CN116640124A - 4-(7-甲氧基-3,4-二氢喹喔啉-2(1h)-酮-4-基)香豆素的制备方法及应用 - Google Patents
4-(7-甲氧基-3,4-二氢喹喔啉-2(1h)-酮-4-基)香豆素的制备方法及应用 Download PDFInfo
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- CN116640124A CN116640124A CN202310523514.4A CN202310523514A CN116640124A CN 116640124 A CN116640124 A CN 116640124A CN 202310523514 A CN202310523514 A CN 202310523514A CN 116640124 A CN116640124 A CN 116640124A
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- coumarin
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了一种4‑(7‑甲氧基‑3,4‑二氢喹喔啉‑2(1H)‑酮‑4‑基)香豆素化合物的制备方法及应用。其由原料I和4‑甲氧基‑1,2‑苯二胺在碱作用下，生成中间体I化合物，将中间体I和碱置于有机溶剂中，加入氯乙酰氯，在‑20～40℃的温度下，生成中间体II化合物，将中间体II置于有机溶剂，在0～160℃的温度下，反应5分钟至48小时，生成式I化合物，则为4‑(7‑甲氧基‑3,4‑二氢喹喔啉‑2(1H)‑酮‑4‑基)香豆素，其能够有效抑制非小细胞肺癌肿瘤细胞的体外增殖；能够抑制微管的聚集。
Description
技术领域
本发明属于医药化学技术领域，具体地说，涉及一种4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素化合物及其制备方法与应用。
背景技术
微管由α-微管蛋白和β-微管蛋白异二聚体组成，是细胞骨架的主要组成部分，在维持细胞形态、细胞***、信号转导及物质输送等过程中起着重要作用。以微管为靶点的抗肿瘤药物利用微管蛋白聚合、解聚的动力学特性，或促进其聚合、或抑制其聚合，从而直接影响细胞的有丝***，使停止于G2/M期。微管上存在多个不同的药物结合位点，其中，作用于秋水仙碱结合位点的化合物可抑制微管蛋白二聚体进一步组装成微管，对多种肿瘤耐药细胞具有较好的增殖抑制活性。近年来还发现作用于秋水仙碱结合位点的化合物能破坏已形成的肿瘤血管，与靶向肿瘤血管生成抑制剂联用具有良好的临床效果，因此得到研究者的重视。
中国发明专利CN103608341B，发现了一类N-芳基不饱和稠环叔胺类化合物，该类化合物作用于微管蛋白秋水仙碱结合位点，为多数具有良好的体外肿瘤细胞增殖抑制活性和裸鼠体内肿瘤生长抑制活性，化合物结构特征为含N原子的芳香环与不饱和稠环叔胺相连接，其中体外活性最好的为化合物A，对多个肿瘤细胞系的增殖抑制活性在2～3nM，但在动物体内试验中表现出较大的毒性。
中国发明专利CN108349959B，发现了一类含4位取代的香豆素衍生物，体外对测试肿瘤细胞系显示出较好的增殖抑制活性，但该类化合物尽管也显示出一定的微管聚集抑制活性，但活性较弱。其中，4位取代苯并饱和杂环类化合物对肿瘤细胞活性均较弱，IC50值均小于100nM，尤其是化合物B的IC50值均小于5μM。
上述化合物A、B的结构式如下所示：
目前癌症是所有疾病中导致死亡例数最多的疾病，临床中所使用药物存在毒性反应大、易产生耐药性等特点，迫切需要开发新型安全、有效、低毒的药物。
发明内容
针对上述现有技术中存在的不足，本发明提供一种具有式I结构的化合物及其制备方法和应用。该化合物是一种新型的小分子微管蛋白聚集抑制剂，经试验进一步证实，其对人非小细胞肺癌细胞具有强大的增殖抑制作用，有关活性数据未见报导。本发明对于增强药物特异性、有效性、减少毒副作用和防止耐药性等具有重要意义。
为实现上述目的，本发明采用下述技术方案：
本发明的第一个方面，提供一种化合物或其可药用盐，其具有式I所示的结构：
本发明的第二个方面，提供上述化合物的制备方法，所述方法按如下反应路线进行：
进一步的，所述制备方法包括以下步骤：
(1)将4-溴香豆素(原料I)溶于有机溶剂中，加入4-甲氧基-1,2-苯二胺反应和碱，搅拌反应，得到中间体I，即4-(2-氨基-4-甲氧基)苯胺基香豆素；
更具体地说，在1至10当量的碱(例如：碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、三乙胺、N,N-二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯或N,N-二甲氨基吡啶)存在下，原料I和4-甲氧基-1,2-苯二胺在溶剂，例如DMF、乙腈、乙醇、叔丁醇、丙酮、异丙醇、甲醇、THF、甲苯、三氟甲苯、1,4-二氧六环或DMSO中，在40～200℃的温度下(油浴或者微波控制温度)，反应5分钟-24小时，生成中间体I化合物，其中反应物原料I/4-甲氧基-1,2-苯二胺投料摩尔比为1:1～1:4。
(2)将步骤(1)所得4-(2-氨基-4-甲氧基)苯胺基香豆素(中间体I)溶于有机溶剂中，加入碱，加入氯乙酰氯，搅拌反应，得到中间体II，即4-(2-氯乙酰氨基-4-甲氧基)苯胺基香豆素；
更具体地说，将中间体I置于有机溶剂例如DMF、乙腈、乙醇、叔丁醇、丙酮、异丙醇、甲醇、THF、甲苯、三氟甲苯、1,4-二氧六环或DMSO中，加入1至10当量的碱(例如：碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、三乙胺、N,N-二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯或N,N-二甲氨基吡啶)，在-20～40℃的温度下(乙醇浴或者冰浴控制温度)，反应5分钟-2小时，生成中间体II化合物，其中反应物中间体I/氯乙酰卤投料摩尔比为1:1～1:5。
(3)将步骤(2)所得4-(2-氯乙酰氨基-4-甲氧基)苯胺基香豆素(中间体II)溶于有机溶剂中，加入碱搅拌反应，得到式I化合物，即4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素。
更具体地说，将中间体I置于有机溶剂例如DMF、乙腈、乙醇、叔丁醇、丙酮、异丙醇、甲醇、THF、甲苯、三氟甲苯、1,4-二氧六环或DMSO中，加入1至10当量的碱(例如：碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、三乙胺、N,N-二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯或N,N-二甲氨基吡啶)，在0～160℃的温度下(冰浴、油浴或者微波控制温度)，反应5分钟-48小时，生成式I化合物。
本发明的第三个方面，提供一种组合物，其含有有效量的上述化合物或其异构体或溶剂化物或可药用盐。本发明化合物既可以其本身也可以其可药用盐或溶剂化物的形式使用。式I化合物的可药用盐包括与药学上可接受的无机酸或有机酸、或者与可药用的无机碱或有机碱形成的盐。合适的酸加成盐的例子包括与盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括与钠、锂、钾、镁、铝、钙、锌、N,N'-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。本文中涉及到本发明化合物时，包括式I化合物及其可药用盐或溶剂化物。
本发明的第四个方面，提供一种药物制剂，其含有有效量的上述化合物或其异构体或溶剂化物或可药用盐或上述组合物。药物组合物包含本发明式I化合物与常规药用载体或赋形剂。该药物组合物可通过例如口服或非肠道等途径给药。本发明的药物组合物可按本领域常规方法制备成各种剂型，包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等，经例如口服或非肠道等途径给药。
本发明的第五个方面，提供上述化合物或其异构体或溶剂化物或可药用盐或上述组合物或上述药物制剂在制备微管蛋白聚集抑制剂药物中的应用。
本发明的第六个方面，提供上述化合物或其异构体或溶剂化物或可药用盐或上述组合物或上述药物制剂在制备抗肿瘤药物中的应用。
另外需要指出，本发明化合物使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于0.01-100mg/kg体重/天。
本发明的有益效果：
(1)本发明发现的4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素作用于微管蛋白秋水仙碱结合位点，通过抑制微管蛋白聚集形成微管而破坏其功能，从而导致肿瘤细胞凋亡，结构新颖，对于增强药物的特异性、有效性，减少毒副作用和防止耐药性等都有很重要的意义。
(2)本发明发现的4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素为结构新颖的微管蛋白聚集抑制剂，通过抑制人非小细胞肺癌A549细胞中的微管蛋白聚集形成微管，从而使处于快速增殖的A549细胞发生凋亡，具有很强的A549细胞增殖抑制活性，作用机制与秋水仙碱相似，具有良好的潜在开发应用之价值。
附图说明
图1中间体I的1H NMR谱图
图2中间体I的HR-ESI-MS谱图
图3前体I的1H NMR谱图
图4前体I的HR-ESI-MS谱图
图5中间体II的1H NMR谱图
图6中间体II的HR-ESI-MS谱图
图7式I化合物的1H NMR谱图
图8式I化合物的HR-ESI-MS谱图
图9式I化合物的体外微管蛋白聚集抑制试验结果
图10式I化合物的体外微管蛋白聚集抑制
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。
实施例1：式I化合物的制备
(1)室温下，将4-溴香豆素(原料I，1.02g，4mmol)和4-甲氧基苯基-1,2-二胺(692mg，5mmol)溶于6mL异丙醇中，然后加入N,N-二异丙基乙基胺(700μL，4mmol)，氮气保护下回流反应22h。冷却至室温，析出固体物，抽滤，干燥，得到4-(2-氨基-4-甲氧基)苯胺基香豆素(中间体I)671mg，浅黄色固体，收率59％；熔点：215～217℃。1H NMR(500MHz,d-DMSO)δ(ppm)δ8.81(s,1H),8.23(dd,J＝8.0,1.0Hz,1H),7.64～7.60(m,1H),7.38～7.33(m,2H),6.91(d,J＝8.5Hz,1H),6.39(d,J＝3.0Hz,1H),6.21(dd,J＝8.5,3.0Hz,1H),5.11(s,2H),4.66(s,1H),3.71(s,3H)；HR-ESI-MS m/z 305.090 1[M+Na]+(计算值305.089 7,C16H14N2NaO3),见图1和图2。
中间体I存在异构体可能，其结构经以下合成方法确证：
室温下，将4-溴香豆素(原料I，191mg，0.8mmol)和2-叔丁氧羰基胺基-4-甲氧基苯胺(180mg，0.8mmol)溶于4mL N,N-二甲基乙酰胺中，然后加入N,N-二异丙基乙基胺(700μL，4mmol)，氮气保护下加热至120℃反应36h。冷却至室温，将反应物倒入冰水中，乙酸乙酯萃取(30mL×3)，合并有机相，饱和氯化钠溶液洗，无水硫酸钠干燥过夜，减压除去乙酸乙酯，粗品经Flash柱层析(乙酸乙酯：石油醚＝0～30％)，得到4-(2-叔丁氧羰基胺基-4-甲氧基)苯胺基香豆素(前体I)80mg，白色固体，收率26％；熔点：156～158℃。1HNMR(500MHz,d-DMSO)δ(ppm)δ1H NMR(500MHz,DMSO)δ8.75(d,J＝10.5Hz,2H),8.18(d,J＝7.5Hz,1H),7.65(t,J＝7.5Hz,1H),7.41～7.35(m,3H),7.20(d,J＝9.0Hz,1H),6.78(dd,J＝9.0,3.0Hz,1H),4.70(s,1H),3.79(s,3H),1.40(s,9H)。HR-ESI-MS m/z 405.142 2[M+Na]+(计算值405.142 1,C21H22N2NaO5)，见图3和图4。
将4-(2-叔丁氧羰基胺基-4-甲氧基)苯胺基香豆素(前体I，40mg，0.10mmol)溶于5mL乙酸乙酯中，加入0.5mL浓盐酸，回流反应3小时，冷却至室温，加入20mL 2.5％碳酸氢钠溶液，乙酸乙酯萃取(20mL×3)，合并有机相，饱和氯化钠溶液洗，无水硫酸钠干燥过夜，减压除去乙酸乙酯，粗品经Flash柱层析(乙酸乙酯：二氯甲烷：环己烷＝1：1：1)，得到浅黄色固体，收率67％；经1H NMR和HR-ESI-MS鉴定，与中间体I相同。
(2)室温下，将4-(2-氨基-4-甲氧基)苯胺基香豆素(中间体I，471mg，1.67mmol)溶于6mL DMF中，加入碳酸氢钠(281mg，3.34mmol)，冰浴冷却至0℃后，滴加氯乙酰氯(160μL,2mmol)，加完后继续在此温度下反应30min。将反应物倒入冰水中，析出固体物，抽滤，干燥，得到4-(2-氯乙酰胺基-4-甲氧基)苯胺基香豆素(中间体II)495mg，浅黄色固体，收率83％；熔点：206～208℃。1H NMR(500MHz,d-DMSO)δ(ppm)1H NMR(500MHz,d-DMSO)δ(ppm)δ9.64(s,1H),8.89(s,1H),8.20(dd,J＝8.0,1.5Hz,1H),7.67～7.64(m,1H),7.61(d,J＝2.5Hz,1H),7.42～7.39(m,1H),7.37(dd,J＝8.5,2.5Hz,1H),7.29(d,J＝9.0Hz,1H),6.88(dd,J＝9.0,3.0Hz,1H),4.72(s,1H),4.28(s,2H),3.80(s,3H)；HR-ESI-MS m/z 381.061 3[M+Na]+(计算值381.061 3,C18H15ClN2NaO4)，见图5和图6。
(3)室温下，将4-(2-氯乙酰胺基-4-甲氧基)苯胺基香豆素(中间体II，450mg，1.25mmol)溶于6mL DMF中，加入碳酸铯(611mg，1.87mmol)，室温下搅拌过夜。将反应物倒入约60mL冰水中，用2N HCl调pH至中性，析出固体物，抽滤，干燥，得到黄色固体物378mg，收率94％；熔点：265～266℃(碳化)。1H NMR(400MHz,d-DMSO)δ(ppm)δ10.75(s,1H),7.55～7.57(m,1H),7.40(dd,J＝8.0,1.2Hz,1H),7.21(dd,J＝8.0,1.6Hz,1H),7.17～7.10(m,1H),6.64(d,J＝2.8Hz,1H),6.57(d,J＝8.8Hz,1H),6.42(dd,J＝8.8,2.8Hz,1H),6.07(s,1H),4.24(s,2H),3.70(s,3H)；HR-ESI-MS m/z 323.103 2[M+H]+(计算值323.102 6,C18H15N2O4)，见图7和图8。
实施例2式1化合物的体外肿瘤细胞增殖抑制试验
1.试验方法：
取处于对数生长期的人非小细胞肺癌A549细胞接种于96孔板中，密度为1×104cells/孔，每孔加入100μL细胞悬液，空白组不加细胞培养基，四周边孔中加入PBS防止边缘效应。37℃下培养24h后弃去上清液，空白组和对照组各加入100μL不含药物的培养基，实验组分别加入质量浓度为100μg/mL倍比浓度梯度稀释的100μL含阳性药和10μM、3.3μM、1μM、333nM、100nM、33nM、10nM、3.3nM和1nM的式I化合物(实施例1制备)，置37℃，5％CO2的培养箱中孵育72h，用磺酰罗丹明(SRB)比色法测定化合物对肿瘤细胞的抑制率。根据药物浓度与抑制率作图，计算IC50值，实验平行3次。阳性对照药为紫杉醇，结果见表1。
2.试验结果：
表1本发明化合物A549肿瘤细胞的抑制活性
实施例3式I化合物的A549细胞周期抑制实验
1.试验药物：实施例1制备的化合物I、康普瑞丁(CA-4，阳性对照药)和二甲基亚砜(DMSO，空白对照)。
2.试验方法：
细胞以每孔1×105个接种于六孔板中，培养24h后，分别加入0.1％DMSO，式25nM I化合物和25nM紫杉醇。继续孵育24h后，收集细胞，500g离心5min，弃上清，PBS重悬后再离心弃上清，重复1次；70％的乙醇悬浮细胞，置4℃冰箱过夜，取出后500g离心，PBS洗1次，加150μLPBS配制的RNAase(50μg/mL)，37℃水浴中放置30min；加150μL染液，室温避光30min后于FACS Calibur流式细胞仪进行检测，由DNA含量分析细胞在G0/G1，S，G2/M期的分布情况。
3.试验结果
式I化合物(记作07-22B)作用A549细胞24h，测定结果如图1所示，受试化合物实验结果的现象与阳性药物紫杉醇相似。正常对照组细胞在G0/G1，S，G2/M期的分布分别为61.01％、28.88％和10.11％；经紫杉醇和式I化合物作用后，在25nM浓度下，G0/G1比例明显减少，分别为21.83％和5.87％，而G2/M期比例明显增高，分别为21.46％和72.25％，以上结果说明受试化合物及阳性药均导致A549细胞阻滞于G2/M期，见图9。
实施例4式I化合物的体外微管蛋白聚集抑制实验
1.试验药物
实施例1制备的化合物I、康普瑞丁(CA-4，阳性对照药)和二甲基亚砜(DMSO，空白对照)。
2.试验方法
利用循环离心法制备猪脑微管蛋白。具体方法如下：取新鲜猪脑，剥离血管和脑膜，生理盐水清洗2次，剪成大块后再次清洗脑组织表面血液。称量脑组织，剪碎并加入预冷的MES缓冲液(每克脑组织加入0.8～1ml，实验中所用MES中均含有lmM ATP)，冰浴下匀浆(每次10秒左右至匀浆呈均匀乳状)，匀浆液100，000g超速离心1h，取上清液并加入等体积MES一甘油缓冲液，37℃水浴孵育30rain，间隔几分钟进行搅拌，之后将该液体于35℃，100，000g离心l h，收集离心沉淀，用冷MES缓冲液将沉淀吹起，再用少量MES洗管并将洗管液一并倒入小烧杯，冰浴孵育30min后0℃100，000g离心1h，再收集沉淀，重复37℃水浴孵育、0℃离心步骤各1次。将离心沉淀物用MES缓冲液或不含ATP的在冰浴重新悬浮溶解，分装于0.2ml离心管内，置-80℃贮存备用。
采用BCA蛋白定量试剂盒，依照说明书方法对制备的蛋白进行定量。将微管蛋白与3μM、6μM、12.5μM、25μM、50μM或100μM的式I化合物或对照品混合在含有1mm GTP和5％甘油的PEM缓冲液(100mm PIPES,1mm MgCl2和1mm EGTA)中。使用MAX 190分光光度计在37℃下测定340nm的吸光度值，绘制标准曲线并计算制备微管的蛋白浓度。试验平行3次。
3.实验结果
见图10。由图10可以看出，式I化合物(记作07-22B)可以抑制微管蛋白聚集，与CA-4作用方式相似。式I化合物抑制微管蛋白聚集的IC50值为6.2μM。
应注意的是，以上实例仅用于说明本发明的技术方案而非对其进行限制。尽管参照所给出的实例对本发明进行了详细说明，但是本领域的普通技术人员可根据需要对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围。
Claims (8)
1.4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素的制备方法，
其具有式I所示的结构：
其制备方法按如下反应路线进行：
(1)在1至10当量的碱存在下，将1当量的4-溴香豆素和1至4当量的4-甲氧基-1,2-苯二胺加入到有机溶剂，在40～200℃的温度下，反应5分钟～24小时，生成中间体I化合物；
(2)将1当量的中间体I置于有机溶剂(5mL/mmol)中，加入1至10当量的碱，在-20～40℃的温度下，加入1至5当量的氯乙酰卤，反应5分钟～2小时，生成中间体II化合物；
(3)将1当量的中间体II化合物置于有机溶剂(5mL/mmol)中，加入1至10当量的碱，在0～160℃的温度下，反应5分钟～48小时，将反应物倒入冰水中，用2N HCl调pH至7，析出固体物，抽滤，干燥，得生成式I化合物。
2.根据权利要求1所述的4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素的制备方法，所述的碱为碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、三乙胺、N,N-二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯或N,N-二甲氨基吡啶的任意一种。
3.根据权利要求1所述的4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素的制备方法，所述的有机溶剂为DMF、乙腈、乙醇、叔丁醇、丙酮、异丙醇、甲醇、THF、甲苯、三氟甲苯、1,4-二氧六环、DMSO中任意一种。
4.根据权利要求1所述的4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素应用，其用于组合物，该组合物含有有效量的权利要求1所述化合物或其异构体或溶剂化物或可药用盐。
5.根据权利要求4所述的4-(7-甲氧基-3,4-二氢喹喔啉-2(1H)-酮-4-基)香豆素应用于药物制剂，其特征在于，其含有有效量的权利要求1所述化合物或其异构体或溶剂化物或可药用盐。
6.如权利要求5所述的药物制剂，其特征在于，所述药物制剂为口服制剂或肠胃外给药制剂，选自片剂、丸剂、胶囊剂或注射剂。
7.如权利要求1所述化合物或其异构体或溶剂化物或可药用盐或权利要求4所述组合物或权利要求5任一项所述药物制剂在制备微管蛋白聚集抑制剂药物中的应用。
8.如权利要求4所述化合物或其异构体或溶剂化物或可药用盐或权利要求4所述组合物或权利要求5-6任一项所述药物制剂在制备抗肿瘤药物中的应用，其特征在于，所述肿瘤疾病选自非小细胞肺癌、白血病、结肠癌、中枢神经***肿瘤、黑色素瘤、卵巢癌、肾癌、***癌或卵巢癌。
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