CN101564535A - 癌症治疗方法 - Google Patents
癌症治疗方法 Download PDFInfo
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- CN101564535A CN101564535A CNA2009101415491A CN200910141549A CN101564535A CN 101564535 A CN101564535 A CN 101564535A CN A2009101415491 A CNA2009101415491 A CN A2009101415491A CN 200910141549 A CN200910141549 A CN 200910141549A CN 101564535 A CN101564535 A CN 101564535A
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Abstract
本发明涉及N－{3－氯－4－[(3－氟苯甲基)氧]苯基}－6－[5－({[2－(甲烷磺酰基)乙基]氨基}甲基)－2－呋喃基]－4－喹唑啉胺和其盐及溶剂合物在制备与至少一种其它抗肿瘤化合物联合施用的用于治疗哺乳动物中癌症的药物中的应用。
Description
本申请系申请日为2005年6月3日、申请号为200580018262.X、发明名称为“癌症治疗方法”的发明专利申请的分案申请。
本发明涉及N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺及其盐和溶剂合物在制备与其它抗肿瘤化合物联合施用的用于治疗哺乳动物中癌症的药物中的应用。
发明背景
本发明涉及通过给药哺乳动物4-喹唑啉胺联合其它抗肿瘤化合物来治疗癌症的方法。具体而言，该方法涉及通过给药N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺和其盐及溶剂合物并联合其它抗肿瘤化合物来治疗癌症的方法。
在肿瘤领域，癌症治疗的有效化学疗法是一个持续的目标。通常，癌症由控制细胞分裂、分化和凋亡细胞死亡的正常过程反常引起。细胞凋亡(编程性细胞死亡)在胚胎发育和多种疾病例如退化性神经元疾病、心血管疾病和癌症的发病中起重要作用。最通常研究的途径之一，其涉及细胞凋亡的激酶调节，为从细胞表面的生长因子受体向核的细胞信号传递(Crews和Erikson，Cell，74：215-17，1993)。尤其是来自erbB家族生长因子受体的细胞信号传递。
ErbB家族中存在明显的相互作用，其调节这些受体介导的细胞作用。结合EGFR的六个重要的配体包括EGF、转化生长因子、双向调节因子、肝素结合EGF、β细胞调节素(betacellulin)和epiregulin(Alroy & Yarden，FEBS Letters，410：83-86，1997；Burden & Yarden，Neuron，18：847-855，1997；Klapper等人，ProcNatiAcadSci，4994-5000，1999)。Heregulins，其为另一类型的配体，直接结合HER3和/或HER4(Holmes等人，Science，256：1205，1992；Klapper等人，1997，Oncogene，14：2099-2109；Peles等人，Cell，69：205，1992)。特定配体的结合包括erbB家族成员内的同源或异源二聚化(Carraway & Cantley，Cell，78：5-8，1994；Lemmon & Schlessinger，TrendsBiochemSci，19：459-463，1994)。与其它的erbB受体成员相比，还没有鉴定出用于HER2的可溶性配体，HER2似乎是在异源二聚化后转激活的(transactivated)。erbB-2受体与EGFR、HER3或HER4受体的异二聚化优于同源二聚化(Klapper等人，1999；Klapper等人，1997)。受体二聚化导致ATP结合至受体的催化位点、受体的酪氨酸激酶的激活、C-末端酪氨酸残基的自磷酸化。然后，磷酸化的酪氨酸残基起到蛋白质例如Grb2、Shc和磷脂酶C的停泊位点的作用，即进而激活下游的信号通路，包括Ras/MEK/Erk和P13K/Akt通路，其调节转录因子和参与生物反应的其它蛋白，所述生物反应例如增殖、细胞运动性、血管生成、细胞存活和分化(Alroy & Yarden，1997；Burgering & Coffer，Nature，376：599-602，1995；Chan等人，AnnRevBiochem，68：965-1014，1999；Lewis等人，AdvCanRes，74：49-139，1998；Liu等人，Genes and Dev，13：786-791，1999；Muthuswamy等人，Mol & CellBio，19，10：6845-6857，1999；Riese &Stern，Bioessays，20：41-48，1998)。
已研究包括单克隆抗体(Mab)、免疫交联物、抗-EGF疫苗和酪氨酸激酶抑制剂的某些策略来靶向erbB家族受体，和阻断它们在癌症细胞中的激活((Sridhar等人，Lancet，4，7：397-406，2003)中的评论)。因为包含异二聚体的erbB2最稳定，因此，用于发送信号、同时阻断erbB2和EGFR的优选启动事件为最感兴趣的治疗策略。已经合成了在癌症的临床前治疗中有功效的一系列6-噻唑喹唑啉双重erbB-2/EGFR TK抑制剂(Cockerill等人，BiorgMedChemLett，1l：1401-1405，2001；Rusnak等人，CanRes，61：7196-7203，2001a；Rusnak等人，MolCanTher，1：85-94，2001b)。GW572016为6-呋喃喹唑啉，口服活性，可逆的EGFR和erbB2蛋白酶的双重激酶抑制剂(Rusnak等人，2001b)。在人类异种移植物的研究中，GW572016已显示有剂量依赖性抑制作用，并选择性抑制肿瘤细胞过表达EGFR或erbB2(Rusnak等人，2001b；Xia等人，Oncogene，21：6255-6263，2002)。
联合治疗正在快速成为癌症治疗中的规范，而非特例。肿瘤学专家正在不懈地寻求抗肿瘤化合物，当其被联合利用时，给遭受癌症影响的个体提供了更为有效和/或改善的治疗。通常，成功的联合治疗提供了比单一治疗更为改进且甚至协同的效果。
目前，本发明人已经发现了新的癌症治疗方法，包括给药N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺(GW572016)及其盐和/或溶剂合物，联合额外的抗肿瘤化合物。
发明内容
在本发明的第一方面，提供一种治疗哺乳动物中乳癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)曲妥单抗。
在本发明的第二方面，提供一种治疗哺乳动物中乳癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)来曲唑。
在本发明的第三方面，提供一种治疗哺乳动物中乳癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)卡培他滨。
在本发明的第四方面，提供一种治疗哺乳动物中乳癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)托泊替康。
在本发明的第五方面，提供一种治疗哺乳动物中肺癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)多西紫杉醇。
在本发明的第六方面，提供一种治疗哺乳动物中肺癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)托泊替康。
在本发明的第七方面，提供一种治疗哺乳动物中结肠直肠癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)托泊替康。
在本发明的第八方面，提供一种治疗哺乳动物中乳癌的方法，包括：给药所述哺乳动物治疗有效量的
(i)式(I″)化合物
(ii)抗雌激素化合物。
发明详述
如本文使用的术语“赘生物”指细胞或组织的异常增长，可理解为包括良性的，即，非癌性生长，和恶性的，即癌性生长。术语“肿瘤的”指赘生物或与其有关。
如本文使用的术语“有效量”指能引出例如由研究者或临床医师可探求的组织、全身性、动物或人体的生物或医学反应的药物或药用药剂的用量。而且，术语“治疗有效量”指与没有接受这种剂量的相应受试者相比，该剂量产生提高的治疗、治愈、预防或改善疾病、病症或副作用，或疾病或病症的发展率降低。该术语也包括在其范围内，能有效地增强正常生理功能的用量。
如本领域已知的，肿瘤经常转移，因为癌性肿瘤生长的第一(原发性)位点会蔓延至一个或多个解剖学分散的位点。如本文所用，对患者中的术语“肿瘤”的引用不仅包括原发性肿瘤，还包括转移性肿瘤生长。以相似方式对癌症或癌症治疗的引用包括原发性和转移性癌症和对原发性以及转移性癌性位置的治疗。
“EGFR”，也已知为“erbB-1”和“erbB-2”，为erbB家族的蛋白酪氨酸激酶跨膜生长因子受体。蛋白酪氨酸激酶催化参与调节细胞生长和分化的各种蛋白质中特定酪氨酸残基的磷酸化(A.F.Wilks，Progress in Growth Factor Research，1990，2，97-111；S.A.Courtneidge，Dev.Supp.1，1993，57-64；J.A.Cooper，Semin.Cell Biol.，1994，5(6)。377-387；R.F.Paulson，Semin.Immunol.，1995，7(4)，267-277；A.C.Chan，Curr.Opin.Immunol.，1996，8(3)，394-401)。I型受体酪氨酸激酶的ErbB家族包括ErbB1(也已知为上皮生长因子受体(EGFR或HER1))、erbB2(也已知为Her2)、erbB3和erbB4。这些受体酪氨酸激酶在上皮、间质和神经元组织中广泛表达，其中它们起调节细胞增殖、存活和分化的作用(Sibilia和Wagner，Science，269：234(1995)；Threadgill等人，Science，269：230(1995))。野生型erbB2或EGFR的表达增加，或构成活化的受体突变体的表达，使体外细胞发生转变(Di Fiore等人，1987；DiMarco等人，Oncogene，4：831(1989)；Hudziak等人，Proc.NatI.Acad.Sci.USA.，84：7159(1987)；Qian等人，Oncogene，10：211(1995))。在某些乳癌和多种其它恶性肿瘤中，erbB2或EGFR的表达增加与较差的临床结果有关(Slamon等人，Science，235：177(1987)；Slamon等人，Science，244：707(1989)；Bacus等人，Am.J.Clin.Path，102：S13(1994))。
其)和溶剂。用于本发明目的的这些溶剂可不影响溶解物的生物活性。适宜溶剂的实例包括，但不限于水、甲醇、乙醇和醋酸。优选使用的溶剂为可药用溶剂。适宜的可药用溶剂的实例包括，但不限于水、乙醇或醋酸。最优选使用的溶剂为水。
如上所述，本发明涉及通过给药N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺(GW572016)和其盐和/或溶剂合物并联合其它抗肿瘤化合物来治疗癌症的方法。
本文公开的癌症治疗方法，包括给药式(I)化合物或其盐或溶剂合物：
在另一个实施方案中，所述化合物为式(I′)化合物，其为式(I)化合物的二甲苯磺酸盐，或其脱水物或其水合物形式。式(I)化合物的二甲苯磺酸盐具有化学名N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺(GW572016)二甲苯磺酸盐，也已知为拉帕替尼(lapatinib)。
在一个实施方案中，化合物为式(I′)化合物的无水二甲苯磺酸盐。在另一个实施方案中，化合物为其为式(I′)化合物的一水合物二甲苯磺酸盐的式(I″)化合物。
式(I)化合物的游离碱、HCl盐和二甲苯磺酸盐可根据1999年1月8日提交的国际专利申请No.PCT/EP99/00048，且1999年7月15日公开为WO 99/35146，引用上述的文献和2001年6月28日提交的国际专利申请No.PCT/US01/20706，且2002年1月10日公开为WO02/02552中的方法，以及根据下述的适宜实施例中的方法制备。一种这样的制备式(I)化合物二甲苯磺酸盐的方法在下述方案1中列出：
方案1
在方案1中，式(III)化合物二甲苯磺酸盐的制备分四个阶段进行：阶段1：所示二环化合物和胺反应，得到所示碘代喹唑啉衍生物；阶段2：制备相应的乙醛盐；阶段3：制备喹唑啉二甲苯磺酸盐；和阶段4：制备一水合物二甲苯磺酸盐。
典型地，本发明的盐为可药用盐。在术语“可药用盐”内包括的盐指本发明化合物的无毒盐。本发明化合物的盐可包括衍生自本发明化合物取代基上氮的酸式加成盐。代表性的盐包括下述盐：醋酸盐、苯磺酸酯、苯甲酸酯、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、乙二胺四乙酸钙、樟脑磺酸盐、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、二盐酸化物、乙二胺四乙酸盐、乙二磺酸盐、丙酸酯月桂硫酸酯、乙磺酸盐、富马酸盐、葡庚酸盐、葡糖酸盐、谷氨酸盐、glycollylarsanilate、己基间苯二酚盐(hexylresorcinate)、哈胺盐(hydrabamine)、氢溴化物、盐酸化物、羟萘酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、扁桃酸盐、甲磺酸盐、溴甲烷、甲基硝化盐、甲基硫酸盐、马来酸一钾、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡胺盐、草酸盐、扑酸盐(双羟萘酸盐)、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、钾盐、水杨酸盐、纳盐、硬脂酸盐、次醋酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、8-氯茶碱、甲苯磺酸盐、三乙基碘化物、三乙基铵和戊酸盐。其它非可药用盐可用于制备本发明的化合物，这些形成本发明的另一个方面。
在一个实施方案中，该癌症治疗方法是治疗乳癌的方法，其中式(I″)的化合物与曲妥单抗联合给药。
曲要单抗是重组DNA-衍生的人化单克隆抗体，其选择性结合于HER2(erbB2)的胞外域；其可作为市售的用于I.V.注射的冻干粉末获得。曲妥单抗被指明为单一药剂，用于治疗具有转移性乳癌(其过表达erbB2)的患者(其之前接受过一或二个化疗方案)。
在一个实施方案中，该癌症治疗方法是治疗乳癌的方法，其中式(I″)的化合物与至少一种抗雌激素化合物联合给药。该抗雌激素化合物可以是雌激素受体拮抗剂或者雌激素合成抑制剂。示例性的雌激素受体拮抗剂包括但不限于氟维司群、他莫昔芬和其代谢产物4-OH-他莫昔芬、和托瑞米芬。示例性的雌激素合成抑制剂包括芳香酶抑制剂来曲唑、阿那曲唑和依西美坦。
氟维司群，7-α-[9-(4，4，5，5-五氟亚磺酰基)壬基]雌体(estra)-1，3，5-(10)-三烯-3，17-β-二醇；可作为市售的可注射溶液
获得。氟维司群被指明用于治疗在抗雌激素治疗之后，绝经后妇女中的激素阳性转移性乳癌。氟维司群是以竞争性方式结合于雌激素受体并且减量调节人类乳癌细胞中的ER蛋白的雌激素受体拮抗剂。
他莫昔芬，(Z)2-[4-(1，2-联苯基-1-丁烯基)苯氧基]-N，N-二甲基乙胺2羟基-1，2，3-丙烷三羧酸盐(1∶1)；其可作为市售的10或20mg片剂
获得。他莫昔芬被指明用于治疗男性和女性的转移性乳癌，并且作为乳癌的辅助治疗。他莫昔芬是以竞争性方式结合于雌激素受体的雌激素受体拮抗剂。
托瑞米芬，2-{p((Z)-4氯-1，2-联苯基-1-丁烯基]苯氧基}-N，N-二甲基乙胺柠檬酸盐(1∶1)；其可作为市售的60mg片剂获得。托瑞米芬被指明用于治疗绝经后妇女中转移性乳癌的雌激素受体阳性或未知肿瘤。托瑞米芬是选择性的雌激素受体调节剂，其结合于雌激素受体并且可以根据所选治疗时间、种类、性别、靶器官或终点产生雌激素或抗雌激素活性。
在另一个实施方案中，该癌症治疗方法是治疗乳癌的方法，其中式(I″)的化合物与来曲唑联合给药。
来曲唑是4-4′-(1H-1，2，4-三唑-1-基亚甲基)苄腈；其可作为市售的2.5mg片剂
获得。来曲唑是经口给药的非甾体芳香酶抑制剂。具体而言，它是抑制雄激素转化为雌激素的雌激素合成抑制剂。来曲唑被指明为用于治疗在抗雌激素治疗之后具有疾病进展的绝经后妇女中的晚期乳癌。
阿那曲唑是1，3-苯二乙腈α，α，α′，α′-四甲基-5-(1H-1，2，4-三唑-1-基甲基)；其可作为市售的1mg片剂
获得。阿那曲唑是经口给药的非甾体芳香酶抑制剂。具体而言，它是抑制雄激素转化为雌激素的雌激素合成抑制剂。阿那曲唑被指明为绝经后妇女中的早期乳癌辅助治疗。
依西美坦是6-亚甲基雄烷-1，4-二烯-3，17-二酮；其可作为市售的25mg片剂
获得。依西美坦是经口给药的甾体芳香酶抑制剂。具体而言，它是抑制雄激素转化为雌激素的雌激素合成抑制剂。依西美坦被指明为用于治疗在他莫昔芬治疗之后具有疾病进展的绝经后妇女中的晚期乳癌。
在一个实施方案中，该癌症治疗方法是治疗乳癌的方法，其中式(I″)的化合物与卡培他滨联合给药。
卡培他滨，5′-脱氧-5-氟-N-[(戊氧基)羰基]-胞啶；其可作为市售的150或500mg片剂
获得。卡培他滨是经口给药的5′-脱氧-5-氟尿苷(5′-DFUR)(其在体内转化为5-氟尿嘧啶)的前药。卡培他滨被指明为用于治疗对含有紫杉醇和蒽环类抗生素的治疗方案具有抗性的转移性乳癌。
在一个实施方案中，该癌症治疗方法是治疗乳癌的方法，其中式(I″)的化合物与托泊替康联合给药。
托泊替康HCl，(S)-10-[(二甲基氨基)甲基]-4-乙基-4，9-二羟基-1H-吡喃[3′，4′，6，7]吲嗪[1，2-b]喹啉-3，14-(4H，12H)-二酮单盐酸盐，可作为市售的可注射溶液
获得。托泊替康是结合于拓扑异构酶I-DNA复合物的喜树碱衍生物并且防止响应于DNA分子扭转张力的拓扑异构酶I引起的单链破裂再连接。托泊替康被指明为卵巢和小细胞肺癌的转移性肿瘤的二线治疗。托泊替康HCl的剂量限制副作用是骨髓抑制，主要是嗜中性白血球减少。
在一个实施方案中，该癌症治疗方法是治疗肺癌的方法，其中式(I″)的化合物与多西紫杉醇联合给药。在一个实施方案中，该肺癌是非小细胞肺癌。
多西紫杉醇，(2R，3S)-N-羧基-3-苯基异丝氨酸，N-叔丁酯，具有具有5β-20-环氧-1，2[α]，4，7β，10β，13α-六羟基紫衫烷-11-烯-9-酮4-乙酸酯2-苯甲酸酯的13-酯，三水合物；多西紫杉醇被指明用于治疗乳癌。多西紫杉醇是紫杉醇的半合成衍生物，采用天然前体10-脱乙酰基-浆果赤霉素III(从European Yew tree的针叶提取)来适量(q.v.)制备。多西紫杉醇的剂量限制毒性是嗜中性白血球减少。
在一个实施方案中，该癌症治疗方法是治疗肺癌的方法，其中式(I″)的化合物与托泊替康联合给药。在一个实施方案中，该肺癌是非小细胞肺癌。
托泊替康为如上所述。
在一个实施方案中，该癌症治疗方法是治疗结肠直肠癌的方法，其中式(I″)的化合物与托泊替康联合给药。
托泊替康为如上所述。
在一个实施方案中，该癌症治疗方法是治疗乳癌的方法，其中式(I″)的化合物与至少一种bcl-2抑制剂联合给药。
细胞凋亡或编程性细胞死亡是体内过量、不需要、或被破坏的细胞被消除的机制。大多数恶性肿瘤是由异常细胞凋亡途径产生，其中细胞凋亡被阻断或抑制，导致改进的细胞生存并且可能对治疗具有抗性。Bcl-2是细胞凋亡调节剂家族的一员。Bcl-2是细胞凋亡途径的抑制剂并且当在癌细胞中过表达时，可能在促进癌症发展和生长方面起到作用。如此，bcl-2抑制剂被认为可能在癌症治疗方面是有效的。(Sara等人，Current Med Chem，11：1031-1040，2004；Lie等人，CurrMed Chem-AntiCancer Agents，3：217-223，2003。)一种已知的bcl-2抑制剂是HA14-1，即[2-氨基-6-溴-4-(1-氰基-2-乙氧基-2氧乙基)]-4H-色烯-3-羧酸乙酯，可获自San Diego，California。
因此，根据本发明的联合治疗包括给药至少一种式(I″)化合物和任选地应用至少一种其它抗肿瘤剂。这样的药剂组合可以一起或分开给药，当分开给药时，可以以任意顺序同时或顺次，在相近或相隔的时间给药。选择式(I″)的化合物和其它药用活性试剂的用量以及给药时间以得到所需联合治疗效果。
本发明中，还预期包括式(I″)的化合物和至少一种抗肿瘤治疗的药物组合。该式(I″)的化合物和至少一种抗肿瘤剂如上所述，并且可以在本发明治疗癌症的方法中以上述任一组合使用。
尽管在本发明的癌症治疗方法中使用的治疗有效量的式(I″)化合物和其盐或溶剂合物可以以未加工的化学品给药，其也可以将活性成分制成药物组合物。因此，本发明还提供可以在本发明的癌症治疗方法中给药的药物组合物。所述药物组合物包括治疗有效量的式(I″)化合物和其盐或溶剂合物，和一种或多种可药用载体、稀释剂或赋形剂。所述载体、稀释剂或赋形剂与制剂的其它成分可相容和对其接受者无毒。
药物制剂可以以每单元剂量包含预定量活性成分的单元剂型存在。这样的单元可以包含，例如0.5mg至1g，优选1mg至700mg，更优选5mg至100mg的式(I)化合物，取决于受治疗的病症、给药途径和患者的年龄、体重和状况，或者药物组合物可以以每单元剂量包含预定量活性成分的单元剂型存在。优选的单元剂型为那些包含日剂量或分剂量(sub-dose)，如上所述，或其适宜部分的活性成分。而且，这样的药物组合物可以通过药物领域众所周知的任意方法制备。
式(I″)的化合物可以通过任意给药途径给药。适宜的给药途径包括口服、直肠、鼻腔、局部(包括口腔或舌下)、阴道和胃肠外(包括皮下、肌内、静脉内、真皮内、膜内或硬膜外)。应当理解，优选的给药途径可以根据例如接收者的情况的综合而改变。
适于口服给药的药物组合物可以为分离的单元例如胶囊或片剂；粉剂或颗粒剂；水性或非水性液体中的溶液或混悬液；可食用泡沫剂(foam)或搅拌剂(whip)；或水包油型液体乳剂或油包水型液体乳剂。
例如，对于片剂或胶囊形式的口服给药而言，活性药物组分可以与口服、无毒可药用惰性载体联合，所述载体例如乙醇、甘油、水等。粉剂可通过将化合物捣碎成适宜的细小尺寸并且与类似的捣碎药物载体例如可食用糖类例如淀粉或甘露醇混合制备。也可包含调味剂、防腐剂、分散剂和着色剂。
胶囊可通过制备如上所述的粉末混合物并填充入成形的明胶鞘来制备。在填充操作之前，可给粉末混合物中加入助流剂和润滑剂例如胶体二氧化硅、滑石、硬脂酸镁、硬脂酸钙或固体聚乙二醇。也可加入崩解剂或增溶剂例如琼脂-琼脂、碳酸钙或碳酸钠来改善当摄取胶囊时的药物利用度。
而且，当需要或必要时，适宜的粘合剂、润滑剂、崩解剂和着色剂也可掺入到混合物中。适宜的粘合剂包括淀粉、明胶、天然树糖类例如葡萄糖或β-乳糖、玉米甜味剂、天然和合成树胶例如阿拉伯胶、西黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡类等。在这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠等。崩解剂包括，但不限于，淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂通过制备粉末混合物、制粒或预压，加入润滑剂和崩解剂，并压成片来制备。粉末混合物是通过将该化合物与如上所述的稀释剂或基质，任选地与粘合剂例如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮，溶液延缓剂例如石蜡，吸收促进剂例如四价盐和/或吸收剂例如膨润土、高岭土或磷酸二钙混合，并适当地捣碎来制备。粉末混合物可以通过与粘合剂例如糖浆、淀粉糊、阿卡迪亚粘胶、或纤维质或聚合材料溶液润湿，并加压过筛网来制备。作为备选制粒方法，粉末混合物可以用压片机来制备，结果为不完全成形的预压片破裂为颗粒。可通过加入硬脂酸、硬脂酸盐、滑石或矿物油来润滑颗粒以防止对片剂成形模的粘合。然后，将润滑的混合物压制成片。本发明的化合物也可与自由流动的惰性载体混合而直接压制成片，不需要经过制粒或预压步骤。可提供由虫胶密封涂层、糖或聚合材料的涂层和蜡的抛光涂层组成的清澈或不透明的防护涂层。可将染料加入到这些涂层中以区分不同单元剂型。
口服液体例如溶液、糖浆和酏剂可以制备成剂量单元，以便给定的剂量包含预定量的化合物。糖浆剂可以通过将化合物溶于适宜的有香料的液体溶液中制备，而酏剂可以通过使用无毒的含醇溶媒来制备。混悬剂可通过将化合物分散在无毒溶媒中来制备。也可加入增溶剂和乳化剂例如乙氧化的异硬脂醇和聚氧乙烯山梨醇酯、防腐剂、香味添加剂例如薄荷油或天然甜味剂或糖精或其它人工甜味剂等。
当适宜时，口服给药的剂量单元制剂可以被微囊化。也可以制备该制剂以延缓或持续释放，例如通过包衣或将颗粒物质包埋在聚合物、蜡类中等。
根据本发明使用的药剂也可以脂质体递送系统给药，例如小的单层囊泡、大的单层囊泡和多层囊泡。脂质体可由多种磷脂例如胆固醇、硬脂酰胺或磷酸卵磷脂来制备。
根据本发明使用的药剂也可以通过使用单克隆抗体作为化合物分子偶合的独立载体来递送。所述化合物也可以与可溶性聚合物例如靶向药物载体偶合。这样的聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-酚、聚羟乙基门冬酰胺酚、或用棕榈酰残基取代的聚乙烯氧聚赖氨酸。而且，化合物可以与一类用于得到药物控释释放的生物可降解的聚合物偶合，所述聚合物例如聚乳酸、聚ε-己内酯、多羟基丁酸、多正酯类、聚羧醛、聚二氢吡喃类、聚腈基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
适于经皮给药的药物制剂可以为分离的贴剂，其预期可保持与接受者的表皮长期直接接触。例如，活性成分可通过离子透入法递送，如通常在Pharmaceutical Research，3(6)，(1986)中描述的。
适于局部给药的药物制剂可配制成软膏、乳膏、混悬剂、粉剂、溶液、糊剂、凝胶剂、喷雾剂、气溶剂或油。
对于治疗眼部或其它外部组织例如口和皮肤而言，制剂优选以局部软膏或乳膏应用。当制剂成软膏时，活性成分可以与石蜡或水混溶性乳膏基质一起应用。另外，活性成分可以被配制成含有水包油型乳膏基质或油包水型基质的乳膏。
适于用于局部给药至眼部的药物制剂包含滴眼剂，其中活性成分溶解或混悬于适宜的载体中，尤其是水溶液中。
适于口内局部给药的药物制剂包含锭剂、软锭剂和口腔洗剂。
适于直肠给药的药物制剂可以是栓剂或灌肠剂。
适于鼻腔给药的其中载体是固体的药物制剂包括粗粉，其具有的粒径为20至500微米，其以摄取其中嗅剂的方式给药，即，从靠近鼻子的含有粉末的容器通过鼻腔快速吸入。用于以喷鼻剂或滴鼻剂给药的其中载体是液体的适宜制剂包括活性成分的水或油溶液。
适于通过吸入给药的药物制剂包括细颗粒粉剂或雾剂，其可通过多种类型计量的剂量加压气溶胶、喷雾器或吸入器产生。
适于阴道给药的药物制剂可以为阴道栓剂、棉塞、乳膏、凝胶剂、糊剂、泡沫剂或喷雾制剂。
适于胃肠外给药的药物制剂包括含水或不含水无菌注射液，其可包含抗氧剂、缓冲剂、抑菌剂和使制剂与预期的接受者等渗的溶质；和含水或不含水无菌混悬剂，其可包含助悬剂和增稠剂。该制剂可装入单位剂量或多剂量容器中，例如密封的安瓿和药瓶，可贮存在冷冻干燥(冻干)条件下，在立即使用前，仅需要加入无菌液体载体，例如注射用水。临时注射溶液或混悬剂可由无菌粉末、颗粒和片剂制备。
应当理解，除了上述成分，所述制剂还可包含其它和涉案的制剂类型有关的本领域常用药剂，例如适于口服给药的那些可包括调味剂。
如所指出的，将治疗有效量的式(I)的特定化合物给药哺乳动物。典型地，给药本发明药剂之一的治疗有效量取决于多种因素，包括例如哺乳动物的年龄、体重、需要治疗的精确情况、病症的严重程度、制剂的性质、给药途径。总之，治疗有效量将由护理医师或兽医慎重确定。
典型地，式(I)化合物的给药范围为0.1至100mg/kg接受者(哺乳动物)体重/天，更通常为1至10mg/kg体重/天。
以下实施例仅用于阐述且无意于以任何方式限制本发明的范围。
实施例
如本文中使用的，在这些方法、方案和实施例中使用的标记和惯例与当前科学文献中例如Journal of the American Chemical Society或Journal of Biological Chemistry中使用的那些一致。标准的单一字母或三个字母的缩写通常用于表示氨基酸残基，除非另有说明，假定其为L-构型。除非另有说明，所有起始物质得自市售供应商，不需进一步纯化使用。
具体地，可在实施例和通篇说明书中使用下述缩写：
g(克)； mg(毫克)；
L(升)； mL(毫升)；
μL(微升) psi(磅/平方英寸)；
M(摩尔)； mM(毫摩尔)；
N(当量)； Kg(千克)；
i.v.(静脉注射)； Hz(赫兹)；
MHz(兆赫) mol(摩尔)；
mmol(毫摩尔)； RT(室温)；
min(分钟) h(小时)；
mp(熔点)； TLC(薄层色谱)；
Tr(停留时间)； RP(反相)；
DCM(二氯甲烷)； DCE(二氯乙烷)
DMF(N，N-二甲基甲酰胺)； HOAc(醋酸)；
TMSE(2-(三甲基硅烷基)乙基)；TMS(三甲基硅烷基)；
TIPS(三异丙基甲硅烷基)； TBS(叔丁基二甲基甲硅烷基)；
HPLC(高压液相色谱法)；
THF(四氢呋喃)； DMSO(二甲亚砜)；
EtOAc(乙酸乙酯)； DME(1，2-二甲氧基乙烷)；
EDTA 乙二胺四乙酸；
FBS 胎牛血清
IMDM Iscove’s Modified Dulbecco’s介质
IMS 工业甲基化酒精；
PBS 磷酸盐缓冲生理盐水；
RPMI Roswell Park Memorial Institute
RIPA缓冲液 ＊
RT 室温
＊150mM NaCl，50mM Tris-HCI，pH 7.5，0.25％(w/v)-脱氧胆酸，1％NP-40，5mM原钒酸钠，2mM氟化钠和蛋白酶抑制剂鸡尾酒。
除非另有说明，所有的温度用℃(摄氏度)表示。除非另有说明，所有的反应在惰性条件和室温下进行。
GW572016F为拉帕替尼，其化学名为N-{3-氮-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺二甲苯磺酸盐一水合物。
实施例1
GW572016F的制备
阶段1
在20至25℃下，用三正丁胺(1.2当量)处理搅拌的3H-6-喹唑啉-4-酮(化合物A)的甲苯(5体积)混悬液，然后，加热至90℃。加入氯氧化磷(Phosphorous oxychloride)(1.1当量)，然后加热回流反应混合物。将反应混合物冷却至50℃，加入甲苯(5体积)。加入固体形式的化合物C(1.03当量)，加热浆液返回至90℃，搅拌1小时。将浆液转移至第二个容器中；用甲苯(2体积)洗涤第一个容器，并且与反应混合物混合。将反应混合物冷却至70℃，在1小时内滴加1.0M水性氢氧化钠溶液(16体积)至搅拌的浆液中，保持成分温度为68-72℃。在65-70℃搅拌1小时，然后在1小时内冷却至20℃。在20℃搅拌混悬液2小时，过滤收集产物，连续用水(3x 5体积)和乙醇洗涤，然后在50-60℃真空干燥。体积数根据使用的化合物A的数量引用。观察到的百分收率范围：90％至95％，白色或黄色晶体。
阶段2
将N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-碘-4-喹唑啉胺-化合物D(1wt)、硼酸-化合物E(0.37wt，1.35当量)和活性炭上(0.028wt，50％水分)10％钯的混合物在IMS(15体积)中匀浆。搅拌得到的混悬液5分钟，用二异丙基乙胺(0.39体积，1.15当量)处理，然后加热至70℃约3小时，直到反应完全(用HPLC分析确定)。用四氢呋喃(THF，15体积)稀释混合物，然后热滤除去催化剂。容器用IMS洗涤(2体积)。
在5-10分钟内，将对甲苯磺酸一水合物(1.5wt，4当量)的水溶液(1.5体积)加入到滤过的保持在65℃的溶液中。当在60-75℃搅拌混悬液1小时结晶后，在1小时内冷却至约25℃，再次室温搅拌2小时。过滤收集固体，用IMS(3体积)洗涤，然后在约50℃真空干燥，得到化合物F，呈桔黄色结晶固体(从包含约5％w/w EtOH的乙醇溶剂合物中分离)。
阶段3
将化合物F(1重量)和2-(甲磺酰基)乙胺盐酸盐(0.4重量，1.62当量)悬浮于THF(10体积)中。连续加入醋酸(0.354体积，4当量)和二异丙基乙胺(DIPEA，1.08体积，4.01当量)。在30-35℃搅拌得到的溶液约1小时，冷却至约22℃。然后，在约15分钟内不断装料加入三乙酰氧基硼氢化钠(0.66重量，2.01当量)(在该点可看到某些泡腾现象)。在约22℃搅拌得到的混合物约2小时，然后取样用于HPLC分析。加入水性氢氧化钠(25％w/w，3体积)淬灭反应，然后再加入水(2体积)，搅拌约30分钟(在开始加入苛性钠时可看到某些泡腾现象)。
然后，分离水相。用THF(2体积)萃取，然后用25％w/v水性氯化铵溶液(2x 5体积)2洗涤混合的THF萃取物2次。制备对甲苯磺酸一水合物(p-TSA，0.74wt，2.5当量)的水溶液(1体积)1，加热至约60℃，加入GW572016F(化合物G)(0.002wt)晶种。
在至少30分钟内给GW572016的游离碱THF溶液中加入对TSA溶液，同时保持批料温度(batch temperature)在60±3℃。在约60℃搅拌得到的混悬液1-2小时，在1小时内冷却至20-25℃，在该温度老化约1小时。过滤收集固体，用95∶5THF∶水(3x 2体积)洗涤，在约35℃真空干燥，得到GW572016F-化合物G，亮黄色结晶固体。预期产率80％，理论产率117％w/w。
1最小反应体积约1体积。
2最大反应体积为约17体积。
#分析矫正
阶段4
将N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺-化合物G(1wt)的二甲苯磺酸盐一水合物盐的四氢呋喃(THF，14体积)和水(6体积)的混悬液加热至约55-60℃，加热30分钟，得到溶液，其通过过滤澄清，用THF/水(7∶3比例，2体积)引流(line)洗涤到结晶容器中。加热回流得到的溶液，在大气压下，蒸除四氢呋喃(9vol，与水95％w/w的共沸混合物)。
所述溶液由N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺二甲苯磺酸盐一水合物(0.002wt)作为晶种。一旦开始结晶，加入水(6体积)，同时保持反应温度高于55℃。在约2小时内，冷却混合物至5-15℃。过滤收集固体，用四氢呋喃/水(3∶7比例，2体积)，然后用四氢呋喃/水(19∶1比例，2体积)洗涤，在45℃真空干燥，得到N-{3-氯-4-[(3-氟苯甲基)氧]苯基}-6-[5-({[2-(甲烷磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺二甲苯磺酸盐一水合物-化合物G，呈亮黄色固体结晶。
实施例2
通过拉帕替尼和多西紫杉醇或托泊替康给药
细胞系得自American Type Culture Collection。所述细胞保存在含有RPMI 1640(Invitrogen # 22400-089)的组织培养瓶中，RPMI1640中含有10％的胎牛血清(FBS，HyClone # SH30071.03)，并且在37℃于含有5％CO2的大气中培养，直到用于确定IC50的平皿接种。为了确定IC50，将细胞以5,000细胞/孔接种于96孔组织培养皿中的适宜培养基中，放回培养器过夜。在最初引种约24小时后，将细胞暴露于GW572016的二甲苯磺酰盐形式、单独的GW 572016F、单独的托泊替康或多西紫杉醇、或GW 572016F与托泊替康或多西紫杉醇的联合之中。细胞在50％RPMI和50％低葡萄糖DMEM介质中，其包含5％FBS、50微克/ml庆大霉素和0.3％DMSO。所有服药均相伴执行，并且每种药剂与GW 572016F的服药比率被适当调节以反映各药剂对各细胞系的相对药效。在大多数情况下，药剂以单一固定比率服药。在一些情况下，该数据也包括通过以矩阵形式服药产生的CI值。当在两种服药形式中服药比率为1∶1时，将来自矩阵服药的CI值包括在内。参见以下服药形式。
在化合物暴露三天后，抽吸除去生长介质。用0.1ml每孔的亚甲蓝(Sigma # M9140，0.5％的50∶50乙醇∶水溶液)染色细胞，然后室温培养至少30分钟来评价细胞生物量。抽吸染剂，将培养皿浸渍在去离子水中洗涤，然后空气干燥。通过加入0.1ml的增溶溶液(1.0％N-1月桂基肌氨酸、钠盐、Sigma # L5121的PBS溶液)使细胞释放染剂。室温培养培养皿40分钟。用Tecan Spectra全自动定量绘图酶标仪在620nM读数吸收率。计算相对于未处理的对照细胞的细胞生长抑制百分比。使用Levenberg和Marquardt方法(Mager，1972)和方程y＝Vmax＊[1-(xn/(Kn+xn))](其中“K”等于IC50)来计算IC50值。
为各单独或联合药剂生成IC50值。将IC50值插入来自Chou和Talalay的联合指数方程：
Da，comb/Da+Db，comb/Db，其中Da和Db是各单独药剂的IC50。Da，comb是产生50％抑制效果的联合中试剂a的量。Db，comb是产生50％抑制效果的联合中试剂b的量。若实际以彼此1∶1比率服药，则Da，comb＝Db，comb。大于1的值表示拮抗作用。小于1的值表示协同作用。可假定通过与1.0的差值来反映拮抗或协同程度，即0.5比0.8更具协同性且2.0比1.5更具拮抗性。需要重点指出数值1.0是预测的加和性。联合给药可能比任一单独药剂得到更大的抑制效果，但是仍被考虑为具有拮抗性。这种情况发生在当联合效果的幅度并非该数学模型能够预测的时候。正在开发另一种分析模板来比较该联合与最佳单一药剂。Chou和Talalay模型也假定该单独药剂正独立作用或者处于独立途径并且相互排斥。对该假定药剂通过与GW 572016F相同的机制工作的模型的采用增加了一部分CI值，但是并未改变该数据组中药剂的排序。下表包括了对于相互排斥和相互未排斥的CI定值(determjnation)的联合指数值。
表1
| 联合 | 细胞系 | CI相互排斥 | CI相互未排斥 |
| 拉帕替尼/多西紫杉醇 | A549 | 1.22 | 1.29 |
| 拉帕替尼/多西紫杉醇 | Colo205 | 1.50 | 1.80 |
| 拉帕替尼/多西紫杉醇 | H1299 | 0.58 | 0.61 |
| 拉帕替尼/多西紫杉醇 | MDA-MB-468 | 1.16 | 1.47 |
| 拉帕替尼/托泊替康 | A549 | 0.46 | 0.48 |
| 拉帕替尼/托泊替康 | Colo205 | 0.59 | 0.68 |
| 拉帕替尼/托泊替度 | H1299 | 0.84 | 0.88 |
| 拉帕替尼/托泊替康 | MDA-MB-468 | 0.90 | 1.04 |
实施例3
BT474vs.拉帕替尼和多西紫杉醇的联合
具有BT474肿瘤的大鼠被单独给药拉帕替尼(200和100mg/kg；SID×21天，或在多西紫杉醇的前2天和1天)，且联合多西紫杉醇(25和50mg/kg IP，一周一次×3周)。
在两个试验中，单独的50mg/kg的多西紫杉醇且联合拉帕替尼是高效的。然而，在两个试验中，25和50mg/kg的泰索帝在3周的服药后引起体重损失。在第一个试验中没有死亡，且在第二个试验中在接受了多西紫杉醇(25mg/kg)和拉帕替尼(200mg/kg×21天)的8只大鼠组中有1只死亡。所有存活的大鼠在服药完成时迅速恢复体重。治疗组和结果如下。
| 治疗组 | ％抑制 |
| 1.HPMCT80溶酶(qd×21天) | ND |
| 2.Tax-25(3、10、17天) | 77 |
| 3.Tax-50(3、10、17天) | 98 |
| 4.GW016-200(sid×21天) | 102 |
| 5.GW016-100(sid×21天) | 79 |
| 6.GW016-200(以连续日每周2次×3周) | 58 |
| 7.GW016-200(以连续日每周2次×3周)+泰索帝-50(每周一次×3周) | 98 |
| 8.GW016-100(sid×21天)+泰索帝-50(每周一次×3周) | 103 |
| 9.GW016-200(sid×21天)+Tax-25(每周一次×3周) | 109 |
实施例4
拉帕替尼联合曲妥单抗的临床研究
登记患有晚期或转移性乳癌(过表达erbB2蛋白2+或3+，由免疫组织化学和/或原位杂交荧光确认)的患者(pts)。每日给药增加的拉帕替尼剂量水平(750-1500mg)，每4周重复(q4weeks)，联合曲妥单抗的周标准服药(4mg/kg负荷剂量，随后每周2mg/kg输注)。三个pts以每种剂量水平治疗，在剂量-限制毒性事件中扩充到6个。获得有限的药物代谢动力学样本来确定峰浓度和治疗相关的毒性之间的任何关联。在1500mg/d的剂量水平个别地各报导了一次剂量-限制3级疲劳和3级恶心发病率。1-2级腹泻、食欲缺乏、疲劳和皮疹是通常的毒性。在第8周以及随后每8周进行每个RECIST标准的临场应答评估。
治疗了26个pts(750组(cohort)-3；1000组-10；1250组-10；1500组-3)。中值年龄为54岁(30-81)。完成了75个治疗周期(4周＝1个治疗周期)：中值为2。20个pts的应答值得评价：4PR，期间1-4月；9SD，期间1-5月，和7PD，在1-6月内。
在152个治疗周期之后的应答评价：5PR，期间分别为1.9、2.6、3.9、5.0+，和6.9+月和1个7.7+月的CR。
CR-定义为靶损伤的消失的完全应答
PR-定义为至少30％靶损伤减少的部分应答
SD-定义为没有生长或某些靶损伤减少的稳定疾病
实施例5
拉帕替尼联合来曲唑的临床研究
登记患有晚期乳癌、ER或PR阳性、或可能应答于该联合治疗的其它肿瘤(例如卵巢、子宫内膜)的患者(pts)。给药增加的拉帕替尼剂量(1250-1500mg)，每4周重复，联合来曲唑的标准剂量(2.5mg/d)。三个患者(pts)以每种剂量水平治疗，在剂量-限制毒性事件(DLT)中扩充到6个。
在2个剂量水平(1250mg组-4pts，1500mg组-13pts)登记了17个pts(17F，中值年龄50，32-74岁，Karnofsky PS中值为90％)完成了33个治疗周期(4周＝1个治疗周期)：中值为2。在1500mg/d的剂量水平报导了一次DLT(gr 3腹泻)发病率。理想的耐受方案确定为来曲唑2.5mg+拉帕替尼1500mg/d。1-2级腹泻、食欲缺乏、疲劳和皮疹是通常的血液毒性。在16个可评估的患者中，3个pts经历了≥2月的SD(乳癌-1pt，膀胱癌-1pt，子宫内膜癌-1pt和子宫颈癌-1pt)且4个患者在2-4月内经历了PD。
实施例6
拉帕替尼联合卡培他滨的临床研究
在45个患有晚期实体瘤的患者(pts)中进行联合拉帕替尼和卡培他滨的2-部分相(Phase)I研究：(A)剂量-增大相(24pts)和(B)处于最佳耐受方案(OTR)的药物代谢动力学相(21pts)：M/F(23∶22)，年龄中值57yrs(34-78)，ECOG(0/1/2:29/13/3)，深度：轻度预治疗(23∶22)，肿瘤类型(H&N(8)；乳癌(8)，结肠直肠癌(7)，肺癌(6)，其它(16))和中值周期3(1-9)。每3周，Pts由14天的卡培他滨(C)(1500-2500mg/m2)和每日的拉帕替尼(L)(1250-1500mg)治疗。
剂量-限制毒性(DLT)为：3级粘膜炎，疲劳和食欲缺乏-1250L/2000C(n＝1)；3级皮疹(n＝1)，3级腹泻(n＝1)-1500L/2000C和2级出血性口腔炎(n＝1)，3级腹泻(n＝1)-1250L/2500C。其它毒性包括口腔炎(36％)，恶心/呕吐(30％)，腹泻(45％)，非结合性高胆红素血症(14％)，疲劳(19％)，皮疹(38％)和手足综合征(29％)。OTR为1250L/2000C。应答(RECIST标准)包括在具有trastuzimab和化疗耐受性的炎性乳癌的妇女中的1个CR。她的肿瘤过表达ErbB2(3+)，具有低TS。此外，观察到4个PR(1个erlotinib-抗性H&N；紫杉烷耐受性-H&N；乳癌；胃癌)和6个＞12周的SD。
实施例7
拉帕替尼与Bcl-2抑制剂的联合
检查了拉帕替尼与Bcl-2抑制剂(HA14-1)对MCF-7人类乳癌细胞，HER-2/神经鞘转染MCF-7细胞系和他莫昔芬(TAM)抗性MCF-7细胞系的生长的联合效果。采用MTT四唑盐染料试验确定细胞生长。对细胞给药拉帕替尼和HA14-1作为单一治疗。拉帕替尼(1-10uM)和HA14-1(1-10uM)均给出对该3种细胞系中每一种的剂量依赖性生长抑制。用EGFR/erbB-2抑制剂拉帕替尼和Bcl-2抑制剂HA14-1的联合治疗得到了对所有3种细胞系的协同生长抑制。
Claims (7)
1.下式(I″)化合物
在制备与曲妥单抗联合施用的用于治疗哺乳动物中乳癌的药物中的应用。
2.下式(I″)化合物
在制备与来曲唑联合施用的用于治疗哺乳动物中乳癌的药物中的应用。
3.下式(I″)化合物
在制备与托泊替康联合施用的用于治疗哺乳动物中乳癌的药物中的应用。
4.下式(I″)化合物
在制备与多西紫杉醇联合施用的用于治疗哺乳动物中肺癌的药物中的应用。
5.下式(I″)化合物
在制备与托泊替康联合施用的用于治疗哺乳动物中肺癌的药物中的应用。
6.下式(I″)化合物
在制备与托泊替康联合施用的用于治疗哺乳动物中结肠直肠癌的药物中的应用。
7.下式(I″)化合物
在制备与抗雌激素化合物联合施用的用于治疗哺乳动物中乳癌的药物中的应用。
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| CN (2) | CN101564535A (zh) |
| AU (2) | AU2005251769B2 (zh) |
| BR (1) | BRPI0511765A (zh) |
| CA (1) | CA2569139A1 (zh) |
| IL (1) | IL179323A0 (zh) |
| MA (1) | MA28901B1 (zh) |
| MX (1) | MXPA06013952A (zh) |
| NO (1) | NO20066079L (zh) |
| RU (2) | RU2361589C2 (zh) |
| WO (1) | WO2005120512A2 (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2426007T3 (es) * | 2004-12-17 | 2013-10-18 | Smithkline Beecham (Cork) Limited | Método para el tratamiento del cáncer |
| WO2007143483A2 (en) * | 2006-06-01 | 2007-12-13 | Smithkline Beecham Corporation | Combination of pazopanib and lapatinib for treating cancer |
| US20080051422A1 (en) * | 2006-08-22 | 2008-02-28 | Concert Pharmaceuticals Inc. | 4-Aminoquinazoline derivatives and methods of use thereof |
| CL2007002878A1 (es) | 2006-10-06 | 2008-08-01 | Takeda Pharmaceutical | Agente farmaceutico que comprende 1) un inhibidor de her2 que tiene un esqueleto de pirrolopirimidina o de pirazolopirimidina y 2) un agente terapeutico hormonal o anticancerigeno en combinacion; y uso pra la prevencion o el tratamiento del cancer. |
| WO2008067144A2 (en) * | 2006-11-28 | 2008-06-05 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
| EP2126117A2 (en) | 2007-01-18 | 2009-12-02 | University Of Southern California | Gene polymorphisms predictive for dual tki therapy |
| EP2255830A1 (en) | 2008-03-03 | 2010-12-01 | Takeda Pharmaceutical Company Limited | Concomitant drug |
| WO2009137714A2 (en) | 2008-05-07 | 2009-11-12 | Teva Pharmaceutical Industries Ltd. | Forms of lapatinib ditosylate and processes for preparation thereof |
| CN102405044A (zh) | 2009-02-06 | 2012-04-04 | 南加利福尼亚大学 | 含有单萜的治疗组合物 |
| US8568968B2 (en) | 2009-04-13 | 2013-10-29 | University Of Southern California | EGFR polymorphisms predict gender-related treatment |
| US20140302050A1 (en) * | 2011-11-09 | 2014-10-09 | Albert Einstein College Of Medicine Of Yeshiva University | Targeting an amphiregulin-derived cell surface neo-epitope |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5786344A (en) * | 1994-07-05 | 1998-07-28 | Arch Development Corporation | Camptothecin drug combinations and methods with reduced side effects |
| KR100615783B1 (ko) * | 1997-05-27 | 2006-08-25 | 아이박스 리서치 인코포레이티드 | 탁산 치료를 받고 있는 인체를 제외한 포유동물의 과민증 또는 알러지 반응을 경감시키기 위한 방법 및 약학적 키트 |
| GB9800569D0 (en) * | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
| AU785467B2 (en) * | 2000-02-28 | 2007-07-26 | Pfizer Inc. | A composition comprising camptothecin and a pyrimidine derivative for the treatment of cancer |
| TWI307339B (en) * | 2000-06-30 | 2009-03-11 | Glaxo Group Ltd | Quinazoline ditosylate salt comprounds |
| ES2236481T3 (es) * | 2001-01-16 | 2005-07-16 | Glaxo Group Limited | Combinacion farmaceutica que contiene una 4-quinazolinamina y paclitaxel, carboplatino o vinorelbina para el tratamiento de cancer. |
| PA8578001A1 (es) * | 2002-08-07 | 2004-05-07 | Warner Lambert Co | Combinaciones terapeuticas de inhibidores de quinasa de erb b y terapias antineoplasicas |
| US20060204966A1 (en) * | 2003-08-01 | 2006-09-14 | Spector Neil L | Treatment of cancers expressing p95 erbb2 |
| US8211030B2 (en) * | 2009-03-26 | 2012-07-03 | The General Electric Company | NIBP target inflation pressure automation using derived SPO2 signals |
-
2005
- 2005-06-03 CN CNA2009101415491A patent/CN101564535A/zh active Pending
- 2005-06-03 CA CA002569139A patent/CA2569139A1/en not_active Abandoned
- 2005-06-03 CN CN200580018262XA patent/CN1984656B/zh not_active Expired - Lifetime
- 2005-06-03 BR BRPI0511765-8A patent/BRPI0511765A/pt not_active IP Right Cessation
- 2005-06-03 KR KR1020067027698A patent/KR20070034536A/ko not_active Ceased
- 2005-06-03 EP EP05758577A patent/EP1765344A4/en not_active Withdrawn
- 2005-06-03 MX MXPA06013952A patent/MXPA06013952A/es active IP Right Grant
- 2005-06-03 JP JP2007515618A patent/JP2008501708A/ja active Pending
- 2005-06-03 RU RU2006142418/14A patent/RU2361589C2/ru not_active IP Right Cessation
- 2005-06-03 US US11/569,878 patent/US20090317383A1/en not_active Abandoned
- 2005-06-03 WO PCT/US2005/019568 patent/WO2005120512A2/en not_active Ceased
- 2005-06-03 AU AU2005251769A patent/AU2005251769B2/en not_active Expired
-
2006
- 2006-11-16 IL IL179323A patent/IL179323A0/en unknown
- 2006-12-25 MA MA29554A patent/MA28901B1/fr unknown
- 2006-12-29 NO NO20066079A patent/NO20066079L/no not_active Application Discontinuation
-
2008
- 2008-10-09 AU AU2008229859A patent/AU2008229859A1/en not_active Abandoned
- 2008-12-19 RU RU2008150250/14A patent/RU2008150250A/ru not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| IL179323A0 (en) | 2007-05-15 |
| MA28901B1 (fr) | 2007-10-01 |
| AU2005251769A1 (en) | 2005-12-22 |
| AU2008229859A1 (en) | 2008-10-30 |
| CN1984656B (zh) | 2010-05-26 |
| US20090317383A1 (en) | 2009-12-24 |
| WO2005120512A3 (en) | 2006-04-27 |
| EP1765344A2 (en) | 2007-03-28 |
| RU2361589C2 (ru) | 2009-07-20 |
| WO2005120512A2 (en) | 2005-12-22 |
| AU2005251769B2 (en) | 2008-10-02 |
| MXPA06013952A (es) | 2007-02-08 |
| BRPI0511765A (pt) | 2008-01-08 |
| KR20070034536A (ko) | 2007-03-28 |
| RU2006142418A (ru) | 2008-07-20 |
| CN1984656A (zh) | 2007-06-20 |
| JP2008501708A (ja) | 2008-01-24 |
| NO20066079L (no) | 2007-01-12 |
| EP1765344A4 (en) | 2009-12-02 |
| RU2008150250A (ru) | 2010-06-27 |
| CA2569139A1 (en) | 2005-12-22 |
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