CN102869352A - 治疗肿瘤及纤维变性疾病的新组合疗法 - Google Patents
治疗肿瘤及纤维变性疾病的新组合疗法 Download PDFInfo
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Abstract
本发明涉及治疗肿瘤及纤维变性疾病的新方法,其包括并同Aurora激酶抑制剂一起组合给予细胞信号传导和/或血管生成抑制剂。
Description
本发明涉及用于治疗肿瘤及纤维变性疾病的新颖方法,所述方法包括组合给予细胞信号传导和/或血管生成抑制剂(尤其是血管内皮生长因子受体(VEGFR)的抑制剂)与Aurora激酶抑制剂(AKI),且涉及包含这些活性成分的药物组合或组合物。
化合物(3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧基羰基-2-吲哚满酮)(下文称为BIBF 1120)是具有有价值药理学性质的创新活性成分,其尤其用于治疗肿瘤及纤维变性疾病、免疫性疾病或涉及免疫性组份的病况、或纤维变性疾病。此化合物的化学结构如式1所示
此化合物的碱形式描述于WO 01/27081中,单乙磺酸盐形式描述于WO2004/013099中且各种其它盐形式描述于WO 2007/141283中。此分子用于治疗免疫性疾病或涉及免疫性组份的病况的用途阐述于WO 2004/017948中,用于治疗肿瘤疾病的用途描述于WO 2004/096224中且用于治疗纤维变性疾病的用途描述于WO 2006/067165中。
BIBF 1120是可同时抑制以下三种生长因子受体的高效、口服生物可利用的三重血管激酶(angiokinase)抑制剂:血管内皮生长因子受体(VEGFR)、血小板衍生的生长因子受体(PDGFR)及纤维母细胞生长因子受体(FGFR)。全部三种生长因子皆重要地参与血管形成(血管生成),且抑制这些生长因子可在预防、抑制或阻止肿瘤新生血管形成、肿瘤生长及扩散(转移)中发挥重要作用。人们认为BIBF 1120抑制VEGFR及FGFR对新肿瘤血管形成具有影响,且其抑制FGFR及PDGFR对维持肿瘤血管完整性具有影响。已显示此化合物通过抑制肿瘤新生血管形成的机制阻止肿瘤生长并抑制在内皮细胞-及平滑肌细胞及周皮细胞中的信号传导,并降低肿瘤血管密度。因此,BIBF 1120适用于治疗涉及血管生成或细胞增殖的疾病。
丝氨酸/苏氨酸激酶Aurora B参与调节若干有丝分裂过程,其包括染色体浓缩、集合及分离以及胞质分裂。Aurora B的失活废除纺锤体组装检查点(SAC)并使得过早退出有丝分裂而无胞质分裂,从而产生最终终止进一步DNA复制的多倍体细胞。Aurora B抑制剂诱导有丝分裂覆盖(mitotic override)(有丝分裂滑移)。化合物X(本发明的Aurora B激酶的有效的抑制剂)阻断各种人癌细胞系中的增殖并诱导多倍性、衰老及细胞凋亡。化合物X在裸小鼠中的多种癌症异种移植模型中显示极佳的活体内活性。
本发明的目的是提供用于治疗肿瘤及纤维变性疾病的新颖疗法。
发明详述
本发明涉及用于治疗肿瘤及纤维变性疾病的新方法,其包括组合给予细胞信号传导和/或血管生成抑制剂,尤其是具有下式的化合物1(BIBF 1120),
任选呈其互变异构体及药学上可接受的盐形式;
及Aurora激酶抑制剂2,尤其是Aurora B激酶的抑制剂。
在本发明中,应当理解,本发明的组合、组合物或组合使用可设想为同时、依次或分别给予活性成分。应当理解,细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂可经非独立地或独立地调配后给予,例如细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂可作为同一药物组合物/剂型的一部分或以分别药物组合物/剂型来给予。
上下文中,“组合”或“组合的”在本发明含义内包括但不限于固定及非固定(例如自由)的形式(包括试剂盒)及使用(例如同时、依次或分别使用这些组份或成分)。
细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂的给予可按以下方式进行:通过一起给予活性组份或成分,例如通过以一种单一制剂或剂型或以两种分别制剂或剂型同时给予。或者,细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂的给予可按以下方式进行:通过依次给予活性组份或成分,例如以两种分别制剂或剂型连续给予。
细胞信号传导和/或血管生成抑制剂可包括但不限于靶向(例如抑制)下列的试剂:内皮-特异性受体酪氨酸激酶(Tie-2)、表皮生长因子受体(EGFR)、胰岛素样生长因子-1受体(IGF-1R)、纤维母细胞生长因子受体(FGFR)、血小板衍生的生长因子受体(PDGFR)、或血管内皮生长因子(VEGF)或VEGF受体(VEGFR);以及凝血酶敏感蛋白类似物、基质金属蛋白酶(例如MMP-2或MMP-9)抑制剂、沙立度胺(thalidomide)或沙立度胺类似物、整联蛋白(integrin)、血管他丁(angiostatin)、内皮他丁(endostatin)、血管阻断剂(vasculardisrupting agents,VDA)、蛋白激酶C(PKC)抑制剂等等。
本发明的特定血管生成抑制剂为靶向(例如抑制)血管内皮生长因子(VEGF)或VEGF受体(VEGFR)的试剂。
靶向(例如抑制)VEGF/VEGFR的试剂涉及靶向(例如抑制)VEGF或VEGFR家族(VEGFR1、VEGFR2、VEGFR3)中一或多个成员的化合物,且包括任一血管内皮生长因子(VEGF)配体的抑制剂(例如配体抗体或可溶受体)以及任一VEGF受体(VEGFR)的抑制剂(例如VEGFR酪氨酸激酶抑制剂、VEGFR拮抗剂或受体抗体)。
VEGFR抑制剂为靶向血管内皮生长因子(VEGF)受体家族(尤其是酪氨酸激酶VEGFR家族)中一或多个成员的试剂(作为单一激酶抑制剂或作为多激酶抑制剂),其包括小分子受体酪氨酸激酶抑制剂及抗-VEGFR抗体。
小分子VEGFR抑制剂的实例包括但不限于索拉非尼(sorafenib)(多吉美(Nexavar),亦为Raf、PDGFR、Flt3、Kit及RETR的抑制剂)、舒尼替尼(sunitinib)(舒癌特(Sutent),亦为Kit、Flt3及PDGFR的抑制剂)、帕唑帕尼(pazopanib)(GW-786034,亦为Kit及PDGFR的抑制剂)、西地尼布(cediranib)(瑞司汀(Recentin)、AZD-2171)、阿西替尼(axitinib)(AG-013736,亦为PDGFR及Kit的抑制剂)、凡德他尼(vandetanib)(Zactima、ZD-6474,亦为EGFR及Ret的抑制剂)、瓦他拉尼(vatalanib)(亦为PDGFR及Kit的抑制剂)、莫特塞尼(motesanib)(AMG-706,亦为PDGFR及Kit的抑制剂)、brivanib(亦为FGFR的抑制剂)、利那法尼(linifanib)(ABT-869,亦为PDGFR、Flt3及Kit的抑制剂)、tivozanib(KRN-951,亦为PDGFR、Kit及MAP的抑制剂)、E-7080(亦为Kit及Kdr的抑制剂)、regorafenib(BAY-73-4506,亦为Tek的抑制剂)、foretinib(XL-880,亦为Flt3、Kit及Met的抑制剂)、telatinib(BAY-57-9352)、MGCD-265(亦为c-MET、Tie2及Ron的抑制剂)、多韦替尼(dovitinib)(亦为PDGFR、Flt3、Kit及FGFR的抑制剂)、BIBF-1120(亦为FGFR及PDGFR的抑制剂)、XL-184(亦为Met、Flt3、Ret、Tek及Kit的抑制剂)。
抑制VEGF(R)的生物实体的实例包括但不限于抗-VEGF配体抗体,例如贝伐单抗(bevacizumab)(安维汀(Avastin));可溶受体,例如阿柏西普(aflibercept)(VEGF-Trap);抗-VEGF受体抗体,例如ramucirumab(IMC-1121b)或IMC-18F1;VEGFR拮抗剂,例如CT-322或CDP-791。
小分子VEGFR-1(Flt-1)抑制剂的实例包括但不限于舒尼替尼、西地尼布及多韦替尼。
小分子VEGFR-2(Flk-1、Kdr)抑制剂的实例包括但不限于索拉非尼、舒尼替尼、西地尼布及多韦替尼。
小分子VEGFR-3(Flt-4)抑制剂的实例包括但不限于索拉非尼、舒尼替尼及西地尼布。
靶向(例如抑制)PDGFR的试剂涉及靶向(例如抑制)PDGFR家族中一或多个成员的化合物,且包括血小板衍生的生长因子受体(PDGFR)家族酪氨酸激酶抑制剂(作为单一激酶抑制剂或作为多激酶抑制剂)以及抗-PDGFR抗体。
PDGFR抑制剂为靶向PDGFR家族(尤其是酪氨酸激酶PDGFR家族)中一或多个成员的试剂(作为单一激酶抑制剂或作为多激酶抑制剂),其包括小分子受体酪氨酸激酶抑制剂及抗-PDGFR抗体。
小分子PDGFR抑制剂的实例包括但不限于BIBF-1120(亦为VEGFR及FGFR的抑制剂)、阿西替尼(亦为VEGFR及Kit的抑制剂)、多韦替尼(亦为VEGFR、Flt3、Kit及FGFR的抑制剂)、舒尼替尼(亦为VEGFR、Flt3及Kit的抑制剂)、莫特塞尼(亦为VEGFR及Kit的抑制剂)、帕唑帕尼(亦为VEGFR及Kit的抑制剂)、尼罗替尼(nilotinib)(亦为Abl及Kit的抑制剂)、坦度替尼(tandutinib)(亦为Flt3及Kit的抑制剂)、瓦他拉尼(亦为VEGFR及Kit的抑制剂)、tivozanib(KRN-951,亦为VEGFR、Kit及MAP的抑制剂)、AC-220(亦为Flt3及Kit的抑制剂)、TSU-68(亦为FGFR及VEGFR的抑制剂)、KRN-633(亦为VEGFR、Kit及Flt3的抑制剂)、利那法尼(亦为Flt3、Kit及VEGFR的抑制剂)、索拉非尼(多吉美,亦为Raf、VEGFR、Flt3、Kit及RETR的抑制剂)、伊马替尼(imatinib)(格列卫(Glevec),亦为Abl及Kit的抑制剂)。抗-PDGFR抗体的实例包括但不限于IMC-3G3。
靶向FGFR的试剂涉及靶向FGFR家族中一或多个成员的化合物,且包括纤维母细胞生长因子受体家族酪氨酸激酶抑制剂(作为单一激酶抑制剂或作为多激酶抑制剂)。
FGFR抑制剂为靶向FGFR家族(例如FGFR1、FGFR2、FGFR3)(尤其是酪氨酸激酶FGFR家族)中一或多个成员的试剂(作为单一激酶抑制剂或作为多激酶抑制剂),其包括小分子受体酪氨酸激酶抑制剂及抗-FGFR抗体。
小分子FGFR抑制剂的实例包括但不限于BIBF-1120(亦为VEGFR及PDGFR的抑制剂)、多韦替尼(亦为VEGFR、Flt3、Kit及PDGFR的抑制剂)、KW-2449(亦为Flt3及Abl的抑制剂)、brivanib(亦为VEGFR的抑制剂)、TSU-68(亦为PDGFR及VEGFR的抑制剂)。
靶向(例如抑制)EGFR的试剂涉及靶向(例如抑制)表皮生长因子受体家族(erbB1、erbB2、erbB3、erbB4)中一或多个成员的化合物,且包括表皮生长因子受体(EGFR)家族激酶中一或多个成员的抑制剂(作为单一激酶抑制剂或作为多激酶抑制剂)以及结合至表皮生长因子受体(EGFR)家族中一或多个成员的抗体。
EGFR抑制剂为靶向EGFR家族(尤其是酪氨酸激酶EGFR家族)中一或多个成员的试剂(作为单一激酶抑制剂或作为多激酶抑制剂),其包括小分子受体酪氨酸激酶抑制剂及抗-EGFR抗体。
小分子表皮生长因子受体(EGFR)抑制剂的实施例包括但不限于厄洛替尼(erlotinib)(特罗凯(Tarceva))、吉非替尼(gefitinib)(伊瑞莎(Iressa))、BIBW-2992、拉帕替尼(lapatinib)(泰克泊(Tykerb))、凡德他尼(Zactima,亦为VEGFR及RETR的抑制剂)、来那替尼(neratinib)(HKI-272)、varlitinib、AZD-8931、AC-480、AEE-788(亦为VEGFR的抑制剂)。
抗表皮生长因子受体(EGFR)的抗体的实例包括但不限于抗-ErbB1抗体西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)或尼妥珠单抗(nimotuzumab);抗-ErbB2抗体曲妥珠单抗(trastuzumab)(贺癌平(Herceptin))、帕妥珠单抗(pertuzumab)(Omnitarg)或厄妥索单抗(ertumaxomab);及抗-EGFR抗体zalutumumab。
EGFR抑制剂在本发明含义中可能是指可逆EGFR酪氨酸激酶抑制剂,例如吉非替尼、厄洛替尼、凡德他尼或拉帕替尼,或是指不可逆EGFR酪氨酸激酶抑制剂,例如来那替尼或PF-299804。
EGFR抑制剂在本发明含义中可能是指erbB选择性抑制剂,例如erbB1抑制剂(例如厄洛替尼、吉非替尼、西妥昔单抗、帕尼单抗)、或erbB2抑制剂(例如曲妥珠单抗)、双重erbB1/erbB2抑制剂(例如拉帕替尼、BIBW-2992)或泛erbB抑制剂(pan-erbB inhibitors)(例如PF-299804)。
IGF(R)抑制剂为靶向胰岛素样生长因子(IGF)家族(尤其是酪氨酸激酶IGFR家族)中一或多个成员(例如IGFR-1)(作为单一激酶抑制剂或作为多激酶抑制剂)和/或胰岛素受体途径的试剂,且可包括但不限于IGFR酪氨酸激酶抑制剂BMS-754807及OSI-906、以及抗-IGF(R)抗体芬妥木单抗(gitumumab)、西妥木单抗(cixutumumab)、达妥珠单抗(dalotuzumab)及罗妥木单抗(robatumumab)。
血管靶向剂(VTA)可包括但不限于血管损伤剂或阻断剂(例如5,6-二甲基呫吨酮-4-乙酸(DMXAA、vadimezan))、考布他汀(combretastatin)A4磷酸盐(Zybrestat))或考布他汀A4类似物(例如ombrabulin(AVE-8062))。
凝血酶敏感蛋白类似物可包括但不限于ABT-510。
基质金属蛋白酶(MMP)抑制剂可包括但不限于马立马司他(marimastat)。
PKC抑制剂为抑制蛋白激酶C(PKC)家族中一或多个成员的试剂(作为单一激酶抑制剂或作为多激酶抑制剂),且可包括但不限于enzastaurin、苔藓抑素(bryostatin)及米哚妥林(midostaurin)。
在一个实施方案中,本发明的细胞信号传导和/或血管生成抑制剂优选是指血管生成抑制剂,例如靶向VEGF或VEGFR的试剂。
优选的本发明的血管生成抑制剂可选自贝伐单抗(安维汀)、阿柏西普(VEGF-Trap)、凡德他尼、西地尼布、阿西替尼、索拉非尼、舒尼替尼、莫特塞尼、瓦他拉尼、帕唑帕尼、多韦替尼及BIBF 1120。
更优选的本发明的血管生成抑制剂为BIBF 1120。
在又一个实施方案中,本发明的细胞信号传导和/或血管生成抑制剂优选1是指细胞信号传导抑制剂,例如靶向EGFR的试剂。
优选的本发明的细胞信号传导抑制剂为BIBW-2992。
在一个实施方案(实施方案A)中,Aurora激酶抑制剂2的实例可见于WO2007/003596、WO 2007/122219、WO 2007/132010、WO 2008/077885、WO2008/152013、WO 2008/152014及WO 2010/012747,这些专利的全部公开内容以引用方式并入本文中。
在实施方案A的特定子实施方案中,Aurora激酶抑制剂2选自下表i中化合物(嘧啶或吲哚满酮(indolinone)衍生物)(化合物1至36),任选呈其互变异构体及药学上可接受的盐形式。
表i:AKI化合物编号1-36:
在另一个实施方案(实施方案B)中,Aurora激酶抑制剂2选自以下:Barasertib(AZD-1152)、AT-9283 1-环丙基-3-[3-(5-吗啉-4-基甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]脲(参见WO 2006/070195,实施例24)、MLN-8237 4-{[9-氯-7-(2-氟-6-甲氧基苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂-2-基]氨基}-2-甲氧基苯甲酸(参见WO 2008/063525,实施例1)、及AS703569/R763(1R,2R,3S,4S)-N4-(3-氨基羰基二环[2.2.1]庚-5-烯-2-基)-5-氟-N2-[(3-甲基-4-(4-甲基哌嗪-1-基)]苯基-2,4-嘧啶二胺(参见WO 2005/118544),任选呈其前药及其互变异构体及药学上可接受的盐形式。
本文所提及的Aurora激酶抑制剂、其制备方法及用途公开于本文所指出的文件中。因此,关于(例如)所述化合物或其盐的制备、调配或使用方法的细节参照相应文件。
根据本发明,细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如化合物1与2、或化合物3与2)可以以单一制剂或以两种分别制剂来给予。因此,在一个优选的实施方案中,本发明涉及药物组合物,其包含细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式)及Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式)。
在另一个优选的实施方案中,本发明涉及包含第一药物组合物及第二药物组合物的试剂盒,该第一药物组合物包含细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式),该第二药物组合物包含Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式)。
本发明进一步涉及细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式),其用于治疗肿瘤及纤维变性疾病的方法中,其中该方法还包括使用Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式)。
本发明进一步涉及Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式),其用于治疗肿瘤及纤维变性疾病的方法中,其中该方法还包括使用细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式)。
本发明进一步涉及细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式)的用途,其用于制备用于治疗肿瘤及纤维变性疾病的药物,其中该治疗还包含使用Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式)。
本发明进一步涉及Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式)的用途,其用于制备用于治疗肿瘤及纤维变性疾病的药物,其中该方法还包括使用细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式)。
本发明进一步涉及用于治疗肿瘤或纤维变性疾病的方法,其包括向需要该治疗的患者(尤其是人患者)给予治疗量的细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂,其各如本文所述。
在特定实施方案中,本发明的药物组合、组合物、方法及用途是指血管生成抑制剂(其为BIBF 1120)与Aurora激酶抑制剂(其选自表i中化合物1至36)的组合。
在另一特定实施方案中,本发明的药物组合、组合物、方法及用途是指细胞信号传导抑制剂(其为BIBW-2992)与Aurora激酶抑制剂(其选自表i中中化合物1至36)的组合。
在本发明的上下文中,化合物1任选以其互变异构体及药学上可接受的盐形式施用。药学上可接受的盐优选选自以下:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、甲磺酸盐、乙磺酸盐、硝酸盐、马来酸盐、乙酸盐、苯甲酸盐、柠檬酸盐、富马酸盐、酒石酸盐、乳酸盐、草酸盐、琥珀酸盐、苯甲酸盐及对-甲苯磺酸盐,优选为盐酸盐、氢溴酸盐、乙磺酸盐、硫酸盐、磷酸盐、马来酸盐、富马酸盐及甲磺酸盐。在尤其优选的实施方案中,化合物1以下所示的其乙磺酸盐形式(1a)施用。
在本发明的上下文中,尤其优选的式1a的盐任选亦是指式1化合物的单乙磺酸盐。本发明包括使用化合物1的盐的溶剂合物及水合物。
除非另有说明,本文所提及的激酶抑制剂包括特定地抑制一种激酶和/或一种激酶同种型的单一激酶抑制剂、或抑制两种或更多种激酶和/或两种或更多种激酶同种型的多激酶抑制剂(例如双重或三重激酶抑制剂或泛激酶的抑制剂)。
取决于所确诊疾病,若将至少一种本发明的活性成分(例如血管生成抑制剂1和/或Aurora激酶抑制剂2)与一或多种常用于相应疾病的其它活性物质(例如一或多种选自其它抗癌剂的活性物质,尤其是本文所提及的那些化学治疗剂)组合,则可获得改良的治疗结果。所述组合治疗可以以这些物质的自由组合形式或以固定组合形式(包括分部分的试剂盒(kit-of-parts))给出。组合治疗所需的组合组份的药物制剂可以以药物组合物形式购得或可由技术人员使用常用方法调配而成。
尽管本发明的重点涉及血管生成抑制剂与Aurora激酶抑制剂的组合(例如化合物1与化合物2的组合),然而本发明的活性成分(例如血管生成抑制剂和/或Aurora激酶的抑制剂)亦可成功联合一或多种其它化学治疗剂(例如erbB1受体(EGFR)及erbB2(Her2/neu)受体酪氨酸激酶抑制剂,尤其是BIBW-2992)给予。在特定实施方案中,1与2的组合与式3化合物(本文称为BIBW-2992)一起给予
任选呈其互变异构体及药学上可接受的盐形式。
式3化合物为erbB1受体(EGFR)及erbB2(Her2/neu)受体酪氨酸激酶的有效及选择性双重抑制剂。此外,3经设计以共价方式结合至EGFR及HER2,因此使其已结合的受体分子不可逆地失活。此化合物3、其盐(例如马来酸氢盐)、其制备以及包含3或其盐的药物制剂、拟用3治疗的适应症及包括的3组合公开于WO 02/50043、WO 2005/037824、WO 2007/054550及WO2007/054551中。
其它可与本发明的活性成分(血管生成抑制剂和/或Aurora激酶的抑制剂)联合给予的化学治疗剂可选自下列:
(i)烷基化或氨基甲酰化试剂,例如氮芥类(具有双-(2-氯乙基)基团),例如环磷酰胺(CTX,例如癌得星(Cytoxan)、癌得散(Cyclostin)、安道生(Endoxan))、苯丁酸氮芥(chlorambucil)(CHL,例如瘤可宁(Leukeran))、异环磷酰胺(例如和乐生(Holoxan))或美法仑(melphalan)(例如爱克兰(Alkeran));烷基磺酸酯类,例如白消安(busulphan)(例如马利兰(Myleran))、mannosulphan或曲奥舒凡(treosulphan);亚硝基脲类,例如链脲菌素(streptozocin)(例如链佐星(Zanosar))或氯乙基亚硝基脲类CENU(例如卡莫司汀(carmustine)BCNU或洛莫司汀(lomustine)CCNU);肼类,例如丙卡巴肼(procarbazine);三氮烯类/咪唑并四嗪类,例如氨烯咪胺(decarbazine)或替莫唑胺(temozolomide)(例如泰道(Temodar));或乙烯亚胺类/氮丙啶类/甲基蜜胺类,例如丝裂霉素C(mitomycin C)、塞替派(thiotepa)或六甲蜜胺(altretamine)等等;
(ii)铂衍生物,例如顺铂(cisplatin)(CisP,例如铂帝尔(Platinex)、普拉汀诺(Platinol))、奥沙利铂(oxaliplatin)(例如乐沙定(Eloxatin))、沙铂(satraplatin)或卡波铂(carboplatin)(例如卡铂(Carboplat))等等;
(iii)抗代谢药,例如叶酸拮抗剂,例如甲氨喋呤(methotrexate)(MTX,例如法米喋呤(Farmitrexat))、雷替曲塞(raltitrexed)(例如拓优得(Tomudex))、依达曲沙(edatrexate)或培美曲塞(pemetrexed)(例如力比泰(Alimta));嘌呤拮抗剂,例如6-巯嘌呤(6MP,例如乐疾宁(Puri-Nethol))、6-硫鸟嘌呤、喷司他丁(pentostatin)、克拉屈滨(cladribine)、克罗拉滨(clofarabine)或氟达拉滨(fludarabine)(例如福达华(Fludara));或嘧啶拮抗剂,例如阿糖胞苷(cytarabine)(Ara-C,例如爱力生(Alexan)、赛得萨(Cytosar))、氟尿苷(floxuridine)、5-氟尿嘧啶(5-FU)(单独或与甲酰四氢叶酸(leucovorin)组合)、替加氟(tegafur)、5-氮胞苷(例如阿扎胞苷(Vidaza))、卡培他滨(capecitabine)(例如希罗达(Xeloda))、地西他滨(decitabine)(例如达克金(Dacogen))或吉西他滨(gemcitabine)(例如健择(Gemzar))等等;
(iv)抗肿瘤/细胞毒性抗生素类,例如蒽环类,例如柔红霉素(daunorubicin)(包括其盐酸盐)(包括脂质体制剂)、多柔比星(doxorubicin)(包括其盐酸盐及柠檬酸盐)(例如阿霉素(Adriblastin)、亚德里亚霉素(Adriamycin),包括脂质体制剂,例如多喜(Doxil)或楷莱(Caelyx))、表柔比星(epirubicin)或伊达比星(idarubicin)(包括其盐酸盐)(例如去甲氧柔红霉素(Idamycin));蒽二酮类,例如米托蒽醌(mitoxantrone)(例如诺消灵(Novantrone));或链霉菌属,例如博来霉素(bleomycin)、丝裂霉素或放线菌素D(actinomycin D)/更生霉素(dactinomycin)等等;
(v)拓扑异构酶(包括I型及II型)抑制剂,例如喜树碱(camptothecin)及喜树碱类似物,例如伊立替康(irinotecan)(例如坎普土沙(Camptosar))(包括其盐酸盐)、托泊替康(topotecan)(例如和美新(Hycamtin))、卢比替康(rubitecan)或二氟替康(diflomotecan);表鬼臼毒素(epipodophyllotoxin),例如依托泊苷(etoposide)(例如凡毕复(Etopophos))或替尼泊苷(teniposide);蒽环类(参见上文)、米托蒽醌、洛索蒽醌(losoxantrone)或放线菌素D;或氨萘非特(amonafide)等等;
(vi)微管干扰剂,例如长春花生物碱类(vinca alkaloids),例如长春碱(vinblastine)(包括其硫酸盐)、长春新碱(vincristine)(包括其硫酸盐)、长春地辛(vindesine)或长春瑞滨(vinorelbine)(包括其酒石酸盐);紫杉烷类(类紫杉醇),例如多西紫杉醇(docetaxel)(例如泰索帝(Taxotere))、紫杉醇(例如泰素(Taxol))或其类似物、衍生物或缀合物(例如莱龙太素(larotaxel));或埃博霉素类(epothilones),例如埃博霉素B(帕土匹龙(patupilone))、氮杂埃博霉素(伊沙匹隆(ixabepilone))、ZK-EPO(沙戈匹隆(sagopilone))或KOS-1584或其类似物、衍生物或缀合物等等;
(vii)激素治疗药物,例如抗雄激素类,例如氟他胺(flutamide)、尼鲁米特(nilutamide)或比卡鲁胺(bicalutamide)(康士得(casodex));抗雌激素类,例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)或氟维司群(fulvestrant);LHRH激动剂,例如戈舍瑞林(goserelin)、亮丙瑞林(leuprolide)、布舍瑞林(buserelin)或曲普瑞林(triptorelin);GnRH拮抗剂,例如阿巴瑞克(abarelix)或地盖瑞利(degarelix);芳香酶抑制剂,例如类固醇(例如依西美坦(exemestane)或福美坦(formestane))或非类固醇(例如来曲唑(letrozole)、法倔唑(fadrozole)或阿那曲唑(anastrozole))。
本发明的治疗组合或组合治疗可进一步涉及或包含手术和/或放射疗法。
本发明的组合治疗在肿瘤疾病的治疗中尤其令人感兴趣。
优选,该疾病选自实体肿瘤,例如泌尿生殖器癌症(例如前列腺癌、肾细胞癌、膀胱癌)、妇科癌症(例如卵巢癌、宫颈癌、子宫内膜癌)、肺癌、胃肠癌(例如非转移性或转移性结肠直肠癌、胰腺癌、胃癌、食道癌、肝细胞癌、胆管细胞癌)、头颈癌(例如头颈鳞状上皮细胞癌)、恶性胶质母细胞瘤、恶性间皮细胞瘤、非转移性或转移性乳腺癌(例如激素顽固性转移性乳腺癌)、恶性黑色素瘤或骨与软组织肉瘤;及血液瘤,例如多发性骨髓瘤、急性髓细胞性白血病、慢性髓细胞性白血病、骨髓增生异常综合征及急性成淋巴细胞性白血病。在优选的实施方案中,该疾病为非小细胞肺癌(NSCLC)、乳腺癌(例如激素顽固性转移性乳腺癌)、头颈癌(例如头颈鳞状上皮细胞癌)、恶性胶质母细胞瘤、转移性结肠直肠癌、激素敏感性或激素顽固性前列腺癌、结肠直肠癌、卵巢癌、肝细胞癌、肾细胞癌、软组织肉瘤或小细胞肺癌。
此外,可用本发明的组合治疗以下癌症疾病(但不限于以下):脑肿瘤例如听神经鞘瘤,星形细胞瘤例如毛细胞性星形细胞瘤、纤维性星形细胞瘤、原浆性星形细胞瘤、饲肥星形细胞瘤、退行性星形细胞瘤及成胶质细胞瘤,脑淋巴瘤,脑转移,垂体性肿瘤例如催乳素瘤、产生HGH(人生长激素)的肿瘤及产生ACTH(促肾上腺皮质激素)的肿瘤,颅咽管瘤,成神经管细胞瘤,脑膜瘤及少突神经胶质瘤;神经肿瘤(赘生物),例如植物神经系统肿瘤例如交感神经系统神经母细胞瘤(neuroblastoma sympathicum)、神经节瘤、神经节细胞瘤(嗜铬细胞瘤及副神经节瘤)及颈动脉球瘤,末梢神经系统肿瘤例如截肢性神经瘤、神经纤维瘤、神经细胞瘤(neurinoma)(神经鞘瘤(neurilemmoma)、许旺氏细胞瘤(Schwannoma))及恶性许旺氏细胞瘤,以及中枢神经系统肿瘤例如脑和脊髓肿瘤;肠癌例如直肠癌、结肠癌、肛门癌、小肠肿瘤及十二指肠肿瘤;眼睑肿瘤例如基底细胞癌或基细胞癌;胰腺癌(pancreatic gland cancer或pancreatic carcinoma);膀胱癌(bladder cancer或bladder carcinoma);肺癌(支气管癌)例如小细胞支气管癌(燕麦细胞癌)及非小细胞支气管癌例如鳞状上皮癌、腺癌及大细胞支气管癌;乳腺癌(breast cancer)例如乳腺肿瘤(mammarycarcinoma),例如浸润性管癌、胶样癌、浸润性小叶癌、管状癌、腺样囊性癌、及乳头状癌;非霍奇金氏淋巴瘤(NHL)例如伯基特氏(Burkitt’s)淋巴瘤、低度恶性非霍奇金氏淋巴瘤(NHL)及蕈样肉芽肿(mucosis fungoides);子宫癌或子宫内膜癌或子宫体癌;CUP综合征(未知原发性癌症);卵巢癌(ovarian cancer或ovarian carcinoma)例如黏液样癌、子宫内膜癌或浆液性癌;胆囊癌;胆管癌例如克拉斯汀氏瘤(Klatskin’s tumour);睾丸癌例如精原细胞瘤及非精原细胞瘤;淋巴瘤(淋巴肉瘤)例如恶性淋巴瘤,霍奇金氏病(Hodgkin’s disease),非霍奇金氏淋巴瘤(NHL)例如慢性淋巴性白血病,毛细胞白血病、免疫细胞瘤、浆细胞瘤(多发性骨髓瘤)、免疫母细胞瘤,伯基特氏淋巴瘤、T-区蕈样真菌病、大细胞退形性成淋巴细胞瘤及淋巴母细胞瘤;喉癌,例如声带肿瘤、声门上、声门及声门下喉肿瘤;骨癌,例如骨软骨瘤、软骨瘤、软骨母细胞瘤、软骨黏液样纤维瘤、骨瘤、骨样骨瘤、骨母细胞瘤、嗜酸细胞性肉芽肿、巨细胞肿瘤、软骨肉瘤、骨肉瘤、尤因氏肉瘤(Ewing's sarcoma)、网状细胞肉瘤、浆细胞瘤、纤维性发育不良、青少年骨囊肿及动脉瘤性骨囊肿;头/颈肿瘤,例如唇、舌、口腔底、口腔、齿龈、上颚、唾液腺、咽、鼻腔、鼻窦、喉及中耳的肿瘤;肝癌,例如肝细胞癌(liver cell carcinoma或hepatocellular carcinoma(HCC));白血病,例如急性白血病例如急性淋巴性/淋巴母细胞性白血病(ALL)、急性髓性白血病(AML);慢性白血病,例如慢性淋巴性白血病(CLL)、慢性髓性白血病(CML);胃癌(stomach cancer或stomach carcinoma),例如乳头状、管状及黏液腺癌、印戒细胞癌、腺样鳞状上皮细胞癌、小细胞癌及未分化癌;黑素瘤,例如表浅扩散性黑素瘤、结节性恶性雀斑黑素瘤及肢端着色斑性黑素瘤;肾癌,例如肾细胞癌或肾上腺样瘤或格拉维茨氏肿瘤(Grawitz'stumour);食道癌(oesophageal cancer或oesophageal carcinoma);阴茎癌;前列腺癌;咽癌(pharyngeal cancer或pharyngeal carcinomas),例如鼻咽癌、口咽癌及喉咽癌;视网膜母细胞瘤;阴道癌(vaginal cancer或vaginal carcinoma);鳞状上皮癌,腺癌,原位癌,恶性黑素瘤及肉瘤;甲状腺癌,例如乳头状、滤泡性及髓性甲状腺癌,以及退形性癌症;脊髓瘤、皮肤的棘细胞癌及鳞状上皮癌;胸腺瘤,尿道癌及外阴癌。
在另一个实施方案中,本发明的组合可用于预防或治疗选自以下的具体纤维变性疾病:慢性阻塞性肺病(COPD)、慢性支气管炎及肺气肿中的肺组织纤维化及重塑;具有纤维变性成分的肺纤维化及肺疾病,包括但不限于特发性肺纤维化(IPF)、巨细胞间质性肺炎(GIP)、肉样瘤病(sarcodosis)、囊性纤维化、呼吸性窘迫综合征(ARDS)、肉芽肿病、硅肺、药物诱导的肺纤维化(例如,由诸如博来霉素、双-氯亚硝基脲、环磷酰胺、胺碘酮(amiodarone)、普鲁卡因胺(procainamide)、青霉胺(penicillamine)、金或呋喃妥因(gold ornitrofurantoin)等药物诱导的)、硅肺、石棉肺、全身性硬皮病;哮喘中的纤维化及重塑;类风湿性关节炎中的纤维化;病毒诱导的肝硬化(例如丙型肝炎);辐射诱导的纤维化;血管成形术后再狭窄;肾病症,包括慢性肾小球肾炎、接受环孢菌素的患者的肾纤维化及因高血压引起的肾纤维化;具有纤维变性成分的皮肤疾病,包括但不限于硬皮病、肉样瘤病、全身性红斑狼疮;过度瘢痕。在一个实施方案中,该疾病为特发性肺纤维化(IPF)。
适于本发明的组合治疗的特定疾病为肺癌(例如非小细胞肺癌(NSCLC))。
可改变本发明的组合及组合物中活性成分的剂量,但活性成分(尤其是活性成分1与2或3与2)的量应使得可获得适宜剂型。因此,所选剂量及所选剂型应视期望的治疗效果、给予途径及治疗持续时间而定。适用于组合的剂量范围是对单一试剂的最大耐受剂量至较低剂量,例如至最大耐受剂量的十分之一。
优选,为实施本发明药物疗法,每天一次或数次给予5mg至1000mg之间、尤其优选10mg至500mg式1化合物。尤其优选,每天一次或两次、优选每天两次给予25mg至300mg、更优选50mg至200mg化合物1。
静脉内使用的化合物2(尤其是实施方案A中者)的剂量为1mg/小时至1000mg/小时、优选为5mg/小时至500mg/小时之间。然而,取决于体重、给予途径、个体对药物的反应、其制剂的性质及药物给予时间或间隔而定,有时可能需要偏离指定量。因此,在一些情形下,使用低于上文给出的最低剂量可能已足矣,而在其它情形下可能不得不超出上限。当大量给予时,可适当地将其分成许多较小剂量在一天中不同时间给予。
上述剂量基于化合物1及2的游离碱。若化合物1及2以其药学上可接受的盐形式施用,则技术人员可容易地计算适当盐的量。
对于本发明的组合疗法而言,细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如组份1与2、或组份3与2)可分别给予(此暗示它们分别配制)或一起给予(此暗示它们一起配制)。因此,本发明的组合中的一种成分可在该组合中另一成分给予之前、与其同时或在其之后给予。优选,细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如组份1与2、或组份3与2)以不同制剂给予。
如上文所提及,本发明涉及包含细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式)以及Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式)的药物组合或组合物。因此,除非在本专利申请案通篇公开内容中另有说明,否则提及细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂的组合(例如1与2的组合或3与2的组合)时欲理解为提及细胞信号传导和/或血管生成抑制剂(例如化合物1或3,其各任选呈其互变异构体及药学上可接受的盐形式)与Aurora激酶抑制剂(例如化合物2,任选呈其互变异构体及药学上可接受的盐形式)的组合。
细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂的组合(例如1与2的组合或3与2的组合)中的成分可通过口服(包括口含或舌下)、经肠、非经肠(例如,肌内、腹膜内、静脉内、经皮或皮下注射或植入)、经鼻、经阴道、经直肠或局部(例如眼部用滴眼剂)给予途径给予,且可在含有适于各给予途径的常用药学上可接受的无毒载体、佐剂及媒剂的适宜剂量单元制剂中分别地或一起调配。
在优选的实施方案中,细胞信号传导和/或血管生成抑制剂(例如本发明的组合中的成分1或3)通过口服、经肠、经皮、经静脉内、经腹膜或通过注射给予,优选口服给予。在另一个优选的实施方案中,Aurora激酶抑制剂(例如组合中的组份2)亦优选口服给予。在又一个优选的实施方案中,Aurora激酶抑制剂(例如组合中的组份2)优选经静脉内给予(例如从推注到长时间输注),优选通过输注给予。
亦涵盖连续给予,例如通过(例如)输注泵、输注袋或输注容器(其可任选为植入式或可携式)静脉内输注包含一或多种活性试剂的用于输注的(液体)溶液或悬浮液。
用于给予细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如本发明的组份1与2或组份3与2)的药物组合物可方便地以剂量单元形式存在,且可通过制药领域熟知的任一方法进行制备。所有方法均包括使活性成分与由一或多种辅助成分组成的载体结合的步骤。一般而言,这些药物组合物可通过使活性成分与液体载体或精细分割的固体载体或两者均匀且紧密地结合、且然后(若必要)使该产物成形为期望剂型来制备。活性化合物以足以产生期望药理效果的量纳入药物组合物中。
适于口服给予的含有细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如活性成分1与2或活性成分3与2)的药物组合物可分别地或一起呈离散单元形式,例如硬或软胶囊、片剂、含片或锭剂,其各含有预定量的活性成分,或呈可分散粉末或颗粒形式,或呈存于水性液体或非水性液体中的溶液或悬浮液形式,或呈糖浆或酏剂形式,或呈水包油乳液或油包水乳液形式。
意欲口服使用的剂型可根据制备药物制剂及这些组合物的领域已知的任一方法来制备。
所用赋形剂可为(例如):(a)惰性稀释剂;(b)成粒剂及崩解剂;(c)黏合剂;及(d)润滑剂。
在一些情形下,口服使用的制剂可呈硬明胶或HPMC(羟丙甲基纤维素)胶囊形式,其中细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如活性成分1或2或活性成分3与2)分别地或一起与惰性固体稀释剂混合,或通过小药丸(pellet)制剂分配。其亦可呈软明胶胶囊形式,其中该活性成分与水或油介质混合。
这些片剂、胶囊或微粒可无包衣或其可通过已知技术包衣(例如)以延迟在胃肠道中的崩解及吸收,并由此提供较长时间段的延迟作用或持续作用。举例而言,可使用普通片剂包衣材料或延时材料或持续释放材料。片剂亦可包含若干层。
口服给予的本发明的液体剂型包括含有本领域内常用的惰性稀释剂(例如水)的药学上可接受的乳液、溶液、悬浮液、糖浆及酏剂。除这些惰性稀释剂以外,组合物亦可包括佐剂,例如,润湿剂、乳化剂、增稠剂及助悬剂、及甜味剂、矫味剂、芳香剂及防腐剂。
本发明水性悬浮液通常分别地或一起含有细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如活性材料1与2或活性材料3与2)以及适于制备水性悬浮液的赋形剂。这些赋形剂可为(a)助悬剂;(b)分散剂或润湿剂,其可为(b.1)天然存在的磷脂、(b.2)烯烃氧化物与脂肪酸的缩合产物、(b.3)环氧乙烷与长链脂肪醇的缩合产物、(b.4)环氧乙烷与衍生自脂肪酸与己糖醇的偏酯的缩合产物、或(b.5)环氧乙烷与衍生自脂肪酸与己糖醇酐的偏酯的缩合产物。
水性悬浮液亦可含有:一或多种防腐剂;一或多种着色剂;一或多种矫味剂;及一或多种甜味剂。
本发明的油性悬浮液可通过将细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如活性成分1与2或活性成分3与2)分别地或一起悬浮于植物油中进行调配。油性悬浮液可含有增稠剂。可添加甜味剂及矫味剂以提供可口的口服制剂。这些组合物可通过添加抗氧化剂来制备。
可分散粉末及颗粒是用于制备本发明水性悬浮液的适宜制剂。在这些制剂中,细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如活性成分1与2或活性成分3与2)分别地或一起以与分散剂或润湿剂、助悬剂及一或多种防腐剂的混合物的形式存在。分散剂或润湿剂、助悬剂及防腐剂的适宜实施例如上文所提及。亦可存在其它赋形剂,例如甜味剂、矫味剂及着色剂。赋形剂的适宜实施例如上文所提及。
本发明药物组合物亦可呈水包油乳液形式。油性相可为植物油或矿物油或其混合物。
适宜的乳化剂可为(a)天然存在的树胶、(b)天然存在的磷脂、(c)衍生自脂肪酸与己糖醇酐的酯或偏酯、(d)这些偏酯与环氧乙烷的缩合产物。乳液亦可含有甜味剂及矫味剂。
本发明糖浆及酏剂可用甜味剂调配。这些制剂亦可含有防腐剂及矫味剂及着色剂。
用于非经肠给予的分别地或一起含有细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如1与2或3与2)的本发明制剂包括无菌水性、半水性、非水性、油性或混合溶剂系统、注射或输注溶液、悬浮液或乳液。
含有细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如1与2或3与2)的药物组合物可分别地或一起呈以下形式:无菌等渗水性或半水性注射或输注溶液或悬浮液、或用于拟在使用前制备(例如通过用等渗水性介质稀释)的这些溶液或悬浮液的浓缩物或冻干物。
含有细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如1与2或3与2)的药物组合物可分别地或一起呈无菌可注射或可输注的水性或油质悬浮液或溶液形式。该悬浮液可根据习知方法使用那些上文已提及的适宜分散剂或润湿剂及助悬剂来调配。适宜的无菌可注射或可输注制剂亦可为存于无毒的非经肠-可接受的稀释剂或溶剂中的无菌可注射或可输注溶液或悬浮液。可使用的可接受的媒剂及溶剂的实施例为水、葡萄糖溶液、林格氏溶液(Ringer's solution)以及等渗氯化钠溶液。另外,通常可使用无菌的不挥发性油作为溶剂或悬浮介质。就此目的而言,可使用任一温和的不挥发性油,包括合成甘油单酯或甘油二酯。另外,脂肪酸可用于制备可注射制剂或可输注制剂。本发明这些制剂中所包含的非水性溶剂或媒剂可包括(例如)丙二醇、聚乙二醇、单-或多官能基醇、植物油、或可注射或可输注有机酯。这些剂型亦可含有佐剂,例如防腐剂、润湿剂、乳化剂、分散剂或pH调节剂。
其可通过(例如)以下方式来灭菌:藉助细菌截留过滤器过滤,将灭菌剂纳入组合物中,辐照组合物,或加热组合物。其亦可以无菌固体组合物形式制备,该无菌固体组合物可在使用前立即在无菌水或一些其它无菌可注射或可输注介质中重新构成。
用于注射及输注的溶液以常用方式制备,例如通过添加一或多种适宜的水性和/或非水性溶剂(例如等渗剂)并任选添加防腐剂、稳定剂、乳化剂、分散剂和/或pH调节剂,而若使用例如水作为稀释剂,则可任选使用有机溶剂作为溶剂化试剂或溶解助剂,并将其转移至注射小瓶或安瓿瓶或输注瓶中。举例而言,可藉助包含添加一或多种适宜有机溶剂(例如单-或多官能基醇、聚丙二醇或聚乙二醇)及pH调节剂的工艺来制备用于输注溶液的有机浓缩物,可任选将其冻干。在施用至患者之前,用适当输注溶液(例如5%葡萄糖水溶液)稀释该有机浓缩物以提供可应用形式。
细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如本发明的组合中的成分1与2或成分3与2)亦可以用于直肠给予的栓剂形式给予。这些组合物可通过将活性成分与适宜的非刺激性赋形剂混合来制备,该赋形剂在常温为固体但在直肠温度为液体且因此将在直肠中融化以释放活性成分。
用于口含、鼻或舌下给予的本发明的组合物可由本领域内熟知的标准赋形剂来制备。
对于局部给予而言,细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(例如本发明的组合中要素1与2或要素3与2)可分别地或一起调配于液体或半液体制剂中。适宜制剂的实施例为:搽剂、洗剂、敷剂;水包油或油包水乳液,例如霜剂、软膏剂、凝胶剂或糊剂(包括牙膏);溶液或悬浮液,例如滴剂。
在优选的实施方案中,活性成分1或其药学上可接受的盐经调配呈包含胶囊壳及胶囊调配物的胶囊(例如硬明胶或羟丙甲基纤维素(HPMC)胶囊)形式,其中胶囊调配物包含活性成分1或其药学上可接受的盐的悬浮液、优选为包含载体及增稠剂的黏稠悬浮液、更优选为载体为脂质(亲脂性)载体的粘稠悬浮液。
本发明的范围并不受本文所述具体实施方案限制。除那些本文所述的以外,本领域技术人员自本发明公开内容可了解本发明的各种修改。这些修改意欲属于随附申请专利范围。
本文所引用的所有专利申请案的全文皆以引用方式并入本文中。
自以下实施例可了解本发明的其它实施方案、特征及优点。以下实施例以举例方式用来阐释本发明的原理而非对其加以限制。
实验部分
A)包含1的剂型的优选的实施例:
下表显示1的药物组合物。
所有实施例中的活性物质皆为3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧基羰基-2-吲哚满酮-单乙磺酸盐。
实施例1
含有50mg活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成分 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成分 | 60.20 | 60.20 | 60.20 |
中链甘油三酯 | 载体 | 40.95 | 53.70 | 54.00 |
硬脂 | 增稠剂 | 38.25 | 25.50 | 25.50 |
卵磷脂 | 湿润剂/助流剂 | 0.60 | 0.60 | 0.30 |
明胶 | 成膜剂 | 72.25 | 72.25 | 72.25 |
85%甘油 | 增塑剂 | 32.24 | 32.24 | 32.24 |
二氧化钛 | 着色剂 | 0.20 | 0.20 | 0.20 |
氧化铁A | 着色剂 | 0.32 | 0.32 | 0.32 |
氧化铁B | 着色剂 | 0.32 | 0.32 | 0.32 |
胶囊总重量 | 245.33 | 245.33 | 245.33 |
*该符号是指等效于标示量游离碱的乙磺酸盐的量(以干重计)
实施例1a
含有75mg活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成分 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成分 | 90.3 | 90.3 | 90.3 |
中链甘油三酯 | 载体 | 61.425 | 80.55 | 80.1 |
硬脂 | 增稠剂 | 57.375 | 38.25 | 38.25 |
卵磷脂 | 湿润剂/助流剂 | 0.9 | 0.9 | 1.35 |
明胶 | 成膜剂 | 107.11 | 107.11 | 107.11 |
85%甘油 | 增塑剂 | 46.84 | 46.84 | 46.84 |
二氧化钛 | 着色剂 | 0.35 | 0.35 | 0.35 |
氧化铁A | 着色剂 | 0.058 | 0.058 | 0.058 |
氧化铁B | 着色剂 | 0.16 | 0.16 | 0.16 |
胶囊总重量 | 364.518 | 364.518 | 364.518 |
* 该符号是指等效于标示量游离碱的乙磺酸盐的量(以干重计)
实施例2
含有100mg活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成分 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成分 | 120.40 | 120.40 | 120.40 |
中链甘油三酯 | 载体 | 81.90 | 107.40 | 106.8 |
硬脂 | 增稠剂 | 76.50 | 51.00 | 51.00 |
卵磷脂 | 湿润剂/助流剂 | 1.20 | 1.20 | 1.80 |
明胶 | 成膜剂 | 111.58 | 111.58 | 111.58 |
85%甘油 | 增塑剂 | 48.79 | 48.79 | 48.79 |
二氧化钛 | 着色剂 | 0.36 | 0.36 | 0.36 |
氧化铁A | 着色剂 | 0.06 | 0.06 | 0.06 |
氧化铁B | 着色剂 | 0.17 | 0.17 | 0.17 |
胶囊总重量 | 440.96 | 440.96 | 440.96 |
* 该符号是指等效于标示量游离碱的乙磺酸盐的量(以干重计)
实施例3
含有125mg活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成分 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成分 | 150.50 | 150.50 | 150.50 |
中链甘油三酯 | 载体 | 102.375 | 134.25 | 133.5 |
硬脂 | 增稠剂 | 95.625 | 63.75 | 63.75 |
卵磷脂 | 湿润剂/助流剂 | 1.50 | 1.50 | 2.25 |
明胶 | 成膜剂 | 142.82 | 142.82 | 142.82 |
85%甘油 | 增塑剂 | 62.45 | 62.45 | 62.45 |
二氧化钛 | 着色剂 | 0.47 | 0.47 | 0.47 |
氧化铁A | 着色剂 | 0.08 | 0.08 | 0.08 |
氧化铁B | 着色剂 | 0.22 | 0.22 | 0.22 |
胶囊总重量 | 556.04 | 556.04 | 556.04 |
* 该符号是指等效于标示量游离碱的乙磺酸盐的量(以干重计)
实施例4
含有150mg活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成分 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成分 | 180.60 | 180.60 | 180.60 |
中链甘油三酯 | 载体 | 122.85 | 161.10 | 160.20 |
硬脂 | 增稠剂 | 114.75 | 76.50 | 76.50 |
卵磷脂 | 湿润剂/助流剂 | 1.80 | 1.80 | 2.70 |
明胶 | 成膜剂 | 142.82 | 142.82 | 142.82 |
85%甘油 | 增塑剂 | 62.45 | 62.45 | 62.45 |
二氧化钛 | 着色剂 | 0.47 | 0.47 | 0.47 |
氧化铁A | 着色剂 | 0.08 | 0.08 | 0.08 |
氧化铁B | 着色剂 | 0.22 | 0.22 | 0.22 |
胶囊总重量 | 626.04 | 626.04 | 626.04 |
* 该符号是指等效于标示量游离碱的乙磺酸盐的量(以干重计)
实施例5
含有200mg活性物质的软明胶胶囊
制剂A | 制剂B | 制剂C | ||
成分 | 功能 | mg/胶囊 | mg/胶囊 | mg/胶囊 |
活性物质* | 活性成分 | 240.80 | 240.80 | 240.80 |
中链甘油三酯 | 载体 | 163.30 | 214.80 | 216.00 |
硬脂 | 增稠剂 | 153.50 | 102.00 | 102.00 |
卵磷脂 | 湿润剂/助流剂 | 2.40 | 2.40 | 1.20 |
明胶 | 成膜剂 | 203.19 | 203.19 | 203.19 |
85%甘油 | 增塑剂 | 102.61 | 102.61 | 102.61 |
二氧化钛 | 着色剂 | 0.57 | 0.57 | 0.57 |
氧化铁A | 着色剂 | 0.90 | 0.90 | 0.90 |
氧化铁B | 着色剂 | 0.90 | 0.90 | 0.90 |
胶囊总重量 | 868.17 | 868.17 | 868.17 |
* 该符号是指等效于标示量游离碱的乙磺酸盐的量(以干重计)
实施例6
下表显示本发明的其它药物组合物。D、E及F为片剂,可在加热/冷却式高剪切混合器中将活性物质与微晶纤维素和聚乙二醇6000一起热熔造粒后将G压缩以形成片剂。在所获得颗粒与其它赋形剂的进一步混合步骤后,在常用压片机上制备片剂。或者,可直接以口服颗粒形式分散于小袋中。
片剂D及F可通过直接掺和组份且随后在常用压片机上压缩来制备。或者,可将其挤制成小药丸并填充于硬胶囊中。
片剂E可通过以下方式来制备:将药物与乳糖一水合物及微晶纤维素一起经共聚维酮水溶液湿法造粒。在与交联聚维酮、胶体二氧化硅及硬脂酸镁的进一步掺和步骤后,在常用压片机上压缩片剂。
制剂 | D | E | F | G | H | I |
活性物质* | 180.6mg | 150.5mg | 120.4mg | 150.5mg | 60.2mg | 60.2mg |
山梨醇 | - | - | - | - | - | 125.0mg |
乳糖一水合物 | 50.0mg | 125.0mg | - | - | - | - |
微晶纤维素 | - | 20.0mg | 150.0mg | 80.0mg | - | 20.0mg |
磷酸钙 | 30.0mg | - | 150.0mg | - | - | - |
大豆油 | - | - | - | - | 145.0mg | - |
聚乙二醇6000 | - | - | - | 80.0mg | - | - |
共聚维酮 | 2.0mg | 10.0mg | - | - | - | - |
淀粉羟乙酸钠 | 5.0mg | - | - | - | - | - |
交联聚维酮 | - | 5.0mg | 5.0mg | - | - | 5.0mg |
Cremophor RH 40 | - | - | - | - | 20.0mg | - |
胶体二氧化硅 | 1.0mg | 1.0mg | 1.0mg | - | 10.0mg | 1.0mg |
固体调味剂 | - | - | - | 5.0mg | - | 4.0mg |
硬脂酸镁 | 4.0mg | 4.0mg | 4.0mg | - | - | - |
总计 | 272.6mg | 315.5mg | 430.4mg | 315.5mg | 235.2mg | 215.2mg |
* 该符号是指乙磺酸盐1a的量
制剂H是制成悬浮活性物的液体填充混合物(fillmix)。在均质化后,将其填充于硬或软明胶胶囊中。制剂I为口服粉剂。
B)Aurora激酶抑制剂的体外研究结果:
化合物X(本发明表i中的Aurora B激酶的强效抑制剂(IC50=9nM))阻断多种人癌细胞系增殖(EC50=2-14nM)并诱导多倍性、衰老及细胞凋亡。
方法.在酶的激酶分析中以及在对多种人癌细胞系的增殖分析中评估化合物X。通过DNA含量分析(Cellomics ArrayScan,FACScalibur)来评估细胞周期状态。通过免疫荧光(Cellomics ArrayScan)来测定组蛋白H3磷酸化。通过对解离的PARP的蛋白质印迹法及显示细胞核片段的DAPI染色细胞的显微镜计数来检测细胞凋亡。通过SA-β-Gal活性的染色来识别衰老细胞。
结果.化合物X抑制人Aurora B激酶活性(其中IC50值为9nM)、Aurora A及C激酶(其中IC50值分别为70nM及17nM)。在代表人激酶组的46种其它激酶的一组调查对象中,化合物X在1000nM对7/46的激酶抑制超过50%。大于20种人癌细胞系增殖抑制的EC50值在2nM至14nM范围内。在非小细胞肺癌细胞系NCI-H460中,用化合物X处理导致快速(<1小时)抑制组蛋白H3磷酸化。在治疗48小时内,多倍体细胞的分数自<5%增加至>80%,伴随细胞体积显著增加。在治疗72小时及96小时后,观察到解离的聚(ADP-核糖)聚合酶增加且具有细胞核片段的细胞的分数随之自<1%增加至7%。在96小时内观察到群体中衰老细胞自<3%显著增加至25%。
C)Aurora激酶抑制剂的体内研究结果:
化合物X(本发明表i中的Aurora B激酶的抑制剂)在多个癌症模型中在良好耐受剂量下显示强效抗肿瘤活性;经处理的肿瘤显示Aurora B抑制作用的特征。与推注式给予相比,经24小时连续输注提供优异的治疗指数。
方法.将NCI-H460非小细胞肺癌(突变体KRAS,野生型p53)、HCT 116结肠癌(突变体KRAS,野生型p53)或BxPC-3胰腺腺癌细胞(野生型KRAS,突变体p53)经皮下移植到BomTac:NMRI-Foxn1nu小鼠。当肿瘤达到约50mm3体积时开始治疗。每周1次或2次以单次推注形式注射或每日2次经静脉内注射BI 811283,或者,经皮下植入渗透性迷你泵,通过每周1次连续24小时输注给予该化合物。对多个剂量水平及给药方案进行评价。
结果.在人非小细胞肺癌、结肠癌及胰腺癌模型中,以20mg/kg至75mg/kg的每周总剂量使用化合物X治疗多个周期可达成肿瘤生长的剂量依赖性抑制或肿瘤衰退。每周1次经24小时以20mg/kg连续皮下输注,明显优于所有每周递送剂量高达75mg/kg的推注式注射方案。此外,在HCT 116结肠癌模型中诱导大肿瘤(350mm3)衰退。HCT 116肿瘤的生物标记分析表明治疗剂量的化合物X抑制组蛋白H3(Aurora B的直接底物)磷酸化。组织学检测显示变大的多核细胞的累积与预期作用机制一致。
剂量及方案依赖性:
化合物X在AML癌症模型中也是强效的(THP-1,其中T/C值为7%及MV-4-11,其中T/C值为5%)。
D)肺癌模型中临床前体内研究结果:
为分析通过干扰VEGFR信号传导级联抑制肿瘤血管生成与抑制Aurora激酶B的抗肿瘤活性的组合抗肿瘤效果,进行以下体内实验。将携带已建立的皮下Calu-6异种移植物(人NSCLC肿瘤细胞系)的裸小鼠随机分组,并用本发明Aurora B激酶抑制剂化合物X或BIBF 1120分别进行治疗或使用该两种药物的组合进行治疗。结束治疗后,经治疗的对照小鼠的肿瘤(图1中带有圆形的线)平均体积为约1100mm3。图1的结果显示,与分别使用化合物X(图1中带有三角形的线)及使用BIBF 1120(图1中带有菱形的线)的单一试剂治疗相比,化合物X与BIBF 1120的组合(图1中最下方带有正方形的线)对大肿瘤(在开始治疗时为约350mm3)产生改良的抗肿瘤效力。
与单独使用化合物X治疗在第40天时T/C值为45%及单独使用BIBF1120治疗在第40天时T/C值为50%相比,使用化合物X及BIBF 1120的组合治疗在第40天时具有的中值T/C值为16%。
附图说明
图1:Calu-6 NSCLC模型、BIBF 1120+化合物X的组合,方案(参见附图;对照组:带有圆形的线;BIBF 1120治疗组:带有菱形的线;化合物X(AKI)治疗组:带有三角形的线;Combo BIBF 1120+化合物X(AKI)治疗组:带有正方形的线)。
Claims (23)
1.药物组合或组合物,其包含细胞信号传导和/或血管生成抑制剂与Aurora激酶抑制剂(AKI),优选以同时、分别或依次使用这些活性成分。
2.权利要求1的药物组合或组合物,其中该细胞信号传导和/或血管生成抑制剂为血管生成抑制剂。
3.权利要求1的药物组合或组合物,其中该细胞信号传导和/或血管生成抑制剂为细胞信号传导抑制剂。
4.权利要求2的药物组合或组合物,其中该血管生成抑制剂为靶向血管内皮生长因子VEGF或VEGF受体的化合物。
5.权利要求2的药物组合或组合物,其中该血管生成抑制剂选自贝伐单抗、阿柏西普(VEGF-Trap)、凡德他尼、西地尼布、阿西替尼、索拉非尼、舒尼替尼、莫特塞尼、瓦他拉尼、帕唑帕尼及BIBF 1120。
6.权利要求2的药物组合或组合物,其中该血管生成抑制剂选自贝伐单抗、凡德他尼、索拉非尼、舒尼替尼及BIBF 1120。
7.权利要求2的药物组合或组合物,其中该血管生成抑制剂是具有下式的化合物1,
任选呈其互变异构体或药学上可接受的盐形式。
8.权利要求3的药物组合或组合物,其中该细胞信号传导抑制剂为靶向表皮生长因子受体EGFR的化合物。
11.权利要求1或2的药物组合或组合物,
其中该血管生成抑制剂为如权利要求7中所定义的化合物1,任选呈其互变异构体或药学上可接受的盐形式,且
其中该Aurora激酶抑制剂为如权利要求10中所定义的化合物2,任选呈其互变异构体或药学上可接受的盐形式。
12.权利要求1或3的药物组合或组合物,
其中该细胞信号传导抑制剂为如权利要求9中所定义的化合物3,任选呈其互变异构体或药学上可接受的盐形式,且
其中该Aurora激酶抑制剂为如权利要求10中所定义的化合物2,任选其呈互变异构体或药学上可接受的盐形式。
15.试剂盒,其包括:药物组合物,其包含如权利要求7中所定义的化合物1,该化合物1任选呈其互变异构体或药学上可接受的盐形式;以及另一种药物组合物,其包含如权利要求10中所定义的化合物2,该化合物2任选呈其互变异构体或药学上可接受的盐形式。
16.试剂盒,其包括:药物组合物,其包含如权利要求9中所定义的化合物3,该化合物3任选呈其互变异构体或药学上可接受的盐形式;以及另一种药物组合物,其包含如权利要求10中所定义的化合物2,该化合物2任选呈其互变异构体或药学上可接受的盐形式。
17.权利要求1至16中任一项的药物组合或组合物在制备用于治疗肿瘤及纤维变性疾病的药物中的用途。
18.权利要求17的用途,其中该疾病选自实体肿瘤、泌尿生殖器癌症、妇科癌症、肺癌、胃肠癌、头颈癌、恶性胶质母细胞瘤、恶性间皮细胞瘤、非转移性或转移性乳腺癌、恶性黑色素瘤或骨与软组织肉瘤;及血液瘤,例如多发性骨髓瘤、急性髓细胞性白血病、慢性髓细胞性白血病、骨髓增生异常综合征及急性成淋巴细胞性白血病。
19.权利要求7中所定义的化合物1,任选呈其互变异构体或药学上可接受的盐形式,其用于治疗肿瘤或纤维变性疾病的方法,该方法包括组合给予该化合物1以及如权利要求10中所定义的任选呈其互变异构体或药学上可接受的盐形式的化合物2。
20.权利要求10中所定义的化合物2,任选呈其互变异构体或药学上可接受的盐形式,其用于治疗肿瘤或纤维变性疾病的方法,该方法包括组合给予该化合物2以及如权利要求7中所定义的任选呈其互变异构体或药学上可接受的盐形式的化合物1。
21.权利要求9中所定义的化合物3,任选呈其互变异构体或药学上可接受的盐形式,其用于治疗肿瘤或纤维变性疾病方法,该方法包括组合给予该化合物3以及如权利要求10中所定义的任选呈其互变异构体或药学上可接受的盐形式的化合物2。
22.权利要求10中所定义的化合物2,任选呈其互变异构体或药学上可接受的盐形式,其用于治疗肿瘤或纤维变性疾病的方法,该方法包括组合给予该化合物2以及如权利要求9中所定义的任选呈其互变异构体或药学上可接受的盐形式的化合物 3。
23.权利要求19至22中任一项的用于治疗肿瘤疾病的方法中的化合物,该方法还包括手术和/或放射疗法。
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