CN113164474A - 维奈托克的水溶性高分子衍生物 - Google Patents
维奈托克的水溶性高分子衍生物 Download PDFInfo
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- CN113164474A CN113164474A CN202080005631.6A CN202080005631A CN113164474A CN 113164474 A CN113164474 A CN 113164474A CN 202080005631 A CN202080005631 A CN 202080005631A CN 113164474 A CN113164474 A CN 113164474A
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Abstract
本发明的目的在于提供维奈托克的新型施予手段,所述维奈托克的新型施予手段能减轻因服药对患者造成的负担,且具有效果与安全性的优异均衡性,本发明涉及包含多个维奈托克而成的水溶性高分子衍生物,所述多个维奈托克分别以酰胺键键合于多臂型水溶性聚合物的末端羧基。
Description
技术领域
本发明涉及以维奈托克键合于多臂型水溶性聚合物的末端而成的水溶性高分子衍生物为有效成分的、用于治疗或缓解癌症的药物或方法。
背景技术
维奈托克(Venetoclax)具有针对Bcl-2选择性地结合及抑制的作用。在许多癌症中,观察到Bcl-2的过度表达,由此阻止癌症细胞的自然死亡、自我破坏(凋亡)的过程。维奈托克具有抑制该Bcl-2、恢复癌症细胞的凋亡过程的作用。维奈托克已在临床上用作复发及难治性的慢性淋巴细胞性白血病、不适应强力化疗法的初次急性骨髓性白血病的治疗药。另一方面,维奈托克与人蛋白质的结合率高(99.9%以上),另外,经口吸收率也低,因此一次经口施予量过大,对于癌症患者而言存在难以服用的情况。另外,由于维奈托克的服用,有时会产生嗜中性粒细胞数量减少等强烈的副作用,如果没有医生的严格服药指导,则存在无法充分确保癌症患者的安全性的情况。
复发及难治性的慢性淋巴细胞性白血病、不适应强力化疗法的初次急性骨髓性白血病的患者大部分体力弱,也有高龄者。因此,期待用以容易施予维奈托克、且减轻其副作用的根本改善。
需要说明,如下所述,已知有几种利用水溶性的高分子物质来提高水难溶性的抗癌剂的水溶性从而提高作为医药品的有用性的方法。
(1)Abraxane(非专利文献1)被批准为晚期复发性乳腺癌、胃癌、非小细胞肺癌及胰腺癌的治疗剂,所述Abraxane通过使紫杉醇包载于来自人血液的白蛋白来提高紫杉醇的静脉内施予量从而提高肿瘤缩小效果。然而,由于使用来自人血液的白蛋白,因此无法消除肝炎、艾滋病感染症等的发病风险。来自人血液的白蛋白资源是有限的,稳定供给的课题仍然存在。能够通过基因工程而制造的合成白蛋白的代用尚未解决。
(2)NKTR-102(非专利文献2)具有以晚期复发性乳腺癌患者等为对象实施了临床开发的历史,该NKTR-102是分子量为4万的4条链的聚乙二醇(也称为“多臂型PEG”。)的4处末端的羟基被-OCH2COOH取代而得的衍生物(也称为“多臂型CTPEG”。)介由甘氨酸而与伊立替康的羟基进行酯键合而成的。然而,由于易于受到人血液中的酯酶、羧化酶的分解酶的代谢分解,因此为了显示出恰当的效果,需要大幅增加NKTR-102的施予量。结果,毒性增高,无法改善现有药伊立替康的治疗效果,作为新药未获得批准。
(3)专利文献1~3是本申请的发明人提出的,公开了将具有氨基的抗癌物质以酰胺键键合于水溶性高分子的多臂型CTPEG而成的、该抗癌物质的水溶性高分子衍生物。
现有技术文献
专利文献
专利文献1:日本专利第6542799号公报
专利文献2:美国专利第10111955号公报
专利文献3:俄罗斯专利第2697551号公报
非专利文献
非专利文献1:Sparreboom A等人,Clinical Cancer Research,2005年第11号:4136-4143页
非专利文献2:Edith A Perez等人,The Lancet Oncology,2015年第16号:556-1568页
发明内容
发明所要解决的课题
本发明的目的在于提供维奈托克的新型施予手段,所述维奈托克的新型施予手段能减轻因服药对患者造成的负担(过大的服用量、副作用等),具有效果与安全性的优异均衡性。
用于解决课题的手段
本申请的发明人为了解决上述课题而进行了深入研究,结果发现,多个维奈托克分别以酰胺键键合于多臂型水溶性聚合物的末端而得到的化合物与现有的维奈托克相比具有高的水溶性,能够对癌细胞有效地发挥作用,能够减轻因服药对患者造成的负担。
即,本发明包含以下的发明。
[1]包含多个维奈托克而成的化合物或其药理学上可接受的盐,所述多个维奈托克分别以酰胺键键合于多臂型水溶性聚合物的末端。
[2]根据[1]的化合物或其药理学上可接受的盐,其是多臂型水溶性聚合物的末端羧基与多个维奈托克的吡咯环的仲氨基分别进行酰胺缩合而成的。
[3]根据[1]或[2]的化合物或其药理学上可接受的盐,其中,多臂型水溶性聚合物是末端羧基化多臂型聚乙二醇。
[4]根据[3]的化合物或其药理学上可接受的盐,其由下述式(II)表示:
[化学式1]
[式中,n表示50~2000]。
[5]用于治疗或缓解癌症的药物组合物,其包含[1]~[4]中任一项的化合物或其药理学上可接受的盐。
[6]根据[5]的药物组合物,其中,癌症为血癌。
[7]根据[6]的药物组合物,其中,血癌为急性骨髓性白血病或慢性淋巴细胞性白血病。
[8]根据[1]~[4]中任一项的化合物或其药理学上可接受的盐,其在治疗或缓解癌症的方法中使用。
[9]根据[8]的化合物或其药理学上可接受的盐,其中,癌症为血癌。
[10]根据[9]的化合物或其药理学上可接受的盐,其中,血癌为急性骨髓性白血病或慢性淋巴细胞性白血病。
[11]治疗或缓解癌症的方法,其包括对患者施予[1]~[4]中任一项的化合物或其药理学上可接受的盐的步骤。
[12]根据[11]的方法,其中,癌症为血癌。
[13]根据[12]的方法,其中,血癌为急性骨髓性白血病或慢性淋巴细胞性白血病。
[14][1]~[4]中任一项的化合物或其药理学上可接受的盐在用于治疗或缓解癌症的药物的制造中的用途。
[15]根据[14]的用途,其中,癌症为血癌。
[16]根据[15]的用途,其中,血癌为急性骨髓性白血病或慢性淋巴细胞性白血病。
本说明书包含作为本申请的优先权基础的日本专利申请2020-084919号的说明书和/或附图所记载的内容。
本说明书中引用的所有出版物、专利及专利申请直接作为参考并入本说明书中。
发明的效果
根据本发明,可提供能减轻因服药对患者造成的负担(过大的服用量、副作用等)、具有效果与安全性的优异均衡性的维奈托克的新型施予手段。
另外,根据本发明,能够将维奈托克作为能够静脉内施予、且安全性经提高的医药品来提供。
附图说明
[图1]图1(1)是证实式(I)的化合物的化学结构式的质子核磁共振(以下,称为“H-NMR”。)的谱图。图1(2)是证实式(II)的化合物的化学结构式的H-NMR的谱图。
[图2]图2是示出式(II)的化合物的纯度及杂质的高效液相色谱(以下,称为“HPLC”。)的谱图。纯度及杂质的量示于该图的下段。
[图3]图3是示出式(I)的化合物和式(II)的化合物的细胞杀伤效果的浓度依赖性的曲线图。示出了分别使用(1)人急性骨髓性白血病细胞株的MV4-11、(2)人胰腺癌细胞株的PANC-1、(3)人肺癌细胞株的A549而得的结果。
[图4]图4是示出U937(人组织细胞淋巴瘤细胞株)、MV4-11(人急性骨髓性白血病细胞株)、PANC-1(人胰腺癌细胞株)以及A549(人肺癌细胞株)的蛋白酶活性的图。
[图5]图5是示出使用将人急性骨髓性白血病细胞株的OCI-AML-2移植到小鼠的皮下而制作的模型的、对照组、将式(II)的化合物以100mg/kg、200mg/kg、300mg/kg的各施予量以每周1次的方式进行2周静脉内施予的组、将式(I)的化合物以100mg/kg的施予量在2周内每天经口施予的组的肿瘤增殖抑制效果(1)以及各组的体重抑制作用(2)的图。
[图6]图6是示出使用将人急性骨髓性白血病细胞株的MV4-11移植到小鼠的皮下而制作的模型的、对照组、将式(II)的化合物以300mg/kg的施予量以每周1次的方式进行3周静脉内施予的组、将式(I)的化合物以50mg/kg的施予量在3周内每天经口施予的组的肿瘤增殖抑制效果(1)以及各组的体重抑制作用(2)的图。
[图7]图7是示出使用将人组织细胞淋巴瘤细胞株的U937移植到小鼠的皮下而制作的模型的、对照组、将式(II)的化合物以200mg/kg和300mg/kg的各施予量以每周1次的方式进行2周静脉内施予的组、将式(I)的化合物以100mg/kg的施予量在2周内每天经口施予的组的肿瘤增殖抑制效果(1)以及各组的体重抑制作用(2)的图。
[图8]图8示出在添加了式(I)的化合物或式(II)的化合物的培养基中培养的人急性骨髓性白血病细胞的MV4-11的线粒体组分及细胞质组分中的BAX量的测定结果。
[图9]图9示出在添加了式(I)的化合物或式(II)的化合物的培养基中培养的人急性骨髓性白血病细胞MV4-11的线粒体组分及细胞质组分中的细胞色素C量的测定结果。
[图10]图10示出在添加了式(I)的化合物或式(II)的化合物的培养基中培养的人急性骨髓性白血病细胞MV4-11的半胱天冬酶活性的测定结果。(1)示出以各种浓度添加式(I)的化合物或式(II)的化合物时的结果,(2)示出以0.1μM使用式(I)的化合物或式(II)的化合物时的半胱天冬酶活性的测定结果。
[图11]图11(1)为示出将式(I)的化合物加入包含5%浓度的CMC(羧甲基纤维素)的生理盐水中并利用超声波照射操作等操作、以10mg/ml的浓度均匀地悬浮而得的溶液的照片图。图11(2)为示出将式(II)的化合物加入40℃~50℃的生理盐水中并施加超声波照射操作等操作、以10mg/ml及20mg/ml的浓度制备的均匀水溶液的照片图。
具体实施方式
本发明涉及在用于治疗或缓解癌症的药物以及用于治疗或缓解癌症的方法中能够作为有效成分利用的、包含分别以酰胺键键合于多臂型水溶性聚合物的末端的多个维奈托克而成的化合物(以下,有时记为“本发明的化合物”)或其药理学上可接受的盐。
“维奈托克”是下述式(I)所示的化合物:
[化学式2]
维奈托克是作为复发或难治性的慢性淋巴细胞性白血病(包含小淋巴细胞性淋巴瘤)的治疗药的Venclexta(注册商标)的有效成分而使用的化合物。在本发明中,维奈托克可以通过现有已知的方法而工业合成、或者可以利用作为医药品用而市售的产品。需要说明的是,本说明书中,有时将式(I)的化合物仅记为“维奈托克”。
所谓“多臂型水溶性聚合物”,是指由其一端与成为核的原子、分子、或结构连接的、多个(例如,2、3、4、5、6、7、8或其以上)的水溶性聚合物(也称为“臂”)形成的结构体。臂可以是直链状聚合物,也可以是支链状聚合物,还可以是支链状聚合物高度支化的聚合物(也称为“树枝状聚合物”、“超支化聚合物”)。臂的水溶性聚合物能够利用生物降解性的任意聚合物,例如可举出聚乙二醇(本说明书中,有时记为“PEG”)、聚丙烯酸、聚马来酸、聚乙烯亚胺、聚羧基乙烯、聚乙烯醇、聚乙烯基吡咯烷酮、聚丙二醇、羧甲基纤维素、羟甲基纤维素等(不限于这些)。多臂型水溶性聚合物的重均分子量为约3kDa~约100kDa,例如能够设为约4kDa~约80kDa、约5kDa~约60kDa、约8kDa~约40kDa、约10kDa~约20kDa。多个臂可以全部为相同的水溶性聚合物,也可以组合使用不同种类或不同长度的物质。
在本发明中,多臂型水溶性聚合物能够利用在各臂的末端(未连接于核的一侧)具有羧基的物质。水溶性聚合物末端的羧基化能够使用以往惯用的方法来进行。
优选地,在本发明中,多臂型水溶性聚合物是具有2~8个、优选为2个、4个、6个或8个、更优选为4个末端羧基化PEG(本说明书中有时记为“CTPEG”)作为臂的多臂型CTPEG。多臂型CTPEG例如能够通过在季戊四醇核上根据需要介由间隔物键合各种重均分子量的CTPEG而得到。多臂型CTPEG能够利用市售品,例如能够从JenKem Technology等获取。
多臂型水溶性聚合物与维奈托克的键合能够通过多臂型水溶性聚合物的各臂的末端羧基与维奈托克的氨基之间的缩合反应形成的酰胺键来进行。认为:因多臂型水溶性聚合物和维奈托克介由酰胺键而键合,从而在生物体内受到蛋白酶(半胱天冬酶等)等催化酰胺键水解的酶的作用,作为有效成分的维奈托克能够从多臂型水溶性聚合物分离而发挥作用。用于与多臂型水溶性聚合物键合的维奈托克的氨基能够利用任意的氨基,但优选利用吡咯环的仲氨基。
在一个实施方式中,本发明的化合物为下述式(II)所示的化合物:
[化学式3]
即,具有以下结构:在具有4个臂的多臂型PEG的末端分别使维奈托克在其吡咯环的仲氨基的位置进行酰胺键合。式中,n没有特别限定,能够设为50以上,例如为50~2000,优选为100~2000,更优选为150~1000,进一步优选为200~500,特别优选为230。以及/或者,该化合物的重均分子量没有特别限定,例如为10kDa~60kDa,优选为20kDa~60kDa,特别优选为40kDa。需要说明的是,本说明书中,有时将式II的化合物记为“PEG-维奈托克”。
“药理学上可接受的盐”是指能够对生物体施予的可接受的盐,例如可举出酸加成盐、碱性加成盐等。作为“酸加成盐”,例如可举出盐酸盐、硫酸盐、硝酸盐、磷酸盐、氢溴酸盐、碳酸盐、乙酸盐、三氟乙酸盐、对甲苯磺酸盐、丙酸盐、酒石酸盐、富马酸盐、苹果酸盐、马来酸盐、柠檬酸盐、甲磺酸盐等(不限于这些),作为“碱性加成盐”,例如可举出碱金属盐(钠盐、钾盐等)、碱土金属盐(钙盐等)、镁盐、铵盐等(不限于这些)。
上述本发明的化合物或其药理学上可接受的盐在治疗或缓解癌症的方法中、以及在用于治疗或缓解癌症的药物组合物中,能够作用有效成分使用。
本发明中,所谓“癌症”,可举出血癌及实体癌(脑肿瘤·神经胶质瘤、垂体腺瘤、听觉神经鞘瘤、葡萄膜恶性黑色素瘤、脑膜瘤、咽喉癌、喉癌、舌癌、甲状腺癌、乳腺癌、肺癌、胸腺瘤、胸腺癌、间皮瘤、食道癌、胃癌、大肠癌、肝细胞癌、胆管癌、胰腺癌、肾细胞癌、膀胱癌、前列腺癌、肾盂·输尿管癌、阴茎癌、睾丸肿瘤、子宫癌、卵巢癌、外阴癌、皮肤癌、恶性黑色素瘤(皮肤)、基底细胞癌、皮肤癌的前体、表皮内癌、棘细胞癌、蕈样肉芽肿、恶性骨肿瘤(骨肉瘤)、软组织肉瘤、软骨肉瘤、恶性纤维组织细胞瘤等)及它们的转移癌,但不限于它们。优选地,本发明中,“癌症”是指血癌及其转移癌。“血癌”是指由造血器官产生的癌症,例如可举出急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、骨髓增殖性肿瘤(MPN)、恶性淋巴瘤、多发性骨髓瘤等,但不限于它们。本发明中,更优选地,血癌为急性骨髓性白血病(AML)或慢性淋巴细胞性白血病。
本发明中,所谓“治疗或缓解癌症”,不仅是指癌症完全消失的状态,还指暂时地或永久地使癌症缩小或消失的状态、癌症不恶化而稳定的状态。例如,包含癌症尺寸的降低、肿瘤标记物水平的降低、与癌症相关的症状改善、总生存期、无恶化生存期、中值生存期等尺度的延长等中的一种以上。
本发明的化合物或其药理学上可接受的盐在治疗或缓解癌症的方法中,可以直接(单独)使用,或者也可以以药物组合物(以下,有时记为“本发明的药物组合物”)的形态使用,所述药物组合物包含在药物的制造中通常使用的赋形剂、结合剂、崩解剂、润滑剂等并制成适于所设想的施予途径的剂型。
作为赋形剂,例如可举出糖(单糖、二糖类、环糊精及海藻酸等多糖类)、金属盐、高岭土、硅酸、聚乙二醇及它们的混合物等。
作为结合剂,例如可举出单糖浆、葡萄糖液、淀粉液、明胶溶液、聚乙烯醇、聚乙烯醚、聚乙烯基吡咯烷酮、羧甲基纤维素、虫胶、甲基纤维素、乙基纤维素及它们的混合物等。
作为崩解剂,例如可举出干淀粉、海藻酸钠、琼脂粉末、昆布多糖粉末、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨糖醇脂肪酸酯类、月桂基硫酸钠、硬脂酸单甘油酯、淀粉、乳糖及它们的混合物等。
作为润滑剂,例如可举出精制滑石、硬脂酸盐、硼砂、聚乙二醇及它们的混合物等。
药物组合物中根据需要能够还适当包含在药物的制造中通常使用的稀释剂、稳定化剂、等渗剂、pH调整剂、缓冲剂、助溶剂、悬浮剂、着色剂、矫味剂、矫臭剂、包覆剂、保存剂、防腐剂、抗氧化剂等。
例如,本发明的药物组合物能够制成适于经口施予的剂型,能够以片剂、丸剂、胶囊剂、颗粒剂、粉剂、糖浆剂、悬浮剂等形式提供。具有固体剂型的药物组合物能够根据需要施加包覆(例如,糖衣片、明胶包衣片、肠溶片等)。
另外,例如本发明的药物组合物能够制成适于非经口施予的剂型,能够以注射剂、滴注剂等形式提供。这些剂型可以为以能够冷冻干燥并保存的状态提供,使用时用包含水、生理盐水等的缓冲液等溶解并制备成适当的浓度后使用。
本发明的化合物或其药理学上可接受的盐、或者本发明的药物组合物的施予量及施予途径可以根据癌症的种类、严重程度、患者的年龄、体重、状态等因素而变化,能够使用任意的施予途径(经口施予、或非经口施予)以对于治疗或缓解癌症而言充分的量进行施予。
例如,就本发明的化合物或其药理学上可接受的盐、或者本发明的药物组合物而言,关于作为有效成分的上述本发明的化合物的量,能够将选自50~1000mg/kg、优选为100mg/kg~500mg/kg的量以1~3周1次、更优选为每周1次的频率进行非经口施予。作为“非经口施予”,能够举出静脉内施予用(静脉内注射、滴注等)、皮下注射、皮内注射、肌肉内注射等。优选地,本发明的化合物或其药理学上可接受的盐、或者本发明的药物组合物能够用于静脉内施予,例如能够将上述的量用5分钟~120分钟、优选为10分钟~60分钟、更优选为15分钟~30分钟、特别优选为20分钟左右进行静脉内施予。
本发明的化合物或其药理学上可接受的盐、或者本发明的药物组合物不仅以其自身(单独)使用,还能够与可用于治疗或缓解癌症的癌症化疗剂、癌症分子靶向药物、癌症免疫疗法剂等抗癌剂、放射线疗法组合使用。本发明中,“组合使用”不仅包括将各成分同时施予的情况,还包括在治疗期间将各成分分别以规定的间隔依次施予的情况。所组合使用施予的各成分的施予途径、施予手段可以相同,也可以不同。作为可组合使用施予的抗癌剂,例如能够举出阿糖胞苷、阿扎胞苷、地西他滨、Vyxeos、环磷酰胺、塞替派、异环磷酰胺、白消安、达卡巴嗪、美法仑、雷莫司汀、尼莫司汀、多柔比星、阿克拉霉素、伊达比星、柔红霉素、丝裂霉素C、吡柔比星、表柔比星、培洛霉素、氨柔比星、巯基嘌呤、氟达拉滨、羟基脲、甲氨蝶呤、克拉屈滨、依诺他滨、利妥昔单抗、达沙替尼、硼替佐米、他米巴罗汀、替伊莫单抗、维甲酸、吉妥单抗、恩西地平、格拉吉布、奎扎替尼、尼鲁单抗(商品名:Opdivo(注册商标))、派姆单抗(商品名:Keytruda(注册商标))、伊匹单抗(商品名:Yervoy(注册商标))、阿特珠单抗(商品名:Tecentriq(注册商标))等(不限于它们),能够根据癌症的种类、严重程度、患者的年龄、体重、状态等因素而适当选择一种或多种。
抗癌剂与单独使用的情况相比,能够以减少至90%、80%、70%、60%、50%、40%或其以下的量的用量,以具有减少的施予期间和/或扩大的停药期的用法进行施予。由此,能够抑制或延缓可能由抗癌剂的施予而引起的副作用(例如,骨髓抑制、溶血性贫血、弥散性血管内凝血综合症、暴发性肝炎、脱水症状、肠炎、间质性肺炎、口腔炎、消化道溃疡、消化道出血、消化道穿孔、急性肾衰竭、皮肤粘膜眼综合症、中毒性表皮坏死症、精神神经障碍、急性胰腺炎、横纹肌溶解症、嗅觉丧失等,不限于它们)的发病,以及/或者,能够大幅减轻与抗癌剂的使用相关的癌症患者的经济负担、国家和自治团体的医疗保险财政的负担。
此外,本发明涉及治疗或缓解癌症的方法,其包括对癌症患者施予本发明的化合物或其药理学上可接受的盐或者本发明的药物组合物的步骤。本方法中,成为治疗或缓解的对象的癌症、以及本发明的化合物或其药理学上可接受的盐或者本发明的药物组合物的用法·用量如上文所述。
实施例
以下,通过实施例来具体地说明本发明,但本发明不限于这些实施例。
[实施例1]式(II)的化合物的合成及分析
在氮气氛下,将CTPEG(4.530g,1当量)加入DMF溶剂55mL中,于50℃进行加热而均匀溶解。依次添加N,N-二异丙基乙胺(以下,称为“DIC”。)(0.296g,20当量)、1-羟基苯并三唑(以下,称为“HOBT”。)(0.258g,6当量)及维奈托克(0.474g,4.8当量)。于60℃继续搅拌6小时后冷却至40℃,然后一边搅拌一边经20分钟滴加被加热至30℃的甲基四丁基醚(以下称为“MTBE”。),然后经60分钟进行冷却,搅拌30分钟后,将生成的结晶过滤并收集,用20mL的MTBE洗涤,将得到的结晶溶解于被加热至40℃的20mL的无水乙醇中,经20分钟滴加70mL的MTBE,经60分钟冷却至0℃,搅拌30分钟,将生成的沉淀物过滤并收集。利用相同的方法重复几次重结晶纯化操作,在35℃的真空干燥器中干燥5小时以上,用HPLC分析,得到了式(II)的化合物的纯度为97%以上、各杂质为1%以下的物质,因此放入了填充有氮气的塑料袋中,于-20℃保存。利用H-NMR的分析(参见图1)来鉴定所得的式(II)的化合物的化学结构、以及式(I)的化合物的化学结构。另外,通过HPLC的分析,确认了式(II)的化合物的纯度高(参见图2)。
[实施例2]式(I)的化合物和式(II)的化合物的细胞杀伤效果
按下述方式对式(I)的化合物和式(II)的化合物的细胞杀伤效果的浓度依赖性进行研究。
使用人急性骨髓性白血病细胞株的MV4-11,研究式(I)的化合物及式(II)的化合物各自的IC50(50%抑制率)(参见图3(1))。结果,式(I)的化合物的IC50(50%抑制率)为0.16pM,式(II)的化合物的IC50为0.85pM,确认了两个化合物均具有高的抑制率。其中,式(I)的化合物的蛋白质结合率高(≥99.9%),因此使用血清含量少的培养基(Opti-MEM)。
使用人胰腺癌的细胞株的PANC-1,研究式(I)的化合物及式(II)的化合物各自的IC50(50%抑制率)(参见图3(2))。结果,式(I)的化合物的IC50为0.99μM,式(II)的化合物的IC50为18.9μM。
使用人肺癌细胞株的A549,研究式(I)的化合物及式(II)的化合物各自的IC50(50%抑制率)(参见图3(3))。结果,式(I)的化合物的IC50为0.99μM,式(II)的化合物的IC50为15.5μM。
[实施例3]式(II)的化合物的细胞杀伤效果和癌细胞的蛋白酶活性
将U937(人组织细胞淋巴瘤细胞株)、MV4-11(人急性骨髓性白血病细胞株)、PANC-1(人胰腺癌细胞株)及A549(人肺癌细胞株)的蛋白酶活性的测定结果示于图4。蛋白酶活性使用AAT Bioquest公司的“AmpliteTM Universal Fluorimetric Protease ActivityAssay Kit*Green Fluorescence*”进行测定,利用由Bio-Rad公司的“DC ProteinAssay”测得的蛋白质量对所得的荧光强度进行校正。结果,在上述实施例2中测得的式(II)的化合物对于MV4-11、PANC-1及A549的50%抑制浓度、与癌细胞株的蛋白酶活性之间确认到相关性。即,确认了癌细胞的蛋白酶活性越高,基于式(II)的化合物的抑制率越高。由此表明:在蛋白酶高的癌细胞的周围,式(II)的化合物的酰胺键被酶代谢,从而式(I)的化合物被选择性地释放。
[实施例4]人急性骨髓性白血病(OCI-AML-2)模型小鼠中的效果
使用将人急性骨髓性白血病细胞株OCI-AML-2移植到小鼠的皮下的模型,将对照组、将式(II)的化合物以100mg/kg、200mg/kg及300mg/kg的各施予量以每周1次的方式进行2周静脉内施予的组、以及将式(I)的化合物以100mg/kg的施予量在2周内每天经口施予的组之间的肿瘤的增殖抑制效果进行比较(参见图5(1))。
结果,观察到式(II)的化合物为100mg/kg、200mg/kg、300mg/kg的各施予量时均用量依赖性地抑制肿瘤的增殖。另外,就式(II)的化合物而言,无论何种施予量,均几乎不抑制体重,与对照组的体重变化大致相同。就式(I)的化合物而言,观察到体重抑制(参见图5(2))。
式(I)的化合物的总施予量为1,400mg/kg(100mg/天的2周连续施予),而式(II)的物质的总施予量为16mg/kg、32mg/kg、48mg/kg(以式(I)的施予量换算),式(II)的化合物的施予量为式(I)的化合物的35分之1时,观察到与式(I)的化合物相当的肿瘤增殖抑制效果。可知从体重抑制方面研究的安全性也高。
[实施例5]人急性骨髓性白血病(MV4-11)模型小鼠中的效果
使用将人急性骨髓性白血病细胞株的MV4-11移植到小鼠的皮下的动物模型,在对照组、将式(II)的化合物以300mg/kg的施予量(以式(I)物质的施予量换算时为24mg/kg)以每周1次的频率进行3周静脉内施予的组、将式(I)的化合物以50mg/kg的施予量在3周内连续经口施予的组这3组之间比较肿瘤的增殖抑制效果。
结果,尽管式(II)的化合物的3周总施予量(72mg/kg)远低于式(I)的化合物的3周总施予量(1,050mg/kg)(15分之1的量),但式(II)的化合物的肿瘤增殖抑制效果与式(I)的化合物的肿瘤增殖抑制效果相当(参见图6(1))。另外,可知式(II)的化合物的安全性高于式(I)的化合物(参见图6(2))。
[实施例6]人组织细胞淋巴瘤模型小鼠中的效果
使用将人组织细胞淋巴瘤细胞株的U937移植到小鼠的皮下而制作的模型,在对照组、将式(II)的化合物以200mg/kg及300mg/kg的施予量以每周1次的频率进行2周静脉内施予的组、将式(I)的化合物以100mg/kg的施予量在2周内每天经口施予的组这3组之间比较肿瘤的增殖抑制效果。
结果,所有组均未显示出明显的肿瘤增殖抑制效果(参见图7(1))。另外,各组的体重抑制作用也没有差别(参见图7(2))。如实施例3所示,U937(人组织细胞淋巴瘤细胞株)显示出最强的蛋白酶活性,但表明式(I)的化合物对于U937(人组织细胞淋巴瘤细胞株)没有增殖抑制效果,即使利用蛋白酶使式(II)的化合物的酰胺键断开,在肿瘤细胞附近高效地释放式(I)的化合物,也无法显示肿瘤增殖抑制效果。
[实施例7]凋亡诱导蛋白质BAX/BAK的表达变化
在Venclexta(注册商标)片10mg、Venclexta(注册商标)片50mg、Venclexta(注册商标)片100mg的药物评估表(日文:医薬品インタビューフォーム)(日本医院药剂师会,2019年11月制作(第2版))中,记载了“维奈托克是选择性地抑制作为凋亡抑制蛋白质的BCL-2且可经口施予的低分子物质。BCL-2通过与凋亡促进性蛋白质(BAX/BAK,BIM等)相互作用而发挥凋亡抑制性功能。认为维奈托克通过直接结合BCL-2从而使凋亡促进性蛋白质游离,诱导肿瘤细胞加速凋亡,显示出抗肿瘤作用”。据报道BAX是在细胞质中表达的蛋白质,在通过BCL-2的抑制来诱导凋亡时,BAX在线粒体的外膜上蓄积。
将人急性骨髓性白血病细胞的MV4-11接种于培养基,培养一夜后,以0.1μM及1μM的浓度添加式(I)的化合物,以0.01μM、0.1μM及1μM的浓度添加式(II)的化合物,孵育5小时后,提取细胞质组分和线粒体组分,研究BAX的表达情况。
结果,在细胞质组分中,对于式(I)的化合物、式(II)的化合物而言,均观察到浓度依赖性的BAX的减少(参见图8)。
[实施例8]细胞色素C释放量的变化
在上述药物评估表中,作为“凋亡促进性蛋白质”,示出了从线粒体流出到细胞质中的“细胞色素C”。因此,将人急性骨髓性白血病细胞的MV4-11接种于培养基,培养一夜后,分别以0.1μM及1μM的浓度添加式(I)的化合物,或者分别以0.01μM、0.1μM及1μM的浓度添加式(II)的化合物,孵育5小时后,提取细胞质组分及线粒体组分,研究细胞色素C的释放。
结果,从线粒体向细胞质释放细胞色素C的释放量依赖于式(I)的化合物的添加浓度、并且依赖于式(II)的化合物的添加浓度而增大(参见图9)。
[实施例9]半胱天冬酶活性的变化
在上述药物评估表中,示出了从线粒体流出到细胞质中的细胞色素C使半胱天冬酶活化而诱导凋亡。因此,将人急性骨髓性白血病细胞的MV4-11接种于培养基,培养一夜后,分别以1pM、0.01nM、0.1nM、1nM、0.01μM、0.1μM及1μM的浓度添加式(I)的化合物,或者分别以1pM、0.01nM、0.1nM、1nM、0.01μM及0.1μM的浓度添加式(II)的化合物,孵育24小时后,回收培养基,利用现有已知的方法研究半胱天冬酶活性。
结果,半胱天冬酶活性依赖于式(I)的化合物的添加浓度、并且依赖于式(II)的化合物的添加浓度而增大(参见图10(1))。在以维奈托克的换算浓度为0.1μM的情况下,式(I)的化合物及式(II)的化合物均显示出完全相同的半胱天冬酶活性(图10(2))。就式(II)的化合物而言,与式(I)的化合物同样地抑制BCL-2,从而证实了其对肿瘤细胞进行凋亡诱导,显示出抗肿瘤作用。
[实施例10]化合物的水溶解性
将式(I)的化合物加入包含0.5%浓度的CMC(羧甲基纤维素)的生理盐水中,施加超声波照射等操作,结果以10mg/mL的浓度得到均匀、鲜黄色不透明的悬浮液(参见图11(1))。
另一方面,将式(II)的化合物加入40℃~50℃的生理盐水中,施加超声波照射等操作,结果得到浓度为10mg/mL及20mg/mL的均匀、黄色透明的水溶液,即使恢复到室温也完全不产生沉淀。确认了式(II)的化合物的水溶解性高(参见图11(2))。
Claims (7)
1.包含多个维奈托克而成的化合物或其药理学上可接受的盐,所述多个维奈托克分别以酰胺键键合于多臂型水溶性聚合物的末端。
2.根据权利要求1所述的化合物或其药理学上可接受的盐,其是多臂型水溶性聚合物的末端羧基与多个维奈托克的吡咯环的仲氨基分别进行酰胺缩合而成的。
3.根据权利要求1或2所述的化合物或其药理学上可接受的盐,其中,多臂型水溶性聚合物是末端羧基化多臂型聚乙二醇。
5.用于治疗或缓解癌症的药物组合物,其包含权利要求1~4中任一项所述的化合物或其药理学上可接受的盐。
6.根据权利要求5所述的药物组合物,其中,癌症为血癌。
7.根据权利要求6所述的药物组合物,其中,血癌为急性骨髓性白血病或慢性淋巴细胞性白血病。
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