CN111757734A - 通过组合疗法的ezh2抑制剂的药代动力学增强 - Google Patents
通过组合疗法的ezh2抑制剂的药代动力学增强 Download PDFInfo
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Abstract
本文提供了药物组合物,其包含有效量的(R)‑N‑((4‑甲氧基‑6‑甲基‑2‑氧代‑1,2‑二氢吡啶‑3‑基)甲基)‑2‑甲基‑1‑(1‑(1‑(2,2,2‑三氟乙基)哌啶‑4‑基)乙基)‑1H‑吲哚‑3‑羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐。还提供了有效量的(R)‑N‑((4‑甲氧基‑6‑甲基‑2‑氧代‑1,2‑二氢吡啶‑3‑基)甲基)‑2‑甲基‑1‑(1‑(1‑(2,2,2‑三氟乙基)哌啶‑4‑基)乙基)‑1H‑吲哚‑3‑羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐用于治疗癌症的用途。
Description
相关申请
本申请要求于2017年12月28日提交的美国临时专利申请号62/611,119的优先权权益,该专利申请的全部内容通过引用并入本文。
背景技术
(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺,在本文中称为化合物1,是Zeste同源物2(EZH2)的增强子的一种有效抑制剂,并且用于治疗多种实体瘤和血液学恶性肿瘤。参见,例如,美国专利号9,085,583,该专利的内容通过引用并入本文。然而,化合物1的缺点在于它具有相对短的半衰期以及多剂量施用时降低的暴露(采用多剂量时,AUC降低约60%)。这导致了一次施用多个剂量的化合物1的令人不满的负担,诸如一天两次或三次的此类剂量的频繁施用,以及可阻止长期活性的慢性标准浓度。为尝试减轻该负担并有利于严格的患者依从性,以及为了改善长期抗肿瘤活性的机会,仍需要改善的药物暴露。
发明内容
现已发现化合物1主要通过肝酶CYP3A代谢,并且化合物1似乎还是CYP3A的较强的诱导剂。现已发现可比司他(Cobicistat)的共施用增强了化合物1的药代动力学。照此,有效量的可比司他与有效量的化合物1现在可以用于改善化合物1的暴露并减轻目前对于一次施用多个剂量的需求。因此,本文提供了包含有效量的可比司他和有效量的化合物1的组合物,以及它们用于治疗一种或多种癌症的用途。
源自导致化合物1的暴露增加的可比司他的施用的显著效果为最小血浆浓度(Cmin)的增加、最大血清浓度(Cmax)的增加、通过曲线下面积(AUC)所表示的实际机体暴露的增加以及表观分布容积(Vz/F)的降低。例如,在一个方面,当与可比司他组合使用时,化合物1的Cmin、Cmax和AUC分别平均增加超过29倍、超过3倍和超过6倍。参见例如图3。另外,化合物1的Vz/F平均降低6倍。参见例如图3。这些结果具有重要意义,因为它们影响增强型药物的给药频率以及充分的药代动力学增强所需的可比司他剂量。
然而,有趣的是,当相比于与抗病毒剂如埃替格韦和达芦那韦的共施用时,化合物1与可比司他的使用具有一些显著不同的效果。例如,虽然可比司他将这些药物的半衰期(T1/2)增加了3至4倍,但它对化合物1的T1/2具有很少的影响或不具有影响。此外,源自化合物1和可比司他的组合的分布容积显著不同于与抗病毒剂的组合(6倍降低相对于对于抗病毒剂而言的最大3倍降低)。参见例如图3。
附图说明
图1是汇总健康志愿者中使用和不使用可比司他预处理的单剂量化合物1药代动力学参数结果的表格。CBST=可比司他预处理,且化合物1以400mg单剂量形式施用;首先单独施用,然后是3个日剂量的可比司他150mg,在化合物1的剂量之间有7天的清除期。
图2是汇总当在研究01中以1600mg剂量向淋巴瘤患者施用化合物1以及在研究02中以400mg剂量连同可比司他预处理向健康志愿者施用化合物1时,化合物1的平均单剂量药代动力学参数的比较的表格。a=在3个每天1次剂量的可比司他之后施用化合物1400mg。
图3是汇总相对于可比司他对化合物1的药代动力学增强作用,利托那韦对多种抗病毒剂的比较性药代动力学增强作用的表格。
图4是汇总在人受试者中化合物1连同其它试剂以及使用和不使用可比司他的平均药代动力学参数的表格。
具体实施方式
本文提供了药物组合物,其包含有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐。
还提供了药物组合物,其包含有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐;有效量的可比司他或其药学上可接受的盐;以及药学上可接受的载体。
本文还提供了用于治疗受试者中癌症的方法,其包括向所述受试者施用有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐。
本文还提供了有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐在制造用于治疗癌症的药物中的用途。
还提供了有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐,其用于治疗癌症。
还提供了用于治疗癌症的药物组合物,其包含有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐。
(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺,在本文中称为化合物1,其具有以下化学结构:
术语“药学上可接受的载体”是指不会不利地影响与其一起配制的化合物的药理学活性,并且对于人类使用也是安全的无毒载体、佐剂或媒介物。可以在本发明公开的组合物中使用的药学上可接受的载体、佐剂或媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、硬脂酸镁、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、交替二氧化硅、三硅酸镁、聚乙烯基吡咯烷酮、纤维素基物质(例如,微晶纤维素、羟丙基甲基纤维素、乳糖一水合物、月桂基硫酸钠和交联甲羧纤维素钠)、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
化合物1和/或可比司他的药学上可接受的盐的形式包括药学上可接受的酸/阴离子盐。本文所述的化合物的适合的药学上可接受的酸加成盐包括例如无机酸(如盐酸、氢溴酸、磷酸、硝酸和硫酸)和有机酸(如乙酸、苯磺酸、苯甲酸、甲磺酸和对甲苯磺酸)的盐。
除非另有说明,否则在本发明的方法和用途中,可以在施用可比司他之前、同时或之后施用有效量的化合物1。因此,出于治疗目的,同时施用不是必需的。然而,在一个方面,化合物1与可比司他同时施用。在另一个方面,在向受试者施用化合物1之前,用可比司他预处理受试者(即,在可比司他之后施用化合物1)一段时间,例如0.5、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5或6.0小时或更长时间。
如本文所用,术语“治疗”是指逆转、减轻或者抑制癌症或其一种或多种症状的发展。
示例性的癌症类型包括例如肾上腺癌、腺泡细胞癌、听神经瘤、肢端雀斑痣样黑素瘤、肢端汗腺瘤、急性嗜酸粒性白血病、急性红白血病、急性淋巴母细胞性白血病、急性巨核细胞白血病、急性单核细胞性白血病、急性早幼粒细胞白血病、腺癌、腺样囊性癌、腺瘤、牙源性腺样瘤、腺鳞癌、脂肪组织肿瘤、肾上腺皮质癌、成人T细胞白血病/淋巴瘤、侵袭性NK细胞白血病、AIDS相关淋巴瘤、腺泡状横纹肌肉瘤、腺泡状软组织肉瘤、成釉细胞纤维瘤、间变性大细胞淋巴瘤、未分化甲状腺癌、血管免疫母细胞性T-细胞淋巴瘤、血管肌脂瘤、血管肉瘤、星形细胞瘤、非典型畸胎样横纹肌样瘤、B细胞慢性淋巴细胞白血病、B细胞幼淋巴细胞白血病、B细胞淋巴瘤、基底细胞癌、胆管癌、膀胱癌、胚细胞瘤、骨癌、卵巢布伦纳氏瘤、棕色瘤、伯基特氏淋巴瘤、乳腺癌、脑癌、癌瘤、原位癌、癌肉瘤、软骨瘤、牙骨质瘤、髓系肉瘤、软骨瘤、脊索瘤、绒毛膜癌、脉络丛***状瘤、肾透明细胞肉瘤、颅咽管瘤、皮肤T细胞淋巴瘤、***、结肠直肠癌、Degos病、促***增生性小圆细胞肿瘤、弥漫性大B细胞淋巴瘤、胚胎发育不良性神经上皮瘤、无性细胞瘤、胚胎癌、内分泌腺瘤、内胚窦瘤、肠病-相关性T细胞淋巴瘤、食道癌、胎内胎、纤维瘤、纤维肉瘤、滤泡性淋巴瘤、滤泡性甲状腺癌、节细胞神经瘤、胃肠癌、生殖细胞瘤、妊娠性绒毛膜癌、巨细胞成纤维细胞瘤、骨巨细胞瘤、神经胶质瘤、多形性胶质母细胞瘤、神经胶质瘤、脑胶质瘤病、胰升血糖素瘤、性腺胚细胞瘤、粒导细胞瘤、两性胚细胞瘤、胆囊癌、胃癌、毛细胞白血病、成血管细胞瘤、头颈癌、血管外皮瘤、血液恶性肿瘤、肝胚细胞瘤、肝T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、浸润性小叶癌、肠癌、肾癌、喉癌、恶性小痣、致死中线癌、白血病、睾丸非生殖细胞瘤、脂肪肉瘤、肺癌、***瘤、***肉瘤、淋巴上皮癌、淋巴瘤、急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、肝癌、小细胞肺癌、非小细胞肺癌、MALT淋巴瘤、恶性纤维组织细胞瘤、恶性周围神经鞘膜肿瘤、恶性蝾螈瘤、外套细胞淋巴瘤、边缘带B细胞淋巴瘤、肥大细胞白血病、纵隔生殖细胞瘤、乳腺髓样癌、髓样甲状腺癌、成神经管细胞瘤、黑素瘤、脑膜瘤、梅克尔细胞癌、间皮瘤、转移性尿路上皮癌、苗勒氏混合瘤、粘液瘤、多发性骨髓瘤、肌肉组织赘生物、阿利贝尔氏病、粘液样脂肪肉瘤、粘液瘤、粘液肉瘤、鼻咽癌、神经鞘瘤、成神经细胞瘤、纤维神经瘤、神经瘤、结节性黑素瘤、眼癌、少突星形细胞瘤、寡枝神经胶质细胞瘤、嗜酸粒细胞腺瘤、视神经鞘脑膜瘤、视神经瘤、口腔癌、骨肉瘤、卵巢癌、潘科斯特瘤、***状甲状腺癌、副神经节瘤、松果体母细胞瘤、松果体细胞瘤、垂体细胞瘤、垂体腺瘤、垂体瘤、浆细胞瘤、多胚瘤、前体T-淋巴母细胞淋巴瘤、原发性中枢神经***淋巴瘤、原发性渗出性淋巴瘤、原发性腹膜癌、***癌、胰腺癌、咽癌、腹膜假粘液瘤、肾细胞癌、肾髓样癌、成视网膜细胞瘤、横纹肌瘤、横纹肌肉瘤、Richter转化、直肠癌、肉瘤、施旺细胞瘤、***瘤、睾丸足细胞瘤、性索-性腺基质细胞瘤、印戒细胞癌、皮肤癌、小蓝圆细胞肿瘤、小细胞癌、软组织肉瘤、生长抑素瘤、煤烟疣、脊髓肿瘤、脾边缘区淋巴瘤、鳞状细胞癌、滑膜肉瘤、Sezary病、小肠癌、鳞状癌、胃癌、T细胞淋巴瘤、睾丸癌、卵泡膜细胞瘤、甲状腺癌、转移细胞癌、咽喉癌、脐尿管癌、泌尿生殖器癌、尿路上皮癌、葡萄膜黑素瘤、子宫癌、疣状癌、视觉传导路胶质瘤、外阴癌、***癌、Waldenstrom巨球蛋白血症、Warthin瘤和威尔姆氏瘤。
在一个方面,待治疗的癌症选自黑素瘤、***癌、乳腺癌、结肠癌、卵巢癌、膀胱癌、肺腺癌和胰脏癌瘤。在另一个方面,癌症选自多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、成人急性髓细胞白血病(AML)、急性B淋巴细胞白血病(B-ALL)和T谱系急性淋巴细胞白血病(T-ALL)。
在一个方面,待治疗的癌症为淋巴瘤、白血病或实体瘤如***癌。
在一个方面,待治疗的癌症选自霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病和多发性骨髓瘤。
在一个方面,待治疗的癌症为淋巴瘤或实体瘤如***癌。
在另一个方面,待治疗的癌症为非霍奇金淋巴瘤。
术语“有效量”或“治疗有效量”是指将引起受试者的生物学或医学反应的本文所述的化合物的量,例如,0.001-100mg/kg体重/天之间的剂量。
如本文所用的术语“患者”是指动物,例如哺乳动物且例如人。术语“受试者”和“患者”可以互换使用。
本文中的组合物和施用方法可以通过口服、肠胃外、通过吸入喷雾、局部、直肠、鼻部、口腔、***或通过植入储库(implanted reservoir)。如本文所用的术语“胃肠外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。在一个方面,本文所述的组合物经配制用于口服施用。
在WO 2013/075083、WO 2013/075084、WO 2013/078320、WO 2013/120104、WO2014/124418、WO 2014/151142和WO 2015/023915中描述了其它施用形式,以上专利内容通过引用并入本文。
在一个方面,向受试者施用的化合物1和/或可比司他的有效量或者在所提供的组合物中配制的化合物1和/或可比司他的有效量使得可以向所述受试者施用0.01-100mg/kg体重/天之间的剂量。将理解的是,针对任何特定患者的具体剂量和治疗方案将取决于多种因素,包括年龄、体重、一般健康状况、性别、饮食、施用时间、***速率、药物组合、治疗医师的判断以及正在治疗的癌症的严重程度。
在一个方面,化合物1的有效量在每天施用1次、2次或3次的50mg至3.5克的范围内。例如,在一个方面,化合物1的有效量在每天施用1次、2次或3次的100mg至3.5克,200mg至3.0克,200mg至2.5克,200mg至1.0克,200mg至1.5克,200mg至1克,300mg至800mg,400mg至800mg或者400mg至600mg的范围内。在另一个方面,化合物1的有效量在每天施用1次、2次或3次的100mg至3.5克,200mg至3.0克,200mg至2.5克,200mg至1.0克,200mg至1.5克,200mg至1克,300mg至800mg,400mg至800mg,400mg至600mg,1.0克至2.0克,1.4克至1.7克,500mg至700mg,550mg至650mg,700mg至900mg,750mg至850mg,300mg至500mg或者350mg至450mg的范围内。在另一个方面,化合物1的有效量为每天施用1次、2次或3次的3.5克、3.4克、3.3克、3.2克、3.1克、3.0克、2.9克、2.8克、2.7克、2.6克、2.5克、2.4克、2.3克、2.2克、2.1克、2.0克、1.9克、1.8克、1.7克、1.6克、1.5克、1.4克、1.3克、1.2克、1.1克、1.0克、900mg、800mg、700mg、600mg、500mg、400mg或300mg。在另一个方面,化合物1的有效量为每天施用1次、2次或3次的3.2克、2.4克、1.6克、1.2克、800mg。在另一个方面,化合物1的有效量为每天施用两次的1.6克,每天施用三次的800mg,每天施用两次的800mg,每天施用两次的600mg或者每天施用两次的400mg。
在一个方面,可比司他的有效量在每天施用1次、2次或3次的75mg至500mg的范围内。在另一个方面,可比司他的有效量在每天施用1次、2次或3次的100mg至400mg,100mg至300mg和100至200mg的范围内。在另一个方面,可比司他的有效量为每天施用1次的150mg。在另一个方面,可比司他的有效量为每天施用2次的150mg。
在一个方面,每天1次或2次向所述受试者施用1.6克、800mg、600mg或者400mg的化合物1,并且每天1次向所述受试者施用150mg的可比司他。
例证
可以根据美国专利号9,085,583中所述的程序制备(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺,该专利的内容通过引用并入本文。
在健康受试者中,可比司他对化合物1的暴露的影响
在使用或不使用可比司他预处理的情况下,用化合物1处理健康受试者。在禁食条件下施用单一400mg剂量的化合物1。在两次单剂量的化合物1的施用之间存在7天清除期。在1期的第1天单独施用化合物1,并在2期的第1天在存在可比司他的情况下施用化合物1。以150mg的剂量每天1次施用可比司他3天,其中第3剂在单剂量化合物1之前2小时。在每期的第1天,在单剂量化合物1之后的以下时间点采集血液样品用于化合物1的药代动力学分析:0(剂量前)、0.5、1、1.5、2、3、4、6、8、10和24小时。
全部6位受试者为年龄在31至52岁之间的男性。在使用和不使用可比司他的情况下用化合物1处理的6位受试者中有3位(50%)报告了总计6起不良事件。在2位受试者中报告的腹泻是超过1位受试者报告的唯一不良事件。单一受试者报告的其它不良事件各自包括:腹痛、背痛、腹股沟疼痛和上呼吸道感染。认为6起不良事件中的3起与研究药物有关:腹泻和腹痛的并发事件以及另一例腹泻。在完成了所有研究药物的剂量施用后,在2期中报告了所有不良事件。除了在接受上一剂量的化合物1之后7天所报告的中度上呼吸道感染病例外,认为所有不良事件的严重程度较轻且无后遗症地得到解决。
采用可比司他预处理成功增加了400mg化合物1的暴露。如图1所示,在存在可比司他的情况下,Cmax增加了平均3.6倍,同时AUC增加了6.9倍。所有受试者具有至少2.8倍的Cmax增加和4.9倍的AUC增加。在存在可比司他的情况下,Cmin也显著增加;所有受试者经历了至少19倍的Cmin增加(平均增加29倍)。Tmax和终未半衰期不受可比司他存在的影响。相比之下,清除率和分布容积分别降低了6.9倍和6.1倍。这些结果提示可比司他通过首过效应的变化而非由于药物清除的减少来增加化合物1的暴露。如图2所示,在健康受试者中采用单剂量化合物1 400mg与可比司他150mg所实现的暴露明显类似于在淋巴瘤患者中采用单独的单一1600mg剂量的化合物1所实现的暴露。
利托那韦/可比司他对抗病毒剂的PK增强相对于可比司他对化合物1的PK增强的比较
图3中的数据汇总了当与单剂量和多剂量的埃替格韦(EVG)、阿扎那韦(ATV)和达芦那韦(DRV)共施用时,采用利托那韦(发现可比司他与之是生物学等价的)所实现的药代动力学增强,以及当与单剂量的化合物1共施用时,COBI所实现的药代动力学增强。
EVG研究1为HIV感染患者中EVG的多剂量递增研究。每组6位患者接受单独或与RTV(100mg QD)组合的50mg EVG 10天。在第1天(图3中的单剂量研究1a)和第10天(图3中的多剂量研究1a)评估EVG的药代动力学。在EVG研究2中,在12位健康志愿者的组中,前10天单独施用50mg EVG,然后另外10天增加RTV(100mg BID)。比较了在第11天单剂量RTV 100mg后第10天或第20天EVG/RTV 100/100mg QD10天后单独施用时,EVG的药代动力学。图3中显示了来自该研究的比较倍数效果。
还在HIV患者中评价了当单独施用以及与RTV 100mg QD组合施用时300mg ATV的药代动力学(Achenbach等人,2011)。图3中显示了来自该研究的比较倍数效果。
在DRV研究1中,在交叉设计中,在使用和不使用100mg RTV的情况下用单一150mgIV剂量的DRV,以及在使用或不使用100mg RTV的情况下用单一口服剂量的600mg DRV处理8位健康志愿者。BID施用RTV总计5天,其在DRV施用之前2天开始并在DRV施用之后3天结束。图3中显示了来自该研究的比较倍数效果。
如自结果所示,在使用可比司他连同化合物1以及使用可比司他等价物RTV连同抗病毒剂之间不同的三种药代动力学参数为半衰期、最小血浆浓度和表现分布容积。有趣的是,尽管可比司他是已知的CYP3A抑制剂,但它对化合物1的半衰期具有很小影响或无影响。这与针对抗病毒剂所提供的数据相反,在针对抗病毒剂的数据中,半衰期延长至它们的给药频率可降低至每天一次的程度。在用化合物1和可比司他处理的所有受试者中,化合物1的半衰期低于5小时,表明每天应至少给药2次化合物1。
当用可比司他增强时,还观察到与通过抗病毒剂和利托那韦所实现的相比,化合物1的谷值浓度的增加幅度的显著差异。用化合物1和可比司他处理的受试者具有平均29倍的Cmin变化,相比之下,在单一给药抗病毒剂和RTV后,最大平均增加为2倍至8倍。最后,化合物1的表观分布容积的减小幅度也大于采用抗病毒剂所观察的减小幅度(针对化合物1减小6倍,相对于针对抗病毒剂最大减小3倍)。
该数据显示,当与EZH2抑制剂化合物1共施用时,可比司他的表现不同于当其与抗病毒剂共施用时,从而导致相比于采用抗病毒剂所观察到的化合物1的终未半衰期、谷值浓度和分布容积的差异。尽管存在这些差异,但可比司他充分增强了化合物1的药代动力学,以致可以实现一次给与患者的整体剂量量的降低。该发现应增强患者的依从性和施用的整体满意度。
此外,这些结果延伸至可比司他与化合物1及其它试剂,如抗雄激素恩杂鲁胺和阿比特龙/***和免疫调节剂普利木单抗和派姆单抗的组合使用。参见图4。
在整个本申请中引用的所有参考文献(包括文献参考、授权专利、公开的专利申请和在审专利申请)的内容在此明确地以其全部内容通过参照并入本文。除非另有定义,否则本文所使用的所有技术和科学术语与本领域普通技术人员通常已知的含义一致。
Claims (34)
1.药物组合物,其包含有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐。
2.权利要求1所述的药物组合物,其还包含药学上可接受的载体。
3.权利要求1或2所述的药物组合物,其中所述药物组合物包含100mg至3.5克,200mg至3.0克,200mg至2.5克,200mg至1.0克,200mg至1.5克,200mg至1克,300mg至800mg,400mg至800mg以及400mg至600mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺。
4.权利要求1至3中任一项所述的药物组合物,其中所述药物组合物包含1.6克、800mg、600mg或400mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺。
5.权利要求1至4中任一项所述的药物组合物,其中所述药物组合物包含100mg至400mg,100mg至300mg以及100至200mg、150mg的可比司他。
6.权利要求1至5中任一项所述的药物组合物,其中所述药物组合物包含150mg的可比司他。
7.权利要求1至5中任一项所述的药物组合物,其中所述药物组合物配制用于口服施用。
8.治疗有此需要的受试者中的癌症的方法,其包括以下步骤:向所述受试者施用有效量的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐以及有效量的可比司他或其药学上可接受的盐。
9.权利要求8所述的方法,其中所述癌症选自多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、成人急性髓细胞白血病(AML)、急性B淋巴细胞白血病(B-ALL)和T谱系急性淋巴细胞白血病(T-ALL)。
10.权利要求8或9所述的方法,其中所述癌症选自霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病和多发性骨髓瘤。
11.权利要求8所述的方法,其中所述癌症为实体瘤或淋巴瘤。
12.权利要求8或11所述的方法,其中所述癌症是***癌或非霍奇金淋巴瘤。
13.权利要求8至12中任一项所述的方法,其中(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐的有效量在100mg至3.5克,200mg至3.0克,200mg至2.5克,200mg至1.0克,200mg至1.5克,200mg至1克,300mg至800mg,400mg至800mg以及400mg至600mg的范围内。
14.权利要求8至13中任一项所述的方法,其中(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐的有效量为3.2克、2.4克、1.6克、1.2克或800mg。
15.权利要求8至14中任一项所述的方法,其中向所述受试者每天两次施用1.6克的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
16.权利要求8至14中任一项所述的方法,其中向所述受试者每天三次施用800mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
17.权利要求8至14中任一项所述的方法,其中向所述受试者每天两次施用800mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
18.权利要求8至14中任一项所述的方法,其中向所述受试者每天两次施用600mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
19.权利要求8至14中任一项所述的方法,其中向所述受试者每天两次施用400mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
20.权利要求8至14中任一项所述的方法,其中所述癌症为淋巴瘤,并且向所述受试者施用100mg至3.5克,200mg至3.0克,200mg至2.5克,200mg至1.0克,200mg至1.5克,200mg至1克,300mg至800mg,400mg至800mg,400mg至600mg,1.0克至2.0克,1.4克至1.7克,500mg至700mg,550mg至650mg,700mg至900mg,750mg至850mg,300mg至500mg或350mg至450mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
21.权利要求8至14中任一项所述的方法,其中所述癌症为淋巴瘤,并且向所述受试者每天两次施用1.6克的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
22.权利要求8至14中任一项所述的方法,其中所述癌症为淋巴瘤,并且向所述受试者每天三次施用800mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
23.权利要求8至14中任一项所述的方法,其中所述癌症为淋巴瘤,并且向所述受试者每天两次施用800mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
24.权利要求8至14中任一项所述的方法,其中所述癌症为淋巴瘤并且向所述受试者每天两次施用600mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
25.权利要求8至14中任一项所述的方法,其中所述癌症为淋巴瘤,并且向所述受试者每天两次施用400mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
26.权利要求8至14中任一项所述的方法,其中所述癌症为实体瘤,并且向所述受试者施用100mg至3.5克,200mg至3.0克,200mg至2.5克,200mg至1.0克,200mg至1.5克,200mg至1克,300mg至800mg,400mg至800mg,400mg至600mg,1.0克至2.0克,1.4克至1.7克,500mg至700mg,550mg至650mg,700mg至900mg,750mg至850mg,300mg至500mg或者350mg至450mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
27.权利要求8至14中任一项所述的方法,其中所述癌症为实体瘤,并且向所述受试者每天两次施用1.6克的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
28.权利要求8至14中任一项所述的方法,其中所述癌症为实体瘤,并且向所述受试者每天三次施用800mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
29.权利要求8至14中任一项所述的方法,其中所述癌症为实体瘤,并且向所述受试者每天两次施用800mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
30.权利要求8至14中任一项所述的方法,其中所述癌症为实体瘤,并且向所述受试者每天两次施用600mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
31.权利要求8至14中任一项所述的方法,其中所述癌症为实体瘤,并且向所述受试者每天两次施用400mg的(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐。
32.权利要求8至31中任一项所述的方法,其中可比司他或其药学上可接受的盐的有效量为100mg至400mg,100mg至300mg和100至200mg。
33.权利要求8至32中任一项所述的方法,其中向所述受试者每天两次施用150mg的可比司他或其药学上可接受的盐。
34.权利要求8至33中任一项所述的方法,其中在(R)-N-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-甲基-1-(1-(1-(2,2,2-三氟乙基)哌啶-4-基)乙基)-1H-吲哚-3-羧酰胺或其药学上可接受的盐之前施用可比司他或其药学上可接受的盐。
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- 2018-12-27 US US16/958,468 patent/US20210000815A1/en not_active Abandoned
- 2018-12-27 EP EP18840130.1A patent/EP3731842A1/en not_active Withdrawn
- 2018-12-27 WO PCT/US2018/067623 patent/WO2019133674A1/en unknown
- 2018-12-27 CN CN201880089927.3A patent/CN111757734A/zh active Pending
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EP3731842A1 (en) | 2020-11-04 |
US20210000815A1 (en) | 2021-01-07 |
WO2019133674A1 (en) | 2019-07-04 |
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