CN104755455B - 可用于治疗癌症的巨大戟醇衍生化合物 - Google Patents
可用于治疗癌症的巨大戟醇衍生化合物 Download PDFInfo
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- CN104755455B CN104755455B CN201380057344.XA CN201380057344A CN104755455B CN 104755455 B CN104755455 B CN 104755455B CN 201380057344 A CN201380057344 A CN 201380057344A CN 104755455 B CN104755455 B CN 104755455B
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Abstract
本发明涉及用于治疗癌症的新的巨大戟醇衍生化合物。在其它方面,本发明涉及药物组合物、药物、癌症治疗方法和剂型。
Description
发明领域
本发明一般而言涉及可用于治疗癌症的新的巨大戟醇(ingenol)衍生化合物。在其它方面,本发明涉及用于治疗癌症的药物组合物、药物、用途、方法和剂型。
发明背景
癌症是给予一组超过100种疾病的名称,其通常具有侵入组织和器官的紊乱的细胞生长,并且可以扩散到身体的其它区域,这称为转移。
不同类型的癌症对应于身体的不同细胞类型。例如,有若干类型的皮肤癌,因为皮肤包含不止一种细胞类型。如果癌症开始于上皮组织例如皮肤或粘膜,就称为癌。如果它开始于结缔组织例如骨、肌肉或软骨,就称为肉瘤。将一类癌症与其它区分开来的其它特征是细胞繁殖速度和它们在其起源附近或远离其起源而侵入组织和器官的能力。
有效治疗癌症的困难涉及确定身体的恶性细胞和正常细胞之间的区别。这两者都起源于相同来源并且非常类似,因此,,免疫系统对于威胁没有有效识别。迄今为止,癌症可以通过手术、化疗、放疗和免疫治疗(单克隆抗体治疗)来治疗。治疗的选择取决于位置、肿瘤分级和疾病分期、以及患者的一般状况。完全去除肿瘤而不破坏生物体的其余部分,是治疗的主要目标。有时,可通过手术达到这一点,但该疾病侵入邻近组织或扩散到远端位点(转移)的倾向常常限制了其有效性。化疗有效性,在大多数情况下,受到其对于生物体的其它组织(细胞)的毒性的限制,而放疗也可破坏正常组织。在免疫治疗中,致癌细胞发展出逃逸免疫应答的机制,已知这是一种抵抗治疗的现象。
附图描述
下述附图是指通过将人类肿瘤系暴露给本发明的化合物而得到的IC50值。
图1-乳癌相关的HB4A、MDA-MB-231、MDA-MB-468、BT20、HT587T、MCF7和MCF7/AZ系。
图2-结直肠癌相关的SW480、SW620、CO115、HCT15、HT29、SK-CO-10、DLD1、LOVO、DIFI和Caco2系。
图3–头颈癌相关的JHU28、JHU13、JHU12、HN13、SCC25、SCC4、SCC14和FADU系。
图4-肺癌相关的H292和A549系;黑素瘤相关的GRM、COLO858、COLO679、A375、WN1617、WN9、WMM852、WN793和SKMEL37系;鳞状细胞癌相关的A431m系;和成神经管细胞瘤相关的DAOY和ONS76系;
图5-前列腺癌相关的PC-3LNCaP和PNT2系;膀胱癌相关的T24、5637、HT1376和MCR系;绒毛膜癌相关的JEG3系;宫颈癌相关的SIHA、CASKI、C33和HELA系。
图6–食道癌相关的KYSE30、KYSE70、KYSE279和KYSE410系;胰腺癌相关的MiaPaCa-2、PANC1、PSN-1和BXPC-3系。
图7-胶质瘤相关的U87-MG、U373、U251、GAMG、SW1088、SW1783、NHA、SNB19、RES186、RES259、KNS42、UW479和SF188系。
图8–白血病的Jurkat系,和卵巢癌相关的PA-1和SW626系。
图9-一些癌细胞系,与用替莫唑胺化合物(表示为TMZ,一种用于治疗脑癌的药物)而得到的值比较。
发明详述
寻求治疗癌症的新方式是一个不断发展的过程,在该动态过程中,开发出新的有效成分用于治疗癌症,并具有低毒性。
在第一方面,本发明涉及用于治疗癌症的源自巨大戟醇的式I化合物:
式I
其中
A为苯基、CH3-或CH2=CH-,
和B为-CH=CH-、[-CH2-]x或[-CH2-]y,
其中x为介于1-10之间的整数,优选介于2-6之间的整数,和y为介于1-10之间的整数,优选介于8-10之间的整数,
条件是:
当A为苯基时,B为-CH=CH-;
当A为CH3-时,B为[-CH2-]x;
当A为CH2=CH-时,B为[-CH2-]y。
特别地,并且不排除其它选择,本发明的巨大戟醇衍生化合物适合治疗乳癌、结直肠癌、头颈癌、脑癌(例如胶质瘤和成神经管细胞瘤)、前列腺癌、膀胱癌、绒毛膜癌、宫颈癌、白血病、皮肤癌(例如,鳞状细胞癌和黑素瘤)、食道癌、胰腺癌和卵巢癌。
在非限制性含义上,适合本发明的巨大戟醇衍生物的具体实例是:
3-肉桂酰基-巨大戟醇
3-己酰基-巨大戟醇
3-十二烷酰基-巨大戟醇
3-十二-11-烯酰基-巨大戟醇
式I包括本文所述结构的异构体、及其药学活性衍生物,例如盐、前药、代谢物、晶体、水合物和溶剂合物。
药学活性衍生物是通常表现出类似于游离碱分子的行为的那些。
式I化合物的药学上可接受的盐在药学活性衍生物范围内。一种具体的反荷离子(其是本发明化合物的任何盐的部分),通常不呈现关键性能,条件是盐作为整体是药理学上可接受的并且条件是反荷离子不促成盐作为整体的不想要的特性。
不排除任何其它,酸加成盐可以引用作为药学上可接受的盐,例如无机盐,例如盐酸盐、氢溴酸盐、硫酸盐、硝酸盐和磷酸盐;或有机盐,例如乙酸盐、丙酸盐、己酸盐、庚酸盐、乙醇酸盐、丙酮酸盐、乳酸盐、丙二酸盐、琥珀酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、肉桂酸盐、甲磺酸盐、对氯苯磺酸盐、2-萘磺酸盐、对甲苯磺酸盐、樟脑磺酸盐、三甲基乙酸盐、叔丁基乙酸盐、月桂基硫酸盐、葡萄糖酸盐、戊二酸盐、羟基萘甲酸盐、水杨酸盐、硬脂酸盐、粘康酸盐、扁桃酸盐和2-羟基乙烷磺酸盐。
不排除任何其它,碱加成盐可以引用作为药学上可接受的盐,例如铵盐;碱金属盐例如钠、钾、锂、钙或镁盐;与有机碱的盐,例如伯、仲或叔胺的盐(例如,异丙胺、三甲胺、二乙胺、三异丙基胺、三正丙基胺、乙醇胺、2-二甲氨基乙醇、氨丁三醇、二环己基胺、N-甲基-D-葡糖胺;和与氨基酸的盐,例如精氨酸盐、赖氨酸盐、组氨酸盐;咖啡因、普鲁卡因、海巴胺(hydrabamine)、胆碱、甜菜碱、1,2-乙二胺、葡糖胺、可可碱、嘌呤、吗啉等。在一些可能的实施方案中,可以用卤代烷型试剂将含氮的碱性基团季铵化,所述试剂例如甲基、乙基、丙基或丁基的氯化物、溴化物和碘化物;长链卤化物,例如癸基、月桂基、豆蔻基和硬脂酰基的氯化物、溴化物和碘化物。
另一方面,本发明涉及药物组合物,其包含一种或多种式I化合物、和一种或多种药学上可接受的赋形剂。以下出版物可引用作为这类赋形剂的信息来源:"Remington:TheScience and Practice of Pharmacy",第20版或更新版,Lippincott,Williams和WilkinsPublishing House;"Pharmaceutical Dosage Forms and Drug Delivery Systems(1999)H.C.Ansel等人,第7版,Lippincott,Williams&Wilkins Publishing House;“Handbook ofPharmaceutical Excipients”(2000)A.H.Kibbe等人,第3版,American PharmaceuticalAssociation Publishing House。
本发明的巨大戟醇衍生物以及含有它们的组合物可通过任何合适途径给予人或动物(非人)患者,所述途径例如口服、胃肠外、静脉内、动脉内、腹膜内、透皮、舌下、直肠、肌内、经口含化(transbuccal)、鼻内、脂质体、吸入、阴道(vaginal)、皮下、脂肪内、眼内、关节内或鞘内途径,通过使用导管或支架等。
对于含有本发明的巨大戟醇衍生化合物的剂型,没有特别限制,例如片剂、锭剂、胶囊剂、颗粒剂、丸剂等都可用于固体口服给药。对于液体口服给药,溶液剂、分散剂、混悬剂、乳剂、油剂等都可以采用。其它合适的剂型是脂质体和纳米粒,或本领域技术人员已知的任何其它形式。剂型可以是即时释放的、持续释放的或控制释放的。
在具体方面,本发明的组合物除了包含一种或多种式I的巨大戟醇衍生化合物外,还包含与之不同的至少一种另外有效成分,例如选自抗肿瘤药、抗逆转录病毒药、抗生素、抗肿瘤药、抗恶病质药、神经系统药(neurological agent)、抗糖尿病药、抗高血压药、质子泵抑制剂等。
另一方面,本发明涉及药物,其包含一种或多种式I的巨大戟醇衍生化合物。
另一方面,本发明涉及一种或多种式I的巨大戟醇衍生化合物在制备用于治疗癌症的产品中的用途。在另一具体方面,本发明涉及治疗癌症的方法,特征在于将一种或多种式I的巨大戟醇衍生化合物本身或以组合物形式给予患者。
在另一具体方面,本发明涉及一种或多种式I的巨大戟醇衍生化合物在治疗癌症中的用途。
在另一具体方面,本发明涉及用于治疗癌症的剂型,特征在于含有0.01至5000mg的一种或多种权利要求1的式I的巨大戟醇衍生物。依照本发明,用于治疗的合适剂量可以给予一次,或在一段时间内给予数次。
实施例
以下给出一些巨大戟醇衍生物相关的本发明实施方案的具体实施例,但并不意图以任何方式将本发明限制在这样的实施例中。
在以下实施例中,使用下文说明的以下式I的巨大戟醇衍生物,为了便于引用,其在本文中称为巨大戟醇A、巨大戟醇B和巨大戟醇C。要注意的是,对于每一种化合物都指明了立体空间构象。
巨大戟醇A
巨大戟醇B
巨大戟醇C
实施例1
在体外测试了若干癌细胞系,以测定50%抑制浓度(IC50),这是抑制50%细胞活性所需的浓度,单位是μm(微摩尔);所述试验描述于以下。
制备用于试验的细胞
在37℃,5%CO2和90%湿度中,将所测试的癌细胞培养在DEMEM培养基(Dulbecco氏改良Eagle培养基)或RPMI培养基(Roswell Park Memorial Institute)1640中直至达到汇合,这两种培养基都由American company Life Technologies供应,其中在25或75cm2的聚乙烯培养管或培养板中添加有10%胎牛血清(Life Technologies)和1%青霉素/链霉素(Life Technologies),平均密度为1x 106。汇合后,细胞经胰蛋白酶水解(0.05%胰蛋白酶溶液/0.53mM EDTA–TripLE Express product,Life Technologies),铺板并维持在上述条件下,用于以下试验。
IC50测定
在水溶液中的细胞活力测定法用于该测定,使用由American company Promega供应的产品"Cell Titer 96Aqueous One Solution Cell Proliferation Assay”,按照制造商描述的比色方法,在增殖或细胞毒性测定法中测定活细胞数。CellTiter 96含有四唑化合物[(3-(4,5-二甲基-2-基)-5-(3-羧基甲氧基苯基)-2-(4-硫代苯基)-2H-四唑内盐;MTS]和电子偶联试剂(吩嗪硫酸乙酯(phenazine ethosulfate);PES)。PES具有改进的化学稳定性,这允许它与MTS结合而形成稳定的有色溶液。在不同试验和对照样品时测定的吸光度,允许确定各样品中的活细胞数是否类似。对于该测定,将3-5x 103细胞接种在96孔板上,一式三份,并将本发明化合物的稀释液(0;2.5;5;7.5;10和20μM–在DMSO-二甲基亚砜中稀释)加入其中。制备所述化合物的稀释液,使得细胞仅经受1%DMSO/孔。在处理72小时后,用ELISA板读数器(Flash Varioskan equipment,由American company ThermoScientific供应)在490nm处测定吸光度。采集数据并相对于仅用DMSO处理的样品平均存活率(被认为是100%活力)而标准化。在实验的和生物学的一式三份中进行实验。
将吸光度值的结果转化为细胞活力的百分率,其中在溶媒(DMSO)存在时的细胞用作对照,相当于100%的存活率。使用程序Graphpad Prism(由American company GraphpadSoftware供应),对于可行性结果进行非线性回归分析,得到的方程用于计算产生细胞活力下降50%(IC50)所需的物质浓度。
如图1-8所示,对于大多数癌系,本发明的巨大戟醇衍生化合物具有在体外IC50试验(50%最大抑制浓度)中证明的抗癌活性。
如图9所示,与替莫唑胺(一种在肿瘤学临床中用于治疗脑癌的抗肿瘤产品)相比,用本发明的巨大戟醇衍生物进行试验的产品,更强力和有效。
本领域技术人员可以借助本文所含的教导容易地评价本发明的优势,并且将会知道如何对实施方案进行未明确描述的修改和等同替代,而不偏离所附权利要求书中定义的本发明的范围。
Claims (9)
1.一种或更多种式I的巨大戟醇衍生化合物的用途,
式I
其中A为苯基、CH3-或CH2=CH-,且B为-CH=CH-,[-CH2-]x或[-CH2-]y,
其中x为介于1-10之间的整数,
其中y为介于1-10之间的整数,
条件是:
当A为苯基时,B为-CH=CH-;
当A为CH3-时,B为[-CH2-]x;
当A为CH2=CH-时,B为[-CH2-]y,
特征在于所述用途是用于制备用于降低癌细胞生存能力的产品,所述癌选自:乳癌、结直肠癌、头颈癌、脑癌、前列腺癌、绒毛膜癌、宫颈癌、白血病、皮肤癌。
2.根据权利要求1的用途,特征在于x在介于2-6之间变化,和y在介于8-10之间变化。
3.根据权利要求1的用途,特征在于所述巨大戟醇衍生化合物是以下的一种或多种:3-肉桂酰基-巨大戟醇、3-己酰基-巨大戟醇、3-十二烷酰基-巨大戟醇或3-十二-11-烯酰基-巨大戟醇。
4.根据权利要求1的用途,特征在于所述巨大戟醇衍生化合物包含以下结构之一:
或
5.包含一种或多种权利要求1中定义的式I化合物和一种或多种药学上可接受的赋形剂的药物组合物的用途,特征在于所述用途是用于制备可用于治疗癌症的产品。
6.根据权利要求5的药物组合物的用途,特征在于所述药物组合物含有并非式I化合物的至少一种另外的有效成分。
7.根据权利要求5的药物组合物的用途,特征在于所述至少另外的有效成分选自抗肿瘤药、抗逆转录病毒药、抗生素、抗恶病质药、神经学有效成分、抗糖尿病药、抗高血压药和质子泵抑制剂。
8.药物,特征在于其含有至少一种权利要求1中定义的式I化合物。
9.用于治疗癌症的剂型,特征在于其包含0.01至5000mg的一种或多种权利要求1的式I化合物。
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