CN115466205B - 分离的3-(2-溴-3,4-二羟基-苯基)-n-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体 - Google Patents
分离的3-(2-溴-3,4-二羟基-苯基)-n-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体 Download PDFInfo
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Abstract
本发明公开了分离的3‑(2‑溴‑3,4‑二羟基‑苯基)‑N‑(3,4,5‑三羟基‑苄基)‑硫代丙烯酰胺的基本上纯的反式异构体、其制备方法以及其在治疗癌症中的用途。
Description
技术领域
本发明涉及分离的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体及其在治疗癌症中的用途。
背景技术
癌症是一种全球常见的疾病,在组织中具有广泛的靶点。它的特点是由于各种因素(从污染物到遗传倾向)导致细胞不受控制的增殖。当前的癌症疗法包括去除实体瘤的手术干预和使用化疗剂、激素和免疫治疗剂的全身性癌症疗法。尽管有多种现有药物可有效治疗不同类型的癌症,但在许多情况下,癌症会对药物产生抗药性。因此,需要新的治疗策略。
WO 2008/068751公开了对***1受体(IGF1R)、血小板衍生生长因子受体(PDGFR)、表皮生长因子受体(EGFR)和IGF1R相关胰岛素受体(IR) 活化和信号转导的抑制特性增加的化合物。
WO 2009/147682公开了充当蛋白激酶(PK)和受体激酶(RK)信号转导调节剂的化合物。WO 2009/147682中进一步公开了此类化合物的制备方法、包含此类化合物的药物组合物,以及使用这些化合物和组合物的方法,尤其是作为用于预防和治疗PK和RK相关紊乱的化疗剂,如代谢性、炎症、纤维化和细胞增殖性紊乱,尤其是癌症。
WO 2012/117396描述了WO 2008/068751或WO 2009/147682的化合物与用于治疗癌症的抗癌剂的组合。
WO 2016/125169描述了WO 2008/068751或WO 2009/147682的化合物与下列物质组合用于治疗癌症:(i)表皮生长因子受体抑制剂(EGFR抑制剂)和EGFR抗体;(ii)哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂;(iii)丝裂原活化蛋白激酶(MEK) 抑制剂;(iv)突变的B-Raf抑制剂;(v)免疫治疗剂;和(vi)化疗剂。
WO 2019/097503涉及使用联合疗法治疗癌症,该联合疗法包括胰岛素受体底物(IRS)和信号转导和转录激活剂3(Stat3)的双重调节剂,联合抗程序性细胞死亡1(PD-1)蛋白的抗体、抗程序性细胞死亡蛋白1配体(PD-L1)抗体或其组合。该组合可用于通过增强肿瘤对抗PD-1和/或抗PD-L1抗体的响应,将无响应的肿瘤转化为响应者和/或阻止肿瘤进展,从而使可能对抗PD-1和/或抗PD-L1抗体产生或已经产生抗性的肿瘤重新敏感。
WO 2009/147682中首次公开的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺(化合物5)是胰岛素受体底物(IRS)和信号转导和转录激活剂3(Stat3)的双重调节剂。它包括与两个儿茶酚环之间桥接的硫代酰胺共轭的双键。WO 2009/147682教导了该化合物以及其中公开的其他化合物可以是任何结构和几何异构体,尤其包括顺式和反式异构体。
对可用于治疗癌症的具有改进的IRS和Stat3抑制特性的化合物的需求仍未得到满足。
发明内容
本发明提供了一种分离的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体,它的制备方法及其治疗癌症的用途。
现在首次公开了3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体提供与3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺反混合物相比改进的抗增殖活性。与包含不旋转的双键的常规顺-反立体异构体相反,意外地发现在3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺中双键的旋转可以在光照下自由发生,从而在溶液中提供反式和顺式异构体之间的相互转化。出乎意料地表明,由于光诱导异构化,该化合物的抗增殖活性随着顺式异构体含量的增加而降低。进一步出乎意料地表明,反式异构体对癌细胞有效,而反式-顺式混合物在相同浓度下效果较差。因此,与顺式异构体或含有超过20%的顺式异构体的反式-顺式混合物相比,预期基本上纯的反式异构体在治疗癌症中具有增加的效力。
根据第一方面,本发明提供了3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或其药学上可接受的盐,所述反式异构体具有以下结构式:
如本文所用且除非另有说明,术语“基本上纯的”是指基本上不含顺式异构体的反式构型的化合物3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺。例如,在一些实施方案中,该化合物的基本上纯的反式异构体包含大于约 80%重量的该化合物的反式异构体和小于约20%重量的该化合物的顺式异构体。在其他实施方案中,该化合物的基本上纯的反式异构体包含大于约85%重量的该化合物的反式异构体和小于约15%重量的该化合物的顺式异构体。在其他实施方案中,该化合物的基本上纯的反式异构体包含大于约90%重量的该化合物的反式异构体和小于约10%重量的该化合物的顺式异构体。在当前优选的实施方案中,该化合物的基本上纯的反式异构体包含大于约95%重量的该化合物的反式异构体和小于约5%重量的该化合物的顺式异构体。在另外的当前优选的实施方案中,该化合物的基本上纯的反式异构体包含大于约97%重量的该化合物的反式异构体和小于约3%重量的该化合物的顺式异构体。
根据一些实施方案,本发明提供了一种药物组合物,其包含作为活性成分的 3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
在某些实施方案中,该药物组合物是溶液、悬浮液或乳液的形式。每种可能性代表一个单独的实施方案。
根据另外的实施方案,药学上可接受的载体或赋形剂是羟丙基-β-环糊精(HPCD)。根据进一步的实施方案,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或药学上可接受的盐与HPCD之间的重量比为约1∶1至约1∶12,包括其间的任何比例。根据特定实施方案,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或药学上可接受的盐与HPCD之间的重量比为约1∶4至约1∶8,包括其间的任何比例。
根据一些实施方案,保护药物组合物免受可见光的影响。在特定实施方案中,将药物组合物保持在不透可见光的装置中。在进一步的实施方案中,不透光装置在可见光波长范围内的透光率小于约20%,优选小于约10%,更优选小于约5%。
根据其他实施方案,将药物组合物储存在不透可见光的容器中。在特定实施方案中,不透光容器在可见波长范围内的透光率小于约20%,优选小于约10%,更优选小于约5%。
根据进一步的实施方案,药物组合物被提供在适合静脉内施用的不透可见光的试剂盒中。在特定实施方案中,不透光试剂盒在可见光波长范围内的透光率小于约20%,优选小于约10%,更优选小于约5%。
根据一些实施方案,保护药物组合物免受UV光照射。在特定实施方案中,将药物组合物保持在UV光不可透过的装置中。在进一步的实施方案中,不透光装置在UV波长范围内的透光率小于约20%,优选小于约10%,更优选小于约5 %。
根据其他实施方案,将药物组合物储存在不透UV光的容器中。在特定实施方案中,不透光容器在UV波长范围内的透光率小于约20%,优选小于约10%,更优选小于约5%。
根据进一步的实施方案,药物组合物被提供在适合静脉内施用的不透UV光的试剂盒中。在特定实施方案中,不透光试剂盒在UV波长范围内的透光率小于约20%,优选小于约10%,更优选小于约5%。
根据一些实施方案,药物组合物可用于治疗癌症。在某些实施方案中,本发明提供了治疗癌症的方法,该方法包括向有需要的受试者施用本文公开的基本上纯的反式异构体或包含其的药物组合物。在其他实施方案中,本发明提供了本文公开的基本上纯的反式异构体在制备用于治疗癌症的药物中的用途。在进一步的实施方案中,癌症选自头颈癌、肉瘤、多发性骨髓瘤、卵巢癌、乳腺癌、肾癌、胃癌、造血***癌(hematopoietic cancers)、淋巴瘤、白血病、肺癌、黑色素瘤、胶质母细胞瘤、肝癌、食管癌、胃食管交界处癌、***癌、胰腺癌和结肠癌。每种可能性代表一个单独的实施方案。
根据其他实施方案,本发明的药物组合物联合抗癌剂共同施用。根据一些实施方案,抗癌剂包含下列至少一种:(i)选自表皮生长因子受体抑制剂(EGFR抑制剂)和EGFR抗体的蛋白激酶(PK)调节剂;(ii)哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂;(iii)丝裂原活化蛋白激酶(MEK)抑制剂;(iv)突变的B-Raf抑制剂;(v)化疗剂;和(vi)免疫治疗剂,其包含针对程序性细胞死亡1(PD-1)蛋白、程序性细胞死亡蛋白1配体(PD-L1)、细胞毒性T淋巴细胞相关蛋白4(CTLA4)或其组合的抗体。每种可能性代表一个单独的实施方案。根据特定实施方案,共同施用以任何顺序同时或依次进行。每种可能性代表一个单独的实施方案。
从下文给出的详细描述中,本发明的进一步的实施方案和全部适用范围将变得显而易见。然而,应当理解,详细描述和具体实施例虽然表明了本发明的优选实施方案,但仅以说明的方式给出,因为根据这个详细描述,在本发明的精神和范围内的各种变化和修改对于本领域技术人员来说将是显而易见的。
本发明将从以下附图及其优选实施方案的详细描述中得到更充分的理解。
附图说明
图1. 3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体的化学结构和原子注释。
图2. 3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体的化学结构和原子注释。
图3.UV光照射后的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式和顺式混合物的1H NMR谱。
图4A-4B.3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式(图4A)和顺式(图4B)异构体的UV光谱(从HPLC峰获得)。
图5A-5F.3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺溶液短期稳定性测试的HPLC色谱图:(图5A)溶液X1;(图5B)溶液X2;(图 5C)溶液Y1;(图5D)溶液Y2;(图5E)溶液Z1;(图5F)溶液Z2。
图6.不同比例的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺反异构体溶液对人黑色素瘤A375细胞的抗增殖活性。
具体实施方式
本发明涉及3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或其药学上可接受的盐,所述反式异构体具有以下结构式:
本发明进一步涉及药物组合物,其包含作为活性成分的3-(2-溴-3,4-二羟基- 苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
本发明还涉及使用3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或其药学上可接受的盐,或包含其的药物组合物治疗癌症的方法。
本发明部分基于令人惊讶的发现,与不允许顺式和反式异构体之间自由互变的常规双键相反,3-(2-溴-3,4-二羟基-苯基)中的双键-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺在UV-VIS下可以自由地从反式异构体到顺式异构体的相互转化。虽然基本上纯的反式异构体在抑制人黑色素瘤A375细胞增殖方面表现出很高的功效,但两种异构体的混合物在抑制A375细胞增殖方面表现出较低的功效。因此,与含有反式和顺式异构体两者的混合物相比,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5- 三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体提供增强的抗增殖功效。
根据本发明的原理,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体包含至少80%重量的图1所示的反式异构体和小于20%重量的图2所示的顺式异构体。优选地,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5- 三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体包含至少85%重量的图1所示的反式异构体和小于15%重量的图2所示的顺式异构体。更优选地,3-(2-溴-3,4- 二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体包含至少90%重量的图1所示的反式异构体和小于10%重量的图2所示的顺式异构体。甚至更优选地,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体包含至少95%重量的图1所示的反式异构体和小于5%重量的图2所示的顺式异构体。最优选地,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体包含至少97%重量的图1所示的反式异构体和少于3%重量的图2所示的顺式异构体。
3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体的合成可以如本领域已知的那样进行。简而言之,合成包括以下步骤:首先,2-溴-3,4-二甲氧基苯甲醛和丙二酸在Knoevenagel缩合反应中反应得到2- 溴-3,4-二甲氧基肉桂酸。其次,2-溴-3,4-二甲氧基肉桂酸接着转化为酰氯衍生物,该衍生物进一步与3,4,5-三甲氧基苄胺反应得到3-(2-溴-3,4-二甲氧基-苄基)- N-(3,4,5-二甲氧基-苄基)-丙烯酰胺。第三,然后使用劳森试剂作为硫代试剂,从之前的化合物中得到3-(2-溴-3,4-二甲氧基-苄基)-N-(3,4,5-二甲氧基-苄基)-硫代丙烯酰胺。最后,使用三溴化硼切开甲氧基保护基团,得到最终产品。
本发明的基本上纯的反式异构体可以以其药学上可接受的盐存在。术语“盐”包括碱性和酸加成盐,包括但不限于羧酸盐或具有胺氮的盐,并且包括与下面讨论的有机和无机的阴离子和阳离子形成的盐。此外,该术语包括通过与碱性基团 (例如氨基)和有机或无机酸的标准酸碱反应形成的盐。这些酸包括盐酸、氢氟酸、三氟乙酸、硫酸、磷酸、乙酸、琥珀酸、柠檬酸、乳酸、马来酸、富马酸、棕榈酸、胆酸、帕莫酸、粘液酸、D-谷氨酸、D-樟脑、戊二酸、邻苯二甲酸、酒石酸、月桂酸、硬脂酸、水杨酸、甲磺酸、苯磺酸、山梨酸、苦味酸、苯甲酸、肉桂酸等。每种可能性代表本发明的单独实施方案。
术语“有机或无机阳离子”是指盐阴离子的反离子。反离子包括但不限于碱金属和碱土金属(如锂、钠、钾、钡、铝和钙);铵和单-、二-和三-烷基胺,例如三甲胺、环己胺;和有机阳离子,如二苄基铵、苄基铵、2-羟乙基铵、双(2-羟乙基)铵、苯乙基苄基铵、二苄基乙二铵等。参见,例如,Berge等,J.Pharm.Sci. (1977),66:1-19,在此引入作为参考。
在本发明的范围内的是药物组合物,其包含本发明的基本上纯的反式异构体或其药学上可接受的盐以及药学上可接受的载体或赋形剂。药物组合物可以是液体制剂的形式,例如但不限于液体溶液、悬浮液或乳剂,或者是固体制剂的形式,例如但不限于片剂、粉剂、胶囊或丸剂。每种可能性代表一个单独的实施方案。
为了避免基本上纯的反式异构体与顺式异构体的相互转化,优选地将药物组合物屏蔽可见光和/或紫外光,例如使用耐光装置和/或容器。使用以下任何一种或它们的组合进行合适的遮光:使用琥珀色容器(例如琥珀色玻璃钳口小瓶)、铝箔覆盖物、黑色塑料覆盖物、暗室、双套夹克、有盖输液套件等。每种可能性代表一个单独的实施方案。具体地,耐光装置、容器或覆盖物在UV-VIS波长范围内具有小于约20%,优选小于约10%,更优选小于约5%的透光率。
因此,本发明进一步包括防止3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体转化为3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体的方法,该方法包括将基本上纯的反式异构体或包含其的组合物保持在如上详述的耐光装置、容器或覆盖物中。根据一些实施方案,耐光装置、容器或覆盖物基本上不可透过UV-VIS波长范围内的光。
在本发明的范围内,本文公开的药物组合物中任选包含至少一种药学上可接受的载体或赋形剂。合适的药学上可接受的载体或赋形剂包括但不限于稀释剂、防腐剂、增溶剂、乳化剂、佐剂等。每种可能性代表一个单独的实施方案。此类组合物是液体或冻干或以其他方式干燥的制剂,并且包括各种缓冲物质(例如, Tris-HCl、乙酸盐、磷酸盐)的稀释剂、pH值和离子调节剂、添加剂(例如白蛋白或明胶以防止被表面吸收)、洗涤剂(例如,吐温20、吐温80、普朗尼克 (Pluronic)F68、胆汁酸盐)、增溶剂(例如甘油、聚甘油)、抗氧化剂(例如抗坏血酸、焦亚硫酸钠)、防腐剂(例如硫柳汞、苯甲醇、对羟基苯甲酸酯),和膨胀物质或张力调节剂(例如,乳糖、甘露醇)。每种可能性代表一个单独的实施方案。
此外,如本文所用,“药学上可接受的载体”是本领域技术人员公知的,包括但不限于0.01-0.1M,优选0.05M磷酸盐缓冲液或0.8%盐水。此外,此类药学上可接受的载体可以是水性或非水性溶液、悬浮液和乳液。每种可能性代表一个单独的实施方案。非水溶剂的例子是丙二醇、聚乙二醇、植物油如橄榄油,和可注射的有机酯如油酸乙酯。水性载体包括水、酒精/水溶液、乳液或悬浮液,包括盐水和缓冲介质。每种可能性代表一个单独的实施方案。
肠胃外载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸林格氏液或固定油。每种可能性代表一个单独的实施方案。静脉内载体包括流体和营养补充剂、电解质补充剂例如基于林格氏葡萄糖的那些等。也可以存在防腐剂和其他添加剂,例如抗微生物剂、抗氧化剂等。每种可能性代表一个单独的实施方案。
控释或缓释组合物包括处于亲脂性贮库(例如脂肪酸、蜡、油)中的制剂。本发明还包括涂覆有聚合物(例如泊洛沙姆或泊洛沙胺)和保护涂层的颗粒组合物。
药学上可接受的载体还可包括树胶、淀粉、糖、纤维素材料、乳糖、***胶、明胶、藻酸、硬脂酸或硬脂酸镁。每种可能性代表一个单独的实施方案。
合适的油性赋形剂或溶剂的实例是植物油或动物油,例如葵花油或鱼肝油,石油,或源自动物、植物或合成来源的油,例如花生油、大豆油或矿物油。每种可能性代表一个单独的实施方案。合适的水基赋形剂的例子是水、盐水、葡萄糖水溶液和相关的糖溶液,以及二醇如丙二醇或聚乙二醇、甘油或乙醇。每种可能性代表一个单独的实施方案。此外,如果需要,组合物可包含少量辅助物质,例如润湿剂或乳化剂和/或pH缓冲剂。
在当前优选的实施方案中,本文公开的药物组合物含有螯合剂。本发明范围内的合适螯合剂包括但不限于环糊精(改性的或未改性的),例如但不限于α-环糊精、β-环糊精、γ-环糊精、2-羟丙基-β-环糊精、甲基-β-环糊精、磺丁基醚β-环糊精及其混合物或其组合。每种可能性代表一个单独的实施方案。在当前优选的实施方案中,螯合剂是羟丙基-β-环糊精(HPCD)。通常,螯合剂例如HPCD以导致基本上纯的反式异构体和HPCD之间的重量比为约1∶1至约1∶12的量存在于组合物中。本发明范围内的基本上纯的反式异构体和HPCD之间的合适重量比包括但不限于约1∶1、约1∶2、约1∶3、约1∶4、约1∶5、约1∶6、约1∶7、约1∶8、约1∶9、约1∶10、约1∶11或约1∶12,每种可能性代表一个单独的实施方案。根据特定实施方案,基本上纯的反式异构体与HPCD之间的重量比为约1∶4至约1∶8,例如约 1∶6。
根据本发明的原理,基本上纯的反式异构体或包含其的组合物可用于治疗癌症。
因此,本发明提供了一种治疗癌症的方法,包括向有需要的受试者施用治疗有效量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或包含其的药物组合物。
如本文所用,“治疗有效量”是指在向受试者单次或多次施用后有效地为受试者提供治疗益处的药剂的量。在一个实施方案中,治疗益处是治疗癌症。在治疗中有效的量将取决于紊乱或病情的性质,并且可以通过标准临床技术确定。此外,可以任选地采用体外测定来帮助确定最佳剂量范围。使用的精确剂量也将取决于给药途径和疾病或紊乱的进展,并且应根据从业者的判断和每个患者的情况来决定。优选的剂量在0.01mg/kg至1000mg/kg体重、0.1mg/kg至100mg/kg、1mg/kg 至100mg/kg、10mg/kg至75mg/kg的范围内,0.1mg/kg至1mg/kg等,包括指定范围内的每个值。示例性的、非限制性的量包括0.1mg/kg、0.2mg/kg、0.5mg/kg、 1mg/kg、5mg/kg、10mg/kg、20mg/kg、50mg/kg、60mg/kg、75mg/kg和100mg/kg。每种可能性代表一个单独的实施方案。
或者,施用量可以被测量并表示为施用化合物的摩尔浓度。作为说明而非限制,3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体可以施用0.1-10mM的范围,例如0.1、0.25、0.5、1和2mM。每种可能性代表一个单独的实施方案。或者,施用量可以被测量并表示为mg/ml、μg/ml 或ng/ml。作为说明而非限制,典型的量包括1ng/ml至1,000mg/ml,例如1-1,000 ng/ml、1-100ng/ml、1-1,000μg/ml、1-100μg/ml、1-1,000mg/ml、1-100mg/ml 等,包括指定范围内的每个值。有效剂量可以从体外或动物模型试验生物测定或***得到的剂量响应曲线中推断出来。
本发明上下文中的术语“癌症的治疗”包括下列至少-种:癌症生长速度降低(即,癌症仍然生长但速度较慢);癌症生长停止,即肿瘤生长停滞,并且在优选的情况下,肿瘤缩减或缩小。该术语还包括转移数目减少、形成的新转移数目减少、癌症从一个阶段到另一个阶段的进展减慢以及由癌症诱导的血管生成减少。在最优选的情况下,肿瘤被完全消除。该术语另外包括延长接受治疗的受试者的存活期、延长疾病进展的时间、肿瘤消退等。应理解,术语“治疗癌症”还指抑制恶性(癌)细胞增殖,包括肿瘤形成、原发性肿瘤、肿瘤进展或肿瘤转移。与癌细胞相关的术语“增殖抑制”可进一步指下列至少一种的减少:与对照相比的细胞数量(由于细胞死亡,可能是坏死、凋亡或任何其他类型的细胞死亡或其组合);细胞生长速率降低,即细胞总数可能增加,但水平或速率低于对照的增加;与对照相比,即使它们的总数没有改变,细胞的侵袭性(例如通过软琼脂测定法确定)降低;从分化程度较低的细胞类型发展为分化程度较高的细胞类型;肿瘤转化减速;或者减慢癌细胞从一个阶段到下一个阶段的进展。
如本文所用,术语“癌症”是指其中细胞群在不同程度上变得对通常控制增殖和分化的控制机制无响应的紊乱。癌症是指各种类型的恶性瘤和肿瘤,包括原发肿瘤和肿瘤转移。可以通过基本上纯的反式异构体或包含其的药物组合物治疗的癌症的非限制性实例是脑癌、卵巢癌、结肠癌、***癌、肾癌、膀胱癌、乳腺癌、肺癌、口腔癌和皮肤癌。每种可能性代表一个单独的实施方案。癌症的具体实例是:癌、肉瘤、骨髓瘤、白血病、淋巴瘤和混合型肿瘤。每种可能性代表一个单独的实施方案。特定类别的肿瘤包括淋巴组织增生性紊乱、乳腺癌、卵巢癌、***癌、***、子宫内膜癌、骨癌、肝癌、胃癌、结肠癌、胰腺癌、甲状腺癌、头颈癌、中枢神经***癌症、周围神经***癌症、皮肤癌、肾癌,以及上述所有疾病的转移。每种可能性代表一个单独的实施方案。特定类型的肿瘤包括肝细胞癌、肝细胞瘤、肝母细胞瘤、横纹肌肉瘤、食管癌、甲状腺癌、神经节母细胞瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨源性肉瘤、脊索瘤、血管肉瘤、内皮管肉瘤、血管内皮肉瘤、浸润性血管内皮肉瘤、***状腺癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌(高分化、中分化、低分化或未分化)、肾细胞癌、肾上皮瘤、肾样腺癌、胆管癌、绒毛膜癌、***瘤、胚胎癌、维尔姆斯瘤、睾丸肿瘤、肺癌(包括小细胞癌、非小细胞和大细胞肺癌)、膀胱癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、视网膜母细胞瘤、神经母细胞瘤、结肠癌、直肠癌、造血***恶性肿瘤(包括所有类型的白血病和淋巴瘤,包括:急性髓性白血病、急性髓细胞性白血病、急性淋巴细胞性白血病、慢性髓性白血病、慢性淋巴细胞性白血病、肥大细胞白血病、多发性骨髓瘤、髓性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤)和肝癌。每种可能性代表一个单独的实施方案。
在一些代表性实施方案中,癌症选自下列组成的组:头颈癌、肉瘤、多发性骨髓瘤、卵巢癌、乳腺癌、肾癌、胃癌、造血***癌、淋巴瘤、白血病(包括淋巴细胞性白血病)、肺癌、黑色素瘤、胶质母细胞瘤、肝癌、食管癌、胃食管交界处癌、***癌和结肠癌。每种可能性代表一个单独的实施方案。
给药途径包括但不限于口服、局部、经皮、动脉内、鼻内、腹膜内、肌肉内、皮下、静脉内、气管内、支气管内、肺泡内、经粘膜、心室内、颅内和肿瘤内。每种可能性代表一个单独的实施方案。本发明进一步提供了3-(2-溴-3,4-二羟基- 苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体与至少一种额外的抗癌剂在联合疗法中的施用。根据本发明原理的此类额外的抗癌剂包括但不限于表皮生长因子受体抑制剂(EGFR抑制剂),包括厄洛替尼、吉非替尼、拉帕替尼、凡德他尼、来那替尼、埃克替尼、阿法替尼、达克替尼、波齐替尼、 AZD9291、CO-1686、HM61713和AP26113;EGFR抗体包括曲妥珠单抗、西妥昔单抗、耐昔妥珠单抗和帕尼单抗;哺乳动物雷帕霉素靶蛋白抑制剂(mTOR抑制剂),包括西罗莫司(Sirolimus)、利达福莫司(Ridaforolimus)(AP23573)、 NVP-BEZ235、依维莫司(Everolimus)(Afinitor,RAD-001)、替西罗莫司(Temsirolimus)(CCI-779)、OSI-027、XL765、INK128、MLN0128、AZD2014、 DS-3078a和Palomid529;丝裂原活化蛋白激酶抑制剂(MEK抑制剂)包括曲美替尼(GSK1120212)、司美替尼、比美替尼(MEK162)、PD-325901、考比替尼(Cobimetinib)、CI-1040和PD035901;突变的B-Raf抑制剂,包括维莫非尼(Vemurafenib)(PLX-4032)、PLX4720、索拉非尼(Sorafenib)(BAY43-9006)和达拉菲尼(Dabrafenib);化疗剂,包括拓扑异构酶抑制剂、纺锤体毒长春花:长春碱、长春新碱、长春瑞滨(紫杉醇)、紫杉醇、多西紫杉醇;烷化剂:甲氯乙胺、苯丁酸氮芥、环磷酰胺、美法仑、异环磷酰胺;甲氨蝶呤;6-巯基嘌呤;5- 氟尿嘧啶、阿糖胞苷、吉西他滨;鬼臼毒素:依托泊苷、伊立替康、拓扑替康;含有醌基团的抗癌化学品:咔嗪醌;抗生素:阿霉素(阿霉素)、柔红霉素、伊达比星、表柔比星、博来霉素、丝裂霉素;亚硝基脲类:卡莫司汀(BCNU)、洛莫司汀;无机离子:顺铂、卡铂、奥沙利铂;干扰素、天冬酰胺酶;激素:他莫昔芬、亮丙瑞林、氟他胺、醋酸甲地孕酮和达卡巴嗪;以及包含针对选自程序性细胞死亡蛋白1(PD-1)、程序性细胞死亡蛋白1配体(PD-L1)和细胞毒性T 淋巴细胞相关蛋白4(CTLA4)的靶标的抗体的免疫治疗剂,包括派姆单抗 (Keytruda)、纳武单抗(Opdivo)、AGEN-2034、AMP-224、BCD-100、BGBA-317、BI-754091、CBT-501、CC-90006、西米普利单抗(Cemiplimab)、GLS-010、IBI-308、 JNJ-3283、JS-001、MEDI-0680、MGA-012、MGD-013、PDR-001、PF-06801591、 REGN-2810、SHR-1210、TSR-042、LZM-009、ABBV-181、匹地利珠单抗(Pidilizumab)、阿维鲁单抗(Avelumab)(Bavencio)、德瓦鲁单抗(Durvalumab)(Imfinzi)、阿特珠单抗(Atezolizumab)(Tecentriq)、BMS-936559、CX-072、 SHR-1316、M-7824、LY-3300054、FAZ-053、KN-035、CA-170、CK-301、CS-1001、 HLX-10、MCLA-145、MSB-2311和MEDI-4736。每种可能性代表一个单独的实施方案。
与免疫治疗剂的组合在本发明的联合治疗的范围内,所述免疫治疗剂是针对包含CD20、CD30、CD33、CD52、VEGF和ErbB2中任一种的靶标的抗体。每种可能性代表一个单独的实施方案。
进一步预期联合疗法将包括两种或更多种活性成分在单一药物组合物中以及在两种分开的药物组合物中同时或以技术人员确定的时间间隔施用给同一受试者。例如,本文公开的药物组合物的施用可以在施用其他抗癌剂之前、之后或同时进行。其他抗癌剂可以在用本文公开的药物组合物治疗开始之前或在用本文公开的药物组合物治疗之后施用。此外,其他抗癌剂可以在本文公开的药物组合物的施用期间给予,但不需要在整个治疗期间发生。在另一个实施方案中,治疗方案包括用一种药剂(本文公开的药物组合物或另一种抗癌剂)进行预处理,然后加入另一种或多种药剂。还考虑了本领域已知的交替施用顺序。
如本文和所附权利要求中所用,术语“约”是指±10%。
如本文和权利要求中所用,除非上下文另有明确规定,否则单数形式“一个”、“一种”和“该”包括复数指称。因此,例如,提及“一种抗癌剂”包括多种这样的药剂。应当注意,除非上下文另有明确规定,否则术语“和”或术语“或”通常以其包括“和/或”的含义使用。
本发明的原理通过以下非限制性实施例来说明。
实施例
实施例1:3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的
反式异构体的合成
用于化学合成的所有化学品均购自Sigma。
2-溴-3,4-二甲氧基肉桂酸的合成
将催化量的哌啶(0.2当量)加入到含2-溴-3,4-二甲氧基苯甲醛(1当量)和丙二酸(1.5当量)的吡啶(4ml/mmol醛)溶液中。将反应混合物加热至120℃6 小时。将溶液冷却至0℃,并滴加浓盐酸至pH<3。过滤收集沉淀物,用水洗涤并减压干燥,得到2-溴-3,4-二甲氧基肉桂酸,产率为62%,为白色固体。1H NMR(400 MHz,CDCl3+丙酮-d6):δ8.07(d,J=15.6Hz),7.45(d,J=8.8Hz,1H),6.95(d,J= 8.8Hz,1H),6.31(d,J=15.6Hz,1H),3.93(s,3H),3.85(s,3H)。
3-(2-溴-3,4-二甲氧基苯基)-N-(3,4,5-三甲氧基-苄基)-丙烯酰胺的反式异构体的合成
将草酰氯(4当量)加入到含2-溴-3,4-二甲氧基肉桂酸(1当量)的CH2Cl2的冷却溶液中,并将该溶液在室温下搅拌1-2小时。蒸馏除去过量的草酰氯并将混合物蒸发至干。将残余物溶解在CH2Cl2中并逐滴加入到含3,4,5-三甲氧基苄胺(0.9当量)和Et3N(4当量)的CH2Cl2的冷却溶液中。将反应混合物在室温下搅拌过夜(直到TLC表明胺消失),然后用水处理。减压蒸发CH2Cl2并将残余物过滤并用乙酸乙酯洗涤。滤液用乙酸乙酯萃取两次,合并的有机相用Na2SO4干燥,过滤,蒸发溶剂,得到棕色固体。粗固体通过快速色谱法(乙酸乙酯/己烷)纯化,得到3- (2-溴-3,4-二甲氧基-苄基)-N-(3,4,5-三甲氧基苯基-苄基)-丙烯酰胺,产率为 55%,为白色固体。1H NMR(400MHz,CDCl3):δ7.96(d,J=15.6Hz,1H),7.31(d, J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),6.55(s,2H),6.28(d,J=15.6Hz,1H),5.91 (bt,1H),4.50(d,J=5.6Hz,2H),3.90(s,3H),3.85(s,9H),3.84(s,3H)。
3-(2-溴-3,4-二甲氧基苯基)-N-(3,4,5-三甲氧基-苄基)-硫代丙烯酰胺的反式异构体的合成
3-(2-溴-3,4-二甲氧基-苄基)-N-(3,4,5-三甲氧基苯基)-丙烯酰胺(1当量)和劳森试剂(0.55当量)在甲苯中回流3小时(直到TLC表明酰胺消失)。将反应混合物冷却至室温。将粗混合物吸附到硅胶上并通过柱色谱法(乙酸乙酯/己烷)纯化,得到3-(2-溴-3,4-二甲氧基-苄基)-N-(3,4,5-三甲氧基苯基)-硫代丙烯酰胺,产率为50%,为淡黄色固体。1HNMR(400MHz,CDCl3):δ8.05(d,J=15.6Hz,1H), 7.45(bt,1H),7.33(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),6.73(d,J=15.6Hz, 1H),6.60(s,2H),4.89(d,J=5.2Hz,2H),3.91(s,3H),3.86(s,6H),3.85(s,3H), 3.83(s,3H)。
3-(2-溴-3,4-二羟基苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体的合成
将三溴化硼(每个甲氧基过量2.5当量)加入到含3-(2-溴-3,4-二甲氧基苯基)-N-(3,4,5-三甲氧基-苄基)-硫代丙烯酰胺的CH2Cl2的冰***液(约20ml/mmol) 中。使反应混合物升温至室温并搅拌5小时。将溶液冷却至0℃,然后用冷水处理。蒸发DCM并用乙酸乙酯萃取溶液3次。合并的有机层用Na2SO4干燥并减压蒸发溶剂。黄色粗品可用乙腈重结晶或用水/乙醇或丙酮/氯仿的溶剂/反溶剂体系结晶得到3-(2-溴-3,4-二羟基苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺,产率为 50-60%,为黄色晶体。1H NMR(300MHz,CDCl3):δ4.77(d,2H,J=5.2Hz,CH2N), 6.43(s,2H,芳香族),6.86(d,1H,J=8.4Hz,芳香族),7.01(d,1H,J=15.2Hz,烯烃),7.16(d,1H,J=8.4Hz,芳香族),8.27(d,1H,J=15.2Hz,烯烃),8.99(br.s.,1H, NH)。
实施例2:将3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺
的反式异构体暴露于紫外线下-1H NMR分析
3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺在10%d6-DMSO缓冲液(pH 7.4)用人工日光照射5小时。此后,通过1H-NMR分析表征该溶液。该溶液显示基本上纯的反式异构体显著转化为顺式异构体,产生反式和顺式异构体的混合物。图3显示了由曝光产生的顺反混合物的代表性1H-NMR 光谱。
表1总结了3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式和反式异构体的1H-NMR化学位移。可以看出两种异构体之间的明显差异,特别是在双键偶联(注释8和9)中。顺式异构体的JHH偶联为12.3Hz,而反式异构体的偶联为15.1Hz。因此,可以使用1H-NMR分析来区分两种异构体。
表1:3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式和反式异构体的原子注释
实施例3:制备在HPCD中的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-
硫代丙烯酰胺的反式异构体的制剂
在10L玻璃双夹套反应器中制备在2-羟丙基-β-环糊精(HPCD)中的3-(2-溴 -3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体的制剂(4L,密度1.15g/mL),该反应器配备有聚四氟乙烯涂层的可控速度搅拌器。特别地,将1,680克HPCD加入到注射用水(WFI)(2,040克)中,同时在50℃/约250RPM下混合。在HPCD完全溶解后,将溶液冷却至室温。向溶液中加入3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体(280g)并在室温避光条件下混合直至完全溶解。
将另外的WFI(600g)加入到溶液中,在室温/约250RPM下混合并在避光条件下洗涤反应器的内表面并达到制剂中总共2,640g WFI的体积。使用无菌和去热原 0.22μm过滤装置将散装溶液过滤和灭菌,放入避光无菌容器中。将制剂于-20℃储存在避光琥珀色小瓶中直至使用。
实施例4:3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的
反式异构体暴露在光-UV分析
溶于600mg/mL HPCD的含100mg/mL的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5- 三羟基-苄基)-硫代丙烯酰胺的反式异构体的溶液,用0.025%磷酸稀释成0.5mg/mL 3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的溶液,并在暴露于室内照明的透明玻璃小瓶中在长凳上放置几天。暴露导致反式异构体转化为顺式异构体。反式和顺式异构体的紫外光谱分别如图4A和4B所示。
实施例5:稀释制剂的短期稳定性
评估了反式异构体在人工日光下的稳定性。制备了以下溶液:
D5W-(含5%w/v葡萄糖的DDW):将5g葡萄糖溶解在100ml DDW中并使用0.22μm过滤器过滤。
储备溶液X-(1,000mM溶液,DMSO中):将4.12mg的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺溶解在10μL二甲基亚砜。显示储备溶液含有2.3%的顺式异构体和97.6%的反式异构体。然后通过添加915μL D5W 将储备溶液X稀释至3.6mM的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)- 硫代丙烯酰胺的浓度,并进一步将300μL后一种溶液稀释于600μL D5W中。将稀释的溶液分成两份,一份在4℃下避光(溶液X1),另一份在室温(约20℃) 下暴露于人工日光下4小时(溶液X2)。
储备溶液Y-(169.9mM溶液,HPCD中):如实施例3中所述,通过将HPCD 溶解在注射用水中并加入3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺来制备在420mg/mL的HPCD注射用水溶液中的70mg/mL的3-(2-溴-3,4- 二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的溶液。显示储备溶液含有 0.3%的顺式异构体和99.1%的反式异构体。然后向1,958μL D5W中添加42.4μL 储备溶液Y,将储备溶液稀释至3.6mM的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的浓度。将稀释的溶液分成两份,一份在4℃避光(溶液Y1),另一份在室温(约20℃)下暴露于人工日光下4小时,然后用铝箔包裹并进一步保持在4℃(溶液Y2)。
储备溶液Z-(10mM溶液,DMSO中):将4.12mg的3-(2-溴-3,4-二羟基- 苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺溶解在1ml二甲基亚砜中。显示储备溶液含有0.4%的顺式异构体和99.5%的反式异构体。然后向600μL D5W中添加300 μL储备溶液,将储备溶液稀释至3.6mM的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的浓度。将稀释的溶液分成两份,一份在4℃避光(溶液Z1),另一份在室温(约20℃)下在人工日光下照射4小时,然后用铝箔包裹并进一步保持在4℃(溶液Z2)。
对各种溶液进行HPLC分析以确定顺反比。结果示于表2和图5A-5F中。具体是,图5A、5C和5E显示了避光溶液(分别为溶液X1、溶液Y1和溶液Z1) 的HPLC色谱图,图5B、5D和5F显示了暴露光下4小时的HPLC色谱图(分别为溶液X2、溶液Y2和溶液Z2)。
表2:溶液的HPLC分析
结果表明,曝光诱导了基本上纯的反式异构体(~16.7分钟)向顺式异构体 (~15.0分钟)的显著转化。
实施例6:3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺异
构体的抗增殖活性
测试制剂
3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的储备溶液是通过将1.5mg的化合物在避光管中溶解在1.8mL乙醇中而制备的,得到2mM 溶液。然后将1.48mL溶液加入2.52mL无菌DDW以提供0.74mM(0.3mg/mL) 的在37%EtOH水溶液中的浓度。将溶液分成4管,#0管在4℃下保持在黑暗中,用铝箔包裹,而其他管在室温下暴露在日光下1小时、4小时和24小时,分别标记为#1、#4和#24。将溶液用于细胞增殖研究并进一步冷冻以进行化学分析,包裹在铝箔中。使用HPLC在特别注意光线的情况下分析每种溶液中顺式和反式异构体的含量。
细胞培养
A375(恶性人类黑色素瘤)细胞购自ATCC(美国典型培养物保藏中心)。细胞在RPMI1640培养基中避光、95%空气和5%CO2的潮湿气氛中、37℃培养和生长,该培养基补充有10%胎牛血清、1%谷氨酰胺、1%青霉素和1%链霉素(完全培养基)。
实验设计
该研究的设计包括人黑色素瘤A375细胞的5个测试***,用最终浓度为0、 0.1、0.3、1、3和10μM的溶液处理,一式五份(每个浓度5个孔)。
将人黑色素瘤A375细胞接种在完全培养基(180μL/孔)中的96孔板(1,500 个细胞/孔)中。在处理细胞之前,将溶液(0.74mM,管#0、#1、#4、#24)用无菌水中5%的EtOH稀释至0、1、3、10、30和100μM的浓度(细胞增殖试验中的最终浓度×10)。
接种后一天(第0天),以上述浓度(20μL/孔)添加3-(2-溴-3,4-二羟基- 苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺3天。处理3天后,用戊二醛固定细胞,并使用亚甲蓝定量细胞活力。
在第0天用戊二醛固定额外的A375细胞板,并与所有其他板一起用亚甲蓝染色,以量化处理开始时的细胞活力。结果的分析通过计算对照(无药物)的%OD 进行,并使用Prism软件计算IC50值。
在0.3μM浓度(IC50值附近),通过单向方差分析和Post Hoc Tukey的HSD 检验评估处理之间差异的统计显著性。
结果
0.3mg/mL(0.74mM)的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺溶液暴露在日光下1、4和24小时产生的溶液的顺式与反式异构体的比例增加。在所有比例的异构体中都检测到A375细胞增殖的显著抑制,证明了剂量依赖性效应(表3和图6)。
表3:溶液中顺式和反式异构体的百分比与IC50值
重要的是,虽然含有80-100%反式异构体的样品(无光或光照1小时)显示IC50值(226-222nM)没有显著变化,但在顺反比为~50∶50(#4)(352nM)观察到明显增加。在光照24小时(753nM)后顺反比增加到~80∶20时,IC50值也有增加的趋势,即使在基于整体化合物(顺+反)测定标准化IC50值(686nM)时也是如此。差异具有统计学意义。因此,结果表明反式异构体向顺反混合物的相互转化伴随着抗增殖活性的丧失,并且基本上纯的反式异构体是更有效的抗增殖剂。
使用以下细胞系进一步评估基本上纯的反式异构体相对于顺-反混合物的抗增殖活性:肺癌:NCI-H1975;头颈癌:SCC-9;结直肠癌:HCT116;肉瘤:SK-ES.1;肝细胞癌:HepG2;乳腺癌:MDA-MB-468和MDA-MB-231;多发性骨髓瘤: MM1S和RPMI-8226;卵巢癌:A2780;胃癌:NCI-N87;表皮样癌:A431;淋巴瘤:KARPAS;骨肉瘤:Saos2;胰腺癌:Panc1;膀胱癌:T24P;胶质母细胞瘤:U138MG;***癌:DU145;和白血病:K562。将细胞暴露于浓度为0、 0.1、0.3、1、3和10μM 3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺,其含有各种顺反比。细胞增殖和活力通过亚甲蓝或线粒体活性测定(例如Cell Titer-Glo、WST-1测定)来测量。
虽然已经说明和描述了本发明的某些实施方案,但明显本发明不限于这里描述的实施方案。在不脱离权利要求所描述的本发明的精神和范围的情况下,许多修改、变化、变型、替换和等同物对于本领域技术人员来说将是显而易见的。
Claims (21)
1.一种保存药物组合物的方法,所述药物组合物包含作为活性成分的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或其药学上可接受的盐,所述反式异构体具有下列结构式:
所述药物组合物包含至少80%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体和少于20%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体;所述方法包括将所述药物组合物避光保存。
2.根据权利要求1所述的方法,其中所述药物组合物包含至少85%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体和少于15%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体。
3.根据权利要求1所述的方法,其中所述药物组合物包含至少90%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体和少于10%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体。
4.根据权利要求1所述的方法,其中所述药物组合物包含至少95%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体和少于5%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体。
5.根据权利要求1所述的方法,其中所述药物组合物包含至少97%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体和少于3%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体。
6.根据权利要求1至5中任一项所述的方法,其中所述药物组合物还包含药学上可接受的载体或赋形剂。
7.根据权利要求6所述的方法,其中所述药物组合物为溶液、悬浮液或乳液的形式。
8.根据权利要求6所述的方法,其中所述药学上可接受的载体或赋形剂是羟丙基-β-环糊精(HPCD)。
9.根据权利要求8所述的方法,其中3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体或其药学上可接受的盐与HPCD之间的重量比为1:1至1:12。
10.根据权利要求1所述的方法,其中所述药物组合物被保持在不透可见光的装置中,其中所述装置在可见光波长范围内的透光率小于20%。
11.根据权利要求1所述的方法,其中所述药物组合物被储存在不透可见光的储存容器中,其中所述储存容器在可见光波长范围内的透光率小于20%。
12.根据权利要求1所述的方法,其中所述药物组合物被提供在适合静脉内施用的不透可见光的试剂盒中,其中所述试剂盒在可见光波长范围内的透光率小于20%。
13.根据权利要求1所述的方法,其中所述药物组合物被保持在不透UV光的装置中,其中所述装置在UV波长范围内的透光率小于20%。
14.根据权利要求1所述的方法,其中所述药物组合物被储存在不透UV光的储存容器中,其中所述储存容器在UV波长范围内的透光率小于20%。
15.根据权利要求1所述的方法,其中所述药物组合物被提供在适合静脉内施用的不透UV光的试剂盒中,其中所述试剂盒在UV波长范围内的透光率小于20%。
16.根据权利要求1至5中任一项所述的方法,其中所述药物组合物用于治疗癌症。
17.根据权利要求16所述的方法,其中所述癌症选自头颈癌、肉瘤、多发性骨髓瘤、卵巢癌、乳腺癌、肾癌、胃癌、造血***癌、淋巴瘤、白血病、肺癌、黑色素瘤、胶质母细胞瘤、肝癌、食管癌、胃食管交界处癌、***癌、胰腺癌和结肠癌。
18.根据权利要求16所述的方法,其中所述组合物联合抗癌剂共同施用。
19.根据权利要求18所述的方法,其中所述抗癌剂包含下列至少一种:(i)选自表皮生长因子受体抑制剂(EGFR抑制剂)和EGFR抗体的蛋白激酶(PK)调节剂;(ii)哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂;(iii)丝裂原活化蛋白激酶(MEK)抑制剂;(iv)突变的B-Raf抑制剂;(v)化疗剂;和(vi)免疫治疗剂,其包含针对程序性细胞死亡1(PD-1)蛋白、程序性细胞死亡蛋白1配体(PD-L1)、细胞毒性T淋巴细胞相关蛋白4(CTLA4)或其组合的抗体。
20.一种防止3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的基本上纯的反式异构体转化为顺式异构体的方法,所述反式异构体具有下列结构式:
所述方法包括将所述基本上纯的反式异构体保持在避光的装置或容器中;
所述基本上纯的反式异构体包含至少80%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的反式异构体和少于20%重量的3-(2-溴-3,4-二羟基-苯基)-N-(3,4,5-三羟基-苄基)-硫代丙烯酰胺的顺式异构体。
21.根据权利要求20所述的方法,其中所述避光的装置或容器基本上不透过UV-VIS波长范围内的光。
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