CN102727470A - 双酚芴及其衍生物在制备防治癌症药物中的应用 - Google Patents
双酚芴及其衍生物在制备防治癌症药物中的应用 Download PDFInfo
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Abstract
本发明公开了双酚芴及其衍生物在制备防治癌症药物中的应用。研究发现，双酚芴及其衍生物是雌激素受体及雌激素受体相关受体反向激动剂，试验证明这类化合物能有效抑制雌激素阳性癌细胞的增长，从而能有效治疗有雌激素促长效应的乳腺癌、卵巢癌、子宫内膜癌、宫颈癌、前列腺癌、结肠癌和肺癌等癌症，可作为预防恶性肿瘤和治疗癌症的药物。
Description
技术领域
本发明涉及一种化合物及其衍生物在制备防治癌症药物中的应用，属于预防和治疗癌症的药物技术领域。
背景技术
大量研究表明雌激素(estrogen)及其受体通道与很多癌症相关。化学物质通过抗雌激素活性可以达到抗肿瘤效果。通过竞争性抑制雌激素介导的受体通道，抑制雌激素调节基因的表达，包括肿瘤细胞生长因子和血管生成因子的表达分泌，最终造成细胞处于分裂周期GO和G1期，使细胞的增殖减速(Abe O，Abe R，Enomoto K，et al.2005.LANCET.365：1687-1717)。目前，最广泛应用于治疗乳腺癌、子宫内膜癌等雌激素受体阳性癌症的化学物质是他莫昔芬，或称三苯氧胺(美国专利4536516)。他莫昔芬代谢产物4羟基他莫昔芬是一种较强的雌激素受体拮抗剂(antagonist)和雌激素受体相关受体拮抗剂，它的抗肿瘤效果主要基于这些受体拮抗剂的活性(Jordan VC.2006.Br J Pharmacol.147(Suppl 1)：S269-276.)。但他莫昔芬药物有多种毒副作用，如面部潮红、呕吐、恶心、头疼、疲劳、体重增加、多毛症、脱发、皮疹、血小板减少、白细胞减少、皮肤干燥、血栓以及肺栓塞，长期大量使用可出现视力障碍，并且目前市售他莫昔芬的价格较为昂贵，因此亟待开发他莫昔芬的替代药物。
发明内容
本发明的目的是提供一种他莫昔芬的替代药物，以用于对哺乳动物包括人类的癌症进行治疗和预防。
本发明提出下述式I表示的化合物(双酚芴及其衍生物)或其药用盐，将它们应用于制备预防和治疗癌症的药物：
式I
式I中，R0表示氢，甲基或氨基；R1、R2、R3、R4、R5和R6各自独立地表示氢，卤素，羟基，氰基，C1-3烷酰基，未取代的或被羟基或氰基取代的C1-3烷基；R7表示氢，氰基，氨基，C1-9烷酰基，未取代的或被氰基、羟基、羰基、氨基、C3-9脂环烃基、C3-9杂环基、C6-10芳基、C1-9烷胺基或C2-7环氧烷基取代的C1-9脂肪烃基；X表示氧，碳或氮。
术语“C1-3烷酰基”是指具有1～3个碳原子的酰基。
术语“C1-9烷酰基”是指具有1～9个碳原子的酰基，所述C1-9烷酰基优选为C1-4烷酰基，例如醛基(formyl，即甲酰基)和乙酰基(acetyl)。
术语“C1-3烷基”是指具有1～3个碳原子的烷基。
术语“C1-9脂肪烃基”是指具有1～9个碳原子的直链或支链的烷基、烯基或炔基，所述C1-9脂肪烃基优选为C1-6脂肪烃基，例如甲基(methyl)、乙基(ethyl)、丙基(propyl)、异丙基(isopropyl)、丁基、异丁基、仲丁基、叔丁基、丙烯基、二丁烯基、异戊烯基、丙炔基等。所述被羰基取代的C1-9脂肪烃基例如2-羰基丙基(2-oxopropyl)等。所述被氰基取代的C1-9脂肪烃基例如甲氰基(cyanomethyl)、乙氰基(cyanoethyl)、丙氰基(cyanopropyl)等。所述被羟基取代的C1-9脂肪烃基例如羟甲基(hydroxy methyl)、2-羟乙基(2-hydroxyethyl)等。
术语“C3-9脂环烃基”是指具有3～9个碳原子的脂环烃基，所述C3-9脂环烃基优选为C3-6脂环烃基，例如环丙烷基、环丁烷基、环己烯基等。所述被C3-9脂环烃基取代的C1-9脂肪烃基例如环丙基乙基。
术语“C3-9杂环基”是指具有3～9个碳原子的杂环基，例如吡咯基、哌啶基等。所述被C3-9杂环基取代的C1-9脂肪烃基例如吡咯基乙基和哌啶基乙基等。
术语“C6-10芳基”是指具有6～10个碳原子的芳基，例如苯基。所述被C6-10芳基取代的C1-9脂肪烃基例如苯乙基。
术语“C1-9烷胺基”即指-NR′R″，其中R′和R″各自独立地表示氢或C1-9烷基，且不同时为氢。所述C1-9烷胺基优选为C1-6烷胺基。所述被C1-9烷胺基取代的C1-9脂肪烃基例如2-(二甲胺基)乙基[2-(dimethylamino)ethyl]、2-(二乙胺基)乙基[2-(diethylamino)ethyl]等。
术语“C2-7环氧烷基”是指2～7个碳原子和氧原子构成的环氧烷基，被C2-7环氧烷基取代的C1-9脂肪烃基例如环氧乙基-2-甲基(oxiran-2-ylmethyl)等。
下面给出了本发明所述化合物的一些具体例子：
(1)双酚芴，英文名为9，9-Bis(4-hydroxyphenyl)fluorine，4，4′-(9-fluorenylidene)diphenol或fluorene-9-bisphenol，简称BHPF，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝R7＝H，X为氧，其结构式如下：
(2)4-(9-(4-(2-(二甲胺基)乙氧基)苯基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-(2-(dimethylamino)ethoxy)phenyl)-9H-fluoren-9-yl)phenol，简称DEPF，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为2-(二甲胺基)乙基，其结构式如下：
(3)4-(9-(4-(环氧乙基-2-甲氧基)苯基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-(oxiran-2-ylmethoxy)phenyl)-9H-fluoren-9-yl)phenol，简称OPFP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为环氧乙基-2-甲基，其结构式如下：
(4)4-(9-(4-(2-羟乙氧基)苯基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-(2-hydroxyethoxy)phenyl)-9H-fluoren-9-yl)phenol，简称HPFP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为2-羟乙基，其结构式如下：
(5)4-(9-(4-氨基苯基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-aminophenyl)-9H-fluoren-9-yl)phenol，简称APFP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝R7＝H，X为氮，其结构式如下：
(6)2-氨基-4-(9-(4-丙氧基苯)-9氢-芴-9-基)苯酚，英文名为2-amino-4-(9-(4-propoxyphenyl)-9H-fluoren-9-yl)phenol，简称APPFP，式I中R1＝R2＝R3＝R4＝R5＝R6＝H，R0为氨基，X为氧，R7为丙基，其结构式如下：
(7)4-(9-(4-乙氧苯基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-ethoxyphenyl)-9H-fluoren-9-yl)phenol，简称EPFP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为乙基，其结构式如下：
(8)4-(9-(4-(2-(哌啶-1--基)乙氧基)苯基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-9H-fluoren-9-yl)phenol，简称PEPFP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为哌啶基乙基，其结构式如下：
(9)1-(4-(9-(4-羟基苯基)-9氢-芴-9-基)苯氧基)丙酮，英文名为1-(4-(9-(4-hydroxyphenyl)-9H-fluoren-9-yl)phenoxy)propan-2-one，简称HFPP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为2-羰基丙基(丙酮基)，其结构式如下：
(10)4-(9-(4-(2-丙炔氧基)苯基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-(prop-2-yn-1-yloxy)phenyl)-9H-fluoren-9-yl)phenol，简称PYPFP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为2-丙炔基，其结构式如下：
(11)4-(9-(4-苯乙氧基苯)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-phenethoxyphenyl)-9H-fluoren-9-yl)phenol，简称PPFP，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为苯乙基，其结构式如下：
(12)2-(4-(9-(4-羟基苯基)-9氢-芴-9-基)苯氧基)乙腈，英文名为2-(4-(9-(4-hydroxyphenyl)-9H-fluoren-9-yl)phenoxy)acetonitrile，简称HFPA，式I中R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X为氧，R7为乙腈基，其结构式如下：
(13)4-(9-(4-(2-羟乙氧基)苯基)-3-(羟甲基)-9氢-芴-9-基)苯酚，英文名为4-(9-(4-(2-hydroxyethoxy)phenyl)-3-(hydroxymethyl)-9H-fluoren-9-yl)phenol，简称HHFP，式I中R0＝R1＝R3＝R4＝R5＝R6＝H，R2为羟甲基，X为氧，R7为2-羟乙基，其结构式如下：
(14)2-羟基芴双酚，英文名为4，4′-(2-hydroxy-9H-fluorene-9，9-diyl)diphenol，简称HFDP，式I中R0＝R2＝R3＝R4＝R5＝R6＝R7＝H，R1为羟基，X为氧，其结构式如下：
(15)4-(9-(4-羟基苯基)-9氢-芴-9-基)-2-甲基苯酚，英文名为4-(9-(4-hydroxyphenyl)-9H-fluoren-9-yl)-2-methylphenol，简称HFMP，式I中R1＝R2＝R3＝R4＝R5＝R6＝R7＝H，R0为甲基，X为氧，其结构式如下：
(16)4-(2，7二碘-9-(4-甲氧基苯基)-9氢-芴-9-基)苯酚，英文名为4-(2，7-diiodo-9-(4-methoxyphenyl)-9H-fluoren-9-yl)phenol，简称DIMFP，式I中R0＝R2＝R3＝R4＝R5＝H，R1＝R6＝I，X为氧，R7为甲基，其结构式如下：
本发明所述的化合物的药用盐是指药学上可接受的盐，例如与盐酸、硫酸、磷酸、硝酸等无机酸形成的盐，或是与柠檬酸、琥珀酸、枸橼酸、醋酸、酒石酸、甲磺酸等有机酸形成的盐。
本发明提出的化合物或其药用盐可抑制雌激素受体(estrogen receptors)配体依赖性转录活性，亦可抑制雌激素受体相关受体(estrogen-related receptors)的非配体依赖性转录活性，是雌激素受体及雌激素受体相关受体的反向激动剂。研究表明本发明化合物与4羟基-他莫昔酚(他莫昔酚的活性代谢产物，简称4OHT)的抗雌激素活性相似，具有显著的抗雌激素效应，能有效抑制雌激素受体阳性癌细胞(雌激素促长性癌细胞)的生长，杀死癌细胞，故能有效治疗例如乳腺癌、卵巢癌、子宫内膜癌、宫颈癌、前列腺癌、结肠癌和肺癌等有雌激素促长效应的癌症。本发明的化合物或其盐可单独或与其他化疗药物或放疗联合使用来治疗癌症，还可作为预防恶性肿瘤的药物，尤其是对特定癌症的高危人群。试验结果显示，本发明提出的化合物毒性较低，在连续三天暴露小鼠500微克/千克体重/天剂量下，未发现死亡情况。因本发明化合物及其盐无需代谢就具有较强抗雌激素活性，因此不仅可以作为口服药物，亦可作为针剂使用。
附图说明
图1为实施例1中双酚芴(BHPF)对MCF7癌细胞生长和存活的影响。
图2为通过分子对接方法计算得到的BHPF在人类雌激素受体α配体反向激动剂口袋中的姿态。
图3为不同浓度BHPF与1nM 17β-雌二醇(E2)共存下对雌激素受体E2配体依赖性转录活性的影响。
图4为通过分子对接方法计算得到的DEPF在人类雌激素受体α配体反向激动剂口袋中的姿态。
图5为通过分子对接方法计算得到的OPFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图6为通过分子对接方法计算得到的HPFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图7为通过分子对接方法计算得到的APFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图8为通过分子对接方法计算得到的APPFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图9为通过分子对接方法计算得到的EPFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图10为通过分子对接方法计算得到的HFDP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图11为通过分子对接方法计算得到的HFPA在人类雌激素受体α配体反向激动剂口袋中的姿态。
图12为通过分子对接方法计算得到的HFPP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图13为通过分子对接方法计算得到的HHFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图14为通过分子对接方法计算得到的HFMP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图15为通过分子对接方法计算得到的PEPFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图16为通过分子对接方法计算得到的PPFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图17为通过分子对接方法计算得到的PYPFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
图18为通过分子对接方法计算得到的DIMFP在人类雌激素受体α配体反向激动剂口袋中的姿态。
具体实施方式
以下实施例可更详细地说明本发明，但不以任何形式限制本发明的范围。
实施例1：双酚芴(BHPF)对MCF7癌细胞生长和存活的影响
本实施例中所用的MCF7乳腺癌细胞株购于北京金紫晶生物医药技术有限公司。BHPF购自Sigma-Aldrich公司(美国)。MCF7细胞在5％CO2、37℃及湿度饱和条件下，采用24孔板(Corning，NY，USA)DMEM培养基+10％胎牛血清(Gibco)培养，每孔接种2万个细胞，细胞贴壁后对它们用化合物进行处理(BHPF用DMSO溶解后设立10-5-10-10M暴露组，单独DMSO作为阴性对照组)或者不予处理(空白组)，经过24小时的暴露，采用
细胞计数法[
Technology Cell Counter(Innovatis，Reutlingen，Germany)]检测每孔的细胞数。
MCF7乳腺癌细胞在BHPF溶液中暴露24小时后，每组细胞数量如图1所示，从左至右依次是空白对照组、阴性对照组和不同浓度的BHPF实验组，BHPF的浓度在10μM (10-5M)和1μM(10-6M)时，MCF7活细胞数分别降低到阴性对照组细胞数(单独DMSO)的19.64％和43.04％，这里更值得注意的是10μM暴露组细胞数量比接种的活细胞数下降超过一半，而1μM浓度组的细胞数没有明显升高。这表明BHPF可以显著抑制MCF7细胞的生长，甚至在短期内杀伤癌细胞，致癌细胞死亡。
实施例2：双酚芴(BHPF)抑制雌激素受体配体依赖性转录活性
通过分子对接方法(参见Nose T，et al.2009.Toxicol.Lett.191：33-39)计算证实BHPF能很好地与人类雌激素受体α配体反向激动剂口袋结合，图2显示所得的BHPF在人类雌激素受体α配体反向激动剂口袋中的姿态，其结合能约为61.3千卡/摩尔。
通过受体-配体-转录共激活因子结合试验(参见Kanayama et al.2003.J Biochem 133：791-797)，发现人类雌激素受体α在1nM雌激素存在时能很好的与转录共激活因子SRC2很好的结合，形成受体-配体-转录共激活因子复合物。但是在加入BHPF后，转录共激活因子SRC2与人类雌激素受体α的结合活性显著下降。如图3所示，不同浓度BHPF与1nM 17β-雌二醇(E2)共存的情况下，雌激素受体E2配体依赖性转录活性受到影响。BHPF的IC50值约为7.5微摩，仅略高于同样方法做出的4羟基-他莫昔酚(他莫昔酚的高活性代谢产物，简称4OHT)的IC50值(6.8微摩)。试验还发现在浓度较高时，BHPF的抗雌激素活性强于4OHT。
实施例3：双酚芴(BHPF)对OVCAR-3卵巢癌细胞、Hela子宫颈癌细胞、PC3前列腺癌细胞和子宫内膜癌细胞生长和存活的影响
本实施例中所用的OVCAR-3卵巢癌细胞、Hela子宫颈癌细胞、PC3前列腺癌细胞和子宫内膜癌细胞株购于北京金紫晶生物医药技术有限公司，在5％CO2、37℃及饱和湿度条件下，采用24孔板(Corning，NY，USA)，DMEM培养基+10％胎牛血清(Gibco)培养，每孔接种2万个细胞，细胞贴壁后对它们用化合物进行处理(BHPF用DMSO溶解后设立10-5和10-6M处理组，DMSO作为溶剂对照组)，经过72小时的暴露，采用
细胞计数法检测每孔的细胞数。结果如表1所示，表明BHPF可以显著抑制这些癌细胞的生长或杀死这些细胞。
表1.
实施例4：DEPF、OPFP、HPFP、HFPA、EPFP、PPFP、PEPFP、HFPP、PYPFP、APFP、HHFP、HFDP、APPFP、HFMP和DIMFP的抗雌激素活性
通过分子对接方法计算证实DEPF、OPFP、HPFP、HFPA、EPFP、PPFP、PEPFP、HFPP、PYPFP、APFP、HHFP、HFDP、APPFP、HFMP和DIMFP能很好地与人类雌激素受体α配体反向激动剂口袋结合。图4至图18显示了这些化合物在人类雌激素受体α配体反向激动剂口袋中的姿态，其结合能约为从-51.32到-62.42千卡/摩尔；具体结合能数据和附图情况参考表2。因为本发明的所涉及化合物抗癌效果基于其抗雌激素活性，而且这些BHPF衍生物的抗雌激素活性与BHPF相似，而BHPF已被证明具有抗癌效果，因此可以认为DEPF、OPFP、HPFP、HFPA、EPFP、PPFP、PEPFP、HFPP、PYPFP、APFP、HHFP、HFDP、APPFP，HFMP和DIMFP也具有抗癌效果。
表2.
实施例5：BHPF的CD1小鼠暴露实验
实验一、实验动物：20日龄雌性CD1健康小鼠，体重10g左右，随机分组10只/组，共分4组：3个药物处理组和1个对照组，药物为BHPF化合物；每次给药剂量分别为：0mg/kg体重(对照组)、125mg/kg体重、250mg/kg体重、500mg/kg体重。方法：自由饮水，灌胃给药，每天一次连续三天。观察时间：连续4天，在最后一次给药的24小时后杀鼠称量子宫湿重。实验结果没有发现任何实验组中有小鼠死亡，各BHPF处理组的子宫重量与对照组的都没有显著差异(P＞0.05)。
实验二、实验动物：20日龄雌性CD1健康小鼠，体重10g左右，随机分组10只/组，共分4组：1个雌激素组(400μgE2/kg体重)，3个联合用药组(125mg BHPF+400μgE2/kg体重、250mg BHPF+400μgE2/kg体重、500mg BHPF+400μgE2/kg体重)。方法：自由饮水，灌胃给药，每天一次连续三天。观察时间：连续4天，在最后一次给药的24小时后杀鼠称量子宫湿重。实验结果没有发现任何实验组中有小鼠死亡，各BHPF与E2联合用药组的子宫重量显著低于雌激素组的子宫重量(P＜0.01)。
Claims (9)
1.式I所示化合物或其药用盐在制备预防和治疗癌症的药物中的应用：
式I
式I中，R0表示氢，甲基或氨基；R1、R2、R3、R4、R5和R6各自独立地表示氢、卤素、羟基、氰基、C1-3烷酰基、未取代的或被羟基或氰基取代的C1-3烷基；R7表示氢，氰基，氨基，C1-9烷酰基，未取代的或被氰基、羟基、氨基、C3-9脂环烃基、C3-9杂环基、C6-10芳基、C1-9烷酰基、C1-9羰基、C1-9烷胺基或C2-7环氧烷基取代的C1-9脂肪烃基；X表示-O-、-CH2-或-NH-。
2.如权利要求1所述的应用，其特征在于，所述C1-9烷胺基指-NR′R″，其中R′和R′各自独立地表示氢或C1-9烷基，且不同时为氢。
3.如权利要求1所述的应用，其特征在于，R7选自下述基团之一：氢、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、异戊烯基、醛基、乙酰基、氰基、甲氰基、乙氰基、丙氰基、羟甲基、2-羟乙基、2-(二甲胺基)乙基、环氧乙基-2-甲基、吡咯基乙基、哌啶基乙基、2-羰基丙基、2-丙炔基和苯乙基。
4.如权利要求1所述的应用，其特征在于，R1、R2、R3、R4、R5和R6各自独立选自下述基团之一：氢、卤素、甲基、乙基、丙基、异丙基、羟基、羟甲基、2-羟乙基、醛基、乙酰基、氰基、甲氰基、乙氰基或丙氰基。
5.如权利要求1所述的应用，其特征在于，所述化合物为下述化合物1)～16)之一：
1)R0＝R1＝R2＝R3＝R4＝R5＝R6＝R7＝H，X＝-O-；
2)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为2-(二甲胺基)乙基；
3)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为环氧乙基-2-甲基；
4)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为2-羟乙基；
5)R0＝R1＝R2＝R3＝R4＝R5＝R6＝R7＝H，X＝-NH-；
6)R0＝-NH2，R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为丙基；
7)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为乙基；
8)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为哌啶基乙基；
9)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为2-羰基丙基；
10)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为2-丙炔基；
11)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为苯乙基；
12)R0＝R1＝R2＝R3＝R4＝R5＝R6＝H，X＝-O-，R7为乙腈基；
13)R0＝R1＝R3＝R4＝R5＝R6＝H，R2＝-CH2OH，X＝-O-，R7为2-羟乙基；
14)R0＝R2＝R3＝R4＝R5＝R6＝R7＝H，R1＝-OH，X＝-O-；
15)R0＝-CH3，R1＝R2＝R3＝R4＝R5＝R6＝R7＝H，X＝-O-；
16)R0＝R2＝R3＝R4＝R5＝H，R1＝R6＝I，X＝-O-，R7为甲基。
6.如权利要求1所述的应用，其特征在于，所述化合物的药用盐是指药学上可接受的该化合物与无机酸或有机酸形成的盐。
7.如权利要求6所述的应用，其特征在于，所述无机酸是盐酸、硫酸、磷酸或硝酸，所述有机酸是柠檬酸、琥珀酸、枸橼酸、醋酸、酒石酸或甲磺酸。
8.如权利要求1所述的应用，其特征在于，所述癌症是雌激素受体阳性癌症。
9.如权利要求8所述的应用，其特征在于，所述癌症是乳腺癌、卵巢癌、子宫内膜癌、宫颈癌、前列腺癌、结肠癌或肺癌。
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| WO2002056880A1 (en) * | 2001-01-19 | 2002-07-25 | Cytokinetics, Inc. | Triphenylmethane kinesin inhibitors |
| CN1291959C (zh) * | 2005-12-01 | 2006-12-27 | 哈尔滨工程大学 | 用杂多酸催化合成双酚芴的方法 |
| CN101003466A (zh) * | 2007-01-19 | 2007-07-25 | 哈尔滨工程大学 | 强酸性阳离子交换树脂催化合成双酚芴的方法 |
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| WO2002056880A1 (en) * | 2001-01-19 | 2002-07-25 | Cytokinetics, Inc. | Triphenylmethane kinesin inhibitors |
| CN1291959C (zh) * | 2005-12-01 | 2006-12-27 | 哈尔滨工程大学 | 用杂多酸催化合成双酚芴的方法 |
| CN101003466A (zh) * | 2007-01-19 | 2007-07-25 | 哈尔滨工程大学 | 强酸性阳离子交换树脂催化合成双酚芴的方法 |
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| Title |
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| 高庆平等: "双酚芴的合成及应用进展研究", 《化工科技》, vol. 14, no. 1, 31 December 2005 (2005-12-31), pages 58 - 61 * |
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