CN111727183A - 5-氟-4-(4-氟-2-甲氧基苯基)-n-{4-[(s-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺用于治疗弥漫性大b细胞淋巴瘤中的用途 - Google Patents
5-氟-4-(4-氟-2-甲氧基苯基)-n-{4-[(s-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺用于治疗弥漫性大b细胞淋巴瘤中的用途 Download PDFInfo
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- CN111727183A CN111727183A CN201980013294.2A CN201980013294A CN111727183A CN 111727183 A CN111727183 A CN 111727183A CN 201980013294 A CN201980013294 A CN 201980013294A CN 111727183 A CN111727183 A CN 111727183A
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Abstract
本发明涉及5‑氟‑4‑(4‑氟‑2‑甲氧基苯基)‑N‑{4‑[(S‑甲基磺亚胺酰基)甲基]吡啶‑2‑基}吡啶‑2‑胺(化合物A),更特别是(+)5‑氟‑4‑(4‑氟‑2‑甲氧基苯基)‑N‑{4‑[(S‑甲基磺亚胺酰基)甲基]吡啶‑2‑基}吡啶‑2‑胺(化合物A’),用于治疗弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥漫性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤的用途。
Description
本发明涉及5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)、更特别是(+)5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)用于治疗弥漫性大B细胞淋巴瘤(DLBCL)的用途,尤其是在生发中心B细胞型弥漫性大B细胞淋巴瘤中,并且尤其是在其细胞具有MYC基因和/或BCL2基因的扩增或易位,和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤中。
细胞周期蛋白依赖性激酶(CDK)蛋白家族由作为细胞分裂周期的关键调节因子的成员(细胞周期CDK)、参与基因转录的调控的成员(转录CDK)和具有其他功能的成员组成。CDK需要激活与调控细胞周期蛋白亚基的结合。细胞周期CDK——CDK1/细胞周期蛋白B、CDK2/细胞周期蛋白A、CDK2/细胞周期蛋白E、CDK4/细胞周期蛋白D和CDK6/细胞周期蛋白D被依次激活,以驱动细胞进入和通过细胞分裂周期。转录CDK——CDK9/细胞周期蛋白T和CDK7/细胞周期蛋白H通过羧基末端结构域(CTD)的磷酸化来调节RNA聚合酶II的活性。阳性转录因子b(P-TEFb)是CDK9的异质二聚体,并且是四个细胞周期蛋白伴侣(细胞周期蛋白T1、细胞周期蛋白K、细胞周期蛋白T2a或T2b)之一。
CDK9(NCBI GenBank基因ID 1025)专门参与转录调控,而CDK7作为CDK激活激酶(CAK)另外参与细胞周期调控。
通过RNA聚合酶II的基因转录是通过在启动子区域组装预起始复合物并通过CDK7/细胞周期蛋白H使CTD的Ser 5和Ser 7磷酸化来启动的。对于大部分基因,在mRNA沿着DNA模板移动了20-40个核苷酸后,RNA聚合酶II停止了mRNA转录。RNA聚合酶II的这种启动子近端暂停是由负伸长因子介导的,并且被认为是用于调节对多种刺激响应的快速诱导基因表达的主要调控机制(Cho等人,Cell Cycle 2010,9,1697)。P-TEFb关键性地参与了克服RNA聚合酶II的启动子近端暂停和通过使CTD的Ser 2磷酸化以及通过使负伸长因子磷酸化和失活来转变为生产性伸长状态。
P-TEFb本身的活性受多种机制调节。大约一半的细胞P-TEFb存在于具有7SK小核RNA(7SK snRNA)、La相关蛋白7(LARP7/PIP7S)和六亚甲基双乙酰胺诱导蛋白1/2的失活复合物中(HEXIM1/2,He等人,Mol.Cell 2008,29,588)。其余一半P-TEFb存在于含有溴结构域蛋白Brd4的活性复合物中(Yang等人,Mol.Cell 2005,19,535)。Brd4通过与乙酰化组蛋白的相互作用以将P-TEFb募集到染色质区域,预备进行基因转录。通过与其正调节剂和负调节剂的交替相互作用,P-TEFb保持功能平衡:与7SK snRNA复合体结合的P-TEFb相当于储库,可根据细胞转录和细胞增殖的需求从中释放活性P-TEFb(Zhou&Yik,Microbiol.Mol.Biol.Rev.2006,70,646)。此外,P-TEFb的活性受到翻译后修饰的调节,包括磷酸化/去磷酸化、泛素化和乙酰化(综述,Cho等人,Cell Cycle 2010,9,1697)。
P-TEFb异质二聚体的CDK9激酶活性失调与多种人类病理状况相关,诸如过度增生性疾病(例如癌症)、病毒引起的传染性疾病或心血管疾病。
癌症被认为是由增殖和细胞死亡(细胞凋亡)的失衡所介导的过度增殖性障碍。在各种人类肿瘤中发现了高水平的抗凋亡Bcl-2家族蛋白,并且其可延长肿瘤细胞的存活率和治疗耐受性。已证明,抑制P-TEFb激酶活性会降低RNA聚合酶II的转录活性,导致短寿命的抗凋亡蛋白(尤其是Mcl-1和XIAP)减少,从而重新建立了肿瘤细胞进行细胞凋亡的能力。与转化的肿瘤表型相关的许多其他蛋白(例如Myc、NF-kB响应基因转录物、有丝分裂激酶)是短寿命蛋白或者由短寿命转录物编码,所述转录物对由P-TEFb抑制介导的RNA聚合酶II活性降低具有敏感性(综述,Wang&Fischer,Trends Pharmacol.Sci.2008,29,302)。
许多病毒依靠宿主细胞的转录机制来进行其自身基因组的转录。对于HIV-1,RNA聚合酶II被募集到病毒LTR中的启动子区域。病毒转录激活子(Tat)蛋白与新生病毒转录物结合,并通过募集P-TEFb克服了启动子近端RNA聚合酶II暂停,这进而促进了转录延伸。此外,Tat蛋白通过替换7SK snRNA复合物中的P-TEFb抑制蛋白HEXIM1/2来增加活性P-TEFb的比例。最近的数据显示,在对宿主细胞无细胞毒性的激酶抑制剂浓度下,抑制P-TEFb的激酶活性足以阻止HIV-1复制(综述,Wang&Fischer,Trends Pharmacol.Sci.2008,29,302)。类似地,据报道,对于其他病毒,例如核抗原EBNA2蛋白与P-TEFb相互作用的与B细胞癌相关的Epstein-Barr病毒(Bark-Jones等人,Oncogene 2006,25,1775),以及转录激活子Tax募集P-TEFb的人类嗜T细胞病毒1型(HTLV-1)(Zhou等人,J.Virol.2006,80,4781),通过病毒蛋白募集P-TEFb。
心脏肥大是心脏对机械负荷和压力(血液动力学压力,例如高血压、心肌梗塞)的适应性反应,从长远来看会导致心力衰竭和死亡。已证明,心脏肥大与心肌细胞中转录活性增加和RNA聚合酶II CTD磷酸化有关。发现P-TEFb通过与非活性的7SK snRNA/HEXIM1/2复合物解离而被激活。这些发现表明药理学上抑制P-TEFb激酶活性是治疗心脏肥大的一种治疗方法(综述,Dey等人,Cell Cycle 2007,6,1856)。
总之,多条证据表明选择性抑制P-TEFb异质二聚体的CDK9激酶活性(=CDK9和四个细胞周期蛋白伴侣之一,细胞周期蛋白T1、细胞周期蛋白K、细胞周期蛋白T2a或T2b)代表了一种创新的治疗疾病(例如癌症、病毒性疾病和/或心脏疾病)的方法。CDK9属于至少13个密切相关的激酶家族,其细胞周期CDK的亚组在调节细胞增殖中起多种作用。因此,预期细胞周期CDK(例如CDK1/细胞周期蛋白B、CDK2/细胞周期蛋白A、CDK2/细胞周期蛋白E、CDK4/细胞周期蛋白D、CDK6/细胞周期蛋白D)和CDK9的共抑制作用会影响正常的增生组织,如肠粘膜、淋巴和造血器官,以及生殖器官。为了最大化CDK9激酶抑制剂的治疗余地,因此需要对CDK9具有高选择性的分子。
总体而言,CDK抑制剂以及CDK9抑制剂记载于许多不同的出版物中:
WO2008129070和WO2008129071在总体上描述了2,4-二取代的氨基嘧啶作为CDK抑制剂。还认为这些化合物中的一些可以分别作为选择性CDK9抑制剂(WO2008129070)和CDK5抑制剂(WO2008129071),但未示出具体的CDK9 IC50(WO2008129070)或CDK5 IC50(WO200812971)数据。
WO2008129080公开了4,6-二取代的氨基嘧啶,并证明了这些化合物对多种蛋白激酶(例如CDK1、CDK2、CDK4、CDK5、CDK6和CDK9)的蛋白激酶活性具有抑制作用,优选抑制CDK9(实施例80)。
EP1218360B1记载了三嗪衍生物作为激酶抑制剂,但未公开有效或选择性的CDK9抑制剂。
WO2008079933公开了氨基吡啶和氨基嘧啶衍生物及其作为CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8或CDK9抑制剂的用途。
WO2011012661记载了用作CDK抑制剂的氨基吡啶衍生物。
Wang等人(Chemistry&Biology 2010,17,1111-1121)记载了2-苯胺基-4-(噻唑-5-基)嘧啶转录CDK抑制剂,其在动物模型中显示出抗癌活性。
WO2004009562公开了取代的三嗪激酶抑制剂。对于所选化合物,示出了CDK1和CDK4测试数据,但没有示出CDK9数据。
WO2004072063记载了杂芳基(嘧啶、三嗪)取代的吡咯作为蛋白激酶(例如ERK2、GSK3、PKA或CDK2)的抑制剂。
WO2010009155公开了三嗪和嘧啶衍生物作为组蛋白脱乙酰基酶和/或细胞周期蛋白依赖性激酶(CDK)的抑制剂。对于所选化合物,描述了CDK2测试数据。
WO2003037346(对应于US7618968B2、US7291616B2、US2008064700A1、US2003153570A1)涉及芳基三嗪及其用途,包括抑制溶血磷脂酸酰基转移酶β(LPAAT-β)活性和/或细胞如肿瘤细胞的增殖。
WO2008025556记载了具有嘧啶核的氨基甲酰基亚磺酰亚胺,其可用作激酶抑制剂。没有示出CDK9数据。
WO2002066481记载了嘧啶衍生物,未提及细胞周期蛋白依赖性激酶抑制剂CDK9,并且没有示出CDK9数据。
WO2008109943涉及苯基氨基吡啶(嘧啶)化合物及其作为激酶抑制剂、特别是作为JAK2激酶抑制剂的用途。具体实例集中于具有嘧啶核的化合物。
WO2009032861记载了取代的嘧啶胺作为JNK激酶抑制剂。具体实例集中于具有嘧啶核的化合物。
WO2011046970涉及作为TBKL和/或IKKε抑制剂的氨基嘧啶化合物。具体实例集中于具有嘧啶核的化合物。
WO2012160034记载了本发明的化合物。公开了化合物抑制HeLa细胞(宫颈癌)、HeLa/MaTu/ADR细胞(宫颈癌)、NCI-H460细胞(非小细胞肺癌)、DU145细胞(非激素依赖性人前列腺癌)、Caco-2细胞(结直肠癌)和B16F10细胞(黑色素瘤)的细胞增殖。
本发明的目的是改进弥漫性大B细胞淋巴瘤(DLBCL)的治疗。
弥漫性大B细胞淋巴瘤的治疗
B淋巴细胞和T淋巴细胞的恶性肿瘤可宽泛地描述为霍奇金淋巴瘤和非霍奇金淋巴瘤。进而,非霍奇金淋巴瘤代表大量的各种疾病,每种疾病都有独特的流行病学、病原学、形态学、免疫表型和临床特征。世界卫生组织(WHO)在2008年对非霍奇金淋巴瘤进行了重新分类,并且现已更好地反映了我们对疾病实体及其与免疫系统的关系的理解(JaffeES.The 2008WHO classification of lymphomas:implications for clinical practiceand translational research.Hematology Am Soc Hematol Educ Program 2009:523-531)。
DLBCL是一种攻击性疾病,并且是非霍奇金淋巴瘤最常见的亚型,占西方国家新诊断病例的最高达30-40%(Roman E,Smith AG.Epidemiology oflymphomas.Histopathology.2011;58:4–14)。晚期DLBCL的主要疗法是联合化学免疫疗法,特别是R-CHOP(利妥昔单抗(rituximab)、环磷酰胺(cyclophosphamide)、阿霉素(doxorubicin)、长春新碱(vincristine)和泼尼松(prednisone))。将利妥昔单抗引入该化学治疗方案是持续且有意义地改善DLBCL患者预后的基础。然而,约30%至40%的患者会在R-CHOP治疗后发展为对R-CHOP治疗没有良好反应的复发性或难治性疾病,或者复发(Camicia R等人.Novel drug targets for personalized precision medicine inrelapsed/refractory diffuse large B-cell lymphoma:a comprehensive review.MolCancer.2015;14:207)。结果,已经探索了多种治疗方法以试图改善预后,包括提供更多的化疗疗程、剂量密集化与替代药物组合,以及大剂量化疗,然后进行自体干细胞移植。但是,几乎没有证据表明这些疗法具有比R-CHOP更好的疗效。
基因表达谱(GEP)研究已经鉴定出两种不同的分子亚型,称为生发中心B细胞(GCB)-DLBCL和活化B细胞(ABC)-DLBCL,分别占DLBCL-NOS病例的最高达45%和35%(Martelli M,Ferreri AJ,Agostinelli C,Di Rocco A,Pfreundschuh M,PileriSA.Diffuse large B-cell lymphoma.Crit Rev Oncol Hematol.2013;87:146–71)。多种研究已将接受R-CHOP治疗的DLBCL患者的MYC易位与预后较差相关联,但较新的研究表明,与BCL2并发的二次打击(double-hit)易位导致难治性患者组具有较低的中位生存期。这种类型的二次打击易位在GCB-DLBCL中更常见,并且占所有病例的约5%,而这两种蛋白的双重过表达甚至更常见(占DLBCL病例的25%),在ABC-DLBCL中更常见,并且导致与仅表达一种蛋白或两种蛋白均不表达的患者相比明显较差的预后(Johnson NA,Slack GW,SavageKJ等人,Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphomatreated with rituximab plus cyclophosphamide,doxorubicin,vincristine,andprednisone.J Clin Oncol.2012;30:3452-3459)。
在DLBCL的发展中涉及的特定分子途径的治疗靶向最终可改善患者预后。正在进行评估的几种新型药物——既可作为复发性疾病状况中的单一药物,也可与R-CHOP结合——包括免疫调节药物(IMiD)、蛋白激酶C抑制剂、组蛋白脱乙酰基酶抑制剂、蛋白酶体抑制剂和mTOR(雷帕霉素的哺乳动物靶标)抑制剂、BTK抑制剂、SYK抑制剂、PKCβ抑制剂、PI3K抑制剂以及BCL2抑制剂(Sehn LH,Gascoyne RD.Diffuse large B-cell lymphoma:optimizing outcome in the context of clinical and biologicheterogeneity.Blood.2015;125:22–32;Boyle J等人,Improving Outcomes in AdvancedDLBCL:Systemic Approaches and Radiotherapy.Oncology(Williston Park)2014;28(12):pii:202929;Nastoupil LJ等人,Diffuse Large B-Cell Lymphoma:CurrentTreatment Approaches.Oncology(Williston Park)2012;26(5):488-95)。
因此,需要针对DLBCL、特别是针对复发性或攻击性疾病亚群的替代疗法。
现已发现,化合物5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A,式(I)),
更特别地,
(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’),
在以前尚未考虑的特定肿瘤类型中起作用,即在弥漫性大B细胞淋巴瘤(DLBCL)中,尤其是在生发中心B细胞型弥漫性大B细胞淋巴瘤中,并且尤其是在其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤中。
5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)是选定的亚磺酰亚胺取代的苯胺嘧啶衍生物,其可以分离为两种立体异构体,即:
(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’),和
(-)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A”)。
化合物A'是优选的,并且作为化合物A'用于临床开发中。
在下文提及化合物A的情况下,均意为纯的立体异构体A'和A”,以及这两者的任何混合物。
本发明涉及5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一,用于治疗和/或预防弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥漫性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤的用途。
本发明还涉及5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A′)或其生理上可接受的盐之一,用于制备用于治疗弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥漫性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤的药物的用途。
本发明的另一方面是式(I)的5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,
更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一,
在制备用于治疗受试者的癌症的药物中的用途,其中制备该药物用于治疗弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥散性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤。
本发明还提供式I的5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,
更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一,
其用于治疗弥漫性大B细胞淋巴瘤(DLBCL),特别是生发中心B细胞型弥散性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤。
本发明还涉及式I的5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,
更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一,
其用于治疗和/或预防弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥散性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤的方法。
本发明的另一方面是一种治疗和/或预防弥散性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥散性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤的方法,所述方法使用有效量的式I的5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,
更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一。
本发明进一步提供了药物组合物,其包含5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一,用于治疗弥漫性大B细胞淋巴瘤(DLBCL)。
本发明还涉及药物组合物,其包含式I的5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,
更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一和至少一种惰性、无毒、药学上合适的佐剂,用于治疗和/或预防弥漫性大B细胞淋巴瘤(DLBCL)。
本发明进一步提供5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一与至少一种其他活性成分的组合物,用于治疗弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥漫性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥漫性大B细胞淋巴瘤。
本发明还涉及药物组合物,其包含式I的5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A)或其生理上可接受的盐或对映异构体之一,
更特别地,(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’)或其生理上可接受的盐之一和至少一种或更多种其他活性成分,用于治疗和/或预防弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥漫性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥漫性大B细胞淋巴瘤。
使用化合物A的生理上可耐受的盐同样应被认为由本发明所涵盖。
化合物A的生理上安全的盐包括无机酸、羧酸和磺酸的酸加成盐,例如,盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
化合物A的生理上安全的盐还包括常用碱的盐,例如,作为示例且优选地,碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如钙盐和镁盐),和衍生自氨或具有1至16个C原子的有机胺(例如,作为示例且优选地,乙胺、二乙胺、三乙胺、乙基二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己胺、二甲基氨基乙醇、普鲁卡因、二苄胺、N-甲基吗啉、精氨酸、赖氨酸、乙二胺和N-甲基哌啶)的铵盐。
本发明还提供了包含化合物A和至少一种或更多种其他活性成分的药物,用于治疗弥漫性大B细胞淋巴瘤(DLBCL),特别是生发中心B细胞型弥漫性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥漫性大B细胞淋巴瘤。
化合物A可以具有全身和/或局部活性。为此,其可以以合适的方式给药,例如,口服、肠胃外、经肺途径、经鼻、舌下、舌、颊、直肠、阴道、皮肤、经皮、结膜(conjuntivally)、经眼(otically),或作为植入物或支架。
对于这些给药途径,本发明化合物A可以合适的给药形式来给药。
适用于根据现有技术起作用并迅速和/或以改良的方式递送本发明化合物A且包含结晶和/或无定形和/或溶解形式的本发明的化合物A的口服给药形式为例如,片剂(未包衣或包衣的片剂,例如具有抗胃液或延迟溶解或不溶解并控制本发明化合物释放的包衣的片剂)、在口腔中迅速崩解的片剂、或薄膜/薄片(wafer)、薄膜/冻干物、胶囊(例如硬或软明胶胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、悬浮剂、气雾剂或溶液剂。
肠胃外给药可以在避免吸收步骤(例如静脉内、动脉内、心内、脊柱内或腰内)或包括吸收(例如肌内、皮下、皮内、经皮或腹膜内)的情况下进行。适于肠胃外给药的给药形式尤其是溶液剂、悬浮剂、乳剂、冻干物或灭菌粉末形式的注射和输注用制剂。
适用于其他给药途径的实例为用于吸入的药物形式[尤其是粉末吸入器、喷雾器]、滴鼻剂、鼻溶液、鼻喷雾;以舌、舌下或颊给药的片剂、薄膜/薄片或胶囊;栓剂;用于眼和耳的制剂、洗眼器、眼用插入剂、滴耳剂、耳粉剂、洗耳剂、耳塞;阴道胶囊、水性悬浮剂(洗剂、振荡混合物(mixturae agitandae))、亲脂性悬浮剂、软膏、乳膏、经皮治疗系统(例如,贴剂)、乳、糊剂、泡沫剂、撒粉剂、植入物或支架。
可将化合物A转化为所述给药形式。这可以本身已知的方式通过与惰性、无毒、药学上合适的佐剂混合来进行。这些佐剂尤其包括:
·软膏基质(例如凡士林、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水性软膏、聚乙二醇),
·用于栓剂的基质(例如聚乙二醇、可可脂、固体脂肪)
·溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中等链长的甘油三酯脂肪油、液态聚乙二醇、石蜡),
·表面活性剂、乳化剂、分散剂或润湿剂(例如十二烷基硫酸钠、卵磷脂、磷脂、脂肪醇(例如,)、脱水山梨糖醇脂肪酸酯(例如)、聚氧乙烯脱水山梨糖醇脂肪酸酯(例如,)、聚氧乙烯脂肪酸甘油酯(例如,)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(例如,),
·缓冲剂以及酸和碱(例如磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨丁三醇、三乙醇胺),
·等渗剂(例如葡萄糖、氯化钠),
·吸附剂(例如高分散性二氧化硅),
·包衣材料(例如糖、虫胶)和快速或以改良方式溶解的薄膜或扩散膜的成膜剂(例如聚乙烯吡咯烷酮(例如)、聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素、醋酸纤维素邻苯二甲酸酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如)),
·胶囊材料(例如明胶、羟丙基甲基纤维素),
·增塑剂(例如聚乙二醇、丙二醇、甘油、三醋精、柠檬酸三乙酰基酯、邻苯二甲酸二丁酯),
·渗透促进剂,
·稳定剂(例如抗氧化剂,例如抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基苯甲醚、丁基羟基甲苯、没食子酸丙酯),
·防腐剂(例如对羟基苯甲酸酯、山梨酸、硫柳汞、苯扎氯铵、乙酸氯己定、苯甲酸钠),
·着色剂(例如无机颜料,例如氧化铁、二氧化钛),
·矫味剂、甜味剂、味道和/或气味掩蔽剂。
本发明还涉及药物,其包含至少一种本发明的化合物,常规地连同一种或更多种惰性、无毒、药学上合适的佐剂,以及所述药物用于上述目的的用途。
剂量和治疗方案
剂量和治疗方案可以且必须根据癌症类型和治疗目标而变化。
日剂量通常是在20mg至850mg之间,并且可以分为多个相同或不同的剂量单位,优选地可以同时或根据一定的时间表服用的2个剂量单位。
特别地,日剂量是在30mg至500mg之间,并且可以分为多个相同或不同的剂量单位,优选地可以同时或根据一定的时间表服用的2个剂量单位。
优选的日剂量是在20mg至400mg之间,并且可以分为多个相同或不同的剂量单位,优选地可以同时或根据一定的时间表服用的2个剂量单位。
更特别地,日剂量是在40mg至300mg之间,并且可以分为多个相同或不同的剂量单位,优选地可以同时或根据一定的时间表服用的2个剂量单位。
更优选的日剂量是在20mg至200mg之间,并且可以分为多个相同或不同的剂量单位,优选地可以同时或根据一定的时间表服用的2个剂量单位。
甚至更优选的日剂量是在50mg至180mg之间,并且可以分为多个相同或不同的剂量单位,优选地可以同时或根据一定的时间表服用的2个剂量单位。
这既适用于单一疗法,也适用于与其他抗过度增殖、抑制细胞生长或细胞毒性的物质的联合疗法,联合疗法可能需要减少剂量。
该治疗可以以定期重复周期的方式进行。治疗周期可具有变化的持续时间,如21天或28天,由此连续地或间断地给药。优选的周期长度为28天,由此连续地或间断地给药。
连续时间表包括每日给药,例如,在21天的周期中服用21个日剂量,或在28天的周期中服用28个日剂量。优选的连续时间表是在28天的周期中服用28个日剂量。
间歇时间表包括一段治疗期之后是一段非治疗期,例如在21天的周期或28天的周期中。间歇时间表的优选周期持续时间为28天。
在给定的治疗周期中,治疗期可以多于一次地被重复。
治疗期可以是例如1至21天,更优选地是3至14天。
甚至更优选的间歇时间表包括治疗3天,然后不治疗4天,以这样的方式每周重复,以完成28天的治疗周期。
当至少存在疾病稳定并且不良反应发生的程度易于治疗但至少易于接受时,治疗就成功了。因此,根据治疗反应和耐受性,所应用的治疗周期数可因患者而不同。
当至少存在疾病稳定并且不良反应发生的程度易于治疗但至少易于接受时,治疗就成功了。
化合物A可以单独使用,或者(视需要)与一种或多种其他药理有效物质组合使用,条件是所述组合物不会导致不期望和不可接受的不良反应。因此,本发明还提供了包含本发明的化合物A和一种或更多种其他活性成分的药物,特别是用于治疗和/或预防上述疾病。
例如,化合物A可以与已知的抗过度增殖、抑制细胞生长或细胞毒性的物质组合用于治疗癌症。特别建议将本发明的化合物A与用于癌症治疗的其他物质组合,或者与放射治疗组合。
用于组合目的的合适的活性成分的实例包括:
白蛋白结合性紫杉醇(abraxane)、飞尼妥(afinitor)、阿地白介素(aldesleukin)、阿仑膦酸(alendronic acid)、阿尔法酮(alfaferone)、阿利维A酸(alitretinoin)、别嘌呤醇(allopurinol)、别嘌呤醇钠(aloprim)、阿洛西(aloxi)、六甲蜜胺(altretamine)、氨鲁米特(aminoglutethimide)、氨磷汀(amifostine)、氨柔比星(amrubicin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、多拉司琼(anzemet)、阿法达贝泊汀(aranesp)、小白菊内酯衍生物(arglabin)、三氧化二砷(arsenic trioxide)、阿诺新(aromasin)、5-氮杂胞嘧啶核苷(5-azacytidine)、咪唑硫嘌呤(azathioprine)、BCG或tice-BCG、贝他定(bestatin)、醋酸倍他米松(betamethasone)、磷酸倍他米松钠、蓓萨罗丁(bexarotene)、硫酸争光霉素(bleomycin)、溴尿苷(broxuridine)、硼替佐米(bortezomib)、白消安(busulfan)、降血钙素(calcitonin)、坎帕斯(campath)、卡培他滨(capecitabine)、卡铂(carboplatin)、康士得(casodex)、cefesone、西莫白介素(celmoleukin)、柔红霉素(cerubidine)、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯屈磷酸(clodronic acid)、环磷酰胺(cyclophosphamide)、阿糖孢苷(cytarabine)、达卡巴嗪(dacarbazine)、放线菌素D(dactinomycin)、柔红霉素(daunoxome)、地塞米松(decadron)、磷酸地塞米松(decadron phosphate)、戊酸雌二醇(delestrogen)、地尼白介素(denileukin diftitox)、狄波美(depo-medrol)、地洛瑞林(deslorelin)、地拉佐生(dexrazoxane)、己烯雌酚(diethylstilbestrol)、大扶康(diflucan)、多西他赛(docetaxel)、去氧氟尿苷(doxifluridine)、阿霉素(doxorubicin)、屈大麻酚(dronabinol)、DW-166HC、醋酸亮丙瑞林(eligard)、拉布立酶(elitek)、盐酸表柔比星(ellence)、阿瑞吡坦(emend)、表柔比星(epirubicin)、阿法依伯汀(epoetin alfa)、红细胞生成素(epogen)、依铂(eptaplatin)、盐酸左旋咪唑(ergamisol)、雌二醇(estrace)、雌二醇(estradiol)、雌莫司汀磷酸钠(estramustine sodium phosphate)、炔雌醇(ethinyl estradiol)、氨磷汀(ethyol)、羟磷酸(etidronic acid)、凡毕复(etopophos)、依托泊甙(etoposide)、法倔唑(fadrozole)、法乐通(fareston)、非格司亭(filgrastim)、非那司提(finasteride)、培非司亭(fligrastim)、氟尿苷(floxuridine)、氟康唑(fluconazole)、氟达拉滨(fludarabine)、5-氟脱氧尿嘧啶核苷单磷酸盐(5-fluorodeoxyuridine monophosphate)、5-氟尿嘧啶(5-fluorouracil)(5-FU)、氟甲睾酮(fluoxymesterone)、氟他胺(flutamide)、福美司坦(formestane)、fosteabine、福莫司汀(fotemustine)、氟维司群(fulvestrant)、丙种球蛋白(gammagard)、吉西他滨(gemcitabine)、吉妥珠单抗(gemtuzumab)、格列卫(gleevec)、卡氮芥(gliadel)、戈舍瑞林(goserelin)、盐酸格拉司琼(granisetron hydrochloride)、组氨瑞林(histrelin)、美新(hycamtin)、氢化可的松(hydrocortone)、赤型-羟基壬基腺嘌呤(erythro-hydroxynonyladenine)、羟基脲(hydroxyurea)、替坦异贝莫单抗(ibritumomabtiuxetan)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、干扰素α(interferonalpha)、干扰素-α2(interferon alpha 2)、干扰素α-2A(interferon alpha 2α)、干扰素α-2B(interferon alpha 2β)、干扰素α-n1(interferon alpha n1)、干扰素α-n3(interferonalpha n3)、干扰素β(interferon beta)、干扰素γ-la(interferon gamma 1α)、白细胞介素-2(interleukin 2)、内含子A(intron A)、易瑞沙(iressa)、依立替康(irinotecan)、凯特瑞(kytril)、拉帕替尼(lapatinib)、硫酸香菇多糖(lentinan sulphate)、来曲唑(letrozole)、甲酰四氢叶酸(leucovorin)、亮丙瑞林(leuprolide)、醋酸亮丙瑞林(leuprolide acetate)、左旋四咪唑(levamisole)、左旋亚叶酸钙盐(levofolinic acidcalcium salt)、左甲状腺素钠(levothroid)、左甲状腺素钠(levoxyl)、洛莫司汀(lomustine)、氯尼达明(lonidamine)、屈大麻酚(marinol)、氮芥(mechlorethamine)、甲钴胺(mecobalamin)、醋酸甲羟孕酮(medroxyprogesterone acetate)、醋酸甲地孕酮(megestrol acetate)、美法仑(melphalan)、酯化雌激素(menest)、6-巯基嘌呤(6-mercaptopurine)、美司钠(mesna)、氨甲蝶呤(methotrexate)、metvix、米替福新(miltefosine)、美满霉素(minocycline)、丝裂霉素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、曲洛司坦(modrenal)、柔比星(myocet)、奈达铂(nedaplatin)、非格司亭(neulasta)、重组人白介素11(neumega)、优保津(neupogen)、尼鲁米特(nilutamide)、三苯氧胺(nolvadex)、NSC-631570、OCT-43、奥曲肽(octreotide)、盐酸昂丹司琼(ondansetron hydrochloride)、orapred、奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、泼尼松磷酸钠制剂(pediapred)、培门冬酶(pegaspargase)、派罗欣(pegasys)、喷司他丁(pentostatin)、picibanil、盐酸匹鲁卡品(pilocarpinehydrochloride)、吡柔比星(pirarubicin)、普卡霉素(plicamycin)、卟吩姆钠(porfimersodium)、泼尼莫司汀(prednimustine)、泼尼松龙(prednisolone)、泼尼松(prednisone)、倍美力(premarin)、丙卡巴肼(procarbazine)、普罗克瑞(procrit)、雷替曲塞(raltitrexed)、RDEA119、利比(rebif)、依替膦酸铼-186(rhenium-186etidronate)、利妥昔单抗(rituximab)、力度伸-A(roferon-A)、罗莫肽(romurtide)、毛果芸香碱(salagen)、奥曲肽(sandostatin)、沙莫司亭(sargramostim)、司莫司汀(semustine)、西佐喃(sizofiran)、索布佐生(sobuzoxane)、甲泼尼龙(solumedrol)、链脲菌素(streptozocin)、氯化锶-89、左旋甲状腺素钠(synthroid)、他莫昔芬(tamoxifen)、坦舒洛辛(tamsulosin)、他索那明(tasonermin)、睾内酯(tastolactone)、泰索帝(taxotere)、替西白介素(teceleukin)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、丙酸睾酮(testosterone propionate)、甲睾酮(testred)、硫鸟嘌呤(thioguanine)、噻替哌(thiotepa)、促甲状腺激素(thyrotropin)、替鲁膦酸(tiludronic acid)、拓扑替康(topotecan)、托瑞米芬(toremifene)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、曲奥舒凡(treosulfan)、维A酸(tretinoin)、甲氨喋呤(trexall)、三甲基密胺(trimethylmelamine)、三甲曲沙(trimetrexate)、醋酸曲普瑞林(triptorelinacetate)、双羟萘酸曲普瑞林(triptorelin pamoate)、优福定(UFT)、尿苷(uridine)、戊柔比星(valrubicin)、维司力农(vesnarinone)、长春碱(vinblastine)、长春新碱(vincristine)、长春酰胺(vindesine)、长春瑞滨(vinorelbine)、维鲁利秦(virulizin)、zinecard、净司他丁斯酯(zinostatin stimalamer)、枢复宁(zofran);ABI-007、阿考比芬(acolbifene)、丙型干扰素-1b(actimmune)、affinitak、氨基喋呤(aminopterin)、阿佐昔芬(arzoxifene)、asoprisnil、阿他美坦(atamestane)、阿曲生坦(atrasentan)、BAY 43-9006(索拉非尼(sorafenib))、阿瓦斯丁(avastin)、CCI-779、CDC-501、西乐葆(celebrex)、西妥昔单抗(cetuximab)、克立那托(crisnatol)、醋酸环丙孕酮(cyproterone acetate)、地西他滨(decitabine)、DN-101、阿霉素-MTC(doxorubicin MTC)、dSLIM、度他雄胺(dutasteride)、edotecarin、依氟鸟氨酸(eflornithine)、依喜替康(exatecan)、芬维A胺(fenretinide)、二盐酸组胺(histamine dihydrochloride)、组氨瑞林水凝胶植入物(histrelin hydrogel implant)、钬-166DOTMP(holmium-166DOTMP)、伊班膦酸(ibandronic acid)、干扰素γ(interferon gamma)、内含子-PEG(intron-PEG)、伊沙匹隆(ixabepilone)、匙孔形血蓝蛋白(keyhole limpet hemocyanin)、L-651582、兰乐肽(lanreotide)、拉索昔芬(lasofoxifene)、libra、洛那法尼(lonafarnib)、米泼昔芬(miproxifen)、米诺屈酸酯(minodronate)、MS-209、脂质体MTP-PE(liposomal MTP-PE)、MX-6、那法瑞林(nafarelin)、奈莫柔比星(nemorubicin)、新伐司他(neovastat)、诺拉曲特(nolatrexed)、奥利默森(oblimersen)、onco-TCS、osidem、紫杉醇聚谷氨酸酯(paclitaxelpolyglutamate)、帕米膦酸二钠(pamidronate disodium)、PN-401、QS-21、夸西泮(quazepam)、R-1549、雷洛昔芬(raloxifene)、ranpirnase、13-顺维A酸(13-cis-retinoicacid)、赛特铂(satraplatin)、西奥骨化醇(seocalcitol)、T-138067、特罗凯(tarceva)、taxoprexin、胸腺素αl(thymosin alpha 1)、噻唑羧胺核苷(tiazofurin)、替吡法尼(tipifarnib)、替拉扎明(tirapazamine)、TLK-286、托瑞米芬、反式MID-lo7R(transMID-107R)、valspodar、伐普肽(vapreotide)、瓦他拉尼(vatalanib)、维替泊芬(verteporfin)、长春氟宁(vinflunine)、Z-100、唑来膦酸(zoledronic acid),以及其组合。
在优选的实施方案中,本发明的化合物A可以与以下活性成分组合:
131I-chTNT、阿巴瑞克(abarelix)、阿比特龙(abiraterone)、阿柔比星(aclarubicin)、阿地白介素、阿伦单抗(alemtuzumab)、阿利维A酸、六甲密胺、氨鲁米特、氨柔比星、安吖啶、anastrozole、小白菊内酯衍生物、三氧化二砷、天冬酰胺酶(asparaginase)、阿扎胞苷(azacitidine)、巴利昔单抗(basiliximab)、BAY 80-6946、贝洛替康(belotecan)、苯达莫司汀(bendamustine)、贝伐单抗(bevacizumab)、蓓萨罗丁、比卡鲁胺(bicalutamide)、比生群(bisantrene)、争光霉素、硼替佐米、布舍瑞林(buserelin)、白消安、卡巴他赛(cabazitaxel)、亚叶酸钙(calcium folinate)、左亚叶酸钙(calciumlevofolinate)、卡培他滨、卡铂、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡妥索单抗(catumaxomab)、塞来昔布(celecoxib)、西莫白介素、西妥昔单抗、苯丁酸氮芥、氯地孕酮(chlormadinone)、氯芥(chlormethine)、顺铂、克拉屈滨、氯屈瞵酸、氯法拉滨(clofarabine)、crisantaspase、环磷酰胺、环丙孕酮(cyproterone)、阿糖胞苷、达卡巴嗪、放线菌素D、生成素α(darbepoetin alfa)、达沙替尼(dasatinib)、道诺霉素(daunorubicin)、地西他滨、地加瑞克(degarelix)、地尼白介素、狄诺塞麦(denosumab)、地洛瑞林、二溴螺氯铵(dibrospidium chloride)、多西他赛、去氧氟尿苷、阿霉素、阿霉素+雌激素酮、依库丽单抗、依决洛单抗(edrecolomab)、依利醋铵(elliptinium acetate)、艾曲波帕(eltrombopag)、内皮抑素(endostatin)、依诺他宾(enocitabine)、表柔比星、环硫雌醇(epitiostanol)、阿法依泊汀、倍他依泊汀、依铂、艾瑞布林(eribulin)、埃罗替尼(erlotinib)、雌二醇、雌莫司汀(estramustine)、依托泊甙、依维莫司(everolimus)、依西美坦(exemestane)、法倔唑(fadrozole)、非格司亭、氟达拉滨、氟尿嘧啶(fluorouracil)、氟他胺、福美司坦、福莫司汀、氟维司群、硝酸镓(gallium nitrate)、加尼瑞克(ganirelix)、易瑞沙(gefitinib)、吉西他滨、吉妥珠单抗、达托霉素(glutoxim)、戈舍瑞林、二盐酸组胺、组氨瑞林、羟基尿素(hydroxycarbamide)、I-125籽源、伊班膦酸、替坦异贝莫单抗、伊达比星、异环磷酰胺、伊马替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、干扰素α、干扰素β、干扰素γ、易普利姆玛(ipilimumab)、依立替康、伊沙匹隆、兰乐肽、拉帕替尼、来那度胺(lenalidomide)、来格司亭(lenograstim)、香菇多糖(lentinan)、来曲唑、亮丙瑞林(leuprorelin)、左旋四咪唑、麦角乙脲(lisuride)、洛铂(lobaplatin)、洛莫司汀、氯尼达明、马索罗酚(masoprocol)、甲羟孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美法仑、美雄烷(mepitiostane)、巯基嘌呤(mercaptopurine)、氨甲蝶呤、甲氧沙林(methoxsalen)、氨基酮戊酸甲酯(methylaminolevulinate)、甲基睾酮(methyltestosterone)、米伐木肽(mifamurtide)、米替福新、米铂(miriplatin)、二溴甘露醇(mitobronitol)、米托胍腙(mitoguazone)、二溴卫矛醇(mitolactol)、丝裂霉素、米托坦、米托蒽醌、奈达铂、奈拉滨(nelarabine)、尼罗替尼(nilotinib)、尼鲁米特、尼妥珠单抗(nimotuzumab)、尼莫司汀(nimustine)、硝氨丙吖啶(nitracrine)、奥法木单抗(ofatumumab)、奥美拉唑(omeprazole)、奥普瑞白介素(oprelvekin)、奥沙利铂、p53基因治疗、紫杉醇、帕利夫明(palifermin)、钯-103籽源、帕米膦酸(pamidronic acid)、帕尼单抗(panitumumab)、帕唑帕尼(pazopanib)、培门冬酶(pegaspargase)、PEG-依泊汀β(epoetin beta)(甲氧基-PEG-依泊汀β)、培非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b(peginterferon alfa 2b)、培美曲塞(pemetrexed)、潘他唑新(pentazocine)、喷司他丁、培洛霉素(peplomycin)、培磷酰胺(perfosfamide)、picibanil、吡柔比星(pirarubicin)、普乐沙福(plerixafor)、普卡霉素、壳聚糖(poliglusam)、磷酸聚雌二醇(polyestradiol phosphate)、多糖-K、卟吩姆钠、普拉曲沙(pralatrexate)、泼尼莫司汀、丙卡巴肼、喹高利特(quinagolide)、氯化镭-223、雷洛昔芬、雷替曲塞、雷莫司汀(ranimustine)、雷佐生(razoxane)、瑞法替尼(refametinib)、瑞戈非尼(regorafenib)、利塞膦酸(risedronic acid)、利妥昔单抗、罗米地辛(romidepsin)、罗米司亭(romiplostim)、沙莫司亭、sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索拉非尼、链脲菌素、舒尼替尼(sunitinib)、他拉泊芬(talaporfin)、他米巴罗汀(tamibarotene)、他莫昔芬、他索那明、替西白介素、喃氟啶(tegafur)、喃氟啶+吉莫斯特(gimeracil)+奥替拉西(oteracil)、替莫卟吩(temoporfin)、替莫唑胺、西罗莫司脂化物(temsirolimus)、替尼泊苷、睾丸素、替曲膦(tetrofosmin)、沙利度胺(thalidomide)、噻替派(thiotepa)、胸腺法新(thymalfasin)、硫鸟嘌呤(tioguanine)、托珠单抗(tocilizumab)、拓扑替康、托瑞米芬、托西莫单抗、曲贝替定(trabectedin)、曲妥珠单抗、曲奥舒凡、维A酸、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、三芥环磷酰胺(trofosfamide)、色氨酸(tryptophan)、乌苯美司(ubenimex)、戊柔比星、凡德他尼(vandetanib)、伐普肽、维莫非尼(vemurafenib)、长春碱、长春新碱、长春酰胺、长春氟宁、长春瑞滨、伏立诺他(vorinostat)、伏氯唑(vorozole)、钇-90玻璃微球(yttrium-90glass microspheres)、新制癌菌素(zinostatin)、净司他丁斯酯、唑来膦酸、佐柔比星(zorubicin)、ibrunitib、fostamatinib二钠、enzastaurin、艾代拉利司(idelalisib)、ABT-199、奥滨尤妥珠单抗(obinutuzumab)、carfilzomib、本妥昔单抗(brentuximab vedotin)、帕比司他(panobinostat)以及其组合。
有希望地,化合物A还可以与生物治疗剂如抗体(例如,阿瓦斯汀(avastin)、利妥昔单抗(rituxan)、爱必妥(erbitux)、赫赛汀(herceptin)、西妥昔单抗)和重组蛋白组合。
化合物A还可以与针对血管新生的其他治疗剂(例如,阿瓦斯汀、阿昔替尼(axitinib)、瑞戈非尼、洛丁林(recentin),索拉非尼或舒尼替尼)结合而获得积极效果。由于其在不良反应方面的有利属性,与蛋白酶体和mTOR的抑制剂以及抗激素和甾体代谢酶抑制剂的组合特别有用。
通常,化合物A与其他抑制细胞生长剂或细胞毒性剂的组合可以实现以下目标:
·与使用单独的活性成分进行治疗相比,在减缓肿瘤生长、减小肿瘤大小或甚至完全消除肿瘤方面具有改进的功效;
·可以以比单一疗法更低的剂量使用化学疗法;
·与单独给药相比,可产生一种耐受性更强、不良反应更少的疗法;
·可治疗更广谱的肿瘤疾病;
·获得更高的治疗反应率;
·与目前的标准疗法相比,患者的生存时间更长。
此外,本发明的化合物A还可以与放射疗法和/或外科手术结合使用。
实施例
1.化合物A’的制备
根据WO2014/076091的实施例2中记载的方法制备化合物A’。
2.体外实验
2.1.方法
2.1.1细胞系
表1:所研究的DLBLC细胞系的列表。
肿瘤指征 | 亚型 | 细胞系的实施例 | 易位(TL)或扩增(ampl)情形 |
DLBCL | ABC<sup>a</sup> | HBL1 | MYC TL |
DLBCL | ABC | OCI-LY-3 | MYC ampl/BCL2 ampl |
DLBCL | ABC | TMD8 | MYC TL |
DLBCL | GCB<sup>b</sup> | DB | BCL2 TL |
DLBCL | GCB | SU-DHL-6 | MYC TL |
DLBCL | GCB | HT | - |
DLBCL | GCB | OCI-LY-19 | MYC TL |
DLBCL | GCB | SU-DHL-8 | MYC TL/BCL2 TL |
DLBCL | GCB | SU-DHL-10 | MYC TL/BCL2 TL |
DLBCL | GCB | SU-DHL-4 | MYC ampl/BCL2 TL |
DLBCL | GCB | SU-DHL-5 | - |
a激活的B细胞型,b生发中心B细胞型
2.1.2细胞增殖试验
使用CellTiter Glo试剂盒(Promega Corporation,Madison,WI)评估在不同浓度的化合物A’或FR化合物的存在下所有(DLCBL)细胞系的增殖,持续72小时。所有表示的值均是一式三份实验的平均值,并根据制造商的说明使用GraphPad Prism 5(GraphPad软件,San Diego,CA)或MTS软件,计算IC50。
FR化合物是WO2012/160034的实施例4,并且具有式II的结构:
2.2体外结果
表2总结了使用化合物A'或FR化合物进行增殖试验的结果。表2:所研究的细胞系列表以及使用化合物A’或FR化合物进行增殖试验的结果。
实施例 | 化合物A’ | FR化合物 | ||
肿瘤指征 | 亚型 | 细胞系 | IC<sub>50</sub>[nmol/l] | IC<sub>50</sub>[nmol/l] |
DLBCL | ABC | HBL1 | 196 | 540 |
DLBCL | ABC | OCI-LY-3 | 83 | 340 |
DLBCL | ABC | TMD8 | 100 | n/a |
DLBCL | GCB | DB | 88 | 570 |
DLBCL | GCB | SU-DHL-6 | 37 | 360 |
DLBCL | GCB | HT | 81 | 710 |
DLBCL | GCB | OCI-LY-19 | 39 | 480 |
DLBCL | GCB | SU-DHL-8 | 93 | 610 |
DLBCL | GCB | SU-DHL-10 | 129 | 600 |
DLBCL | GCB | SU-DHL-4 | 90 | 170 |
DLBCL | GCB | SU-DHL-5 | 105 | n/a |
这些体外数据表明,化合物A’有效抑制了弥漫性大B细胞淋巴瘤(DLBCL)的ABC(激活的B细胞型)和GCB(生发中心B细胞型)亚型的增殖。这些数据推荐化合物A’用于治疗DLBCL患者。
3.在小鼠中使用OCL-LY-3弥漫性大B细胞淋巴瘤(DLBCL)异种移植物模型进行体内实验
本实验的目的是评估在SCID小鼠中经皮下植入的DLBCL OCI-LY-3肿瘤模型中,化合物A’在单一疗法中的体内效力和耐受性。
在携带皮下DLBCL OCI-LY-3异种移植物的雌性SCID小鼠中测定体内效力。在单一疗法中以一种剂量水平评估了化合物A’。使用赋形剂对照组作为参考,评估治疗组的抗肿瘤活性和耐受性。
为此,将OCI-LY-3细胞(0.1ml 100%基质胶(Matrigel)中4x106个细胞)皮下注射于雌性SCID小鼠(Charles River)的右胁腹。每天监测动物和肿瘤植入物,直到最大数量的植入物表现出开始实体瘤生长的明显迹象。随机地,最初确定了生长中的肿瘤的面积。根据研究方案,将具有一个面积为25-35mm2的肿瘤的动物分配到实验组中。将随机化的日期指定为实验的第0天。动物每7天一次(q7d)以10mg/kg的剂量静脉注射接受化合物A’(以30%PEG400/10%乙醇/60%的水配制),或者接受赋形剂对照(每天一次(qd),口服(po)),持续14天。
在化合物A’组中,未发生致命毒性,并且最大体重损失为-6%,而在赋形剂组中为-4%,表明化合物A’在剂量为10mg/kg,每7天一次,静脉注射(iv)时具有良好的耐受性。
在实验结束时,根据化合物A’治疗组和赋形剂对照组中平均肿瘤面积和平均肿瘤重量,计算出治疗与对照的比率(T/C)。平均肿瘤重量和平均肿瘤面积分别在统计学上具有显著性差异。化合物A’的面积T/C是0.29,重量T/C是0.24,表明该模型中化合物A’的体内活性中等。
4.在小鼠中使用SU-DHL-10弥漫性大B细胞淋巴瘤(DLBCL)异种移植物模型进行体内实验
本实验的目的是评估在SCID小鼠中经皮下植入的DLBCL SU-DHL-10肿瘤模型中,化合物A’在单一疗法中的体内效力和耐受性。
在携带皮下DLBCL SU-DHL-10异种移植物的雌性SCID小鼠中测定体内效力。在单一疗法中以一种剂量水平评估了化合物A’。使用赋形剂对照组作为参考,评估治疗组的抗肿瘤活性和耐受性。
为此,将SU-DHL-10细胞(0.2ml 50%基质胶中10x106个细胞)皮下注射于雌性SCID小鼠(Taconic M&B A/S,Denmark)的右胁腹。每天监测动物和肿瘤植入物,直到最大数量的植入物表现出开始实体瘤生长的明显迹象。随机地,最初确定了生长中的肿瘤的面积。根据研究方案,将具有一个面积为25-35mm2的肿瘤的动物分配到实验组中。将随机化的日期指定为实验的第0天。动物每7天一次(q7d)以15mg/kg的剂量静脉注射接受化合物A’(以30%PEG400/10%乙醇/60%的水配制),或者接受赋形剂对照(每7天一次,静脉注射),持续16天。
在化合物A’组中,最大体重损失为-9%,而赋形剂组为-4%,表明化合物A’在剂量为7mg/kg,每7天一次,静脉注射时具有中等耐受性。
实验结束时,根据化合物A’治疗组和赋形剂对照组的平均肿瘤面积计算出治疗与对照的比率(T/C)。平均肿瘤面积在统计学上具有显著性差异。化合物A’的面积T/C为0.02,表明在该模型中化合物A'的体内活性非常高,相当于完全缓解。
4.5.总结与结论
这些数据表明化合物A’在弥漫性大B细胞淋巴瘤(DLBCL)患者中具有显著且有意义的抗肿瘤活性。
Claims (16)
2.根据权利要求1所述的式(I)化合物的用途,其中所制备的药物用于治疗其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤。
3.根据权利要求1或2所述的式(I)化合物的用途,其中使用对映异构体(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺或其生理上可接受的盐之一。
5.根据权利要求4所述的化合物,用于治疗其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥漫性大B细胞淋巴瘤。
6.根据权利要求4或5所述的化合物,其中使用对映异构体(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺或其生理上可接受的盐之一。
8.根据权利要求7所述的式(I)化合物的用途,用于治疗和/或预防其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥漫性大B细胞淋巴瘤。
9.根据权利要求7或8所述的式(I)化合物的用途,其中使用对映异构体(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺或其生理上可接受的盐之一。
12.根据权利要求10或11所述的药物结合物或药物组合物,用于治疗和/或预防其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥漫性大B细胞淋巴瘤。
13.根据权利要求12至25中任一项所述的药物结合物或药物组合物,其中包括对映异构体(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺或其生理上可接受的盐之一。
15.根据权利要求14所述的治疗和/或预防的方法,其中治疗其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥漫性大B细胞淋巴瘤。
16.根据权利要求14或15所述的治疗的方法,其中使用对映异构体(+)-5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺或其生理上可接受的盐之一。
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