CN111499577A - 邻二苯基取代五元含氮芳杂环类类化合物及其应用 - Google Patents
邻二苯基取代五元含氮芳杂环类类化合物及其应用 Download PDFInfo
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- CN111499577A CN111499577A CN201910089862.9A CN201910089862A CN111499577A CN 111499577 A CN111499577 A CN 111499577A CN 201910089862 A CN201910089862 A CN 201910089862A CN 111499577 A CN111499577 A CN 111499577A
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Abstract
本发明公开了一类由结构式(I)~(III)所示的邻二苯基取代五元含氮杂环类化合物或药学上可接受的盐,以及含有此类化合物的药物组合物。本发明还公开了所述化合物或药学上可接受的盐在用于制备治疗各种恶性肿瘤以及肿瘤转移的相关疾病的药物中的应用,本发明式(I)~(III)所示的化合物能够浓度梯度依赖性地抑制胰腺癌、乳腺癌细胞、前列腺癌细胞、结肠癌细胞、肝癌细胞、非小细胞肺癌细胞和膀胱癌细胞等肿瘤细胞的增殖、侵袭和浸润等,具有低毒性,在生物医药行业具有广泛的应用前景。
Description
技术领域
本发明属于生物医药化学领域,涉及一类邻二苯基取代五元含氮芳杂环类化合物及其应用。
背景技术
肿瘤是目前严重威胁着全人类的健康最主要的死亡性疾病之一。随着生存环境的恶化,水土和空气污染的加重,癌症的发病率和死亡率呈现迅猛增长的态势。据美国癌症协会的统计显示,肿瘤转移是临床上癌症患者死亡的主要原因,因此研发新型抗肿瘤转移药物具有非常重大的临床和现实意义。
临床上肿瘤患者的治疗方案一般根据肿瘤病人的发展阶段来制定,主要包括手术切除、放射治疗和化学药物及靶向治疗等。早期肿瘤患者的治疗一般是手术切除配合放射疗法和化学药物疗法。然而,手术切除无法根治已经发生转移的中晚期肿瘤患者,所以中晚期的患者主要采用化学药物疗法,化学药物疗法在肿瘤的治疗过程中不可或缺。
在化学药物疗法的发展过程中,与传统的广谱细胞毒性治疗药物相比,分子靶向类药物由于具备对肿瘤细胞的选择性杀伤作用而越来越广泛地用于肿瘤患者的治疗。靶向治疗药物是以肿瘤发生发展中促进肿瘤的生长和迁移的关键蛋白为靶点,通过调控肿瘤发生发展中的密切相关的信号通路或者肿瘤必需的物质来抑制肿瘤的生长和转移。
在上皮细胞的癌变过程中,细胞极性出现丧失,极化蛋白被呈递,细胞形态也发生改变,细胞增殖、运动和浸润活动都有所增加。这些过程都需要膜泡运输相关物质。因此,膜泡运输相关蛋白可以调控细胞癌变中的多个过程。靶向细胞膜泡运输过程可以抑制肿瘤细胞(Goldenring J R.Nat.Rev.Cancer,2013,13,813-820)。第一,细胞表面具有多种蛋白受体,受体底物需要通过膜泡转运呈递到细胞膜上正确位置,转运位置的错误会导致细胞信号通路的异常。第二,转运过程的异常可以引起细胞间粘结分子(例如整合素intergins)的重分布。整合素信号和细胞增殖和运动的应答密切相关,影响癌细胞表型变化(Kuwada SK,Li X,Brugge.Mol.Biol.Cell,2000,11,2485-2496)。第三,细胞极性的丧失可以导致基质金属蛋白酶(MMPs)不能正常呈递到细胞表面,因此会促进细胞的浸润和细胞形态的改变。这些研究都表明膜泡转运过程对上皮细胞早期癌变是必不可少的。因此靶向在膜泡运输中起重要作用的蛋白是抑制癌细胞的增殖和迁移的可行策略之一。
Myoferlin蛋白属于Ferlin蛋白家族的成员,其结构较复杂,含有2061个氨基酸,分子量约为230KD。Myoferlin含有7个串联的细胞质C2结构域,包括一个高度保守的N-末端-C2B-Fer1-C2C结构域,一个C2D结构域,两个位于单次跨膜结构域附近的C-末端C2结构域(C2E-C2F)。研究发现,myoferlin参与膜泡运输和融合过程,通过调节序列模块C2结构域实现其生物学功能。C2结构域可协调负电性结合口袋内的钙离子去调节钙离子激活的生理过程,包括经典的囊泡融合过程。除此之外,C2结构域具有突触结合蛋白、蛋白激酶C和磷脂酶的功能特征,可以结合磷脂、磷酸化酪氨酸以及与其他蛋白相互作用。
目前myoferlin的C2A结构域已经被解析出来,晶体结构证实了经典的八beta折叠链和与磷酸酯酶A2相似的II型链拓扑结构的存在(Nagashima,T.,Hayashi,F.,Yokoyama,S,http://wwwrcsborg/structure/2DMH,2006)。Myoferlin C2A结构建模显示了其推定的结合钙离子的能力。脂结合研究表明myoferlin C2A结构域可以和富磷脂酰丝氨酸的脂质体以钙离子依赖的形式结合,从而直接调节膜泡运输(Davis D B,Doherth K R,DelmonteA J,et al,J.Biol.Chem.2002,277:22883-22888)。Myoferlin的C2B结构域可以直接同EHD2结合,参与网格蛋白(clathrin)介导的内吞和内吞的循环(Doherth K R,DemonbreunA R,Wallace G Q,et al,J.biol.Chem.2008,283:20252-20260)。Myoferlin与VEGFR2等形成复合体,保护VEGFR2免受泛素化降解。敲低Myoferlin会降低VEGFR2的表达及其磷酸化(Bernatchez P N,Acevedo L,Fernandez-Hernando C,et al.J.biol.Chem.2007,282,30745-30753)。
Myoferlin在多种肿瘤,包括胰腺癌(Turoi A,Musmeci D,Wang Y H,etal.J.Proteome Res.2011,10,4302-4313),乳腺癌(Blomme A,Costanza B,De Tullio P,et al.Oncogene,2016),B-细胞淋巴癌(Sachen K L,Strohman M J,Singletary J,etal.Blood,2012,120,4182-4190)和肺癌(LEUNG C,YU C,LIN M I,et al.Ame.J.Pathol,2013,182,1900-1909)中表达量高,但在大多数的正常细胞中表达量低(Blomme A,Costanza B,De Tullio P,et al.Oncogene,2016,36,2116-2130)。Myoferlin可以促进肿瘤细胞的增殖、迁移和浸润(Blomme A,Fahmy K,Peulen O,et al.Oncotarget,2016,7,83669-83683)。另外,Myoferlin还可以影响肿瘤细胞的细胞脂质代谢和线粒体的功能,从而影响肿瘤在生长和转移过程中的能量需求,促进三阴性乳腺癌的转移(Blomme A,Costanza B,De Tullio P,et al.Oncogene,2016,36,2116-2130)。Myoferlin可能是通过影响物质的转运,影响肿瘤发展的过程中的多条重要信号通路。
Myoferlin可以下调在血管新生过程中的两个重要酪氨酸激酶受体Tie-2和VEGFR2的表达,阻碍血管新生过程(Yu C,Sharma A,Trane A,et al.Vascular Pharma,2011,55,26-33)。Myoferlin可以调控血管内皮生长因子受体2的稳定性和功能,影响肿瘤生长和转移(BernatchezE P N,Acevedo,Fernandez C,et al.J.Biol.Chem.2007,282,30745-30753)。另外,有研究表明Myoferlin可以被酶剪切释放有特定功能的小模块来激活ERK1/2(Piper A K,Ross S E,Redpath G M,et al.Cell Signal,2017,33,30-40)。
临床研究表明,Myoferlin的高表达和癌症患者的生存率有关。免疫组织化学的结果表明,Myoferlin在胰腺癌恶化程度高的组织比在胰腺癌恶化程度低的组织中表达量更高,而在胰腺周边未发生癌变的组织中几乎不表达(Wang W S,Liu X H,Liu L X,etal.i.J.Proteomics,2013,91,453-65)。除此之外,肿瘤组织中的Myoferlin表达量低的三阴性乳腺癌的病人生存期更长(Blomme A,Costanza B,De Tullio P,et al.Oncogene,2016)。另外,在临床口咽鳞状细胞癌患者中也表现了相似的规律,Myoferlin高表达的患者临床预后较差(Kumar B,Brown N V,Swanson B J,et al.Oncotarget,2016,7,18665-18677)。
Myoferlin是治疗肿瘤转移的可行性的靶点,并且目前市场上尚无靶向myoferlin的化疗药物,因此靶向myoferlin蛋白的抗肿瘤药物具有广阔的市场前景。在前期研究中,本实验室找到一类噻唑啉酮环类的化合物可以靶向myoferlin有效抑制肿瘤细胞的迁移(Zhang T,Li J,He Y,Yang F,et al.Nat Commun.2018,9,3726)。在此基础上引入一类新型的邻二苯基五元含氮杂环类抗肿瘤化合物。五元含氮芳杂环类化合物广泛地存在于多种生物活性化合物的结构中,在抗抑郁、抗痉挛、抗细菌、抗病毒、抗真菌和抗寄生虫等药物研发上都发挥着重要的生理药理作用,是药学上一类重要的药效团。本发明为创造一类靶向myoferlin蛋白的新型抑制剂并用于制备抗肿瘤转移的新型候选药物,在前期大量研究工作的基础上创造性地设计合成了一类新型的邻二苯基取代五元含氮芳杂环结构的化合物。经大量研究后发现,本发明化合物可与myoferlin蛋白结合,抑制肿瘤细胞的增殖和迁移,体内实验也表明该类化合物可显著抑制肿瘤转移,可发展为潜在的肿瘤候选药物。
发明内容
本发明的目的在于提供一类邻二苯基取代五元含氮芳杂环类化合物及相关类似物可作为抗肿瘤先导化合物,包括其可用盐以及酯等。
本发明的目的还在于寻找上述化合物或含有上述化合物的药物组合物在制备预防和/或治疗各种恶性肿瘤,特别是胰腺癌、乳腺癌、肺癌、肝癌、前列腺癌、皮肤癌、结肠癌、白血病、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌等疾病以及相关的癌症转移和复发过程中的药物应用。
本发明提出了一种邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐,其结构如式(I)所示:
其中,
m是0-3;
X为CH2、O或者S;
D,E,G,J,K中任意两个或三个为N,其余为C;
R1独自选自下列基团中的一个:氢、C1-C3烷基、C1-C3烷氧基乙基、2-羟基乙基、2-氨基乙基、2-溴乙基、2-叔丁氧羰基乙基、2-(4-甲基哌嗪-1-基)乙基;
R3独自选自下列基团中的一个或多个:氢、C1-C3烷基,卤素、C1-C3烷氧基。
本发明所述式(I)中,当m=2,X为CH2时,其结构如式(II)所示:
其中,
D,E,G,J,K中任意相邻两个为C,其余为N;
R1独自选自下列基团中的一个:氢、C1-C3烷基、C1-C3烷氧基乙基、2-羟基乙基、2-氨基乙基、2-溴乙基、2-叔丁氧羰基乙基、2-(4-甲基哌嗪-1-基)乙基;
R3独自选自下列基团中的一个或多个:氢、C1-C3烷基,卤素、C1-C3烷氧基。
本发明所述式(II)中,当D和E为C,G、J和K为N时,其结构如式(III)所示:
其中,
R1独自选自下列基团中的一个:氢、C1-C3烷基、C1-C3烷氧基乙基、2-羟基乙基、2-氨基乙基、2-溴乙基、2-叔丁氧羰基乙基、2-(4-甲基哌嗪-1-基)乙基;
R3独自选自下列基团中的一个或多个:氢、C1-C3烷基,卤素、C1-C3烷氧基。
本发明还提出了一种邻二苯基取代五元含氮芳杂环化合物或其水合物或药学上可接受的盐,是所述邻二苯基取代五元含氮芳杂环类化合物与酸形成的酸加成盐;其中,所述酸是盐酸、氢溴酸、硫酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸或琥珀酸等。
本发明还提出了一种邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐,是所述邻二苯基取代五元含氮芳杂环类化合物与放射性基团、荧光基团或者生物素结合形成标记物。
本发明还提出了邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐,包括:
3-(5-(4-甲氧基苯基)-1H-咪唑-1-基)-N-(4-苯丁基)苯甲酰胺,
3-(1-(4-甲氧基苯基)-1H-咪唑-5-基)-N-(4-苯丁基)苯甲酰胺,
3-(4-(4-甲氧基苯基)-1H-吡唑-3-基)-N-(4-苯丁基)苯甲酰胺,
3-(5-(4-甲氧基苯基)-2-甲基-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(5-(4-甲氧基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-乙基-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(5-(4-甲氧基苯基)-2-丙基-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-羟基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-甲氧基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-乙基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-乙氧基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-氨基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-溴乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯基丁基)苯甲酰胺,
2-(4-(4-甲氧基苯基)-5-(3-((4-苯丁基)氨基甲酰)苯基)-2H-1,2,3-三氮唑-2-基)乙酸叔丁酯,
3-(5-(4-甲氧基苯基)-2-(2-(4-甲基哌嗪-1-基)乙基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺。
上述邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐可以与放射性基团、荧光基团或者生物素结合形成标记物。
本发明还提出了一种药物组合物,其中含有本发明式(I)-(III)所述的邻二苯基取代五元含氮芳杂环类化合物及相关类似物或药学上可接受的盐,以及药学上可接受的载体。本发明所述药物组合物被配制成可注射流体、气雾剂、乳膏、凝胶剂、丸剂、胶囊剂、糖浆剂、透皮贴剂或赋形剂。
本发明还提出了邻二苯基取代五元含氮芳杂环类化合物及相关类似物或药学上可接受的盐在制备抑制或者结合myoferlin蛋白药物中的运用。
本发明还提出了所述的邻二苯基取代五元含氮芳杂环类化合物及相关类似物或药学上可接受的盐在制备抗肿瘤药物中的应用。
本发明还提出了所述的邻二苯基取代五元含氮芳杂环类化合物及相关类似物或药学上可接受的盐在制备抑制肿瘤细胞的增殖、生长、迁移和浸润的药物中的应用;其中,所述肿瘤细胞包括黑色素瘤细胞、肝癌细胞、肺癌细胞、前列腺癌细胞、乳腺癌细胞、皮肤癌细胞、结肠癌细胞、胰腺癌细胞、白血病细胞、卵巢癌细胞、胃癌细胞、膀胱癌细胞、肾癌细胞和口腔癌细胞。
本发明还提出了所述的邻二苯基取代五元含氮芳杂环类化合物及相关类似物或药学上可接受的盐在制备预防和/或治疗恶性肿瘤的药物中的应用;其中,所述恶性肿瘤包括胰腺癌、乳腺癌、黑色素瘤、肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、白血病、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌。
本发明还提出了所述的邻二苯基取代五元含氮芳杂环类化合物及相关类似物或药学上可接受的盐在制备抑制恶性肿瘤转移与复发的药物中的应用;其中,所述恶性肿瘤包括胰腺癌、乳腺癌、黑色素瘤、肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、白血病、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌。
本发明中,所述邻二苯基取代五元含氮芳杂环类化合物及相关类似物或其水合物或药学上可接受的盐可以单独使用或与其他药物联合使用。
本发明的有益效过在于:本发明提出的邻二苯基取代五元含氮杂环类化合物能够浓度梯度依赖性地抑制胰腺癌、乳腺癌细胞、前列腺癌细胞、结肠癌细胞、肝癌细胞、非小细胞肺癌细胞和膀胱癌细胞等肿瘤细胞的增殖、侵袭和浸润等,具有低毒性,在生物医药行业具有广泛的应用前景。
附图说明
图1为Biacore结合实验中不同浓度的本发明化合物MF004与myoferlin蛋白之间的结合响应值曲线图。
图2为本发明化合物MF001-MF014在无毒剂量下对多种高表达myoferlin的肿瘤细胞增殖的抑制效果图;A为本发明化合物在1μmol/L对胰腺癌细胞PANC1增殖的抑制百分率,B为本发明化合物MF004浓度梯度依赖性地抑制乳腺癌细胞MDA-MB-231、胰腺癌细胞PANC1、结肠癌细胞HCT116、肺癌细胞A549、肝癌细胞HUH7和前列腺癌细胞PC3的增殖,C为本发明化合物MF004浓度梯度依赖性地抑制皮肤癌细胞A431、白血病细胞K562、口腔癌细胞NOK、肾癌细胞ACHN和卵巢癌细胞SKOV3的增殖效果示意图。
图3为MF004和MF006在不同浓度下对乳腺癌细胞MDA-MB-231和胰腺癌细胞PANC1侵袭浸润的抑制效果图;左实图为MF004或MF006在100nM时抑制乳腺癌细胞MDA-MB-231和胰腺癌细胞PANC1侵袭的代表图,右柱状图为MF004或MF006梯度依赖性抑制乳腺癌细胞MDA-MB-231和胰腺癌细胞PANC1侵袭的统计图。
图4为MF004对裸鼠胰腺癌细胞肺转移的抑制效果图;A为MF004能够浓度梯度依赖性抑制裸鼠胰腺癌转移,B为化合物MF004处理组肿瘤的荧光信号值相较对照组明显减弱,C为化合物MF004有效延长裸鼠的生存周期。
具体实施方式
结合以下具体实施例和附图,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
1H-NMR用Bruker 400或500MHz型仪测定。所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得;除说明外,所有反应均是在氩气保护下进行并用TLC跟踪,后处理时均经饱和食盐水洗和无水硫酸钠干燥过程;产品的纯化除说明外均使用硅胶(200-300目)的柱色谱法;所使用的硅胶,包括200-300目和GF254为青岛海洋化工厂或烟台缘博硅胶公司生产。
实施例一:各化合物的制备
实施例1-1、3-(5-(4-甲氧基苯基)-1H-咪唑-1-基)-N-(4-苯丁基)苯甲酰胺(MF001)
取间苯氨基甲酸酯(302mg,2mmol)和对甲氧基苯甲醛(277mg,2.04mmol)溶于THF中(8mL),再加入无水硫酸镁(361mg,3mmol),常温搅拌10h,然后抽滤去除无水硫酸镁,再减压蒸除除溶剂,加入乙二醇二甲醚/甲醇(7mL/3mL),然后再加入K2CO3(552mg,4mmol)和4-甲苯磺酰乙腈(586mg,3mmol),继续常温搅拌12h。之后减压蒸除溶剂,再有柱色谱纯化得到3-(5-(4-甲氧基苯基)-4-甲基苯磺酸基-4,5-二氢-1H-咪唑-1-基)苯甲酸甲酯(418mg,产率45%)。取3-(5-(4-甲氧基苯基)-4-甲基苯磺酸基-4,5-二氢-1H-咪唑-1-基)苯甲酸甲酯(232mg,0.5mmol)溶于甲醇中(5mL),再加入碳酸钾(138mg,1mmol)回流一个小时。
将得到的粗产物3-(5-(4-甲氧基苯基)-1H-咪唑-1-基)苯甲酸酯的甲醇溶液在冰水浴下,直接滴加氢氧化锂的水溶液(84mg,2mmol,溶于1.25mL水中)。反应4h后,减压蒸除甲醇,加入1M盐酸(2mL),再用乙酸乙酯萃取三次,有机相合并后用饱和食盐水洗,再用无水硫酸镁干燥后蒸干。之后将粗产物直接投下一步的酰胺化反应,取化合物3-(5-(4-甲氧基苯基)-1H-咪唑-1-基)苯甲酸(62mg,0.2mmol),EDC·HCl(50mg,0.26mmol)和HOBt(30mg,0.22mmol)与烧瓶中,在0℃时,氩气保护冰浴下注入2mL DMF,5min后滴加4-苯基丁胺(45mg,0.3mmol),15min后撤去冰浴,常温反应3h。乙酸乙酯萃取后减压浓缩成相应的酰胺粗产物。柱层析纯化后得产物(53mg,以上三步总产率25%)。1H NMR(500MHz,CDCl3)δ8.13(s,1H),7.71(d,J=7.7Hz,1H),7.63(s,1H),7.41(d,J=7.8Hz,1H),7.34–7.29(m,2H),7.28–7.23(m,3H),7.20–7.15(m,4H),6.96(s,1H),6.84(d,J=8.7Hz,2H),3.80(s,3H),3.53–3.48(m,2H),2.67(t,J=7.3Hz,2H),1.75–1.65(m,4H).13C NMR(125MHz,CDCl3)δ166.42,160.06,152.83,151.06,141.94,135.42,131.07,130.66,129.17,128.91,128.36,128.31,127.63,126.80,126.75,125.80,114.64,55.53,39.91,35.41,29.08,28.64.HR MS(ESI):calcd for[C27H27N3O2+Na]+448.1995,found 448.1999。
实施例1-3、3-(4-(4-甲氧基苯基)-1H-吡唑-3-基)-N-(4-苯丁基)苯甲酰胺(MF003)
取3-(2-(4-甲氧基苯基)乙酰基)苯甲酸酯(284mg,1mmol)和N,N-二甲基甲酰胺二甲基缩醛(477mg,4mmol)溶于DMF(5mL)中,升温至100℃,加热两个小时。之后冷却至室温,用油泵抽去溶剂。再加入甲醇,水合肼(1.12mmol),冰乙酸(0.1mmL)室温搅拌30h。减压蒸除甲醇后,用乙酸乙酯萃取,有机相饱和食盐水洗后再用无水硫酸镁干燥后蒸干。柱色谱纯化得到产物3-(4-(4-甲氧基苯基)-1H-吡唑-3-基)苯甲酸酯(154mg,产率50%)。之后水解和成酰胺的反应参照化合物MF001的合成。1H NMR(500MHz,CDCl3)δ8.13(s,1H),7.71(d,J=7.7Hz,1H),7.63(s,1H),7.41(d,J=7.8Hz,1H),7.34–7.29(m,2H),7.28–7.23(m,3H),7.20–7.15(m,4H),6.96(s,1H),6.84(d,J=8.7Hz,2H),3.80(s,3H),3.53–3.48(m,2H),2.67(t,J=7.3Hz,2H),1.75–1.65(m,4H).13C NMR(125MHz,CDCl3)δ166.42,160.06,152.83,151.06,141.94,135.42,131.07,130.66,129.17,128.91,128.36,128.31,127.63,126.80,126.75,125.80,114.64,55.53,39.91,35.41,29.08,28.64.HR MS(ESI):calcdfor[C27H27N3O2+Na]+448.1995,found 448.1999。
实施例1-4、3-(5-(4-甲氧基苯基)-2-甲基-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF004)
化合物间羧基苯甲醛和4-苯基丁胺的酰胺化反应可参考化合物MF001的酰胺化反应,纯化后即可得到化合物3-甲酰基-N-(4-苯基丁基)苯甲酰胺。取3-甲酰基-N-(4-苯基丁基)苯甲酰胺(246mg,2mmol)和对甲氧基苯乙腈(294mg,2mmol)溶于甲醇(3mL)中,再加入甲醇钠(5mg,0.1mmol),升温回流1h。减压蒸除甲醇,加入稀盐酸(0.1mL,1M),再加入乙酸乙酯萃取,再用饱和碳酸氢钠和饱和氯化铵洗有机相,再用饱和食盐水洗,然后无水硫酸镁干燥后减压蒸干。柱层析纯化得产物3-(2-氰基-2-(4-甲氧基苯基)乙烯基)-N-(4-苯基丁基)苯甲酰胺(229mg,产率28%)。
取3-(2-氰基-2-(4-甲氧基苯基)乙烯基)-N-(4-苯基丁基)苯甲酰胺(205mg,0.5mmol),溶于DMF(5mL)中,再加入NaN3(98mg,1.5mmol)和NH4Cl(80mg,1.5mmol),然后滴入少量水(0.5mL),升温回流5h。之后冷却到室温,用EA萃取,再用饱和食盐水洗,无水硫酸镁干燥后蒸干,用柱层析纯化得产物3-(5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯基丁基)苯甲酰胺(160mg,产率75%)。取3-(5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯基丁基)苯甲酰胺(107mg,0.25mmol)溶于丙酮(5mL)内,再加入碳酸钾(346mg,2.5mmol),滴加碘甲烷(31μM,0.5mmol)。升温回流12h。再蒸除溶剂,EA萃取,有机相饱和食盐水洗后无水硫酸镁干燥后蒸干,柱层析纯化产物得到3-(5-(4-甲氧基苯基)-2-甲基-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺MF004(50mg,产率45%)。1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.77(d,J=7.7Hz,1H),7.61(d,J=7.6Hz,1H),7.45–7.35(m,3H),7.30–7.22(m,2H),7.20–7.12(m,3H),6.87(d,J=8.5Hz,2H),6.05(s,1H),4.23(s,3H),3.79(s,3H),3.46–3.38(m,2H),2.64(t,J=7.3Hz,2H),1.72–1.54(m,4H).13C NMR(125MHz,CDCl3)δ167.08,159.80,144.56,143.17,141.99,135.23,131.42,130.79,129.48,128.93,128.37,128.31,127.17,125.84,125.80,123.03,114.07,55.23,41.71,39.86,35.43,29.14,28.63.HR MS(ESI):calcd for[C28H30N4O2+Na]+477.2261,found 477.2270.
表1实施例1-1到1-14(MF001-014)所示邻苯二芳基五元含氮杂环类化合物的制备
实施例二:本发明化合物与myoferlin蛋白的结合检测
BIACORE是表面等离子共振开发的生物分析传感技术,可以检测生物分子之间是否存在结合作用。实验中将一种配体生物分子固定在传感器芯片的葡聚糖表面,将与之相互作用的待测分析物溶于溶液流过芯片表面。SPR检测器能跟踪溶液中的待测分析物与芯片表面的分子结合、解离整个过程的变化,记录对应的信号响应值,提供亲和力数据。本实验中本发明采用Biacore生物大分子相互作用仪检测本发明化合物MF004与myoferlin-C2D结构域之间的结合力。
实验结果如图1所示,根据不同浓度的本发明化合物MF004与myoferlin-C2D结构域之间的结合响应值曲线作图,拟合出所测化合物与蛋白之间的亲和力。图1中本发明化合物MF004与myoferlin-C2D结构域的结合具有浓度依赖性,说明本发明化合物MF004和myoferlin片段蛋白能特异性的结合。
相似的实验结果也发现,本发明其它化合物都能与myoferlin-C2D蛋白结合,显示出明显的亲和作用。
实施例三:本发明化合物抑制多种肿瘤细胞增殖
1、细胞的培养
本实验中所用细胞均购买于美国标准生物收藏中心(ATCC)。各株细胞所用培养基中均加入10%胎牛血清(Front)和100U/mL青霉素、100μg/mL链霉素(Gibco),将细胞贴壁培养在37℃恒温培养箱(95%湿度,5%CO2)中。
2、SRB(磺酰罗丹明)法测定细胞增殖
将各株高表达myoferlin的肿瘤细胞以适当密度接种至96孔板(Corning),培养24h后,依次加入不同浓度本发明化合物,使其终浓度分别为0.01μmol/L,0.05μmol/L,0.1μmol/L,0.5μmol/L,1μmol/L,对照组加入等量的DMSO,各组设3个副孔。继续培养48h后,加入预冷的TCA(三氯乙酸,50%,w/V)25μl/孔,轻轻混匀。4℃孵育2h固定细胞,蒸馏水轻轻冲洗5遍,风干。每孔加入50μSRB染液(4%,w/V),室温孵育10min染色。将染液吸出,每孔加入1%醋酸100μl冲洗5遍,除去未结合染料。风干后,每孔加入浓度为10mmol/L Tris溶液100μl,震荡溶解结合的SRB染料。将96孔板置于酶标仪(SPECTRA MAX 190)中,在515nm波长下测定OD值。按照以下公式计算细胞存活率,统计分析化合物对于细胞增殖的影响。
图2A显示本发明化合物在1μmol/L对胰腺癌PANC1细胞增殖的抑制效果。由图2A可见绝大多数化合物在1μmol/L浓度下对此株胰腺癌细胞PANC1生长的抑制效果非常明显,在所列举的化合物中,化合物MF001,MF002,MF003,MF004,MF005,MF006,MF007,MF008,MF009,MF012,MF013在1μmol/L浓度下对胰腺癌细胞PANC1生长抑制的抑制率都达到50%以上,说明这些化合物对此肿瘤细胞增殖的半数抑制浓度(IC50)都在1μmol/L以下;部分化合物在此浓度下可以达到80%以上,可见本发明化合物能显著抑制胰腺癌PANC1细胞的增殖。图2B显示的是部分结果,显示本发明化合物能够浓度梯度依赖性地抑制乳腺癌细胞MDA-MB231、胰腺癌PANC1、结肠癌细胞HCT116、肺癌细胞A549、肝癌细胞HUH7和前列腺癌细胞PC3的增殖,在1μmol/L均取得了显著的抑制效果。图2C显示本发明化合物能够浓度梯度依赖性抑制皮肤癌细胞A431、白血病细胞K562、口腔癌细胞NOK、肾癌细胞ACHN,卵巢癌细胞SKOV3。此外,将本发明化合物对其它肝癌细胞、肺癌细胞、前列腺癌细胞、皮肤癌细胞、结肠癌细胞、乳腺癌细胞、白血病细胞、卵巢癌细胞、胃癌细胞、膀胱癌细胞、肾癌细胞和口腔癌细胞等多种肿瘤细胞进行增殖抑制效果实验,均取得了相似的显著抑制效果。
实施例四:本发明化合物抑制乳腺癌细胞和胰腺癌细胞的侵袭和浸润
Transwell浸润实验采用Boyden小室。Transwell小室上室预先铺一层胶原基质Matrigel,再将细胞重悬于无血清培养基后接种在上室。在下室中加入含有血清的完全培养基,具有侵袭能力的细胞在血清诱导下开始穿膜运动。上室面的肿瘤细胞若要成功侵袭至下室,必须先利用自身释放的各种生物因子如基质金属蛋白酶溶解胶原基质,再通过溶解出的空洞迁移至下室面。这一实验过程可模拟肿瘤细胞在体内的浸润过程,可以用来反映肿瘤细胞的侵袭浸润能力。
取对数生长期的乳腺癌细胞MDA-MB-231和胰腺癌细胞PANC1,以5×104个/孔接种于Transwell小室的上室中,分别加入0.1μmol/L,0.5μmol/L,2.5μmol/L的本发明化合物MF004和MF006,对照组加入等量的DMSO。下室中加入完全培养基。在培养箱中培养12h后,取出Transwell小室,用棉签蘸擦拭Transwell小室的上室一面,将未穿膜的细胞擦掉。用4%多聚甲醛室温固定小室30min后用1%结晶紫染色10min,自来水充分清洗。显微镜下拍照,对每孔内上下左右中5个视野的细胞数目计数,获得穿膜细胞数/视野。每组平均设3个重复。统计比较不同剂量药物组穿膜细胞数量,确定药物对细胞浸润能力的影响。
图3是MF004和MF006的抗迁移效果图和浸润率的统计。结果表明,在乳腺癌细胞MDA-MB-231和胰腺癌细胞PANC1的Transwell浸润实验模型中,本发明化合物MF004和MF006能够抑制胰腺癌细胞和乳腺癌细胞浸润的半数有效浓度IC50在0.1-0.5μmol/L之间,说明此类化合物在浸润模型中表现出显著的抑制胰腺癌细胞和乳腺癌细胞浸润的能力。
此外,将本发明化合物对肝癌细胞、肺癌细胞、前列腺癌细胞、皮肤癌细胞、结肠癌细胞、白血病细胞、卵巢癌细胞、胃癌细胞、膀胱癌细胞、肾癌细胞和口腔癌细胞等多种肿瘤细胞进行迁移抑制效果实验,均取得了相似的显著抑制效果。
实施例五:本发明化合物抑制裸鼠胰腺癌肺转移
该实验通过裸鼠尾静脉注射细胞,胰腺癌细胞随着血液循环到达肺部,因无法穿透肺部毛细血管而截留在肺组织中,从而模拟了胰腺癌细胞的肺转移。
将PANC1-荧光素酶细胞尾静脉注射到BALB/C裸鼠体内(n=8)。小鼠根据它们的荧光值均分成四组:阴性对照组(DMSO);阳性对照组(胰腺癌一线治疗药物吉西他滨,25mg/kg/d);本发明化合物MF004药物处理组(25mg/kg/d和50mg/kg/d)。肺转移的程度用小动物活体成像仪检测肺部胰腺癌细胞荧光值进行监测(每十天一次)。如图4所示,本发明化合物MF004可以浓度依耐性地抑制胰腺癌细胞的肺转移。在和阳性对照组剂量相同的情况下,本发明化合物MF004抑制胰腺癌细胞转移的效果更优。在20天时,药物处理组(25mg/kg/d;50mg/kg/d)的平均荧光量降低了3倍和5倍,这表明本发明化合物MF004可以显著降低胰腺癌细胞肺转移的负担。三周后,各组的生存率分别为25%(阴性对照组),60%(阳性对照组),75%(MF004加药组,25mg/kg/d);87.5%(MF004加药组,50mg/kg/d)。这表明本发明化合物MF004可以有效延长总的生存期。
以下实施例1-5到1-14提供了本发明化合物MF005-14的制备方法及产物检测结果。
实施例1-5、3-(5-(4-甲氧基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF005)
化合物MF005是化合物MF004未加甲基前的合成中间体,产率45%。1H NMR(500MHz,CDCl3)δ8.14(br s,1H),7.83(d,J=7.7Hz,1H),7.56(d,J=7.7Hz,1H),7.44(d,J=8.7Hz,2H),7.41–7.36(m,1H),7.30–7.21(m,2H),7.17–7.11(m,3H),6.90(d,J=8.8Hz,2H),6.83(s,1H),6.20(s,1H),4.87(s,1H),3.81(s,3H),3.42–3.36(m,2H),2.60(t,J=7.3Hz,2H),1.68–1.52(m,4H).13C NMR(125MHz,CDCl3)δ167.74,160.17,142.09,135.59,130.78,129.79,129.67,129.09,128.35,128.27,127.83,126.35,125.74,121.44,114.30,55.28,40.05,35.44,29.10,28.67.HR MS(ESI):calcd for[C27H28N4O2+Na]+463.2104,found 463.2108。
实施例1-6、3-(2-乙基-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF006)
采用与制备化合物MF004类似的方法,将溴甲烷替换成溴乙烷,柱层析纯化后得化合物MF006,产率39%。1H NMR(500MHz,DMSO-d6)δ8.51(t,J=5.5Hz,1H),8.02(s,1H),7.83(d,J=7.7Hz,1H),7.55–7.50(m,1H),7.49–7.44(m,1H),7.43–7.35(m,2H),7.26(dd,J=7.6,7.6Hz,2H),7.22–7.13(m,3H),7.00–6.91(m,2H),4.51(q,J=7.3Hz,2H),3.77(s,3H),3.29–3.23(m,2H),2.60(t,J=7.5Hz,2H),1.67–1.45(m,7H).13C NMR(125MHz,CDCl3)δ167.13,159.78,144.29,142.90,142.02,135.24,131.64,130.88,129.54,128.95,128.40,128.34,127.11,125.86,125.83,123.27,114.08,55.26,50.15,39.88,35.46,29.18,28.66,14.97.HR MS(ESI):calcd for[C28H30N4O2+Na]+477.2261,found 477.2270。
实施例1-7、3-(5-(4-甲氧基苯基)-2-丙基-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF007)
采用与制备化合物MF004类似的方法,将溴甲烷替换成1-溴丙烷,柱层析纯化后得化合物MF007,产率40%。1H NMR(500MHz,DMSO-d6)δ8.51(t,J=5.1Hz,1H),8.01(s,1H),7.83(d,J=7.6Hz,1H),7.52(d,J=7.7Hz,1H),7.46(dd,J=7.7,7.7Hz,1H),7.38(d,J=8.7Hz,2H),7.30–7.23(m,2H),7.23–7.13(m,3H),6.96(d,J=8.7Hz,2H),4.44(t,J=6.9Hz,2H),3.77(s,3H),3.30–3.20(m,2H),2.69–2.57(m,2H),2.03–1.92(m,2H),1.68–1.45(m,4H),0.94(t,J=7.4Hz,3H).13C NMR(125MHz,CDCl3)δ167.13,159.77,144.24,142.85,142.02,135.24,131.66,130.89,129.55,128.94,128.40,128.34,127.09,125.88,125.83,123.28,114.07,56.70,55.26,39.88,35.46,29.17,28.66,23.30,11.19.HR MS(ESI):calcd for[C29H32N4O2+Na]+491.2417,found 491.2424。
实施例1-8、3-(2-(2-羟基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF008)
采用与制备化合物MF004类似的方法,将溴甲烷替换成2-羟基溴乙烷,柱层析纯化后得化合物MF008,产率32%。1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.79(d,J=7.8Hz,1H),7.63(d,J=7.7Hz,1H),7.47–7.37(m,3H),7.33–7.24(m,3H),7.18(m,3H),6.89(d,J=8.4Hz,2H),6.06–5.99(m,1H),4.65–4.59(m,2H),4.22–4.16(m,2H),3.82(s,3H),3.48–3.96(m,2H),2.66(t,J=7.2Hz,2H),1.74–1.55(m,4H).13C NMR(125MHz,CDCl3)δ167.09,131.22,130.93,129.58,129.00,128.40,128.35,127.28,126.04,125.85,114.14,61.02,56.89,55.29,39.94,35.46,29.17,28.66.HR MS(ESI):calcd for[C28H30N4O3+Na]+493.2210,found 493.2213。
实施例1-9、3-(2-(2-甲氧基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-乙基)-N-(4-苯丁基)苯甲酰胺(MF009)
采用与制备化合物MF004类似的方法,将溴甲烷替换成2-甲氧基溴乙基,产率36%。1H NMR(500MHz,CDCl3)δ7.89(br s,1H),7.79(d,J=7.8Hz,1H),7.63(d,J=7.8Hz,1H),7.48–7.42(m,2H),7.40(dd,J=7.9,7.9Hz,1H),7.31–7.27(m,3H),7.21–7.15(m,3H),6.88(d,J=8.8Hz,2H),6.11–5.99(m,1H),6.05(br,s,1H),4.64(t,J=5.7Hz,2H),3.98(t,J=5.7Hz,2H),3.81(s,3H),3.49–3.41(m,2H),3.39(s,3H),2.66(t,J=7.4Hz,2H),1.80–1.53(m,4H).13C NMR(125MHz,CDCl3)δ167.25,159.83,144.70,143.28,142.01,135.11,131.45,130.99,129.62,128.92,128.40,128.34,127.24,125.98,125.82,123.09,114.05,70.39,58.97,55.25,54.57,39.91,35.44,29.12,28.64.HR MS(ESI):calcd for[C29H32N4O3+Na]+507.2367,found 507.2370。
实施例1-10、3-(2-(2-乙氧基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF010)
采用与制备化合物MF004类似的方法,将溴甲基替换成2-乙氧基溴乙烷,柱层析纯化后得MF010,产率37%。1H NMR(500MHz,CDCl3)δ7.92(d,J=1.2Hz,1H),7.85–7.76(m,1H),7.70–7.62(m,1H),7.53–7.45(m,2H),7.43(dd,J=7.7Hz,7.8Hz,1H),7.35–7.27(m,2H),7.24–7.16(m,3H),6.95–6.86(m,2H),6.09(s,1H),4.66(t,J=5.2Hz,2H),4.04(t,J=0.75Hz,2H),3.83(d,J=1.4Hz,3H),3.62–3.53(m,2H),3.49–3.40(m,2H),2.68(t,J=7.2Hz,2H),1.74–1.59(m,4H),1.21(t,J=2Hz,3H).13C NMR(126MHz,CDCl3)δ167.11,159.79,144.58,143.19,142.00,135.19,131.52,130.90,129.57,128.88,128.38,128.32,127.14,125.96,125.80,123.15,114.03,68.25,66.58,55.23,54.66,39.86,35.43,29.14,28.64,15.03.HR MS(ESI):calcd for[C30H34N4O3+Na]+521.2523,found 521.2527。
实施例1-11、3-(2-(2-氨基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF011)
采用与制备化合物MF004类似的方法,将溴甲烷替换成2-氨基溴乙烷氢溴酸盐,柱层析纯化后得化合物MF011,产率25%。1H NMR(500MHz,CDCl3)δ7.93(s,1H),7.80(d,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),7.48–7.44(m,2H),7.42(dd,J=7.7Hz,7.7Hz,1H),7.30–7.26(m,2H),7.22–7.16(m,3H),6.94–6.84(m,2H),6.20(s,1H),4.56–4.50(m,2H),3.83(s,3H),3.45(dd,J=7.4,7Hz,2H),3.38–3.28(m,2H),2.67(t,J=7.4Hz,2H),1.74–1.67(m,2H),1.66–1.50(m,4H).HR MS(ESI):calcd for[C28H31N5O2+H]+470.2551,found470.2555。
实施例1-12、3-(2-(2-溴乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯基丁基)苯甲酰胺(MF012)
在冰浴的条件下向化合物MF009(0.5mmol)的二氯甲烷溶液中,滴入三苯基二溴(0.6mmol)。反应液在室温下搅拌过夜,析出白色固体,过滤。将白色固体用硅胶柱纯化得到产物MF012。产率25%。1H NMR(500MHz,CDCl3)δ7.92(br s,1H),7.85–7.78(m,1H),7.69–7.63(m,1H),7.50–7.40(m,3H),7.34–7.27(m,2H),7.23–7.15(m,3H),6.97–6.86(m,2H),6.06(br s,1H),4.91–4.82(m,2H),3.95–3.87(m,2H),3.84(s,3H),3.49–3.43(m,2H),2.68(t,J=7.2Hz,2H),1.76–1.60(m,4H).13C NMR(125MHz,CDCl3)δ167.04,145.08,143.70,142.01,135.31,131.25,130.93,129.60,128.99,128.41,128.35,127.31,126.01,125.85,122.80,114.13,55.88,55.28,39.90,35.46,29.18,28.67,28.16.HR MS(ESI):calcd for[C28H29BrN4O2+Na]+555.1366,found 555.1371。
实施例1-13、2-(4-(4-甲氧基苯基)-5-(3-((4-苯丁基)氨基甲酰)苯基)-2H-1,2,3-三氮唑-2-基)乙酸叔丁酯(MF013)
采用与制备化合物MF004类似的方法,将溴甲烷替换成2-溴乙酸叔丁酯,柱层析纯化后得化合物MF013,产率30%。1H NMR(500MHz,DMSO)δ8.52(t,J=5.3Hz,1H),8.01(s,1H),7.83(d,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),7.42(t,J=7.7Hz,1H),7.35(d,J=8.4Hz,2H),7.25–7.20(m,2H),7.18–7.08(m,3H),6.90(d,J=8.3Hz,2H),5.11(s,2H),3.76(s,3H),3.29–3.22(m,2H),2.59(t,J=7.4Hz,2H),1.59–1.52(m,4H),1.38(s,9H)。。
实施例1-14、3-(5-(4-甲氧基苯基)-2-(2-(4-甲基哌嗪-1-基)乙基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺(MF014)
化合物MF014由化合物MF012(1mmol)加4-甲基哌嗪(3mmol)和K2CO3(5mmol),在丙酮中50℃过夜,产率58%。1H NMR(500MHz,CDCl3)δ8.01(s,1H),7.82(d,J=7.7Hz,1H),7.61(d,J=7.7Hz,1H),7.48–7.39(m,3H),7.32–7.26(m,3H),7.23–7.12(m,3H),6.91(d,J=8.7Hz,2H),6.34(s,1H),4.61(t,J=6.3Hz,2H),3.84(s,3H),3.53–3.42(m,2H),3.18(t,J=6.3Hz,2H),2.91(s,8H),2.68(t,J=7.3Hz,2H),2.64(s,3H),1.80–1.56(m,4H)。
Claims (10)
4.根据权利要求1-3之任一项所述的邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐,其特征在于,所述药学上可接受的盐是邻二苯基取代五元含氮芳杂环类化合物与酸形成的酸加成盐;其中,所述酸是盐酸、氢溴酸、硫酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸、琥珀酸。
5.根据权利要求1-3之任一项所述的邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐,其特征在于,包括:
3-(5-(4-甲氧基苯基)-1H-咪唑-1-基)-N-(4-苯丁基)苯甲酰胺,
3-(1-(4-甲氧基苯基)-1H-咪唑-5-基)-N-(4-苯丁基)苯甲酰胺,
3-(4-(4-甲氧基苯基)-1H-吡唑-3-基)-N-(4-苯丁基)苯甲酰胺,
3-(5-(4-甲氧基苯基)-2-甲基-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(5-(4-甲氧基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-乙基-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(5-(4-甲氧基苯基)-2-丙基-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-羟基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-甲氧基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-乙基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-乙氧基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-氨基乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺,
3-(2-(2-溴乙基)-5-(4-甲氧基苯基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯基丁基)苯甲酰胺,
2-(4-(4-甲氧基苯基)-5-(3-((4-苯丁基)氨基甲酰)苯基)-2H-1,2,3-三氮唑-2-基)乙酸叔丁酯,
3-(5-(4-甲氧基苯基)-2-(2-(4-甲基哌嗪-1-基)乙基)-2H-1,2,3-三氮唑-4-基)-N-(4-苯丁基)苯甲酰胺。
6.一种药物组合物,其特征在于,其包含权利要求1-3之任一项所述的邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐,以及药学上可接受的载体。
7.根据权利要求1-3之任一项所述的邻二苯基取代五元含氮芳杂环类化合物或药学上可接受的盐、或如权利要求6所述的药物组合物在制备抑制或者结合myoferlin蛋白药物中的运用。
8.根据权利要求1-3之任一项所述的邻二苯基取代五元含氮芳杂环类化合物及药学上可接受的盐、或如权利要求6所述的药物组合物在制备抑制肿瘤细胞的增殖、生长、迁移和浸润的药物中的应用;其中,所述肿瘤细胞选自黑色素瘤细胞、肝癌细胞、肺癌细胞、前列腺癌细胞、乳腺癌细胞、皮肤癌细胞、结肠癌细胞、胰腺癌细胞、白血病细胞、卵巢癌细胞、胃癌细胞、膀胱癌细胞、肾癌细胞和口腔癌细胞。
9.根据权利要求1-3之任一项所述的邻二苯基取代五元含氮芳杂环类化合物及药学上可接受的盐、或如权利要求6所述的药物组合物在制备预防和/或治疗恶性肿瘤的药物中的应用;其中,所述恶性肿瘤选自胰腺癌、乳腺癌、黑色素瘤、肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、白血病、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌。
10.根据权利要求1-3之任一项所述的邻二苯基取代五元含氮芳杂环类类化合物或药学上可接受的盐、或如权利要求6所述的药物组合物在制备抑制恶性肿瘤转移与复发的药物中的应用;其中,所述恶性肿瘤选自胰腺癌、乳腺癌、黑色素瘤、肝癌、肺癌、前列腺癌、皮肤癌、结肠癌、白血病、卵巢癌、胃癌、膀胱癌、肾癌、口腔癌。
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