CN109729716A - Pi3k-抑制剂的组合产品 - Google Patents
Pi3k-抑制剂的组合产品 Download PDFInfo
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- CN109729716A CN109729716A CN201780057273.1A CN201780057273A CN109729716A CN 109729716 A CN109729716 A CN 109729716A CN 201780057273 A CN201780057273 A CN 201780057273A CN 109729716 A CN109729716 A CN 109729716A
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- Prior art keywords
- base
- quinazoline
- methoxyl group
- morpholine
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- 239000013066 combination product Substances 0.000 title claims abstract description 114
- 229940127555 combination product Drugs 0.000 title claims abstract description 114
- 239000012828 PI3K inhibitor Substances 0.000 title description 12
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 title description 12
- 210000004027 cell Anatomy 0.000 claims abstract description 87
- 108091007960 PI3Ks Proteins 0.000 claims abstract description 47
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- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims abstract description 31
- 208000021937 marginal zone lymphoma Diseases 0.000 claims abstract description 28
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims abstract description 23
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
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- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims abstract description 13
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- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 claims abstract description 9
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 42
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Abstract
本发明涉及至少两种组分——组分A和组分B的组合产品,组分A是PI3K激酶的抑制剂,且组分B是维奈托克或帕博西尼。本发明的另一个方面涉及使用如本文所述的这样的组合产品制备用于治疗或预防疾病,特别是用于治疗或预防非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)的药物。
Description
本发明涉及至少两种组分(组分A和组分B)的组合产品,组分A是PI3K-抑制剂,且组分B是维奈托克(Venetoclax)或帕博西尼(Palbociclib)。
本发明的另一个方面涉及如本文所述的这样的组合产品用于制备用于治疗或预防疾病、特别是用于治疗癌症的药物的用途。
本发明的又另一个方面涉及治疗或预防对象中的癌症的方法,其包括向所述对象施用治疗有效量的如本文所述的组合产品。
进一步,本发明涉及包含以下的组合产品的试剂盒:
- 一种或多种如本文所定义的组分A,或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
- 如上文定义的组分B,或其溶剂化物或水合物;和任选的
- 一种或多种药剂C;
其中任选地所述组分A和B中的任一种或两种呈即用于同时、共同、分开或依次施用的药物制剂的形式。
组分A可以通过口服、静脉内、外用、局部安装、腹膜内或经鼻途径施用。
组分B可以通过口服、静脉内、外用、局部安装、腹膜内或经鼻途径施用。
发明背景
癌症是美国第二普遍的死因,每年引起450,000例死亡。尽管在鉴定癌症的一些可能的环境和遗传病因中已经取得实质性进展,但需要靶向癌症和相关疾病的额外治疗方式。具体而言,需要治疗与生长/增殖失调相关的疾病的治疗方法。
癌症是具有获得性功能能力如增强的存活/针对细胞凋亡的抗性和无限增殖潜力的细胞的选择过程之后产生的复杂疾病。因此,优选开发用于解决确立肿瘤的显著特征的癌症疗法的药物。
在许多类型的癌症中组成型活化的PI3K/AKT/mTOR途径是促进肿瘤细胞存活的突出途径之一。PI3K/AKT/mTOR途径的初始活化发生在细胞膜,其中通过IA类PI3K传播途径活化的信号。PI3K的活化可以通过酪氨酸激酶生长因子受体(例如,血小板衍生的生长因子受体(PDGF-R)、人表皮生长因子1/2/3受体(EGFR,HER2/3)或胰岛素样生长因子1受体(IGF-1R))、通过整联蛋白连接激酶(ILK)的细胞粘附分子、Ca2+/钙调蛋白依赖性激酶激酶(CaMKK)、核DNA依赖性蛋白激酶(DNA-PK)、G蛋白偶联受体和致癌蛋白诸如Ras发生。一旦PI3K被活化,其催化磷酸肌醇上的D-3位置的磷酸化以生成生物活性的磷脂酰肌醇-3,4,5-三磷酸酯[PI(3,4,5)P3, PIP3]和磷脂酰肌醇-3,4-双磷酸酯[PI(3,4)P2, PIP2]。PIP3结合至磷酸肌醇依赖性激酶1(PDK-1)、AKT和其它含有PH结构域的蛋白诸如Rho和PLC上的普列克底物蛋白同源(PH)结构域。作为结合至PIP3的结果,蛋白易位至细胞膜,并随后被活化。肿瘤抑制基因PTEN(染色体10上缺失的磷酸酶和张力蛋白同系物)通过使PIP3去磷酸化而拮抗PI3K,由此防止PDK1、AKT和其它信号传导蛋白的易位和活化。1,2。
AKT是PI3K的主要效应物,其引发广泛范围的下游信号传导事件。当被疏水性残基包围时,其识别和磷酸化共有序列RXRXX(S/T)。由于该序列存在于许多蛋白质中,因此已经鉴定并验证了约50个AKT底物。3,4这些底物控制关键的细胞过程如细胞凋亡、细胞周期进程、转录和翻译、应激适应、代谢和肿瘤细胞的转移。例如,AKT磷酸化叉头家族转录因子的FOXO亚家族,其抑制几种促细胞凋亡基因(例如Fas-L、IGFBP1和Bim)的转录。5,6另外,AKT可以通过磷酸化和灭活促细胞凋亡蛋白(例如Bad,其控制细胞色素c从线粒体中的释放)和凋亡信号调节激酶-1(一种涉及应激诱导的和细胞因子诱导的细胞死亡的促分裂原活化蛋白激酶激酶)来直接调节细胞凋亡。7相反,AKT可以磷酸化IκB激酶,其间接增加核因子κB的活性并刺激促存活基因的转录。8细胞周期进程也可以通过AKT对细胞周期蛋白依赖性激酶抑制剂p21WAF1/CIP1和p27KIP1的抑制性磷酸化而在G1/S过渡时受AKT的影响。此外,AKT可以磷酸化小鼠双微体 2(MDM2),导致其核易位和促进p53的降解。这由此导致p21Cip1mRNA的减少。9此外,AKT也在G2/M转换的控制中具有重要作用,通过例如Myt1和FOXO3a的磷酸化。10, 11。
AKT的研究最多的下游底物是丝氨酸/苏氨酸激酶mTOR。AKT可以直接磷酸化和活化mTOR,以及通过磷酸化和灭活TSC2(结节性硬化症复合物2,也称为结节蛋白)而引起mTOR的间接活化,所述TSC2通常通过GTP结合蛋白Rheb(脑中富集的Ras同系物)而抑制mTOR。当通过磷酸化灭活TSC2时,GTP酶Rheb被保持在其GTP结合状态,允许mTOR的活化增加。mTOR以两种复合物存在:TORC1复合物,其中mTOR与Raptor结合,和TORC2复合物,其中mTOR与Rictor结合。12在TORC1复合物中,mTOR使其下游效应子S6激酶(S6K1)和4EBP-1磷酸化。S6K1然后可以磷酸化其底物,被称为S6的核糖体蛋白。4EBP-1,当被磷酸化时,不能有效地结合至其结合伴侣,eIF4E。累积作用是增加蛋白质翻译,尤其是高度结构化的、加帽的mRNA种类的蛋白质翻译。13虽然mTOR通常被认为是AKT的下游底物,与Rictor的复合物中的mTOR也可以在S473处磷酸化AKT,由此提供途径上的正反馈的水平。14最后,S6K1也可以通过催化胰岛素受体底物蛋白(IRS)上的抑制性磷酸化调节该途径。这防止IRS活化PI3K,其间接地降低AKT的活化。该反馈途径对于开发PI3K/AKT/mTOR途径抑制剂是非常重要的,因为在评估PI3K途径抑制剂的抗肿瘤效力的过程中必须考虑PI3K的再活化。15, 16。
除了充分描述的PI3K信号传导途径的PI3K/AKT/mTOR轴以外,PI3K、AKT和mTOR还接收和分支独立于该轴的差异信号传导事件。例如,mTOR与MAPK途径具有串扰(crosstalk),并且通过ERK和RSK调节的TSC2的磷酸化被MAPK途径活化。17 存在描述AKT/mTOR-非依赖性PI3K-介导的信号传导事件的汇集数据。首先,PI3K下游信号传导分子PDK1响应于PIP3的升高的水平并且不仅激活AKT,还激活一组AGC激酶,包括S6K、RSK、SGK和PKC同种型,它们在调节肿瘤细胞生长、增殖、存活和代谢中发挥重要作用。18此外,许多PIK3CA突变癌细胞系和人乳腺肿瘤显示出只有最少的AKT活化和对于不依赖支持物生长而言对AKT的减弱的依赖性。相反,这些细胞保留稳健的PDK1活化和膜定位,并且表现出对PDK1底物SGK3的依赖性。SGK3在PIK3CA突变体癌细胞中经历PI3K-和PDK1-依赖性活化。因此,PI3K可以通过AKT依赖性和AKT非依赖性机制促进癌症。19除了PDK1和AGC激酶以外,PI3K还调节其它癌症相关的信号传导蛋白,诸如PLC、Rac、Rho、ITK和BTK,等。
在人类中,I类PI3K具有p110催化性亚基的四种同种型,p110α、p110β、p110γ和p110δ。p110α和p110β存在于所有细胞类型中,而p110δ和p110γ在白细胞中高度富集。p110亚基分为结合p85调节亚基的IA类组(p110α、p110β和p110δ)和不结合p85调节亚基的IB类组(p110γ)。p85调节性亚基含有Src同源区2(SH2)结构域且结合磷酸化的酪氨酸(pTyr),这导致IA类p110催化性亚基的活化。另一方面,p110γ通过G蛋白偶联受体(GPCR)被直接活化。新近的数据表明,p110也直接通过Gβγ蛋白被GPCR活化。20。
向各I类PI3K的信号传导输入是多种多样的,并且充分描述于基因分析中。因此,在被经典RTK配体(EGF、胰岛素、IGF-1和PDGF)刺激后,AKT的激活在p110α-缺乏的MEF中受损。21另一方面,其中p110β被去除或被p110β的激酶失活的等位基因替换的MEF通常响应于通过RTK的生长因子刺激。22反而,p110·催化活性实际上是响应于GPCR配体(如LPA)的AKT活化所需的。因此,p110α似乎携带经典RTK信号传导中的大部分PI3K信号,并且负责肿瘤细胞生长、增殖、存活、血管生成和代谢,而p110β介导来自促丝裂原和趋化因子的GPCR信号传导,因此,可以调节肿瘤细胞增殖、代谢、炎症和侵袭。23, 24。
尽管来自四种I类PI3K同种型的信号传导输出的差异仍然在很大程度上是未知的,但似乎PI3Kβ与PTEN一起确定肿瘤细胞中的PIP3的基础水平,而PIP3的RTK刺激的升高主要由PI3Kα控制。特定PI3K同种型下游的差异信号传导输出的潜能以及可能更普遍的Akt活化尚未被发现。
PI3K/AKT激酶的活化促进营养素摄取增加,将细胞转化至葡萄糖依赖性代谢,其使脂质前体和氨基酸再导向至支持细胞生长和增殖的合成代谢过程。这些具有过度活化的AKT的代谢表型导致表现出向有氧糖酵解的代谢转变(Warburg作用)的恶性肿瘤。在此方面,尽管生长条件不利(诸如葡萄糖耗竭或缺氧),但PI3K/AKT途径被讨论为对存活至关重要。
活化的PI3K/AKT途径的一个进一步方面是保护细胞免于程序性细胞死亡("细胞凋亡"),因此被认为转导存活信号。通过充当肿瘤细胞中的抗细胞凋亡信号转导的调节剂,PI3K/AKT途径,特别是PI3K本身是癌症疗法的靶标。活化的PI3K/AKT磷酸化并调节几种靶标,例如BAD、GSK3或FKHRL1,其影响不同的信号转导途径,如细胞存活、蛋白合成或细胞移动。该PI3K/AKT途径还在肿瘤细胞对常规抗癌疗法的抗性中发挥主要作用。因此,阻断PI3K/AKT途径可以同时抑制肿瘤细胞的增殖(例如,经由代谢作用的抑制)并使其对促凋亡剂敏感。PI3K抑制使肿瘤细胞对细胞凋亡刺激如Trail、喜树碱(Campthothecin)和多柔比星(Doxorubicin)选择性敏感。
许多类型的癌症对化疗和靶向性治疗的抗性代表了成功癌症治疗的主要障碍。癌细胞可以逃逸最常用的药物的作用,尽管它们具有不同的化学结构和细胞内靶标。许多治疗药物失败的潜在机制已经得到充分研究。PI3K/AKT途径的活化在不同的细胞功能诸如生长、迁移、存活和分化中发挥关键作用。过去十年中累积的数据已经确定,该途径对化学、放射和靶向性治疗剂的抗性中也均发挥关键作用。汇集数据描述了已经发展对常规化疗和放疗以及其它靶向性疗法诸如EGFR拮抗的抗性的细胞中的组成型或残余途径活化。例如,在多柔比星抗性CML细胞系中的实验证明了高水平的PI3K/AKT活性;重要的是,通过降低PI3K/AKT活性可以克服多柔比星抗性。在其中降低水平的磷酸化AKT可以增加吉西他滨诱导的细胞凋亡的两种胰腺癌细胞系中观察到进一步实验证据。在肺癌的异种移植物模型中也证实与顺铂的协同抗肿瘤活性。
PI3K/AKT途径与对化学和靶向性治疗剂两者的抗性相关联。PI3Kβ的抑制可能呈现克服对放射和DNA靶向性疗法的抗性的有希望的策略。核PI3Kb可以响应于IR或DNA损伤剂多柔比星而诱导在T308和S473两者上磷酸化的核AKT。
总之,PI3K在对于肿瘤发生、肿瘤生长/增殖和存活、肿瘤细胞粘附、侵袭和转移以及肿瘤血管生成关键的许多癌症相关的信号传导途径的下游发挥关键作用。此外,PIK3CA的功能获得突变在几种人癌症中是常见的,并且已经在一些肿瘤诸如前列腺癌中观察到肿瘤抑制基因PTEN和PI3Kβ之间的联系。已经在一些结肠和膀胱肿瘤中和胶质母细胞瘤中观察到p110β和p110δ同种型的表达增加。此外,核 PI3Kβ在DNA合成和修复中发挥作用。35再者,p110δ控制急性髓性白血病(AML)中的增殖和乳腺癌细胞的迁移,36而p110γ在肿瘤血管生成、CML细胞的耐药性,和胰腺肿瘤的生长和存活中起作用。37因此,开发用于在单和联合疗法中治疗的PI3K抑制剂是治疗癌症和克服癌症治疗抗性的有希望的策略。
未能经历细胞凋亡(程序性细胞死亡)是癌症的标志之一,也是血液学癌症的一个定义性特征。此外,已经显示未能经历细胞凋亡导致对细胞毒性药物的抗性。对细胞凋亡的抗性通常由包括B细胞淋巴瘤2(BCL2)的促存活蛋白的过表达引起。在健康的淋巴样细胞中,BCL2和其它BCL2家族成员抑制促凋亡蛋白BAX和BAK的活性,从而维持细胞活力。在应激条件下,BCL2可以被仅BH3家族的成员结合和灭活,导致BAX/ABK的活化和细胞凋亡的诱导。在血液学病症中,该途径通常由于BCL2的过表达或未能激活仅BH3的蛋白质(由于肿瘤抑制基因TP53的丧失)而中断。已经在多发性骨髓瘤、套细胞淋巴瘤(MCL)、弥漫性大B细胞淋巴瘤和急性成淋巴细胞性白血病中观察到BCL2过表达。
因此,靶向BCL2已被鉴定为具有BCL2过表达的肿瘤的治疗策略。靶向和灭活BCL2的小分子抑制剂允许细胞经历细胞凋亡。在慢性淋巴细胞白血病(CLL)和几种非霍奇金淋巴瘤亚型中针对BCL2的小分子抑制剂的早期临床试验已经证明了有希望的功效。维奈托克(ABT-199)是一种选择性BCL2抑制剂,最近已在美国被批准用于治疗CLL。此外,它正在被开发治疗非霍奇金淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)和急性髓性白血病(AML)。临床前地,当与其它癌症药物如苯达莫司汀和利妥昔单抗联合应用于套细胞淋巴瘤、弥漫性大B细胞淋巴瘤和骨髓瘤时,维奈托克已被证明具有协同抗肿瘤功效。例如,维奈托克与PI3K抑制剂艾代拉里斯(idelalisib)的组合产品证实了在套细胞淋巴瘤细胞中的协同性细胞凋亡(Choudhary, G. S., S. Al-Harbi, 等人(2015). "MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199can be overcome by preventing PI3K/AKT/mTOR activation in lymphoidmalignancies." Cell Death Dis 6: e159)。
由于它们在细胞周期调节中的作用,细胞周期蛋白和细胞周期蛋白依赖性激酶的失调的活性与癌症发展有关。癌症中存在多种CDK失调的机制。例如,在套细胞淋巴瘤中,t(11:14)易位导致细胞周期蛋白D1的过表达。因此,这类蛋白质一直是治疗药物开发的焦点。第一代pan-CDK抑制剂的功效受到不利的副作用谱的困扰,表明更具选择性的CDK抑制剂可能表现出更好的耐受性。CDK4/6是许多癌症中细胞周期的G1期转变为S期所必需的,并且已经开发了几种CDK4/6选择性抑制剂。帕博西尼是CDK4/6的口服施用的、有效的和特异性的抑制剂。临床上,帕博西尼已经显示出在具有激素受体(HR)阳性转移性乳腺癌的患者(其在之前的内分泌治疗中进展)中的抗肿瘤功效的迹象。临床前模型显示在其它几种癌症适应症中的功效。此外,已经探索了与靶向和细胞毒性剂组合的可能性。
因此,PI3K的抑制剂代表应当不仅作为单一药剂、而且与其它药物(例如DNA靶向剂和放射疗法)组合的补充治疗选择的有价值的化合物。鉴于多种信号传导途径驱动肿瘤生长的事实,组合产品治疗是一种有吸引力的治疗选择并值得进一步评估。
不同的PI3K抑制剂公开于例如WO2008/070150、WO2012/062743、WO2012/062745、WO2012/062748。
然而,现有技术没有公开包含特定的PI3K抑制剂库潘尼西(copanlisib)或其生理学上可接受的盐和维奈托克或帕博西尼的本发明的组合产品。
发明概述
令人惊讶地,观察到通过与维奈托克或帕博西尼组合施用库潘尼西或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,可以在代表淋巴瘤亚型套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)和脾边缘区淋巴瘤(SMZL)的细胞系中实现协同抗增殖作用。
因此,根据第一个方面,本发明提供了至少两种组分(组分A和组分B)的组合产品,组分A是库潘尼西(PI3K-激酶的抑制剂)或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,且组分B是维奈托克或帕博西尼。
根据第二个方面,本发明涵盖至少两种组分A和B的组合产品,组分A是PI3K-激酶的抑制剂,且组分B是维奈托克或帕博西尼。
根据第三个方面,本发明包含至少两种组分A和B的组合产品,组分A是PI3K-激酶的抑制剂或其生理学上可接受的盐,且组分B是维奈托克或帕博西尼。
如本文描述和定义的包含至少两种组分A和B的组合产品也被称为"本发明的组合产品"。
进一步,本发明涉及:
试剂盒,其包含:
- 以下物质的组合产品:
组分A:一种或多种如上文和下文所述的PI3K-激酶抑制剂,或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
组分B:维奈托克或帕博西尼或其溶剂化物或水合物;以及,任选的,
组分C:一种或多种其它药剂;
其中任选地任何上述组合产品中的所述组分A和B中的任一种或两种呈即用于同时、共同、分开或依次施用的药物制剂/组合物的形式。所述组分可以彼此独立地通过口服、静脉内、外用、局部安装、腹膜内或经鼻途径施用。
根据另一个方面,本发明涵盖如上文所述的组合产品,其用于治疗或预防疾病,特别是癌症,特别是非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)。
根据另一个方面,本发明涵盖这种如上文所述的组合产品用于制备用于治疗或预防疾病,特别是癌症,特别是非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)的药物的用途。
发明详述
定义
本文本中提及的术语优选具有如下含义:
术语"烷基"是指仅由碳和氢原子组成的直链或支链烃链基团,其仅含有碳和氢原子,不含不饱和度,具有一至八个碳原子,并且其通过单键与分子的剩余部分连接,诸如说明性地,甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基和1,1-二甲基乙基(叔丁基)。
术语"烯基"是指含有碳-碳双键的脂肪族烃基团,其可以是具有约2至约10个碳原子的直链或支链或支链,例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基。
术语"炔基"是指具有至少一个碳-碳三键的直链或支链烃基,并且具有范围为约2至最高达12个碳原子(目前优选具有范围为约2至最高达10个碳原子的基团),例如乙炔基。
术语"烷氧基"表示经由氧连接与分子的剩余部分连接的本文定义的烷基基团。那些基团的代表性实例是甲氧基和乙氧基。
术语"烷氧基烷基"表示经由氧连接与烷基连接的本文定义的烷氧基,所述烷基然后在来自烷基的任何碳处与主结构连接,导致产生分子剩余部分的稳定的结构。那些基团的代表性实例是–CH2OCH3、--CH2OC2H5。
术语"环烷基"表示约3至12个碳原子的非芳族单环或多环环系,诸如环丙基、环丁基、环戊基、环己基,且多环环烷基的实例包括全氢萘基(perhydronapththyl)、金刚烷基和降冰片基桥环基团或螺二环基团,例如螺(4,4)壬-2-基。
术语"环烷基烷基"是指含有与烷基直接连接的范围为约3至最高达8个碳原子的含环基团,所述烷基然后还在来自所述烷基的任何碳处与主结构连接,导致产生稳定的结构,诸如环丙基甲基、环丁基乙基、环戊基乙基。
术语"芳基"是指具有范围为6至最高达14个碳原子的芳族基团,诸如苯基、萘基、四氢萘基、茚满基、联苯。
术语"芳基烷基"是指与如本文定义的烷基直接连接的如本文定义的芳基,所述烷基然后在来自烷基的任何碳处与主结构连接,导致产生分子剩余部分的稳定的结构,例如--CH2C6H5、--C2H5C6H5。
术语"杂环"是指由碳原子和一至五个选自氮、磷、氧和硫的杂原子组成的稳定的3-15元环基团。为了本发明的目的,所述杂环基可以是单环、双环或三环体系,其可包括稠环、桥环或螺环体系,并且所述杂环基中的氮、磷、碳、氧或硫原子可以任选地被氧化为各种氧化状态。此外,氮原子可任选被季化;并且环基团可以是部分或完全饱和的(即杂芳族的或杂芳基芳族的)。这种杂环基团的实例包括但不限于氮杂环丁基、吖啶基、苯并间二氧杂环戊烯基、苯并二噁烷基、苯并呋喃基(benzofurnyl)、咔唑基、噌啉基、二氧戊环基、中氮茚基、萘啶基、全氢氮杂䓬基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基(phthalazil)、吡啶基、蝶啶基、嘌呤基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基、四唑基、咪唑基、四氢异喹啉基(tetrahydroisouinolyl)、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂䓬基、氮杂䓬基、吡咯基、4-哌啶酮基、吡咯烷基、吡嗪基、嘧啶基、哒嗪基、噁唑基、噁唑啉基、噁唑烷基(oxasolidinyl)、三唑基、茚满基、异噁唑基、异噁唑烷基(isoxasolidinyl)、吗啉基、噻唑基、噻唑啉基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、吲哚基、异吲哚基、二氢吲哚基、异二氢吲哚基、八氢吲哚基、八氢异吲哚基、喹啉基、异喹啉基、十氢异喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、苯并噁唑基、呋喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噻吩基、硫吗啉基、硫吗啉基亚砜(thiamorpholinyl sulfoxide)、硫吗啉基砜(thiamorpholinyl sulfone)、二氧磷杂环戊烷基(dioxaphospholanyl)、噁二唑基、色满基、异色满基。
术语"杂芳基"是指芳香的如本文定义的杂环基团。所述杂芳基环基团可以在任何杂原子或碳原子处与主结构连接,导致产生稳定的结构。
所述杂环基团可以在任何杂原子或碳原子处与主结构连接,导致产生稳定的结构。
术语"杂芳基烷基"是指与烷基直接键合的如本文定义的杂芳基环基团。所述杂芳基烷基可以在来自烷基的任何碳原子处与主结构连接,导致产生稳定的结构。
术语"杂环基"是指如本文定义的杂环基团。所述杂环基团可以在任何杂原子或碳原子处与主结构连接,导致产生稳定的结构。
术语"杂环基烷基"是指与烷基直接键合的如本文定义的杂环基团。所述杂环基烷基可以在所述烷基中的碳原子处与主结构连接,导致产生稳定的结构。
术语"羰基"是指通过双键与分子的碳原子键合的氧原子。
术语"卤素"是指氟、氯、溴和碘的基团。
术语"任选取代的"是指被具体基团、原子团或部分任选取代。
环系统的取代基指与芳族或非芳族环系统连接的取代基,例如所述取代基代替所述环系统上可用的氢。
如本文所用,术语“一次或多次”,例如在本发明的化合物(例如组分A、B或C)的取代基的定义中,应理解为表示“一、二、三、四或五次,特别是一、二、三或四次,更特别是一、二或三次,甚至更特别是一或二次”。
当本文中使用化合物、盐、多晶型物、水合物、溶剂化物等词的复数形式时,应理解为还表示单数的化合物、盐、多晶型物、异构体、水合物、溶剂化物等。
"稳定的化合物"或"稳定的结构"是指一个化合物是足够稳固的,以经受从反应混合物中的分离而达到有用的纯度和制备成为有效的治疗制剂。
术语"羰基"是指通过双键与分子的碳原子键合的氧原子。
根据期望的各种取代基的位置和性质,本发明的化合物可以含有一个或多个不对称中心。不对称的碳原子可以以(R)-和/或(S)-构型存在,在单一不对称中心的情况下导致外消旋混合物,并且在多个不对称中心的情况下导致非对映异构体混合物。在某些情况下,由于围绕特定键的旋转受阻还可能存在不对称性,例如该中心键连接特定化合物的两个被取代的芳环。环上的取代基还可以顺式或反式形式存在。意图所有的此类构型(包括对映体和非对映体)均包括于本发明的范围内。优选的化合物是产生更多所需生物活性的那些。本发明化合物的分离的、纯净的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映体混合物均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
互变异构体,有时被称为质子-移位互变异构体,是通过氢原子的迁移、伴随一个或多个单键和一个或多个相邻双键的转换关联的两种或更多种化合物。本发明的化合物可以以一种或多种互变异构形式存在。例如,式I的化合物可以以互变异构形式Ia、互变异构形式Ib或互变异构形式Ic存在,或者可以作为任何这些形式的混合物。所有此类互变异构形式意欲包括在本发明的范围内。
本发明还涉及如本文公开的化合物的有用形式,诸如所有实施例化合物的药学上可接受的盐、共沉淀物、代谢物、水合物、溶剂化物和前药。术语"药学上可接受的盐"是指本发明的化合物的相对无毒、无机或有机酸加成盐。例如,参见S. M. Berge, 等人“Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19。药学上可接受的盐包括通过使作为碱发挥功能的主要化合物与无机或有机酸反应以形成盐而获得的那些盐,例如盐酸、硫酸、磷酸、甲磺酸、樟脑磺酸、草酸、马来酸、琥珀酸和柠檬酸的盐。药学上可接受的盐还包括其中使作为酸发挥功能的主要化合物与适当的碱反应形成的那些盐,例如钠、钾、钙、镁、铵盐和氯盐。本领域技术人员将进一步认识到请求保护的化合物的酸加成盐可以经由任何多种已知方法使化合物与适当的无机或有机酸反应来制备。或者,本发明的酸性化合物的碱金属和碱土金属盐经由各种已知方法使本发明化合物与适当的碱反应来制备。
本发明化合物的代表性盐包括常规的无毒盐和季铵盐,其由例如通过本领域众所周知的方式从无机或有机酸或碱形成。例如,这样的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、肉桂酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、反丁烯二酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氯化物、溴化物、碘化物、2-羟基乙烷磺酸盐、衣康酸盐、乳酸盐、马来酸盐、扁桃酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、巴莫酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、磺酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。
碱式盐包括碱金属盐诸如钾盐和钠盐、碱土金属盐诸如钙盐和镁盐,以及与有机碱诸如二环己胺和N-甲基-D-葡萄糖胺形成的铵盐。此外,含碱性氮的基团可以用如低基烷基卤化物(例如甲基、乙基、丙基或丁基的氯化物、溴化物和碘化物);硫酸二烷基酯(如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯或硫酸二戊酯)、长链卤化物(例如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物)、芳烷基卤化物(例如苄基溴化物和苯乙基溴化物)等试剂季化。
用于本发明目的的溶剂化物是溶剂和本发明化合物的固体状态的络合物(complex)。示例性的溶剂化物将包括但不限于:本发明的化合物与乙醇或甲醇的络合物。水合物是其中溶剂为水的溶剂化物的具体形式。
按照本文的规定任选取代的组成部分,可以彼此独立地在任何可能的位置被取代一或多次,除非另外指明。当任何变量在任何组分中出现超过一次时,每个定义是独立的。
除非另有说明,本文所提及的杂芳基或杂环基可在任何可能位置处(诸如例如在任何可取代的环碳原子或环氮原子处)被其给定取代基或母体分子基团取代。类似地,应理解,如果化学上合适的话,任何杂芳基或杂环基可以通过任何合适的原子与分子的其余部分连接。除非另有说明,假定具有本文所提及的不饱和化合价的杂芳基环的任何杂原子具有一个或多个氢原子以满足化合价。除非另有说明,含有可季化氨基-或亚氨基型环氮原子(-N=)的环可优选不在这些氨基-或亚氨基型环氮原子上被所提及的取代基或母体分子基团季化。
优选的化合物是产生更期望的生物活性的那些化合物。本发明化合物的分离的、纯净的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映体混合物均包括于本发明范围内。这样的物质的纯化和分离可通过本领域已知的标准技术实现。
通过根据常规方法拆分外消旋混合物,例如通过使用旋光酸或碱形成非对映异构体盐,或者通过形成共价非对映体可获得旋光异构体。适当的酸的实例为酒石酸、二乙酰基酒石酸、二甲苯酰基酒石酸和樟脑磺酸。非对映异构体的混合物可基于它们的物理和/或化学差异,通过本领域已知的方法例如通过色谱法或分级结晶而分离成它们的单一的非对映体。然后,从分离的非对映体盐中释放旋光碱或酸。一种不同的分离旋光异构体的方法涉及在进行或不进行常规衍生化的条件下使用手性色谱法(例如手性HPLC柱),其可经过最佳选择以将对映体的分离最大化。合适的手性HPLC柱由Daicel制造,尤其例如均常规可选的Chiracel OD和Chiracel OJ。在进行或不进行衍生化的条件下,酶分离也是有用的。同样地,可通过使用旋光原料的手性合成来获得本发明的旋光化合物。
如果在本发明的上下文中提及"实施方案",其应当理解为包括多个可能的组合产品。
为了将不同类型的异构体相互之间区分开来,参考了IUPAC Rules Section E(Pure Appl Chem 45, 11-30, 1976)。
本发明还包括本发明化合物的所有合适的同位素变体。本发明化合物的同位素变体定义为:其中至少一个原子被原子序数相同但原子量不同于自然界中通常或主要发现的原子量的原子替代的本发明的化合物。可以掺入本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,例如分别为2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的某些同位素变体,例如,其中引入一个或多个放射性同位素(例如,3H或14C)的那些变体可用于药物和/或底物组织分布研究。尤其优选氚和碳-14(即,14C)同位素,这是由于它们的容易制备和可检测性。进一步,用同位素诸如氘取代可以提供由更好的代谢稳定性导致的确定的治疗优点,例如增加的体内半衰期或减小的剂量需求,并且因此在一些情况下可以是优选的。通常可以利用本领域技术人员已知的常规方法,例如,利用说明性方法或下文实施例所描述的制备方法,使用合适试剂的合适的同位素变体来制备本发明化合物的同位素变体。
本发明包括作为单一立体异构体或呈任何比率的所述立体异构体的任何混合物的本发明的化合物的所有可能的立体异构体。可通过任意适合的现有技术方法例如色谱法,特别是例如手性色谱法实现本发明化合物的单一立体异构体例如单一对映体或单一非对映体的分离。
本发明包括本发明化合物的所有可能的互变异构体,其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。
另外,本发明包括本发明化合物的所有可能的结晶形式或多晶型物,其作为单一多晶型物或多于一种多晶型物的任意比例的混合物。
所述组合产品的组分A
组分A可以选自例如如上面提及的出版物(其通过引用并入本文)中具体或一般地公开的PI3K-激酶的抑制剂。
在一个实施方案中,所述组分A是通式(A)的化合物:
其中:
X代表CR5R6或NH;
Y1代表CR3或N;
Y2 ------ Y3之间的化学键代表单键或双键,
条件是当Y2 ------ Y3代表双键时,Y2和Y3独立地代表CR4或N,和
当Y2 ------ Y3代表单键时,Y2和Y3独立地代表CR3R4或NR4;
Z1、Z2、Z3和Z4独立地代表CH、CR2或N;
R1代表任选具有1至3个选自R11的取代基的芳基,任选具有1至3个选自R11的取代基的C3-8环烷基,
任选被芳基、杂芳基、C1-6烷氧基芳基、芳基氧基、杂芳基氧基或1个或多个卤素取代的C1-6烷基,
任选被羧基、芳基、杂芳基、C1-6烷氧基芳基、芳基氧基、杂芳基氧基或1个或多个卤素取代的C1-6烷氧基,
或
3至15元单环或双环杂环,其为饱和或不饱和的,任选具有1至3个选自R11的取代基,并含有1至3个选自N、O和S的杂原子,
其中
R11 代表卤素、硝基、羟基、氰基、羧基、氨基、N-(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基、N-(甲酰基)-N-(C1-6烷基)氨基、N-(C1-6烷磺酰基)氨基、N-(羧基C1-6烷基)-N-(C1-6烷基)氨基、N-(C1-6烷氧基羰基)氨基、N-[N,N-二(C1-6烷基)氨基亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基 (C1-6烷基)亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基 C2-6烯基]氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、C3-8环烷基、C1-6 烷基硫基、C1-6烷磺酰基、氨磺酰基、C1-6烷氧基羰基,
N-芳基氨基,其中所述芳基基团任选具有1至3个选自R101的取代基,N-(芳基 C1-6烷基)氨基,其中所述芳基基团任选具有1至3个选自R101的取代基,芳基 C1-6烷氧基羰基,其中所述芳基基团任选具有1至3个选自R101的取代基,
任选被单-、二-或三-卤素、氨基、N-(C1-6烷基)氨基或N,N-二(C1-6烷基)氨基取代的C1-6烷基,
任选被单-、二-或三-卤素、N-(C1-6烷基)磺酰胺或N-(芳基)磺酰胺取代的C1-6烷氧基 ,
或
5至7元饱和或不饱和环,其具有1至3个选自O、S和N的杂原子,且任选具有1至3个选自R101的取代基
其中
R101代表卤素、羧基、氨基、N-(C1-6 烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、吡啶基,
任选被氰基或单-、二-或三-卤素取代的C1-6烷基,
和
任选被氰基、羧基、氨基、N-(C1-6 烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基或单-、二-或三-卤素取代的C1-6烷氧基;
R2 代表羟基、卤素、硝基、氰基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N-(羟基C1-6烷基)-N-(C1-6烷基)氨基、C1-6酰基氧基、氨基C1-6酰基氧基、C2-6烯基、芳基,
5-7元饱和或不饱和杂环,其具有1至3个选自O、S和N的杂原子且任选被以下取代
羟基、C1-6 烷基、C1-6烷氧基、氧代、氨基、氨基 C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、N-(C1-6烷基)羰基氨基、苯基、苯基 C1-6 烷基、羧基、C1-6烷氧基羰基、氨基羰基、N-(C1-6烷基)氨基羰基或N,N-二(C1-6烷基)氨基、-C(O)- R20
其中
R20代表C1-6 烷基、C1-6烷氧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基,或具有1至3个选自O、S和N的杂原子,且任选被C1-6 烷基、C1-6烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、苯基或苄基取代的5-7元饱和或不饱和杂环,
任选被R21取代的C1-6烷基,
或
任选被R21取代的C1-6烷氧基,
其中
R21代表氰基、单-、二或三-卤素、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6 烷基)氨基、N- (卤代苯基C1-6 烷基) 氨基、氨基 C2-6 烯基(alkylenyl)、C1-6烷氧基、羟基C1-6烷氧基、-C(O)- R201、-NHC(O)- R201、C3-8环烷基、异吲哚啉子基(isoindolino)、邻苯二甲酰亚胺基、2-氧代-1,3-噁唑烷基、芳基或具有1至4个选自O、S和N的杂原子,且任选被羟基、C1-6烷基、C1-6烷氧基、C1-6烷氧基羰基、羟基C1-6烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基取代的5或6元饱和或不饱和杂环,
其中
R201 代表羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N- (卤代苯基C1-6 烷基) 氨基、C1-6烷基、氨基C1-6 烷基、氨基C2-6 烯基(alkylenyl)、C1-6烷氧基、具有1至4个选自O、S和N的杂原子,且任选被羟基、C1-6 烷基、C1-6烷氧基、C1-6烷氧基羰基、羟基C1-6烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基取代的5或6元饱和或不饱和杂环;
R3代表氢、卤素、氨基羰基或任选被芳基 C1-6烷氧基或单-、二-或三-卤素取代的C1-6烷基;
R4代表氢或C1-6 烷基;
R5代表氢或C1-6 烷基;和
R6代表卤素、氢或C1-6 烷基,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是选自下列的上文通式(A)的化合物:
N-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
2-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1-吡啶-3-基乙烯醇;
N-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
6-(乙酰氨基)-N-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-{5-[2-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1-羟基乙烯基]吡啶-2-基}乙酰胺;
2-({5-[2-羟基-2-吡啶-3-基乙烯基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-8-基}氧基)-N,N-二甲基乙酰胺;
2-[7-甲氧基-8-(四氢-2H-吡喃-2-基甲氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-吡啶-3-基乙烯醇;
2-[8-(2-羟基乙氧基)-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-吡啶-3-基乙烯醇;
({5-[2-羟基-2-吡啶-3-基乙烯基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-8-基}氧基)乙酸;
4-({5-[2-羟基-2-吡啶-3-基乙烯基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-8-基}氧基)丁酸;
({5-[2-羟基-2-吡啶-3-基乙烯基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-8-基}氧基)乙腈;
2-[7-甲氧基-8-(2H-四唑-5-基甲氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-吡啶-3-基乙烯醇;
2-[7-甲氧基-8-(4-吗啉-4-基-4-氧代丁氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-吡啶-3-基乙烯醇;
5-[1-羟基-2-(8-吗啉-4-基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)乙烯基]吡啶-3-醇;
N-(2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-5-羟基烟酰胺;
6-(乙酰氨基)-N-(7,9-二甲氧基-8-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-5-羟基烟酰胺;
5-羟基-N-(7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-5-[(4-甲氧基苄基)氧基]烟酰胺;
N-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-5-羟基烟酰胺;
5-羟基-N-[8-(三氟甲基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{8-[3-(1,3-二氧代-1,3-二氢-2H-异吲哚-2-基)丙氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-(7-溴-8-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
6-氨基-N-(8-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
1-(1H-苯并咪唑-5-基)-2-(8,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)乙烯醇;
2-(8,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1-(2,4-二甲基-1,3-噻唑-5-基)乙烯醇;
N-(9-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
N-(8-溴-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-溴-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
N-(8-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
N-(8-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
N-[8-(三氟甲基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1H-苯并咪唑-5-甲酰胺;
N-(7-氟-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
N-(7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-氯-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
6-(乙酰氨基)-N-(8-吗啉-4-基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
1-(1H-苯并咪唑-5-基)-2-(8-吗啉-4-基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)乙烯醇;
N-{5-[1-羟基-2-(8-吗啉-4-基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)乙烯基]吡啶-2-基}乙酰胺;
6-甲基-N-(8-吗啉-4-基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
1-(1H-苯并咪唑-5-基)-2-[8-(4-甲基哌嗪-1-基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]乙烯醇;
N-(2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-3H-咪唑并[4,5-b]吡啶-6-甲酰胺;
N-(7,8-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-3H-咪唑并[4,5-b]吡啶-6-甲酰胺;
N-[7-(三氟甲基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1H-苯并咪唑-5-甲酰胺;
N-(7,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1H-苯并咪唑-5-甲酰胺;
N-{5-[2-(7,9-二甲氧基-8-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1-羟基乙烯基]吡啶-2-基}乙酰胺;
N-{5-[2-(7-溴-9-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1-羟基乙烯基]吡啶-2-基}乙酰胺;和
2-(8,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-1-吡啶-3-基乙烯醇;
在一个实施方案中,所述组分A是具有式(I)的化合物:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,其中:
R1 代表–(CH2)n-(CHR4)-(CH2)m-N(R5)(R5’);
R2代表任选被1、2或3个R6基团取代的杂芳基;
R3代表烷基或环烷基;
R4代表氢或烷氧基;和
R5和R5’可以是相同或不同的且独立地代表氢、烷基、环烷基烷基(alklyl)或烷氧基烷基或R5和R5’可以与它们所结合的氮原子一起形成任选含有至少一个选自氧、氮或硫的额外杂原子且可以任选被1个或多个R6’基团取代的3-7元含氮杂环,或R4和R5可以与它们所结合的原子一起形成任选含有1个或多个氮、氧或硫原子且可以任选被1个或多个R6’基团取代的5-6元含氮杂环;
R6的每次出现可以是相同或不同的且独立地为卤素、烷基、烯基、炔基、环烷基、环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环、杂环基烷基、烷基-OR7、烷基-SR7、烷基-N(R7)(R7’)、烷基-COR7、-CN、-COOR7、-CON(R7)(R7’)、-OR7、-SR7、-N(R7)(R7’)或–NR7COR7,其各自可任选被1个或多个R8基团取代;
R6’的每次出现可以是相同或不同的且独立地为烷基、环烷基烷基或烷基-OR7;
R7和R7’的每次出现可以是相同或不同的且独立地为氢、烷基、烯基、炔基、环烷基、环烷基烷基、环烯基、芳基、芳基烷基、杂芳基、杂环、杂环基烷基或杂芳基烷基;
R8的每次出现独立地为硝基、羟基、氰基、甲酰基、乙酰基、卤素、氨基、烷基、烷氧基、烯基、炔基、环烷基、环烷基烷基、环烯基、芳基、芳基烷基、杂芳基、杂环、杂环基烷基或杂芳基烷基;
n是1-4的整数且m是0-4的整数,条件是当R4和R5与它们所结合的原子一起形成5-6元含氮环时,n + m ≤ 4;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是具有上文式(I)的化合物,其中R2是任选被1、2或3个R6基团取代的含氮杂芳基,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是上文通式(I)的化合物,其中R5和R5’独立地为烷基,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是上文通式(I)的化合物,其中R5和R5’与它们所结合的氮原子一起形成含有至少一个选自氧、氮或硫的额外杂原子且可以任选被1个或多个R6’基团取代的5-6 元含氮杂环,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是式(I)的化合物,其中R4和R5与它们所结合的原子一起形成任选含有1个或多个氮、氧或硫原子且可以任选被1个或多个R6基团取代的5-6元含氮杂环,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是式(I)的化合物,其中R3是甲基,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是式(I)的化合物,其中R2是任选被1、2或3个R6基团取代的吡啶、哒嗪、嘧啶、吡嗪、吡咯、噁唑、噻唑、呋喃或噻吩;更优选任选被1、2或3个R6基团取代的吡啶、哒嗪、嘧啶、吡嗪、吡咯、噁唑或噻唑,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是式(Ia)的化合物:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,其中R2如上文对于式(I)所定义。
在一个实施方案中,所述组分A是式(Ib)的化合物:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,其中R2如上文对于式(I)所定义。
在一个实施方案中,所述组分A是式(Ic)的化合物:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,其中R2如上文对于式(I)所定义。
在一个实施方案中,所述组分A是式(Id)的化合物:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,其中R2和R4如上文对于式(I)所定义。
在一个实施方案中,所述组分A是式(Ie)的化合物:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,其中R2和R4如上文对于式(I)所定义。
在一个实施方案中,所述组分A是式(I)-(Ie)的化合物,其中R2是任选被1、2或3个R6基团取代的吡啶、哒嗪、嘧啶、吡嗪、吡咯、噁唑、噻唑、呋喃或噻吩;更优选其中R2是任选被1、2或3个R6基团取代的吡啶、哒嗪、嘧啶、吡嗪、吡咯、噁唑或噻唑,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在一个实施方案中,所述组分A是选自下列的化合物:
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-2,4-二甲基-1,3-噻唑-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噻唑-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]异烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-甲基-1,3-噻唑-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-丙基嘧啶-5-甲酰胺;
N-{8-[2-(4-乙基吗啉-2-基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺 1-氧化物;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(2-吡咯烷-1-基乙基)烟酰胺;
6-(环戊基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[8-(2-羟基-3-吗啉-4-基丙氧基)-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{7-甲氧基-8-[3-(3-甲基吗啉-4-基)丙氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-{2-[4-(环丁基甲基)吗啉-2-基]乙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(7-甲氧基-8-{2-[4-(2-甲氧基乙基)吗啉-2-基]乙氧基}-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-{8-[(4-乙基吗啉-2-基)甲氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-(7-甲氧基-8-{[4-(2-甲氧基乙基)吗啉-2-基]甲氧基}-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-{7-甲氧基-8-[(4-甲基吗啉-2-基)甲氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-4-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-4-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-甲基-1H-咪唑-4-甲酰胺;
rel-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)嘧啶-5-甲酰胺;
rel-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-6-甲基烟酰胺;
rel-6-乙酰氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-甲基-1H-咪唑-5-甲酰胺;
6-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-甲基烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-甲基嘧啶-5-甲酰胺;
6-氨基-5-溴-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噁唑-5-甲酰胺;
N-[7-甲氧基-8-(吗啉-2-基甲氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
2-{[2-(二甲基氨基)乙基]氨基}-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
2-氨基-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-1,3-噻唑-5-甲酰胺;
rel-2-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)嘧啶-5-甲酰胺;
rel-6-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
2-[(2-羟基乙基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-[(3-甲氧基丙基)氨基]嘧啶-5-甲酰胺;
2-氨基-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-[(3-吗啉-4-基丙基)氨基]嘧啶-5-甲酰胺;
2-[(2-甲氧基乙基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
2-{[2-(二甲基氨基)乙基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
6-氨基-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-吡咯烷-1-基嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(4-甲基哌嗪-1-基)嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-吗啉-4-基嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-哌嗪-1-基烟酰胺盐酸盐;
6-[(3S)-3-氨基吡咯烷-1-基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺盐酸盐水合物;
6-[(3R)-3-氨基吡咯烷-1-基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺盐酸盐;
6-[(4-氟苄基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-[(2-呋喃基甲基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-[(2-甲氧基乙基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(1H-吡咯-1-基)烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-吗啉-4-基烟酰胺;
N-{7-甲氧基-8-[3-(甲基氨基)丙氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
6-[(2,2-二甲基丙酰基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-[(环丙基羰基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(2,2,2-三氟乙氧基)烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(三氟甲基)烟酰胺;
6-(异丁酰基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{7-甲氧基-8-[3-(4-甲基哌嗪-1-基)丙氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-{[(甲基氨基)羰基]氨基}-1,3-噻唑-4-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-{[(甲基氨基)羰基]氨基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(甲基氨基)-1,3-噻唑-4-甲酰胺;
N-[7-甲氧基-8-(2-吗啉-4-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-2,4-二甲基-1,3-噻唑-5-甲酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-6-甲基烟酰胺;
6-{[(异丙基氨基)羰基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-吡咯烷-1-基烟酰胺;
6-(二甲基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-哌啶-1-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(2-吡咯烷-1-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(2-哌啶-1-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-{[(乙基氨基)羰基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-氟-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噁唑-4-甲酰胺;
2-(乙基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噻唑-4-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]吡嗪-2-甲酰胺;
N-[8-(2-氨基乙氧基)-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]异烟酰胺;
N-{8-[3-(二乙基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二异丙基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二乙基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(甲基氨基)嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(甲基硫基)嘧啶-5-甲酰胺;
N-[8-(3-氨基丙氧基)-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺三氟乙酸盐;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]噻吩-2-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2,4-二甲基-1,3-噻唑-5-甲酰胺;
2-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-3-糠酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]噻吩-3-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-甲基-1,3-噻唑-4-甲酰胺;
6-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
5-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-甲基烟酰胺;
6-(乙酰基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在另一个实施方案中,所述组分A是选自下列的化合物:
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-甲基烟酰胺;
5-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2,4-二甲基-1,3-噻唑-5-甲酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
6-{[(异丙基氨基)羰基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-2,4-二甲基-1,3-噻唑-5-甲酰胺;
N-[7-甲氧基-8-(2-吗啉-4-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
rel-6-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
rel-2-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)嘧啶-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在另一个实施方案中,所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
在另一个实施方案中,所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐。
当所述化学名称和化学结构之间存在差异时,所述化学结构优先于给出的化学名称。
不受理论或机制所束缚,与现有技术的那些化合物相比,本发明的化合物表现出令人惊讶的抑制磷脂酰肌醇-3-激酶的活性以及化学和结构稳定性。据信该令人惊讶的活性基于所述化合物的化学结构,特别是由于R1是任选地被R5和R5'取代的氨基而导致的化合物的碱性。此外,R3和R2的适当选择针对适当的同种型提供必要活性,以产生体内活性。
上述所列化合物的合成描述于国际专利申请号PCT/EP2003/010377(作为WO2004/029055 A1公开)和国际专利申请号PCT/US2007/024985(作为WO 2008/070150公开),其两者在此均以其整体通过引用并入本文。
所述组分A可以呈即用于同时、共同、分开或依次施用的药物制剂的形式。所述组分可以彼此独立地通过口服、静脉内、外用、局部安装、腹膜内或经鼻途径施用。
现有技术中以及上述列表中提及的PI3K-抑制剂已经被公开用于治疗或预防不同的疾病,尤其是癌症。
如上所公开的列表的具体化合物优选为是所述组合产品的组分A,最优选的是实验部分中使用的化合物。
本文用在实施例部分中作为化合物A具体公开的PI3K抑制剂之一表明本发明的组合产品的协同行为。
此外,本发明的包含如上提及的化合物A和维奈托克或帕博西尼的组合产品是本发明的优选方面。
在另一个方面,本发明的组合产品包含如上提及的化合物A或其药学上可接受的盐和维奈托克或帕博西尼。
应当理解的是,本发明还涉及上述组分A的实施方案的任何组合产品。
所述组合产品的组分B
组分B是维奈托克或帕博西尼。
维奈托克(ABT-199、GDC-0199)和帕博西尼(PD-0332991)HCl购自SelleckChemicals(产品编号S8048、S1116)。
根据一个实施方案,本发明涉及本文提及的任何组分A与本文提及的任何组分B、任选地与本文提及的任何组分C的组合产品。
在一个实施方案中,所述组合产品的组分A是实验部分中使用的化合物,且组分B是实验部分中使用的维奈托克或帕博西尼。
在一个具体实施方案中,本发明涉及如本文实施例部分中提及的组分A与组分B、任选地与组分C的组合产品。
进一步,本发明涉及:
试剂盒,其包含:
-以下物质的组合产品:
组分A:一种或多种PI3K-激酶抑制剂,或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
成分B:维奈托克或帕博西尼或其溶剂化物或水合物;和任选的,
组分C:一种或多种其它药剂;
其中任选地任何上述组合产品中的所述组分A和B中的任一种或两种呈即用于同时、共同、分开或依次施用的药物制剂的形式。
作为至少一种药剂的术语"组分C"包括有效化合物本身以及其药学上可接受的盐、溶剂化物、水合物或立体异构体以及包含这样的有效化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体的任何组合物或药物制剂。下面进一步提供这样的即用药剂的列表。
所述组分可以彼此独立地通过口服、静脉内、外用、局部安装、腹膜内或经鼻途径施用。
组分A静脉内、腹膜内施用,优选地其口服施用。
组分B静脉内、腹膜内施用,优选地其口服施用。
组分C视情况而定施用。
术语"药学上可接受的"与术语"生理学上可接受的"同义使用。
组分A的术语"药学上或生理学上可接受的盐"指本发明的化合物的相对无毒的、无机或有机酸加成盐。例如,参见S. M. Berge, 等人 “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19。药学上可接受的盐包括通过使作为碱发挥功能的主要化合物与无机或有机酸反应以形成盐而获得的那些盐,例如盐酸、硫酸、磷酸、甲磺酸、樟脑磺酸、草酸、马来酸、琥珀酸和柠檬酸的盐。药学上可接受的盐还包括其中使作为酸发挥功能的主要化合物与适当的碱反应形成的那些盐,例如钠、钾、钙、镁、铵盐和氯盐。本领域技术人员将进一步认识到请求保护的化合物的酸加成盐可以经由任何多种已知方法使化合物与适当的无机或有机酸反应来制备。或者,本发明的酸性化合物的碱金属和碱土金属盐经由各种已知方法使本发明化合物与适当的碱反应来制备。
本发明的组分A的代表性盐包括常规的无毒盐和季铵盐,其由例如通过本领域众所周知的方式从无机或有机酸或碱形成。例如,这样的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、肉桂酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、反丁烯二酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氯化物、溴化物、碘化物、2-羟基乙烷磺酸盐、衣康酸盐、乳酸盐、马来酸盐、扁桃酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、巴莫酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、磺酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。
碱式盐包括碱金属盐诸如钾盐和钠盐、碱土金属盐诸如钙盐和镁盐,以及与有机碱诸如二环己胺和N-甲基-D-葡萄糖胺形成的铵盐。此外,含碱性氮的基团可以用如低基烷基卤化物(例如甲基、乙基、丙基或丁基的氯化物、溴化物和碘化物);硫酸二烷基酯(如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯或硫酸二戊酯)、长链卤化物(例如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物)、芳烷基卤化物(例如苄基溴化物和苯乙基溴化物)等试剂季化。
用于本发明目的的溶剂化物是溶剂和本发明化合物的固体状态的络合物(complex)。示例性的溶剂化物将包括但不限于:本发明的化合物与乙醇或甲醇的络合物。水合物是其中溶剂为水的溶剂化物的具体形式。
本发明的组分可以用常规片剂基质诸如乳糖、蔗糖和玉米淀粉与如下组分的组合压片:粘合剂诸如阿拉伯胶、玉米淀粉或明胶,施用后意图帮助片剂崩解和溶出的崩解剂诸如马铃薯淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍胶、阿拉伯胶,意图改善片剂颗粒流动和防止片剂材料与片剂模具和冲头表面粘附的润滑剂例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌,意图增强片剂的美学品质和使它们更容易被患者接受的染料、着色剂和矫味剂诸如薄荷、冬青油或樱桃香精。用于口服液体剂型中的合适的赋形剂包括磷酸二钙和稀释剂,例如水和醇(例如乙醇、苯甲醇和聚乙烯醇类),其添加或不添加药学上可接受的表面活性剂、助悬剂或乳化剂。各种其它材料可以以包衣的方式存在或者以其它方式改变剂量单位的物理形式。例如,可以用虫胶、糖或二者将片剂、丸剂或胶囊剂进行包衣。
可分散的粉剂和颗粒剂适合用于制备水性混悬剂。它们以与分散剂或润湿剂、助悬剂以及一种或多种防腐剂混合的方式提供活性成分。合适的分散或润湿剂和悬浮剂通过上述已提及的那些而例示。也可存在额外的赋形剂,例如上述那些甜味剂、矫味剂和着色剂。
本发明的组分也可以呈水包油乳剂形式。油相可为植物油,例如液体石蜡或者植物油的混合物。合适的乳化剂可以是(1)天然存在的胶,例如阿拉伯胶和黄蓍胶,(2)天然存在的磷脂类,例如大豆和卵磷脂,(3)衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯,(4)所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳剂也可含有甜味剂和调味剂。
可以通过将活性成分悬浮于植物油诸如例如落花生油、橄榄油、芝麻油或椰子油或矿物油诸如液体石蜡中而配制油性混悬剂。油性混悬剂可以包含增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。混悬剂也可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯;一种或多种着色剂;一种或多种矫味剂;和一种或多种甜味剂例如蔗糖或糖精。
可以用甜味剂,诸如例如甘油、丙二醇、山梨糖醇或蔗糖配制糖浆剂和酏剂。这样的制剂也可以含有缓和剂和防腐剂,诸如尼泊金甲酯和尼泊金丙酯和矫味剂和着色剂。
本发明的组分也可以肠胃外施用,即皮下、静脉内、眼内、滑膜内、肌内或腹膜间,作为优选在生理学上可接受的稀释剂与药物载体中的化合物的可注射剂量施用,所述药物载体可以是无菌液体或液体的混合物,诸如水、盐水、右旋糖水溶液和相关糖溶液,醇诸如乙醇、异丙醇或十六醇,二醇类诸如丙二醇或聚乙二醇,甘油缩酮类诸如2,2-二甲基-1,1-二氧杂环戊烷-4-甲醇,醚类诸如聚(乙二醇)400、油、脂肪酸、脂肪酸酯或脂肪酸甘油酯或乙酰化脂肪酸甘油酯,加入或不加入药学上可接受的表面活性剂诸如皂或洗涤剂,助悬剂诸如果胶、卡波姆、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素,或乳化剂和其它药物助剂。
可以在本发明的肠胃外制剂中使用的油的示例是石油、动物、植物或合成来源的那些,例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄榄油、矿脂和矿物油。合适的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。合适的脂肪酸酯是例如油酸乙酯和肉豆蔻酸异丙酯。合适的皂包括脂肪酸碱金属、铵和三乙醇胺盐且合适的洗涤剂包括阳离子洗涤剂,例如二甲基二烷基卤化铵、烷基吡啶鎓卤化物和烷基胺乙酸盐;阴离子洗涤剂,例如烷基、芳基和烯烃的磺酸盐,烷基、烯烃、醚和单酸甘油酯的硫酸盐,和磺基琥珀酸盐;非离子型洗涤剂,例如脂肪胺氧化物、脂肪酸烷醇酰胺和聚(氧乙烯-氧丙烯)或环氧乙烷或环氧丙烷共聚物;和两性洗涤剂,例如,烷基-β-氨基丙酸盐,和2-烷基咪唑啉季铵盐,以及混合物。
本发明的肠胃外组合物将通常在溶液中包含约0.5重量%至约25重量%的活性成分。还可以有利地使用防腐剂和缓冲剂。为了最小化或消除在注射部位的刺激,这样的组合物可含有优选具有约12至约17的亲水-亲油平衡值(HLB)的非离子表面活性剂。表面活性剂在这样的制剂中的量优选为约5重量%至约15重量%。表面活性剂可以是具有上述HLB的单一组分,或者可以是两种或更多种具有所需的HLB的组分的混合物。
在肠胃外制剂中使用的表面活性剂的示例是聚乙烯脱水山梨糖醇脂肪酸酯类,例如脱水山梨糖醇单油酸酯,以及环氧乙烷与疏水性基质的高分子量加合物,所述疏水性基质通过缩合环氧丙烷和丙二醇而形成。
药物组合物可以呈无菌可注射含水混悬剂的形式。这种混悬剂可以根据已知的方法使用合适的分散剂或润湿剂和助悬剂(例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶);分散剂或润湿剂,其可为天然存在的磷脂(例如卵磷脂)、氧化烯与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如十七乙烯氧基鲸蜡醇)、环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨糖醇单油酸酯)、或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚氧乙烯脱水山梨糖醇单油酸酯)配制。
无菌可注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬剂。可以使用的稀释剂和溶剂是例如水、林格溶液、等渗氯化钠溶液和等渗葡萄糖溶液。此外,无菌固定油方便地用作溶剂或悬浮介质。为此目的,任何温和的、固定油都可以使用,包括合成的单或二甘油酯。此外,脂肪酸例如油酸可用于制备可注射制剂。
本发明的组分还可以以用于药物的直肠施用的栓剂的形式施用。这些组分可以通过将药物与在平常温度下为固体、但在直肠温度下为液体、从而会在直肠中融化以释放药物的合适的无刺激性赋形剂混合来制备。这样的材料例如为可可脂和聚乙二醇。
用于本发明的方法的另一种制剂采用透皮递送装置(“贴剂”)。这种透皮贴剂可用于以受控量提供本发明的化合物的连续或不连续输注。用于递送药剂的透皮贴剂的构建和使用是本领域熟知的(参见,例如,1991年6月11日授权的美国专利号5,023,252,通过引用并入本文)。这种贴剂可以构建用于连续、脉冲或按需递送药剂。
用于肠胃外施用的控释制剂包括本领域已知的脂质体、聚合物微球和聚合物凝胶制剂。
可能需要或必须通过机械输送装置将本发明的组分引入患者。用于递送药剂的机械递送装置的构建和使用在本领域中是公知的。用于例如直接向脑施用药物的直接技术通常涉及将药物递送导管放置到患者的脑室系统中以绕过血脑屏障。在1991年4月30日授权的美国专利号5,011,472中描述了一种这样的可植入递送系统,其用于将药剂运输到身体的特定解剖学区域。
在必要时或期望时,本发明的组合物还可以含有其它常规药学上可接受的混合成分,通常被称作载体或稀释剂。可以利用用于将这样的组合物制成适当剂型的常规程序。这样的成分和程序包括以下参考文献中描述的那些,其每一篇通过引用并入本文:Powell,M.F.等人, "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311;Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology1999, 53(6), 324-349;和Nema, S.等人, "Excipients and Their Use in InjectableProducts" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4),166-171。
可以适当时使用以针对其预期的施用途径而配制组合物的常用药物成分包括:
酸化剂(实例包括但不限于乙酸、柠檬酸、富马酸、盐酸、硝酸);
碱化剂(实例包括但不限于氨溶液、碳酸铵、二乙醇胺、一乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺(triethanolamine)、三乙醇胺(trolamine));
吸附剂(实例包括但不限于粉状纤维素和活性碳);
气雾剂抛射剂(实例包括但不限于二氧化碳、CCl2F2、F2ClC-CClF2和CClF3)
空气置换剂(实例包括但不限于氮气和氩气);
抗真菌防腐剂(实例包括但不限于苯甲酸、尼泊金丁酯、尼泊金乙酯、尼泊金甲酯、尼泊金丙酯、苯甲酸钠);
抗微生物防腐剂(实例包括但不限于苯扎氯铵、苄索氯铵、苯甲醇、西吡氯铵、氯丁醇、苯酚、苯乙醇、硝酸苯汞和硫柳汞);
抗氧化剂(实例包括但不限于抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴醚、丁羟甲苯、次磷酸、单硫代甘油、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛合次硫酸氢钠、焦亚硫酸钠);
粘合物质(实例包括但不限于嵌段聚合物、天然和合成橡胶、聚丙烯酸酯、聚氨酯、硅酮、聚硅氧烷和苯乙烯-丁二烯共聚物);
缓冲剂(实例包括但不限于偏磷酸钾、磷酸氢二钾、乙酸钠、无水柠檬酸钠以及柠檬酸钠二水合物);
载体(实例包括但不限于阿拉伯胶糖浆、芳香糖浆、芳香酏剂、樱桃糖浆、可可糖浆、桔子糖浆、糖浆、玉米油、矿物油、花生油、芝麻油、抑菌的氯化钠注射剂和抑菌的注射用水);
螯合剂(实例包括但不限于依地酸二钠和依地酸);
着色剂(实例包括但不限于FD&C Red No. 3、FD&C Red No. 20、FD&C Yellow No. 6、FD&C Blue No. 2、D&C Green No. 5、D&C Orange No. 5、D&C Red No. 8、焦糖以及氧化铁红);
澄清剂(实例包括但不限于皂土);
乳化剂(实例包括但不限于阿拉伯胶、聚西托醇(cetomacrogol)、鲸蜡醇、单硬脂酸甘油酯、卵磷脂、脱水山梨糖醇单油酸酯、聚氧乙烯50单硬脂酸酯);
成胶囊剂(实例包括但不限于明胶和邻苯二甲酸乙酸纤维素);
香料(实例包括但不限于茴香油、肉桂油、可可、薄荷醇、橙油、薄荷油和香草醛);
保湿剂(实例包括但不限于甘油、丙二醇和山梨糖醇);
研磨剂(实例包括但不限于矿物油和甘油);
油(实例包括但不限于落花生油、矿物油、橄榄油、花生油、芝麻油和植物油);
软膏基质(实例包括但不限于羊毛脂、亲水性软膏、聚乙二醇软膏、矿脂、亲水性矿脂、白色软膏、黄色软膏和玫瑰水软膏);
渗透增强剂(透皮递送) (实例包括但不限于单羟基或多羟基醇、一价或多价醇、饱和或不饱和脂肪醇、饱和或不饱和脂肪酯、饱和或不饱和二羧酸、精油、磷脂酰衍生物、脑磷脂、萜稀、酰胺、醚、酮和脲);
增塑剂(实例包括但不限于邻苯二甲酸二乙酯和甘油);
溶剂(实例包括但不限于乙醇、玉米油、棉籽油、甘油、异丙醇、矿物油、油酸、花生油、纯净水、注射用水、无菌注射用水和无菌冲洗用水);
硬化剂(实例包括但不限于鲸蜡醇、十六烷基酯蜡、微晶蜡、石蜡、硬脂醇、白蜡和黄蜡);
栓剂基质(实例包括但不限于可可脂和聚乙二醇(混合物));
表面活性剂(实例包括但不限于苯扎氯铵、壬苯醇醚10、辛苯昔醇9、聚山梨酯80、十二烷基硫酸钠和脱水山梨糖醇单棕榈酸酯);
助悬剂(实例包括但不限于琼脂、皂土、卡波姆、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、高岭土、甲基纤维素、黄蓍胶和硅酸镁铝(veegum));
甜味剂(实例包括但不限于阿司帕坦、右旋糖、甘油、甘露醇、丙二醇、糖精钠、山梨糖醇和蔗糖);
片剂抗粘附剂(实例包括但不限于硬脂酸镁和滑石);
片剂粘合剂(实例包括但不限于阿拉伯胶、藻酸、羧甲基纤维素钠、可压缩糖、乙基纤维素、明胶、液体葡萄糖、甲基纤维素、非交联聚乙烯吡咯烷酮和预胶化淀粉);
片剂和胶囊剂稀释剂(实例包括但不限于磷酸氢钙、高岭土、乳糖、甘露醇、微晶纤维素、粉状纤维素、沉淀碳酸钙、碳酸钠、磷酸钠、山梨糖醇和淀粉);
片剂包衣剂(实例包括但不限于液体葡萄糖、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、邻苯二甲酸乙酸纤维素和虫胶);
直接压片赋形剂(实例包括但不限于磷酸氢钙);
片剂崩解剂(实例包括但不限于藻酸、羧甲基纤维素钙、微晶纤维素、聚克立林钾、交联聚乙烯吡咯烷酮、藻酸钠、淀粉羟乙酸钠和淀粉);
片剂助流剂(实例包括但不限于胶体二氧化硅、玉米淀粉和滑石);
片剂润滑剂(实例包括但不限于硬脂酸钙、硬脂酸镁、矿物油、硬脂酸和硬脂酸锌);
片剂/胶囊剂遮光剂(实例包括但不限于二氧化钛);
片剂抛光剂(实例包括但不限于巴西棕榈蜡和白蜡);
增稠剂(实例包括但不限于蜂蜡、鲸蜡醇和石蜡);
张度剂(实例包括但不限于右旋糖和氯化钠);
增粘剂(实例包括但不限于藻酸、皂土、卡波姆、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮、藻酸钠和黄蓍胶);和
润湿剂(实例包括但不限于十七乙烯氧基鲸蜡醇(heptadecaethylene oxycetanol)、卵磷脂、山梨糖醇单油酸酯、聚氧乙烯山梨糖醇单油酸酯和聚氧乙烯硬脂酸酯)。
根据本发明的药物组合物可以举例如下:
无菌IV溶液剂:可以使用无菌可注射水制备所期望的本发明的化合物的5 mg/mL溶液,并且如果需要,则调整pH。用无菌5%右旋糖将所述溶液稀释至1-2 mg/mL用于施用,并且在约60分钟内作为IV输注施用。
用于IV施用的冻干粉:可用(i)100-1000mg的作为冻干粉的本发明的期望化合物,(ii)32-327mg/mL柠檬酸钠,和(iii)300-3000mg 右旋糖酐40制备无菌制剂。用无菌注射用盐水或右旋糖5%将该制剂重构至10-20 mg/mL的浓度,然后用盐水或右旋糖5%进一步稀释至0.2-0.4mg/mL,并且经15-60分钟IV推注或通过IV输注施用。
肌内混悬剂: 可制备以下溶液剂或混悬剂用于肌内注射:
50 mg/mL的期望的、水不溶性的本发明的化合物
5 mg/mL羧甲基纤维素钠
4 mg/mL吐温80
9 mg/mL氯化钠
9 mg/mL苯甲醇。
硬壳胶囊剂: 通过各自用100 mg粉状活性成分、150 mg乳糖、50 mg纤维素和6 mg硬脂酸镁填充标准的两片式硬明胶胶囊来制备大量的单位胶囊剂。
软明胶胶囊剂: 制备活性成分在可消化的油(例如大豆油、棉籽油或橄榄油)中的混合物并且通过容积式泵将其注入熔化的明胶中以形成含有100 mg活性成分的软明胶胶囊。清洗并干燥胶囊。可以将活性成分溶解于聚乙二醇、甘油和山梨糖醇的混合物中以制备水混溶性药物混合物。
片剂: 通过常规程序制备大量片剂,使得剂量单位为100mg活性成分、0.2mg胶体二氧化硅、5mg硬脂酸镁、275mg微晶纤维素、11mg淀粉和98.8mg乳糖。可施用适当的水性和非水性包衣以增加适口性、改善雅观和稳定性或延迟吸收。
速释片剂/胶囊剂:这些是通过常规方法和新方法制备的固体口服剂型。为了药物的即刻溶出和递送,以不用水的方式口服这些单位。将活性成分混合在包含成分例如糖、明胶、果胶和甜味剂的液体中。通过冷冻干燥和固态提取技术使这些液体固化成固体片剂或囊片。可以将药物化合物与粘弹性和热弹性的糖以及聚合物或泡腾组分一起压片以生产多孔基质,所述多孔基质意图用于不需要水而速释。
商业用途
组分A
根据上述组合产品的式(A)和(I)的化合物及其立体异构体是组分A。根据该组合产品的化合物具有有价值的药学性质,这使得它们是在商业上可以使用的。具体而言,它们抑制PI3K/AKT途径并表现出细胞活性。预期它们可商业适用于治疗疾病(例如依赖于过度活化的PI3K/AKT的疾病)。PI3K/AKT途径的异常活化是引发和维持人肿瘤的必要步骤,因此,其抑制(例如用PI3K抑制剂抑制)被理解为治疗人肿瘤的有效方法。对于最近的综述,参见Garcia-Echeverria等人(Oncogene, 2008, 27, 551-5526。
组分B
由于如引言部分中讨论的机制,组分B特别适合于对肿瘤疾病、特别是通过抗细胞凋亡途径或细胞周期激活发展抗性机制的那些具有效果。
组合产品
本发明的组合产品因此可以用于治疗或预防不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫反应或不适当的细胞炎症反应的疾病,或者伴随有不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫反应或不适当的细胞炎症反应的疾病,特别是其中不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫反应或不适当的细胞炎症反应,诸如例如血液肿瘤和/或其转移、实体瘤和/或其转移,例如白血病、其多发性骨髓瘤和骨髓增生异常综合征、恶性淋巴瘤、乳腺肿瘤(包括和其骨转移)、胸部肿瘤(包括非小细胞肺肿瘤和小细胞肺肿瘤和其骨转移)、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其它妇科肿瘤和其骨转移、泌尿系统肿瘤(包括肾肿瘤、膀胱肿瘤和前列腺肿瘤)、皮肤肿瘤和肉瘤、和/或其转移。
一个实施方案涉及如本文所定义的组合产品用于制备用于治疗或预防癌症,特别是非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)的药物的用途。
一个实施方案涉及如本文所定义的组合产品在治疗或预防癌症,特别是非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)中的用途。
在一个实施方案中,本发明涉及包含组分A或其药学上可接受的盐和组分B的组合产品,其静脉内、腹膜内施用,优选其口服施用。
在本发明的上下文中、特别是在如本文所使用的"不适当的细胞免疫应答或不适当的细胞炎症应答"的上下文中,术语"不适当的"应理解为优选是指与正常相比应答更弱或更强,并且与所述疾病的病理相关、是所述疾病的病理的原因或者导致所述疾病的病理的应答。
可利用本发明的组合产品来抑制、阻断、降低、减少等细胞增殖和/或细胞分裂和/或产生细胞凋亡。
本发明包括这样的方法,所述方法包括向有需要的哺乳动物(包括人)施用有效地治疗所述病症的量的本发明的组分A和该量的本发明的组分B或其药学上可接受的盐、异构体、多晶型物、代谢物、水合物、溶剂化物或酯等。
过度增殖性病症包括但不限于,例如银屑病、瘢痕疙瘩和其它影响皮肤的增生、良性前列腺增生(BPH)以及恶性肿瘤。可用根据本发明的化合物治疗的恶性肿瘤的实例包括实体瘤和血液瘤。实体瘤可以例举为乳房、膀胱、骨、脑、中枢和外周神经系统、结肠、肛门(anum)、内分泌腺(例如甲状腺和肾上腺皮质)、食道、子宫内膜、生殖细胞、头和颈、肾、肝、肺、喉和下咽的肿瘤、间皮瘤、卵巢、胰腺、前列腺、直肠、肾、小肠、软组织、睾丸、胃、皮肤、输尿管、阴道和外阴的肿瘤。恶性肿瘤包括遗传性癌症,例如视网膜母细胞瘤和Wilms肿瘤。此外,恶性肿瘤包括所述器官中的原发性肿瘤及在远端器官中的相应继发性肿瘤("肿瘤转移")。血液肿瘤可以是例如侵袭性和惰性形式的白血病和淋巴瘤,即非霍奇金病、慢性和急性髓样白血病(CML/AML)、急性成淋巴细胞性白血病(ALL)、霍奇金病、多发性骨髓瘤和T-细胞淋巴瘤。还包括骨髓增生异常综合征、浆细胞瘤形成、类肿瘤性综合征和未知原发部位的癌症以及AIDS相关的恶性肿瘤。
乳腺癌的实例包括但不限于侵袭性导管癌、侵袭性小叶癌、原位导管癌和原位小叶癌,特别是具有骨转移。
呼吸道癌的实例包括但不限于小细胞和非小细胞肺癌、以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的实例包括但不限于脑干和下丘脑(hypophtalmic)胶质瘤、小脑和大脑星形细胞瘤、髓母细胞瘤、室管膜瘤以及神经外胚层和松果体瘤。
男性生殖器官肿瘤包括但不限于前列腺和睾丸癌。女性生殖器官肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌、和外阴癌、以及子宫肉瘤。
消化道肿瘤包括但不限于肛门癌、结肠癌、结肠直肠癌、食管癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌、和唾液腺癌。
泌尿道肿瘤包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌、尿道癌和人乳头状肾癌。
眼癌包括但不限于眼内黑素瘤和视网膜母细胞瘤。
肝癌的实例包括但不限于肝细胞癌(具有或不具有纤维板层变体的肝细胞癌)、胆管上皮癌(肝内胆管癌)、和混合型肝细胞胆管上皮癌。
皮肤癌包括但不限于鳞状细胞癌、卡波济氏肉瘤、恶性黑素瘤、Merkel细胞皮肤癌和非黑素瘤皮肤癌。
头部和颈部癌包括但不限于喉癌、下咽癌、鼻咽癌、口咽癌、唇癌和口腔癌以及鳞状细胞。淋巴瘤包括但不限于AIDS相关的淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、伯基特淋巴瘤、霍奇金病以及中枢神经系统淋巴瘤。
肉瘤包括但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤、和横纹肌肉瘤。
白血病包括但不限于急性髓样白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病和毛细胞白血病。
这些病症已在人类中得到良好表征,但还以相似的病因学存在于其它哺乳动物中,并且可通过施用本发明的药物组合物进行治疗。
整个本文件中所声明的术语"治疗(treating)"或"治疗(treatment)"是常规地使用的,例如以抵抗、减轻、减少、缓解、改善疾病或病症例如癌的病况等为目的来管理或护理对象。
本发明的组合产品还可用于治疗与过度和/或异常的血管生成相关的病症和疾病。
血管生成的不适当和异位表达对生物体可以是有害的。大量病理性的病症与新异的血管生长有关。这些包括例如糖尿病性视网膜病、缺血性视网膜静脉闭塞和早产儿视网膜病[Aiello 等人 New Engl. J. Med. 1994, 331, 1480;Peer 等人 Lab. Invest.1995, 72, 638]、年龄相关的黄斑变性[AMD;参见, Lopez 等人 Invest. Opththalmol.Vis. Sci. 1996, 37, 855]、新生血管性青光眼、银屑病、晶状体后纤维增生症、血管纤维瘤、炎症、类风湿性关节炎(RA)、再狭窄、支架内再狭窄、血管移植物再狭窄等。此外,与癌性和肿瘤组织相关的血液供应增加促进生长,导致迅速的肿瘤扩大和转移。此外,肿瘤中的新血管和淋巴管的生长为脱离的细胞(renegade cells)提供逃逸途径,促进转移并且导致癌症扩散。因此,本发明的组合产品可用于治疗和/或预防任何上述血管生成病症,例如通过抑制和/或减少血管形成;通过抑制、阻断、减少、降低等血管生成中涉及的内皮细胞增殖或其它类型,以及引起这些细胞类型的细胞死亡或细胞凋亡。
剂量和施用
组分A和组分B
基于已知用以评价可用于治疗过度增殖性病症和血管生成性病症的化合物的标准实验室技术,通过标准毒性试验并且通过用于确定上文指出的哺乳动物中的病况的治疗的标准药理学测定,并且通过将这些结果与用于治疗这些病况的已知药物的结果进行比较,可以容易地针对每一种期望适应症的治疗确定本发明的化合物的有效剂量。在这些状况之一的治疗中待施用的活性成分的量可以根据诸如以下的考量而在很大程度上变化:使用的具体组分和剂量单位、施用模式、疗程、所治疗患者的年龄和性别、所治疗状况的性质和程度。
待施用的活性成分的总量通常范围为约0.001mg/kg-约200mg/kg体重/天,并且优选约0.01mg/kg-约20mg/kg体重/天。化合物的临床上有用的施用方案范围为每日一次至三次的施用至每四周一次的施用。此外,其中在某一段时间内不给予患者药物的"停药期"对于药理学作用和耐受性之间的整体平衡而言可以是有利的。单位剂量可以包含约0.5 mg至约1500 mg的活性成分,并且可每日一次或多次地施用,或者少于每日一次地施用。对于通过注射,包括静脉内、肌内、皮下和肠胃外注射以及使用输注技术来进行的施用而言,平均每日剂量将优选为0.01至200 mg/kg总体重。平均每日直肠剂量方案将优选为0.01至200mg/kg总体重。平均每日阴道剂量方案将优选为0.01至200 mg/kg总体重。平均每日外用剂量方案将优选为每日一次至四次施用0.1至200 mg。透皮浓度将优选为维持0.01至200 mg/kg的每日剂量所需要的浓度。平均每日吸入剂量方案将优选为0.01至100 mg/kg总体重。
当然,对每个患者而言,具体的起始剂量和持续剂量方案将根据下述因素而变化:主治诊断医生所确定的病况的性质和严重程度、所使用的具体化合物的活性、患者的年龄和整体状况、施用时间、施用途径、药物的排泄速率、药物组合等。本发明的化合物或者其药学上可接受的盐或酯或组合物的期望的治疗方式和剂量数量可由本领域技术人员利用常规的治疗试验来确定。
本发明的组合产品
本发明的组合产品可以以进行或者不进行肿瘤生长的预治疗的方式特别地用于治疗和防止(即预防)所有适应症和阶段的肿瘤的生长和转移,包括实体和血液学肿瘤。
对特定的药理学或药物特性的测试方法是本领域技术人员众所周知的。
本发明的组分A和组分B的组合产品可以作为唯一的药剂或与一种或多种其它药剂C组合(其中所得的组分A、B和C的组合产品不会引起不可接受的副作用)施用。例如,本发明的组分A和B的组合产品可以与组分C、即一种或多种其它药剂、诸如已知的抗血管生成剂、抗过度增殖剂、抗炎剂、镇痛剂、免疫调节剂、利尿剂、抗心律失常剂、抗高胆固醇血症剂、抗血脂障碍剂、抗糖尿病剂或抗病毒剂等,以及与其混合物和组合产品进行组合。
组分C可以是一种或多种药剂,诸如131I-chTNT、阿巴瑞克、阿比特龙、阿柔比星、ado-trastuzumab emtansine、阿法替尼、阿柏西普、阿地白介素、艾乐替尼、阿仑珠单抗、阿仑膦酸、阿利维A酸、六甲蜜胺、氨磷汀、氨鲁米特、氨基酮戊酸己酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴香脑二硫杂环戊二烯硫酮(anethole dithiolethione)、anetumabravtansine、血管紧张素II、抗凝血酶III、阿瑞匹坦、阿西莫单抗、阿格拉宾、三氧化二砷、门冬酰胺酶、阿西替尼、阿扎胞苷、巴利昔单抗、贝洛替康、苯达莫司汀、贝索单抗、贝林司他、贝伐珠单抗、贝沙罗汀、比卡鲁胺、比生群、博来霉素、兰妥莫单抗、硼替佐米、布舍瑞林、波舒替尼(bosutinib)、brentuximab vedotin、白消安、卡巴他赛(cabazitaxel)、卡博替尼、降钙素、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡波醌、卡非佐米、卡莫氟、卡莫司汀、卡妥索单抗、塞来考昔、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨、考比替尼、库潘尼西、克立他酶(crisantaspase)、克唑替尼、环磷酰胺、环丙特龙、阿糖胞苷、达卡巴嗪、更生霉素、达雷木单抗、达促红素α、达拉非尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素2、地舒单抗、地普奥肽、地洛瑞林、环氧乳醇、右雷佐生、二溴螺氯铵、二去水卫矛醇、双氯芬酸、dinutuximab、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、依库珠单抗、依屈洛单抗、依利醋铵、依洛珠单抗、艾曲泊帕、内皮他丁、依诺他滨、恩杂鲁胺、表柔比星、环硫雄醇、促红素α、促红素β、促红素ζ、依他铂、艾立布林、厄洛替尼、埃索美拉唑、雌二醇、雌莫司汀、炔雌醇、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、非格司亭、氟甲睾酮、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、钆特醇、钆特酸葡甲胺、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥珠单抗、谷卡匹酶、氧化型谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林、格拉司琼、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林、羟基脲、I-125种子(I-125 seeds)、兰索拉唑、伊班膦酸、替伊莫单抗、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫德、英丙舒凡、吡地司琼、英卡膦酸、丁烯英酯、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、伊匹木单抗、伊立替康、伊曲康唑、伊沙匹隆、伊克昔佐米、兰瑞肽、兰索拉唑、拉帕替尼、lasocholine、来那度胺、乐伐替尼、来格司亭、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、左炔诺孕酮、左甲状腺素钠、利舒脲、洛铂、洛莫司汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯嘌呤、美司钠、美沙酮、甲氨蝶呤、甲氧沙林、氨基酮戊酸甲酯、甲基泼尼松龙、甲睾酮、甲酪氨酸、米法莫肽、米替福新、米立铂、二溴甘露醇、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫派达醇、盐酸吗啡、硫酸吗啡、大麻隆、nabiximols、那法瑞林、纳洛酮 + 喷他佐辛、纳曲酮、那托司亭、奈昔木单抗、奈达铂、奈拉滨、奈立膦酸、奈妥匹坦/帕洛诺司琼、nivolumabpentetreotide、尼洛替尼、尼鲁米特、尼莫拉唑、尼妥珠单抗、尼莫司汀、尼达尼布、尼曲吖啶、纳武单抗、阿托珠单抗、奥曲肽、奥法木单抗、奥拉帕利、美琥他辛(omacetaxine mepesuccinate)、奥美拉唑、昂丹司琼、奥普瑞白介素、奥古蛋白(orgotein)、orilotimod、奥希替尼、奥沙利铂、羟考酮、羟甲烯龙、ozogamicine、p53基因疗法、紫杉醇、帕博西尼、帕利夫明、钯-103种子(palladium-103 seed)、帕洛诺司琼、帕米膦酸、帕木单抗、帕比司他、泮托拉唑、帕唑帕尼、培门冬酶、PEG-促红素β(甲氧基PEG-促红素β)、派姆单抗、培非司亭、培干扰素α-2b、培美曲塞、喷他佐辛、喷司他丁、培洛霉素、全氟丁烷、培磷酰胺、帕妥珠单抗、毕西巴尼、匹鲁卡品、吡柔比星、匹克生琼、普乐沙福、普卡霉素、聚氨葡糖、聚磷酸雌二醇、聚乙烯吡咯烷酮 + 透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙、泼尼莫司汀、强的松、丙卡巴肼、丙考达唑、普萘洛尔、喹高利特、雷贝拉唑、雷妥莫单抗、氯化镭-223、雷多替尼、雷洛昔芬、雷替曲塞、雷莫司琼、雷莫芦单抗、雷莫司汀、拉布立酶、雷佐生、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、依替膦酸铼-186、利妥昔单抗、罗拉匹坦、罗米地新、罗米司亭、罗莫肽、roniciclib、来昔决南钐(153Sm)、沙格司亭、沙妥莫单抗、胰泌素、司妥昔单抗、西普鲁塞-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索尼吉布、索拉非尼、司坦唑醇、链佐星、舒尼替尼、他拉泊芬、talimogene laherparepvec、他米巴罗汀、他莫昔芬、他喷他多、他索纳明、替西白介素、锝(99mTc)巯诺莫单抗、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美拉西+奥替拉西、替莫泊芬、替莫唑胺、坦罗莫司、替尼泊苷、睾酮、替曲膦、沙立度胺、塞替派、胸腺法新、促甲状腺素α、硫鸟嘌呤、托珠单抗、托泊替康、托瑞米芬、托西莫单抗、曲贝替定、曲美替尼、曲马多、曲妥珠单抗、曲妥珠单抗 emtansine、曲奥舒凡、维甲酸、三氟尿苷 + tipiracil、曲洛司坦、曲普瑞林、曲美替尼、曲磷胺、促血小板生成素、色氨酸、乌苯美司、瓦他拉尼、戊柔比星、凡他尼布、伐普肽、vemurafenib、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、维莫德吉、伏林司他、伏罗唑、钇-90玻璃微球、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星或其组合产品。
可替代地,所述组分C可以是一种或多种其它药剂,所述药剂选自:吉西他滨、紫杉醇、顺铂、卡铂、丁酸钠、5-FU、多柔比星、他莫昔芬、依托泊苷、曲妥珠单抗、吉非替尼、甘乐能(intron A)、雷帕霉素、17-AAG、U0126、胰岛素、胰岛素衍生物、PPAR配体、磺酰脲类药物、α-葡萄糖苷酶抑制剂、双胍类、PTP-1B抑制剂、DPP-IV抑制剂、11-β-HSD抑制剂、GLP-1、GLP-1衍生物、GIP、GIP衍生物、PACAP、PACAP衍生物、胰泌素或胰泌素衍生物。
可以作为组分C添加至本发明的组分A和B的组合产品的任选的抗过度增殖剂包括但不限于Merck Index, (1996) 第11版中的癌症化疗药物方案上列出的化合物,其据此通过引用并入,所述化合物诸如门冬酰胺酶、博来霉素、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、左旋门冬酰胺酶、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、柔红霉素、多柔比星(阿霉素)、表柔比星、依托泊苷、5-氟尿嘧啶、六甲蜜胺、羟基脲、异环磷酰胺、伊立替康、亚叶酸、洛莫司汀、氮芥、6-巯基嘌呤、美司钠、甲氨蝶呤、丝裂霉素C、米托蒽醌、泼尼松龙、泼尼松、丙卡巴肼、雷洛昔芬、链佐星、他莫昔芬、硫鸟嘌呤、托泊替康、长春碱、长春新碱和长春地辛。
适合作为组分C与本发明的组分A和B的组合产品一起使用的其它抗过度增殖剂包括但不限于Goodman和Gilman的 The Pharmacological Basis of Therapeutics(第九版), 编辑Molinoff等人, 由McGraw-Hill公开, 第1225-1287页,(1996)中的认可用于治疗肿瘤性疾病的那些化合物,其特此通过引用并入,所述化合物诸如氨鲁米特、L-门冬酰胺酶、硫唑嘌呤、5-氮杂胞苷克拉屈滨(5-azacytidine cladribine)、白消安、己烯雌酚、2',2'-二氟脱氧胞苷(2',2'-difluorodeoxycytidine)、多西他赛、赤式-羟基壬基腺嘌呤、乙炔雌二醇、5-氟脱氧尿苷、单磷酸5-氟脱氧尿苷、磷酸氟达拉滨、氟甲睾酮、氟他胺、己酸羟孕酮、伊达比星、干扰素、醋酸甲羟孕酮、醋酸甲地孕酮、美法仑、米托坦、紫杉醇(当组分B本身不是紫杉醇时)、喷司他丁、N-膦酰基乙酰基-L-天冬氨酸(PALA)、普卡霉素、司莫司汀、替尼泊苷、丙酸睾酮、塞替派、三甲基三聚氰胺、尿核苷和长春瑞滨。
适合作为组分C与本发明的组分A和B的组合产品一起使用的其它抗过度增殖剂包括但不限于其它抗癌剂,诸如爱波喜龙及其衍生物、伊立替康、雷洛昔芬和托泊替康。
一般而言,将作为组分C的细胞毒性剂和/或细胞抑制剂与本发明的组分A和B的组合产品组合使用会起到下述作用:
(1) 与单独施用任一种药剂相比,在减少肿瘤生长和/或转移或甚至消除肿瘤和/或转移方面产生更好的功效,
(2) 提供较少量的施用的化学治疗剂的施用,
(3) 提供与用单药剂化学疗法和某些其它联合疗法观察到的相比在患者中具有良好耐受性(具有较少的有害药理学并发症)的化学治疗,
(4) 提供在哺乳动物,特别是人类中更广谱的不同癌症类型的治疗,
(5) 提供在治疗的患者中更高的响应率,
(6) 提供与标准化学疗法治疗相比在治疗的患者中的更长的存活时间,
(8) 为肿瘤进展提供更长的时间,和/或
(9) 与其中其它癌症药剂组合产品产生拮抗作用的已知情况相比,产生至少与单独使用的那些药剂同样良好的功效和耐受性结果。
实验部分
证明本发明的组分A和B的组合产品的协同作用的实施例
组分A:
在该实验部分和图中,术语“化合物A”是组分A的实例并且是如本文所示的WO 2008/070150 A1的化合物实施例13:它是以下结构的2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺:
或其溶剂化物、水合物或立体异构体。
在该实验部分和图中,术语“化合物A’”是指以下结构的2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐,或“库潘尼西”:
或其溶剂化物、水合物或立体异构体。
化合物A’的合成描述于欧洲专利申请号EP 11 161 111.7,以及在WO 2012/136553下公布的PCT申请号PCT/EP2012/055600,其两者均特此以其整体通过引用并入本文。
组分B:
在该实验部分和图中,术语“化合物B”是指“维奈托克”(或“ABT-199”),且“化合物B’”是指“帕博西尼”,它们是从Selleck Chemicals获得的(产品编号S8048、S1116)。
证明本发明的化合物A'和化合物B或化合物B'的组合产品的协同作用的实施例
通过72小时细胞增殖测定的联合指数(COMBINATION INDEX,CI)评估在一组细胞系中
的库潘尼西和ABT-199或帕博西尼的组合产品
使用用于体外评估的联合指数等效线图分析评估本发明的组合产品的效果。功效参数是在72小时细胞增殖测定中的效果。简而言之,将3000个细胞接种在具有适当生长培养基的384孔板中。通过HP D300数字分配器以10步2,5倍稀释系列将测试化合物添加到细胞中:
● 单独的库潘尼西,
● 单独的ABT-199,
● 单独的帕博西尼,
和
● 库潘尼西和ABT-199的组合产品
和
● 库潘尼西和帕博西尼的组合产品。
使用不同比例(1:0;0.85:0.15;0.7:0.3;0.5:0.5;0.3:0.7;0.15:0.85;0:1)进行连续2,5倍稀释以产生10个浓度的响应曲线。将细胞处理72小时,然后通过Cell Titer Glo测定(Promega)评估细胞活力。实验一式两份地进行。计算绘制的(mapping)IC50值。计算库潘尼西和ABT-199或帕博西尼的相应组分浓度并用于绘制等效线图。如Chou(PharmacologyReviews 2006)所述分析效果,并使用下式计算联合指数:
联合指数= [Ax]/A'+ [Bx]/B'
[Ax]和[Bx]指的是组分A和组分B。
A'和B'分别表示作为单一药剂的A和B的IC50值。将0-0.3、0.3-0.6和0.6-0.9的平均联合指数(CI)分别定义为表示非常强的协同作用、强的协同作用和协同作用。0.9-1.1的CI被定义为相加作用。大于1.1的CI被定义为拮抗作用。
表的描述
表1
用于使用库潘尼西和帕博西尼或维奈托克的组合产品的增殖测定的细胞系。
表1
* DSMZ = 位于德国的德国微生物和细胞培养物保藏中心:Deutsche Sammlung für Mikroorganismen und Zelllinien:https://www.dsmz.de/
** ATCC = 美国典型培养物保藏中心:
*** OISI = 瑞士南部肿瘤学研究所(IOSI);。
表2:来自用库潘尼西和维奈托克的组合产品处理的细胞系的增殖测定的计算的IC50、联合指数(CI)和观察到的作用。
表2
细胞系 | 库潘尼西IC50 | 维奈托克IC50 | 联合指数:库潘尼西/维奈托克组合产品 | 联合作用 |
GRANTA-519 | 1,11E-07 | 1,77E-08 | 0,58 | 强协同作用 |
JEKO-1 | 4,09E-08 | 3,43E-06 | 0,26 | 非常强协同作用 |
JVM-2 | 2,17E-08 | 5,74E-06 | 0,41 | 强协同作用 |
MAVER-1 | 1,04E-07 | 1,86E-09 | 0,36 | 强协同作用 |
MINO | 1,02E-07 | 1,28E-09 | 0,70 | 协同作用 |
REC-1 | 6,00E-09 | 2,03E-08 | 0,64 | 协同作用 |
Z-138 | 2,05E-08 | 1,00E-06 | 0,91 | 相加 |
SP-49 | 2,50E-09 | 1,72E-06 | 0,78 | 协同作用 |
SP-53 | 1,43E-09 | 1,00E-05 | 0,68 | 协同作用 |
UPN1 | 1,50E-08 | 1,00E-05 | 1,30 | 拮抗 |
ESKOL | 9,88E-08 | 1,00E-05 | 1,06 | 相加 |
HAIR-M | 5,39E-09 | 2,56E-07 | 0,25 | 非常强协同作用 |
HC-1 | 1,83E-07 | 1,00E-05 | 0,63 | 协同作用 |
KARPAS-1718 | 1,51E-08 | 3,72E-09 | 0,37 | 强协同作用 |
SSK41 | 5,08E-08 | 6,23E-06 | 0,97 | 相加 |
VL51 | 2,07E-08 | 1,49E-06 | 0,31 | 强协同作用 |
表3:来自用库潘尼西和帕博西尼的组合产品处理的细胞系的增殖测定的计算的IC50、联合指数(CI)和观察到的作用。
表3
细胞系 | 库潘尼西IC50 | 帕博西尼IC50 | 联合指数:库潘尼西/帕博西尼组合产品 | 联合作用 |
GRANTA-519 | 1,11E-07 | 1,00E-05 | 0,45 | 强协同作用 |
JEKO-1 | 4,09E-08 | 4,04E-07 | 0,37 | 强协同作用 |
JVM-2 | 2,17E-08 | 5,66E-06 | 0,81 | 协同作用 |
MAVER-1 | 1,04E-07 | 4,70E-07 | 0,45 | 强协同作用 |
MINO | 1,02E-07 | 5,75E-07 | 0,25 | 非常强协同作用 |
REC-1 | 6,00E-09 | 4,71E-06 | 0,90 | 协同作用 |
Z-138 | 2,05E-08 | 1,29E-06 | 0,87 | 协同作用 |
SP-49 | 2,50E-09 | 2,05E-07 | 1,09 | 相加 |
SP-53 | 1,43E-09 | 9,59E-08 | 0,84 | 协同作用 |
UPN1 | 1,50E-08 | 3,40E-06 | 0,78 | 协同作用 |
ESKOL | 9,88E-08 | 2,07E-06 | 0,37 | 强协同作用 |
HAIR-M | 5,39E-09 | 1,56E-06 | 0,87 | 协同作用 |
HC-1 | 1,83E-07 | 2,30E-06 | 0,28 | 非常强协同作用 |
KARPAS-1718 | 1,51E-08 | 7,65E-06 | 1,37 | 拮抗 |
SSK41 | 5,08E-08 | 2,31E-06 | 0,60 | 强协同作用 |
VL51 | 2,07E-08 | 1,00E-05 | 1,11 | 拮抗 |
结论:
在GRANTA-519,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示中度、强和没有抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致非常强的协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致强的协同作用。
在JEKO-1,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、弱和中度抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致强的协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致强的协同作用。
在JVM-2,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、弱和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致强的协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致协同作用。
在MAVER-1,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示中度、非常强和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致强的协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致强的协同作用。
在MINO,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示中度、非常强和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致非常强的协同作用。
在REC-1,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示非常强、强和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致协同作用。
在Z-138,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、弱和弱的抗增殖活性。库潘尼西和维奈托克的组合产品没有进一步增强抗增殖作用,但导致相加作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致协同作用。
在SP-49,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示非常强、弱和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致协同作用。库潘尼西和帕博西尼的组合产品没有进一步增强抗增殖作用,但导致相加作用。
在SP-53,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示非常强、没有和强的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致协同作用。
在UPN-1,一种套细胞淋巴瘤(MCL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、没有和弱的抗增殖活性。库潘尼西和维奈托克的组合产品导致拮抗作用。库潘尼西和帕博西尼的组合产品增强了抗增殖作用,导致协同作用。
在ESKOL,一种边缘区淋巴瘤(MZL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、没有和弱的抗增殖活性。库潘尼西和维奈托克的组合产品没有进一步增强抗增殖作用,但导致相加作用。库潘尼西和帕博西尼的组合产品增强了抗增殖作用,导致强的协同作用。
在HAIR-M,一种边缘区淋巴瘤(MZL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示非常强、中度和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致非常强的协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致协同作用。
在HC-1,一种边缘区淋巴瘤(MZL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示中度、没有和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致强的协同作用。库潘尼西和帕博西尼的组合产品也增强了抗增殖作用,导致非常强的协同作用。
在KARPAS-1718,一种脾边缘区淋巴瘤(SMZL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、非常强和弱的抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致协同作用。库潘尼西和帕博西尼的组合产品导致拮抗作用。
在SSK41,一种脾边缘区淋巴瘤(SMZL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、弱和弱的抗增殖活性。库潘尼西和维奈托克的组合产品没有进一步增强抗增殖作用,但导致相加作用。库潘尼西和帕博西尼的组合产品增强了抗增殖作用,导致强的协同作用。
在VL51,一种脾边缘区淋巴瘤(SMZL)细胞系中,库潘尼西、维奈托克和帕博西尼的单一疗法治疗分别显示强、弱和没有抗增殖活性。库潘尼西和维奈托克的组合产品增强了抗增殖作用,导致强的协同作用。库潘尼西和帕博西尼的组合产品导致拮抗作用。
总之,在10个套细胞淋巴瘤(MCL)、3个边缘区淋巴瘤(MZL)和3个脾边缘区淋巴瘤(SMZL)细胞系中,库潘尼西单一疗法治疗显示非常强至中度的抗增殖活性,维奈托克单一疗法治疗显示非常强至没有抗增殖活性且帕博西尼显示中度至没有抗增殖活性。
库潘尼西和维奈托克的组合产品在7个套细胞淋巴瘤(MCL)中的6个、3个边缘区淋巴瘤(MZL)和3个脾边缘区淋巴瘤(SMZL)细胞系中显示直接和协同至相加的抗肿瘤活性。
库潘尼西和帕博西尼的组合产品在所有7个套细胞淋巴瘤(MCL)、3个边缘区淋巴瘤(MZL)和3个脾边缘区淋巴瘤(SMZL)细胞系中的2个中显示直接和协同至相加的抗肿瘤活性。
总之,我们的数据表明了PI3K抑制剂库潘尼西和维奈托克或帕博西尼在抑制肿瘤细胞增殖方面的协同作用,并值得进一步临床评估这种用于治疗癌症,包括套细胞淋巴瘤、边缘区淋巴瘤和脾边缘区淋巴瘤的有希望的联合疗法。
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Claims (23)
1.至少两种组分——组分A和组分B的组合产品,其包含为PI3K的抑制剂或其生理学上可接受的盐、溶剂化物、水合物或立体异构体的组分A和为维奈托克或帕博西尼的组分B。
2.根据权利要求1的至少两种组分——组分A和组分B的组合产品,其中所述组分A是以下通式的化合物:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,其中:
R1代表–(CH2)n-(CHR4)-(CH2)m-N(R5)(R5’);
R2代表任选被1、2或3个R6基团取代的杂芳基;
R3 代表烷基或环烷基;
R4 代表氢或烷氧基;
R5和R5’可以是相同或不同的且独立地为氢、烷基、环烷基烷基或烷氧基烷基或R5和R5’可以与它们所结合的氮原子一起形成任选含有至少一个选自氧、氮或硫的额外杂原子且可以任选被1个或多个R6’基团取代的3-7元含氮杂环,或R4和R5可以与它们所结合的原子一起形成任选含有1个或多个氮、氧或硫原子且可以任选被1个或多个R6’基团取代的5-6元含氮杂环;
R6的每次出现可以是相同或不同的且独立地为卤素、烷基、烯基、炔基、环烷基、环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、杂环、杂环基烷基、烷基-OR7、烷基-SR7、烷基-N(R7)(R7’)、烷基-COR7、-CN、-COOR7、-CON(R7)(R7’)、-OR7、-SR7、-N(R7)(R7’)或–NR7COR7,其各自可任选被1个或多个R8基团取代;
R6’的每次出现可以是相同或不同的且独立地为烷基、环烷基烷基或烷基-OR7;
R7和R7’的每次出现可以是相同或不同的且独立地为氢、烷基、烯基、炔基、环烷基、环烷基烷基、环烯基、芳基、芳基烷基、杂芳基、杂环、杂环基烷基或杂芳基烷基;
R8的每次出现独立地为硝基、羟基、氰基、甲酰基、乙酰基、卤素、氨基、烷基、烷氧基、烯基、炔基、环烷基、环烷基烷基、环烯基、芳基、芳基烷基、杂芳基、杂环、杂环基烷基或杂芳基烷基;
n是1-4的整数且m是0-4的整数,条件是当R4和R5与它们所结合的原子一起形成3-7元含氮环时,n + m ≤ 4;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
3.根据权利要求1或2的组合产品,其中所述组分A是权利要求2的式(I)的化合物,其中R4和R5与它们所结合的原子一起形成任选含有1个或多个氮、氧或硫原子且可以任选被1个或多个R6’基团取代的5-6元含氮杂环,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
4.根据权利要求1-3中任一项的组合产品,其中所述组分A是权利要求2的式(I)的化合物,其中R2是任选被1、2或3个R6基团取代的吡啶、哒嗪、嘧啶、吡嗪、吡咯、噁唑、噻唑、呋喃或噻吩,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
5.根据权利要求1-4中任一项的组合产品,其中所述组分A是式(I)的化合物,其具有下式:
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
6.权利要求5的组合产品,其中,在所述式(I)的化合物中,R2是任选被1、2或3个R6基团取代的吡啶、哒嗪、嘧啶、吡嗪、吡咯、噁唑、噻唑、呋喃或噻吩,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
7.权利要求1-6中任一项的组合产品,其中所述组分A是选自下列的化合物:
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-2,4-二甲基-1,3-噻唑-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噻唑-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]异烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-甲基-1,3-噻唑-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-丙基嘧啶-5-甲酰胺;
N-{8-[2-(4-乙基吗啉-2-基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺 1-氧化物;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(2-吡咯烷-1-基乙基)烟酰胺;
6-(环戊基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[8-(2-羟基-3-吗啉-4-基丙氧基)-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{7-甲氧基-8-[3-(3-甲基吗啉-4-基)丙氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(8-{2-[4-(环丁基甲基)吗啉-2-基]乙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-(7-甲氧基-8-{2-[4-(2-甲氧基乙基)吗啉-2-基]乙氧基}-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-{8-[(4-乙基吗啉-2-基)甲氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-(7-甲氧基-8-{[4-(2-甲氧基乙基)吗啉-2-基]甲氧基}-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-{7-甲氧基-8-[(4-甲基吗啉-2-基)甲氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-4-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-4-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-甲基-1H-咪唑-4-甲酰胺;
rel-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)嘧啶-5-甲酰胺;
rel-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-6-甲基烟酰胺;
rel-6-乙酰氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1-甲基-1H-咪唑-5-甲酰胺;
6-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-甲基烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-甲基嘧啶-5-甲酰胺;
6-氨基-5-溴-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噁唑-5-甲酰胺;
N-[7-甲氧基-8-(吗啉-2-基甲氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
2-{[2-(二甲基氨基)乙基]氨基}-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
2-氨基-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-1,3-噻唑-5-甲酰胺;
rel-2-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)嘧啶-5-甲酰胺;
rel-6-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
2-[(2-羟基乙基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-[(3-甲氧基丙基)氨基]嘧啶-5-甲酰胺;
2-氨基-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-[(3-吗啉-4-基丙基)氨基]嘧啶-5-甲酰胺;
2-[(2-甲氧基乙基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
2-{[2-(二甲基氨基)乙基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
6-氨基-N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-吡咯烷-1-基嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(4-甲基哌嗪-1-基)嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-吗啉-4-基嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-哌嗪-1-基烟酰胺盐酸盐;
6-[(3S)-3-氨基吡咯烷-1-基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺盐酸盐水合物;
6-[(3R)-3-氨基吡咯烷-1-基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺盐酸盐;
6-[(4-氟苄基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-[(2-呋喃基甲基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-[(2-甲氧基乙基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(1H-吡咯-1-基)烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-吗啉-4-基烟酰胺;
N-{7-甲氧基-8-[3-(甲基氨基)丙氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
6-[(2,2-二甲基丙酰基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-[(环丙基羰基)氨基]-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(2,2,2-三氟乙氧基)烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(三氟甲基)烟酰胺;
6-(异丁酰基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{7-甲氧基-8-[3-(4-甲基哌嗪-1-基)丙氧基]-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-{[(甲基氨基)羰基]氨基}-1,3-噻唑-4-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-{[(甲基氨基)羰基]氨基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(甲基氨基)-1,3-噻唑-4-甲酰胺;
N-[7-甲氧基-8-(2-吗啉-4-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-2,4-二甲基-1,3-噻唑-5-甲酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-6-甲基烟酰胺;
6-{[(异丙基氨基)羰基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-吡咯烷-1-基烟酰胺;
6-(二甲基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-哌啶-1-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(2-吡咯烷-1-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(2-哌啶-1-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-{[(乙基氨基)羰基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-氟-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噁唑-4-甲酰胺;
2-(乙基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噻唑-4-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]吡嗪-2-甲酰胺;
N-[8-(2-氨基乙氧基)-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
6-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]异烟酰胺;
N-{8-[3-(二乙基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二异丙基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二乙基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(甲基氨基)嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-(甲基硫基)嘧啶-5-甲酰胺;
N-[8-(3-氨基丙氧基)-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺三氟乙酸盐;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]噻吩-2-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2,4-二甲基-1,3-噻唑-5-甲酰胺;
2-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-3-糠酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]噻吩-3-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2-甲基-1,3-噻唑-4-甲酰胺;
6-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
5-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-甲基烟酰胺;
6-(乙酰基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
优选地,
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-甲基烟酰胺;
5-甲氧基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-2,4-二甲基-1,3-噻唑-5-甲酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺;
6-{[(异丙基氨基)羰基]氨基}-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}-2,4-二甲基-1,3-噻唑-5-甲酰胺;
N-[7-甲氧基-8-(2-吗啉-4-基乙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺;
rel-6-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺;
rel-2-氨基-N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)嘧啶-5-甲酰胺;
2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺;
N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
8.权利要求1-7中任一项的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺,
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,特别是生理学上可接受的盐,或它们的混合物。
9.权利要求1-8中任一项的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺。
10.权利要求1-8中任一项的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐。
11.权利要求1-10中任一项的组合产品,其中组分B是维奈托克或帕博西尼。
12.权利要求1-11中任一项的组合产品,其中组分B是维奈托克。
13.权利要求1-11中任一项的组合产品,其中组分B是帕博西尼。
14.根据权利要求1-7中任一项的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺且所述组分B是维奈托克。
15.根据权利要求1-7中任一项的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐且所述组分B是维奈托克。
16.根据权利要求1-7中任一项的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺且所述组分B是帕博西尼。
17.根据权利要求1-7中任一项的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐且所述组分B是帕博西尼。
18.根据权利要求1-17中任一项的组合产品,其用于治疗或预防非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)。
19.根据权利要求1-17中任一项的组合产品用于治疗或预防非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)的用途。
20.根据权利要求1-17中任一项的组合产品用于制备用于治疗或预防非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)的药物的用途。
21.治疗或预防对象中的癌症,特别是非霍奇金淋巴瘤(以下简称为“NHL”),特别是第1线、第2线、复发性、难治性、惰性或侵袭性非霍奇金淋巴瘤(NHL),特别是滤泡性淋巴瘤(以下简称为“FL”)、慢性淋巴细胞白血病(以下简称为“CLL”)、边缘区淋巴瘤(以下简称为“MZL”)、脾边缘区淋巴瘤(以下简称为“SMZL”)、弥漫性大B细胞淋巴瘤(以下简称为“DLBCL”)、套细胞淋巴瘤(MCL)、转化的淋巴瘤(以下简称为“TL”)或外周T细胞淋巴瘤(以下简称为“PTCL”)的方法,其包括向所述对象施用治疗有效量的根据权利要求1-17中任一项的组合产品。
22.包含以下的组合产品的试剂盒:
一种或多种如权利要求1-12中任一项中所定义的组分A;
一种或多种如权利要求1或12中所定义的组分B;
和任选的一种或多种其它药剂C;
其中任选地所述组分A和B中的两种或任一种呈即用于同时、共同、分开或依次施用的药物制剂的形式。
23.含有根据权利要求1-17的组合产品以及药学上可接受的成分的组合物。
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- 2017-09-15 US US16/329,502 patent/US10925880B2/en active Active
- 2017-09-15 CA CA3037626A patent/CA3037626A1/en active Pending
- 2017-09-15 EP EP17764848.2A patent/EP3515911A1/en active Pending
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2022
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CA3037626A1 (en) | 2018-03-29 |
JP2019532922A (ja) | 2019-11-14 |
CN109729716B (zh) | 2022-03-15 |
US20190255063A1 (en) | 2019-08-22 |
JP2022177113A (ja) | 2022-11-30 |
WO2018054782A1 (en) | 2018-03-29 |
US10925880B2 (en) | 2021-02-23 |
EP3515911A1 (en) | 2019-07-31 |
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