CN106397427A - 3‑[(3‑{[4‑(4‑吗啉基甲基)‑1h‑吡咯‑2‑基]亚甲基}‑2‑氧代‑2,3‑二氢‑1h‑吲哚‑5‑基)甲基]‑1,3‑噻唑烷‑2,4‑二酮和egfr tyr激酶抑制剂的组合 - Google Patents
3‑[(3‑{[4‑(4‑吗啉基甲基)‑1h‑吡咯‑2‑基]亚甲基}‑2‑氧代‑2,3‑二氢‑1h‑吲哚‑5‑基)甲基]‑1,3‑噻唑烷‑2,4‑二酮和egfr tyr激酶抑制剂的组合 Download PDFInfo
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- CN106397427A CN106397427A CN201610603485.2A CN201610603485A CN106397427A CN 106397427 A CN106397427 A CN 106397427A CN 201610603485 A CN201610603485 A CN 201610603485A CN 106397427 A CN106397427 A CN 106397427A
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
本发明涉及式(I)的3‑[(3‑{[4‑(4‑吗啉基甲基)‑1H‑吡咯‑2‑基]亚甲基}‑2‑氧代‑2,3‑二氢‑1H‑吲哚‑5‑基)甲基]‑1,3‑噻唑烷‑2,4‑二酮或其Z或E异构体和/或其与可药用酸或碱的加成盐与人表皮生长因子受体(EGFR)酪氨酸激酶抑制剂的组合。本发明还涉及药物。
Description
技术领域
本发明涉及式(I)的3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)-甲基]-1,3-噻唑烷-2,4-二酮:
或其Z或E异构体和/或其与可药用酸或碱的加成盐与人表皮生长因子受体(EGFR)酪氨酸激酶抑制剂的新的组合,其用于治疗非小细胞肺癌、更尤其是对EGFR酪氨酸激酶抑制剂有抗性的患者的非小细胞肺癌。
背景技术
非小细胞肺癌是当今世界上癌症死亡的主要原因(Goldstraw,P.,D.Ball,J.R.Jett,C.T.Le,E.Lim,A.G.Nicholson,和F.A.Shepherd,2011,Non-small-cell lungcancer:Lancet,第378卷,第9804期,第1727-1740页;Jemal,A.,F.Bray,M.M.Center,J.Ferlay,E.Ward,和D.Forman,2011,Global cancer statistics:CA Cancer J Clin,第61卷,第2期,第69-90页)。在诊断时,大多数患者具有晚期病理学病变,一年存活率30%和五年存活率10%(美国国立卫生研究院,国家癌症研究所http://seer.cancer.gov/archive/csr/1975_2011/results_merged/topic_delaygraphs_overview.pdf;http://www.cancerresearchuk.org/cancer-info/cancerstats/types/lung/survival/lung-cancer-survival-statistics)。EGFR基因的激活突变导致癌基因成瘾,换言之癌症细胞变得依赖该变异型以实现其生长和存活。所述突变常见于肺的腺癌的中,在高加索患者中占病例的15%,在亚洲患者中占病例的40-50%(Shigematsu,H.等人,2005,Clinical andbiological features associated with epidermal growth factor receptor genemutations in lung cancers:J Natl Cancer Inst,第97卷,第5期,第339-346页)。在具有EGFR基因突变的患者中,EGFR酪氨酸激酶抑制剂与化学疗法相比显著延缓疾病的进程,被认为是基准治疗。目前市场上的治疗手段包括第一代抑制剂的吉非替尼和厄洛替尼和第二代治疗剂的阿法替尼等,各代都靶向EGFR的活化的突变。不幸地是,通过获得其它基因的和蛋白质改变(其能产生EGFR酪氨酸激酶抑制剂的抗性)大多数患者在治疗后数月复发。已经鉴定了一些抗性机制,尤其是在大多数对治疗有抗性的患者中发现了一种新的EGFR受体的突变(T790M:在790位甲硫氨酸替代苏氨酸)。在对EGFR酪氨酸激酶抑制剂产生抗性后,预后变得非常差,为患者提供的化学疗法功效非常低。在这点上,为了改善无疾病进展的生存期的、对非小细胞肺癌(尤其是对EGFR酪氨酸激酶抑制剂有抗性的患者的非小细胞肺癌)的新的治疗供选方案的研究仍然是目前的问题。尤其是,使对EGFR酪氨酸激酶抑制剂有抗性的患者再敏感化,是需要研究的一个坚定的治疗策略。目前正在开发专门作用于获得了诸如T790M的次级突变的患者的第三代EGFR酪氨酸激酶抑制剂,且似乎恢复了治疗的活性。作用于除T790M突变之外的抗性途径和/或涉及其他细胞受体的其他供选方案仍然是需要的并且是患者期待已久的,可以尤其与第三代抑制剂进行组合。
发明内容
下文除非另外指定,“3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮”被理解为以下含义:“3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]-亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮及其Z或E异构体和/或与可药用酸或碱的加成盐”。
3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮是癌细胞转移的强效抑制剂,尤其可用于治疗癌症、且尤其用于治疗转移的实体瘤。其在专利申请WO2011/015728和WO2015/004395中有描述。
根据本发明,已证明了在之前用EGFR酪氨酸激酶抑制剂抑制剂治疗过的动物模型中,3-{[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基]甲基}-1,3-噻唑烷-2,4-二酮的作用能除去对EGFR酪氨酸激酶抑制剂的抗性。
这些作用使得3-{[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基]甲基}-1,3-噻唑烷-2,4-二酮和EGFR酪氨酸激酶抑制剂的组合可以应用于所关注的非小细胞肺癌的治疗中,尤其是在尽管治疗过但仍观察到疾病的进展或复发的患者的非小细胞肺癌。
在根据本发明的组合中更尤其是,该3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮为Z异构体形式。
优选在根据本发明的组合中,该3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮为盐形式、尤其是盐酸盐或甲磺酸盐。
还更有利地是,本发明的组合包含3-[((3Z)-3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐。
在根据本发明的EGFR酪氨酸激酶抑制剂中,提及的可以是第一代和第二代抑制剂厄洛替尼、吉非替尼和阿法替尼和第三代抑制剂AZD9291(奥斯替尼)或卢瑟替尼(rociletinib)。
根据一个有利的实施方案,根据本发明的组合的EGFR酪氨酸激酶抑制剂是式(II)的N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)-喹唑啉-4-胺或厄洛替尼:
或其与可药用酸或碱的加成盐、尤其是其盐酸盐。
根据另一个有利的实施方案,根据本发明的组合的EGFR酪氨酸激酶抑制剂是式(III)的N-(3-氯-4-氟-苯基)-7-甲氧基-6-(3-吗啉-4-基丙氧基)喹唑啉-4-胺或吉非替尼:
或其与可药用酸或碱的加成盐。
优选地,根据本发明的组合包含3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮的Z异构体或其可药用盐,以及吉非替尼或其可药用盐。
还更特别地是,本发明涉及3-[((3Z)-3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)-甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐和吉非替尼或其可药用盐的组合。
本发明还涉及药物组合物,其包含3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮和EGFR酪氨酸激酶抑制剂的组合,以及一种或多种可药用赋形剂。
本发明还涉及所述药物组合物在治疗非小细胞肺癌中的用途,更尤其是在治疗对EGFR酪氨酸激酶抑制剂有抗性的患者的非小细胞肺癌中的用途。
在本发明的药物组合物中,提及的更尤其可以是适合用于口服、胃肠外、肌内和静脉内、透皮或经皮、鼻、直肠、经舌、眼或呼吸途径施用的那些,更具体是片剂、糖锭剂、舌下片剂、明胶胶囊剂、glossettes、胶囊剂、锭剂、注射剂、气雾剂、滴眼剂或滴鼻剂、栓剂、霜剂、软膏剂、皮肤凝胶剂等。
在一个优选的实施方案中,3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮以口服形式施用。
除了3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮和EGFR酪氨酸激酶抑制剂之外,本发明的药物组合物还包含一种或多种选自稀释剂、润滑剂、粘合剂、崩解剂、稳定剂、防腐剂、吸收剂、着色剂、甜味剂、矫味剂等的赋形剂或载体。
可提及的实例无任何限制性地包括:
-用作稀释剂的:乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素、甘油;
-用作润滑剂的:二氧化硅、滑石粉、硬脂酸及其镁盐和钙盐、聚乙二醇;
-用作粘合剂的:硅酸铝和硅酸镁、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮;
-用作崩解剂的:琼脂、藻酸及其钠盐、泡腾混合物。
所述组合中的各化合物可以同时或相继施用。相应的药物组合物可以允许活性成分的立即或延迟释放。此外,所述组合中的各化合物可以以两种独立的药物组合物的形式施用,每种药物组合物包含所述活性成分中的一种,或以单一的药物组合物(其中各活性成分是混合的)的形式施用。
使用的剂量根据患者的性别、年龄和重量、施用途径、癌症的性质和任何组合治疗的性质而不同,范围为每天300至1500mg 3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮的游离碱的等同物、且更优选为每天400至800mg游离碱的等同物、还更尤其是每天500至600mg游离碱的等同物。EGFR酪氨酸激酶抑制剂的剂量将等于当其独自施用时使用的量或更低。例如,在吉非替尼的情况中,施用的剂量为每天250mg。对于厄洛替尼,为每天25至150mg。
附图说明
图1显示厄洛替尼-抗性的HCC827肿瘤的生长的抑制。
具体实施方式
药物组合物
包含100mg 3-[3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐的游离碱的等同物的1000片,Z异构体.............................................................121g
羟乙酸淀粉钠......................................................20g
玉米淀粉.........................................................133g
乳糖一水合物.....................................................357g
硬脂酸镁.........................................................6.7g
二氧化硅.........................................................1.3g
聚维酮..........................................................46.6g
临床前试验
A)对厄洛替尼-抗性细胞系HCC827的细胞生存测试
使用的是能测定抗肿瘤化合物的抗增殖能力的细胞生存测试。选择的细胞系是细胞系HCC827、非小细胞肺癌细胞系,其存活依赖于EGFR。使用的参数为IC50,即与未处理的对照细胞相比抑制50%细胞增殖的产品的浓度。在试验前2天将细胞以适合的密度接种(150μl)于96-孔板的孔中。1列包含代表100%增殖的未处理的对照细胞。将其它列与测试产品一起孵育4个倍增时间。EGFR酪氨酸激酶抑制剂厄洛替尼用于细胞系HCC827的细胞存活的中位抑制剂浓度为10nM。通过将细胞系HCC827长期暴露于厄洛替尼产生对厄洛替尼的获得性抗性:以在培养基中1μM的剂量将细胞暴露于厄洛替尼直至倍增时间稳定,即约2个月。然后厄洛替尼对该抗性细胞系HCC827的细胞存活的中位抑制浓度约为11.5μM,其比如上文所述的对非抗性细胞系HCC827的中位抑制浓度高约1000倍。然后将抗性细胞暴露于3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮盐酸盐(100nM的浓度)及与之组合的增加剂量的厄洛替尼。3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮盐酸盐独自对存活没有作用。在组合中,厄洛替尼对抗性细胞系HCC827的中位抑制浓度回到约3.8nM,其接近对非-抗性细胞系HCC827的中位抑制浓度。
该结果显示3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮能在对EGFR酪氨酸激酶抑制剂有抗性的非小细胞肺癌细胞系中恢复对EGFR酪氨酸激酶抑制剂的敏感性。
B)厄洛替尼-抗性的HCC827肿瘤的生长的抑制
将在体外产生对厄洛替尼的抗性的细胞系HCC827(非小细胞肺癌细胞系)在皮下部位以5.106细胞/小鼠的量移植至雌性SCID小鼠。当肿瘤体积达到约200mm3,将肿瘤随机分配至具有八只小鼠的各组。历经19天的时期,使用50mg/kg的剂量的化合物A(3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮盐酸盐)和12.5mg/kg的剂量的厄洛替尼进行每日治疗,其为口服施用(载体分别为醋酸铵/HEC和PEG300/乙醇/水缓冲液),如图1上的三角形所示。使用游标卡尺每周测量肿瘤体积两次至三次。在图上记录中位肿瘤体积(包括四分位距)。
在治疗末尾的第19天,对于厄洛替尼,使用所述化合物独自治疗的生长抑制为65%,且对于3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮盐酸盐(化合物A),为83%。当这两种化合物组合使用,肿瘤完全消退,且当停止治疗后,所述消退随时间持续至第30天。观测到的这两种产品之间的协同作用在研究期间是统计学显著的(p<0.001)。
临床研究
具有非小细胞肺癌的患者出现对使用EGFR酪氨酸激酶抑制剂(吉非替尼、厄洛替尼、阿法替尼、奥斯替尼或卢瑟替尼)的治疗的抗性,对所述治疗不再敏感,且疾病进展。
概念验证性研究(proof of concept study)正在进行中以证实临床前试验中所观测到的结果,且显示在当前吉非替尼情况中,3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮能够在已经变得有抗性的罹患非小细胞肺癌的患者中恢复对EGFR抑制剂的敏感性。根据患者的分子谱将患者囊括进来。该研究包括I期,目标为评估耐受谱并测定用于持续发展的推荐剂量。将包括约20位患者。在该期期间,将在28天的周期内使用以下剂量治疗患者:每天400、500或600mg 3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮游离碱的等同物,以及每天250mg的吉非替尼。所述治疗将被保持,直至疾病进展。在该期末尾,将开始II期,目标为评估3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮和吉非替尼的组合的活性。所述II期将包括约150个患者。将每2个月评价肿瘤。将在28-天的周期内使用I期中确定的3-[(3-{[4-(4-吗啉基-甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮的推荐剂量以及每天250mg吉非替尼来治疗患者。
Claims (12)
1.式(I)的3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮及其Z或E异构体和/或与可药用酸或碱的加成盐:
与人表皮生长因子受体(EGFR)酪氨酸激酶抑制剂的组合产品。
2.根据权利要求1的组合产品,其特征在于3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮以Z异构体形式使用。
3.根据权利要求1或权利要求2的组合产品,其特征在于3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮以盐酸盐形式使用。
4.根据权利要求1或权利要求2的组合产品,其特征在于3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮以甲磺酸盐形式使用。
5.根据权利要求1至4中任意一项的组合产品,其特征在于所述EGFR酪氨酸激酶抑制剂是吉非替尼或厄洛替尼。
6.用于治疗非小细胞肺癌的根据权利要求1至5中任意一项的组合产品。
7.根据权利要求1至5中任意一项的组合产品,其用于治疗对EGFR酪氨酸激酶抑制剂有抗性的患者的非小细胞肺癌。
8.药物组合物,其包含作为活性成分的3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮或其Z或E异构体和/或其与可药用酸或碱的加成盐,以及与之组合的根据权利要求1至7中任意一项的EGFR酪氨酸激酶抑制剂,以及一种或多种可药用赋形剂。
9.用于治疗非小细胞肺癌的根据权利要求8的药物组合物。
10.根据权利要求9的药物组合物,其用于治疗对EGFR酪氨酸激酶抑制剂有抗性的患者的非小细胞肺癌。
11.根据权利要求1至7中任意一项的组合产品在治疗非小细胞肺癌中的用途。
12.根据权利要求1至7中任意一项的组合产品在治疗对EGFR酪氨酸激酶抑制剂有抗性的患者的非小细胞肺癌中的用途。
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