CN114436822A - 一枝蒿酮酸和生物碱复盐及其制备方法和用途 - Google Patents
一枝蒿酮酸和生物碱复盐及其制备方法和用途 Download PDFInfo
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- CN114436822A CN114436822A CN202210032992.0A CN202210032992A CN114436822A CN 114436822 A CN114436822 A CN 114436822A CN 202210032992 A CN202210032992 A CN 202210032992A CN 114436822 A CN114436822 A CN 114436822A
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- rupestonic acid
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Abstract
Description
技术领域
本发明属于医药技术领域。具体涉及一枝蒿酮酸和生物碱复盐及其制备方法和其在治疗肿瘤/癌症方面的用途。
背景技术
癌症已成为世界范围内最主要的致死性疾病。癌症可于任何年龄在各种器官及组织中发生,导致死亡的主要癌症种类有:肺癌、胃癌、肝癌、结肠癌和乳腺癌等。虽然部分小分子抗癌药物已用于临床,部分化合物抗癌药物也正在进行临床前的研究。然而大部分癌症患者发觉病情时已是中期至晚期,临床治疗总体效果较差,尤其是多药耐药性的不断出现,使得癌症的治疗困难重重。因此,开发出活性高、副作用低的新型抗癌药物来满足临床的需求迫在眉睫。中药在我国用药历史悠久,毒副作用相对较低。从传统中药中发现新的候选药物或先导药物是当今药物研发的主流。
苦参碱、氧化苦参碱、槐果碱、槐定碱都是从豆科植物苦参(Sophora flavescensAit)的干燥根、株及果实中得到的生物碱,具有广泛的药理活性(张明发,沈雅琴. 苦参碱类生物碱抗肉瘤药理作用的研究进展.药物评价研究,2018, 41(11):2117-2122)。苦参素注射液,临床上用于治疗慢性乙型病毒性肝炎及肿瘤放疗、化疗引起的白细胞低下和其它原因引起的白细胞减少症。
新疆一枝蒿(Artemisia Rupestris L.)主要分布于我国新疆、中亚、欧洲等地。在新疆民间用药历史悠久。临床上用于治疗消化不良、腹胃胀痛、肝炎、蛇咬伤及感冒发烧等疾病。其中以新疆一枝蒿为主要成分的复方制剂“复方一枝蒿颗粒”,批准文号:国药准字Z200226711,临床上用于解表祛风、治疗病毒性感冒、咽喉肿痛等疾病。一枝蒿酮酸是新疆一枝蒿中的特征化合物之一,是含多官能团的倍半萜类化合物,一枝蒿酮酸及其衍生物具有较强的抗流感病毒及疱疹病毒活性 [(1)一枝蒿酮酸衍生物及用途.ZL200710180021.6;(2)Advances in Studies on the Rupestonic Acid Derivatives as Anti-influenzaAgents.Mini-Reviews in Medical Chemistry.2013,13(2):310-315]。
本发明通过一枝蒿酮酸和生物碱,如苦参碱、氧化苦参碱、槐果碱、槐定碱,制备得到的复盐。结果表明该复盐具有抗肿瘤活性,可用于治疗肿瘤/癌症疾病。
发明内容
本发明提供了一种式(I)所示的化合物与生物碱形成的复盐:
其中,所述生物碱可以选自苦参碱、氧化苦参碱、槐果碱或槐定碱。
根据本发明的实施方案,所述式(I)所示的化合物与生物碱的摩尔比可以为1:(0.5-5),例如1:(0.8-2),示例性为1:1。
根据本发明的实施方案,所述式(I)化合物结构如式(II)所示:
根据本发明的实施方案,所述复盐可以选自一枝蒿酮酸苦参碱复盐、一枝蒿酮酸氧化苦参碱复盐、一枝蒿酮酸槐果碱复盐或一枝蒿酮酸槐定碱复盐,具体如以下结构:
本发明还提供了上述复盐的制备方法:将式(I)化合物与生物碱溶于有机溶剂,混合得到所述复盐。
根据本发明的实施方案,所述式(I)化合物与生物碱的摩尔比可以为1:(0.5-5),例如1:(0.8-2),示例性为1:1;
根据本发明的实施方案,所述有机溶剂选自甲醇、乙醇、氯仿、丙酮、甲苯、二氯甲烷、乙酸乙酯等能溶解两种化合物的单一溶剂或混合溶剂。优选为甲醇或丙酮。
本发明还提供一种药物组合物,其包含治疗有效量的所述复盐或他们的组合物。
根据本发明的实施方案,所述药物组合物还包括一种或多种药学上可接受的辅料。
根据本发明的实施方案,所述药物组合物还可以进一步含有一种或多种额外的治疗剂。
本发明提供了所述复盐或它们的组合物在治疗肿瘤/癌症中的用途。
根据本发明的实施方案,所述癌症可以为肺癌、乳腺癌、胃癌、宫颈癌。
本发明提供了所述复盐或它们的组合物在制备治疗肿瘤/癌症药物中的用途。
本发明还提供治疗肿瘤/癌症的方法,包括给予患者预防或治疗有效量的式(I)所示复盐化合物。
在一些实施方案中,所述患者是人。
作为药物时,可按药物组合物的形式给予本发明所述复盐。所述的药物组合物可以制备成任何可药用的制剂形式。如固体口服制剂、注射制剂、乳剂、霜剂、酊剂、软膏剂,所述注射剂可以为小针注射剂、冻干注射剂。可按药剂领域中熟知的方式制备这些组合物,可通过多种途径给予它们,这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如,透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如,通过吸入或吹入粉末或气雾剂,包括通过喷雾器;气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药,或可通过例如连续灌注泵给药。局部给予的药用组合物和制剂可包括透皮贴剂、软膏、洗剂、霜剂、凝胶剂、滴剂、栓剂、喷雾剂、液体剂和散剂。常规药物载体、水、粉末或油性基质、增稠剂等可能是必须的或需要的。
在制备本发明的组合物时,通常将活性成分与赋形剂混合,通过赋形剂稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当赋形剂用作稀释剂时,它可以是固体、半固体或液体物质,用作溶媒、载体或活性成分的介质。因此,组合物可以是以下形式:片剂、颗粒剂、缓释剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒);含例如高达10%重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
适宜的赋形剂的某些实例包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂还可含有:润滑剂例如滑石粉、硬脂酸镁和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂例如苯甲酸甲酯和苯甲酸羟基丙酯;甜味剂和矫味剂。可通过使用本领域中已知的方法配制本发明组合物,以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。
可按单位剂型配制组合物,每一剂量含约5~1000mg,更通常约100~500mg 活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位,各单位含有与适宜的药物赋形剂混合的经计算可产生所需疗效的预定量的活性物质。
活性化合物的有效剂量的范围可很大,通常按药用有效量给药。但是,可以理解实际给予的化合物的量通常由医师根据相关情况决定,它们包括所治疗的病症、所选择的给药途径、所给予的实际化合物;患者个体的年龄、重量和反应;患者症状的严重程度等。
对于制备固体组合物例如片剂,将主要的活性成分与药物赋形剂混合,形成含本发明化合物的均匀混合物的固体预制剂组合物。当称这些预制剂组合物为均匀时,是指活性成分通常均匀地分布在整个组合物中,致使该组合物可容易地划分为同等有效的单位剂型例如片剂、丸剂和胶囊剂。然后将该固体预制剂划分为上述类型的含例如约0.1~1000mg本发明活性成分的单位剂型。
可将本发明片剂或丸剂包衣或复合,得到提供长效作用优点的剂型。例如,片剂或丸剂含内剂量和外剂量组分,后者是前者的被膜形式。可通过肠溶层将两种组分隔离,肠溶层用于在胃中阻止崩解,以使内组分完整通过十二指肠或延迟释放。多种物质可用于此类肠溶层或包衣剂,此类物质包括多种高分子酸和高分子酸与此类物质如虫胶、鲸蜡醇和醋酸纤维素的混合物。
其中可掺入本发明化合物和组合物,用于口服或注射给药的液体形式包括水溶液、适当矫味的糖浆剂、水或油混悬液;和用食用油例如棉子油、芝麻油、椰子油或花生油矫味的乳剂;以及酏剂和类似的药用溶媒。
用于吸入或吹入的组合物包括溶于药学上可接受的水或有机溶剂或其混合物的溶液剂和混悬液、散剂。液体或固体组合物可含有如上所述适宜的药学上可接受的赋形剂。在某些实施方案中,通过口服或鼻呼吸途径给予组合物,实现局部或全身作用。可通过使用呈惰性的气体,使组合物成雾化。可直接由雾化装置吸入雾化溶液,或雾化装置可与面罩帷或间歇正压呼吸机连接。可通过口服或由按适当方式递送制剂的装置通过鼻给予溶液、混悬液或粉末组合物。
给予患者的化合物或组合物的量不固定,取决于给予的药物、给药的目的例如预防或治疗;患者的状态、给药的方式等。在治疗应用时,可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断,该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌,将这些组合物灭菌。可将水溶液包装原样使用,或冻干,给药前,将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3~11,更优选5~9,最优选7~8。可以理解,使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
本发明化合物的治疗剂量可根据例如以下而定:治疗的具体用途、给予化合物的方式、患者的健康和状态,以及签处方医师的判断。本发明化合物在药用组合物中的比例或浓度可不固定,取决于多种因素,它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1~10%w/v该化合物的生理缓冲水溶液提供本发明化合物,用于肠胃外给药。某些典型剂量范围为约1μg/kg~约1g/kg 体重/日。在某些实施方案中,剂量范围为约0.01mg/kg~约100mg/kg体重/日。剂量很可能取决于此类变量,如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推,得到有效剂量。
根据本发明的实施方案,所述的辅料包括填充剂、粘合剂、崩解剂、润滑剂、矫味剂、肠溶衣或缓释材料中的一种或几种混合物。
根据本发明的实施方案,所述的填充剂包括:乳糖、蔗糖、糊精、淀粉、甘露醇、山梨醇、磷酸氢钙、碳酸钙、微晶纤维素中的一种或几种混合物;
根据本发明的实施方案,所述的粘合剂包括蔗糖、淀粉、羧甲基纤维素钠、甲基纤维素、聚乙二醇、水中的一种或几种混合物;
根据本发明的实施方案,所述的崩解剂包括淀粉、交联聚微酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基纤维素钠中的一种或几种混合物;
根据本发明的实施方案,所述的润滑剂包括滑石粉、硬脂酸镁、硬脂酸、微粉硅胶、聚乙二醇-4000、聚乙二醇-6000中一种或几种混合物;
根据本发明的实施方案,所述的矫味剂包括蔗糖、山梨醇、糖精钠、麦芽糖醇、甜菊糖苷、阿斯巴甜中的一种或几种混合物;
根据本发明的实施方案,所述的缓释材料包括不同规格粘度的羟丙甲纤维素、瓜尔胶中的一种或几种混合物。
有益效果
本发明提供了式(I)所示的复盐化合物及其制备方法和用途,通过对一枝蒿酮酸分别和苦参碱、氧化苦参碱、槐果碱、槐定碱的复盐进行测试,发现其具有抗肿瘤作用。该复盐化合物或其组合物具有治疗肿瘤/癌症疾病的潜在功效。
附图说明
图1:苦参碱的HPLC谱图,色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm;
图2:一枝蒿酮酸的HPLC谱图,色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸), 7:3;检测波长:254nm;
图3:一枝蒿酮酸和苦参碱复盐的HPLC谱图,色谱条件:C18柱;流动相:V 甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm;
图4:氧化苦参碱HPLC谱图,色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸), 7:3;检测波长:254nm;
图5:一枝蒿酮酸氧化苦参碱复盐的HPLC谱图,色谱条件:C18柱;流动相: V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm;
图6:槐果碱HPLC谱图,色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm;
图7:一枝蒿酮酸槐果碱复盐的HPLC谱图,色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm;
图8:槐定碱HPLC谱图,色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm;
图9:一枝蒿酮酸槐定碱复盐的HPLC谱图,色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
仪器与试剂:
一枝蒿酮酸(98%,由中科院新疆理化技术研究所阿吉艾克拜尔·艾萨研究员提供);苦参碱、氧化苦参碱、槐果碱、槐定碱均购自山西玉宁生物科技有限公司(纯度均大于98%);LC3000N型高效液相色谱仪(北京创新通恒色谱技术有限公司);日立L2000高效液相色谱仪(日立HITACHI);CCK8(上海贝博生物科技有限公司);DMEM高糖培养基(赛默飞世尔(苏州)仪器有限公司);EDTA(胰酶)(gibco);Foetal Bovine Serum(BiologicalIndustries);磷酸缓冲盐溶液;96孔细胞培养板;多功能酶标仪。
实施例1:一枝蒿酮酸苦参碱复盐的制备
将0.124g(0.5mmol)一枝蒿酮酸和0.124g(0.5mmol)苦参碱加入20mL圆底烧瓶中,加入5mL干燥的甲醇,室温搅拌30min后,HPLC检测反应完成后,减压浓缩即得一枝蒿酮酸苦参碱复盐粗品。该粗品通过制备HPLC分离纯化即得无色粘稠油状物(色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm), HPLC纯度:98.9%。
实施例2:一枝蒿酮酸氧化苦参碱复盐的制备
将0.124g(0.5mmol)一枝蒿酮酸和0.132g(0.5mmol)氧化苦参碱加入20mL圆底烧瓶中,加入5mL干燥的甲醇,室温搅拌30min后,HPLC检测反应完成后,减压浓缩即得一枝蒿酮酸氧化苦参碱复盐粗品。该粗品通过制备HPLC分离纯化即得无色粘稠油状物(色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长:254nm),HPLC纯度:97.3%。
实施例3:一枝蒿酮酸槐果碱复盐的制备
将0.124g(0.5mmol)一枝蒿酮酸和0.123g(0.5mmol)槐果碱加入20mL圆底烧瓶中,加入5mL干燥的甲醇,室温搅拌30min后,HPLC检测反应完成后,减压浓缩即得一枝蒿酮酸槐果碱复盐粗品。该粗品通过制备HPLC分离纯化即得无色粘稠油状物(色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长: 254nm),HPLC纯度:95.3%。
实施例4:一枝蒿酮酸槐定碱复盐的制备
将0.124g(0.5mmol)一枝蒿酮酸和0.123g(0.5mmol)槐定碱加入20mL圆底烧瓶中,加入5mL干燥的甲醇,室温搅拌30min后,HPLC检测反应完成后,减压浓缩即得一枝蒿酮酸槐定碱复盐粗品。该粗品通过制备HPLC分离纯化即得无色粘稠油状物(色谱条件:C18柱;流动相:V甲醇:V水(含0.3%磷酸),7:3;检测波长: 254nm),HPLC纯度:98.1%。
实施例5:体外抗肿瘤活性测试
对获得的一枝蒿复盐进行了体外抗肿瘤活性测试,主要研究了其对肺腺癌细胞株(A549)和宫颈癌细胞株(Hela)的体外抑制活性。具体的测试过程以对肺腺癌细胞株(A549)的测试过程为例进行阐述:
1.测试样品浓度配制
称取制备的一枝蒿复盐,加入5mL的塑料离心管中,用DMSO稀释至1mL。即得初始浓度。然后将初始浓度用DMSO进行倍比稀释,依次获得5 个不同的浓度梯度,置于4℃冰箱保存待用。
2.肺腺癌细胞株(A549)的培养及抑制活性测试
将肺腺癌细胞株(A549)置于37℃,饱和湿度,含有5%的CO2培养箱中培养 24小时,当细胞处于对数生长期时,吸弃上层培养液,并用0.25%胰蛋白酶-EDTA 溶液消化后,使用高糖培养基终止消化。并将细胞接种于96孔板中,使得细胞密度为5000个/孔。将96孔板置于培养箱中培养24小时。随之吸弃96孔板中的细胞培养液。并向96孔板中补加100μL的高糖培养基,然后每孔加入不同浓度的测试样品1μL(每个浓度设置5个复孔),接着置于37℃,饱和湿度,5%CO2的培养箱中继续培养48h后,每孔加入10μL CCK8,继续在37℃培养箱中孵育 1-4h后。在多功能酶标仪上测定450nm波长下每孔的吸光度值。按照抑制率%=[(OD对照细胞-OD加药细胞)/(OD对照细胞-OD空白)]×100。阴性对照为V高糖培养基/VDMSO:10:1 的混合溶液。
该类化合物抑制宫颈癌细胞株(Hela)的测试过程同上。其对两种肿瘤细胞株的抑制结果如表1。
表1 该类化合物对两种肿瘤细胞株的活性测试结果
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
4.根据权利要求1或2所述的复盐,其特征在于,所述式(I)所示的化合物与生物碱的摩尔比为1:(0.5-5),例如1:(0.8-2)。
5.权利要求1-4任一项所述复盐的制备方法,其特征在于,包括以下步骤:将式(I)化合物与生物碱溶于有机溶剂,混合得到所述复盐;
所述式(I)化合物与生物碱的摩尔比可以为1:(0.5-5),例如1:(0.8-2)。
6.权利要求5所述复盐的制备方法,其特征在于,所述有机溶剂选自甲醇、乙醇、氯仿、丙酮、甲苯、二氯甲烷、乙酸乙酯等能溶解两种化合物的单一溶剂或混合溶剂。
7.一种药物组合物,其包含治疗有效量的权利要求1-4任一项所述复盐或他们的组合物。
8.权利要求8所述的药物组合物,其特征在于,所述药物组合物还包括一种或多种药学上可接受的辅料;
优选地,所述药物组合物还进一步含有一种或多种额外的治疗剂。
9.权利要求1-4任一项所述复盐或它们的组合物在制备治疗肿瘤/癌症药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述癌症为肺癌、乳腺癌、胃癌、宫颈癌。
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