CN101346137B - 含有孔布勒塔斯塔坦与抗癌剂的组合物 - Google Patents
含有孔布勒塔斯塔坦与抗癌剂的组合物 Download PDFInfo
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Abstract
一种抗肿瘤组合，它含有1，2-二苯乙烯衍生物和选自VEGF抑制剂，更特别地VEGF Trap的抗癌化合物。还提供了在治疗固体癌与类似物中使用这些药物制剂的方法。
Description
本发明涉及含有1，2-二苯乙烯衍生物与像VEGF抑制剂的抗癌剂的治疗组合物。
这些VEGF抑制剂是内皮血管生长因子抑制剂，它们在大多数情况下是选自可溶受体、antisens、RNA的aptamère和抗体的生物产品。
本发明涉及使用1，2-二苯乙烯衍生物与VEGF抑制剂的组合治疗癌，更特别地固体肿瘤；治疗时使用这种组合改善抗癌与使用这种处理(治疗)的这些有效组分，消除和改善肿瘤与类似物。
目前，使用各种各样的化疗剂治疗与消除肿瘤，特别是恶性固体肿瘤。尽管这些化疗剂对这些肿瘤会有缩小的作用，但由于这种癌对这种化疗剂有抗性，肿瘤复发，于是继续治疗，因此这些已知化疗剂往往不可能达到治愈。因此，需要其它的优异抗肿瘤剂。
而人们知道这些1，2-二苯乙烯衍生物，其中有作为主要骨架的顺式1，2-二苯乙烯，具有有丝分裂和细胞毒性强抑制活性，大多数1，2-二苯乙烯衍生物因在水中溶解度低而还不能用作药物剂。
近来，已发现具有微管素聚合抑制活性的某些1，2-二苯乙烯衍生物还具有改进的水溶性。它们包括孔布勒塔斯塔坦(combretastatine)-A4(参见专利US 5561122)的磷酰基化前体与专利US 5674906描述的1，2-二苯乙烯衍生物。看出这些1，2-二苯乙烯衍生物在临床上的应用是大有希望的。
本发明的主题是研制一种特别优异疗效的抗肿瘤剂组合，研制一种能提高1，2-二苯乙烯衍生物疗效的药物制剂，特别研制并提供一些在治疗恶性肿瘤中使用安全，疗效优异的抗肿瘤剂。
已发现1，2-二苯乙烯衍生物与其它抗癌剂，例如VEGF抑制剂并用具有提高抑制肿瘤发展的治疗效果。
专利申请WO 00/75319描述了在本发明中优选使用的VEGF抑制剂(VEGF-Trap嵌合体蛋白)说明与制备。有多种嵌合体蛋白的实施方式。
相应于VEGF-Trap的实施方式是图24(序列)描述的。本发明使用的VEGFTrap是包括与VEGFR1受体域Ig D2熔合的VEGFR1信号序列的熔合蛋白，它本身与VEGFR2受体的域Ig D3熔合，而VEGFR2受体反过来也与称之VEGFR1R2-FcΔc1或F1t1D2.F1k1D3.FcΔC1的IgG1域Fc熔合。
现在已发现，这种与1，2-二苯乙烯衍生物组合的新抗癌剂在治疗固体肿瘤方面是特别有效的。在有效的1，2-二苯乙烯衍生物中，有孔布勒塔斯塔坦A-4和该化合物衍生物，(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3，4，5-三甲氧基苯基)乙烷，它将称之式II产品。这两种化合物具有强的有丝分裂抑制活性，细胞毒素，它们抑制微管素的聚合作用。
孔布勒塔斯塔坦A-4是下式：
式(II)产品是下式：
这些孔布勒塔斯塔坦是几乎不溶于水的，并且它们能以盐形式使用，例如盐酸盐、乙酸盐、磷酸盐、甲烷磺酸盐和氨基酸盐。
专利US 5525632、5731353和5674906描述了式(II)产品与前体的呈在药物上可接受盐、水合物与溶剂化物形式的1，2-二苯乙烯衍生物的生产方法，与含有上述化合物、一种或多种赋形剂和/或一种或多种在药物上可接受稀释剂的组合物的生产方法。本文件将这些专利作为参考文献加以引用，它们披露了1，2-二苯乙烯衍生物，其中包括式(II)孔布勒塔斯塔坦产品，它们在单独使用时具有活体内抑癌效果。
现在发现，与根据有肿瘤的哺乳动物单独用药每种化合物所预计的相比，式(II)孔布勒塔斯塔坦丝氨酸盐与VEGF Trap组合显著地降低了肿瘤体积增加。
因此，本发明是大有希望的，因为本发明提供一种新的抗肿瘤剂，例如同时或分开含有两类活性组分，即1，2-二苯乙烯衍生物和VEGFTrap的抗癌化疗药品(癌的化疗剂)。
本发明还包括配合治疗，其中1，2-二苯乙烯衍生物与VEGF Trap是作为两种不同的药物制剂制备的，并且给需要的病人同时、半-同时、分开或按时间间隔给药。
给药本发明抗肿瘤剂的肿瘤包括在动物，特别是在人上出现的所有种类肿瘤。优选地，本发明的抗肿瘤剂可以用于抑制人体内的肿瘤细胞增生。本发明的抗肿瘤剂是一些药物制剂，其中使用至少两种化合物治愈(治疗)或消除一些肿瘤。
这些抗肿瘤剂的给药剂型没有任何特别的限制。这些抗癌剂通过静脉内、肠胃外与口服途径给药。本发明还包括含有两种不同给药剂型化合物组合的抗肿瘤剂。
本发明使用的1，2-二苯乙烯衍生物具有作为主要骨架的顺式1，2-二苯乙烯，它具有在活体内抑制微管素聚合作用活性和/或抗肿瘤活性。本发明的这些1，2-二苯乙烯衍生物还包括在活体内可以转化成1，2-二苯乙烯衍生物的前体。所有在药物上可接受的合适的衍生物形式，例如它们的盐、酯、酰胺、溶剂化物(溶剂化产物)和水合物，在本发明中都可以用作1，2-二苯乙烯衍生物，因为这些衍生物在活体内使用时都具有抗肿瘤活性。
这些式(II)产品前体优选地是氨基酸盐。
这些氨基酸可以列举出α氨基酸、β氨基酸和Y氨基酸。优选氨基酸实例包括甘氨酸、丙氨酸、亮氨酸、丝氨酸、赖氨酸、谷氨酸、天门冬氨酸、苏氨酸、缬氨酸、异亮氨酸、鸟氨酸、谷氨酰胺、天门冬酰胺、酪氨酸、苯基丙氨酸、半胱氨酸、蛋氨酸、精氨酸、丙氨酸、色氨酸、脯氨酸、组氨酸等。特别地，从药效与使用安全来看，苏氨酸和丝氨酸是优选的。尽管所有这些氨基酸能够呈L、D或DL形式，但L形式是优选的。
如前面所描述的，本发明的1，2-二苯乙烯衍生物是在其结构中具有顺式1，2-二苯乙烯骨架的化合物，并且它具有抑制微管素聚合作用活性和/或抗肿瘤活性。这样一些1，2-二苯乙烯衍生物可以使用在现有技术公开，例如专利US 4996237、5561122和5430062中描述的孔布勒塔斯塔坦A-4和式(II)产品进行说明。在这些专利公开中描述的现有技术1，2-二苯乙烯衍生物，与专利US 5525632和5731353描述的式(II)孔布勒塔斯塔坦都可以用于本发明的1，2-二苯乙烯衍生物，只要它们符合在本发明中1，2-二苯乙烯衍生物的定义。
上述的1，2-二苯乙烯衍生物可以采用包括在这些上述已知公开中描述方法的常规技术进行制备。
在本发明的1，2-二苯乙烯衍生物中，有盐、酯和其它1，2-二苯乙烯衍生物以及在活体内可以转化成1，2-二苯乙烯衍生物的衍生物，只要这些1，2-二苯乙烯衍生物在动物体内显示出上述表达的活性。
在用上式(II)表示的化合物中，有用下式(1Ia)表示的化合物：
式(1Ia)化合物是可溶于水的，并且它可以呈盐的形式，例如盐酸盐、乙酸盐、甲烷磺酸盐与类似物。
作为本发明目的的结果，这些组合并不专门地限于通过将一些组分物理混合得到的组合，但是它们还包括允许分开给药的组合，这种分开给药可以是同时或间隔一定时间给药。
在本发明中，其中一种优选实施方式是使用有效量的化合物IIa与VEGF Trap组合抑制肿瘤生长。
本发明的抗肿瘤剂可以通过肠胃道外途径给药，如前面已讨论的。在这种情况下，该抗肿瘤剂以填塞物方式通过静脉内给药，或采用本技术领域的技术人员已知的不同方法，使用在药物上可接受的载体制备成静脉滴入囊。优选地，采用常规技术生产这种药物剂，例如单位盖仑剂型和冻干制剂剂型，在给药时再用水或其它合适液体将这种药物剂制成静脉滴入。
在本发明抗肿瘤剂的药物制剂中两种组分的比可以根据许多因素，例如使用时期望给药量和在药物上可接受载体量，在很宽范围内改变。关于在该药物制剂中作为本发明抗肿瘤剂的1，2-二苯乙烯衍生物给药的量或组合，在该药物制剂中优选使用每1重量份VEGF Trap为约0.01-100重量份，特别地约0.1-10重量份1，2-二苯乙烯衍生物。因此，应该给病人给药含有两种活性组分的本发明药物制剂时，其制剂以前面确定给药范围的给药量给药。
如果该药物制剂应分段给药，可以将前面确定给药范围规定是这些分开药物制剂的平均比。
现在参看本发明的优选实施方式更详细地解释本发明。应该指出它们是作为实施例给出的，并不打算限制本发明。
通过测定治疗协同作用可以证明一种组合的疗效。如果一种组合在治疗上优于在其最佳剂量时单独使用较好剂，该组合表明有治疗协同作用(T.H.Corbett等人，《Cancer Treatment Reports》，66，1187(1982))。
将一种组合的最大耐受剂量与在上述研究中每个组分各自最大耐受剂量进行比较，也可以证明该组合的疗效。这种疗效例如可以用下式确定杀死细胞的log10进行定量：
杀死细胞的Log10＝T-C(天)/3.32×Td
式中T-C表示肿瘤生长期限，它是这些处理组肿瘤(T)达到预定值(例如1g)与这些对照组肿瘤(C)达到同样值以天计的平均时间，Td表示双倍对照组肿瘤体积所需要的以天计的时间。在肿瘤生长指数期期间(T.H.Corbett等人，《癌》，40，2660-2680(1977)；F.M.Schabel等人，《癌药品研制》(Cancer Drug Development)，B部，癌研究方法(Methodsin Cancer Research)，17，3-51，New York，Academie Press Inc.(1979))。如果杀死细胞的log10大于或等于0.7，则认为产品是有效的。如果杀死细胞的log10大于2.8，则认为产品是非常有效的。
每当与单个给药的较好组分杀死细胞的log10值比较，杀死细胞的log10大于至少1个log10时，以其固有的最大耐受剂量使用的组合，其中每个组分的剂量一般不超过最大耐受剂量，应表现出治疗的协同作用。
肿瘤生长的抑制作用是治疗反应的结果，其中包括为患有癌的人们给药有效量的孔布勒塔斯塔坦和如下面描述的有效量的第二种抗癌化合物。在可接受的情况下，这种给药使肿瘤生长大大减慢，因此减小肿瘤的可测量尺寸。在最佳情况下，这种肿瘤会完全消退。
如前面所描述的，为治疗哺乳动物给药本发明抗肿瘤剂的方法没有任何特别的限制。它们可以采用口服或非肠道给药，如通过静脉、皮下或肌肉内途径给药。为了快速有效，孔布勒塔斯塔坦的非肠道给药，例如通过静脉内、以填塞物方式通过静脉滴入给药是优选的。在本发明药物制剂的给药方法中，孔布勒塔斯塔坦可以与其它抗癌剂抗癌剂同时给药，或其两种可以按照随意顺序相继地给药。本技术领域的技术人员借助常规技术与本文中包含的信息可以对孔布勒塔斯塔坦与第二种抗癌剂给药的最佳方法与顺序进行适当选择。
孔布勒塔斯塔坦与VEGF Trap组合与抑制肿瘤生长的有效量，相应于患有对这种组合组分敏感的肿瘤的人们可以给药的治疗单位。实际期望的治疗单位需根据使用孔布勒塔斯塔坦个别盖仑剂型、使用辅助抗癌剂个别盖仑剂型、被处理个别肿瘤细胞与被处理个别宿主而改变。本技术领域的技术人员借助试验治疗单位与本文中包含的信息可以适当地选择在预定条件下最佳治疗剂量。
本发明的抗肿瘤剂是一种含有至少如前面描述的孔布勒塔斯塔坦和VEGF Trap的药物制剂，要使得这两种活性组分以混合物形式处在一种药物制剂中。不过，本发明中的这两种活性组分也可以分别处在相继与结合使用的不同药物制剂中。应该指出，本发明自然地包括这样一种药物制剂，它含有其它的剂(第三种和第四种药品组分等)，例如其它抗肿瘤剂，只要本发明使用的这些有效组分都处在该药物制剂中。另外，可能的是，在本发明抗肿瘤剂中含有任何一种本发明药物制剂在药物上可接受的这些载体、稀释剂和其它物质(含有本发明这两种组分的唯一一种药物制剂，与多种分开药物制剂，每种药物制剂分别含有结合使用两种组分中的一种组分)。
本发明现在参照其优选实施方式更详细地解释本发明。应该指出，这些是作为实施例给出的，不是打算限制本发明。
按照下述组成，使用这些化合物，即用下述化学式分别表示的式(IIa)和A4孔布勒塔斯塔坦制备静脉滴入药物制剂：
化合物(I)(呈磷酸盐形式) 10mg
和
生理血清 9.5ml
化合物(IIa)(呈盐酸盐形式) 5mg
0.5ml和
生理血清 9.5ml
抗肿瘤作用与试验
以下述方式从实验上可以测定这些组合对固体肿瘤的疗效：
进行实验的动物，即C3H/HeN雌性小鼠，它们在0天通过皮下途径两侧对称地移植30-60mg MA13/C鼠乳腺癌肿瘤片段。在治疗早发性肿瘤的情况下，这些植入动物随机分成打算接受或不接受(对照)这种或这些治疗的不同组。涉及早发性肿瘤治疗的情况，肿瘤达到预定肿瘤尺寸并大于200mg的动物分成不同治疗与对照组，以便肿瘤尺寸范围与其它组是可比较的。没有肿瘤的动物也可以进行与有肿瘤动物同样处理，以便能将对肿瘤的毒性作用与特效性作用联系起来。一般而言，按照肿瘤类型与希望肿瘤尺寸，在移植后3-22天开始化疗。每天观察这些动物并称重。诱发失重最低20％或20％以上(该组平均)或死亡10％或10％以上的剂量被认为是毒性的。采用无毒性最大剂量进行肿瘤活性评价。
每星期测量这些肿瘤2或3次，直到该肿瘤达到约2g或直到该肿瘤未达到2g就突然发生动物死亡。这些动物宰杀后进行解剖。
按照不同的记录参数，例如剂量(mg/kg)、给药方式、给药时间、毒性和与肿瘤生长期限相关的杀死细胞log以及肿瘤倍增时间，确定抗肿瘤活性。
Claims (2)
1.药物组合物，它含有有效量的选自VEGF Trap的抗癌化合物与有效量的治疗乳腺癌的孔布勒塔斯塔坦，其中所述的孔布勒塔斯塔坦符合下式：
2.根据权利要求1所述的组合物，其中所述的孔布勒塔斯塔坦呈盐酸盐的盐形式。
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| US20030060429A1 (en) * | 2001-03-15 | 2003-03-27 | Marie-Christine Bissery | Combination comprising combretastatin and anticancer agents |
| WO2005000895A2 (en) * | 2003-06-30 | 2005-01-06 | Regeneron Pharmaceuticals, Inc. | Vegf traps and therapeutic uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4996237A (en) | 1987-01-06 | 1991-02-26 | Arizona Board Of Regents | Combretastatin A-4 |
| US5430062A (en) | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
| TW325458B (en) | 1993-09-08 | 1998-01-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer |
| US5731353A (en) | 1993-09-08 | 1998-03-24 | Ajinomoto Co., Inc. | Stilbene derivatives and pharmaceutical compositions containing them |
| US5626862A (en) | 1994-08-02 | 1997-05-06 | Massachusetts Institute Of Technology | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
| US5561122A (en) | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
| TW334418B (en) | 1995-03-07 | 1998-06-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions |
| EP1068870B1 (en) * | 1998-04-03 | 2006-06-07 | Ajinomoto Co., Inc. | Antitumor agents |
| UA74146C2 (uk) | 1999-06-08 | 2005-11-15 | Редженерон Фармасьютікалс, Інк. | Модифікований хімеричний поліпептид з покращеними фармакокінетичними властивостями |
| JP2004501955A (ja) | 2000-06-30 | 2004-01-22 | アイネックス ファーマシューティカルズ コーポレイション | リポソーム抗新生物薬剤およびその使用 |
| US6919324B2 (en) * | 2001-10-26 | 2005-07-19 | Oxigene, Inc. | Functionalized stilbene derivatives as improved vascular targeting agents |
| AU2004226889B2 (en) | 2003-04-02 | 2007-12-20 | Celator Pharmaceuticals, Inc. | Combination compositions of camptothecins and fluoropyrimidines |
| CA2519875C (en) * | 2003-06-06 | 2014-01-14 | Regeneron Pharmaceuticals, Inc. | Method of tumor regression with vegf inhibitors |
| AR046510A1 (es) * | 2003-07-25 | 2005-12-14 | Regeneron Pharma | Composicion de un antagonista de vegf y un agente anti-proliferativo |
| WO2005027972A2 (en) * | 2003-09-23 | 2005-03-31 | Novartis Ag | Combination of a vegf receptor inhibitor with a chemotherapeutic agent |
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2005
- 2005-12-22 FR FR0513114A patent/FR2895258B1/fr not_active Expired - Fee Related
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2006
- 2006-12-18 RU RU2008130043/15A patent/RU2396952C2/ru not_active IP Right Cessation
- 2006-12-18 CA CA002631108A patent/CA2631108A1/fr not_active Abandoned
- 2006-12-18 AU AU2006334306A patent/AU2006334306B2/en not_active Ceased
- 2006-12-18 WO PCT/FR2006/002771 patent/WO2007077309A1/fr active Application Filing
- 2006-12-18 KR KR1020087014997A patent/KR20080099234A/ko not_active Application Discontinuation
- 2006-12-18 JP JP2008546511A patent/JP2009520774A/ja active Pending
- 2006-12-18 CN CN2006800485720A patent/CN101346137B/zh not_active Expired - Fee Related
- 2006-12-18 EP EP06841974A patent/EP1965784A1/fr not_active Withdrawn
- 2006-12-18 BR BRPI0620242-0A patent/BRPI0620242A2/pt not_active IP Right Cessation
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2008
- 2008-06-12 IL IL192144A patent/IL192144A0/en unknown
- 2008-06-19 US US12/142,130 patent/US7851443B2/en not_active Expired - Fee Related
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2009
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030060429A1 (en) * | 2001-03-15 | 2003-03-27 | Marie-Christine Bissery | Combination comprising combretastatin and anticancer agents |
| WO2005000895A2 (en) * | 2003-06-30 | 2005-01-06 | Regeneron Pharmaceuticals, Inc. | Vegf traps and therapeutic uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| WO 2005000895 A2,说明书0001、0016、0024、0050、0052. |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2895258B1 (fr) | 2008-03-21 |
| BRPI0620242A2 (pt) | 2011-11-08 |
| KR20080099234A (ko) | 2008-11-12 |
| RU2008130043A (ru) | 2010-01-27 |
| AU2006334306A1 (en) | 2007-07-12 |
| CN101346137A (zh) | 2009-01-14 |
| IL192144A0 (en) | 2008-12-29 |
| FR2895258A1 (fr) | 2007-06-29 |
| RU2396952C2 (ru) | 2010-08-20 |
| AU2006334306B2 (en) | 2012-08-30 |
| US7851443B2 (en) | 2010-12-14 |
| EP1965784A1 (fr) | 2008-09-10 |
| JP2009520774A (ja) | 2009-05-28 |
| HK1128234A1 (en) | 2009-10-23 |
| US20110054035A1 (en) | 2011-03-03 |
| CA2631108A1 (fr) | 2007-07-12 |
| WO2007077309A1 (fr) | 2007-07-12 |
| US20090023656A1 (en) | 2009-01-22 |
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