CN105418480B - 2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-n-羟基乙酰胺的制备和应用 - Google Patents
2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-n-羟基乙酰胺的制备和应用 Download PDFInfo
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Abstract
本发明属于药物化学技术领域，尤其涉及组蛋白去乙酰化酶抑制剂及其制备方法和应用。本发明提供了一种强效的组蛋白去乙酰化酶抑制剂，本发明涉及具有结构式(I)的化合物，还涉及其药学上可接受的盐，溶剂合物以及前药。本发明还涉及含有结构式(I)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。式(I)化合物的结构式为：
Description
技术领域
本发明属于药物化学技术领域，尤其涉及2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢 -吲哚-3-基)-N-羟基乙酰胺作为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。
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(Surface Recognition Domain)。锌离子螯合基团可以螯合HDACs活性中心的锌离子，从而抑制酶的活性。目前已知的活性最强，应用最广的锌离子螯合基团是异羟肟酸基团。然而，现在很多处于临床研究的化合物没有很好的药效，虽然它们在临床前的研究中表现出了很优异的活性。但是，上市的HDAC抑制剂(SAHA 和FK228)在治疗实体瘤方面药效很差，它们还存在着半衰期短，难吸收和药物代谢动力学性质较差的缺点。
本发明针对现有技术的不足，提供一种组蛋白去乙酰酶抑制剂2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺(I)及其制备方法和应用，本发明采用异羟肟酸基团为锌离子螯合基团，吲哚美辛是一种上市抗炎药，已经表现出了较好的抗炎、抗肿瘤、抗氧化等作用，将其引入到HDACi结构中可以改善其脂水分配系数，促进药物的吸收。因此，化合物I作为HDAC抑制剂，具有很高的成药性和很大的药用开发价值。
发明内容
具有结构式I的组蛋白去乙酰化酶抑制剂，2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1 氢-吲哚-3-基)-N-羟基乙酰胺，其药学上可接受的盐，溶剂合物或前药，
本发明还提供了这些化合物在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。所述的与组蛋白去乙酰化酶活性异常表达的相关哺乳动物疾病包括：癌症，神经变性疾病，病毒感染，炎症，动脉粥样硬化和糖尿病等。
因此，本发明还涉及含有结构式I化合物的药物组合物。
本发明的技术方案如下：
发明详述
所用的定义和术语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。
结构式(I)化合物还可以其它被保护的形式或衍生物的形式存在，这些形式对本领域技术人员而言是显而易见的，均应该包含于本发明的范围内。
所述化合物的制备方法，反应步骤及反应式如下：
制备方法包括如下步骤：
合成路线1：以吲哚美辛为原料，通过缩合直接得到终产物，反应式如下：
合成路线1：
上述合成路线1反应式中的试剂：氯甲酸异丁酯，三乙胺，四氢呋喃，盐酸羟胺；
合成路线2：以吲哚美辛为原料，先进行羧基保护，再与羟胺钾亲核反应，最后制得终产物；反应式如下：
合成路线2：
上述合成路线2反应式中的试剂：(1)乙酰氯，甲醇；(2)羟胺钾，无水甲醇；
制备所述组蛋白去乙酰酶抑制剂的中间体，该中间体是：甲基2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)乙酸酯。
本领域技术人员可以对上述步骤进行变动以提高收率，他们可据本领域的基本知识确定合成的路线，如选择反应物，溶剂和温度，可以通过使用各种常规保护基以避免副反应的发生从而提高收率。这些常规的保护方法可参见例如T.Greene,Protecting Groupsin Organic Synthesis.。
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。
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)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。
通式(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。
本发明的2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺在空间上与组蛋白去乙酰化酶的活性位点相匹配，因此在体外显示了较高的抑制活性。
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。
含有本发明化合物的药物组合物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。
本发明中的化合物2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺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2-(1-(4-氯苯甲酰基)-5- 甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺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
下面结合实施例对本发明做进一步的说明，但不限于此。
实施例1.本发明化合物的合成
合成路线1：
吲哚美辛(1.79g,5mmol)溶于50mL四氢呋喃中，加入三乙胺(0.51g,5mmol)，冰浴，加入氯甲酸异丁酯(0.75g,5.5mmol)。反应10min后加入羟胺((0.33g,10mmol))。室温反应8小时后，蒸除反应液中的溶剂，并用饱和柠檬酸溶液酸化，然后用乙酸乙酯萃取三次，有机相合并后用饱和食盐水洗涤，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1.06g白色固体。产率：57％,1H NMR(400MHz,(CD3)2SO)δ10.67(s,1H),8.84(s, 1H),7.70-7.4(m,4H),7.15(s,1H),6.91(d,J＝9.2Hz,1H),6.71(d,J＝9.2Hz,1H),3.77(s,2H), 2.51(s,6H).ESI-MS:m/z:219.3[M+H]+。
合成路线2：
甲基2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)乙酸酯吲哚美辛(3.94g,10mmol)溶于50mL甲醇中，冰浴条件下滴加2.4g乙酰氯。加毕，75 ℃回流4小时，蒸除甲醇和剩余的乙酰氯，用乙醚重结晶得白色结晶。产率：79％，ESI-MS m/z：358.8[M+H+]。
2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺羟胺钾(NH2OK)溶液的制备：14mL氢氧化钾的饱和无水甲醇溶液滴加到24mL含有4.67 g(67mmol)盐酸羟胺的无水甲醇溶液中，控制内温低于40℃，滴加完毕，冷却反应液，滤除白色氯化钾沉淀，所得滤液密闭保存备用。
甲基2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)乙酸酯(0.71g,2mmol)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0.32g白色粉末。产率：44％。
实施例2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1.2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺
(I)的体外抑酶试验结果
| 编号 | IC<sub>50</sub>(<u>μM</u>) |
| I | 0.37 |
| SAHA | 1.25 |
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，2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺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3目标化合物抑制细胞增殖的活性试验(In vitro)
对2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺进行体外抑制癌细胞增殖的活性试验，结果见表2。
术语说明：
U937：人组织细胞淋巴瘤细胞株。
K562：人红白血病细胞株。
HL60：人急性白血病细胞株。
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。
DMSO：二甲基亚砜。
IC50：半数抑制浓度。
1.[材料]U937，K562，HL60细胞株，四甲基偶氮唑蓝MTT，10％胎牛血清，96孔板。
2.[方法]
细胞培养U937，K562，HL60三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。
细胞生长检测(MTT法)HCT116，SKOV3，HL60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50ul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、0.32ug/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，200ul/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：
表2细胞增殖实验结果
a表中数值为三次试验的平均值，“±”后的数值表示标准偏差。
上表测试数据表明，化合物2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N- 羟基乙酰胺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，具有良好的开发前景。
Claims (4)
1.化合物2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基)-N-羟基乙酰胺的制备方法，所述化合物的结构如式I所示：
其特征在于，制备方法包括如下步骤：
合成路线1：以吲哚美辛为原料，通过缩合直接得到终产物，反应式如下：
合成路线1：
上述合成路线1反应式中的试剂：氯甲酸异丁酯，三乙胺，四氢呋喃，盐酸羟胺；
将5mmol吲哚美辛溶于50ml四氢呋喃中，加入5mmol三乙胺，冰浴，加入5.5mmol氯甲酸异丁酯，反应10min后加入10mmol羟胺，室温反应8小时后，蒸除反应液中的溶剂，并用饱和柠檬酸溶液酸化，然后用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤，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到终产物。
2.权利要求1所述的制备方法制备得到的化合物在制备组蛋白去乙酰酶抑制剂中的应用。
3.权利要求1所述的制备方法制备得到的化合物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。
4.根据权利要求3所述的应用，其特征在于，所述的与组蛋白去乙酰化酶活性异常表达的相关哺乳动物疾病包括：癌症，神经变性疾病，病毒感染，炎症，动脉粥样硬化和糖尿病。
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