500MHz,dmso)δ11.23(s,1H),10.18(s,1H),8.94(s,1H),7.88(dd,J＝23.2,8.6Hz,4H),7.72(d,J＝8.5Hz,2H),6.84(d,J＝8.7Hz,2H),3.79(dd,J＝20.2,5.8Hz,8H).
实施例2：化合物D3的制备
(1)制备对氨基苯甲酸甲酯盐酸盐
将对氨基苯甲酸(13.7g,100mmol)溶于100mL甲醇中，冰浴条件下滴加23.6g乙酰氯。加毕，7540℃回流4小时后，蒸除甲醇和剩余的乙酰氯，用乙醚重结晶得白色结晶，即为对氨基苯甲酸甲酯盐酸盐。产率：86％，ESI-MS m/z：152.2[M+H+]。
(2)制备甲基4-(双(2-羟基乙基)胺基)苯甲酸酯
将对氨基苯甲酸甲酯盐酸盐(0.5g,2.67mmol)溶于20mL水/冰醋酸(1/1)中，加2mL环氧乙烷，室温反应18小时后，用1M NaOH调至中性，用乙酸乙酯萃取，重结晶，制得甲基4-(双(2-羟基乙基)胺基)苯甲酸酯。产率：74％，ESI-MS m/z：240.3[M+H+]。
(3)制备甲基4-(双(2-氯乙基)胺基)苯甲酸酯
将甲基4-(双(2-羟基乙基)胺基)苯甲酸酯(0.48g,2mmol)溶于20mL甲苯中，加2mL三氯氧磷，回流4小时后，蒸除溶剂，用乙酸乙酯/正己烷(1/3)重结晶，制得甲基4-(双(2-氯乙基)胺基)苯甲酸酯。产率：66％，ESI-MS m/z：277.2[M+H+]。
(4)制备4-(双(2-氯乙基)胺基)苯甲酸
将甲基4-(双(2-氯乙基)胺基)苯甲酸酯(0.56g,2mmol)溶于20mL盐酸(6M)中，回流2小时后，蒸除溶剂，用乙酸乙酯/正己烷(1/1)重结晶，制得甲基4-(双(2-氯乙基)胺基)苯甲酸。产率：89％，ESI-MS m/z：263.1[M+H+]。
(5)制备4-4-(双(2-氯乙基)胺基)苯甲酰甲胺基)苯甲酸甲酯
将4-(双(2-氯乙基)胺基)苯甲酸(1.3g,5mmol)溶于25mL四氢呋喃中，加入三乙胺(0.55g,5.5mmol)，加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)(1.8g,5.5mmol)。室温反应20分钟后，加入对甲氨基苯甲酸甲酯盐酸盐(1.01g,50mmol)，再加三乙胺(0.5g,5mmol)。室温反应6小时后，蒸除反应液中的四氢呋喃，用乙酸乙酯溶解产物，分别用1mol/L的柠檬酸溶液，饱和碳酸氢钠溶液，饱和食盐水各洗涤3遍，无水硫酸镁干燥，蒸干溶剂得粗品，粗品经乙酸乙酯重结晶得1.4g浅白色固体。产率：30％，ESI-MS m/z：410.3[M+H+]。
(6)制备4-(双(2-氯乙基)胺基)-N-(4-(羟基氨甲酰基)苯甲基)苯甲酰胺(D3)
将4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸甲酯(1.0g,2.4mmol)溶于10mL无水甲醇后，向其中加入3.5mL上述羟胺钾(NH2OK)溶液。0.5小时后，蒸除甲醇，2mol/L的盐酸溶液酸化至pH3-4，然后用乙酸乙酯萃取，合并乙酸乙酯层后用饱和食盐水洗涤，经无水硫酸镁干燥，蒸干溶剂得粗品，粗品经乙酸乙酯重结晶得0.36g白色粉末，即为化合物D3。产率：43％，1H NMR(500MHz,dmso)δ11.20(s,1H),8.99(s,1H),8.86(t,J＝5.5Hz,1H),7.82(t,J＝20.6Hz,2H),7.70(d,J＝7.9Hz,2H),7.39(dd,J＝52.0,26.9Hz,2H),6.79(d,J＝8.6Hz,2H),4.47(d,J＝5.6Hz,2H),3.73(dd,J＝20.2,5.8Hz,8H).
实施例3：化合物E1的制备
(1)制备对氨基苯甲酸甲酯盐酸盐
将对氨基苯甲酸(13.7g,100mmol)溶于100mL甲醇中，冰浴条件下滴加23.6g乙酰氯。加毕，7540℃回流4小时后，蒸除甲醇和剩余的乙酰氯，用乙醚重结晶得白色结晶，即为对氨基苯甲酸甲酯盐酸盐。产率：86％，ESI-MS m/z：152.2[M+H+]。
(2)制备甲基4-(双(2-羟基乙基)胺基)苯甲酸酯
将对氨基苯甲酸甲酯盐酸盐(0.5g,2.67mmol)溶于20mL水/冰醋酸(1/1)中，加2mL环氧乙烷，室温反应18小时后，用1M NaOH调至中性，用乙酸乙酯萃取，重结晶，制得甲基4-(双(2-羟基乙基)胺基)苯甲酸酯。产率：74％，ESI-MS m/z：240.3[M+H+]。
(3)制备甲基4-(双(2-氯乙基)胺基)苯甲酸酯
将甲基4-(双(2-羟基乙基)胺基)苯甲酸酯(0.48g,2mmol)溶于20mL甲苯中，加2mL三氯氧磷，回流4小时后，蒸除溶剂，用乙酸乙酯/正己烷(1/3)重结晶，制得甲基4-(双(2-氯乙基)胺基)苯甲酸酯。产率：66％，ESI-MS m/z：277.2[M+H+]。
(4)制备4-(双(2-氯乙基)胺基)苯甲酸
将甲基4-(双(2-氯乙基)胺基)苯甲酸酯(0.56g,2mmol)溶于20mL盐酸(6M)中，回流2小时后，蒸除溶剂，用乙酸乙酯/正己烷(1/1)重结晶，制得甲基4-(双(2-氯乙基)胺基)苯甲酸。产率：89％，ESI-MS m/z：263.1[M+H+]。
(5)制备4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸甲酯
将4-(双(2-氯乙基)胺基)苯甲酸(1.3g,5mmol)溶于25mL四氢呋喃中，加入三乙胺(0.55g,5.5mmol)，加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU)(1.8g,5.5mmol)。室温反应20分钟后，加入对氨基苯甲酸甲酯盐酸盐(0.94g,50mmol)，再加三乙胺(0.5g,5mmol)。室温反应6小时后，蒸除反应液中的四氢呋喃，用乙酸乙酯溶解产物，分别用1mol/L的柠檬酸溶液，饱和碳酸氢钠溶液，饱和食盐水各洗涤3遍，无水硫酸镁干燥，蒸干溶剂得粗品，粗品经乙酸乙酯重结晶得1.2g浅白色固体。产率：29％，ESI-MS m/z：396.3[M+H+]。
(6)制备4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸
将4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸甲酯(1.0g,2.5mmol)溶于20mL盐酸水溶液(6M/L)，回流2h。过滤得到白色固体0.8g。产率：81％，ESI-MS m/z：382.3[M+H+]。
(7)制备N-(2-氨基苯基)-4-(4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酰胺(E1)
将4-4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酸(0.29g,0.76mmol)溶于20mL四氢呋喃中，加入CDI(0.18g,1.1mmol)。回流3小时后，加入邻苯二胺(0.65g,6mmol)。室温反应16小时后，蒸除反应液中的四氢呋喃，用乙酸乙酯溶解产物，分别用1mol/L的柠檬酸溶液，饱和碳酸氢钠溶液，饱和食盐水各洗涤3遍，无水硫酸镁干燥，蒸干溶剂得粗品，粗品经乙酸乙酯重结晶得白色固体0.31g，即为化合物E1。产率：65％，ESI-MS m/z：472.4[M+H+]。1H NMR(500MHz,dmso)δ10.18(d,J＝24.1Hz,1H),9.57(s,1H),8.16–7.73(m,6H),7.16(d,J＝7.5Hz,1H),6.96(t,J＝7.1Hz,1H),6.87(d,J＝8.9Hz,2H),6.78(d,J＝7.4Hz,1H),6.59(t,J＝7.6Hz,1H),4.87(s,2H),4.00–3.59(m,8H).
实施例4：目标化合物抑制组蛋白去乙酰化酶活性试验(In vitro)
组蛋白去乙酰化酶(HDACs)活性荧光分析方法主要分两步：第一步，含一个乙酰化侧链的赖氨酸HDACs荧光底物(Boc-Lys(acetyl)-AMC)，用含组蛋白去乙酰化酶的Hela细胞提取物样本(包含HDAC1,HDAC2,HDAC3和HDAC8)孵育，使底物脱去乙酰基，激活底物。第二步，用胰酶水解Boc-Lys-AMC，产生AMC这一荧光基团(即发色团)，在发射波长/激发波长(390nm/460nm)测定荧光强度，从而根据抑制剂组及对照组的荧光强度计算抑制率，并求算IC50值。酶活性测试原理见本专利说明书部分相关内容。实验结果见表1。
表1.芳香氮芥类组蛋白去乙酰化酶抑制剂的体外抑酶试验结果
| 化合物 | D1 | D2 | D3 | E1 | E2 | E3 | SAHA |
| IC<sub>50</sub>(μM) | 0.18 | 0.27 | 0.09 | 0.22 | 0.36 | 0.17 | 1.02 |
SAHA商品名为Zolinza，通用名为Vorinostat，为美国食品药品监督管理局(FDA)于2006年批准上市的组蛋白去乙酰化酶抑制剂。
上述测试结果表明，化合物D1-E3均表现出对组蛋白去乙酰化酶较强的抑制活性，并且在测试中对组蛋白去乙酰化酶的抑制活性优于阳性对照药Vorinostat(SAHA)，具有良好的开发前景，并可作为发现新型高效组蛋白去乙酰化酶抑制剂的先导化合物。
实施例5：目标化合物抑制细胞增殖的活性试验(In vitro)
1.试验材料：
U937：人组织细胞淋巴瘤细胞株；OPM2：人多发性骨髓瘤细胞株；SPC-A-1：人肺癌细胞株。
四甲基偶氮唑蓝MTT，10％胎牛血清，96孔板。
SAHA：商品名为Zolinza，通用名为Vorinostat，为美国食品药品监督管理局(FDA)于2006年批准上市的组蛋白去乙酰化酶抑制剂。
2.试验方法：
(1)细胞培养：U937，K562，HL60和HCT116四种肿瘤细胞株都采用常规培养。实验时均用对数生长期细胞。
(2)细胞生长检测(MTT法)：
U937，OPM2和SPC-A-1细胞悬液均调整至1×105/ml，分别接种于96孔板(50μl/孔)，5000个细胞/孔。铺板4h后，每孔中加入50μl含不同浓度化合物的培养基，使孔中化合物终浓度分别为：1000、200、40、8、1.6、0.32μg/ml，每个浓度设三个复孔，不加细胞的孔读数时作空白，加细胞不加化合物的孔作化合物空白孔，SAHA作化合物阳性对照。于37℃，5％二氧化碳中孵育48h，每孔加入10μl 0.5％的MTT染色液，继续孵育4h后，2500rpm，离心30min，然后抛弃板孔中培养基，加入二甲基亚砜，200μl/孔。酶标仪上于570nm处测定每孔的吸光度OD值，细胞生长抑制率按下式计算：
3.试验结果：
试验结果见表2.
表2：芳香氮芥类组蛋白去乙酰化酶抑制剂细胞增殖测试结果IC50(μM)
a表中数值为三次试验的平均值，“±”后的数值表示标准偏差。
表2测试数据表明，芳香氮芥类组蛋白去乙酰化酶抑制剂D3在体外抗肿瘤细胞增殖的试验中显示出优于阳性对照SAHA的活性，并且明显优于NA(N-(2-胺基苯基)-4-(双(2-氯乙基)胺基)苯甲酰胺)具有良好的开发前景。
以上所述仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。
Claims (10)
1.式I所示的化合物，或其药学上可接受的盐；
其中，X是-NH-或-NHCH2-；
Y是-CO-或-CH=CHCO-；
R是-OH或2-氨基苯基。
2.根据权利要求1所述的式I所示的化合物，或其药学上可接受的盐，其特征在于，式I所示的化合物，是下述化合物之一：
4-(双(2-氯乙基)胺基)-N-(4-(羟基氨甲酰基)苯基)苯甲酰胺 (D1) ；
4-(双(2-氯乙基)胺基)-N-(4-(3-(羟基胺基)-3-羰基丙-1-烯-1-基)苯基)苯甲酰胺(D2)；
4-(双(2-氯乙基)胺基)-N-(4-(羟基氨甲酰基)苯甲基)苯甲酰胺(D3) ；
N-(2-氨基苯基)-4-(4-(双(2-氯乙基)胺基)苯甲酰胺基)苯甲酰胺(E1)；
N-(4-(3-((2-氨基苯基)胺基)-3-羰基丙-1-烯-1-基)苯基)-4-(双(2-氯乙基)胺基)苯甲酰胺(E2)；
N-(2-氨基苯基)-4-((4-(双(2-氯乙基)胺基)苯甲酰胺基)甲基)苯甲酰胺(E3)。
3.权利要求1或2所述的式I所示的化合物的制备方法，其特征在于，包括如下步骤：
以对氨基苯甲酸为原料，先进行羧基保护，再分别进行亲电取代和亲核反应，羧基脱保护，引入linker，再进行羧基脱保护，最后引入异羟肟酸或与邻苯二胺缩合，制得式I所示化合物。
4.权利要求1或2所述的式I所示的化合物，或其药学上可接受的盐在制备组蛋白去乙酰化酶抑制剂中的应用。
5.权利要求1或2所述的式I所示的化合物，或其药学上可接受的盐在制备预防或治疗与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病的药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病包括：癌症，神经变性疾病，病毒感染，炎症和糖尿病。
7.一种药物组合物，其特征在于，所述药物组合物的活性成分为权利要求1或2所述的式I所示的化合物，或其药学上可接受的盐。
8.根据权利要求7所述的药物组合物，其特征在于，所述药物组合物中还包括一种或多种药学上可接受的载体或赋形剂。
9.根据权利要求7或8所述的药物组合物，其特征在于，所述药物组合物为口服制剂或注射制剂。
10.权利要求7或8所述的药物组合物在制备治疗肿瘤疾病的药物制剂中的应用。
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